CN107998085A - A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof - Google Patents
A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof Download PDFInfo
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- CN107998085A CN107998085A CN201711230583.7A CN201711230583A CN107998085A CN 107998085 A CN107998085 A CN 107998085A CN 201711230583 A CN201711230583 A CN 201711230583A CN 107998085 A CN107998085 A CN 107998085A
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- atorvastatin calcium
- solid dispersion
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- atorvastatin
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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
- A61K9/20—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
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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
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
Abstract
The present invention provides a kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof, and the solid dispersions are made of Atorvastatin calcium, water solubility copolymer and pH adjusting agent.The tablet adds filler by solid dispersions, disintegrant, lubricant are prepared, and has that dissolution rate is good, stability is high, body absorption is rapid, and individual difference is small and the characteristics of multiple dosing uniform absorption.Preparation process is simple at the same time, suitable for large-scale production.
Description
Technical field
The invention belongs to technical field of medicine, contains Atorvastatin calcium alkali solid in particular to one kind
Tablet of dispersion and preparation method thereof.
Technical background
Atorvastatin calcium (Atorvastatin Calcium) is a kind of blood lipid-lowering medicine, can reduce hypercholesterolemia
The low-density lipoprotein cholesterol level of patient, for hypercholesterolemia, the treatment of coronary heart disease, the Warner of the U.S. in 1991-orchid
Atorvastatin was invented by Bert company, in Initial Public Offering in 1997.Atorvastatin calcium it is chemical entitled：[R-(R*,
R*)] -2- (4- fluorophenyls)-β, δ-dihydroxy -5- (Methylethyl) -3- phenyl-[(aniline) carbonyl] -1- hydrogen-pyrroles -1- heptan
Sour calcium trihydrate.
Structural formula is as follows：
Atorvastatin is the selectivity of hydroxyl first glutaryl (HMG-CoA) reductase, competitive inhibitor, by suppressing liver
The synthesis of dirty interior HMG-CoA reductase and cholesterol is and thin by increasing so as to reduce cholesterol and lipoprotein levels in blood plasma
The hepatic LDL receptor of cellular surface is to strengthen the intake of LDL and metabolism.
Angiocardiopathy is one of disease for endangering the most common most serious of human body health (particularly person in middle and old age), blood fat
Exception is the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases.Atorvastatin calcium conduct
A kind of HMG-CoA reductase inhibitor, in occupation of very important status in reducing blood lipid, has compared with other statinses
Advantages below：(1) effect for reducing blood fat is stronger：There are many experiments to compare the Atorvastatin of various dose and other a few class statins
The effect of class medicine, it is found that Atorvastatin is strong compared with its a few class statins, and wherein CURY ES experiments compare all first
The effect of statins, it is found that the more the same dose of Simvastatins of Atorvastatin, Pravastatin, Lovastatin, fluorine cut down him
Spit of fland effect is strong, and blood fat reduces the therapeutic purpose ratio value highest for reaching U.S.'s Cholesterol Education Program (NCEP).It is most noticeable
Be that Atorvastatin and angiopoiesis comparative studies (AvERT) result were confirmed in the prevention patients with coronary heart disease heart ischemia time
In terms of generation, positive lipid-lowering effect through intracutaneous coronary angioplasty at least with having the effect of same.(2) adverse reaction is few,
Atorvastatin can be well tolerated, and adverse reaction is mostly slight and transient.
Atorvastatin calcium stability is poor, sensitive to wet, hot, low PH condition etc., is particularly easily dropped under low PH condition
Solution.Atorvastatin calcium dissolubility in sour environment is poor.After testing, commercially available product 10min in PH1.2 hydrochloric acid mediums dissolves
Less than 60%.
Chinese patent CN1630510A discloses the Atorvastatin calcium of medicament forms, its composition and cuts down him comprising atropic
The pharmaceutical preparation of spit of fland calcium, using wet granulation technique, adds calcium carbonate as stabilizer, to ensure that medicine is in alkali in prescription
Property environment in, avoid drug degradation, improve drug dissolution.
Chinese patent CN02309462A provides a kind of atorvastatin agent, using the secondary granulation technique of dry method, technique
Complex, stability is poor, and cannot complete dissolution in acid.
Chinese patent CN102910675A discloses a kind of atorvastatin agent and preparation method thereof, using wet method system
Grain tabletting.The patent, as filler, and is surrounded by thin clothing film added with 22.01 parts of calcium carbonate, while added with polyoxyethylene sorbitan monoleate conduct
Dissolution accelerating agent, calcium carbonate therein can play stabilization, but still cannot be fully solved related material during storage
The problem of rise.
Therefore, how atorvastatin to be prepared into stripping property is good, stability is high and the high product of bioavilability
It is that field of medicaments technical staff puts forth effort to solve the problems, such as.
Solid dispersions (solid dispersion) mean that insoluble drug is uniform with states such as molecule, colloidal state, crystallites
It is dispersed in the dispersion formed in a certain solid carrier materials.Solid dispersions technique is put forward indissoluble within 1961
The medicine of property is highly dispersed at the technology of preparing in another solid carrier, and purpose is exactly to improve the dissolution of insoluble drug
Speed and solubility, and then absorption and the bioavilability of medicine are improved, solid dispersions are one in pharmaceutical preparation new
Technology, the solid dispersions that insoluble drug is prepared can only be as the intermediate of a preparation, and preparation intermediate will also
It is processed further being prepared into powder, granule, capsule, tablet, pill, supensoid agent, implant or suppository etc..
Atorvastatin calcium is fabricated to alkali solid dispersion by the present invention, to improve its stripping property, stability and body
Interior bioavilability.
The content of the invention
In view of the deficiencies in the prior art, the invention is intended to provide a kind of Atorvastatin calcium alkali solid dispersion of stabilization
And its preparation method of dispersible tablet, which stablizes in preparing, storing, dissolution rate is good and bioavilability is high.
In order to achieve the object of the present invention, the present invention starts with from the dissolution rate for providing Atorvastatin calcium first, by right
The technology for improving drug-eluting is analyzed and found by a large number of experiments, and Atorvastatin calcium is fabricated to alkali solid disperses
Body is mixed with suitable auxiliary material, tabletting, can effectively improve the dissolution rate of medicine.Accelerated experiment investigation, related material increase
Unobvious, have good stability.
Specifically, the purpose of the present invention is be achieved through the following technical solutions：
A kind of tablet containing Atorvastatin calcium alkali solid dispersion, the Atorvastatin calcium alkali solid point
Granular media is made of Atorvastatin calcium, water solubility copolymer and basifier, and Atorvastatin calcium alkali solid dispersion is added and filled out
Agent, disintegrant, lubricant are filled, the tablet is made in direct powder compression；
By weight, the prescription component of solid dispersions is：
Atorvastatin calcium 6.5~30%
Water solubility copolymer 40~77%
Basifier 5~42%
By weight, the composition of tablet is：
One or more of the water solubility copolymer in povidone, copolyvidone, hydroxypropyl methylcellulose.
The one kind or more of the basifier in sodium carbonate, sodium hydroxide, calcium hydroxide, calcium carbonate, calcium monohydrogen phosphate
Kind.
One or more of the filler in lactose, microcrystalline cellulose, mannitol, pregelatinized starch.
One kind in crospovidone, Ac-Di-Sol, sodium carboxymethyl starch of the disintegrant or
It is a variety of.
One or more of the lubricant in magnesium stearate, talcum powder, sodium stearyl fumarate.
The preparation method of the tablet containing Atorvastatin calcium alkali solid dispersion, includes the following steps：
(1) Atorvastatin calcium is dissolved in 30% methanol solution, adds water solubility copolymer dissolving, add basifier tune
Section, removes solvent with fluid-bed drying, obtains solid dispersions；
(2) by Atorvastatin calcium solid dispersions and filler, disintegrant and mix lubricant, direct powder compression,
Plain piece is made.
The plain piece can be with coated obtained coating tablet.
The present invention has the following advantages that and marked improvement compared with prior art：(1) dissolution rate is high, (2) vivo biodistribution
Availability is high, and (3) stability is good.
Embodiment
Now the preparation process of invention formulation and implementation result are further described by following embodiments, but the present invention
Protection domain is not limited to following embodiments.
Embodiment 1
Atorvastatin agent and preparation process
Preparation process
(1) Atorvastatin calcium of recipe quantity is dissolved in 30% methanol solution, adds the copolyvidone dissolving of recipe quantity,
Add calcium hydroxide and adjust pH to 9.0, remove solvent with fluid-bed drying, it is spare to obtain solid dispersions.
(2) the Atorvastatin calcium solid dispersions of recipe quantity, lactose, microcrystalline cellulose, crospovidone are mixed 10
After minute, the magnesium stearate of recipe quantity is added, mixes 2 minutes, tabletting is carried out again by theoretical piece, plain piece is made.
(3 use high-efficiency coating machine, and Atorvastatin calcium plain piece is put into coating pan, and control sheet bed tempertaure is about 50 DEG C, stream
Speed is 40g/min, coating.
Embodiment 2
Atorvastatin agent and preparation process
Preparation process
(1) Atorvastatin calcium of recipe quantity is dissolved in 30% methanol solution, adds the copolyvidone dissolving of recipe quantity,
Add calcium hydroxide and adjust pH to 10.0, remove solvent with fluid-bed drying, it is spare to obtain solid dispersions.
(2) the Atorvastatin calcium solid dispersions of recipe quantity, lactose, microcrystalline cellulose, crospovidone are mixed 10
After minute, the magnesium stearate of recipe quantity is added, mixes 2 minutes, tabletting is carried out again by theoretical piece, plain piece is made.
(3) high-efficiency coating machine to be used, Atorvastatin calcium plain piece is put into coating pan, control sheet bed tempertaure is about 50 DEG C,
Flow velocity is 40g/min, coating.
Embodiment 3
Atorvastatin agent and preparation process
Preparation process
(1) Atorvastatin calcium of recipe quantity is dissolved in 30% methanol solution, adds the copolyvidone dissolving of recipe quantity,
Add calcium hydroxide and adjust pH to 11.0, remove solvent with fluid-bed drying, it is spare to obtain solid dispersions.
(2) the Atorvastatin calcium solid dispersions of recipe quantity, lactose, microcrystalline cellulose, crospovidone are mixed 10
After minute, the magnesium stearate of recipe quantity is added, mixes 2 minutes, tabletting is carried out again by theoretical piece, plain piece is made.
(3) high-efficiency coating machine to be used, Atorvastatin calcium plain piece is put into coating pan, control sheet bed tempertaure is about 50 DEG C,
Flow velocity is 40g/min, coating.
Comparative example 1
Atorvastatin agent and preparation process
Preparation process
(1) supplementary material of above-mentioned recipe quantity is weighed, in addition to magnesium stearate, all supplementary materials are carried out to after mixing
Dry granulation, carries out 24 mesh, the sieving of 60 mesh, collects the dry particl A between 24~60 mesh respectively；
After (2) 24 mesh above crushing materials and the following material of 60 mesh carries out secondary granulation, gained pellet through sieves, more than 24 mesh
Crushing material whole grain, collects whole particle B after pelletizing second
(3) by after particle A, B for making and magnesium stearate mixing 2min, tabletting；
(4) plain piece pressed in (3) is coated with stomach dissolved film coating pre-mix dose.
Comparative example 2
Atorvastatin agent and preparation process
Preparation process
(1) supplementary material of above-mentioned recipe quantity is weighed, in addition to magnesium stearate, all supplementary material mixing 10min are added hard
Fatty acid magnesium, mixes 2min, carries out tabletting；
(2) plain piece pressed in (1) is coated with stomach dissolved film coating pre-mix dose.
Comparative example 3
Atorvastatin agent and preparation process
Preparation process
(1) the hypromellose E5 of recipe quantity is weighed, is added in 80 DEG C of the purified water of 800g and disperses, adding
The purified water of 3070g, stirring add the polyoxyethylene sorbitan monoleate of 50g, to dissolving, obtained adhesive is spare for stirring to dissolving；
(2) Atorvastatin calcium of above-mentioned recipe quantity, lactose monohydrate, microcrystalline cellulose 101, calcium carbonate, 50% are weighed
Ac-Di-Sol is placed in wet granulator and is uniformly mixed, and with obtained adhesive softwood in (1), granulation, is flowing
Change in bed with 50 DEG C of dryings, with 20 mesh sieve whole grains, add remaining Ac-Di-Sol, magnesium stearate always mixes, tabletting；
(3) plain piece pressed in (2) is coated with stomach dissolved film coating pre-mix dose.
The related material research of 5 atorvastatin of embodiment.
Above sample is subjected to related material detection, related substance detecting method is as follows：
Chromatographic condition
Solution is prepared
The related substance-measuring result of atorvastatin
Table 1：40 DEG C of relative humidity 75%：Sample within 1 month, 3 months, 6 months
It was found from from the result of the test of table 1, the change of 1~3 related material of embodiment is smaller and is substantially better than original and grinds；Comparative example
The change of the related material of 1-3 is more apparent and all more former grinds difference.
4 atorvastatin dissolution study of embodiment
Measured according to dissolution method (two the second methods of annex XC of Chinese Pharmacopoeia version in 2015).Using water 900ml as solvent,
Rotating speed is 50 turns per minute, is operated in accordance with the law, during through 30 minutes, takes solution appropriate, is filtered, and it is appropriate that precision measures subsequent filtrate, as
Test solution；It is another to take Atorvastatin calcium reference substance appropriate (being approximately equivalent to Atorvastatin 25mg), it is accurately weighed, put 25ml
In measuring bottle, adding methanol to dissolve and be diluted to scale, shake up, precision measures 1ml, puts in 100ml measuring bottles, is diluted with water to scale,
Shake up, as reference substance solution.Test solution and reference substance solution are taken respectively, it is purple according to Chinese Pharmacopoeia 2015 editions (annex IVA)
Outside-visible spectrophotometry, trap is measured at the wavelength of 241nm respectively, calculates the stripping quantity of every.Dissolution results
It is shown in Table 2.
Table 2：Atorvastatin dissolution determination result (%)
| Sample source | 0 day | 40 DEG C of 75%RH accelerate 6 months |
| Embodiment 1 | 100.10 | 99.18 |
| Embodiment 2 | 99.90 | 98.70 |
| Embodiment 3 | 100.50 | 99.40 |
| Comparative example 1 | 92.39 | 85.01 |
| Comparative example 2 | 94.92 | 87.36 |
| Comparative example 3 | 95.41 | 91.02 |
| Original is ground | 98.77 | 96.50 |
It was found from from the experimental result of table 2, after atorvastatin agent before acceleration prepared by 1-3 of the embodiment of the present invention
Dissolution rate it is higher and ground unanimously with original, reason is to use containing tablet made from alkaline Atorvastatin calcium solid dispersions, can
Discharged with the disintegration of immediate stability；And the dissolution of atorvastatin agent prepared by comparative example 1-3 is substantially poorer than the present invention.
Embodiment 5
The pre- BE experiments of first time human body：
Normal adults are respectively adopted in sample prepared by according to embodiments of the present invention 1~3 formula and carry out pharmacokinetics
Experiment, while using the commercially available medicine Lipitor of import (specification 10mg, Pfizer pharmaceutical Co. Ltd) as control, 20 are tested
12h fasting before person's (numbering 1 to 20) administration, free water during experiment.0 after administration, 0.25,0.5,1,1.5,2.0,
3.0,4.0,5.0,6.0,8.0,12,24,36,48h extracting vein blood 4ml (take blood vessel to add heparin), put in 4 DEG C of refrigerators, place
After 30min, centrifuge (5000r/min, 10min), take supernatant blood plasma.Atorvastatin in blood plasma is detected with LCMS/MS methods
Concentration, statistical analysis mean serum pharmacokinetic parameter result such as following table：
It was found from from the experimental result of upper table, atorvastatin agent prepared by the embodiment of the present invention 1~3 is inhaled in vivo
Receipts are ground rapidly than original, and individual difference is small, and bioavilability is ground apparently higher than original, and reason is to use Atorvastatin calcium alkali solid
Tablet made from dispersion, can help to absorb in intestines and stomach uniformly disintegration release rapidly.
Embodiment 6
The pre- BE experiments of second of human body：
Sample prepared by according to embodiments of the present invention 1~3 formula is respectively adopted same normal adults are carried out again
The pharmacokinetic trial of administration, while the commercially available medicine Lipitor of import (specification 10mg, the limited public affairs of Pfizer pharmacy used
Department) as control, 12h fasting before 20 subject's (with embodiment 5) administrations, free water during experiment.After administration
0,0.25,0.5,1,1.5,2.0,3.0,4.0,5.0,6.0,8.0,12,24,36,48h extracting vein blood 4ml (takes blood vessel to add liver
Element), put in 4 DEG C of refrigerators, after placing 30min, centrifuge (5000r/min, 10min), take supernatant blood plasma.Detected with LCMS/MS methods
The concentration of Atorvastatin calcium in blood plasma, statistical analysis mean serum pharmacokinetic parameter result such as following table：
The experimental data of comparative example 5 and 6, is shown in Table 3, demonstrates again that atropic prepared by the embodiment of the present invention 1~3 cuts down him
Spit of fland calcium tablet in vivo grind rapidly by absorptance original, and individual difference is small, also confirms that atropic prepared by the embodiment of the present invention 1~3 cuts down him
Uniform absorption when spit of fland calcium tablet is to same people's multiple dosing, grinds more stable than original in vivo, and bioavilability is ground apparently higher than original,
Reason is that the tablet containing Atorvastatin calcium alkali solid dispersion is disintegrated into that particle diameter is of the same size tiny to be contained in vivo
Medicine particle, medicine-containing particle can evenly and rapidly discharge medicine, help to absorb, and reduce the difference that individual and multiple dosing absorb
It is different.
The experimental data of 3 embodiment 5 and 6 of table compares
Claims (7)
- A kind of 1. tablet containing Atorvastatin calcium alkali solid dispersion, it is characterised in that the Atorvastatin calcium alkali Property solid dispersions are made of Atorvastatin calcium, water solubility copolymer and basifier, and Atorvastatin calcium alkali solid disperses Body adds filler, disintegrant, lubricant, and the tablet is made in direct powder compression；By weight, the prescription component of solid dispersions is：Atorvastatin calcium 6.5~30%Water solubility copolymer 40~77%Basifier 5~42%By weight, the composition of tablet is：
- 2. the tablet according to claim 1 containing Atorvastatin calcium alkali solid dispersion, it is characterised in that described One or more of the water solubility copolymer in povidone, copolyvidone, hydroxypropyl methylcellulose.
- 3. the tablet according to claim 1 containing Atorvastatin calcium alkali solid dispersion, it is characterised in that：It is described One or more of the basifier in sodium carbonate, sodium hydroxide, calcium hydroxide, calcium carbonate, calcium monohydrogen phosphate.
- 4. the tablet according to claim 1 containing Atorvastatin calcium alkali solid dispersion, it is characterised in that：It is described One or more of the filler in lactose, microcrystalline cellulose, mannitol, pregelatinized starch.
- 5. the tablet according to claim 1 containing Atorvastatin calcium alkali solid dispersion, it is characterised in that：It is described One or more of the disintegrant in crospovidone, Ac-Di-Sol, sodium carboxymethyl starch.
- 6. the tablet according to claim 1 containing Atorvastatin calcium alkali solid dispersion, it is characterised in that：It is described One or more of the lubricant in magnesium stearate, talcum powder, sodium stearyl fumarate.
- 7. a kind of preparation method of the tablet containing Atorvastatin calcium alkali solid dispersion described in claim 1, it is special Sign is：This method comprises the following steps：(1) Atorvastatin calcium is dissolved in 30% methanol solution, adds water solubility copolymer dissolving, added basifier and adjust, Solvent is removed with fluid-bed drying, obtains solid dispersions；(2) by Atorvastatin calcium solid dispersions and filler, disintegrant and mix lubricant, direct powder compression, is made Plain piece.
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| CN111643471A (en) * | 2020-07-04 | 2020-09-11 | 上海安必生制药技术有限公司 | Atorvastatin calcium tablet and preparation method thereof |
| CN113546050A (en) * | 2021-07-07 | 2021-10-26 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
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| CN113546050B (en) * | 2021-07-07 | 2022-11-29 | 海南锦瑞制药有限公司 | Atorvastatin calcium tablet and preparation method thereof |
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