CN100387233C - Use of levo morpholine nidazole for preparing medicine for antiparasitic infection - Google Patents
Use of levo morpholine nidazole for preparing medicine for antiparasitic infection Download PDFInfo
- Publication number
- CN100387233C CN100387233C CNB200610083198XA CN200610083198A CN100387233C CN 100387233 C CN100387233 C CN 100387233C CN B200610083198X A CNB200610083198X A CN B200610083198XA CN 200610083198 A CN200610083198 A CN 200610083198A CN 100387233 C CN100387233 C CN 100387233C
- Authority
- CN
- China
- Prior art keywords
- levo
- dosage form
- nitre azoles
- morpholine
- morpholine nitre
- 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.)
- Expired - Fee Related
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- 239000003814 drug Substances 0.000 title claims abstract description 16
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 title abstract 3
- 229960000282 metronidazole Drugs 0.000 title abstract 3
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- 238000002360 preparation method Methods 0.000 claims abstract description 43
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- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
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- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- TYAOMZHTXNPJIN-UHFFFAOYSA-L magnesium 2,3-dihydroxybutanedioic acid octadecanoate Chemical compound C(CCCCCCCCCCCCCCCCC)(=O)[O-].[Mg+2].C(C(O)C(O)C(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)(=O)[O-] TYAOMZHTXNPJIN-UHFFFAOYSA-L 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000010292 orthophenyl phenol Nutrition 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides an application of laevo morpholine nidazole (R-(-)-1-(2-methyl-5-nitroimidazole-1-group)-3-morpholinyl propane-2-ethanol) or the medicinal salt of the laevo morpholine nidazole in the preparation of medicine for preventing parasitization. Particularly an application in the preparation of medicine for preventing ameba infection and trichomonas vaginalis infection.
Description
Technical field
The present invention relates to the new purposes of levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts, i.e. purposes in the preparation medicine for antiparasitic infection.
Background technology
Levo morpholine nitre azoles is R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol.2-methyl-5-Ambilhar azole derivative has good anti-anaerobic activity, and much more preparation method has open.Publication number is that the Chinese patent application of CN1605586A discloses 2-methyl-5-nitro imidazoles-1-alcohol derivative of alpha-substituted and its production and use, but for the optical activity of the 2-methyl-5-nitro imidazoles-1-alcohol derivative of alpha-substituted explanation is not arranged.Levo morpholine nitre azoles is not seen at present its relevant report.
Summary of the invention
The new purposes that the purpose of this invention is to provide levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts.
The invention provides levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts purposes in the anti-parasitic-infectious medicine of preparation.
According to the present invention, levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts are particularly useful for preparing the medicine of anti-ameba insect infection and anti-trichomonas vaginalis infection.
According to the present invention, described anti-parasitic-infectious medicine can be oral administration, intravenously administrable or vagina administration dosage form.
According to one embodiment of the invention, described anti-parasitic-infectious medicine of the present invention is an oral administered dosage form.Preferably, described oral administered dosage form is tablet, capsule or granule.The dosage of described oral administered dosage form is 10～40mg/kg/ days, is preferably 20～30mg/kg/ days.
According to another embodiment of the invention, described anti-parasitic-infectious medicine of the present invention is the intravenously administrable dosage form.Preferably, described intravenously administrable dosage form is high capacity infusion preparation, low capacity infusion preparation or freeze-dried powder injection.The dosage of described intravenously administrable dosage form is 5～40mg/kg/ days, is preferably 10～20mg/kg/ days.
According to another embodiment of the invention, described anti-parasitic-infectious medicine of the present invention is the vagina administration dosage form.Preferably, described vagina administration dosage form is vaginal suppository, vagina gel or vagina effervescence agent.The dosage of described vagina administration dosage form is 10～40mg/kg/ days, is preferably 20～30mg/kg/ days.
As test confirmation, levo morpholine nitre azoles has obviously the better effect of trichomonacide and amoeba histolytica compared to dextrorotation morpholine nitre azoles and racemization morpholine nitre azoles external, promptly levo morpholine nitre azoles has obviously better effect aspect anti-parasitic-infectious.Levo morpholine nitre azoles or its pharmaceutical salts can be used to prepare anti-parasitic-infectious medicine, the medicine of particularly anti-ameba insect infection and anti-trichomonas vaginalis infection.
In this application, the pharmaceutical salts of levo morpholine nitre azoles refers to levo morpholine nitre azoles and inorganic or organic acid salt, described mineral acid example hydrochloric acid, phosphoric acid etc., and organic acid such as tartaric acid, methanesulfonic acid etc., it is atoxic to live organism.
In the present invention, anti-parasitic-infectious oral Preparation comprises principal agent levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts and adjuvant, and adjuvant is selected from one or more mixing in disintegrating agent, binding agent, lubricant, the filler.
The adjuvant of oral Preparation can be combination in any in disintegrating agent, binding agent, lubricant, the filler according to the present invention.Wherein filler can be one or more mixing in pregelatinized Starch, starch, dextrin, sucrose, lactose, glucose, mannitol, microcrystalline Cellulose, calcium sulfate, calcium carbonate, the light magnesium oxide, preferred starch; Lubricant is one or more mixing in stearic acid, calcium stearate, magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, Macrogol 4000 or 6000 or 8000, sodium lauryl sulphate, the Stepanol MG, preferred magnesium stearate; Disintegrating agent is one or more mixing in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, the sodium lauryl sulphate, preferred cross-linking sodium carboxymethyl cellulose; Binding agent is preferably one or more mixing of gumwater, cellulose and derivant thereof of gelatin solution, the 10%-25% of hydroxypropyl cellulose, polyvidone, starch slurry, dextrin, sucrose, syrup, 10-20%, preferred polyvidone.
The consumption of principal agent levo morpholine nitre azoles or its pharmaceutical salts is preferably 20-100%, more preferably 25-50%.The disintegrating agent consumption is preferably 0.01%-20%.Lubricant quantity is preferably 0.1%-5.0%, and surplus is a filler, and binder dosage is decided on particulate flowability in the concrete production and disintegrate situation.
Concrete preparation method is as follows:
With directly compressible or capsule charge behind principal agent and the adjuvant mix homogeneously; Or with principal agent with binding agent system soft material, granulate, drying, granulate directly is packaged into granule; Or with principal agent with binding agent system soft material, granulate, drying, granulate, or after adding disintegrating agent, lubricant mixing, compacting in flakes or be filled into capsule.But wherein tablet coating or not coating, coating material can be the stomach dissolution type coating material, also can be the enteric solubility coating material.Wherein disintegrating agent can add, Nei Jia or in add.
In the present invention, anti-parasitic-infectious intravenous administration formulation contains levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts as principal agent, adds the intravenous administration formulation that different adjuvants can be made as different dosage form.
1. levo morpholine nitre azoles or its pharmaceutical salts bulk capacity injection.Can be made as infusion preparation when adding adjuvant for osmotic pressure regulator, preferred osmotic pressure regulator is one or more any proportioning combination of sodium chloride, glucose, potassium gluconate, gluconic acid sodium salt, calcium gluconate, Ferrous gluconate, magnesium gluconate, carboxyethyl starch, low molecular dextran, glycerol, sodium bicarbonate, potassium hydrogen phosphate, magnesium sulfate, calcium chloride, potassium chloride, sodium lactate, xylitol, sorbic acid, maltose, fructose, any proportioning combination of one or more of sodium chloride, glucose more preferably.The concentration of wherein said isoosmotic adjusting agent can calculate according to the colligative property principle of weak solution, also can reduce the data method by freezing point obtains, and can expand its amount ranges to degree of oozing such as 0.5～3, but preferred and the isoosmotic concentration of blood plasma according to the tolerance degree of human body.
2. levo morpholine nitre azoles or its pharmaceutical salts small-volume injection.Because levo morpholine nitre azoles or its pharmaceutical salts are regulated suitable pH value and just can be dissolved in the water for injection, so can not add adjuvant and directly dissolve levo morpholine nitre azoles or its pharmaceutical salts and be made as preparation maybe can to add organic solvent be that adjuvant increases stability of formulation.Alternative organic solvent has propylene glycol, glycerol, ethanol, Macrogol 200, Liquid Macrogol, PEG400 or Macrogol 600, is preferably propylene glycol, and organic solvent concentration is 1%-50% (ml/ml).Levo morpholine nitre azoles or its pharmaceutical salts consumption and injection w/v are 1-25 (mg/ml).
3. levo morpholine nitre azoles or its pharmaceutical salts freeze-dried powder injection.The sterile powder for injection pin preparation of levo morpholine nitre azoles or its pharmaceutical salts comprises injectable sterile powder and freeze-dried powder injection, wherein levo morpholine nitre azoles or its pharmaceutical salts injectable sterile powder adopt solvent crystallization to make or lyophilization makes after pulverizing, so need not add adjuvant; Adding adjuvant in levo morpholine nitre azoles or its pharmaceutical salts freeze-dried powder injection is excipient, and excipient can be for being one or more the mixture in mannitol, sorbitol, dextran, lactose, sodium chloride, the polyvidone, preferred mannitol.Levo morpholine nitre azoles or its pharmaceutical salts consumption account for the 5%-50% of gross weight, preferred 10%-30%, more preferably 20%; Amount of excipient accounts for the 50%-95% of gross weight, is preferably 70%-90%, and more preferably 80%.
Concrete preparation method:
A. take by weighing levo morpholine nitre azoles or its pharmaceutical salts and adjuvant (adding required adjuvant), add part water for injection, stirring and dissolving or suspendible according to the intravenously administrable dosage form;
B. make levo morpholine nitre azoles or its pharmaceutical salts sterilized powder after adopting solvent crystal or lyophilization to pulverize.Or, be preferably 4.0～7.0 with transferring pH to 3.0～8.0 for the acid of venoclysis, and add the injection water to aequum, add needle-use activated carbon and stir evenly, the titanium rod takes off charcoal, filters fine straining to clear and bright through micropore again; Through the aseptic filtration postlyophilization, get the lyophilized injectable powder of levo morpholine nitre azoles or its pharmaceutical salts; Or directly embedding is in ampoule bottle or infusion bottle or soft bag, and moist heat sterilization promptly gets the low capacity or the bulk capacity injection of levo morpholine nitre azoles or its pharmaceutical salts.
Wherein can be hydrochloric acid, lactic acid, methanesulfonic acid, sulphuric acid, acetic acid, tartaric acid, aminoacid, phosphoric acid or its pharmaceutical salts, citric acid or its pharmaceutical salts, preferred hydrochloric acid and lactic acid for the acid of venoclysis.
According to another embodiment of the invention, described anti-parasitic-infectious medicine of the present invention is the vagina administration dosage form.Preferably, described vagina administration dosage form is vaginal suppository, vagina gel or vagina effervescence agent.
(1) levo morpholine nitre azoles or its pharmaceutical salts vagina effervescence agent:
Composition: principal agent levo morpholine nitre azoles or its pharmaceutical salts and pharmaceutic adjuvant, described pharmaceutic adjuvant mainly comprises the acid system of excipient, acid or acid salt composition, alkali system, binding agent, lubricant, the fluidizer that carbonate is formed, and also can add disintegrating agent, foaming agent as required.
Preparation method: adopt technique of direct powder compression or wet granulation technology.Technique of direct powder compression mainly may further comprise the steps: after the supplementary material pulverize separately was sieved, mix homogeneously was pressed into every principal agent amount and contains circular piece or special-shaped sheet for 10%-80%.Wet granulation technology mainly may further comprise the steps: after the supplementary material pulverize separately sieves, the acid system that all or part of principal agent, all or part of excipient, acid or acid salt are formed, make granule A with an amount of binding agent, the alkali system that all or part of principal agent, all or part of excipient, carbonate are formed, make granule B with an amount of binding agent, after granule A and granule B difference drying, add lubricant or fluidizer mix homogeneously again, be pressed into every and contain circular piece or the special-shaped sheet that the principal agent amount is 10%-80%.
Above-mentioned levo morpholine nitre azoles or its pharmaceutical salts are preferably 30%-70%, and more preferably 50%.
Wherein excipient is selected from one or more in starch, pregelatinized Starch, lactose, microcrystalline Cellulose, dextrin, glucose, the mannitol, preferred starch, pregelatinized Starch, microcrystalline Cellulose, more preferably starch, consumption accounts for the heavy 5%-75% of sheet, preferred 10%-40%, more preferably 20～30%.
Acid in the above-mentioned acid system comprises citric acid, tartaric acid, succinic acid, fumaric acid, adipic acid, malic acid, water-soluble amino acid, acid salt comprises potassium hydrogen tartrate, sodium bitartrate, citric acid potassium dihydrogen, citric acid sodium dihydrogen, fumaric acid sodium or ore deposit acid, as in the boric acid one or more, preferred tartaric acid; Carbonate comprises in sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium bicarbonate or the calcium carbonate one or more in the alkali system, preferred sodium bicarbonate; The consumption of acid, alkali system accounts for the heavy 5%-60% of sheet respectively, preferred 10%-30%, more preferably 15%～25%.
Binding agent can be in starch slurry, polyvinylpyrrolidonesolution solution, hypromellose solution, dextrin slurry, syrup, rubber cement, cellulose and the derivant thereof one or more, it is fixed that preferred 5～20% polyvinylpyrrolidone ethanol solutions, consumption are looked practical operation.
Lubricant or fluidizer can be in stearic acid, magnesium stearate, calcium stearate, Pulvis Talci, hydrogenated vegetable oil, Macrogol 4000 and 6000, Stepanol MG, sodium lauryl sulphate, the micropowder silica gel one or more, preferred magnesium stearate.Consumption accounts for the heavy 0.01%-3% of sheet.
Disintegrating agent can be in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, starch and derivant thereof, low substituted hydroxy-propyl fiber rope, the surfactant one or more, preferably carboxymethyl cellulose sodium.Consumption accounts for the heavy 0.01%-10% of sheet.
Foaming agent is in the surfactant that has stronger hydrophilic and higher H LB value for sodium lauryl sulphate, polysorbate 20-80 etc. one or more, preferably sodium dodecyl sulfate.Consumption accounts for the heavy 0.01%-2% of sheet.
(2) levo morpholine nitre azoles or its pharmaceutical salts vaginal suppository:
Composition: principal agent levo morpholine nitre azoles or its pharmaceutical salts and adjuvant suppository base.
Preparation method: principal agent is sieved, and the suppository base heating and melting adds principal agent and stirs insulation filling mould.
Wherein principal agent levo morpholine nitre azoles or its pharmaceutical salts content are 10%-50%, more preferably 30%.
Wherein the adjuvant suppository base is selected from cocoa butter, semi-synthetic or complete synthesis fatty glyceride, glycerin gelatine, polyethylene glycols, polyoxyethylene (40) monostearate class, poloxamer, preferred semi-synthetic fatty acid glyceride; Consumption accounts for the 50%-90% of every dose of weight, and more preferably 70%.
(3) levo morpholine nitre azoles or its pharmaceutical salts vagina gel:
Composition: principal agent levo morpholine nitre azoles or its pharmaceutical salts and adjuvant gel-type vehicle, gel-type vehicle can be aqueous gel substrate or oil-base gel substrate, and adds transdermal enhancer, antiseptic, pH regulator agent.
Preparation method:, stir promptly with the direct adding of principal agent or with joining in the gel-type vehicle after the medicinal solvent dissolving.
Wherein medicinal solvent is ethanol, propylene glycol, glycerol, Polyethylene Glycol or water, preferred propylene glycol.
Wherein principal agent levo morpholine nitre azoles or its pharmaceutical salts content are 0.25%-10%.
The water-soluable gel substrates quantity is 70%-99.7%, for adding water-soluble expanding, thickening agent forms, wherein thickening agent can be selected from one or more in tragcanth, carbopol, gelatin, starch and cellulose derivative, carbopol, the sodium alginate, preference card POP, consumption account for substrate gross weight 0.1%-20%.
Oil-base gel substrate can be selected from liquid paraffin and polyoxyethylene or fatty oil and colloid silicon or aluminium soap, zinc soap, and consumption is 80%-99.7%.
Transdermal enhancer is selected from one or more in laurocapram, oleic acid, Oleum menthae, the propylene glycol, preferred laurocapram, and consumption is 0.1%-20%.
Antiseptic is selected from that parabens, benzoic acid and sodium benzoate, sorbic acid or its medicinal salts, benzalkonium bromide, acetic acid chloroethene are fixed, in the o-phenyl phenol, benzyl alcohol, chlorobutanol one or more, preferred benzalkonium bromide, and consumption is 0.001%-5%.
The pH regulator agent is selected from one or more in sodium hydroxide, potassium hydroxide, aluminium hydroxide, triethanolamine, hydrochloric acid, citric acid, the glacial acetic acid, and preferred sodium hydroxide is regulated the substrate pH value to 5-9.
The specific embodiment
Embodiment 1. preparation levo morpholine nitre azoles tablets
Prescription is formed:
Levo morpholine nitre azoles 100mg/ sheet
Pregelatinized Starch 100mg/ sheet
Microcrystalline Cellulose 40mg/ sheet
Starch 50mg/ sheet
Carboxymethyl starch sodium 5mg/ sheet
Magnesium stearate 5mg/ sheet
Polyvidone aqueous solution (6%) is an amount of
Preparation technology: to make 1000 tablets of levo morpholine nitre azoles tablets is example, concrete preparation method is earlier principal agent and adjuvant to be crossed 100 mesh sieves respectively, take by weighing levo morpholine nitre azoles, pregelatinized Starch, microcrystalline Cellulose, starch, the carboxymethyl starch sodium mix homogeneously of recipe quantity, with 6% polyvidone aqueous solution system soft material, 20 sieve series wet granulars, in 40 ℃ of oven dry, with 18 mesh sieve granulate, the magnesium stearate that in granule, adds recipe quantity, mix homogeneously, tabletting, or with 8% Opadry 95% alcoholic solution coating to label weightening finish 2～3%, promptly get the Film coated tablets of this product.
Embodiment 2. preparation levo morpholine nitre danazol capsule preparations
Prescription is formed:
Levo morpholine nitre triazole hydrochloride 300mg/ sheet
Starch 45mg/ sheet
Magnesium stearate 5mg/ sheet
6% starch slurry is an amount of
Preparation technology: supplementary material is crossed 100 mesh sieves respectively.Take by weighing the levo morpholine nitre triazole hydrochloride of recipe quantity, starch, mix homogeneously, with 6% starch slurry system soft material, 22 mesh sieves are granulated, in 40 ℃ of oven dry, with 20 order granulate.The magnesium stearate that adds recipe quantity, behind the mix homogeneously, with grain packing in No. 1 capsule, every about 350mg.
Embodiment 3. preparation levo morpholine nitre azoles granular preparations
Prescription is formed:
Levo morpholine nitre azoles 300mg/ bag
Sucrose 400mg/ bag
Microcrystalline Cellulose 150mg/ bag
Starch 150mg/ bag
6% starch slurry is an amount of
Preparation technology: supplementary material is crossed 100 mesh sieves respectively.Take by weighing levo morpholine nitre azoles, sucrose, microcrystalline Cellulose, the starch of recipe quantity, mix homogeneously, with 6% starch slurry system soft material, 16 mesh sieves are granulated, in 40 ℃ of oven dry, with 14 order granulate.Remove fine powder with 40 mesh sieves sieve, by every bag of 1g packing.
Embodiment 4. preparation levo morpholine nitre azoles vagina effervescence agent
Prescription is formed:
Levo morpholine nitre azoles 100g
Sodium bicarbonate 145g
Sodium lauryl sulphate 1.6g
Microcrystalline Cellulose 180g
Low-substituted hydroxypropyl cellulose 45g
Tartaric acid 140g
Magnesium stearate 10g
Preparation technology: levo morpholine nitre azoles is crossed 100 mesh sieves, and all the other each adjuvants are crossed 80 mesh sieves respectively, take by weighing the levo morpholine nitre azoles of recipe quantity, sodium bicarbonate, sodium lauryl sulphate, microcrystalline Cellulose, low substituted hydroxy-propyl fiber rope, the tartaric acid magnesium stearate, mix homogeneously, tabletting.The heavy 620mg/ sheet of sheet.
Embodiment 5. preparation levo morpholine nitre azoles vaginal suppositories
Prescription is formed:
Levo morpholine nitre azoles 100g
Polyethylene Glycol-4000 1200g
Preparation technology: the Polyethylene Glycol-4000 that takes by weighing recipe quantity after the heating for dissolving, adds the levo morpholine nitre azoles of recipe quantity in 60 ℃ water-bath, stir, fill while hot in the suppository mould, put cold, treat that substrate is solidified after, take out, promptly get the suppository of wanting.
Embodiment 6. preparation levo morpholine nitre azoles infusion preparations
Prescription is formed:
Levo morpholine nitre azoles 300g
Sodium chloride 900g
Water for injection adds to 100L
Preparation technology: the levo morpholine nitre azoles that takes by weighing recipe quantity, osmotic pressure regulator is added in the 80% about 40 ℃ water for injection, stirring makes dissolving, regulate about pH to 6.0 with 1mol/LNaOH, benefit adds to the full amount of water for injection, the needle-use activated carbon that adds 0.05% (w/v), stir 20min, solution titanium rod circulation decarburization, measure intermediate content and pH value, qualified after, medicinal liquid through embedding behind the 0.22um microporous filter membrane in the infusion bottle of 100ml, at 115 ℃ of pressure sterilizing 30min, cooling gets product then.
Embodiment 7. preparation levo morpholine nitre azoles lyophilized formulations
Prescription is formed:
Levo morpholine nitre azoles 300g
Mannitol 100g
Water for injection adds to 2L
Preparation technology: take by weighing the levo morpholine nitre azoles of recipe quantity, mannitol is added in the 80% about 40 ℃ water for injection, stirs and makes dissolving, regulate about pH to 6.0 with 1mol/LNaOH, benefit adds to the full amount of water for injection, and adds the needle-use activated carbon of 0.05% (w/v), stir 20min, solution is measured intermediate content and pH value with titanium rod circulation decarburization, qualified after, medicinal liquid behind the 0.22um microporous filter membrane embedding in the cillin bottle of 2ml, lyophilization to moisture less than 2.0%, gland, packing gets product.
Embodiment 8. preparation levo morpholine nitre azoles injection formulations
Prescription is formed:
Levo morpholine nitre azoles 300g
Water for injection adds to 2L
Preparation technology: the levo morpholine nitre azoles that takes by weighing recipe quantity is added in the 80% about 40 ℃ water for injection, stirring makes dissolving, regulates about pH to 6.0 with 1mol/LNaOH, and benefit adds to the full amount of water for injection, the needle-use activated carbon that adds 0.05% (w/v), stir 20min, solution is measured intermediate content and pH value with titanium rod circulation decarburization, after qualified, in the ampoule bottle of 2ml, at 115 ℃ of pressure sterilizing 30min, cooling gets product medicinal liquid then through embedding behind the 0.22um microporous filter membrane.
Embodiment 9. preparation levo morpholine nitre azoles gels
Prescription is formed:
Levo morpholine nitre azoles 100g
Carbopol 100g
Sodium hydroxide 40g
Distilled water 10000g
Preparation technology: the carbopol that takes by weighing recipe quantity is soaked in the distilled water of 3000g, makes its complete swelling.The NaOH of recipe quantity is dissolved in the distilled water of 2000g, and is poured in the carbopol after the swelling, stir.Levo morpholine nitre azoles is dissolved in the distilled water of 5000g, and this solution is mixed with above-mentioned solution, after stirring fully, it is poured in the aluminum pipe, every about 10g.
The drug effect of infection of embodiment 10. levo morpholine nitre azoles trichomonacides and anti-amoeba histolytica insect infection
Levo morpholine nitre azoles, dextrorotation morpholine nitre azoles and racemization morpholine nitre azoles are carried out trichomonacide infection and the external drug effect comparison of anti-amoeba histolytica insect infection.Get levo morpholine nitre azoles, dextrorotation morpholine nitre azoles and racemization morpholine nitre azoles with culture fluid be diluted to 4,40, three kinds of concentration of 400ug/ml, be added in the culture tube respectively, in pipe, add polypide, when the worm in pastille or the contrast culture pipe in 36 ± 0.5 ℃ cultivate 48 hours after, draw the cultivation drop on microscope slide from the nearly bottom of culture tube, go up the coverslip microscopy again, find that the polypide person is positive, and do the relative property Quantitative Comparison, do not find that the polypide person is negative.For avoiding omission, negative culture is remake the cultivation of normally going down to posterity of not dosing, observe again after 48 hours, make the result and judge.
The results are shown in following table.
Annotate :+show that every high power lens infusorian number is 1-20; ++ be 21-50; +++be 51-100;＞100 of +++are.
* do switching kind of cultivation
Clinical isolating Trichomonas hominis through 48 hours, promptly presents certain inhibition in the levo morpholine nitre azoles of 4ug/ml.Compare with the blank group, borer population reduces, and activity is slower, and the part polypide becomes circle, and contains a large amount of granules or structural fuzzy, inertia.Do not see active polypide during 40ug/ml, visible several circles, structural fuzzy or be the polypide of granular degeneration in indivedual visuals field are cultivated through transferred species and were not seen also that active polypide was arranged in 48 hours, illustrate that whole polypides are all killed by levo morpholine nitre azoles under this concentration.The polypide growing multiplication of blank group is good, and polypide resembles a pear in shape, and is movable normal.
The amoeba histolytica worm was cultivated in the levo morpholine nitre azoles solution of 4ug/ml concentration after 48 hours, and borer population all obviously reduces, and some polypide diminishes, and is condensed to circle, and pseudopodial movement is not obvious, and indivedual polypides present muddiness and are at death's door.Trained sample 48 hours in 40ug/ml concentration, do not see movable polypide, seeing in indivedual visuals field has 2-3 to shorten circular and less polypide into, structural fuzzy or be granular degeneration, preliminary judgement is dead, and switching is planted after 48 hours and also do not seen active or dead polypide, shows that polypide is all dead.Cultivated 48 hours in the levo morpholine nitre azoles culture fluid of 400ug/ml concentration, polypide is also all dead.
This experiment repeats twice, come to the same thing, show that levo morpholine nitre azoles has obviously the better effect of trichomonacide and amoeba histolytica compared to dextrorotation morpholine nitre azoles and racemization morpholine nitre azoles external, promptly levo morpholine nitre azoles has obviously better effect aspect anti-parasitic-infectious.
Claims (11)
1. levo morpholine nitre azoles (R-(-)-1-(2-methyl-5-nitro imidazoles-1-yl)-morpholinyl propane-2-alcohol) or its pharmaceutical salts purposes in the medicine of preparation anti-ameba insect infection or anti-trichomonas vaginalis infection.
2. purposes according to claim 1, wherein said medicine are oral administration, intravenously administrable or vagina administration dosage form.
3. purposes according to claim 2, wherein said oral administered dosage form are tablet, capsule or granule.
4. purposes according to claim 3, the dosage of wherein said oral administered dosage form are 10～40mg/kg/ days.
5. purposes according to claim 3, the dosage of wherein said oral administered dosage form are 20～30mg/kg/ days.
6. purposes according to claim 2, wherein said intravenously administrable dosage form are high capacity infusion preparation, low capacity infusion preparation or freeze-dried powder injection.
7. purposes according to claim 6, the dosage of wherein said intravenously administrable dosage form are 5～40mg/kg/ days.
8. purposes according to claim 6, the dosage of wherein said intravenously administrable dosage form are 10～20mg/kg/ days.
9. purposes according to claim 2, wherein said vagina administration dosage form are vaginal suppository, vagina gel or vagina effervescence agent.
10. purposes according to claim 9, the dosage of wherein said vagina administration dosage form are 10～40mg/kg/ days.
11. purposes according to claim 9, the dosage of wherein said vagina administration dosage form are 20～30mg/kg/ days.
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| CN1995036B (en) * | 2006-01-06 | 2010-04-14 | 连云港恒邦医药科技有限公司 | Optical purity alpha-substituted 2-methyl-5-nitro imidazole-1-ethanol derivative |
| CN106674124A (en) * | 2015-11-09 | 2017-05-17 | 陕西合成药业股份有限公司 | Levomorinidazole hydrochloride crystal form and preparation method and purpose thereof |
| CN111973569A (en) * | 2019-05-21 | 2020-11-24 | 江苏豪森药业集团有限公司 | Pharmaceutical composition containing nitroimidazole derivatives and preparation method thereof |
| CN112137955A (en) * | 2020-11-05 | 2020-12-29 | 江苏豪森药业集团有限公司 | Morpholine ornidazole injection and preparation method thereof |
| CN114907250B (en) * | 2021-02-06 | 2024-11-22 | 华创合成制药股份有限公司 | A deuterated morpholiniazole and its use |
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