CN102614145B - Stable febuxostat tablet and preparation method thereof - Google Patents
Stable febuxostat tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a stable febuxostat tablet and a preparation method thereof. Specifically, the invention relates to a febuxostat tablet, which comprises: (i) febuxostat or a pharmaceutically-acceptable salt thereof, a solvent complex and multiple crystal forms, (ii) microcrystalline cellulose, (iii) pregelatinized starch, and (iv) sodium carboxymethyl starch and an optional bonding agent, a wetting agent, a lubricating agent and a flow aid. The febuxostat tablet disclosed by the invention has high dissolving performance and/or high stable performance, and an effective febuxostat oral solid preparation, particularly a tablet is provided clinically.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of pharmaceutical composition of xanthine oxidase inhibitor Febuxostat, particularly relate to the Febuxostat tablet.Also relate to the method for preparing this tablet.Febuxostat tablet provided by the invention has good pharmaceutical properties.
Background technology
Hyperuricemia is that it is the most dangerous factor of bringing out gout because the uric acid generation increases and/or the kidney uric acid is secreted due to the minimizing.Using medicine to reduce the interior uric acid concentration of blood is one of common method of prevention gout generation, and this class medicine comprises can block uricosuric and the xanthine oxidase/xanthine dehydrogenase inhibitor that renal tubules chamber film absorbs uric acid.But uricosuric is forbidden in the renal dysfunction patient, and the patient with normal renal function then can cause the urine alkalization with this type of medicine; Allopurinol then is the xanthine oxidase/xanthine dehydrogenase inhibitor of present unique listing, but it only is used for following 3 kinds of patients: the uricosuric medicine can not make that uric acid concentration in its blood is lower than the patient of 70mg/L, the patient that can not tolerate the uricosuric medicine and cause gout simultaneously with the patient of renal dysfunction because uric acid produces to increase, and allopurinol has obvious untoward reaction, such as hepatitis, nephropathy and anaphylaxis etc.
In view of the inhibition to xanthine oxidase is the mechanism that the prevention gout occurs, thereby research worker has been targeted than the safer effective drug development of allopurinol.Look back nearly 2 years gout treatment medicine market, be not difficult to find out to be difficult to see the new product listing in this field, market is still take allopurinol and benzbromarone as main.These two kinds of medicines all are the catabasis medications, and the former is to suppress uricopoiesis as main, and the latter is to promote drainage as main.
Febuxostat (febuxostat) is the synthetic anti-gout drugs of new generation of Supreme Being people (Teijin) company, demonstrates fabulous activity, and it is a kind of selectivity xanthine oxidase/xanthine dehydrogenase inhibitor, has a good application prospect.The SK Chemical company exploitation of European Ipsen company and Korea S has been given in the application that Supreme Being people company has submitted Febuxostat sheet 20～40mg dosage in April, 2004 in Japan, Febuxostat compound by special permission.The Febuxostat (Adenuric) of in May, 2008 European Union's approval Ipsen company goes on the market, and is used for the treatment of the chronic hyperuricemia of gout.The Febuxostat (ULORIC) of in February, 2009 FDA approval TAKEDA company is at U.S.'s listing, specification 40mg, 80mg.
The present kind of antigout drug is few, and clinical treatment is mainly take colchicine, nonsteroidal antiinflammatory drug, hormone, promotion urate excretion medicine (such as probenecid, sulfinpyrazone and benzbromarone) and inhibition uric acid synthetic drug (allopurinol) as main.These medicines are defectiveness all in treatment.Weak curative effect, side effect become greatly the bottleneck of its clinical practice.But not the effectiveness of Bu Suotan and specificity all are better than the standard drug allopurinol of present treatment gout, are the new drugs of first treatment hyperuricemia over 40 years.
Febuxostat is a non-purines xanthine oxidase inhibitor, and its basic role mechanism is similar with allopurinol.Yet allopurinol is followed obvious anaphylaxis, and Febuxostat does not but show with allopurinol to have cross reaction.And Febuxostat is used for Renal Failure Patients and has higher-security.About the effectiveness aspect, Febuxostat 80mg/d shows that the reduction for uric acid is better than allopurinol 300mg/d.
Multicenter, double blinding, at random evaluation in clinical Febuxostat safety and to the curative effect of gout.Always have 136 male and 17 women's gout patients and accept at random placebo or this product (40,80 or 120mg/d), detect after 4 weeks and find, before treating, each dosage group patients serum uric acid (sUA) concentration of this product all significantly reduces, according to dosage each group is average respectively from low to high reduces by 37%, 44% and 59%, and placebo group patient sUA concentration has only reduced by 2%; And placebo group and from low to high in each dosage group sUA concentration drop to the following patient of 60mg/L and account for respectively 0%, 56%, 76% and 94%; Most humans adheres to having finished test, and Febuxostat is close with the placebo group adverse reaction rate, is respectively 54% and 50%, and these untoward reaction are mostly slight, have self limiting.
The same with allopurinol, the formation of Febuxostat uric acid capable of blocking, and uric acid crystal is deposited on the joint of gout patients, causes painful swelling.But allopurinol can suppress the enzyme of a series of participation uric acid paths, and Febuxostat then only suppresses xanthine oxidase, thereby its effect has more specificity.Doctor MacDonald of TAP company thinks that this difference between the effects is in theory so that Febuxostat is more safer than allopurinol.Allopurinol can cause about 1%～2% patient and side effect occur, and wherein 25% or even fatal.Especially, this product may more be applicable to the renal failure patient, and allopurinol is via renal excretion mainly at liver metabolism.
Febuxostat is that a kind of nonhygroscopic white crystals powder is easy, is dissolved in dimethyl formamide, is dissolved in dimethyl sulfoxide; Be slightly soluble in ethanol; Slightly be slightly soluble in methanol and acetonitrile, substantially water insoluble.205 ℃ to 208 ℃ of melting ranges.There is multiple crystal formation in Febuxostat, and there is the possibility that turns brilliant between each crystal formation, for example just may under certain condition, change into other crystal formation between several crystal formations of CN1275126A record, the conversion of crystal formation for the dissolution of medicament character such as pharmaceutical preparation or stability wait existence replace impact.The above-mentioned character of the Febuxostat for example dissolubility in the water makes this medicine particularly during tablet, particularly run into challenge at the preparation solid preparation when preparation has the tablet of good dissolving out capability and/or stability.
Therefore, those skilled in the art expectation febuxostat solid preparation that has a kind of new method to prepare to have Good Pharmacy feature tablet particularly.
Summary of the invention
The object of the invention is to be the clinical febuxostat solid preparation that a kind of novelty is provided tablet particularly, said preparation has good pharmacy feature.The inventor finds that the Febuxostat tablet with specific prescription not only has good dissolving out capability, but also has good stability.The present invention is based on this discovery and be accomplished.
First aspect present invention provides a kind of Febuxostat tablet, and it comprises:
I) Febuxostat or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose,
Iii) pregelatinized Starch, and
Iv) carboxymethyl starch sodium,
And optional binding agent, wetting agent, lubricant, fluidizer.
According to the Febuxostat tablet of first aspect present invention, it comprises:
I) Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose of 20-200 weight portion,
Iii) pregelatinized Starch of 5-150 weight portion, and
Iv) carboxymethyl starch sodium of 2-100 weight portion,
And optional binding agent, wetting agent, lubricant, fluidizer.
According to the Febuxostat tablet of first aspect present invention, it comprises:
I) Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose of 20-200 weight portion,
Iii) pregelatinized Starch of 5-150 weight portion,
Iv) carboxymethyl starch sodium of 2-100 weight portion,
V) binding agent, and
Vi) lubricant.
According to the Febuxostat tablet of first aspect present invention, it comprises:
I) Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose of 20-200 weight portion,
Iii) pregelatinized Starch of 5-150 weight portion,
Iv) carboxymethyl starch sodium of 2-100 weight portion,
V) binding agent of 1-20 weight portion, and
Vi) lubricant of 1-15 weight portion.
According to the Febuxostat tablet of first aspect present invention, it comprises:
I) Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose of 25-180 weight portion,
Iii) pregelatinized Starch of 7.5-140 weight portion,
Iv) carboxymethyl starch sodium of 2-75 weight portion,
V) binding agent of 1-15 weight portion, and
Vi) lubricant of 1-10 weight portion.
According to the Febuxostat tablet of first aspect present invention, it comprises:
I) Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic,
Ii) microcrystalline Cellulose of 30-160 weight portion,
Iii) pregelatinized Starch of 10-120 weight portion,
Iv) carboxymethyl starch sodium of 3-50 weight portion,
V) binding agent of 1-10 weight portion, and
Vi) lubricant of 1-10 weight portion.
Febuxostat tablet according to first aspect present invention, in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the amount of the microcrystalline Cellulose that wherein contains is the 20-200 weight portion, 25-180 weight portion for example, for example 30-160 weight portion, for example 40-160 weight portion.
Febuxostat tablet according to first aspect present invention, in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the amount of the pregelatinized Starch that wherein contains is the 5-150 weight portion, 7.5-140 weight portion for example, for example 10-120 weight portion, for example 15-120 weight portion.
Febuxostat tablet according to first aspect present invention, in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the amount of the carboxymethyl starch sodium that wherein contains is the 2-100 weight portion, for example 2-75 weight portion, for example 3-50 weight portion.
Febuxostat tablet according to first aspect present invention, in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the amount of the binding agent that wherein contains is the 1-20 weight portion, for example the 1-15 weight portion, for example 1-10 weight portion, for example 1-5 weight portion.
According to the Febuxostat tablet of first aspect present invention, in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the amount of the lubricant that wherein contains is the 1-15 weight portion, for example the 1-10 weight portion.
According to the Febuxostat tablet of first aspect present invention, the acceptable salt of the pharmacy of wherein said Febuxostat is its sodium salt, potassium salt, calcium salt, magnesium salt, lithium salts.
According to the Febuxostat tablet of first aspect present invention, the solvate of wherein said Febuxostat is its hydrate, alcohol adduct, ethanol compound.
According to the Febuxostat tablet of first aspect present invention, a kind of crystalline state of the polymorphic right and wrong Bu Suotan of wherein said Febuxostat, or the mixture of two or more crystalline state.In one embodiment, the crystal formation of described Febuxostat is selected from: crystal form A, B, C, D, G, amorphous (their preparation example is as being recorded in CN1275126A), crystal formation H, I, J (their preparation example is as being recorded in CN1970547A), crystal form K, L (their preparation example is as being recorded in CN101759656A), crystal form M (their preparation example is as being recorded in CN101891702A), crystal formation N (their preparation example is as being recorded in CN101891703A), crystal form P (their preparation example is as being recorded in CN101824006A), crystal form Q (their preparation example is as being recorded in CN101824005A), crystal formation R, S, T (their preparation example is as being recorded in CN101928260A), crystal form X, Y, Z (their preparation example is as being recorded in CN101684107A).Those skilled in the art know, and some above-mentioned crystal formations itself are exactly solvate, and for example crystal formation G is hydrate.In the present invention, term " crystalline state " comprises crystal and amorphous.
Febuxostat tablet according to first aspect present invention, wherein said binding agent is to be selected from following one or more: hydroxypropyl cellulose, polyvinylpyrrolidone (are polyvidone, PVP, such as PVPK15, PVP K30 etc.), hydroxypropyl emthylcellulose (such as the HPMC of viscosity grade 3 or 6cps), starch slurry, Polyethylene Glycol (such as PEG2000, PEG4000 etc.) etc.In the present invention, described binding agent is to add in the mode of its aqueous solution (for example 1～20% aqueous solution, for example 1～10% aqueous solution) by wet granulation.In a special embodiment, the inventor find with polyvidone particularly PVP K30 also have good performance aspect the friability of tablet as binding agent, for example when film-making, use 1～10% aqueous solution of polyvidone, 2-8% aqueous solution for example, for example the 3-7% aqueous solution as binding agent (in the Febuxostat of per 40 weight portions or the acceptable salt of its pharmacy, solvate, polymorphic, the binding agent that wherein contains is by its dry weight basis, amount is the 1-20 weight portion, 1-15 weight portion for example, for example 1-10 weight portion, for example 1-5 weight portion).In addition, in the present invention, can not use binding agent, and directly use wetting agent such as water, concentration to be lower than 80% the soft materials processed such as alcoholic solution, granulate.
According to the Febuxostat tablet of first aspect present invention, wherein said lubricant can be to have lubricated effect, can also be the effect with fluidizer, and the term " lubricant " that namely uses in the present invention broadly comprises lubricant and fluidizer.Lubricant of the present invention is to be selected from following one or more: magnesium stearate, aluminium stearate, calcium stearate, PEG4000 to 8000, Pulvis Talci, castor oil hydrogenated, stearic acid and salt thereof or glyceride, sodium stearyl fumarate etc., and silica sol, magnesium silicate, Pulvis Talci.Most preferred lubricant is magnesium stearate, Pulvis Talci or silica sol.
According to the Febuxostat tablet of first aspect present invention, wherein said carboxymethyl starch sodium has disintegration.Therefore, in one embodiment of the invention, carboxymethyl starch sodium uses as disintegrating agent.Tablet of the present invention preferably uses wet granule compression tablet, disintegrating agent carboxymethyl base Starch Sodium can with add, in add, in the mode such as add and add.In one embodiment of the invention, disintegrating agent carboxymethyl base Starch Sodium preferably with add, in the mode that adds add.In one embodiment of the invention, disintegrating agent carboxymethyl base Starch Sodium preferably adds in the mode that adds.
Febuxostat tablet according to first aspect present invention, the Febuxostat that wherein contains in every or the acceptable salt of its pharmacy, solvate, polymorphous amount are 20mg～100mg, for example 40mg～80mg, for example about 20mg, about 40mg, about 50mg, about 60mg, about 80mg, about 100mg.
According to the Febuxostat tablet of first aspect present invention, it is further by coating, and the material of described coating can be stomach dissolution type coating or enteric solubility coating.In the present invention, more than the quality of the plain sheet of preparation is influential for follow-up preparation coating operation, if for example the friability of plain sheet is well-behaved (it is few that the friability test subtracts weight loss), then is conducive to follow-up preparation coating operation.
In the present invention, refer to make a general reference this material when, mentioning " Febuxostat " if be not specifically noted, and comprise the free acid of Febuxostat, and the acceptable salt of its pharmacy, solvate, polymorphic.
Second aspect present invention provides the preparation method of the described Febuxostat tablet of preparation first aspect present invention, and it may further comprise the steps:
I) each material is pulverized respectively and sieved less than 60 purposes by the aperture;
Ii) with Febuxostat, microcrystalline Cellulose, pregelatinized Starch and an amount of carboxymethyl starch sodium mix homogeneously of recipe quantity;
Iii) water perhaps uses optional binder aqueous solution as binding agent as wetting agent, to above mixed material soft material processed, granulates drying, granulate;
Iv) to step I ii) add the carboxymethyl starch sodium of surplus in the gained granule, add optional lubricant, mix homogeneously with mixed granule tabletting at the end that obtains thus, namely gets the Febuxostat tablet; Randomly
V) step I v gained Febuxostat tablet is carried out coating.
According to the method for second aspect present invention, step I ii wherein) use binder aqueous solution as binding agent soft material processed in.
The amount of the carboxymethyl starch sodium that uses according to the method for second aspect present invention, step I i wherein) is 0～50% of the total consumption of carboxymethyl starch sodium, preferred 0～40%, preferred 0～30%, preferred 0～20%.In one embodiment, carboxymethyl starch sodium is that add mode joins in the tablet of the present invention in addition.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.The below is further described with characteristics to various aspects of the present invention.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
When the inventor found to prepare the tablet that comprises Febuxostat, having as described herein, the tablet of specific prescription had good pharmaceutics performance.
The specific embodiment
Further specify the present invention below by specific embodiment/experimental example, still, should be understood to, these embodiment and experimental example are only used for the more detailed usefulness that specifically describes, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Although for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and operational approach are well known in the art.In following examples, such as not in addition explanation, used Febuxostat is its free acid.Use the Febuxostat of concrete crystal formation to prepare with reference to the pertinent literature method.
Below the tablet of each embodiment and reference examples compacting, such as in addition explanation, tablet is all suppressed with the tablet machine of same model.And various tablets are in when compacting, the hardness of tablet all is controlled at 5-6kgf (namely (uses the tablet hardness tester mensuration tablet hardness of same model) in 49～59N) the scope.In the example of following each sample preparation, such as not in addition explanation, preparation is 5000 slices/batch in batches.
Embodiment 1: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 50 |
| Pregelatinized Starch | 40 |
| Carboxymethyl starch sodium | 15 |
| PVP K30 | 3＊ |
| Magnesium stearate | 2 |
* PVP K30 powder 3mg, water is mixed with solution and granulates as binding agent, and similar meaning is hereinafter all arranged.
Preparation method:
I) each material is pulverized respectively and sieved less than 80 purposes by the aperture;
Ii) with Febuxostat, microcrystalline Cellulose, the pregelatinized Starch mix homogeneously of recipe quantity;
Iii) with binding agent to above mixed material soft material processed, granulate drying, granulate;
Iv) to step I ii) add carboxymethyl starch sodium and magnesium stearate in the gained granule, mix homogeneously with mixed granule tabletting at the end that obtains thus, namely gets Febuxostat tablet (every contains active component 40mg).
Can be further the Bu Suotan tablet of above preparation be carried out coating.In addition, can change the punch die of tablet machine, be pressed into every tablet of Febuxostat tablet that contains active component 80mg with mixing granule above end.But in situation about not specifying, all using step I v in the test of back) the plain sheet (40mg specification) of preparation tests.
Embodiment 2: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 80 |
| Pregelatinized Starch | 40 |
| Carboxymethyl starch sodium | 30 |
| PVP K30 | 5 |
| Magnesium stearate | 5 |
Preparation method: basically with embodiment 1.
Embodiment 3: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 120 |
| Pregelatinized Starch | 90 |
| Carboxymethyl starch sodium | 35 |
| PVP K30 | 10 |
| Magnesium stearate | 5 |
Preparation method: basically with embodiment 1.
Embodiment 4: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 40 |
| Pregelatinized Starch | 15 |
| Carboxymethyl starch sodium | 3 |
| PVP K30 | 1 |
| Magnesium stearate | 1 |
Preparation method: basically with embodiment 1.
Embodiment 5: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 160 |
| Pregelatinized Starch | 125 |
| Carboxymethyl starch sodium | 50 |
| PVP K30 | 15 |
| Magnesium stearate | 10 |
Preparation method: basically with embodiment 1.
Embodiment 6: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 25 |
| Pregelatinized Starch | 25 |
| Carboxymethyl starch sodium | 2 |
| PVP K30 | 1 |
| Magnesium stearate | 1 |
Preparation method: basically with embodiment 1.
Embodiment 7: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 50 |
| Pregelatinized Starch | 7.5 |
| Carboxymethyl starch sodium | 15 |
| PVP K30 | 2 |
| Magnesium stearate | 2 |
Preparation method: basically with embodiment 1.
Embodiment 8: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 180 |
| Pregelatinized Starch | 140 |
| Carboxymethyl starch sodium | 75 |
| PVP K30 | 15 |
| Magnesium stearate | 10 |
Preparation method: basically with embodiment 1.
Embodiment 8: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 60 |
| Pregelatinized Starch | 40 |
| Carboxymethyl starch sodium | 5 (adding in the granule) |
| Carboxymethyl starch sodium | 10 (granule adds outward) |
| PVP K30 | 4 |
| Magnesium stearate | 2 |
Preparation method: basically with embodiment 1, wherein the 5mg disintegrating agent adds before soft material processed, and the 10mg disintegrating agent adds behind particle drying in addition.
Embodiment 9: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat sodium | 40 |
| Microcrystalline Cellulose | 60 |
| Pregelatinized Starch | 50 |
| Carboxymethyl starch sodium | 15 |
| PVP K30 | 3 |
| PVP K30 | 3 |
| Magnesium stearate | 2 |
Preparation method: basically with embodiment 1, wherein the PVP K30 of 3mg is used for the preparation binding agent, and the PVP K30 of 3mg adds behind particle drying in addition.Febuxostat uses its sodium salt.
Embodiment 10: preparation contains the tablet of Febuxostat
Prescription:
| Composition | Amount (mg/ sheet) |
| Febuxostat (A crystal formation) | 40 |
| Microcrystalline Cellulose | 80 |
| Pregelatinized Starch | 40 |
| Carboxymethyl starch sodium | 20 |
| PVP K30 | 5 |
| Magnesium stearate | 3 |
Preparation method: basically with embodiment 1.
Embodiment 11: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat B crystal formation.
Embodiment 12: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat C crystal formation.
Embodiment 13: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat D crystal formation.
Embodiment 14: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat G crystal formation.
Embodiment 15: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat H crystal formation.
Embodiment 16: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat K crystal formation.
Embodiment 17: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat M crystal formation.
Embodiment 18: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat P crystal formation.
Embodiment 19: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat R crystal formation.
Embodiment 20: preparation contains the tablet of Febuxostat
Basically with prescription and the method for embodiment 1, different is to use Febuxostat X crystal formation.
Reference examples 1: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into, carboxymethyl starch sodium replaces with cross-linking sodium carboxymethyl cellulose, PVP K30 replaces with hydroxy propyl cellulose, and magnesium stearate replaces with silicon dioxide/magnesium stearate (1/1).
Reference examples 2: prescription: Febuxostat H crystal formation 80g, pregelatinized Starch 110.5g, low substituted hydroxy-propyl methylcellulose 10.5g, magnesium stearate 0.8g, make 1000.Technique: each material is crossed respectively 100 orders; Febuxostat and pregelatinized Starch, the aqueous solution made from the low substituted hydroxy-propyl methylcellulose are granulated drying, granulate as binding agent soft material processed; Add magnesium stearate, tabletting is used for hereinafter test.In addition, this is write out a prescription when direct powder compression, and it is higher more than 0.75% than above wet granule compression tablet to subtract weight loss in its friability test.
Reference examples 3: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into.
Reference examples 4: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein microcrystalline Cellulose changes lactose monohydrate into.
Reference examples 5: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein carboxymethyl starch sodium changes sodium carboxymethyl cellulose into.
Reference examples 6: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein carboxymethyl starch sodium changes polyvinylpolypyrrolidone (CROSPOVIDONE) into.
Reference examples 7: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein PVP K30 changes hydroxypropyl emthylcellulose (6cps) into, make the tablet of reference examples 7, this tablet subtracts weight loss in the friability test higher more than 0.45% than the tablet of embodiment 1.In other test, the inventor attempts the PVP K30 among the embodiment 1 is changed to PVP K15,3 kinds of consumptions of its consumption design, be respectively among the embodiment 1 PVP K30 consumption 80%, 100% and 120%, 3 kinds of tablets of gained subtract weight loss all the tablet than embodiment 1 are high more than 0.3% in friability test thus.
Reference examples 8: preparation contains the tablet of Febuxostat: the prescription of reference example 1 and method, different is that wherein PVP K30 changes PEG4000 into.The gained tablet subtracts weight loss in the friability test higher more than 0.5% than the tablet of embodiment 1.
Reference examples 9: preparation contains the tablet of Febuxostat: the prescription of reference example 11 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into.
Reference examples 10: preparation contains the tablet of Febuxostat: the prescription of reference example 12 and method, different is that wherein microcrystalline Cellulose changes lactose monohydrate into.
Reference examples 11: preparation contains the tablet of Febuxostat: the prescription of reference example 13 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into.
Reference examples 12: preparation contains the tablet of Febuxostat: the prescription of reference example 14 and method, different is that wherein microcrystalline Cellulose changes lactose monohydrate into.
Reference examples 13: preparation contains the tablet of Febuxostat: the prescription of reference example 16 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into.
Reference examples 14: preparation contains the tablet of Febuxostat: the prescription of reference example 18 and method, different is that wherein microcrystalline Cellulose changes lactose monohydrate into.
Reference examples 15: preparation contains the tablet of Febuxostat: the prescription of reference example 19 and method, different is that wherein pregelatinized Starch changes lactose monohydrate into.
Reference examples 16: preparation contains the tablet of Febuxostat: the prescription of reference example 20 and method, different is that wherein microcrystalline Cellulose changes lactose monohydrate into.
Test example 1: the friability inspection of tablet
Get the above tablet (all getting the not plain sheet of coating) of embodiment and reference examples preparation, check their friability.Carry out according to the method under " tablet friability inspection technique " item among two appendix XG of Pharmacopoeia of the People's Republic of China version in 2010, calculating subtracts weight loss (%), and whether the observation tablet has the abnormal conditions such as fracture, be full of cracks and/or pulverizing.
The result shows that each sample of embodiment 1-20 subtracts weight loss (%) all between 0.2%～0.6%, there are no abnormal conditions such as fracture, be full of cracks and/or pulverizing.Each sample of reference examples 1～16 subtracts weight loss (%) all between 0.75%～1.6%, and some sample has the abnormal conditions such as fracture, be full of cracks and/or pulverizing.For example reference examples 2,5,6,9,11, each sample of 12 subtract weight loss (%) all between 1.2%～1.6%, and reference examples 2,6, each sample of 11 have the abnormal conditions such as fracture, be full of cracks and/or pulverizing.
Test example 2: the assay method of Dissolution of Tablet
Get the tablet (all getting the not plain sheet of coating) of above embodiment and reference examples preparation and measure dissolution, according to dissolution method (two appendix XC of Pharmacopoeia of People's Republic of China version in 2010 first method), (get potassium dihydrogen phosphate 6.80g and sodium hydroxide 0.90g with phosphate buffer, be dissolved in water into 1000ml, adjusting pH value to 6.8) 1000ml is dissolution medium, rotating speed is that per minute 100 turns, in accordance with the law operation, in the time of 45 minutes, it is an amount of to get solution, filters, and it is an amount of that precision is measured subsequent filtrate, quantitatively dilute with dissolution medium, measure with the HPLC method.The result shows that the dissolution of each tablet of embodiment of the invention 1-20 all reaches 86～96% scope.And the dissolution of each tablet of reference examples 1-16 is in 60～89% scope, and the embodiment sample is all higher more than 8% than the dissolution of its corresponding reference examples sample, and for example, embodiment 1 sample is higher more than 8% than its corresponding reference examples 3 sample dissolutions; The dissolution of reference examples 1 and reference examples 2 samples is between 76～81%; It is high that these results show that tablet of the present invention is compared the dissolution of photo generally.Wherein, the stripping quantity of Febuxostat adopts document (foundation of Febuxostat sheet determination of related substances method, Chinese Journal of New Drugs, the 22nd phase in the 2011) method of Zhang Xiaoyan etc. to measure.
Test example 3: stability test
Tablet with above each embodiment and reference examples preparation, aluminium foil bag packs, place 40 ℃ of calorstats to place June, measure respectively the dissolution of these samples when 0 month and the June according to the method for test example 2, be calculated as follows each sample stripping stability percent %:
The result shows that the stripping stability percent % of each tablet of embodiment of the invention 1-20 is all more than 93%.And the stripping of each tablet of reference examples 1-16 stability percent % is in 72～89% scope.These results show that prescription of the present invention is suitable for polytype crystal formation.Below listed the measurement result of the stripping stability percent % of some samples:
| Sample | Stripping stability percent | Sample | Stripping stability percent |
| Embodiment 1 | 95％ | Reference examples 1 | 88％ |
| Embodiment 2 | 96％ | Reference examples 2 | 76％ |
| Embodiment 3 | 93％ | Reference examples 3 | 85％ |
| Embodiment 4 | 95％ | Reference examples 4 | 81％ |
| Embodiment 11 | 96％ | Reference examples 9 | 85％ |
| Embodiment 14 | 94％ | Reference examples 12 | 86％ |
Claims (1)
1.
A kind of Febuxostat tablet, it consists of:
The Febuxostat of 40 weight portions or the acceptable salt of its pharmacy, hydrate, polymorphic, the microcrystalline Cellulose of 25-180 weight portion, the pregelatinized Starch of 7.5-140 weight portion, the carboxymethyl starch sodium of 2-75 weight portion, the binding agent of 1-15 weight portion, and
The lubricant of 1-10 weight portion;
Wherein said binding agent is PVP K30, and the polymorphic of described Febuxostat is to be selected from following crystal formation: crystal form A, B, C, D, G, H, K, M, P, R, X.
2. according to claim 1 Febuxostat tablet, the Febuxostat that wherein contains in every or the acceptable salt of its pharmacy, hydrate, polymorphous amount are 20mg ~ 100mg.
3. according to claim 1 Febuxostat tablet, wherein said lubricant are to be selected from following one or more: magnesium stearate, aluminium stearate, calcium stearate, PEG4000 to 8000, Pulvis Talci, castor oil hydrogenated, stearic acid, sodium stearyl fumarate.
4. according to claim 1 Febuxostat tablet, the acceptable salt of the pharmacy of wherein said Febuxostat is its sodium salt.
5. the preparation method of each described Febuxostat tablet of claim 1-4, it is comprised of following steps:
I) each material is pulverized respectively and sieved less than 60 purposes by the aperture;
Ii) with Febuxostat, microcrystalline Cellulose, pregelatinized Starch and an amount of carboxymethyl starch sodium mix homogeneously of recipe quantity;
Iii) use binder aqueous solution as binding agent, to above mixed material soft material processed, granulate drying, granulate;
Iv) to step I ii) add the carboxymethyl starch sodium of surplus in the gained granule, add lubricant, mix homogeneously with mixed granule tabletting at the end that obtains thus, namely gets the Febuxostat tablet; Randomly
V) step I v gained Febuxostat tablet is carried out coating.
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| CN101658505A (en) * | 2009-09-29 | 2010-03-03 | 北京华禧联合科技发展有限公司 | Sustained-release preparation of uloric and preparation method thereof |
| CN101711751A (en) * | 2009-12-04 | 2010-05-26 | 山东淄博新达制药有限公司 | Febuxostat dispersing tablet preparation and preparation method thereof |
| CN101716132A (en) * | 2008-10-09 | 2010-06-02 | 北京方策方程医药科技有限公司 | Febuxostat enteric preparation |
| CN101862326A (en) * | 2009-04-20 | 2010-10-20 | 北京德众万全药物技术开发有限公司 | Medicine compound containing febuxostat |
| CN101953814A (en) * | 2009-07-17 | 2011-01-26 | 北京本草天源药物研究院 | Febuxostat solid preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101716132A (en) * | 2008-10-09 | 2010-06-02 | 北京方策方程医药科技有限公司 | Febuxostat enteric preparation |
| CN101862326A (en) * | 2009-04-20 | 2010-10-20 | 北京德众万全药物技术开发有限公司 | Medicine compound containing febuxostat |
| CN101953814A (en) * | 2009-07-17 | 2011-01-26 | 北京本草天源药物研究院 | Febuxostat solid preparation |
| CN101658505A (en) * | 2009-09-29 | 2010-03-03 | 北京华禧联合科技发展有限公司 | Sustained-release preparation of uloric and preparation method thereof |
| CN101711751A (en) * | 2009-12-04 | 2010-05-26 | 山东淄博新达制药有限公司 | Febuxostat dispersing tablet preparation and preparation method thereof |
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