CN103012421B - Iloquinoline derivative medicine and preparation thereof and purposes - Google Patents
Iloquinoline derivative medicine and preparation thereof and purposes Download PDFInfo
- Publication number
- CN103012421B CN103012421B CN201210521407.XA CN201210521407A CN103012421B CN 103012421 B CN103012421 B CN 103012421B CN 201210521407 A CN201210521407 A CN 201210521407A CN 103012421 B CN103012421 B CN 103012421B
- Authority
- CN
- China
- Prior art keywords
- hydrate
- berbamine
- preparation
- berbamine hydrochloride
- water
- 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
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to iloquinoline derivative medicine and its production and use, its molecular formula is C
37h
40n
2o
62HClnH
2o, wherein, n=3,3.5.This iloquinoline derivative medicine has good storage stability, is applicable to prepare the application in the treatments of disease such as promoting leucocyte hyperplasia, preventing cancer radiotherapy, Leukocytes after Chemotherapy minimizing, anti-inflammatory, tuberculosis, anti-silicosis, antitumor, hypotensive, anti-myocardial anoxia ischemic, anti-arrhythmia or the medicine of prevention.
Description
Technical field
The present invention relates to medical art, be specifically to provide the bisbenzylisoquinoline alkaloid effect of berbamine derivative and preparation thereof and purposes that have and promote the effects such as leucocyte hyperplasia, anti-inflammatory, hypertension, anti-myocardial anoxia ischemic, anti-arrhythmia, tuberculosis, antitumor, anti-silicosis.
Background technology
Berbamine system isoquinoline alkaloid, has effects such as promoting leucocyte hyperplasia, anti-inflammatory, hypertension, anti-myocardial anoxia ischemic, anti-arrhythmia, tuberculosis, antitumor, anti-silicosis.Disclosed document only reports Berbamine hydrochloride [C at present
37h
40n
2o
62HCl, molecular weight: 681.65], and the pharmacology of Berbamine and clinical application situation, as document: pharmaceutical action of EBB analysis [Tropical China medical science 2005,5 (1): 109-110)], cardiovascu-lar effects progress [the Chinese combination of Chinese tradiational and Western medicine magazine of Berbamine, 2005, ] etc., but up to the present, still there is no disclosed bibliographical information Berbamine hydrochloride crystalline hydrate of the present invention [C both at home and abroad 25 (8): 765-768)
37h
40n
2o
62HClnH
2o, wherein n=3.0,3.5] and its production and use.
Summary of the invention
Involved in the present invention is has the bisbenzylisoquinoline alkaloid effect of berbamine derivative promoting the effect such as leucocyte hyperplasia, anti-inflammatory, hypertension, anti-myocardial anoxia ischemic, anti-arrhythmia, tuberculosis, antitumor, anti-silicosis, i.e. Berbamine hydrochloride crystalline hydrate and preparation thereof and purposes.Its molecular formula is C
37h
40n
2o
62HClnH
2o, wherein, n=3,3.5.
The Berbamine hydrochloride crystalline hydrate containing crystal water that the present invention obtains, surprisingly, Berbamine hydrochloride hydrate containing crystal water draws moist far below Berbamine hydrochloride anhydride, Berbamine hydrochloride hydrate containing crystal water more can be stable than Berbamine hydrochloride anhydride existence, be convenient to store and transport, be 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.
Distinctive, thermal analyses (TG-DTA etc.) collection of illustrative plates of hydrate of the present invention can find out that weightless platform has the endotherm(ic)peak of strong correspondence, and thermal analyses collection of illustrative plates demonstrates Berbamine hydrochloride crystalline hydrate [C
37h
40n
2o
62HCl3H
2o], [C
37h
40n
2o
62HCl3.5H
2o], match by Karl_Fischer method mensuration moisture result and thermal analyses result.
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, and this area needs Berbamine hydrochloride crystalline hydrate or its polymorph.
Surprisingly, distinctive, have corresponding endotherm(ic)peak under the weightless platform of thermal analyses (TG-DSC or the TG-DTA) collection of illustrative plates of hydrate of the present invention, thermal analyses collection of illustrative plates demonstrates Berbamine hydrochloride crystalline hydrate etc.
Berbamine hydrochloride crystalline hydrate of the present invention, for off-white color is to pale yellow powder, can stable storage.By above-mentioned Berbamine hydrochloride crystalline hydrate matter sample respectively airtight with cillin bottle in carry out accelerated stability test, with reference to the content assaying method of China National Drug Standard [WS-10001-(HD-1242)-2002], measure Berbamine hydrochloride crystalline hydrate prepared by various embodiments of the invention, have been surprisingly found that, the content of Berbamine hydrochloride 3 hydrate of the present invention does not have considerable change (30 DEG C, under RH75%).The results are shown in Table 1.
Table 1. Berbamine hydrochloride hydrate of the present invention accelerated stability test different time sampling result
Chromatographic condition (the chromatographic condition: chromatographic column: C of reference literature [Du Zhimao etc., Chinese Journal of Pharmaceuticals, 2005,36 (1): 4041]
l8(150mm × 4.6mm, 5 μm); Moving phase: acetonitrile-0.02mol/L potassium dihydrogen phosphate [phosphorus acid for adjusting pH is to 7.0] (70:30); Flow velocity: lml/min; Temperature: 35 DEG C; Determined wavelength: 282nm), the content of Berbamine hydrochloride 3 hydrate of the present invention and related substance do not have considerable change (30 DEG C, under RH75%), illustrate that Berbamine hydrochloride crystalline hydrate of the present invention has better storage stability.
Isoquinilone derivatives---Berbamine hydrochloride crystalline hydrate is preparation method comprise:
Method A. takes Berbamine or Berbamine solvate crude product, is added to the water of 2-12 times amount, C
1-C
6low mass molecule alcohol in one or more reaction vessels in, add hydrochloric acid soln, be stirred to dissolve, regulate (preferable ph is about 2.6) between pH to 1.0-3.5, add proper amount of active carbon, stir, filter, filtrate is alkalized, precipitation is fully separated out, filter, by gained solid, add hydrochloric acid soln, be stirred to dissolve, between adjust ph to 1.2-3.5 (preferable ph is about 2.6), add proper amount of active carbon, stir, filter, gained filtrate is concentrated, by gained filtrate C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone in one or more recrystallizations, cooling, place, precipitation is fully separated out, filter, gained solid drying, obtains Berbamine hydrochloride crystalline hydrate; By gained Berbamine hydrochloride crystalline hydrate water and C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone in one or more, one or many recrystallization operation can be carried out further.
Or method B., by Berbamine or Berbamine solvate, is added to the water of 2-12 times amount, C
1-C
6low mass molecule alcohol in one or more reaction vessels in, add hydrochloric acid soln, be stirred to dissolve, between adjust ph to 1.0-3.5 (preferable ph is about 2.6), add proper amount of active carbon, stir, filter, filtrate is concentrated, in filtrate, adds C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone in one or more, cooling, make crystallization, filter, with water, the C of less than 0 DEG C
2-C
6rudimentary ether, by gained solid drying, obtain Berbamine hydrochloride crystalline hydrate; By gained Berbamine hydrochloride crystalline hydrate water and C
1-C
6low mass molecule alcohol, C
2-C
6rudimentary nitrile, C
3-C
8low molecule ketone in one or more, one or many recrystallization operation can be carried out further.
One or more preferably in: water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, acetone, hexone, methylene dichloride 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.; C
2-C
6the carbonatoms of rudimentary nitrile be defined as C
2-C
6, as acetonitrile, propionitrile etc.; C
3-C
8low molecule ketone be defined as the ketone of 3-8 carbon atom, comprise acetone, butanone, pentanone, hexanone, hexone etc.; The carbonatoms of rudimentary ether or low molecule ether is defined as C
2-C
8, as ether, isopropyl ether, butyl ether 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 for differing temps (as 10-80 DEG C), time of drying (1 hour to a few days) or with the envrionment conditions of other siccative (comprising silica gel, Vanadium Pentoxide in FLAKES, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate etc.) under or use the mode of normal pressure or decompression to carry out drying to last product.Its drying temperature preferably 50 DEG C or within.
Moisture determination of the present invention adopts Karl_Fischer method.The fusing point of Berbamine hydrochloride hydrate of the present invention measures at different time melting point apparatus, and 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 different crystalline hydrate of Berbamine hydrochloride.
The present invention on the other hand, the preparation method of the crystalline hydrate providing Berbamine hydrochloride different.
The present invention provides a kind of medicinal compositions on the other hand, comprising any one or the multiple Berbamine hydrochloride hydrate prepared by method of the present invention, and the acceptable vehicle of one or more pharmacy.
The present invention further provides the method for useful in preparing drug formulations, comprising the merging of any one or the multiple Berbamine hydrochloride hydrate prepared by method of the present invention and at least one or the acceptable vehicle of pharmacy.
The present invention further provides Berbamine hydrochloride hydrate, for the preparation for the treatment of people or mammiferous promotion leucocyte hyperplasia, the leukopenia caused for a variety of causes, for the purposes in the treatment such as preventing cancer radiotherapy, Leukocytes after Chemotherapy minimizings, anti-inflammatory, tuberculosis, anti-silicosis, antitumor, hypotensive, anti-myocardial anoxia ischemic, anti-arrhythmia or the pharmaceutical composition that prevents.
Berbamine hydrochloride hydrate of the present invention can be used for preparing solid preparation, comprises the application in tablet, capsule etc.
The solid preparation of Berbamine hydrochloride hydrate of the present invention comprises tablet, capsule, granule 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 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.
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.
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.
Prepared by dosing eyes preparation
In the preparation of Berbamine hydrochloride crystalline hydrate eye drop, the parts by weight of each component can be: Berbamine hydrochloride crystalline hydrate 0.1-1, solubility promoter 0.1-1, antioxidant 0.02-0.5, metal chelating agent 0.01-0.2, osmotic pressure regulator 0.5-10, sanitas 0.002-0.4, water is 10-100 part, separately adds pH adjusting agent appropriate.
Its preparation method can be: added by Berbamine hydrochloride hydrate in appropriate water for injection, add solubility promoter, stir, examination is dissolved, add oxidation inhibitor, sanitas, osmotic pressure regulator, stablizer, pH adjusting agent, water, stirs, and becomes solution shape, make pH=5.0-7.0, filter in the mode such as millipore filtration or ultrafiltration, detect, aseptic subpackaged in sterilized clean plastics eyedrops bottle and get final product.
Berbamine hydrochloride hydrate injection, its preparation method is:
The preparation method of freeze-dried powder is: get Berbamine hydrochloride hydrate, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, injects with water, add pharmaceutically acceptable soda acid, be stirred to dissolve, regulate pH to be 2.0 ~ 5.5, add activated carbon 0.005 ~ 0.5%(W/V) stir 15 ~ 45min, filter, moisturizing, sterile filtration, by 20 ~ 600mg/ bottle (in main ingredient) packing, lyophilize, tamponade, obtains finished product.
Berbamine hydrochloride hydrate injection with small volume and preparation technology thereof: Berbamine 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 ~ 5.5.
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, propionic 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, FUMARIC ACID TECH GRADE, maleic acid, trihydroxy-aminomethane, diethanolamine, thanomin, α-amino isopropyl alcohol, 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 and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and salt, thiolactic acid and pharmaceutical salts thereof, thio-2 acid and salt, phenol compound, as gallic acid and pharmaceutical salts thereof, coffic acid and pharmaceutical salts thereof, forulic acid and pharmaceutical salts thereof, di-t-butyl Pyrogentisinic Acid, 2, 5-resorcylic acid, 2, 5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt, amino acid and its salt, xitix and ascorbate salt, saccharosonic acid and erythorbate, niacinamide, tartrate, nitrate, phosphoric acid salt, 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.
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.
Berbamine hydrochloride hydrate of the present invention, is applicable to prepare following to people or mammiferous promotion leucocyte hyperplasia, the leukopenia caused for a variety of causes, application for medicine aspects such as preventing cancer radiotherapy, Leukocytes after Chemotherapy minimizing, anti-inflammatory, tuberculosis, anti-silicosis, antitumor, hypotensive, anti-myocardial anoxia ischemic, anti-arrhythmias.
Consumption usage: generally, in adult; get the freeze-dried powder of Berbamine hydrochloride hydrate of the present invention 0.020 ~ 0.2g or little liquid drugs injection in 0.9% sodium-chlor or 5 ~ 10% glucose 20 ~ 500 milliliters; do intravenous injection or instillation; every day 1 ~ 2 time; 0.9% sodium-chlor of Berbamine hydrochloride hydrate or the route of administration of 5 ~ 10% glucose great transfusion preparations are intravenous injection, and dosage is the same; Intramuscularly: get medicine 0.020 ~ 0.2g freeze-dried powder of the present invention and be dissolved in water for injection, intramuscularly, every day 1 ~ 2 time; More than children's amount of reducing by half use.Through gastrointestinal administration dosage, be generally oral: 25-100mg/ time, 1-3 times/day, more than children's amount of reducing by half uses.The usage of eye drops: adult's usual amounts 0.1-1% Berbamine hydrochloride hydrate eye drop one time 1 ~ 2, in instillation eyelid, closes order 3 ~ 5 minutes.Every day 1-3 time.
Accompanying drawing explanation
Fig. 1 is the thermal analyses collection of illustrative plates (embodiment 1) of Berbamine hydrochloride 3 hydrate,
Fig. 2 is the thermal analyses collection of illustrative plates (embodiment 2) of Berbamine hydrochloride 3 hydrate,
Fig. 3 is the thermal analyses collection of illustrative plates (embodiment 3) of Berbamine hydrochloride 3.5 hydrate,
Fig. 4 is the X powder diffraction collection of illustrative plates (embodiment 2) of Berbamine hydrochloride 3 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 purity level is separated the compound obtained, and described purity level includes but not limited to be greater than 90%, the purity level of 95%, 96%, 97%, 98% and 99%.Described purity level can pass through high-performance liquid chromatogram determination.
The color of crystalline hydrate that the present invention obtains is the solid between off-white color or pale yellow powder or off-white color-pale yellow powder.
Pharmaceutical composition
" pharmaceutical composition " used herein refers to the composition of medicine, and 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, Berbamine hydrochloride 3 hydrate can optionally and one or more pharmaceutically acceptable mixed with excipients, and can with following form oral administration: tablet, capsule, dispersible powder, granule or the suspensoid containing such as about 0.05-5% suspending agent, or with the form parenteral admin of sterile solution agent or suspensoid, the suspending agent of described suspensoid also containing 0.05-5% in isotonic medium, these pharmaceutical preparations can contain activeconstituents and the carrier of such as about 25% to about 90%, more generally containing 5% to 60%(weight) active ingredient.
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.
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.
Surprisingly, distinctive, have corresponding endotherm(ic)peak under the weightless platform of thermal analyses (TG-DTA or the TG-DSC) collection of illustrative plates of hydrate of the present invention, thermal analyses collection of illustrative plates demonstrates Berbamine hydrochloride crystalline hydrate; It is worthy of note, the thermal analyses collection of illustrative plates of Berbamine hydrochloride hydrate about heats from room temperature, be a platform to TG curvilinear characteristic approximation behavior between 50 DEG C, almost there is no obvious weightlessness, and show as obvious weightlessness at about 50 DEG C to about 145 DEG C, corresponding endotherm(ic)peak is obvious, and Karl_Fischer method test proves that this weightlessness is water molecules.
Powder X-ray diffraction approach
Utilize D/MX-III AX x ray diffractometer x, voltage: 35kv, electric current: 30mA, sweep velocity: 10 °/min, step-length: 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 Berbamine hydrochloride 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 °, measures sample.
In embodiments, powder X-ray diffractometry is utilized to measure, in diffraction angle 2 θ (3-60 °) useful range, Berbamine hydrochloride 3 hydrate of the present invention, 3.5 hydrates can have corresponding eigenwert in the position comprising following 2 θ values:
Embodiment 2(accompanying drawing 4), in the position about 6.37,7.30,9.28,10.32,11.15 of following 2 θ values, 11.67,12.71,13.36,13.80,14.40,15.04,15.64,16.66,17.16,18.30,19.26,19.92,20.71,21.20,23.62,24.61,25.46,26.64,27.14,27.86,29.04,29.97,30.53,31.90,33.45 etc. have characteristic peak
The unsharp place of data on accompanying drawing 4, visible data below, specific as follows in detail:
PEAK:21-pts/ParabolicFilter,Threshold=3.0,Cutoff＝1.0%,BG=3/1.0,Peak-Top=CentroidFit
In another embodiment (embodiment 3), powder X-ray diffractometry is utilized to measure, in diffraction angle 2 θ (3-60 °) useful range, Berbamine hydrochloride 3.5 hydrate of the present invention can have corresponding eigenwert in the position comprising following 2 θ values, about 6.31, 6.84, 7.24, 11.05, 11.61, 12.67, 13.77, 14.31, 14.83, 15.59, 16.56, 17.13, 18.20, 19.02, 19.62, 20.69, 21.13, 21.64, 22.22, 22.68, 23.58, 24.75, 25.37, 25.72, 26.51, 27.08, 27.76, 28.29, 29.26, 30.41, 30.52, 33.37, 37.83.
Specific embodiment
Embodiment 1 Berbamine hydrochloride 3 hydrate be prepared in 250ml flask, add water 60ml, Berbamine hydrate 10g, add 6M hydrochloric acid soln, after being stirred to dissolve, control pH value of solution=about 1.5-3.5, continue stirring about 30 minutes, add proper amount of active carbon, stir, filter, filtrate concentrates, add appropriate Virahol, cooling, place and separate out solid crystal, filter, gained solids make thinner about 30 DEG C dry about 2 days, be placed in the glass desicator being placed with discolour silica gel siccative again to dry under the room temperature of about 20 DEG C, dry 6 hours of about 45 DEG C vacuum (the vacuum meter reading of vacuum drying oven is approximately about 0.08MPa), obtain off-white color to light yellow crystalline powder 8.3g, differentiate: (1) is got product of the present invention and is about 10mg, the 5ml that adds water dissolves, split in two test tubes, bismuth potassium iodide test solution 1 is added in first pipe, namely salmon precipitation is generated, add potassiumiodide iodine test solution 1 in second pipe, namely generate brown precipitate.(2) get product of the present invention and be about 10mg, the 5ml that adds water dissolves, and adds iron trichloride test solution 2 and iron potassuim cyanide test liquid 1, namely aobvious blue.(3) get product of the present invention, add water the solution made containing 40mg in every 1ml, measures, have maximum absorption at the wavelength place of 281nm according to spectrophotometry (China's coastal port two annex IVA); ESI-MS:m/z:609 ［ M+H-2HCl ］
+; Infrared spectra: ν
kBr maxcm
-13393,3038,2942,2799,2842,2707,2630,1610,1588,1514,1439,1419,1355,1280,1218,1170,1115,1081,1062,1019,896,869,843; It is 7.53% that Ka Shi method measures moisture, and thermal analyses collection of illustrative plates: platform weightlessness about 7.44%, this and sample contain the result (theoretical value 7.35%) (see accompanying drawing 1) in limit of error of 3 crystal water.Elemental Analysis theory: C60.41%, H6.58%, N3.81%Cl9.64%; Measured value: C60.29%, H6.69%, N3.94%Cl9.72%.
The preparation of embodiment 2 Berbamine hydrochloride 3 hydrate gets Berbamine 16.1g(by dry product), processing industry ethanol 50ml, water 5ml is in 250ml flask, add the hydrochloric acid soln that concentration is approximately 4M, be stirred to dissolve rear pH value of solution=about 1.2-3.5, continue stirring about 30 minutes, after concentrated, add appropriate Virahol, place, be cooled to about 0 DEG C, place, abundant precipitation to be precipitated, filter, gained solids make thinner about 30 DEG C dry about 2 days, be placed in the glass desicator being placed with discolour silica gel siccative again to dry under the room temperature of about 20 DEG C, about 42 DEG C vacuum-drying 6 hours again, obtain off-white color to faint yellow solid 14.2 grams, with appropriate water, Virahol, ethyl alcohol recrystallization three times, cooling, place, treat that solid is fully separated out, filter, gained solids about 42 DEG C vacuum-dryings 6 hours (vacuum tightness is approximately about 0.08MPa), obtain off-white color solid 7.0 grams, differentiate: (1) is got product of the present invention and is about 10mg, and the 5ml that adds water dissolves, and splits in two test tubes, adds bismuth potassium iodide test solution 1, namely generate salmon precipitation in the first pipe, add potassiumiodide iodine test solution 1 in second pipe, namely generate brown precipitate.(2) get product of the present invention and be about 10mg, the 5ml that adds water dissolves, and adds iron trichloride test solution 2 and iron potassuim cyanide test liquid 1, namely aobvious blue.(3) get product of the present invention, add water the solution made containing 40mg in every 1ml, measures, have maximum absorption at the wavelength place of 281nm according to spectrophotometry (China's coastal port two annex IVA); ESI-MS:m/z:609 ［ M+H-2HCl ］
+; Infrared spectra: ν
kBr maxcm
-13415,3037,2942,2799,2634,1611,1514,1439,1356,1278,1218,1171,1116,1082,1061,1019,896,870,842; It is 7.64% that Ka Shi method measures moisture, thermal analyses TG-DTA: platform weightlessness about 7.44%, and this and sample contain the result (theoretical value 7.35%) (see accompanying drawing, 2) in limit of error of 3 crystal water; X-ray powder diffraction is shown in accompanying drawing 3; Ultimate analysis, theoretical value: C60.41%, H6.58%, N3.81%Cl9.64%; Measured value: C60.32%, H6.67%, N3.96%Cl9.77%.
Berbamine 12.6g is got in the preparation of embodiment 3 Berbamine hydrochloride 3.5 hydrate, add ethanol 50ml, water 5ml is in 250ml flask, add the hydrochloric acid soln that concentration is approximately 6M, be stirred to dissolve rear pH value of solution=about 1.0-3.5, continue stirring about 30 minutes, after concentrated, add appropriate Virahol, place, be cooled to about 0 DEG C, place, abundant precipitation to be precipitated, filter, by the appropriate water of gained solid, Virahol, acetone recrystallization twice, cooling, place, treat that solid is fully separated out, filter, gained solids make thinner about 30 DEG C dry about 1 day, be placed in the glass desicator being placed with discolour silica gel siccative again to dry under the room temperature of about 20 DEG C, dry 6 hours of gained solids about 42 DEG C, obtain off-white color solid 6.1 grams, differentiate: (1) is got product of the present invention and is about 10mg, and the 5ml that adds water dissolves, and splits in two test tubes, adds bismuth potassium iodide test solution 1, namely generate salmon precipitation in the first pipe, add potassiumiodide iodine test solution 1 in second pipe, namely generate brown precipitate.(2) get product of the present invention and be about 10mg, the 5ml that adds water dissolves, and adds iron trichloride test solution 2 and iron potassuim cyanide test liquid 1, namely aobvious blue.(3) get product of the present invention, add water the solution made containing 40mg in every 1ml, measures, have maximum absorption at the wavelength place of 281nm according to spectrophotometry (China's coastal port two annex IVA); ESI-MS:m/z:609 ［ M+H-2HCl ］
+; Infrared spectra: ν
kBr maxcm
-13423,2942,2841,2633,1609,1589,1515,1453,1439,1421,1384,1357,1274,1250,1220,1169,1117,1083,1065,1020,984,895,874,839,808; It is 8.58% that Ka Shi method measures moisture, thermal analyses TG-DTA: platform weightlessness about 8.37%(is shown in accompanying drawing 3), this and sample contain the result (theoretical value 8.47%) of 3.5 crystal water in limit of error; Ultimate analysis, theoretical value: C59.67%, H6.63%, N3.76%Cl9.52%; Measured value: C59.73%, H6.70%, N3.83%Cl9.64%; Powder x-ray diffraction: there is corresponding eigenwert, about 6.31,6.84,7.24,11.05,11.61 in the position comprising following 2 θ values, 12.67,13.77,14.31,14.83,15.59,16.56,17.13,18.20,19.02,19.62,20.69,21.13,21.64,22.22,22.68,23.58,24.75,25.37,25.72,26.51,27.08,27.76,28.29,29.26,30.41,30.52,33.37,37.83.
Embodiment 4 gets Berbamine hydrochloride 3 hydrate 20g, add glucose or N.F,USP MANNITOL or Xylitol 2.0 ~ 5g to add fresh water for injection 420ml and stir, with phosphoric acid or and the sodium hydroxide solution of 1M regulate pH to be 3.0 ~ 5.0, make to be dissolved into solution, add activated carbon 0.01 ~ 0.5%(W/V) stir 15 ~ 45min, filter, moisturizing to 500ml, with 0.22 micrometer Millipore membrane filtration, by 50mg/ bottle, 100mg/ bottle or 200mg/ bottle (in main ingredient) packing, lyophilize, tamponade, obtains finished product.
Embodiment 5 gets Berbamine hydrochloride 3 hydrate 20g, with N.F,USP MANNITOL 40g, add 40-60 DEG C of water for injection 430ml to stir, with the Citric Acid of 1M or and sodium hydroxide regulate pH to be 3.0 ~ 5.0, make to be dissolved into solution, add activated carbon 0.01 ~ 0.5%(W/V) stir 15 ~ 45min, filter, moisturizing is to 500ml, the ultrafiltration membrance filter of relative molecular mass 1000-8000 is retained with 0.22 micrometer Millipore membrane filtration or employing, by 50,100mg/ bottle or 200mg/ bottle (by Berbamine hydrochloride 3 hydrated basis) packing, lyophilize, tamponade, obtains finished product.
The little hydro-acupuncture preparation of embodiment 6 prepare Berbamine hydrochloride hydrate 10.2g (standby or embodiment 2 method of embodiment 1 legal system or embodiment 3 method), add cysteine hydrochloride 0.8g, EDETATE SODIUM 0.1g, injecting blunges makes dissolving, 2M lactic acid and Sodium.alpha.-hydroxypropionate regulate pH to be 3.0 ~ 4.5, add activated carbon 0.01%(W/V) stir 15 ~ 45min, filter, moisturizing is to 500ml, the ultrafiltration membrance filter of relative molecular mass 3000-8000 is retained with 0.22 micrometer Millipore membrane filtration or employing, by the packing of 5ml/ bottle, sterilizing obtains finished product.
Embodiment 7 Berbamine hydrochloride 3 hydrate 10g, inject and stir with water 400ml, with phosphoric acid or and the sodium hydroxide solution of 1M regulate pH to be 2.0 ~ 4.0, make to be dissolved into solution, add activated carbon 0.01%(W/V) stir 15 ~ 45min, filter, moisturizing, to 500ml, retains the ultrafiltration membrance filter of relative molecular mass 3000-10000 with 0.22 micrometer Millipore membrane filtration or employing, by the packing of 5ml/ bottle, lyophilize, tamponade, obtains finished product.
The preparation of embodiment 8 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, standby or embodiment 2 method or embodiment 3 method by Berbamine hydrochloride hydrate embodiment 1 legal system) 10.1g, dissolve completely with fresh water for injection, mix with above-mentioned filtrate, add L-cysteine hydrochloride 1g, EDETATE SODIUM 0.2g, 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 0.01%, about heated and stirred 10-30 minute, filtering decarbonization, the ultrafiltration membrance filter of relative molecular mass 3000-2000 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, finished product inspection, pack and get final product.
The preparation of embodiment 9 Berbamine hydrochloride hydrate sodium-chlor transfusion: by Berbamine hydrochloride hydrate 10g (standby or embodiment 2 method of embodiment 1 legal system or embodiment 3 method), sodium-chlor 85g, Sodium Pyrosulfite 1.1g, EDETATE SODIUM 0.2g, 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, finished product inspection, pack and get final product.
Embodiment 10 Berbamine hydrochloride 3 hydrate tablet (50mg/ sheet)
Berbamine hydrochloride 3 hydrate (embodiment 1 method or embodiment 2 method), Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves, 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, inspection, packaging.
Embodiment 11 Berbamine hydrochloride hydrate capsule (100mg/ grain)
Berbamine hydrochloride hydrate (standby or embodiment 2 method of embodiment 1 legal system or embodiment 3 method), Microcrystalline Cellulose, lactose are crossed 100 mesh sieves, 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.
The granule (100mg/ wraps, by Berbamine hydrochloride 3 hydrated basis) of embodiment 12 Berbamine hydrochloride 3 hydrate
Berbamine hydrochloride 3 hydrate (embodiment 2 legal system is standby), N.F,USP MANNITOL, lactose, Sodium Cyclamate, food flavour are crossed 100 mesh sieves, PVP K-30 aqueous ethanolic solution with 8% softwood processed in right amount, cross 18-24 mesh sieve to granulate, less than 60 DEG C dry, added the xanthan gum of 100 mesh sieves, after crossing the whole grain of 14-20 mesh sieve, mixing, added the xanthan gum of 100 mesh sieves, point packaging.
The eye drop of embodiment 13 acid hydrochloride salt Berbamine 3 hydrate
By Berbamine hydrochloride 3 hydrate 5g (embodiment 2 legal system is standby), glycerine 10ml, PVP K-30 2g, add the water for injection that people is appropriate, after stirring makes it dissolve, again by sodium bisulfite 0.6g, EDETATE SODIUM 0.3g, 5% Benza 1ml, sodium-chlor 3.1g adds people in above-mentioned solution, be stirred to dissolve, 5.0-7.0 is adjusted to sodium hydrogen phosphate and disodium phosphate soln, then people's water for injection is added to 500ml, stir, detect, with 0.22-0.45 μm of filtering with microporous membrane to clear and bright, be sub-packed in sterilized clean eyedrops bottle, sterilizing, let cool, obtain.
Be appreciated that the change of a lot of details is possible, therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to above-described embodiment.
Claims (9)
1. isoquinoline class derivate, is characterized in that: isoquinoline class derivate is Berbamine hydrochloride crystalline hydrate, and its molecular formula is C
37h
40n
2o
62HClnH
2o, wherein n=3.0,3.5.
2. isoquinoline class derivate according to claim 1, is characterized in that: isoquinoline class derivate is Berbamine hydrochloride 3 hydrate.
3. Berbamine hydrochloride 3 hydrate according to claim 2, it is characterized in that: utilize powder X-ray diffractometry to measure, at diffraction angle 2 θ, in the useful range of 3-60 °, in the position of following 2 θ values, there is corresponding eigenwert: 6.37, 7.30, 9.28, 10.32, 11.15, 11.67, 12.71, 13.36, 13.80, 14.40, 15.04, 15.64, 16.66, 17.16, 18.30, 19.26, 19.92, 20.71, 21.20, 23.62, 24.61, 25.46, 26.64, 27.14, 27.86, 29.04, 29.97, 30.53, 31.90, 33.45.
4. isoquinoline class derivate according to claim 1, is characterized in that: isoquinoline class derivate is Berbamine hydrochloride 3.5 hydrate.
5. Berbamine hydrochloride 3.5 hydrate according to claim 4, it is characterized in that: utilize powder X-ray diffractometry to measure, at diffraction angle 2 θ, in the useful range of 3-60 °, in the position of following 2 θ values, there is corresponding eigenwert: 6.31, 6.84, 7.24, 11.05, 11.61, 12.67, 13.77, 14.31, 14.83, 15.59, 16.56, 17.13, 18.20, 19.02, 19.62, 20.69, 21.13, 21.64, 22.22, 22.68, 23.58, 24.75, 25.37, 25.72, 26.51, 27.08, 27.76, 28.29, 29.26, 30.41, 30.52, 33.37, 37.83.
6. prepare isoquinoline class derivate as claimed in claim 1, it is characterized in that:
By Berbamine, be added to the water of 2-12 times amount, C
1-C
6low mass molecule alcohol in one or more reaction vessels in, add hydrochloric acid soln, be stirred to dissolve, between adjust ph to 1.0-3.5, add proper amount of active carbon, stir, filter, filtrate is concentrated, in filtrate, adds C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone in one or more, cooling, make crystallization, filter, by gained solid drying, obtain Berbamine hydrochloride crystalline hydrate; By gained Berbamine hydrochloride crystalline hydrate water and C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone in one or more, one or many recrystallization operation can be carried out further.
7. in isoquinoline class derivate preparation method as claimed in claim 6, its crystallization or recrystallization solvent are selected from: one or more in water and methyl alcohol, ethanol, Virahol, acetone, hexone.
8. the purposes of isoquinoline class derivate according to claim 1, it is characterized in that: be applicable to preparation injection freeze-dried powder or little water needle injection, great transfusion preparation, application on gastrointestinal administration preparation, dosing eyes preparation, be wherein selected from tablet, capsule, granule through gastrointestinal administration preparation.
9. the purposes of isoquinoline class derivate according to claim 1, is characterized in that: be applicable to prepare following to the application in the caused treatment of humans and animals disease or the medicine of prevention: for the preparation of the application promoted in the medicine of leucocyte hyperplasia, preventing cancer radiotherapy, Leukocytes after Chemotherapy minimizing, anti-inflammatory, tuberculosis, anti-silicosis, antitumor, hypotensive, anti-myocardial anoxia ischemic, antiarrhythmic treatment or prevention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210521407.XA CN103012421B (en) | 2012-12-06 | 2012-12-06 | Iloquinoline derivative medicine and preparation thereof and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210521407.XA CN103012421B (en) | 2012-12-06 | 2012-12-06 | Iloquinoline derivative medicine and preparation thereof and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012421A CN103012421A (en) | 2013-04-03 |
| CN103012421B true CN103012421B (en) | 2016-01-20 |
Family
ID=47961573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210521407.XA Expired - Fee Related CN103012421B (en) | 2012-12-06 | 2012-12-06 | Iloquinoline derivative medicine and preparation thereof and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012421B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113908160A (en) * | 2021-11-29 | 2022-01-11 | 深圳市第三人民医院(深圳市肝病研究所) | Application of berbamine in anti-mycobacterium tuberculosis drugs |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181932A (en) * | 1996-11-07 | 1998-05-20 | 何浩 | Berbamine used as medicine for preventing and curing cataract |
| US20100298369A1 (en) * | 2009-05-19 | 2010-11-25 | David Horne | Berbamine derivatives |
| CN102002074A (en) * | 2010-11-18 | 2011-04-06 | 浙江大学 | Chemical modification method for glycosylated berbamine new molecule of traditional Chinese medicine berbamine |
| WO2012025054A1 (en) * | 2010-08-27 | 2012-03-01 | 杭州本生药业有限公司 | Diimidated derivative of berbamine, and preparation method therefor and use thereof |
-
2012
- 2012-12-06 CN CN201210521407.XA patent/CN103012421B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181932A (en) * | 1996-11-07 | 1998-05-20 | 何浩 | Berbamine used as medicine for preventing and curing cataract |
| US20100298369A1 (en) * | 2009-05-19 | 2010-11-25 | David Horne | Berbamine derivatives |
| WO2012025054A1 (en) * | 2010-08-27 | 2012-03-01 | 杭州本生药业有限公司 | Diimidated derivative of berbamine, and preparation method therefor and use thereof |
| CN102002074A (en) * | 2010-11-18 | 2011-04-06 | 浙江大学 | Chemical modification method for glycosylated berbamine new molecule of traditional Chinese medicine berbamine |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸小檗胺的提取及精制;温普红，等;《西北大学学报(自然科学版)》;20011231;第31卷(第6期);第489-491页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012421A (en) | 2013-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103209967B (en) | Meglumine salt of 6-fluoro-3-hydroxy-2-pyrazine carboxamide | |
| JP5479912B2 (en) | Amorphous form of heterocyclic compound, solid dispersion containing the same, drug, and method for producing the same | |
| US6258821B1 (en) | Compositions comprising trimetrexate and methods of their synthesis and use | |
| CA2874815C (en) | Pharmaceutical compositions comprising rifaximin and amino acids, preparation method and use thereof. | |
| TW201039865A (en) | Lyophilized preparations of proteasome inhibitors | |
| CN102180890B (en) | Cefathiamidine hydrate and preparation method and application thereof | |
| CN101633683B (en) | Antihepatitis medicament, preparation method thereof and use thereof | |
| BR112012009660B1 (en) | liposome having internal water phase containing sulfobutyl ether cyclodextrin salt, its preparation process, its use and liposomal pharmaceutical preparation | |
| CN102180889A (en) | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof | |
| CN104628796A (en) | Gastrodin medicine, and composition and use thereof | |
| CN103012421B (en) | Iloquinoline derivative medicine and preparation thereof and purposes | |
| US9475759B2 (en) | Tigecycline crystalline hydrate and preparation method therefor and use thereof | |
| CN110384803B (en) | Application of macrocyclic host molecule as drug solubilizer | |
| CN104803860A (en) | Ambroxol hydrochloride compound and medicine composition thereof | |
| CN102250123B (en) | Cefodizime sodium hydrate and application thereof | |
| CN105566316A (en) | Dibenzo quinolizine compound entity and application thereof | |
| CN105837646A (en) | Flavonoid new chemical entity, composition and use | |
| CN101525360A (en) | Hydrates of macrolides organic acid salts, preparation and application thereof | |
| CN102911226B (en) | Erythromycin octadecanoate compounds thing entity and uses thereof | |
| CN102212074A (en) | Cefonicid sodium hydrate and preparation method and application thereof | |
| TW202140006A (en) | Novel medicament for treating hepatic encephalopathy | |
| CN103183722A (en) | Glyoxalase I inhibitor, preparation method and medical application thereof | |
| CN110551038B (en) | Novel antitumor compounds and uses thereof | |
| CN108264465B (en) | Dapoxetine hydrochloride monohydrate, preparation method and application thereof | |
| KR20160115827A (en) | Preparation comprising indole compound and process for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160120 Termination date: 20191206 |