CN108815119B - Pharmaceutical composition containing besifloxacin hydrochloride and preparation method thereof - Google Patents
Pharmaceutical composition containing besifloxacin hydrochloride and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition containing besifloxacin hydrochloride and a preparation method thereof, wherein the prescription comprises the following components in percentage by mass: 5-10% of besifloxacin hydrochloride, 5-65% of amphiphilic block polymer carrier, 0.01-2% of bacteriostatic agent, 0.01-20% of thickening agent, 0.01-40% of osmotic pressure regulator, 0.01-10% of pH regulator, 0.01-2% of metal ion chelating agent and water for injection. The prepared besifloxacin hydrochloride eye drops have good stability, can obviously prolong the acting time of the besifloxacin hydrochloride in eyes and improve the curative effect of the besifloxacin hydrochloride eye drops.
Description
Technical Field
The invention relates to a pharmaceutical composition containing besifloxacin hydrochloride and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Liposomes (liposomes) are a drug carrier, which was first discovered in 1965 by Bangham, and the starting materials are lipid compounds such as phospholipids, cholesterol, etc. Because the phospholipid and the cholesterol have amphiphilicity, namely one end is a hydrophobic group, the other end is a hydrophilic group, and meanwhile, the intermolecular hydrophilic and hydrophobic effects can spontaneously form a phospholipid bilayer closed vesicle, and the drug can be encapsulated in the vesicle. Liposome technology is also being likened to the fourth generation targeted drug delivery technology of "biolistic" technology.
Phospholipids are main membrane materials used for preparing liposomes, and mainly include lecithin, Phosphatidylethanolamine (PE), soybean phospholipids, cholesterol, cephalin, cholesterol acetyl ester, synthetic DPPC, synthetic PS, Phosphatidylinositol (PI), Sphingomyelin (SPH), and the like. The liposome technology can reduce the toxicity of the encapsulated medicine, enhance the pharmacological action, prolong the action time, increase the stability and the like. The invention of the long-circulating liposome further improves the defects of the traditional liposome and improves the circulating time and the targeting property of liposome medicaments. In addition, the research on novel liposomes such as pH sensitive liposome, heat sensitive liposome, enzyme-guided liposome, light sensitive liposome, antibody-guided liposome and the like is also in the process of fire and heat, and the positive application of liposome technology in the field of drug delivery is highlighted. At present, many medicines are prepared into liposome administration forms, mainly belong to the field of antitumor medicines, and in addition, antibiotics, antifungal medicines, antiparasitic medicines, vaccines and the like are also provided. The prepared administration forms are mainly injections, but also have application in oral preparations, ophthalmic preparations and the like.
The polyethylene glycol-derived phosphatidylethanolamine (PEG-PE) is a degradable drug carrier material approved by the United states Food and Drug Administration (FDA) and applicable to human bodies, and has good biocompatibility and safety. PEG-PE is a linear polymer, which has a partially extended conformation on the surface of liposome, has very long polar groups, can improve the hydrophilicity of the surface of the liposome, and can be used as a long-acting liposome. Due to the very low Critical Micelle Concentration (CMC) of PEG-PE (10) -6 ~10 -5 mol/L), the formed micelle is stable, the particle size is smaller (less than 50 nm), and the drug carrier has wide application prospect.
Chinese patent (CN 103860467A) prepared bromfenac sodium liposome eye drops using polyethylene glycol-phosphatidylethanolamine as a carrier. The bromfenac sodium liposome eye drop can obviously enhance the permeability of the drug to the cornea, prolong the acting time of the drug in the eyes and improve the curative effect. Similarly, Chinese patent (CN 103860466A) also adopts polyethylene glycol-phosphatidyl ethanolamine as a carrier to prepare loteprednol etabonate eye drops. The loteprednol etabonate nano micelle eye drop can also obviously enhance the penetration of loteprednol etabonate to the cornea and prolong the action time of the loteprednol etabonate in eyes.
Besifloxacin hydrochloride (Besifloxacin hydrochloride) is a new generation of fluoroquinolone antibacterial drugs, developed by bosch & Lomb Inc, usa, and approved by FDA in usa to be marketed 5 months in 2009, and is the first non-systemic fluoroquinolone drug developed specifically for ophthalmic use. The besifloxacin hydrochloride suspension is marketed in a dosage form and 0.6% in specification, is under the commercial name of Besivance, and is clinically used for treating bacterial conjunctivitis. Besifloxacin hydrochloride has the chemical name (R) -7- [ 3-aminohexahydro-1H-azepin-1-yl ] -8-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate, and its chemical structural formula is shown as follows:
the besifloxacin hydrochloride system is an 8-chlorofluoroquinolone drug with N-cyclopropyl, and plays a role in resisting gram positive bacteria and gram negative bacteria by inhibiting bacterial DNA gyrase and topoisomerase IV. DNA gyrase is a key enzyme required for bacterial DNA replication, transcription and repair; topoisomerase iv is a key enzyme required for chromosomal DNA separation during bacterial division. The besifloxacin hydrochloride shows a very good bactericidal effect in clinical tests and has broad-spectrum antibacterial activity on eye pathogenic bacteria causing bacterial conjunctivitis.
Although the besifloxacin hydrochloride has strong bactericidal effect and wide antibacterial spectrum, if the besifloxacin hydrochloride is prepared into a common solution type eye drop, the following problems exist: (1) the stability of the besifloxacin hydrochloride is poor, the besifloxacin hydrochloride is easier to degrade in a solution, and particularly the stability to light is greatly reduced; (2) the solubility of the besifloxacin hydrochloride is not good, and the besifloxacin hydrochloride is not easy to prepare into a solution type ophthalmic preparation; (3) the common solution type eye drops are easy to run off in the blinking process, and are not beneficial to the besifloxacin hydrochloride to play the antibacterial effect in eyes.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing besifloxacin hydrochloride and a preparation method thereof, and aims to solve the problems in the method for preparing the besifloxacin hydrochloride eye drops.
The object of the invention can be achieved by the following measures:
the invention provides a pharmaceutical composition containing besifloxacin hydrochloride, which is a liposome nano micelle eye drop, and the prescription comprises the following components in percentage by mass: 5-10% of besifloxacin hydrochloride, 5-65% of amphiphilic block polymer carrier, 0.01-2% of bacteriostatic agent, 0.01-20% of thickening agent, 0.01-40% of osmotic pressure regulator, 0.01-10% of pH regulator, 0.01-2% of metal ion chelating agent and the balance of water for injection.
The invention provides besifloxacin hydrochloride lipidosome nano micelle eye drops, wherein a carrier adopted by the eye drops is an amphiphilic block polymer consisting of two polymers, a hydrophilic region of the eye drops is made of one of polyethylene glycol, polyoxyethylene and polyvinylpyrrolidone, and a hydrophobic region of the eye drops is made of one of polyoxypropylene, polystyrene, polylactic acid and phosphatidylethanolamine. The preferred amphiphilic block polymer carrier is polyethylene glycol-phosphatidylethanolamine. The polyethylene glycol-phosphatidylethanolamine polymer is a pharmaceutical adjuvant approved by FDA and applicable to intravenous injection, has the advantages of no toxicity, low immunogenicity, in vivo degradability and the like, and is produced by the Germany Lipoid company.
The invention provides a pharmaceutical composition containing besifloxacin hydrochloride, wherein a bacteriostatic agent in the composition is one of benzalkonium chloride, benzalkonium bromide and ethylparaben.
The invention provides a pharmaceutical composition containing besifloxacin hydrochloride, wherein a thickening agent in the composition is one or more of hydroxypropyl methyl cellulose, polycarbophil, polyvinyl alcohol and hydroxypropyl cellulose.
The invention provides a pharmaceutical composition containing besifloxacin hydrochloride, wherein an osmotic pressure regulator in the composition is one or more of sodium chloride, glucose, mannitol, glycerol, xylitol, sorbitol and boric acid.
There are two common methods for preparing nanomicelles, one is a direct dissolution method and the other is a dialysis method, and the method for preparing the micelles depends on the solubility of the polymer in water. At normal temperature or higher temperature, the polymer with good water solubility can be directly dissolved in water or aqueous solution (PBS buffer solution or normal saline), and when the water solubility is higher than CMC, a clear and transparent micelle solution is formed. The polymer with poor water solubility must be dissolved in an organic solvent which is mutually soluble with water, and then the organic solvent is removed by a solvent evaporation method or a dialysis method, and in the process, the polymer gradually forms nano-micelle with stable structure. Dialysis is a common method for preparing polymer micelles in the laboratory, but is not suitable for large-scale production. As the organic solvent, ethanol, dimethyl sulfoxide, N-dimethylformamide and the like are usually used.
The preparation method of the nano micelle eye drop containing besifloxacin hydrochloride provided by the invention comprises the following steps:
(1) weighing the polycarbophil, the edetate disodium and the mannitol according to the prescription amount, adding the polycarbophil, the edetate disodium and the mannitol into a proper amount of water for injection, and stirring and swelling for 10-12 hours at room temperature to prepare a solution 1;
(2) weighing benzalkonium chloride and sodium chloride according to the prescription amount, adding a proper amount of water for dissolving, adding the solution into the solution 1, and uniformly stirring to prepare a solution 2;
(3) weighing polyethylene glycol-phosphatidylethanolamine and besifloxacin hydrochloride according to the prescription amount, dissolving the polyethylene glycol-phosphatidylethanolamine and the besifloxacin hydrochloride into 300mL of absolute ethyl alcohol, stirring the mixture until the mixture is completely dissolved, removing the solvent by adopting a nitrogen blow-drying instrument, then adding the mixture into 300mL of water for injection, stirring the mixture evenly, then adding the mixture into a solution 2, adjusting the pH value to 6.2-6.5 by using a 10% sodium hydroxide solution, and adding the water for injection to adjust the volume to 1000 mL.
According to the pharmaceutical composition containing besifloxacin hydrochloride and the preparation method thereof, the prepared liposome nano micelle eye drop has good stability of the besifloxacin hydrochloride, can obviously prolong the acting time of the besifloxacin hydrochloride in eyes, and improves the curative effect of the besifloxacin hydrochloride.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.
Example 1: preparation of eye drops of besifloxacin hydrochloride
The prescription composition is as follows:
bexifloxacin hydrochloride 6.56g
39.36g of polyethylene glycol-phosphatidylethanolamine
Polycarbophil 3.28g
0.03g of edetate disodium
Benzalkonium chloride 0.03g
Mannitol 6.56g
Sodium chloride 3.28g
Proper amount of 10% sodium hydroxide solution
Adding water for injection to 1000mL
The preparation method comprises the following steps:
(1) weighing the polycarbophil, the edetate disodium and the mannitol according to the prescription amount, adding the polycarbophil, the edetate disodium and the mannitol into a proper amount of water for injection, and stirring and swelling for 10-12 hours at room temperature to prepare a solution 1;
(2) weighing benzalkonium chloride and sodium chloride according to the prescription amount, adding a proper amount of water for dissolving, adding the solution into the solution 1, and uniformly stirring to prepare a solution 2;
(3) weighing polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride according to the formula, dissolving the polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride into 300mL of absolute ethanol, stirring the mixture until the mixture is completely dissolved, removing the solvent by using a nitrogen blow-drying instrument, adding the mixture into 300mL of water for injection, stirring the mixture uniformly, adding the mixture into the solution 2, adjusting the pH value to 6.2-6.5 by using a 10% sodium hydroxide solution, and adding the water for injection to adjust the volume to 1000 mL.
Example 2: preparation of eye drops of besifloxacin hydrochloride
The prescription composition is as follows:
bexifloxacin hydrochloride 6.56g
52.26g of polyethylene glycol-phosphatidylethanolamine
4.20g of polycarbophil
0.10g disodium edetate
Benzalkonium chloride 0.10g
Mannitol 22.00g
Sodium chloride 4.50g
Proper amount of 10% sodium hydroxide solution
Adding water for injection to 1000mL
The preparation method comprises the following steps:
(1) weighing the polycarbophil, the edetate disodium and the mannitol according to the prescription amount, adding the polycarbophil, the edetate disodium and the mannitol into a proper amount of water for injection, and stirring and swelling for 10-12 hours at room temperature to prepare a solution 1;
(2) weighing benzalkonium chloride and sodium chloride according to the prescription amount, adding a proper amount of water for dissolving, adding the solution into the solution 1, and uniformly stirring to obtain a solution 2;
(3) weighing polyethylene glycol-phosphatidylethanolamine and besifloxacin hydrochloride according to the prescription amount, dissolving the polyethylene glycol-phosphatidylethanolamine and the besifloxacin hydrochloride into 300mL of absolute ethyl alcohol, stirring the mixture until the mixture is completely dissolved, removing the solvent by adopting a nitrogen blow-drying instrument, then adding the mixture into 300mL of water for injection, stirring the mixture evenly, then adding the mixture into a solution 2, adjusting the pH value to 6.2-6.5 by using a 10% sodium hydroxide solution, and adding the water for injection to adjust the volume to 1000 mL.
Example 3: preparation of eye drops of besifloxacin hydrochloride
The prescription composition is as follows:
bexifloxacin hydrochloride 6.56g
65.60g polyethylene glycol-phosphatidyl ethanolamine
Polycarbophil 4.20g
0.10g disodium edetate
Benzalkonium chloride 0.10g
Mannitol 22.00g
Sodium chloride 4.50g
Proper amount of 10 percent sodium hydroxide solution
Adding water for injection to 1000mL
The preparation method comprises the following steps:
(1) weighing the polycarbophil, the edetate disodium and the mannitol according to the prescription amount, adding the polycarbophil, the edetate disodium and the mannitol into a proper amount of water for injection, and stirring and swelling for 10-12 hours at room temperature to prepare a solution 1;
(2) weighing benzalkonium chloride and sodium chloride according to the prescription amount, adding a proper amount of water for dissolving, adding the solution into the solution 1, and uniformly stirring to obtain a solution 2;
(3) weighing polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride according to the formula, dissolving the polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride into 300mL of absolute ethanol, stirring the mixture until the mixture is completely dissolved, removing the solvent by using a nitrogen blow-drying instrument, adding the mixture into 300mL of water for injection, stirring the mixture uniformly, adding the mixture into the solution 2, adjusting the pH value to 6.2-6.5 by using a 10% sodium hydroxide solution, and adding the water for injection to adjust the volume to 1000 mL.
Example 4: stability comparison of besifloxacin hydrochloride eye drops
The checking method comprises the following steps: HPLC method (appendix V D of second division of 2010 edition, Chinese pharmacopoeia);
an instrument device: shimadzu LC-20AD high Performance liquid chromatograph, Shimadzu corporation, Japan;
a detector: an ultraviolet detector;
the test conditions are as follows: the chromatographic column is a Kromasil-C18 chromatographic column (specification: 250mm multiplied by 4.6mm, 5 m), the detection wavelength is 275nm, and the mobile phase is: acetonitrile: water =75: 25.
The stability comparison results are shown below:
Claims (5)
1. the pharmaceutical composition containing besifloxacin hydrochloride comprises the following components in percentage by mass: 5 to 10 percent of besifloxacin hydrochloride, 5 to 65 percent of amphiphilic block polymer carrier, 0.01 to 2 percent of bacteriostatic agent, 0.01 to 20 percent of thickening agent, 0.01 to 40 percent of osmotic pressure regulator, 0.01 to 10 percent of pH regulator, 0.01 to 2 percent of metal ion chelating agent and the balance of water for injection; the amphiphilic block polymer carrier is polyethylene glycol-phosphatidylethanolamine.
2. The pharmaceutical composition of claim 1, wherein the bacteriostatic agent contained in the formulation is one of benzalkonium chloride, benzalkonium bromide, and ethylparaben.
3. The pharmaceutical composition of claim 1, wherein the formulation comprises one or more thickening agents selected from the group consisting of hydroxypropylmethylcellulose, polycarbophil, polyvinyl alcohol, and hydroxypropylcellulose.
4. The pharmaceutical composition containing besifloxacin hydrochloride according to claim 1, wherein the osmotic pressure regulator contained in the formulation is one or more of sodium chloride, glucose, mannitol, glycerol, xylitol, sorbitol and boric acid.
5. The pharmaceutical composition containing besifloxacin hydrochloride according to any one of claims 1 to 4, which is prepared by the following steps:
(1) weighing the polycarbophil, the edetate disodium and the mannitol according to the prescription amount, adding the polycarbophil, the edetate disodium and the mannitol into a proper amount of water for injection, and stirring and swelling for 10-12 hours at room temperature to prepare a solution 1;
(2) weighing benzalkonium chloride and sodium chloride according to the prescription amount, adding a proper amount of water for dissolving, adding the solution into the solution 1, and uniformly stirring to obtain a solution 2;
(3) weighing polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride according to the formula, dissolving the polyethylene glycol-phosphatidyl ethanolamine and besifloxacin hydrochloride into 300mL of absolute ethanol, stirring the mixture until the mixture is completely dissolved, removing the solvent by using a nitrogen blow-drying instrument, adding the mixture into 300mL of water for injection, stirring the mixture uniformly, adding the mixture into the solution 2, adjusting the pH value to 6.2-6.5 by using a 10% sodium hydroxide solution, and adding the water for injection to adjust the volume to 1000 mL.
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