CN111643448A - Moxifloxacin hydrochloride ophthalmic gel and preparation method thereof - Google Patents
Moxifloxacin hydrochloride ophthalmic gel and preparation method thereof Download PDFInfo
- Publication number
- CN111643448A CN111643448A CN202010122668.9A CN202010122668A CN111643448A CN 111643448 A CN111643448 A CN 111643448A CN 202010122668 A CN202010122668 A CN 202010122668A CN 111643448 A CN111643448 A CN 111643448A
- Authority
- CN
- China
- Prior art keywords
- xyloglucan
- gel
- poloxamer
- moxifloxacin hydrochloride
- moxifloxacin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 title claims abstract description 39
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229940100655 ophthalmic gel Drugs 0.000 title abstract description 10
- 229920002000 Xyloglucan Polymers 0.000 claims abstract description 34
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229920001992 poloxamer 407 Polymers 0.000 claims abstract description 31
- 229940044476 poloxamer 407 Drugs 0.000 claims abstract description 31
- 230000003204 osmotic effect Effects 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960003702 moxifloxacin Drugs 0.000 claims abstract description 11
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims abstract description 11
- 239000008215 water for injection Substances 0.000 claims abstract description 11
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 6
- 239000011159 matrix material Substances 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract 2
- 238000011065 in-situ storage Methods 0.000 claims description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 229910021538 borax Inorganic materials 0.000 claims description 16
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 239000004327 boric acid Substances 0.000 claims description 11
- 239000003889 eye drop Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 10
- 229940012356 eye drops Drugs 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 229920002148 Gellan gum Polymers 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
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- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000004328 sodium tetraborate Substances 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 229960004365 benzoic acid Drugs 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 229960005323 phenoxyethanol Drugs 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims 2
- 239000008228 bacteriostatic water for injection Substances 0.000 claims 1
- 229940067107 phenylethyl alcohol Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 12
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- 230000003115 biocidal effect Effects 0.000 abstract 1
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- 238000001879 gelation Methods 0.000 description 8
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 8
- 230000003628 erosive effect Effects 0.000 description 7
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 6
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- 229920001661 Chitosan Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
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- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
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- 125000005619 boric acid group Chemical group 0.000 description 1
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 1
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- -1 compound sodium borate Chemical class 0.000 description 1
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Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Ophthalmology & Optometry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an ophthalmic gel and a preparation method thereof. The main purpose is to provide a novel antibiotic ophthalmic gel composition with simple preparation method, transparent appearance and good stability and a preparation method thereof. Specifically, the invention relates to an ophthalmic gel, which has a pH range of 6.5-8.5, and comprises active ingredients of preferably 0.5% (W/V) moxifloxacin hydrochloride, a gel matrix agent of poloxamer 407 and xyloglucan, and an osmotic pressure regulator, water for injection, and/or a pH regulator, and/or a bacteriostatic agent. The gel component mainly acts to prolong the action time of the moxifloxacin on the eyes, and simultaneously acts as a drug delivery carrier of the moxifloxacin.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an ophthalmic in-situ gel pharmaceutical composition of moxifloxacin hydrochloride and a preparation method thereof, in particular to an ophthalmic in-situ gel pharmaceutical gel preparation taking poloxamer 407 and xyloglucan as main gel matrixes.
Background
In situ gel, also known as in situ gel, is a liquid preparation that is in a free-flowing liquid state at room temperature or storage conditions, and after administration in solution, undergoes a phase transition rapidly at the site of administration to form a semi-solid gel.
The ophthalmic medicine market in China shows an annual growth trend, more than twenty antibacterial and anti-inflammatory ophthalmic medicines are clinically applied at home at present, but the product dosage form still mainly takes eye drops as main material.
Moxifloxacin gel reported in the existing literature generally adopts gellan gum, chitosan, guar gum/polyvinyl alcohol, HPMC, carbomer and the like as a gel system, and sodium alginate and hydroxypropyl cellulose as thickeners. The disadvantage is that the comfort of the patient is poor when the common gel is administered. The gel is unevenly coated in eyes, has strong foreign body sensation, and easily stimulates the secretion of tears, thereby reducing the curative effect.
The invention adopts poloxamer 407 and xyloglucan as a temperature-sensitive in-situ gel system. When the gel is used at room temperature, the gel enters eyes of a patient in a liquid state, the medicine can be uniformly covered on the surfaces of cornea and sclera through good fluidity, and then a uniform gel layer is formed after gelation under physiological conditions, so that the foreign body sensation of eye administration can be reduced, and the use comfort of the gel is improved. The in-situ gel prepared by combining poloxamer 407 and xyloglucan has strong affinity with the medicine application part, especially mucosa tissue, long retention time and good drug release control performance. In addition, the gelation temperature can be conveniently and accurately controlled by adjusting the proportion of the two. Meanwhile, compared with the pH in-situ gel represented by chitosan and the ion sensitive in-situ gel represented by gellan gum, the in-situ gel prepared by the method has the advantages that the gelation process is only related to temperature and is slightly influenced by pH and ion concentration, so that the influence of individual difference of patients on the gelation process is far smaller than that of the pH in-situ gel and the ion sensitive in-situ gel, and the pharmaceutical performance of the product prepared by the method is more stable and reliable.
Moxifloxacin hydrochloride is a fourth-generation fluoroquinolone antibiotic. Moxifloxacin exhibits broad-spectrum antibacterial activity against gram-positive, gram-negative, anaerobic, acid-fast and atypical microorganisms in vitro. The antibacterial action mechanism is interference with II and IV topoisomerase. Research also shows that the moxifloxacin hydrochloride eye drops are mainly usedIt can be used for treating bacterial conjunctivitis, is safe and effective for adults and children of one year and older, and has good antibacterial effect on various pathogenic bacteria causing eye surface infection, including Staphylococcus and Streptococcus which cause 80% of eye infection. The commercial moxifloxacin hydrochloride ophthalmic preparation is prepared by
Eye drops are representative.
The eye has very effective protection mechanism such as lacrimation and blink reflex, so that the liquid medicine dropped into the eye can be rapidly eliminated from the precorneal area, such as the traditional eye preparation
The moxifloxacin hydrochloride eye drops have the biggest defects that the slow release effect is lacked, the mucosa adhesiveness is low, and the active ingredients cannot effectively stay in the eyes for a long time. The retention time is short, so that the bioavailability of the compound is extremely low and is only 1 to 10 percent of the administration dosage; in addition, the biological barrier of the cornea limits the drug from reaching the target tissue in the eye. The above disadvantages make the development of long-acting moxifloxacin ophthalmic formulations a very challenging task.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an ophthalmic moxifloxacin hydrochloride in-situ gel pharmaceutical composition taking poloxamer 407 and xyloglucan as gel matrixes and a preparation method thereof.
The technical scheme is as follows: a moxifloxacin hydrochloride in situ gel taking poloxamer 407(P407) and xyloglucan as a gel matrix comprises the following components: the active ingredients of the gel are 0.2-2% (W/V) moxifloxacin hydrochloride, the gel matrix is 15-30% poloxamer 407, 0.1-10% xyloglucan and optional pharmaceutically acceptable pharmaceutical excipients.
Furthermore, the ophthalmic in-situ gel optionally comprises a pharmaceutically acceptable pharmaceutical adjuvant, an osmotic pressure regulator, and/or a pH regulator, and water for injection. An osmotic pressure regulator selected from the group consisting of sodium chloride, glucose, boric acid, borax, glycerol, propylene glycol, mannitol, sorbitol, and polyethylene glycol; a pH regulator selected from hydrochloric acid, citric acid or its salt, glacial acetic acid or its salt, phosphoric acid or its salt, diethanolamine, boric acid, and borax.
Furthermore, the ophthalmic in situ gel may further comprise a bacteriostatic agent selected from sorbic acid or its salt, benzyl alcohol, phenethyl alcohol, chlorobutanol, benzoic acid, benzalkonium chloride, benzalkonium bromide, phenoxyethanol, esters of paraben, and thimerosal.
Furthermore, the ophthalmic in-situ gel may further comprise one or more of carbomer, hypromellose, hydroxyethyl cellulose, methylcellulose, sodium alginate, hypromellose, gellan gum, xyloglucan, sodium hyaluronate, and PVPK 30.
Preferably, the moxifloxacin hydrochloride in-situ gel comprises the following components: 0.4-0.6 wt% moxifloxacin hydrochloride, more preferably the proportion is 0.5 wt%; 20% -30% of poloxamer 407 and 1% -8% of xyloglucan, more preferably 20% -26.5% of poloxamer 407 and 2% -6% of xyloglucan; 0.01-0.6 wt% of an isotonic regulator and a pH regulator, the balance being water for injection, the pH regulator being added so that the pH of the composition is 5.5-8.5, more preferably 6.5-7.5; the addition of the osmotic pressure regulator makes the osmotic pressure of the drug combination isotonic or close to isotonic with lacrimal fluid, and the osmotic pressure molar concentration of the in-situ gel solution is regulated to be 250-350mOsmol/kg by using the osmotic pressure regulator.
The preferred osmotic pressure regulator is sodium chloride and the preferred pH regulator is boric acid and/or sodium borate.
A preparation method of an ophthalmic in-situ gel pharmaceutical composition of moxifloxacin hydrochloride comprises the following steps:
(1) weighing poloxamer 407(P407) and xyloglucan in a formula amount, dissolving the poloxamer 407 and the xyloglucan in water for injection, adding moxifloxacin hydrochloride in the formula amount into a mixed solution of the poloxamer 407 and the xyloglucan, and stirring until the mixture is fully dissolved;
(2) and (2) weighing an osmotic pressure regulator, and/or a pH regulator, and/or a bacteriostatic agent in proportion into the solution obtained in the step (1), stirring to dissolve the osmotic pressure regulator, regulating the pH to be 6.5-7.5, regulating the osmotic pressure molar concentration to be 250-350mOsmol/kg, filtering, and performing sterile subpackaging to obtain the product.
The invention has the beneficial effects that: poloxamer 407(P407) and xyloglucan are bioadhesive, well tolerated, low toxic, and almost completely non-irritating to the skin and mucous membranes. The moxifloxacin in situ gel for eyes prepared by using the moxifloxacin in situ gel exists in a liquid form below a Lower Critical Solution Temperature (LCST) of the moxifloxacin in situ gel, and is gelatinized when the temperature of the environment reaches or is higher than the LCST. The use mode of the ophthalmic gel is greatly simplified, the ophthalmic gel can be used by dropping into eyes by referring to the use method of the eye drop, and the use comfort of the ophthalmic gel is improved. The moxifloxacin hydrochloride in-situ gel preparation for eyes prepared by the moxifloxacin hydrochloride gel preparation can slowly release medicine property and prolong the action time of the medicine, and
compared with eye drops, the eye drops have longer drug action time.
Drawings
FIG. 1: experimental example 3 in example 3, results of the in situ gel release investigation of moxifloxacin hydrochloride ophthalmic solution, wherein a. erosion behavior of the gel b. cumulative drug release curve c. correlation between drug release and gel erosion.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The embodiments of the present invention have been presented for purposes of illustration and description, and are not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
Example 1
1. Pharmaceutical formulation
Which comprises the following components: 0.5 wt% of moxifloxacin hydrochloride, 20% of poloxamer 407 and 6% of xyloglucan, 0.6 wt% of sodium chloride and borate buffer, wherein the borate buffer is added in an amount to ensure that the pH value of the composition is 6.5, and the rest is water for injection.
2. Pharmaceutical composition and process for preparing same
(1) Weighing poloxamer 407 and xyloglucan according to the formula amount, dissolving the poloxamer 407 and the xyloglucan in water for injection, adding moxifloxacin hydrochloride according to the formula amount into the mixed solution of the poloxamer 407 and the xyloglucan, and stirring until the mixture is fully dissolved;
(2) and (2) weighing sodium chloride, boric acid and sodium borate according to the proportion, dissolving the sodium chloride, the boric acid and the sodium borate in the solution obtained in the step (1) by stirring, adjusting the pH to be 6.5 and the osmotic pressure molar concentration to be 290mOsmol/kg, filtering, and performing sterile subpackaging to obtain the compound sodium borate.
Example 2
1. Pharmaceutical formulation
Which comprises the following components: 0.5 wt% of moxifloxacin hydrochloride, 24% of poloxamer 407 and 3% of xyloglucan, 0.5 wt% of sodium chloride and borate buffer, wherein the borate buffer is added in an amount to ensure that the pH value of the composition is 7.0, and the rest is water for injection.
2. Pharmaceutical composition and process for preparing same
(1) Weighing poloxamer 407 and xyloglucan according to the formula amount, dissolving the poloxamer 407 and the xyloglucan in water for injection, adding moxifloxacin hydrochloride according to the formula amount into the mixed solution of the poloxamer 407 and the xyloglucan, and stirring until the mixture is fully dissolved;
(2) and (2) weighing sodium chloride, boric acid and sodium borate according to the proportion, dissolving the sodium chloride, the boric acid and the sodium borate in the solution obtained in the step (1) by stirring, adjusting the pH to 7.0 and the osmotic pressure molar concentration to 300mOsmol/kg, filtering, and performing sterile subpackaging to obtain the sodium borate.
Example 3
1. Pharmaceutical formulation
Which comprises the following components: 0.6 wt% of moxifloxacin hydrochloride, 24% of poloxamer 407, 3% of xyloglucan, 0.5 wt% of sodium chloride and borate buffer, wherein the borate buffer is added in an amount to ensure that the pH value of the composition is 6.5, 0,01 wt% of benzalkonium chloride, and the balance of water for injection.
2. Pharmaceutical composition and process for preparing same
(1) Weighing poloxamer 407 and xyloglucan according to the formula amount, dissolving the poloxamer 407 and the xyloglucan in water for injection, adding moxifloxacin hydrochloride according to the formula amount into the mixed solution of the poloxamer 407 and the xyloglucan, and stirring until the mixture is fully dissolved;
(2) and (2) weighing sodium chloride, boric acid, sodium borate and benzalkonium chloride in proportion into the solution obtained in the step (1), stirring to dissolve the sodium chloride, the boric acid, the sodium borate and the benzalkonium chloride, adjusting the pH to 6.0 and the osmotic pressure molar concentration to 298mOsmol/kg, filtering, and performing sterile subpackaging to obtain the compound preparation.
Test example 1
Determination of the Lower Critical Solution Temperature (LCST) by the tube inversion method
Simulated Tears (STF) were prepared, which included 6.78g of sodium chloride, 2.18g of sodium bicarbonate, 1.384g of potassium chloride, 0.085g of calcium chloride dihydrate per liter, depending on the electrolyte composition of the tears.
Multiple experiments prove that the in-situ gel preparation prepared in example 1 generates gelation at 31 ℃ and the gelation temperature after being completely mixed with simulated tears is 35.5 ℃.
Test example 2
Determination of the Lower Critical Solution Temperature (LCST) by the tube inversion method
Simulated Tear Fluid (STF) preparation was as in test example 1.
Multiple experiments prove that the in-situ gel preparation prepared in example 3 generates gelation at 29.5 ℃, and the gelation temperature after being completely mixed with simulated tears is 33 ℃.
Test example 3
And (4) observing the in-vitro release degree of the ophthalmic gel.
The actions of blinking, eye movement, tear secretion, etc. may all affect the release of the drug. The filmless dissolution model provides a choice for researching drug release along with gel erosion, the method uses an oscillator to simulate artificial tears to generate a shearing effect similar to blinking on the surface of the gel, erosion of the water-soluble gel and drug release are carried out synchronously, and the method conforms to the real process of the in-vivo ophthalmic gel.
At room temperature of 20 ℃, about 0.65g of moxifloxacin hydrochloride ophthalmic in situ gel prepared in example 1 was added to a test tube weighed in advance, and the container was put into a shaker preheated to 35 ℃ to completely gel the polymer. Adding 2.4mL of artificial tears preheated in advance into the test tube as release media, oscillating at constant temperature of 75r/min for 20min, pouring out all the release media immediately, sucking the inner and outer surfaces of the container, weighing and recording quickly, placing the test tube into the oscillator again for balancing for 5min, adding the artificial tears and continuing oscillating for 20 min. The operation is repeated in this way. The decanted release medium was diluted 10 times and filtered through a 0.22 μm microporous membrane, and 20 μ L was taken for HPLC assay. The accumulated erosion amount of the gel and the accumulated release amount of the drug are respectively used for carrying out regression on the time, and the result shows a good linear relation and accords with the zero-order kinetic characteristic. The cumulative erosion of the gel was regressed by the cumulative release of the drug and also in a good linear relationship, as shown in figure 1, showing that the drug release and erosion of the gel, which is the main factor limiting the drug release, proceed at the same rate.
Release tests show that the moxifloxacin hydrochloride ophthalmic in-situ gel prepared by the pharmaceutical composition and the preparation method thereof
Compared with the eye drops, the moxifloxacin hydrochloride in-situ gel for eyes has long in-situ gel in-eye retention time, and the active ingredients can effectively stay in the eyes for a long time. Thereby slowly releasing the medicine and prolonging the action time of the medicine.
Test example 4
The in-situ gel stability under different conditions of illumination and temperature of the moxifloxacin hydrochloride eye prepared in the example 1 is inspected, and the results are shown in the table 1:
table 1: in-situ gel stability investigation result of moxifloxacin hydrochloride eye
The sample is a light yellow transparent liquid with fluidity under the conditions of new preparation, irradiation of a fluorescent lamp and low temperature, and the sample remained under the condition of high temperature is converted into light yellow transparent gel. The sample content under various sample conditions is not obviously changed, which shows that the moxifloxacin hydrochloride ophthalmic in-situ gel prepared by the pharmaceutical composition and the preparation method thereof provided by the invention has good stability.
Test example 5
Examination of the bacteriostatic efficacy of ophthalmic gels
According to the guiding principle of the 'bacteriostatic efficacy test method' (general rule 1121) of the 'Chinese pharmacopoeia' 2015 edition, the moxifloxacin hydrochloride ophthalmic in-situ gel prepared in the patent examples 1, 2 and 3 is subjected to bacteriostatic efficacy test. The counting method of 5 strains is established by checking the applicability of the culture medium and verifying the recovery rate by a counting method of the number of surviving bacteria. Test samples were prepared according to the guidelines and samples were taken at defined time points for viable bacteria count determination. The results show that: the number of the surviving bacteria in the embodiments 1, 2 and 3 meets the judgment standard, and the moxifloxacin hydrochloride ophthalmic in-situ gel prepared by the pharmaceutical composition and the preparation method thereof meets the regulation of the bacteriostatic efficacy. The test data are shown in tables 2-4.
TABLE 2 lg values corresponding to in situ gel bacteriostatic efficacy results for moxifloxacin eyes
Note: in the table, "-" indicates that the lg value could not be calculated.
TABLE 3 bacteriostatic efficacy criteria for ophthalmic formulations
NR: the test bacteria did not recover growth.
NI: no increase means that the number of test bacteria increased by not more than 0.5lg for the previous measurement period.
Note: according to the guideline of the "checking method of bacteriostatic efficacy" (generic rule 1121) in the 'Chinese pharmacopoeia' 2015 edition, the judgment standard A of the bacteriostatic efficacy of the ophthalmic preparation is shown in the table.
TABLE 4 Moxifloxacin hydrochloride ophthalmic in situ gel reduction lg-worthwhile results
Note: in the table, "-" indicates that the lg value could not be calculated.
Test example 6
Draize rabbit eye irritation test.
Rabbits were randomly divided into 5 groups of 8 rabbits each, and the groups were designated as W1, W2, Y1, Y2, and X groups. The W group was a single administration group, and the Y group was a multiple administration group. Dripping the in-situ gel of the example 1 into the conjunctival sac of the W1 group of rabbits, 1 time per day, and 0.1mL each time; dripping vitamin and moins eye drops into conjunctival sac of W2 group of rabbits, 1 time per day, 0.1mL each time; and observing and recording the eye irritation conditions of 0, 1, 2, 3, 5 and 7 days after the administration. The Y1 rabbit groups are dripped into the conjunctival sac of the embodiment 1 for 3 times a day, and each time is 0.1 mL; w2 drop into conjunctival sac of rabbit
Eye drops are continuously applied for 7 days for 3 times a day, 0.1mL each time; and the group X is a physiological saline control group, eye irritation conditions of 0, 1, 2, 3, 5 and 7 days are observed during and after the administration, the eye irritation conditions are graded according to conjunctival congestion degree, edema degree, secretion amount, iris congestion degree, corneal opacity degree and iris congestion degree, the values of all the components are recorded, and an average value is taken. The test data are shown in tables 5 to 6
TABLE 5 Draize eye irritation test Scoring criteria
| Evaluation score/ | Evaluation results | |
| 0～＜4 | No |
|
| 4～＜9 | Slight stimulation | |
| 9～＜13 | Moderate stimulation | |
| 13～＜16 | Severe irritation |
TABLE 6 Draize eye irritation test results
| Group of | Evaluation score/point | |
| W1 | ||
| 0 | Has no | |
| W2 | ||
| 1 | Has no | |
| Y1 | ||
| 0 | Has no | |
| Y2 | ||
| 1 | Has no | |
| X | ||
| 0 | Has no irritation |
Experiments show that the moxifloxacin hydrochloride ophthalmic in-situ gel prepared by the pharmaceutical composition and the preparation method thereof has no irritation.
Claims (10)
1. The moxifloxacin temperature-sensitive in-situ gel pharmaceutical composition comprises 0.2-2% (W/V) moxifloxacin hydrochloride as an active ingredient, 15-30% of poloxamer 407(P407) and 0.1-10% of xyloglucan as a gel matrix, and optionally pharmaceutically acceptable pharmaceutical excipients.
2. The pharmaceutical combination of claim 1, wherein the concentration of moxifloxacin hydrochloride is preferably 0.5% (W/V).
3. The pharmaceutical composition of claim 1, wherein the gel matrix comprises 20-30% poloxamer 407 and 1-8% xyloglucan, and more preferably 20-26.5% poloxamer 407 and 2-6% xyloglucan.
4. The pharmaceutical composition of claims 1-3, which is for ophthalmic use, characterized in that: optionally a pharmaceutically acceptable combination of excipients comprising: osmotic pressure regulator, and/or pH regulator, and/or bacteriostatic agent, and water for injection.
5. The pharmaceutical composition of claims 1-4, wherein the gel matrix further comprises one or more of carbomer, hypromellose, hydroxyethyl cellulose, methyl cellulose, sodium alginate, hypromellose, gellan gum, xyloglucan, sodium hyaluronate, and PVPK 30.
6. The pharmaceutical composition of claims 1-5 further comprising an osmotic pressure regulator selected from the group consisting of sodium chloride, glucose, boric acid, borax, glycerol, propylene glycol, mannitol, sorbitol, and polyethylene glycol.
7. The pharmaceutical composition of claims 1-6 further comprising a pH adjusting agent selected from the group consisting of hydrochloric acid, citric acid or a salt thereof, glacial acetic acid or a salt thereof, phosphoric acid or a salt thereof, diethanolamine, boric acid, borax.
8. The pharmaceutical composition of claims 1-7, further comprising a bacteriostatic agent selected from the group consisting of sorbic acid or its salts, benzyl alcohol, phenylethyl alcohol, chlorobutanol, benzoic acid, benzalkonium chloride, benzalkonium bromide, phenoxyethanol, parabens esters, and thimerosal.
9. The pharmaceutical combination according to claims 1-8, wherein the pH-adjusting agent is added in an amount such that the pH of the pharmaceutical combination is in the range of 5.5-8.5, the osmolality of the pharmaceutical combination is in or near iso-osmolality with tear fluid, and the osmolality of the eye drops is adjusted to 250-350mOsmol/kg using the osmolality-adjusting agent.
10. A process for the preparation of a pharmaceutical combination according to claims 1-9 which comprises: weighing poloxamer 407 and xyloglucan in proportion, adding into water for injection, and stirring to dissolve completely; adding moxifloxacin hydrochloride with the formula amount into the mixed solution of poloxamer 407 and xyloglucan, stirring until the moxifloxacin hydrochloride and the xyloglucan are fully dissolved, then weighing an osmotic pressure regulator and/or a pH regulator and/or a bacteriostatic agent according to the proportion, stirring to dissolve the moxifloxacin-containing mixed solution of poloxamer 407 and xyloglucan, filtering, and carrying out sterile subpackaging to obtain the moxifloxacin hydrochloride.
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