CN1833643A - Entikawei solid dispersion compsns. and prepn. thereof - Google Patents

Abstract

A dispersing solid composition of entecavir with high dispersity and solubility is prepared from entecavir and polyvinyl pyrrolidone or citric acid. Its preparing process is also disclosed.

Description

Entikawei solid dispersion compositions and preparation method thereof

Technical field

The invention belongs to medical technical field.The present invention relates generally to Entecavir and polyvinylpyrrolidone solid dispersion compositions and Entecavir and citric acid solid dispersive composition and their preparation method, also relates to the pharmaceutical preparation that this solid dispersion compositions is main active ingredient.

Background technology

Entecavir, its structural formula is:

Entecavir is the antiviral property material of treatment hepatitis B virus infection.On April 8th, 2005, every day, dosage was 0.5mg in U.S.'s listing.

U.S. Pat 5206244 discloses the purposes of Entecavir and its treatment hepatitis B virus.Entecavir has good tolerability, and untoward reaction is slight and have a reversibility.The improvement synthetic method of Entecavir is disclosed in WO98/09964 and the WO04/052310 description.Disclosed in these files is the Entecavir of crystal habit, and the feature to crystalline state is not described.Entecavir is slightly water-soluble, because dissolubility is little, the dissolution of its solid preparation is had considerable influence.

At present, the preparation technique of Entecavir has following deficiency:

1. the day dose of Entecavir only is 0.5mg, is 100mg as if the solid preparation that Entecavir is made such as the weight of tablet or capsule, and then Entecavir shared weight in preparation only is 0.5%.So in the process of preparation solid pharmaceutical preparation, Entecavir and pharmaceutic adjuvant are difficult to mix homogeneously, often cause the solid preparation product content uniformity defective.File CN1310999 discloses a kind of method for preparing the pharmaceutical preparation of low content Entecavir, be by earlier Entecavir and adhesive material being formed aqueous solution, in the mode of spraying or liquid stream the solution calmness is arrived the particle surface of carrier matrix then, heat drying is removed the solvent on the carrier surface, again with other adjuvant such as disintegrating agent and/or mix lubricant, and then make solid preparation.This method complex process, Entecavir/carrier matrix granule are assembled easily and are not easy to make the well-distributed solid preparation of Entecavir content uniformity.

2. the dissolubility of Entecavir in water be in molten and slightly molten between because dissolubility is undesirable, so be unfavorable for the bioavailability raising of its solid preparation.File CN1699365A has announced that the dissolubility of Entecavir in water less than 4g/100ml, also announced Entecavir is made sodium salt and method.Entecavir is made sodium salt, is that the carbon back in its structure is converted into rare pure formula structure, and the hydrogen on the hydroxyl is replaced by sodium ion.Water solublity is greatly improved like this, but in fact Entecavir has changed into another kind of material.Variation on this structure of matter, regulation in " the medicine registration management way " of State Food and Drug Administration's promulgation should be treated by another kind of new drug.

Description of drawings

Entecavir and polyvinylpyrrolidone solid dispersion compositions X-ray powder diffraction.

Collection of illustrative plates shows that Entecavir is present in this solid dispersion compositions with no crystal habit.

Summary of the invention

For overcoming the deficiencies in the prior art, we are surprised to find that, Entecavir and polyvinylpyrrolidone solid dispersion compositions and Entecavir and citric acid solid dispersive composition can prepare with spray drying method or concentrating under reduced pressure seasoning, and technology is simple and easy to do.The active ingredient of products obtained therefrom has highly uniformly dispersed, very helps the preparation of solid preparation; Water-soluble increases greatly, can improve the dissolution rate of medicine significantly, is significant to improving bioavailability.

One of the object of the invention provides the solid dispersion compositions that Entecavir and polyvinylpyrrolidone or citric acid are prepared into.Wherein the part by weight of Entecavir and polyvinylpyrrolidone or citric acid is 1: 1-1: 100, preferred 1: 5-1: 10.Described Entecavir is crystal habit, noncrystalline form, also can be in solvent dissolved state (not carrying out crystalline reactant liquor) as refined; The molecular weight of described polyvinylpyrrolidone is 15000-60000, preferred 30000; Described citric acid is the citric acid that contains a part water of crystallization, also can select no water of crystallization citric acid for use.

Another purpose of the present invention is to put forward the preparation method of the solid dispersion compositions of a kind of Entecavir of arch and polyvinylpyrrolidone or citric acid.A kind of pharmaceutical preparation and preparation method that contains solid dispersion compositions is provided simultaneously.

The preparation method of solid dispersion compositions of the present invention:

A, get Entecavir, polyvinylpyrrolidone or citric acid, part by weight is 1: 1-1: 100, mix after adding dissolution with solvents or adding dissolution with solvents separately, then solution is carried out spray drying, the gained solid matter carries out drying under reduced pressure to constant weight at 30-50 ℃, pulverize, promptly get solid dispersion compositions of the present invention.

B, get Entecavir, polyvinylpyrrolidone or citric acid, part by weight is 1: 1-1: 100, mix after adding an amount of dissolution with solvents or adding dissolution with solvents separately, solution becomes solid at 30-50 ℃ of concentrating under reduced pressure, drying under reduced pressure is pulverized to constant weight again, promptly gets solid dispersion compositions of the present invention.

When wherein preparing Entecavir and polyvinylpyrrolidone solid dispersion compositions, optionally solvent has methanol, ethanol, acetone, preferred alcohol; Optional solvent has methanol, ethanol, water or their mixture, the mixture of preferred alcohol and water when preparation Entecavir and citric acid solid dispersive composition.

Solubility test:

A, get Entecavir and polyvinylpyrrolidone solid dispersion compositions (1: 4) 10g, put in the 25ml volumetric flask in room temperature, thin up fully rocks to scale, can get transparency liquid; Other gets Entecavir 1g, puts in the 25ml volumetric flask, adds water to scale, fully rocks, and has the part Entecavir not dissolve.As seen Entecavir polyvinylpyrrolidone solid dispersion compositions of the present invention can make the dissolubility of Entecavir reach 8%, and the dissolubility of Entecavir in water is less than 4%.

B, get Entecavir and citric acid solid dispersive composition (1: 3) 10g, put in the 25ml volumetric flask in room temperature, thin up fully rocks to scale, can get transparency liquid; Illustrate that the dissolubility of Entecavir in water reached 13.3%, improved greatly Entecavir in water less than 4% dissolubility.

After measured, the melt temperature of Entecavir and polyvinylpyrrolidone solid dispersion compositions is greater than 150 ℃, and heating differential analysis can only be found glass transition temperature, no fusing point.It is better mobile to pulverize the back.The X-ray powder diffraction shows that Entecavir is the amorphism attitude in this solid dispersion compositions.

Second one of Pharmacopoeia of the People's Republic of China version in 2005 is to solid preparations such as tablet, capsule regulation, if the weight content of principal agent in preparation less than 5% o'clock, should be checked uniformity of dosage units.This be because drug content less than 5% o'clock, principal agent and pharmaceutic adjuvant are difficult for mix homogeneously, occur the formulation content non-uniform phenomenon easily, thereby have a strong impact on product quality.

According to the using dosage of Entecavir, the content of every (grain) Entecavir should be 0.1mg-0.5mg.If the weight of tablet (or capsule) is 100mg, drug content be 0.1%-0.5% only so, 5% the boundary that is significantly less than that pharmacopeia stipulates.The present invention makes highly uniformly dispersed solid dispersion compositions with Entecavir, just obtained the effect same of relative raising Entecavir percentage composition in preparation, make the uniformity of dosage units of product qualified easily, thereby can avoid unnecessary loss, improve the effectiveness and the safety of medication.

The uniformity of dosage units test is checked according to second appendix XE of Pharmacopoeia of the People's Republic of China version in 2005 method.

Assay is taked high performance liquid chromatography (PHLC) method, and condition is: AlltechC18,150mm * 4.6mm pillar is with acetonitrile/phosphate buffer gradient elution.Earlier with 5% acetonitrile/95%PH=6.0 phosphate buffer eluting 5 minutes, used gradient elution from the 5th minute to 30 minutes, eluent is increased to the phosphate buffer of 50% acetonitrile/50%PH=6.0 from the phosphate buffer linearity of 5% acetonitrile/95%PH=6.0, keeps 15 minutes eluting again in this solvent ratio then.Molten fast 1.0ml/ minute, wavelength 225nm was with calculated by peak area.

Check 1

Get 1g Entecavir and polyvinylpyrrolidone solid dispersion compositions (1: 4), pulverize, be divided into 10 equal portions, each precision takes by weighing 2.5mg in every duplicate samples, is 100 relative amount with HPLC method mensuration with labelled amount, sees Table 1.

Table 1

The sample sequence number	1	2	3	4	5	6	7	8	9	10	Meansigma methods X
												Content x	101	101.1	100.91	100.3	100.8	100.8	101.2	100.65	100	100.7	100.746

Standard deviation $(S=\sqrt{\frac{\mathrm{\Σ}{(X-\stackrel{\‾}{X})}^2}{n-1}})$ As calculated, S=0.1317

The absolute value A=|100-X|=|100-100.746|=0.746 of the difference of labelled amount and average

A+1.80S=0.746+1.8 * 0.1317=0.9830 then

The pharmacopeia regulation, A+1.80S≤15.0 show that promptly uniformity of dosage units is up to specification, and the A+1.80S=0.9830 of solid dispersion compositions of the present invention illustrates that content has high homogeneity.

Check 2

Get 1g Entecavir and citric acid solid dispersive composition (1: 4), pulverize, be divided into 10 equal portions, each precision takes by weighing 2.5mg in every duplicate samples, is 100 relative amount with HPLC method mensuration with labelled amount, sees Table 2.

Table 2

The sample sequence number	1	2	3	4	5	6	7	8	9	10	Meansigma methods X
												Content X	98.5	98.7	98.7	98.2	98.3	98.2	98.4	98.1	98.0	98.9	98.4

Standard deviation $S(S=\sqrt{\frac{\mathrm{\Σ}{(X-\stackrel{\‾}{X})}^2}{n-1}})$ S=0.2944 as calculated

The absolute value A=|100-X|=|100-98.4|=1.6 of labelled amount and equal value difference

A+1.80S=1.6+1.8 * 0.2944=2.13 then

The pharmacopeia regulation, A+1.80S≤15.0 show that promptly uniformity of dosage units is up to specification, and the A+1.80S=2.13 of solid dispersion of the present invention illustrates that content has high homogeneity.

Experiment shows, Entecavir has highly uniformly dispersed in solid dispersion compositions, when the Entecavir that has highly evenly been diluted by solid adjuvant material (polyvinylpyrrolidone or citric acid) mixes with pharmaceutically acceptable carrier more like this, just than being easier to mix homogeneously.During the preparation solid preparation, the uniformity of dosage units of Entecavir is just qualified easily.

The specific embodiment

The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.

Embodiment 1

Get Entecavir 1g, add ethanol 20ml dissolving; Get polyvinylpyrrolidone 4g, add ethanol 20ml dissolving after, join in the Entecavir alcoholic solution mix homogeneously.Solution is evaporated to solid at 35-50 ℃, and gained solid vacuum drying again or directly carries out spray drying with solution to constant weight, obtains solid, and vacuum drying promptly obtains Entecavir polyvinylpyrrolidone solid dispersion compositions to constant weight again.

Embodiment 2

Get Entecavir 1g, add ethanol 20ml dissolving; Get citric acid 4g, add water 20ml dissolving after, join in the Entecavir alcoholic solution mix homogeneously.Solution is evaporated to solid at 35-50 ℃, and gained solid vacuum drying again or directly carries out spray drying with solution to constant weight, obtains solid, is dried to constant weight again, promptly obtains Entecavir citric acid solid dispersive composition.

Embodiment 3

Tablet formulation: solid dispersion compositions 15% of the present invention, microcrystalline Cellulose 35%, starch 45%, polyvinylpolypyrrolidone 3%, Pulvis Talci 1%, magnesium stearate 1%.

Preparation technology: a, principal agent and adjuvant are crossed 100 mesh sieves respectively, standby.

B, with the adjuvant mix homogeneously of recipe quantity, again with the abundant mixing of principal agent.Add 10% starch slurry and make soft material in right amount, cross 24 mesh sieves, dry in 50 ℃ of ventilated drying ovens.

C, dried granule are crossed 20 mesh sieve granulate, add Pulvis Talci and magnesium stearate, tabletting.

Embodiment 4

Capsule prescription: solid dispersion compositions 15% of the present invention, microcrystalline Cellulose 35%, lactose 45%, methylcellulose 3%, magnesium stearate 2%.

Preparation technology: a, principal agent and adjuvant are crossed 100 mesh sieves respectively, standby.

B, with the adjuvant mix homogeneously of recipe quantity, again with the abundant mixing of principal agent.Add 5% polyvidone and make soft material in right amount, cross 30 mesh sieves, dry in 50 ℃ of ventilated drying ovens.

C, dried granule are crossed 30 mesh sieve granulate, add magnesium stearate, and be promptly encapsulated.

Claims (15)

1, a kind of Entecavir and polyvinylpyrrolidone solid dispersion compositions is characterized in that Entecavir and polyvinylpyrrolidone in the dispersive composition are no crystal formation attitudes, and Entecavir has the high degree of dispersion uniformity therein.

2, solid dispersion compositions according to claim 1 is characterized in that described solid dispersion compositions dissolubility in water is bigger, and wherein the weight ratio of Entecavir and polyvinylpyrrolidone is 1: 1～1: 100

3, solid dispersion compositions according to claim 1 is characterized in that described solid dispersion compositions is carried out heating differential analysis can only find glass transition temperature, no fusing point, and melt temperature is higher, pulverizes the back flowability better.

4, solid dispersion compositions according to claim 1 is characterized in that not showing in the X-ray powder diffraction spectrogram of this solid dispersion compositions the crystal diffraction peak of Entecavir.

5, the preparation method of a kind of Entecavir and polyvinylpyrrolidone solid dispersion compositions is characterized in that preparing as follows;

It is an amount of to get Entecavir, is dissolved in an amount of solvent; Get polyvinylpyrrolidone and join in right amount in the above-mentioned solvent, stir and make dissolving, solution is at 35-50 ℃ of concentrating under reduced pressure, make solid, or make solid with spray drying process, with the solid drying under reduced pressure to constant weight, porphyrize makes Entecavir and polyvinylpyrrolidone solid dispersion compositions.

6, the preparation method of Entecavir according to claim 5 and polyvinylpyrrolidone solid dispersion compositions, it is characterized in that used Entecavir be crystal habit, noncrystalline form or in solvent the Entecavir of dissolved state.

7, solid dispersion compositions according to claim 5 is characterized in that preferred molecular weight is 30000 polyvinylpyrrolidone.

8, the preparation method of solid dispersion compositions according to claim 5 is characterized in that solvent can select methanol, ethanol, acetone, preferred alcohol for use.

9, the solid dispersion compositions of a kind of Entecavir and citric acid, it is characterized in that Entecavir has the high degree of dispersion uniformity in this solid dispersion compositions, solid dispersion compositions has good water-solubility, and wherein the weight ratio of Entecavir and citric acid is 1: 1-1: 100.

10, the preparation method of a kind of Entecavir and citric acid solid dispersive composition is characterized in that preparing as follows:

It is an amount of to get Entecavir, is dissolved in an amount of solvent; Get citric acid and be dissolved in right amount in an amount of solvent,, remove with distillation under vacuum with spray drying method or at 30～50 ℃ and to desolvate above-mentioned two kinds of solution mix homogeneously, obtain solid, the solid matter drying under reduced pressure to constant weight, is pulverized, promptly got Entecavir and citric acid solid dispersive composition.

11, the preparation method of solid dispersion compositions according to claim 10, it is characterized in that used Entecavir be crystal habit, noncrystalline form or in solvent the Entecavir of dissolved state.

12, the preparation method of solid dispersion compositions according to claim 10 is characterized in that solvent can select methanol, ethanol, water or their mixed liquor, the mixed liquor of preferred alcohol and water for use.

13, a kind of medicine for the treatment of hepatitis contains right requirement 1 or described solid dispersion compositions of claim 9 and pharmacy acceptable carrier.

14, a kind of medicine as claimed in claim 13 is characterized in that minimum preparation unit contains Entecavir 0.1mg to 0.5mg.

15, medicine according to claim 13 is characterized in that medicament form of pharmaceutical preparation is tablet, colloid, powder, drop pill.

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