CN105748443A - Ambroxol hydrochloride sustained release capsule and production process thereof - Google Patents
Ambroxol hydrochloride sustained release capsule and production process thereof Download PDFInfo
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Abstract
The invention discloses an ambroxol hydrochloride sustained release capsule and a production process thereof.The ambroxol hydrochloride sustained release capsule is composed of a plain pill and a sustained release coating according to the mass ratio of 100: (6.0-7.5); the plain pill is prepared from, by weight, 55 parts of 30-40-mesh saccharose pill cores, 75 parts of ambroxol hydrochloride, 70-75 parts of saccharose, 15-20 parts of starch, 0-3 parts of silicon dioxide, 0-1 part of magnesium stearate and 55-75 parts of adhesive solution; the sustained release coating is prepared from, by weight, 6 parts of Eudragit L100, 3 parts of saccharose, 1.0-1.5 parts of talcum powder, 100-270 parts of ethyl alcohol and 15-35 parts of pure water.On the premise of ensuring good quality, a simple matching and preparation method is adopted.
Description
Technical field
The present invention relates to a kind of Sustained Release Ambroxol Hydrochloride Capsules and production technology thereof, belong to pharmaceutical preparations technology field.
Background technology
Ambroxol hydrochloride, molecular formula is C13H18Br2N2O·HCl.It can promote the eliminating of the internal thick secretions of respiratory tract and reduce the delay of mucus, thus has the function remarkably promoting expectoration, it is adaptable to secrete abnormal and expectoration dysfunction acute, chronic respiratory system diseases with sputum.Nineteen sixty-five, ambroxol hydrochloride was succeeded in developing by Boehringer Ingelheim company first, within 1978, listed in Germany using mucosolvan as trade name first, and afterwards, ambroxol hydrochloride is successively in the listing of many countries such as France, Italy, Japan, Spain.
Within 1993, China starts Imported Ambroxol Hydrochloride oral formulations.Recently, the market space huge due to good ambroxol hydrochloride and development potentiality good from now on, many enterprises of China set foot in the production of ambroxol hydrochloride one after another.Now, the total ambroxol hydrochloride production approval number 75 in the whole nation.Wherein, slow releasing capsule has 4 to produce approval literary composition.The domestic and international commercialized product of Sustained Release Ambroxol Hydrochloride Capsules belongs to the slow releasing capsule in capsule dosage form, and its content is slow-release micro-pill and (or) slow-releasing granules, and specification is 75mg, 25mg or 45mg (Japan's listing).Other dosage form includes conventional capsule (30mg), ordinary tablet (15mg and 30mg), dispersible tablet (30mg), chewable tablet (15mg and 30mg), slow releasing tablet (75mg), granule (15mg and 30mg), syrup, oral liquid, injection etc..
At present, the research aspect of Sustained Release Ambroxol Hydrochloride Capsules mostly have employed more complicated formula and technique, is ensureing on the basis of Sustained Release Ambroxol Hydrochloride Capsules good quality, researches and develops formula and the technique of a kind of simple, low cost, is the problem being currently needed for solving.
Summary of the invention
Instant invention overcomes above-mentioned the deficiencies in the prior art, it is provided that a kind of Sustained Release Ambroxol Hydrochloride Capsules and production technology thereof.The method adopts simple dispensing in conjunction with the technique of the present invention, can be prepared by meeting the Sustained Release Ambroxol Hydrochloride Capsules of requirement.
The technical scheme is that a kind of Sustained Release Ambroxol Hydrochloride Capsules, it is characterized in that, being made up of element ball and sustained release coating, the mass ratio of the two is 100:6.0～7.5；
Described element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, silicon dioxide (pharmaceutical grade) 0～3 part, magnesium stearate 0～1 part, binder solution 55～75 parts；
Described sustained release coating is made up of the raw material of following weight parts: especially strange L1006 part, sucrose 3 parts, Pulvis Talci 1.0～1.5 parts, ethanol 100～270 parts, purified water 15～35 parts.
Wherein, sucrose needs to pulverize, cross 100 mesh sieves, and ambroxol hydrochloride, silicon dioxide (pharmaceutical grade) and magnesium stearate all needed 100 mesh sieves.Solubility >=95% of ethanol used.
Preferred version one: element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, magnesium stearate 0～1 part, binder solution 55～75 parts.The preparation method of binder solution is: take sucrose, purified water and ethanol, being dissolved in by sucrose to clear in purified water, add ethanol afterwards, the concentration being finally configured to ethanol is 50% (volume ratio), sucrose concentration is the binder solution of 40% (mass ratio), standby.50% alcoholic solution of 40% sucrose ensure that product hardness is moderate, and will not be adhered, lump.Program Easy dosing, method is simple.But require that the later stage is fully dry, so that the residual quantity of ethanol meets the requirements.
Preferred version two: described element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, silicon dioxide (pharmaceutical grade) 2～3 parts, magnesium stearate 0.5～1 part, binder solution 55～75 parts.The preparation method of binder solution is: after taking purified water heated and boiled, adds sucrose, and stirring and dissolving also continues to boil 20-40min, makes the sucrose solution of 25%, then adds the magnesium laurylsulfate of 0.1～0.3% in this solution, forms binder solution.The program adopts silicon dioxide, magnesium laurylsulfate and magnesium stearate improve the hardness of product, mobility, adopt magnesium laurylsulfate to reduce the viscosity of solution, will not produce to be adhered, lump.The program is completely without using ethanol.
Production technology:
(1) preparation of element ball
A) preparation of binder solution: preparation method is described above；
B) for powder material mixing: take ambroxol hydrochloride, cane sugar powder, starch, silicon dioxide and stearic acid, put in mixer, mix homogeneously；
C) prepared by element ball: with sucrose capsule core for parent nucleus, and adopting be powder and binder solution for powder material is whitewashing, adopts centrifugal granulating seed-coating machine, by powder bed area method preparation element ball；
D) dry: adopting fluid bed drying, baking temperature is 50 DEG C, 1～2 hour drying time, is dried to moisture≤2%；
E) screening: cross 24 orders, 30 mesh sieves, take the plain ball between 24～30 orders, standby；
(2) preparation of sustained release coating liquid: Youteqi L100 is dissolved in clear in ethanol, standby；Being dissolved in purified water by sucrose to clear to add residue ethanol and Pulvis Talci, high-shear homogenizing uniformly then proceed to especially in strange L100 alcoholic solution, coating process is continuously stirred, standby；
(3) sustained release coating: adopt Multifunctional coating granulator equipment, by spraying coating mode at the bottom of fluid bed, is coated on coating solution the plain ball surface of 24～30 orders, constitutes sustained-release coating layer；
(4) dry: baking temperature is 50 DEG C, remove the ethanol of coating residual, control moisture lower than 2%.Inlet temperature 50 DEG C, drying time >=2h；
(5) screening: cross 20 orders, 40 mesh sieves, screen out adhesion and broken micropill；Then capsule is loaded, packaging, warehouse-in.
Preferred step c, particularly as follows: add in pelletize pot by sucrose capsule core, adjusts engine speed 100～180rpm, whiff pressure 0.12～0.16MPa, spray air flow 10～16L/min and air blast flux 5～10L/min, makes sucrose capsule core present good rollover states；Meanwhile, will be added in feeder for powder material, standby；It is gradually increased spray pump rotating speed to 15～20rpm, to the abundant moistening of sucrose capsule core；Open for powder, control for powder machine rotating speed 40～50rpm, adjust for powder/whitewashing balance, make the uniform lamination of powder on parent nucleus.
Preferred step (3), particularly as follows: add in machine material trough by element ball, sets inlet temperature 35 ± 5 DEG C, leaving air temp 25 ± 5 DEG C, blower fan frequency 30～35Hz, whiff pressure 0.1～0.2MPa；Start, reach after design temperature until temperature of charge, start hydrojet and terminate to coating, hydrojet frequency 6～14Hz；Subsequently into drying stage.
The present invention controls heating-up temperature≤50 DEG C of material.
Each raw material and effect:
Sucrose capsule core: what be mainly used as the slow controlled release micro pill of Chinese medicine and western medicine plays body core grain, is prepare the requisite molding parent nucleus of film controlled piller, and it is directly connected to the quality of preparation, and only high-quality capsule core just can produce satisfactory medicinal micro.Commercially available sucrose capsule core difference in particle size distribution, density, friability, roundness etc. is less, and the impact of formulation properties is not notable.Wherein, cane sugar content in sucrose capsule core: calculate by dry product, containing sucrose (C12H22O11) it is 62.5%～91.5%, all the other are starch.
Sucrose: have four kinds of use in prescription: 1, the filler of blank sucrose capsule core；2, prepare filler during micropill, sucrose is pulverized and sieved (100 order)；3, binding agent, is configured to syrup；4, porogen, is added in sustained release coating suspension.These four purposes, when being only used as filler purposes, need to pulverize and sieve sucrose (100 order).
Especially strange L100: main extended release coatings membrane material, containing carboxyl, is easy to generate salt with alkali and dissolve in water.The impact of formulation properties is included two aspects by it: 1, clothing film dissolves and has pH dependency, dissolves in the medium of more than pH6；2, after coating, if there being water to penetrate between coating and label, and label medicine is strong acid weak base salt, then medicine chance water can dissolve, and discharges hydrion and penetrates into coating, and result can strengthen the capacity antacid of coating, delay the intestinal juice dissolving to coating, release being had a certain impact, and ambroxol hydrochloride is strong acid weak base salt, release may be had impact by this character.The present invention is added with and adds the water-soluble swollen mode antiacid with magnesium stearate that combine of starch chance, and the overall release making slow releasing capsule of the present invention is stable.
Pulvis Talci: almost insoluble in water, ethanol, is mainly used as the antiplastering aid of sustained release coating suspension, is added in sustained release coating liquid, plays the effect of antiplastering aid and (or) porogen.During coating, general selection 1250 orders, play suspension stable, reduce sedimentation and coating blocks the problems such as spray gun.
Silicon dioxide: be used as the novel adjuvant of one of medicine preparation, is a kind of high-purity, good white powder of mobility.Being fabulous flow improver additive in tablet manufacturing process, it is possible to significantly improve mobility of particle, improve bulk density, make the tablet hardness prepared increase, disintegration shortens, thus improving drug-eluting speed.
Magnesium laurylsulfate: water soluble surfactant active, has good lubricant effect, can not only strengthen the hardness of tablet, and can promote disintegrate and the dissolution of tablet.
Magnesium stearate: be mainly used as lubricant, antiplastering aid, fluidizer.
In sustained release coating of the present invention, especially strange L100 is slow-release material, and sucrose is porogen, and Pulvis Talci is antiplastering aid, wherein L100 and sucrose 2:1 compatibility in mass ratio, and its release is satisfied by requiring (to put speed 1hr:15%～45%；2hr:45%～80%；4hr: >=85%).The modest viscosity of coating solution, does not have micropill and is adhered phenomenon simultaneously.
The 50% alcoholic solution binding agent that binder solution is 40% sucrose of the plain ball scheme one of the present invention.Sucrose is consisted of due to sucrose capsule core, contact soluble tacky with water, the present invention by adding 50% ethanol in sucrose solution, while ensureing binding agent dosage of sucrose, reducing the viscosity (preventing the element easy adhesion of ball, the caking) powder in conjunction with the present invention of syrup, the final guarantee outward appearance of ambroxol hydrochloride element ball, roundness, hardness friability meet requirement.
The plain ball scheme one of the present invention is simple, but uses ethanol in element ball, can improve the Residual ethanol of slow releasing capsule, and the requirement that element ball is dried is higher.The present invention program two, on the basis being added without ethanol, reduces the concentration of sucrose, in conjunction with magnesium laurylsulfate add binding agent lubricity and with the compatibility of powder, make powder and binding agent mixing ratio more uniform.Magnesium stearate, silicon dioxide increase the mobility of powder, lubricity simultaneously, also make powder mix homogeneously with bonding；Add the hardness (hardness is suitable with scheme one) of element ball, disintegration (more excellent than scheme one) simultaneously, discharge more complete.
The invention has the beneficial effects as follows: under ensureing good quality premise, have employed simple dispensing and preparation method.
Accompanying drawing explanation
Fig. 1 is the process chart of the embodiment of the present invention 2.
Detailed description of the invention
Embodiment 1: the selection of element ball formula
According to prescription composition, supplementary material compatibility test result, with the outward appearance of micropill, roundness, friability for index, test as follows, screen binding agent and for powder material prescription.
Judge index: a) outward appearance, roundness: being judged by microscope and perusal, flat appearance is smooth, globulate is excellent, and flat appearance, almost spherical are good, and outward appearance is rough and uneven in surface, globulate is not for poor.B) friability :≤5% is judged to excellent, and≤10% is judged to qualified, and > 10% is defective.Method: adopt fluidized-bed coating machine, setup parameter: blower fan frequency 30Hz, whiff pressure 0.12Mpa, time 10min, being used that regulation screen cloth (60 mesh sieve) is weighed after sieving before and after sample fluidisation, the percetage by weight that secondary weighing alleviates is friability.
1, the kind of binding agent
Forming according to prescription, binding agent may select: the ethanol water of sucrose solution (syrup), starch slurry and especially strange L100, investigates 3% hypromellose (HPMC5CP) aqueous solution as binding agent etc. simultaneously.Preliminary result shows: starch slurry atomizing effect is bad, and 1～3% especially strange L100 alcoholic solution, micropill adhesion is serious.Therefore mainly with sucrose solution and hypromellose aqueous solution for binding agent during formulation study.
Result is as shown in table 2: a) simple with sucrose solution (10～30%) or hypromellose aqueous solution for binding agent, the plain ball friability prepared is slightly worse, even unqualified, and coating process occurs that micropill crushes.B) in order to increase micropill hardness, increasing sucrose solution concentration (40～60%), viscosity also increases therewith, and operation critical point is less susceptible to control, and adhesion, caking easily occurs, but micropill hardness significantly improves.It is similar that this too much improves micropill hardness to the whitewashing of low concentration sucrose solution, and same problem is also the easy adhesion of micropill, caking.C) in order to, while increasing binding agent dosage of sucrose, reduce the viscosity of solution, add a certain amount of ethanol wherein, through screening 50% alcoholic solution of 40% sucrose, meet requirement.
2, for powder material consumption
Ambroxol hydrochloride element ball (24～30 order) is prepared for initial capsule core according to selecting sucrose capsule core (particle size distribution 30～40 order), for powder material: the ratio of initial capsule core is 1.5～3: 1, can jointly determine the ratio for powder material with initial capsule core according to content of dispersion, micropill granule size etc..
3, for powder material prescription composition
Ambroxol hydrochloride element ball preparation prescription is composed as follows, and result is in Table 1.
The different prescription of table 1
Table 2 prescription result
Result: a) above prescription all can prepare the pastille element ball of 24～30 orders, but friability differs greatly, and wherein the consumption of binding agent plays key effect.In pelletizing process, only micropill surface, under the abundant wetting conditions of binding agent, is started for the long ball of powder, and the friability of guarantee micropill meets coating requirement, namely increases binder dosage.Consisting of sucrose due to sucrose capsule core, contact with water soluble tacky, therefore, the present invention by adding certain proportion ethanol in sucrose solution, it is ensured that while binding agent dosage of sucrose, reduces the viscosity of syrup.Final 50% alcoholic solution selecting 40% sucrose is binding agent.B) by adjusting sucrose capsule core consumption, binder dosage, supplying powder material prescription and consumption, the final guarantee outward appearance of ambroxol hydrochloride element ball, roundness and friability meet requirement.
Conclusion: according to prescription screening and optimum results, the plain ball that 6. final prescription prepares, outward appearance is good, smooth, and roundness is good, and friability is excellent, meets coating requirement.Therefore, ambroxol hydrochloride element ball preparation prescription is substantially determined.
Simultaneously, the present invention is on this basis, with on prescription basis 6., the preparation method of binder solution is: after taking purified water heated and boiled, adding sucrose, stirring and dissolving also continues to boil 20-40min, makes the sucrose solution of 25%, then add the magnesium laurylsulfate of 0.1～0.3% in this solution, form binder solution.Simultaneously adding silicon dioxide (pharmaceutical grade) 1.5% and magnesium stearate 0.5% on formula basis 6., result is: outward appearance is good, surfacing, and roundness is good；Friability is excellent, qualified, and micropill is broken few, meets coating demand.
Embodiment 2 (20,000/batches)
Element ball formula (weight): sucrose capsule core 1.10Kg, ambroxol hydrochloride 1.5Kg, sucrose 1.5Kg, starch 0.30Kg, binder solution raw material: sucrose 0.536Kg, purified water 0.402Kg；Ethanol 0.402Kg；
Sustained release coating: especially strange L100192.0g, sucrose 96.0g, Pulvis Talci 38.4g, purified water 0.911Kg, ethanol 5.163Kg.
Production technology:
(1) preparation of element ball
A) preparation of binder solution: take sucrose, purified water and ethanol, being dissolved in by sucrose to clear in purified water, add ethanol afterwards, the concentration being finally configured to ethanol is 50% (volume ratio), sucrose concentration is the binder solution of 40% (mass ratio), standby；
B) for powder material mixing: take ambroxol hydrochloride, cane sugar powder and starch, put in mixer, mix homogeneously；
C) prepared by element ball: with sucrose capsule core for parent nucleus, and adopting be powder and binder solution for powder material is whitewashing, adopts centrifugal granulating seed-coating machine, by powder bed area method preparation element ball；Particularly as follows: sucrose capsule core is added in pelletize pot, adjust engine speed 100～180rpm, whiff pressure 0.12～0.16MPa, spray air flow 10～16L/min and air blast flux 5～10L/min, make sucrose capsule core present good rollover states；Meanwhile, will be added in feeder for powder material, standby；It is gradually increased spray pump rotating speed to 15～20rpm, to the abundant moistening of sucrose capsule core；Open for powder, control for powder machine rotating speed 40～50rpm, adjust for powder/whitewashing balance, make the uniform lamination of powder on parent nucleus.
D) dry: adopting fluid bed drying, baking temperature is 50 DEG C, 2 hours drying times, is dried to moisture≤2%, ethanol content≤0.05%；
E) screening: cross 24 orders, 30 mesh sieves, take the plain ball between 24～30 orders, standby；
(2) preparation of sustained release coating liquid: Youteqi L100 is dissolved in clear in ethanol, standby；Being dissolved in purified water by sucrose to clear to add residue ethanol and Pulvis Talci, high-shear homogenizing uniformly then proceed to especially in strange L100 alcoholic solution, coating process is continuously stirred, standby；
(3) sustained release coating: adopt Multifunctional coating granulator equipment, by spraying coating mode at the bottom of fluid bed, is coated on coating solution the plain ball surface of 24～30 orders, constitutes sustained-release coating layer；Particularly as follows: add in machine material trough by element ball, set inlet temperature 35 ± 5 DEG C, leaving air temp 25 ± 5 DEG C, blower fan frequency 30～35Hz, whiff pressure 0.1～0.2MPa；Start, reach after design temperature until temperature of charge, start hydrojet and terminate to coating, hydrojet frequency 6～14Hz；Subsequently into drying stage.
(4) dry: baking temperature is 50 DEG C, remove the ethanol of coating residual, control moisture lower than 2%, ethanol content≤0.05%；Inlet temperature 50 DEG C, drying time >=2h；
(5) screening: cross 20 orders, 40 mesh sieves, screen out adhesion and broken micropill；
(6) intermediate detection: micropill content of dispersion after mensuration coating；
(7) filling capsule: according to intermediate testing result, calculates capsule weight, and loads capsule.
(8) packaging: aluminum-plastic packaged, mounted box, vanning, warehouse-in.The examination and test of products is reported as shown in Table 3-5.
Table 3 Sustained Release Ambroxol Hydrochloride Capsules criticizes survey report
| The inspection name of an article claims | Sustained Release Ambroxol Hydrochloride Capsules | Specification | 75mg |
| Censorship unit | Double; two crane favorable to the people Pharmaceutical (Jinan) company limited in China Resources | Lot number | 130708 |
| The date of inspection | 2013.8.1 | Reporting date | 2013.8.12 |
| Specification standards | Report production quality standard | Inspection purpose | Quan Jian |
| Trier | King * * | The person of checking | Grandson * * |
Assay:
Conclusion: this product is by the inspection of appended Sustained Release Ambroxol Hydrochloride Capsules production quality standard, and result meets regulation.
Table 4 methodology sample survey summary sheet
Table 5 standard stability investigates result
The long-term stable experiment of this product is as follows.
(1) accelerated test
This product 130708 batches being put into climatic chamber 6 months, sampled respectively at 0,1,2,3,6 months, measure indices, result is in Table 6.
Table 6 Sustained Release Ambroxol Hydrochloride Capsules 40 DEG C, RH75% accelerated test result (130708 batches)
(2) intermediate experiment
This product 130708 batches being put into climatic chamber 6 months, sampled respectively at 0,1,2,3,6 months, measure indices, result is in Table 7.Investigation condition: temperature 30 DEG C ± 2 DEG C, humidity 65% ± 5%.
Table 7 Sustained Release Ambroxol Hydrochloride Capsules 30 DEG C, RH65% accelerated test result (130708 batches)
(3) long term test
By this product 130708 batches, sampling respectively at 0,3,6,9,12 months, measure indices, result is in Table 8.
Investigation condition: temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 5%.
Table 8 Sustained Release Ambroxol Hydrochloride Capsules long-term test results (130708 batches)
Note: " " represents that not carrying out this checks.
Table 9 research conclusion
| Interior packaging material | Aluminium-plastic bubble plate packing |
| Holding conditions | Shading, seals and preserves. |
| Effect duration | Fix tentatively is 24 months |
| To the prompting of related content in description | Shading, seals and preserves. |
Embodiment 3 (20,000/batches)
Element ball formula (weight): sucrose capsule core 1.10Kg, ambroxol hydrochloride 1.5Kg, sucrose 1.5Kg, starch 0.30Kg, silicon dioxide (pharmaceutical grade) 0.05kg, magnesium stearate 0.01kg；Binder solution raw material: sucrose 0.3333Kg, purified water 1.0Kg；Magnesium laurylsulfate 2.6g；
Sustained release coating: especially strange L100192.0g, sucrose 96.0g, Pulvis Talci 38.4g, purified water 0.56Kg, ethanol 3.84Kg.
Production technology:
(1) preparation of element ball
A) preparation of binder solution: after taking purified water heated and boiled, adds sucrose, and stirring and dissolving also continues to boil 30min, makes the sucrose solution of 25%, then adds magnesium laurylsulfate in this solution, forms binder solution；
B) for powder material mixing: take ambroxol hydrochloride, cane sugar powder and starch, put in mixer, mix homogeneously；
C) prepared by element ball: with sucrose capsule core for parent nucleus, and adopting be powder and binder solution for powder material is whitewashing, adopts centrifugal granulating seed-coating machine, by powder bed area method preparation element ball；Particularly as follows: sucrose capsule core is added in pelletize pot, adjust engine speed 100～180rpm, whiff pressure 0.12～0.16MPa, spray air flow 10～16L/min and air blast flux 5～10L/min, make sucrose capsule core present good rollover states；Meanwhile, will be added in feeder for powder material, standby；It is gradually increased spray pump rotating speed to 15～20rpm, to the abundant moistening of sucrose capsule core；Open for powder, control for powder machine rotating speed 40～50rpm, adjust for powder/whitewashing balance, make the uniform lamination of powder on parent nucleus.
D) dry: adopting fluid bed drying, baking temperature is 50 DEG C, 1～2 hour drying time, is dried to moisture≤2%；
E) screening: cross 24 orders, 30 mesh sieves, take the plain ball between 24～30 orders, standby；
(2) preparation of sustained release coating liquid: Youteqi L100 is dissolved in clear in ethanol, standby；Being dissolved in purified water by sucrose to clear to add residue ethanol and Pulvis Talci, high-shear homogenizing uniformly then proceed to especially in strange L100 alcoholic solution, coating process is continuously stirred, standby；
(3) sustained release coating: adopt Multifunctional coating granulator equipment, by spraying coating mode at the bottom of fluid bed, is coated on coating solution the plain ball surface of 24～30 orders, constitutes sustained-release coating layer；Particularly as follows: add in machine material trough by element ball, set inlet temperature 35 ± 5 DEG C, leaving air temp 25 ± 5 DEG C, blower fan frequency 30～35Hz, whiff pressure 0.1～0.2MPa；Start, reach after design temperature until temperature of charge, start hydrojet and terminate to coating, hydrojet frequency 6～14Hz；Subsequently into drying stage.
(4) dry: baking temperature is 50 DEG C, remove the ethanol of coating residual, control moisture lower than 2%, ethanol content≤0.05%；Inlet temperature 50 DEG C, drying time >=2h；
(5) screening: cross 20 orders, 40 mesh sieves, screen out adhesion and broken micropill；Then capsule is loaded, packaging, warehouse-in.
The examination and test of products is reported as Table 10-11.
Table 10 Sustained Release Ambroxol Hydrochloride Capsules criticizes survey report
| The inspection name of an article claims | Sustained Release Ambroxol Hydrochloride Capsules | Specification | 75mg |
| Censorship unit | Double; two crane favorable to the people Pharmaceutical (Jinan) company limited in China Resources | Lot number | 131001 |
| The date of inspection | 2013.10.1 | Reporting date | 2013.11.10 |
| Specification standards | Report production quality standard | Inspection purpose | Quan Jian |
| Trier | King * * | The person of checking | Grandson * * |
Assay:
Conclusion: this product is by the inspection of appended Sustained Release Ambroxol Hydrochloride Capsules production quality standard, and result meets regulation.
Table 11 standard stability investigates result
Long term test: it sampled respectively at 0,3,6,9,12 months, measures indices, and result is in Table 12.Investigation condition: temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 5%.
Table 12 Sustained Release Ambroxol Hydrochloride Capsules long-term test results (131001 batches)
Note: " " represents that not carrying out this checks.
Claims (7)
1. a Sustained Release Ambroxol Hydrochloride Capsules, is characterized in that, is made up of element ball and sustained release coating, and the mass ratio of the two is 100:6.0～7.5；
Described element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, silicon dioxide 0～3 part, magnesium stearate 0～1 part, binder solution 55～75 parts；
Described sustained release coating is made up of the raw material of following weight parts: especially strange L1006 part, sucrose 3 parts, Pulvis Talci 1.0～1.5 parts, ethanol 100～270 parts, purified water 15～35 parts.
2. a kind of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 1, is characterized in that, the particle diameter of described element ball is 24～30 orders.
3. a kind of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 1, it is characterized in that, described element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, magnesium stearate 0～1 part, binder solution 55～75 parts；The preparation method of described binder solution is: take sucrose, purified water and ethanol, is dissolved in by sucrose to clear in purified water, adds ethanol afterwards, and the concentration being finally configured to ethanol is 50%, and sucrose concentration is the binder solution of 40%, standby.
4. a kind of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 1, it is characterized in that, described element ball is made up of the raw material of following weight parts: the sucrose capsule core of 30～40 orders 55 parts, ambroxol hydrochloride 75 parts, sucrose 70～75 parts, starch 15～20 parts, silicon dioxide 2～3 parts, magnesium stearate 0.5～1 part, binder solution 55～75 parts；The preparation method of described binder solution is: after taking purified water heated and boiled, adds sucrose, and stirring and dissolving also continues to boil 20-40min, makes the sucrose solution of 25%, then adds the magnesium laurylsulfate of 0.1～0.3% in this solution, forms binder solution.
5. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as described in any one in claim 1-4, is characterized in that, comprise the following steps:
(1) preparation of element ball
A) binder solution is prepared；
B) for powder material mixing: take element ball raw material except sucrose capsule core and binder solution, put in mixer, mix homogeneously；
C) prepared by element ball: with sucrose capsule core for parent nucleus, and adopting be powder and binder solution for powder material is whitewashing, adopts centrifugal granulating seed-coating machine, by powder bed area method preparation element ball；
D) dry: adopting fluid bed drying, baking temperature is 50 DEG C, is dried to moisture≤2%；
E) screening: cross 24 orders, 30 mesh sieves, take the plain ball between 24～30 orders, standby；
(2) preparation of sustained release coating liquid: Youteqi L100 is dissolved in clear in ethanol, standby；Being dissolved in purified water by sucrose to clear to add residue ethanol and Pulvis Talci, high-shear homogenizing uniformly then proceed to especially in strange L100 alcoholic solution, make coating solution, coating process is continuously stirred, standby；
(3) sustained release coating: adopt Multifunctional coating granulator equipment, by spraying coating mode at the bottom of fluid bed, is coated on coating solution the plain ball surface of 24～30 orders, constitutes sustained-release coating layer；
(4) dry: baking temperature is 50 DEG C, drying time >=2h；
(5) screening: cross 20 orders, 40 mesh sieves, screen out adhesion and broken micropill；Then capsule is loaded, packaging, warehouse-in.
6. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 5, it is characterized in that, described step c is: sucrose capsule core added in pelletize pot, adjust engine speed 100～180rpm, whiff pressure 0.12～0.16MPa, spray air flow 10～16L/min and air blast flux 5～10L/min, make sucrose capsule core present rollover states；Meanwhile, will be added in feeder for powder material, standby；It is gradually increased spray pump rotating speed to 15～20rpm, to the abundant moistening of sucrose capsule core；Open for powder, control for powder machine rotating speed 40～50rpm, adjust for powder/whitewashing balance, make the uniform lamination of powder on parent nucleus.
7. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 5; it is characterized in that; described step (3) is: is added by element ball in the machine material trough of Multifunctional coating granulator, sets inlet temperature 35 ± 5 DEG C, leaving air temp 25 ± 5 DEG C, blower fan frequency 30～35Hz, whiff pressure 0.1～0.2MPa；Start, reach after design temperature until temperature of charge, start hydrojet and terminate to coating, hydrojet frequency 6～14Hz；Subsequently into drying stage.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0546846A1 (en) * | 1991-12-11 | 1993-06-16 | Therapicon Srl | Programmed-release pharmaceutical compositions |
| CN103211789A (en) * | 2012-01-18 | 2013-07-24 | 北京天衡药物研究院 | Ambroxol hydrochloride film-controlled slow-release pellet capsule |
-
2016
- 2016-04-25 CN CN201610265690.2A patent/CN105748443B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0546846A1 (en) * | 1991-12-11 | 1993-06-16 | Therapicon Srl | Programmed-release pharmaceutical compositions |
| CN103211789A (en) * | 2012-01-18 | 2013-07-24 | 北京天衡药物研究院 | Ambroxol hydrochloride film-controlled slow-release pellet capsule |
Non-Patent Citations (2)
| Title |
|---|
| ABDUL ALTHAF. S ETAL: "Modified release capsules of Ambroxil, Preformulation and evaluation", 《PELAGIA RESEARCH LIBRARY》 * |
| 张立超等: "盐酸氨溴索包衣小丸的制备及其释药特性", 《中国医院药学杂志》 * |
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