CN114732786A - Lornoxicam liposome for injection - Google Patents
Lornoxicam liposome for injection Download PDFInfo
- Publication number
- CN114732786A CN114732786A CN202110019861.4A CN202110019861A CN114732786A CN 114732786 A CN114732786 A CN 114732786A CN 202110019861 A CN202110019861 A CN 202110019861A CN 114732786 A CN114732786 A CN 114732786A
- Authority
- CN
- China
- Prior art keywords
- lornoxicam
- liposome
- parts
- injection
- buffer
- 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
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- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 title claims abstract description 116
- 229960002202 lornoxicam Drugs 0.000 title claims abstract description 116
- 239000002502 liposome Substances 0.000 title claims abstract description 82
- 238000002347 injection Methods 0.000 title claims abstract description 48
- 239000007924 injection Substances 0.000 title claims abstract description 48
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 44
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- 238000004108 freeze drying Methods 0.000 claims abstract description 20
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- 239000000872 buffer Substances 0.000 claims abstract description 14
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 14
- 239000003223 protective agent Substances 0.000 claims abstract description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 239000006172 buffering agent Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 34
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
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- 238000002156 mixing Methods 0.000 claims description 23
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- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 claims description 10
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 8
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- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 2
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- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims description 2
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
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- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
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- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims 1
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims 1
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Images
Classifications
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- 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]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
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Abstract
The invention belongs to the technical field of chemistry and biological medicine, and particularly relates to a lornoxicam liposome for injection. The lornoxicam liposome for injection comprises, by weight, 1-10 parts of lornoxicam, 2-20 parts of phospholipid, 1-8 parts of cholesterol, 0.1-5 parts of surfactant, 1-10 parts of buffer, 1-10 parts of freeze-drying excipient and 1-10 parts of freeze-drying protective agent. The lornoxicam liposome for injection disclosed by the invention has the advantages that through the mutual matching of a plurality of components such as specific lornoxicam, phospholipid, cholesterol, surfactant, buffering agent, freeze-drying auxiliary materials (protective agent and excipient) and the like, the product has a milder pH value, a slow release property and a longer half-life period. Can reduce the administration times of the lornoxicam in the use of the medicine and can quickly and continuously play the analgesic effect of the lornoxicam.
Description
Technical Field
The invention belongs to the technical field of chemistry and biological medicine, and particularly relates to a lornoxicam liposome for injection.
Background
Lornoxicam, chemical name 6-chloro-4-hydroxy-2-methyl-N-pyridin-2-yl-2H-thieno [2,3-E][1,2]Thiazine-3-carboxamide 1, 1-dioxide of formula C13H10ClN3O4S2Molecular weight of 371.82, structural formulaComprises the following steps:
the lornoxicam belongs to a nonsteroidal anti-inflammatory analgesic, is a thiazine derivative, has strong anti-inflammatory and analgesic effects, and mainly comprises the following action mechanisms: (1) inhibition of prostaglandin synthesis by inhibition of Cyclooxygenase (COX) activity; (2) activate the opium neuropeptide system and play the role of central analgesia. Can be used for treating acute and chronic pain caused by inflammation, such as postoperative pain, arthritis, rheumatism, soft tissue injury, etc., and is suitable for treating acute and moderate postoperative pain, pain related to acute sciatica, etc. The lornoxicam parenteral administration has obvious effect on relieving postoperative pain, good tolerance and low adverse reaction incidence rate, and is recommended by WHO as the first-step drug for controlling cancer pain.
The Chinese patent CN101015555A and the Chinese patent CN101278906A improve the solubility of the lornoxicam in water by a cyclodextrin inclusion technology and a mode of preparing a solution respectively for oral administration, the Chinese patent CN1947706A, the Chinese patent CN101342177A and the Chinese patent CN101185640A all prepare the lornoxicam into a sustained-release preparation for oral administration, and the CN101637451A prepares the lornoxicam into a liposome to improve the solubility of the lornoxicam and then prepares the obtained lornoxicam liposome into an oral administration preparation. However, the lornoxicam is difficult to dissolve in water and acid solution, the release degree in gastric juice is low during oral administration, the therapeutic concentration is slow after the administration, the oral administration needs to enter blood circulation after being absorbed by gastrointestinal tract, the effect is slow, the rapid alleviation of clinical pain symptoms is not facilitated, the half-life period of the lornoxicam in vivo is short, the lornoxicam needs to be repeatedly taken during clinical oral administration for maintaining the effective therapeutic concentration, the administration dosage is large, the compliance is poor, and the toxic and side effects are large after long-term use; the lornoxicam injection administration can avoid the process of gastrointestinal absorption and the first pass effect of the drug, and the lornoxicam can quickly exert the pain relieving and pain relieving effects of the lornoxicam after being injected and rapidly enters the blood circulation, and the injection administration is an ideal administration mode of the lornoxicam as the analgesic drug.
Lornoxicam is insoluble in water and easy to dissolve under alkaline conditions, but the dissolved solution is unstable and easy to hydrolyze to produce other impurities, so lornoxicam preparation for injection is generally prepared into alkaline liquid medicine and freeze dried powder for injection. Lornoxicam for injection was first approved in denmark by nychomd (now wutian pharmaceutical) in 1998 under the trade name XEFO, and its pH requirement is 8.5-9.5. The lornoxicam powder injection prepared under the alkaline condition has high pH value and poor compliance in clinical use, and because the half-life period of the lornoxicam injection administration is only 3-4 h, a patient still needs to take multiple administrations every day in clinical use.
Therefore, the research of a lornoxicam sustained release preparation for injection, which has a mild pH value, improves the clinical use compliance, has sustained release property and longer half-life period, reduces the administration times of lornoxicam, and can quickly and continuously exert the analgesic effect of lornoxicam, is urgently needed in the field. The prepared lornoxicam sustained release preparation for injection has good clinical significance and commercial value.
Disclosure of Invention
In order to solve the problems, the invention provides a lornoxicam liposome for injection.
The lornoxicam liposome for injection consists of lornoxicam 1-10 weight portions, phospholipid 2-20 weight portions, cholesterol 1-8 weight portions, surfactant 0.1-5 weight portions, buffering agent 1-10 weight portions, excipient 1-10 weight portions and protecting agent 1-10 weight portions.
Further, the lornoxicam liposome for injection comprises, by weight, 2-8 parts of lornoxicam, 5-10 parts of phospholipid, 1-5 parts of cholesterol, 2-5 parts of surfactant, 1-5 parts of buffer, 3-8 parts of excipient and 3-8 parts of protective agent.
Further, the phospholipid comprises one or more of hydrogenated soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, egg yolk lecithin and soybean phospholipid.
Further, the combination of the plurality includes a combination of hydrogenated soybean phosphatidylcholine and distearoyl phosphatidylcholine, a combination of distearoyl phosphatidylcholine and lecithin, and a combination of hydrogenated soybean phosphatidylcholine and lecithin.
Further, the surfactant comprises one or more of alkyl glucoside, fatty glyceride, sorbitan fatty acid, polysorbate, sodium dodecyl sulfate, tricaprylin, sodium dodecyl benzene sulfonate, polyethylene glycol, and poloxamer. Preferably, the surfactant comprises sodium lauryl sulfate and/or polyethylene glycol.
The buffer comprises one or more of acetate buffer, citrate buffer, phosphate buffer, Tris-hydrochloric acid buffer and glycine-hydrochloric acid buffer. Preferably, the buffer comprises a phosphate buffer and/or glycine-hydrochloric acid.
The freeze-drying auxiliary materials comprise one or more of mannitol, trehalose, sucrose, glucose, lactose, glucan, L-serine, sodium glutamate, alanine, glycine, sarcosine and human serum albumin. Preferably the freeze-drying adjuvant comprises mannitol or/and human serum albumin.
Further, the preparation method of the lornoxicam liposome for injection comprises the following steps:
(1) weighing the lornoxicam, the phospholipid, the cholesterol and the surfactant according to the proportion, mixing and dissolving the lornoxicam, the phospholipid, the cholesterol and the surfactant with an organic solvent, and removing the organic solvent after uniformly mixing to obtain a dry oil phase mixture;
(2) mixing and dissolving the buffer agent and water to obtain an aqueous phase solution;
(3) mixing the dried oil phase mixture with the water phase solution, and emulsifying to obtain an emulsion;
(4) granulating the emulsion to obtain lornoxicam liposome;
(5) and adding freeze-drying auxiliary materials into the lornoxicam liposome, mixing and dissolving, sterilizing, filtering, filling and freeze-drying to obtain the lornoxicam liposome for injection.
Furthermore, the dissolving temperature and the emulsifying temperature in the preparation process are 2-90 ℃.
Further, the organic solvent in the step (1) comprises one or more of chloroform, dichloromethane, ethanol (with the concentration of 20-100%), a methanol/chloroform mixed solvent and an ethanol/chloroform mixed solvent.
Further, the manner of removing the solvent in step (1) includes a reduced pressure evaporation method, a spray drying method or a rotary evaporation method.
Further, the emulsification mode in the step (3) comprises ultrasonic emulsification, stirring emulsification or high-speed shearing machine emulsification.
Further, homogenizing liposome with high pressure homogenizer, high pressure micro jet homogenizer or nanometer extruder at 25-90 deg.C, and making liposome particle size of 30-300nm, preferably 50-150 nm.
Furthermore, freeze-drying auxiliary materials are added into the liposome.
Further, the sterilization is performed by using a 0.22 μm microporous filter membrane for sterilization, and freeze-drying is performed.
Further, the concentration of lornoxicam in the liposome is 0.1-10 mg/ml.
As a preferred technical scheme of the invention, the preparation method specifically comprises the following steps:
(1) according to the formula, the lornoxicam, the phospholipid, the cholesterol, the surfactant and the organic solvent are mixed and dissolved at the temperature of 25-90 ℃ to obtain an oil phase solution.
(2) According to the formula, the buffer and water are mixed and dissolved at 25-90 ℃ to obtain an aqueous phase solution.
(3) And (3) removing the organic solvent from the oil phase solution in the step (1) by using a reduced pressure evaporator, a spray dryer or a rotary evaporator.
(4) And (3) mixing the aqueous phase solution in the step (2) with the oil phase in the step (3), and performing ultrasonic emulsification, stirring emulsification or high-speed shearing machine emulsification.
(5) Homogenizing the emulsified sample in step (4) with a high-pressure homogenizer, a high-pressure microjet homogenizer or a nanometer extruder at 25-90 deg.C to make liposome particle diameter 50-150 nm. Removing unencapsulated lornoxicam by an ultrafiltration system, and concentrating the sample to 0.1-10mg/ml to obtain lornoxicam liposome.
(6) And (3) adding freeze-drying auxiliary materials into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing by a 0.22um microporous filter membrane, filling, and freeze-drying in a freeze dryer to obtain the lornoxicam liposome for injection.
Compared with the prior art, the invention has the following beneficial effects:
the lornoxicam liposome for injection disclosed by the invention has the advantages that through mutual matching of various components such as specific lornoxicam, phospholipid, cholesterol, surfactant, buffering agent, freeze-drying auxiliary materials and the like, the product has a milder pH value, a slow release property and a longer half-life period. The administration frequency of the lornoxicam can be reduced in the use of the medicine, and the analgesic effect of the lornoxicam can be quickly and continuously exerted.
The lornoxicam liposome for injection can be used for preparing liposome solution with the concentration of the lornoxicam being 0.1-10mg/ml through a specific preparation process, so that the dosage and the specification of the medicament can be conveniently adjusted according to the actual medication condition; the particle size of the liposome is 30-300nm under the specific liposome homogenization process parameters, and the nano liposome particles with different particle sizes have different drug release behaviors, so that the liposome with the required release behaviors can be prepared by selecting corresponding process parameters according to different drug release effects. The preparation process of the lornoxicam liposome for injection comprises the steps of water phase preparation, oil phase preparation, solvent removal, oil-water phase mixing, liposome particle homogenization, concentration, filtration and freeze-drying, and multiple times of experiments prove that each process has good stability and reproducibility through amplification preparation process, equipment required by each process is researched and researched to obtain the same type of products suitable for amplification production, and the research and commercial production of the lornoxicam liposome for injection can be met.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is an in vitro release profile of lornoxicam liposomes for injection of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments, and it should be understood 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 embodiment provides lornoxicam liposome for injection, which comprises, by weight, 5 parts of lornoxicam, 8 parts of hydrogenated soybean phosphatidylcholine, 2 parts of cholesterol, 3 parts of PEG 4003 parts of phosphate buffer, and 3 parts of trehalose.
The preparation method comprises the following steps:
(1) according to the formula, the lornoxicam, the hydrogenated soybean phosphatidylcholine, the cholesterol and the PEG400 are dissolved in the chloroform at 50 ℃ to obtain an oil phase solution.
(2) According to the formula, a phosphate buffer is mixed with water at 50 ℃ and dissolved to obtain an aqueous phase solution.
(3) And (2) placing the oil phase solution in the step (1) in a reduced pressure evaporator to remove chloroform.
(4) And (3) mixing the water phase solution in the step (2) with the oil phase in the step (3), and emulsifying by placing under a high-speed shearing machine.
(5) And (4) placing the emulsified sample in the step (4) into a high-pressure micro-jet homogenizer, homogenizing the liposome at 60 ℃, removing the unencapsulated lornoxicam by an ultrafiltration system, and concentrating the sample to 4mg/ml to obtain the lornoxicam liposome.
(6) And (3) adding trehalose into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing by a 0.22um microporous filter membrane, filling, and freeze-drying to obtain the final product.
Example 2
The embodiment provides lornoxicam liposome for injection, which comprises 1 part of lornoxicam, 5 parts of refined egg yolk lecithin, 1 part of cholesterol, 3 parts of poloxamer, 5 parts of phosphate buffer and 5 parts of mannitol in parts by weight.
The preparation method comprises the following steps:
(1) according to the formula, the lornoxicam, the refined egg yolk lecithin, the cholesterol and the poloxamer are dissolved in a chloroform/ethanol mixed solvent at 70 ℃ to obtain an oil phase solution.
(2) According to the formula, the buffer is mixed with water at 70 ℃ and dissolved to obtain an aqueous phase solution.
(3) And (3) placing the oil phase solution in the step (1) in a rotary evaporator to remove the chloroform/ethanol mixed solvent.
(4) And (3) mixing the aqueous phase solution in the step (2) with the oil phase in the step (3), and emulsifying under ultrasound.
(5) And (4) placing the emulsified sample in the step (4) into a high-pressure homogenizer, homogenizing the liposome at 60 ℃, removing the unencapsulated lornoxicam by an ultrafiltration system, and concentrating the sample to 2mg/ml to obtain the lornoxicam liposome.
(6) And (3) adding mannitol into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing through a 0.22um microporous filter membrane, filling, and freeze-drying to obtain a final product.
Example 3
The embodiment provides a lornoxicam liposome for injection, which comprises, by weight, 2 parts of lornoxicam, 10 parts of phosphatidylcholine dipalmitate, 2 parts of cholesterol, 1 part of poloxamer, 5 parts of phosphate buffer and 5 parts of sucrose.
The preparation method comprises the following steps:
(1) dissolving lornoxicam, phosphatidylcholine dipalmitate, cholesterol and poloxamer in chloroform at 50 deg.C to obtain oil phase solution.
(2) According to the formula, the buffer is mixed with water at 50 ℃ and dissolved to obtain an aqueous phase solution.
(3) And (3) placing the oil phase solution in the step (1) in a reduced pressure evaporator to remove chloroform.
(4) And (3) mixing the aqueous phase solution in the step (2) with the oil phase in the step (3), and emulsifying under a high-speed shearing machine.
(5) And (3) homogenizing the emulsified sample in the step (4) in a nitrogen extruder at 60 ℃, removing unencapsulated lornoxicam through an ultrafiltration system, and concentrating the sample to 0.5mg/ml to obtain the lornoxicam liposome.
(6) Adding sucrose and mannitol into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing through a 0.22um microporous filter membrane, filling, and freeze-drying to obtain the final product.
Example 4
The embodiment provides lornoxicam liposome for injection, which comprises, by weight, 10 parts of lornoxicam, 20 parts of hydrogenated soybean phosphatidylcholine, 5 parts of cholesterol, 5 parts of PEG 4005 parts of phosphate buffer, and 8 parts of trehalose.
The preparation method comprises the following steps:
(1) according to the formula, the lornoxicam, the hydrogenated soybean phosphatidylcholine, the cholesterol and the PEG400 are dissolved in the chloroform at 50 ℃ to obtain an oil phase solution.
(2) According to the formula, a phosphate buffer is mixed with water at 50 ℃ and dissolved to obtain an aqueous phase solution.
(3) And (3) placing the oil phase solution in the step (1) in a reduced pressure evaporator to remove chloroform.
(4) And (3) mixing the aqueous phase solution in the step (2) with the oil phase in the step (3), and emulsifying under a high-speed shearing machine.
(5) And (4) placing the emulsified sample in the step (4) into a high-pressure micro-jet homogenizer, homogenizing the liposome at 60 ℃, removing the unencapsulated lornoxicam by an ultrafiltration system, and concentrating the sample to 4mg/ml to obtain the lornoxicam liposome.
(6) And (3) adding trehalose and mannitol into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing through a 0.22um microporous filter membrane, filling, and freeze-drying to obtain the final product.
Example 5
The embodiment provides lornoxicam liposome for injection, which comprises, by weight, 5 parts of lornoxicam, 8 parts of hydrogenated soybean phosphatidylcholine, 8 parts of cholesterol, 3 parts of PEG 4003 parts of phosphate buffer, and 10 parts of trehalose.
The preparation method comprises the following steps:
(1) according to the formula, the lornoxicam, the hydrogenated soybean phosphatidylcholine, the cholesterol and the PEG400 are dissolved in the chloroform at 50 ℃ to obtain an oil phase solution.
(2) According to the formula, a phosphate buffer is mixed with water at 50 ℃ and dissolved to obtain an aqueous phase solution.
(3) And (3) placing the oil phase solution in the step (1) in a reduced pressure evaporator to remove chloroform.
(4) And (3) mixing the aqueous phase solution in the step (2) with the oil phase in the step (3), and emulsifying under a high-speed shearing machine.
(5) And (4) placing the emulsified sample in the step (4) into a high-pressure micro-jet homogenizer, homogenizing the liposome at 60 ℃, removing the unencapsulated lornoxicam by an ultrafiltration system, and concentrating the sample to 4mg/ml to obtain the lornoxicam liposome.
(6) And (3) adding trehalose and mannitol into the lornoxicam liposome obtained in the step (5), mixing and dissolving, sterilizing through a 0.22um microporous filter membrane, filling, and freeze-drying to obtain the final product.
Example 6
This example provides a lornoxicam liposome, the composition of which differs from that of example 2 only in that the phosphate buffer is citrate buffer, and the rest remains the same.
Example 7
This example provides a lornoxicam liposome for injection, which has a composition different from that of example 2 only in that poloxamer and PEG400 are each 1.5 parts, and the others are kept unchanged.
The liposomes of examples 1-7 were evaluated experimentally as follows:
(1) each group of liposomes was stored under accelerated conditions for 6 months, and the particle size and pH change were measured at 0 month, 1 month, 2 months, 3 months, and 6 months, respectively, and the results are shown in tables 1 and 2. Experimental results show that the lornoxicam liposome for injection has good stability, the particle size and the pH value of the liposome are not obviously changed under the acceleration condition of 40 ℃ and RH 75%, the pH value of each group of liposome is mild, and the improvement of the compliance of injection administration is facilitated.
TABLE 1
| Particle size/nm | For 0 month | 1 month | 2 months old | 3 months old | 6 months old |
| Example 1 | 90.2±5.6 | 93.2±2.3 | 89.9±2.6 | 90.9±3.2 | 91.7±3.7 |
| Example 2 | 70.4±8.2 | 72.1±2.2 | 71.4±5.0 | 71.7±3.6 | 70.9±6.2 |
| Example 3 | 100.6±3.3 | 98.6±4.0 | 99.5±3.6 | 102.6±4.3 | 104.6±5.1 |
| Example 4 | 83.9±2.5 | 82.7±3.0 | 84.4±3.7 | 83.4±4.2 | 85.0±2.8 |
| Example 5 | 76.7±3.3 | 75.6±4.1 | 76.9±5.3 | 74.7±3.8 | 74.4±5.4 |
| Example 6 | 73.2±4.7 | 74.3±5.4 | 73.6±6.1 | 70.2±4.9 | 71.2±4.8 |
| Example 7 | 75.5±5.1 | 72.5±5.7 | 74.3±4.3 | 76.7±3.4 | 77.0±4.6 |
TABLE 2
(2) And respectively filling each group of liposome into a dialysis bag, carrying out in-vitro release test under corresponding conditions after clamping two ends of the liposome, taking liquid medicine in a diffusion cell for measuring the content of lornoxicam in 0, 1, 2, 4, 8, 12 and 24 hours respectively, and drawing an in-vitro release curve of the lornoxicam liposome for injection according to the release time and the cumulative release rate, wherein the release curve result is shown in figure 1. The 4h release of the lornoxicam liposome for injection reaches 45-50%, and the 80-90% release of the lornoxicam liposome needs 12h, which shows that the lornoxicam liposome for injection has a certain slow release effect.
The present invention is described in detail with reference to the above examples, but the present invention is not limited to the above examples, and it is not intended to be limited to the above examples. It should be clear to those skilled in the art that any modifications to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. The lornoxicam liposome for injection is characterized by comprising, by weight, 1-10 parts of lornoxicam, 2-20 parts of phospholipid, 1-8 parts of cholesterol, 0.1-5 parts of surfactant, 1-10 parts of buffering agent, 1-10 parts of excipient and 1-10 parts of protective agent.
2. The lornoxicam liposome for injection according to claim 1, wherein the components include 2-8 parts of lornoxicam, 5-10 parts of phospholipid, 1-5 parts of cholesterol, 2-5 parts of surfactant, 1-5 parts of buffering agent, 3-8 parts of excipient and 3-8 parts of protective agent.
3. The liposome of lornoxicam for injection according to claim 1, wherein the phospholipids include one or more of hydrogenated soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, egg yolk lecithin, soybean phospholipid, distearoylphosphatidylglycerol sodium, dipalmitoylphosphatidylglycerol sodium, dioleoylphosphatidylcholine.
4. The lornoxicam liposome for injection according to claim 1, wherein the surfactant includes one or more of alkyl glucoside, fatty glyceride, sorbitan fatty acid, polysorbate, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, polyethylene glycol, poloxamer;
the buffer comprises one or more of acetate buffer, citrate buffer, phosphate buffer, Tris-hydrochloric acid buffer and glycine-hydrochloric acid buffer;
the freeze-drying protective agent comprises one or more of mannitol, trehalose, sucrose, glucose, lactose, dextran, L-serine, sodium glutamate, alanine, glycine and sarcosine.
5. The lornoxicam liposome for injection according to any of claims 1 to 4, wherein the preparation method comprises:
(1) weighing the lornoxicam, the phospholipid, the cholesterol and the surfactant according to the proportion, mixing and dissolving the lornoxicam, the phospholipid, the cholesterol and the surfactant with an organic solvent, and removing the organic solvent after uniformly mixing to obtain a dry oil phase mixture;
(2) mixing and dissolving the buffer agent and water to obtain an aqueous phase solution;
(3) mixing the dried oil phase mixture with the water phase solution, and emulsifying to obtain an emulsion;
(4) granulating the emulsion to obtain lornoxicam liposome;
(5) and adding a protective agent and an excipient into the lornoxicam liposome, mixing and dissolving, sterilizing, filtering, filling and freeze-drying to obtain the lornoxicam liposome for injection.
6. The lornoxicam liposome for injection according to claim 5, wherein the preparation process has a dissolution temperature and an emulsification temperature of 2-90 ℃.
7. The liposome of lornoxicam for injection according to claim 5, wherein the organic solvent in step (1) comprises one or more of chloroform, dichloromethane, ethanol (different concentration), methanol/chloroform mixed solvent, ethanol/chloroform mixed solvent, tetrahydrofuran.
8. The liposome of lornoxicam for injection according to claim 5, wherein the emulsification method in step (3) comprises ultrasonic emulsification, stirring emulsification or high speed shearing emulsification.
9. The lornoxicam liposome for injection according to claim 5, wherein the liposome is homogenized by high pressure homogenizer, micro-jet or nano-extruder during the whole granule process, the temperature of whole granule is 25-90 ℃, and the particle size of liposome after whole granule process is 30-300 nm.
10. The liposome of lornoxicam for injection according to claim 5, wherein the concentration of lornoxicam in the liposome is 0.1-10 mg/ml.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101637451A (en) * | 2009-06-12 | 2010-02-03 | 陶灵刚 | Lomoxicam liposome medical composition and solid formulation thereof |
| US20120114740A1 (en) * | 2010-10-28 | 2012-05-10 | Pacira Pharmaceuticals, Inc | Sustained release formulation of a non-steroidal anti-inflammatory drug |
| CN106474066A (en) * | 2016-10-26 | 2017-03-08 | 沈阳医学院附属中心医院 | Lornoxicam flexible lipidosome is prepared in Box Behnken effect surface method optimization |
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- 2021-01-07 CN CN202110019861.4A patent/CN114732786A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101637451A (en) * | 2009-06-12 | 2010-02-03 | 陶灵刚 | Lomoxicam liposome medical composition and solid formulation thereof |
| US20120114740A1 (en) * | 2010-10-28 | 2012-05-10 | Pacira Pharmaceuticals, Inc | Sustained release formulation of a non-steroidal anti-inflammatory drug |
| CN106474066A (en) * | 2016-10-26 | 2017-03-08 | 沈阳医学院附属中心医院 | Lornoxicam flexible lipidosome is prepared in Box Behnken effect surface method optimization |
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| 潘卫三, 中国医药科技出版社 * |
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