CN1493292A - Mezloxicon liquid preparation using HPCD as solubilizing and stabilizing agent and its preparation method - Google Patents
Mezloxicon liquid preparation using HPCD as solubilizing and stabilizing agent and its preparation method Download PDFInfo
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- CN1493292A CN1493292A CNA031108024A CN03110802A CN1493292A CN 1493292 A CN1493292 A CN 1493292A CN A031108024 A CNA031108024 A CN A031108024A CN 03110802 A CN03110802 A CN 03110802A CN 1493292 A CN1493292 A CN 1493292A
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Abstract
A liquid preparation of meloxican is prepared from the meloxicam or its medical salt and water-soluble cyclodextrin derivative HP-beta-CD used as solubilizer and stabilizer, proportionally mixing, adding cosolvent, pH regulator and water for injection, heating and membrane filtering. It has long storage time at low temp.
Description
Technical field:
The present invention relates to medical technical field, exactly it is meloxicam liquid preparation of doing with HPCD by solubilizing agent and stabilizing agent and preparation method thereof.
Background technology:
Meloxicam is the non-steroid antiinflammatory drug of new generation by the exploitation of German BOEDIRINGER INGELHEIM company, is the cox 2 inhibitor of first listing.These product have remarkable and persistent antiinflammatory action and certain antipyretic effect, the meloxicam that is higher than pharmacodynamics test dosage to central nervous system, cardiovascular system, exhale breath system, autonomic nervous system etc. not to make significant difference.Clinical trial shows that meloxicam is equal to now NSAID mutually to osteoarthritis, rheumatoid arthritis, sciatica patient's therapeutic effect, even better, and every day, dosage was more much lower than pyrroles's former times health, voltaren see diclofenac, indometacin and naproxen.
Meloxicam still has good pharmacokinetics character, as absorb fast, blood drug level is high, bioavailability is high, plasma protein binding rate is also very high, particularly alternative enters inflamed sites, thereby antiinflammatory action is strong and lasting.There are some researches show that meloxicam exists the metabolism polymorphism in the intravital pharmacokinetics behavior of Chinese subjects, may cause in the intravital first pass metabolism degree difference of Chinese owing to meloxicam, but be as general as tangible slow inactivation; Adjust dosage and select suitable parenteral administration dosage form for use simultaneously because meloxicam still has certain gastrointestinal side effect, and Chinese clinically meloxicam consumption should consider suitably to be lower than white consumption, and according to individual variation.
Meloxicam is a water-insoluble faintly acid chemical compound, Pk
1=1.01, pK
2=4.1, dissolubility is a pH dependent form, and its solution degree of separating is minimum when PH4, increases to some extent with the rising of PH, and is molten in the part omitted of the NaOH of 0.1M solution.So in dosage form requires suitable PH scope, make the meloxicam dissolving, and guarantee the stable key and the difficult point place that have become meloxicam liquid preparation preparation process of solution in storage process.Thereby external like product obtains the solution of the meloxicam suitable concentration under the suitable PH as solubilizing agent with surfactant, and China one does not have the surfactant that injectable is used, even two come adding one nonionic surfactant of surfactant that certain toxicity zest is also arranged, and produce the possibility of haemolysis in addition, and the toxicity zest of cationic and anionic surfactant and haemolysis are more strong, generally be not used in injection and eye drop, being the difficult point in the preparation process of domestic meloxicam liquid preparation, is how to obtain being suitable for clinical practice in the presence of surfactant-free, storage can not separated out the supernatant liquid of the various dosage of solid meloxicam under low temperature or the room temperature.
Summary of the invention:
The present invention is for solving key issue---the solubility on the meloxicam liquid preparation technology, the HPCD substitution list surface-active agent of selecting almost non-toxic sexual stimulus under using dosage for use is as solubilizing agent, thereby a kind of meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD and preparation method thereof is provided.Carried out the serial experiment screening operation for this reason, in experimentation, find, all HPCD have certain solubilization to meloxicam, but its Stabilization to solution is more remarkable, thereby when solving problems of dissolution, make prepared liquid preparation have that toxicity is little, zest is little and process stabilizing, easy, can be under low temperature long-term storage and do not produce characteristics such as precipitation.Be suitable for making liquid dosage forms such as injection, eye drop and oral administration solution.
The present invention with solution is being the main pointer of investigating, and carries out on the basis that the clarity of meloxicam solutions sample after storing for 4～6 weeks under different PH, the different temperatures that contains variable concentrations HPCD taken an exam.The inventor finds that by serial experiment HPCD has certain solubilizing effect (seeing accompanying drawing 1, accompanying drawing 2) to meloxicam
When a small amount of alkaline cosolvent combined effect, meloxicam is dissolved fully, when not adding HPCD, strengthen that the alkaline auxiliary solvent load also can obtain clear and bright solution but extremely unstable, easily separate out solid precipitation during low-temp storage.But after adding an amount of HPCD (data is seen accompanying drawing 3), in the suitable PH scope of liquid preparation pharmaceutically as 6.5～8.5, also do not have that solids is separated out and low temperature under still stable.Show that HPCD has appreciable impact to the stability of meloxicam solutions.
Purpose of the present invention can reach by following measure: contain the water-soluble fluidity cyclodextrin derivative that can increase drug solubility---HP-β-CD (HP-) in the meloxicam liquid preparation, with it as solubilizing agent and solution stabilizer.Wherein the ratio ranges of HP-β-CD and meloxicam is 1～30.The meloxicam liquid preparation mainly comprises solution dosages such as meloxicam eye drop and meloxicam oral liquid.Described meloxicam injection is made up of meloxicam, HP-β-CD, cosolvent, cosolvent, solvent, osmotic pressure regulator, PH regulator, and its ratio is: 0.1～2.0%: 2.5～30%: 0.05～3.0%: 5.0～50%: 50～95%: 0.3～3.0%: 0.1～8.0%.The used HP-β-CD of meloxicam injection dosage form is low substituted hydroxy-propyl-beta-schardinger dextrin-that higher solubilising power is arranged, and substitution value is 2.7～6.5, and consumption can be 5～25%.Used cosolvent can be organic bases or inorganic base and combination thereof, organic bases such as meglumine, carbamide etc.; The inorganic base of cosolvent is mainly solubility bases materials such as sodium hydroxide, potassium hydroxide and sodium hydrogen phosphate, dipotassium hydrogen phosphate, and used solvent and cosolvent can be water: as water for injection; Normal saline such as injection normal saline and alcohols, as injectable grade ethanol, ethylene glycol, propylene glycol, glycerol and Macrogol 200, PEG400, PEG600, its PH regulator is for can carry out neutral various acidic materials and the solution that can be used for injection to excessive alkaline auxiliary solvent, can be mineral acid or organic acid and buffer thereof, the mineral acid in its PH regulator can be boric acid, hydrochloric acid, phosphoric acid; Organic acid such as aminoacid, acetic acid etc.; Buffer such as acetic acid-sodium-acetate buffer, perborate tetrahydrate sodium buffer or phosphate buffer etc., used aminoacid such as glycine, arginine etc. in its PH regulator, its isoosmotic adjusting agent can be inorganic salts, as sodium chloride, potassium chloride, sodium sulfite etc.The meloxicam eye drop, it comprises meloxicam, solubilizing agent and stabilizing agent, cosolvent, viscosifier, solvent, antibacterial, osmotic pressure regulator, PH regulator, and its ratio is 0.01～0.5%, 2.0～25%, 0.05～3.0%, 0.5～15%: 50～95%: 0.001～0.5%: 0.3～3.0%: 0.1～8.0%.Used solubilizing agent and stabilizing agent are smart paste of low substituted hydroxy-propyl-β-ring that higher solubilising power is arranged, and substitution value is 2.7～6, and its consumption can be 5～20%, and used cosolvent is inorganic base or organic base and composition thereof; Water soluble alkali such as inorganic base such as sodium hydroxide, potassium hydroxide, organic base such as meglumine; The common application of its mixture such as sodium hydroxide and meglumine, viscosifier can be water-soluble poly dimension ketone; As PVPK30; The water soluble Beta-cyclodextrin class, as low substituted hydroxy-propyl-beta-schardinger dextrin-, the PH regulator is for can carry out neutral various acidic materials and the solution that can be used for ophthalmic preparation to excessive alkaline auxiliary solvent, can be mineral acid or organic acid and buffer, the mineral acid in the PH regulator can be boric acid, hydrochloric acid, phosphoric acid; Organic acid such as aminoacid, acetic acid etc.; Buffer such as acetic acid-sodium-acetate buffer, boric acid-sodium borate buffer liquid or phosphate buffer etc., used aminoacid can be glycine, arginine etc. in the PH regulator, ooze regulator and be mainly inorganic salts, as sodium chloride, potassium chloride, sodium sulfite, Chile saltpeter, potassium nitrate etc., used antibacterial can be pharmaceutically acceptable soda acid and its esters such as boric acid, Borax and buffer thereof, and the alcohols that also can be neutral compound such as suitable concentration is as 20% glycerol; Perhaps use the hydrargyrum compounds of extremely low concentration such as the thimerosal of 0.001%r, 0.002% phenylmercuric nitrate, solvent for use is aquesterilisa or normal saline or buffer such as boric acid-sodium borate buffer liquid.
For injection: the HPCD aqueous solution of suitable concentration is added in the suspension of medicine and cosolvent, the cosolvent that adds recipe quantity under 60 ℃～80 ℃ heated and stirred, complete molten back adds injectable with osmotic pressure regulator, at last with PH regulator accent PH to 6.5～8.5, water for injection is mended to specified volume, continue heating 15～20min, use the 0.22um membrane filtration, the filtrate 100 divided dose branch ampoule bottle of packing into that circulates behind the steam sterilizations, sealing by fusing, promptly.
Solvent described in the above-mentioned preparation method and cosolvent can be water: as water for injection; Normal saline such as injection normal saline and alcohols are as injectable grade ethanol, ethylene glycol, propylene glycol, glycerol and Macrogol 200, PEG400, PEG600.
Cosolvent described in the above-mentioned preparation method is the inorganic alkaline compound of pharmaceutically acceptable appropriate level such as NaOH, KOH, Na
2HPO
4Deng; Organic base such as meglumine;
Osmotic pressure regulator described in the above-mentioned preparation method is pharmaceutically acceptable inorganic salts such as sodium chloride, potassium chloride and sodium thiosulfate etc.
PH regulator described in the above-mentioned preparation method can be mineral acid such as boric acid, hydrochloric acid, phosphoric acid; Glycine in organic acid such as acetic acid and the aminoacid, arginine etc.; Buffer such as acetic acid-sodium-acetate buffer, boric acid-sodium borate buffer liquid or phosphate buffer etc.
The meloxicam injection that utilizes the present invention to prepare can be deposited for 4 weeks and not have solid and separate out in 4 ℃ in refrigerator, deposit to take out after treating in 2 days fully to freeze for-18 ℃ under room temperature, to thaw, still clear liquid.
Advantage of the present invention is: the meloxicam injection that utilizes the present invention to prepare, started the medicinal novel form of domestic meloxicam, intramuscular injection once a day, be used for the treatment of acute osteitis and sciatica, when having avoided the issuable gastrointestinal side effect of oral administration, also can reduce the individual variation that meloxicam is caused in state's human body endogenous cause of ill first pass metabolism degree difference when oral, thereby can improve the safety of medication, and rapid-action, the bioavailability height can meet clinical needs.
Description of drawings:
Fig. 1 is that HPCD is to meloxicam solubilizing effect statistical table
Fig. 2 is that HPCD is to meloxicam solubilizing effect figure
Fig. 3 is that HPCD is to meloxicam liquid preparation stability action chart
Annotate: As, A100 refer to that respectively room temperature was deposited some days and the trap value of measuring in 361nm wavelength place behind the 3hr is heated in water-bath 100 among Fig. 3; Clarity refers to that if 4 ℃ are deposited 6 weeks back perusal clarity situation: "+" expression has solids to separate out; The no solids of "-" expression is separated out.
The specific embodiment:
Embodiment 1: the meloxicam injection of solubilizing agent and stabilizing agent is made in preparation with HPCD
| 100ml | ?1.0ml | |
| Meloxicam | 502mg | ?5mg |
| ?10.0％HPCD | 30ml | ?0.3mg |
| ?0.1MNaOH | 10ml | |
| Propylene glycol | 5.0g | ?50mg |
| Sodium chloride | 0.3g | ?3mg |
| Glycine | 1.0g | ?10mg |
| Water for injection | Add to 100ml |
Preparation: the HPCD aqueous solution of suitable concentration is added in the suspension of medicine and propylene glycol, add 0.1MnaOH solution under 60～80 ℃ of heated and stirred, the clarification back adds injectable with sodium chloride, at last with glycine accent PH to 6.5～8.5, water for injection is mended to specified volume, continue heating 15～20min, use the 0.22min membrane filtration, the filtrate 100 divided dose branch ampoule bottle of packing into that circulates behind the steam sterilizations, sealing by fusing, promptly.
Embodiment 2:
| 100ml | ?1.0ml | |
| Meloxicam | 502mg | ?5mg |
| ?20％HPCD | 50ml | ?0.3mg |
| Meglumine | 811mg | ?8.1mg |
| Propylene glycol | 5.0g | ?50mg |
| Sodium chloride | 300mg | ?0.3mg |
| Glycine | 1.0g | ?10mg |
| Water for injection |
Preparation: the HPCD aqueous solution of suitable concentration is added in the suspension of medicine and propylene glycol, the meglumine that adds recipe quantity under 60～80 ℃ of heated and stirred, complete molten back adds injectable sodium chloride, transfers PH to 8 ± 0.5 with glycine, water for injection is mended to 100ml, continue heating 15～20min, use the 0.22um membrane filtration, the divided dose branch ampoule bottle of packing into behind 100 ℃ of steam sterilizations that circulate of filtrate, sealing by fusing, promptly.
Embodiment 3:
| 100ml | ?1.0ml | |
| Meloxicam | 502mg | ?5mg |
| ?30.0％HPCD | 50ml | |
| ?0.1MNaOH | 5ml | |
| Meglumine | 300mg | |
| Propylene glycol | 10.0g | |
| Sodium chloride | 0.3g | |
| Glycine | 600mg | |
| Water for injection |
Preparation: the HPCD aqueous solution of suitable concentration is added in the suspension of water medicine and propylene glycol, the cosolvent that adds recipe quantity under 60～80 heated and stirred, complete molten back adds injectable with osmotic pressure regulator, at last with glycine accent PH to 7.5～8.5, water for injection is mended to specified volume, continue heating 15～20min, use the 0.22um membrane filtration, the filtrate 100 divided dose branch 2ml ampoule bottle of packing into that circulates behind the steam sterilizations, sealing by fusing, promptly.
Embodiment: 4
| ?100ml | ?1.0ml | |
| Meloxicam | ?754mg | ?7.5mg |
| ?20％HPCD | ?30ml | ?60mg |
| ?NaOH | ?120ml | ?1.2mg |
| ?PEG400 | ?8.0 | ?80mg |
| Sodium chloride | ?0.3g | ?3mg |
| PH4.5 acetic acid-sodium acetate buffer is slow | Transfer PH to 8.0 ± 0.5 | |
| Water for injection | About 60ml | ?600mg |
Preparation: the HPCD aqueous solution of suitable concentration is added in the suspension of medicine and PEG400, adding the 0.1MnaOH heating under 60～80 ℃ of heated and stirred makes molten entirely, add sodium chloride for injection, transfer PH to 6.5～8.5 with the PH regulator at last, water for injection is mended to specified volume, continue heating 15～20min, use the 0.22um membrane filtration, the filtrate 100 divided dose branch 2ml ampoule bottle of packing into that circulates behind the steam sterilizations, 1.5ml/ a sealing by fusing, promptly.
For eye drop: will meloxicam, viscosifier stir down and add in the aqueous solution of HPCD, add the cosolvent isoosmotic adjusting agent, 50～60 ℃ of heating 10～20min, complete molten back adds the PH regulator makes solution PH to 7.5 ± 0.5 back add antibacterial, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, the filtrate divided dose pours into 2ml, and 5ml or 10ml seal in plastic bottle or the little ampoule bottle, sealing by fusing, promptly.
Solvent described in the above-mentioned preparation method can be aquesterilisa, reason saline, or buffer salt such as boric acid-sodium borate buffer liquid.
Cosolvent described in the above-mentioned preparation method is the inorganic alkaline compound of pharmaceutically acceptable appropriate level such as NaOH, KOH, Na
2HPO
4Deng; Organic base such as meglumine.
Osmotic pressure regulator described in the above-mentioned preparation method is pharmaceutically acceptable inorganic salts such as sodium chloride, potassium chloride, sodium sulfate, Chile saltpeter or potassium nitrate.
PH regulator described in the above-mentioned preparation method can be mineral acid such as boric acid, hydrochloric acid, phosphoric acid; Glycine in organic acid such as acetic acid and the aminoacid, arginine etc.; Buffer such as acetic acid-sodium-acetate buffer, boric acid-sodium borate buffer liquid or phosphate buffer etc.
Antibacterial described in the above-mentioned preparation method can be the pharmaceutically acceptable multiple material that bacteriostasis is arranged in neutral environment, as alcohols as 20% glycerol; Can be soda acid and its esters such as boric acid and sodium salt thereof; Other is also available such as parachlorometacresol, thimerosal etc.
Viscosifier described in the above-mentioned preparation method can be water soluble Beta-cyclodextrin class such as HPCD or polyvidone such as PVPk30
The meloxicam eye drop that utilizes the present invention to prepare can be deposited for 4 weeks and not have solid and separate out in 4 ℃ in refrigerator, deposit to take out after treating in 2 days fully to freeze for-18 ℃ under room temperature, to thaw, still clear liquid.
The meloxicam eye drop that utilizes the present invention to prepare can be used for treating microorganism and the viral ocular infection that causes.
Embodiment 5:
| Meloxicam | 0.1g |
| The 15%HPCD aqueous solution | 20ml |
| ?0.1MKOH | 10ml |
| ?PVPk30 | 7.5g |
| Borax | 3.0g |
| Boric acid | 1.2g |
| Aquesterilisa | Add to 100ml |
Preparation: the stirring of recipe quantity meloxicam is added in the aqueous solution of HPCD down, add 0.1MKOH50～60 ℃ heating 10～20min, complete molten back adds PVPk30, and transfers solution PH to 7.5 ± 0.5 back adding Borax, aquesterilisa to add to 100ml, 60 ℃ of heating 15～20min with boric acid, cold slightly, with the filtering with microporous membrane of 0.22 μ m, filtrate pours into 2ml through 100 ℃ of divided doses, and 5ml or 10ml seal in plastic bottle or the little ampoule bottle, seal, promptly.
Embodiment 6:
| Meloxicam | ?0.1g |
| The 25%HPCD aqueous solution | ?30ml |
| ?0.1MKOH | ?10ml |
| ?PVPk30 | ?10g |
| Borate buffer solution | Transfer PH to 7.4 |
| Sodium borate | ?1.5g |
| Water for injection | Add to 100ml |
Preparation: the stirring of recipe quantity meloxicam is added in the aqueous solution of HPCD down, add 0.1MKOH50～60 ℃ heating 10～20min, solution PH to 7.5 ± 0.5 is transferred with borate buffer solution in complete molten back, and adds PVPk30, Chile saltpeter, water for injection adds to 100ml, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, filtrate pours into 2ml through 100 ℃ of divided doses, 5ml or 10ml seal in plastic bottle or the little ampoule bottle, seal, promptly.
Embodiment 7:
| Meloxicam | 0.1g |
| The 20%HPCD aqueous solution | 50ml |
| Meglumine | 90mg |
| Glycerol | 20.0g |
| Glycine | 50mg |
| Water for injection | Add to 100ml |
Preparation: add in recipe quantity meloxicam and the glycerol suspension under the aqueous solution stirring with HPCD, add 0.1MKOH50～60 ℃ heating 10～20min, complete molten back adds glycine and transfers solution PH to 7.5 ± 0.5 and add PVPk30, normal saline and antibacterial, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, filtrate pours into 2ml through 100 ℃ of divided doses, 5ml or 10ml seal in plastic bottle or the little ampoule bottle, seal, promptly.
For oral liquid: meloxicam stirred down add in the aqueous solution of HPCD, add cosolvent, 50～60 heating, 10～20min adds the PH regulator after molten and makes solution PH to 7.0 ± 0.5 entirely, and add antibacterial, correctives, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, the filtrate divided dose pours into 2ml, 5ml or 10ml seal in plastic bottle or the little ampoule bottle, sealing by fusing, promptly.
Solvent described in the above-mentioned preparation method can be aquesterilisa, cosolvent such as ethanol, propylene glycol and glycerol.
Cosolvent described in the above-mentioned preparation method is the inorganic alkaline compound of pharmaceutically acceptable appropriate level such as NaOH, KOH, Na
2HPO
4Deng; Organic base such as meglumine;
Correctives described in the above-mentioned preparation method is pharmaceutically acceptable various soluble perfume: as apple essence, and sweeting agent such as aspartame and sucrose etc.
PH regulator described in the above-mentioned preparation method can be mineral acid such as boric acid, hydrochloric acid, phosphoric acid; Glycine in organic acid such as acetic acid and the aminoacid, arginine etc.; Buffer such as acetic acid-sodium-acetate buffer, boric acid-sodium borate buffer liquid or phosphate buffer etc.
Antibacterial described in the above-mentioned preparation method can be ethanol, the glycerol of pharmaceutically acceptable alcohols such as suitable concentration; Also can be parabens such as ethyl hydroxybenzoate etc.
Embodiment 8:
| Meloxicam | 75.0mg |
| ?20％HPCD | 20ml |
| 0.1MnaOH solution | 5ml |
| Pure water | About 90ml |
| Glycine | 500mg |
| Apple essence | 5mg |
| Glycerol | 20.0g |
Preparation: the aqueous solution stirring of HPCD is added in the suspension of meloxicam and glycerol down, add 0.1MnaOH solution, 50～60 ℃ of heating 10～20min make complete molten after, add glycine and transfer solution PH to 7.0 ± 0.5, and add antibacterial and in advance with water-soluble recipe quantity essence, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, the filtrate divided dose pours into 10ml and seals in plastic bottle or the little ampoule bottle, sealing by fusing, promptly.
Embodiment 9:
| Meloxicam | ?75.0mg |
| ?20％HPCD | ?20ml |
| 0.1MnaOH solution | ?10ml |
| Phosphate buffer | Transfer PH to 7.0 ± 0.5 |
| Apple essence | ?5mg |
| Ethyl hydroxybenzoate | ?10mg |
| Pure water | Add to 100ml |
Preparation: the meloxicam stirring is added in the aqueous solution of HPCD down, add cosolvent, 50～60 ℃ of heating 10～20min add the PH regulator after molten and make solution PH to 7.0 ± 0.5 entirely, and add antibacterial, correctives, and be diluted with water to 100ml, 60 ℃ of heating 15～20min are cold slightly, filtering with microporous membrane with 0.22 μ m, the filtrate divided dose pours into 5ml or 10ml seals in plastic bottle or the little ampoule bottle, sealing by fusing, promptly.
Embodiment 10:
| Meloxicam | 1500mg |
| ?20％HPCD | 400ml |
| 0.1MNaOH solution | 20ml |
| Mannitol | 1.0g |
| Glycine | 800mg |
| Menthol | 10mg |
| Pure water | Add to 1000ml |
Preparation: the meloxicam stirring is added in the aqueous solution of HPCD down, add cosolvent, 50～60 ℃ of heating 10～20min add and add the PH regulator after molten and make solution PH to 7.0 ± 0.5, antibacterial, correctives entirely, 60 ℃ of heating 15～20min, cold slightly, with the filtering with microporous membrane of 0.22 μ m, the filtrate divided dose pours into 5ml or 10ml seals in plastic bottle or the little ampoule bottle, sealing by fusing, promptly.
Claims (10)
1, makes the meloxicam liquid preparation and preparation method thereof of solubilizing agent and stabilizing agent with HPCD, it is characterized in that: contain water-soluble fluidity cyclodextrin derivative---the HP-β-CD that can increase medicine dissolubility and stability of solution in water, with it as solubilizing agent and solution stabilizer.
2, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 1 is characterized in that: active ingredient is meloxicam and pharmaceutically useful salt thereof in the preparation, and wherein the ratio ranges of HP-β-CD and meloxicam is 1～30.
3, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 1, it is characterized in that: the meloxicam liquid preparation mainly comprises solution dosages such as meloxicam eye drop and meloxicam oral liquid.
4, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 1 is characterized in that: its used HP-β-CD is low substituted hydroxy-propyl-beta-schardinger dextrin-, and substitution value is 2.7～6.5.
5, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 3, it is characterized in that: described meloxicam injection is made up of meloxicam, HP-β-CD, cosolvent, cosolvent, solvent, osmotic pressure regulator, PH regulator, and its ratio is: 0.1～2.0%: 2.5～30%: 0.05～3.0%: 5.0～50%: 50～95%: 0.3～3.0%: 0.1～8.0%.
6, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 3, it is characterized in that: it comprises meloxicam, solubilizing agent and stabilizing agent, cosolvent, viscosifier, solvent, antibacterial, osmotic pressure regulator, PH regulator the meloxicam eye drop, and its ratio is 0.01～0.5%: 2.0～25%: 0.05～3.0%: 0.5～15%: 50～95%: 0.001～0.5%: 0.3～3.0%: 0.1～8.0%.
7, the meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 3, it is characterized in that: it comprises meloxicam, solubilizing agent and stabilizing agent, cosolvent, solvent and cosolvent, PH regulator, correctives, antibacterial the meloxicam oral liquid, and its ratio is: 0.05～2.0%: 1.0～20%: 0.05～2.0%: 70～98%: 0.1～6.0%: 0.005～0.1%: 0～0.5%.
8, according to claim 3 or the 4 or 5 described Lip river former times health liquid preparations of making solubilizing agent and stabilizing agent with HPCD, it is characterized in that: used HP-β-CD is for supplying the pharmaceutic adjuvant of injection, eye drip and oral level; Used cosolvent can be organic bases or inorganic base and combination thereof; Used solvent and cosolvent can be water or alcohols; The PH regulator can be mineral acid or organic acid and buffer thereof for can excessive alkaline auxiliary solvent be carried out neutral pharmaceutically acceptable acidic materials or solution.
9, a kind of preparation method of making the meloxicam liquid preparation of solubilizing agent and stabilizing agent with HPCD as claimed in claim 1, it is characterized in that: the HPCD aqueous solution of suitable concentration is added in the suspension of medicine and cosolvent, the cosolvent that adds recipe quantity under 60 ℃～80 ℃ heated and stirred, complete molten back adds the injectable osmotic pressure regulator, transfer PH to 6.5～8.5 with the PH regulator at last, water for injection is mended to specified volume, continue heating 15～20min, use the 0.22um membrane filtration, the divided dose branch ampoule bottle of packing into behind the filtrate 100 circulation steam sterilizations, sealing by fusing, promptly.
10, meloxicam liquid preparation of making solubilizing agent and stabilizing agent with HPCD according to claim 9 and preparation method thereof, it is characterized in that: used solubilizing agent and stabilizing agent are smart paste of low substituted hydroxy-propyl-β-ring that higher solubilising power is arranged, substitution value is 2.7～6, its consumption can be 5～20%, and used cosolvent is inorganic base or organic base and composition thereof; Water soluble alkali such as inorganic base such as sodium hydroxide, potassium hydroxide, organic base such as meglumine; The common application of its mixture such as sodium hydroxide and meglumine, viscosifier can be water-soluble poly dimension ketone; As PVPK30; The water soluble Beta-cyclodextrin class, as low substituted hydroxy-propyl-beta-schardinger dextrin-, the PH regulator is for can carry out neutral various acidic materials and the solution that can be used for ophthalmic preparation to excessive alkaline auxiliary solvent, can be mineral acid or organic acid and buffer, the mineral acid in the PH regulator can be boric acid, hydrochloric acid, phosphoric acid; Organic acid such as aminoacid, acetic acid etc.; Buffer such as acetic acid-sodium-acetate buffer, boric acid-sodium borate buffer liquid or phosphate buffer etc., used aminoacid can be glycine, arginine etc. in the PH regulator, ooze regulator and be mainly inorganic salts, as sodium chloride, potassium chloride, sodium sulfite, Chile saltpeter, potassium nitrate etc., used antibacterial can be pharmaceutically acceptable soda acid and its esters such as boric acid, Borax and buffer thereof, and the alcohols that also can be neutral compound such as suitable concentration is as 20% glycerol; Perhaps use the hydrargyrum compounds of extremely low concentration such as the thimerosal of 0.001%r, 0.002% phenylmercuric nitrate, solvent for use is aquesterilisa or normal saline or buffer such as boric acid-sodium borate buffer liquid.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031108024A CN1493292A (en) | 2003-01-04 | 2003-01-04 | Mezloxicon liquid preparation using HPCD as solubilizing and stabilizing agent and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031108024A CN1493292A (en) | 2003-01-04 | 2003-01-04 | Mezloxicon liquid preparation using HPCD as solubilizing and stabilizing agent and its preparation method |
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| CN1493292A true CN1493292A (en) | 2004-05-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA031108024A Pending CN1493292A (en) | 2003-01-04 | 2003-01-04 | Mezloxicon liquid preparation using HPCD as solubilizing and stabilizing agent and its preparation method |
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| CN103110575A (en) * | 2013-03-07 | 2013-05-22 | 宁夏康亚药业有限公司 | Meloxicam eye drop as well as preparation method and application thereof |
| CN107625967A (en) * | 2016-07-15 | 2018-01-26 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of Te Kaoweirui medicinal composition for injections and preparation method thereof |
| CN107638571A (en) * | 2016-07-15 | 2018-01-30 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of Te Kaoweirui combination of oral medication and preparation method thereof |
| WO2019214715A1 (en) * | 2018-05-11 | 2019-11-14 | 南京清普生物科技有限公司 | Meloxicam composition, preparation and preparation method and use thereof |
| CN112823786A (en) * | 2019-11-21 | 2021-05-21 | 北京泰德制药股份有限公司 | Pharmaceutical composition containing meloxicam and application |
| CN115844820A (en) * | 2022-11-23 | 2023-03-28 | 石家庄四药有限公司 | Meloxicam suspension injection and preparation method thereof |
| CN116077435A (en) * | 2023-04-07 | 2023-05-09 | 山东恒邦中科生物工程有限公司 | Preparation method of high-concentration meloxicam injection for livestock |
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| CN103110575A (en) * | 2013-03-07 | 2013-05-22 | 宁夏康亚药业有限公司 | Meloxicam eye drop as well as preparation method and application thereof |
| WO2014134922A1 (en) * | 2013-03-07 | 2014-09-12 | 宁夏康亚药业有限公司 | Meloxicam eye drops and preparation method and use thereof |
| CN103110575B (en) * | 2013-03-07 | 2014-11-05 | 宁夏康亚药业有限公司 | Meloxicam eye drop as well as preparation method and application thereof |
| US9393314B2 (en) | 2013-03-07 | 2016-07-19 | Kangya Of Ningxia Pharmaceuticals Co., Ltd | Meloxicam eye drops and preparation method and use thereof |
| CN107625967A (en) * | 2016-07-15 | 2018-01-26 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of Te Kaoweirui medicinal composition for injections and preparation method thereof |
| CN107638571A (en) * | 2016-07-15 | 2018-01-30 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of Te Kaoweirui combination of oral medication and preparation method thereof |
| US11369587B2 (en) | 2016-07-15 | 2022-06-28 | Institute of Pharmacology and Toxicology Academy of Military Medical Sciences PLA China | Injectable pharmaceutical composition of tecovirimat and preparation method thereof |
| US11318115B2 (en) | 2016-07-15 | 2022-05-03 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Oral pharmaceutical composition of Tecovirimat and preparation method thereof |
| JP2021521212A (en) * | 2018-05-11 | 2021-08-26 | 南京清普生物科技有限公司 | Meloxicam compositions, formulations and methods and applications thereof |
| WO2019214715A1 (en) * | 2018-05-11 | 2019-11-14 | 南京清普生物科技有限公司 | Meloxicam composition, preparation and preparation method and use thereof |
| JP7374501B2 (en) | 2018-05-11 | 2023-11-07 | 南京清普生物科技有限公司 | Meloxicam compositions, preparations and their manufacturing methods and applications |
| US12059423B2 (en) | 2018-05-11 | 2024-08-13 | Nanjing Delova Biotech Co., Ltd. | Meloxicam composition, pharmaceutical preparation and preparation method and use thereof |
| CN112823786A (en) * | 2019-11-21 | 2021-05-21 | 北京泰德制药股份有限公司 | Pharmaceutical composition containing meloxicam and application |
| CN115844820A (en) * | 2022-11-23 | 2023-03-28 | 石家庄四药有限公司 | Meloxicam suspension injection and preparation method thereof |
| CN115844820B (en) * | 2022-11-23 | 2023-08-29 | 石家庄四药有限公司 | Meloxicam suspension injection and preparation method thereof |
| CN116077435A (en) * | 2023-04-07 | 2023-05-09 | 山东恒邦中科生物工程有限公司 | Preparation method of high-concentration meloxicam injection for livestock |
| CN116077435B (en) * | 2023-04-07 | 2023-06-02 | 山东恒邦中科生物工程有限公司 | Preparation method of high-concentration meloxicam injection for livestock |
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