CN112245402A - Indapamide tablet and preparation method thereof - Google Patents
Indapamide tablet and preparation method thereof Download PDFInfo
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- CN112245402A CN112245402A CN202011368022.5A CN202011368022A CN112245402A CN 112245402 A CN112245402 A CN 112245402A CN 202011368022 A CN202011368022 A CN 202011368022A CN 112245402 A CN112245402 A CN 112245402A
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- indapamide
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- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 title claims abstract description 111
- 229960004569 indapamide Drugs 0.000 title claims abstract description 111
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 21
- 239000000314 lubricant Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000011248 coating agent Substances 0.000 claims abstract description 17
- 238000000576 coating method Methods 0.000 claims abstract description 17
- 239000007888 film coating Substances 0.000 claims abstract description 16
- 238000009501 film coating Methods 0.000 claims abstract description 16
- 239000010410 layer Substances 0.000 claims abstract description 16
- 239000000843 powder Substances 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 15
- 239000000945 filler Substances 0.000 claims abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 12
- 239000000853 adhesive Substances 0.000 claims abstract description 11
- 230000001070 adhesive effect Effects 0.000 claims abstract description 11
- 238000007908 dry granulation Methods 0.000 claims abstract description 11
- 238000005303 weighing Methods 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 229920002774 Maltodextrin Polymers 0.000 claims description 13
- 239000005913 Maltodextrin Substances 0.000 claims description 13
- 229940035034 maltodextrin Drugs 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000011812 mixed powder Substances 0.000 claims 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 description 11
- 229920000881 Modified starch Polymers 0.000 claims description 11
- 239000008187 granular material Substances 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- 235000012239 silicon dioxide Nutrition 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 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 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 31
- 239000003814 drug Substances 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 12
- 238000009826 distribution Methods 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 109
- 238000012360 testing method Methods 0.000 description 17
- 239000012535 impurity Substances 0.000 description 13
- 239000012738 dissolution medium Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000005550 wet granulation Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 5
- 239000008055 phosphate buffer solution Substances 0.000 description 5
- 238000011020 pilot scale process Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 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 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- BBXVGZSHLMEVIP-UHFFFAOYSA-N dodecylsilane Chemical group CCCCCCCCCCCC[SiH3] BBXVGZSHLMEVIP-UHFFFAOYSA-N 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- FYYHWMGAXLPEAU-OUBTZVSYSA-N magnesium-25 atom Chemical group [25Mg] FYYHWMGAXLPEAU-OUBTZVSYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011028 process validation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an indapamide tablet, which consists of a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 20-30 parts of indapamide, 600-800 parts of a filler, 100-300 parts of an adhesive, 8-50 parts of a lubricant and 2-25 parts of a flow aid; the mass of the film coating layer is 2-5% of the mass of the tablet core. The preparation method comprises the steps of raw material and auxiliary material pretreatment, weighing and proportioning, dry powder mixing, dry granulation, total mixing, tabletting and coating. The invention is dry granulation, the operation process is simple, the difference between batches is small, the particle size distribution of the powder is uniform and stable, the difference of tablet weight and the tablet hardness are easy to control in the tabletting process; no water or organic solvent is added, and high-temperature drying is not needed, so that the main active ingredients are slightly damaged; compared with the original medicine, the indapamide tablet has the same dissolution; the indapamide tablet prepared by the invention has more uniform API distribution and is not easy to cause burst release phenomenon.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an indapamide tablet and a preparation method thereof.
Background
Hypertension is the most common chronic disease in modern society and is also the most major risk factor for cardiovascular and cerebrovascular diseases. Indapamide is a diuretic of sulfonamides, has the functions of dilating vascular smooth muscle and inducing diuresis, is mainly used for treating mild and moderate hypertension, is one of the commonly used antihypertensive drugs, and has the characteristics of quick oral absorption, obvious antihypertensive effect with small dose, small and light adverse reaction and the like. Has definite curative effect, has no adverse effect on blood fat and blood sugar, has protective effect on heart vessels and kidneys, can reverse the damage of target organs, and has no report of adverse reaction caused by interaction with other medicines. The single drug or the combined drug can be used as the first choice drug for various types of hypertension.
At present, the conventional indapamide tablet is mainly prepared by a wet granulation process or a direct compression process. The wet granulation process is a main means, for example, a patent with publication number CN110538160A discloses an indapamide tablet and a preparation method thereof, the wet granulation process is adopted, the indapamide tablet prepared by the invention is 90mg in specification, and the content uniformity of the small-specification indapamide tablet is not investigated. In addition, the wet granulation process is easy to cause the problem that the dissolution rate of the indapamide is influenced due to uneven particle sizes of raw and auxiliary materials, so that the dissolution of a medicament is too fast or too slow, the release amount of the medicament is not easy to control, and impurities are easy to generate in the wet granulation process. The direct compression process causes the API (API is an active pharmaceutical ingredient) to be unevenly distributed, and the poor powder flowability causes the tablet weight to be greatly different, thereby causing the intra-batch or inter-batch variation to be large.
Disclosure of Invention
The invention provides an indapamide tablet and a preparation method thereof, aiming at solving the problems of too high or too low dissolution rate of the indapamide tablet and uneven distribution of API (American Petroleum institute) caused by a direct tabletting process in the existing wet granulation process.
The invention adopts the following technical scheme:
an indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 20-30 parts of indapamide, 600-800 parts of a filler, 100-300 parts of an adhesive, 8-50 parts of a lubricant and 2-25 parts of a flow aid; the mass of the film coating layer is 2-5% of the mass of the tablet core (namely the weight of the coated tablet core is increased by 2-5%, and the coating powder is prepared into coating liquid with the concentration of about 15% to coat the tablet core to meet the requirement).
Further, the filler is one or more of lactose, starch and sodium carboxymethyl starch; the adhesive is one or more of maltodextrin, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose; the lubricant is magnesium stearate; the glidant is silicon dioxide. The adjuvants selected are suitable for dry granulation, and colloidal silica may also be used as the silica.
Further, the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 600-665 parts of lactose, 150-250 parts of pregelatinized starch, 50-150 parts of maltodextrin, 8-50 parts of magnesium stearate and 2-5 parts of silicon dioxide; the total weight of the pregelatinized starch and the maltodextrin is less than or equal to 300 parts.
Further, the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 665 parts of lactose, 200 parts of pregelatinized starch, 100 parts of maltodextrin, 8 parts of magnesium stearate and 2 parts of silicon dioxide.
Further, the specification of the indapamide tablet is 2.5 mg.
A preparation method of indapamide tablets is characterized by comprising the following steps:
(1) pretreating raw materials and auxiliary materials: the indapamide, the filler, the adhesive, the lubricant and the glidant are respectively sieved by a 100-mesh sieve;
(2) weighing and batching: the pretreated raw and auxiliary materials are respectively weighed according to the weight of the raw materials;
(3) mixing dry powder: adding indapamide and a filler into a mixer, and mixing for 5min to obtain mixed powder 1; adding the adhesive into a mixer, and mixing for 5min to obtain mixed powder 2; adding part of the lubricant into the mixer to mix for 10min to obtain mixed powder 3 for later use;
(4) and (3) dry granulation: slowly adding the mixed powder 3 into a hopper of a dry press to obtain dry particles 1;
(5) total mixing: adding the dry granules 1 and the flow aid into a mixer, and mixing for 5min to obtain dry granules 2; adding the dry particles 2 and the rest of the lubricant into a mixer to mix for 5min to obtain final mixed particles for later use;
(6) tabletting: tabletting the final mixed granules obtained in the step (5) to obtain tablet cores;
(7) coating: and preparing the coating powder into a coating solution, and coating the tablet core to obtain the indapamide tablet.
Further, the weight ratio of the lubricant of step (3) to the lubricant of step (5) is 3: 5.
Further, the mixer is a multi-directional motion mixer, and the main shaft frequency of the mixer is 35 Hz.
Further, the coating powder is Opadry.
Compared with the prior art, the invention has the following technical effects:
the invention is dry granulation, the operation process is simple, the difference between batches is small, the particle size distribution of the powder is uniform and stable, the difference of tablet weight and the tablet hardness are easy to control in the tabletting process; in the preparation process, no water or organic solvent is needed to be added, and high-temperature drying is not needed, so that the main active ingredients are slightly damaged; compared with the original medicine, the indapamide tablet has the same dissolution; the indapamide tablet prepared by the invention has more uniform API distribution and is not easy to cause burst release phenomenon.
According to the preparation method of the dry granulation, dry powder is firstly mixed, so that the API and the auxiliary materials can be uniformly mixed, and the dry granulation is convenient; the total mixing after dry granulation is to mix the lubricant, glidant and dry-pressed granules for convenient tabletting.
The invention is a small-specification preparation, in the dry granulation in the step (4), indapamide is mixed with a filler, and then an adhesive is added for mixing, and the purpose of mixing twice is to ensure that API and auxiliary materials are fully and uniformly mixed and ensure the content uniformity; blend powder 2 was mixed with an additional portion of lubricant (magnesium stearate), and this third mixing increased the flowability of the dry granulated blend powder.
Drawings
FIG. 1 is a process flow diagram of a process for preparing an indapamide tablet of the present invention;
FIG. 2 is a dissolution profile of 207001 batches of indapamide tablets in each dissolution medium;
figure 3 is a dissolution profile of indapamide tablets in batches 200702 in various dissolution media;
fig. 4 is a dissolution profile of indapamide tablets in batches 200703 in various dissolution media;
FIG. 5 is a graph showing the dissolution profiles of the original drug indapamide tablets in various dissolution media;
Detailed Description
The invention is further described with reference to the following figures and detailed description.
Example 1
An indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 600 parts of lactose, 200 parts of starch, 100 parts of maltodextrin, 50 parts of magnesium stearate and 25 parts of colloidal silicon dioxide. The mass of the film coating layer is 3% of the mass of the tablet core.
Example 2
An indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 650 parts of lactose, 200 parts of sodium carboxymethylcellulose, 100 parts of maltodextrin, 30 parts of magnesium stearate and 5 parts of silicon dioxide. The mass of the film coating layer is 3% of the mass of the tablet core.
Example 3
An indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 665 parts of lactose, 200 parts of pregelatinized starch, 100 parts of maltodextrin, 8 parts of magnesium stearate and 2 parts of silicon dioxide. The mass of the film coating layer is 3% of the mass of the tablet core.
Example 4
An indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 665 parts of lactose, 250 parts of pregelatinized starch, 50 parts of maltodextrin, 8 parts of magnesium stearate and 2 parts of silicon dioxide. The mass of the film coating layer is 3% of the mass of the tablet core.
Example 5
An indapamide tablet comprises a tablet core and a film coating layer, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 665 parts of lactose, 150 parts of pregelatinized starch, 150 parts of maltodextrin, 8 parts of magnesium stearate and 2 parts of silicon dioxide. The mass of the film coating layer is 3% of the mass of the tablet core.
Example 6
Experiments are carried out according to the raw materials and the mixture ratio of the indapamide tablets in the embodiments 1 to 5, the specific dosage of each embodiment is calculated by preparing 1500 indapamide tablets, the specific dosage is shown in table 2, and the following is the preparation method of the indapamide tablets in the embodiments 1 to 5, and the preparation method comprises the following steps:
(1) pretreating raw materials and auxiliary materials: respectively sieving the raw materials and the auxiliary materials with a 100-mesh sieve according to any one of the embodiments 1 to 5;
(2) weighing and batching: the pretreated raw and auxiliary materials are respectively weighed according to the weight part ratio in the embodiment;
(3) mixing dry powder: adding indapamide and a filler into a mixer, and mixing for 5min to obtain mixed powder 1; adding the adhesive into a mixer, and mixing for 5min to obtain mixed powder 2; adding part of the lubricant into the mixer to mix for 10min to obtain mixed powder 3 for later use;
(4) and (3) dry granulation: slowly adding the mixed powder 3 into a hopper of a dry press to obtain dry particles 1; see table 1 for parameter settings for the dry press:
table 1 parameter settings for a dry press
(5) Total mixing: adding the dry granules 1 and the flow aid into a mixer, and mixing for 5min to obtain dry granules 2; adding the dry particles 2 and the rest of the lubricant into a mixer to mix for 5min to obtain final mixed particles for later use;
(6) tabletting: tabletting the final mixed granules obtained in the step (5) to obtain tablet cores; the tablet press is provided with a shallow concave punch die with the diameter of 6.0mm, and the hardness is set to be 3.0kg-4.0 kg.
(7) Coating: and weighing the coating powder according to the amount of the tablet core, preparing a coating solution with the concentration of 15%, and coating the tablet core to obtain the indapamide tablet.
(8) Packaging: detecting the coated indapamide tablets, and packaging after the indapamide tablets are qualified.
TABLE 2 consumption of raw and auxiliary materials (unit: g) and measurement data of indapamide tablets of examples 1 to 5
In Table 2N/A indicates blank (i.e. indicating no addition of this material) core. The plain tablet is a tablet core, which means a tablet core without a coating layer.
The indapamide tablets are mainly researched by taking indexes of dissolution curves and content uniformity of the tablets, the bulk density and repose angle of granules, hardness and weight difference of plain tablets, weight gain of film-coated tablets and the like as indexes; the dissolution curve and the content uniformity are important parameters for measuring the stability and uniformity of the tablet, and can indicate whether the prescription is reasonable or not. The bulk density and the angle of repose can indicate the flowability of the material, the smooth tabletting of the material is related to the uniformity of each dosage unit (namely each package), the hardness and the weight difference of the plain tablets are related to the content uniformity and the quality of the film-coated tablets, and the weight gain of the film-coated tablets is related to the quality of the dissolution curve of the finished product.
As can be seen from table 2, the indapamide tablets of the present invention were all good products, and especially, the indapamide tablet prepared in example 3 was most preferable, and pilot scale-up was performed on example 3.
Example 7
Pilot scale-up was performed on the raw materials and the compounding ratio of the indapamide tablet of example 3. Pilot scale sample preparation, three batches: 207001, 207002 and 207003 batches with a sample size of 1 ten thousand tablets each were used for process validation and stability studies. Table 3 below shows the raw materials and the amounts thereof of the indapamide tablets in pilot scale.
Table 3 shows the experimental amplification of Indapamide tablets and their amounts
Three batches of indapamide tablets from batches 207001, 207002 and 207003 were tested for comparative performance with the reference formulation. The reference preparation is prepared from original research drug (coated tablet) of Indapamide.
1. In vitro dissolution test
The dissolution curves of the indapamide tablets produced in three batches in a pilot scale mode and a reference preparation under different media are compared, and the curve similarity of the three batches and the reference preparation is compared by using a factor f 2.
(1) Dissolution media
Water, a 1.2 hydrochloric acid solution, a ph4.0 phosphate buffer solution and a ph6.8 phosphate buffer solution were used as dissolution media, respectively.
Wherein the phosphate buffer solution with the pH value of 4.0 is disodium hydrogen phosphate-citric acid buffer solution, the molar ratio of the disodium hydrogen phosphate to the citric acid is 1:1, and the pH value of the prepared solution is adjusted to be 4.0 by using the citric acid; the phosphate buffer solution with the pH value of 6.8 is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, and the molar concentration ratio of the sodium dihydrogen phosphate to the disodium hydrogen phosphate is 1: 1; the two phosphate buffer solutions are both prepared by dissolving with degassed water.
(2) Measurement method
The indapamide tablets and the original medicines in the three batches of pilot-scale samples are respectively placed in 900mL of dissolution medium according to a second method for measuring dissolution rate and release rate, and the four methods of 'Chinese pharmacopoeia' 2015 edition are used for measuring, 10mL of dissolution medium is respectively sampled in 10min, 30min, 45min, 60min, 90min and 120min, the samples are filtered by a filter membrane, the primary filtrate (about 6mL) is discarded, the dissolution medium is supplemented in an operation container, and the subsequent filtrate is taken as a sample solution.
Accurately weighing about 25mg of indapamide standard substance, placing the indapamide standard substance in a 50mL volumetric flask, adding 30mL of absolute ethyl alcohol, fully shaking to dissolve the indapamide standard substance, and then using the absolute ethyl alcohol to fix the volume and shaking up; accurately measuring 5mL of the constant volume solution, and respectively diluting 200 times with different dissolution media to serve as control solutions;
the absorption peaks of the sample solution and the control solution were measured by high performance liquid chromatography according to general regulation 0512 of the fourth part of the 'Chinese pharmacopoeia' 2015 edition, which comprises the following steps: using dodecylsilane bonded silica gel as a filler (specification: 4.6mm gamma 150mm, 5um), 0.1% phosphoric acid solution-acetonitrile-methanol solution (60:30:10) was selected as a mobile phase, and the detection wavelength was set: and (3) 240nm, setting the column temperature to be 40 ℃, adjusting the flow rate to ensure that the retention time of the indapamide peak is about 6min, respectively injecting the sample solution and the contrast solution into a high performance liquid chromatograph according to the sample introduction amount of 50uL, recording a chromatogram, and calculating the measurement result by the peak area according to an external standard method.
(3) Results and analysis
The dissolution curves of the indapamide tablets in various media under different conditions are shown in the graphs in fig. 1 to 4, and the specific results are shown in tables 4 to 7;
TABLE 4207001 dissolution data of indapamide tablets (specification: 2.5mg) in batches in each medium
TABLE 5207002 dissolution data of indapamide tablets (specification: 2.5mg) in batches in each medium
TABLE 6207003 dissolution data of indapamide tablets (specification: 2.5mg) in batches in each medium
TABLE 7 dissolution data of Indapamide tablets (specification: 2.5mg) as a primary drug in each medium
The f2 values calculated by comparing the indapamide tablets in three pilot test batches with the original medicine under different medium conditions are shown in table 8;
TABLE 8 test f2 values of indapamide tablets of three batches and reference formulation in different dissolution media
The test data show that the indapamide tablet has similar dissolution curve with the reference preparation of the original medicine, namely the in vitro dissolution behavior is basically consistent, the process reproducibility is good, the process is simple, and the industrial production is easy to realize.
2. In order to investigate the in vivo bioequivalence of the prepared indapamide tablet and a reference preparation after administration, the indapamide tablet can exempt from postprandial BE research according to the indapamide tablet released by the State drug administration, a single-dose, two-preparation, two-cycle and two-cross fasting test is adopted, a cleaning period is separated by one week every time, and the concentration of the indapamide in whole blood at different time after administration is measured;
the subjects were: male and female volunteers, above 18 years of age, 36, were in compliance with health standards by physical examination; the biological test results of 207002 batches of indapamide tablets and reference preparations are shown in the table 9;
TABLE 9207002 comparison of in vivo bioequivalence of Indapamide tablets to reference formulation
Analysis shows that no significant difference (P >0.05) exists between the test groups taking the 200702 batches of the indapamide tablets and the reference preparation, which indicates that the indapamide tablets in the 200702 batches have the same biological equivalence with the reference preparation.
3. Test for impurities and stability
In order to investigate the impurity content and the change of the prepared indapamide tablets compared with a reference preparation, three batches of indapamide tablets and the reference preparation are subjected to impurity determination and a pharmaceutical acceleration test (which is an industry universal method), the test temperature is 40 +/-2 ℃, the humidity is 75 +/-5%, and the test results are shown in a table 10;
TABLE 10 accelerated stability test results of Indapamide tablets from three lots tested with reference formulation
As can be seen from the test results in Table 10, after accelerated for 6 months, the indapamide tablets prepared by the invention have no single impurity or total impurity exceeding that of the reference preparation, and have similar dissolution rate to that of the original medicine.
In summary, the results of the three batches are shown in Table 11 below:
table 11 Pilot scale-up of the results of each of the three batches of samples
As can be seen from the test results in the table above, the indexes of the pilot-scale samples of the three batches of indapamide tablets are basically consistent with those of the original medicine, and further proved that the formula and the process are reasonable and stable, and the industrial amplification is easy.
In summary, the general oral solid preparation proposed in the "determination of dissolution curves and comparative guiding principle" can be used to evaluate the quality of the imitation preparation by comparing the similarities of multiple dissolution curves in vitro between the preparation for prevention and the preparation for worn coin. The similarity of the dissolution curves does not mean that the two are necessarily bioequivalent, but the method can reduce the risk of the two appearing different in clinical efficacy; when the similarity of the dissolution curves is compared by the similarity factor (f2) method, the dissolution curves are generally considered to be similar when the value of the similarity factor between the two dissolution curves is not less than 50.
Compared with a reference preparation, the indapamide tablet prepared by the invention has the advantages that the similar factor f2 in different dissolution media is more than 50, which shows that the indapamide tablet obtained by the invention has similar dissolution curves with the reference preparation, namely the in vitro dissolution is basically consistent, so that the indapamide tablet is close to the reference preparation in quality and curative effect; in vivo bioequivalence test tests show that no significant difference (P >0.05) exists between the test groups taking the indapamide tablets and the reference preparation, which indicates that the indapamide tablets and the reference preparation have the same bioequivalence; impurity determination and stability acceleration tests show that the contents of genotoxic impurity A, impurity B, impurity C and single impurity and total impurity thereof in the obtained indapamide tablet are lower than those of a reference preparation, and 6-month acceleration tests show that the impurity content, the drug dissolution rate and the indapamide content in the indapamide tablet are not significantly changed, so that the indapamide tablet meets the requirements; the comparison result fully proves that the indapamide tablet prepared by the invention is a stable medicinal preparation which has lower impurity content and bioequivalence compared with the reference preparation of the original medicine, and has simple process and easy industrial production.
The above-mentioned embodiments are merely preferred embodiments of the present invention, which are merely illustrative and not restrictive, and it should be understood that other embodiments may be easily implemented by those skilled in the art by means of replacement or modification according to the technical contents disclosed in the specification, and therefore, all changes and modifications that come within the spirit and technical conditions of the present invention should be included in the claims of the present invention.
Claims (9)
1. An indapamide tablet comprises a tablet core and a film coating layer, and is characterized in that the tablet core is prepared from the following raw materials in parts by weight: 20-30 parts of indapamide, 600-800 parts of a filler, 100-300 parts of an adhesive, 8-50 parts of a lubricant and 2-25 parts of a flow aid; the mass of the film coating layer is 2-5% of the mass of the tablet core.
2. An indapamide tablet as claimed in claim 1, wherein the filler is one or more of lactose, starch, sodium carboxymethyl starch; the adhesive is one or more of maltodextrin, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and sodium carboxymethyl cellulose; the lubricant is magnesium stearate; the glidant is silicon dioxide.
3. The indapamide tablet of claim 2, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 600-665 parts of lactose, 150-250 parts of pregelatinized starch, 50-150 parts of maltodextrin, 8-50 parts of magnesium stearate and 2-5 parts of silicon dioxide; the total weight of the pregelatinized starch and the maltodextrin is less than or equal to 300 parts.
4. The indapamide tablet of claim 2, wherein the tablet core is prepared from the following raw materials in parts by weight: 25 parts of indapamide, 665 parts of lactose, 200 parts of pregelatinized starch, 100 parts of maltodextrin, 8 parts of magnesium stearate and 2 parts of silicon dioxide.
5. An indapamide tablet as claimed in claim 1, wherein the specification of said indapamide tablet is 2.5 mg.
6. A method for preparing an indapamide tablet as claimed in any one of claims 1 to 5, comprising the steps of:
(1) pretreating raw materials and auxiliary materials: the indapamide, the filler, the adhesive, the lubricant and the glidant are respectively sieved by a 100-mesh sieve;
(2) weighing and batching: the pretreated raw materials and auxiliary materials are respectively weighed according to the weight of each raw material in claim 1;
(3) mixing dry powder: adding indapamide and a filler into a mixer, and mixing for 5min to obtain mixed powder 1; adding the adhesive into a mixer, and mixing for 5min to obtain mixed powder 2; adding part of the lubricant into the mixer to mix for 10min to obtain mixed powder 3 for later use;
(4) and (3) dry granulation: slowly adding the mixed powder 3 into a hopper of a dry press to obtain dry particles 1;
(5) total mixing: adding the dry granules 1 and the flow aid into a mixer, and mixing for 5min to obtain dry granules 2; adding the dry particles 2 and the rest of the lubricant into a mixer to mix for 5min to obtain final mixed particles for later use;
(6) tabletting: tabletting the final mixed granules obtained in the step (5) to obtain tablet cores;
(7) coating: and preparing the coating powder into a coating solution, and coating the tablet core to obtain the indapamide tablet.
7. A process for preparing indapamide tablets as claimed in claim 6, wherein the weight ratio of the lubricant of step (3) to the lubricant of step (5) is 3: 5.
8. The method for producing indapamide tablets of claim 6, wherein the mixer is a multi-directional motion mixer, and the main shaft frequency of the mixer is 35 Hz.
9. The method for preparing indapamide tablets as claimed in claim 6, wherein the coating powder is Opadry.
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| CN113274363A (en) * | 2021-04-29 | 2021-08-20 | 珠海润都制药股份有限公司 | Indapamide preparation |
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