CN105395497A - Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof - Google Patents
Stable alpha-crystalline form perindopril tert-butylamine tablet and preparation method thereof Download PDFInfo
- Publication number
- CN105395497A CN105395497A CN201510885002.8A CN201510885002A CN105395497A CN 105395497 A CN105395497 A CN 105395497A CN 201510885002 A CN201510885002 A CN 201510885002A CN 105395497 A CN105395497 A CN 105395497A
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- CN
- China
- Prior art keywords
- butylamine
- perindopril tert
- preparation
- crystal form
- lactose
- 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
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- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 28
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 22
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 22
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 22
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 22
- 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 21
- 239000008101 lactose Substances 0.000 claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 14
- 239000002274 desiccant Substances 0.000 claims abstract description 7
- 229920003023 plastic Polymers 0.000 claims abstract description 7
- 239000004033 plastic Substances 0.000 claims abstract description 7
- 238000005070 sampling Methods 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims description 42
- 229960001375 lactose Drugs 0.000 claims description 17
- 239000002671 adjuvant Substances 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000005030 aluminium foil Substances 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 238000010348 incorporation Methods 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 12
- 238000004090 dissolution Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000004806 packaging method and process Methods 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 2
- 238000007873 sieving Methods 0.000 abstract 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 abstract 1
- 230000006399 behavior Effects 0.000 abstract 1
- 239000002131 composite material Substances 0.000 abstract 1
- 238000007907 direct compression Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 16
- 238000005755 formation reaction Methods 0.000 description 15
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 12
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 229960002582 perindopril Drugs 0.000 description 11
- 229940079593 drug Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000009702 powder compression Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- 238000012356 Product development Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 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 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BSZZSBSELAVBAG-QXKUPLGCSA-N ethyl (2s)-2-[(3s,5as,9as,10as)-3-methyl-1,4-dioxo-5a,6,7,8,9,9a,10,10a-octahydro-3h-pyrazino[1,2-a]indol-2-yl]pentanoate Chemical compound C([C@@H]12)CCC[C@H]1C[C@@H]1N2C(=O)[C@H](C)N([C@@H](CCC)C(=O)OCC)C1=O BSZZSBSELAVBAG-QXKUPLGCSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 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 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- RYCSJJXKEWBUTI-YDYAIEMNSA-N perindopril arginine Chemical class OC(=O)[C@@H](N)CCCNC(N)=N.C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 RYCSJJXKEWBUTI-YDYAIEMNSA-N 0.000 description 1
- ODAIHABQVKJNIY-PEDHHIEDSA-N perindoprilat Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(O)=O)[C@H]21 ODAIHABQVKJNIY-PEDHHIEDSA-N 0.000 description 1
- 229960005226 perindoprilat Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a stable alpha-crystalline form perindopril tert-butylamine tablet, which consists of perindopril tert-butylamine, lactose, microcrystalline cellulose and magnesium stearate. A preparation method, by virtue of a powder direct compression process, comprises the following steps: firstly, sieving and mixing the lactose and the microcrystalline cellulose, and drying the lactose and the microcrystalline cellulose; respectively sieving and mixing some lactose and microcrystalline cellulose with perindopril tert-butylamine; finally, adding the magnesium stearate and mixing; sampling and detecting, tabletting and packaging an obtained tablet with an aluminum-plastic foamed mask, wherein the interior of the aluminum-plastic foamed mask contains a drying agent and the exterior of the aluminum-plastic foamed mask is covered by a composite film bag. The perindopril tert-butylamine tablet prepared by the method disclosed by the invention has no significant change with published products in character, dissolution rate, moisture, content, crystalline form as well as dissolution behaviors in mediums at different pH values, and the perindopril tert-butylamine tablet is more stable than the published products in production and storage stability, so that the clinical effectiveness and safety of the medicine during taking are guaranteed. The perindopril tert-butylamine tablet preparation method provided by the invention is simple, and the production cost of the medicine is reduced.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of stable alpha-crystal form perindopril tert-butylamine sheet and preparation method thereof.
Background technology
Perindopril and its esters belong to angiotensin, are widely used in the treatment of cardiovascular disease, especially have good effect in the field such as hypertension and heart failure.Although originally perindopril is be synthesized into the form of sodium salt, its stability is not good enough, and therefore more stable perindopril tert-butylamine and arginine salt are synthesized in succession, also reduce security risks simultaneously.Perindopril arginine salt and perindopril tert-butylamine are developed to folk prescription or the compound preparation preparation of various ways, adopt filler (as lactose in traditional perindopril tert-butylamine slice prescription more, microcrystalline Cellulose), binding agent is (as hydroxypropyl cellulose, polyvidone, hydroxypropyl methylcellulose), disintegrating agent (carboxymethyl starch sodium), lubricant (magnesium stearate, Pulvis Talci) etc. prepare through wet granulation technology, concrete preparation method is that perindopril tert-butylamine sieves with filler and appropriate disintegrating agent equal increments successively and mixes, add binding agent soft material processed in right amount, to sieve granulation, dry, granulate, mix with residue disintegrating agent, then add lubricant always to mix, tabletting, obtain.Commercialized product adopts aluminium-plastic bubble plate packing, put add desiccant aluminium foil bag in deposit, and require to be stored in less than 30 DEG C, although greatly added the stability of product by starvation and moisture, but result of study shows that preparation is not sufficient to ensure the stable of perindopril tert-butylamine in this condition, namely also there is high temperature degradation in it, and this packaging is also very big simultaneously adds cost.
The related substance adopting liquid chromatography to carry out perindopril tablets detects, its degradation impurity is mainly B, D, F, K, the structural weakness of binding analysis perindopril itself, as the ethyl acetate base in structure makes it that perindoprilat (impurity B of hydrolysis generation carboxyl structure more easily occur, EP8.0), it is main metabolites in perindopril tert-butylamine body; In addition; carboxyl in perindopril structure and peri position amino; add and the perindopril diketopiperazine (impurity F that acylation reaction cyclization generation has lactam structure occurs; EP8.0); except above-mentioned degradation impurity, the synthesis technique of perindopril tert-butylamine own is complicated, relates to numerous process contaminants and by-product; as hydrolysis of ester group impurity in products C and the epimer impurity D thereof of impurity F, other if not over time and increase process contaminants E.The impurity degradation of perindopril tert-butylamine is shown in Fig. 1.
Except there is aforementioned stable sex chromosome mosaicism, also there is polymorphous characteristic in perindopril tert-butylamine, openly report has α, beta, gamma, the crystal formations such as δ, ε at present, and each crystal formation all has corresponding Pharmaceutical composition patent, and domestic former grinding is gone on the market kind and adopt alpha-crystal form.As aforementioned, because perindopril exists structural unstability, therefore it hydrothermal stability problem, but when research shows that commercialized product places 10 and 30 days under 40 DEG C of conditions, not only related substance significantly increases the limit even exceeding standard and specify, more seriously its crystal formation also can change, and infers that its stability may be relevant with crystal formation, and current research data all clearly not different carry out consequent stability problem.In sum, in the stability of perindopril, the degradation rate of impurity and crystal conversion are the difficult points of product development.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, a kind of stable alpha-crystal form perindopril tert-butylamine sheet be provided, be made up of according to parts by weight following component:
Alpha-crystal form perindopril tert-butylamine: 1-5 part;
Lactose: 60-80 part;
Microcrystalline Cellulose: 20-33 part;
Magnesium stearate: 0.8-1.5 part.
As preferably, described alpha-crystal form perindopril tert-butylamine sheet is made up of according to parts by weight following component:
Alpha-crystal form perindopril tert-butylamine: 4 parts;
Lactose: 65 parts;
Microcrystalline Cellulose: 20 parts;
Magnesium stearate: 1 part.
Above-mentioned perindopril tert-butylamine is alpha-crystal form, and lactose is lactose monohydrate, and microcrystalline Cellulose is pH102.
Another object of the present invention is to provide a kind of preparation method of stable alpha-crystal form perindopril tert-butylamine sheet, is realized by following steps:
(1) get lactose and microcrystalline Cellulose respectively 30 order-60 orders sieve, mixing, is dried to moisture lower than 5.0%, is divided into 3 parts;
(2) get portion and mix through the perindopril tert-butylamine of 50 order-80 mesh sieves, cross 30 order-60 mesh sieves, mixing; The particle size distribution of perindopril tert-butylamine is MEAND (4,3) for 30-50um, D90 are 70 ~ 90um.
(3) continue to add a adjuvant in step (1), mixing;
(4) mix 10 minutes-30 minutes by remaining adjuvant in the mixture of step (3) and step (1), preparation process ambient humidity is lower than 40%RH;
(5) add magnesium stearate and mix 1 minute-10 minutes, sampling detects intermediates content, and adopt 4mm*8mm tabletting, tabletting hardness is 40 ~ 70N;
(6) adopt aluminium-plastic bubble plate packing, built-in desiccant is silica gel or molecular sieve.Cover compound membrane bag outward.
Alpha-crystal form perindopril tert-butylamine sheet provided by the invention is compared with commercialized product, without significant change on outward appearance, dissolution, moisture, content, and its impurity degradation speed is less than commercialized product in stability experiment process, its stability of crystal form and commercialized product no significant difference.
The present invention is to prepare the concrete advantage in perindopril tert-butylamine sheet method as follows:
Preparation method of the present invention has adjuvant and uses few, the technique of kind simple, the advantage that with short production cycle, cost is low.Avoid in prescription using disintegrating agent (carboxymethyl starch sodium etc.), fluidizer (silicon dioxide), binding agent (HPC etc.) functional auxiliary material.Perindopril tert-butylamine sheet specification and sheet weight average less, and itself is soluble in water, and in the present invention, lactose is soluble in water, and microcrystalline Cellulose also can serve the effect of disintegrate, and therefore lactose and crystallite combinationally use and serve as filler and can promote disintegration of tablet again.The damp and hot instability of perindopril tert-butylamine sheet, formula for a product of the present invention is avoided using binding agent, thus effectively can reduce a difficult problem for moisture Control that wet granulation brings and disintegrate risk, simultaneously because perindopril tert-butylamine is very easily water-soluble, reduce its water-soluble after turn brilliant problem, and think at present and turn the brilliant stability that can reduce product.Avoid the use of silicon dioxide in formula, have patent to show acidic excipient, as silicon dioxide can accelerate the degraded of perindopril.
The present invention investigates the lactose model in embodiment 1 formula and crystallite model.When result shows to adopt Lactis Anhydrous and microcrystalline Cellulose pH112 tabletting, in stability experiment, its impurity degradation speed and crystal conversion comparatively commercialized product are fast, and even 0 day crystal formation will change.Analysis reason Lactis Anhydrous and microcrystalline Cellulose pH112 are low water material, it belongs to relative unstable state, and in tablet stability, its moisture pick-up properties certainly will than the lactose monohydrate of stable state and fast many of microcrystalline Cellulose pH102, cause local moment high humidity, accelerate degraded under the high temperature conditions.
The present invention specifies the humidity of process environments and moisture, and namely product moisture is lower than 4.5%, and process environments humidity should lower than 40%RH, and adopt the present invention effectively can solve the content homogeneity question of perindopril tert-butylamine sheet.
The present invention adopts direct powder compression, conventional wet can be avoided to granulate after tabletting production process in the wet impact with heat, avoid the probability of high temperature or high humidity impact, the content of impurity B and F reduces greatly, more be conducive to the stable of product, be more conducive to the safety of product.
The present invention adopts direct powder compression, compared with the dry tablet forming technique of wet granulation, has adjuvant and uses the advantage that kind is few, technique is simple, with short production cycle, cost is low.
Impurity degradation speed obvious reduction compared with commercialized product in its stability of alpha-crystal form perindopril tert-butylamine sheet of the present invention, and stability of crystal form is identical with commercialized product with change.
Preparation method of the present invention is reasonable in design, the Recipe of safe, effective, stable, quality controllable and simple, economic perindopril tert-butylamine, meets the principle of imitation medicine Conformance Assessment when the industry realizing product is declared, and will become highly significant.
Accompanying drawing explanation
Fig. 1 is the structural degradation schematic diagram of the process contaminants of perindopril tert-butylamine.
Fig. 2 is the crystal formation figure of commercialized product, made products, crude drug and blank auxiliary, result display deduction blank auxiliary peak, and made products, crude drug are consistent with commercialized product crystal formation, (PER-11-150309: crude drug; PER2007410: commercialized product; PER150901: made products; KBFL: blank auxiliary).
Fig. 3 is commercialized product, made products, the crude drug crystal formation figure of 10 days and 30 days under influence factor's illumination, high temperature, super-humid conditions respectively, and result is presented at made products under illumination, super-humid conditions, crude drug is consistent with commercialized product crystal formation.And under hot conditions all there is a turn crystalline substance in commercialized product, made products, crude drug; PER-11-150309 in figure: crude drug, PER2007410: commercialized product, PER150901: made products, PER-11-150309: crude drug; L10d:5000Lux illumination 10 days, H10d:75%RH places 10 days, places 10 days for T10d:40 DEG C.
Fig. 4 be commercialized product, made products, crude drug respectively under acceleration conditions 30 days wake up with a start figure, result display made products consistent with commercialized product crystal formation; PER-2007410 in figure: commercialized product; PER150706: made products; Lower 90 days of T90d:40 DEG C/75%RH condition (Acceleration study).
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the invention will be further described.
Embodiment 1:
A kind of perindopril tablets, described perindopril tablets is made up of according to parts by weight following component:
Alpha-crystal form perindopril tert-butylamine: 4 parts;
Lactose: 65 parts;
Microcrystalline Cellulose: 20 parts;
Magnesium stearate: 1 part.
The tablet of the sheet finally made heavily about 90mg, its preparation technology comprises the steps:
(1) get lactose and microcrystalline Cellulose mistake 50 mesh sieves respectively, mixing, be dried to moisture lower than 4.5%, be divided into 3 parts, Controlling Technology process humidity is lower than 40%RH.
(2) get portion to mix with the perindopril tert-butylamine through 80 mesh sieves, cross 60 mesh sieves mixings;
(3) continue to add mixed accessories in portion (1), mixing;
(4) 20 minutes are mixed by remaining adjuvant in (3) and (1);
(5) finally add magnesium stearate and mix 5 minutes, sampling detection level, adopt 4mm*8mm, tabletting, hardness is 56N;
(6) adopt PVC and aluminium foil blister packaging, built-in silica-gel desiccant, covers compound membrane bag outward.
By carrying out compatibility experiments to the supplementary material of above-described embodiment.The filler microcrystalline Cellulose of large usage quantity and lactose, in principal agent: the ratio mixing of adjuvant=1:5, silicon dioxide and magnesium stearate lubricant, in principal agent: the ratio mixing of adjuvant=20:1, by factors affecting stability test method, place 10 days, 30 days under the condition of high light, high temperature, high humidity respectively, investigate related substance change before and after placing, observe the change of appearance character etc. simultaneously.Experimental result shows, and degradation impurity B, F, K increase in time under hot and humid condition, and this phenomenon and the in theory damp and hot unstable phase of perindopril tert-butylamine meet, and under should there is adjuvant, easy moisture absorption causes high temperature and super-humid conditions to produce degraded.And before and after the mixing of each adjuvant, impurity there is no obvious increase, particularly increases without obvious unknown impuritie, therefore can think that the supplementary material compatibility used in the present invention is good, produce and storage should avoid hot and humid impact at preparation.
Table 1 supplementary material compatibility experiments
Embodiment 2:
A kind of perindopril tablets, described perindopril tablets is made up of according to parts by weight following component:
Alpha-crystal form perindopril tert-butylamine: 4 parts;
Lactose: 60 parts;
Microcrystalline Cellulose: 25 parts;
Magnesium stearate: 1 part.
The tablet of the sheet finally made heavily about 90mg, its preparation technology comprises the steps:
(1) get lactose and microcrystalline Cellulose mistake 50 mesh sieves respectively, mixing, be dried to moisture lower than 4.5%, be divided into 3 parts, Controlling Technology process humidity is lower than 40%RH;
(2) get portion to mix with the perindopril tert-butylamine through 60 mesh sieves, cross 60 mesh sieves mixings;
(3) continue to add mixed accessories in portion (1), mixing;
(4) 20 minutes are mixed by remaining adjuvant in (3) and (1);
(5) finally add magnesium stearate and mix 5 minutes, sampling detection level and uniformity of dosage units, adopt 4mm*8mm, tabletting, hardness is 50-60N;
(6) adopt PVC and aluminium foil blister packaging, built-in silica-gel desiccant, covers compound membrane bag outward.
Adopt the parallel preparation of formula 3 batches of above-described embodiment, carry out quality versus.As a result, the product prepared by the present invention is consistent with commercialized product crystal formation, the Key Quality attributes such as character, related substance, dissolution, uniformity of dosage units, moisture, content all consistent (table 2).
The quality versus of table 2 made products and commercialized product
Note: ND is not for detect
Carry out influence factor (high temperature 40 DEG C, illumination 5000lux/h, high humidity RH75%) to above-described embodiment product and commercialized product to place and study for 10 days, 30 days, the contrast of character, related substance, dissolution, content, crystal formation simultaneously.The character of each time point of result made products, dissolution, content are all consistent with commercialized product, and related substance changes trend and is better than commercialized product, and crystal formation change is consistent with commercialized product, in table 3 and accompanying drawing 2 and Fig. 3.
The influence factor quality versus of table 3 made products and commercialized product
Carry out under influence factor's condition respectively to above-described embodiment product and commercialized product and acceleration environment (40 DEG C/RH75%) carries out placing the contrast that January, 3 carries out character, related substance, dissolution, content, crystal formation below the moon.The character of each time point of result made products, dissolution, content are all consistent with commercialized product, and the degradation rate of related substance is lower than commercialized product, and the change law of crystal formation is consistent with commercialized product.In table 4 and accompanying drawing 4.
The Acceleration study quality versus of table 4 made products and commercialized product
Claims (9)
1. a stable alpha-crystal form perindopril tert-butylamine sheet, is characterized in that, described perindopril tert-butylamine sheet is made up of according to parts by weight following component: perindopril tert-butylamine: 1-5 part, lactose: 60-80 part, microcrystalline Cellulose: 20-33 part; Magnesium stearate: 0.8-1.5 part.
2. a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 1, it is characterized in that, described perindopril tert-butylamine sheet is made up of according to parts by weight following component: perindopril tert-butylamine: 4 parts; Lactose: 65 parts; Microcrystalline Cellulose: 20 parts; Magnesium stearate: 1 part.
3. a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 1 or 2, it is characterized in that, described perindopril tert-butylamine is alpha-crystal form, and lactose is lactose monohydrate, and microcrystalline Cellulose is pH102.
4. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 1 and 2, be is characterized in that, realized by following steps:
(1) get lactose and microcrystalline Cellulose crosses 30 order-60 mesh sieves, be mixed into adjuvant, be dried to moisture lower than 5.0%, be divided into 3 parts;
(2) get portion to mix with the perindopril tert-butylamine sieved, cross 30 order-60 mesh sieves, mixing;
(3) continue to add the adjuvant in a step (1), mixing;
(4) mix remaining adjuvant in step (3) mixture and step (1);
(5) finally add magnesium stearate mixing, sampling detects intermediates content, adopts 4mm*8mm tabletting;
(6) adopt aluminium-plastic bubble plate packing, built-in desiccant, covers compound membrane bag outward.
5. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 4, it is characterized in that: the sieve mesh that in step (2), perindopril tert-butylamine sieves is 50 order-80 orders, the particle size distribution of perindopril tert-butylamine is MEAND(4,3) for 30-50um, D90 are 70 ~ 90um.
6. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 4, it is characterized in that, the incorporation time of step (4) is 10 minutes-30 minutes, and preparation process ambient humidity is lower than 40%RH.
7. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 4, it is characterized in that, the incorporation time of step (5) is 1 minute-10 minutes, and tabletting hardness is: 40 ~ 70N.
8. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 4, it is characterized in that, the aluminium-plastic bubble plate packing of step (6) is PVC+ aluminium foil.
9. the preparation method of a kind of stable alpha-crystal form perindopril tert-butylamine sheet according to claim 4, is characterized in that, in step (6), desiccant is silica gel or molecular sieve.
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| CN109700774A (en) * | 2019-03-05 | 2019-05-03 | 上药东英（江苏）药业有限公司 | A kind of perindopril tert-butylamine piece and its powder vertical compression technique |
| CN111419810A (en) * | 2020-04-29 | 2020-07-17 | 南京长澳医药科技有限公司 | High-stability perindopril tert-butylamine tablet and preparation method thereof |
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Effective date of registration: 20211209 Address after: 315700 No. 85, Binhai West Road, Daxie Development Zone, Ningbo, Zhejiang Patentee after: NINGBO MENOVO TIANKANG PHARMACEUTICAL Co.,Ltd. Address before: 310015 502-516, building C, No. 37, Xiangyuan Road, Gongshu District, Hangzhou City, Zhejiang Province Patentee before: HANGZHOU XINNUOHUA PHARMACEUTICAL Co.,Ltd. |