CN1934109A - Composition for solid pharmaceutical preparation of solifenacin or salt thereof - Google Patents
Composition for solid pharmaceutical preparation of solifenacin or salt thereof Download PDFInfo
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- CN1934109A CN1934109A CNA2005800094953A CN200580009495A CN1934109A CN 1934109 A CN1934109 A CN 1934109A CN A2005800094953 A CNA2005800094953 A CN A2005800094953A CN 200580009495 A CN200580009495 A CN 200580009495A CN 1934109 A CN1934109 A CN 1934109A
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Abstract
A solid pharmaceutical preparation of solifenacin or a salt thereof, the preparation being stable and inhibited from decomposing with time when supplied to clinical fields. In a pharmaceutical preparation containing solifenacin or a salt thereof, the compound in an amorphous form was revealed to be causative of cardinal-drug decomposition with time. The composition for a solid pharmaceutical preparation of solifenacin or a salt thereof contains solifenacin or its salt each in a crystalline form, and the content of the compound in an amorphous form in the composition is within the range which exerts no influence on product stability. Also provided are: a process for producing the composition; and a medicinal composition for solid pharmaceutical preparations which contains solifenacin and an amorphization inhibitor.
Description
Technical field
The present invention relates to be used for the Solifenacin (solifenacin) of solid preparation or the composition of its salt, described composition comprises the crystal of Solifenacin or its salt, the content of wherein unbodied Solifenacin or its salt is in the scope that can not influence products therefrom stability, the invention still further relates to the described method for compositions of preparation.In addition, the invention still further relates to a kind of pharmaceutical composition, it comprises Solifenacin or its salt and amorphous substance inhibitor.
Background technology
Solifenacin is shown in following structural formula (I):
[Chemical formula 1]
Structural formula (I)
It chemically is being called as 1-phenyl-1,2,3,4-tetrahydrochysene-2-1-isoquinolinecarboxylic acid (1R, 3 ' R)-quinuclidinyl ester.
It is reported that a series of quinuclidine derivatives that comprise Solifenacin or its salt are to muscarine M
3Acceptor has splendid selection antagonistic action, and can be used as the preventive or the therapeutical agent (referring to patent documentation 1) of urinary disorders (for example nervosa frequent micturition, neurogenic bladder, nycturia, unstable bladder, contracture of bladder and chronic cystitis) and respiratory disease (for example chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis).
Having described the preparation method of hydrochloric acid Solifenacin in the embodiment 8 of patent documentation 1, is 212-214 ℃ and its specific optical rotation [α] by carry out its fusing point of crystal that crystallization obtains in mixed solvent (being made of acetonitrile and ether) wherein
25 D(c=1.00 is 98.1 EtOH).
But, do not relate to the description or the suggestion of following problem in the patent documentation 1, described problem is: when preparing the YM 905 product with general pharmacy preparation method, can As time goes on and significantly degrade as the amorphous Solifenacin of the active pharmaceutical ingredient in the preparation or the salt or the YM 905 of amorphous Solifenacin.
In by the non-patent literature 1 (public publication in June, 2003) of MHLW's public publication of Japan, drug specifications (that is, with the stability test of new medicine in a relevant notion of viewed degraded product (impurity)) is described.According to the document, when the every day of former medicine, dosage was lower than 10mg, lower one among the threshold value of its degraded product of drug safety specification of quality is 1.0% (in the per-cent of the degraded product that comprised in the medicine) or the 50 μ g (in the daily ingestion total amount of degraded product).When the former dose of administration every day equals 10mg to being lower than when equaling 100mg for being higher than, lower one among the threshold value of its degraded product of drug safety specification of quality is 0.5% (in the per-cent of the degraded product that comprised in the medicine) or the 200 μ g (in the daily ingestion total amount of degraded product).Therefore, generally can be in the specification value that does not need the drug degradation product is carried out to determine under the situation of any safety certification degraded product, for example, when the medicament contg of preparation was 5mg, former medicine degraded product was 1.0% or lower (in the per-cent of the degraded product that comprised in the former medicine); For example, when the medicament contg of preparation was 10mg, the per-cent of the degraded product that is comprised in the former medicine was 0.5% or lower.
According to the result of clinical trial, the Solifenacin preparation of planning list marketing at present is the tablet of 2.5mg, 5mg and 10mg.In order to make these preparations possess the stability described in the non-patent literature 1, think YM 905 main degradation products (being abbreviated as F1 hereinafter) amount and YM 905 with and the ratio of the total amount of degraded product should be set to 0.5% or lower, difference and testing error between considering batch should be controlled at this ratio below 0.4% and (contain 0.4%).
The specification sheets of patent documentation 1:EP 801 067
Non-patent literature 1: No. the 0624001st, medical Trial development " new effective constituent contain pharmaceuticals ぅ ち System agent not Pure Wu に Seki The そ ガ ィ De ラ ィ Application change decide To っ ぃ て "
Disclosure of the Invention
The problem to be solved in the present invention
In order to develop the YM 905 as frequent micturition and the splendid therapeutical agent of the urinary incontinence, the inventor is under the condition that those skilled in the art use always, granulate YM 905 and it is prepared into tablet with fluidized bed granulation method.Then, under the accelerated test of the inventor in general stability test (40 ℃ and 75% RH (relative humidity), the use air-tight bottle) condition, the tablet of gained carried out 6 months preliminarily stabilised test.As a result, the residual rate that the inventor observes YM 905 reduces, thereby the ratio of the growing amount that shows F1 and the total amount of YM 905 and degraded product thereof has surpassed 0.4% (table 2 that vide infra and describe in detail).The inventor thinks: be difficult to obtain pharmaceutically very stable Solifenacin preparation with the general manufacture method of medicine of this class.
Provide as the splendid therapeutical agent of the frequent micturition and the urinary incontinence, the ratio of the growing amount of F1 and the total amount of Solifenacin or its salt and degraded product thereof can be suppressed at (contain 0.4%) below the 0.4% such Solifenacin or the solid preparation of its salt, promptly, develop and As time goes on keep the stable Solifenacin or the solid preparation of its salt, this be people eagerly wish.
Solve the method for described problem
The degraded of the medicine in the preparation is usually directed to for example redox reaction, hydrolysis reaction, racemization, photodegradation and polymer degradation.According to description, these reactions and heat, oxygen, light, water and relevant with the interaction of other component.As mentioned above, should consider that the multiple factor relevant with drug degradation is to obtain stable medicine.Under the state of the art of this state, the inventor studies the stability of Solifenacin product.The inventor illustrates: be unexpectedly, the unbodied YM 905 that in the medicine manufacturing processed, is produced be cause active pharmaceutical ingredient As time goes on and the degraded major cause.
In addition, the inventor also finds: when using conventional adhesive solution to prepare described medicine by wet granulation method, can suppress the content of amorphous substance in the medicine by the moisture content of adjusting medicine in manufacturing processed or by resultant composition after this Manufacturing Method of Products is heated and/or humidification.The inventor finds, when unbodied Solifenacin when shared ratio is equal to or less than particular value in crystalline and unbodied Solifenacin, can make the stable Solifenacin solid preparation or the solid preparation of its salt, the situation that As time goes on degraded takes place Solifenacin can be inhibited.
In addition, the inventor also finds: when (another name is Macrogol with polyoxyethylene glycol; Be abbreviated as PEG hereinafter) during as binding agent, no matter take any manufacture method, can make the Solifenacin preparation that As time goes on degraded takes place Solifenacin wherein situation can be inhibited, but PEG itself is that a kind of being generally used for medication preparation is the material of amorphous state.Finished the present invention in this case, they are different with the aforementioned stable method.
That is, the present invention relates to following these contents.
1. be used for the Solifenacin of solid preparation or the composition of its salt, said composition comprises the crystal of Solifenacin or its salt, and wherein the stability that is in medicine of the content of amorphous substance does not have in the scope of influence.
2. as top the 1st the described Solifenacin of solid preparation or the composition of its salt of being used for, the content of wherein said amorphous substance is 77% or lower.
3. as top the 1st or 2 the described composition that is used for solid preparation, said composition is made by a kind of like this manufacture method, and this method is included under the situation of not using any solvent Solifenacin or its salt and mixed with excipients, the step of compression molding subsequently.
4. as top the 1st or 2 the described composition that is used for solid preparation, said composition is made by a kind of like this manufacture method, this method comprises the step that adds solvent in Solifenacin or its salt, and the meltage of Solifenacin or its salt is lower than 0.1mg in the described solvent of wherein every 1mL.
5. as top the 4th the described composition that is used for solid preparation, the described solvent that wherein is added in Solifenacin or its salt is acetone or hexane or its mixture.
6. as top the 1st or 2 the described composition that is used for solid preparation, said composition is made by a kind of like this manufacture method, this method comprises that adding solvent is prepared into the step of metamict with Solifenacin or its salt, and the meltage of Solifenacin or its salt is 10mg or higher in the described solvent of wherein every 1mL.
7. as top the 6th the described composition that is used for solid preparation, the described solvent that wherein is used for Solifenacin or its salt are prepared into metamict is water, methyl alcohol or ethanol or its mixture.
8. as top the 1st to 7 the described composition that is used for solid preparation, said composition is made by a kind of like this manufacture method, and this method comprises the salt crystalline step that promotes unbodied Solifenacin or unbodied Solifenacin.
9. the mixture of a Solifenacin or its salt, wherein this mixture comprises unbodied and crystalline Solifenacin or the salt of unbodied Solifenacin and the salt of crystalline Solifenacin, and the stability that the content of wherein unbodied Solifenacin or its salt is in product does not have in the scope of influence.
10. solid preparation pharmaceutical composition, said composition comprises the salt of crystalline and unbodied Solifenacin or crystalline Solifenacin and the salt and the amorphous substance inhibitor of unbodied Solifenacin.
11. as top the 10th described pharmaceutical composition, wherein said amorphous substance inhibitor is the material with ethylene oxide chain.
12. as top the 11st described pharmaceutical composition, wherein said material with ethylene oxide chain is a polyoxyethylene glycol.
The known technology of suppressing according to the prescription that is mixed with additive comprises: stablize (E)-1-[4-(2-dimethylamino) oxyethyl group by reducing moisture] technology of phenyl-2-(4-isopropyl phenyl)-1-(4-phosphonato) phenyl-1-butylene, this material has following character and has the effect of breast cancer treatment agent, described character is: contained moisture in being subjected to such as above-mentioned additive, make the increase that contacts of former medicine and additive in the tablet through pressure moulding, and through the pressurization degree of crystallinity is reduced under the condition of these factor affecting, As time goes on the increase of its degraded product is quickened (referring to document Chemical ﹠amp; Pharmaceutical Bulletin, 42 (12), 2582 (1994)); And by the next stable technology that contains certain compound compositions of melt granulation working system (referring to the flat 9-110698 of patent documentation JP-A-), for example stablize the N-anilides technology of (being used for multiple sclerosis), because it has produced the different compound of the main compound with in the solid preparation of 6-9% between the shelf lives, so the N-anilides as main ingredient is existing very big difficulty aspect the accurate administration, in this case, make the solid preparation of tablet form by substantially anhydrous method, thereby stablize this compound (referring to the flat 10-007547 of patent documentation JP-A-).
But, do not relate to any description of its structure and physical chemistry or pharmacological property and the diverse Solifenacin of disclosed compound or its salt in these technical literatures at all; Also do not relate to any description or any suggestion of following content in these technical literatures, described content is at all: thus contain amorphous substance solid preparation its As time goes on problem of degraded taking place or is adjusted to by the content with the amorphous substance in the solid preparation of gained is lower than the method that appropriate vol is stablized this solid preparation.
The flat 5-194218 communique of patent documentation JP-A-discloses a kind of technology of stablizing nitrogenous heterocyclic alkyl phenyl derivative, this technology comprises the steps: low-melting oily matter (for example PEG) and this alkyl phenyl derivative are carried out fusion, to stablize the oral preparations of gained; This derivative has the effect of antiangiotensin II and has following characteristics: when according to the prescription that is mixed with other composition this alkyl phenyl derivative being mixed with preparation; because applied pressure, friction, heat and similarly effect in the kneading in the preparation process and granulation or the pressure moulding process; and produce the crystallization distortion, quickened the reduction of its content thus.In this case, carrying out stable mechanism with low melting point is: by with described low-melting oily matter and active pharmaceutical ingredient uniform mixing, suppress the thermal destruction of active pharmaceutical ingredient.Do not relate to the such description of crystallinity that low-melting material helps active pharmaceutical ingredient in this patent documentation.This mechanism is different fully with stable mechanism of the present invention.
In addition, document: International Journal of Pharmaceutics, 216 (2001), 43-49 has reported also at lactose and PEG and has been total in molten and the crystalline situation that the lactose of separating out exists with the crystalline state.On the other hand, document: International Journal of Pharmaceutics, 127 (1996), 261-272 and International Journal of Pharmaceutics, 262 (2003), 125-137 has reported at medicine and PEG and has been total in molten and the crystalline situation that medicine exists with unbodied state.Be total in molten and the crystalline situation at active pharmaceutical ingredient and polymkeric substance (for example PEG), the active pharmaceutical ingredient of gained is generally unbodied state, but this depends on the character of active pharmaceutical ingredient.Carry out blending in order to carry out solubilising by the medicine to microsolubility to obtain amorphous substance, such research work is known.Disclosed all compounds all have and the diverse structure of the chemical structure of Solifenacin in these technical literatures.Do not relate in these documents at all and have unique physicochemical property and the Solifenacin of pharmacological property or any description of its salt, do not relate at all yet by Solifenacin and PEG fusion being prepared any enlightenment of crystalline Solifenacin or unbodied this conception of Solifenacin.Even the stabilization of relating to, these documents do not have to describe yet or a kind of like this scheme of suggestion at all: can be by utilizing the crystallization that forms by means of polymkeric substance (for example PEG), As time goes on and the degraded of generation suppress active pharmaceutical ingredient.
Below describe composition of the present invention in detail.
Term used herein " salt of Solifenacin " comprising: acid salt and quaternary ammonium salt thereof that Solifenacin and mineral acid (for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid) or organic acid (for example formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, citric acid, tartrate, carbonic acid, picric acid, methylsulfonic acid, ethyl sulfonic acid and L-glutamic acid) form, and as described in patent documentation 1.Particularly, preferred YM 905 when medicine is provided, according to the present invention, YM 905 can also reach the most significant stabilising effect.Therefore, select the succinate of Solifenacin especially.
Term used herein " Solifenacin or its salt " can easily obtain with the method described in the patent documentation 1, perhaps can easily obtain according to method as herein described and ordinary method.Being admixed to solid preparation of the present invention is the described material that the preparation of per unit dosage preferably comprises significant quantity with the amount of the Solifenacin in the composition or its salt; Its amount is preferably 0.001 weight % to 97 weight %, 0.05 weight % to 50 weight % more preferably, and more preferably 0.05 weight % to 20 weight % most preferably is 0.05 weight % to 10 weight %.When pharmaceutical composition of the present invention is particle (for example small-particle), according to drug type or its medical applications (indication), select to be incorporated into the dose in the particle medicinal composition aptly usually.Have no particular limits for its treatment significant quantity or prevention significant quantity.
In addition, the day dosage of Solifenacin or its salt is preferably 0.01mg to 100mg, 0.5mg to 50mg more preferably, and more preferably 0.5mg to 20mg most preferably is 0.5mg to 10mg.
" crystal " of Solifenacin or its salt or " crystallisate " are meant Solifenacin or the such material of its salt with crystalline structure, have the crystalline structure of this term indication in the crystallography field.According to the present invention, As time goes on crystal or crystallisate are meant, the material that the Solifenacin degraded is few.Term crystal or crystallisate are meant a kind of material different with amorphous substance, and when the amount of this material existence did not have the scope of influence above the stability to medicine, in described amorphous substance, As time goes on Solifenacin took place by significant the degraded.
On the other hand, according to the present invention, " amorphous substance " of term " unbodied " Solifenacin or its salt or Solifenacin or its salt is meant the material with the amorphous structure on the crystallography meaning.Simultaneously, according to the present invention, term " salt of unbodied Solifenacin or unbodied Solifenacin " or " amorphous substance of Solifenacin or its salt " are meant a kind of when its amount does not have the scope of influence above the stability to medicine, the significantly material of degraded can take place in Solifenacin, in addition, this term is meant also and " crystal " or " crystallisate " different material that in described " crystal " or " crystallisate ", As time goes on the Solifenacin degraded is few.
In addition, according to the present invention, term " content of amorphous substance " is meant the ratio of the amount of amorphous substance and the total amount of unbodied and crystalline Solifenacin (or its unbodied and total amount crystalline salt).
According to the present invention, the product that phrase " scope that the stability of medicine is not had influence " is meant Solifenacin or its salt is stable under the condition of strictness in the circulation of commodities process.Particularly, under the condition of the RH that uses air-tight bottle and 40 ℃ and 75%, when Solifenacin or its salt are carried out 6 months preliminarily stabilised test, the growing amount of the main degradation products of Solifenacin and Solifenacin or its salt with and the ratio of the total amount of degraded product, can be suppressed to 0.4% or lower.
Therefore, according to the present invention, in situation about measuring with near-infrared spectrophotometry, the concrete content that is in stability to product and does not have the amorphous substance in the scope of influence is: be less than or equal to unbodied and crystalline Solifenacin total amount (or its unbodied and total amount crystalline salt) 77%, be preferably 73% or lower, more preferably 71% or lower, most preferably be 63% or lower.In addition, the content of initial amorphous substance has exceeded the scope that the stability of product is not had influence, but As time goes on it develop into crystallisate immediately after preparation, thereby the stability that makes the content of amorphous substance drop to product does not have in the scope of influence, and such Solifenacin or its salt are also included within the scope of the present invention.Therefore, the selection of time to the content of measuring amorphous substance does not have particular restriction.The content of considering amorphous substance will guarantee the stability of product in the process of circulation, so preferably, and at time that the circulation of this product begins or the assay that carries out amorphous substance at suitable time thereafter.
The method of content that is used for estimating the amorphous substance of Solifenacin of the present invention or its salt normally is used for determining any method of the crystalline texture of the Solifenacin of composition or its salt, includes but not limited to for example powder x-ray diffraction method, DSC method, solid NMR and near-infrared spectrophotometry.For for the crystalline texture of measuring the lower medicine of content in containing the blend compositions of other component, particularly preferably be to use solid NMR or near-infrared spectrophotometry to measure crystalline texture.The simpler method that is used to measure described structure is a near-infrared spectrophotometry.
As the used method of content of measuring the YM 905 amorphous substance, the near-infrared spectrophotometry that for example has use to carry out as follows: with fourier transformation near infrared spectrometer (Vector 22/N is produced by the Bruker Optik GmbH company that is positioned at Germany) (useful range: 10000cm
-1To 4000cm
-1, resolving power: 2cm
-1Scanning times: 126 times) measures its spectrum, and the spectrum of gained carried out second differential (Savitzky-Golay convolution method), thereby analyze with near-infrared spectrum analysis software (for example OPUS is produced by the Bruker OptikGmbH company that is positioned at Germany).Before the spectrum of measuring tablet, earlier the spectrum of following product is carried out regression analysis with partial least square method (PLS), thereby make typical curve, described product makes by the following method: the crystalline YM 905 is arrived with multiple mixed with previously prepared unbodied YM 905 (by the aqueous solution spraying drying of YM 905 is made).By with the spectrum interpolation of described tablet to this typical curve, just can determine the content of the amorphous substance in the YM 905.
As the method for measuring the content of the amorphous substance in the YM 905 with solid NMR, for example, with solid NMR instrument (CMX-300 for example, make by the Chemagnetics company that is positioned at the U.S.) (for example, used probe: probe that make by pottery, 7.5mm, duration of contact: 9 milliseconds, the pulse repetition time: 38 seconds, sample rotation frequency: 5kHz) measure the spectrum of this tablet.To the spectrum of gained carry out data processing (for example, the window index function: broadening factor 30Hz, Trapezoid Window Function: t1=0, t2=0, t3=0.5, t4=0.6).In addition, the crystalline YM 905 is arrived with multiple mixed with previously prepared unbodied YM 905 (by the aqueous solution spraying drying of YM 905 is made).Then, as interior mark, the peak/height by measuring the crystalline YM 905 is the preparation standard curve recently with lactose.Being inserted on this typical curve in the peak/height ratio of the crystalline YM 905 that obtains by described tablet, can determine the content of crystallisate of YM 905 and the content of amorphous substance thus.
Term among the present invention " composition that is used for solid preparation " or " solid preparation composition " are any pharmaceutical compositions that is used for solid preparation, there is not specific limited, wherein, As time goes on and the degraded that takes place because the stability that the content of amorphous substance is in product does not have in the scope of influence, so can suppress Solifenacin or its salt.This term is meant oral compositions and parenteral admin composition, for example tablet, pill, powder, particle and capsule.
Term among the present invention " mixture of Solifenacin or its salt; described mixture comprises unbodied and crystalline Solifenacin or the salt of unbodied Solifenacin and the salt of crystalline Solifenacin; wherein the content of amorphous substance is in the scope that the stability to product not have to influence " is meant the mixture of unbodied Solifenacin and crystalline Solifenacin, or the mixture of the salt of the salt of unbodied Solifenacin and crystalline Solifenacin, wherein the degraded that As time goes on takes place of Solifenacin or its salt has been subjected to inhibition, and its content of salt of unbodied Solifenacin that this mixture comprised or unbodied Solifenacin is in the scope that the stability to product not have to influence basically.
About being incorporated into solid preparation of the present invention with the Solifenacin in the composition or the amount of its salt, the Solifenacin in the said composition or the content of its salt are preferably: the Solifenacin or its salt that comprise significant quantity in the preparation of per unit dosage.
About " be used for the Solifenacin of solid preparation or the composition of its salt; wherein; said composition comprises crystalline Solifenacin or its salt; and the stability that the content of unbodied Solifenacin or its salt is in product does not have in the scope of influence ", its preparation method is any one in the following method: need not any solvent and Solifenacin or its salt are prepared into the method for metamict; Or the method that may further comprise the steps, described step is: Solifenacin or its salt are being dissolved in the solvent, make Solifenacin or its salt formation metamict, generate thus in the process of amorphous substance, reduce the contacting of Solifenacin or its salt and this solvent (wherein, the content of amorphous substance is in the scope that the stability to product do not have to influence); Or the method that may further comprise the steps, described step is for during preparation or after making, the content of wherein amorphous substance is exceeded the such composition of scope that the stability to product do not exert an influence heat and/or humidification, be in not in the scope that the stability to product exerts an influence thereby the content of amorphous substance is adjusted to.Instrument or the device used to these methods do not have particular restriction.
Be adjusted to the stability that is in product and do not have used preparation condition in the scope of influence about content, can propose multiple preparation condition unbodied Solifenacin or its salt.Particularly, wherein a kind of preparation condition is characterised in that: need not any solvent and Solifenacin or its salt are prepared into the preparation method of metamict.For phrase " do not use any solvent and Solifenacin or its salt are prepared into the preparation method of metamict ", the preparation method who comprises direct compression, it comprises the steps: under the situation of not using any solvent, with Solifenacin or its salt with suitable mixed with excipients to, and as required the mixture compression molding of gained is obtained tablet.If this method comprises the step of adding solvent, this method comprises uses such solvent, this solvent is difficult to Solifenacin or its salt are prepared into metamict, wherein in the solvent of 1mL, the meltage of Solifenacin or its salt is lower than 0.1mg, and described solvent for example is acetone, hexane or its mixture that is used for wet granulation.
In the situation of the manufacture method that Solifenacin or its salt is prepared into metamict, at the adding solvent Solifenacin or its salt are prepared in the manufacturing step of metamict, the addition of solvent for use (for example water) and adding under the creating conditions of speed in reducing this manufacturing step, and under the preparation condition that guarantees the required quality of acquisition gained particulate, the content of amorphous substance can be adjusted to the stability that is in product does not have in the scope of influence, thereby can make the stable composition of the used Solifenacin of solid preparation or its salt.Be meant such solvent at this related solvent that is used for Solifenacin or its salt are prepared into metamict, wherein in the solvent of 1mL, the meltage of Solifenacin or its salt is 10mg or higher, and described solvent for example is water, methyl alcohol or ethanol or its mixture, more preferably water.Particularly, when the preparation solid preparation is used composition, in the aqueous solution that will be dissolved with binding agent is sprayed to step on the powder that comprises Solifenacin or its salt as binder solution, preferably prepare such particle product, this particle is by in the spray process of binder solution, the particulate moisture content is adjusted to set-point or lower value is made.In the spray process of binder solution or after spraying, the moisture content in the particle preferably is adjusted to 9% or lower, and more preferably 6% or lower, be preferably 5% or lower especially, most preferably be 4% or lower.
Even composition be not with above-mentioned manufacture method but make with general wet granulation process, wherein the content of the amorphous substance in Solifenacin or its salt be 77% or higher situation under, also can be by promoting the crystallisation process of said composition, thus the content that obtains unbodied Solifenacin or its salt is in the composition in the scope that the stability to product not have to influence.Promotion crystallisation process described herein can be finished by promoting unbodied Solifenacin or any manufacture method of its salt crystalline, and without particular restriction.Described manufacture method for example comprises: method, microwave irradiation, low frequency radiation method, ultrasonic wave radiation method and the thermoelectron radiation method of heating and/or humidification.The heating and/or the method for humidification comprise: place material climatic chamber (for example under the condition of 25 ℃ and 75% RH) to leave standstill a week separately, carry out subsequently exsiccant method again.Any can heating equably and/or the manufacture method of humidification can meet the demands composition do not have particular restriction to its used instrument and device.About microwave irradiation, for example can adopt 10MHz to the wavelength of 25GHz.In addition, the treatment time is depended on primary crystallization degree and selected base, adopts above-mentioned wavelength radiation for example 10 seconds to 60 minutes.Can continuous gamma radiation or intermittent radiation.Carry out above-mentioned crystallization and promote that can be such any time the opportunity of process, can obtain being used for the Solifenacin of solid preparation or the stable composition of its salt in this moment, but to not having particular restriction described opportunity; For example, can be after the particle of making Solifenacin or its salt, perhaps make solid preparation with composition after.
The manufacture method of product for example comprises: the direct compression process that Solifenacin or its salt is mixed, also as required this mixture compression molding obtained tablet with the additive that suits; Solifenacin or its salt are mixed with suitable additive, then sprinkling binder solution and make the particulate wet granulation process on the gained mixture; And Solifenacin or its salt mixed with suitable low melting point, and with the melt granulation of this mixture heating up and granulation.Because Solifenacin or its salt have the intensive aggregation, so direct compression process is difficult to guarantee the homogeneity of content, and this mixture can adhere on the drift in compression process; And melt granulation is difficult to the meltage of control low melting point, so preferably use wet granulation process as manufacture method of the present invention.
Wet granulation process comprises for example following steps: with pulverizer with Solifenacin or its salt pulverize, subsequently with the powder of gained with pharmaceutically useful additive (for example vehicle and disintegrating agent) thus admixed together, make particle, in this particle, mix lubricant and this mixture is pressed into tablet to sprinkling binder solution on this mixture.According to this method, should be understood that spray that binder solution is granulated and subsequent drying gained particulate step in, crystalline Solifenacin or its crystalline salt are dissolved in the spray solution of binding agent, thereby produce unbodied product.Spray velocity, the total amount that reduces binder solution or the rising inlet air temperature etc. of binder solution during can granulating by reduction, reduce Solifenacin or the solvability of its salt in described binder solution, thereby reduce the unbodied form that is generated, can provide the solid preparation pharmaceutical composition thus.
The preferred spray velocity of binder solution depends on manufacture method or manufacturing scale.When making with the scale of 5kg with fluidized bed granulation method, spray velocity is preferably 40-100g/ minute, more preferably 50-80g/ minute.The preferred total amount of binder solution depends on manufacture method or manufacturing scale.For the production of being carried out with the scale of 5kg with fluidized bed process, its total amount is preferably 1000kg to 2500kg, more preferably 1500kg to 2200kg.The preferred temperature of air inlet is according to preparation method and preparative scale different the variation.But for the production of being carried out with the scale of 5kg with fluidized bed process, this temperature is preferably 50-80 ℃, more preferably 60-80 ℃.
Described pulverizer for example comprises: hammer mill, ball mill, jet mill and colloidal mill.Generally speaking, any method that can pulverize medicine can meet the demands, and its device or method are not had particular restriction.
The fusion device of each component of next using after pulverizing comprises: for example V-type mixing tank, banding pattern mixing tank, container mixing tank and high speed agitator.Generally speaking, any method that each component pharmacy can be mixed equably can meet the demands, and its device or method are not had particular restriction.
Granulation device (method) for example comprises: high-speed stirring granulation, fluidized bed granulation method, extrusion granulator method and round as a ball granulation.The granulation of any use binder solution can meet the demands, and its device or method are not had particular restriction.
Preforming device for example comprises: rotary tablet machine and Singlepunchtabletpress.Generally speaking, any method that can prepare compression molding product (being preferably tablet) can meet the demands, and its device or method are not had particular restriction.
The binding agent that is used for wet granulation process for example comprises: Vltra tears and polyvinylpyrrolidone.Generally speaking, any binding agent with pharmaceutically acceptable powder adhesion ability can meet the demands, and it is not had particular restriction.
Generally speaking, the consumption of described binding agent is the amount that can obtain pharmaceutically acceptable particulate product, but it is not had particular restriction.Generally speaking, its consumption is the 0.5-50 weight % of per unit dosage, is preferably the 0.5-10 weight % of per unit dosage, more preferably the 2-5 weight % of per unit dosage.
In addition, for described solid preparation pharmaceutical composition of the present invention, can also suitably use various pharmaceutical excipients to prepare.Described pharmaceutical excipient can be any pharmaceutically useful and acceptable vehicle of pharmacology, to it without any particular restriction.For example, can use binding agent, disintegrating agent, acidic flavoring agent, whipping agent, artificial sweetening agent, correctives, lubricant, tinting material, stablizer, buffer reagent, oxidation inhibitor and tensio-active agent.Described binding agent for example comprises: Vltra tears and gum arabic.Described disintegrating agent for example comprises: W-Gum, yam starch, calcium carboxymethylcellulose and Xylo-Mucine.Described acidic flavoring agent for example comprises: citric acid, tartrate and oxysuccinic acid.Described whipping agent comprises for example sodium bicarbonate.Described artificial sweetening agent for example comprises: soluble saccharin, Rizinsan K2 A2, aspartame, stevia rebaudianum and Suo Matian.Described correctives for example comprises: lemon flavour, lemon-lime flavour, orange essence and menthol.Described lubricant for example comprises: Magnesium Stearate, calcium stearate, sucrose fatty ester, polyoxyethylene glycol, talcum powder and stearic acid.Described tinting material for example comprises: blue No. 3 of yellow ferric oxide, red ferric oxide, food dye yellow No. 4 and No. 5, food dye red No. 3 and No. 102 and food dye.Described buffer reagent for example comprises: citric acid, succsinic acid, fumaric acid, tartrate, xitix or its salt, L-glutamic acid, glutamine, glycine, aspartic acid, L-Ala, arginine or its salt, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid or its salt.Described oxidation inhibitor for example comprises: xitix, butylated hydroxytoluene and Tenox PG.Described tensio-active agent for example comprises: Polysorbate 80, sodium lauryl sulphate and polyoxyethylene hardened castor oil.Can add a kind of described vehicle in right amount, or add the combination of two or more described vehicle.
In addition, term " amorphous substance inhibitor " is meant: in the situation of the composition of the Solifenacin that is used for solid preparation with solvent preparation or its salt, Solifenacin or its salt are being dissolved in the described solvent, when by drying etc. it being solidified then, can suppress the material that the salt of unbodied Solifenacin or unbodied Solifenacin produces.
The amorphous substance inhibitor is preferably the material with ethylene oxide chain.Be meant any material at this related material with ethylene oxide chain with ethylene oxide chain, and without any particular restriction.This material can be any molecule type and can have any molecular weight or any polymerization degree, as long as can add the purpose of this material with the amorphous substance that reaches inhibition Solifenacin of the present invention or its salt, to this material without any particular restriction.About molecular weight, its molecular-weight average is preferably 400 to 1,000,000, and more preferably 2,000 to 200,000.About having the material of ethylene oxide chain, can mix and use two or more these materials.Particularly, the material with ethylene oxide chain of the present invention for example comprises: PEG, polyoxyethylene, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene hardened castor oil (being abbreviated as HCO hereinafter) and cithrol.Wherein, preferred especially PEG, polyoxyethylene-polyoxypropylene block copolymers or HCO.More preferably PEG.
Polyoxyethylene-polyoxypropylene block copolymers of the present invention can be the multipolymer of propylene oxide and ethylene oxide.According to the difference of its proportion of composing, can there be multiple such multipolymer.Any described multipolymer just can meet the demands as long as its ratio of components has the character of the amorphous substance that suppresses Solifenacin or its salt.Particularly, for example, can use polyoxyethylene (105) polyoxytrimethylene (5) two pure and mild polyoxyethylene (160) polyoxytrimethylene (30) glycol (another name is poloxamer F68).
The consumption of amorphous substance inhibitor is preferably the 0.1-90 weight % that accounts for the preparation total amount, more preferably accounts for the 1-60 weight % of preparation total amount.When with PEG (PEG is dissolved in the distilled water) during as the binding agent that uses in wet granulation process, its consumption is preferably the 3-20 weight % that accounts for the granulation powder, more preferably accounts for the 4-10 weight % of granulation powder.At crystalline and unbodied Solifenacin or its salt with respect to 1 weight part, when detecting the amount of amorphous substance inhibitor, the umber ratio of the amount of described inhibitor is preferably 0.001-100,000 weight %, 1-1 more preferably, 000 weight %, more preferably 10-600 weight %.
According to the present invention, phrase " comprises " and is meant that Solifenacin or its salt (it is as active pharmaceutical ingredient) and amorphous substance inhibitor mix.Preferably, Solifenacin or its salt are contacted with the amorphous substance inhibitor, thereby make Solifenacin or its salt distributions with mixture.Get rid of such pharmaceutical composition, wherein, activeconstituents Solifenacin or its salt do not contact with described amorphous substance inhibitor or do not mix, thereby make this activeconstituents exist with the state of concentration of local; The example of this pharmaceutical composition is as follows: in using according to the situation of amorphous substance inhibitor of the present invention (PEG) as the Drug coating of Solifenacin preparation, Solifenacin or its salt and amorphous substance inhibitor are in middle layer (using other additive etc. in this layer) and do not produce the physics state of contact.
Below the Solifenacin that is used for solid preparation of the present invention or the pharmaceutical composition of its salt are described in detail.Among below the embodiment and comparative example, the present invention has been carried out more detailed description.But this does not also mean that the present invention will be subjected to the restriction of these examples.
[reference example 1]
60 parts of YM 905 are dissolved in 140 parts of water, with gained solution spray drying, obtain a kind of spray-dried product with spray-dryer (DL-41 is made by Yamato Science company).
Measure the degree of crystallinity of the YM 905 spray dried prod of gained with X-ray diffraction device (RINT 1400, made by Rigaku Denki Co., Ltd).The result observes the diffraction corona pattern, and this shows that this product is unbodied.
The stability in storage of＜crystalline product and amorphous products 〉
The crystalline product before the spraying drying and the stability result of above-mentioned amorphous products are as shown in table 1.With high-efficient liquid phase chromatogram technique measuring the table shown in condition of storage under, the amount of the degraded product that As time goes on product is produced.The maximum of each degraded product has been shown in the table.In a short time, amorphous YM 905 product has generated degraded product, and its stability is than the poor stability of crystalline product after beginning to store.Therefore, by inference: the amorphous YM 905 that in the manufacturing processed of said preparation, is produced be active pharmaceutical ingredient As time goes on and the degraded major cause.
The crystalline product of YM 905 and the stability result of amorphous products
Condition of storage: 40 ℃ and 75% RH
Packaged form: vial
Test subject: related substances (maximum value of each material)
[table 1]
| Condition of storage | The crystalline product | Amorphous products | |
| When beginning to store | ND | ND | |
| The sealed glass bottle | After one week | ND | 0.03％ |
| After two weeks | ND | 0.05％ | |
| The vial of opening | After one week | ND | 0.16％ |
| After two weeks | ND | 0.16％ | |
Embodiment 1
204 parts of METHOCEL E15LVs are joined in 1836 parts of water, and, make binder solution (concentration is 10.0W/V%) with air motor agitator (AM-GC-1 is made by central natural sciences Co., Ltd.) stirring and dissolving.Then, 340 parts of YM 905 and 1360 parts of lactose are admixed together.Then, the mixture of gained is pulverized with hammer mill (sample mill AP-S, it uses the sieve of 1mm, is made by Hosokawa Micron Co., Ltd.).Add 2125 parts of lactose and 1020 parts of W-Gums in the product after mixing and pulverizing, then it is loaded in the fluidised bed granulator (WSG-5 is made by Powlec scientific ﹠ technical corporation), at 65 ℃ inlet air temperature, 4m
3/ minute binder solution spray velocity, the 1.5kg/cm of air flow quantity, 75g/ minute
2Spray pressure and such condition of spraying/jolting cycle of 30 seconds/10 seconds under, with this binder solution spraying to implement the operation of granulating.After whole binder solutions had all sprayed, the moisture content in the particle was 3.9%.After granulation,, obtain particle of the present invention with this particle under 50 ℃ inlet air temperature dry 10 minutes.In the particulate product of 1188 parts of dryings, add 12 parts of Magnesium Stearates, and mix with mixing tank (the DC type is made by Yamanouchi Co., Ltd.).Afterwards, use rotary tablet machine (HT P-22 is made by Hata Tekkosho institute) with the drift of 7.5mm φ, under the compressing tablet pressure that about 700kgf/ dashes with the mixture compressing tablet of gained, obtain sheet and heavily be the tablet of 150mg.In addition, with aeration dressing machine (high speed dressing machine HCT-30, make by Freud industrial), under the heavy such condition of Drug coating/sheet of the coating liquid input speed of the rotary speed of 60 ℃ inlet air temperature, 13rpm and 5g/ minute and 2.7%, use is carried out spray coating by solution that 84.3 parts of Vltra tearss, 6000,25.3 parts of talcum powder of 15.8 parts of Macrogol, 10.5 parts of titanium dioxide and 0.03 part of red ferric oxide dissolution are made to the tablet of 800 parts of gained in 1223 parts, obtain film garment piece of the present invention.
Embodiment 2
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 65 ℃; Air flow quantity is 4m
3/ minute; The spray velocity of binder solution is 75g/ minute; Spray pressure is 0.7kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 5.5%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
Embodiment 3
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 65 ℃; Air flow quantity is 4m
3/ minute; The spray velocity of binder solution is 95g/ minute; Spray pressure is 1.5kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 5.7%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
Embodiment 4
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 55 ℃; Air flow quantity is 4m
3/ minute; The spray velocity of binder solution is 75g/ minute; Spray pressure is 1.5kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 8.4%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
[comparative example 1]
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 65 ℃; Air flow quantity is 4m
3/ minute; The spray velocity of binder solution is 115g/ minute; Spray pressure is 1.5kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 10.6%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
[comparative example 2]
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 65 ℃; Air flow quantity is 3m
3/ minute; The spray velocity of binder solution is 75g/ minute; Spray pressure is 1.5kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 10.6%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
[comparative example 3]
By above-mentioned binder solution spraying being operated to implement to granulate under following granulation condition with fluidised bed granulator, described condition is: inlet air temperature is 45 ℃; Air flow quantity is 4m
3/ minute; The spray velocity of binder solution is 75g/ minute; Spray pressure is 1.5kg/cm
2And the spraying/jolting cycle is 30 seconds/10 seconds.After whole binder solutions had all sprayed, the moisture content in the particle was 10.8%.After granulation, prepare film garment piece of the present invention with the method described in the embodiment 1.
＜content of amorphous YM 905 in particulate moisture content, the tablet during granulating and the amount of the back degraded product of degrading along with the time of storage are measured
During creating conditions during change granulating, the content of particulate moisture content, amorphous YM 905 and as shown in table 2 behind the sprinkling binder solution that records with the result of air-tight bottle condition placement its preliminarily stabilised after 6 months under 40 ℃, 75%RH.Binder solution has sprayed back particulate moisture content to be represented with the observed value of dry weight-loss method (80 ℃, 2 months), and the content of amorphous YM 905 is represented with the observed value of near-infrared spectrophotometry.Near-infrared spectrophotometry is by (useful range is 10000cm with fourier transformation near infrared spectrometer (Vector 22/N is produced by the Bruker Optik GmbH company that is positioned at Germany)
-1To 4000cm
-1, resolving power: 2cm
-1, scanning times: 126 times) and measure spectrum carries out.Spectrum to gained carries out second differential (Savitzky-Golay convolution method), and analyzes with near-infrared spectrum analysis software (OPUS is produced by the Bruker Optik GmbH company that is positioned at Germany).Before the spectrum of measuring tablet, earlier the spectrum of following product is carried out regression analysis with partial least square method (PLS), thereby make typical curve, described product makes by the following method: the crystalline YM 905 is arrived with multiple mixed with previously prepared unbodied YM 905 (by the aqueous solution spraying drying of YM 905 is made).By with the spectrum interpolation of described tablet to this typical curve, just can determine the amount of amorphous YM 905.In addition, adopt the amount of high-efficient liquid phase chromatogram technique measuring degraded product after storing 6 months under the condition of 40 ℃, 75%RH and air-tight bottle.In the amount of the degraded product that records thus, the ratio of the growing amount of main degradation products (F1) and the total amount of YM 905 and degraded product thereof is also shown in the following table.As index, examine or check the stability of YM 905 with the ratio of F1 growing amount.
The content and preliminarily stabilised test (6 months) result of amorphous YM 905 are as follows in the particulate moisture content of the YM 905 tablet of 10mg during granulating, the tablet.
(table 2)
| Test subject | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Comparative example 1 | Comparative example | Comparative example 3 |
| Spraying back particulate moisture content | 3.9％ | 5.5％ | 5.7％ | 8.4％ | 10.6％ | 10.6％ | 10.8％ |
| The content of the amorphous YM 905 in the tablet (when beginning to store) *1 | 63％ | 73％ | 71％ | 77％ | 92％ | 90％ | 92％ |
| The ratio of F1 growing amount *2 | 0.31％ | 0.29％ | 0.35％ | 0.38％ | 0.48％ | 0.44％ | 0.43％ |
*1: record with near infrared spectrophotometric spectra method
*2: the ratio of the main degradation products of YM 905 and the total amount of YM 905 and degraded product thereof
As shown in table 2, during granulating, the tablet of the 10mg that makes under various the creating conditions has different moisture contents.Generally, along with the moisture content in the particle reduces, the content of amorphous substance also reduces in the tablet.
In the comparative example 1 to 3 as conventional manufacture method, the moisture content after binder solution has sprayed in the particle is higher than the moisture content among the embodiment.Therefore, the content height to 90% of its amorphous Solifenacin or higher.In addition, the amount of main degradation products F1 surpassed YM 905 and degraded product thereof total amount 0.4%.This shows: by the composition of the Solifenacin that provide, that be used for clinical practice of the method in the comparative example or its salt, As time goes on keeping stable this respect to exist serious problem.
In embodiment 1 to 4, moisture content in the particle is controlled as few as much as possible, on the other hand, in this case, under the controlled condition of moisture content, the content of amorphous substance is 77% or lower, and the amount of main degradation products F1 be YM 905 and degraded product thereof total amount 0.4% or lower.
Therefore, can be controlled to be 77% or lower by the content of the amorphous substance in the preparation that will comprise YM 905 or its salt, a kind of stable Solifenacin preparation that As time goes on keeps is provided.
Embodiment 5
(commodity are called Macrogol 6000 with 270 parts of PEG, make by Sanyo Chemical Industries, Ltd.) add in 1080 parts of water, and with air motor agitator (AM-GC-1 is made by central natural sciences Co., Ltd.) stirring and dissolving, thereby make binder solution (concentration is 20.0W/V%).Then, 90 parts of YM 905 and 360 parts of lactose (commodity are called Lactose200M, are made by DMV Co., Ltd.) are admixed together.Then, the mixture of gained is pulverized with hammer mill (sample mill AP-S, it uses the sieve of 1mm, is made by Hosokawa Micron Co., Ltd.).(commodity are called Avicel PH 102 to add 3906 parts of lactose and crystalline cellulose in the product after mixing and pulverizing; make by Asahi Kasei Corporation); then it is loaded into fluidized bed pelletizer (WSG-5; make by Powlec scientific ﹠ technical corporation) in, at binding agent spray velocity, the 1.5kg/cm of 70 ℃ inlet air temperature, 100g/ minute
2Spray pressure and such condition of spraying/jolting cycle of 30 seconds/10 seconds under, with this binder solution spraying to implement the operation of granulating.After granulation,, thereby obtain particle of the present invention with particle under 70 ℃ inlet air temperature dry 10 minutes.In 1188 parts of dried particulate product, add 12 parts of Magnesium Stearates (making), and mix with mixing tank (the DC type is made by Yamanouchi Co., Ltd.) by NOF company., use rotary tablet machine (HT P-22 by HataTekkosho institute made) with the drift of 5.5mm-φ, mixture under compressing tablet pressure that about 500kgf/ dash to gained compress, obtain sheet and heavily be the tablet of 60mg thereafter.In addition, with aeration dressing machine (high speed dressing machine HCT-30, make by Freud industrial), inlet air temperature at 60 ℃, the rotary speed of 13rpm, under the heavy such condition of 5g/ minute coating liquid input speed and 3.3% dressing component/sheet, (commodity are called TC-5R with 18.6 parts of HPMC 2910 with passing through, make by chemical company of SHIN-ETSU HANTOTAI), 3.5 (commodity are called Macrogol 6000 to a part PEG, make by the Sanyo company that changes into), 5.6 part talcum powder (making) by Kihara Chemical company, 2.3 part titanium dioxide (making) by Freund industrial, with 0.05 part of yellow ferric oxide (by certain herbaceous plants with big flowers oneself change into Co., Ltd. make) dissolution in 270 parts of water and the solution that makes carries out spray coating to the tablet of 900 parts of gained, obtain film garment piece of the present invention.
[comparative example 4]
(commodity are called TC-5R with 180 parts of HPMC 2910, make by chemical company of SHIN-ETSU HANTOTAI) add in 1620 parts of water, and with air motor agitator (AM-GC-1 is made by central natural sciences Co., Ltd.) stirring and dissolving, thereby make binder solution (concentration is 10.0W/V%).Then, 75 parts of YM 905 and 300 parts of lactose are admixed together.Then, the mixture of gained is pulverized with hammer mill (sample mill AP-S, it uses the sieve of 1mm, is made by HosokawaMicron Co., Ltd.).Add 2700 parts of lactose and 900 parts of W-Gums (making) in the product after mixing and pulverizing by japanese food Co., Ltd.; then it is loaded into fluidized bed pelletizer (WSG-5; make by Powlec scientific ﹠ technical corporation) in, at binding agent spray velocity, the 1.5kg/cm of 60 ℃ inlet air temperature, 75g/ minute
2Spray pressure and such condition of spraying/jolting cycle of 30 seconds/10 seconds under, with this binder solution spraying to implement the operation of granulating.After granulation,, thereby obtain particle of the present invention with particle under 60 ℃ inlet air temperature dry 10 minutes.In 1188 parts of dried particulate product, add 12 parts of Magnesium Stearates (making), and mix with mixing tank (the DC type is made by Yamanouchi Co., Ltd.) by NOF company., use rotary tablet machine (HT P-22 by Hata Tekkosho institute made) with the drift of 5.5mm-φ, mixture under compressing tablet pressure that about 500kgf/ dash to gained compress, obtain sheet and heavily be the tablet of 60mg thereafter.In addition, with the method shown in the embodiment 5 tablet of 900 parts of gained is carried out dressing, thereby obtain film garment piece of the present invention.
[comparative example 5]
108 parts of W-Gums (being made by japanese food Co., Ltd.) are added in 2592 parts of water, W-Gum is dissolved in the water being heated under 80 ℃ the condition then.Then, the solution of gained is cooled to room temperature, thereby makes binder solution.Then, 90 parts of YM 905 and 360 parts of lactose are admixed together.Then, the mixture of gained is pulverized with hammer mill (sample mill AP-S, it uses the sieve of 1mm, is made by Hosokawa Micron Co., Ltd.).Add 3708 parts of lactose and 1080 parts of W-Gums in the product after mixing and pulverizing; then it is loaded into fluidized bed pelletizer (WSG-5; make by Powlec scientific ﹠ technical corporation) in, at binding agent spray velocity, the 1.5kg/cm of 70 ℃ inlet air temperature, 90g/ minute
2Spray pressure and such condition of spraying/jolting cycle of 30 seconds/10 seconds under, with this binder solution spraying to implement the operation of granulating.After granulation,, thereby obtain particle of the present invention with particle under 70 ℃ inlet air temperature dry 10 minutes.In 129 parts of dried particulate product, add 13 parts of Magnesium Stearates, mix with mixing tank (the DC type is made by Yamanouchi Co., Ltd.)., use rotary tablet machine (HT P-22 by Hata Tekkosho institute made) with the drift of 5.5mm-φ, mixture under compressing tablet pressure that about 500kgf/ dash to gained compress, obtain sheet and heavily be the tablet of 60mg thereafter.In addition, with the method shown in the embodiment 5 tablet of 800 parts of gained is carried out spray coating, thereby obtain film garment piece of the present invention.
The result of＜its preliminarily stabilised test of Solifenacin preparation made from wet granulation process 〉
The YM 905 tablet of making use different binder solutions in pelletization carries out preliminarily stabilised test (under the condition of 25 ℃ and 60%RH).The result is as shown in table 3.
Its stability of tablet with the HPMC preparation in the comparative example 4 is not enough.Even when the binding agent of other type is examined or check, as shown in comparative example 5, starch can not improve stability.Simultaneously, shown in embodiment 5, use PEG can improve stability, this means: even more under harsh temperatures and the humidity condition, also can keep the Solifenacin stability of formulation than the condition of 25 ℃ and 60%RH.
The preliminarily stabilised test-results of YM 905 tablet
Condition of storage: 25 ℃ and 60%RH
Packaged form: be packaged in the HDPE bottle of band crown cap
Test subject: related substances (growing amount of main degradation products F 1)
[table 3]
| Embodiment 5 | Comparative example 4 | Comparative example 5 | |
| When beginning to store | 0.07％ | 0.10％ | 0.07％ |
| After 3 months | 0.11％ | 0.12％ | 0.17％ |
| After 6 months | 0.11％ | 0.34％ | 0.35％ |
| After 12 months | 0.17％ | - | - |
HDPE: high density polyethylene(HDPE)
Industrial applicibility
Technical characterictic of the present invention is: illustrated in the preparation that comprises solifenacin or its salt, the salt of unbodied solifenacin or unbodied solifenacin is the reason that active pharmaceutical ingredient was degraded along with the time. The present invention by preparation wherein the content of amorphous thing be adjusted to the preparation that (contains set-point) below the set-point, thereby the stable solid pharmaceutical preparation of solifenacin or its salt is provided first, this has a significant advantage industrial. In addition, in the preparation that comprises solifenacin or its salt, also contain amorphous thing inhibitor, thereby can be provided for the stable pharmaceutical composition in the solid pharmaceutical preparation, this has a significant advantage industrial.
Therefore, the present invention is the technology of stable composition a kind of ardent hope of medicine development institute for the treatment of frequent micturition and the urinary incontinence, that can be used for providing the used solifenacin of solid pharmaceutical preparation or its salt.
Claims (12)
1. be used for the Solifenacin of solid preparation or the composition of its salt, said composition comprises the crystal of Solifenacin or its salt, and wherein the stability that is in product of the content of amorphous substance does not have in the scope of influence.
2. the Solifenacin of solid preparation or the composition of its salt of being used for according to claim 1, the content of wherein said amorphous substance is 77% or lower.
3. the composition that is used for solid preparation according to claim 1 and 2, said composition is made by a kind of like this manufacture method, and this method is included under the situation of not using any solvent Solifenacin or its salt and mixed with excipients, the step of compression molding subsequently.
4. the composition that is used for solid preparation according to claim 1 and 2, said composition is made by a kind of like this manufacture method, this method comprises the step that adds solvent in Solifenacin or its salt, and the meltage of Solifenacin or its salt is lower than 0.1mg in the described solvent of wherein every 1mL.
5. the composition that is used for solid preparation according to claim 4, the described solvent that wherein is added in Solifenacin or its salt is acetone or hexane or its mixture.
6. the composition that is used for solid preparation according to claim 1 and 2, said composition is made by a kind of like this manufacture method, this method comprises that adding solvent is prepared into the step of metamict with Solifenacin or its salt, and the meltage of Solifenacin or its salt is 10mg or higher in the described solvent of wherein every 1mL.
7. the composition that is used for solid preparation according to claim 6, the described solvent that wherein is used for Solifenacin or its salt are prepared into metamict is water, methyl alcohol or ethanol or its mixture.
8. according to the described composition that is used for solid preparation of claim 1 to 7, said composition is made by a kind of like this manufacture method, and this method comprises the salt crystalline step that promotes unbodied Solifenacin or unbodied Solifenacin.
9. the mixture of a Solifenacin or its salt, wherein this mixture comprises the salt of unbodied Solifenacin and crystalline Solifenacin or unbodied Solifenacin and the salt of crystalline Solifenacin, and the stability that the content of wherein unbodied Solifenacin or its salt is in product does not have in the scope of influence.
10. solid preparation pharmaceutical composition, said composition comprises the salt of crystalline Solifenacin and unbodied Solifenacin or crystalline Solifenacin and the salt and the amorphous substance inhibitor of unbodied Solifenacin.
11. pharmaceutical composition according to claim 10, wherein said amorphous substance inhibitor is the material with ethylene oxide chain.
12. pharmaceutical composition according to claim 11, wherein said material with ethylene oxide chain is a polyoxyethylene glycol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US55602504P | 2004-03-25 | 2004-03-25 | |
| US60/556,025 | 2004-03-25 | ||
| US63838804P | 2004-12-27 | 2004-12-27 | |
| US60/638,388 | 2004-12-27 | ||
| PCT/JP2005/005377 WO2005092889A1 (en) | 2004-03-25 | 2005-03-24 | Composition for solid pharmaceutical preparation of solifenacin or salt thereof |
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| RU2712148C2 (en) * | 2014-12-19 | 2020-01-24 | Мерк Шарп И Доум Корп. | (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridine-1(2n)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations |
| CN110407808B (en) * | 2018-04-27 | 2022-04-15 | 燃点(南京)生物医药科技有限公司 | Novel crystal form of (1S) -1-phenyl-3, 4-dihydro-1H-isoquinoline-2-carbonyl imidazole and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO2005012I1 (en) * | 1994-12-28 | 2005-06-06 | Debio Rech Pharma Sa | Triptorelin and pharmaceutically acceptable salts thereof |
| MXPA04000124A (en) * | 2001-07-10 | 2004-05-21 | Yamanouchi Pharma Co Ltd | Medicinal composition for treatment of interstitial cystitis. |
| JP4173670B2 (en) * | 2002-03-08 | 2008-10-29 | 旭化成ファーマ株式会社 | Orally disintegrating preparation |
| WO2003103659A1 (en) * | 2002-06-07 | 2003-12-18 | 山之内製薬株式会社 | Therapeutic agent for overactive bladder |
-
2005
- 2005-03-24 CN CN2009101599531A patent/CN101601673B/en not_active Ceased
- 2005-03-24 ZA ZA200608614A patent/ZA200608614B/en unknown
- 2005-03-24 CN CN2005800094953A patent/CN1934109B/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104411687A (en) * | 2012-07-02 | 2015-03-11 | 法尔玛赞公司 | A process for the preparation of solifenacin or a salt thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1934109B (en) | 2010-06-23 |
| ZA200608614B (en) | 2008-06-25 |
| CN101601673B (en) | 2012-07-18 |
| CN101601673A (en) | 2009-12-16 |
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