CN109833294B - Lomefloxacin hydrochloride eye drops and preparation process thereof - Google Patents
Lomefloxacin hydrochloride eye drops and preparation process thereof Download PDFInfo
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Abstract
The invention discloses lomefloxacin hydrochloride eye drops and a preparation process thereof, and relates to the field of ophthalmic pharmaceutical preparations. The eye drop is prepared by screening sodium alginate as a thickening excipient, swelling with a solubilizing additive and water for injection to form a transparent solution, mixing with an isotonic regulator glycerol, an intraocular pressure regulator mannitol and a biodegradation aid, regulating the pH value by a buffer solution, filtering and carrying out aseptic packaging. The lomefloxacin hydrochloride eye drops have the advantages of simple and controllable preparation method, no need of harsh conditions, good stability, uniformity and absorbability, strong osmotic action during use, obvious reduction of intraocular pressure, and obvious curative effect on treating external eye infection caused by sensitive pathogenic bacteria, such as acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and the like.
Description
Technical Field
The invention relates to the field of ophthalmic medicinal preparations, in particular to lomefloxacin hydrochloride eye drops and a preparation process thereof, which are used for treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
Background
Lomefloxacin has the chemical name 1-ethyl-6, 8-difluoro-7- (3-methyl-1-piperazine) -4-oxo-3-quinolinecarboxylic acid. The lomefloxacin hydrochloride has a pH value of 3.5-4.5, is slightly soluble in water and is almost insoluble in ethanol or chloroform; is easy to dissolve in sodium hydroxide test solution and dissolve in ammonia test solution; heating the mixture with malonic acid and acetic anhydride in a water bath at the temperature of 30-90 ℃ for 5-10 minutes to obtain reddish brown, wherein the chemical structural formula of the mixture is as follows:
lomefloxacin hydrochloride belongs to antibiotic drugs, is a difluoroquinolone broad-spectrum antibacterial drug, has a bactericidal effect mainly by inhibiting DNA gyrase of bacteria, and also has a certain antibacterial effect on pseudomonas such as acinetobacter, pseudomonas aeruginosa and the like, staphylococcus, pneumococcus, hemolytic streptococcus and the like. Lomefloxacin hydrochloride was first produced by north japan pharmaceutical company and the salt wilderness pharmaceutical company of japan in 1985, first marketed in argentina in 1989, followed by the product of Searle company of the united states.
Chinese patent application No. 201210159065.1 discloses lomefloxacin hydrochloride eye drops and a preparation method and application thereof, wherein the active ingredient of the eye drops accounts for 0.3 percent of lomefloxacin hydrochloride, and the eye drops further comprise a tackifier, a buffer salt system, a wetting agent, an isotonic regulator, a pH regulator and a bacteriostatic agent thereof; the preparation is suitable for treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomitis, dacryocystitis, keratitis and corneal ulcer caused by sensitive pathogenic bacteria. The product improves the viscosity of lomefloxacin hydrochloride eye drops, changes the fluidics property of the lomefloxacin hydrochloride eye drops, ensures the full absorption of the medicine, improves the bioavailability, improves the compliance of patients and achieves the treatment effect. The Chinese patent with application number 201510866019.9 discloses a lomefloxacin hydrochloride injection and a preparation method thereof, wherein the injection is prepared by mixing and stirring lomefloxacin hydrochloride, a salt forming agent, a cosolvent, a stabilizer, an adsorbent and water for injection according to a certain proportion, filtering, filling nitrogen and sealing. The lomefloxacin injection has the advantages of convenient and rapid administration, high stability, small preparation volume, convenient transportation and low cost.
In the prior art, the lomefloxacin eye drops have the following problems: 1. stability, uniformity, absorbency are not good enough; 2. when in use, the medicine has poor osmosis effect, can not obviously reduce intraocular pressure, and has further enhanced curative effect on treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide lomefloxacin hydrochloride eye drops and a preparation process thereof. The preparation method is simple and controllable, does not need harsh conditions, has good stability, uniformity and absorbability, has strong osmosis effect when in use, obviously reduces intraocular pressure, and has obvious curative effect on treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
The purpose of the invention can be realized by the following technical scheme:
the invention provides lomefloxacin hydrochloride eye drops which are prepared from the following substances in percentage by mass: 0.3-0.5% of lomefloxacin hydrochloride, 3.4-5.5% of a dissolution aid additive, 0.05-0.12% of propyl p-hydroxybenzoate, 0.04-0.08% of sodium alginate, 0.12-0.19% of glycerol, 0.01-0.03% of buffer solution, 0.04-0.07% of mannitol, 0.15-0.32% of a biodegradation auxiliary agent and the balance of water for injection;
the preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 45-55 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 35-45 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
In order to achieve good stability, absorbability and drug permeability, the lomefloxacin hydrochloride eye drops disclosed by the invention are prepared by taking lomefloxacin hydrochloride as a main drug component and carrying out a large amount of research and screening on other auxiliary materials and additive components, and finding that sodium alginate is selected as a thickening excipient, is swelled with a dissolution assistant additive with good combination, lubrication and dissolution assistant properties and water for injection to form a transparent solution, is mixed with an isotonic regulator glycerol, an intraocular pressure regulator mannitol and a biodegradation assistant, is subjected to pH regulation by a buffer solution, and is filtered and aseptically packaged. The preparation method is simple and controllable, does not need harsh conditions, has various auxiliary material additives to assist the main drug lomefloxacin hydrochloride, has good stability and uniformity, good absorbability and strong osmosis, reduces intraocular pressure, and has obvious curative effect on treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
As a further scheme of the invention, the preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting at 45 ℃ for 4-5h under stirring, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The biodegradable additive, β -cyclodextrin, is grafted on a polymer chain of chitosan under the action of a coupling agent, namely N-hydroxysuccinimide, and a carboxyl activating agent, EDC, and the wrapping effect of cyclodextrin and the antibacterial degradation effect of chitosan are exerted synergistically, so that the irritation of lomefloxacin hydrochloride serving as a main drug is effectively reduced, the retention time of drugs in eyes is prolonged, and the sterilizing and inflammation diminishing effects are improved.
As a further scheme of the invention, the buffer solution is one or a mixture of more of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, boric acid-borax buffer solution, acetic acid-ammonium acetate buffer solution, acetic acid-sodium acetate buffer solution and citric acid buffer solution.
As a further scheme of the invention, the preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolution system for 15-20min, and heating in an oven at 55-65 ℃ for 3-4h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 10000-12000rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with the mass of 0.05-0.08% of that of the cooked silk, mixing uniformly, pouring into a dialysis bag, and dialyzing with polyethylene glycol solution with the molecular weight of 20000 and 15 wt% for 24 h; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
The silk fibroin is natural polymer fibrin extracted from silk, accounts for 70-80% of the silk, has excellent physical and chemical properties, is non-toxic, non-irritant and good in biocompatibility, can be biodegraded, and can meet the requirements of biological materials to a great extent. The silk fibroin has excellent processing performance, can be used for preparing film-forming materials, gels, microspheres, porous scaffolds and the like, and can be applied to drug carriers. The silk fibroin is dissolved in a ternary dissolving system consisting of calcium chloride, ethanol and water, other fiber impurities with good water solubility can be removed through dialysis and high-speed centrifugal separation, the purity of the silk fibroin fiber is improved, and the silk fibroin fiber is mixed with hydroxypropyl methyl cellulose serving as a common ophthalmological lubricant and then dialyzed through polyethylene glycol to obtain the solubilizing additive. The additive has the combination effect of silk fibroin and the lubrication effect of hydroxypropyl methyl cellulose, and lomefloxacin hydrochloride with poor water solubility and alcohol solubility is combined through the hydrophobic acting force of hydrophobic regions among silk fibroin molecules, so that the sustained release effect is achieved when the eye medicine is taken, and no toxic or side effect is generated.
The invention also provides a preparation process of the lomefloxacin hydrochloride eye drops, which comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 45-55 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 35-45 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The invention has the beneficial effects that:
1. the lomefloxacin hydrochloride eye drops disclosed by the invention are obtained by taking lomefloxacin hydrochloride as a main medicine component, carrying out a large amount of research and screening on other auxiliary materials and additive components, finding that sodium alginate is selected as a thickening excipient, swelling with a dissolution assistant additive with good combination, lubrication and dissolution assistant properties and water for injection to form a transparent solution, mixing with an isotonic regulator glycerol, an intraocular pressure regulator mannitol and a biodegradation aid, regulating the pH value through a buffer solution, filtering and carrying out aseptic packaging. The preparation method is simple and controllable, does not need harsh conditions, has various auxiliary material additives to assist the main drug lomefloxacin hydrochloride, has good stability and uniformity, good absorbability and strong osmosis, reduces intraocular pressure, and has obvious curative effect on treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
2. According to the biodegradable auxiliary agent, β -cyclodextrin is grafted on a polymer chain of chitosan, the wrapping effect of the cyclodextrin and the antibacterial degradation effect of the chitosan are synergistically exerted, the irritation of lomefloxacin hydrochloride serving as a main drug is effectively reduced, the residence time of a drug in eyes is prolonged, the sterilization and inflammation diminishing effects are improved, the surface and the interior of the auxiliary agent are porous due to low-temperature quick cooling and vacuum freezing after dialysis, heat sources and bacteria in the chitosan are fully killed, and the sterile environment and the safety of the biodegradable auxiliary agent are guaranteed.
3. The dissolving aid additive is prepared by dissolving silk fibroin in a ternary dissolving system consisting of calcium chloride, ethanol and water, dialyzing, centrifuging at high speed, removing other fiber impurities with good water solubility, improving the purity of silk fibroin fiber, mixing with hydroxypropyl methyl cellulose serving as a common ophthalmological lubricant, and dialyzing with polyethylene glycol. The additive has the combination effect of silk fibroin and the lubrication effect of hydroxypropyl methyl cellulose, and lomefloxacin hydrochloride with poor water solubility and alcohol solubility is combined through the hydrophobic acting force of hydrophobic regions among silk fibroin molecules, so that the sustained release effect is achieved when the eye medicine is taken, and no toxic or side effect is generated.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. 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
The lomefloxacin hydrochloride eye drops of the embodiment are prepared from the following substances in percentage by mass: 0.36% of lomefloxacin hydrochloride, 4.2% of a dissolution assisting additive, 0.07% of propyl p-hydroxybenzoate, 0.05% of sodium alginate, 0.16% of glycerol, 0.016% of a buffer solution, 0.046% of mannitol, 0.25% of a biodegradation auxiliary agent and the balance of water for injection.
The preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 52 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 38 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting for 4.6h under stirring at 45 ℃, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The buffer solution is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution.
The preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolving system for 18min, and then placing the degummed cooked silk in a 62 ℃ oven for heating for 3.5h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 11000rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with cooked silk mass of 0.06%, mixing, pouring into dialysis bag, and dialyzing with polyethylene glycol solution with molecular weight of 20000 and 15 wt% for 24 hr; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
Example 2
The lomefloxacin hydrochloride eye drops of the embodiment are prepared from the following substances in percentage by mass: 0.42% of lomefloxacin hydrochloride, 4.5% of a dissolution assisting additive, 0.09% of propyl p-hydroxybenzoate, 0.06% of sodium alginate, 0.17% of glycerol, 0.017% of a buffer solution, 0.058% of mannitol, 0.28% of a biodegradation auxiliary agent and the balance of water for injection.
The preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 53 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 43 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting for 4.8h under stirring at 45 ℃, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The buffer solution is prepared by mixing boric acid-borax buffer solution and acetic acid-ammonium acetate buffer solution according to the ratio of 1: 1.
The preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolution system for 20min, and then placing the degummed cooked silk in a 63 ℃ oven for heating for 3.2h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 12000rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with a weight of 0.07% of that of the cooked silk, mixing, pouring into a dialysis bag, and dialyzing with polyethylene glycol solution with molecular weight of 20000 and 15 wt% for 24 hr; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
Example 3
The lomefloxacin hydrochloride eye drops of the embodiment are prepared from the following substances in percentage by mass: 0.45% of lomefloxacin hydrochloride, 5.3% of dissolution assisting additive, 0.10% of propyl p-hydroxybenzoate, 0.07% of sodium alginate, 0.18% of glycerol, 0.023% of buffer solution, 0.055% of mannitol, 0.28% of biological degradation auxiliary agent and the balance of water for injection.
The preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 49 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 42 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting for 4.6h under stirring at 45 ℃, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The buffer solution is prepared by mixing sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution and acetic acid-sodium acetate buffer solution according to the mass ratio of 1: 2.
The preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolution system for 20min, and then placing the degummed cooked silk in a 62 ℃ oven for heating for 3.6h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 11500rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with the weight of 0.07% of that of the cooked silk, mixing, pouring into a dialysis bag, and dialyzing with polyethylene glycol solution with molecular weight of 20000 and 15 wt% for 24 hr; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
Example 4
The lomefloxacin hydrochloride eye drops of the embodiment are prepared from the following substances in percentage by mass: 0.46% of lomefloxacin hydrochloride, 5.3% of a dissolution assisting additive, 0.11% of propyl p-hydroxybenzoate, 0.072% of sodium alginate, 0.18% of glycerol, 0.025% of a buffer solution, 0.062% of mannitol, 0.31% of a biodegradation auxiliary agent and the balance of water for injection.
The preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 53 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 42 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting at 45 ℃ for 4-5h under stirring, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g of N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The buffer solution is one or a mixture of more of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, boric acid-borax buffer solution, acetic acid-ammonium acetate buffer solution, acetic acid-sodium acetate buffer solution and citric acid buffer solution.
The preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolution system for 20min, and then placing the degummed cooked silk in a 63 ℃ oven for heating for 3.5h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 11500rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with cooked silk mass of 0.068%, mixing, pouring into dialysis bag, and dialyzing with polyethylene glycol solution with molecular weight of 20000 and 15 wt% for 24 hr; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
Example 5
The lomefloxacin hydrochloride eye drops of the embodiment are prepared from the following substances in percentage by mass: 0.47% of lomefloxacin hydrochloride, 5.3% of dissolution assisting additive, 0.12% of propyl p-hydroxybenzoate, 0.055% of sodium alginate, 0.18% of glycerol, 0.025% of buffer solution, 0.06% of mannitol, 0.30% of biological degradation auxiliary agent and the balance of water for injection.
The preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of injection water preheated to 55 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 42 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
The preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, stirring at 45 ℃ for reaction for 5 hours, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring at the temperature of 2 ℃ in a water bath, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at the room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, placing in a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation.
The buffer solution is one or a mixture of more of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, boric acid-borax buffer solution, acetic acid-ammonium acetate buffer solution, acetic acid-sodium acetate buffer solution and citric acid buffer solution.
The preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolving system for 16min, and then placing the degummed cooked silk in a 62 ℃ oven for heating for 3.8h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 12000rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with cooked silk mass of 0.08%, mixing, pouring into dialysis bag, and dialyzing with polyethylene glycol solution with molecular weight of 20000 and 15 wt% for 24 hr; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
Comparative example 1
This comparative example differs from example 1 in that no sodium alginate was added.
Comparative example 2
This comparative example differs from example 1 in that mannitol was not added.
Comparative example 3
This comparative example differs from example 1 in that no fluxing additive is added.
Comparative example 4
This comparative example differs from example 1 in that no biodegradation aid was added.
Comparative example 5
The lomefloxacin hydrochloride eye drops prepared in example 3 of the patent with reference to application No. 201210159065.1 are prepared by mixing 3.32g of lomefloxacin hydrochloride, 0.8g of sodium hyaluronate, 0.20g of sodium dihydrogen phosphate-disodium hydrogen phosphate, 0.20g of benzalkonium chloride, 2.00g of glycerol, 6.80g of sodium chloride and water for injection to a constant volume of 1000 mL. The preparation method comprises the following steps: (1) dispersing the sodium hyaluronate of the prescription amount in a proper amount of water for injection at the temperature of 40-55 ℃ to swell and prepare transparent solution; (2) dissolving lomefloxacin hydrochloride as a main drug in a prescription amount in a proper amount of injection water at 60-70 ℃, adding a mixed solution of sodium dihydrogen phosphate-disodium hydrogen phosphate, sodium chloride, benzalkonium chloride and glycerol in a prescription amount, stirring and mixing, transferring into the step (1), adjusting the pH to 6.0 by using 0.1mol/L sodium hydroxide solution, adding the total amount of the injection water, filtering by using a 0.22 mu m microporous membrane, checking to be qualified, and carrying out aseptic packaging to obtain the lomefloxacin hydrochloride injection.
Stability test
The lomefloxacin hydrochloride eye drops prepared in the groups of examples 1 to 5 and comparative examples 1 to 5 are placed at the temperature of 40 ℃ and the relative humidity of 65% for 6 months, and samples are taken once at the time points of 1 month, 2 months, 3 months and 6 months respectively for detection. Wherein, the appearance shape is light yellow green clear liquid, the detection of pH value, viscosity and impurity content is carried out, and the specific test result is shown in table 1.
TABLE 1 stability test results
As can be seen from the above table, the lomefloxacin hydrochloride eye drops in the embodiments of the present invention have good pH stability, viscosity stability, and impurity content stability, which indicate that the components are stable and uniform, and the mixture ratio of the buffer solution and the thickener is proper, compared with the comparative examples. Comparative example 1 the viscosity decreased significantly with time due to the absence of the thickener sodium alginate. And compared with the comparative example 3, no dissolving aid additive is added, so that the compatibility and the bonding force between the main medicine and other components are poor, and the impurity content is obviously increased.
Rabbit eye irritation test
Taking 10 healthy rabbits, each of which corresponds to the group of examples 1-5 and the group of comparative examples 1-5, dripping 0.1mL of physiological saline into the conjunctival sac of the left eye as a control, dripping 0.1mL of lomefloxacin hydrochloride eye drops into the conjunctival sac of the right eye, slightly closing the eyelid after eye dropping for 10s, 4 times every day for 7 days continuously, and inspecting the eyes 1h, 24h, 48h and 72h before and after the last administration every day, and according to the record of eye irritation response evaluation standard score of the State food and drug administration 2005, the result shows that compared with the group of comparative examples, the cornea of the group of examples is transparent, the iris is clear, the conjunctiva is hyperemia and edema and secretion are avoided, and the flashlight is equipped with a magnifying glass to inspect pathological changes, the score is 0, and the result shows that the rabbit is safe and non-irritating.
The lomefloxacin hydrochloride eye drops have good stability, uniformity and absorbability, have strong osmosis effect when in use, obviously reduce intraocular pressure, and have obvious curative effect on treating acute and chronic bacterial conjunctivitis, blepharitis, hordeolum, meibomian gland adenitis, dacryocystitis, keratitis, corneal ulcer and other external eye infections caused by sensitive pathogenic bacteria.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.
Claims (3)
1. The lomefloxacin hydrochloride eye drops are characterized by being prepared from the following substances in percentage by mass: 0.3-0.5% of lomefloxacin hydrochloride, 3.4-5.5% of a dissolution aid additive, 0.05-0.12% of propyl p-hydroxybenzoate, 0.04-0.08% of sodium alginate, 0.12-0.19% of glycerol, 0.01-0.03% of buffer solution, 0.04-0.07% of mannitol, 0.15-0.32% of a biodegradation auxiliary agent and the balance of water for injection;
the preparation method of the eye drops comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 45-55 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 35-45 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering with a 0.22 mu m microporous filter membrane, and aseptically packaging;
the preparation method of the biodegradation auxiliary agent comprises the following steps:
1) placing 10.3g of β -cyclodextrin and 29.1g of 25 wt% of sodium hydroxide into a flask, adding 1.15g of sodium chloroacetate under stirring, reacting at 45 ℃ for 4-5h under stirring, dropwise adding hydrochloric acid to adjust the pH of a system to 7, adding methanol until the precipitation amount is not increased any more after the temperature of the system is reduced to room temperature, filtering, and drying a filter cake in a dryer at 45 ℃ to obtain powdery carboxyl substituted β -cyclodextrin;
2) dissolving 8.5g of carboxyl-substituted β -cyclodextrin and 1.26g N-hydroxysuccinimide in 50mL of distilled water, stirring in a water bath at the temperature of 2 ℃, adding 2.1g of EDC, reacting for 2 hours at the temperature of heat preservation, slowly adding 11.2g of chitosan, reacting for 1 hour at the temperature of 2 ℃, reacting for 24 hours at room temperature, filtering to remove insoluble substances, dialyzing for 48 hours in a dialysis bag, putting into a refrigerator at the temperature of-15 ℃ for low-temperature and rapid cooling, and transferring to a vacuum freeze dryer at the temperature of-25 ℃ for freeze preservation;
the preparation method of the solubilizing additive comprises the following steps: soaking the degummed cooked silk in a ternary dissolution system for 15-20min, and heating in an oven at 55-65 ℃ for 3-4h to obtain a silk fibroin solution after complete dissolution; pouring the silk fibroin solution into a dialysis bag, and dialyzing with deionized water for 3 d; centrifuging at 10000-12000rpm to remove insoluble impurities, adding hydroxypropyl methylcellulose with the mass of 0.05-0.08% of that of the cooked silk, mixing uniformly, pouring into a dialysis bag, and dialyzing with polyethylene glycol solution with the molecular weight of 20000 and 15 wt% for 24 h; wherein the ternary dissolution system is prepared by mixing calcium chloride, ethanol and water according to the molar ratio of 1:2: 8.
2. The lomefloxacin hydrochloride eye drops according to claim 1, wherein the buffer is one or more of a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, a boric acid-borax buffer, an acetic acid-ammonium acetate buffer, an acetic acid-sodium acetate buffer and a citric acid buffer.
3. A process for preparing lomefloxacin hydrochloride eye drops according to claim 1 or 2, which comprises the following steps:
s1, dispersing sodium alginate and a solubilizing additive into a proper amount of water for injection preheated to 45-55 ℃ in advance to swell the system into a transparent solution;
s2, dispersing lomefloxacin hydrochloride in a proper amount of water for injection, mixing and stirring uniformly with a transparent solution preheated to 35-45 ℃, then adding glycerol, mannitol, a biodegradation aid and a proper amount of water for injection, stirring and mixing, adding a buffer solution to adjust the pH value, and adding the rest of water for injection;
s3, filtering through a 0.22 mu m micropore filter membrane, and carrying out aseptic packaging.
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