Background technology
Migraine is a kind of so that inclined to one side side or the bilatenal headache vascular headache as feature to occur repeatedly, is a kind of clinical common chronic neural blood vessel illness, and prevalence women is 3.3%~32.6%, and the male is 0.7%~16.1%.Migraine is very large on the impact of quality of life, and the headache of the patient over 1/2 can affect work or study, but patient's excuse of nearly 1/3 lacks work or absent from school bitterly.Migrainous outbreak repeatedly also can cause decrease of cognitive function, is mainly the decline of verbal ability.Migraine except disease itself can cause damage, can also further cause other infringements, is an independent hazard factor of apoplexy as migraine.Migraine also can be suffered from altogether with various diseases, as epilepsy, depression and affective disorders.Women's migraine without aura patient occurs that the ratio of depression and the depressed anxiety that occurs together is high than the Migraine without aura person.
The 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, with 5HT1B and 5HT1D receptor, high affinity is arranged, being powerhouse in the triptan medicine to the affinity of 5HT1B, is mainly to reach and treat migrainous effect by suppressing brain overdistension outer and entocranial artery.This product is similar to other triptan curative effect of medication, it has overcome the shortcoming that first generation 5-HT1B/1D receptor stimulating agent oral administration biaavailability is low, the half-life is short, relapse rate is high (this product headache relapse rate minimum in the triptan medicine), than rizatriptan, Zolmitriptan more lasting with effect Almogran, toleration is better.Test and the clinical trial confirmation by pharmacological toxicology, this product treatment is migrainous evident in efficacy, safe.Be in the adult, effective medicine of severe migraine, can provide better medication to select for clinical.
This product is by GlaxoSmithKline company exploitation, after transfer Vernalis company.In June, 2002 is in U.S.'s Initial Public Offering, and commodity are called FROVA (Endo Pharmaceuticals company obtains the attorneyship of this product in the U.S.), and clinical have or the acute treatment of the migraine of absence of aura for the adult.Now in a plurality of European countries such as Germany and Britain, go on the market, and price is more expensive.At present, domesticly there is no this product list marketing, also have no the report of declaring and researching and developing.In China, migrainous sickness rate is also in rising trend, and this product is as second filial generation triptan medicine, has that effect is more lasting, relapse rate is lower, the better advantage of toleration, can provide better medication to select for clinical, also be conducive to the patient and can use more economical first-line drug.Therefore, exploitation this product has good clinical value and more wide market prospect.
Summary of the invention
By research, we find, succinic acid Frova crude drug all has obvious compatibility reaction with most adjuvants under high temperature (60 ℃), high humidity (75%) compound condition, former product (the trade name: FROVA) in selected adjuvant of grinding, microcrystalline Cellulose and carboxymethyl starch sodium all also have obvious compatibility reaction with raw material, former grind product and place with this understanding 10 days after, 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 product of more stable quality, we are with principal agent succinic acid Frova and some adjuvant, carry out compatibility as lactose, starch, hypromellose, copolyvidone, high hyprolose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, magnesium stearate, the Pulvis Talci etc. of replacing, make oral solid formulation,, as tablet, capsule, granule etc., has good stability.
The purpose of this invention is to provide a kind of succinic acid Frova that makes and keep stable Pharmaceutical composition.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 a kind of or its mixture in lactose, starch, and consumption is 40%~90%, and preferred 70%~90%.Binding agent is selected from hypromellose, copolyvidone, high one or more of hyprolose of replacing, and consumption is 1%~30%, and preferred 2%~10%.Disintegrating agent is selected from a kind of of low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone or its mixture, and consumption is 1%~25%, and preferred 3%~8%; Lubricant be selected from magnesium stearate, Pulvis Talci one or both, consumption is 0.5%~4.0%, preferred 0.5%~2%.
Another object of the present invention is to provide a kind of preparation method that makes the stable Pharmaceutical composition of succinic acid Frova maintenance.First with principal agent succinic acid Frova and other solid preparation molding excipient, as mixed in lactose, low-substituted hydroxypropyl cellulose etc.; (1) add wetting agent or binding agent to carry out wet granulation, the granule of preparation sieves after drying, and with the mixed rear tabletting of magnesium stearate, perhaps the fill capsule, perhaps prepare granule; Perhaps (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 a certain amount of other solid preparation molding adjuvant,, as lactose, low-substituted hydroxypropyl cellulose etc., cross 40 order to 80 mesh sieve mix homogeneously.
B. water or non-water-soluble matchmaker are wetting agent, or use certain density binding agent,, with above-mentioned mixed material soft material processed, cross 18 order to 20 mesh sieve wet granulars processed, and wet granular dryly must be done granule through 40 ℃ to 60 ℃.Wherein non-water-soluble matchmaker is a kind of in ethanol, acetone, is preferably ethanol; Binding agent is hypromellose, high one or more that replace in hyprolose, copolyvidone, and concentration is 1%~10%.
C. add a certain amount of lubricant in dried granule, cross 14 order to 16 mesh sieves mixed, according to the compacting of clinical application demand, contain the tablet that the active component Frova is 1%-5%, perhaps directly the fill capsule prepares capsule, and perhaps direct packaging becomes granule.Wherein lubricant is preferably a kind of or its mixture in magnesium stearate, Pulvis Talci, and consumption is 0.5%~4.0% of whole weight of material.
D. also the supplementary material mixture of a preparation after mixing with a certain amount of lubricant, dry granulation technique or technique of direct powder compression be can be adopted, without wet-granulation process, tablet or capsule directly prepared.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.
The specific embodiment
Below by the specific embodiment, the present invention is further described.Here want to be pointed out that, below the specific embodiment only be used for illustrating the present invention, those skilled in the art are understanding under the prerequisite of spirit of the present invention, can carry out corresponding conversion to the present invention according to prior art and the knowledge of the art, within these technical schemes all fall into scope of the present invention.
Embodiment 1
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 2
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 3
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 4
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 5
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 6
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and lactose, starch, copolyvidone, low-substituted hydroxypropyl cellulose were merged 60 mesh sieves to mixing homogeneously, adopt 80% alcoholic solution that height is replaced hyprolose and be mixed with 5% solution as binding agent, with above-mentioned mixed material soft material processed, cross 18 order to 20 mesh sieve wet granulars processed, wet granular dryly must be done granule through 40 ℃ to 60 ℃.Dried granule adds polyvinylpolypyrrolidone and magnesium stearate mix homogeneously, and the tabletting preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 7
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and lactose, copolyvidone, low-substituted hydroxypropyl cellulose (in add) were merged 60 mesh sieves to mixing homogeneously, adopt 80% alcoholic solution that hypromellose is mixed with 5% solution as binding agent, with above-mentioned mixed material soft material processed, cross 18 order to 20 mesh sieve wet granulars processed, wet granular dryly must be done granule through 40 ℃ to 60 ℃.Dried granule adds low-substituted hydroxypropyl cellulose (additional) and magnesium stearate mix homogeneously, and the tabletting preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
Embodiment 8
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.The direct powder compression preparation is heavily 140mg in flakes, and the sheet footpath is the succinic acid Frova tablet (also directly No. 3 capsules of fill prepare succinic acid Frova capsule) of 7mm.
The comparative example 1
Formula:
Preparation technology:
Take supplementary material according to formula proportion, raw material and adjuvant were merged 60 mesh sieves to mixing homogeneously.It is 2.5mg that direct powder compression prepares specification, and sheet is heavily 140mg, and the 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 Welch materials AQ C18 post (250 * 4.6mm, 5 μ m), mobile phase is that the 50mmol/L ammonium acetate buffer (contains 0.5% triethylamine, with glacial acetic acid adjust pH 3.5)-acetonitrile (93:7), the detection wavelength is 244nm, flow velocity is 1ml/min, and sample size is 20 μ l.
Related substance (catabolite) algoscopy: get 20 of test specimens, accurately weighed, porphyrize, it is appropriate that precision takes fine powder, add suitable quantity of water the succinic acid Frova is dissolved, then thin up made the solution that contains 0.1mg in every 1ml, filter, get subsequent filtrate as need testing solution.Precision measures need testing solution 20 μ l, and the injection liquid chromatography records to main constituent peak retention time 3 times of chromatogram, by areas of peak normalization method, measures its amount of degradation products (%).
Experimental example 2 compares without the high-temperature sample high humidity influence factor stability of packing
Naked 60 ℃ of the high temperature that are placed in of all formula samples (formula 1 is to formula 4) with embodiment and comparative example, under relative humidity RH75% condition, respectively at sampling in 0 day, 5 days, 10 days, the appearance color of observing preparation changes, and the method for employing test example 1 is measured the variation of the amount of its catabolite (related substance).The results are shown in Table 1.
Respectively the fill a prescription stability result of sample of table 1
Conclusion: by upper table 1 as can be known, sample (temperature 60 C, relative humidity 75%) under acceleration environment is placed after 5 days, 10 days, it is consistent with commercially available product that embodiment 1 to embodiment 8 sample quality obviously is better than the supplementary product kind that comparative example 1(adopts), be mainly manifested in the variation of the variation of preparation appearance color and catabolite.Comparative example's 1 obviously variable color of preparation outward appearance (by white, becoming lark), 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 preparation appearance color change degree weak (by white, become I am light yellow), it is less (by changing the most obvious embodiment 7 as can be known 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 by new recipe design after, preparation stability obviously improves.
Experimental example 3 is through the long-term stable experiment of aluminium-plastic bubble plate packing sample
With embodiment 4 and comparative example 1 simulation commercially available product with aluminium-plastic bubble plate packing after, place at ambient temperature, carry out sample analysis every half a year, the appearance color of observing preparation changes, and the method for employing test example 1 is investigated the variation of the amount of its catabolite (related substance).The results are shown in Table 2,3.
The stability result of table 2 sample after aluminium-plastic bubble plate packing (preparation appearance color)
The stability result (related substance) of table 3 sample after aluminium-plastic bubble plate packing
Conclusion: by table 2, table 3 as can be known, embodiment 4 samples and comparative example's 1 sample (supplementary product kind that adopts is consistent with commercially available product) are after packing, placed at ambient temperature 42 months, the preparation appearance color is all unchanged, but the variation of catabolite differs greatly.After sample was placed 42 months at ambient temperature, comparative example's 1 total impurities surpassed 1%, and single maximum contaminant surpasses 2%, apparently higher than embodiment 4.Catabolite is non-active ingredient, but also may have certain toxicity.Therefore, the present invention, by changing the former factory's formula that grinds, can obtain the more stable product of quality,, to reduce the risk of the untoward reaction that causes because of catabolite, reaches simultaneously the purpose that extends the limit date of using a drug after its production limit.