CN107028912B - A kind of preparation method of Irbesartan Capsules - Google Patents
A kind of preparation method of Irbesartan Capsules Download PDFInfo
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- CN107028912B CN107028912B CN201710397882.3A CN201710397882A CN107028912B CN 107028912 B CN107028912 B CN 107028912B CN 201710397882 A CN201710397882 A CN 201710397882A CN 107028912 B CN107028912 B CN 107028912B
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
The invention discloses a kind of preparation methods of Irbesartan Capsules, and the application in imitation medicine Conformance Assessment.After Irbesartan is mixed softwood processed with various auxiliary materials by the present invention, pelletized by the method for squeezing granulation, it is uniform with mix lubricant after dry, fill capsule.The Irbesartan Capsules of preparation process production of the present invention, external a plurality of dissolution curve and original grind product (name of product: Irbesartan Tablets；Trade name: An Bowei；Specification: 0.15g；Production firm: Sanofi Winthrop Industrie) unanimously, during accelerated test and long term test study on the stability, related substance grinds product bioequivalence with original without significant change.
Description
Technical field
The present invention relates to a kind of preparation methods of Irbesartan Capsules, and answering in imitation medicine Conformance Assessment field
With.
Background technique
With the variation of socio-economic development and people life style, China's Prevalence of Hypertension is in growing situation.
According to statistics, there are more than 300,000,000 hypertensive patients in China in 2014, and 18 years old and the above adult hypertension illness rate are 27.2%, with 2010
Ling≤18 data (of year Chinese residents nourishment and chronic disease status investigation year old crowd's Prevalence of Hypertension is 25.2%) it compares,
Prevalence of Hypertension is in rise appreciably.It therefore is the sanitarian great work in China for the control of hypertension and treatment
Journey.
Hypertension is a kind of long-term chronic disease, needs life-long therapy in many cases.However, most of hypertension
Patient even needs combination therapy to can be only achieved target blood pressure (BP), i.e. 140/90 millimetres of mercury of <.Clinically used drug is β
Receptor blocker, nitrate, hypertensinⅡreceptorretarder etc..
Irbesartan Tablets are a kind of effective, Orally active selective angiotensin-ii receptor (AT1 hypotype) antagonisms
Agent, can with high selectivity in body circulation and local organization comprehensive antagonism Ang II receptor AT1 hypotype, block different metabolic way
Diameter synthesis Ang II, irreversible or noncompetitive inhibition is generated to AT1 receptor, therefrom generate inhibit vessel retraction and
The effects of Aldosterone Secretion, thus reduce blood pressure, improve heart function effect, and have treatment congestive failure, diabetic nephropathy etc.
Effect, compared to other clinical treatment drugs, Irbesartan has antihypertensive effect significant, and adverse drug reaction is small (if do not caused
Irritation dry cough etc.), the advantages that oral absorption is good, in addition, also having one with heart failure and Type II diabetic nephropathy to hypertension
Constant current modulation effect.
Irbesartan structural formula
Thomson Newport database displaying, on August 31st, 1997, French Sino luxuriant and rich with fragrance (SANOFI AVENTIS) are public
Department has listed Irbesartan Tablet (trade name: APROVEL) in Holland, and specification 75mg, 150mg, 300mg are used for
Treat essential hypertension, the treatment of the diabetes B nephrosis of complicated hypertension.The same year lists after obtaining FDA approval in the U.S., quotient
The name of an article is " AVAPRO ", specification 75mg, 150mg, 300mg.Currently, match Norfin, Inc, France is in global 71 countries
Have listed Irbesartan tablet, specification includes 75mg, 150mg, 300mg.Irbesartan Capsules only list in China, Central America,
Specification has 75mg, 150mg, 300mg.
FDA is about describing the research of a PPK1690 in " AVAPRO " the Medical Review of Sanofi.One
In single centre, random open, four periods cross matching, 12 healthy male volunteers are randomly divided into four groups, take orally on an empty stomach
5mg, 25mg, 100mg capsule, postprandial (FDA standard meal) take orally 25mg capsule, and the cleaning phase is 2 weeks.Before medication and after medication
0.5,1,1.5,2,2.5,3,4,6,8,10,12,24,36,48,72,96,120h acquisition blood sample, wherein on an empty stomach and postprandial oral
The test data of 25mg capsule shows: postprandial Tmax delay 30min or so, but Cmax、AUC0-tIt is not influenced by food, 90%
CI meets bioequivalence regulation, therefore, it is considered that food is on the bioavilability of Irbesartan without influence, the sky of Irbesartan Capsules
Abdomen and there is bioequivalence after the meal.Detailed data is referring to table 1.
Irbesartan Capsules empty stomach and postprandial pharmacokinetic parameter in 1 PPK1690 of table research
FDA is about describing the research of CV131-056 in " AVAPRO " the Medical Review of Sanofi.At one
Opening, single centre, single dose, in binary cycle cross matching, 16 healthy male subjects are randomly divided into two groups, and subject exists
300mg Irbesartan Tablets are taken orally on an empty stomach or under the conditions of postprandial (FDA high fat diet), and the cleaning phase is 1 week.The kimonos before medication
0.17,0.33,0.67,1,1.5,2,3,4,6,8,12,16,24,30,36,48,60,72h acquisition blood sample after medicine.As a result table
It is bright: postprandial Tmax delay, CmaxIncrease by 9.1%, AUC0-∞Increase by 3.4%, but the two 90%CI provides model in bioequivalence
It encloses in (80%~125%), therefore, it is considered that Cmax、AUC0-∞Substantially it is not influenced by food intake, medicine of the food to Irbesartan
It is not statistically significant for dynamics.Detailed data is referring to table 2.
Irbesartan Capsules empty stomach and postprandial pharmacokinetic parameter in 2 CV131-056 of table research
| On an empty stomach | After the meal | P value | Ratio (90%CI) | |
| Cmax(ng/mL) | 2988±929 | 3277±1103 | 0.306 | 1.09(0.94-1.26) |
| AUC0-t | 22841±7293 | 24611±12143 | 0.638 | 1.07(0.92-1.17) |
| Tmax(hr) | 1.0(0.3-4.0) | 1.75(1.0-8.0) | 0.140 | NS |
| T1/2(hr) | 15.0±5.3 | 18.3±9.8 | 0.123 | NS |
PMDA is about describing the research of ALI2487 in the declaration material summary of Irbesartan Tablets.One random open, hands over
In fork test, 6 Japanese healthy adult male volunteers are randomly divided into two groups, take orally 25mg strategic point in empty stomach or postprandial (standard meal)
Bei Shatan capsule, cleaning phase are 2 weeks.Before medication and 0.5,1,1.5,2,3,4,6,8,10,12,16,24,36,48h after medication
Acquire blood sample, the results showed that compared on an empty stomach, postprandial Tmax significantly extends, clinically statistically significant, CmaxIt reduces,
AUC0-∞It is slight to reduce 16%, therefore, it is considered that food acts on very little to the Pharmacokinetic effect of Irbesartan.Detailed data referring to
Table 3.
Irbesartan Capsules empty stomach and postprandial pharmacokinetic parameter in 3 ALI2487 of table research
| Medicine is for parameter | On an empty stomach | After the meal | P value |
| Cmax(ng/mL) | 618.27±237.64 | 418.95±159.77 | 0.0578 |
| AUC0-∞(ng.hr/mL) | 2268.13±597.77 | 1906.67±554.18 | 0.0093* |
| Tmax(hr) | 1.42±0.49 | 3.00±1.10 | 0.0270* |
| T1/2, α (hr) | 1.05±0.15 | 18.3±9.8 | 0.2302 |
| T1/2, β (hr) | 14.43±6.16 | 17.77±14.56 | 0.4869 |
By FDA, PMDA etc. about the clinical test of Irbesartan it can be seen that, even if food leads to the medicine generation of Irbesartan
Dynamics changes, such as Cmax、AUC0-t、AUC0-∞It reduces or increases, but this species diversity is extremely small, and 90%CI is in regulation model
In enclosing, clinical meaning is had no effect on, it is believed that there is bioequivalence on an empty stomach and after the meal.
Application No. is 201210230661.4 patent, (patentee: the auspicious medicine company in Yangzijiang Pharmaceutical Group, sea, Guangzhou is limited
Company), disclose " a kind of Irbesartan Capsules and preparation method thereof ", the Irbesartan Capsules mainly include Irbesartan,
Pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate, using a step of boiling
Granulation is once completed mixing, granulation, dry three steps in the closed container of boiling one-step-granulating method, obtained
Grain graininess uniformity, good fluidity, capsule content uniformity is small, and dissolution rate is good, and fewer than conventional wet lay granulating process step,
Production equipment is few, and production cost is low, high-efficient, and yield is high.The patent only describes its preparation process, the product not prepared to it
Carry out comprehensive quality evaluation, the especially dissolution curve in different dissolution mediums, related substance etc., also do not ground with original product into
Row is comprehensive relatively.
Application No. is 201410233928.4 patent (applicants: the limited public affairs of Yangzijiang Pharmaceutical Group's Beijing petrel medicine company
Department), disclose " pharmaceutical composition of Irbesartan and its preparation method and application ".The invention is using hot-melt extruded granulator heat
Grain or aerosol type solid dispersions draft machine is melted, Irbesartan solid dispersions are made in Irbesartan and carrier material, then will
Tablet is made with suitable diluent, disintegrating agent, surfactant, adhesive, glidant and mix lubricant in it.The present invention is logical
Cross and solid dispersions be made in Irbesartan, and then tablet is made, improve the dissolution rate of drug, obtain it is preferable absorb and
Bioavilability.Although Irbesartan is at 105 DEG C, rs is more stable for 24 hours, the fusing point of Irbesartan is about 180~181
DEG C, when using hot-melt extrusion process, temperature of charge need to rise to 180~181 DEG C or more, and Irbesartan bulk pharmaceutical chemicals and various auxiliary materials can
It can degrade, increase the unstable risk of drug.
Irbesartan is white to off-white color crystalline powder, is practically insoluble in water, is slightly soluble in ethyl alcohol and methylene chloride.Acid
Soda balance FACTOR P ka is 4.70 ± 0.06, and Determination of oil-water partition coefficient Log P is 5.03.Our company's product is solvent-free conjunction object or water
It closes object to exist, for this product there are polymorphism, our company's product is crystal form A.Irbesartan is low solubility, high osmosis medicine
Object, for BCS II class of classification.
Irbesartan is more stable under the conditions of high temperature (105 DEG C, for 24 hours rs)；In acid (1M HCl, 4hrs) and alkalinity
It is unstable under the conditions of (1M NaOH, 2hrs), it is easy to happen degradation, generates related substance I；In oxidation (30%H2O2, rs for 24 hours) and item
It is also unstable under part, it can also generate some oxidative degradation objects.
Related substance I structural formula
According to selection principle in " selection of normal oral solid pharmaceutical preparation reference preparation and the determining guideline " of CFDA publication
First, " original of the preferred domestic listing of reference preparation grinds drug ".Irbesartan Tablets (the ProductName of match Norfin, Inc, France production
Claim: Irbesartan Tablets；Trade name: An Bowei；Specification: 0.15g；Production firm: Sanofi Winthrop Industrie) be
It is first overseas to be approved to list, there is the drug of complete and sufficient safety, efficacy data, and with this product work having the same
Property ingredient and administration route, it is thus determined that its as Zhuhai Rundu Pharmaceutical Co., Ltd.'s Irbesartan Capsules (specification:
Reference preparation 0.15g).
In Irbesartan Capsules conformance assessment process, goldstandard is that Irbesartan Capsules and match Norfin, Inc, France are raw
The Irbesartan Tablets bioequivalence of production, this is no any dispute.Tablet is due to there is the process of a disintegration, in dissolution medium
In first 15~30 minutes, dissolution be considerably slower than capsule.Since capsule is different from the In Vitro Dissolution feature of tablet,
It is very difficult that one kind, which is developed, with the consistent capsule of tablet In Vitro Dissolution curve.The method that the present invention uses extrusion granulator
Irbesartan Capsules are prepared, external a plurality of dissolution curve and original grind product (name of product: Irbesartan Tablets；Trade name: An Bo
Dimension；Specification: 0.15g；Production firm: Sanofi Winthrop Industrie) unanimously, it is steady in accelerated test and long term test
During qualitative investigation, related substance grinds product bioequivalence with original without significant change.
Summary of the invention
It is an object of the invention to provide a kind of preparation methods of Irbesartan Capsules.
The present invention prepares Irbesartan Capsules using the method for extrusion granulator, and external a plurality of dissolution curve and original grind product
(name of product: Irbesartan Tablets；Trade name: An Bowei；Specification: 0.15g；Production firm: Sanofi Winthrop
Industrie) unanimously, during accelerated test and long term test study on the stability, related substance is ground without significant change with original
Product bioequivalence.
Irbesartan Capsules of the present invention pharmaceutical composition made of medicament active composition and pharmaceutic adjuvant and commonly
Capsule shells composition.Described pharmaceutical composition is made of medicament active composition, filler, disintegrating agent, adhesive, lubricant.
After softwood is made by Irbesartan, filler, disintegrating agent, adhesive in the content of capsule of the present invention, pass through extruding
Granulating process is prepared into drug granule, forms after dry with mix lubricant.
Specifically, preparation method of the invention, comprising the following steps:
(1) it stocks up
It leads and expects by prescription, mark.
(2) processing of former auxiliary material
Former auxiliary material is sieved through 60 meshes in vibration.
(3) it weighs
Bulk pharmaceutical chemicals and auxiliary material are weighed by Formulation amount.
(4) preparation of binder solution
Adhesive is got, binder solution is prepared with 75% ethyl alcohol.
(5) softwood processed
The auxiliary material of original of weighing is successively put into wet mixing pelletizer, stirs, mixes 5 minutes.Adhesive is added
It extremely plus in sizing device, opens manually plus starches, softwood processed, reach wet granular and hold agglomerating, the i.e. bulk state of touching.
(6) it pelletizes
The above-mentioned softwood made is set and is squeezed in granulator, sieve diameter control is in 10 mesh.
(7) dry
The Irbesartan particle that above-mentioned extruding is pelletized is set in fluidized bed and is dried, temperature of charge is arranged 50
DEG C, until moisture content is not higher than 2%, rewinding.
(8) whole grain
The Irbesartan particle of above-mentioned drying is set into whole grain in the pelletizing machine that sieve partial size is 2mm.
(9) total mix
After the completion of whole grain, lubricant is added, sets in three-dimensional mixer and mixes 5 minutes.
(10) intermediate detects
After total mix, sampling, detection level.
(11) it fills
Loading is calculated by actually detected content, is filled in capsule filling machine.
(12) aluminum-plastic blister
By filled product aluminum-plastic blister machine plastic-aluminum and bubble-cap.
(13) outsourcing
By the good product outsourcing of plastic-aluminum and bubble-cap.
Preferably, the preparation method of Irbesartan Capsules of the invention, comprising the following steps:
Irbesartan and auxiliary material are taken, 60 meshes excessively are spare, and Irbesartan and filler, disintegrating agent is taken to be placed in wet granulator
In equipment, mix 5 minutes.Adhesive is weighed, binder solution is prepared with 75% ethyl alcohol.Adhesive is added to adding sizing device
In, it opens manually plus starches, softwood processed, reach wet granular and hold agglomerating, the i.e. bulk state of touching.The above-mentioned softwood made is set into sieve
Net diameter is rotary squeezing granulation in the rotary extrusion granulator of 10 mesh.50 DEG C of temperature of charge of setting, above-mentioned extruding is pelletized
Obtained Irbesartan particle, which is set in boiling drier, to be dried, until moisture content is not higher than 2%, rewinding.16 mesh whole grains.Profit is added
Lubrication prescription is set in three-dimensional mixer and is mixed 5 minutes.Sampling detects intermediates content.Loading is calculated by actually detected content,
It is filled in capsule filling machine.Aluminum-plastic blister, outsourcing.Take the inspection of cost sample presentation then.
Wherein, the Irbesartan is the Irbesartan that crystal form is A type, and the range of size distribution D90 is 50 μm~80
μm, the range of D50 is less than 10 μm.
Wherein, the filler selects cornstarch, pregelatinized starch, dextrin, lactose, mannitol, sucrose, microcrystalline cellulose
Any one or more of element, preferably cornstarch.
Wherein, the disintegrating agent selective cross-linking povidone, croscarmellose sodium, it is a kind of in sodium carboxymethyl starch or
It is a variety of, preferred crospovidone.
Wherein, one of described adhesive selection hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone or a variety of,
It is preferred that hydroxypropyl methylcellulose.
Wherein, one of the lubricant selection superfine silica gel powder, magnesium stearate, talcum powder, sodium stearyl fumarate or more
Kind, preferably sodium stearyl fumarate.
Wherein, the medicament active composition, filler, disintegrating agent, adhesive, lubricant, medicament active composition, filling
Agent, disintegrating agent, adhesive, lubricant, mass ratio are respectively (750~2000): (500~1000): (75~125): (50
~150): (50~125).
According to one of embodiment, the usage ratio of bulk pharmaceutical chemicals of the invention and auxiliary material are as follows:
Irbesartan 750g, dextrin 500g, croscarmellose sodium 75g, povidone 75g, superfine silica gel powder 75g.
Alternatively, Irbesartan 1000g, mannitol 750g, sodium carboxymethyl starch 100g, povidone 150g, magnesium stearate
100g。
Alternatively, Irbesartan 1500g, cornstarch 825g, crospovidone 100g, hydroxypropyl methylcellulose 50g, stearic richness
Horse acid sodium 50g.
Alternatively, Irbesartan 2000g, cornstarch 1000g, sodium carboxymethyl starch 125g, hydroxypropyl methylcellulose 100g, cunning
Mountain flour 150g.
The present invention in terms of existing technologies, improves, the extrusion especially taken in formula and preparation method
Preparation process produces Irbesartan Capsules, solves the problems, such as to validity that capsule and tablet In Vitro Dissolution curve are inconsistent,
The dissolution rate and stability of Irbesartan Capsules are significantly improved, while also reducing production cost, shortens preparation time.
Detailed description of the invention
The X-Ray diffraction that Fig. 1, Irbesartan own product (by test preparation A) and original grind product (reference preparation R) compares
The Irbesartan bulk pharmaceutical chemicals for the different particle size distribution that Fig. 2, this patent use
The Irbesartan bulk pharmaceutical chemicals for the different particle size distribution that Fig. 3, this patent use
Fig. 4,8 subjects distinguish the average blood of empty stomach oral administration Irbesartan in blood plasma after by test preparation A and reference preparation R
Concentration-time graph
Fig. 5,8 subjects distinguish the average blood of empty stomach oral administration Irbesartan in blood plasma after by test preparation A and reference preparation R
Concentration-time semilog plot
Specific embodiment
It is right combined with specific embodiments below in order to make those skilled in the art more fully understand technical solution of the present invention
The present invention is described in further detail.
The material that the present invention uses is provided by following manufacturing enterprise or supplier: Irbesartan bulk pharmaceutical chemicals are all made by Zhuhai profit
The production of medicine limited liability company；Dextrin is supplied by Shandong Hua Lu pharmaceutic adjuvant Co., Ltd；Cornstarch is by Dongguan City Eastern Mountain Portugal
The supply of grape sugar refinery Co., Ltd；Mannitol is by the production and supply of Merck KGaA company；Carboxyrnethyl starch sodium is by Distributions in Liaocheng of Shandong Province A Hua system
The supply of medicine Co., Ltd；Cross-linked carboxymethyl cellulose sodium is supplied by JRS company, the U.S.；Crospovidone XL is by Ya Shilan company, the U.S.
Supply；Hydroxypropyl methylcellulose E5 is supplied by Dalian Ye Jian trading company；PVP K29 is supplied by Ya Shilan company, the U.S.；Dioxy
SiClx is by the supply of Huzhou prospect medicine company limited liability company；Magnesium stearate is by the supply of Huzhou prospect pharmaceutic adjuvant company；Talcum powder
By the magnificent talcum development corporation, Ltd. production and supply of LONGSHENG IN GUANGXI；Sodium stearyl fumarate is that medical auxiliary materials technology has by upper Hydron
The supply of limit company；Ethyl alcohol (95%) is by GuangDong Shunguan Gas Solvent Co., Ltd's production and supply；Purified water is all made by Zhuhai profit
The production of medicine limited liability company；Wet mixing pelletizer (device model: GM400) is supplied by Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.
It answers；Rotary extrusion granulator (ZLB-100) is supplied by Chuan Cheng Machinery Manufacturing Co., Ltd., Zhangjagang City；Fluidized drying pelletizer
(device model: 2BarFL-200) is supplied by Chongqing Seiko pharmaceutical machine Co., Ltd；Pelletizing machine (device model: FZB-
450) it is supplied by Wenzhou pharmaceutical equipment factory；Mixers with Multi-direction Movement (HDA-1500) is supplied by Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.
It answers；Autocapsulefillingmachine (NJP-3500C) is supplied by Zhejiang Fuchang Machinery Co., Ltd.；Aluminium-plastic bubble plate packing machine
(DPP260K2) it is supplied by Shanghai Jiangnan Pharmaceutical Machinary Co., Ltd；Box packing machine (HDZ-150B) is by the mechanical limited duty in ten thousand Shen of Jiangxi
The supply of Ren company.Original grinds product (name of product: Irbesartan Tablets；Trade name: An Bowei；Specification: 0.15g；Production firm:
Sanofi Winthrop Industrie)
The preparation of 1 Irbesartan Capsules of embodiment (specification: 0.15g)
Material is led by the material variety of Formulation, vibrates and is sieved through 60 meshes.Bulk pharmaceutical chemicals and various are weighed by Formulation amount
Auxiliary material is set in wet granulation machine equipment, is mixed 5 minutes.Adhesive is weighed, binder solution is prepared with 75% ethyl alcohol.It will glue
Mixture is added to adding in sizing device, opens manually plus starches, softwood processed, reaches wet granular and holds agglomerating, the i.e. bulk state of touching.It will
The above-mentioned softwood made is set in the rotary extrusion granulator that sieve diameter is 10 mesh, rotary squeezing granulation.Temperature of charge is set
50 DEG C, the Irbesartan particle that above-mentioned extruding is pelletized is set in boiling drier and is dried, until moisture content is not higher than 2%,
Rewinding.16 mesh whole grains.Lubricant is added, sets in three-dimensional mixer and mixes 5 minutes.Sampling detects intermediates content.By practical inspection
It surveys content and calculates loading, filled in capsule filling machine.Aluminum-plastic blister, outsourcing.Take the inspection of cost sample presentation then.
The Irbesartan Capsules prepared by the present invention of embodiment 2 (prescription 1, prescription 2, prescription 3, prescription 4) and original grind product (R)
The comparison of In Vitro Dissolution curve
Irbesartan Capsules (prescription 1, prescription 2, prescription 3, prescription 4) and original prepared by Example 1 grind product (R) each 12
Grain, detects it in the hydrochloric acid solution of pH1.0, the acetate buffer salting liquid of pH4.0, pH6.8 phosphate buffer by the following method
With the In Vitro Dissolution curve in water.Prescription is shown in Table 4.
Method of 5 Irbesartan Capsules of table in 4 kinds of different dissolution mediums
| Dissolution medium | Method | Revolving speed | Surfactant |
| The hydrochloric acid solution of pH1.0 | Basket method | 75 revs/min | Nothing |
| The acetate buffer solution of pH4.0 | Basket method | 100 revs/min | 0.2%SDS |
| The phosphate buffer of pH6.8 | Basket method | 75 revs/min | Nothing |
| Water | Basket method | 75 revs/min | 0.5%SDS |
Measurement result is shown in Table 6,7,8,9.
Hydrochloric acid solution of 6 Irbesartan Capsules A of table (prescription 1, prescription 2, prescription 3, prescription 4) the He Yuanyan product R in pH1.0
In average accumulated dissolution determination result (n=12)
Acetate buffer of 7 Irbesartan Capsules A of table (prescription 1, prescription 2, prescription 3, prescription 4) the He Yuanyan product R in pH4.0
Average accumulated dissolution determination result (n=12) in liquid
Phosphoric acid buffer of 8 Irbesartan Capsules A of table (prescription 1, prescription 2, prescription 3, prescription 4) the He Yuanyan product R in pH6.8
Average accumulated dissolution determination result (n=12) in liquid
9 Irbesartan Capsules A of table (prescription 1, prescription 2, the prescription 3, prescription 4) average accumulated of He Yuanyan product R in water is molten
Out-degree measurement result (n=12)
By 6,7,8,9 testing result of table it is found that A and R prescription products are in the hydrochloric acid solution of pH1.0, the acetate buffer of pH4.0
In Vitro Dissolution curve and original in salting liquid, pH6.8 phosphate buffer and water grind product (name of product: Irbesartan Tablets；Commodity
Name: An Bowei；Specification: 0.15g；Production firm: Sanofi Winthrop Industrie) it is consistent.
3 Irbesartan Capsules prepared by preparation method of the present invention (prescription 3) of embodiment and original grind the accelerated test of product (R)
Stability study comparison
Take Irbesartan Capsules A and R, after carrying out aluminium-plastic bubble plate packing to it, in temperature be 40 ± 2 DEG C, humidity RH75%
Placed in ± 5% climatic chamber, in 0 month, 1 month, 2 months, 3 months, 6 the end of month it is separately sampled primary, check it
Character, content, dissolution rate and related substance, the results are shown in Table 10.
Table 10 is as the result is shown: by Irbesartan Capsules prepared by the present invention (A) at 40 ± 2 DEG C of temperature, humidity RH75% ±
It is placed 6 months in 5% climatic chamber, related substance, dissolution rate and content are showed no significant change, and related substance is more former grinds
Product are lower, show that Irbesartan Capsules stability prepared by the present invention is more preferable.
The Irbesartan Capsules prepared by preparation method of the present invention of embodiment 4 (A, prescription 3) and original grind product (R) in the medicine of human body
It is compared for dynamics research
This test objective is that (specification: 0.15g is manufactured experimently evaluation healthy Chinese subjects empty stomach oral administration Irbesartan Capsules
Agent) and Irbesartan Tablets (reference preparation, trade name: An Bonuo, specification: 0.15g, match Norfin, Inc production) after medicine for power
Feature and bioequivalence.Once subject is selected, and 8 subject's randomizations are divided into 2 groups, every group of 4 people.Subject's fasting 12
After hour, test morning on the same day is given by test preparation 1 or reference preparation 1 (0.15g/ people) on an empty stomach, and 240mL warm water is sent
Clothes.Forbid free water in 2 hours after subject's medication, and unifies after 4 hours into low fat meal.
A remaining needle is placed before administration at subject's ulnar vein, 0.3mL is taken out before blood sampling every time and discards, respectively at administration
It is preceding and administration after 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, for 24 hours, 36h, 48h (totally 15 points) blood drawing
4.0mL is placed in and has posted in the heparinized tubes of label in advance, places in ice-water bath, and 3500 rpm are centrifuged 10min,
Blood plasma is transferred in 2mL EP pipe, to be measured in -70 DEG C of freezen protectives after high speed vortex 2min.During test to subject into
Row clinical monitoring, in time observation and record adverse events.Subject fasting cigarette, wine, tea and various beverages during test, sternly
Prohibit strenuous exercise.
Subject gives " screening number " according to the sequencing of signature informed consent form, and the subject of medical fitness is according to sieve
It selects successive sequence to obtain " tested number ", and enrolled 8 subjects is randomly divided into 2 groups, every group of 4 people, according in random table
Random demand distribute an order of administration number.
The tested number of subject is EBST-01~EBST-08.Drop by the wayside test if any subject, should select substitute by
Examination person completes to test according to same randomizing scheme, and the number for the subject that substitutes is to exit the number of subject to add 100.If such as
No. 5 are exited, then its number of substituting is 5+100=105.If substitute subject midway also exit test, be selected in second substitute by
Examination person, number are that first substitute person's number adds 100, and example as above is 105+100=205.
This test establishes the LC-MS/MS measuring method of Irbesartan in blood plasma, and endogenous substance in plasma does not interfere sample
The standard curve quantification range of the measurement of product, Irbesartan is 5ng/mL~4000ng/mL, and linear relationship is good.Trial test is raw
3 analyses batch of object sample point are measured, the plasma sample of first analysis batch measurement subject 001~004, second analysis
The plasma sample of measurement subject 005~008 is criticized, the 3rd analysis batch carries out ISR investigation.The Quality Control of basic, normal, high three kinds of concentration
In 100 ± 15.0% ranges, ISR retest-ok rate is 70.83% for the accuracy of sample.Referring to table 11-14.
The ln C of table 15 Irbesartan Capsules A and RmaxVariance analysis
| SS | DF | MS | F-value | P-value | |
| Subject | 0.547 | 7 | 0.078 | 4.731 | 0.038 |
| Drug | 0.028 | 1 | 0.028 | 1.678 | 0.243 |
| Period | 0.011 | 1 | 0.011 | 0.676 | 0.442 |
| Error | 0.099 | 6 | 0.017 | ||
| It is overall | 0.685 | 15 | 0.046 |
16 ln Cmax Equivalence analysis of table: 1-2 α confidence interval method (A:R)
The In AUCt variance analysis of table 17 Irbesartan Capsules A and R
| SS | DF | MS | F-value | P-value | |
| Subject | 0.777 | 7 | 0.111 | 7.031 | 0.015 |
| Drug | 0.006 | 1 | 0.006 | 0.359 | 0.571 |
| Period | 0.001 | 1 | 0.001 | 0.061 | 0.813 |
| Error | 0.095 | 6 | 0.016 | ||
| It is overall | 0.879 | 15 | 0.059 |
18 ln AUCt Equivalence analysis of table: 1-2 α confidence interval method (A:R)
Table 15~18 is it is found that 8 health volunteer's single orals after by test preparation A and reference preparation R, use LC-MS/MS
Method measures the concentration of Irbesartan in blood plasma simultaneously.Using the estimation of DAS 3.2.8 software by test preparation A's and reference preparation B
The AUC of Irbesartan0-tRespectively (8959.43 ± 1916.29) ngh/mL, (9405.32 ± 2591.30) ngh/mL；It reaches
Peak time TmaxRespectively (1.56 ± 0.73) h and (1.31 ± 0.46) h；Up to Cmax CmaxRespectively (2148.75 ±
501.30) ng/mL and (2307.5 ± 428.94) ng/mL.It is calculated respectively according to lower area of blood concentration-time curve AUC0-t
Individual Relative biological expenditure f, A preparation is compared with R preparation, individual mean bioavailability are as follows: (99.6 ± 1.8) %.Overall phase
To bioavilability (F): with AUC0-tIt calculates, is 96.3%, confidence interval is calculated in [1-2 α] confidence interval method are as follows:
85.2%~108.8%；With AUC0-∞It is calculated as 96.3%, confidence interval are as follows: 85.8%~108.2%；With CmaxIt is calculated as
92.0%, confidence interval are as follows: 81.2%~104.3%；
When through non-parametric test, P > 0.05, by test preparation dissolution and absorb that there was no significant difference with reference preparation.Using
6.4 software of Phoenix WinNonlin is calculated by test preparation and reference preparation data, 90% confidence interval, Cmax90% set
Believe section (81.71%~103.61%)； AUC0-t90% confidence interval be (85.52%~108.41%)；AUC0-∞'s
90% confidence interval (85.29%~108.75%).By the C of test preparation A and reference preparation Rmax、AUC0-tAnd AUC0-∞Mean value
It is 92.01%, 96.29%, 96.31% than (A/R).Take the pharmacokinetic parameters C of A, R preparationmax, AUC0-tAnd AUC0-∞It is equal
In equivalent section of the value than all falling within (80.00%~125.00%).
In conclusion after 8 subject oral test preparation A and R, bioequivalence.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (7)
1. a kind of preparation method of Irbesartan Capsules, which is characterized in that the content of the capsule is by Irbesartan, filling
After softwood is made in agent, disintegrating agent, adhesive, be prepared into drug granule by squeezing granulating process, it is dry after with mix lubricant
It forms；The Irbesartan, filler, disintegrating agent, adhesive, lubricant mass ratio be respectively (750~2000): (500~
1000): (75~125): (50~150): (50~125)；The filler is selected from cornstarch, pregelatinized starch, dextrin, cream
Any one or more of sugar, mannitol, sucrose, microcrystalline cellulose；The disintegrating agent is selected from crospovidone, crosslinking carboxylic first
It is one or more in base sodium cellulosate, sodium carboxymethyl starch；Described adhesive is selected from hydroxypropyl methylcellulose, carboxymethyl cellulose
One of sodium, povidone are a variety of；The lubricant is in superfine silica gel powder, magnesium stearate, talcum powder, sodium stearyl fumarate
It is one or more；
The preparation method includes the following steps: to take Irbesartan and auxiliary material, and it is spare to cross 60 meshes, takes Irbesartan and filling
Agent, disintegrating agent are placed in wet granulation machine equipment, are mixed 5 minutes, are weighed adhesive, and it is molten to prepare adhesive with 75% ethyl alcohol
Adhesive is added to adding in sizing device liquid, opens manually plus slurry, softwood processed, make wet granular reach hold it is agglomerating, touching it is i.e. scattered
State sets the above-mentioned softwood made in the rotary extrusion granulator that sieve diameter is 10 mesh, rotary squeezing granulation, arranging thing
Expect temperature 50 C, the Irbesartan particle that above-mentioned extruding is pelletized is set in boiling drier and is dried, until moisture content is not high
In 2%, rewinding, 16 mesh whole grains are added lubricant, set in three-dimensional mixer and mix 5 minutes, sample, and detect intermediates content, press
Actually detected content calculates loading, fills in capsule filling machine, aluminum-plastic blister, outsourcing, and finished product sample presentation is taken to detect.
2. preparation method according to claim 1, which is characterized in that Irbesartan is the Irbesartan that crystal form is A type, grain
The range of degree distribution D90 is 50 μm~80 μm, and the range of D50 is less than 10 μm.
3. preparation method according to claim 1, which is characterized in that the filler is selected from cornstarch.
4. preparation method according to claim 1, which is characterized in that the disintegrating agent is selected from crospovidone.
5. preparation method according to claim 1, which is characterized in that described adhesive is selected from hydroxypropyl methylcellulose.
6. preparation method according to claim 1, which is characterized in that the lubricant is selected from sodium stearyl fumarate.
7. preparation method according to claim 1, which is characterized in that the usage ratio of bulk pharmaceutical chemicals and auxiliary material are as follows: E Beisha
Smooth 750g, dextrin 500g, croscarmellose sodium 75g, povidone 75g, superfine silica gel powder 75g,
Alternatively, Irbesartan 1000g, mannitol 750g, sodium carboxymethyl starch 100g, povidone 150g, magnesium stearate 100g,
Alternatively, Irbesartan 1500g, cornstarch 825g, crospovidone 100g, hydroxypropyl methylcellulose 50g, stearyl fumarate
Sodium 50g,
Alternatively, Irbesartan 2000g, cornstarch 1000g, sodium carboxymethyl starch 125g, hydroxypropyl methylcellulose 100g, talcum powder
150g。
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| CN111175385B (en) * | 2018-11-12 | 2023-02-07 | 珠海润都制药股份有限公司 | Irbesartan isomer testing method in irbesartan |
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| WO2011010316A1 (en) * | 2009-07-20 | 2011-01-27 | Hetero Research Foundation | Pharmaceutical compositions of irbesartan |
| CN102697754B (en) * | 2012-07-04 | 2014-08-13 | 扬子江药业集团广州海瑞药业有限公司 | Irbesartan capsules and preparation method thereof |
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