CN105461713A - New benzonaphthyridine compound, and composition and use thereof - Google Patents
New benzonaphthyridine compound, and composition and use thereof Download PDFInfo
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- CN105461713A CN105461713A CN201410499619.1A CN201410499619A CN105461713A CN 105461713 A CN105461713 A CN 105461713A CN 201410499619 A CN201410499619 A CN 201410499619A CN 105461713 A CN105461713 A CN 105461713A
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Abstract
The invention relates to a benzonaphthyridine compound with small hygroscopicity and good storage stability, and an application of the compound in the preparation of drugs for treating or preventing human or animal falciparum malaria, tertian malaria, silicosis, reverse tumor multiple drug resistant hepatitis b and sinus resistant arrhythmia induced by cerebral malaria, pernicious malaria and chloroquine resistant strains.
Description
Technical field
The present invention relates to medical art, be specifically to provide the new compound---the preparation of malanidine crystalline hydrate and composition thereof and the purposes that have and the schizont of people Plasmodium vivax and plasmodium falciparum is all had to the benzo naphthyridine type of killing action etc.
Background technology
The polymorphic of chemicals has critical role in drug research, and in field of pharmacology, the research range that scientific and technological key special subjects formulated by country's 12 great new drugs has been listed in the research work of drug crystal forms and drug hydrate or drug solvent compound.The solvated compounds of compound comprises hydrate many being produced and applying in medicine very early, the antitumor drug endoxan normal temperature that for example American Pharmacopeia 36 editions, European Pharmacopoeia 6.1 editions and Chinese Pharmacopoeia 2010 editions record only exists with monohydrate form in the solid state, this compound just starts to lose crystal water at about 40 DEG C, and 72 DEG C just lose whole crystal water.Since nearest two more than ten years, be not only the crystal formation with same molecular formula medicine to be constantly found, and there is same parent but the research of differing molecular formula drug solvent compound also constantly obtains new progress, even regulate hypoglycemic medicament dapagliflozin all studied take dapagliflozin propylene glycol hydrate as the pharmaceutical preparation of core.Heat analysis method has important value and status in Materials science, chemistry or pharmaceutical analysis etc., can be used for separately the change (Li Zengyu of crystal formation in the polymorphic of detection compound or process, " thermal analyses ", press of Tsing-Hua University, in August, 1987 first version).Differential thermal analysis (DTA) is the analytical procedure comparatively commonly used, and it both can be used for the qualitative identification of material, also can be used for quantitative analysis, in the international thermal analyses meeting of Second Committee of nineteen sixty-eight, is just used for identifying unknown compound by Barta etc.The pharmacopeia of external many countries records differential thermal analysis already, and the method especially has unique advantage for the discriminating of the same compound of tool different crystal forms.Before more than ten years, differential thermal analysis is not only just widely applied in chemical industry, chemical pharmacy system in China, and also start to apply (Zhang Hanming in the identification of Chinese materia medica of complexity, Deng, the differential thermal analysis research of pearl powder and adulterant thereof, Chinese patent medicine, 1999,21 (4): 173-175).In crystal formation research, differential scanning (DSC) can complete multinomial research (application of Zhu Bing, Liu Ji great waves .DSC in pharmaceutical analysis, the process industries such as pharmaceutical purity assessment, discriminating, polycrystalline state analysis, 2008,15:64-66), (Lin Kejiang, Chen Wei, You Qidong. DETECTION OF CRYSTAL POLYMORPHS OF NATEGLINIDE BY DSC, Acta Pharmaceutica Sinica, 2002,37 (1): 46-49).And the polymorphic of medicine not could be prepared in rare or expensive solvent, can the polymorphic (Du Qing of unexpected acquisition compound by conventional solvent, temperature, time etc. or other trickle change, its energy flat. the polymorphic research of Travin, China Medicine University's journal, 2000,31 (2): 102-104).In thermal analyses field, the coupling of TG-DTA or TG-DSC brings more facility to especially the analysis of compound.
Many bibliographical information anti-malarial agents Sulphadoxines, Pyrimethamine hcl, Azythromycin, clindamycin, Clindamycin Phosphate, uncle's quinoline or primaquine, naphthols quinoline, PIPERAQUINE, quinine, chloroquine, nitroquine, Plaquenil, Quinidine, amodiaquine, Mefloquine hydrochloride, benzfluorenol, mirincamycin, atovaquone, halofantrine, Artemisinin, Dihydroartemisinin, arteether, Artemether, the acid of wormwood artemisia ether woods and Artesunate, the collaborative enhancing anti-malarial effect that the individually dosed or Combined Preparation of Malaridine etc. shows [such as, reference: 1, ChenC.Developmentofantimalarialdrugsandtheirapplicationi nChina:ahistoricalreview.InfectDisPoverty.2014Mar20, 3 (1): 9.doi:10.1186/2049-9957-3-9.2, HenrichPP, O'BrienC, S á enzFE, CremersS, KyleDE, FidockDA.Evidenceforpyronaridineasahighlyeffectivepartne rdrugfortreatmentofartemisinin-resistantmalariainarodent model.AntimicrobAgentsChemother.
2014；58(1):183-95.doi:10.1128/AAC.01466-13.Epub2013Oct21.3、LiuDQ,LinSG,FengXP,etal.[Studyontreatmentofmulti-drugresistantfalciparummalariabyusingacombinationofdihydroartemisininandpyronaridine].ZhongguoJiShengChongXueYuJiShengChongBingZaZhi.2002；20(4):193-6.
4、BukirwaH,UnnikrishnanB,KramerCV,etal.ArtesunatepluspyronaridinefortreatinguncomplicatedPlasmodiumfalciparummalaria.CochraneDatabaseSystRev.2014Mar4；3:CD006404.doi:10.1002/14651858.CD006404.pub2.
5、KayentaoK,DoumboOK,PénaliLK,etal.Pyronaridine-artesunategranulesversusartemether-lumefantrinecrushedtabletsinchildrenwithPlasmodiumfalciparummalaria:arandomizedcontrolledtrial.MalarJ.2012Oct31；11:364.doi:10.1186/1475-2875-11-364.
6、CroftSL,DuparcS,Arbe-BarnesSJ,etal.Reviewofpyronaridineanti-malarialpropertiesandproductcharacteristics.MalarJ.2012Aug9；11:270.doi:10.1186/1475-2875-11-270.
7、RueangweerayutR,PhyoAP,UthaisinC,etal；Pyronaridine–ArtesunateStudyTeam.Pyronaridine-artesunateversusmefloquineplusartesunateformalaria.NEnglJMed.2012Apr5；366(14):1298-309.doi:10.1056/NEJMoa1007125.
8、KurthF,BélardS,BasraA,RamharterM.Pyronaridine:anew'old'drugonthevergeofenteringtheantimalarialarmamentarium.ExpertRevAntiInfectTher.2011Apr；9(4):393-6.doi:10.1586/eri.11.17.
9、KurthF,BélardS,BasraA,RamharterM.Pyronaridine-artesunatecombinationtherapyforthetreatmentofmalaria.CurrOpinInfectDis.2011Dec；24(6):564-9.doi:10.1097/QCO.0b013e32834cabdb.
10、RamharterM,KurthF,SchreierAC,etal.Fixed-dosepyronaridine-artesunatecombinationfortreatmentofuncomplicatedfalciparummalariainpediatricpatientsinGabon.JInfectDis.2008Sep15；198(6):911-9.doi:10.1086/591096.
11、VivasL,RattrayL,StewartL,etal.Anti-malarialefficacyofpyronaridineandartesunateincombinationinvitroandinvivo.ActaTrop.2008Mar；105(3):222-8.doi:10.1016/j.actatropica.2007.12.005.Epub2007Dec23.
12、DavisTM,KarunajeewaHA,IlettKF.Artemisinin-basedcombinationtherapiesforuncomplicatedmalaria.MedJAust.2005Feb21；182(4):181-5.
13、RingwaldP,EboumbouEC,BickiiJ,BascoLK.Invitroactivitiesofpyronaridine,aloneandincombinationwithotherantimalarialdrugs,againstPlasmodiumfalciparum.AntimicrobAgentsChemother.1999Jun；43(6):1525-7.
14、ChenC,ZhengX.Developmentofthenewantimalarialdrugpyronaridine:areview.BiomedEnvironSci.1992Jun；5(2):149-60.
15、DuttaGP,PuriSK,AwasthiA,etal.Pyronaridine:aneffectiveantimalarialagainstmultidrug-resistantmalaria.LifeSci.2000Jul7；67(7):759-63.)]。
Above-mentioned document refer to Malaridine (malaridine), the derivative of Malaridine system benzo naphthyridines, all killing action is had to the schizont of people Plasmodium vivax and plasmodium falciparum, the effects such as anti-fibrosis, have efficient, low toxicity, with the excellent characteristics of chloroquine without cross-resistance, be used for the treatment of brain type, dangerous type and the subtertian malaria caused by the strain of resistance to chloroquine worm, also vivax malaria is used for the treatment of, silicosis is treated, can reverse multiple drug resistance of tumor and there is antitumor action, there is Anti-HBV activity biologic activity and treat for resisting HBV virus, and have anti-sinus arrhythmia effect.According to the literature, the drug combination research of Malaridine shows that the combined utilization such as Malaridine one Artesunate or Dihydroartemisinin can obtain effect more better than the single antimalarial drug of use, combined utilization can delay the resistance of plasmodium to Malaridine, and can be issued to same complete curative effect in the condition of the dosage reducing Artesunate etc.Further, the Combined Preparation such as malanidine and Sulphadoxine, Pyrimethamine hcl, Artemisinin, Dihydroartemisinin, Artemether, arteether, Artesunate obtains collaborative anti-malarial therapy effect preferably.At present (Chinese Pharmacopoeia 2010 editions two, MalaridinePhosphate, molecular formula is disclosed bibliographical information malanidine: C
29h
32clN
5o
24H
3pO
4, molecular weight: 910.04), and pharmacology and clinical application situation etc., as Chinese literature: Li Nana, Yang Zhaoqing, the progress of Pyronaridine, An Antimalarial, Tropical China medical science, 2012,12 (2): 249-251; Slaughter cry of a deer, Yang Lan. compound dihydroartemisinin as new antimalarial [Chinese patent Authorization Notice No.: CN1137683C]; Car founds firm Huang founds state, the observation of curative effect of two kinds of Combined Therapies For Treatmant of Chloroquine-resistant Falciparum Malarias, Chinese preventing and treating verminosis magazine, 1990 the 3rd volume the 1st phase 24-26 pages; Yang Chunzheng, Qi Jing, Wang Caiyun, etc., the application of Malaridine in the medicine preparing antitumor drug and reverse multiple drug resistance of tumor [Chinese patent Authorization Notice No.: CN1135977C; Sun Jinlin etc., the antiarrhythmic effect of malanidine, the Chinese Journal of Clinical Pharmacology, nineteen ninety, etc.].First Malaridine sees composite membrane swelling to the Ultrastructural impact of P. berghei erythrocytic stage, becomes in multilayer screw thread film, and food vacuole merges, pigment aggegation, and these changes increase the weight of in Progressive symmetric erythrokeratodermia; Plastosome, endoplasmic reticulum, nuclear membrane swelling, rrna densification subsequently, chromatin agregation.After drug effect 4 hours, trophont structure was disintegrated.Schizont is influenced slightly slow, also occurs mitochondrial swelling and pigment aggegation.Malanidine can play rapid insecticidal action by the destruction structure and fuction of composite membrane and the metabolic activity of food vacuole.Within oral latter 1.4 hours, Plasma Concentration reaches peak, and oral administration biaavailability is about 40%, transformation period T
1/2for 2-3 day, the highest with liver intensive amount after absorption, from urine, drain 1-2%.After intramuscular injection Malaridine 3.8mg/kg 40 minutes, Plasma Concentration reached peak, intramuscular injection bioavailability 90%, and the transformation period is 2 ~ 3, the highest with liver intensive amount after absorption, excretion 1 ~ 2% from urine.Be used for the treatment of brain type, dangerous type and the subtertian malaria caused by the strain of resistance to chloroquine worm, be also used for the treatment of vivax malaria, silicosis, energy reverse multiple drug resistance of tumor and antitumor, resistance of hepatitis B HBV virus, anti-sinus arrhythmia etc.But up to the present, both at home and abroad still without any disclosed bibliographical information malanidine crystalline hydrate of the present invention and its production and use.
Summary of the invention
New chemical entities-malanidine the crystalline hydrate of antimalarial benzo naphthyridine type that involved in the present invention is, all has killing action to the schizont of people Plasmodium vivax and plasmodium falciparum.The malanidine crystalline hydrate that the present invention obtains, its molecular formula is C
29h
32clN
5o
24H
3pO
4h
2o.Surprisingly, drawing of the malanidine containing crystal water is moist far below malanidine anhydride, the existence that the malanidine hydrate containing crystal water more can be stable than malanidine anhydride, is convenient to store and transport, is easy to make preparation.In addition, the deliquescence of anhydride makes will to completely cut off air when processing and prevents adhesion etc., and crystalline hydrate has good sliding, thus improves the operability of preparation.Moreover crystalline solid has chemical stability higher than amorphous form and low-crystallinity form and physical stability, they also can show as the water absorbability of raising, bulk properties and or mobility.
Surprisingly, distinctive, thermal analyses (TG-DSC or the TG-DTA etc.) collection of illustrative plates of crystalline hydrate of the present invention demonstrates the endotherm(ic)peak that weightless platform has strong correspondence, and thermal analyses collection of illustrative plates demonstrates malanidine crystalline hydrate [C
29h
32clN
5o
24H
3pO
4h
2o], match by Karl_Fischer method mensuration moisture result and thermal analyses result.
From pharmaceutically, even if the preparation of the different crystal forms of same compound or acquisition, pharmacology all has the potential or following meaning of reality or value, say nothing of be the acquisition of the different crystalline hydrate of same medicine to pharmacology all having the potential or following meaning of reality or value, the research range that scientific and technological key special subjects formulated by the great new drug of China national 12 has been listed in the work of related drugs crystal and drug crystallization hydrate.The discovery of the useful compound on the medicine of new crystal provides new chance once improving the action characteristic of medicament production, it expands the storehouse of formulation science man design example as the pharmaceutical dosage form and the material obtained with the medicine of targeted release profile or other desired characteristic, the construction in the storehouse of the compound of medicine is extremely important, be not only and can be used for comparative study etc., the crystalline hydrate that this area needs malanidine new or its new crystalline form.
Malanidine crystalline hydrate of the present invention is yellow crystal, can stable storage.Malanidine crystalline hydrate and anhydride sample are carried out drawing moist test: get malanidine anhydride and standby product (malanidine 1 hydrate) the about 2g of 3 different embodiment legal systems of the present invention respectively, be placed in the watch-glass of dry constant weight respectively, precise weighing, 25 DEG C are about in temperature, relative humidity is about 60%, respectively at test 0h and 12h sampling, calculate the percentage drawing wet weightening finish, result shows, anhydride draws and moistly has significant difference than crystalline hydrate of the present invention, malanidine crystalline hydrate of the present invention can stable storage better, the results are shown in Table 1.As can be seen here, malanidine crystalline hydrate of the present invention, can stable storage.By the shading be enclosed within cillin bottle the accelerated stability test carried out 6 months respectively of above-mentioned malanidine crystalline hydrate matter sample, with reference to the content assaying method of 2010 editions Chinese Pharmacopoeias two of malanidine, the malanidine crystalline hydrate that mensuration various embodiments of the invention 1, embodiment 2 method, embodiment 3 legal system are standby, have been surprisingly found that, the content of malanidine crystalline hydrate of the present invention does not have considerable change (30 DEG C, under RH75%).
Table 1. draws wet test result
The chemical entities preparation method of Malaridine compounds---malanidine crystalline hydrate comprises:
(weight unit gram g), is added to water, the C of 1-50 times amount (weightmeasurement ratio=gram g: milliliter ml) to take Malaridine or Malaridine solvate
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone one or more in one or more in reaction vessel in, add phosphoric acid solution, be stirred to dissolve, below regulator solution pH value to 4.0, preferably between 1.0 ~ 4.0, then use C in the solution
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
1-C
6low molecule hydrochloric ether, C
2-C
8one or more in low molecule ester carry out crystallization operation, place, and cooling, makes crystallization fully separate out, and filter, with cold C
1-C
6low mass molecule alcohol, C
2-C
8low molecule ether, C
1-C
6low molecule hydrochloric ether in one or more washing solids, filter, obtain solid; Again by gained solid water and C
1-C
6low mass molecule alcohol, C
2-c
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8one or more in low molecule ester, carry out one or many recrystallization, filter, with organic solvent washing, dry, obtain malanidine new compound entity of the present invention---malanidine crystalline hydrate.
In preparation process of the present invention, especially in dissolving with crystallisation process, water and organic solvent C
1-C
6low mass molecule alcohol, C
2-c
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8the volume ratio of one or more in low molecule ester is usually at about 1:3-50.
One or more preferably in: water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, isopropyl ether, acetone, hexone, ethyl acetate of the crystallization of product of the present invention or recrystallization solvent.
Lower alcohol in the present invention or the carbonatoms of low mass molecule alcohol are defined as C
1-C
6(that is: the alcohol of 1-6 carbon atom), as methyl alcohol, ethanol, Virahol, butanols etc.; The carbonatoms of the rudimentary nitrile of 2-6 carbon atom is defined as C
2-C
6, as acetonitrile, propionitrile etc.; The low molecule ketone of the ketone of 3-8 carbon atom is defined as C
3-C
8, comprise acetone, butanone, pentanone, hexanone, hexone etc.; Rudimentary ether or the low molecule ether of 2-8 carbon atom are defined as C
2-C
8, as ether, isopropyl ether, butyl ether etc.; Hydrocarbon containing 1-4 elemental chlorine and 1-6 carbon atom is defined as C
1-C
6low molecule hydrochloric ether, as methylene dichloride, chloroform, ethylene dichloride etc.; The low molecule ester of 2-8 carbon atom is defined as C
2-C
8, as ethyl acetate, propyl acetate, butylacetate etc.; Be described as " low molecule ", " rudimentary " as long as the marking method of the amount of carbon atom of compound occurs once in the text of the application about any class, other any unmarked carbonatoms being described as the similar compound of " low molecule " is consistent with the quantity indicated herein.
The drying mode of product of the present invention can be differing temps (as 20-60 DEG C), time of drying (as, 0.5 hour to a few days) or with under the envrionment conditions of other siccative (comprising silica gel, Vanadium Pentoxide in FLAKES, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate etc.) or use the mode of normal pressure or decompression to carry out drying to last product.Its drying temperature preferably 60 DEG C or within, more preferably at about 35-50 DEG C.
The preparation of malanidine anhydride can be obtained through different drying meanss by crystalline hydrate of the present invention, its preparation can at differing temps (as 40-100 DEG C), time of drying (a few hours are to a few days), or (comprise silica gel with other siccative, molecular sieve, Vanadium Pentoxide in FLAKES, sodium hydroxide, anhydrous sodium carbonate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous magnesium sulfate etc.) envrionment conditions under, or and use the mode of normal pressure or decompression to carry out drying to last product, also first the method for placing a few days process or distillation band water can be mixed by dry-out benzene, and obtain in conjunction with after other drying means drying described herein.
The discriminating of malanidine and assay with reference to 2010 editions Chinese Pharmacopoeias two malanidine item under Part Methods.Moisture determination of the present invention adopts Karl_Fischer method.Melting point detector corrects.
Powder X-ray diffraction can be used to characterize and/or differentiate polymorph usually, for powder X-ray diffraction when characterizing and/or differentiate, before report peak value, uses modifier " about ".In view of the intrinsic change of peak value, this is the practice of solid-state chemical arts.The usual accuracy of the 2 θ x-axle values at powder collection of illustrative plates peak in ± 0.2 ° of 2 θ rank, therefore, so that " the powder X-ray diffraction peak that about 8.0 ° of 2 θ occurs means when measuring on most of x-ray diffractometer, and peak may between 7.8 ° of 2 θ and 8.2 ° of 2 θ.The change of peak intensity is each crystal result relative to external X-ray source how orientation in sampling receptacle, and orientation effect does not provide the structural information about crystal.
The present invention on the one hand, provides the new compound entity of malanidine---malanidine crystalline hydrate.
The present invention on the other hand, provides the preparation method of malanidine new compound entity.
The present invention on the one hand, provides the different new crystal of malanidine crystalline hydrate.
The present invention on the other hand, provides the preparation method of the different crystalline hydrate of malanidine.
The present invention provides a kind of medicinal compositions on the other hand, comprising any one or the multiple malanidine chemical entities prepared by method of the present invention, and the acceptable vehicle of one or more pharmacy, diluent or carrier composition.The present invention also provides a kind of solid preparation of the medicinal compositions containing high unitary dose Malaridine, and this contributes to saving work time cost, and brings better conformability to clinical application or treatment.
The present invention further provides the method for useful in preparing drug formulations, comprising the merging of any one or the multiple malanidine chemical entities prepared by method of the present invention and at least one or the acceptable vehicle of pharmacy.
The invention provides malanidine chemical entities, for the preparation of containing this malanidine chemical entities and Sulphadoxine, Pyrimethamine hcl, Azythromycin, clindamycin, Clindamycin Phosphate, uncle's quinoline or primaquine, naphthols quinoline, PIPERAQUINE, quinine, chloroquine, nitroquine, Plaquenil, Quinidine, amodiaquine, Mefloquine hydrochloride, benzfluorenol, mirincamycin, atovaquone, halofantrine, Artemisinin, Dihydroartemisinin, arteether, Artemether, medicinal compositionss of one or more compositions in the acid of wormwood artemisia ether woods and Artesunate and their salts of pharmacologically allowing.Various main ingredient compositions containing therapeutic dose in above-mentioned composition.The angle of pharmaceutical preparation is prepared into from various component, malanidine chemical entities and their weight ratio are 20:1 ~ 1:10, its weight ratio is excellent comparatively elects 10:1 ~ 1:6 as, and wherein the weight of malanidine chemical entities can calculate with the weight of effective constituent Malaridine.
Composition of the present invention can for the malanidine new compound entity 1 ~ 20 part of the present invention containing (weight ratio), artemisinin-based drug 10 ~ 1 parts, simultaneously also containing conventional pharmaceutical excipient.Said artemisinin-based drug comprises: Artemisinin, dihydroarteannuin, Artemether, arteether, Artesunate, the acid of wormwood artemisia ether woods etc.The preparation of the anti-malaria composition of above-mentioned formation gained, the consumption of minimizing Malaridine or other anti-malaria medicaments, toxicity is little, curative effect improves, and two kinds of main ingredients have combined obvious synergism according to the above ratio and reduced recrudescence rate effect etc.Artemisinin-based drug comprises Artemisinin, Dihydroartemisinin, arteether, Artemether, the acid of wormwood artemisia ether woods and Artesunate and pharmaceutical salts, as Artesunate, sodium artesunate etc.Uncle's quinoline or primaquine, PIPERAQUINE, chloroquine, naphthols quinoline comprise PRIMAQUINE PHOSPHATE, piperaquine phosphate, chloroquini phosphas, naphthoquine phosphate; Halofantrine, Mefloquine hydrochloride comprise halofantrine hydrochloride, Mefloquine Hydrochloride etc.
The present invention further provides malanidine hydrate, for the preparation of the subtertian malaria caused by treatment people or mammiferous brain type, dangerous type and the strain of resistance to chloroquine worm, be also used for the treatment of the purposes in the pharmaceutical composition of the treatment such as vivax malaria, silicosis treatment, antitumor and reverse multiple drug resistance of tumor, resisting HBV virus, anti-sinus arrhythmia or prevention.
Malanidine crystalline hydrate of the present invention, its purposes is, for the preparation of the application on the medicinal compositions containing malanidine crystalline hydrate, this medicinal compositions contains the vehicle, the diluent or carrier that pharmaceutically accept; This medicinal compositions can show as on pharmaceutical dosage forms, preparing injection (wherein injection comprises: injection freeze-dried powder or little water needle injection, great transfusion preparation), application on gastrointestinal administration preparation, per rectum or vagina administration preparation, be selected from tablet, capsule, granule, pill, soft capsule etc. through gastrointestinal administration preparation.
The solid preparation of malanidine chemical entities of the present invention comprises tablet, capsule, granule, pill etc.; Tablet (comprising ordinary tablet, buccal tablet, fast disintegrating tablet, effervescent tablet etc.), capsule (comprising capsule for vagina), granule, wherein can contain pharmaceutically acceptable weighting agent, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent, as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent (sodium lauryl sulphate etc.); Pharmaceutically acceptable wetting agent and tackiness agent, as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant, as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence, as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
Obtaining composition for the preparation of tablet or capsule filling can by wet granulation in preparation, in wet-granulation process, the activeconstituents of some or all or the vehicle of powder type mixed, and then mix further under the existence of liquid, this causes powder grumeleuse to become particle.This particle is sieved and or grinding, dry, then sieve, to the granularity expected, then this particle can make tablet, or before preparation, add other vehicle, such as glidant and/or lubricant.
The tablet, capsule, granule, pill, soft capsule, suppository etc. of product of the present invention, the weight ratio of its main ingredient and auxiliary material can be made up of the auxiliary material of 1 part of main ingredient and 0.01-10 part weight.
The composition being prepared into tablet can be prepared by being dry mixed usually.Such as, the composition after activeconstituents and mixed with excipients can be compacted into as small pieces or thin slice, and be then ground into the particle of compacting, the particle of this compacting can be suppressed into tablet subsequently.
Substituting as dry granular method, mixed composition can dry method direct compression, direct compression obtain evenly tablet.The vehicle being particularly suitable for direct compression comprises Microcrystalline Cellulose, spray-dired lactose calcium phosphate and colloid silica.These and other vehicle is proper use of in direct compression is be known to the technician in this area with experience and technical ability.With reference to the content of the malanidine of preparation in Chinese Pharmacopoeia 2010 editions standard test embodiments 8 of malanidine sheet and embodiment 9, find its content all between the 90-110% of labelled amount.
Capsule filling of the present invention can comprise any above-mentioned mixture and particle or particle, and it describes with reference to being prepared into tablet, but they do not carry out the last step being prepared into tablet.
Prepared by pill: be dissolved in by the product of the present invention of 1 part of weight in the pharmaceutically acceptable matrix of the melting of 1-10 part weight, fully stir evenly, prepare dripping pill with dropping method in refrigerant, throw away the refrigerant, be drying to obtain dripping pill.Pharmaceutically acceptable matrix of the present invention comprises and is singly not limited to poloxamer, glycogelatin, S40, stearic acid, stearyl alcohol, hexadecanol, single stearic acid glycerine lipoprotein, polyethylene glycol 6000, Macrogol 4000 etc.; Refrigerant includes but not limited to dimethyl silicone oil, vegetables oil, whiteruss, ethanol, water etc.
Suppository preparation containing malanidine chemical entities of the present invention: malanidine chemical entities 1 ~ 50%, suppository base 50 ~ 99% form, matrix can be water, ethanol, glycerine, glycogelatin, Macrogol 200 ~ 8000, poloxamer, semi-synthetic hard fatty acids fat, carbomer series (931,934,940,974, AA-1,1342 etc.), one or more in polysorbate60 ~ 80.Preparation method: mixed with matrix by main ingredient, heats, stirs, waits to melt, and is stirred to even, rapid impouring and has scribbled in the mould of the suppository of lubricant, to overflowing bolt mould a little, scabbles after cold, molding and get final product.
The preparation of the soft capsule preparation containing malanidine chemical entities of the present invention, the auxiliary materials such as available gelatin, gum arabic, glycerine, refining edible oil such as sunflower seed oil, Semen Maydis oil, peanut oil, sesame oil are prepared as basis.
The deliquescence that crystalline hydrate of the present invention is different from anhydride makes will to completely cut off air when processing and prevents adhesion etc., and crystalline hydrate has good sliding, thus improves the operability of preparation; And make the solid preparation of preparation have good dissolving out capability, make it easily be rapidly absorbed into blood circulation, improve bioavailability, and be conducive to its effect of fast onset.
The injection of malanidine chemical entities, its preparation method is:
Malanidine hydrate injection with small volume and preparation technology thereof: malanidine hydrate injects with water and pharmaceutically acceptable additives, such as: pharmaceutically acceptable pH adjusting agent, pharmaceutically acceptable oxidation inhibitor, rare gas element, filter, degermingly make sterilizing injection with small volume, its pH value is between 2.0 ~ 6.0.
Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be Lewis acid or the alkali of broad sense, one or several can be contained, can be hydrochloric acid, phosphoric acid, acetic acid and acetate, as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, Citric Acid pharmaceutical salts, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, succinic acid, caproic acid, hexanodioic acid, trans or maleic acid, trihydroxy-aminomethane, diethanolamine, thanomin, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1, ammediol amine, 1, 2-hexanediamine, N-methyl glucose amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid, one or several in amino acid and amino acid salts etc.
Pharmaceutically acceptable oxidation inhibitor in pharmaceutical compositions of the present invention and stablizer can be sulfurous acid and salt, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and pharmaceutical salts thereof, thiolactic acid and pharmaceutical salts, thio-2 acid and salt, phenol compound, as gallic acid and pharmaceutical salts, coffic acid and pharmaceutical salts thereof, forulic acid and pharmaceutical salts, di-t-butyl Pyrogentisinic Acid, DHB and pharmaceutical salts thereof; Amino acid and its pharmaceutical salts; Xitix and pharmaceutical salts, saccharosonic acid and pharmaceutical salts thereof, niacinamide, tartrate, nitrate, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, as one or several in EDETATE SODIUM, EDTA tetra-sodium, N-bis-(2-hydroxyethyl) glycine etc.; The salt of above-mentioned substance all selects its pharmacy acceptable salt.
Pharmaceutically acceptable isotonic regulator can be one or more in glucose, fructose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, Nulomoline, maltose, dextran, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate etc.
Source and the degerming mode of reducing phlegm and internal heat can be that the gac adding dosing amount 0.005 ~ 3% reduces phlegm and internal heat source, and the degerming and pressure sterilizing of millipore filtration, also can adopt heat sterilization, source of reducing phlegm and internal heat.In hyperfiltration process, ultra-fine filter can select flat, rolling, tubular type, hollow fiber form or circle boxlike etc., preferred rolling and hollow fiber form ultra-fine filter, adopt retain relative molecular mass be 5 ten thousand to 30 ten thousand filter membrane remove most of heat generation material and bacterium after, adopt the ultra-filtration membrane removing residue thermal source retaining relative molecular mass 3000 ~ 60000 again, the ultra-filtration membrane of preferred relative molecular mass 3000 ~ 20000.
The individually dosed consumption usage of malanidine new compound of the present invention when treating malaria: generally, oral, total dose 0.6-1.2g/ day, takes 2 times on 1st, and second day takes 1 time (calculating with Malaridine).2, the oral TDD of children's's usual amounts is by body weight 12-24mg/kg, point 3 clothes.Deep intramuscular injection, generally, each 2mg ~ 3mg/kg, 2 times/day.Quiet: generally, each 3mg ~ 6mg/kg, dilutes with 5% glucose saline 500ml, dripped off in 2 ~ 3 hours.Interval after 6 hours more quiet 1 time; More than children's amount of reducing by half use.
Accompanying drawing explanation
Fig. 1 is the thermal analyses collection of illustrative plates (embodiment 1) of malanidine 1 hydrate;
Fig. 2 is the X powder diffraction collection of illustrative plates (embodiment 1) of malanidine 1 hydrate;
Fig. 3 is the thermal analyses collection of illustrative plates (embodiment 2) of malanidine 1 hydrate;
Fig. 4 is the X powder diffraction collection of illustrative plates (embodiment 2) of malanidine 1 hydrate
Embodiment
During except there being instruction in an embodiment and separately, in specification sheets and claims, all numerical value used should be understood to be in all examples and modify with term " about ", therefore, unless the contrary indication, numerical parameter given in this specification sheets and appending claims is approximation, it can change according to by character required for sought by present disclosure, at least, and not the application being intended to limit doctrine of equivalents right, each numerical parameter should consider that the number of significant figure and the routine method of rounding up are explained.
Although numerical range and the parameter of the wide region of setting disclosure are approximations.But numerical value given in a particular embodiment is as far as possible accurately reported, any number comprises some error certainly led to by the standard deviation found in their respective tests in essence.
Unless it is pointed out that in literary composition and illustrated in addition clearly, the singulative " " used in this specification and the appended claims, " one " and " being somebody's turn to do " comprise the plural form referring to thing, so, such as.If comprise the mixture of two or more compounds when mentioning the composition containing " a kind of compound ", unless it should be noted that in addition and illustrate in addition clearly herein, term "or" generally includes "and/or".
As used herein, term " obtains " referring to that valuable content or purity level are separated the compound obtained, and described content and purity level include but not limited to the content and the purity level that are greater than 90%, 95%, 96%, 97%, 98% and 99%.
This " solvate " refers to the crystal formation of molecule, atom and/or the ion also comprising the solvent molecule penetrated in crystalline structure herein, the solvent molecule of solvate can be in regularly arranged and/or lack of alignment, and solvate of the present invention is aqueous solvent compound.
Polymorphic refers to have identical chemical constitution but form the different crystal of the spatial disposition of the molecule of crystal, atom and/or ion herein.
Pharmaceutical composition: " pharmaceutical composition " used herein refers to the composition of medicine, described pharmaceutical composition can contain the pharmaceutically acceptable carrier of at least one.
" pharmaceutically acceptable vehicle " used herein refers to the pharmaceutical carrier or solvent that are applicable to the compound administration occasionally provided herein, it comprises any examples of such carriers that well known to a person skilled in the art and be applicable to specific administration mode, such as, sterile diluent (such as, water for injection, salts solution, non-volatile wet goods) can be comprised for the solution of parenteral, intradermal, subcutaneous or topical application or suspension agent; The fatty solvent (such as, polyoxyethylene glycol, glycerine, propylene glycol etc.) of synthesis; Antiseptic-germicide (such as, benzylalcohol, to hydroxyl third methyl-formiate, to hydroxyl third ethyl formate etc.); Antioxidant (such as, xitix, sodium bisulfite etc.); Sequestrant (such as, EDTA etc.); Buffer reagent (phosphoric acid salt, Citrate trianion etc.); With or for tonicity-adjusting substances (e.g., sodium-chlor, glucose etc.), or their mixture.Other example comprises, and when intravenous administration, suitable carrier comprises physiological saline, phosphate buffered saline buffer and the solution containing thickening material, such as glucose, polyoxyethylene glycol etc. and their mixture.
As non-limiting example, malanidine crystalline hydrate can optionally and one or more pharmaceutically acceptable mixed with excipients, and can with following form oral administration: tablet, capsule, granule or pill or the form parenteral admin with sterile solution agent, these pharmaceutical preparations can contain activeconstituents and the carrier of such as about 25% to about 90%, the active ingredient more generally containing 5% to 60% (weight).
In order to understand the present invention further, below in conjunction with embodiment, the preferred embodiment of the invention is described, but should be appreciated that these describe just for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
With specific embodiment, effect of the present invention is described below, but protection scope of the present invention is not limited by the following examples.
Infrared spectra: pressing potassium bromide troche, working sample ir data, the instrument used comprises power & light company of U.S. NICOLET5700FTIRSpectrometer, the intelligent Fourier transformation infrared spectrometer of Nexus (ThermoNicolet) etc.
Heat analysis method
Thermal analyses test condition: Setaram company Setsys16, about sample size 3-10mg, heat-up rate: 10K/min, N
2flow velocity: 50ml/min, temperature: about room temperature ~ 400 DEG C.
In the present invention, surprisingly, distinctive, there is under the weightless platform of thermal analyses (TG-DTA or the TG-DSC) collection of illustrative plates of hydrate of the present invention corresponding endotherm(ic)peak, under the weightless platform of its thermal analyses collection of illustrative plates between 35-115 DEG C, correspondence shows obvious endotherm(ic)peak, thermal analyses collection of illustrative plates demonstrates malanidine crystalline hydrate, and this weightlessness of Karl_Fischer method test evidence is water molecules.
Powder X-ray diffraction approach
Utilize D/MX-III AX x ray diffractometer x, voltage: about 30-60kv, electric current: about 30-100mA, sweep velocity: about 10 °/min, step-length: about 0.02 °/step; Copper target, monochromator: graphite monochromator; Wavelength
diffraction angle 2 θ, sweep limit 3-60 °, determine the x-ray diffractogram of powder of malanidine crystalline hydrate, and whole peak position is in ± 0.2 ° of 2 θ; Or utilize the D8AdvanceX x ray diffractometer x of German Bruker company, wavelength
diffraction angle 2 θ, sweep limit 3-60 °, other (index such as voltage, electric current) is approximately the same, measures sample.Each accompanying drawing in this specification sheets and data are proved each other.
Specific embodiment
Under the preparation room temperature of embodiment 1 malanidine 1 hydrate, get Malaridine 4g in 250ml flask, add ethanol 10ml, stir, heating, add the phosphoric acid solution of appropriate 4M, be stirred to dissolve, about controlling pH value of solution=2.0, continue to stir about 2h, add appropriate ethanol, Virahol, place, slowly be cooled to about-4 ~-22 DEG C, place, abundant precipitation to be precipitated, filter, with cold ethanol and isopropyl alcohol wash solids, suction filtration, gained solids is placed in flask, the water adding appropriate volume also heats makes dissolving, appropriate ethanol and Virahol (volume ratio of ethanol and Virahol is about 9:1) is used to carry out recrystallization operation again, to about-4 ~-22 DEG C, place, abundant precipitation to be crystallized, suction filtration, gained crystallization is gone up method recrystallization once for another example, to about-4 ~-10 DEG C, place, abundant precipitation to be crystallized, suction filtration, gained crystallization is made thinner, in about 25 DEG C lucifuge forced air dryings about 1 day, again in about 45 DEG C dry 5 hours, to the basic constant weight of twice weighing in half an hour, obtain yellow solid 4.78 grams, fusing point: 225.1-228.6 DEG C variable color (melting point apparatus does not correct), differentiate: 1) get product 10mg prepared by the present embodiment, add 1ml water dissolution, add trinitrophenol test solution number and drip, namely produce yellow mercury oxide, (2) get product 20mg prepared by the present embodiment, add 5ml water dissolution, add ammonia solution and make precipitation complete, filter, filtrate presents phosphatic identification, 3) get product 10mg prepared by the present embodiment, add phosphate buffered saline buffer (pH7.0) and make every 1ml about containing the solution of 10 μ g, measure according to ultraviolet visible spectrophotometry, have maximum absorption at 260nm and 276nm place, it is 2.35% that Ka Erfei amends the law to measure moisture, thermal analyses TG-DTA: platform weightlessness about 2.212% (see accompanying drawing 1), and this and sample contain the result (theoretical value 2.03%) of 1 crystal water in limit of error, infrared spectra: ν
kBr maxcm
-13397.4,3226.4,2951.5,2738.5,1632.1,1576.9,1551.3,1526.2,1489.8,1459.4,1389.0,1350.5,1283.9,1238.2,1190.9,1090.4,1035.8,989.3,532.3, X-ray powder diffraction (see accompanying drawing 2) about etc. has characteristic peak in the position of following 2 θ values: 7.43,8.66,12.14,13.08,13.82,14.17,17.83,18.29,18.74,19.67,20.51,21.87,22.31,22.78,23.89,24.92,26.07,26.15,26.90,28.87, ultimate analysis, theoretical value: C37.53%, H5.00%, N7.55%, Cl3.82%, P13.35%, measured value: C37.39%, H4.92%, N7.43%, Cl3.72%, P13.21%.
Under the preparation room temperature of embodiment 2 malanidine 1 hydrate, get Malaridine 5g in 250ml flask, add methyl alcohol 10ml, acetone 1ml, stir, add the phosphoric acid solution of appropriate 5M, heating, be stirred to dissolve, about controlling pH value of solution=2.5, continue stirring 3 hours, with about 90ml ethanol, 6ml ether, acetone 1ml carries out crystallization operation, place, slowly be cooled to be cooled to-4 ~-10 DEG C, place, abundant precipitation to be precipitated, filter, solids is washed with cold ethanol and ether, suction filtration, gained solids is placed in flask, and with appropriate water dissolution solids, be heated to about 50-80 DEG C, add 90ml ethanol, 5ml ether carries out recrystallization operation, then-4 ~-22 DEG C are slowly cooled to, place 1, abundant precipitation to be crystallized, filter, solids is washed with cold ethanol and ether, suction filtration, by gained crystallization again according to upper method recrystallization once, slowly be cooled to-4 ~-22 DEG C, place 1, abundant precipitation to be crystallized, filter, by gained crystallization in about 25 DEG C lucifuge forced air dryings 8 hours, again in about 42 DEG C dry 6 hours, to the basic constant weight of twice weighing in half an hour, obtain yellow solid 5.22 grams, fusing point: 225.3-228.9 DEG C variable color (melting point apparatus does not correct), differentiate: 1) get product 10mg prepared by the present embodiment, add 1ml water dissolution, add trinitrophenol test solution number and drip, namely produce yellow mercury oxide, (2) get product 20mg prepared by the present embodiment, add 5ml water dissolution, add ammonia solution and make precipitation complete, filter, filtrate presents phosphatic identification, 3) get product 10mg prepared by the present embodiment, add phosphate buffered saline buffer (pH7.0) and make every 1ml about containing the solution of 10 μ g, measure according to ultraviolet visible spectrophotometry, have maximum absorption at 260nm and 276nm place, it is 2.16% that the Ka Erfei method that amends the law measures moisture, thermal analyses TG-DTA: platform weightlessness about 2.095%, and this and sample contain the result (theoretical value 2.03%) (see accompanying drawing 3) in limit of error of 1 crystal water, infrared spectra: ν
kBr maxcm
-13399.0,3232.7,3062.5,2951.2,2726.9,1632.3,1576.4,1550.5,1525.4,1489.5,1459.1,1389.7,1350.4,1284.8,1239.4,1194.8,1091.2,992.9,934.3,538.7, X-ray powder diffraction (see accompanying drawing 4) about etc. has characteristic peak in the position of following 2 θ values: 6.48,7.86,8.99,9.28,11.53,12.58,12.93,13.32,14.27,14.70,16.15,16.66,17.17,18.04,18.27,18.64,19.38,19.81,20.84,21.28,22.18,22.80,23.65,24.16,25.29,25.93,26.78,27.46,27.95,28.82,32.28, ultimate analysis, theoretical value: C37.53%, H5.00%, N7.55%, Cl3.82%, P13.35%, measured value: C37.41%, H5.07%, N7.63%, Cl3.70%, P13.22%.
Under the preparation room temperature of embodiment 3 malanidine 1 hydrate, get Malaridine 5g in 250ml flask, add water 1ml, methyl alcohol 10ml, stir, heating, adds the phosphoric acid solution of appropriate 6M, is stirred to dissolve, and about controlling pH value of solution=2.0, continues stirring 1 hours, adds appropriate ethanol, Virahol, acetonitrile, methylene dichloride, ethyl acetate (ethanol, Virahol, acetonitrile, methylene dichloride, the volume ratio of ethyl acetate is about 12:1:0.4:0.1:0.1), place, be slowly cooled to about-4 ~-22 DEG C, place, abundant precipitation to be precipitated, filter, ether is washed, suction filtration, gained solids is placed in flask, and the water adding appropriate volume makes dissolving, heating, then uses appropriate ethanol, Virahol, acetonitrile (ethanol, Virahol, the volume ratio of acetonitrile is about 12:1:0.4) carry out recrystallization operation, to about 0 ~-8 DEG C, place, abundant precipitation to be crystallized, suction filtration, with a small amount of cold ethanol and washed with isopropyl alcohol solid, suction filtration, makes thinner gained solid crystal, about 25 DEG C lucifuge forced air dryings about 1 day, about 46 DEG C dry 4 hours of lucifuge, obtain yellow solid 6.38 grams again, fusing point: 224.2-227.6 DEG C variable color (melting point apparatus does not correct), differentiate: differentiate: 1) get product 10mg prepared by the present embodiment, add 1ml water dissolution, add trinitrophenol test solution number and drip, namely produce yellow mercury oxide, (2) get product 20mg prepared by the present embodiment, add 5ml water dissolution, add ammonia solution and make precipitation complete, filter, filtrate presents phosphatic identification, it is 2.18% that Ka Erfei amends the law to measure moisture, thermal analyses TG-DTA: platform weightlessness about 2.07%), this and sample contain the result (theoretical value 2.03%) of 1 crystal water in limit of error.
Malanidine 1 hydrate 3.59g (standby by embodiment 1 legal system) is got in the preparation of embodiment 4 freeze-dried powder, add fresh water for injection 80ml with N.F,USP MANNITOL or Xylitol 2.0 ~ 5g to stir, with phosphoric acid or and 1M sodium hydroxide solution regulate pH be 3.0 ~ 4.0, make to be dissolved into solution, moisturizing is to 100ml, add activated carbon 0.01 ~ 0.5% (W/V) and stir 15 ~ 45min, filter, with 0.22 micrometer Millipore membrane filtration, by 40mg/ bottle or 80mg/ bottle (in Malaridine) packing, lyophilize, tamponade, obtains finished product.
The little hydro-acupuncture preparation of embodiment 5 prepare malanidine hydrate 71.66g (by embodiment 1 legal system standby or embodiment 2 legal system is standby), add cysteine hydrochloride 0.8g, Ethylenediaminetetraacetic Acid Calcium Salt 0.1g, injects and is stirred to dissolve with water 800ml, and 2M lactic acid and Sodium.alpha.-hydroxypropionate regulate pH to be 3.0 ~ 4.0, add activated carbon 0.01% (W/V) and stir 15 ~ 45min, filter, moisturizing to 1000ml, with 0.22 micrometer Millipore membrane filtration, by the packing of 2ml/ bottle, sterilizing obtains finished product.
The preparation of embodiment 6 high-capacity injection takes glucose 500g and adds in water for injection, is stirred to dissolve completely, adds the gac of dosing amount 0.05%, heat about 10-30 minute, let cool, through sand stick filtering decarbonization; By malanidine hydrate (by embodiment 1 legal system standby or embodiment 2 legal system is standby) 3.59g, dissolve completely with fresh water for injection, mix with above-mentioned filtrate, add L-cysteine hydrochloride 1g, Ethylenediaminetetraacetic Acid Calcium Salt 0.02g, by 1M lactic acid solution adjust ph in the scope of 3.2-5.0, inject water to 5000ml, add the gac of dosing amount 0.03%, about heated and stirred 10-30 minute, filtering decarbonization, again through the filter of 0.22um millipore filtration essence, embedding is in the vial of 50ml or 100ml or 200ml, and sterilizing, packs and get final product.
The preparation of embodiment 7 malanidine hydrate sodium-chlor transfusion: by malanidine hydrate 4g (by embodiment 1 legal system standby or embodiment 2 legal system is standby), sodium-chlor 85g, Sodium Pyrosulfite 1.1g, Ethylenediaminetetraacetic Acid Calcium Salt 0.05g, add in water for injection, be stirred to dissolve completely, by the Citric Acid of 1M and liquor sodii citratis adjust ph in the scope of 4.0-6.5, inject water to 10000ml, add the gac of dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, the ultrafiltration membrance filter of relative molecular mass 3000-20000 is retained again through the filter of 0.22um millipore filtration essence or employing, chemically examine through work in-process, treat its content, pH value and clarity qualified after, embedding is in the vial of 50ml or 100ml or 200ml, sterilizing, packaging.
Embodiment 8 malanidine 1 hydrate tablet (100mg/ sheet, in Malaridine)
Mix after malanidine crystalline hydrate (standby by embodiment 2 legal system), Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, with PVP K-30 ethanol water (7:3) the solution softwood processed in right amount of 10%, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
Embodiment 9 malanidine 1 hydrate tablet (200mg/ sheet)
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, PVP K-30 ethanol water (ethanol: water=8:2) solution softwood processed in right amount with 10%, cross 24 mesh sieves to granulate, dry, after crossing the whole grain of 20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
Embodiment 10 malanidine 1 hydrate tablet (300mg/ sheet)
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
Embodiment 11 malanidine hydrate tablet (50mg/ sheet)
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby), pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 14 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet, packaging.
Embodiment 12 malanidine hydrate capsule (25mg/ grain)
The malanidine hydrate (by embodiment 1 legal system standby or embodiment 2 method) of recipe quantity, Microcrystalline Cellulose, lactose are mixed after crossing 100 mesh sieves respectively, gelling starch with 10% is softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate mixing, filling capsule.
Embodiment 13 malanidine hydrate enteric coated capsule (50mg/ grain)
Mix after the malanidine hydrate (standby by embodiment 3 legal system) of recipe quantity, Microcrystalline Cellulose, lactose are crossed 100 mesh sieves respectively, gelling starch with 10% is softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate mixing, filling enteric coated capsule.
Embodiment 14 malanidine hydrate capsule (100mg/ grain)
Get after the malanidine crystalline hydrate raw material (standby by embodiment 3 legal system) of recipe quantity, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross 100 mesh sieves respectively and mix, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, filling capsule, packaging.
The granule (50mg/ bag) of embodiment 15 malanidine hydrate
The malanidine hydrate of recipe quantity (by embodiment 1 legal system standby or embodiment 2 legal system is standby), N.F,USP MANNITOL, lactose, Sodium Cyclamate, food flavour are mixed after crossing 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 8% softwood processed in right amount, cross 24 mesh sieves to granulate, less than 60 DEG C dry, after crossing the whole grain of 20 mesh sieve, mixing, point packaging.
The tablet (Malaridine 100mg/ Dihydroartemisinin 20mg/ sheet) of the composition of embodiment 16 malanidine hydrate and Dihydroartemisinin
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby) pulverized 100 mesh sieves, mix with the Dihydroartemisinin of mistake 100 mesh sieve of recipe quantity, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 14 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet.
The tablet (Malaridine 25mg/ Dihydroartemisinin 100mg/ sheet) of the composition of embodiment 17 malanidine hydrate and Dihydroartemisinin
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby), Dihydroartemisinin, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 14 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet, packaging.
The tablet (Malaridine 100mg/ Artesunate 20mg/ sheet) of the composition of embodiment 18 malanidine hydrate and Artesunate
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby), Artesunate, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet, inspection, packaging.
The capsule (malanidine hydrate 20mg/ Artesunate 100mg/ grain) of the composition of embodiment 19 malanidine hydrate and Artesunate
Get recipe quantity malanidine hydrate feed (by embodiment 1 method or embodiment 2 legal system standby), Artesunate, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, filling capsule, packaging.
The tablet (Malaridine 100mg/ Artesunate 40mg/ sheet) of the composition of embodiment 20 malanidine hydrate and Artesunate
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby), Artesunate, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, PVP K-30 ethanol water (ethanol: water=8:2) solution softwood processed in right amount with 10%, cross 18-24 mesh sieve to granulate, about 50 DEG C dry 3 hours, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet, packaging.
The composition tablet (Malaridine 100mg/ arteether 30mg/ sheet) of embodiment 21 malanidine hydrate and arteether
Get recipe quantity malanidine crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby), arteether, pregelatinized Starch, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum cross after 100 mesh sieves respectively and mix, PVP K-30 ethanol water (ethanol: water=9:1) solution softwood processed in right amount with 10%, cross 18-24 mesh sieve to granulate, about 50 DEG C dry 3 hours, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, compressing tablet, packaging.
The composition tablet (200mg/80mg/ sheet) of embodiment 22 malanidine 1 hydrate and arteether
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, arteether, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
The composition tablet (100mg/100mg/ sheet) of embodiment 23 malanidine 1 hydrate and dihydroarteannuin
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, dihydroarteannuin, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
The composition tablet (50mg/100mg/ sheet) of embodiment 24 malanidine 1 hydrate and dihydroarteannuin
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, dihydroarteannuin, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
The enteric coated capsule (100mg/25mg/ grain) of embodiment 25 malanidine hydrate and Artemether compound
The malanidine hydrate of recipe quantity (embodiment 1 legal system standby or embodiment 2 method), Artemether, Microcrystalline Cellulose, lactose are mixed after crossing 100 mesh sieves respectively, gelling starch with 10% is softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate mixing, filling enteric coated capsule.
The tablet (200mg/20mg/ sheet) of embodiment 26 malanidine hydrate and Artemether compound
The malanidine hydrate of recipe quantity (embodiment 1 legal system standby or embodiment 3 method), Artemether, Microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose are mixed after crossing 100 mesh sieves respectively, gelling starch with 10% is softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate mixing, compressing tablet, packaging.
The preparation (10000) of embodiment 27 malanidine hydrate and Artemether compound dripping pill
Prescription: malanidine hydrate 30g
Artemether 10g
Polyethylene glycol 6000 60g
The malanidine hydrate of recipe quantity (embodiment 1 method or embodiment 2 legal system standby), Artemether are mixed after crossing 100 mesh sieves respectively, is added in the polyethylene glycol 6000 matrix of melting, fully stirs evenly, take dimethyl silicone oil as refrigerant, dropping method pill, dry, packaging.
The preparation (20000) of embodiment 28 malanidine hydrate and dihydroarteannuin composition dripping
Mix after malanidine hydrate (embodiment 1 method or embodiment 3 legal system standby), dihydroarteannuin are crossed 100 mesh sieves respectively, be added in the polyethylene glycol 6000 of melting and the matrix of poloxamer, fully stir evenly, take dimethyl silicone oil as refrigerant, dropping method pill, dry, packaging.
The preparation (tablet format is by the weighing scale of feed components: 358mg/250mg/12.5mg/ sheet) of embodiment 29 malanidine hydrate and Sulphadoxine, Pyrimethamine hcl composition tablet
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, Sulphadoxine, Pyrimethamine hcl, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
The preparation (tablet format is by the weighing scale of the active base component that feeds intake: Malaridine 200mg/ Sulphadoxine 250mg/ primaquine 11.25mg/ sheet) of embodiment 30 malanidine hydrate and Sulphadoxine, Primaquine diphosphate compound tablet
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, Sulphadoxine, PRIMAQUINE PHOSPHATE, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 24 mesh sieves to granulate, dry, after crossing the whole grain of 18 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
The preparation (1000) of embodiment 31 malanidine hydrate suppository
Prescription: malanidine hydrate 40g
Polyethylene glycol 1500 160g
Polyethylene glycol 6000 800g
The malanidine hydrate of recipe quantity (embodiment 1 method or embodiment 2 legal system standby) is crossed 80 mesh sieves, be added in the polyethylene glycol 1500 of melting, polyethylene glycol 6000 matrix, main ingredient is mixed with matrix, heating in water bath, be stirred to even, rapid impouring and scribbled in the mould of the suppository of lubricant, to overflowing bolt mould a little, scabble after cold, molding and get final product.
The preparation (tablet format presses the weighing scale of activeconstituents: Malaridine 100mg/ Sulphadoxine 200mg/ Pyrimethamine hcl 10mg/ sheet) of embodiment 32 malanidine hydrate and Sulphadoxine, Pyrimethamine hcl composition tablet
Mix after the malanidine crystalline hydrate (standby by embodiment 2 legal system) of recipe quantity, Sulphadoxine, Pyrimethamine hcl, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose are crossed 100 mesh sieves respectively, PVP K-30 aqueous ethanolic solution with 10% softwood processed in right amount, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, packaging.
Industrial applicibility etc. and explanation etc. thereof:
Below through the specific embodiment and the embodiment to invention has been detailed description; but should understand; these explanations do not form any restriction to scope of the present invention; person skilled obviously can in the case of without departing from the spirit and scope of protection of the present invention; multiple modification, improvement and replacement and combination can be carried out to technical solutions and their implementation methods of the present invention; realize the technology of the present invention, these are all because falling within the scope of protection of the present invention.Special needs to be pointed out is, be appreciated that the change of a lot of details is possible, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in spirit of the present invention, scope and content, and the present invention is not limited to above-described embodiment.
Claims (10)
1. benzo naphthyridine type compound, is characterized in that: benzo naphthyridine type compound is malanidine 1 hydrate, and its molecular formula is C
29h
32clN
5o
24H
3pO
4h
2o.
2. malanidine 1 hydrate according to claim 1, it is characterized in that: utilize powder X-ray diffractometry to measure, in the useful range that diffraction angle is 2 θ and 3-60 °, in the position of following 2 θ values, there is corresponding eigenwert: 6.48, 7.86, 8.99, 9.28, 11.53, 12.58, 12.93, 13.32, 14.27, 14.70, 16.15, 16.66, 17.17, 18.04, 18.27, 18.64, 19.38, 19.81, 20.84, 21.28, 22.18, 22.80, 23.65, 24.16, 25.29, 25.93, 26.78, 27.46, 27.95, 28.82, 32.28.
3. malanidine 1 hydrate according to claim 1, it is characterized in that: utilize powder X-ray diffractometry to measure, in the useful range that diffraction angle is 2 θ and 3-60 °, in the position of following 2 θ values, there is corresponding eigenwert: 7.43,8.66,12.14,13.08,13.82,14.17,17.83,18.29,18.74,19.67,20.51,21.87,22.31,22.78,23.89,24.92,26.07,26.15,26.90,28.87.
4. benzo naphthyridine type compound according to claim 1, it is characterized in that, its preparation method is:
Take appropriate Malaridine, be added to the water, the C that fill 1-50 times amount (weightmeasurement ratio=gram g: milliliter ml)
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone in one or more reaction vessels in, add phosphoric acid solution, below adjust ph to 4.0, be stirred to dissolve, use C
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
1-C
6low molecule hydrochloric ether, C
2-C
8one or more in low molecule ester carry out crystallization operation, and cooling, makes crystallization fully separate out, and filter, gained solid water and C
1-C
6low mass molecule alcohol, C
2-C
8low molecule ether, C
3-C
8low molecule ketone, C
1-C
6low molecule hydrochloric ether, C
2-C
8low molecule ester in one or more carry out one or many recrystallization for recrystallisation solvent, filter, washing, dry, obtain malanidine 1 hydrate of the present invention.
5. benzo naphthyridine type compounds process for production thereof according to claim 4, it is characterized in that, described crystallization or recrystallization solvent are selected from: one or more in water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, isopropyl ether, acetone, hexone, ethyl acetate.
6. benzo naphthyridine type compound according to claim 1, it is characterized in that: for the preparation of malanidine 1 hydrate and Sulphadoxine, Pyrimethamine hcl, Azythromycin, clindamycin, Clindamycin Phosphate, primaquine, naphthols quinoline, PIPERAQUINE, quinine, chloroquine, nitroquine, Plaquenil, Quinidine, amodiaquine, Mefloquine hydrochloride, benzfluorenol, mirincamycin, atovaquone, halofantrine, Artemisinin, Dihydroartemisinin, arteether, Artemether, one or more medicinal compositions in the acid of wormwood artemisia ether woods and Artesunate and their salts of pharmacologically allowing.
7. medicinal compositions according to claim 6, is characterized in that: in this malanidine 1 hydrate and Sulphadoxine, Pyrimethamine hcl, Azythromycin, clindamycin, Clindamycin Phosphate, primaquine, naphthols quinoline, PIPERAQUINE, quinine, chloroquine, nitroquine, Plaquenil, Quinidine, amodiaquine, Mefloquine hydrochloride, benzfluorenol, mirincamycin, atovaquone, halofantrine, Artemisinin, Dihydroartemisinin, arteether, Artemether, the acid of wormwood artemisia ether woods and Artesunate and its salt pharmacologically allowed, one or more weight ratio is 20:1 ~ 1:10.
8. medicinal compositions according to claim 7, is characterized in that: in malanidine 1 hydrate and Sulphadoxine, Pyrimethamine hcl, Azythromycin, clindamycin, Clindamycin Phosphate, primaquine, naphthols quinoline, PIPERAQUINE, quinine, chloroquine, nitroquine, Plaquenil, Quinidine, amodiaquine, Mefloquine hydrochloride, benzfluorenol, mirincamycin, atovaquone, halofantrine, Artemisinin, Dihydroartemisinin, arteether, Artemether, the acid of wormwood artemisia ether woods and Artesunate and their salts of pharmacologically allowing, one or more weight ratio is 10:1 ~ 1:6.
9. benzo naphthyridine type compound according to claim 1, it is characterized in that: its purposes is for the preparation of the application in pharmaceutical preparation, pharmaceutical preparation is selected from: injection, through gastrointestinal administration preparation, per rectum or vagina administration preparation, wherein, tablet, capsule, granule, pill, soft capsule is selected from through gastrointestinal administration preparation; Containing the vehicle, the diluent or carrier that pharmaceutically accept in this pharmaceutical preparation.
10. benzo naphthyridine type compound according to claim 1, it is characterized in that: its purposes is, be applicable to prepare the application in the treatment of following humans and animals disease or the medicine of prevention: the application in brain type, dangerous type and the subtertian malaria caused by the strain of resistance to chloroquine worm, vivax malaria, silicosis, anti-sinus arrhythmia, reverse multiple drug resistance of tumor, the treatment of anti-hepatitis B virus or the medicine of prevention.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209926A (en) * | 2019-07-12 | 2021-01-12 | 中国中医科学院中药研究所 | Polymorphic substance of pyronaridine phosphate and preparation method and application thereof |
| CN112500408A (en) * | 2021-02-04 | 2021-03-16 | 湖北美林药业有限公司 | Pyronaridine phosphate compound and preparation method thereof |
| WO2021209477A1 (en) | 2020-04-17 | 2021-10-21 | Merck Patent Gmbh | Crystalline forms of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol and salts thereof |
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| CN103373995A (en) * | 2012-04-28 | 2013-10-30 | 上海迪赛诺药业有限公司 | Method for preparing pyronaridine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209926A (en) * | 2019-07-12 | 2021-01-12 | 中国中医科学院中药研究所 | Polymorphic substance of pyronaridine phosphate and preparation method and application thereof |
| WO2021209477A1 (en) | 2020-04-17 | 2021-10-21 | Merck Patent Gmbh | Crystalline forms of 4-[(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol and salts thereof |
| CN112500408A (en) * | 2021-02-04 | 2021-03-16 | 湖北美林药业有限公司 | Pyronaridine phosphate compound and preparation method thereof |
| CN112500408B (en) * | 2021-02-04 | 2024-01-12 | 湖北美林药业有限公司 | Pyrrolephidine phosphate compound and preparation method thereof |
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Application publication date: 20160406 |