CN1900078A - Entecavir potassium salt compound and its preparing method and medicine use - Google Patents
Entecavir potassium salt compound and its preparing method and medicine use Download PDFInfo
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- CN1900078A CN1900078A CN 200610077945 CN200610077945A CN1900078A CN 1900078 A CN1900078 A CN 1900078A CN 200610077945 CN200610077945 CN 200610077945 CN 200610077945 A CN200610077945 A CN 200610077945A CN 1900078 A CN1900078 A CN 1900078A
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Abstract
The present invention relates to entecavir potassium salt compound and its preparation process and application in preparing medicine. Entecavir potassium salt is prepared through dissolving entecavir in the water solution of potassium hydroxide to react with potassium hydroxide, precipitating with low carbon chain single alcohol or ketone, and drying. Entecavir potassium has excellent water solubility, is used as material medicine, and can result in high medicine bioavailability.
Description
Technical field the invention belongs to medical technical field, the potassium 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:
U.S. Pat 5,206,244 disclose Entecavir and its purposes in the treatment hepatitis B.International publication WO98/09964 and WO2004/052310 disclose the synthetic method of two kinds of Entecavirs that improved respectively.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 potassium salt compound of Entecavir------entecavir kalium specifically, the invention still further relates to the hydrate of entecavir kalium, 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 entecavir kalium 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 entecavir kalium or its hydrate, the invention still further relates to the preparation compositions and the preparation of compositions method thereof of entecavir kalium or its hydrate.
The potassium salt compound of Entecavir provided by the invention has following molecular structural formula
Molecular formula C
12H
14N
5O
3K.
Entecavir kalium 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 entecavir kalium, and its molecular structural formula is as follows:
, molecular formula C
12H
14N
5O
3K.xH
2O, wherein x is the number of the contained crystal water of per molecule entecavir kalium, 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 1～2.，
Should be noted that, solid chemical compound has crystal water and is subjected to condition effect such as crystallization method, crystalline environment (as temperature, solvent, 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 entecavir kalium respectively.Especially, the span of x is 1～2, especially refers to entecavir kalium sesqui hydrate, i.e. x=1.5.
By molecular structural formula as can be seen, entecavir kalium provided by the invention, as the sylvite derivative of Entecavir, its molecular structure is compared with Entecavir, is introducing potassium (K
+) 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 entecavir kalium of the present invention.
The contriver is by a large amount of experiments and analyze discovery, and Entecavir is 7.9～8.O 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 entecavir kalium of the present invention, that is: Entecavir can be prepared into potassium salt form, therefore, Entecavir and strongly alkaline compound potassium hydroxide (KOH) are carried out neutralization reaction, make K
+Substituted imido
On protium, make it to become the sylvite structure
(as follows shown in the formula); But reaction does not stop, because the electronegativity of oxygen element is greater than the nitrogen element, at K
+Participation under, the polarity price difference difference of the oxygen on the purine group, nitrogen, potassium, 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-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 K simultaneously
+Form a kind of potassium salt compound of new, stable Entecavir with the oxygen element coordination, entecavir kalium promptly of the present invention.This series reaction process is as shown in the formula expression:
As can be seen, this because K
+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 entecavir kalium of the present invention is a species specific potassium salt compound of Entecavir, and this is the constructional feature of entecavir kalium of the present invention.
But, also should be appreciated that sylvite or its hydrate of Entecavir of the present invention, for its various solids or dissolved sylvite, under which kind of situation, the molecular structural formula of above-mentioned expression can not be understood that all it has shown the actual relative arrangement of potassium ion and organic anion.Potassium ion also can be arranged in another position of the atom of relative negatively charged ion, and for example it can be the nitrogen-atoms coordinate with-CO-N-group, and this coordinate position also is the embodiment of resonance motion between the element of intramolecule structure.
A kind of method for preparing entecavir kalium of the present invention or its hydrate comprises the following steps the step:
(1) reaction:
Entecavir is dissolved in the potassium hydroxide aqueous 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 potassium 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.
Because Entecavir and potassium hydroxide are the equimolar amount reactions, and it is valuable raw material that Entecavir is compared potassium hydroxide, under normal conditions, the aspect is considered in order to make Entecavir fully react, improve yield and to reduce cost etc., when feeding intake reaction, should make the mole number of the mole number of potassium hydroxide greater than Entecavir.In actually operating,, all can make Entecavir and potassium hydroxide fully, fully react usually as long as the pH value that Entecavir can fully be dissolved in potassium hydroxide aqueous solution and solution is not less than 10.Usually, can adopt concentration usually is potassium hydroxide aqueous solution and the Entecavir reaction of 0.01～2mol/L, the potassium hydroxide aqueous solution of preferred 1mol/L; In addition, optionally can heat, can also add that activated carbon decolours to reaction soln, refining degerming, filtration treatment reaction soln, to can also be when producing precipitation to the reaction solution processing of lowering the temperature.
(2) drying:
Two kinds of following methods can be carried out drying and obtain entecavir kalium 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 entecavir kalium or entecavir kalium 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 entecavir kalium or entecavir kalium hydrate.
The technical scheme of entecavir kalium produced according to the present invention, 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 technical scheme of entecavir kalium produced according to the present invention is characterized in that the reaction of Entecavir and potassium 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.
Entecavir kalium 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 entecavir kalium and noncrystal form can transform mutually, for example non-crystal entecavir kalium can be dissolved in the alcoholic acid aqueous solution, its crystallization is separated out and obtain the compound of the crystal habit of entecavir kalium, again for example with the entecavir kalium of crystal habit quick freezing soluble in water, carry out lyophilize and can obtain the entecavir kalium of noncrystal form, but no matter be crystal, noncrystal or crystal and non-crystal mixture, all have the molecular structural formula of entecavir kalium of the present invention.
Certainly, the invention still further relates to the sesqui hydrate of hydrate or solvate, the especially entecavir kalium of entecavir kalium.Also be to be understood that, entecavir kalium and entecavir kalium hydrate also can transform mutually, for example the entecavir kalium hydrate being heated to 120 ℃ makes crystal water discrete and not with the entecavir kalium of crystal water, for example will not make its precipitation again, can obtain the hydrate of entecavir kalium with the entecavir kalium of the crystal water ethanol (or acetone or alcohol/acetone mixed solution) that adds soluble in water.
Entecavir kalium of the present invention and hydrate thereof, the application that is used for preparing the hepatitis b virus infected medicine of treatment.
Entecavir kalium or its hydrate are used for the treatment of hepatitis b virus infected as active ingredient, the general chemical substance that does not directly give the simple entecavir kalium of patient or its hydrate, usually all be form appearance with the pharmaceutical composition that contains pharmaceutical carrier, therefore, the present invention also provides corresponding pharmaceutical compositions and preparation method.
A kind ofly be used for the treatment of hepatitis b virus infected pharmaceutical composition, contain pharmaceutically acceptable carrier and entecavir kalium of the present invention or entecavir kalium hydrate, wherein the content of entecavir kalium or entecavir kalium hydrate is 0.01mg～20mg, the content of preferred entecavir kalium or entecavir kalium hydrate is 0.1mg～5mg, and more preferably the content of entecavir kalium or entecavir kalium hydrate is 0.3mg～1.5mg.Above-described composition, the wherein preferred entecavir kalium sesqui of entecavir kalium hydrate hydrate.
Entecavir kalium provided by the present invention and hydrate thereof are compared Entecavir, has good water dissolution performance, it is a kind of ideal raw material medicine, with entecavir kalium 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), granule, 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, entecavir kalium 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, neat much fixed, Abacavirs, Clevudine, 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.
Aforesaid preparation of drug combination method, this method comprises makes acceptable any pharmaceutical dosage form on the pharmaceutics with entecavir kalium or its hydrate and pharmaceutically acceptable pharmaceutical carrier thorough mixing, and preferred pharmaceutical dosage form is tablet (comprising dispersible tablet, slow releasing tablet, enteric coated tablet, effervescent tablet, orally disintegrating tablet, special-shaped tablets etc.), capsule (comprise that stomach is molten, enteric, slow releasing capsule), granule, oral solution, injection (comprising powder ampoule agent for injection and injection liquid) etc.Under the usual condition, entecavir kalium or its hydrate and pharmaceutically acceptable pharmaceutical carrier exist with pulverulence, its thorough mixing there is crucial effect for the steady quality of medicine preparation, because it is very little as the entecavir kalium or the content of its hydrate in medicament of active ingredient, assemble in order to prevent that active ingredient from forming, can not active ingredient and pharmaceutical carrier be made evenly good preparation of content by simple blending means, and should just may make entecavir kalium or its hydrate and pharmaceutical carrier thorough mixing by stepped mixing; Perhaps especially, entecavir kalium or its hydrate be dissolved in the water form solution (having the very advantage of good water-solubility) based on entecavir kalium or its hydrate, use this solution with the pharmaceutical carrier thorough mixing is even in the mode of spraying or liquid stream then, and help in operation subsequently (as granulations, drying, stirring, mechanical workout etc.) make the abundant mixing of active ingredient with make lose drop to minimum.
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.
Entecavir kalium of the present invention and hydrate thereof, the application that is used for preparing the hepatitis b virus infected medicine of treatment.
The performance test of the external hepatitis B virus resisting HBV-DNA of entecavir kalium 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 entecavir kalium 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 entecavir kalium group, Entecavir group, blank group, and wherein the entecavir kalium group adopts that to contain the Entecavir potassium 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.
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 table 1:
Table 1
Can find out by last table data, entecavir kalium group and Entecavir group are organized with respect to blank, its HBV-DNA virus to cultured cell in vitro has fabulous restraining effect, and entecavir kalium and the anti-HBV-DNA's of Entecavir is active close, and wherein entecavir kalium is better than Entecavir.
Entecavir kalium of the present invention has beat all, good water-soluble, through measuring, the water solubility of entecavir kalium is greater than 250mg/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 entecavir kalium is more than 100 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 entecavir kalium.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 entecavir kalium, 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 entecavir kalium, the efficacy component entecavir kalium 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 entecavir kalium, 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.According to the notion of pharmaceutics, bioavailability (Bioavailability) refers to that medicine is absorbed to enter and sanguimotorly utilizes degree and utilize speed.Entecavir kalium or its hydrate have very good water-soluble, enter aspect sanguimotor degree and the speed in absorption for the oral drug preparation that with it is active ingredient, have important promoter action and meaning.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 entecavir kalium, 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 entecavir kalium is significant; Also have, Entecavir and entecavir kalium 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 entecavir kalium 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 entecavir kalium.With following diffusion experiment, understand medicine dissolution rate, absorption rate, the absorbing sets moderate of entecavir kalium in stomach and intestine.
Entecavir kalium and the Entecavir diffusion experiment in the aqueous solution.
Method: precision takes by weighing entecavir kalium 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) 10ml, place two identical rectangle glass guide channel A of length * wide * height=10cm * 1cm * 5cm respectively, among the B, respectively at A, form the rectangle aqueous solution volume of a 10cm * 1cm * 1cm in the B groove, the thin slice of the entecavir kalium that suppresses and Entecavir is placed the end of rectangle glass guide channel A and B respectively, got solution 10 μ l at the other end of rectangular slot respectively every 5 minutes, measure the concentration content of the entecavir kalium of the period of taking a sample and Entecavir and calculate the per-cent of stripping degree; And observe thin slice disintegration diffusion phenomena in solution, compare entecavir kalium and Entecavir concentration content, data such as following table 2 at each time point:
Table 2
| 15 minutes | Stripping degree per-cent | 91.0％ | 5.8％ |
| Phenomenon | Tablet dissolves fully | Tablet has dissolving slightly | |
| 20 minutes | Concentration (* 10 -1mg/ml) | 4.80 | 0.37 |
| Stripping degree per-cent | 96.0％ | 7.4％ | |
| Phenomenon | Tablet dissolves fully | Dissolving is arranged slightly, be the medicine island |
Conclusion: compare both diffusion experiments under the same conditions, velocity of diffusion and the stripping degree of entecavir kalium in water is much better than Entecavir as can be seen.
Description of drawings relevant accompanying drawing provided by the invention is as follows:
Fig. 1 is the carbon-13 nmr spectra figure of entecavir kalium
13C NMR (150MHz, DMSO-d
6);
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of entecavir kalium
1H NMR (600MHz, DMSO-d
6);
Fig. 3 is the infrared absorption spectra (KBr compressing tablet) of entecavir kalium;
Fig. 4 is the thermal weight loss and the differential thermal analysis collection of illustrative plates of entecavir kalium sesqui hydrate.
For the ease of resolving relatively, the present invention also provides the relevant collection of illustrative plates of Entecavir,
Fig. 5 is the carbon-13 nmr spectra figure of Entecavir
13C NMR (150MHz, DMSO-d
6);
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of Entecavir
1H NMR (600MHz, DMSO-d
6);
Fig. 7 is the infrared absorption spectra (KBr compressing tablet) of Entecavir.
Fig. 4 is that entecavir kalium sesqui hydrate carries out thermal weight loss and differential thermal analysis curve with differential thermal-thermal weight loss coupling analyser, at 60 ℃～110 ℃ endotherm(ic)peak is arranged, and weightlessness 7.473%, and this is consistent with the theoretical value 7.892% that contains 1.5 crystal water.
Embodiment in implementation process of the present invention, 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 entecavir kalium 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 entecavir kalium and preparation method thereof
Getting Entecavir 5g, add potassium hydroxide aqueous solution (pH=14) 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 aqueous solutions of potassium, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be entecavir kalium, molecular formula C
12H
14N
5O
3K, results of elemental analyses (%): C 45.67, and H 4.45, and N 22.37, and K 12.35; Li Lun value (%): C 45.70, and H 4.48, and N 22.22, and K 12.37, 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 entecavir kalium and preparation method thereof
Getting Entecavir 5g, add potassium hydroxide aqueous solution (pH=13) 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 aqueous solutions of potassium, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be entecavir kalium, molecular formula C
12H
14N
5O
3K, results of elemental analyses (%): C 45.77, and H 4.43, and N 22.35, and K 12.31; Li Lun value (%): C45.70, H 4.48, and N 22.22, and K 12.37, 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 entecavir kalium and preparation method thereof
Getting Entecavir 5g, add potassium hydroxide aqueous solution (pH=14) dissolving, is 12 with the pH value of ethanol regulator solution, under agitation add acetone 55ml 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 aqueous solutions of potassium, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be entecavir kalium, molecular formula C
12H
14N
5O
3K, results of elemental analyses (%): C 44.68, and H 4.55, and N 22.18, and K 12.42; Li Lun value (%): C45.70, H 4.48, and N 22.22, and K 12.37, 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 entecavir kalium and preparation method thereof
Getting Entecavir 5g, add potassium hydroxide aqueous solution (1.5mol/L) 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), continue to stir after 10 minutes, left standstill 2 hours until producing precipitation, suction filtration, behind filtering precipitate usefulness washing with acetone 2～3 times, be dissolved in water, make 5% Entecavir aqueous solutions of potassium, adopt cryodesiccated method to its freeze-drying, obtain the white solid powder, be entecavir kalium, molecular formula C
12H
14N
5O
3K, results of elemental analyses (%): C 45.71, and H 4.47, N22.26, K 12.35; Li Lun value (%): C 45.70, and H 4.48, and N 22.22, and K 12.37, 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. entecavir kalium sesqui hydrate and preparation method thereof
Getting Entecavir 5g, add the potassium hydroxide aqueous solution dissolving, is 12 with the pH value of ethanol regulator solution, under agitation add ethanol 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 the off-white color solid in 55 ℃ of drying under reduced pressure, contain 1.5 crystal water through thermal weight loss and differential thermal analysis, be entecavir kalium sesqui hydrate, molecular formula C
12H
14N
5O
3K.1.5H
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. entecavir kalium sesqui hydrate and preparation method thereof
Getting Entecavir 5g, add the potassium hydroxide aqueous 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, behind filtering precipitate usefulness washing with acetone 2～3 times, to constant weight, obtain white solid in 65 ℃ of drying under reduced pressure, contain 1.5 crystal water through thermal weight loss and differential thermal analysis, be entecavir kalium sesqui compound, molecular formula C
12H
14N
5O
3K.1.5H
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 kalium sesqui hydrate and preparation method thereof
Getting embodiment one prepared entecavir kalium 0.5 restrains, add 2.0ml distilled water its dissolving is clear and bright solution, slowly stir and in solution, drip 240ml acetone down, a large amount of turbidity sediments promptly appear, leave standstill and make its abundant sedimentation after-filtration, filter cake is dried to constant weight after cleaning 3～4 times with acetone 6ml, promptly gets entecavir kalium sesqui hydrate.
Embodiment eight. Entecavir potassium tablets and preparation
Get entecavir kalium 0.5g and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Entecavir kalium 0.5g
Starch 51.8g
Lactose 50.1g
Polyvidone (K
30) 2.5g
Magnesium Stearate 0.5g
Water is an amount of
By above prescription, carry out wet granulation, make entecavir kalium and said medicine carrier thorough mixing even, dry whole grain back and make 1000 with tabletting machine, every contains the active ingredient entecavir kalium 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 entecavir kalium dressing diaphragm.
Embodiment nine. the entecavir kalium capsule
Get entecavir kalium sesqui hydrate 1.24g (being equivalent to contain entecavir kalium 1.14g) and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Entecavir kalium sesqui hydrate 1.24g
Lactose 85g
Methylcellulose gum 3.2g
Xylo-Mucine 4.0g
Magnesium Stearate 1.9g
Water is an amount of
By above prescription, carrying out wet granulation makes entecavir kalium sesqui hydrate and said medicine carrier thorough mixing even, dry in 1000 Capsuleses of packing into behind the whole grain, containing active ingredient entecavir kalium sesqui hydrate in every capsules is 1.24mg/ grain (being equivalent to the 1.14mg entecavir kalium), for orally using.
Embodiment ten. Entecavir potassium tablets and preparation
Get entecavir kalium 0.57g (being equivalent to contain Entecavir 0.5g) and other pharmaceutical carrier auxiliary material, the composition of specifically writing out a prescription is as follows:
Entecavir kalium 0.57g
N.F,USP MANNITOL 70g
Cross-linked carboxymethyl cellulose 37g
Starch 1.5g
Stearic acid 0.3g
Water is an amount of
By above prescription, carrying out wet granulation makes entecavir kalium and said medicine carrier thorough mixing even, dry whole grain back and make 1000 with tabletting machine, every contains the active ingredient entecavir kalium is 0.57mg/ sheet (being equivalent to contain Entecavir 0.5mg), for orally using.
Embodiment 11. the entecavir kalium enteric coated tablet
Similarly, get entecavir kalium 0.5g, add an amount of carrier auxiliary material of people (as Microcrystalline Cellulose, lactose, polyvinylpyrrolidone, Magnesium Stearate etc.), wet grain is granulated and is made entecavir kalium and said medicine carrier thorough mixing even, whole grain back is made 1000 with tabletting machine, and making every, to contain the active ingredient entecavir kalium be the 0.5mg/ sheet, and this sheet is wrapped up with enteric coated solution, promptly getting specification is the entecavir kalium enteric coated 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 12. the entecavir kalium powder ampoule agent for injection
Get entecavir kalium 0.5g, N.F,USP MANNITOL 150g, add the dissolving of injection water and be diluted to 1800 milliliters, regulate pH with phosphate buffer and add injection water to 2000 milliliter after 9, 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 kalium lyophilized injectable powders, every bottle contains entecavir kalium 0.5mg.
Embodiment 13. the entecavir kalium injection liquid
Get entecavir kalium sesqui hydrate 0.62g (being equivalent to 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 kalium injection liquids, every bottle contains entecavir kalium sesqui hydrate 0.62mg (being equivalent to Entecavir 0.5mg).
Embodiment 14. the entecavir kalium oral liquid
Get entecavir kalium sesqui hydrate 6.2mg (being equivalent to contain entecavir kalium 5.7mg), maltose alcohol 60g, 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 and contains the entecavir kalium sesqui hydrate 0.62mg oral liquid of (being equivalent to contain entecavir kalium 0.57mg).
Embodiment 15. the Entecavir k particle
Get entecavir kalium 10mg, other gets Xylitol 30g, potassium benzoate 0.4g.With suitable quantity of water that entecavir kalium dissolving back adding strawberry flavour is an amount of, wet granulation, abundant mixing, oven dry, whole grain are packaged into 10 bags, promptly make every bag of granule that contains entecavir kalium 1mg.
Embodiment 16. the Entecavir potassium dispersible tablets
Prescription: entecavir kalium 0.57g
Lactose 60g
Sodium starch glycolate 13g
Microcrystalline Cellulose 28g
Water is an amount of
Magnesium Stearate 1g
Preparation method: earlier above-mentioned material separated pulverizing is crossed 100 sieves.Lactose, sodium starch glycolate, Microcrystalline Cellulose thorough mixing is even, be sprayed to pressed powder after the above-mentioned mixing with the Entecavir aqueous solutions of potassium, make entecavir kalium and said medicine carrier thorough mixing even, 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 entecavir kalium 0.57mg.This tablet can disperse in water in speed fast (in three minutes) disintegration, reaches the effect of quick-release onset.
Embodiment 17. entecavir kalium sheet (slow release formulation)
Prescription: entecavir kalium 1000mg
Vltra tears (K
4M) 68g
Lactose 31g
Magnesium Stearate 1g
The 8% polyvidone aqueous solution is an amount of
Preparation method: with entecavir kalium, Vltra tears (K
4M), lactose makes entecavir kalium and said medicine carrier thorough mixing even with 8% polyvidone aqueous solution wet granulation, behind oven dry, the whole grain, add the Magnesium Stearate mixing, the control tablet weight, be pressed into 1000, promptly getting content is the Entecavir potassium sustained release tablets 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 entecavir kalium is to play the effect of slowly-releasing.
Embodiment 18. the composite tablet of entecavir kalium 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 entecavir kalium 0.5mg and lamivudine 100mg.
Embodiment 19. the composite tablet of entecavir kalium 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 entecavir kalium 1mg and didanosine 200mg.
Embodiment 20. the composite tablet of entecavir kalium 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 entecavir kalium 0.5mg and adefovir ester 10mg.
Embodiment 21. by entecavir kalium or its hydrate that embodiment one to embodiment seven makes, be used for preparing the application of the hepatitis b virus infected medicine of treatment.
Claims (12)
1. the potassium salt compound of an Entecavir is characterized in that having following molecular structural formula
2. the hydrate of an entecavir kalium, its molecular structural formula is as follows
3. hydrate according to claim 2, more preferably entecavir kalium sesqui hydrate, i.e. x=1.5.
4. the preparation method of claim 1 or 2 described entecavir kaliums or its hydrate, this method comprises the following steps:
(1) reaction:
Entecavir is dissolved in the potassium hydroxide aqueous 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 entecavir kalium or entecavir kalium 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 entecavir kalium or entecavir kalium 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 potassium hydroxide.
7. a pharmaceutical composition contains pharmaceutically acceptable carrier and entecavir kalium or entecavir kalium hydrate.
8. the described pharmaceutical composition of claim 7, the content of wherein said entecavir kalium or entecavir kalium hydrate is 0.01mg～20mg, the content of preferred entecavir kalium or entecavir kalium hydrate is 0.1mg～5mg, and more preferably the content of entecavir kalium or entecavir kalium 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, the wherein preferred entecavir kalium sesqui of entecavir kalium hydrate hydrate.
11. be used to prepare claim 7,8 or 9 described arbitrary method for compositions, this method comprises makes acceptable any pharmaceutical dosage form on the pharmaceutics with entecavir kalium or its hydrate and pharmaceutically acceptable pharmaceutical carrier thorough mixing, and preferred pharmaceutical dosage form is tablet, capsule, granule, oral solution, injection.
12. entecavir kalium and hydrate thereof the application in the hepatitis b virus infected medicine of preparation treatment.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610077945 CN1900078A (en) | 2005-07-20 | 2006-04-27 | Entecavir potassium salt compound and its preparing method and medicine use |
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| CN200510085893.5 | 2005-07-20 | ||
| CN200510085893 | 2005-07-20 | ||
| CN 200610077945 CN1900078A (en) | 2005-07-20 | 2006-04-27 | Entecavir potassium salt compound and its preparing method and medicine use |
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| CN103142527A (en) * | 2013-03-25 | 2013-06-12 | 福建天泉药业股份有限公司 | Entecavir potassium tablet and preparation method thereof |
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| CN103142527A (en) * | 2013-03-25 | 2013-06-12 | 福建天泉药业股份有限公司 | Entecavir potassium tablet and preparation method thereof |
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