CN103613633A - Ammonium glycyrrhizinate compound and pharmaceutical composition containing ammonium glycyrrhizinate - Google Patents
Ammonium glycyrrhizinate compound and pharmaceutical composition containing ammonium glycyrrhizinate Download PDFInfo
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- -1 Ammonium glycyrrhizinate compound Chemical class 0.000 title claims abstract description 54
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 28
- 229940079593 drug Drugs 0.000 claims abstract description 21
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 17
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960001305 cysteine hydrochloride Drugs 0.000 claims abstract description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 15
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 5
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 29
- 239000012046 mixed solvent Substances 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 24
- 239000007924 injection Substances 0.000 claims description 16
- 238000002347 injection Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 238000005262 decarbonization Methods 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000009413 insulation Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- USOFGNNPVJLTIU-UHFFFAOYSA-K trisodium chloride sulfite Chemical compound [Cl-].[Na+].[Na+].S(=O)([O-])[O-].[Na+] USOFGNNPVJLTIU-UHFFFAOYSA-K 0.000 claims description 5
- 238000003556 assay Methods 0.000 claims description 4
- 229960002433 cysteine Drugs 0.000 claims description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 4
- 235000018417 cysteine Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 17
- 238000004090 dissolution Methods 0.000 abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract 2
- 229940101006 anhydrous sodium sulfite Drugs 0.000 abstract 1
- 229940124274 edetate disodium Drugs 0.000 abstract 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 abstract 1
- 238000000691 measurement method Methods 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- 208000006454 hepatitis Diseases 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- 206010008909 Chronic Hepatitis Diseases 0.000 description 9
- 231100000283 hepatitis Toxicity 0.000 description 6
- 229910017488 Cu K Inorganic materials 0.000 description 5
- 229910017541 Cu-K Inorganic materials 0.000 description 5
- 206010019759 Hepatitis chronic persistent Diseases 0.000 description 5
- 230000005260 alpha ray Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010019755 Hepatitis chronic active Diseases 0.000 description 2
- 206010019799 Hepatitis viral Diseases 0.000 description 2
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 2
- 229940087511 calcium disodium versenate Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 201000001862 viral hepatitis Diseases 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019842 Hepatomegaly Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 206010041519 Spider naevus Diseases 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 231100000354 acute hepatitis Toxicity 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 229940119744 dextran 40 Drugs 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 238000007449 liver function test Methods 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of a medicine, and particularly relates to an ammonium glycyrrhizinate compound and a pharmaceutical composition containing the ammonium glycyrrhizinate compound. The ammonium glycyrrhizinate compound disclosed by the invention is crystal, and is determined by a powder X-ray diffraction measurement method, the molecular formula is C42H65NO16.2H2O; an X-ray powder diffraction pattern represented by a diffraction angle of 2theta+/-0.2 degrees is shown in the figure 1. The pharmaceutical composition provided by the invention contains the ammonium glycyrrhizinate compound disclosed by the invention, cysteine hydrochloride and pharmaceutical acceptable auxiliary materials, and preferably comprises the following components in parts by weight: 1-200 parts of ammonium glycyrrhizinate, 1-200 parts of cysteine hydrochloride, 1-1,000 parts of sodium chloride, 1-200 parts of anhydrous sodium sulfite and 1-100 parts of edetate disodium. The ammonium glycyrrhizinate compound disclosed by the invention has good solubility in water, and is fast in dissolution rate, good in redissolution ability, and convenient to use, and the medication safety of a sufferer is greatly improved.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of monoammonium glycyrrhizinate compound and containing the pharmaceutical composition of monoammonium glycyrrhizinate.
Background technology
Hepatitis is a kind of common disease and frequently-occurring disease, and according to incompletely statistics, China's hepatitis and virus carrier account for 10% of total population.Wherein take viral hepatitis as main, and viral hepatitis can be divided into type: acute hepatitis, chronic hepatitis, hepatitis gravis and courage type hepatitis.Chronic hepatitis can be again chronic persistent hepatitis and active hepatitis two classes:
(1) chronic persistent hepatitis: the delay of the anicteric hepatitis course of disease surpasses half a year, is chronic persistent hepatitis.The course of disease is lighter, has slight weak and symptom of digestive tract, dull pain in liver, the lighter's enlargement, liver function mile abnormality or recurrent fluctuations.The sustainable several months of chronic persistent hepatitis, to the several years, through suitably treatment, can get well mostly.
(2) active hepatitis: hepatitis symptom is obvious, continues or outbreak repeatedly, and weak, symptom of digestive tract is obvious, has hepatic face, jaundice, and hepatomegaly, moderate hardness, splenomegaly, can have liver palms, spider angioma etc.Liver function test, serum paddy the third ammonia enzyme reactivity continues or repeatedly raises, and sphaeroprotein increases, and albumin reduces, can be with the outer multisystem infringement of liver, as sacroiliitis, ephritis, fash etc.
Although it is many that the medicine of current treatment hepatopathy has, and because the pathogenesis of hepatopathy is not illustrated completely, mostly is and improves liver function, promotes liver cell regeneration, strengthens the medicine of the functions such as detoxification ability of liver.
The liver-protecting medicine product that have a kind of Qianglining injection by name on domestic market, it is in nineteen fifty at Japan's prescription first, and this composition is: monoammonium glycyrrhizinate, L-cysteine hydrochloride, glycine, the effect that have protection liver cell, recovers liver function.It is generally small-volume injection, can add glucose and instil, owing to cannot solving the unsettled problem of bulk capacity injection (infusion solutions).
Application number is that 201010113018.4 Chinese patent application discloses a kind of compound monoammonium glycyrrhizinate S pharmaceutical composition and method for preparing high-capacity injection thereof.Described composition is compound monoammonium glycyrrhizinate S sodium chloride injection, it consists of: monoammonium glycyrrhizinate S 40-160g, cysteine hydrochloride 30-120g, glycine 400-1600g, sodium sulphite anhydrous 99.3 40-160g, Trisodium Citrate 4-16g, sodium-chlor 900-1800g, sodium hydroxide is appropriate, and water for injection adds to 100-200L.
Application number is that 03157562.5 Chinese patent application discloses a kind of hepatic pharmaceutical composition, Its Preparation Method And Use.Described hepatic pharmaceutical composition comprises that following component and proportioning are the medicament that raw material is made: 1～200 part of monoammonium glycyrrhizinate, 1～200 part of L-cysteine hydrochloride, and one or more the mixing in sodium-chlor, sodium sulphite anhydrous 99.3 and Calcium Disodium Versenate, wherein sodium-chlor is 1～1000 part, 1～200 part of sodium sulphite anhydrous 99.3,1～100 part of Calcium Disodium Versenate; Also disclosing hepatic pharmaceutical composition is compound preparation, can be used for anti-liver poisoning, reduces gpt, recovers hepatocyte function; Mainly for the preparation for the treatment of chronic persistent hepatitis, the medicine of the diseases such as chronic active hepatitis.
Yet the monoammonium glycyrrhizinate adopting in preparation of the prior art water-soluble poor, is only soluble in hot water, is insoluble in hot water.In order to find the monoammonium glycyrrhizinate compound that a kind of performance is more good, special proposition the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of monoammonium glycyrrhizinate compound, and the solubleness of described monoammonium glycyrrhizinate compound in water is higher, and the dissolution rate in water is very fast.
The second object of the present invention is to provide the preparation method of above-mentioned monoammonium glycyrrhizinate compound.
The 3rd object of the present invention is to provide the pharmaceutical composition that contains above-mentioned monoammonium glycyrrhizinate compound.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A monoammonium glycyrrhizinate compound, described monoammonium glycyrrhizinate compound is crystal, its molecular formula is C
42h
65nO
162H
2o, described monoammonium glycyrrhizinate compound is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is as shown in Figure 1.
Same bulk drug, different solid inner molecule arranging structures causes its lattice energy different, the difference in size of lattice energy has reflected lattice varying in size to the binding force of molecule, this means that the physicals of compound when different crystal forms is also different, as the dissolution rate of compound when the different crystal forms, stability, solubleness, also each is variant, so the same compound of different crystal forms can have different apparent solubilities and dissolution rate, this has great meaning to improving the solubility property of insoluble chemical compound.
The invention provides a kind of brand-new monoammonium glycyrrhizinate compound, this monoammonium glycyrrhizinate compound has brand-new solid interior molecule arranging structure, compare with the monoammonium glycyrrhizinate of prior art, lattice weakens the binding force of monoammonium glycyrrhizinate molecule provided by the invention, monoammonium glycyrrhizinate molecule is more easily shaken off out and is entered in solvent from lattice, and monoammonium glycyrrhizinate compound provided by the invention has larger solubleness.Contriver tests by solubility property, and result shows that monoammonium glycyrrhizinate Compound Phase provided by the present invention is for monoammonium glycyrrhizinate of the prior art, and the solubleness in water is larger, and dissolution rate is faster, has better solubility property.
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for described monoammonium glycyrrhizinate compound, the method is:
The single ammonium bulk drug of extracting Radix Glycyrrhizae acid, adds the mixed solvent of DMF/ethanol, and the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:6～10ml, then adds gac, whip attachment, and filtering decarbonization degerming, obtains settled solution; 2～the 3h that refluxes under 45～50 ℃ of conditions, is cooled to 30～40 ℃, insulation, and drip chloroform under agitation condition, drip follow-up continuous insulated and stirred 20～30min, stop stirring, be cooled to 0～5 ℃, at this temperature standing 2～6 hours, filter, by washing with alcohol, drying under reduced pressure, obtains.
The inventor is through test repeatedly, with commercially available monoammonium glycyrrhizinate (C
42h
65nO
162H
2o) bulk drug is raw material, constantly change and comprise the test conditionss such as pressure, temperature, solvent, pH, anti-solvent, finally obtain a kind of brand-new monoammonium glycyrrhizinate compound, its X-RD spectrogram shows, the solid interior molecule arranging structure of monoammonium glycyrrhizinate compound provided by the invention is different from monoammonium glycyrrhizinate of the prior art.
In preparation method of the present invention, wherein, in described mixed solvent, the volume ratio of DMF and ethanol is 1:3～5.
The volume ratio of described chloroform and mixed solvent is 3～7:1.
The speed of described stirring is 25～30r/min.
In the present invention, described monoammonium glycyrrhizinate is commercially available monoammonium glycyrrhizinate S bulk drug, and its molecular formula is C
42h
65nO
162H
2o.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition contains monoammonium glycyrrhizinate compound of the present invention, cysteine hydrochloride and pharmaceutically acceptable auxiliary material.
The present invention is by changing the solid interior molecule arranging structure of monoammonium glycyrrhizinate compound, the monoammonium glycyrrhizinate compound obtaining has better solubility property, dissolution rate is fast, the pharmaceutical composition made from this monoammonium glycyrrhizinate compound is more soluble in water, and solubleness is larger, this had both been conducive to composition and had carried out compatibility, was conducive to again stripping and the absorption of monoammonium glycyrrhizinate in patient body, had improved the bioavailability of monoammonium glycyrrhizinate.
In pharmaceutical composition of the present invention, described pharmaceutically acceptable auxiliary material is one or more mixing in sodium-chlor, sodium sulphite anhydrous 99.3 or Zonon D.
Described pharmaceutical composition by weight, comprises 1～100 part of 1～200 part of monoammonium glycyrrhizinate, 1～200 part of cysteine hydrochloride, 1～1000 part, sodium-chlor, 1～200 part of sodium sulphite anhydrous 99.3 and Zonon D;
Preferably, 1～100 part of monoammonium glycyrrhizinate, 1～50 part of cysteine hydrochloride, 400～1000 parts, sodium-chlor, 1～50 part of sodium sulphite anhydrous 99.3 and Zonon D are 1～20 part;
More preferably, 10～80 parts of monoammonium glycyrrhizinates, 20～40 parts of cysteine hydrochlorides, 600～900 parts, sodium-chlor, 1～50 part of sodium sulphite anhydrous 99.3 and Zonon D are 1～20 part;
Most preferably, 60 parts of monoammonium glycyrrhizinates, 30 parts of cysteine hydrochlorides, 850 parts, sodium-chlor, 30 parts of sodium sulphite anhydrous 99.3s and Zonon D are 3 parts.
Pharmaceutical composition of the present invention can be prepared into pharmaceutically acceptable formulation, and the present invention is preferably bulk capacity injection, small-volume injection or lyophilized injectable powder, more preferably bulk capacity injection.
The various formulations of pharmaceutical composition of the present invention can be prepared with reference to the similar formulation of prior art, and pay more creative work without those skilled in the art, can obtain the various formulations of pharmaceutical composition of the present invention.
Compared with prior art, monoammonium glycyrrhizinate provided by the present invention and pharmaceutical composition tool thereof have the following advantages:
(1) solubleness of monoammonium glycyrrhizinate compound of the present invention in water is high, and dissolution rate is fast, and solubility is good;
(2) monoammonium glycyrrhizinate pharmaceutical composition solubility of the present invention is good, and dissolution rate is fast, easy to use, has greatly improved patient's drug safety.
Accompanying drawing explanation
Fig. 1 is the X-powdery diffractometry spectrogram of the monoammonium glycyrrhizinate compound of the embodiment of the present invention 1 preparation.
Embodiment
With embodiment, further describe the present invention below, be conducive to the present invention and advantage thereof, understand to better effects if, but described embodiment is only for illustrating the present invention rather than restriction the present invention.
The preparation of embodiment 1, monoammonium glycyrrhizinate compound
Single ammonium (the C of extracting Radix Glycyrrhizae acid
42h
65nO
162H
2o) bulk drug 50g, add N, the mixed solvent of dinethylformamide/ethanol, wherein the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:6ml, and in mixed solvent, the volume ratio of DMF and ethanol is 1:3, add again 0.10g gac, whip attachment, filtering decarbonization degerming, obtains settled solution.The 2h that refluxes under 45 ℃ of conditions, is cooled to 30 ℃, insulation, and drip chloroform under the condition of stir speed (S.S.) 25r/min, the volume ratio of described chloroform and mixed solvent is 3:1, drips follow-up continuous insulated and stirred 20min, then stops stirring, be cooled to 0 ℃, at this temperature standing 2 hours, filter, by washing with alcohol three times, drying under reduced pressure 3h, obtains.
The X-ray powder diffraction spectrogram that the monoammonium glycyrrhizinate use Cu-K alpha-ray obtaining measures as shown in Figure 1.
The preparation of embodiment 2, monoammonium glycyrrhizinate compound
Single ammonium (the C of extracting Radix Glycyrrhizae acid
42h
65nO
162H
2o) bulk drug 50g, add N, the mixed solvent of dinethylformamide/ethanol, wherein the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:10ml, and in mixed solvent, the volume ratio of DMF and ethanol is 1:5, add again 0.10g gac, whip attachment, filtering decarbonization degerming, obtains settled solution.The 3h that refluxes under 50 ℃ of conditions, is cooled to 40 ℃, insulation, and drip chloroform under the condition of stir speed (S.S.) 30r/min, the volume ratio of described chloroform and mixed solvent is 7:1, drips follow-up continuous insulated and stirred 30min, then stops stirring, be cooled to 5 ℃, at this temperature standing 6 hours, filter, by washing with alcohol three times, drying under reduced pressure 3h, obtains.
The X-ray powder diffraction spectrogram that the monoammonium glycyrrhizinate obtaining is used Cu-K alpha-ray to measure is consistent with embodiment 1.
The preparation of embodiment 3, monoammonium glycyrrhizinate compound
Single ammonium (the C of extracting Radix Glycyrrhizae acid
42h
65nO
162H
2o) bulk drug 50g, add N, the mixed solvent of dinethylformamide/ethanol, wherein the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:8ml, and in mixed solvent, the volume ratio of DMF and ethanol is 1:4, add again 0.10g gac, whip attachment, filtering decarbonization degerming, obtains settled solution.The 2.5h that refluxes under 47 ℃ of conditions, is cooled to 34 ℃, insulation, and drip chloroform under the condition of stir speed (S.S.) 28r/min, the volume ratio of described chloroform and mixed solvent is 5:1, drips follow-up continuous insulated and stirred 25min, then stops stirring, be cooled to 2 ℃, at this temperature standing 3 hours, filter, by washing with alcohol three times, drying under reduced pressure 3h, obtains.
The X-ray powder diffraction spectrogram that the monoammonium glycyrrhizinate obtaining is used Cu-K alpha-ray to measure is consistent with embodiment 1.
The preparation of embodiment 4, monoammonium glycyrrhizinate compound
Single ammonium (the C of extracting Radix Glycyrrhizae acid
42h
65nO
162H
2o) bulk drug 50g, add N, the mixed solvent of dinethylformamide/ethanol, wherein the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:7ml, and in mixed solvent, the volume ratio of DMF and ethanol is 1:4.5, add again 0.10g gac, whip attachment, filtering decarbonization degerming, obtains settled solution.The 2.8h that refluxes under 48 ℃ of conditions, is cooled to 35 ℃, insulation, and drip chloroform under the condition of stir speed (S.S.) 26r/min, the volume ratio of described chloroform and mixed solvent is 6:1, drips follow-up continuous insulated and stirred 28min, then stops stirring, be cooled to 3 ℃, at this temperature standing 4 hours, filter, by washing with alcohol three times, drying under reduced pressure 3h, obtains.
The X-ray powder diffraction spectrogram that the monoammonium glycyrrhizinate obtaining is used Cu-K alpha-ray to measure is consistent with embodiment 1.
The preparation of embodiment 5, monoammonium glycyrrhizinate compound
Single ammonium (the C of extracting Radix Glycyrrhizae acid
42h
65nO
162H
2o) bulk drug 50g, add N, the mixed solvent of dinethylformamide/ethanol, wherein the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:8.5ml, and in mixed solvent, the volume ratio of DMF and ethanol is 1:3.2, add again 0.10g gac, whip attachment, filtering decarbonization degerming, obtains settled solution.The 2.2h that refluxes under 49 ℃ of conditions, is cooled to 38 ℃, insulation, and drip chloroform under the condition of stir speed (S.S.) 27r/min, the volume ratio of described chloroform and mixed solvent is 6.5:1, drips follow-up continuous insulated and stirred 22min, then stops stirring, be cooled to 1 ℃, at this temperature standing 4.5 hours, filter, by washing with alcohol three times, drying under reduced pressure 3h, obtains.
The X-ray powder diffraction spectrogram that the monoammonium glycyrrhizinate obtaining is used Cu-K alpha-ray to measure is consistent with embodiment 1.
FORMULATION EXAMPLE 1, composite monoammonium glycyrrhizinate bulk capacity injection
Prescription:
Preparation method:
Take monoammonium glycyrrhizinate 150g, cysteine hydrochloride 75g, sodium-chlor 2125g, sodium sulphite anhydrous 99.3 75g and the Zonon D 7.5g(of embodiment 1 in order to prepare 1000 bottles of 250ml specification bulk capacity injections) standby.In dense preparing tank, add the water for injection of 125 liters 90 ℃, in dense preparing tank, add Zonon D, cysteine hydrochloride, sodium-chlor, sodium sulphite anhydrous 99.3 and monoammonium glycyrrhizinate, fully stir and make to dissolve completely, by 0.02% of preparation cumulative volume, add gac, heat 90 ℃, be incubated 20 minutes, be cooled to 40 ℃, liquid decarbonization filtering, to dilute preparing tank, is mended to the dosing amount that injects water in dilute preparing tank, and adjusting pH is 6.5 ± 0.1, liquid is again through end-filtration, embedding is in infusion bottle, and sterilizing, obtains great transfusion preparation.
FORMULATION EXAMPLE 2, composite monoammonium glycyrrhizinate small-volume injection
Prescription:
Preparation method:
Take monoammonium glycyrrhizinate 200g, cysteine hydrochloride 155g, sodium-chlor 800g, sodium sulphite anhydrous 99.3 200g and the Zonon D 20g(of embodiment 2 in order to prepare 100000ml small-volume injection) standby.In dense preparing tank, add 500 liters of 85 ℃ of waters for injection, in dense preparing tank, add Zonon D, cysteine hydrochloride, sodium-chlor, sodium sulphite anhydrous 99.3 and monoammonium glycyrrhizinate, fully stir and make to dissolve completely, by 0.04% of preparation cumulative volume, add gac, heat 80 ℃, be incubated 20 minutes, be cooled to 45 ℃, liquid decarbonization filtering, to dilute preparing tank, is mended to the dosing amount that injects water in dilute preparing tank, adjusting pH is 6.6, liquid is again through end-filtration, and embedding is cutd open in bottle in peace, and during embedding, peace is cutd open bottle by filling nitrogen, sterilizing, obtains small-volume injection.
FORMULATION EXAMPLE 3, composite monoammonium glycyrrhizinate lyophilized injectable powder
Prescription:
Preparation method:
Take monoammonium glycyrrhizinate 8g, cysteine hydrochloride 5g, sodium sulphite anhydrous 99.3 4g and the Zonon D 0.4g(of embodiment 3 in order to prepare 100 lyophilized injectable powders) standby.In preparing tank, add the water for injection of appropriate 80 ℃, add Zonon D, cysteine hydrochloride, sodium sulphite anhydrous 99.3 and monoammonium glycyrrhizinate, be stirred to dissolve, add Dextran 40 as vehicle, mend and inject water to dosing amount, adjust pH to 6.5, after liquid cooling again through end-filtration, carry out degerming filling, lyophilize, makes lyophilized injectable powder product.
Test example 1
This test example detects the related substance in the prepared monoammonium glycyrrhizinate compound crystal of embodiment 1～5, this test is carried out according to 2010 editions second appendix VIII P residual solvent assay method of < < Chinese Pharmacopoeia > >, appendix XIX F medicine impurity analysis governing principle, and it the results are shown in Table 1:
The assay of table 1, related substance
| Preparation | DMF | Ethanol | Chloroform | Other related substance |
| Embodiment 1 product | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 2 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 3 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 4 products | Up to specification | Up to specification | Up to specification | Up to specification |
| Embodiment 5 products | Up to specification | Up to specification | Up to specification | Up to specification |
Test example 2
This test example has been measured monoammonium glycyrrhizinate compound crystal that embodiment of the present invention 1-3 provides and commercially available monoammonium glycyrrhizinate (C by OT-42 method
42h
65nO
162H
2o) solubleness in water.Commercially available monoammonium glycyrrhizinate (C
42h
65nO
162H
2o) be purchased from Wuhan Ding Hui Chemical Co., Ltd..
The solubleness of table 2, different monoammonium glycyrrhizinate compound
From this experimental example, with the monoammonium glycyrrhizinate Compound Phase ratio of prior art, adopt the monoammonium glycyrrhizinate compound crystal that recrystallization method of the present invention obtains in water, to there is extraordinary solubleness.
The prepared monoammonium glycyrrhizinate of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Test example 3
Solubility test
Sample 1 is the product of the embodiment of the present invention 1; Sample 2 is the product of the embodiment of the present invention 2; Sample 3 is commercially available monoammonium glycyrrhizinate (C
42h
65nO
162H
2o) bulk drug, is purchased from Wuhan Ding Hui Chemical Co., Ltd..
Every kind of sample by sample amount, be 50mg at every turn, under envrionment temperature respectively at 15 ℃ and 25 ℃, measure the dissolution time again of 3 kinds of samples, during mensuration, in every bottle, add physiological saline 5ml, after jolting makes to dissolve completely, investigate again the proterties after dissolution time and dissolving.
Table 3, redissolution time and proterties
| ? | Sample 1 | Sample 2 | Sample 3 |
| Proterties | White loose powder | White loose powder | White |
| 10 ℃ of dissolution times again | 10.1s | 9.3s | Can not all dissolve |
| 10 ℃ dissolve rear proterties again | Clear and bright colourless solution | Clear and bright colourless solution | Solution is muddy |
| 25 ℃ of dissolution times again | 7.0s | 6.4s | 27.0s |
| 25 ℃ dissolve rear proterties again | Clear colorless solution | Clear colorless solution | Clear colorless solution |
From this test example, to compare with the monoammonium glycyrrhizinate of prior art, monoammonium glycyrrhizinate prepared by the present invention solubleness in water is high, dissolution rate is fast, during dissolving, do not need to add solubility promoter or adopt other hydrotropy means, easy to use, greatly improved patient's drug safety.
The prepared monoammonium glycyrrhizinate of other embodiment of the present invention has also been carried out to above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a monoammonium glycyrrhizinate compound, is characterized in that, described monoammonium glycyrrhizinate compound is crystal, and its molecular formula is C
42h
65nO
162H
2o, described monoammonium glycyrrhizinate compound is measured by powder x-ray diffraction assay method, and the X-ray powder diffraction collection of illustrative plates representing with 2 θ ± 0.2 ° diffraction angle is as shown in Figure 1.
2. the preparation method of a monoammonium glycyrrhizinate compound claimed in claim 1, the method is: the single ammonium bulk drug of extracting Radix Glycyrrhizae acid, add N, the mixed solvent of dinethylformamide/ethanol, the amount ratio of monoammonium glycyrrhizinate bulk drug and mixed solvent is 1g:6～10ml, then adds gac, whip attachment, filtering decarbonization degerming, obtains settled solution; 2～the 3h that refluxes under 45～50 ℃ of conditions, is cooled to 30～40 ℃, insulation, and drip chloroform under agitation condition, drip follow-up continuous insulated and stirred 20～30min, then stop stirring, be cooled to 0～5 ℃, at this temperature standing 2～6 hours, filter, by washing with alcohol, drying under reduced pressure, obtains.
3. preparation method according to claim 2, is characterized in that, in described mixed solvent, the volume ratio of DMF and ethanol is 1:3～5.
4. preparation method according to claim 2, is characterized in that, the volume ratio of described chloroform and mixed solvent is 3～7:1.
5. preparation method according to claim 2, is characterized in that, the speed of described stirring is 25～30r/min.
6. a pharmaceutical composition, is characterized in that, described pharmaceutical composition contains monoammonium glycyrrhizinate compound claimed in claim 1, cysteine hydrochloride and pharmaceutically acceptable auxiliary material.
7. pharmaceutical composition according to claim 6, is characterized in that, described pharmaceutically acceptable auxiliary material is one or more the mixing in sodium-chlor, sodium sulphite anhydrous 99.3 or Zonon D.
8. pharmaceutical composition according to claim 7, it is characterized in that, described pharmaceutical composition by weight, comprises 1～100 part of 1～200 part of monoammonium glycyrrhizinate, 1～200 part of cysteine hydrochloride, 1～1000 part, sodium-chlor, 1～200 part of sodium sulphite anhydrous 99.3 and Zonon D;
Preferably, 1～100 part of monoammonium glycyrrhizinate, 1～50 part of cysteine hydrochloride, 400～1000 parts, sodium-chlor, 1～50 part of sodium sulphite anhydrous 99.3 and Zonon D are 1～20 part;
More preferably, 10～80 parts of monoammonium glycyrrhizinates, 20～40 parts of cysteine hydrochlorides, 600～900 parts, sodium-chlor, 1～50 part of sodium sulphite anhydrous 99.3 and Zonon D are 1～20 part;
Most preferably, 60 parts of monoammonium glycyrrhizinates, 30 parts of cysteine hydrochlorides, 850 parts, sodium-chlor, 30 parts of sodium sulphite anhydrous 99.3s and Zonon D are 3 parts.
9. pharmaceutical composition according to claim 8, is characterized in that, described pharmaceutical composition can be prepared into pharmaceutically acceptable formulation.
10. pharmaceutical composition according to claim 9, is characterized in that, described pharmaceutical composition can be prepared into bulk capacity injection, small-volume injection or lyophilized injectable powder, preferably bulk capacity injection.
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| CN201410094003.6A CN103819530B (en) | 2013-12-12 | 2014-03-13 | Monoammonium glycyrrhizinate compound and pharmaceutical composition containing monoammonium glycyrrhizinate |
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| CN104138385A (en) * | 2014-08-14 | 2014-11-12 | 广州一品红制药有限公司 | Composition containing compound ammonium glycyrrhetate S |
| CN109331002A (en) * | 2018-10-30 | 2019-02-15 | 湖北康沁药业股份有限公司 | The preparation method of compound monoammonium glycyrrhizinate S sodium chloride injection |
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| CN102302502A (en) * | 2011-06-30 | 2012-01-04 | 北京秦武田制药有限公司 | Compound glycyrrhizin preparation and preparation method thereof |
| CN103193856A (en) * | 2013-04-10 | 2013-07-10 | 宁夏紫荆花制药有限公司 | Method for preparing mono-ammonium glycyrrhizinate |
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| CN104138385A (en) * | 2014-08-14 | 2014-11-12 | 广州一品红制药有限公司 | Composition containing compound ammonium glycyrrhetate S |
| CN109331002A (en) * | 2018-10-30 | 2019-02-15 | 湖北康沁药业股份有限公司 | The preparation method of compound monoammonium glycyrrhizinate S sodium chloride injection |
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