CN108938591A - A kind of solid composite medicament containing Febustat - Google Patents

A kind of solid composite medicament containing Febustat Download PDF

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Publication number
CN108938591A
CN108938591A CN201810956431.3A CN201810956431A CN108938591A CN 108938591 A CN108938591 A CN 108938591A CN 201810956431 A CN201810956431 A CN 201810956431A CN 108938591 A CN108938591 A CN 108938591A
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China
Prior art keywords
febustat
taking
solid composite
enteric
composite medicament
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不公告发明人
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Tianjin Double Medicine Technology Co Ltd
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Tianjin Double Medicine Technology Co Ltd
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Abstract

The present invention relates to a kind of solid composite medicament containing Febustat, specially inventor avoids drug from being disintegrated in stomach, it is made to be disintegrated and discharge in small intestine site by way of preparing enteric coated preparations.So, on the one hand stomach adverse reaction caused by it is disintegrated in stomach is solved, on the other hand since intestinal fluid pH value is higher, after preparation is disintegrated and dissolves out, bulk pharmaceutical chemicals are directly dissolved and are absorbed under high pH conditions, effectively increase the dissolution rate of preparation, up to Cmax and bioavilability, finally, to ensure that drug is dissolved due to high ph-values in small intestine site, basifier sodium citrate is added in the formulation, it is ensured that the liquid environment pH after Febustat dissolution is about 8.0.Test proves that gained enteric coated preparations are disintegrated in small intestine site and dissolve out well, and have good stability, and simple process is easy to amplify, and is suitble to industrialized production.

Description

A kind of solid composite medicament containing Febustat
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of solid composite medicament and its system containing Febustat Preparation Method and purposes.
Background technique
Gout is that uric acid is excessive and the decline of kidney Scavenging activity, the interior accumulation of uric acid body cause due to generating in vivo Urate crystal deposits in joint and each internal organs.As ratio is continuously increased the food rich in purine in diet structure, promote Increasing for gout disease incidence, especially is easier to occur in mid-aged population, chronic cardiovascular disease and diabetic population.
The means that the treatment of gout is usually taken at present are promotion uric acid excretions and uric acid are inhibited to generate, and are used suitably Measure improves related symptoms.The generation of internal uric acid is related with purine metabolism, in purine metabolism process finally, hypoxanthine exists Xanthine is generated under the action of xanthine oxidase/xanthine dehydrogenase (XOR), further generates uric acid.Inhibit the enzyme Activity can effectively reduce the generation of uric acid.Allopurinol has inhibiting effect to XOR, is clinically to be uniquely used for pressing down over 30 years The drug that antidiuresis acid generates, is the first-line treatment drug of current gout.But it due to the analog that allopurinol is purine, can inhibit A series of enzymes for participating in uric acid access, unavoidably will cause the influence for being related to being metabolized other enzymatic activitys, therefore adverse reaction is more.
Febustat (febuxostat), and translations Febuxostat are that a new generation of Supreme Being people (Teijin) company synthesis is anti- Gout drug shows fabulous activity, it is a kind of selective xanthine oxidase/xanthine dehydrogenase (XOR) inhibitor, It has a good application prospect.Di Ren company is in April, 2004 in the Japanese Shen for having submitted Febustat piece 20~40mg dosage Please, Febustat compound has been given the SK Chemical company exploitation of the Ipsen company and South Korea in Europe by special permission.2008 Febustat tablet (Adenuric) listing of year European Union in May approval Ipsen company, for treating the chronic antihyperuricemic of gout Disease.The Febustat tablet (ULORIC) of 2 months 2009 FDA approval TAKEDA companies lists in the U.S., specification 40mg, 80mg. Currently, its in the granted specification of Japan there are also 10mg, two kinds of 20mg.
Febustat, entitled 2- [(3- cyano-4-isobutoxy) the phenyl] -4- methyl-5-thiazole carboxylic acid of chemistry, molecular formula For C16H16N2O3S, molecular weight 316.38, structural formula is as follows:
Febustat is non-hygroscopic white powder, is soluble in dimethylformamide, is dissolved in dimethyl sulfoxide, be insoluble in second Alcohol is slightly soluble in methanol and acetonitrile, it is extremely difficult to be dissolved in water, fusing point is 205 DEG C~208 DEG C.
Chinese patent 201410155591.X discloses dissolution of the Febustat bulk pharmaceutical chemicals in different pH buffer Property, it is as shown in the table:
According to upper table data, when solution ph increases to 8.0 or more, non-cloth can be dissolved in 100ml aqueous solution The quality for taking charge of him is greater than 150mg.
Since dissolubility is poor in low ph value aqueous solution for Febustat, existing conventional tablet bioavilability is lower, greatly About 49%.
Simultaneously inevitably there is certain side effect while playing therapeutic effect in Febustat, provide according to open Material shows that common adverse reactions caused by Febustat are dysfunction of liver, nausea, diarrhea, headache, fash etc..
It does not solve still to improve tablet bioavilability simultaneously in the prior art and reduces the technical solution of adverse reaction.
Summary of the invention
As described above, Febustat bulk pharmaceutical chemicals are water-soluble poor at low ph conditions, existing thin membrane coated tablet biological utilisation Spend low, and there are certain stomach adverse reactions.
To avoid drug stomach adverse reaction, while increasing its water solubility, and then improve biological utilisation, inventor is by grinding Study carefully, is prepared into enteric coated preparations.Said preparation is embodied in a kind of solid composite medicament containing Febustat, by main ingredient Febustat, filler, basifier, disintegrating agent, glidant, lubricant, enteric material composition, the composition is as follows It is further prepared into enteric coated preparations:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier, filler, and disintegrating agent is uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant, and lubricant is uniformly mixed, and is preparation intermediate Material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting, packet separation layer is enteric coated, is Febustat enteric coatel tablets Agent；Step 6: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat capsulae enterosolubilis；
It is characterized in that, the basifier is sodium citrate, the filler is microcrystalline cellulose, and disintegrating agent is cross-linked carboxymethyl Sodium cellulosate, glidant are superfine silica gel powder, and lubricant is magnesium stearate, and the separation layer is common stomach dissolution type film coating agent Europe Bar generation.
The enteric coating agents are with Utech L100D-55 for main filmogen.
The enteric-coating material is refined gram suitable, and with plain piece piece restatement, enteric coating weight gain is 20%-25%.
Unit dose Febustat content is 20mg, 40mg, 80mg.
The solid composite medicament containing Febustat, unit enteric coated tablet composition are as follows:
The solid composite medicament containing Febustat, is further prepared into enteric coated tablet as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet.
The solid composite medicament containing Febustat, unit enteric capsule prescription composition are as follows:
The solid composite medicament containing Febustat, is further prepared into capsulae enterosolubilis as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat enteric capsule.
Present patent application is further illustrated through the following experiment.
Water-soluble poor at low ph conditions for Febustat bulk pharmaceutical chemicals, existing thin membrane coated tablet bioavilability is low, And there is technical issues that certain stomach, the prior art does not provide satisfactory answer.
Inventor furthers investigate this drug, existing common stomach dissolution type thin membrane coated tablet is found, due to gastric juice pH It is lower, lead to Febustat bulk pharmaceutical chemicals poorly water-soluble, after preparation disintegration, the particle that can not be completely dissolved, and be formed after being disintegrated, It is influenced by gastric emptying, small intestines is continued by stomach, cause drug lower up to Cmax, and then influence bioavilability It is lower.There are certain stomach adverse reaction, such as nausea, vomiting, diarrhea etc. for existing preparation simultaneously.It is equally since preparation is in stomach Middle disintegration causes it to generate caused by stimulation stomach.
To solve the above problems, inventor is quasi- by way of preparing enteric coated preparations, avoids drug from being disintegrated in stomach, make it It is disintegrated and discharges in small intestine site.In this way, on the one hand solving stomach adverse reaction caused by it is disintegrated in stomach, on the other hand Since intestinal fluid pH value is higher, after preparation is disintegrated and dissolves out, bulk pharmaceutical chemicals are directly dissolved and are absorbed under high pH conditions, are effectively mentioned The high dissolution rate of preparation, reaches Cmax and bioavilability, finally, to ensure original of the drug in small intestine site due to high ph-values It thus dissolves, basifier sodium citrate is added in the formulation, it is ensured that the liquid environment pH after Febustat dissolution is about 8.0.
Test proves that gained enteric coated preparations are disintegrated in small intestine site and dissolve out well, and have good stability, technique letter It is single, it is easy to amplify, is suitble to industrialized production.
Experiment one: auxiliary material compatibility test
By Febustat bulk pharmaceutical chemicals；Febustat bulk pharmaceutical chemicals respectively with filler microcrystalline cellulose, mannitol, lactose monohydrate, alkali Agent sodium citrate, sodium bicarbonate, disintegrating agent croscarmellose sodium, the common stomach dissolution type coating powder of Opadry, refined gram preferably Enteric coating powder is uniformly mixed by weight 1:5, Febustat bulk pharmaceutical chemicals and glidant superfine silica gel powder, magnesium stearate lubricant It by weight 20:1, is uniformly mixed, sets the thin layer spread out in culture dish into < 5mm thickness respectively.Sample number into spectrum is respectively A, B, C, D, E, F, G, H, I, J, K.
Above-mentioned sample is set 60 DEG C respectively, RH20% ± 5%；Illumination 4500Lx ± 500Lx, the strong light of RH20% ± 5% Under the conditions of place 10 days, sampled in the 5th day and the 10th day, detect Febustat content and related substance.Detection data such as following table It is shown.
1 Febustat bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result (60 DEG C, RH20% ± 5%) to be selected
2 Febustat bulk pharmaceutical chemicals of table and auxiliary material compatibility experiments result to be selected (strong light 4500Lx ± 500Lx, RH20% ± 5%)
It can be seen that selected auxiliary material from the above experimental result to pass through under the conditions of RH20% ± 5% with bulk pharmaceutical chemicals Febustat Cross 60 DEG C of high temperature and the storage of 4500Lx ± 500Lx intense light conditions, compared with Febustat bulk pharmaceutical chemicals, no significant change.I.e. non-cloth It is good with selected auxiliary material compatibility to take charge of him, can be in solid states the following group at composition, and it is further prepared into solid pharmaceutical preparation, and And microcrystalline cellulose is more suitable for filler than lactose monohydrate, sodium citrate is more suitable for making basifier than sodium bicarbonate.
Experiment two: prescription screening test
Rule of thumb design following composition:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet.
Test result analysis:
Above-mentioned prescription 1-4 tablet formability is preferable, wherein best with prescription 3, prescription granulation gained grain graininess is uniform, flowing Property is good, and tabletting is without loose pieces, and sticking is puckery to rush phenomenon, and tablet hardness is up to 7kg or more.It is suitble to coating operations.
Label obtained by above-mentioned prescription 1-4, after disintegration, pH value of solution increases with the dosage of sodium citrate and is increased, but last Reach platform, it is minimum with sodium citrate dosage in prescription 3, while pH higher.Conducive to the dissolution of main ingredient Febustat.
Experiment three: final tablet formulation and technique determine
By above-mentioned screening, it is determined that the prescription and preparation process of the Febustat tablet of a specification (20mg), by this specification Prescription amplifies 2 times and 4 times respectively, obtains following prescription.
The above-mentioned solid composite medicament containing Febustat, is further prepared into enteric coated tablet as follows:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet.
Experiment four: final capsule prescription and technique determine
It is similar with enteric coated tablet, it is as follows to have obtained enteric capsule prescription:
The above-mentioned solid composite medicament containing Febustat, is further prepared into capsulae enterosolubilis as follows:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and it is Febustat enteric that being fitted into, which is suitable in model enteric capsule shell, Capsule.
Experiment five: accelerated stability experiment in 6 months
Above-mentioned 3 specification tablets are taken, capsule (embodiment 1-6) and the auspicious 40mg that raises of commercially available product are (containing packaging, Jiangsu Hengrui Medicine stock The production of part Co., Ltd) number A-G sets 40 DEG C ± 2 DEG C to seven groups of samples respectively respectively, 12 are stored under the conditions of 75% ± 5%RH Month, respectively at 0 month, in January, in March, in June, December was measured by sampling relevant nature (dissolution detection method is with embodiment seven), obtains Corresponding data, as shown in the table:
3 embodiment 1-6 of table is compared with marketed tablet sample stability
According to Fei Busi prepared by prescription described in embodiment 1-6 of the present invention and technique it can be seen from upper table data His enteric coated tablet and enteric capsule, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environment, after storage in 12 months, content, Related substance is varied, but content, more than 98.5%, less than 0.1%, total impurities are below largest single impurity matter 0.5%, dissolution rate is qualified；It corresponds, after accelerating storage in 12 months, content drops to commercially available Febustat tablet About 95%, largest single impurity matter rises to about 0.35%, and total impurities are then more than 4.0%.
Based on analysis as above, according to Febustat enteric prepared by prescription described in embodiment 1-6 of the present invention and technique Under acceleration conditions, the data after storage 12 months show that stability is slightly better than marketed tablet, and its to tablets and capsules Quality requirement of the pharmacopeia about enteric coated preparations is complied fully with, the dissolution rate of preparation can be effectively increased, reaches Cmax and biology Availability.Prescription and technique i.e. through the invention enhances the stability of Febustat tablet, and preparation dissolution rate reaches Cmax and bioavilability are significantly improved so that the present invention have substantive distinguishing features outstanding and significantly into Step, and there is practicability.
Specific embodiment
Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this field Technical staff on the basis of the present invention made by, do not depart from the equivalent substitute or transformation of substantive content of the present invention, also this Within the protection scope of invention.
Embodiment 120mg specification Febustat enteric coated tablets prepare (unit: g)
Prescription:
The above-mentioned solid composite medicament containing Febustat, is further prepared into enteric coated tablet as follows:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet；
Step 6: taking Febustat enteric coated tablet obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains into Product.
2 40mg specification Febustat enteric coated tablets of embodiment prepare (unit: g)
Prescription:
The above-mentioned solid composite medicament containing Febustat, is further prepared into enteric coated tablet as follows:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet；
Step 6: taking Febustat enteric coated tablet obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains into Product.
3 80mg specification Febustat enteric coated tablets of embodiment prepare (unit: g)
Prescription:
The above-mentioned solid composite medicament containing Febustat, is further prepared into enteric coated tablet as follows:
Preparation process:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet；
Step 6: taking Febustat enteric coated tablet obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains into Product.
Embodiment 420mg specification Febustat capsulae enterosolubilis prepares (unit: g)
Prescription:
The solid composite medicament containing Febustat, is further prepared into capsulae enterosolubilis as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat enteric capsule；
Step 6: taking Febustat enteric capsule obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains into Product.
5 40mg specification Febustat capsulae enterosolubilis of embodiment prepares (unit: g)
Prescription:
The solid composite medicament containing Febustat, is further prepared into capsulae enterosolubilis as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat enteric capsule；
Step 6: taking Febustat enteric capsule obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains into Product.
6 80mg specification Febustat capsulae enterosolubilis of embodiment prepares (unit: g)
Prescription:
The solid composite medicament containing Febustat, is further prepared into capsulae enterosolubilis as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat enteric capsule.
Step 6: taking Febustat enteric capsule obtained by step 5, carries out blister package by packaging material of PVC/ aluminium foil, obtains Finished product.
Preparation obtained by 7 embodiment 1-6 of embodiment is compared with commercially available product Dissolution behaviours
Respectively 3 specification piece enteric coated tablets each 6 obtained by Example 1-6, capsulae enterosolubilis each 6, commercially available product (it is auspicious to raise, 40mg tablet) number A~G, according to 2015 editions four dissolution rates of Chinese Pharmacopoeia and drug release determination method, (0,931 first method of annex turns Blue laws), using enteric coated preparations dissolution determination method 1, using hydrochloric acid solution (9 → 1000mL) 750mL as dissolution medium, dissolution fluid Temperature is 37 ± 0.5 DEG C, and revolving speed is 100 turns per minute, is operated according to methods, through 120 minutes, sample detection, after sampling, immediately in acid Addition is preheated to 37 DEG C of 0.2mol/L sodium radio-phosphate,P-32 solution 250ml (adjusting pH value of solution is 6.8) in liquid, continues to operate, through 45 points Zhong Shi, sample detection, as a result as shown in the table:
4 three different size Febustat enteric coated tablets of table, capsule dissolution rate (%) investigate (n=6)
Table data as above can be seen that commercially available product general thin coating tablet, in normal gastric acid environment (pH is about 1.0), Dissolution rate is only about 30%.It after entering small intestine with gastric emptying, can absorb, so absorb after stomach disintegration Journey, undoubtedly will cause preparation reduces up to Cmax, and then bioavilability is low, and available data shows general thin coating tablet Bioavilability be only 47%.It is disintegrated in stomach, but and do not dissolve, but as gastric emptying progresses into enteron aisle, into And dissolve and absorb, hence it is evident that extends soak time, elongate absorption process, reduce drug maximum plasma concentration.And by non-cloth It takes charge of him to be prepared into after enteric coated preparations, be not disintegrated in stomach, in small intestine site due to the influence of alkaline ph values, be disintegrated and release completely Drug is put, under ph basic conditions, water solubility enhancing dissolves out drug completely, although having postponed soak time, and then postpones and reaches peak Time, but clearly enhance up to Cmax, that is, maximum plasma concentration is increased, to significantly increase the biological utilisation of drug Degree.

Claims (10)

1. a kind of solid composite medicament containing Febustat, by main ingredient Febustat, filler, basifier, disintegrating agent helped Agent, lubricant are flowed, enteric material forms, and the composition is further prepared into enteric coated preparations as follows:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier, filler, and disintegrating agent is uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant, and lubricant is uniformly mixed, and is preparation intermediate Material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting, packet separation layer is enteric coated, is Febustat enteric coatel tablets Agent；
Step 6: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat capsulae enterosolubilis；
It is characterized in that, the basifier is sodium citrate, the filler is microcrystalline cellulose, and disintegrating agent is cross-linked carboxymethyl Sodium cellulosate, glidant are superfine silica gel powder, and lubricant is magnesium stearate, and the separation layer is common stomach dissolution type film coating agent Europe Bar generation.
2. as described in claim 1 containing the solid composite medicament of Febustat, which is characterized in that the enteric coating material Preferably for refined gram, with plain piece piece restatement, enteric coating weight gain is 20%-25% to material, and unit dose Febustat content is 20mg, 40mg, 80mg.
3. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
4. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
5. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
6. any solid composite medicament containing Febustat as described in claim 3-5, which is characterized in that by walking as follows Suddenly it is further prepared into enteric coated tablet:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, and tabletting is separation layer, preferably with refined gram with Opadry film coating Aqueous dispersion is enteric coated, obtains Febustat enteric coated tablet.
7. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
8. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
9. as claimed in claim 2 containing the solid composite medicament of Febustat, which is characterized in that unit formulation prescription group At as follows:
10. any solid composite medicament containing Febustat as described in claim 7-9, which is characterized in that by as follows Step is further prepared into capsulae enterosolubilis:
Step 1: taking Febustat bulk pharmaceutical chemicals to crush, and crosses 200 meshes, spare；
Step 2: the Febustat raw material for taking step 1 to obtain sequentially adds basifier sodium citrate, filler microcrystalline cellulose Element, disintegrating agent croscarmellose sodium are uniformly mixed；
Step 3: taking step 2 resulting material, and purified water softwood is added, and 20 mesh screens are pelletized, dry, 24 mesh screen whole grains, Medicine dry particl must be carried；
Step 4: taking and carry medicine dry particl obtained by step 3, sequentially adds glidant superfine silica gel powder, magnesium stearate lubricant, mixing It uniformly, is preparation intermediate material；
Step 5: taking preparation intermediate material obtained by step 4, be fitted into enteric capsule shell, is Febustat enteric capsule.
CN201810956431.3A 2018-08-21 2018-08-21 A kind of solid composite medicament containing Febustat Withdrawn CN108938591A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101966163A (en) * 2010-10-27 2011-02-09 江苏万邦生化医药股份有限公司 Febuxostat dispersible tablet and preparation method thereof
CN102000040A (en) * 2010-11-29 2011-04-06 天津市汉康医药生物技术有限公司 Febuxostat capsule drug combination and preparation method thereof
CN102871980A (en) * 2012-10-17 2013-01-16 扬子江药业集团有限公司 Enteric-coated tablet of S-pantoprazole or salt of S-pantoprazole, and preparation method thereof
CN104887640A (en) * 2015-06-30 2015-09-09 杨玉廷 Solid pharmaceutical composition with valsartan
US20160317505A1 (en) * 2010-06-16 2016-11-03 Takeda Pharmaceuticals U.S.A., Inc. Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
CN106176738A (en) * 2016-08-31 2016-12-07 辰欣药业股份有限公司 A kind of Febustat pharmaceutical composition and tablet producing technology thereof
CN107233327A (en) * 2017-06-06 2017-10-10 天津双硕医药科技有限公司 A kind of pharmaceutical composition containing ambroxol hydrochloride

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160317505A1 (en) * 2010-06-16 2016-11-03 Takeda Pharmaceuticals U.S.A., Inc. Novel modified release dosage forms of xanthine oxidoreductase inhibitor or xanthine oxidase inhibitors
CN101966163A (en) * 2010-10-27 2011-02-09 江苏万邦生化医药股份有限公司 Febuxostat dispersible tablet and preparation method thereof
CN102000040A (en) * 2010-11-29 2011-04-06 天津市汉康医药生物技术有限公司 Febuxostat capsule drug combination and preparation method thereof
CN102871980A (en) * 2012-10-17 2013-01-16 扬子江药业集团有限公司 Enteric-coated tablet of S-pantoprazole or salt of S-pantoprazole, and preparation method thereof
CN104887640A (en) * 2015-06-30 2015-09-09 杨玉廷 Solid pharmaceutical composition with valsartan
CN106176738A (en) * 2016-08-31 2016-12-07 辰欣药业股份有限公司 A kind of Febustat pharmaceutical composition and tablet producing technology thereof
CN107233327A (en) * 2017-06-06 2017-10-10 天津双硕医药科技有限公司 A kind of pharmaceutical composition containing ambroxol hydrochloride

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Application publication date: 20181207