CN104739808A - Trospium chloride double-release capsules and preparation method thereof - Google Patents
Trospium chloride double-release capsules and preparation method thereof Download PDFInfo
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Abstract
The invention discloses trospium chloride double-release capsules and a preparation method thereof. The trospium chloride double-release capsules are composed of trospium chloride sustained-release pellets with a weight percentage content of 20-90% and trospium chloride delayed-release pellets with a weight percentage content of 10-80%, wherein the trospium chloride sustained-release pellets and the trospium chloride delayed-release pellets are both obtained by coating by taking trospium chloride quick-release pellets as materials. According to the trospium chloride double-release capsules and the preparation method thereof disclosed by the invention, the sustained-release pellets and the delayed-release pellets are mixed in a specific ratio, on one hand, the medicine is slowly released to maintain a stable blood concentration and improve the medication safety; on the other hand, the release speed of the medicine in small intestines is reasonably controlled to improve the bioavailability, improve the treatment effect and save the cost.
Description
Technical field
The present invention relates to a kind of slow releasing capsule and preparation method thereof, especially relate to two release capsule of a kind of trospium chloride and preparation method thereof.
Background technology
Overactive bladder (overactive bladder, OAB) be one of common clinical manifestation of urinary dysfunction, international Niao Kong association (international continence society, ICS) the unconscious contraction of detrusor is defined as, do not comprise the symptom caused by acute urinary tract infection or other forms of vesicourethral local patholoic change, show as frequent micturition, urgent micturition, nocturia, with or do not accompany the symptoms such as urge incontinence.2007, OAB was defined as by " the overactive bladder diagnoses and treatment guide " promulgated by urology branch of Chinese Medical Association: " a kind of take urgent micturition as the syndrome of feature, often with frequent micturition and nocturia, can accompany or not accompany urge incontinence ".
Trospium chloride is used for the treatment of overactive bladder (OAB) clinically, is a kind of cholinolytic class medicine.Cholinolytic class medicine is also the first-line drug of current clinical treatment OAB, and it is by selectively acting bladder, and the m receptor of retardance mediation detrusor contractions, blockage of acetylcholine is combined with m receptor, suppresses detrusor not spontaneous contractions, improves bladder function.Be different from other several Antimuscarinic drugs, trospium chloride is quaternary ammonium salt, there is very low Determination of oil-water partition coefficient, be difficult to pass through cell membrane, central nervous system's permeability is lower, be difficult to pass through blood brain barrier, thus relevant untoward reaction is treated to OAB relatively less, but because the course for the treatment of of OAB treatment is longer, therefore, patient still can be made clinically to produce untoward reaction, as xerostomia, constipation, headache etc., the untoward reaction that these Clinical practice produce causes the main cause of patients stopping treatment often, therefore the untoward reaction reducing trospium chloride becomes problem demanding prompt solution in OAB Drug therapy.
At present, domestic listing be trospium chloride fast dissolving dosage form, as trospium chloride sheet and trospium chloride capsule (20mg, twice daily).Such medicine belongs to and improves symptom medicine, need life-time service, the medicine of these rapid release types, take often, long-term prescription is difficult to adhere to, easily forget, and also can produce because prominent releasing that the regurgitation, the eye that cause are dry, the side effect such as constipation and central nervous system toxicity.
To this, the trospium chloride slow releasing capsule of ALLERGAN INC company of U.S. exploitation listing, this trospium chloride slow releasing capsule is the capsule that three kinds of different releasing properties micropill mixing are filled, and relates to rapid release, slow release, slowbreak (enteric solubility) three kinds of micropills.
Because pharmaceutical dosage form is changed into slow release formulation from conventional tablet or capsule, the bioavailability of active medicine generally all can be affected.And because in ALLERGAN INC company trospium chloride slow releasing capsule, slowbreak micropill material therefor is colon release type, because the major absorption site of trospium chloride is at small intestinal, colon and caecum site absorption less, although stable blood drug level can be maintained after the selection of prescription makes to take this slow releasing capsule, but it is too low to cause this capsule absolute bioavailability, can only about 1.8 be reached, thus patient is after drug administration, enter the medicine minimizing that blood plays a major role, major part medicine is discharged from kidney, very large pressure can be brought to kidney, and the risk with renal excretion compatibility of drugs can be increased, increase cost of drugs simultaneously.
Summary of the invention
For above-mentioned trospium chloride slow releasing capsule defect, the object of this invention is to provide the two release capsule of a kind of trospium chloride, be characterized in that slow-release micro-pill mixes with special ratios with slowbreak micropill, medicine (pH6.8) in small intestinal is made namely to start slow releasing on the one hand, therefore its bioavailability is turn improved under the prerequisite maintaining stable blood drug level, the dosage of active substance can be reduced, reduce untoward reaction, improve drug safety; On the other hand, conservative control medicine, at the rate of release of small intestinal, increases bioavailability, improves therapeutic effect, cost-saving; Moreover the present invention uses the sealing coat of unique fast release micropill, makes coating membrane more smooth even, slows down fast release micropill stripping, reduce slow release and slowbreak material usage, shorten the process time, greatly cost-saving.To achieve these goals, the two release capsule of a kind of trospium chloride involved in the present invention, by trospium chloride fast release micropill basis being carried out respectively trospium chloride slow-release micro-pill that coating obtains and trospium chloride slowbreak micropill forms, by weight percentage, trospium chloride slow-release micro-pill is 20-90%, trospium chloride slowbreak micropill is 10-80%, and weight specification is 20-100mg; Preferably, trospium chloride slow-release micro-pill is 40-70%, and trospium chloride slowbreak micropill is 30-60%, and weight specification is 40-80mg.
In the present invention, the active substance in described trospium chloride fast release micropill is trospium chloride; Described fast release micropill is made up of celphere, trospium chloride, binding agent, antitackiness agent and sealing coat, by weight percentage, celphere 40-80%, trospium chloride 10-50%, binding agent 1-10%, antitackiness agent 1-10%, sealing coat is 1-10%; Preferably: celphere 50-70%, trospium chloride 20-40%, binding agent 1-5%, antitackiness agent 2-5%, sealing coat is 1-5%.
In the present invention, described celphere is one or more combination in any of cane sugar type, starch type and microcrystalline Cellulose type, and preferably, the particle diameter of celphere is 30-35 order;
In the present invention, described binding agent is one or more of hypromellose or hydroxy methocel, and preferably, antitackiness agent is one or more combination in any of Pulvis Talci, micropowder silica gel and magnesium stearate.
In the present invention, preferably, described sealing coat is polyvinyl alcohol.
The physical property of polyvinyl alcohol is subject to the impact of 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 weight 12 ~ 150,000) and low polymerization degree (weight average molecular weight 2.5 ~ 3.5 ten thousand).In general, the degree of polymerization increases, and solution viscosity increases, and the intensity after film forming and solvent resistance improve, but percentage elongation decline after dissolubility, film forming in water.
Polyvinyl alcohol in the present invention be preferably in, polyvinyl alcohol with low degree of polymerization, as the EG-05 series (low polymerization degree) of Japanese synthetic chemistry, Kuraray PVA103 (the middle degree of polymerization), PVA105 (the middle degree of polymerization) etc.
In the present invention; described trospium chloride slow-release micro-pill is made up of trospium chloride fast release micropill, Sustained release coating materials, porogen and slow release protective layer coating material; by weight percentage: trospium chloride fast release micropill 45-90%, Sustained release coating materials 5-50%, porogen 1-5%; slow release protective layer coating material 1-5%; preferably, trospium chloride fast release micropill 65-80%, Sustained release coating materials 15-30%; porogen 1-3%, slow release protective layer coating material 1-3%.
In the present invention, described Sustained release coating materials is Aquacoat, ethyl cellulose, especially strange NE30D, Eudragit RL 30D and Eudragit RS 30D, especially strange RS100 and any one or more combination in any especially in strange RL100, preferably, Sustained release coating materials is Aquacoat.Described porogen is one or more combination in any in Polyethylene Glycol, sodium chloride and hypromellose; Described slow release protective layer coating material is one or both combinations in hypromellose and Opadry; As Opadry YS-1-7003 and hydroxypropyl methylcellulose
one or both combinations of Premium LV.
In the present invention, described trospium chloride slowbreak micropill is made up of trospium chloride fast release micropill, delayed release coat material, plasticizer, slowbreak protective layer coating material, 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%, delayed release coat material 30-40%, plasticizer 2-4%, slowbreak protective layer coating material 2-4%.
In the present invention, described porogen is any one or more combination in any in Polyethylene Glycol, sodium chloride and hypromellose, and preferably, porogen is hypromellose.
In the present invention, described slowbreak protective layer coating material is any one or two kinds of combinations of hypromellose and Opadry; As Opadry YS-1-7003 and hydroxypropyl methylcellulose
one or both combinations of Premium LV.
In the present invention, described delayed release coat material is any one or more combination in any especially in strange FS30D, especially strange S100, polyacrylic acid No. two resins and polyacrylic acid No. three resins, preferably, delayed release coat material is especially strange FS30D, polyacrylic acid No. three resins.
In the present invention, described plasticizer is any one or more combination in any of o-benzoate, triethyl citrate and Polysorbate.
Preferably, plasticizer is Polysorbate.
In addition, another object of the present invention is to provide the two preparation method releasing capsule of a kind of trospium chloride, adopts fluid bed to cut pressure spray process, make coating of pellets film evenly, reduce supplementary product consumption, save time, reduce costs.
The preparation method of the two release capsule of a kind of trospium chloride involved in the present invention, adopts fluidized bed coating technique, comprises the following steps:
(1) micropill medicine carrying: take trospium chloride crude drug, binding agent and antitackiness agent according to percentage by weight, is dispersed in solvent and obtains medicine carrying coating solution, obtains medicine carrying micropill with medicine carrying coating solution coating on celphere;
(2) sealing coat coating: take insolated layer materials according to percentage by weight, is dispersed in solvent, obtains sealing coat coating solution, carries out coating, obtain trospium chloride fast release micropill with sealing coat coating solution to the medicine carrying micropill in step (1);
(3) sustained release coating: take Sustained release coating materials, porogen according to percentage by weight, be dispersed in solvent, as sustained release coating liquid, coating is carried out to the trospium chloride fast release micropill of prescription ratio in step (2), take slow release protective layer coating material according to percentage by weight, be dispersed in solvent, as slow release protective layer coating solution, micropill after sustained release coating carries out coating, obtains trospium chloride slow-release micro-pill;
(4) delayed release coat: take delayed release coat material, plasticizer according to percentage by weight, be dispersed in solvent, as delayed release coat liquid, with delayed release coat liquid, coating is carried out to the trospium chloride fast release micropill of prescription ratio in step (2), slowbreak protective layer coating material is taken according to percentage by weight, be dispersed in solvent according to coating solution percent weight in volume content, as slowbreak protective layer coating solution, with slowbreak protective layer coating solution, coating is carried out to the micropill after delayed release coat, obtain trospium chloride slowbreak micropill;
(5) according to weight percent when specification, above-mentioned trospium chloride slow-release micro-pill and trospium chloride slowbreak micropill are filled in capsule.
In the present invention, preferably, fluid bed is adopted to cut pressure spray process.
In the present invention, preferably, fluid bed is cut pressure spray process parameter and is: inlet temperature is 40-80 DEG C, and air intake frequency is 25-40HZ, and atomisation pressure is 0.1-0.3MPa.
In the present invention, in step (1), be percent by volume be 0-80% ethanol water for disperseing the solvent of trospium chloride crude drug, binding agent and antitackiness agent, preferably, the percent weight in volume content of medicine carrying coating solution is 20-40%.
In the present invention, in step (2), the solvent of dispersion is percent by volume is in 0-80% ethanol water, and preferably, 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 percent by volume is in 0-80% ethanol water, and preferably, the percent weight in volume content of sustained release coating liquid is 5-20%; The dispersion medium of slow release protective layer coating material is percent by volume is in 0-80% ethanol water, and preferably, the percent weight in volume content of slow release protective layer coating solution is 5-15%.
In the present invention, step (4) delayed release coat, the dispersion medium of delayed release coat material is percent by volume is in 0-80% ethanol water, and preferably, the percent weight in volume content of delayed release coat liquid is 5-30%; The dispersion medium of slowbreak protective layer coating material is percent by volume is in 0-80% ethanol water, and preferably, the percent weight in volume content of delayed release coat liquid is 5-15%.
Good effect of the present invention is:
(1) the two release capsule of trospium chloride of the present invention, compared with conventional formulation, takes number of times few, easily adheres to, improve the compliance of patient consumes, be convenient to patient's long-term treatment.
(2) the two release capsule of the trospium chloride adopting technical solution of the present invention to prepare, compared with traditional quick releasing formulation, blood drug level is steady, reduce quick releasing formulation owing to prominently releasing that the regurgitation, the eye that cause are dry, the side effect such as constipation and central nervous system toxicity, improve drug safety.
(3) the two release capsule of the trospium chloride adopting technical solution of the present invention to prepare, compared with the trospium chloride slow releasing capsule of having gone on the market with the U.S., improve bioavailability, reducing the dosage of active substance, simultaneously because using unique fast release micropill sealing coat, reducing supplementary product consumption, shorten the process time, cost-saving, reduce untoward reaction, improve drug safety.
(4) technical scheme preparing the two release capsule of trospium chloride provided by the invention, fluid bed is adopted to cut pressure spray process, compare traditional bottom pressure spray process, in whole coating process, can reach 20-30g/min for flow velocity, sample size measures RSD<1.0%, coating evenly, coating efficiency is higher, shortens the process time, reduces process costs.
Accompanying drawing explanation
Fig. 1 represents the stripping curve during capsule dissolubility relatively
Fig. 2 represents the stripping curve in fast release micropill stripping relatively
Fig. 3 represents Drug-time curve in pharmacokinetic
Fig. 4 represents isuria frequency variation curve in clinical trial
Fig. 5 represents average urge incontinence frequency variation curve in clinical trial
Fig. 6 represents isuria amount change curve in clinical trial
Detailed description of the invention
Be further described the specific embodiment of the present invention below in conjunction with embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiments are only exemplary, do not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
The Ou Daiba used in invention is purchased from Shanghai Colorcon Coating Technology Co., Ltd; The especially strange RL100, the especially strange RS100 that use in the present invention, Eudragit RL 30D, Eudragit RS 30D, especially strange NE30D, especially strange S100, especially strange FS30D are all purchased from German Romo Co., Ltd.Following reagent unless specifically stated otherwise, all can obtain from regular channel routine.
Embodiment 1: two release capsule of trospium chloride and preparation method thereof
The preparation method of the two release capsule of trospium chloride, comprises following step:
(1) micropill medicine carrying: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, inlet temperature 40 DEG C, air intake frequency is 25HZ, atomizing pressure is 0.1MPa, step (2)-(4) herewith, according to the proportioning shown in table 1, take trospium chloride crude drug, binding agent and antitackiness agent, with 80% ethanol water for solvent, preparation percent weight in volume content is the medicine carrying coating solution of 20%, medicine carrying on 30-35 object sucrose ball core;
(2) sealing coat coating: according to the proportioning shown in table 1, take insolated layer materials (EG-05 series), with 80% ethanol water for solvent, preparation percent weight in volume content is the sealing coat coating solution of 5%, coating is carried out to the medicine carrying micropill in step (1), obtains fast release micropill.
(3) sustained release coating: according to the proportioning shown in table 1, take Sustained release coating materials, porogen, take water as solvent, preparation percent weight in volume content is the sustained release coating liquid of 20%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, with 80% ethanol water for solvent, preparation percent weight in volume content is the protective layer coating solution of 5%, coating is carried out to the micropill after sustained release coating, obtains slow-release micro-pill;
(4) delayed release coat: according to the proportioning shown in table 1, take delayed release coat material, plasticizer, take water as solvent, preparation percent weight in volume content is the delayed release coat liquid of 30%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, with 80% ethanol water for solvent, preparation percent weight in volume content is the protective layer coating solution of 5%, coating is carried out to the micropill after delayed release coat, obtains slowbreak micropill;
(5) according to the ratio of slow-release micro-pill and slowbreak micropill 40:60, specification is that two kinds of micropills are filled in Capsules by 60mg.Dissolution profiles is shown in Fig. 1.
In whole coating process, can reach 20-30g/min for flow velocity, 10 sample sizes measure RSD<1.0%.
Embodiment 2: two release capsule of trospium chloride and preparation method thereof
The preparation method of the two release capsule of trospium chloride, comprises following step:
(1) micropill medicine carrying: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, inlet temperature 60 DEG C, air intake frequency is 30HZ, and atomizing pressure is 0.3MPa, step (2)-(4) herewith, according to the proportioning shown in table 1, taking trospium chloride crude drug, binding agent and antitackiness agent, take pure water as solvent, preparation percent weight in volume content is the medicine carrying coating solution of 30%, medicine carrying on 30-35 object sucrose ball core;
(2) sealing coat coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) end pressure spray process, according to the proportioning shown in table 1, take insolated layer materials (PVA103), take pure water as solvent, preparation percent weight in volume content is the sealing coat coating solution of 15%, carries out coating, obtain fast release micropill to the medicine carrying micropill in step (1).
(3) sustained release coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take Sustained release coating materials, porogen, take water as solvent, preparation percent weight in volume content is the sustained release coating liquid of 10%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, with 50% ethanol water for solvent, preparation percent weight in volume content is the protective layer coating solution of 10%, coating is carried out to the micropill after sustained release coating, obtain slow-release micro-pill,
(4) delayed release coat: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take delayed release coat material, plasticizer, take water as solvent, preparation percent weight in volume content is the delayed release coat liquid of 30%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, with 50% ethanol water for solvent, preparation percent weight in volume content is the protective layer coating solution of 10%, coating is carried out to the micropill after delayed release coat, obtain slowbreak micropill,
(5) according to the ratio of slow-release micro-pill and slowbreak micropill 70:30 (weight ratio), weight specification is that two kinds of micropills are filled in Capsules by 100mg.
In whole coating process, can reach 20-30g/min for flow velocity, 10 sample sizes measure RSD<1.0%.
Two release capsule of embodiment 3, trospium chloride and preparation method thereof
The preparation method of the two release capsule of trospium chloride, comprises following step:
(1) micropill medicine carrying: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, inlet temperature 80 DEG C, air intake frequency is 40HZ, atomizing pressure is 0.2MPa, step (2)-(4) herewith, according to the proportioning shown in table 1, take trospium chloride crude drug, binding agent and antitackiness agent, take concentration expressed in percentage by volume as the ethanol water of 50% be solvent, preparation percent weight in volume content is the medicine carrying coating solution of 40%, medicine carrying on 30-35 object sucrose ball core;
(2) sealing coat coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) end pressure spray process, according to the proportioning shown in table 1, take insolated layer materials (PVA103), with concentration expressed in percentage by volume 50% ethanol water for solvent, preparation percent weight in volume content is the sealing coat coating solution of 10%, carries out coating, obtain fast release micropill to the medicine carrying micropill in step (1).
(3) sustained release coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take Sustained release coating materials, porogen, take concentration expressed in percentage by volume as the ethanol water of 50% be solvent, preparation percent weight in volume content is the sustained release coating liquid of 8%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, take pure water as solvent, preparation percent weight in volume content is the protective layer coating solution of 15%, coating is carried out to the micropill after sustained release coating, obtain slow-release micro-pill,
(4) delayed release coat: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take delayed release coat material, plasticizer, take concentration expressed in percentage by volume as the ethanol water of 50% be solvent, preparation percent weight in volume content is the delayed release coat liquid of 10%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, take pure water as solvent, preparation percent weight in volume content is the protective layer coating solution of 15%, coating is carried out to the micropill after delayed release coat, obtain slowbreak micropill,
(5) according to the ratio of slow-release micro-pill and slowbreak micropill 90:10 (weight ratio), weight specification is that two kinds of micropills are filled in Capsules by 40mg.
Capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
In whole coating process, can reach 20-30g/min for flow velocity, 10 sample sizes measure RSD<1.0%.
Two release capsule of embodiment 4 trospium chloride and preparation method thereof
A preparation method for the two release capsule of trospium chloride, comprises following step:
(1) micropill medicine carrying: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, inlet temperature 50 DEG C, air intake frequency is 35HZ, atomizing pressure is 0.25MPa, step (2)-(4) herewith, according to the proportioning shown in table 1, take trospium chloride crude drug, binding agent and antitackiness agent, take concentration expressed in percentage by volume as the ethanol water of 50% be solvent, preparation percent weight in volume content is the medicine carrying coating solution of 35%, medicine carrying on 30-35 object sucrose ball core;
(2) sealing coat coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) end pressure spray process, according to the proportioning shown in table 1, take insolated layer materials (PVA105), take concentration expressed in percentage by volume as the ethanol water of 50% be solvent, preparation percent weight in volume content is the sealing coat coating solution of 10%, carries out coating, obtain fast release micropill to the medicine carrying micropill in step (1).
(3) sustained release coating: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take Sustained release coating materials, porogen, concentration expressed in percentage by volume be 80% ethanol water be solvent, preparation percent weight in volume content is the sustained release coating liquid of 5%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, take pure water as solvent, preparation percent weight in volume content is the protective layer coating solution of 15%, coating is carried out to the micropill after sustained release coating, obtain slow-release micro-pill,
(4) delayed release coat: adopt fluid bed (Chongqing Seiko pharmaceutical machine Co., Ltd, DPL 1/3) cut pressure spray process, according to the proportioning shown in table 1, take delayed release coat material, plasticizer, take concentration expressed in percentage by volume as the ethanol water of 80% be solvent, preparation percent weight in volume content is the delayed release coat liquid of 5%, coating is carried out to the fast release micropill of prescription ratio in step (2), again according to the proportioning shown in table 1, take protective layer coating material, take pure water as solvent, preparation percent weight in volume content is the protective layer coating solution of 15%, coating is carried out to the micropill after delayed release coat, obtain slowbreak micropill,
(5) according to the ratio of slow-release micro-pill and slowbreak micropill 20:80 (weight ratio), weight specification is 20mg, and be filled in Capsules by two kinds of micropills, stripping curve is shown in Fig. 1.
In whole coating process, can reach 20-30g/min for flow velocity, 10 sample sizes measure RSD<1.0%.
Embodiment 5
According to the proportioning shown in table 1, the two release capsule of trospium chloride is prepared according to the method for embodiment 1, wherein the ratio of slow-release micro-pill and slowbreak micropill is 60:40 (weight ratio), and weight specification is 30mg, and capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
Embodiment 6
According to the proportioning shown in table 1, the two release capsule of trospium chloride is prepared according to the method for embodiment 1, wherein the ratio of slow-release micro-pill and slowbreak micropill is 55:45 (weight ratio), and weight specification is 70mg, and capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
Embodiment 7
According to the proportioning shown in table 1, prepare the two release capsule of trospium chloride according to the method for embodiment 2, wherein the ratio of slow-release micro-pill and slowbreak micropill is 50:50 (weight ratio), and weight specification is 60mg.
Embodiment 8:
According to the proportioning shown in table 1, prepare the two release capsule of trospium chloride according to the method for embodiment 3, wherein the ratio of slow-release micro-pill and slowbreak micropill is 35:65 (weight ratio), and weight specification is 20mg.
Embodiment 9:
According to the proportioning shown in table 1, prepare the two release capsule of trospium chloride according to the method for embodiment 4, wherein the ratio of slow-release micro-pill and slowbreak micropill is 75:25 (weight ratio), and weight specification is 50mg.
Table 1
Comparative example
Comparative example 1:
According to the proportioning shown in table 2, prepare the two release capsule of trospium chloride according to the method for embodiment 3
Capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
Comparative example 2:
According to the proportioning shown in table 2, prepare the two release capsule of trospium chloride according to the method for embodiment 5.
Capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
Comparative example 3:
According to the proportioning shown in table 2, prepare the two release capsule of trospium chloride according to the method for embodiment 6
Capsule stripping curve is shown in Fig. 1, fast release micropill stripping curve is shown in Fig. 2.
Table 2
Good effect of the present invention is further illustrated below by way of experimental data:
1, dissolution compares
(1) stripping assay method:
Capsule stripping assay method:
Get this product, according to dissolution method (" Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods), front 2h dissolution medium is the HCl solution of pH1.0, volume is that 750mL, 2h-4h add phosphate buffer and sodium hydroxide, regulates dissolution medium pH to be 6.8, volume is 850mL, add phosphate buffer and sodium hydroxide again after 4h, regulate dissolution medium pH to be 6.8, volume is 950mL.Respectively with 1,2,3,4,6,8,12h samples, directly enter efficient liquid phase after filtration and measure.
Fast release micropill assay method:
Get fast release micropill, according to dissolution method (" Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods), front 2h dissolution medium is the HCl solution of pH1.0, and volume is 900mL, respectively with 15,30,45,60min samples, directly enter efficient liquid phase after filtration and measure.
Reference preparation (trade name: SANTURE XR, U.S. ALLERGAN (i.e. product disclosed in US2013089607A1 in background technology)) carry out stripping mensuration, the two release capsule of the trospium chloride prepared with embodiment 1,3,5,6 compares, and the results are shown in accompanying drawing 1.
As can be seen from accompanying drawing 1, the two release capsule of the trospium chloride adopting the method for this patent to prepare is at 2h, and the release of self-control preparation and former triturate is all about 20%, is the release of trospium chloride in slow-release micro-pill; 4h, the release of former triturate is 40%, suitable with the burst size of front 2h, and major part is still discharged by slow-release micro-pill, and the release of making preparation by oneself reaches 80%, illustrates that slowbreak micropill starts release, and is slow releasing; Two kinds of preparations all reach at about 8h and discharge completely.
Can find out, the two release capsule of the trospium chloride adopting preparation method of the present invention obtained, its release in vitro is more steady, for the safe and effective property in body provides foundation.
2, pharmacokinetics
(1) adopt single-dose experimental design, experimenter is Healthy People, and the age, body weight control, in the scope of standard body weight plus-minus 10%, recruited 31 experimenters altogether between 18 ~ 28 years old.Require that test the last fortnight does not take any medicine, signature Informed Consent Form.
(2) packet design, in table 3.
Table 3
(3) detection method: experimenter is according to grouping, (medicine) being taken before meal said medicine, respectively 0,1,2,3,4,5,6,6.5,7,7.5,7.75,8,10,12,16,18,24h sampling, after treatment, HPLC-MS method is adopted to detect the blood drug level of trospium chloride, Drug-time curve is shown in accompanying drawing 2, and pharmacokinetic parameter is in table 4.
Table 4
The effective treatment concentration of trospium chloride to OAB is 0.5-2.0ng/mL, as can be seen from accompanying drawing 2, Sanctura, Sanctura XR onset time is about 16h, and the onset time of the two release capsule of the trospium chloride adopting this patent method to prepare is about 24h; Compared with Sanctura, after the two release capsule of trospium chloride prepared by oral this patent method, the blood drug level of trospium chloride is more steady.
As can be seen from Table 4, compared with the Sanctura XR that the two release capsule of the trospium chloride adopting this patent method to prepare and the U.S. go on the market, bioavailability significantly improves.
3, clinical evaluation
Employing randomized controlled designs, and carry out the clinical trial of 12 weeks, experimenter is OAB patient, and with the symptom such as frequent micturition, urgent micturition, the age, more than 18 years old, recruits 564 experimenters altogether.
(1) screening conditions
Age: more than 18 one full year of life;
Sex: do not limit
Symptom: suffer from OAB more than 6 months, micturition frequency is not less than 30 times/3 days, and the occurrence frequency of urinary incontinence is not less than 1 times/day, and voided volume is not more than 3000mL/ days, is not more than 250mL/ time.
(2) packet design
The clinical trial of table 1 randomized controlled
(3) test endpoint
Primary Endpoint: from by 12 weeks, the change of urinary incontinence frequency in the change of number of micturitions meansigma methods and 24h in 24h;
Secondary endpoints: from by 12 weeks, the change of each voided volume.
Untoward reaction result
Table 2 may be relevant to medicine clinical adverse event
Note: * represents compared with placebo group, significant difference (P < 0.05);
# represents compared with trospium chloride sheet, significant difference (P < 0.05);
& represents compared with trospium chloride slow releasing capsule, significant difference (P < 0.05).
Result of the test as can be seen from upper table, compared with placebo group, the two release capsule untoward reaction of trospium chloride of this patent exploitation mainly contains xerostomia and constipation; With trospium chloride sheet (regular pharmaceutics) group and compared with, significantly can reduce the generation of side effect, especially the effect of nervus centralis significantly be reduced; Compared with trospium chloride slow releasing capsule, the occurrence frequency of side effect is suitable, and the occurrence frequency of xerostomia and constipation slightly reduces.Therefore, the safety of the two release capsule clinical application of the trospium chloride of this patent exploitation is higher.
(4) Drug therapy result
Result of the test as can be seen from upper table, compared with placebo group, the two release capsule of trospium chloride of the present invention all can improve the symptom of bladder excessive activities card compared with comparative example.Wherein, the two release capsule (embodiment 1) of trospium chloride of the present invention is in administration after 12 weeks, micturition frequency can be reduced to 6.5 times/24h from 12.8 times/24h, reach basic level of urinating, compared with 10.1 times/24h of comparative example U.S. trospium chloride slow releasing capsule, curative effect is well a lot; The two release capsule (embodiment 1) of trospium chloride of the present invention reduces by 26.4 times/24h in the average urge incontinence frequency of administration after 12 weeks, reach 2.7 times/24h, compared with 11.1 times/24h of comparative example U.S. trospium chloride slow releasing capsule, greatly reduce urge incontinence frequency;
And the two release capsule (embodiment 1) of trospium chloride of the present invention adds 53.1mL/ time at administration 12 weeks rear isuria volumes, substantially reach normal, and 32.0mL/ time of comparative example U.S. trospium chloride slow releasing capsule, each voiding volumes is 182.4mL/ time, relative or less.
To sum up, the two release capsule of trospium chloride of the present invention, significantly can reduce side effect, compared with the slow releasing capsule of going on the market with the U.S., can improve trospium chloride bioavailability, reduce dosage, reduce side effect, improve therapeutic effect compared with quick releasing formulation.
Claims (19)
1. the two release capsule of trospium chloride, be made up of the trospium chloride slowbreak micropill of weight percentage to be 20-90% trospium chloride slow-release micro-pill and weight percentage be 10-80%, wherein, described trospium chloride slow-release micro-pill and trospium chloride slowbreak micropill all with trospium chloride fast release micropill for material carries out coating acquisition; Described trospium chloride fast release micropill is made up of celphere, trospium chloride, binding agent, antitackiness agent and sealing coat, wherein, and weight percentage: celphere 40-80%, trospium chloride 10-50%, binding agent 1-10%, antitackiness agent 1-10%, sealing coat 1-10%.
2. the two release capsule of trospium chloride according to claim 1, is characterized in that: the weight percentage of described trospium chloride slow-release micro-pill is 40-70%; The weight percentage of described trospium chloride slowbreak micropill is 30-60%.
3. the two release capsule of trospium chloride according to claim 1 and 2, it is characterized in that: in described trospium chloride fast release micropill, the weight percentage of described celphere is 50-70%, the weight percentage of described trospium chloride is 20-40%, the weight percentage of described binding agent is 1-5%, the weight percentage of described antitackiness agent is 2-5%, and the weight percentage of described sealing coat is 1-5%.
4. the two release capsule of trospium chloride as claimed in any of claims 1 to 3, it is characterized in that: in described trospium chloride fast release micropill, described celphere is one or more combination in any of cane sugar type, starch type and microcrystalline Cellulose type; Preferably, described binding agent is one or both combinations in hypromellose and hydroxy methocel; Antitackiness agent is one or more combination in any of Pulvis Talci, micropowder silica gel or magnesium stearate; Preferred, described sealing coat is polyvinyl alcohol; Most preferred, described polyvinyl alcohol is middle degree of polymerization polyvinyl alcohol or polyvinyl alcohol with low degree of polymerization.
5. the two release capsule of trospium chloride as claimed in any of claims 1 to 4, it is characterized in that: in described trospium chloride fast release micropill, the particle diameter of described celphere is 30-35 order.
6. the two release capsule of trospium chloride as claimed in any of claims 1 to 5; it is characterized in that; described trospium chloride slow-release micro-pill is made up of described trospium chloride fast release micropill, Sustained release coating materials, porogen, slow release protective layer coating material; wherein; weight percentage: described trospium chloride fast release micropill 45-90%; described Sustained release coating materials 5-50%, described porogen 1-5%, described protective layer coating material 1-5%.
7. the two release capsule of trospium chloride according to claim 6; it is characterized in that; in described trospium chloride slow-release micro-pill; the weight percentage of described trospium chloride fast release micropill is 65-80%; the weight percentage of described Sustained release coating materials is 15-30%; the weight percentage of described porogen is 1-3%, and the weight percentage of described protective layer coating material is 1-3%.
8. the two release capsule of trospium chloride according to claim 6, it is characterized in that, in described trospium chloride slow-release micro-pill, described Sustained release coating materials is Aquacoat, ethyl cellulose, especially strange NE30D, Eudragit RL 30D and Eudragit RS 30D, especially strange RS100 and any one or more combination in any especially in strange RL100; Described porogen is one or more combination in any in Polyethylene Glycol, sodium chloride and hypromellose; Described slow release protective layer coating material is one or both combinations in hypromellose and Opadry.
9. the two release capsule of trospium chloride as claimed in any of claims 1 to 5; it is characterized in that; described trospium chloride slowbreak micropill is made up of trospium chloride fast release micropill and delayed release coat material, plasticizer, protective layer coating material; weight percentage: described trospium chloride fast release micropill 45-75%; described delayed release coat material 20-50%; described plasticizer 1-5%, described slowbreak protective layer coating material 1-5%.
10. the two release capsule of trospium chloride according to claim 9; it is characterized in that; in described trospium chloride slowbreak micropill; the weight percentage of described trospium chloride fast release micropill is 55-65%; the weight percentage of described delayed release coat material is 30-40%; the weight percentage of described plasticizer is 2-4%, and the weight percentage of described slowbreak protective layer coating material is 2-4%.
The two release capsule of 11. trospium chlorides according to claim 9, it is characterized in that, in described trospium chloride slowbreak micropill, described delayed release coat material is one or more combination in any especially in strange FS30D, especially strange S100, polyacrylic acid No. two resins and polyacrylic acid No. three resins; Described plasticizer is one or more combination in any of o-benzoate, triethyl citrate and Polysorbate; Described slowbreak protective layer coating material is one or both combinations in hypromellose and Opadry.
The two release capsule of 12. trospium chlorides according to claim 11, is characterized in that, described delayed release coat material be especially very FS30D and/or polyacrylic acid No. three resins.
13., according to the two release capsule of the trospium chloride in claim 1 to 12 described in any one, is characterized in that, the weight of the two release capsule of described trospium chloride is 20-100mg, preferred 40-80mg.
The preparation method of 14. 1 kinds of two release capsules of trospium chloride, comprises the following steps:
(1) micropill medicine carrying: take trospium chloride, binding agent and antitackiness agent according to percentage by weight according to claim 1, is dispersed in solvent and obtains medicine carrying coating solution, obtains medicine carrying micropill with medicine carrying coating solution coating on celphere;
(2) sealing coat coating: take insolated layer materials according to percentage by weight according to claim 1, be dispersed in solvent, obtain sealing coat coating solution, with sealing coat coating solution, coating is carried out to the medicine carrying micropill in step (1), obtain trospium chloride fast release micropill;
(3) sustained release coating: take Sustained release coating materials and porogen according to percentage by weight according to claim 6, is dispersed in solvent, as sustained release coating liquid, carries out coating with sustained release coating liquid to trospium chloride fast release micropill in step (2); Take slow release protective layer coating material according to percentage by weight according to claim 6, be dispersed in solvent, as slow release protective layer coating solution, with slow release protective layer coating solution, coating is carried out to the micropill after sustained release coating, obtain trospium chloride slow-release micro-pill;
(4) delayed release coat: take delayed release coat material, plasticizer according to percentage by weight according to claim 9, be dispersed in solvent, as delayed release coat liquid, with delayed release coat liquid, coating is carried out to the trospium chloride fast release micropill in step (2); Take slowbreak protective layer coating material according to percentage by weight according to claim 9, be dispersed in solvent, as slowbreak protective layer coating solution, with slowbreak protective layer coating solution, coating is carried out to the micropill after delayed release coat, obtain trospium chloride slowbreak micropill;
(5) according to percentage by weight according to claim 1, above-mentioned trospium chloride slow-release micro-pill and trospium chloride slowbreak micropill are filled in capsule;
Above-mentioned coating steps all adopts fluidized bed coating technique.
15. methods according to claim 14, is characterized in that: described fluidized bed coating technique is that pressure spray process cut by fluid bed; Pressure spray process parameter cut by fluid bed: inlet temperature is 40-80 DEG C, and air intake frequency is 25-40HZ, and atomisation pressure is 0.1-0.3MPa.
16. methods according to claim 14, it is characterized in that: in described step (1), be percent by volume for disperseing the solvent of trospium chloride crude drug, binding agent and antitackiness agent be 0-80% ethanol water, preferably, medicine carrying coating solution percent weight in volume content be 20-40%.
17. according to claim 14 to the method described in any one in 16, it is characterized in that: in described step (2), be percent by volume for disperseing the solvent of Sustained release coating materials and porogen be 0-80% ethanol water, preferably, sustained release coating liquid percent weight in volume content be 5-15%.
18. according to claim 14 to the method described in any one in 17, it is characterized in that: in described step (3), the dispersion medium of Sustained release coating materials is percent by volume is 0-80% ethanol water, and the percent weight in volume content of sustained release coating liquid is 5-20%; The dispersion medium of slow release protective layer coating material is percent by volume is 0-80% ethanol water, and the percent weight in volume content of slow release protective layer coating solution is 5-15%.
19. according to claim 14 to the method described in any one in 18, it is characterized in that: in described step (4), the dispersion medium of delayed release coat material is percent by volume is in 0-80% ethanol water, and the percent weight in volume content of delayed release coat liquid is 5-30%; The dispersion medium of slowbreak protective layer coating material is percent by volume is in 0-80% ethanol water, and the percent weight in volume content of slowbreak protective layer coating solution is 5-15%.
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| CN106617094A (en) * | 2016-12-30 | 2017-05-10 | 广州新济药业科技有限公司 | Probiotics microcapsule as well as preparation method and application thereof |
| CN106706832A (en) * | 2015-08-06 | 2017-05-24 | 舒泰神（北京）生物制药股份有限公司 | Method for determining content of trospium chloride |
| 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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| CN101596170A (en) * | 2009-07-06 | 2009-12-09 | 沈阳亿灵医药科技有限公司 | Trospium chloride slow-release tablet |
| US20110312986A1 (en) * | 2010-06-16 | 2011-12-22 | Allergan, Inc. | Composition and Method for Treating Overactive Bladder |
| CN103690506A (en) * | 2013-11-08 | 2014-04-02 | 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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| US20050191351A1 (en) * | 2003-11-04 | 2005-09-01 | Shire Laboratories, Inc. | Once daily dosage forms of trospium |
| CN101596170A (en) * | 2009-07-06 | 2009-12-09 | 沈阳亿灵医药科技有限公司 | Trospium chloride slow-release tablet |
| US20110312986A1 (en) * | 2010-06-16 | 2011-12-22 | Allergan, Inc. | Composition and Method for Treating Overactive Bladder |
| CN103690506A (en) * | 2013-11-08 | 2014-04-02 | 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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| CN106706832A (en) * | 2015-08-06 | 2017-05-24 | 舒泰神（北京）生物制药股份有限公司 | Method for determining content of trospium chloride |
| 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 |
| CN106617094A (en) * | 2016-12-30 | 2017-05-10 | 广州新济药业科技有限公司 | Probiotics microcapsule as well as preparation method and application thereof |
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