CN104490801A - Crushable tablet for infants and children and preparation method thereof - Google Patents
Crushable tablet for infants and children and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an oseltamivir crushable tablet for treating infant and children influenza. The oseltamivir crushable tablet comprises, by weight, 10-50% of taste-masking pellets, 20-80% of a filler, 1-10% of a water-soluble polymer, 1-8% of a disintegrating agent, 0-6% of a flavouring agent and 0.5-2.5% of a lubricant. The taste-masking pellet comprises a drug-carrying pellet core and a coating. A drug in the drug-carrying pellet core is oseltamivir or its pharmaceutically acceptable salt, and the weight of the drug is 10-50% the total weight of the taste-masking pellet. The coating is polyacrylic resin IV and the weight of the coating is 5-50% the total weight of the taste-masking pellet.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical field about pharmaceutical preparation, specifically, relating to a kind of take Oseltamivir as the crushed sheet being applicable to infant and child and the preparation method of principal agent.
Technical background
Oseltamivir (Oseltamivir) is as a kind of neuraminidase inhibitor of up-to-date development, be widely used in clinical, its chemistry (3R by name, 4R, 5S)-4-acetamide-5-amino-3 (1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, structural formula is as follows:
Oseltamivir can act on influenza surface glycoprotein-neuraminidase (NA), thus suppresses virus replication and the propagation in respiratory tract, is a kind of high selectivity influenza virus NA inhibitor.Oseltamivir went on the market in 1999 in Switzerland, a large amount of clinical practices after listing confirm that Oseltamivirs have and A, Type B influenza virus had to effect, not easily drug resistance and patient tolerability are good, safety advantages of higher, being the medication of one very safe and effective influenza prevention and therapy, is also anti-avian influenza virus, the most effective medicine of influenza A H1N1 influenza virus of generally acknowledging in the world at present.Only ratify during Oseltamivir in 1999 listing for being grown up A type and with the treatment of influenza B.Through after long-term clinical practice, in December, 2012, through FDA approval, Oseltamivir can be used for infant and child's use in more than 2 weeks age.AAP, WHO unanimously recommend the neonate of just birth to get final product medication.
The recommended drug dosage of table 1 oseltamivir phosphate capsule baby within 1 years old
Note:
FDA-label:
fDA description, 2012.12 revisions
AAP: department of pediatrics association of the U.S., Recommendations for Prevention and Control of Influenza in Children, 2012-2013,2012.9.10, be published in U.S.'s department of pediatrics association website
WHO: World Health Organization (WHO), WHO Guidelines for Pharmacological Management of Pandemic Influenza A (H1N1) 2009and other Influenza Viruses, 2010.4 revisions
Medscape: from Medscape website,
oseltamivir– Tamiflu, 2013.3 revisions
Can crush sheet (Crushable Tablets) is the tablet swallowed after a kind of can crushing, said preparation is easily crushed to broken end, stable in properties, take after can crushing, be the dosage form (see World Health Organization (WHO) child essential drugs standard schedule) of children taking that a kind of WHO recommends, rear surface is long-pending increases through chewing or crushing in vitro for tablet, can promote medicine dissolving in vivo and absorption, side effect is simultaneously relatively low, especially will greatly alleviate the stimulation of stomach.Its taking convenience, both can swallow by conventional tablet, takes, also can not need to take medicine (chew in the oral cavity or suck after clothes make sheet dissolve and swallow) with water swallow after can be placed on again in water dispersion, more can crush after take; Simultaneously, tablet is through chewing or crush the long-pending increase in rear surface, medicine dissolving in vivo and absorption can be promoted, even if also can ensure to take medicine on time under exsiccosis, be particularly useful for old man, children's, some especial patients (psychosis, senile dementia, epileptic patient etc.) and the inconvenient person that fetches water to take medicine and provide conveniently, also can reduce medicine and gastrointestinal is born.Certain method can be adopted in the preparation to improve the mouthfeel of preparation simultaneously, greatly can improve the drug compliance of child patient, solve the problem of taking baby ' difficulty.But sheet can be crushed and usually there is following shortcoming: the sensory issues of medicine, as the difficult problem such as sand type, bitterness; The problem such as the grit that the crushibility of tablet is poor, large, external rate of dispersion are slow.
The Oseltamivir gone on the market now is conventional capsule agent, need swallow or send water to swallow, but infant and child can not or be reluctant independently to complete swallowing act, and do not understand the necessity for the treatment of, simultaneously because Oseltamivir has very strong bitterness, often mismatch treatment, the treatment for disease brings very large difficulty.Therefore, improve the compliance of patient, this for infant and child particularly important.General need add a large amount of sweeting agents to cover the bitterness of medicine, even if but insert a large amount of sweeting agent human body sensories and start sweet but feel bitter subsequently, main cause is that the sensitive part of human body sensory bitterness is the root of the tongue, and the root of the tongue is very strong to the sensitivity of bitterness, take correctives to be in a large number harmful to health, this point is even more important for infant and children preparation simultaneously.Therefore, Many researchers is had to adopt technique for packing such as physical-chemical process to prepare pastille microcapsule, Physical such as fluidized bed coating prepares micropill or granule, spray drying method prepares pastille microcapsule and microsphere, the granule preparing bitter drug carrys out taste masking, and in these methods, physicochemical method is applied more in experimentation, but it can not entrapped drug completely, still can produce certain poor taste, and producing feasibility is poor; The large production of physical method is comparatively feasible, but the grain diameter that fluid bed obtains is larger; The obtained particle diameter of spray-dired method is less, but drug loading and envelop rate lower.The dosage forms such as the Oseltamivir conventional capsule agent of having gone on the market now, specification is 30mg, 45mg and 70mg, but the computational methods of the dosage that department of pediatrics is commonly used are for calculating by pedobarometer, the dosage of the infant that AAP, WHO etc. unanimously recommend and child is also 3mg/kg (see table 1); Like this when giving children, the dosage form of listing usually needs to be divided into some parts again, divides during medicine and not only can cause medicine pollution, can not ensure dose exactly, and may affect the effect of medicine after separating.So, when selecting infant and children, selecting the dosage strengths being applicable to child's application as far as possible, and being convenient to applicable divided dose administration.
For addressing this problem, we have employed new prescription, new technology and new spec take Oseltamivir as principal agent, ensureing under the prerequisite playing drug effect and safety, prepare the crushed sheet that is applicable to infant and child and further optimization has been carried out to prescription and technique, the solid grain size prepared of the method is less and can cover bitterness again, said preparation is taken after can crushing, also can chew in the oral cavity or suck after sheet is dissolved and swallow, also can be oral after aqueous dispersion, also can swallow by conventional tablet; Said preparation mouthfeel is good, and without grittiness, light pressure can form superfine powdery granule, is convenient to take, also just can enters stomach onset by simply chewing or sucking rear swallowing act, greatly comply with the feature of taking medicine of infant and child; Meanwhile, devise according to the dosage of infant and child the dosage strengths being convenient to apply, and adopt many deciles scored tablet to design, farthest can ensure the accuracy of divided dose administration.The present invention adopts and a kind ofly can meet industrialized technology and prepare tasteless Oseltamivir micropill, add tabletting after other adjuvant, be prepared from the feature of taking medicine of both having complied with infant and child and tablet pressure can reach more than 40N be conducive to pack and the preparation of transport, the preparation method of said preparation is simple, drug substance stable good, repeatability is high, be easy to large-scale production.
Summary of the invention
The object of the present invention is to provide a kind of take Oseltamivir as the crushed sheet of active component, it is good that this can crush sheet mouthfeel, without grittiness, light pressure can form superfine powdery granule, be convenient to take, also just can enter stomach onset by simply chewing or sucking rear swallowing act, greatly comply with the pathological characteristic of infant and child, for the prevention and therapy of child especially infant influenza.
It take Oseltamivir as the crushed piece preparation method of active component that another object of the present invention is to provide a kind of, this preparation method can meet the requirement of industrialized great production, the crushed sheet pressure preparing gained can reach being conducive to packaging and transporting of more than 40N, meanwhile, this preparation method is simple, drug substance stable good, repeatability is high, be easy to large-scale production.
Oseltamivir of the present invention can crush sheet, the percentage by weight of each component is as follows: the odor-masking pellet of 10 ~ 50%, the filler of 20 ~ 80%, 1 ~ 10% water-soluble polymer, the disintegrating agent of 1 ~ 8%, the correctives of 0 ~ 6% and 0.5 ~ 2.5% lubricant, each weight percentages of components sum is 100%; Wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, and the medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, and it accounts for the 10%-50% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 5%-50% of micropill gross weight.
Oseltamivir of the present invention can crush sheet, described odor-masking pellet particle diameter 0.10-0.50mm, and preferred particle diameter is 0.15-0.35mm;
Oseltamivir of the present invention refers to Oseltamivir or its derivant, free alkali or salt, is preferably oseltamivir phosphate.
Described filler is selected from: one or more in mannitol, xylitol, erythritol, sucrose, fructose, glucose, maltose, glycine, sorbitol, microcrystalline Cellulose, lactose;
Described water-soluble polymer is selected from: one or more in hypromellose, xanthan gum, sodium alginate, hydroxyethyl-cellulose, arabic gum, polyacrylic acid resin, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol, sodium carboxymethyl cellulose;
Described disintegrating agent is selected from: carboxymethyl starch is received, one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium;
Described correctives is selected from: one or more of the essence and flavoring agent of aspartame, acesulfame potassium, saccharin sodium, glucosan, acesulfame-K, stevioside, citric acid, various fragrance;
Described lubricant is selected from: Pulvis Talci, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, stearyl alcohol, stearic one or more.
Preferably, Oseltamivir of the present invention can crush sheet, and described filler is mannitol and/or microcrystalline Cellulose and/or erythritol; Described water-soluble polymer is polyvidone and/or xanthan gum; Described disintegrating agent is polyvinylpolypyrrolidone and/or cross-linking sodium carboxymethyl cellulose; Described correctives is aspartame and/or citric acid and/or grape essence; Described lubricant is sodium stearyl fumarate and/or magnesium stearate.
Preferably, Oseltamivir of the present invention can crush sheet, and the percentage by weight of each component is as follows: the odor-masking pellet of 15 ~ 45% particle diameter 0.15-0.35mm; 30 ~ 80% mannitol and/or microcrystalline Cellulose and/or erythritol; 3 ~ 8% polyvidones and/or xanthan gum; 2 ~ 6% polyvinylpolypyrrolidone and/or cross-linking sodium carboxymethyl cellulose; 2 ~ 5% aspartames and/or citric acid and/or grape essence; 0.5 ~ 1.5% sodium stearyl fumarate and/or magnesium stearate; Wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, and the medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, and it accounts for the 15%-40% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 5%-40% of micropill gross weight.
Preferred further, Oseltamivir of the present invention can crush sheet, and the percentage by weight of each component is as follows: the odor-masking pellet of 30 ~ 40% particle diameter 0.15-0.35mm; 30 ~ 40% mannitol; 8 ~ 15% microcrystalline Cellulose; 4 ~ 6% xanthan gum; 3 ~ 5% cross-linking sodium carboxymethyl celluloses; 2 ~ 3% aspartames; 0.5 ~ 1% citric acid; 0.5 ~ 1% flavoring orange essence; 1.0 ~ 1.5% magnesium stearate; Wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, and the medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, and it accounts for the 15%-30% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 10%-25% of micropill gross weight.
Further preferred, Oseltamivir of the present invention can crush sheet, and the content of each component is as follows:
Oseltamivir odor-masking pellet 193.3g, mannitol 200.0g, microcrystalline Cellulose 60.0g, xanthan gum 30.0g, cross-linking sodium carboxymethyl cellulose 20.0g, aspartame 14.0g, citric acid 3.0g, flavoring orange essence 3.0g, magnesium stearate 6.0g.
Described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, medicine carrying fine pellet core is made up of Oseltamivir and starch, coatings material therefor is polyacrylic resin IV, the percentage ratio that each component accounts for odor-masking pellet gross weight is as follows: Oseltamivir 300g, starch 300g, polyacrylic resin IV 160g.
The present invention also provides Oseltamivir can crush the preparation method of sheet, comprises the following steps:
A. seed-coating machine is adopted to be prepared into medicine carrying fine pellet core after being pulverized by Oseltamivir, then a certain proportion of polyacrylic resin IV is added in alcoholic solution, adopt fluidized bed coating or coating pan coating to form taste mask layer and be attached to above-mentioned medicine carrying fine pellet core, obtain odor-masking pellet, for subsequent use;
B. the odor-masking pellet of above-mentioned preparation and filler, water-soluble polymer, correctives, disintegrating agent, mix lubricant are even, tabletting.
Wherein, described Oseltamivir medicine carrying fine pellet core, prepares in accordance with the following methods: get starch and Oseltamivir puts into centrifugal coating pan, adds appropriate ethanol coating, obtain medicine carrying fine pellet core.
Preferably, preparation method of the present invention, comprises the following steps:
(1) Oseltamivir odor-masking pellet preparation process
Supplementary material needed for it was all pulverized 100 eye mesh screens, got starch 300.0g and Oseltamivir 300.0g puts into centrifugal coating pan, and 75% ethanol was added to coating in centrifugal coating pan, obtains medicine carrying fine pellet core,
Take polyacrylic resin IV 160g, add 90% alcoholic solution 1440ml and be dissolved to clarification, make coating solution, for subsequent use.Get medicine carrying fine pellet core 480.0g and put into centrifugal coating pan coating, obtain Oseltamivir odor-masking pellet,
(2) Oseltamivir can crush sheet preparation process
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 193.3g, mannitol 200.0g, microcrystalline Cellulose 60.0g, xanthan gum 30.0g, cross-linking sodium carboxymethyl cellulose 20.0g, aspartame 14.0g, citric acid 3.0g, flavoring orange essence 3.0g, magnesium stearate 6.0g.
Preparation process: take above-mentioned material according to prescription and pour in trough type mixing machine and mix, mixed material is poured in tablet machine hopper, and tabletting, to obtain final product.
Oseltamivir of the present invention can crush sheet, has the indentation of 4 ~ 12 deciles above obtained crushed sheet, is preferably the indentation of 6 ~ 12 deciles.Oseltamivir of the present invention can crush sheet, and wherein the effective dose of Oseltamivir is between 5-50mg, is preferably 10-30mg.
Positive beneficial effect of the present invention:
1, the Oseltamivir that prepared by technical solution of the present invention can crush sheet taking convenience, both can swallow by conventional tablet, can be placed on again in water and take after dispersion, also can not need to take medicine (chew in the oral cavity or suck after clothes make sheet dissolve and swallow) with water swallow, take after more can crushing; Simultaneously, tablet is through chewing or crush the long-pending increase in rear surface, medicine dissolving in vivo and absorption can be promoted, even if also can ensure to take medicine on time under exsiccosis, be particularly useful for old man, children's, some especial patients (psychosis, senile dementia, epileptic patient etc.) and the inconvenient person that fetches water to take medicine and provide conveniently, also can reduce medicine and gastrointestinal is born.It is good that this can crush sheet crushibility, and light pressure can form superfine powdery granule, without large grit, is convenient to take, and after mixing, mouthfeel is good, without medicine sense; After taking, because it disperses that rear surface is long-pending to increase in vitro, can promote medicine dissolving in vivo and absorption, side effect is simultaneously relatively low, especially will greatly alleviate the stimulation of stomach.
2, the Oseltamivir utilizing technical solution of the present invention to prepare can crush sheet taking convenience, has no side effect, and mouthfeel is good, without grittiness, be convenient to patient's long-term treatment, significantly improve the compliance of infant and children, be applicable to the prevention and therapy of child's especially infant influenza.Simultaneously, according to infant and the feature in child age stage and the character of medicine, devise the medicine preparation and specification that are applicable to infant and child, pollution when reducing point medicine and waste, adopt many deciles scored tablet to design simultaneously, farthest can ensure that divided dose is accurate, drastically increase the compliance of infant and children.
3, the Oseltamivir that prepared by technical solution of the present invention can crush sheet and have for obvious improving SNR of abnormal flavour such as Oseltamivir bitterness, it improves mouthfeel principle and is mainly the micropill taste masking and taste masking technology that use time prepared by the present invention, selected adjuvant and preparation method are all easy to get feasible, be suitable for expanding suitability for industrialized production, the method adopted has good repeatability.The particularly preferred formula of the present invention and preparation method, be through the preferred plan that screening obtains, select the prescription of optimization, adopt coating of pellets method, and compression produces can crush sheet, can realize crushing the obvious mouthfeel of sheet and improve effect, and the crushed sheet simultaneously preparing different size adapts to the infant of different weight and the needs of child.
4, technical solution of the present invention prepare Oseltamivir can crush the effective dose of sheet between 5 ~ 50mg, there is multiple different specification, the medication object of the corresponding different weight of different size, when dose level is at 1.0 ~ 4.0mg/kg, it is identical that experiment in vivo shows that the Oseltamivir of different size can crush the parameters of the Internal pharmacokinetics of sheet, meets the demand of sufferer treatment to blood drug level.Evaluation is investigated by the mode such as sheet dissolution and disintegration time measuring, ocular estimate, the evaluation of volunteer mouthfeel can be crushed, find that Oseltamivir provided by the invention can crush sheet not only rapid, the rapid-action and good mouthfeel of stripping, greatly comply with the pathological characteristic of infant and child, simultaneously, this can crush sheet in vitro under multiple condition release consistent with the capsule that goes on the market, in body, pharmacokinetic shows, with the capsule that goes on the market, there is bioavailability equivalence, do not produce the problem reducing bioavailability because of taste masking and flavored action.
5, technical solution of the present invention prepare Oseltamivir can crush sheet, preparation process is simple for process, adopt coating of pellets method and tablet forming technique, productive rate reaches more than 90%, and product effect is high, meets large requirement of producing, under laboratory scale, the amplification that can complete 10000 ~ 30000 units is produced, and production efficiency is high, and the Oseltamivir can preparing 5 ~ 50mg different size can crush sheet; Meanwhile, this technique prepares the crushed sheet of gained, and not only stripping is rapid, rapid-action, and hardness can reach more than 40N be conducive to pack, the carrying of transport and patient.
6, product Oseltamivir of the present invention can crush sheet, investigates through accelerated stability test, and in 12 months, character stable, medicament contg, related substance is all in controlled range, and suitability for industrialized is produced.
The present invention crushes compared with sheet with existing, has taking convenience, has no side effect, mouthfeel is good, without features such as grittiness, is convenient to patient's long-term treatment, significantly improve the compliance of infant and children, be applicable to the prevention and therapy of child's especially infant influenza.
Technological improvement part of the present invention is, adopt coating of pellets method, compression produces can crush sheet, and the mouthfeel realizing crushing sheet is improved, and the crushed sheet simultaneously preparing different size adapts to the infant of different weight and the needs of child.
Detailed description of the invention
Be below the specific embodiment of the present invention, embodiment is for further describing the present invention instead of restriction the present invention.The technical scheme of equivalence all and of the present invention all belongs in protection scope of the present invention.
Embodiment 1 Oseltamivir can crush sheet and preparation method thereof
First prepare Oseltamivir odor-masking pellet, then obtain tablet according to prescription preparation tabletting, obtain Oseltamivir and can crush sheet.
(1) Oseltamivir odor-masking pellet preparation process
Supplementary material needed for it is all pulverized 100 eye mesh screens, got starch 300.0g and Oseltamivir 300.0g puts into centrifugal coating pan, regulate centrifugal coating pan temperature to 45 DEG C, adjustment intake 65m
3* h
-175% (mass ratio) ethanol 600.0g peristaltic pump is added to coating in centrifugal coating pan with the flow velocity of 3ml/min, atomizing pressure is 1.0bar, improve feed flow speed gradually to 6ml/min, until binder solution has sprayed, after coating terminates, continue, at centrifugal coating pan inner drying 30min, to obtain medicine carrying fine pellet core.
Take polyacrylic resin IV 160g, add 90% alcoholic solution 1440ml and be dissolved to clarification, make coating solution, for subsequent use.Get medicine carrying fine pellet core 480.0g and put into centrifugal coating pan, regulate centrifugal coating pan temperature to 40 DEG C, adjustment intake 70m
3* h
-1the taste masking coating solution peristaltic pump prepared is added to coating in centrifugal coating pan with the flow velocity of 2ml/min, atomizing pressure is 1.4bar, improve feed flow speed gradually to 6ml/min, until binder solution has sprayed, after coating terminates, improve stream temperature to 45 DEG C, continue fluidized drying in centrifugal coating pan to take out after 30 minutes, choose micropill between particle diameter 0.10 ~ 0.25mm, after passed examination, be Oseltamivir odor-masking pellet.
(2) Oseltamivir can crush sheet preparation process
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 193.3g, mannitol 200.0g, microcrystalline Cellulose 60.0g, xanthan gum 30.0g, cross-linking sodium carboxymethyl cellulose 20.0g, aspartame 14.0g, citric acid 3.0g, flavoring orange essence 3.0g, magnesium stearate 6.0g.
Preparation process: take above-mentioned material according to prescription and pour in trough type mixing machine and mix 45min, mixed material is poured in tablet machine hopper, 6 equal portions indentation punch dies loaded onto by tablet machine, adjustment sheet weighs and pressure, make press tablet hardness remains on 35 ~ 45N,, tabletting, obtains Oseltamivir and can crush sheet.Every batch of detection level uniformity and dissolution, in qualified rear loading lucifuge hermetic container, get product.
Illustrate: the purified water that the present embodiment adds and ethanol are through preparation method, and final drying obtains product, its purified water added and ethanol all evaporate;
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir odor-masking pellet 36.5%, filler mannitol 37.8%, filler microcrystalline Cellulose 11.3%, water-soluble polymer xanthan gum 5.7%, disintegrating agent cross-linking sodium carboxymethyl cellulose 3.8%, correctives aspartame 2.6%, correctives citric acid 0.6%, correctives flavoring orange essence 0.6%, magnesium stearate lubricant 1.1%.
Embodiment 2 Oseltamivir can crush sheet and preparation method thereof
Substantially the same manner as Example 1, difference is:
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 257.7g, erythritol 395.6g, microcrystalline Cellulose 118.7g, polyvidone 70.0g, polyvinylpolypyrrolidone 25.0g, aspartame 36.0g, sodium stearyl fumarate 11.0g.
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir odor-masking pellet 28.2%, filler erythritol 43.3%, filler microcrystalline Cellulose 13.0%, water-soluble polymer polyvidone 7.7%, disintegrating agent polyvinylpolypyrrolidone 2.7%, correctives aspartame 3.9%, lubricant stearic acid fumaric acid sodium 1.2%.
Embodiment 3 Oseltamivir can crush sheet and preparation method thereof
Substantially the same manner as Example 1, difference is:
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 386.6g, mannitol 361.4g, xanthan gum 60.0g, cross-linking sodium carboxymethyl cellulose 51.2g, aspartame 24.4g, citric acid 6.4g, magnesium stearate 7.2g.
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir odor-masking pellet 43.1%, filler mannitol 40.3%, water-soluble polymer xanthan gum 6.7%, disintegrating agent low-substituted hydroxypropyl cellulose 5.7%, correctives aspartame 2.7%, correctives citric acid 0.7%, magnesium stearate lubricant 0.8%.
Embodiment 4 Oseltamivir can crush sheet and preparation method thereof
Substantially the same manner as Example 1, difference is:
Can crush sheet prescription: Oseltamivir odor-masking pellet 128.8g, xylitol 390.4g, sodium alginate 14.8g, carboxymethyl starch receives 14.8g, hydrogenated vegetable oil 11.2g.
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir odor-masking pellet 23.1%, filler xylitol 69.7%, water-soluble polymer sodium alginate 2.6%, disintegrating agent carboxymethyl base starch receives 2.6%, lubricant hydrogenated vegetable oil 2.0%.
Embodiment 5 oseltamivir phosphate can crush sheet and preparation method thereof
First prepare oseltamivir phosphate odor-masking pellet, then obtain tablet according to prescription preparation tabletting, obtain oseltamivir phosphate and can crush sheet.
(1) oseltamivir phosphate odor-masking pellet preparation process
Supplementary material needed for it is all pulverized 100 eye mesh screens, got starch 200.0g and oseltamivir phosphate 100.0g puts into centrifugal coating pan, regulate centrifugal coating pan temperature to 45 DEG C, adjustment intake 65m
3* h
-185% (mass ratio) ethanol 300.0g peristaltic pump is added to coating in centrifugal coating pan with the flow velocity of 3ml/min, atomizing pressure is 1.0bar, improve feed flow speed gradually to 6ml/min, until binder solution has sprayed, after coating terminates, continue, at centrifugal coating pan inner drying 30min, to obtain medicine carrying fine pellet core.
Take polyacrylic resin IV 100g, add 90% alcoholic solution 900ml and be dissolved to clarification, make coating solution, for subsequent use.Get medicine carrying fine pellet core 240.0g and put into centrifugal coating pan, regulate centrifugal coating pan temperature to 40 DEG C, adjustment intake 70m
3* h
-1the taste masking coating solution peristaltic pump prepared is added to coating in centrifugal coating pan with the flow velocity of 2ml/min, atomizing pressure is 1.4bar, improve feed flow speed gradually to 6ml/min, until binder solution has sprayed, after coating terminates, improve stream temperature to 45 DEG C, continue fluidized drying in centrifugal coating pan to take out after 30 minutes, choose micropill between particle diameter 0.10 ~ 0.25mm, after passed examination, be oseltamivir phosphate odor-masking pellet.
(2) oseltamivir phosphate can crush sheet preparation process
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 116.0g, erythritol 111.4g, microcrystalline Cellulose 33.4g, polyvidone 14.4g, cross-linking sodium carboxymethyl cellulose 11.6g, citric acid 2.5g, aspartame 7.1g, magnesium stearate 3.6g.
Preparation process: take above-mentioned material according to prescription and pour in trough type mixing machine and mix 45min, mixed material is poured in tablet machine hopper, 8 equal portions indentation punch dies loaded onto by tablet machine, adjustment sheet weighs and pressure, make press tablet hardness remains on 35 ~ 45N,, tabletting, obtains oseltamivir phosphate and can crush sheet.Every batch of detection level uniformity and dissolution, in qualified rear loading lucifuge hermetic container, get product
Illustrate: the purified water that the present embodiment adds and ethanol are through preparation method, and final drying obtains product, its purified water added and ethanol all evaporate;
Through adjusting, in this example, oseltamivir phosphate can crush the percentage by weight of each component in sheet and is:
Oseltamivir phosphate odor-masking pellet 38.7%, filler erythritol 37.1%, filler microcrystalline Cellulose 11.1%, water-soluble polymer polyvidone 4.8%, disintegrating agent cross-linking sodium carboxymethyl cellulose 3.9%, correctives citric acid 0.8%, correctives aspartame 2.4%, magnesium stearate lubricant 1.2%.
Embodiment 6 Oseltamivir can crush sheet and preparation method thereof
Substantially the same manner as Example 5, difference is:
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 135.3g, xylitol 181.7g, hydroxypropyl cellulose 18.2g, low-substituted hydroxypropyl cellulose 14.6g, acesulfame-K 10.2g, magnesium stearate 4.8g.
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir phosphate odor-masking pellet 37.1%, filler xylitol 49.8%, water-soluble polymer hydroxypropyl cellulose 5.0%, disintegrating agent low-substituted hydroxypropyl cellulose 4.0%, correctives acesulfame-K 2.8%, magnesium stearate lubricant 1.3%.
Embodiment 7 Oseltamivir can crush sheet and preparation method thereof
Substantially the same manner as Example 5, difference is:
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 116.0g, xylitol 60.0g, mannitol 160.0g, xanthan gum 36.6g, carboxymethylcellulose calcium 20.0g, stevioside 2.0g, orange flavor 1.3g, stearic acid 4.1g.
Through adjusting, in this example, Oseltamivir can crush the percentage by weight of each component in sheet and is:
Oseltamivir phosphate odor-masking pellet 29.0%, filler xylitol 15.0%, filler mannitol 40.0%, water-soluble polymer xanthan gum 9.2%, disintegrating agent carboxymethyl base cellulose calcium 5.0%, correctives stevioside 0.5%, correctives orange flavor 0.3%, lubricant stearic acid 1.0%.
Test example 1 gained can crush the physical and chemical property determining of sheet
Friability sample thief is some, its gross weight is made to be about 10.0g, the powder come off is blown away with hair-dryer, precise weighing, put in cylinder, rotate 100 times, test according to Chinese Pharmacopoeia version in 2010 two annex X G tablet friability inspection techniques, less loss weight must not more than 1.0%, and the sheet that must not detect fracture, be full of cracks and pulverize.
Hardness sample thief 6, keeps flat respectively and puts into the hardness that hardness analyzer measures each sample, average.
Dissolution determination gets this product, with reference to the dissolution determination method about oseltamivir in USP36, adopt dissolution second subtraction unit, with 0.1mol/L aqueous hydrochloric acid solution 500ml for release medium, rotating speed is 50 turns per minute, operate in accordance with the law, when 5,10 and 20min, get solution 10ml respectively, filter with 0.45 μm of filter membrane, and immediately add above-mentioned dissolution medium 10ml, get subsequent filtrate as need testing solution; Another precision takes Oseltamivir reference substance, adds release medium appropriate, and heating makes dissolving and the solution product solution in contrast about containing 20 μ g in every 1ml is made in dilution.Get test sample and reference substance solution, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV A), measure absorbance respectively at the wavelength place of 240nm, calculate not stripping quantity in the same time.
Measurement result sees the following form:
Table 2 can crush the physical and chemical property determining result of sheet
The summary analysis that can be crushed the aspect such as friability, hardness, dissolution of sheet by the Oseltamivir obtained each embodiment is bright, it is rapid that the Oseltamivir that the present invention obtains can crush sheet In Vitro Dissolution, 10min all stripping can be greater than 80%, can onset in time, and packed and transported etc. can be stood shake the impact given, complied with the compliance of infant and child, and preparation technology is applicable to industrialized requirement.
Test example 2 investigates the impact of the present composition on pigeon nausea model
1, laboratory animal: healthy pigeon, male and female dual-purpose, body weight 350 ± 50g, regular grade, is purchased from cultivation base.
2, Experimental agents and dosage:
Healthy pigeon 70, is divided into 7 groups at random.Experiment prospective adaptation is raised 1 week, normal diet drinking-water between feeding period, fasting 4h before experiment, and room temperature keeps 22 ~ 24 DEG C, keeps clean, well-ventilated.Respectively by each reagent group administration below, dosage is all same as 30mg Oseltamivir/kg the weight of animals, or the starch of the amount identical with it (blank).Each index of close observation, water inlet of normally taking food after 8h.
(1) test group 1-3,3 groups, the Oseltamivir being respectively embodiment 1,2 and 3 can crush sheet, and dosage is 30mg Oseltamivir/kg the weight of animals.
(2) control group A, 1 group, Oseltamivir crude drug, dosage is 30mg Oseltamivir/kg the weight of animals.
(3) matched group B, 1 group, starch, dosage is 30mg starch/kg the weight of animals.
(4) matched group C, 1 group, form by supplementary material each in embodiment 1 physical mixture be mixed to get, dosage is 30mg Oseltamivir/kg the weight of animals.
(5) matched group D, 1 group, commercially available oseltamivir phosphate capsule, manufacturer's Roche, dosage is 30mg Oseltamivir/kg the weight of animals.
3, experimental technique:
Observation index: vomiting incubation period (time of first time vomiting extremely occurs after showing medicine) occurs pigeon, vomiting number of times (show the number of times that every a burst of vomiting occurs after medicine, wherein a burst of vomiting refer to stretch neck from pigeon, dehisce, shrug, abdominal part be retracted to pigeon restore calm count 1 vomiting) and vomiting frequency (refer to every gust vomit pigeon stretch neck, dehisce, shrug, the number of times of abdominal part contraction).
Give every animal pharmaceuticals 30mg Oseltamivir/kg the weight of animals by above grouping through gavage, vomit incubation period (min) after recording every animal gavage, record the vomiting number of times of every animal from gavage starts in 5 hours and vomiting frequency simultaneously.
In often organizing, statistics occur vomiting number of animals (n), for occur vomiting (including the vomiting of vomitus and the summation without the retch of vomitus) animal calculate they incubation period (min,
), average vomiting number of times and average vomiting frequency.The results are shown in following table:
Table 3 pigeon zoopery vomiting situation compares (
n=10)
From table 3, it is few that Oseltamivir of the present invention can crush the vomiting animals that sheet causes, and incubation period is long and vomit number of times and vomiting frequency is few.
The Oseltamivir of other formula of the present invention composition can crush sheet and also have the therapeutic effect identical or close with above-described embodiment medicine.
Test three, most preferred recipe determination
The most preferred recipe determination of the present invention is as follows:
(1) polyacrylic resin IV
Oseltamivir has very strong bitterness, when we take medicine, if Oseltamivir directly contacts oral mucosa, we obviously can experience bitterness, in order to cover the bitterness of medicine, reducing zest, needing to add one deck sealing coat outside pastille micropill of the present invention, we screen at methylcellulose, polyacrylic resin IV, hypromellose, hydroxypropyl cellulose, polyvidone and ethyl cellulose, and final choice polyacrylic resin IV is as taste masking coating layer material.Polyacrylic resin IV is conventional does taste masking coating layer material, and we select different polyacrylic resin IV layer thicknesses, and namely different polyacrylic resin IV ratios, investigates the impact of its taste masking effect.
Prepare large quantities of pastille micropill, prepare the polyacrylic resin IV alcoholic solution of same prescription, test the taste masking effect of not commensurability polyacrylic resin IV alcoholic solution.Shown by result of the test: under identical circumstances, when taste masking coating layer material polyacrylic resin IV ratio is 12.4%, taste masking effect can satisfy the demands,
(2) Blank Pellets
When adopting fluid bed medicine-feeding or coating pan medicine-feeding, medicated layer suspension needs to adhere on the carrier of certain particle diameter, and empty vectors the most frequently used in suitability for industrialized production is exactly the blank spherical pellets using certain pharmaceutic adjuvant preparation and obtain, i.e. Blank Pellets.According to the difference of the pharmaceutic adjuvant used, sucrose micropill, microcrystalline cellulose pellets, starch micropill, lactose-microcrystalline cellulose pellets, starch-microcrystalline cellulose pellets, sucrose-starch micropill etc. can be divided into.Sucrose micropill is the most frequently used Blank Pellets, and it has easy disintegrating, friability is low, particle size deviation is little, roundness is high, and the advantages such as particle size distribution range is narrow, through overtesting, can meet our demand to Blank Pellets, still select sucrose micropill.
(3) water-soluble polymer
Water-soluble polymer can promote medicine dissolving in vivo and absorption, even if also can ensure to take medicine on time under exsiccosis, be particularly useful for old man, children's, some especial patients (psychosis, senile dementia, epileptic patient etc.) and the inconvenient person that fetches water to take medicine and provide conveniently, also can reduce medicine and gastrointestinal is born.We screen in water-soluble polymer hypromellose, xanthan gum, sodium alginate, hydroxyethyl-cellulose, arabic gum, polyacrylic acid resin, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol, sodium carboxymethyl cellulose, and final choice xanthan gum is as hydrophilicity condiment.
Xanthan gum is a kind of stable adjuvant, and its aqueous solution (pH3 ~ 12) within the scope of wider pH is stablized, and has best stability within the scope of pH4 ~ 10 and temperature 10 ~ 60 DEG C.Experimental result shows, under identical circumstances, adds the xanthan gum of 2.3%, can meet our requirement.
(4) lubricant
Magnesium stearate is hydrophobic lubricant, and its quality is very soft, is therefore mainly used as lubricant, plays and fills and leads up particle surface and cheat recessed effect, use the packing interaction between rear granule to die down, and is easy to each other slide; Easy and granule mixes, and after tabletting, unilateral smooth and beautiful appearance, most widely used.Consumption is generally 0.1% ~ 1%, and when consumption is excessive, because this is as lyophobic dust, and this product covers particle surface again, if the therefore excessive infiltration that may affect water of consumption, can cause the disintegrate (or stripping) of tablet.Magnesium stearate is of many uses, as pharmaceutic adjuvant, has nontoxic, tasteless.
Result of the test shows: under identical circumstances, and it is easily inter-adhesive that the magnesium stearate adding 0.4% can obviously improve pastille micropill, makes mix homogeneously between granule, meet our requirement.
Claims (10)
1. the Oseltamivir being used for the treatment of infant and child's influenza can crush a sheet, and the percentage by weight of each component is as follows: the odor-masking pellet of 10 ~ 50%, the filler of 20 ~ 80%, 1 ~ 10% water-soluble polymer, the disintegrating agent of 1 ~ 8%, the correctives of 0 ~ 6% and 0.5 ~ 2.5% lubricant; Wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, and the medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, and it accounts for the 10%-50% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 5%-50% of micropill gross weight.
2. crushing sheet according to claim 1, is characterized in that, described odor-masking pellet particle diameter 0.10-0.50mm, preferred particle diameter is 0.15-0.35mm.
3. crushing sheet according to claim 1, is characterized in that, described Oseltamivir refers to Oseltamivir or its derivant, free alkali or salt, is preferably oseltamivir phosphate.
4. crushing sheet according to claim 1, it is characterized in that, described filler is selected from: one or more in mannitol, xylitol, erythritol, sucrose, fructose, glucose, maltose, glycine, sorbitol, microcrystalline Cellulose, lactose;
Described water-soluble polymer is selected from: one or more in hypromellose, xanthan gum, sodium alginate, hydroxyethyl-cellulose, arabic gum, polyacrylic acid resin, hydroxypropyl cellulose, polyvidone, polyvinyl alcohol, sodium carboxymethyl cellulose;
Described disintegrating agent is selected from: carboxymethyl starch is received, one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium;
Described correctives is selected from: one or more of the essence and flavoring agent of aspartame, acesulfame potassium, saccharin sodium, glucosan, acesulfame-K, stevioside, citric acid, various fragrance;
Described lubricant is selected from: Pulvis Talci, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate, stearyl alcohol, stearic one or more.
5. crushing sheet according to claim 1, is characterized in that, described filler is mannitol and/or microcrystalline Cellulose and/or erythritol; Described water-soluble polymer is polyvidone and/or xanthan gum; Described disintegrating agent is polyvinylpolypyrrolidone and/or cross-linking sodium carboxymethyl cellulose; Described correctives is aspartame and/or citric acid and/or grape essence; Described lubricant is sodium stearyl fumarate and/or magnesium stearate.
6. crushing sheet according to claim 1, is characterized in that, the percentage by weight of each component is as follows: the odor-masking pellet of 15 ~ 45% particle diameter 0.15-0.35mm; 30 ~ 80% mannitol and/or microcrystalline Cellulose and/or erythritol; 3 ~ 8% polyvidones and/or xanthan gum; 2 ~ 6% polyvinylpolypyrrolidone and/or cross-linking sodium carboxymethyl cellulose; 2 ~ 5% aspartames and/or citric acid and/or grape essence; 0.5 ~ 1.5% sodium stearyl fumarate and/or magnesium stearate; Wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, and the medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, and it accounts for the 15%-40% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 5%-40% of micropill gross weight.
7. crushing sheet according to claim 1, is characterized in that, the percentage by weight of each component is as follows:
The odor-masking pellet of 30 ~ 40% particle diameter 0.15-0.35mm; 30 ~ 40% mannitol; 8 ~ 15% microcrystalline Cellulose; 4 ~ 6% xanthan gum; 3 ~ 5% cross-linking sodium carboxymethyl celluloses; 2 ~ 3% aspartames; 0.5 ~ 1% citric acid; 0.5 ~ 1% flavoring orange essence; 1.0 ~ 1.5% magnesium stearate, wherein, described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, medicine in medicine carrying fine pellet core is Oseltamivir or its pharmaceutically acceptable salt, it accounts for the 15%-30% of micropill gross weight, coatings material therefor is polyacrylic resin IV, and it accounts for the 10%-25% of micropill gross weight.
8. crushing sheet according to claim 1, is characterized in that, the content of each component is as follows:
Oseltamivir odor-masking pellet 193.3g, mannitol 200.0g, microcrystalline Cellulose 60.0g, xanthan gum 30.0g, cross-linking sodium carboxymethyl cellulose 20.0g, aspartame 14.0g, citric acid 3.0g, flavoring orange essence 3.0g, magnesium stearate 6.0g,
Described odor-masking pellet is made up of medicine carrying fine pellet core and coatings, medicine carrying fine pellet core is made up of Oseltamivir and starch, and coatings material therefor is polyacrylic resin IV, and each amounts of components is as follows: Oseltamivir 300g, starch 300g, polyacrylic resin IV 160g.
9. the preparation method of crushing sheet according to claim 1, is characterized in that, comprise the following steps:
A. seed-coating machine is adopted to be prepared into medicine carrying fine pellet core after being pulverized by Oseltamivir, then polyacrylic resin IV is added in alcoholic solution, adopt fluidized bed coating or coating pan coating to form taste mask layer and be attached to above-mentioned medicine carrying fine pellet core, obtain odor-masking pellet, for subsequent use;
B. the odor-masking pellet of above-mentioned preparation and filler, water-soluble polymer, correctives, disintegrating agent, mix lubricant are even, tabletting,
Wherein, the preparation of described Oseltamivir medicine carrying fine pellet core: get starch and Oseltamivir puts into centrifugal coating pan, adds appropriate ethanol coating, obtains medicine carrying fine pellet core.
10. preparation method according to claim 9, is characterized in that, comprises the following steps:
(1) Oseltamivir odor-masking pellet preparation process
Supplementary material needed for it was all pulverized 100 eye mesh screens, got starch 300.0g and Oseltamivir 300.0g puts into centrifugal coating pan, and 75% ethanol was added to coating in centrifugal coating pan, obtains medicine carrying fine pellet core,
Take polyacrylic resin IV 160g, add 90% alcoholic solution 1440ml and be dissolved to clarification, make coating solution, for subsequent use, get medicine carrying fine pellet core 480.0g and put into centrifugal coating pan coating, to obtain final product,
(2) Oseltamivir can crush sheet preparation process
Sheet prescription can be crushed: Oseltamivir odor-masking pellet 193.3g, mannitol 200.0g, microcrystalline Cellulose 60.0g, xanthan gum 30.0g, cross-linking sodium carboxymethyl cellulose 20.0g, aspartame 14.0g, citric acid 3.0g, flavoring orange essence 3.0g, magnesium stearate 6.0g,
Preparation process: take above-mentioned material according to prescription and pour in trough type mixing machine and mix, mixed material is poured in tablet machine hopper, and tabletting, to obtain final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106236714A (en) * | 2015-06-05 | 2016-12-21 | 广东东阳光药业有限公司 | A kind of oseltamivir phosphate tablet and preparation method thereof |
| CN111467312A (en) * | 2020-05-18 | 2020-07-31 | 遂成药业股份有限公司 | Oseltamivir phosphate pharmaceutical composition |
| CN114159397A (en) * | 2021-11-02 | 2022-03-11 | 北京微智瑞医药科技有限公司 | Oseltamivir phosphate micro-tablet and preparation method and preparation thereof |
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| WO2010143207A1 (en) * | 2009-06-11 | 2010-12-16 | Rubicon Research Private Limited | Taste-masked oral formulations of influenza antivirals |
| CN103315965A (en) * | 2013-07-11 | 2013-09-25 | 孙卫东 | Oral solid granule suitable for infants and children, and preparation method thereof |
| CN103340835A (en) * | 2013-07-11 | 2013-10-09 | 孙卫东 | Orally disintegrating tablet suitable for infants and children and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010143207A1 (en) * | 2009-06-11 | 2010-12-16 | Rubicon Research Private Limited | Taste-masked oral formulations of influenza antivirals |
| CN103315965A (en) * | 2013-07-11 | 2013-09-25 | 孙卫东 | Oral solid granule suitable for infants and children, and preparation method thereof |
| CN103340835A (en) * | 2013-07-11 | 2013-10-09 | 孙卫东 | Orally disintegrating tablet suitable for infants and children and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106236714A (en) * | 2015-06-05 | 2016-12-21 | 广东东阳光药业有限公司 | A kind of oseltamivir phosphate tablet and preparation method thereof |
| CN111467312A (en) * | 2020-05-18 | 2020-07-31 | 遂成药业股份有限公司 | Oseltamivir phosphate pharmaceutical composition |
| CN114159397A (en) * | 2021-11-02 | 2022-03-11 | 北京微智瑞医药科技有限公司 | Oseltamivir phosphate micro-tablet and preparation method and preparation thereof |
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Application publication date: 20150408 |