CN1786000A - Sodium salt of Entecavir, its preparation method and pharmaceutical application - Google Patents
Sodium salt of Entecavir, its preparation method and pharmaceutical application Download PDFInfo
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- CN1786000A CN1786000A CN 200510128063 CN200510128063A CN1786000A CN 1786000 A CN1786000 A CN 1786000A CN 200510128063 CN200510128063 CN 200510128063 CN 200510128063 A CN200510128063 A CN 200510128063A CN 1786000 A CN1786000 A CN 1786000A
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Abstract
The present invention relates to a sodium salt compound of enticawei, its hydrate, preparation method and application of them in medicine field. Said invention adopts the following steps: dissolving enticawei in sodium hydroxide aqueous solution, making reaction, then using element alcohol or ketone of low carbon chain to make precipitation, drying purification or freeze-drying so as to obtain the invented product. The enticawei sodium and its hydrate have good water solubility, can be used as raw material medicine for preparing medicine preparation and raising bioavailability of medicine.
Description
Technical field the invention belongs to medical technical field, the sodium salt compound that relates to Entecavir with and preparation method thereof with it in pharmaceutically application.
Background technology Entecavir (Entecavir) is a kind of 2 '-penta ring deoxyguanosine analogue, chemical name is [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one, molecular structural formula is as follows:
, molecular formula C
12H
15N
5O
3
Entecavir is a kind of chipal compounds, and [1S-(1 α, 3 α, 4 β)] optically active isomer has extremely strong resistance of hepatitis B disease (HBV) toxic action.
U.S. Pat 5,206,244 disclose Entecavir and its purposes in the treatment hepatitis B.People such as Bisacchi disclose a kind of synthetic method of the Entecavir that has improved in WO 98/09964.U.S. Patent application US-2001-0033864-A1 and PCT patent application WO01/64421A1 disclose the preparation compositions that contains the low dosage Entecavir.
Entecavir is a kind of antiviral agent efficiently, clinical study has shown the hepatitis B virus good inhibition effect, because the activity of Entecavir hepatitis B virus resisting is very high, low-down dosage just is enough to reach the treatment effect of expectation, and the every day of generally being grown up, oral 0.5mg or 1mg Entecavir can reach good therapeutic action.
In medicinal application, because the water solubility minimum (2.4mg/ml, 25 ± 0.5 ℃) of Entecavir is unfavorable for the preparation of pharmaceutical preparation and the application of medicine.
Summary of the invention the purpose of this invention is to provide a kind of derivative with Entecavir of good water-soluble, be a kind of sodium salt-----sodium entecavir of Entecavir specifically, the invention still further relates to the hydrate of sodium entecavir, the derivative of this Entecavir is compared Entecavir, has better water-solubility.
Another object of the present invention provides a kind of method for preparing sodium entecavir or its hydrate, characteristics such as that this method has is easy, with low cost, steady quality.
The invention still further relates to the application in the hepatitis b virus infected medicine of preparation treatment of sodium entecavir or its hydrate, the invention still further relates to the preparation compositions of sodium entecavir or its hydrate.
The sodium salt compound of Entecavir provided by the invention has following molecular structural formula
Molecular formula C
12H
14N
5O
3Na.
Sodium entecavir of the present invention is a kind of solid chemical compound of white, in preparation process, for keeping peculiar structural form, can contain a certain amount of water molecules, so the present invention also provides the hydrate of sodium entecavir, and its molecular structural formula is as follows:
, molecular formula C
12H
14N
5O
3Na.xH
2O, wherein x is the number of the contained crystal water of per molecule sodium entecavir, and x can be an integer, also can be decimal, and the span of x is 0.5～5, and the span of preferred x is 2～3.
Should be noted that, solid chemical compound has crystal water and is subjected to condition effect such as crystallization method, crystalline environment (as temperature, vapour pressure), crystal seed guiding crystallization and pre-treatment usually, therefore, the present invention has stipulated that the span of x is 0.5～5, usually the x value is 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5, is referred to as semihydrate, monohydrate, sesqui hydrate, dihydrate, two sesquialter hydrates, trihydrate, three sesquialter hydrates, tetrahydrate, four sesquialter hydrates, the pentahydrate of sodium entecavir respectively.
Especially, the span of x is 2～3, especially refers to sodium entecavir two sesquialter hydrate, i.e. x=2.5.
By molecular structural formula as can be seen, sodium entecavir provided by the invention, as the sodium salt derivative of Entecavir, its molecular structure is compared with Entecavir, is introducing sodium (Na
+) after, carbon-nitrogen bond becomes two keys by singly-bound, and the carbonyl of the two keys of carbon-oxygen also becomes carbon-oxygen singly-bound, finally forms sodium entecavir of the present invention.
The contriver is by a large amount of experiments and analyze discovery, and Entecavir is 7.9～8.0 at the pH of saturated aqueous solution, and integral body presents faint alkalescence, yet Entecavir is structural
The protium of functional group but has very faint ionization tendency and manifests extremely weak acidity, this gives the synthetic possibility of bringing of sodium entecavir of the present invention, that is: Entecavir can be prepared into sodium-salt form, therefore, Entecavir and strongly alkaline compound sodium hydroxide (NaOH) are carried out neutralization reaction, make Na
+Substituted imido
On protium, make it to become the sodium salt structure
But reaction does not stop, because the electronegativity of oxygen element is greater than the nitrogen element, at Na
+Participation under, the polarity price difference difference of the oxygen on the purine group, nitrogen, sodium, and Entecavir specific molecule structure under the dual function that forms cyclic conjugated key system structural bond valence fracture, reconstruct reaction taken place further makes the ortho position carbonyl
On bond rupture and form the two keys of carbon one nitrogen, finally make to form stable kinds of aromatic ring conjugation system on the purine group; Owing to the electronegativity difference in size of oxygen element and nitrogen element, cause the current potential on the compound to shift, thereby make Na simultaneously
+Form a kind of sodium salt compound of new, stable Entecavir with the oxygen element coordination, sodium entecavir promptly of the present invention.This series reaction process is as shown in the formula expression:
As can be seen, this because Na
+Participation and a series of bond valence fracture reconstruct, potential transfer, the salifiable process of coordination that take place are not common acid-base neutralisation reactions, but reconfiguring on the molecular linkage bit architecture taken place, therefore, formed sodium entecavir of the present invention is a species specific sodium salt compound of Entecavir, and this is the constructional feature of sodium entecavir of the present invention.
A kind of method for preparing sodium entecavir of the present invention or its hydrate comprises the following steps the step:
(1) reaction:
Entecavir is dissolved in the aqueous sodium hydroxide solution, and the pH value of regulator solution is 10～14, under agitation adds to contain five carbon following unit alcohol or ketone, until producing precipitation, leaves standstill, and obtains throw out behind the suction filtration.
Be to be understood that, regulator solution pH value is in 10～14 purpose, be to make Entecavir and sodium hydroxide fully, fully to react and make precipitation evenly, stably separate out, usually can adopt interpolation to regulate the pH value with the reagent of water mixing, as ethanol, acetone, methyl alcohol, water, the alcoholic acid aqueous solution, or the like.
(2) drying:
Two kinds of following methods can be carried out drying and obtain sodium entecavir of the present invention or its hydrate above-mentioned throw out,
Method one. throw out with after containing five unit alcohol or ketone washing below the carbon, is dissolved in the water it and makes the aqueous solution, carry out freeze-drying, obtain white or off-white color pressed powder, promptly get sodium entecavir or Entecavir sodium hydrate with freeze-drying.
Method two. throw out with after containing five unit alcohol or ketone washing below the carbon, to constant weight, is obtained white or off-white color pressed powder in 35 ℃～120 ℃ drying under reduced pressure, promptly get sodium entecavir or Entecavir sodium hydrate.
The technological method of sodium entecavir produced according to the present invention or its hydrate, the above contains the following unit alcohol of five carbon or ketone is wherein a kind of such as methyl alcohol, ethanol, propyl alcohol, butanols, acetone, also can be two kinds mixture wherein.
The technological method of sodium entecavir produced according to the present invention or its hydrate is characterized in that the reaction of Entecavir and sodium hydroxide.
Be to be understood that, lyophilize is a kind of sophisticated, conventional drying means, lyophilize mainly contains two steps, be refrigerating process and drying process, be that solute is dissolved in water or other solvent that is fit to, make its cryocoagulation at low temperatures, again with its by solidify attitude directly distillation remove and desolvate and obtain dry body, have easily control, material damage is few, do not destroy the structure of matter, do not produce advantage such as impurity.In refrigerating process, speed of cooling can be controlled, speed of cooling is fast, can suppress solute and form the crystalline process, vice versa, and therefore, common dried solute can be in non-crystalline state, speed of cooling in the control refrigerating process also might produce xln or microcrystal or their mixture.
Sodium entecavir of the present invention is a kind of solid chemical compound, and its solid form can be crystal, noncrystal form, also can be crystal and non-crystal mixture; It should also be understood that, the crystal of sodium entecavir and noncrystal form can transform mutually, for example non-crystal sodium entecavir can be dissolved in the alcoholic acid aqueous solution, its crystallization is separated out and obtain the compound of the crystal habit of sodium entecavir, again for example with the sodium entecavir of crystal habit quick freezing soluble in water, carry out lyophilize and can obtain the sodium entecavir of noncrystal form, but no matter be crystal, noncrystal or crystal and non-crystal mixture, all have the molecular structural formula of sodium entecavir of the present invention.
Certainly, sodium entecavir of the present invention also comprises its hydrate or solvate, especially two sesquialter hydrates of sodium entecavir.Also be to be understood that, sodium entecavir and Entecavir sodium hydrate also can transform mutually, for example the Entecavir sodium hydrate being heated to 115 ℃ makes crystal water discrete and not with the sodium entecavir of crystal water, for example will not make its precipitation again, can obtain two sesquialter hydrates of sodium entecavir with the sodium entecavir of the crystal water ethanol (or acetone or alcohol/acetone mixed solution) that adds soluble in water.
Sodium entecavir of the present invention and hydrate thereof, the application that is used for preparing the hepatitis b virus infected medicine of treatment.
A kind ofly be used for the treatment of hepatitis b virus infected pharmaceutical composition, contain pharmaceutically acceptable carrier and sodium entecavir of the present invention or Entecavir sodium hydrate, wherein the content of sodium entecavir or Entecavir sodium hydrate is 0.01mg～20mg, the content of preferred sodium entecavir or Entecavir sodium hydrate is 0.1mg～5mg, and more preferably the content of sodium entecavir or Entecavir sodium hydrate is 0.3mg～1.5mg.Above-described composition, the wherein preferred sodium entecavir two sesquialter hydrates of Entecavir sodium hydrate.
Sodium entecavir provided by the present invention and hydrate thereof are compared Entecavir, has better water dissolution performance, it is a kind of ideal raw material medicine, with sodium entecavir of the present invention or its hydrate is active ingredient, and contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics, comprise oral preparations, injection formulations, non-oral liquid preparation, or the like, as oral tablet, capsule, granule, oral solution, powder agent, pill, sublingual administration agent or the like; And for example injection comprises powder ampoule agent for injection and injection liquid, or the like, the emulsion of non-for another example oral eye drop, nasal drops, [, Transdermal absorption, or the like.Also can be the formulation such as quick-release, slowly-releasing, controlled release of above various formulations, for example oral dispersible tablet, slow releasing tablet, slow releasing capsule, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets, born of the same parents rise particle, or the like.Especially, by the means known in the art preparation, be preferred for preparing the tablet (comprising dispersible tablet, slow releasing tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets) that uses on the pharmaceutics, capsule (comprise that stomach is molten, enteric, slow releasing capsule), oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc., to satisfy the various needs in the clinical use, be used for the treatment of resistance of hepatitis B (HBV-DNA) virus.
Be to be understood that, according to method well known in the art, pharmaceutical carrier is matrix or the auxiliary material that keeps pharmaceutical dosage form, usually select for use or be used in combination according to different medicaments, generally comprise vehicle or thinner, for example Microcrystalline Cellulose, lactose, starch, dextrin, calcium phosphate, sucrose N.F,USP MANNITOL, sorbyl alcohol, glucose, fructose, water, polyoxyethylene glycol, propylene glycol, glycerine, cyclodextrin and derivative thereof, or the like; Also can comprise viscous substance, for example polyvidone, methylcellulose gum, Walocel MT 20.000PV, HPMC, hydroxypropylcellulose, Natvosol, gelatin, guar gum, xanthan gum, or the like; Also comprise lubricant, for example Magnesium Stearate, stearic acid, talcum powder, stearyl fumarate, Sodium Lauryl Sulphate BP/USP, or the like; Also can comprise disintegrating agent, for example Xylo-Mucine, polyvinylpolypyrrolidone, pregelatinized Starch, W-Gum, or the like; Also can comprise pH value conditioning agent or buffer reagent, for example phosphate buffered saline buffer, citric acid, Trisodium Citrate, acetate buffer, dilute hydrochloric acid, yellow soda ash, sodium hydroxide, or the like; Also can comprise sanitas, for example Sodium Benzoate, potassium sorbate, methyl p-hydroxybenzoate, propylparaben, or the like; Also can comprise stablizer and oxidation inhibitor, for example Calcium Disodium Edetate, S-WAT, vitamins C, or the like; Also can comprise the taste conditioning agent, for example maltose alcohol, fructose, sucrose, soluble saccharin, flavoring orange essence, strawberry flavour, or the like; Also can comprise additive other routine, appropriate in addition.
It is also understood that when the agent type is tablet or capsule, can be the film dressing.The material that is used for the film dressing comprises suitable Drug coating, for example HPMC, Natvosol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, or the like; Also can comprise softening agent, for example polyoxyethylene glycol, triethyl citrate, or the like; Also comprise suitable solubilizing agent, as Polyoxyethylene Sorbitan Monooleate; Also can comprise suitable pigment, as titanium dioxide, various ferric oxide, pink pigment, or the like.
Aforesaid pharmaceutical composition, contain one or more pharmaceutically acceptable pharmaceutical carriers, be mixed with form through any suitable administration, can prepare any pharmaceutical dosage form of acceptable on the pharmaceutics, sodium entecavir or its hydrate are active substances wherein, has the effect that suppresses hepatitis B replication, can also comprise the material that other has pharmaceutical active in the pharmaceutical composition, form a kind of pharmaceutical composition of compound, come the hepatitis b virus infected of combination therapy stubbornness and other accompanying infection.The material that is used for the pharmaceutical active of suitable other of this purpose comprises one or more antiviral agents, for example didanosine, lamivudine, zidovudine, Abacavir, Adefovir, adefovir ester, Famciclovir, ganciclovir, emtricitabine, ribavirin, tynofovir, or the like; Can also comprise one or more immunomodulators, for example interferon-' alpha ', interferon-beta, interferon-, Zadaxin, or the like.
Though described concrete associated viscera of the present invention, also should be included within the scope of the invention to conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
The performance test of the external hepatitis B virus resisting HBV-DNA of sodium entecavir of the present invention is as follows.
The 2.2.15 cell strain that application can replication in vitro be expressed the HBV transfection from external angle, is tested the anti-HBV activity of sodium entecavir of the present invention.2.2.15 cell strain the has been transfection full genome of HBV can be secreted the female oncocyte of HBV-DNA particulate people liver system, adopting the change that detects secretor type HBV-DNA titre in the cell culture fluid supernatant liquor is the important indicator that reflection HBV-DNA duplicates.
1. cell cultures: every group of 2.2.15 cell cultivated with the DMEM nutrient solution, and nutrient solution adds 10% foetal calf serum, 0.03% glutaminase, and 100U/ml penicillin, the 100u/ml Streptomycin sulphate, 200 μ g/ml G418 put 37 ℃, 5.00%CO
2The cultivation of going down to posterity in the incubator was gone down to posterity once in per 4 days.
2. detect principle and method: adopting the change that detects secretor type HBV-DNA titre in the cell culture fluid supernatant liquor is the important indicator that reflection HBV-DNA duplicates; The employing fluorescence quantitative PCR method is measured.
3. experiment grouping and measuring: experiment divides three groups, is respectively sodium entecavir group, Entecavir group, blank group, and wherein the sodium entecavir group adopts that to contain the Entecavir na concn be that the 4.0nmol/L nutrient solution is cultivated; It is that the 4.0nmol/L nutrient solution is cultivated that the employing of Entecavir group contains Entecavir concentration; Blank group adopts conventional nutrient solution to cultivate.(annotate: according to existing bibliographical information, the medium effective concentration EC that HBV-DNA duplicates in the HepG2.2.15 cell of Entecavir vitro inhibition transfection
50Be 3.75nmol/L).
Get the cell culture supernatant of respectively organizing same time point, measure its HBV-DNA titre content number (copy/ml), measure numerical value such as following table:
Can find out by last table data, sodium entecavir group and Entecavir group are organized with respect to blank, its HBV-DNA virus to cultured cell in vitro has fabulous restraining effect, and sodium entecavir and the anti-HBV-DNA's of Entecavir is active close, and wherein sodium entecavir is better than Entecavir.
Sodium entecavir of the present invention has beat all, good water-soluble, through measuring, the water solubility of sodium entecavir is greater than 190mg/ml at normal temperatures and pressures, and the water solubility of Entecavir is minimum, be less than 2.5mg/ml, the water-soluble Entecavir that is far longer than of sodium entecavir is more than 76 times of Entecavir, and this has great importance in the preparation of pharmaceutical preparation and the application of medicine and the aspects such as performance of drug effect for sodium entecavir.This good solubleness has improved its bioavailability, and the medicine dissolution rate is significantly accelerated, and makes that human body is easier to absorb.
Entecavir is prepared as water-soluble good sodium entecavir, and is more favourable for the preparation of various medicaments especially injection, liquid preparation, need not to add various solubilizing agent, improved the quality quality and the security of pharmaceutical preparation; In addition, Entecavir is prepared as water-soluble good sodium entecavir, the efficacy component sodium entecavir continues in gastrointestinal fluid, stably discharges, to reach the good slow releasing effect and the lasting performance of drug action when also helping being prepared as slow release formulation (as oral slow releasing tablet, slow releasing capsule); Also have, Entecavir is prepared as water-soluble good sodium entecavir, important meaning is also arranged for absorbing of efficacy component.
Be to be understood that, Entecavir is as the hepatitis B virus inhibitor, need long-term prescription, the medication cycle or the course of treatment are generally all more than 1 year, therefore, be prepared as medicament for oral use, easy to use, the prolonged application and the compliance that help the patient, yet the chemical content of Entecavir very little (0.5mg or 1mg), and oral medicament need just can enter blood of human body reaching antiviral effect through GI absorption, and the quality of oral absorption directly affects the result of treatment of medicine.Medicament enters the absorption process behind the stomach and intestine, divide two stages, be that disintegration dispersion and gastrointestinal wall absorb two stages, at first need in gastric juice or intestinal juice, disintegration scatter, and then contact and be attached to gastrointestinal wall and absorb and enter blood, this two stages all can influence the performance with drug effect of absorbing of medicine, Entecavir is prepared as water-soluble good sodium entecavir, the medicine dissolution rate is significantly accelerated, improved its disintegration dispersive degree and rate of dispersion in gastric juice or intestinal juice greatly, then medicament active composition is more abundant with contacting of gastrointestinal wall, be attached to that gastrointestinal wall absorbs and to enter the active ingredient of blood also more abundant, this raising for the bioavailability of efficacy component sodium entecavir is significant; Also have, Entecavir and sodium entecavir are the hepatitis B virus inhibitor of " concentration dependent ", be that antiviral curative effect and Plasma Concentration are closely related, Plasma Concentration is bigger, antiviral effect better, because water miscible very big spoke degree improves, the absorption rate of sodium entecavir in stomach and intestine is fast, soak time is more concentrated, Plasma Concentration and blood peak concentration (being the maximum value of blood Chinese traditional medicine concentration) after helping improving greatly it and absorbing, this is significant for the hepatitis B virus resisting curative effect that improves sodium entecavir.With following diffusion experiment, understand medicine dissolution rate, absorption rate, the absorbing sets moderate of sodium entecavir in stomach and intestine.
Sodium entecavir and the Entecavir diffusion experiment in the aqueous solution.
Method: precision takes by weighing sodium entecavir and each 5.0mg of Entecavir respectively, and two kinds of powder are made the identical thin slice of size with the tabletting machine punching press, and is standby.
Respectively get the phosphate buffered aqueous solution (pH4.0 in addition, be similar to the potential of hydrogen of human gastric juice) 100ml, place two identical rectangle glass guide channel A, B of length * wide * height=10cm * 5cm * 5cm respectively, in A, B groove, form the rectangle aqueous solution volume of a 10cm * 5cm * 2cm respectively, the thin slice of the sodium entecavir that suppresses and Entecavir is placed the end of rectangle glass guide channel A and B respectively, get solution 10 μ l at the other end of rectangular slot respectively every 5 minutes, measure the sodium entecavir of the period of taking a sample and the concentration content of Entecavir; And observe thin slice disintegration diffusion phenomena in solution, relatively sodium entecavir and Entecavir are at the concentration content of each time point, the following (concentration unit: * 10 of data
-2Mg/ml):
| 15min | 20min | 25min | |||
| Concentration | Phenomenon | Concentration | Phenomenon | Concentration | Phenomenon |
| 4.57 | Tablet dissolves fully | 4.78 | Tablet dissolves fully | 4.84 | Tablet dissolves fully |
| 0.17 | Tablet has dissolving slightly | 0.25 | Tablet has dissolving slightly, is the medicine island | 0.38 | Tablet has dissolving slightly, is the medicine island |
Conclusion: compare both velocity of diffusion under the same conditions, the velocity of diffusion of sodium entecavir in water is much larger than Entecavir as can be seen.
Description of drawings relevant accompanying drawing provided by the invention is as follows:
Fig. 1 is the infrared absorption spectra (KBr compressing tablet) of sodium entecavir;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of sodium entecavir
1H NMR (500MHz, DMSO-d
6);
Fig. 3 is the carbon-13 nmr spectra figure of sodium entecavir
13C NMR (150MHz, DMSO-d
6);
Fig. 4 is thermal weight loss and its crystal water collection of illustrative plates of differential thermal analysis of sodium entecavir two sesquialter hydrates.
For the ease of resolving relatively, the present invention also provides the relevant collection of illustrative plates of Entecavir,
Fig. 5 is the infrared absorption spectra (KBr compressing tablet) of Entecavir;
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of Entecavir
1H NMR (500MHz, DMSO-d
6);
Fig. 7 is the carbon-13 nmr spectra figure of Entecavir
13C NMR (150MHz, DMSO-d
6).
Relatively the nuclear magnetic resonance map information of sodium entecavir and Entecavir demonstrates both existing similar dependencys, and evident difference is also arranged; Relatively the infrared absorption pattern information of sodium entecavir and Entecavir does not have carbonyl on the sodium entecavir infrared absorption spectrum
The characteristic absorbance frequency of functional group is (usually at 1760～1650cm
-1), and on the Entecavir infrared absorption spectrum, carbonyl is arranged
The characteristic absorbance frequency of functional group, this is both the most tangible difference, and carbonyl
It is the exclusive functional group of Entecavir.The analysis diagram spectrum information as can be known, the constitutional features of sodium entecavir of the present invention and collection of illustrative plates characterize in full accord.
Fig. 4 is that sodium entecavir two sesquialter hydrates carry out thermal weight loss and differential thermal analysis curve with differential thermal-thermal weight loss coupling analyser, at 80 ℃～110 ℃ endotherm(ic)peak is arranged, and weightlessness 12.89%, and this is consistent with the theoretical value 13.07% that contains 2.5 crystal water.
Embodiment will appreciate that, in implementation process of the present invention, and various embodiments that those of ordinary skills produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily.Come sodium entecavir of the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
Embodiment one. one of sodium entecavir and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 11 with the pH value of ethanol regulator solution, under agitation continue to add ethanol (about 65ml) until producing precipitation, continue to stir after 10 minutes, left standstill 2 hours, suction filtration, after filtering precipitate usefulness washing with alcohol 2～3 times, be dissolved in water, make 5% Entecavir sodium water solution, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be sodium entecavir, molecular formula C
12H
14N
5O
3Na, results of elemental analyses (%): C 48.20, and H 4.69, and N 23.47, and Na 7.66; Li Lun value (%): C48.14, H 4.72, and N 23.41, and Na 7.69, and the ultimate analysis value is consistent with theoretical value.
Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment two. two of sodium entecavir and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 10 with the pH value of methyl alcohol regulator solution, under agitation add the about 60ml of methyl alcohol and produce precipitation, continue to stir after 25 minutes, left standstill 2 hours, suction filtration, after filtering precipitate usefulness methanol wash 2～3 times, be dissolved in water, make 8% Entecavir sodium water solution, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be sodium entecavir, molecular formula C
12H
14N
5O
3Na, results of elemental analyses (%): C 48.22, and H 4.73, and N 23.35, and Na 7.74; Li Lun value (%): C 48.14, H4.72, and N 23.41, and Na 7.69, and the ultimate analysis value is consistent with theoretical value.
Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment three. three of sodium entecavir and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 12 with the pH value of ethanol regulator solution, under agitation add acetone to producing precipitation, continue to stir after 10 minutes, left standstill 2 hours, suction filtration, behind filtering precipitate usefulness washing with acetone 2～3 times, be dissolved in water, make 8% Entecavir sodium water solution, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be sodium entecavir, molecular formula C
12H
14N
5O
3Na, results of elemental analyses (%): C 48.19, and H 4.70, and N 23.48, and Na 7.63; Li Lun value (%): C 48.14, and H 4.72, N23.41, and Na 7.69, and the ultimate analysis value is consistent with theoretical value.
Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment four. four of sodium entecavir and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 11 with the pH value of ethanol regulator solution, under agitation add acetone and alcohol mixed solution (V: V=1: 1 about 70ml) produce precipitation, continue to stir after 10 minutes, left standstill 2 hours, suction filtration, behind filtering precipitate usefulness washing with acetone 2～3 times, be dissolved in water, make 5% Entecavir sodium water solution, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be sodium entecavir, molecular formula C
12H
14N
5O
3Na, results of elemental analyses (%): C 48.17, and H 4.75, and N 23.35, Na7.65; Li Lun value (%): C 48.14, and H 4.72, and N 23.41, and Na 7.69, and the ultimate analysis value is consistent with theoretical value.
Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment five. sodium entecavir two sesquialter hydrates and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 12 with the pH value of acetone regulator solution, under agitation add acetone to producing precipitation, continue to stir after 10 minutes, left standstill suction filtration 2 hours, behind filtering precipitate usefulness washing with acetone 2～3 times, to constant weight, obtain the off-white color solid in 55 ℃ of drying under reduced pressure, contain 2.5 crystal water through thermal weight loss and differential thermal analysis, be sodium entecavir two sesquialter hydrates, molecular formula C
12H
14N
5O
3Na.2.5H
2O, its crystal water collection of illustrative plates of thermal weight loss and differential thermal analysis is seen accompanying drawing 4.
Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment six. sodium entecavir two sesquialter hydrates and preparation method thereof
Getting Entecavir 5g, add the aqueous sodium hydroxide solution dissolving, is 13.5 with the pH value of ethanol regulator solution, under agitation add acetone and alcohol mixed solution (V: V=1: 1) to producing precipitation, continue to stir after 10 minutes, left standstill suction filtration 2 hours, after filtering precipitate usefulness washing with alcohol 2～3 times, to constant weight, obtain white solid in 70 ℃ of drying under reduced pressure, contain 2.5 crystal water through thermal weight loss and differential thermal analysis, be sodium entecavir two sesquialter compounds, molecular formula C
12H
14N
5O
3Na.2.5H
2O.
Its crystal water collection of illustrative plates of thermal weight loss and differential thermal analysis is seen accompanying drawing 4.Its hydrogen spectrum of infrared absorption and nuclear magnetic resonance spectroscopy and carbon spectrum are consistent with accompanying drawing.
Embodiment seven. Entecavir sodium tablet and preparation
Get sodium entecavir 0.5g and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Sodium entecavir 0.5g
Microcrystalline Cellulose 55.3g
Lactose 41g
Polyvinylpolypyrrolidone 2.7g
Magnesium Stearate 0.5g
Water is an amount of
By above prescription, carry out making 1000 with tabletting machine behind wet granulation, the whole grain of oven dry, every contains the active ingredient sodium entecavir is the 0.5mg/ sheet, for orally using, is used for the treatment of hepatitis b virus infected.
In addition, also can adopt conventional packaging technique that the tablet of above-mentioned preparation is carried out Cotton seeds, can obtain the dressing diaphragm, for example can adopt the dressing solution that contains HPMC, titanium dioxide, polyoxyethylene glycol, Tween-80, iron oxide yellow, red iron oxide, citric acid diethyl ester and water to carry out Cotton seeds, obtain sodium entecavir dressing diaphragm.
Embodiment eight. the sodium entecavir capsule
Get sodium entecavir two sesquialter hydrate 1.15g (being equivalent to contain sodium entecavir 1.0g) and other pharmaceutical carrier auxiliary materials of preparation among the embodiment five, the composition of specifically writing out a prescription is as follows:
Sodium entecavir two sesquialter hydrate 1.15g (being equivalent to sodium entecavir 1.0g)
Lactose 90g
Methylcellulose gum 2.8g
Xylo-Mucine 3.8g
Magnesium Stearate 2g
Water is an amount of
By above prescription, to carry out packing into behind wet granulation, the whole grain of oven dry in 1000 Capsuleses, containing active ingredient sodium entecavir two sesquialter hydrates in every capsules is 1.15mg/ grain (being equivalent to the 1.0mg sodium entecavir), for orally using.
Embodiment nine. sodium entecavir two sesquialter hydrate tablets
Get sodium entecavir two sesquialter hydrate 1.24g (being equivalent to contain sodium entecavir 1.08g) and other pharmaceutical carrier auxiliary materials, the composition of specifically writing out a prescription is as follows:
Sodium entecavir two sesquialter hydrate 1.24g
N.F,USP MANNITOL 90g
Cross-linked carboxymethyl cellulose 4.5g
Cycloheptaamylose 2g
Stearic acid 0.3g
Water is an amount of
By above prescription, carry out making 1000 with tabletting machine behind wet granulation, the whole grain of oven dry, every contains active ingredient sodium entecavir two sesquialter water is 1.24mg/ sheet (being equivalent to contain sodium entecavir 1.08mg), for orally using.
Embodiment ten. the sodium entecavir enteric coated tablet
Similarly, get sodium entecavir 0.5g, add an amount of carrier auxiliary material of people (as starch, lactose, polyvinylpyrrolidone, Magnesium Stearate etc.), wet grain is granulated, whole grain back is made 1000 with tabletting machine, making every, to contain the active ingredient sodium entecavir be the 0.5mg/ sheet, this sheet is wrapped up with enteric coated solution, and promptly getting specification is the Entecavir sodium enteric tablet of 0.5mg/ sheet, for orally using.(wherein, enteric coated solution can be selected the dressing solution of following prescription: cellulose acetate-phthalate 10g, stearyl alcohol 4.0g, diethyl phthalate 1.0ml, Virahol 40ml, acetone 45ml for use.)
Embodiment 11. the sodium entecavir powder ampoule agent for injection
Get sodium entecavir 1g, N.F,USP MANNITOL 200g, add the dissolving of injection water and be diluted to 2200 milliliters, regulate pH with phosphate buffer and add injection water to 2500 milliliter after 10, smart filter divides in can to the 1000 bottle cillin bottle, carries out lyophilize by lyophilized injectable powder preparation technology, can be prepared into 1000 bottles of injection Entecavir sodium freeze-dried powder injections, every bottle contains sodium entecavir 1mg.
Embodiment 12. the Entecavir sodium injection
Get sodium entecavir 0.5g, add the dissolving of injection water and be diluted to 1300 milliliters, add stirring and evenly mixing behind the propylene glycol 200ml again, regulate pH with phosphate buffer again and add injection water to 2000 milliliter after 9 ± 0.5, smart filter divides in can to the 1000 bottle ampoule sealing by fusing bottleneck, can be prepared into 1000 bottles of Entecavir sodium injections, every bottle contains sodium entecavir 0.5mg.
Embodiment 13. the Entecavir sodium oral solution
Get the sodium entecavir two sesquialter hydrate 5.8mg (being equivalent to contain sodium entecavir 5mg) of preparation among the embodiment five, maltose alcohol 20g, methyl p-hydroxybenzoate 0.2g, flavoring orange essence is an amount of, transfer pH to 6.5～7.5 with citric acid buffer agent after above component is dissolved in water, making overall solution volume is 100 milliliters, divides to be filled in 10 vials, encapsulation promptly gets every bottle of oral liquid that contains sodium entecavir two sesquialter hydrate 0.58mg (being equivalent to contain sodium entecavir 0.5mg).
Embodiment 14. the sodium entecavir particle
Get sodium entecavir 10mg, other gets Xylitol 35g, Sodium Benzoate 0.4g.With suitable quantity of water that sodium entecavir dissolving back adding strawberry flavour is an amount of, wet granulation, oven dry, whole grain are packaged into 10 bags, promptly make every bag of granule that contains sodium entecavir 1mg.
Embodiment 15. sodium entecavir sheet (dispersible tablet)
Prescription: sodium entecavir 0.54g
Lactose 65g
Sodium starch glycolate 12g
Microcrystalline Cellulose 28g
Water is an amount of
Magnesium Stearate 1g
Preparation method: earlier above-mentioned material separated pulverizing is crossed 100 mesh sieves.Sodium entecavir, lactose, sodium starch glycolate, Microcrystalline Cellulose thorough mixing is even, add suitable quantity of water and make softwood, oven dry after 40 mesh sieves are granulated, the whole grain of 40 mesh sieves, add the Magnesium Stearate mixing, the control tablet weight is pressed into 1000, promptly gets every dispersible tablet that contains sodium entecavir 0.54mg.This tablet can disperse in water in speed fast (in three minutes) disintegration, reaches the effect of quick-release onset.
Embodiment 16. sodium entecavir sheet (slow release formulation)
Prescription: sodium entecavir 1000mg
Vltra tears (K
4M) 65g
Lactose 33.2g
Magnesium Stearate 0.8g
The 8% polyvidone aqueous solution is an amount of
Preparation method: with sodium entecavir, Vltra tears (K
4M), lactose with 8% polyvidone aqueous solution wet granulation, oven dry, whole grain after, add the Magnesium Stearate mixing, the control tablet weight is pressed into 1000, promptly getting content is the sodium entecavir slow releasing tablet of 1mg.
Vltra tears is a hydrophilic polymer, as framework material, meets the expansion of water or Digestive system and forms the gel barrier in said preparation, and the diffusion of control sodium entecavir is to play the effect of slowly-releasing.
Embodiment 17. the composite tablet of sodium entecavir and lamivudine
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of sodium entecavir 1mg and lamivudine 100mg.
Embodiment 18. the composite tablet of sodium entecavir and didanosine
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of sodium entecavir 1mg and didanosine 200mg.
Embodiment 19. the composite tablet of sodium entecavir and adefovir ester
Select suitable pharmaceutical carrier and auxiliary material for use, press method for preparing tablet thereof, be prepared into the composite tablet that each sheet medicine contains two kinds of active ingredients of sodium entecavir 1mg and adefovir ester 10mg.
Embodiment 20. by sodium entecavir or its hydrate that embodiment one to embodiment six makes, be used for preparing the application of the hepatitis b virus infected medicine of treatment.
Claims (11)
1. the sodium salt compound of an Entecavir is characterized in that having following molecular structural formula
2. the hydrate of a sodium entecavir, its molecular structural formula is as follows
Wherein x is the number of the contained crystal water of per molecule sodium entecavir, and x can be an integer, also can be decimal, and the span of x is 2～3.
3. according to claim 2, the hydrate of sodium entecavir is sodium entecavir two sesquialter hydrate, i.e. x=2.5.
4. the preparation method of claim 1 or 2 described sodium entecavirs or its hydrate, this method comprises the following steps:
(1) reaction:
Entecavir is dissolved in the aqueous sodium hydroxide solution, and the pH value of regulator solution is 10～14, under agitation adds to contain five carbon following unit alcohol or ketone, until producing precipitation, obtains throw out behind the suction filtration;
(2) drying:
Method one. throw out with after containing five unit alcohol or ketone washing below the carbon, is dissolved in the water it and makes the aqueous solution, carry out freeze-drying, promptly get sodium entecavir or Entecavir sodium hydrate with freeze-drying.
Method two. throw out with after containing five unit alcohol or ketone washing below the carbon, is dried to constant weight in 35 ℃～120 ℃, promptly gets sodium entecavir or Entecavir sodium hydrate.
5. preparation method according to claim 4 is characterized in that the described following unit alcohol of five carbon or the ketone of containing is wherein a kind of such as methyl alcohol, ethanol, propyl alcohol, butanols, acetone, also can be two kinds mixture wherein.
6. preparation method according to claim 4 is characterized in that the reaction of Entecavir and sodium hydroxide.
7. a pharmaceutical composition contains pharmaceutically acceptable carrier and sodium entecavir or Entecavir sodium hydrate.
8. the described pharmaceutical composition of claim 7, the content of wherein said sodium entecavir or Entecavir sodium hydrate is 0.01mg～20mg, the content of preferred sodium entecavir or Entecavir sodium hydrate is 0.1mg～5mg, and more preferably the content of sodium entecavir or Entecavir sodium hydrate is 0.3mg～1.5mg.
9. according to claim 7 or 8 described compositions, be any pharmaceutical dosage form of acceptable on the pharmaceutics, preferred pharmaceutical dosage form is tablet, capsule, granule, oral solution, injection.
10. according to claim 7 or 8 described compositions, preferred sodium entecavir two sesquialter hydrates of Entecavir sodium hydrate wherein.
11. sodium entecavir and hydrate thereof the application in the hepatitis b virus infected medicine of preparation treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 200510128063 CN1786000A (en) | 2005-05-23 | 2005-11-25 | Sodium salt of Entecavir, its preparation method and pharmaceutical application |
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| CN 200510074418 CN1699365A (en) | 2005-05-23 | 2005-05-23 | Sodium entecavir and its preparation process and use |
| CN200510074418.8 | 2005-05-23 | ||
| CN 200510128063 CN1786000A (en) | 2005-05-23 | 2005-11-25 | Sodium salt of Entecavir, its preparation method and pharmaceutical application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107213130A (en) * | 2017-05-12 | 2017-09-29 | 上海奥科达生物医药科技有限公司 | A kind of Entecavir Pharmaceutical composition, preparation method and applications |
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2005
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107213130A (en) * | 2017-05-12 | 2017-09-29 | 上海奥科达生物医药科技有限公司 | A kind of Entecavir Pharmaceutical composition, preparation method and applications |
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Effective date of registration: 20061110 Address after: 32F, global Plaza, No. 54, 158, Fujian, Fuzhou Applicant after: Guangshengtang pharmaceutical Industry Co., Ltd. Fujian Address before: Room 1, unit 10, building 36, No. two, 404 Road, Qingdao, Shandong, Anshan Applicant before: Yang Xihong |
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