CN104739808B - Double release capsules of a kind of trospium chloride and preparation method thereof - Google Patents
Double release capsules of a kind of trospium chloride and preparation method thereof Download PDFInfo
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- CN104739808B CN104739808B CN201510079028.3A CN201510079028A CN104739808B CN 104739808 B CN104739808 B CN 104739808B CN 201510079028 A CN201510079028 A CN 201510079028A CN 104739808 B CN104739808 B CN 104739808B
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Abstract
The invention discloses double release capsules of a kind of trospium chloride and preparation method thereof.The double release capsules of the trospium chloride, the trospium chloride slowbreak micropill that by weight percentage be 20 90% trospium chloride sustained release pellets and weight percentage is 10 80% is constituted.Trospium chloride sustained release pellet and trospium chloride the slowbreak micropill is to be coated acquisition using trospium chloride fast release micropill as material.The present invention mixes sustained release pellet with slowbreak micropill with special ratios, on the one hand medicine is slowly discharged, and maintains stable blood concentration, drug safety is improved, on the other hand, medicine is rationally controlled in the rate of release of small intestine, increase bioavilability, improve therapeutic effect, it is cost-effective.
Description
Technical field
The present invention relates to a kind of spansule and preparation method thereof, more particularly, to a kind of double release capsules of trospium chloride and
Its preparation method.
Background technology
Overactive bladder (overactive bladder, OAB) be the common clinical manifestation of urinary dysfunction it
One, international Niao Kong associations (international continence society, ICS) are defined as the unconscious receipts of detrusor
Contracting, not including the symptom caused by the vesicourethral local patholoic change of acute urinary tract infection or other forms, shows as frequent micturition, urine
Anxious, enuresis nocturna, with or not with symptoms such as urge incontinences.2007, promulgated by urinary surgery branch of Chinese Medical Association
《Overactive bladder diagnoses and treatment guide》OAB is defined as：" a kind of syndrome being characterized with urgent urination, is often accompanied by frequent micturition
And nocturia, can with or not with urge incontinence ".
Trospium chloride is clinically used to treat overactive bladder (OAB), is a kind of cholinolytic class medicine.Cholinolytic class
Medicine is also current clinical treatment OAB first-line drug, and it passes through selectively acting bladder, the M of retardance mediation detrusor contractions
Acceptor, blockage of acetylcholine is combined with m receptor, is suppressed detrusor not spontaneous contractions, is improved bladder function.It is different from other several
Antimuscarinic drugs, trospium chloride is quaternary ammonium salt, with very low Determination of oil-water partition coefficient, it is difficult to pass through cell membrane, nervous centralis
System permeability is relatively low, it is difficult to by blood-brain barrier, thus it is relatively fewer with the treatment-related adverse reactions of OAB, but due to OAB
The course for the treatment of of treatment is longer, therefore, patient is produced adverse reaction, such as dry, constipation, headache, these clinics
The use of the adverse reaction of upper generation is often to cause the main cause of patients stopping treatment, therefore reduces the bad anti-of trospium chloride
Urgent problem to be solved in OAB drug therapies should be turned into.
At present, domestic listing is trospium chloride fast dissolving dosage form, such as trospium chloride piece and trospium chloride capsule (20mg,
Twice daily).Such medicine belongs to improvement symptom medicine, it is necessary to be used for a long time, and the medicine of these quick-release types takes number of times
Many, long-term prescription is difficult to adhere to, easily forgotten etc., and gastric disorder causing nausea caused by also producing because of prominent release, eye are done, constipation and central nervous system
The side effects such as toxicity of uniting.
In this regard, the trospium chloride spansule of ALLERGAN INC companies of U.S. exploitation listing, trospium chloride sustained release glue
Capsule is the capsule of three kinds of different releasing properties micropill mixing fillings, is related to quick-release, sustained release, three kinds of micropills of slowbreak (enteric solubility).
Because pharmaceutical dosage form is changed into slow release formulation from conventional tablet or capsule, the biology of active medicine can be generally influenceed
Availability.And because slowbreak micropill material therefor is colon release type in ALLERGAN INC companies trospium chloride spansule,
Because the major absorption site of trospium chloride is in small intestine, less in colon and caecum site absorption, although the selection through prescription makes
It must take and stable blood concentration is able to maintain that after the spansule, but it is too low to cause the capsule absolute bioavailability, only
1.8 or so can be reached, so that patient is after drug administration, reduced into the medicine that blood plays a major role, most of medicine from
Kidney is discharged, and very big pressure can be brought to kidney, and can increase the risk with kidney excretion compatibility of drugs, while increasing medicine
Cost.
The content of the invention
For above-mentioned trospium chloride spansule defect, it is an object of the invention to provide a kind of double release glue of trospium chloride
Capsule, is characterized in that sustained release pellet is mixed with slowbreak micropill with special ratios, on the one hand medicine (pH6.8) in small intestine is opened
Begin slowly to discharge, therefore its bioavilability is improved again on the premise of stable blood concentration is maintained, it is possible to decrease active material
Dosage, reduce adverse reaction, improve drug safety；On the other hand, medicine is rationally controlled in the rate of release of small intestine,
Increase bioavilability, improve therapeutic effect, it is cost-effective；Furthermore, the present invention is made using the separation layer of unique fast release micropill
Coating membrane more smooth even, slows down fast release micropill dissolution, reduces sustained release and slowbreak material usage, shortens the process time, saves significantly
About cost.To achieve these goals, a kind of double release capsules of trospium chloride involved in the present invention, micro- by trospium chloride quick-release
Obtained trospium chloride sustained release pellet and trospium chloride slowbreak micropill composition, by weight percentage are coated on the basis of ball respectively
Than trospium chloride sustained release pellet is 20-90%, and trospium chloride slowbreak micropill is 10-80%, and weight specification is 20-100mg；It is excellent
Selection of land, trospium chloride sustained release pellet is 40-70%, and trospium chloride slowbreak micropill is 30-60%, and weight specification is 40-80mg.
In the present invention, the active material in the trospium chloride fast release micropill is trospium chloride；Described fast release micropill by
Blank capsule core, trospium chloride, adhesive, antitackiness agent and separation layer composition, by weight percentage, blank capsule core 40-80%, Qu Si
Oronain 10-50%, adhesive 1-10%, antitackiness agent 1-10%, separation layer is 1-10%；Preferably：Blank capsule core 50-70%,
Trospium chloride 20-40%, adhesive 1-5%, antitackiness agent 2-5%, separation layer is 1-5%.
In the present invention, the blank capsule core is appointed for the one or more of cane sugar type, starch type and microcrystalline cellulose type
Meaning combination, it is preferable that the particle diameter of blank capsule core is 30-35 mesh；
In the present invention, described adhesive is the one or more of hydroxypropyl methylcellulose or hydroxymethyl cellulose, preferably
Ground, antitackiness agent is one or more kinds of any combination of talcum powder, superfine silica gel powder and magnesium stearate.
In the present invention, it is preferable that the separation layer is polyvinyl alcohol.
The physical property of polyvinyl alcohol is influenceed by chemical constitution, alcoholysis degree, the degree of polymerization.The degree of polymerization of polyvinyl alcohol is divided into
The superelevation degree of polymerization (weight average molecular weight 25~300,000), high polymerization degree (weight average molecular weight 17-22 ten thousand), the middle degree of polymerization (Weight-average molecular
Ten thousand) and low polymerization degree (weight average molecular weight 2.5~3.5 ten thousand) amount 12~15.In general, the degree of polymerization increases, and solution viscosity increases
Greatly, after film forming intensity and solvent resistance is improved, but elongation declines after dissolubility, film forming in water.
Polyvinyl alcohol in the present invention be preferably in, polyvinyl alcohol with low degree of polymerization, such as Japan synthesis chemistry EG-05 series
(low polymerization degree), Kuraray PVA103 (the middle degree of polymerization), PVA105 (the middle degree of polymerization) etc..
In the present invention, described trospium chloride sustained release pellet is by trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent
And sustained release protective layer coating material composition, by weight percentage：Trospium chloride fast release micropill 45-90%, Sustained release coating materials 5-
50%, pore-foaming agent 1-5%, sustained release protective layer coating material 1-5%, it is preferable that trospium chloride fast release micropill 65-80%, sustained release
Coating material 15-30%, pore-foaming agent 1-3%, sustained release protective layer coating material 1-3%.
In the present invention, described Sustained release coating materials are Aquacoat, ethyl cellulose, Utech
Any of NE30D, Eudragit RL 30D and Eudragit RS 30D, Utech RS100 and Utech RL100 or two or more
Meaning combination, it is preferable that Sustained release coating materials are Aquacoat.Described pore-foaming agent is polyethylene glycol, sodium chloride
With the combination of one or both of hydroxypropyl methylcellulose any of the above；Described sustained release protective layer coating material is hypromellose
The combination of one or both of element and Opadry；Such as Opadry YS-1-7003 and HPMC
Premium LV one or two kinds of combinations.
In the present invention, described trospium chloride slowbreak micropill is by trospium chloride fast release micropill, delayed release coat material, plasticising
Agent, slowbreak protective layer coating material composition, by weight percentage：Trospium chloride fast release micropill 45-75%, delayed release coat material
20-50%, plasticizer 1-5%, slowbreak protective layer coating material 1-5%；Preferably, trospium chloride fast release micropill 55-65%, late
Release coating material 30-40%, plasticizer 2-4%, slowbreak protective layer coating material 2-4%.
In the present invention, described pore-foaming agent is any of polyethylene glycol, sodium chloride and hydroxypropyl methylcellulose or two kinds
Any of the above is combined, it is preferable that pore-foaming agent is hydroxypropyl methylcellulose.
In the present invention, described slowbreak protective layer coating material is any one or two kinds of for hydroxypropyl methylcellulose and Opadry
Combination；Such as Opadry YS-1-7003 and HPMCOne or two kinds of groups of Premium LV
Close.
In the present invention, described delayed release coat material is Utech FS30D, Utech S100, No. two resins of polyacrylic acid
With any of No. three resins of polyacrylic acid or two or more any combination, it is preferable that delayed release coat material is Utech
FS30D, No. three resins of polyacrylic acid.
In the present invention, described plasticizer is o-benzoate, triethyl citrate and polysorbate any or two
Plant any of the above combination.
Preferably, plasticizer is polysorbate.
In addition, it is a further object of the present invention to provide a kind of preparation method of trospium chloride double-release capsule, using fluid bed
Pressure spray process is cut, makes coating of pellets film evenly, supplementary product consumption is reduced, the time is saved, reduces cost.
The preparation method of the double release capsules of a kind of trospium chloride involved in the present invention, using fluidized bed coating technique, bag
Include following steps：
(1) micropill carries medicine：Trospium chloride bulk drug, adhesive and antitackiness agent are weighed according to percentage by weight, is dispersed in molten
Obtain carrying medicine coating solution in matchmaker, be coated with load medicine coating solution in blank capsule core and obtain carrying medicine micropill；
(2) spacer layer coating：Insolated layer materials are weighed according to percentage by weight, are dispersed in solvent, separation layer bag is obtained
Clothing liquid, is coated to the load medicine micropill in step (1) with spacer layer coating liquid, produces trospium chloride fast release micropill；
(3) sustained release coating：Sustained release coating materials, pore-foaming agent are weighed according to percentage by weight, is dispersed in solvent, as slow
Coating solution is released, the trospium chloride fast release micropill of prescription ratio in step (2) is coated, sustained release is weighed according to percentage by weight
Protective layer coating material, is dispersed in solvent, as sustained release protective layer coating solution, and the micropill after sustained release coating is coated, i.e.,
Obtain trospium chloride sustained release pellet；
(4) delayed release coat：Delayed release coat material, plasticizer are weighed according to percentage by weight, is dispersed in solvent, as slow
Coating solution is released, the trospium chloride fast release micropill of prescription ratio in step (2) is coated with delayed release coat liquid, according to weight hundred
Divide ratio to weigh slowbreak protective layer coating material, be dispersed according to coating solution percent weight in volume content in solvent, be used as slowbreak
Protective layer coating solution, is coated with slowbreak protective layer coating solution to the micropill after delayed release coat, produces trospium chloride slowbreak micro-
Ball；
(5) according to weight percent when specification, above-mentioned trospium chloride sustained release pellet and trospium chloride slowbreak micropill are filled
Into capsule.
In the present invention, it is preferable that cut pressure spray process using fluid bed.
In the present invention, it is preferable that fluid bed cuts pressure spray process parameter and is：EAT is 40-80 DEG C, and air intake frequency is 25-
40HZ, atomisation pressure is 0.1-0.3MPa.
In the present invention, in step (1), the solvent for disperseing trospium chloride bulk drug, adhesive and antitackiness agent is volume
Percentage is 0-80% ethanol waters, it is preferable that the percent weight in volume content for carrying medicine coating solution is 20-40%.
In the present invention, in step (2), scattered solvent is during percent by volume is 0-80% ethanol waters, it is preferable that
The percent weight in volume content of coating solution is 5-15%.
In the present invention, in step (3), the dispersion medium of Sustained release coating materials is that percent by volume is that 0-80% ethanol is water-soluble
In liquid, it is preferable that the percent weight in volume content of sustained release coating liquid is 5-20%；It is sustained the scattered molten of protective layer coating material
Matchmaker is during percent by volume is 0-80% ethanol waters, it is preferable that the percent weight in volume of sustained release protective layer coating solution contains
Measure as 5-15%.
In the present invention, step (4) delayed release coat, the dispersion medium of delayed release coat material is that percent by volume is 0-80% second
In alcohol solution, it is preferable that the percent weight in volume content of delayed release coat liquid is 5-30%；Slowbreak protective layer coating material
Dispersion medium is during percent by volume is 0-80% ethanol waters, it is preferable that the percent weight in volume of delayed release coat liquid contains
Measure as 5-15%.
The positive effect of the present invention is：
(1) the double release capsules of trospium chloride of the invention, compared with conventional formulation, it is few to take number of times, easily adheres to, improves
The compliance of patient's medication, is easy to patient's long-term treatment.
(2) the double release capsules of trospium chloride prepared using technical solution of the present invention, compared with traditional quick releasing formulation, blood medicine
Concentration is steady, reduces quick releasing formulation and releases the side effects such as caused gastric disorder causing nausea, dry eye, constipation and central nervous system toxicity due to prominent,
Improve drug safety.
(3) the double release capsules of trospium chloride prepared using technical solution of the present invention, the bent department's chlorine listed with the U.S.
Ammonium spansule is compared, and improves bioavilability, reduces the dosage of active material, while the quick-release because using uniqueness
Micropill separation layer, reduces supplementary product consumption, shortens the process time, cost-effective, reduces adverse reaction, improves drug safety.
(4) what the present invention was provided prepares the technical scheme of the double release capsules of trospium chloride, and pressure spray process, phase are cut using fluid bed
For traditional bottom pressure spray process, in whole coating process, feed flow flow velocity can reach 20-30g/min, and sample size determines RSD<
1.0%, it is coated evenly, coating efficiency is higher, shortens the process time, reduces process costs.
Brief description of the drawings
Fig. 1 represent capsule dissolubility relatively in stripping curve
Fig. 2 represents the stripping curve in fast release micropill dissolution relatively
Fig. 3 represents Drug-time curve in pharmacokinetic
Fig. 4 represents isuria frequency variation curve in clinical test
Fig. 5 represents average urge incontinence frequency variation curve in clinical test
Fig. 6 represents isuria amount change curve in clinical test
Embodiment
The embodiment of the present invention is further described with reference to embodiment, advantages of the present invention and feature will
Can be apparent with description.But these embodiments are only exemplary, do not constitute any limitation to the scope of the present invention.
It will be understood by those skilled in the art that without departing from the spirit and scope of the invention can be to technical solution of the present invention
Details and form are modified or replaced, but these modifications and replacement are each fallen within protection scope of the present invention.
Ou Daiba used in invention is purchased from Shanghai Colorcon Coating Technology Co., Ltd；It is outstanding used in the present invention
Special strange RL100, Utech RS100, Eudragit RL 30D, Eudragit RS 30D, Utech NE30D, Utech S100, Utech
FS30D is purchased from German Romo Co., Ltd.Following reagent unless specifically stated otherwise, can routinely be obtained from regular channel.
Embodiment 1：Double release capsules of trospium chloride and preparation method thereof
The preparation method of the double release capsules of trospium chloride, including following steps：
(1) micropill carries medicine：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
40 DEG C of EAT, air intake frequency is 25HZ, and atomizing pressure is 0.1MPa, step (2)-(4) herewith, according to matching somebody with somebody shown in table 1
Than weighing trospium chloride bulk drug, adhesive and antitackiness agent, using 80% ethanol water as solvent, preparing bulking value percentage
Than the load medicine coating solution that content is 20%, medicine is uploaded in the sucrose capsule core of 30-35 mesh；
(2) spacer layer coating：According to the proportioning shown in table 1, insolated layer materials (EG-05 series) are weighed, with 80% ethanol
The aqueous solution is solvent, the spacer layer coating liquid that percent weight in volume content is 5% is prepared, to the load medicine micropill in step (1)
It is coated, produces fast release micropill.
(3) sustained release coating：According to the proportioning shown in table 1, Sustained release coating materials, pore-foaming agent are weighed, using water as solvent, is prepared
Percent weight in volume content is 20% sustained release coating liquid, and the fast release micropill of prescription ratio in step (2) is coated, then
According to the proportioning shown in table 1, protective layer coating material is weighed, using 80% ethanol water as solvent, bulking value percentage is prepared
Than the protective layer coating solution that content is 5%, the micropill after sustained release coating is coated, sustained release pellet is produced；
(4) delayed release coat：According to the proportioning shown in table 1, delayed release coat material, plasticizer are weighed, using water as solvent, is prepared
Percent weight in volume content is 30% delayed release coat liquid, and the fast release micropill of prescription ratio in step (2) is coated, then
According to the proportioning shown in table 1, protective layer coating material is weighed, using 80% ethanol water as solvent, bulking value percentage is prepared
Than the protective layer coating solution that content is 5%, the micropill after delayed release coat is coated, slowbreak micropill is produced；
(5) according to sustained release pellet and slowbreak micropill 40:60 ratio, specification is that two kinds of micropills are filled into hollow glue by 60mg
In capsule.Dissolution profiles are shown in Fig. 1.
In whole coating process, feed flow flow velocity can reach 20-30g/min, and 10 sample sizes determine RSD<1.0%,.
Embodiment 2：Double release capsules of trospium chloride and preparation method thereof
The preparation method of the double release capsules of trospium chloride, including following steps：
(1) micropill carries medicine：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
60 DEG C of EAT, air intake frequency is 30HZ, and atomizing pressure is 0.3MPa, step (2)-(4) herewith, according to matching somebody with somebody shown in table 1
Than weighing trospium chloride bulk drug, adhesive and antitackiness agent, using pure water as solvent, preparing percent weight in volume content is
30% load medicine coating solution, medicine is uploaded in the sucrose capsule core of 30-35 mesh；
(2) spacer layer coating：Work is sprayed using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) bottom
Skill, according to the proportioning shown in table 1, weighs insolated layer materials (PVA103), using pure water as solvent, prepares percent weight in volume and contains
The spacer layer coating liquid for 15% is measured, the load medicine micropill in step (1) is coated, fast release micropill is produced.
(3) sustained release coating：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, Sustained release coating materials, pore-foaming agent are weighed, using water as solvent, preparing percent weight in volume content is
10% sustained release coating liquid, is coated to the fast release micropill of prescription ratio in step (2), according still further to the proportioning shown in table 1, claims
Go bail for sheath coating material, using 50% ethanol water as solvent, prepare the protective layer that percent weight in volume content is 10%
Coating solution, is coated to the micropill after sustained release coating, produces sustained release pellet；
(4) delayed release coat：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, delayed release coat material, plasticizer are weighed, using water as solvent, preparing percent weight in volume content is
30% delayed release coat liquid, is coated to the fast release micropill of prescription ratio in step (2), according still further to the proportioning shown in table 1, claims
Go bail for sheath coating material, using 50% ethanol water as solvent, prepare the protective layer that percent weight in volume content is 10%
Coating solution, is coated to the micropill after delayed release coat, produces slowbreak micropill；
(5) according to sustained release pellet and slowbreak micropill 70:The ratio of 30 (weight ratios), weight specification is that 100mg is micro- by two kinds
Ball is filled into Capsules.
In whole coating process, feed flow flow velocity can reach 20-30g/min, and 10 sample sizes determine RSD<1.0%.
Double release capsules of embodiment 3, trospium chloride and preparation method thereof
The preparation method of the double release capsules of trospium chloride, including following steps：
(1) micropill carries medicine：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
80 DEG C of EAT, air intake frequency is 40HZ, and atomizing pressure is 0.2MPa, step (2)-(4) herewith, according to matching somebody with somebody shown in table 1
Than, weigh trospium chloride bulk drug, adhesive and antitackiness agent, using concentration expressed in percentage by volume be 50% ethanol water as solvent,
The load medicine coating solution that percent weight in volume content is 40% is prepared, medicine is uploaded in the sucrose capsule core of 30-35 mesh；
(2) spacer layer coating：Work is sprayed using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) bottom
Skill, according to the proportioning shown in table 1, weighs insolated layer materials (PVA103), using the ethanol water of concentration expressed in percentage by volume 50% to be molten
Matchmaker, prepares the spacer layer coating liquid that percent weight in volume content is 10%, the load medicine micropill in step (1) is coated,
Produce fast release micropill.
(3) sustained release coating：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, Sustained release coating materials, pore-foaming agent are weighed, is by 50% ethanol water of concentration expressed in percentage by volume
Solvent, prepares the sustained release coating liquid that percent weight in volume content is 8%, the fast release micropill of prescription ratio in step (2) is entered
Row is coated, and according still further to the proportioning shown in table 1, weighs protective layer coating material, using pure water as solvent, prepares percent weight in volume
Content is 15% protective layer coating solution, and the micropill after sustained release coating is coated, sustained release pellet is produced；
(4) delayed release coat：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, delayed release coat material, plasticizer are weighed, is by 50% ethanol water of concentration expressed in percentage by volume
Solvent, prepares the delayed release coat liquid that percent weight in volume content is 10%, the fast release micropill of prescription ratio in step (2) is entered
Row is coated, and according still further to the proportioning shown in table 1, weighs protective layer coating material, using pure water as solvent, prepares percent weight in volume
Content is 15% protective layer coating solution, and the micropill after delayed release coat is coated, slowbreak micropill is produced；
(5) according to sustained release pellet and slowbreak micropill 90:The ratio of 10 (weight ratios), weight specification is 40mg by two kinds of micropills
It is filled into Capsules.
Capsule stripping curve is shown in that Fig. 1, fast release micropill stripping curve are shown in Fig. 2.
In whole coating process, feed flow flow velocity can reach 20-30g/min, and 10 sample sizes determine RSD<1.0%.
Double release capsules of the trospium chloride of embodiment 4 and preparation method thereof
A kind of preparation method of the double release capsules of trospium chloride, including following steps：
(1) micropill carries medicine：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
50 DEG C of EAT, air intake frequency is 35HZ, and atomizing pressure is 0.25MPa, step (2)-(4) herewith, according to matching somebody with somebody shown in table 1
Than, weigh trospium chloride bulk drug, adhesive and antitackiness agent, using concentration expressed in percentage by volume be 50% ethanol water as solvent,
The load medicine coating solution that percent weight in volume content is 35% is prepared, medicine is uploaded in the sucrose capsule core of 30-35 mesh；
(2) spacer layer coating：Work is sprayed using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) bottom
Skill, according to the proportioning shown in table 1, weighs insolated layer materials (PVA105), the ethanol water using concentration expressed in percentage by volume as 50%
For solvent, the spacer layer coating liquid that percent weight in volume content is 10% is prepared, the load medicine micropill in step (1) is wrapped
Clothing, produces fast release micropill.
(3) sustained release coating：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, Sustained release coating materials, pore-foaming agent are weighed, the ethanol water that concentration expressed in percentage by volume is 80% is molten
Matchmaker, prepares the sustained release coating liquid that percent weight in volume content is 5%, and the fast release micropill of prescription ratio in step (2) is carried out
It is coated, according still further to the proportioning shown in table 1, weighs protective layer coating material, using pure water as solvent, prepares percent weight in volume and contain
The protective layer coating solution for 15% is measured, the micropill after sustained release coating is coated, sustained release pellet is produced；
(4) delayed release coat：Pressure spray process is cut using fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3),
According to the proportioning shown in table 1, delayed release coat material, plasticizer are weighed, is by 80% ethanol water of concentration expressed in percentage by volume
Solvent, prepares the delayed release coat liquid that percent weight in volume content is 5%, the fast release micropill of prescription ratio in step (2) is entered
Row is coated, and according still further to the proportioning shown in table 1, weighs protective layer coating material, using pure water as solvent, prepares percent weight in volume
Content is 15% protective layer coating solution, and the micropill after delayed release coat is coated, slowbreak micropill is produced；
(5) according to sustained release pellet and slowbreak micropill 20:The ratio of 80 (weight ratios), weight specification is 20mg, micro- by two kinds
Ball is filled into Capsules, and stripping curve is shown in Fig. 1.
In whole coating process, feed flow flow velocity can reach 20-30g/min, and 10 sample sizes determine RSD<1.0%.
Embodiment 5
Proportioning according to table 1, prepares the double release capsules of trospium chloride, wherein being sustained micro- according to the method for embodiment 1
The ratio of ball and slowbreak micropill is 60:40 (weight ratios), weight specification is 30mg, and capsule stripping curve is shown in that Fig. 1, fast release micropill are molten
Go out curve and see Fig. 2.
Embodiment 6
Proportioning according to table 1, prepares the double release capsules of trospium chloride, wherein being sustained micro- according to the method for embodiment 1
The ratio of ball and slowbreak micropill is 55:45 (weight ratios), weight specification is 70mg, and capsule stripping curve is shown in that Fig. 1, fast release micropill are molten
Go out curve and see Fig. 2.
Embodiment 7
Proportioning according to table 1, prepares the double release capsules of trospium chloride, wherein being sustained micro- according to the method for embodiment 2
The ratio of ball and slowbreak micropill is 50:50 (weight ratios), weight specification is 60mg.
Embodiment 8：
Proportioning according to table 1, prepares the double release capsules of trospium chloride, wherein being sustained micro- according to the method for embodiment 3
The ratio of ball and slowbreak micropill is 35:65 (weight ratios), weight specification is 20mg.
Embodiment 9：
Proportioning according to table 1, prepares the double release capsules of trospium chloride, wherein being sustained micro- according to the method for embodiment 4
The ratio of ball and slowbreak micropill is 75:25 (weight ratios), weight specification is 50mg.
Table 1
Comparative example
Comparative example 1：
Proportioning according to table 2, the double release capsules of trospium chloride are prepared according to the method for embodiment 3
Capsule stripping curve is shown in that Fig. 1, fast release micropill stripping curve are shown in Fig. 2.
Comparative example 2：
Proportioning according to table 2, the double release capsules of trospium chloride are prepared according to the method for embodiment 5.
Capsule stripping curve is shown in that Fig. 1, fast release micropill stripping curve are shown in Fig. 2.
Comparative example 3：
Proportioning according to table 2, the double release capsules of trospium chloride are prepared according to the method for embodiment 6
Capsule stripping curve is shown in that Fig. 1, fast release micropill stripping curve are shown in Fig. 2.
Table 2
The positive effect of the present invention is further illustrated below by way of experimental data：
1st, dissolution rate compares
(1) dissolution assay method：
Capsule dissolution assay method：
Take this product, according to dissolution method (《Chinese Pharmacopoeia》The second methods of C of two annex of version in 2010 Ⅹ), preceding 2h dissolutions are situated between
Matter is pH1.0 HCl solution, and volume is 750mL, and 2h-4h adds phosphate buffer and sodium hydroxide, and regulation dissolution medium pH is
6.8, volume is that phosphate buffer and sodium hydroxide are added after 850mL, 4h, and regulation dissolution medium pH is 6.8, and volume is
950mL.Sampled respectively with 1,2,3,4,6,8,12h, efficient liquid phase measure is directly entered after filtering.
Fast release micropill assay method：
Take fast release micropill, according to dissolution method (《Chinese Pharmacopoeia》The second methods of C of two annex of version in 2010 Ⅹ), preceding 2h is molten
Go out the HCl solution that medium is pH1.0, volume is 900mL, sample, directly enter after filtering efficiently with 15,30,45,60min respectively
Liquid phase measurement.
Reference preparation (trade name：SANTURE XR, U.S. ALLERGAN is (i.e. in background technology in US2013089607A1
Disclosed product)) dissolution measure is carried out, the double release capsules of trospium chloride prepared with embodiment 1,3,5,6 are compared, as a result
See accompanying drawing 1.
As can be seen that the double release capsules of the trospium chloride prepared using the method for this patent are in 2h, self-control system from accompanying drawing 1
Agent and the release of former triturate are each about 20%, are the release of trospium chloride in sustained release pellet；4h, the release of former triturate
Spend for 40%, it is suitable with preceding 2h burst size, it is most of or discharged by sustained release pellet, and the release for making preparation by oneself reaches
80%, illustrate that slowbreak micropill starts release, and be slow release；Two kinds of preparations reach complete release in 8h or so.
As can be seen that using the double release capsules of trospium chloride made from the preparation method of the present invention, its release in vitro is more flat
Surely, foundation is provided for internal safe and effective property.
2nd, pharmacokinetics
(1) single-dose experimental design is used, subject is Healthy People, and the age, body weight control existed between 18~28 years old
In the range of standard weight plus-minus 10%, 31 subjects are recruited altogether.It is required that experiment the last fortnight does not take any medicine, signature is known
Feelings letter of consent.
(2) packet design, is shown in Table 3.
Table 3
(3) detection method：Said medicine is administered at empty stomach according to packet in subject, respectively 0,1,2,3,4,5,6,6.5,
7th, 7.5,7.75,8,10,12,16,18,24h samplings, after processing, detect that the blood medicine of trospium chloride is dense using HPLC-MS methods
Degree, Drug-time curve is shown in accompanying drawing 2, and pharmacokinetic parameter is shown in Table 4.
Table 4
Trospium chloride is 0.5-2.0ng/mL to OAB effective treatment concentration, from accompanying drawing 2 as can be seen that Sanctura,
Sanctura XR onset times are 16h or so, and the action of the double release capsules of the trospium chloride for using this patent method to prepare
Time is 24h or so；Compared with Sanctura, after the double release capsules of trospium chloride prepared by oral this patent method, song department chlorine
The blood concentration of ammonium is more steady.
As can be seen from Table 4, what the double release capsules of trospium chloride prepared using this patent method were listed with the U.S.
Sanctura XR are compared, and bioavilability is significantly improved.
3rd, clinical evaluation
Designed using double-blind, randomized controlled clinical study, carry out the clinical test of 12 weeks, subject is OAB patient, with frequent micturition, urgent urination
Etc. symptom, the age more than 18 years old, recruits 564 subjects altogether.
(1) screening conditions
Age：18 is more than one full year of life；
Sex：Do not limit
Symptom：With OAB more than 6 months, micturition frequency was not less than 30 times/3 days, and the occurrence frequency of the urinary incontinence is not less than 1
Times/day, urination amount is not more than 3000mL/ days, no more than 250mL/ times.
(2) packet design
The double-blind, randomized controlled clinical study clinical test of table 1
(3) test endpoint
Primary Endpoint：From starting by 12 weeks, urinary incontinence frequency in the change of number of micturitions average value and 24h in 24h
Change；
Secondary endpoints：From starting by 12 weeks, the change of each urination amount.
Adverse reaction result
Table 2 may be related to medicine clinical adverse event
Note：* represent compared with placebo, significant difference (P ＜ 0.05)；
# is represented compared with trospium chloride piece, significant difference (P ＜ 0.05)；
＆ is represented compared with trospium chloride spansule, significant difference (P ＜ 0.05).
It is can be seen that from the result of the test in upper table compared with placebo group, the trospium chloride of this patent exploitation is double
Release capsule adverse reaction mainly has dry and constipation；With trospium chloride piece (regular pharmaceutics) group and compared with, can significantly drop
The effect of the generation of low side effect, especially Central nervous is significantly reduced；Compared with trospium chloride spansule, side effect
Quite, the occurrence frequency of dry and constipation slightly has reduction to occurrence frequency.Therefore, the double release capsules of the trospium chloride of this patent exploitation
The security of clinical application is higher.
(4) drug therapy result
It is can be seen that from the result of the test in upper table compared with placebo group, the double releases of trospium chloride of the invention
Capsule can improve the symptom of bladder excessive activities card compared with comparative example.Wherein, the double release glue of trospium chloride of the invention
Micturition frequency from 12.8 times/24h can be reduced to 6.5 times/24h by capsule (embodiment 1) after administration 12 weeks, reached basic
Urination level, compared with 10.1 times/24h of comparative example U.S. trospium chloride spansule, curative effect is well a lot；The song of the present invention
Take charge of average urge incontinence frequency of the double release capsules (embodiment 1) of oronain after being administered 12 weeks and reduce by 26.4 times/24h, reach
To 2.7 times/24h, compared with 11.1 times/24h of comparative example U.S. trospium chloride spansule, urgency urine mistake is greatly reduced
Prohibit frequency；
And the double release capsules (embodiment 1) of the trospium chloride of present invention isuria volume after being administered 12 weeks is added
53.1mL/ times, normal, and 32.0mL/ times of comparative example U.S. trospium chloride spansule is basically reached, each voiding volumes are
It is 182.4mL/ times, relative or less.
To sum up, the double release capsules of trospium chloride of the invention, can significantly reduce side effect compared with quick releasing formulation, with
The spansule of U.S.'s listing is compared, it is possible to increase trospium chloride bioavilability, reduces dosage, is reduced side effect, is carried
High therapeutic effect.
Claims (53)
1. a kind of double release capsules of trospium chloride, are 20-90% trospium chlorides sustained release pellet and weight hundred by weight percentage
Content is divided to be constituted for 10-80% trospium chloride slowbreak micropill, wherein, the trospium chloride sustained release pellet and trospium chloride slowbreak
Micropill is to be coated acquisition using trospium chloride fast release micropill as material；The trospium chloride fast release micropill is by blank pill
Core, trospium chloride, adhesive, antitackiness agent and separation layer composition, wherein, weight percentage：Blank capsule core 40-80%,
Trospium chloride 10-50%, adhesive 1-10%, antitackiness agent 1-10%, separation layer 1-10%；
The separation layer is polyvinyl alcohol.
2. the double release capsules of trospium chloride according to claim 1, it is characterised in that the trospium chloride sustained release pellet
Weight percentage is 40-70%；The weight percentage of the trospium chloride slowbreak micropill is 30-60%.
3. the double release capsules of trospium chloride according to claim 1 or 2, it is characterised in that the trospium chloride quick-release is micro-
In ball, the weight percentage of the blank capsule core is 50-70%, and the weight percentage of the trospium chloride is 20-40%,
The weight percentage of described adhesive is 1-5%, and the weight percentage of the antitackiness agent is 2-5%, the separation layer
Weight percentage is 1-5%.
4. the double release capsules of trospium chloride as claimed in any of claims 1 to 2, it is characterised in that the bent department
In oronain fast release micropill, the blank capsule core is that the one or more of cane sugar type, starch type and microcrystalline cellulose type are any
Combination.
5. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride fast release micropill
In, the blank capsule core is one or more kinds of any combination of cane sugar type, starch type and microcrystalline cellulose type.
6. the double release capsules of trospium chloride as claimed in any of claims 1 to 2, it is characterised in that the bent department
In oronain fast release micropill, described adhesive combines for one or both of hydroxypropyl methylcellulose and hydroxymethyl cellulose.
7. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride fast release micropill
In, described adhesive combines for one or both of hydroxypropyl methylcellulose and hydroxymethyl cellulose.
8. the double release capsules of trospium chloride as claimed in any of claims 1 to 2, it is characterised in that the bent department
In oronain fast release micropill, the antitackiness agent is one or more kinds of any combination of talcum powder, superfine silica gel powder or magnesium stearate.
9. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride fast release micropill
In, the antitackiness agent is one or more kinds of any combination of talcum powder, superfine silica gel powder or magnesium stearate.
10. the double release capsules of trospium chloride as claimed in any of claims 1 to 2, it is characterised in that the bent department
In oronain fast release micropill, the polyvinyl alcohol is middle degree of polymerization polyvinyl alcohol or polyvinyl alcohol with low degree of polymerization.
11. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride fast release micropill
In, the polyvinyl alcohol is middle degree of polymerization polyvinyl alcohol or polyvinyl alcohol with low degree of polymerization.
12. the double release capsules of trospium chloride according to any one in claim 1,2,5,7,9,11, it is characterised in that
In the trospium chloride fast release micropill, the particle diameter of the blank capsule core is 30-35 mesh.
13. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride fast release micropill
In, the particle diameter of the blank capsule core is 30-35 mesh.
14. the double release capsules of trospium chloride according to claim 4, it is characterised in that the trospium chloride fast release micropill
In, the particle diameter of the blank capsule core is 30-35 mesh.
15. the double release capsules of trospium chloride according to claim 6, it is characterised in that the trospium chloride fast release micropill
In, the particle diameter of the blank capsule core is 30-35 mesh.
16. the double release capsules of trospium chloride according to claim 8, it is characterised in that the trospium chloride fast release micropill
In, the particle diameter of the blank capsule core is 30-35 mesh.
17. the double release capsules of trospium chloride according to claim 10, it is characterised in that the trospium chloride fast release micropill
In, the particle diameter of the blank capsule core is 30-35 mesh.
18. the double release capsules of trospium chloride according to any one in claim 1,2,5,7,9,11,13~17, it is special
Levy and be, the trospium chloride sustained release pellet is protected by the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release
Sheath coating material is constituted, wherein, weight percentage：The trospium chloride fast release micropill 45-90%, the sustained release bag
Clothing material 5-50%, the pore-foaming agent 1-5%, the sustained release protective layer coating material 1-5%.
19. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
20. the double release capsules of trospium chloride according to claim 4, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
21. the double release capsules of trospium chloride according to claim 6, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
22. the double release capsules of trospium chloride according to claim 8, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
23. the double release capsules of trospium chloride according to claim 10, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
24. the double release capsules of trospium chloride according to claim 12, it is characterised in that the trospium chloride sustained release pellet
It is made up of the trospium chloride fast release micropill, Sustained release coating materials, pore-foaming agent, sustained release protective layer coating material, wherein, by weight
Percentage composition meter：The trospium chloride fast release micropill 45-90%, the Sustained release coating materials 5-50%, the pore-foaming agent 1-
5%, the sustained release protective layer coating material 1-5%.
25. the double release capsules of trospium chloride according to claim 18, it is characterised in that the trospium chloride sustained release pellet
In, the weight percentage of the trospium chloride fast release micropill is 65-80%, the weight percentage of the Sustained release coating materials
For 15-30%, the weight percentage of the pore-foaming agent is 1-3%, and the weight percent of the sustained release protective layer coating material contains
Measure as 1-3%.
26. the double release capsules of trospium chloride according to claim 18, it is characterised in that the trospium chloride sustained release pellet
In, described Sustained release coating materials are Aquacoat, ethyl cellulose, Utech NE30D, Eudragit RL 30D
And any of Eudragit RS 30D, Utech RS100 and Utech RL100 or two or more any combination；Described pore
Agent is the combination of one or both of polyethylene glycol, sodium chloride and hydroxypropyl methylcellulose any of the above；Described sustained release protective layer
Coating material combines for one or both of hydroxypropyl methylcellulose and Opadry.
27. the double release capsules of trospium chloride according to any one in claim 1,2,5,7,9,11,13~17, it is special
Levy and be, the trospium chloride slowbreak micropill is by trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer
Coating material is constituted, weight percentage：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-
50%, the plasticizer 1-5%, the slowbreak protective layer coating material 1-5%.
28. the double release capsules of trospium chloride according to claim 3, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
29. the double release capsules of trospium chloride according to claim 4, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
30. the double release capsules of trospium chloride according to claim 6, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
31. the double release capsules of trospium chloride according to claim 8, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
32. the double release capsules of trospium chloride according to claim 10, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
33. the double release capsules of trospium chloride according to claim 12, it is characterised in that the trospium chloride slowbreak micropill
It is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, slowbreak protective layer coating material, by weight percentage composition
Meter：The trospium chloride fast release micropill 45-75%, the delayed release coat material 20-50%, the plasticizer 1-5%, it is described slow
Release protective layer coating material 1-5%.
34. the double release capsules of trospium chloride according to claim 27, it is characterised in that the trospium chloride slowbreak micropill
In, the weight percentage of the trospium chloride fast release micropill is 55-65%, the weight percentage of the delayed release coat material
For 30-40%, the weight percentage of the plasticizer is 2-4%, and the weight percent of the slowbreak protective layer coating material contains
Measure as 2-4%.
35. the double release capsules of trospium chloride according to claim 27, it is characterised in that the trospium chloride slowbreak micropill
In, the delayed release coat material is Utech FS30D, Utech S100, No. three trees of No. two resins of polyacrylic acid and polyacrylic acid
One or both of fat any of the above is combined；Described plasticizer is o-benzoate, triethyl citrate and polysorbate
One or more kinds of any combination；The slowbreak protective layer coating material is one kind in hydroxypropyl methylcellulose and Opadry
Or two kinds of combinations.
36. the double release capsules of trospium chloride according to claim 35, it is characterised in that the delayed release coat material is outstanding
No. three resins of special strange FS30D and/or polyacrylic acid.
37. the trospium chloride according to any one in claim 1,2,5,7,9,11,13~17,19~26,28~36
Double release capsules, it is characterised in that the weight of the double release capsules of the trospium chloride is 20-100mg.
38. the double release capsules of trospium chloride according to claim 3, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
39. the double release capsules of trospium chloride according to claim 4, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
40. the double release capsules of trospium chloride according to claim 6, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
41. the double release capsules of trospium chloride according to any one in claim 8, it is characterised in that bent department's chlorine
The weight of the double release capsules of ammonium is 20-100mg.
42. the double release capsules of trospium chloride according to claim 10, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
43. the double release capsules of trospium chloride according to claim 12, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
44. the double release capsules of trospium chloride according to claim 18, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
45. the double release capsules of trospium chloride according to claim 27, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 20-100mg.
46. the double release capsules of trospium chloride according to claim 37, it is characterised in that the double release glue of the trospium chloride
The weight of capsule is 40-80mg.
47. the double release capsules of trospium chloride according to any one in claim 38~45, it is characterised in that the song
The weight for taking charge of the double release capsules of oronain is 40-80mg.
48. a kind of preparation method of the double release capsules of trospium chloride, comprises the following steps：
(1) micropill carries medicine：10-50% trospium chlorides, 1-10% adhesives and 1-10% antitackiness agents are weighed according to percentage by weight,
It is dispersed in solvent and obtains carrying medicine coating solution, is coated with load medicine coating solution in 40-80% blank capsule cores and obtains carrying medicine micropill；
(2) spacer layer coating：1-10% insolated layer materials are weighed according to percentage by weight, is dispersed in solvent, obtains separation layer
Coating solution, is coated to the load medicine micropill in step (1) with spacer layer coating liquid, produces trospium chloride fast release micropill；It is described
Separation layer is polyvinyl alcohol；
(3) sustained release coating：5-50% Sustained release coating materials and 1-5% pore-foaming agents are weighed according to percentage by weight, solvent is dispersed in
In, as sustained release coating liquid, trospium chloride fast release micropill in step (2) is coated with sustained release coating liquid；According to weight hundred
Divide than weighing 1-5% sustained release protective layer coating materials, be dispersed in solvent, as sustained release protective layer coating solution, with sustained release protection
Layer coating solution is coated to the micropill after sustained release coating, produces trospium chloride sustained release pellet；
(4) delayed release coat：20-50% delayed release coats material, 1-5% plasticizer are weighed according to percentage by weight, solvent is dispersed in
In, as delayed release coat liquid, the trospium chloride fast release micropill in step (2) is coated with delayed release coat liquid；According to weight
Percentage weighs 1-5% slowbreak protective layer coating materials, is dispersed in solvent, as slowbreak protective layer coating solution, is protected with slowbreak
Sheath coating solution is coated to the micropill after delayed release coat, produces trospium chloride slowbreak micropill；
(5) according to percentage by weight, by trospium chloride slowbreak described in trospium chloride sustained release pellet described in 20-90% and 10-80%
Micropill is filled into capsule；
Above-mentioned coating steps use fluidized bed coating technique.
49. method according to claim 48, it is characterised in that：The fluidized bed coating technique is that fluid bed cuts spray work
Skill；Fluid bed cuts pressure spray process parameter：EAT is 40-80 DEG C, and air intake frequency is 25-40Hz, and atomisation pressure is 0.1-
0.3MPa。
50. method according to claim 48, it is characterised in that：In the step (1), for disperseing trospium chloride raw material
The solvent of medicine, adhesive and antitackiness agent is that percent by volume is 0-80% ethanol waters, carries the bulking value hundred of medicine coating solution
It is 20-40% to divide than content.
51. the method according to any one in claim 48 to 50, it is characterised in that：In the step (2), for dividing
The solvent for dissipating Sustained release coating materials and pore-foaming agent is that percent by volume is 0-80% ethanol waters, the weight of sustained release coating liquid
Volume percent content is 5-15%.
52. the method according to any one in claim 48 to 50, it is characterised in that：In the step (3), sustained release bag
The dispersion medium of clothing material is that percent by volume is 0-80% ethanol waters, the percent weight in volume content of sustained release coating liquid
For 5-20%；The dispersion medium for being sustained protective layer coating material is that percent by volume is 0-80% ethanol waters, sustained release protection
The percent weight in volume content of layer coating solution is 5-15%.
53. the method according to any one in claim 48 to 50, it is characterised in that：In the step (4), slowbreak bag
The dispersion medium of clothing material is that the percent weight in volume of delayed release coat liquid contains during percent by volume is 0-80% ethanol waters
Measure as 5-30%；The dispersion medium of slowbreak protective layer coating material is slowbreak during percent by volume is 0-80% ethanol waters
The percent weight in volume content of protective layer coating solution is 5-15%.
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| CN106974966A (en) * | 2016-01-18 | 2017-07-25 | 北京海吉星医疗科技有限公司 | Double release capsules of a kind of body resistance-strengthening Zhenqi and preparation method thereof |
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| CN101596170B (en) * | 2009-07-06 | 2011-11-23 | 沈阳亿灵医药科技有限公司 | Trospium chloride slow-release tablet |
| WO2011159824A1 (en) * | 2010-06-16 | 2011-12-22 | Allergan, Inc. | Composition and method for treating overactive bladder |
| CN103690506B (en) * | 2013-11-08 | 2015-05-13 | 舒泰神（北京）生物制药股份有限公司 | Trospium chloride slow-release composition and preparation method thereof |
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