CN102018705A - Pharmaceutical composition containing febuxostat crystals and preparation method thereof - Google Patents

Abstract

The invention discloses a pharmaceutical composition which contains febuxostat crystals and medicinal auxiliary materials, wherein the X-ray powder diffractogram of the febuxostat crystals at 2theta are 6.70+/-0.2, 10.90+/-0.2, 13.40+/-0.2, 15.60+/-0.2, 17.50+/-0.2, 22.00+/-0.2, 24.60+/-0.2 and 25.25+/-0.2; and the medicinal auxiliary materials comprise a filler, an adhesive, a disintegrant, a lubricant and a water-soluble coating agent. The febuxostat tablets prepared by the method have the advantages of simple technique, no surfactant addition, high leaching speed, high preparation stability, low cost and the like, and are suitable for industrial production.

Description

A kind of crystalline pharmaceutical composition of Febustat and preparation method of containing

Technical field

The present invention relates to a kind of crystalline pharmaceutical composition of Febustat and this preparation of drug combination method of containing, belong to technical field of medicine synthesis.

Background technology

Febustat (Febuxostat), the former Febuxostat of translating, it is a kind of selectivity xanthine oxidase inhibitor of novel non-purine class, by the research and development of Japanese Teijin company, registered in European Union first in 2008, specification is 80mg and 120mg, and in March, 2009, in U.S.'s listing, specification was 40mg and 80mg first.The clinical hyperuricemia that is used for the treatment of.Its structure is as follows:

Chemical name: 2-(3-cyano-4-isobutoxy) phenyl-4-methyl-5-thiazole formic acid.

Febustat be white to off-white color crystallization or crystalline powder, this product is easily molten in dimethyl formamide, in dimethyl sulfoxide the dissolving, in ethanol, methanol and acetonitrile slightly soluble, insoluble in water.

Febustat is an insoluble drug, and shaping particles has material impact to dissolution in its crystal formation, granularity and the formulation preparation process.

The crystal formation document of Febustat is a lot, is summarized as follows: patent WO9965885, and the Teijin Ltd of the artificial Japan of application is CN1275126A in the corresponding patent of China, the applying date is 19990618.The polymorphic that this patent relates to amounts to five kinds of A, B, C, D, G.

Patent WO03082279, the Teijin Ltd of the artificial Japan of application is CN1642546 in the corresponding patent of China's application, this patent protection be the Pharmaceutical composition preparation method of B, D, E single crystal form.

Patent 200610030935.X; the application people be Shanghai Institute of Pharmaceutical Industry and Huahai Pharmaceutical Co., Ltd., Zhejiang, this patent protection be I, II crystal formation, this crystal formation is characterized by the X-diffraction; preparation method is that the I crystalline substance is got by re-crystallizing in ethyl acetate, and the II crystalline substance is separated out drying by regulating pH.

Patent 200610095263.0; the applicant is a Chongqing Medicine Industry Academe Co.,Ltd; this patent protection be three kinds of novel crystal forms H, I, the J of finished product; this crystal formation is by X-diffraction and infrared the sign; preparation method is nitrile solvents recrystallization such as acetonitrile, obtains so-called three kinds of crystal formations by different crystallizes and drying condition.

Patent 200810201652.6; the application people is Shanghai Pharmaceutical Inst., Chinese Academy of Sciences and Jiangsu Zhengda Tianqing Drug Industry Co., Ltd; this patent protection be the novel crystal forms K of finished product, this crystal formation is by X-diffraction and infrared the sign, preparation method is dioxane and mixed solvent recrystallization thereof.

Patent 200710043178.4, the application people is Shanghai Huatuo Medical Science Co., Ltd., this patent protection be the crystallite form of finished product, this crystal formation is characterized by the X-diffraction, preparation method is the ethyl acetate solvent recrystallization; Patent 200910068558.2, the application people is Taipu Medicine Science ﹠ Technology Development Co., Ltd., Tianjin, this patent protection be P (2) form of finished product, this crystal formation is characterized by the X-diffraction, preparation method is the mixed solvent recrystallization of ethanol water.

Febustat conventional tablet technology of preparing document is quite a few, CN101474175A discloses the method for preparing tablet thereof that contains four kinds of crystal formations of Febustat, it requires mean diameter to be preferably 3.5～7 μ m at 3.5～10 μ m, guarantees to prepare bioavailability height and stable formulation.

CN101152142A discloses and has contained Febustat as active component and contain the tablet of Polyethylene Glycol as solubilizing agent, in its preparation technology, needs Febustat is dissolved in 50% ethanol with Polyethylene Glycol, spray drying, obtain powder, granulate with the other drug mixed with excipients, tabletting is shaped.

CN101862326A discloses and has contained a kind of crystal formation of Febustat as active component, require the Febustat particle diameter less than 150 μ m (being 106～150 μ m in the example), and with Tween 80, sodium lauryl sulphate, Myrj 52, one or more surfactants of the polyoxyethylene castor oil glycerin ether moral method for preparing tablet thereof as solubilizing agent.

A kind of novel crystal forms that is different from the arbitrary crystal formation of above-mentioned document that Febustat among the present invention adopts ketone reagent recrystallization such as butanone, methyl tertbutyl ketone, butanone to obtain, this crystal form X-ray powder diffraction pattern is 6.70 ± 0.2,10.90 ± 0.2,13.40 ± 0.2,15.60 ± 0.2,17.50 ± 0.2,22.00 ± 0.2,24.60 ± 0.2,25.25 ± 0.2 at 2 θ.Crystal formation does not contain the crystal habit of water and other solvents.

In actual production, below 10 μ m, powder is in unsteady state to the employing micronization technology with raw material pulverizing among the CN101474175A, and easily gathering, flowability and dispersibility are very poor.Concern as can be known that according to raw material pulverizing energy consumption and miniaturization degree degree of grinding is big more, energy consumption is high more.Can reach powder size by the air-flow micronization technology at present is below the 10 μ m, but significant loss is big, and cost is higher.This technology is not suitable for suitability for industrialized production.

Adopt Febustat and Polyethylene Glycol spray drying technology among the CN101152142A, whole process of preparation needs twice granulation, and preparation process is complicated, and preparation is not carried out study on the stability.

Among the CN101862326A, be that the surfactant of representative generally has toxicity with the Tween 80, its lipophilic composition comprises unsaturated fatty acid, the very easy oxidative degradation of these unsaturated fatty acids and produce more toxic substance.Therefore surfactant all has clear and definite content restriction in pharmaceutical preparation.Take the medicine that contains surfactant for a long time and bring unnecessary risk to the patient.

Summary of the invention

Technical problem to be solved by this invention provides and a kind ofly comprises the crystalline pharmaceutical composition of Febustat, and the preparation method of aforementioned pharmaceutical compositions.Containing the crystalline pharmaceutical composition of Febustat, to have preparation technology simple, and surfactant-free adds, and stripping is rapid, better stability of preparation, and low cost and other advantages is suitable for suitability for industrialized production.

In order to solve above-mentioned technical problem, pharmaceutical composition of the present invention contains Febustat crystal and pharmaceutic adjuvant, and described Febustat crystal X-ray powder diffraction pattern is 6.70 ± 0.2,10.90 ± 0.2,13.40 ± 0.2,15.60 ± 0.2,17.50 ± 0.2,22.00 ± 0.2,24.60 ± 0.2,25.25 ± 0.2 at 2 θ; Described pharmaceutic adjuvant comprises filler, binding agent, disintegrating agent, lubricant, water solublity coating materials.

The crystalline particle diameter of described Febustat is 75-100 μ m.

Described binding agent is 10%～60% ethanol water.

Febustat content is 40-120mg in the described pharmaceutical composition.

A kind of method for preparing above-mentioned pharmaceutical composition, it may further comprise the steps:

(1) Febustat is pulverized, obtained the microgranule that average grain reaches 75～100 μ m;

(2) the preparation binder solution for example prepares 10%～60% ethanol water;

(3) the same filler of Febustat, disintegrating agent are boiling shape mix homogeneously in the fluidised bed granulator bed material, spray into suitable amount of adhesive, granulate, get the satisfactory dried granule of moisture;

(4) add disintegrating agent in the dried granule, mix lubricant is even, measures content, adopts suitable punch die tabletting, the plain sheet of Febustat;

(5) adopt the water-soluble film clothing to plain coating tablets, get Febustat Film coated tablets finished product.

By controlling suitable powder diameter, make it reach 75～100 μ m, meet under the dissolution requirement prerequisite in assurance, relax the powder particle diameter requirement, reduced energy consumption, reduced significant loss.Adopt fluidized bed granulation, make porous, the bigger soft granule of surface area, its flowability, compressibility, uniformity and dissolution rate aspect all improve a lot than the granule that wet granulation is made, and will mix, granulate, a dry step finishes, and simplified operating procedure.The potential hazard of having avoided surfactants such as interpolation tween 80 to increase drug dissolution and having brought.

Investigate at 6 months accelerated stabilities (40 ℃, RH75%) in, press two appendix X of Chinese Pharmacopoeia version in 2010 C, second method, be dissolution medium with 0.5% lauryl sodium sulfate aqueous solution, the mensuration dissolution was more than 90% in 15 minutes.

The crystalline pharmaceutical composition of Febustat and preparation method thereof that contains disclosed by the invention, reducing manufacturing cost, guarantee drug dissolution, simplifying the operation, avoid additionally to add aspect such as solubilizing agent and found best joint, be the technology that a kind of suitability for industrialized is produced the Febustat tablet.

The specific embodiment

Embodiment 1

Preparation method:

1. the Febustat raw material pulverizing is 100 μ m to mean diameter, standby.

2. respectively lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are received sodium cellulosate, that magnesium stearate is crossed 80 orders is standby.

3. dispose 45% alcoholic solution, standby.

4. Febustat, lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are contained in and are boiling shape mix homogeneously in the fluidised bed granulator bed material, spray into an amount of 45% alcoholic solution, granulate, must do granule.

5. add the magnesium stearate mix homogeneously in the dried granule, measure content, tabletting gets the plain sheet of Febustat.

6. dispose 10% Opadry II aqueous solution, with the plain coating tablets that makes, weightening finish 2%～5%, promptly.

Embodiment 2

Preparation method:

1. the Febustat raw material pulverizing is 85 μ m to mean diameter, standby.

2. respectively lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are received sodium cellulosate, that magnesium stearate is crossed 80 orders is standby.

3. dispose 10% alcoholic solution, standby.

4. Febustat, lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are contained in and are boiling shape mix homogeneously in the fluidised bed granulator bed material, spray into an amount of 45% alcoholic solution, granulate, must do granule.

5. add the magnesium stearate mix homogeneously in the dried granule, measure content, tabletting gets the plain sheet of Febustat.

6. dispose 10% Opadry II aqueous solution, with the plain coating tablets that makes, weightening finish 2%～3%, promptly.

Embodiment 3

Preparation method:

1. the Febustat raw material pulverizing is 75 μ m to mean diameter, standby.

2. respectively lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are received sodium cellulosate, that magnesium stearate is crossed 80 orders is standby.

3. dispose 60% alcoholic solution, standby.

4. Febustat, lactose, microcrystalline Cellulose, cross-linked carboxymethyl cellulose are contained in and are boiling shape mix homogeneously in the fluidised bed granulator bed material, spray into an amount of 55% alcoholic solution, granulate, must do granule.

5. add the magnesium stearate mix homogeneously in the dried granule, measure content, tabletting gets the plain sheet of Febustat.

6. dispose 10% Opadry II aqueous solution, with the plain coating tablets that makes, weightening finish 2%～3%, promptly.

The crystalline X-ray powder diffraction pattern of Febustat in the foregoing description is 6.70 ± 0.2,10.90 ± 0.2,13.40 ± 0.2,15.60 ± 0.2,17.50 ± 0.2,22.00 ± 0.2,24.60 ± 0.2,25.25 ± 0.2 at 2 θ.

The accelerated stability test result of embodiment:

Accelerated stability investigation condition was 40 ℃ in 6 months, RH75%.

Dissolution in vitro assay method of the present invention adopts second method of two appendix XC of Chinese Pharmacopoeia version in 2010 dissolution method, dissolution medium is 0.5% sodium dodecyl sulfate solution, the dissolution medium volume is that 900ml, rotating speed are 75 rev/mins, temperature is 37 ± 0.5 ℃, and be 15 minutes sample time; Sample size of the present invention is measured according to 2010 editions two appendix VD of Chinese Pharmacopoeia, adopts the Febustat external standard method; Sample related substance of the present invention adopts 0.5% Self-control method to measure according to content assaying method.The result is as follows:

The foregoing description does not limit the present invention in any way, and every employing is equal to replaces or technical scheme that the mode of equivalent transformation obtains all drops in protection scope of the present invention.

Claims (5)

1. pharmaceutical composition, it is characterized in that said composition contains Febustat crystal and pharmaceutic adjuvant, the crystalline X-ray powder diffraction pattern of described Febustat is 6.70 ± 0.2,10.90 ± 0.2,13.40 ± 0.2,15.60 ± 0.2,17.50 ± 0.2,22.00 ± 0.2,24.60 ± 0.2,25.25 ± 0.2 at 2 θ; Described pharmaceutic adjuvant comprises filler, binding agent, disintegrating agent, lubricant, water solublity coating materials.

2. pharmaceutical composition according to claim 1 is characterized in that: the crystalline particle diameter of described Febustat is 75-100 μ m.

3. pharmaceutical composition according to claim 1 is characterized in that: described binding agent is 10%～60% ethanol water.

4. pharmaceutical composition according to claim 1 is characterized in that: Febustat content is 40-120mg in the described pharmaceutical composition.

5. method for preparing pharmaceutical composition according to claim 1 is characterized in that this method may further comprise the steps:

(1) Febustat is pulverized, obtained the microgranule that average grain reaches 75～100 μ m;

(2) preparation binder solution;

(3) the same filler of Febustat, disintegrating agent are boiling shape mix homogeneously in the fluidised bed granulator bed material, spray into suitable amount of adhesive, granulate, get the satisfactory dried granule of moisture;

(4) add disintegrating agent in the dried granule, mix lubricant is even, measures content, adopts suitable punch die tabletting, the plain sheet of Febustat;

(5) adopt the water-soluble film clothing to plain coating tablets, get Febustat Film coated tablets finished product.