Flumetholone suspension eye drops and preparation process thereof

Abstract

The invention relates to the technical field of ophthalmic preparations, in particular to a fluorometholone eye drop and a preparation process thereof, and the fluorometholone eye drop comprises a fluorometholone raw material medicine, cyclodextrin, an auxiliary reagent and water for injection; the auxiliary reagents comprise a bacteriostatic agent, a complexing agent, a dispersing agent, a suspending aid, a tension regulator, a buffering agent and the like; according to the invention, cyclodextrin can form a host-guest inclusion complex with the fluorometholone bulk drug through inclusion action, and through the action of each auxiliary reagent and the synergistic effect of the auxiliary reagent, the fluorometholone bulk drug and cyclodextrin, the solubility and stability of the fluorometholone bulk drug in a water medium are improved, and the redispersibility of the fluorometholone particles is improved; according to the preparation process of the fluorometholone eye drops, the fluorometholone eye drops can be prepared on a large scale, the preparation process is controllable, and the difficulty of cleaning a production line and the risk of bacterial contamination can be effectively reduced; the problems that in the prior art, active ingredients of fluorometholone eye drops are prone to adsorption loss in the large-scale preparation process are solved.

Description

Technical Field

[0001] The invention relates to the technical field of ophthalmic preparations, and in particular to fluorometholone eye drops and a preparation process thereof. Background Art

[0002] As a glucocorticoid drug, fluorometholone has significant anti-inflammatory effects and is widely used in the treatment of dermatitis, eczema and inflammatory eye diseases. However, fluorometholone is a drug that is poorly soluble in water. When it is used as an active ingredient in mass production of eye drops, fluorometholone particles are easily adsorbed on the inner wall of the container, the inner wall of the transmission pipe and other equipment, which will cause the active ingredient to be lost during the production process, making the content of the active ingredient in the prepared eye drops lower than the labeled amount; and the adsorption of fluorometholone particles on the inner wall of the container or the inner wall of the transmission pipe will also increase the uncontrollability of the production process and increase the difficulty of cleaning the production line and the risk of contamination. At the same time, the prepared eye drops are usually dispensed in the form of a suspension in the eye drop bottle, and long-term standing will also cause insoluble fluorometholone particles to precipitate at the bottom of the eye drop bottle; therefore, it is usually necessary to shake the drug before use to redisperse the drug solution to improve the uniformity of the drug, thereby ensuring the stability of the patient's dosage.

[0003] The known existing patent, application number: CN201210259993.5, discloses a fluorometholone eye drop, which is prepared by selecting fluorometholone micropowder with a specific particle size distribution to prepare a suspension, and the prepared suspension is packaged into 2mL or 5mL bottles of eye drops; when the drug micropowder in the packaged eye drops has completely settled to the bottom of the bottle, it can be quickly redispersed after 5-6 shaking or flipping. However, the patent document does not publicly explain that in the process of preparing a large-scale suspension, the problem of active ingredient loss during the preparation process caused by the adsorption of fluorometholone micropowder particles on the wall of the container can be solved by selecting fluorometholone micropowder with a specific particle size distribution.

[0004] The known existing patent, application number: CN200880010531.1, discloses a suspension eye drop containing fluorometholone, which can inhibit the adhesion of fluorometholone to the container by adding polyoxyethylene hydrogenated castor oil or polyoxyethylene castor oil. However, it is common knowledge in the art that polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, etc. can be used as cosolvents in eye drops to increase drug solubility and prevent sticking. At the same time, the patent does not disclose how adding polyoxyethylene hydrogenated castor oil or polyoxyethylene castor oil during the preparation process will affect the adsorption of suspended particles on the surface of metal walls, transmission pipes, etc.

[0005] Cyclodextrins are a class of cyclic oligosaccharide compounds composed of 6 to 12 glucose molecules, with a hollow truncated cone-shaped structure with a hydrophobic cavity and a hydrophilic outer wall. This structure enables cyclodextrins to form host-guest inclusion complexes with a variety of small molecules and polymers through inclusion, thereby achieving regulation of the physical and chemical properties of guest molecules. Many patents are known to disclose that by adding cyclodextrin, cyclodextrin is included in the active ingredients of the drug to achieve the effect of improving the drug stability and drug efficacy; such as application number CN93120402.X, application number CN200810153607.8, application number CN200910070061.4, etc.; however, these patents do not disclose the use of cyclodextrin for batch production of fluorometholone eye drops to achieve the effect of inhibiting the adsorption of fluorometholone particles on the inner wall of the container or the inner wall of the conveying pipeline, and do not disclose the specific process of mass production of suspension eye drops. At the same time, due to the large feed amount of the drug production, the processing equipment and key processes involved are more, and the change of each link will have a greater impact on the quality of the actual product; therefore, it is also necessary to develop a method for mass preparation of fluorometholone eye drops.

[0006] The invention provides a fluorometholone eye drop and a preparation process thereof, so as to solve the problems existing in the prior art that the active ingredients of the existing fluorometholone eye drops are easily lost by adsorption during the mass preparation process, the probability of bacterial contamination is high, and the stability and content uniformity of the fluorometholone eye drops are poor. Summary of the invention

[0007] The purpose of the present invention is to provide a fluorometholone eye drop and a preparation process thereof, so as to solve the problems existing in the prior art that the active ingredients of the existing fluorometholone eye drops are easily lost due to adsorption, the probability of bacterial contamination is high, the stability of the fluorometholone eye drops and the content uniformity are poor, etc. The purpose is to solve the problems existing in the prior art that the active ingredients of the existing fluorometholone eye drops are lost during the large-scale preparation process, resulting in the content of the drug ingredients in the eye drops being lower than the labeled amount, the stability of the drugs in the eye drops and the content uniformity are poor, etc.

[0008] The technical scheme of the present invention is: a fluorometholone eye drop, which comprises, by mass percentage, 0.02-0.2% of fluorometholone raw material, 0.06-0.6% of cyclodextrin, 0.001-0.006% of antibacterial agent, 0.005-0.02% of complexing agent, 0.002-0.01% of dispersant, 0.00005-0.0002% of suspending agent, 0.2-1% of tension regulator, 0.3-1% of buffer and 90-99% of water for injection;

[0009] Wherein, the cyclodextrin is any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or a combination of more than one thereof;

[0010] The antibacterial agent is any one or more of methylparaben, ethylparaben, propylparaben, butylparaben, phenylmercuric nitrate, thimerosal, benzalkonium bromide, benzalkonium chloride and chlorhexidine acetate;

[0011] The complexing agent is any one of disodium edetate, sodium tartrate, and sodium citrate;

[0012] The dispersant is any one of polysorbate 80 (II), polyvinyl alcohol, and polyethylene glycol;

[0013] The suspending agent is any one of methylcellulose, hydroxypropyl methylcellulose and polysorbate;

[0014] The tension regulator is any one or more of glycerol, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol;

[0015] The buffer is any one of disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate, or a combination of the two.

[0016] Preferably, in the fluorometholone eye drops, the mass percentage of the fluorometholone raw material to the cyclodextrin is 1:(1-5).

[0017] Preferably, in the fluorometholone eye drops, the antibacterial agent is benzalkonium chloride; and / or the dispersant is polysorbate 80 (II); and / or the chelating agent is disodium edetate; and / or the suspending agent is methylcellulose; and / or the tension regulator is sodium chloride; and / or the buffer is a mixture of 0.3-1% disodium hydrogen phosphate dodecahydrate and 0.3-1% sodium dihydrogen phosphate dihydrate.

[0018] Preferably, the particle size distribution of the fluorometholone raw material is as follows: the particle size less than 10 μm accounts for no less than 99%, and the particle size less than 5 μm accounts for no less than 90%.

[0019] Preferably, the fluorometholone eye drops further include a pH regulator;

[0020] The pH adjuster is an aqueous solution of any one of phosphoric acid and its salts, boric acid and its salts, citric acid and its salts, acetic acid and its salts, tartaric acid and its salts, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and tromethamine, or a mixed aqueous solution of multiple thereof.

[0021] Preferably, the pH of the fluorometholone eye drops is 6-8.

[0022] The present application also provides a preparation process of the above-mentioned fluorometholone eye drops, which specifically comprises the following steps: S1, in a sterile environment, weighing fluorometholone raw materials, cyclodextrin, antibacterial agent, complexing agent, dispersant, suspending agent, tension regulator, and buffer respectively according to mass percentage for standby use;

[0023] S2, placing the fluorometholone API weighed in step S1 in a dry heat sterilizer and sterilizing at 160°C. After 2 hours, lowering the temperature in the dry heat sterilizer to 80°C and taking out the fluorometholone API;

[0024] S3, adding the cyclodextrin weighed in step S1 to 3-6L of water for injection at a temperature below 40°C, stirring until the cyclodextrin is visually completely dissolved, and preparing a cyclodextrin solution. Similarly, adding the suspending agent, antibacterial agent, and dispersing agent weighed in step S1 to 0.8-1.2L, 0.4-0.6L, and 0.4-0.6L of water for injection at a temperature below 40°C, respectively, shaking until visually completely dissolved, and preparing a suspending agent solution, an antibacterial agent solution, and a dispersing agent solution, respectively;

[0025] S4, add about 15-25L of water for injection at a temperature below 40°C to the first container tank, and then add the tension regulator, buffer, complexing agent weighed in step S1 and the cyclodextrin solution, suspending agent solution, antibacterial agent solution, and dispersant solution prepared in step S3 to the first container tank in sequence, set the stirring speed to 200 rpm, stir for 10-30 minutes, until completely dissolved, to prepare a base solution, and filter the base solution through a 0.45 μm polyethersulfone filter and two 0.2 μm polyethersulfone filters, and then rinse it into the second container tank;

[0026] S5, add about 5-7L of water for injection into the first container tank, filter through a 0.45μm polyethersulfone filter and two 0.2μm polyethersulfone filters, and then rinse into the second container tank, then add the fluorometholone API after aseptic treatment in step S2 into the second container tank and mix with the base solution, set the stirring speed to 300-500rpm, stir for 10-60min, until visually dispersed and uniform, to form a mixed solution, then turn on the high-pressure homogenizer, homogenize the mixed solution into the third container tank, and transfer it to the fourth container tank after high-pressure homogenization in the third container tank once;

[0027] S6, starting from the first container tank, flush the pipeline and the first container tank, the second container tank, and the third container tank with 6-10L of injection water, and collect it in the fourth container tank, then add injection water to the first container tank to flush the pipeline and replenish the liquid to the full amount, then set the stirring speed to 200-300rpm, stir and mix for 30min, then set the stirring speed to 80-120rpm, stir for 10-12h, and obtain a batch of liquid medicine;

[0028] S7. Set the stirring speed in the fourth container tank to 180-220 rpm, fill the batch of liquid medicine under continuous stirring, divide it into low-density polyethylene medicinal eye drop bottles, and cap them with low-density polyethylene bottle stoppers and high-density polyethylene bottle caps.

[0029] Preferably, the bubble point pressure of the 0.45 μm polyethersulfone filter is not less than 0.24 MPa; the bubble point pressure of the 0.2 μm polyethersulfone filter is not less than 0.34 MPa.

[0030] Preferably, in step S5, a pH adjuster is added to the mixed solution; the pH adjuster is 1 mol / L sodium hydroxide aqueous solution or 1 mol / L hydrochloric acid aqueous solution.

[0031] Preferably, in step S5, the pressure parameter of the high pressure homogenizer is 90-120 bar;

[0032] In step S7, the encapsulation volume of the potting is 5.0-5.8 mL / vial; and the duration of the potting is no longer than 9 hours.

[0033] Compared with the prior art, the advantages of the present invention are:

[0034] (1) The present invention provides a fluorometholone eye drop and a preparation process thereof, wherein cyclodextrin and various auxiliary agents are added to the fluorometholone eye drop, wherein the cyclodextrin has a hollow truncated cone-shaped three-dimensional structure with a hydrophobic cavity and a hydrophilic outer wall, and can form a host-guest inclusion complex with the fluorometholone raw material drug through inclusion complexation, and through the action of various auxiliary agents and the synergistic effect between these auxiliary agents, the fluorometholone raw material drug and the cyclodextrin, the solubility and stability of the fluorometholone raw material drug in the aqueous medium are improved, and the redispersibility of the fluorometholone particles is improved; and the inclusion complexation of the cyclodextrin also helps to reduce the exposure of fluorometholone to the degradation mechanism before entering the target organ or tissue, thereby reducing the drug toxicity, controlling The invention can control the drug release rate and regulate its pharmacological activity; at the same time, the preparation process of the fluorometholone eye drops can prepare fluorometholone eye drops in large quantities, and the active ingredients will not be adsorbed on the tank wall during the preparation process, so that the preparation process is controllable, and the difficulty of cleaning the production line and the risk of contamination can be effectively reduced; the prepared fluorometholone eye drops not only have the active ingredients that can reach the labeled amount, but also have excellent redispersion, which helps to ensure the stability of the dosage used by patients; the invention solves the problems existing in the prior art that the active ingredients of the existing fluorometholone eye drops are easy to be adsorbed and lost, the probability of contamination is high, the stability of the fluorometholone eye drops and the content uniformity are poor during the large-scale preparation process.

[0035] (2) The present invention provides a fluorometholone eye drop and a preparation process thereof, wherein cyclodextrin and various auxiliary agents such as an antibacterial agent, a complexing agent, a dispersant, a suspending agent, a tension regulator, and a buffer are added to the fluorometholone eye drop; the cyclodextrin forms a host-guest inclusion complex with the fluorometholone raw material; the suspending agent, the formed inclusion complex, and other auxiliary agents cooperate with each other to increase the redispersibility of the fluorometholone active ingredient, thereby reducing the formation of aggregates in the fluorometholone eye drop; the synergistic effect between the antibacterial agent and the formed inclusion complex and other auxiliary agents can prevent the fluorometholone eye drop from being contaminated by microorganisms during the preparation and use of the drug, maintain the sterile state of the drug, and enhance the antibacterial effect of the drug; the complexing agent can form a complex with metal ions in the solution to reduce the influence of metal ions on the stability of the drug; and the synergistic effect between the complexing agent and the formed inclusion complex and other auxiliary agents can reduce the adsorption of fluorometholone on metal walls and transmission pipelines during production and storage, thereby reducing the loss of active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The present invention will be further described below in conjunction with the accompanying drawings and embodiments:

[0037] Figure 1 The present invention is a flow chart of the preparation process of the fluorometholone eye drops. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below in conjunction with specific embodiments:

[0039] A fluorometholone eye drop comprises a fluorometholone raw material, cyclodextrin, auxiliary agents and water for injection. Adding cyclodextrin to the fluorometholone eye drop can form inclusion complexes with the active ingredient fluorometholone and exert a therapeutic effect; the auxiliary agents include any one or more of an antibacterial agent, a chelating agent, a dispersant, a suspending agent, a tension regulator, a buffer, etc.; through the effects of the auxiliary agents and the synergistic effects of the auxiliary agents, the fluorometholone raw material and the cyclodextrin, the prepared fluorometholone eye drops have the characteristics of excellent stability, redispersibility and content uniformity.

[0040] Among them, the outer layer of the cyclodextrin molecule is composed of oxygen atoms, which are more electronegative than carbon atoms. Therefore, the outer layer of the cyclodextrin is hydrophilic, while the inner layer is composed of carbon atoms and is hydrophobic. This hydrophobic effect leads to the hydrophobic inner wall and hydrophilic outer wall formed by the cyclodextrin molecules in water. When hydrophobic molecules are present in the solution, these molecules tend to enter the internal cavity of the cyclodextrin to reduce their contact with water molecules. Thereby, the aggregation between the fluorometholone particles can be prevented and the stability of the suspension can be increased; the cyclodextrin is one or a combination of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; and, since γ-cyclodextrin has higher solubility than α-cyclodextrin and β-cyclodextrin, in the present application, γ-cyclodextrin is preferred as the cyclodextrin. The antibacterial agent is used to prevent the growth of microorganisms in the eye drops, maintain the sterility of the eye drops, and ensure the shelf life of the eye drops; the antibacterial agent is a combination of one or more of methylparaben, ethylparaben, propylparaben, butylparaben, phenylmercuric nitrate, thimerosal, benzalkonium bromide, benzalkonium chloride, chlorhexidine acetate, etc. The complexing agent is used to increase the solubility of the drug in a solvent, especially water; the complexing agent is one of disodium edetate, sodium gluconate, sodium tartrate, sodium citrate, aminotriacetic acid, etc. The main function of the dispersant is to keep the drug components evenly distributed, prevent the drug particles from aggregating or precipitating, thereby ensuring the stability and therapeutic effect of the eye drops; the dispersant is any one of polysorbate 80 (II), polyvinyl alcohol, polyethylene glycol, dextran, etc. The main function of the suspending agent is to increase the viscosity of the dispersion medium, thereby slowing down the sedimentation rate of the drug particles, preventing or reducing the aggregation and agglomeration between the particles, and maintaining the uniform dispersion of the drug particles; the suspending agent is one of methylcellulose, hydroxypropyl methylcellulose, polysorbate, sodium hyaluronate, etc. The main function of the tension regulator is to adjust the surface tension of the eye drops to optimize the drop volume and spreadability of the drug; the tension regulator is a combination of one or more of glycerol, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, etc. The main function of the buffer is to maintain the pH value of the eye drops within an appropriate range to ensure the stability of the drug and reduce irritation to the eyes; the buffer is a buffer combination of disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate, a buffer combination of citric acid-sodium citrate, etc.

[0041] In the fluorometholone eye drops, calculated by mass percentage, the content of fluorometholone raw material is 0.02-0.2%, the content of cyclodextrin is 0.06-0.6%, the content of antibacterial agent is 0.001-0.006%, the content of complexing agent is 0.005-0.02, the content of dispersant is 0.002-0.01%, the content of suspending agent is 0.00005-0.0002%, the content of tension regulator is 0.2-1%, the content of buffer is 0.3-1% and the rest is water for injection; that is, the content of water for injection in the fluorometholone eye drops is 90-99%. In order to make the fluorometholone raw material particles completely coated in the internal cavity of cyclodextrin as much as possible, a relatively excessive amount of cyclodextrin needs to be added during the preparation of the fluorometholone eye drops; in the present application, the mass ratio of fluorometholone raw material to cyclodextrin is preferably 1: (1-5). At the same time, according to the particle size and particle size distribution determination method stipulated in the third method of General Chapter 0982 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the particle size and particle size distribution of fluorometholone should be: the proportion of particles with a diameter less than 10μm should be no less than 99%, and the proportion of particles with a diameter less than 5μm should be no less than 90%.

[0042] The pH of the fluorometholone eye drops is 6-8, and since the pH of normal tears is about 7.2-7.4, in order to ensure the mildness of the eye drops to the eyes and the effectiveness of the drug, the pH of the eye drops usually needs to be adjusted to close to this range; therefore, the fluorometholone eye drops also include a pH regulator for adjusting the pH of the fluorometholone eye drops. In addition, the pH of the fluorometholone eye drops should be controlled within the range of 6-8; preferably, the pH of the fluorometholone eye drops is adjusted to within the range of 6.8-7.8. The pH regulator can be selected from an aqueous solution of one of phosphoric acid and its salts, boric acid and its salts, citric acid and its salts, acetic acid and its salts, tartaric acid and its salts, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tromethamine, etc., or a mixed aqueous solution of multiple kinds. Since the main purpose of the present application is to mass-produce the fluorometholone eye drops, in order to quickly and accurately control the pH value of the fluorometholone eye drops, it is preferred to use a hydrochloric acid aqueous solution, a sodium hydroxide aqueous solution, etc. that is highly acidic or alkaline; and it is preferred to use a 1 mol / L sodium hydroxide aqueous solution or a 1 mol / L hydrochloric acid aqueous solution.

[0043] The preparation process of the fluorometholone eye drops is as follows: Figure 1 As shown, the specific steps include:

[0044] S1. Under a sterile environment, weigh fluorometholone API, cyclodextrin, and various auxiliary reagents according to mass percentage and set aside.

[0045] S2. Sterilize the symmetrically taken fluorometholone API; that is, place the fluorometholone API weighed in step S1 in a dry heat sterilizer and sterilize it at 160°C. After 2 hours, cool the temperature in the dry heat sterilizer to 80°C and take out the fluorometholone API.

[0046] S3. Add the cyclodextrin weighed in step S1 to 3-6L of water for injection at a temperature below 40°C, stir until the cyclodextrin is visually completely dissolved, and prepare a cyclodextrin solution; similarly, add the suspending agent, antibacterial agent, and dispersing agent to 0.8-1.2L, 0.4-0.6L, and 0.4-0.6L of water for injection at a temperature below 40°C, respectively, shake until visually completely dissolved, and prepare a suspending agent solution, an antibacterial agent solution, and a dispersing agent solution.

[0047] S4. Add about 15-25 L of water for injection at a temperature below 40° C. to the first container tank, and then add the tension regulator, buffer, complexing agent weighed in step S1 and the cyclodextrin solution, suspending agent solution, antibacterial agent solution, and dispersant solution prepared in step S3 to the first container tank in sequence, set the stirring speed to 200 rpm, stir for 10-30 minutes, until completely dissolved, to form a base solution, and filter the base solution through a 0.45 μm polyethersulfone filter and two 0.2 μm polyethersulfone filters, and then rinse it into the second container tank.

[0048] S5, add about 5-7L of water for injection into the first container tank, filter through a 0.45μm polyethersulfone filter and two 0.2μm polyethersulfone filters, and rinse into the second container tank, then add the fluorometholone API after aseptic treatment in step S2 to the second container tank and mix with the base solution, set the stirring speed to 300-500rpm, stir for 10-60min, until visually dispersed and uniform, form a mixed solution, then turn on the high-pressure homogenizer, homogenize the mixed solution into the third container tank, and set the pressure parameter of the high-pressure homogenizer to 90-120bar, perform high-pressure homogenization on the mixed solution once in the third container tank, and then transfer the mixed solution to the fourth container tank. In the process of preparing the mixed solution, it is necessary to add a small amount of pH regulator to make the pH value of the mixed solution within the range of 6-8. In step S4 and step S5, when filtering is performed using a 0.45 μm polyethersulfone filter and a 0.2 μm polyethersulfone filter, the bubble point pressure of the 0.45 μm polyethersulfone filter should be ≥0.24 MPa, and the bubble point pressure of the 0.2 μm polyethersulfone filter should be ≥0.34 MPa.

[0049] S6, starting from the first container tank, flush the pipeline and the first container tank, the second container tank, and the third container tank with 6-10L of injection water, and collect it in the fourth container tank, then add injection water to the first container tank to flush the pipeline and replenish the liquid to the full amount (the density of injection water is 1.002g / mL), then set the stirring speed to 200-300rpm, stir and mix for 30min, then set the stirring speed to 80-120rpm, stir for 10-12h, and obtain a batch of liquid medicine;

[0050] S7. Set the stirring speed in the fourth container tank to 180-220 rpm, fill the batch of liquid medicine under continuous stirring, and divide it into low-density polyethylene medicinal eye drop bottles, and plug them with low-density polyethylene bottle stoppers and high-density polyethylene bottle caps. Among them, the filling packaging volume is 5.05.8mL / vial; the filling time shall not exceed 9 hours, that is, it shall not exceed 9 hours from the start of filling to the end of filling.

[0051] Implementation Method 1

[0052] The purpose of this embodiment is to prepare 50L of bulk drug solution and package the bulk drug solution into 5mL / tube of eye drops.

[0053] S1. According to the proportions of 0.08% of fluorometholone API, 0.2% of cyclodextrin, 0.003% of benzalkonium chloride, 0.01% of disodium edetate, 0.005% of polysorbate 80 (II), 0.0001% of methylcellulose, 0.79% of sodium chloride, 0.63% of disodium hydrogen phosphate dodecahydrate, and 0.06% of sodium dihydrogen phosphate dihydrate, weigh fluorometholone API, cyclodextrin, and auxiliary reagents respectively and set aside for use.

[0054] S2. Place the fluorometholone API weighed in the above step S1 in a dry heat sterilizer and sterilize it at 160°C. After 2 hours, cool the dry heat sterilizer to 80°C and take out the fluorometholone API.

[0055] S3, adding the cyclodextrin weighed in the above step S1 to 5000 mL of water for injection at a temperature of 30° C., stirring until the cyclodextrin is visually completely dissolved, to prepare a cyclodextrin solution; similarly, adding the methylcellulose, benzalkonium chloride, and polysorbate weighed in the above step S1 to 1000 mL, 500 mL, and 500 mL of water for injection at a temperature of 30° C., respectively, shaking until visually completely dissolved, to prepare a methylcellulose solution, a benzalkonium chloride solution, and a polysorbate 80 (II) solution, respectively;

[0056] S4, add about 20L of water for injection at a temperature of 30°C into the first container tank, and then add the sodium chloride, disodium hydrogen phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, edetate disodium weighed in step S1, and the cyclodextrin solution, methylcellulose solution, benzalkonium chloride solution, and polysorbate 80 (II) solution prepared in step S3 into the first container tank in sequence, set the stirring speed to 200 rpm, stir for 10 minutes, until completely dissolved, to prepare a base solution, and filter the base solution through a 0.45 μm polyethersulfone filter and two 0.2 μm polyethersulfone filters in sequence, and then rinse into the second container tank;

[0057] S5, add about 5L of water for injection into the first container tank, filter through a 0.45μm polyethersulfone filter and two 0.2μm polyethersulfone filters, and then rinse into the second container tank, then add the fluorometholone API after aseptic treatment in step S2 into the second container tank and mix with the base solution, set the stirring speed to 300rpm, stir for 30min, until visually dispersed uniformly to form a mixed solution, and adjust the pH value of the mixed solution to 7.2; then, turn on the high-pressure homogenizer, homogenize the mixed solution into the third container tank, and adjust the pressure parameter of the high-pressure homogenizer to 100bar, perform high-pressure homogenization on the mixed solution once in the third container tank, and then transfer the mixed solution to the fourth container tank;

[0058] S6, starting from the first container tank, flush the pipeline and the first container tank, the second container tank, and the third container tank with 6L of injection water, and collect it in the fourth container tank, then add injection water to the first container tank to flush the pipeline and replenish the liquid to the full amount, then set the stirring speed to 300rpm, stir and mix for 30min, then set the stirring speed to 100rpm, stir for 10-12h, and obtain 50L batch of liquid medicine;

[0059] S7. Set the stirring speed in the fourth container tank to 180 rpm, fill 50 L of the batch of liquid medicine under continuous stirring, divide it into low-density polyethylene medicinal eye drop bottles, and cap them with low-density polyethylene stoppers and high-density polyethylene bottle caps to obtain a batch of fluorometholone eye drops with a packaging volume of 5 mL / vial.

[0060] Ten samples were taken at the early stage of filling, the middle stage of filling, and the late stage of filling, and the sealing of the fluorometholone eye drops samples was tested by the color water method. The test results are shown in Table 1; the specific parameters of the sealing inspection are as follows: the dye is methylene blue; the color water concentration is 1g / L; the negative pressure is -50.00kPa; the negative pressure time is 30min; the normal pressure is one standard atmospheric pressure; the normal pressure time is 10min; the detection wavelength is 664nm.

[0061] Table 1. Test results of sealing performance of fluorometholone eye drops samples

[0062]

[0063]

[0064] It can be seen from Table 1 that the colors of the 10 samples taken out at the early, middle and late stages of filling did not change; moreover, the absorbance values ​​of the solutions of these samples were all 0, and the intrusion rate of colored water was also 0; this further indicates that the absorbance value of the sample solution is less than the absorbance value of the lowest concentration of colored water intrusion that can be visually seen; the samples have good sealing properties.

[0065] After the filling is completed, a number of fluorometholone eye drops with a packaging volume of 5 mL / vial prepared in Implementation Method 1 are randomly selected for packaging appearance inspection and light inspection using a clarity inspection instrument to detect visible foreign matter in the fluorometholone eye drops; the test results are shown in Table 2. Afterwards, a number of fluorometholone eye drops with a packaging volume of 5 mL / vial prepared in Implementation Method 1 are randomly selected regularly for light inspection, and the test results are shown in Table 3. Before the light inspection operation, it is necessary to use an illuminance meter to check the illumination of the clarity inspection instrument to detect whether the illumination of the clarity inspection instrument is within the range of 1000-1500LX.

[0066] Table 2. Detection results of visible foreign matter in fluorometholone eye drops

[0067]

[0068] It can be seen from Table 2 that no visible foreign matter was found in the 20 randomly selected fluorometholone eye drops with a packaging volume of 5 mL / tube prepared in Implementation Method 1; furthermore, it is shown that cyclodextrin and fluorometholone API form a host-guest inclusion complex, and through the action of various auxiliary reagents and the synergistic effect between these auxiliary reagents, fluorometholone API and cyclodextrin, the solubility and stability of fluorometholone API in aqueous medium can be improved; at the same time, combined with the preparation process provided in the present application, the risk of bacterial contamination of fluorometholone eye drops can be reduced.

[0069] Table 3. Results of regular sampling inspections for visible foreign matter

[0070]

[0071]

[0072]

[0073]

[0074] 20 samples were randomly selected for light inspection at 10 minutes, 1 hour, 2 hours, and 10 hours after the packaging was completed. It can be seen from Table 3 that no visible foreign matter was found in the 80 samples taken above, which further shows that the fluorometholone eye drops have excellent stability. In the case of long-term standing, such as standing for 10 days, 15 days, 30 days, etc., there may be a few suspended particles in the fluorometholone eye drops, and they can be completely dissolved by just shaking a few times.

[0075] Ten samples of fluorometholone eye drops were randomly selected to test the particle size and particle size distribution of the fluorometholone eye drops. The test results are shown in Table 4.

[0076] Table 4. Particle size and particle size distribution of fluorometholone eye drops

[0077]

[0078] As shown in Table 4, the particle size distribution of the prepared fluorometholone eye drops is relatively uniform, and complies with the provisions of the Chinese Pharmacopoeia on particle size and particle size distribution determination method.

[0079] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the scope of protection of the present invention. For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and the present invention can be implemented in other specific forms without departing from the spirit or basic features of the present invention. Therefore, no matter from which point of view, the embodiments should be regarded as exemplary and non-restrictive. The scope of the present invention is limited by the attached claims rather than the above description, and it is intended to include all changes within the meaning and scope of the equivalent elements of the claims in the present invention.

Claims

1. A fluorometholone eye drops, characterized in that, In terms of mass percentage, the fluorometholone eye drops include: 0.02-0.2% of fluorometholone API, 0.06-0.6% of cyclodextrin, 0.001-0.006% of antibacterial agent, 0.005-0.02% of complexing agent, 0.002-0.01% of dispersant, 0.00005-0.0002% of suspending agent, 0.2-1% of tension regulator, 0.3-1% of buffer and 90-99% of water for injection; Wherein, the cyclodextrin is any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, or a combination of more than one thereof; The antibacterial agent is any one or more of methylparaben, ethylparaben, propylparaben, butylparaben, phenylmercuric nitrate, thimerosal, benzalkonium bromide, benzalkonium chloride and chlorhexidine acetate; The complexing agent is any one of disodium edetate, sodium tartrate, and sodium citrate; The dispersant is any one of polysorbate 80 (II), polyvinyl alcohol, and polyethylene glycol; The suspending agent is any one of methylcellulose, hydroxypropyl methylcellulose and polysorbate; The tension regulator is any one or more of glycerol, propylene glycol, sodium chloride, potassium chloride, sorbitol, and mannitol; The buffer is any one of disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate, or a combination of the two.

2. A fluorometholone eye drop according to claim 1, characterized in that: In the fluorometholone eye drops, the mass percentage of the fluorometholone raw material to the cyclodextrin is 1:(1-5).

3. A fluorometholone eye drops according to claim 2, characterized in that: In the fluorometholone eye drops, the antibacterial agent is benzalkonium chloride; and / or the dispersant is polysorbate 80 (II); and / or the chelating agent is disodium edetate; and / or the suspending agent is methylcellulose; and / or the tension regulator is sodium chloride; and / or the buffer is a mixture of 0.3-1% disodium hydrogen phosphate dodecahydrate and 0.3-1% sodium dihydrogen phosphate dihydrate.

4. A fluorometholone eye drops according to claim 2, characterized in that: The particle size distribution of the fluorometholone raw material is as follows: the proportion of particles with a diameter less than 10 μm is not less than 99%, and the proportion of particles with a diameter less than 5 μm is not less than 90%.

5. A fluorometholone eye drop according to claim 2, characterized in that: The fluorometholone eye drops also include a pH regulator; The pH adjuster is an aqueous solution of any one of phosphoric acid and its salts, boric acid and its salts, citric acid and its salts, acetic acid and its salts, tartaric acid and its salts, hydrochloric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and tromethamine, or a mixed aqueous solution of multiple thereof.

6. A fluorometholone eye drop according to claim 2, characterized in that: The pH of the fluorometholone eye drops is 6-8.

7. A process for preparing the fluorometholone eye drops according to any one of claims 1 to 6, characterized in that: The following steps are involved: S1. Under a sterile environment, weigh the fluorometholone API, cyclodextrin, antibacterial agent, complexing agent, dispersant, suspending agent, tension regulator, and buffer according to mass percentage and set aside; S2, placing the fluorometholone API weighed in step S1 in a dry heat sterilizer and sterilizing it at 160°C. After 2 hours, lowering the temperature in the dry heat sterilizer to 80°C and taking out the fluorometholone API; S3, adding the cyclodextrin weighed in step S1 to 3-6L of water for injection at a temperature below 40°C, stirring until the cyclodextrin is visually completely dissolved, and preparing a cyclodextrin solution. Similarly, adding the suspending agent, antibacterial agent, and dispersing agent weighed in step S1 to 0.8-1.2L, 0.4-0.6L, and 0.4-0.6L of water for injection at a temperature below 40°C, respectively, shaking until visually completely dissolved, and preparing a suspending agent solution, an antibacterial agent solution, and a dispersing agent solution, respectively; S4, add about 15-25L of water for injection at a temperature below 40°C to the first container tank, and then add the tension regulator, buffer, complexing agent weighed in step S1 and the cyclodextrin solution, suspending agent solution, antibacterial agent solution, and dispersant solution prepared in step S3 to the first container tank in sequence, set the stirring speed to 200 rpm, stir for 10-30 minutes, until completely dissolved, to prepare a base solution, and filter the base solution through a 0.45 μm polyethersulfone filter and two 0.2 μm polyethersulfone filters, and then rinse it into the second container tank; S5, add about 5-7L of water for injection into the first container tank, filter through a 0.45μm polyethersulfone filter and two 0.2μm polyethersulfone filters, and then rinse into the second container tank, then add the fluorometholone API after aseptic treatment in step S2 into the second container tank and mix with the base solution, set the stirring speed to 300-500rpm, stir for 10-60min, until visually dispersed and uniform, to form a mixed solution, then turn on the high-pressure homogenizer, homogenize the mixed solution into the third container tank, and transfer it to the fourth container tank after high-pressure homogenization in the third container tank once; S6, starting from the first container tank, flush the pipeline and the first container tank, the second container tank, and the third container tank with 6-10L of injection water, and collect it in the fourth container tank, then add injection water to the first container tank to flush the pipeline and replenish the liquid to the full amount, then set the stirring speed to 200-300rpm, stir and mix for 30min, then set the stirring speed to 80-120rpm, stir for 10-12h, and obtain a batch of liquid medicine; S7. Set the stirring speed in the fourth container tank to 180-220 rpm, fill the batch of liquid medicine under continuous stirring, divide it into low-density polyethylene medicinal eye drop bottles, and cap them with low-density polyethylene bottle stoppers and high-density polyethylene bottle caps.

8. A process for preparing fluorometholone eye drops according to claim 7, characterized in that: The bubble point pressure of the 0.45 μm polyethersulfone filter is not less than 0.24 MPa; the bubble point pressure of the 0.2 μm polyethersulfone filter is not less than 0.34 MPa.

9. A process for preparing fluorometholone eye drops according to claim 7, characterized in that: In step S5, a pH adjuster is added to the mixed solution; the pH adjuster is 1 mol / L sodium hydroxide aqueous solution or 1 mol / L hydrochloric acid aqueous solution.

10. The preparation process of fluorometholone eye drops according to claim 7, characterized in that: In step S5, the pressure parameter of the high pressure homogenizer is 90-120 bar; In step S7, the encapsulation volume of the potting is 5.0-5.8 mL / vial; and the duration of the potting is no longer than 9 hours.

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