Pharmaceutical composition of a kind of Frova and preparation method thereof
Technical field
The present invention relates to pharmaceutical composition of a kind of Frova and preparation method thereof.Particularly relate to a kind of solid preparation of succinic acid Frova, as tablet, capsule and granule etc., and preparation method thereof.
Background technology
Migraine is a kind of repeatedly there is the vascular headache that inclined side or bilatenal headache are feature, and be a kind of clinical common chronic forms vascular illness, prevalence women is 3.3% ~ 32.6%, and male is 0.7% ~ 16.1%.Migraine is very large on the impact of quality of life, and the headache of the patient more than 1/2 can affect work or study, and the patient Ke Yin of nearly 1/3 has a headache and lacks work or absent from school.Migrainous recurrent exerbation also can cause decrease of cognitive function, is mainly the decline of verbal ability.Migraine, except disease itself can cause damage, can also cause other to damage further, if migraine is an independent hazard factor of apoplexy.Migraine also can be suffered from various diseases altogether, as epilepsy, depression and affective disorders.Women's migraine without aura patient occurs occurring together depression and depression, and comparatively Migraine without aura person is high for the ratio of anxiety.
Triptan medicine is migrainous first-line treatment medicine clinically, Frova is second filial generation triptan medicine, belong to selectivity 5HT1B and 5HT1D receptor subtype agonist, high affinity is had with 5HT1B and 5HT1D receptor, being most powerhouse in triptan medicine to the affinity of 5HT1B, mainly treating migrainous effect by suppressing brain overdistension that is outer and entocranial artery to reach.This product is similar to other triptan curative effect of medication, which overcome that first generation 5-HT1B/1D receptor stimulating agent oral administration biaavailability is low, the half-life is short, shortcoming (this product headache relapse rate is minimum in triptan medicine) that relapse rate is high, than rizatriptan, Zolmitriptan with the effect of Almogran is more lasting, toleration is better.Tested by pharmacological toxicology and clinical trial confirm, these product treatment migrainous evident in efficacy, safety is high.Be in adult, effective medicine of severe migraine, better medication can be provided to select for clinical.
This product is developed by GlaxoSmithKline company, after transfer Vernalis company.In June, 2002, commodity were called FROVA (EndoPharmaceuticals company obtains the attorneyship of this product in the U.S.) in U.S.'s Initial Public Offering, and clinical have for being grown up or the acute treatment of migraine of absence of aura.Now in the listing of multiple European countries such as Germany and Britain, and price is more expensive.At present, domesticly there is no this product list marketing, also have no the report declared and research and develop.In China, migrainous sickness rate is also in rising trend, and this product, as second filial generation triptan medicine, has that effect is more lasting, relapse rate is lower, the better advantage of toleration, better medication can be provided to select for clinical, also be conducive to patient and can use more economical first-line drug.Therefore, develop this product and there is good clinical value and more wide market prospect.
Summary of the invention
By research, we find, succinic acid Frova crude drug all has the obvious compatibility to react with most adjuvant under high temperature (60 DEG C), high humidity (75%) compound condition, in the former adjuvant ground selected by product (trade name: FROVA), microcrystalline Cellulose and carboxymethyl starch sodium all also have the obvious compatibility to react with raw material, formerly grind after product place 10 days with this understanding, related substance obviously increases (total impurities increases to 2.96% by 0.26%, and single maximum contaminant increases to 1.01% by 0.11%).In order to obtain the more stable product of quality, we are by principal agent succinic acid Frova and some adjuvant, as lactose, starch, hypromellose, copolyvidone, high hyprolose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, magnesium stearate, the Pulvis Talci etc. of replacing carry out compatibility, make oral solid formulation, as tablet, capsule, granule etc., there is good stability.
The object of this invention is to provide a kind of Pharmaceutical composition making succinic acid Frova keep stable.Said composition comprises a. active component succinic acid Frova; B. other solid preparation molding adjuvant.Diluent in wherein said solid preparation adjuvant is selected from one in lactose, starch or its mixture, and consumption is 40% ~ 90%, and preferably 70% ~ 90%.; Binding agent is selected from hypromellose, copolyvidone, high one or more of hyprolose of replacing, and consumption is 1% ~ 30%, and preferably 2% ~ 10%.; Disintegrating agent is selected from low-substituted hydroxypropyl cellulose, the one of polyvinylpolypyrrolidone or its mixture, and consumption is 1% ~ 25%, and preferably 3% ~ 8%; Lubricant be selected from magnesium stearate, Pulvis Talci one or both, consumption is 0.5% ~ 4.0%, preferably 0.5% ~ 2%.
Another object of the present invention is to provide a kind of preparation method making succinic acid Frova keep stable Pharmaceutical composition.First by principal agent succinic acid Frova and other solid preparation molding excipient, as lactose, low-substituted hydroxypropyl cellulose etc. are mixed; (1) add wetting agent or binding agent carries out wet granulation, the granule of preparation sieves after drying, tabletting after mixed with magnesium stearate, or fill capsule, or prepares granule; Or (2) adopt dry granulation direct compression process or direct powder compression to prepare tablet.Described preparation method specifically comprises:
A. get active component succinic acid Frova, with other solid preparation molding adjuvant a certain amount of, as lactose, low-substituted hydroxypropyl cellulose etc., cross 40 order to 80 mesh sieve mix homogeneously.
B. be wetting agent with water or non-aqueous matchmaker, or use certain density binding agent, above-mentioned mixed material is carried out soft material processed, cross 18 order to 20 mesh sieve wet granulars, wet granular dryly must do granule through 40 DEG C to 60 DEG C.Wherein non-aqueous matchmaker is the one in ethanol, acetone, is preferably ethanol; Binding agent is hypromellose, one or more replacement in hyprolose, copolyvidone high, and concentration is 1% ~ 10%.
C. in dry granule, add a certain amount of lubricant, cross 14 order to 16 mesh sieves and mix, containing active component Frova according to the compacting of clinical application demand is the tablet of 1%-5%, or directly capsule prepared by fill capsule, or direct packaging becomes granule.Wherein lubricant is preferably one in magnesium stearate, Pulvis Talci or its mixture, and consumption is 0.5% ~ 4.0% of whole weight of material.
D. the supplementary material mixture also a can prepared, after mixed with a certain amount of lubricant, adopt dry granulation process or technique of direct powder compression, directly prepares tablet or capsule without wet-granulation process.Wherein lubricant is preferably a kind of in magnesium stearate, Pulvis Talci or wherein several, and consumption is 0.5% ~ 4.0% of whole weight of material.
Detailed description of the invention
Below by way of detailed description of the invention, the present invention is further described.Here want to be pointed out that, detailed description of the invention below is only used for the present invention is described, those skilled in the art are under the prerequisite understanding spirit of the present invention, can carry out corresponding conversion according to the prior art of the art and knowledge to the present invention, these technical schemes all fall within scope of the present invention.
Embodiment 1
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 2
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 3
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 4
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 5
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 6
Formula:
Preparation technology:
Supplementary material is taken according to formula proportion, raw material and lactose, starch, copolyvidone, low-substituted hydroxypropyl cellulose were merged 60 mesh sieves to mixing homogeneously, adopt the alcoholic solution of 80% height to be replaced hyprolose and be mixed with the solution of 5% as binding agent, above-mentioned mixed material is carried out soft material processed, cross 18 order to 20 mesh sieve wet granulars, wet granular dryly must do granule through 40 DEG C to 60 DEG C.Dry granule adds polyvinylpolypyrrolidone and magnesium stearate mix homogeneously, and tabletting preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 7
Formula:
Preparation technology:
Supplementary material is taken according to formula proportion, raw material was merged 60 mesh sieves to mixing homogeneously with lactose, copolyvidone, low-substituted hydroxypropyl cellulose (inside adding), the alcoholic solution of 80% is adopted hypromellose to be mixed with the solution of 5% as binding agent, above-mentioned mixed material is carried out soft material processed, cross 18 order to 20 mesh sieve wet granulars, wet granular dryly must do granule through 40 DEG C to 60 DEG C.Dry granule adds low-substituted hydroxypropyl cellulose (additional) and magnesium stearate mix homogeneously, and tabletting preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Embodiment 8
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.Direct powder compression preparation is in flakes heavily 140mg, and sheet footpath is the succinic acid Frova tablet (also can directly fill No. 3 capsules prepare succinic acid Frova capsule) of 7mm.
Comparative example 1
Formula:
Preparation technology:
Taking supplementary material according to formula proportion, raw material and adjuvant being merged 60 mesh sieves to mixing homogeneously.It is 2.5mg that direct powder compression prepares specification, and sheet is heavily 140mg, and sheet footpath is the succinic acid Frova tablet of 7mm.
Experimental example 1 determination of related substances method (high performance liquid chromatography)
Chromatographic condition: immobile phase is WelchmaterialsAQC18 post (250 × 4.6mm, 5 μm), mobile phase is that 50mmol/L ammonium acetate buffer is (containing 0.5% triethylamine, with glacial acetic acid adjust pH 3.5)-acetonitrile (93:7), determined wavelength is 244nm, flow velocity is 1ml/min, and sample size is 20 μ l.
Related substance (catabolite) algoscopy: get test specimen 20, accurately weighed, porphyrize, it is appropriate that precision takes fine powder, adds suitable quantity of water and succinic acid Frova was dissolved in ultrasonic 5 minutes, then thin up makes the solution containing 0.1mg in every 1ml, filter, get subsequent filtrate as need testing solution.Precision measures need testing solution 20 μ l, injection liquid chromatography, and record chromatogram, to 3 times of main constituent peak retention time, measures its amount of degradation products (%) by areas of peak normalization method.
Experimental example 2 not packaged high-temperature sample high humidity influence factor stability compares
High temperature 60 DEG C is placed in by naked for all formulation samples (formula 1 to formula 4) of embodiment and comparative example, under relative humidity RH75% condition, respectively at sampling in 0 day, 5 days, 10 days, observe the appearance color change of preparation, and adopt the method for test example 1 to measure the change of the amount of its catabolite (related substance).The results are shown in Table 1.
The stability result of each formulation samples of table 1
Conclusion: from upper table 1, sample under acceleration conditions (temperature 60 C, relative humidity 75%) is placed after 5 days, 10 days, it is consistent with commercially available product that embodiment 1 to embodiment 8 sample quality is obviously better than the supplementary product kind that comparative example 1(adopts), be mainly manifested in the change of formulation aesthetics color and the change of catabolite.Comparative example 1 formulation aesthetics obviously variable color (becoming lark from white), catabolite obviously increases (total impurities increases to 1.52% by 0.14%, and single maximum contaminant increases to 1.01% by 0.07%); And embodiment 1 to embodiment 8 formulation aesthetics discoloration more weak (become by white I am light yellow), it is less (from changing the most obvious embodiment 7 that catabolite increases degree, total impurities increases to 0.81% by 0.18%, and single maximum contaminant increases to 0.35% by 0.13%).Therefore, the present invention is by after new recipe design, and preparation stability significantly improves.
Experimental example 3 is through the long-term stable experiment of aluminium-plastic bubble plate packing sample
After embodiment 4 and comparative example 1 are simulated commercially available product aluminium-plastic bubble plate packing, place at ambient temperature, carry out sample analysis every half a year, observe the appearance color change of preparation, and adopt the method for test example 1 to investigate the change of the amount of its catabolite (related substance).The results are shown in Table 2,3.
The stability result (formulation aesthetics color) of table 2 sample after aluminium-plastic bubble plate packing
The stability result (related substance) of table 3 sample after aluminium-plastic bubble plate packing
Conclusion: from table 2, table 3, embodiment 4 sample and comparative example 1 sample (supplementary product kind adopted is consistent with commercially available product) are after packaging, place 42 months at ambient temperature, formulation aesthetics color is all unchanged, but the change of catabolite differs greatly.After sample places 42 months at ambient temperature, comparative example 1 total impurities more than 1%, single maximum contaminant more than 2%, apparently higher than embodiment 4.Catabolite is non-active ingredient, but also may there is certain toxicity.Therefore, the present invention, by changing Yuan Yan factory formula, can obtain the product that quality is more stable, to reduce the risk of the untoward reaction caused because of catabolite, reaches the object extending limit date of using a drug after its production limit simultaneously.