CN101933913A - Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof - Google Patents
Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof Download PDFInfo
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- CN101933913A CN101933913A CN 201010283316 CN201010283316A CN101933913A CN 101933913 A CN101933913 A CN 101933913A CN 201010283316 CN201010283316 CN 201010283316 CN 201010283316 A CN201010283316 A CN 201010283316A CN 101933913 A CN101933913 A CN 101933913A
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Abstract
The invention belongs to the field of medicine, and in particular relates to a dexmethylphenidate hydrochloride dual-release preparation and a preparation method thereof. The preparation of the invention comprises pellets with different release performance, wherein the pellets comprise 10 to 70 percent of quick-response pellets and 20 to 60 percent of enteric-coated pellets based on the total weight of the pellets. The release mode in the preparation can achieve an ideal treatment effect and ensure that the medicament concentration in blood plasma in vivo is maintained as long as 16 to 24 hours. Compared with a dexmethylphenidate hydrochloride common preparation which is taken twice per day, the dual-release preparation can reduce a peak value of the medicament concentration in the blood plasma in vivo after the medicament is taken for the second time, and simultaneously the bioavailability of the medicament is not influenced. The dexmethylphenidate hydrochloride adopted by the invention can effectively reduce toxic and side effects brought by a racemic compound and improve a treatment effect and the medication compliance of a patient.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical field, specifically, relate to a kind of with two release capsule preparations of the right methylphenidate of hydrochloric acid and preparation method thereof about pharmaceutical preparation.
Technical background
The right methylphenidate of hydrochloric acid is a central nervous system stimulant for being the racemic d-of methylphenidate hydrochloride Soviet Union formula enantiomer.Chemical name be (R, R)-(+)-α-phenyl-2-Piperidineacetic acid methyl ester hydrochloride.It is that molecular formula is: C
14H
19NO
2HCl.Molecular weight is 269.77, and structural formula is:
Methylphenidate hydrochloride is a line medicine of treatment attention deficit hyperactivity disorder (ADHD), belongs to a kind of relatively safe and effective medicine, and its effective percentage reaches 78-80%.ADHD is modal Childhood spirit dysplasia disease.The cardinal symptom of this disease is: attention deficit disorder, behavior are got excited, are divert one's attention easily and hyperkinesia, often with learning difficulty and conduct disorder.Prevalence is at 1.5-10% in the domestic children population of investigation discovery, and an actual sick rate is higher because this disease can not get enough paying attention to for a long time.
But find that in clinical application the methylphenidate hydrochloride side effect is obvious, often has following symptom: comprise headache, stomachache, insomnia, inappetence.The methylphenidate ordinary preparation be because need take medicine two to three short every day of half-life, and medicine appears missing in patient easily, poor compliance, and may cause drug addiction and dependency exceeding under the situation of therapeutic dose.
Summary of the invention
The invention provides a kind of is the preparation method of two release capsule preparations of principal agent with the right methylphenidate of hydrochloric acid, purpose be the toxic and side effects of minimizing methylphenidate hydrochloride, for use in patient's long-term treatment.
Another object of the present invention is to overcome the higher nervus centralis side reaction that causes of the blood drug level peak value second time of ordinary preparation every day taking medicine and being brought for twice, improves the medication compliance simultaneously, reduces the patient because of missing the probability of drug induced unsatisfactory curative effect.
The technical solution used in the present invention is:
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention, described preparation has the performance that discharges medicine for twice, comprise fast release micropill part and slowbreak micropill part, this capsule is prepared from by the right methylphenidate of hydrochloric acid, filler, disintegrating agent, binding agent, contagion gown material, coating material, plasticizer, porogen.
Wherein,
(a) the ball core of fast release micropill and slowbreak micropill is identical, comprise one or several mixture in sucrose, lactose, microcrystalline Cellulose, Sargassum polysaccharides, the chitosan by right methylphenidate of hydrochloric acid and filler, be prepared into the medicine carrying micropill by extruding spheronization after adding binding agent and disintegrating agent again, the controllable diameter of gained micropill is built in 0.3-1.5mm, and the micropill of preferred 1.0 ± 0.1mm scope is as the ball core of preparation rapid release or slowbreak micropill.
(b) fast release micropill, select for use one or several isolation coat materials to be prepared under certain process conditions by the medicine carrying micropill, the isolation coat material is selected from: one or more in Opadry I, Opadry II, Opadry AMB, Opadry MP, hydroxypropyl methylcellulose, the polyvinyl alcohol.Make the smooth surface rounding of the micropill that makes, good stable and flowability are arranged.
(c) slowbreak micropill, carry out the coating of slowbreak material by fast release micropill, coating material comprises one or several in ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin, Aquacoat, hydroxypropyl cellulose, hydroxyethyl-cellulose cellulose acetate, cellulose acetate-phthalate, cellulose acetate phthalate ester, vinyl acetate phthalate ester, the hydroxypropyl methylcellulose phthalate ester, also need add the stability that porogen and plasticizer improve enteric coating simultaneously.
Therefore, the two release capsule fast release micropill parts wherein of the right methylphenidate of hydrochloric acid of the present invention, the percentage by weight of each component is as follows:
Its fast release micropill component is:
The right methylphenidate 2-30% of hydrochloric acid
Filler 5-95%
Disintegrating agent 0-10%
Binding agent 0.5-15%
Contagion gown material 0-10%
Slowbreak micropill part wherein, the percentage by weight of each component is as follows:
The right methylphenidate 2-25% of hydrochloric acid
Binding agent 0.3-10%
Filler 50-88%
Disintegrating agent 0-9%
Contagion gown material 0-9%
Coating material 30-68%
Plasticizer 1-8%
Porogen 1-8%
Wherein said fast release micropill partly is the matrix type micropill, and main medicine is the right methylphenidate of hydrochloric acid.
Filler can be selected one or several in lactose, microcrystalline Cellulose, starch, the dextrin, preferably microcrystalline cellulose for use.
In the optional water of binding agent, dehydrated alcohol, water and alcohol mixed solution, hydroxypropyl methylcellulose solution, the hydroxypropyl cellulose solution one or several.
Disintegrating agent can select that carboxymethyl starch is received for use, in the polyvinylpolypyrrolidone, sodium carboxymethyl cellulose, starch slurry one or several.
Isolation clothes material can be selected one or several in Opadry I, Opadry II, Opadry MP, hydroxypropyl methylcellulose, ethyl cellulose, the methylcellulose for use.
Wherein said slowbreak micropill part:
Filler can be selected one or several in lactose, starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, chitosan, the dextrin, preferably microcrystalline cellulose for use.
In the optional water of binding agent, dehydrated alcohol, water and alcohol mixed solution, hydroxypropyl methylcellulose solution, the hydroxypropyl cellulose solution one or several.
Disintegrating agent can select that carboxymethyl starch is received for use, in the polyvinylpolypyrrolidone, sodium carboxymethyl cellulose, starch slurry one or several.
The contagion gown material can be selected one or several in Opadry, Opadry MP, hypromellose, the polyvinyl alcohol for use.
Coating material can be selected one or several in ethyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, methacrylic resin, polylactic acid, the palm wax for use.
Plasticizer can be selected diethyl phthalate, dibutyl phthalate, dibutyl sebacate tristerin, triethyl citrate, tributyl citrate, diethyl succinate, fractionated coconut oil for use.
Porogen can be selected one or several in Polyethylene Glycol, Pulvis Talci, hydroxypropyl methylcellulose, the polyvidone for use.
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention are the piller forms of micropill of packing in the capsule, and micropill wherein comprises ball core and coating, and wherein the preparation method of ball core is as follows:
Medicine and filler, disintegrating agent are crushed to certain particle size range, by behind 80 to 100 eye mesh screens in stirring mixer behind the mix homogeneously, add binding agent, make soft material, the medicine carrying micropill that spheronization makes uniform particle diameter is extruded in employing, according to the cylindrical length that extruding forms, the micropill particle diameter can be controlled in 0.6 to 1.2mm the scope, through preferred control particle diameter at 1.0 ± 0.1mm.
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention, coating method is as follows:
Preferred coating material is adopted fluidized bed coating or coating pan coating, and the clothing membrane material is injected in the fluid bed after atomizing under a suitable pressure, and at a certain temperature, coating material forms the clothing film and is attached on the micropill.Micropill can obtain the uniform medicine carrying micropill of coating under certain fluidizing velocity.Micropill can improve the stability of clothing film through the post processing of placement at a certain temperature, reduces the influence of micropill for the external environment factor such as illumination, high temperature, humidity.
Use method of the present invention, the gained micropill is compared with the total amount that feeds intake, and adopts and extrudes the spheronization productive rate at 90-100%, can reduce the loss of the right methylphenidate crude drug of hydrochloric acid in preparation process than lamination medicine-feeding method.Behind the gained micropill fill capsule, its release performance stable uniform is chosen three batches and is carried out the measuring of release in vitro degree, and the release relative standard deviation is less than 3%. between batch
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention, the mass ratio of contained fast release micropill and slowbreak micropill is between 3: 1 to 1: 3 in the capsule, and the preferred mass ratio is: 358: 431.
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention, the effective dose of the right methylphenidate of hydrochloric acid is between 5-40mg in the described pair of delivery formulations, be preferably 5-20mg, to adapt to different weight crowd's use, has close or identical body giving drugs into nose for dynamic characteristic during different size correspondence different crowd.
The two release capsules of the right methylphenidate of hydrochloric acid of the present invention, wherein the shared part by weight of fast release micropill is at 30-60%, and the part by weight of slowbreak micropill is at 40-60%.
The right methylphenidate of hydrochloric acid is compared the racemization methylphenidate among the present invention, and its therapeutic effect is better, side effect is littler.According to showing among U.S. Pat 6355656 B1, the side effect probability of occurrence of right methylphenidate ordinary preparation is approximately 7.3%, and the side effect probability of occurrence of the two delivery formulations of right methylphenidate only has 1.3%.
The improvement of the two delivery formulations of the right methylphenidate of hydrochloric acid of the present invention, experiment shows that taking the two delivery formulations of the right methylphenidate of hydrochloric acid every day can produce drug release twice in its human body, its therapeutic effect is with to take twice ordinary preparation suitable at every turn, and can stablize control plasma drug level peak value, reduce side effect and addiction that medicine brings, improve bioavailability of medicament to guarantee curative effect.Behind the micropill fill capsule, test investigation by the requirement of preparation stability, its release performance stable uniform, the release relative standard deviation is less than 3%. between batch
The two delivery formulations of the right methylphenidate of hydrochloric acid provided by the present invention add disintegrating agent in carrying pill core, thereby the release of fast release micropill Chinese medicine after accelerating to take medicine reduces the medicine required time of complete stripping; The two delivery formulations of the right methylphenidate of hydrochloric acid provided by the present invention, wherein immediate release section produces release at short notice, plasma drug level reaches first peak value, after about 2.5 hours, medicine begins to discharge for the second time, produces second plasma drug level peak value, and the concentration of two minor peaks should be close, reduce drug level and surpass toxicity and the addiction that the treatment window causes, and take medicine about 10 AM every day and once get final product.
Following data declaration beneficial effect of the present invention by experiment: the capsule of embodiment 1 preparation is adopted in experiment, medicine stability investigation method by routine is investigated, find that preferred prescription of the present invention has high stability, compare with existing product and prior art and have unexpected technique effect.
The study on the stability of the two delivery formulations of the right methylphenidate of hydrochloric acid under the high heat condition of table 1
The study on the stability of the two delivery formulations of the right methylphenidate of hydrochloric acid under table 2 super-humid conditions
The study on the stability of the two delivery formulations of the right methylphenidate of hydrochloric acid under the table 3 strong illumination condition
Test about release of the present invention:
The result shows: the two delivery formulations 2 hours cumulative release degree in acid of the right methylphenidate of this hydrochloric acid reach 50%, and 2 two hours cumulative release degree reach 99.67% in the buffer of pH=6.8.
The invention has the advantages that:
(1) the right methylphenidate capsule of the present invention's hydrochloric acid, preparation process is simple for process, adopts low temperature to extrude spheronizator and fluid bed, under laboratory scale, can finish the amplification production of 10000-30000 unit, the production efficiency height can prepare the right methylphenidate capsule of hydrochloric acid of 5-40mg different size;
(2) two delivery formulations of the present invention, through the animal body giving drugs into nose for dynamics research, with the equivalence of ordinary preparation bioavailability, do not produce the problem that reduces bioavailability because of the effect of part slowbreak, its pair discharges model and reduced by the second plasma drug level peak value, reduce the possibility that has side effects, take the compliance that has improved patient's medication once a day.
(3) preparation of the right methylphenidate of the present invention's hydrochloric acid is investigated through accelerated test, in 3 months stable, the medicament contg of character, related substance all in controlled range, suitability for industrialized production.
Description of drawings
The release in vitro degree that the two delivery formulations of the right methylphenidate of Fig. 1 optimizing prescriptions gained hydrochloric acid are three batches
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention rather than restriction the present invention.All and technical scheme equivalence of the present invention all belongs to protection scope of the present invention.
Embodiment 1
Prescription
(1) fine pellet core
Microcrystalline Cellulose 49g
The right methylphenidate 5.0g of hydrochloric acid
Carboxymethyl cellulose 1g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
6% hydroxypropyl methylcellulose solution 11.2ml
(3) slowbreak micropill
Fine pellet core 100g
The Aquacoat 33.3ml of 15% solids content
Dibutyl phthalate 0.2g
Pulvis Talci 1.6g
Preparation process and technology:
(1) fine pellet core preparation process and technology
Medicine and filler, disintegrating agent are crushed to certain particle size range, after in stirring mixer, mixing 1h behind 80 eye mesh screens, add 2% (w/v) hydroxypropyl methylcellulose solution of 44ml, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 ℃, behind the 10min soft material is put into the cryogenic high pressure extruder by sieve aperture, sieve aperture is selected the sieve plate of 0.9-1.0mm, and extruded velocity is adjusted to 40rpm, form the cylindrical soft material of moderate length, in spheronizator,, can form the medicine carrying micropill of uniform particle diameter with the round as a ball 9min of the speed of 2000rpm, according to the cylindrical length of shearing, the micropill particle diameter can be controlled in 0.6 to 1.2mm the scope.Productive rate with the coating process is an evaluation index, and preferable particle size is carried out coating at the micropill of 1.0 ± 0.1mm, places 40 ℃ of dry 45min in the baking oven, and the micropill of getting the 16-24 mesh sieve carries out the uniformity and water content inspection, qualified after, standby as fine pellet core.
(2) fast release micropill preparation process and technology
Get medicine carrying fine pellet core 56g and put into fluid bed, regulate inlet temperature to 45 ℃, adjust intake at 50m
3About/h, with the 6% hydroxypropyl methylcellulose aqueous solution that configures as the contagion gown material) be added to aerochamber atomizing coating, atomizing pressure 2bar with the pump speed of 1.5ml/min with peristaltic pump earlier by end spray, improve gradually that to pump into speed intact to 6ml/min to the coating solution bag, coating continues to make micropill fluidized drying 30min in fluid bed after finishing, and promptly gets fast release micropill.
(3) slowbreak micropill preparation process and technology
Get release pills and place fluidizing fluid-bedly, regulate stream temperature to 45 ℃, dry air flow 50m
3/ h, get Aquacoat, it is 15% suspension that thin up becomes solid content, the Pulvis Talci and the triethyl citrate that add recipe quantity, pump into aerochamber atomizing coating (atomizing pressure is 2bar) with peristaltic pump with end spray mode 1.5ml/min, improve progressively that to pump into speed intact to 7ml/min to the coating solution bag, continuation fluidized drying 30min in fluid bed takes out, again after solidifying 10h under 45 ℃ of conditions, chose 16-24 mesh sieve piller, check character and release, promptly get the slowbreak micropill after qualified.
(4) the right methylphenidate slowbreak of hydrochloric acid capsule fill
Fast release micropill and slowbreak micropill are packed into capsule respectively by weight 30: 43 ratio, promptly get hydrochloric acid right side methylphenidate finished capsule product.
Embodiment 2
Prescription
(1) fine pellet core
Microcrystalline Cellulose 49g
The right methylphenidate 5.0g of hydrochloric acid
Polyvinylpolypyrrolidone 0.9g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
20% Opadry I aqueous solution 11.2ml
(3) slowbreak micropill
Fine pellet core 250g
You Teqi L30D-55 166.7g
Triethyl citrate 12.5g
Pulvis Talci 12.5g
Water 216ml
Preparation process and technology:
(1) fine pellet core preparation process and technology
Medicine and filler, disintegrating agent are crushed to certain particle size range, after in stirring mixer, mixing 1 hour behind 80 eye mesh screens, add the hydroxypropyl methylcellulose solution of 44ml, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 ℃, behind the 10min clock soft material is put into the cryogenic high pressure extruder and pass through sieve aperture, sieve aperture is selected the sieve plate of 0.9-1.0mm, extruded velocity is adjusted to 40 rpms, form the cylindrical soft material of moderate length, in spheronizator, with 2000 rpms speed round as a ball 9 minutes, can form the medicine carrying micropill of uniform particle diameter, according to the cylindrical length of shearing, the micropill particle diameter can be controlled in 0.6 to 1.2 the scope, through preferred control particle diameter at 1.0 ± 0.1mm, placed in the baking oven 40 degrees centigrade of dryings 45 minutes, the micropill of getting the 16-24 mesh sieve carries out the uniformity and water content inspection, qualified after, standby as fine pellet core.
(2) fast release micropill preparation process and technology
Get medicine carrying fine pellet core 56g and put into fluid bed, regulate inlet temperature to 45 degree centigrade, adjust intake at 50m
3About/h, with the Opadry I solution that configures as the contagion gown material) be added to aerochamber atomizing coating, atomizing pressure 2bar with the pump speed of 1.5ml/min with peristaltic pump earlier by end spray, improve gradually that to pump into speed intact to 6ml/min to the coating solution bag, coating continues to make micropill fluidized drying 30min in fluid bed after finishing, and promptly gets fast release micropill.
(3) slowbreak micropill preparation process and technology
Get release pills and place fluidizing fluid-bedly, regulate stream temperature to 45 ℃, dry air flow 50m
3/ h, getting the strange L30D-55 of 166.7 gram enteric solubility film-coat material You Te is added in the 50ml water, in addition Pulvis Talci and triethyl citrate are joined in the aqueous solution of 166ml, with the high-shear homogenate machine in homogenate under the rotating speed of 10000rpm after 5 minutes, both are mixed and stirred 30 minutes, pump into aerochamber atomizing coating (atomizing pressure is 2bar) with peristaltic pump with end spray mode 1.5ml/min afterwards, improve progressively that to pump into speed intact to 7ml/min to the coating solution bag, continuation fluidized drying in fluid bed was taken out in 30 minutes, again after solidifying 10 hours under 45 ℃ of conditions, choose 16-24 mesh sieve piller, checked the character release, promptly got the slowbreak micropill after qualified.
(4) the right methylphenidate slowbreak of hydrochloric acid capsule fill
Fast release micropill and slowbreak micropill are packed into capsule respectively by weight 30: 43 ratio, promptly get hydrochloric acid right side methylphenidate finished capsule product.
Embodiment 3
Prescription
(1) fine pellet core
Microcrystalline Cellulose 49g
The right methylphenidate 5.0g of hydrochloric acid
Polyvidone 0.5g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
20% Opadry MP solution 11.2ml
(3) slowbreak micropill
Fine pellet core 100g
The Aquacoat 33.33ml of 15% solids content
Preparation process and technology:
(1) fine pellet core preparation process and technology
Medicine and filler, disintegrating agent are crushed to certain particle size range, after in stirring mixer, mixing 1 hour behind 80 eye mesh screens, add the hydroxypropyl methylcellulose solution of 44ml, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 degree centigrade, behind the 10min clock soft material is put into the cryogenic high pressure extruder and pass through sieve aperture, sieve aperture is selected the sieve plate of 0.9-1.0mm, extruded velocity is adjusted to 40 rpms, form the cylindrical soft material of moderate length, in spheronizator, with 2000 rpms speed round as a ball 9 minutes, can form the medicine carrying micropill of uniform particle diameter, according to the cylindrical length of shearing, the micropill particle diameter can be controlled in 0.6 to 1.2 the scope, through preferred control particle diameter at 1.0 ± 0.1mm, placed in the baking oven 40 degrees centigrade of dryings 45 minutes, the micropill of getting the 16-24 mesh sieve carries out the uniformity and water content inspection, qualified after, standby as fine pellet core.
(2) fast release micropill preparation process and technology
Get medicine carrying fine pellet core 56g and put into fluid bed, regulate inlet temperature to 45 degree centigrade, adjust intake at 50m
3About/h, Opadry MP aqueous solution with 20% solid content that configures) is added to aerochamber atomizing coating, atomizing pressure 2bar with the pump speed of 1.5ml/min with peristaltic pump earlier by end spray, improve gradually that to pump into speed intact to 6ml/min to the coating solution bag, coating continues to make micropill fluidized drying 30min in fluid bed after finishing, and promptly gets fast release micropill.
(3) slowbreak micropill preparation process and technology
Get release pills and place fluidizing fluid-bedly, regulate stream temperature to 45 ℃, dry air flow 50m
3/ h, other gets enteric solubility film-coat material and adds 90% ethanol and make 15% aqueous dispersion solution, pump into aerochamber atomizing coating (atomizing pressure is 2bar) with peristaltic pump with end spray mode 1.5ml/min, improve progressively that to pump into speed intact to 7ml/min to the coating solution bag, continuation fluidized drying in fluid bed was taken out in 30 minutes, after solidifying 10 hours under 45 ℃ of conditions, chose 16-24 mesh sieve piller again, check the character release, promptly get the slowbreak micropill after qualified.
(4) the right methylphenidate slowbreak of hydrochloric acid capsule fill
Fast release micropill and slowbreak micropill are packed into capsule respectively by weight 40: 43 ratio, promptly get hydrochloric acid right side methylphenidate finished capsule product.
Embodiment 4
Prescription
(1) fine pellet core
Microcrystalline Cellulose 49g
The right methylphenidate 5.0g of hydrochloric acid
Carboxymethyl cellulose 1g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
20% Opadry II 14ml
(3) slowbreak micropill
Fine pellet core 100g
Hydroxypropyl methylcellulose phthalate ester HP-55 15g
Polyethylene glycol 6000 1.5g
80% alcoholic solution 150ml
Preparation process and technology:
(1) fine pellet core preparation process and technology
Medicine and filler, disintegrating agent are crushed to certain particle size range, after in stirring mixer, mixing 1 hour behind 80 eye mesh screens, add the hydroxypropyl methylcellulose solution of 44ml, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 degree centigrade, behind the 10min clock soft material is put into the cryogenic high pressure extruder and pass through sieve aperture, sieve aperture is selected the sieve plate of 0.9-1.0mm, extruded velocity is adjusted to 40 rpms, form the cylindrical soft material of moderate length, in spheronizator, with 2000 rpms speed round as a ball 9 minutes, can form the medicine carrying micropill of uniform particle diameter, according to the cylindrical length of shearing, the micropill particle diameter can be controlled in 0.6 to 1.2 the scope, through preferred control particle diameter at 1.0 ± 0.1mm, placed in the baking oven 40 degrees centigrade of dryings 45 minutes, the micropill of getting the 16-24 mesh sieve carries out the uniformity and water content inspection, qualified after, standby as fine pellet core.
(2) fast release micropill preparation process and technology
Get medicine carrying fine pellet core 56g and put into fluid bed, regulate inlet temperature to 45 degree centigrade, adjust intake at 50m
3About/h, with the 20% Opadry II aqueous solution that configures) be added to aerochamber atomizing coating, atomizing pressure 2bar with the pump speed of 1.5ml/min with peristaltic pump earlier by end spray, improve gradually that to pump into speed intact to 6ml/min to the coating solution bag, coating continues to make micropill fluidized drying 30min in fluid bed after finishing, and promptly gets fast release micropill.
(3) slowbreak micropill preparation process and technology
Get release pills and place fluidizing fluid-bedly, regulate stream temperature to 40 ℃, dry air flow 50m
3/ h, other gets 80% ethanol that 15g enteric solubility hydroxypropyl methylcellulose phthalate ester HP-55 is dissolved in 150ml, add the 1.5g polyethylene glycol 6000 and pump into aerochamber atomizing coating (atomizing pressure is 2bar) with end spray mode 1.5ml/min with peristaltic pump, improve progressively that to pump into speed intact to 7ml/min to the coating solution bag, continuation fluidized drying in fluid bed was taken out in 30 minutes, after solidifying 10 hours under 45 ℃ of conditions, chose 16-24 mesh sieve piller again, check the character release, promptly get the slowbreak micropill after qualified.
(4) the right methylphenidate slowbreak of hydrochloric acid capsule fill
Fast release micropill and slowbreak micropill are packed into capsule respectively by weight 30: 43 ratio, promptly get hydrochloric acid right side methylphenidate finished capsule product.
Experimental example 1:
With prepared micropill among the embodiment 1 is specimen, and the release experimental technique is as follows:
Get this product, according to drug release determination method (Chinese Pharmacopoeia 2005 editions two appendix X D, second method (2)), adopt dissolution method (2005 editions two appendix X C of Chinese Pharmacopoeia, second method) device, with 0.1mol/L hydrochloric acid solution 500ml is solvent, and rotating speed is that per minute 50 changes, operation in accordance with the law, in the time of 2 hours, it is an amount of to get solution, filters, and gets subsequent filtrate as need testing solution (1).Discard acid solution in above-mentioned each container, add the phosphate buffer 500ml that is preheated to 37 ℃ of pH=7.4 immediately, rotating speed is constant, continues operation in accordance with the law, and in the time of 45 minutes, it is an amount of to get solution, filters, and gets subsequent filtrate as need testing solution (2).Adopt high effective liquid chromatography for measuring need testing solution Chinese medicine amount, precision is measured contrast solution and need testing solution, injects chromatograph of liquid respectively, and the record chromatogram calculates different burst sizes constantly by external standard method.
Experimental result is seen description of drawings, and embodiment 2,3,4 is under identical test condition, and experimental result is identical with embodiment 1, all meets the requirements.
Claims (10)
1. two release capsules of the right methylphenidate of a hydrochloric acid, has the performance that discharges medicine for twice, comprise fast release micropill part and slowbreak micropill part, form by the right methylphenidate of hydrochloric acid, filler, disintegrating agent, binding agent, contagion gown material, coating material, plasticizer, porogen.
2. pair release capsule according to claim 1, wherein contained fast release micropill part, the percentage by weight of each component is as follows:
The right methylphenidate 2-30% of hydrochloric acid
Filler 5-95%
Disintegrating agent 0-10%
Binding agent 0.5-15%
Contagion gown material 0-10%.
3. pair release capsule according to claim 1, wherein contained slowbreak micropill part, the percentage by weight of each component is as follows:
The right methylphenidate 2-25% of hydrochloric acid
Binding agent 0.3-10%
Filler 50-88%
Disintegrating agent 0-9%
Contagion gown material 0-9%
Coating material 30-68%
Plasticizer 1-8%
Porogen 1-8%.
4. pair release capsule according to claim 1 is characterized in that:
Described micropill is the matrix type micropill, and main medicine is the right methylphenidate of hydrochloric acid,
The filler of described fast release micropill can be selected one or several in lactose, microcrystalline Cellulose, starch, the dextrin for use,
The disintegrating agent of described fast release micropill can select that carboxymethyl starch is received for use, in the polyvinylpolypyrrolidone, sodium carboxymethyl cellulose, starch slurry one or several,
In the optional water of the binding agent of described fast release micropill, dehydrated alcohol, water and alcohol mixed solution, hydroxypropyl methylcellulose solution, the hydroxypropyl cellulose solution one or several,
The contagion gown material of described fast release micropill can be selected one or several in Opadry I, Opadry II, Opadry MP, hydroxypropyl methylcellulose, ethyl cellulose, the methylcellulose for use,
The filler of described slowbreak micropill can be selected one or more in following adjuvant: lactose, starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, chitosan, dextrin,
The disintegrating agent of institute's slowbreak micropill can select that carboxymethyl starch is received for use, in the polyvinylpolypyrrolidone, sodium carboxymethyl cellulose, starch slurry one or several,
In the optional water of the binding agent of described fast release micropill, dehydrated alcohol, water and alcohol mixed solution, hydroxypropyl methylcellulose solution, the hydroxypropyl cellulose solution one or several,
The contagion gown material of described slowbreak micropill can be selected one or several in Opadry, Opadry MP, hypromellose, the polyvinyl alcohol for use,
The enteric material of described slowbreak micropill can be selected one or several in ethyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, methacrylic resin, hydroxypropyl methylcellulose phthalate ester, the palm wax for use,
Described slowbreak micropill plasticizer can be selected diethyl phthalate, dibutyl phthalate, dibutyl sebacate tristerin, triethyl citrate, tributyl citrate, diethyl succinate, fractionated coconut oil for use,
Described slowbreak micropill porogen can be selected one or several in Polyethylene Glycol, Pulvis Talci, hydroxypropyl methylcellulose, the polyvidone for use.
5. pair release capsule according to claim 1, wherein the effective dose of the right methylphenidate of hydrochloric acid is between 5-40mg, be preferably 5-20mg,, have close or identical body giving drugs into nose for dynamic characteristic during different size correspondence different crowd to adapt to different weight crowd's use.
6. pair release capsule according to claim 1, wherein the shared part by weight of fast release micropill is at 30-60%, and the part by weight of slowbreak micropill is at 40-60%.
7. pair release capsule according to claim 1,, it is characterized in that: the mass ratio of contained fast release micropill and slowbreak micropill is between 3: 1 to 1: 3 in the capsule, and the preferred mass ratio is: 358: 431.
8. pair release capsule according to claim 1 is characterized in that, and is composed as follows:
(1) fine pellet core
Microcrystalline Cellulose 49g
The right methylphenidate 5.0g of hydrochloric acid
Carboxymethyl cellulose 1g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
6% hydroxypropyl methylcellulose solution 11.2ml
(3) slowbreak micropill
Fine pellet core 100g
The Aquacoat 33.3ml of 15% solids content
Dibutyl phthalate 0.2g
Pulvis Talci 1.6g.
9. pair release capsule according to claim 1 is characterized in that, and is composed as follows:
(1) fine pellet core
Microcrystalline Cellulose 49g
Polyvinylpolypyrrolidone 0.9g
2% hydroxypropyl methylcellulose solution 44ml
(2) fast release micropill
Fine pellet core 56g
20% Opadry I aqueous solution 11.2ml
(3) slowbreak micropill
Fine pellet core 250g
You Teqi L30D-55 166.7g
Triethyl citrate 12.5g
Pulvis Talci 12.5g
Water 216ml.
10. the preparation method of described pair of release capsule of claim 1, it is characterized in that, comprise step: with medicine and filler, disintegrating agent is crushed to certain particle size range, by behind 80 to 100 eye mesh screens in stirring mixer behind the mix homogeneously, add binding agent, make soft material, the medicine carrying micropill that spheronization makes uniform particle diameter is extruded in employing, cylindrical length according to extruding formation, the micropill particle diameter can be controlled in 0.6 to 1.2mm the scope, through preferably controlling particle diameter at 1.0 ± 0.1mm, preferred coating material is adopted fluidized bed coating or coating pan coating, the clothing membrane material is injected in the fluid bed after atomizing under a suitable pressure, and at a certain temperature, coating material forms the clothing film and is attached on the micropill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201010283316 CN101933913A (en) | 2010-09-16 | 2010-09-16 | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010283316 CN101933913A (en) | 2010-09-16 | 2010-09-16 | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof |
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| CN101933913A true CN101933913A (en) | 2011-01-05 |
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| CN 201010283316 Pending CN101933913A (en) | 2010-09-16 | 2010-09-16 | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof |
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| CN102579408A (en) * | 2012-03-19 | 2012-07-18 | 河南中帅医药科技发展有限公司 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
| CN104744342A (en) * | 2015-02-11 | 2015-07-01 | 河南中帅医药科技股份有限公司 | Dexmethylphenidate hydrochloride crystal form and preparation method thereof |
| CN105025883A (en) * | 2013-03-29 | 2015-11-04 | 沃克哈特有限公司 | Modified release pharmaceutical compositions of dexmethylphenidate or salts thereof |
| CN111557929A (en) * | 2020-05-15 | 2020-08-21 | 河南中帅医药科技股份有限公司 | Dexmethylphenidate hydrochloride multiple-release preparation and preparation method thereof |
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| US6344215B1 (en) * | 2000-10-27 | 2002-02-05 | Eurand America, Inc. | Methylphenidate modified release formulations |
| CN1335768A (en) * | 1998-11-02 | 2002-02-13 | 马拉·J·丘奇 | Multiparticulate modified release composition |
| CN101375869A (en) * | 2008-10-10 | 2009-03-04 | 中国药科大学 | Slow/controlled release pellet composition containing ginkgo leaf extracts and preparation method thereof |
| CN101756938A (en) * | 2010-02-09 | 2010-06-30 | 山东新时代药业有限公司 | Ketorolac tromethamine capsule and preparation method thereof |
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| CN1335768A (en) * | 1998-11-02 | 2002-02-13 | 马拉·J·丘奇 | Multiparticulate modified release composition |
| US6344215B1 (en) * | 2000-10-27 | 2002-02-05 | Eurand America, Inc. | Methylphenidate modified release formulations |
| CN101375869A (en) * | 2008-10-10 | 2009-03-04 | 中国药科大学 | Slow/controlled release pellet composition containing ginkgo leaf extracts and preparation method thereof |
| CN101756938A (en) * | 2010-02-09 | 2010-06-30 | 山东新时代药业有限公司 | Ketorolac tromethamine capsule and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102579408A (en) * | 2012-03-19 | 2012-07-18 | 河南中帅医药科技发展有限公司 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
| CN102579408B (en) * | 2012-03-19 | 2013-06-05 | 河南中帅医药科技发展有限公司 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
| CN105025883A (en) * | 2013-03-29 | 2015-11-04 | 沃克哈特有限公司 | Modified release pharmaceutical compositions of dexmethylphenidate or salts thereof |
| CN104744342A (en) * | 2015-02-11 | 2015-07-01 | 河南中帅医药科技股份有限公司 | Dexmethylphenidate hydrochloride crystal form and preparation method thereof |
| CN111557929A (en) * | 2020-05-15 | 2020-08-21 | 河南中帅医药科技股份有限公司 | Dexmethylphenidate hydrochloride multiple-release preparation and preparation method thereof |
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Application publication date: 20110105 |