CN111743858B - Pharmaceutical composition of bromfenac sodium - Google Patents
Pharmaceutical composition of bromfenac sodium Download PDFInfo
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- CN111743858B CN111743858B CN201910252261.5A CN201910252261A CN111743858B CN 111743858 B CN111743858 B CN 111743858B CN 201910252261 A CN201910252261 A CN 201910252261A CN 111743858 B CN111743858 B CN 111743858B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a pharmaceutical composition of sodium bromfenac, which comprises sodium bromfenac sesquihydrate and pharmaceutically acceptable salt thereof, and the weight percentage is 0.01-0.5%; viscosity modifier, dextran; 0.01 to 1 percent by weight; 0.01 to 1 weight percent of surfactant; antioxidant, weight percentage is 0.01% -0.5%; optionally other pharmacologically acceptable adjuvants. The invention has the beneficial effects that when the bromfenac sodium eye drops contain the dextran 40 or the dextran 70, the generation of the impurity U-II can be effectively avoided, and unexpected discovery is made that the addition of the dextran can also ensure the antibacterial effect of benzalkonium chloride, increase the residence time in eyes and improve the drug effect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition of bromfenac sodium.
Background
Chemical name of sodium bromfenac: 2-amino-3- (4-bromobenzoyl) phenylacetic acid (sodium) having the following structural formula:
sodium bromfenac is a non-steroidal anti-inflammatory drug with anti-inflammatory activity. The mechanism of action is to prevent prostaglandin synthesis by inhibition of cyclooxygenase 1 and 2. Prostaglandins are mediators of certain intraocular inflammations, and prostaglandins are capable of disrupting the blood-aqueous barrier, vasodilating, increasing vascular permeability, leukocytosis, and increasing intraocular pressure.
Sodium bromfenac eye drops were developed by Senju corporation in Japan, and commercially available in Japan in 2000 under the trade name of QBY/Point eye drops (BRONUCK OPHTHALMIC SOLUTION), and were 5 ml/count of a 0.1% sodium bromfenac ophthalmic solution (calculated as sodium bromfenac hydrate) twice daily. The trade name Xibrom (twice daily) was marketed in the United states in month 3 2005, and the trade name Bromday (the prescription should be the same as Xibrom, a new once daily dosing regimen) was marketed in 2010. Doctor's solution 2013 (purchased from ISTA corporation) was marketed in the united states as a new prescription of 0.07% sodium bromfenac eye drops (prolens, calculated as bromfenac), once a day. In recent years, ophthalmic anti-inflammatory single preparations always account for about 20 percent of the ophthalmic medicine, and bromfenac sodium eye drops are used for 1 time a day, so that the ophthalmic anti-inflammatory single preparation is convenient to use, high in patient compliance and small in side effect, and therefore, the bromfenac sodium has a good market.
Patent CN103379904 (kilolife) discloses a composition capable of effectively guaranteeing the bacteriostatic effect and safety of sodium bromfenac; breaks through the convention of the reduction of preservation efficiency caused by non-steroidal compounds and quaternary ammonium salts, and uses benzalkonium chloride as a preservative in the bromfenac sodium eye drops; patent 200480000976.3 (Qianshou) discloses a bromfenac sodium eye drop with tetrabutyl phenolic aldehyde as a surfactant, which avoids the reduction of bacteriostatic function caused by the combination of polysorbate 80 and benzalkonium; patent CN1993118B (Qianshou) discloses bromfenac sodium eye drops comprising organic amines, specifically organic amines including alkanolamines and aminoalkylsulfonic acids, to increase the intraocular permeability of bromfenac, increase the intraocular residence time of pharmaceutically effective concentrations, but organic amine agents have an eye-irritating effect.
CN104203224a discloses sodium bromfenac eye drops, which are stabilized by the ratio of p-benzalkonium chloride and polyoxyethylene sorbitan fatty acid ester; CN105451731a (asiabell) discloses a preparation method of bromfenac sodium eye drops, which comprises bromfenac sodium, benzalkonium bromide and polyoxyethylene sorbitan fatty acid ester, wherein the bromfenac sodium eye drops are more stable by limiting the dosage proportion of main and auxiliary materials in the prescription;
patent CN104812370a (doctor's) discloses a stable preservative-efficacy bromfenac sodium preparation, which defines that a nonionic surfactant is used for bromfenac sodium eye drops, and specific surfactant and preservative type combinations are screened; CN104523587a discloses that the formation of formulation impurities U-II can be reduced by replacing povidone with a thickener such as sodium hyaluronate; CN101313899a (deluxe, 2007) solves the problem of long-term placement stability of eye drops by adding the cosolvent hydroxyethyl cellulose.
Through published data and our process of developing bromfenac sodium eye drops, the compatibility of polysorbate 80 and benzalkonium chloride serving as a preservative in an original prescription can reduce the antibacterial effect of benzalkonium chloride, and certain safety risk exists; the bromfenac sodium and the thickener povidone are liable to generate a polymer impurity U-II, the impurity increases along with the extension of the imitation time and the increase of the temperature, and the content of the impurity in the original grinding product in the near-term is about 3 percent.
The bacteriostatic agent (also called preservative) refers to a chemical substance for inhibiting the growth of microorganisms, and if the drug itself does not have sufficient bacteriostatic efficacy according to the rule 1121 of the 2015 edition of Chinese pharmacopoeia, a proper bacteriostatic agent should be added according to the characteristics of the preparation (such as water-soluble preparation) so as to prevent the preparation from damaging the user due to the deterioration of the drug caused by microbial contamination and propagation during normal storage or use, especially the preparation packaged in multiple doses. Benzalkonium chloride is also a bacteriostatic agent, and can destroy the normal moistening and repairing functions of tears of a human body on ocular surface tissue cells after long-term or large-dose use, so that corneal epithelial damage and dry eye are caused.
In the process of drug production, the bacteriostat cannot be used for replacing GMP management of drug production, cannot be used as the only way for reducing microbial contamination of a non-sterile preparation, cannot be used as a means for controlling biological load before sterilization of a multi-dose packaging preparation, has certain toxicity, and the quantity of the bacteriostat in the preparation is the lowest effective dose.
Disclosure of Invention
The invention aims to provide a bromfenac sodium ophthalmic preparation which has the advantages of easily available raw materials, simple process, good stability and high safety.
The technical scheme of the invention is as follows: a pharmaceutical composition of bromfenac sodium comprises
Sodium bromfenac sesquihydrate and pharmaceutically acceptable salts thereof;
viscosity modifier, dextran;
a surfactant;
an antioxidant;
optionally other pharmacologically acceptable adjuvants.
A pharmaceutical composition of bromfenac sodium comprises
Sodium bromfenac sesquihydrate and pharmaceutically acceptable salt thereof, and the weight percentage is 0.01 to 0.5 percent;
viscosity modifier, dextran; 0.01 to 1 percent by weight;
0.01 to 1 weight percent of surfactant;
antioxidant, weight percentage is 0.01% -0.5%;
optionally other pharmacologically acceptable adjuvants.
The dextran is selected from dextran 40 or dextran 70.
In the bromfenac sodium composition, the surfactant is selected from polysorbate 80, poloxamer and tyloxapol.
In the bromfenac sodium composition, the antioxidant is selected from sodium metabisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid and sodium bisulfite.
The bromfenac sodium composition further comprises a preservative; the preservative is selected from benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl alcohol, chlorobutanol, phenethyl alcohol, sorbic acid, chlorhexidine, nitropropanol, o-phenylphenol, methyl/ethyl/propyl p-hydroxybenzoate, phenol, phenylmercuric acetate/phenyl nitrate, sodium benzoate, beta-phenethyl alcohol and merthiolate.
In order to obtain better technical effect, the preservative is selected from benzalkonium chloride, methyl parahydroxybenzoate and ethyl parahydroxybenzoate.
The bromfenac sodium composition further comprises an osmotic pressure regulator; the osmotic pressure regulator is one or more selected from sodium chloride, glucose, mannitol, glycerol, xylitol, sorbitol, boric acid and borax;
in order to obtain better technical effect, the osmotic pressure regulator is selected from sodium chloride, mannitol, boric acid and borax.
The bromfenac sodium composition further comprises a pH regulator, wherein the pH regulator is selected from one or more of sodium hydroxide, calcium hydroxide, sodium citrate, citric acid, hydrochloric acid, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid and borax;
in order to obtain better technical effect, the pH regulator is selected from boric acid, borax and sodium hydroxide, and the pH is regulated to 8.0-8.6.
The bromfenac sodium composition further comprises a complexing agent, wherein the complexing agent is selected from edetate disodium.
A pharmaceutical composition of bromfenac sodium comprises the following components in percentage by weight
Sodium bromfenac sesquihydrate, 0.01-0.5%;
dextran 40;0.01 to 0.5 percent;
80,0.01% -1% of polysorbate;
sodium sulfite, 0.01-0.5%;
benzalkonium chloride, 0.001% -0.01%;
boric acid, 0.5% -1.5%;
borax 0.5-1.5%;
disodium edentate, 0.001% -0.05%;
adjusting the pH to 8.0-8.6 by sodium hydroxide;
the balance being water.
A pharmaceutical composition of bromfenac sodium comprises the following components in percentage by weight
Sodium bromfenac sesquihydrate, 0.05-0.2%;
dextran 40;0.01 to 0.4 percent;
80,0.05 to 0.5 percent of polysorbate;
sodium sulfite, 0.05-0.4%;
benzalkonium chloride, 0.002% -0.003%;
boric acid, 0.5% -1.5%;
borax 0.5-1.5%;
disodium edentate 0.005-0.05%;
adjusting the pH to 8.0-8.6 by sodium hydroxide;
the balance being water.
A pharmaceutical composition of bromfenac sodium comprises the following components in percentage by weight
Sodium bromfenac sesquihydrate, 0.1%;
dextran 40;0.1%;
polysorbate 80,0.15%;
sodium sulfite, 0.2%;
benzalkonium chloride, 0.003%;
boric acid, 1.1%;
borax, 1.1%;
edetate disodium, 0.02%;
adjusting the pH to 8.2-8.4 by sodium hydroxide;
the balance being water.
The invention has the advantages and positive effects that: the physical and chemical properties of a large number of preparation auxiliary materials and the interaction between the preparation auxiliary materials and the main components are researched, and then hundreds of times of formula screening are carried out to finally determine that when the bromfenac sodium eye drops contain the dextran 40 or the dextran 70, the generation of the impurity U-II can be effectively avoided, and unexpected discovery is made that the addition of the dextran can also ensure the antibacterial effect of benzalkonium chloride, increase the residence time in eyes and improve the drug effect.
Detailed Description
The invention will be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions and corresponding modifications to the technical features of the present invention are included within the scope of the present invention.
Example 1
A pharmaceutical composition of sodium bromfenac, 40ml, comprises
Sodium bromfenac sesquihydrate, 41.4mg
Dextran 40, 40mg;
polysorbate 80, 60mg;
sodium sulfite, 80mg;
benzalkonium chloride 1mg;
boric acid, 440mg;
borax, 440mg;
edetate disodium, 8mg;
adding water to 40ml
10% sodium hydroxide adjusts the pH to 8.3.
Example 2-example 5
Examples 6 to 8
Comparative examples 1 to 2
Eye drops prepared according to the recipe and procedure of example 2 of CN104523587a were noted as control example 1;
prescription: 5g of bromfenac sodium, 1g of hydroxypropyl methylcellulose, 1g of carbomer, 27.9g of sodium citrate, 52.5g of disodium hydrogen phosphate, 0.2g of methyl paraben, 0.3g of methyl ester hydroxypropyl, 0.2g of p-hydroxy tertiary butyl anisole, 0.3g of propyl gallate, 0.4g of triethanolamine and 0.2g of tryptophan, and adding 5000ml of water for injection to prepare 1000 branches.
Eye drops prepared according to the recipe and procedure of example 4 of CN104523587a were noted as control example 2;
prescription: 5g of bromfenac sodium with the molecular weight of 1.2x10 6 About 8g of sodium hyaluronate, 27.9g of boric acid, 52.5g of borax, benzalkonium bromide and 1g of weight average molecular weight Mn=2.717x10 5 Seed melon polysaccharide sulfate, anhydrous sodium sulfite 0.5g, disodium edentate 0.5g, and water for injection added to 5000ml to prepare 1000 pieces.
Comparative example 3
The prescriptions for example NGB-10 were consistent according to CN104812370 a: sodium bromfenac 0.07%, boric acid 1.4%, sodium borate 0.74%, sodium sulfite 0.2%, EDTA 0.02%, povidone 1.00%, polyquaternium-10.001%, poloxamer 4070.02%, sodium hydroxide to adjust pH7.8.
Comparative example 4
Example a-04 of patent 200480000976.3 as comparative example 4, prescribed:
0.1g of bromfenac sodium, 1.1g of boric acid, 1.1g of borax, 0.003g of benzalkonium chloride, 0.02g of tetrabutyl phenol, 2.0g of polyvinylpyrrolidone (k-30), 0.02g of sodium ethylenediamine tetraacetate, adding water to 100ml and adjusting the pH to 8.17 by sodium hydroxide.
Comparative example 5
A pharmaceutical composition of bromfenac sodium, 100ml, comprises
Sodium bromfenac sesquihydrate, 80.5mg
Polysorbate 80, 150mg;
sodium sulfite, 200mg;
benzalkonium chloride, 3mg;
propylene glycol, 500mg;
boric acid, 1100mg;
borax, 1100mg;
disodium edentate 20mg;
adding water to 100ml
10% sodium hydroxide adjusts the pH to 8.3.
Stability test
Long-term stability investigation of bromfenac sodium eye drops
After the bromfenac sodium eye drops are prepared, the bromfenac sodium eye drops are placed in a low-density polyethylene medicinal eye drop bottle in a dark place, a long-term stability test is carried out according to pharmacopoeia requirements, and the bromfenac sodium eye drops are stored in a dark place under the conditions of 25 ℃ +/-2 ℃ and 40% +/-5% of humidity.
Inspection item:
[ MEANS ] sodium bromfenac sesquihydrate should be 90% -110% of the indicated amount.
[ PREPARATION ] this herb is a clear liquid of yellow color.
The pH should be 8.0 to 8.6.
The related substances were detected by HPLC method, octadecylsilane chemically bonded silica was used as a filler,
phosphate buffer (pH 7.3) -acetonitrile (30:70) was used as mobile phase for detection by UV detector.
The osmolality ratio should be 0.9 to 1.1.
The product is obtained by membrane filtration and examined according to the method, and the method meets the regulations.
The test results are shown in the following table:
antibacterial efficacy detection
According to the antibacterial efficacy examination method of the rule 1121 of the pharmacopoeia 2015, the antibacterial efficacy of the eye drops in the examples and the comparative examples is detected, and as a result, all the eye drops in the examples meet the A standard in the pharmacopoeia standard; of the control examples, only control example 4 meets the a standard of the pharmacopoeia standard for CP2015 bacteriostatic efficacy examination, and the rest meets either only the B standard or does not meet the CP2015 standard.
The specific data are shown in the following table:
the foregoing describes the general embodiments of the present invention in detail, but the description is merely a preferred embodiment of the present invention and should not be construed as limiting the scope of the invention. All equivalent changes and modifications within the scope of the present invention are intended to be covered by the present invention.
Claims (2)
1. A pharmaceutical composition of sodium bromfenac, characterized in that: comprising
Sodium bromfenac sesquihydrate and pharmaceutically acceptable salts thereof;
a viscosity modifier selected from the group consisting of dextran 40 or dextran 70;
a surfactant selected from polysorbate 80 or tyloxapol;
an antioxidant selected from sodium sulfite;
a preservative selected from benzalkonium chloride;
osmotic pressure regulator, boric acid and borax;
complexing agent selected from disodium edentate;
a pH regulator for regulating the pH to 8.0-8.6;
sodium bromfenac sesquihydrate and pharmaceutically acceptable salt thereof, and the weight percentage is 0.01 to 0.5 percent; viscosity regulator, dextran, 0.01-1 wt%;
0.01 to 1 weight percent of surfactant;
antioxidant, weight percentage is 0.01% -0.5%;
optionally other pharmacologically acceptable adjuvants.
2. A pharmaceutical composition of bromfenac sodium comprises the following components in percentage by weight
Sodium bromfenac sesquihydrate, 0.1%;
dextran 40 or dextran 70,0.1%;
polysorbate 80,0.15%;
sodium sulfite, 0.2%;
benzalkonium chloride, 0.003%;
boric acid, 1.1%;
borax, 1.1%;
edetate disodium, 0.02%;
adjusting the pH to 8.2-8.4 by sodium hydroxide;
the balance being water.
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| CN104812370A (en) * | 2012-11-19 | 2015-07-29 | 博士伦公司 | Aqueous liquid composition containing 2-amino-3-(4-bromobenzoyl) phenylacetic acid |
| CN107854469A (en) * | 2016-09-21 | 2018-03-30 | 刘力 | Topical ophthalmic or the husky star medicine of ear or nose use or external preparation for skin and combinations thereof |
| CN108853074A (en) * | 2017-05-10 | 2018-11-23 | 武汉先路医药科技股份有限公司 | A kind of pharmaceutical aqueous eye drops and preparation method thereof containing bromfenac sodium hydrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8778999B2 (en) * | 2009-03-05 | 2014-07-15 | Insite Vision Incorporated | Non-steroidal anti-inflammatory ophthalmic compositions |
| US20130023575A1 (en) * | 2011-07-22 | 2013-01-24 | Kamran Hosseini | Compositions and methods for the treatment of ocular surface allergies |
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2019
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|---|---|---|---|---|
| CN1993118A (en) * | 2004-11-05 | 2007-07-04 | 千寿制药株式会社 | Aqueous eye drops with accelerated intraocular migration permeability |
| CN1823754A (en) * | 2006-03-28 | 2006-08-30 | 卢秀莲 | Sodium bromophenolate eye drops and its preparation method |
| CN101313899A (en) * | 2007-06-01 | 2008-12-03 | 北京德众万全药物技术开发有限公司 | Medicament composition for eyes containing sodium bromfenac |
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