CN103385876A - Frovatriptan medicine composition and preparation method thereof - Google Patents
Frovatriptan medicine composition and preparation method thereof Download PDFInfo
- Publication number
- CN103385876A CN103385876A CN2012101389431A CN201210138943A CN103385876A CN 103385876 A CN103385876 A CN 103385876A CN 2012101389431 A CN2012101389431 A CN 2012101389431A CN 201210138943 A CN201210138943 A CN 201210138943A CN 103385876 A CN103385876 A CN 103385876A
- Authority
- CN
- China
- Prior art keywords
- preparation
- pharmaceutical composition
- frova
- succinic acid
- consumption
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000000203 mixture Substances 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title abstract description 17
- SIBNYOSJIXCDRI-SECBINFHSA-N frovatriptan Chemical compound C1=C(C(N)=O)[CH]C2=C(C[C@H](NC)CC3)C3=NC2=C1 SIBNYOSJIXCDRI-SECBINFHSA-N 0.000 title 1
- 229960002284 frovatriptan Drugs 0.000 title 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 10
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims abstract description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 10
- 239000008101 lactose Substances 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 8
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 8
- 229920002472 Starch Polymers 0.000 claims abstract description 7
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000008107 starch Substances 0.000 claims abstract description 7
- 235000019698 starch Nutrition 0.000 claims abstract description 7
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 64
- 229940103547 frova Drugs 0.000 claims description 38
- XPSQPHWEGNHMSK-SECBINFHSA-N frovatriptan Chemical compound N1C2=CC=C(C(N)=O)C=C2C2=C1CC[C@@H](NC)C2 XPSQPHWEGNHMSK-SECBINFHSA-N 0.000 claims description 38
- 239000001384 succinic acid Substances 0.000 claims description 32
- 239000002671 adjuvant Substances 0.000 claims description 17
- 239000008187 granular material Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 10
- 238000009702 powder compression Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 229950005770 hyprolose Drugs 0.000 claims description 7
- 229960003943 hypromellose Drugs 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000007779 soft material Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000080 wetting agent Substances 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract 2
- CUETXFMONOSVJA-KLQYNRQASA-N butanedioic acid;(6r)-6-(methylamino)-6,7,8,9-tetrahydro-5h-carbazole-3-carboxamide;hydrate Chemical compound O.OC(=O)CCC(O)=O.N1C2=CC=C(C(N)=O)C=C2C2=C1CC[C@@H](NC)C2 CUETXFMONOSVJA-KLQYNRQASA-N 0.000 abstract 2
- 229960000861 frovatriptan succinate Drugs 0.000 abstract 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract 2
- 229940069328 povidone Drugs 0.000 abstract 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 abstract 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 17
- 239000003826 tablet Substances 0.000 description 14
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 208000019695 Migraine disease Diseases 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 206010027599 migraine Diseases 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 238000012856 packing Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000356 contaminant Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 101710138639 5-hydroxytryptamine receptor 1B Proteins 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 231100000869 headache Toxicity 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 101710138068 5-hydroxytryptamine receptor 1D Proteins 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 206010052787 migraine without aura Diseases 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- 102100027499 5-hydroxytryptamine receptor 1B Human genes 0.000 description 1
- WKEMJKQOLOHJLZ-UHFFFAOYSA-N Almogran Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CS(=O)(=O)N1CCCC1 WKEMJKQOLOHJLZ-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003791 Aura Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001407 Vascular Headaches Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229960002133 almotriptan Drugs 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a medicine composition with which frovatriptan succinate can maintain stable. The composition comprises: a, an active component frovatriptan succinate; and b, other common solid preparation auxiliary materials. The other solid preparation forming auxiliary materials are two or more selected from lactose, starch, hydroxypropyl methyl cellulose, povidone copolymer, high-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked povidone, magnesium stearate, talcum powder, and the like. The invention also discloses a preparation method of the medicine composition.
Description
Technical field
The present invention relates to pharmaceutical composition of a kind of Frova and preparation method thereof.The solid preparation that particularly relates to a kind of succinic acid Frova, as tablet, capsule and granule etc., and preparation method thereof.
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.
Claims (10)
1. a succinic acid Frova pharmaceutical composition, contain a. active component succinic acid Frova; B. other solid preparation adjuvant commonly used, the diluent in wherein said solid preparation adjuvant is selected from lactose, starch; Binding agent is selected from hypromellose, copolyvidone, the high hyprolose that replaces; Disintegrating agent is selected from low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone; Lubricant is selected from magnesium stearate, Pulvis Talci.
2. according to claim 1 pharmaceutical composition, the consumption that it is characterized in that active component succinic acid Frova is 1%～5%.
3. according to claim 2 pharmaceutical composition, the consumption that it is characterized in that active component succinic acid Frova is 2%～3%.
4. according to claim 1 pharmaceutical composition, is characterized in that diluent is selected from a kind of or its mixture in lactose, starch, and consumption is 40%～90%, preferred 70%～90%.
5. according to claim 1 pharmaceutical composition, is characterized in that binding agent is selected from hypromellose, copolyvidone, high one or more that replace in hyprolose, and consumption is 1%～30%, preferred 2%～10%.
6. according to claim 1 pharmaceutical composition, is characterized in that disintegrating agent is selected from a kind of or its mixture in low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, and consumption is 1%～25%, preferred 3%～8%.
7. according to claim 1 the preparation method of pharmaceutical composition comprises:
A. get active component succinic acid Frova and the solid preparation adjuvant except lubricant, cross 40 order to 80 mesh sieve mix homogeneously;
B. water or non-water-soluble matchmaker are wetting agent,, perhaps with 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 selected from ethanol, acetone; Binding agent is selected from hypromellose, high one or more that replace in hyprolose, copolyvidone, and concentration is 1%～10%;
C. add lubricant in dried granule, cross 14 order to 16 mesh sieves mixed, granulate, make preparation.
8. according to claim 1 the preparation method of pharmaceutical composition comprises:
A. get active component succinic acid Frova and the solid preparation adjuvant except lubricant, cross 40 order to 80 mesh sieve mix homogeneously;
B., with the supplementary material mixture, after mixing with lubricant, adopt dry granulation technique or technique of direct powder compression to make preparation.
9. the preparation method of according to claim 7 or 8 pharmaceutical composition, is characterized in that lubricant is one or both in magnesium stearate, Pulvis Talci, and its consumption is 0.5%～4.0%.
10. according to claim 9 the preparation method of pharmaceutical composition, the consumption that it is characterized in that lubricant is 0.5%～2%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210138943.1A CN103385876B (en) | 2012-05-08 | 2012-05-08 | Pharmaceutical composition of a kind of Frova and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210138943.1A CN103385876B (en) | 2012-05-08 | 2012-05-08 | Pharmaceutical composition of a kind of Frova and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103385876A true CN103385876A (en) | 2013-11-13 |
| CN103385876B CN103385876B (en) | 2016-01-13 |
Family
ID=49530411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210138943.1A Expired - Fee Related CN103385876B (en) | 2012-05-08 | 2012-05-08 | Pharmaceutical composition of a kind of Frova and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103385876B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103976964A (en) * | 2014-05-16 | 2014-08-13 | 广东台城制药股份有限公司 | Erythromycin estolate tablet and preparation method thereof |
| CN104758268A (en) * | 2015-04-22 | 2015-07-08 | 青岛正大海尔制药有限公司 | Frovatriptan succinate tablet and preparation method thereof |
| CN109464408A (en) * | 2018-12-28 | 2019-03-15 | 正大制药（青岛）有限公司 | A kind of succinic acid SB 209509 piece |
| CN109528670A (en) * | 2018-12-28 | 2019-03-29 | 正大制药（青岛）有限公司 | A kind of succinic acid SB 209509 piece and preparation method thereof |
| CN110974801A (en) * | 2019-12-11 | 2020-04-10 | 正大制药（青岛）有限公司 | Frovatriptan succinate enteric-coated capsule and preparation method thereof |
| CN115998890A (en) * | 2023-02-01 | 2023-04-25 | 晨光生物科技集团股份有限公司 | Auxiliary material of traditional Chinese medicine extract tablet, traditional Chinese medicine extract tablet and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522697A (en) * | 1998-07-30 | 2004-08-25 | ������ҩ������˾ | Pharmaceutical composition for preventing migraine recurrence |
| CN1543347A (en) * | 2001-08-17 | 2004-11-03 | ���ָ��Ӣ��ķ�������Ϲ�˾ | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraine |
| CN1681493A (en) * | 2002-07-19 | 2005-10-12 | 兰贝克赛实验室有限公司 | Taste masked sumatriptan tablets and processes for their preparation |
| CN101267809A (en) * | 2004-06-07 | 2008-09-17 | 惠氏公司 | Sugar coatings and methods therefor |
| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
| CN101757623A (en) * | 2008-10-09 | 2010-06-30 | 北京德众万全药物技术开发有限公司 | 5-HT receptor agonist solid pharmaceutical composition |
| CN102088966A (en) * | 2008-06-20 | 2011-06-08 | 阿尔法制药有限公司 | Pharmaceutical formulation |
-
2012
- 2012-05-08 CN CN201210138943.1A patent/CN103385876B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522697A (en) * | 1998-07-30 | 2004-08-25 | ������ҩ������˾ | Pharmaceutical composition for preventing migraine recurrence |
| CN1543347A (en) * | 2001-08-17 | 2004-11-03 | ���ָ��Ӣ��ķ�������Ϲ�˾ | Use of BIBN4096 in combination with other anti-migraine drugs for the treatment of migraine |
| CN1681493A (en) * | 2002-07-19 | 2005-10-12 | 兰贝克赛实验室有限公司 | Taste masked sumatriptan tablets and processes for their preparation |
| CN101267809A (en) * | 2004-06-07 | 2008-09-17 | 惠氏公司 | Sugar coatings and methods therefor |
| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
| CN102088966A (en) * | 2008-06-20 | 2011-06-08 | 阿尔法制药有限公司 | Pharmaceutical formulation |
| CN101757623A (en) * | 2008-10-09 | 2010-06-30 | 北京德众万全药物技术开发有限公司 | 5-HT receptor agonist solid pharmaceutical composition |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103976964A (en) * | 2014-05-16 | 2014-08-13 | 广东台城制药股份有限公司 | Erythromycin estolate tablet and preparation method thereof |
| CN103976964B (en) * | 2014-05-16 | 2015-01-14 | 广东台城制药股份有限公司 | Erythromycin estolate tablet and preparation method thereof |
| CN104758268A (en) * | 2015-04-22 | 2015-07-08 | 青岛正大海尔制药有限公司 | Frovatriptan succinate tablet and preparation method thereof |
| CN109464408A (en) * | 2018-12-28 | 2019-03-15 | 正大制药（青岛）有限公司 | A kind of succinic acid SB 209509 piece |
| CN109528670A (en) * | 2018-12-28 | 2019-03-29 | 正大制药（青岛）有限公司 | A kind of succinic acid SB 209509 piece and preparation method thereof |
| CN109528670B (en) * | 2018-12-28 | 2021-05-07 | 正大制药（青岛）有限公司 | Frovatriptan succinate tablet and preparation method thereof |
| CN110974801A (en) * | 2019-12-11 | 2020-04-10 | 正大制药（青岛）有限公司 | Frovatriptan succinate enteric-coated capsule and preparation method thereof |
| CN115998890A (en) * | 2023-02-01 | 2023-04-25 | 晨光生物科技集团股份有限公司 | Auxiliary material of traditional Chinese medicine extract tablet, traditional Chinese medicine extract tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103385876B (en) | 2016-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103385876B (en) | Pharmaceutical composition of a kind of Frova and preparation method thereof | |
| CN103156819A (en) | Benzoic acid alogliptin composition troche and preparation method thereof | |
| CN101695480A (en) | Olopatadine hydrochloride dispersible tablets, preparation method thereof and quality control method thereof | |
| CN102988993A (en) | Screening and composition of main auxiliary materials of compound acetaminophen tablet, and preparation method of compound acetaminophen tablet | |
| CN103393592B (en) | A kind of Sodium Azulenesulfonate gel and its production and use | |
| CN103360386B (en) | A kind of Tropiseiron hydrochloride compound and preparation method thereof and the pharmaceutical composition containing this compound | |
| CN102114004A (en) | Double-layer sustained-release nifedipine tablet and preparation method thereof | |
| CN106018618B (en) | Escitalopram oxalate tablet composition and quality control method | |
| CN102764254B (en) | A kind of levetiracetam medicinal composition and preparation method thereof | |
| CN102114010A (en) | Medicinal composition for treating gastrointestinal disorders as well as preparation method and application thereof | |
| CN103230595A (en) | Composition for treating mental diseases | |
| CN102293759A (en) | Dextral ibuprofen sustained release tablet preparation and preparation method thereof | |
| CN112704668B (en) | Pramipexole dihydrochloride sustained-release composition | |
| CN103385863B (en) | Sodium azulene sulfonate sustained-release preparation | |
| CN102988372A (en) | Screening and composition of main auxiliary materials of compound aspirin tablet, and preparation method of compound aspirin sheet | |
| CN105030707B (en) | Method for preparing clotrimazole buccal tablets based on modified glucose whole powder direct compression method | |
| CN103655499B (en) | Stable X-crystal-shaped agomelatine tablet and preparation method thereof | |
| CN109381431B (en) | Huperzine A sustained-release pellet and preparation method thereof | |
| CN104873470B (en) | Agomelatine tablet, film coating tablet and preparation method thereof | |
| CN101537002B (en) | Diacerein composition with excellent dissolution performance and preparation and application thereof | |
| CN111939133A (en) | Zolpidem tartrate tablet and preparation method thereof | |
| CN104644558A (en) | Solid dispersion of cilnidipine and preparation method thereof | |
| CN109200027A (en) | A kind of imrecoxib tablet and preparation method thereof | |
| CN103142522B (en) | Etoposide tablet | |
| CN101780094B (en) | Slow-release preparation of cucurbitacin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160720 Address after: 650106 Kunming science and Technology Development Zone, Yunnan Province Road No. 45 Patentee after: Dihon Pharmaceutical Group Co., Ltd. Address before: 611731, No. 1, South Road, hi tech West, Sichuan, Chengdu Patentee before: Sichuan Dihon Medical Development Co., Ltd. Patentee before: Dihon Pharmaceutical Group Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160113 Termination date: 20190508 |