CN105748443B - A kind of Sustained Release Ambroxol Hydrochloride Capsules and its production technology - Google Patents
A kind of Sustained Release Ambroxol Hydrochloride Capsules and its production technology Download PDFInfo
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- CN105748443B CN105748443B CN201610265690.2A CN201610265690A CN105748443B CN 105748443 B CN105748443 B CN 105748443B CN 201610265690 A CN201610265690 A CN 201610265690A CN 105748443 B CN105748443 B CN 105748443B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
Abstract
The invention discloses a kind of Sustained Release Ambroxol Hydrochloride Capsules and its production technologies.It is made of vegetable pill and sustained release coating, and the mass ratio of the two is 100：6.0~7.5；The vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, 75 parts of ambroxol hydrochloride, 70~75 parts of sucrose, 15~20 parts of starch, 0~3 part of silica, 0~1 part of magnesium stearate, 55~75 parts of binder solution；The sustained release coating is made of the raw material of following weight parts：6 parts of Utech L100,3 parts of sucrose, 1.0~1.5 parts of talcum powder, 100~270 parts of ethyl alcohol, 15~35 parts of purified water.The present invention uses simple dispensing and preparation method under the premise of ensureing good quality.
Description
Technical field
The present invention relates to a kind of Sustained Release Ambroxol Hydrochloride Capsules and its production technologies, belong to pharmaceutical preparations technology field.
Background technology
Ambroxol hydrochloride, molecular formula C13H18Br2N2O·HCl.It can promote the exclusion of thick secretions inside respiratory tract
And the delay of mucus is reduced, thus have the function of remarkably promoting expectoration, it is suitable for secreting abnormal and expectoration work(with sputum
It can undesirable acute, chronic respiratory disease.Nineteen sixty-five, Boehringer Ingelheim company for the first time succeeded in developing ambroxol hydrochloride,
1978 for the first time using Mucosolvin as trade name Germany list, later, ambroxol hydrochloride successively France, Italy, Japan,
Many country's listings such as Spain.
China starts Imported Ambroxol Hydrochloride oral preparation within 1993.Recently, since good ambroxol hydrochloride is huge
The market space and good development potentiality, many enterprises of China set foot in the production of ambroxol hydrochloride one after another from now on.Now, entirely
State shares ambroxol hydrochloride production approval number 75.Wherein, spansule has 4 production approval texts.Ambroxol hydrochloride sustained-release
For the domestic and international commercialized product of capsule from the spansule belonged in dosage form in capsule, content is sustained release pellet and (or) sustained release
Particle, specification 75mg, 25mg or 45mg (Japan's listing).Other dosage forms include conventional capsule (30mg), ordinary tablet (15mg and
30mg), dispersible tablet (30mg), chewable tablets (15mg and 30mg), sustained release tablets (75mg), granule (15mg and 30mg), syrup,
Oral solution, injection etc..
Currently, mostly using more complicated formula and technique in terms of the research of Sustained Release Ambroxol Hydrochloride Capsules, protecting
On the basis of demonstrate,proving Sustained Release Ambroxol Hydrochloride Capsules good quality, a kind of simple, low cost formula and technique are researched and developed, is currently to need
It solves the problems, such as.
Invention content
The present invention overcomes above-mentioned the deficiencies in the prior art, a kind of Sustained Release Ambroxol Hydrochloride Capsules and its production work are provided
Skill.The technique that this method combines the present invention using simple dispensing, you can the Sustained Release Ambroxol Hydrochloride Capsules met the requirements are made.
The technical scheme is that：A kind of Sustained Release Ambroxol Hydrochloride Capsules, characterized in that by vegetable pill and sustained release coating group
At the mass ratio of the two is 100：6.0~7.5；
The vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, 75 parts of ambroxol hydrochloride,
70~75 parts of sucrose, 15~20 parts of starch, 0~3 part of silica (pharmaceutical grade), 0~1 part of magnesium stearate, binder solution 55
~75 parts；
The sustained release coating is made of the raw material of following weight parts：6 parts of Utech L100,3 parts of sucrose, talcum powder 1.0~
1.5 parts, 100~270 parts of ethyl alcohol, 15~35 parts of purified water.
Wherein, sucrose is needed to crush, be sieved with 100 mesh sieve, and ambroxol hydrochloride, silica (pharmaceutical grade) and magnesium stearate are both needed to
It sieves with 100 mesh sieve.Solubility >=95% of ethyl alcohol used.
Preferred embodiment one：Vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, hydrochloric acid ammonia bromine
75 parts of rope, 70~75 parts of sucrose, 15~20 parts of starch, 0~1 part of magnesium stearate, 55~75 parts of binder solution.Binder solution
Preparation method be：Sucrose, purified water and ethyl alcohol are taken, sucrose is dissolved in purified water to clear, adds ethyl alcohol afterwards, most
It is configured to a concentration of 50% (volume ratio) of ethyl alcohol eventually, sucrose concentration is the binder solution of 40% (mass ratio), spare.40%
50% ethanol solution of sucrose ensure that product hardness is moderate, and will not be adhered, lump.Program Easy dosing, method
Simply.But require the later stage fully dry, so that the residual quantity of ethyl alcohol meets the requirements.
Preferred embodiment two：The vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, hydrochloric acid
75 parts of ambroxol, 70~75 parts of sucrose, 15~20 parts of starch, 2~3 parts of silica (pharmaceutical grade), 0.5~1 part of magnesium stearate,
55~75 parts of binder solution.The preparation method of binder solution is：After taking purified water heating to boil, sucrose is added, stirring is molten
It solves and continues to boil 20-40min, 25% sucrose solution is made, 0.1~0.3% laruyl alcohol is then added in this solution
Magnesium sulfate forms binder solution.The hard of product is improved using silica, magnesium laurylsulfate and magnesium stearate in the program
Degree, mobility are reduced the viscosity of solution using magnesium laurylsulfate, not will produce and be adhered, lump.The program is completely without making
Use ethyl alcohol.
Production technology：
(1) preparation of vegetable pill
A) preparation of binder solution：Preparation method is as described above；
B) it is mixed for powder material：Ambroxol hydrochloride, cane sugar powder, starch, silica and stearic acid are taken, mixing machine is put into
In, it is uniformly mixed；
C) prepared by vegetable pill：Using cane sugar core as parent nucleus, it is whitewashing for powder and binder solution to use for powder material, is used
Centrifugal granulating seed-coating machine prepares vegetable pill by powder bed area method；
D) dry：Using fluidized bed drying, drying temperature is 50 DEG C, 1~2 hour drying time, dry to moisture
≤ 2%；
E) it sieves：24 mesh, 30 mesh sieve are crossed, the vegetable pill between 24~30 mesh is taken, it is spare；
(2) preparation of sustained release coating liquid：Youteqi L100 is dissolved in ethyl alcohol to clear, it is spare；Sucrose is molten
Solution in purified water to being added remaining ethyl alcohol and talcum powder after clear, it is high-shear homogenizing uniformly, then be transferred to Utech L100
In ethanol solution, coating process persistently stirs, spare；
(3) sustained release coating：Using Multifunctional coating granulation machine equipment, coating mode is sprayed by fluid bed bottom, by coating solution
It is coated on the vegetable pill surface of 24~30 mesh, constitutes sustained-release coating layer；
(4) dry：Drying temperature is 50 DEG C, removes and is coated remaining ethyl alcohol, and control moisture is less than 2%.Inlet air temperature 50
DEG C, drying time >=2h；
(5) it sieves：20 mesh, 40 mesh sieve are crossed, adhesion and broken pellet are screened out；Then capsule is loaded, is packed, storage.
It is preferred that step c be specially：Cane sugar core is added and is granulated in pot, 100~180rpm of adjustment engine speed, jet
5~10L/min of 0.12~0.16MPa of pressure, 10~16L/min of spray air flow and air blast flux makes cane sugar core present preferable
Rollover states；Meanwhile will be added in feeder for powder material, it is spare；Whitewashing revolution speed is gradually increased to 15~20rpm,
After fully being soaked to cane sugar core；Powder supply is opened, powder supply machine 40~50rpm of rotating speed is controlled, adjustment powder supply/whitewashing balance makes powder
Expect uniform lamination on parent nucleus.
It is preferred that step (3) be specially：Vegetable pill is added in machine material trough, 35 ± 5 DEG C of inlet air temperature of setting goes out wind-warm syndrome
25 ± 5 DEG C of degree, 30~35Hz of wind turbine frequency, 0.1~0.2MPa of whiff pressure；Start, after temperature of charge reaches set temperature,
Start hydrojet to coating to terminate, 6~14Hz of hydrojet frequency；Subsequently into drying stage.
Heating temperature≤50 DEG C of control material of the present invention.
Each raw material and effect：
Cane sugar core：Be mainly used as that Chinese and Western medicine delays controlled release micro pill plays body core grain, is that prepare film controlled piller essential
Molding parent nucleus, it is directly related to the quality of preparation, and the only capsule core of high quality can just produce satisfactory medicinal micro.
Commercially available cane sugar core is smaller in size distribution, density, friability, roundness etc. difference, and the influence to formulation properties is not shown
It writes.Wherein, cane sugar content in cane sugar core：It is calculated by dry product, (the C containing sucrose12H22O11) it is 62.5%~91.5%, remaining
For starch.
Sucrose：There are four types of use in prescription：1, the filler of blank cane sugar core；2, filler when pellet is prepared,
Sucrose is pulverized and sieved (100 mesh)；3, adhesive is configured to syrup；4, pore-foaming agent adds in sustained release coating suspension.This
Four kinds of purposes need to pulverize and sieve sucrose (100 mesh) when being only used as filler purposes.
Utech L100：Main extended release coatings membrane material is easy to generate salt with alkali and dissolve in water containing carboxyl.Its
Influence to formulation properties includes two aspects：1, clothing film dissolving has pH dependences, is dissolved in the medium of pH6 or more；2、
After coating, if there is water penetrates between coating and label, and label drug is strong acid weak base salt, then drug is met water and can be dissolved,
It releases hydrogen ion and penetrates into coating, as a result can enhance the capacity antacid of coating, delay dissolving of the intestinal juice to coating, have one to release
Fixed influence, and ambroxol hydrochloride is strong acid weak base salt, which may have an impact release.The present invention is added by adding
Enter starch meet it is water-swellable be combined the mode antiacid with magnesium stearate, so that the whole release of spansule of the present invention is stablized.
Talcum powder：It is almost insoluble in water, ethyl alcohol, it is mainly used as the antiplastering aid of sustained release coating suspension, is added into sustained release
In coating solution, play the role of antiplastering aid and (or) pore-foaming agent.It is general to select 1250 mesh when coating, suspension stabilization is played, is subtracted
The problems such as few sedimentation and coating block spray gun.
Silica：It is used as a kind of novel auxiliary material of medicine preparation, is a kind of high-purity, mobility white powder well
End.It is fabulous flow improver additive in tablet manufacturing process, mobility of particle can be significantly improved, bulk density is improved, make
Tablet hardness obtained increases, and disintegration time limited shortens, to improve drug-eluting speed.
Magnesium laurylsulfate：Water soluble surfactant active has good lubricant effect, can not only enhance the hard of tablet
Degree, and the disintegration and dissolution of tablet can be promoted.
Magnesium stearate：It is mainly used as lubricant, antiplastering aid, glidant.
Utech L100 is slow-release material in sustained release coating of the present invention, and sucrose is pore-foaming agent, and talcum powder is antiplastering aid, wherein
L100 and sucrose in mass ratio 2：1 compatibility, release are satisfied by requirement and (put speed 1hr：15%~45%；2hr：45%~
80%；4hr：>=85%).The modest viscosity of coating solution simultaneously, is not in that pellet is adhered phenomenon.
The binder solution of the vegetable pill scheme one of the present invention is 50% ethanol solution adhesive of 40% sucrose.Due to sucrose
The group of capsule core becomes sucrose, contact with water soluble tacky, and the present invention ensures to glue by adding 50% ethyl alcohol in sucrose solution
While mixture dosage of sucrose, the viscosity (preventing the easy adhesion of vegetable pill, caking) for reducing syrup combines the powder of the present invention, final to protect
The appearance, roundness, hardness friability for demonstrate,proving ambroxol hydrochloride vegetable pill are met the requirements.
The vegetable pill scheme one of the present invention is simple, but ethyl alcohol is used in vegetable pill, can improve the Residual ethanol of spansule,
To the more demanding of vegetable pill drying.The present invention program two reduces the concentration of sucrose, in conjunction with the moon on the basis of being added without ethyl alcohol
Cinnamic alcohol magnesium sulfate increases the lubricity of adhesive and the compatibility with powder, so that powder is mixed with adhesive relatively uniform.
Magnesium stearate, silica increase mobility, the lubricity of powder simultaneously, and powder is also made to be uniformly mixed with bonding；Increase simultaneously
The hardness of vegetable pill (hardness is suitable with scheme one), disintegration (more excellent than scheme one), release are more complete.
The beneficial effects of the invention are as follows：Under the premise of ensureing good quality, simple dispensing and preparation method are used.
Description of the drawings
Fig. 1 is the process flow chart of the embodiment of the present invention 2.
Specific implementation mode
Embodiment 1：The selection of vegetable pill formula
According to composition, supplementary material compatibility test as a result, using the appearance of pellet, roundness, friability as index, into
The following experiment of row, screens adhesive and for powder material prescription.
Judge index：A) appearance, roundness：By microscope and visually observe judgement, flat appearance is smooth, is at spherical shape
Excellent, flat appearance, almost spherical are good, and appearance is rough and uneven in surface, is poor not at spherical shape.B) friability：≤ 5% be judged to it is excellent ,≤
10% is judged to qualification, and ＞ 10% is unqualified.Method：Using fluidized-bed coating machine, setup parameter：Wind turbine frequency 30Hz, jet
Pressure 0.12Mpa, time 10min, sample are weighed after being sieved with regulation sieve (60 mesh sieve) before and after fluidizing, and secondary weighing mitigates
Weight percent be friability.
1, the type of adhesive
According to composition, adhesive may be selected：The ethyl alcohol of sucrose solution (syrup), starch slurry and Utech L100 is water-soluble
Liquid, while 3% hydroxypropyl methylcellulose (HPMC 5CP) aqueous solution is investigated as adhesive etc..Preliminary result shows：Starch slurry
Atomizing effect is bad, 1~3% Utech L100 ethanol solutions, and pellet adhesion is serious.Therefore mainly molten with sucrose when formulation study
Liquid and hydroxypropyl methylcellulose aqueous solution are adhesive.
The results are shown in Table 2：A) merely using sucrose solution (10~30%) or hydroxypropyl methylcellulose aqueous solution as adhesive,
The vegetable pill friability being prepared is slightly worse or even unqualified, and it is broken that pellet occurs in coating process.B) in order to increase pellet hardness,
Increase sucrose solution concentration (40~60%), viscosity also increases therewith, and operation critical point is less susceptible to control, and adhesion, knot easily occurs
Block, but pellet hardness significantly improves.This whitewashes to low concentration sucrose solution, and excessive raising pellet hardness is similar, and same problem is also
The easy adhesion of pellet, caking.C) while in order to increase adhesive dosage of sucrose, the viscosity of solution is reduced, is added wherein certain
Ethyl alcohol is measured, by screening 50% ethanol solution of 40% sucrose, is met the requirements.
2, powder supply material amounts
According to cane sugar core (30~40 mesh of particle diameter distribution) is selected ambroxol hydrochloride vegetable pill (24~30 is prepared for starting capsule core
Mesh), for powder material：The ratio for originating capsule core is 1.5~3: 1, can determine powder supply object jointly according to content of dispersion, pellet granule size etc.
The ratio of material and starting capsule core.
3, for powder material composition
Ambroxol hydrochloride vegetable pill preparation prescription composition is as follows, the results are shown in Table 1.
The different prescriptions of table 1
2 prescription result of table
As a result：A) the above prescription can prepare the drug containing vegetable pill of 24~30 mesh, but friability differs greatly, wherein bonding
The dosage of agent plays the role of key.In pelletizing process, only pellet surface is started to supply by under the abundant wetting conditions of adhesive
The long ball of powder just can guarantee that the friability of pellet meets coating and requires, that is, increase binder dosage.Since the group of cane sugar core becomes
Sucrose, contacted with water it is soluble tacky, therefore, the present invention pass through in sucrose solution add certain proportion ethyl alcohol, ensure bonding
While agent dosage of sucrose, the viscosity of syrup is reduced.50% ethanol solution of 40% sucrose of final choice is adhesive.B) pass through
Adjust cane sugar core dosage, binder dosage, for powder material prescription and dosage, the final appearance for ensureing ambroxol hydrochloride vegetable pill,
Roundness and friability are met the requirements.
Conclusion：According to prescription screening and optimum results, 6. vegetable pill that final prescription is prepared, appearance is good, smooth,
Roundness is good, and friability is excellent, meets coating and requires.Therefore, ambroxol hydrochloride vegetable pill preparation prescription is determined substantially.
Meanwhile the present invention is on this basis, with prescription 6. on the basis of, the preparation method of binder solution is：Take purifying
After water heating is boiled, sucrose is added, stirring and dissolving simultaneously continues to boil 20-40min, 25% sucrose solution is made, then herein
0.1~0.3% magnesium laurylsulfate is added in solution, forms binder solution.Simultaneously two are added on the basis of being formulated 6.
Silica (pharmaceutical grade) 1.5% and magnesium stearate 0.5%, the result is that：Appearance is good, surfacing, and roundness is good；Friability is excellent,
Qualification, pellet is broken few, meets coating demand.
Embodiment 2 (20,000/batches)
Vegetable pill formula (weight)：Cane sugar core 1.10Kg, ambroxol hydrochloride 1.5Kg, sucrose 1.5Kg, starch 0.30Kg glue
Mixture solution materials：Sucrose 0.536Kg, purified water 0.402Kg；Ethyl alcohol 0.402Kg；
Sustained release coating：Utech L100 192.0g, sucrose 96.0g, talcum powder 38.4g, purified water 0.911Kg, ethyl alcohol
5.163Kg。
Production technology：
(1) preparation of vegetable pill
A) preparation of binder solution：Sucrose, purified water and ethyl alcohol are taken, sucrose is dissolved in purified water saturating to clarifying
It is bright, ethyl alcohol is added afterwards, is finally configured to a concentration of 50% (volume ratio) of ethyl alcohol, and sucrose concentration is the bonding of 40% (mass ratio)
Agent solution, it is spare；
B) it is mixed for powder material：Ambroxol hydrochloride, cane sugar powder and starch are taken, is put into mixing machine, is uniformly mixed；
C) prepared by vegetable pill：Using cane sugar core as parent nucleus, it is whitewashing for powder and binder solution to use for powder material, is used
Centrifugal granulating seed-coating machine prepares vegetable pill by powder bed area method；Specially：Cane sugar core is added and is granulated in pot, host is adjusted
100~180rpm of rotating speed, 5~10L/ of 0.12~0.16MPa of whiff pressure, 10~16L/min of spray air flow and air blast flux
Min makes cane sugar core that preferable rollover states be presented；Meanwhile will be added in feeder for powder material, it is spare；It gradually increases
Revolution speed whitewash to 15~20rpm, until after cane sugar core fully soaks；Powder supply is opened, powder supply machine 40~50rpm of rotating speed is controlled,
Powder supply/whitewashing balance is adjusted, makes the uniform lamination of powder on parent nucleus.
D) dry：Using fluidized bed drying, drying temperature is 50 DEG C, 2 hours drying times, drying to moisture≤
2%, ethanol content≤0.05%；
E) it sieves：24 mesh, 30 mesh sieve are crossed, the vegetable pill between 24~30 mesh is taken, it is spare；
(2) preparation of sustained release coating liquid：Youteqi L100 is dissolved in ethyl alcohol to clear, it is spare；Sucrose is molten
Solution in purified water to being added remaining ethyl alcohol and talcum powder after clear, it is high-shear homogenizing uniformly, then be transferred to Utech L100
In ethanol solution, coating process persistently stirs, spare；
(3) sustained release coating：Using Multifunctional coating granulation machine equipment, coating mode is sprayed by fluid bed bottom, by coating solution
It is coated on the vegetable pill surface of 24~30 mesh, constitutes sustained-release coating layer；Specially：Will vegetable pill be added machine material trough in, set into
35 ± 5 DEG C of air temperature, 25 ± 5 DEG C of leaving air temp, 30~35Hz of wind turbine frequency, 0.1~0.2MPa of whiff pressure；Start, waits for object
After material temperature degree reaches set temperature, starts hydrojet to coating and terminate, 6~14Hz of hydrojet frequency；Subsequently into drying stage.
(4) dry：Drying temperature is 50 DEG C, removes and is coated remaining ethyl alcohol, and control moisture is less than 2%, ethanol content≤
0.05%；50 DEG C of inlet air temperature, drying time >=2h；
(5) it sieves：20 mesh, 40 mesh sieve are crossed, adhesion and broken pellet are screened out；
(6) intermediate detects：Measure pellet content of dispersion after being coated；
(7) capsule is loaded：According to intermediate testing result, capsule weight is calculated, and load capsule.
(8) it packs：It is aluminum-plastic packaged, mounted box, vanning, storage.Examination and test of products report is as shown in Table 3-5.
3 Sustained Release Ambroxol Hydrochloride Capsules of table batch survey report
| The inspection name of an article claims | Sustained Release Ambroxol Hydrochloride Capsules | Specification | 75mg |
| Censorship unit | Double crane favorable to the people medicine company (Jinan) Co., Ltds in China Resources | Lot number | 130708 |
| The date of inspection | 2013.8.1 | Report the date | 2013.8.12 |
| Specification standards | Report production quality standard | Examine purpose | Full inspection |
| Proofer | King * * | Review person | Grandson * * |
Inspection result：
Conclusion：This product is examined by appended Sustained Release Ambroxol Hydrochloride Capsules production with quality standard, and regulation is as a result met.
4 methodology sample survey summary sheet of table
5 standard stability of table investigates result
The long-term stable experiment of the product is as follows.
(1) accelerated test
By this product, 130708 batches are put into climatic chamber 6 months, are sampled respectively at 0,1,2,3,6 month, measure every
Index the results are shown in Table 6.
40 DEG C of 6 Sustained Release Ambroxol Hydrochloride Capsules of table, RH75% accelerated tests result (130708 batches)
(2) intermediate experiment
By this product, 130708 batches are put into climatic chamber 6 months, are sampled respectively at 0,1,2,3,6 month, measure every
Index the results are shown in Table 7.Investigation condition：30 DEG C ± 2 DEG C of temperature, humidity 65% ± 5%.
30 DEG C of 7 Sustained Release Ambroxol Hydrochloride Capsules of table, RH65% accelerated tests result (130708 batches)
(3) long term test
It by this product 130708 batches, was sampled respectively at 0,3,6,9,12 month, measures indices, the results are shown in Table 8.
Investigation condition：25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 5%.
8 Sustained Release Ambroxol Hydrochloride Capsules long-term test results of table (130708 batches)
Note："-" expression does not carry out this inspection.
9 research conclusion of table
| Interior packaging material | Aluminium-plastic bubble plate packing |
| Holding conditions | Shading is sealed. |
| The term of validity | Fix tentatively is 24 months |
| Prompt to related content in specification | Shading is sealed. |
Embodiment 3 (20,000/batches)
Vegetable pill formula (weight)：Cane sugar core 1.10Kg, ambroxol hydrochloride 1.5Kg, sucrose 1.5Kg, starch 0.30Kg, two
Silica (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：Utech L100 192.0g, sucrose 96.0g, talcum powder 38.4g, purified water 0.56Kg, ethyl alcohol
3.84Kg。
Production technology：
(1) preparation of vegetable pill
A) preparation of binder solution：After taking purified water heating to boil, sucrose is added, stirring and dissolving simultaneously continues to boil
25% sucrose solution is made in 30min, and magnesium laurylsulfate is then added in this solution, forms binder solution；
B) it is mixed for powder material：Ambroxol hydrochloride, cane sugar powder and starch are taken, is put into mixing machine, is uniformly mixed；
C) prepared by vegetable pill：Using cane sugar core as parent nucleus, it is whitewashing for powder and binder solution to use for powder material, is used
Centrifugal granulating seed-coating machine prepares vegetable pill by powder bed area method；Specially：Cane sugar core is added and is granulated in pot, host is adjusted
100~180rpm of rotating speed, 5~10L/ of 0.12~0.16MPa of whiff pressure, 10~16L/min of spray air flow and air blast flux
Min makes cane sugar core that preferable rollover states be presented；Meanwhile will be added in feeder for powder material, it is spare；It gradually increases
Revolution speed whitewash to 15~20rpm, until after cane sugar core fully soaks；Powder supply is opened, powder supply machine 40~50rpm of rotating speed is controlled,
Powder supply/whitewashing balance is adjusted, makes the uniform lamination of powder on parent nucleus.
D) dry：Using fluidized bed drying, drying temperature is 50 DEG C, 1~2 hour drying time, dry to moisture
≤ 2%；
E) it sieves：24 mesh, 30 mesh sieve are crossed, the vegetable pill between 24~30 mesh is taken, it is spare；
(2) preparation of sustained release coating liquid：Youteqi L100 is dissolved in ethyl alcohol to clear, it is spare；Sucrose is molten
Solution in purified water to being added remaining ethyl alcohol and talcum powder after clear, it is high-shear homogenizing uniformly, then be transferred to Utech L100
In ethanol solution, coating process persistently stirs, spare；
(3) sustained release coating：Using Multifunctional coating granulation machine equipment, coating mode is sprayed by fluid bed bottom, by coating solution
It is coated on the vegetable pill surface of 24~30 mesh, constitutes sustained-release coating layer；Specially：Will vegetable pill be added machine material trough in, set into
35 ± 5 DEG C of air temperature, 25 ± 5 DEG C of leaving air temp, 30~35Hz of wind turbine frequency, 0.1~0.2MPa of whiff pressure；Start, waits for object
After material temperature degree reaches set temperature, starts hydrojet to coating and terminate, 6~14Hz of hydrojet frequency；Subsequently into drying stage.
(4) dry：Drying temperature is 50 DEG C, removes and is coated remaining ethyl alcohol, and control moisture is less than 2%, ethanol content≤
0.05%；50 DEG C of inlet air temperature, drying time >=2h；
(5) it sieves：20 mesh, 40 mesh sieve are crossed, adhesion and broken pellet are screened out；Then capsule is loaded, is packed, storage.
Examination and test of products report is as Table 10-11.
10 Sustained Release Ambroxol Hydrochloride Capsules of table batch survey report
| The inspection name of an article claims | Sustained Release Ambroxol Hydrochloride Capsules | Specification | 75mg |
| Censorship unit | Double crane favorable to the people medicine company (Jinan) Co., Ltds in China Resources | Lot number | 131001 |
| The date of inspection | 2013.10.1 | Report the date | 2013.11.10 |
| Specification standards | Report production quality standard | Examine purpose | Full inspection |
| Proofer | King * * | Review person | Grandson * * |
Inspection result：
Conclusion：This product is examined by appended Sustained Release Ambroxol Hydrochloride Capsules production with quality standard, and regulation is as a result met.
11 standard stability of table investigates result
Long term test：It was sampled respectively at 0,3,6,9,12 month, indices is measured, the results are shown in Table 12.Investigate item
Part：25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 5%.
12 Sustained Release Ambroxol Hydrochloride Capsules long-term test results of table (131001 batches)
Note："-" expression does not carry out this inspection.
Claims (5)
1. a kind of Sustained Release Ambroxol Hydrochloride Capsules, characterized in that be made of vegetable pill and sustained release coating, the mass ratio of the two is 100：
6.0~7.5；
The vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, 75 parts of ambroxol hydrochloride, sucrose
70~75 parts, 15~20 parts of starch, 0~1 part of magnesium stearate, 55~75 parts of binder solution；The preparation of described adhesive solution
Method is：Sucrose, purified water and ethyl alcohol are taken, sucrose is dissolved in purified water to clear, adds ethyl alcohol afterwards, it is final to prepare
At a concentration of the 50% of ethyl alcohol, binder solution that sucrose concentration is 40%；
Or the vegetable pill is made of the raw material of following weight parts：55 parts of the cane sugar core of 30~40 mesh, 75 parts of ambroxol hydrochloride,
70~75 parts of sucrose, 15~20 parts of starch, 2~3 parts of silica, 0.5~1 part of magnesium stearate, 55~75 parts of binder solution；
The preparation method of described adhesive solution is：After taking purified water heating to boil, sucrose is added, stirring and dissolving simultaneously continues to boil 20-
25% sucrose solution is made in 40min, and 0.1~0.3% magnesium laurylsulfate is then added in this solution, forms bonding
Agent solution；
The sustained release coating is made of the raw material of following weight parts：6 parts of Utech L100,3 parts of sucrose, talcum powder 1.0~1.5
Part, 100~270 parts of ethyl alcohol, 15~35 parts of purified water.
2. a kind of Sustained Release Ambroxol Hydrochloride Capsules as described in claim 1, characterized in that the grain size of the vegetable pill is 24~30
Mesh.
3. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 1 or 2, characterized in that include the following steps：
(1) preparation of vegetable pill
A) binder solution is prepared；
B) it is mixed for powder material：Raw material of the vegetable pill in addition to cane sugar core and binder solution is taken, is put into mixing machine, mixing is equal
It is even；
C) prepared by vegetable pill：Using cane sugar core as parent nucleus, it is whitewashing for powder and binder solution to use for powder material, using centrifugation
Granulation coating machine prepares vegetable pill by powder bed area method；
D) dry：Using fluidized bed drying, drying temperature is 50 DEG C, dry to moisture≤2%；
E) it sieves：24 mesh, 30 mesh sieve are crossed, the vegetable pill between 24~30 mesh is taken, it is spare；
(2) preparation of sustained release coating liquid：Utech L100 is dissolved in ethyl alcohol to clear, it is spare；Sucrose is dissolved in
It is high-shear homogenizing uniform to the remaining ethyl alcohol of addition after clear and talcum powder in purified water, then it is transferred to Utech L100 ethyl alcohol
In solution, coating solution is made, coating process persistently stirs, spare；
(3) sustained release coating：Using Multifunctional coating granulation machine equipment, coating mode is sprayed by fluid bed bottom, coating solution is coated
On the vegetable pill surface of 24~30 mesh, sustained-release coating layer is constituted；
(4) dry：Drying temperature is 50 DEG C, drying time >=2h；
(5) it sieves：20 mesh, 40 mesh sieve are crossed, adhesion and broken pellet are screened out；Then capsule is loaded, is packed, storage.
4. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 3, characterized in that the step c is：By sugarcane
Sugar-pill core, which is added, to be granulated in pot, and 100~180rpm of adjustment engine speed, 0.12~0.16MPa of whiff pressure, spray air flow 10~
5~10L/min of 16L/min and air blast flux makes cane sugar core that rollover states be presented；Meanwhile charging will be added to for powder material
It is spare in device；Whitewashing revolution speed is gradually increased to 15~20rpm, until after cane sugar core fully soaks；Powder supply is opened, control supplies
Powder machine 40~50rpm of rotating speed, adjustment powder supply/whitewashing balance, makes the uniform lamination of powder on parent nucleus.
5. the production technology of Sustained Release Ambroxol Hydrochloride Capsules as claimed in claim 3, characterized in that the step (3) is：It will
Vegetable pill is added in the machine material trough of Multifunctional coating granulator, 35 ± 5 DEG C of inlet air temperature of setting, 25 ± 5 DEG C of leaving air temp, wind
30~35Hz of unit frequency, 0.1~0.2MPa of whiff pressure；Start, after temperature of charge reaches set temperature, starts hydrojet to packet
Clothing terminates, 6~14Hz of hydrojet frequency；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 |
|---|
| Modified release capsules of Ambroxil, Preformulation and evaluation;Abdul Althaf. S etal;《Pelagia Research Library》;20111231;第2卷(第3期);第1-19页 * |
| 盐酸氨溴索包衣小丸的制备及其释药特性;张立超等;《中国医院药学杂志》;20020131;第22卷(第1期);第11-13页 * |
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