CN102579404A - Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule - Google Patents
Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a sustained-release capsule containing propiverine hydrochloride and a preparation method of the sustained-release capsule. The sustained-release capsule comprises sustained-release micropills and an empty capsule, wherein, the sustained-release micropills comprise pill cores containing drugs accounting for 75 to 97 percent and sustained-release coating layers accounting for 3 to 25 percent by weight percentage. The sustained-release capsule containing propiverine hydrochloride comprises hundreds of the sustained-release micropills with uniform particle sizes, and preparation errors or preparation defects of individual micropills cannot influence the drug release behavior of the whole preparation seriously, so that the sustained-release capsule is safer than a sustained-release tablet, the irritant activity to gastrointestinal tracts is smaller, plasma concentration is smoother, the bioavailability is higher, and the sustained-release capsule can continuously release the drugs for 24 hours if being taken for one time per day so as to treat overactive bladder. The preparation method of the sustained-release capsule prepares the pill cores containing the drugs in an extrusion and spheronization method or a drug added manner, adopts a fluidized bed to coat the sustained-release coating layers, achieves simple technology, and is easy to achieve industrialized mass production.
Description
Technical field
The present invention relates to the technical field of P-4 slow releasing preparation, relate in particular to a kind of P-4 slow releasing capsule and preparation method thereof.It belongs to a kind of slow releasing preparation of spasmolytic.
Background technology
Overactive bladder (Overactive Bladder, OAB) be a kind of be the syndrome of characteristic with the symptoms of urgency, often with frequent micturition and nocturia symptom, can accompany or without urge incontinence; Can show as detrusor over-activity (Detrusor instability, or detrusor overactivity) on the urodynamics, also can be the urethra-vesical dysfunction of other form.OAB is the unconscious contraction of detrusor by world urine control association (ICS), and the no clear and definite cause of disease does not comprise by the symptom due to the bladder urethra local patholoic change of acute urinary tract infection or other form.The symptom of OAB is because in the filling of bladder process due to the nonvoluntary contraction of detrusor; Its cause of disease is still not fully aware of so far; It possibly be because maincenter inhibition efferent pathway, and peripheral sensory afferent pathway or bladder muscle itself suffer damage and cause, and these reasons can separately or be united existence.OAB is 11～22% at its sickness rate such as France, Italy, Sweden, Britain, Spain; And the adult who estimates American-European countries nearly 17% suffers from this disease; Whole world number of patients is greatly about about 5,000 ten thousand to 100,000,000; The women is slightly more than the male among the patient, and its sickness rate increases with the age and rises.China does not still have the epidemiologic data of OAB at present; But Peking University's Urology Surgery institute shows in Beijing area investigation: the incidence rate of male's urge incontinence is that the incidence rate of women's mixed urinary incontinence and urge incontinence is 40.4% more than 16.4%, 18 years old more than 50 years old.Along with China gets into increasing of aging society and diabetes, cerebral thrombosis, nervous system damage property disease, the sickness rate of OAB also rises year by year, the person's that caused the clinical position great attention.
Propiverine (Propiverine) is a spasmolytic class medicine, and the about 60mg/ml of the dissolubility in water is height dissolving high osmosis (1 type of Class) medicine.Propiverine receives body temperature that affinity interaction is arranged to poison cover gill fungus alkali, and smooth muscle of bladder is had direct effect, can suppress by the bladder contraction due to acetylcholine and the calcium chloride, and the bladder contraction due to the untamed electricity irritation of atropine is also had inhibitory action.Animal experiment shows that these article have the effect that increases the bladder available capacity to animal pattern, and reduces the rhythmicity contraction frequency of bladder contraction.Main metabolites 1-methyl after this medicine is oral-4-piperidyl-diphenylprop ethoxyacetic acid-N-oxide (N-oxide of this medicine; Be designated hereinafter simply as M-1) directly act on smooth muscle; 1-methyl-4-piperidyl-benzoic acid-N-oxide (M-1 takes off the propyl group inductor, is designated hereinafter simply as M-2) has cholinolytic effect.This medicine and metabolite thereof suppress being overexcited of smooth muscle through direct smooth muscle effect and cholinolytic effect, thereby reach the effect that reduces the frequency of urinating.Be mainly used in treatment clinically and be associated with the suddenly overactive bladder (OAB) of symptoms such as (tightly) urgent property urinary incontinence, urgent micturition, frequent micturition.
P-4 slow releasing capsule (trade name: Detrunorm XL) go on the market in Britain's approval first by the production of Britain Amdipharm PLC company in April, 2006; A plurality of countries listing in Europe respectively at present once-a-day is used to treat urinary incontinence clinically and congenital detrusor enlivens urgent micturition and the frequent micturition that disease (bladder enlivens disease) causes.The P-4 preparation of present domestic listing has only conventional tablet, does not temporarily have slow releasing preparation production listing and registration to declare, and the P-4 slow releasing preparation that develop once a day, 24 hours discharges has the good clinical application advantage.
Summary of the invention
The objective of the invention is to overcome the shortcoming and defect of prior art, a kind of have persistent, medicining times is few, blood drug level is steady, safety is higher P-4 slow releasing capsule are provided.Based on this, the present invention also provides a kind of method for preparing of P-4 slow releasing capsule.
For solving above technical problem, technical scheme of the present invention is:
A kind of slow releasing capsule of P-4 is made up of slow-release micro-pill and Capsules two parts, counts by weight percentage, and said slow-release micro-pill is made up of 75～97% the sustained release coating layer that contains pill core and 3～25%, wherein:
Containing pill core comprises: 10～40% P-4 and 37～86.5% excipient or celphere, 3～8% binding agent and 0.5～15% sour agent, more than the percentage by weight of each component all to contain the total weight of pill core.
The sustained release coating layer comprises: 3～25% slow-release material, 15～80% antiplastering aid, 10～30% plasticizer and 3～30% porogen; More than in each component; The percentage by weight of slow-release material to be containing the total weight of pill core, and the percentage by weight of antiplastering aid, plasticizer and porogen is all with the total weight of slow-release material.
Preferably, said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose.
Preferably, said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Preferably, said sour agent is one or more the mixture in citric acid, tartaric acid, fumaric acid, phosphoric acid, the sulphuric acid.
Said slow-release material is methacrylic resin polymer or ethyl cellulose; Preferably; The methacrylic resin polymer is one or more the mixture among Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, Eudragit RS, the Eudragit RL, and ethyl cellulose is Surelease or Aquacoat.
Preferably, said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Preferably, said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Preferably, said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
The release in vitro degree of the P-4 slow releasing capsule that above-mentioned optimizing prescriptions makes is: 2 hours 10～25%, and 4 hours 20～45%, 8 hours 40～70%, 12 hours 60～90%, 24 hours＞85%.
Preferably, the described pill core that contains adopts and to extrude spheronization or the preparation of medicine-feeding method, comprises the steps:
(1) contain the preparation of pill core:
Extrude spheronization: with P-4, excipient and sour agent mix homogeneously, the purification of aqueous solutions that adds binding agent is processed soft material, adopts to extrude spheronization and process 20～40 purposes and contain pill core, drying;
Or fluid bed medicine-feeding method: P-4, binding agent and sour agent are dissolved in the purified water, process and contain drug solns, adopt fluid bed that solution is sprayed on 20～40 purpose celphere, drying.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 30 ℃～50 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
The P-4 slow releasing capsule that the present invention makes is made up of 1,100 uniform slow-release micro-pill of particle diameter; Error or the defective of indivedual micropills in preparation is unlikely drug release behavior to total formulation and produces and have a strong impact on; Therefore more safer than slow releasing tablet, littler to the gastrointestinal zest, blood drug level is more steady; Bioavailability is higher, and taking 1 time in one day can lasting release in 24 hours.
Method for preparing employing of the present invention is extruded round as a ball method preparation and is contained pill core, and particle diameter is 20～40 orders, adopts fluid bed bag sustained-release coating layer, and technology is simple, is easy to industrialized great production.
Description of drawings
Fig. 1～Fig. 3: the P-4 slow releasing capsule 24 hours releasing curve diagrams in external multiple release medium that make for the embodiment of the invention one～embodiment three.
The specific embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below in conjunction with accompanying drawing with
Specific embodiment is done further detailed description to the present invention.
Embodiment one:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that P-4 and microcrystalline Cellulose, lactose adopt equivalent to increase progressively, process soft material, adopt and extrude round as a ball machine-processed micropill with purified water; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
The Sulisi of recipe quantity is joined in the purified water, it is fully disperseed, stir 45min, will contain pill core and place fluid bed, adjust each technological parameter, guarantee fluidized state, coating increases weight to 11%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 45～55 ℃, temperature of charge: 40～45 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 50 ℃ of baking oven matured 12 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 8 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 230nm wavelength.The result is following:
Embodiment two:
1, contain the preparation of pill core:
Preparation technology: the method mix homogeneously that adopts equivalent to increase progressively P-4 and lactose, microcrystalline Cellulose, anhydrous citric acid; Process soft material with purified water, adopt and extrude round as a ball machine-processed micropill, the sieve plate particle diameter is 0.8mm; 60 ℃ of oven dryings; Sieve, choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
The Pulvis Talci of recipe quantity joined stir 45min in the purified water, add the strange NE30D aqueous dispersion of You Te it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 3.5%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 8 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 230nm wavelength.The result is following:
Embodiment three:
1, contain the preparation of pill core:
Preparation technology: P-4, PVP-K30 and citric acid are dissolved in the purified water, and stirring uses CL, makes to contain drug solns.The microcrystalline Cellulose celphere places fluid bed, and the above-mentioned drug solns that contains is sprayed on the celphere surface, adopts the medicine-feeding legal system must contain pill core, and drying is sieved and chosen 20～30 orders and contain pill core, and coating is used.
2, bag slow release layer:
The Pulvis Talci of recipe quantity joined stir 45min in the purified water, add triethyl citrate, the strange RS30D of You Te and RL30D aqueous dispersion it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 12%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 8 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 230nm wavelength.The result is following:
Compliance test result
External release test:
Get slow releasing capsule that embodiment one, two, three makes as sample; Pressing the UV method detects; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, carried out the release in vitro degree respectively at 2,4,8,12,24 hours and measure, detect among data and Fig. 1～Fig. 3 and can find out by the release degree; 3 lot sample article discharge in 24 hours evenly in multiple release medium; All meet one-level release dynamic process, be illustrated in the external slow release characteristic that has, the further research of release in the body.
More than the present invention has been carried out detailed introduction, use concrete example in the literary composition principle of the present invention and embodiment set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (4)
1. the slow releasing capsule of a P-4 is characterized in that, is made up of slow-release micro-pill and Capsules two parts, counts by weight percentage, and said slow-release micro-pill is made up of 75～97% the sustained release coating layer that contains pill core and 3～25%, wherein:
Containing pill core comprises: P-4 10～40%, excipient or celphere 37～86.5%, binding agent 3～8% and sour agent 0.5～15%, more than the percentage by weight of each component to contain the total weight of pill core.
The sustained release coating layer comprises: slow-release material 3～25%, antiplastering aid 15～80%, plasticizer 10～30%, porogen 3～30%; More than in each component; The percentage by weight of slow-release material to be containing the total weight of pill core, and the percentage by weight of antiplastering aid, plasticizer and porogen is all with the total weight of slow-release material.
2. P-4 slow releasing capsule according to claim 1 is characterized in that,
Said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose, and celphere is microcrystalline Cellulose celphere or starch celphere.
Said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Said sour agent is one or more the mixture in citric acid, tartaric acid, fumaric acid, phosphoric acid, the sulphuric acid.
Said slow-release material is one or more a mixture of methacrylic resin polymer or ethyl cellulose.
Said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
3. Clomipramine Hydrochloride slow releasing capsule according to claim 1 is characterized in that, the release in vitro degree is: 2 hours 15～30%, and 4 hours 30～55%, 8 hours 55～75%, 12 hours 75～90%, 24 hours＞85%.
4. the method for preparing of P-4 slow releasing capsule according to claim 1 comprises the steps:
(1) contain the preparation of pill core:
Extrude spheronization: with P-4, excipient and sour agent mix homogeneously, the purification of aqueous solutions that adds binding agent is processed soft material, adopts to extrude spheronization and process 20～40 purposes and contain pill core, drying;
Or fluid bed medicine-feeding method: P-4 and sour agent are dissolved in the purification of aqueous solutions of binding agent, adopt fluid bed that solution is sprayed on 20～40 purpose celphere, drying.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 35 ℃～55 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
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| CN2012100209662A CN102579404A (en) | 2012-01-17 | 2012-01-17 | Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule |
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| WO2017026950A1 (en) | 2015-08-07 | 2017-02-16 | Santa Farma Ilac San. A. S. | Controlled release propiverine formulations |
| WO2020101586A1 (en) | 2018-11-16 | 2020-05-22 | Santa Farma İlaç Sanayi̇ A.Ş. | Controlled release propiverine formulations |
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| WO2021101481A1 (en) | 2019-11-19 | 2021-05-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof |
| WO2022115056A1 (en) | 2020-11-27 | 2022-06-02 | Santa Farma Ilac Sanayii A.S. | Sustained release formulation compositions comprising propiverine |
| WO2022132066A1 (en) * | 2020-12-18 | 2022-06-23 | Santa Farma Ilac Sanayii A.S. | Homogenous compositions of propiverine hci formulations |
| WO2023128906A1 (en) * | 2021-12-30 | 2023-07-06 | Santa Farma Ilac Sanayii A.S. | Release of propiverine compositions in gastric conditions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017026950A1 (en) | 2015-08-07 | 2017-02-16 | Santa Farma Ilac San. A. S. | Controlled release propiverine formulations |
| WO2020101586A1 (en) | 2018-11-16 | 2020-05-22 | Santa Farma İlaç Sanayi̇ A.Ş. | Controlled release propiverine formulations |
| WO2021101483A1 (en) * | 2019-11-19 | 2021-05-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical form comprising acidic substance |
| WO2021101481A1 (en) | 2019-11-19 | 2021-05-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof |
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| EP4061369A4 (en) * | 2019-11-19 | 2024-04-10 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A pharmaceutical form comprising acidic substance |
| WO2022115056A1 (en) | 2020-11-27 | 2022-06-02 | Santa Farma Ilac Sanayii A.S. | Sustained release formulation compositions comprising propiverine |
| WO2022132066A1 (en) * | 2020-12-18 | 2022-06-23 | Santa Farma Ilac Sanayii A.S. | Homogenous compositions of propiverine hci formulations |
| WO2023128906A1 (en) * | 2021-12-30 | 2023-07-06 | Santa Farma Ilac Sanayii A.S. | Release of propiverine compositions in gastric conditions |
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