CN107184555A - A kind of Procaterol Hydrochloride granule and preparation method thereof - Google Patents
A kind of Procaterol Hydrochloride granule and preparation method thereof Download PDFInfo
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- CN107184555A CN107184555A CN201710409682.5A CN201710409682A CN107184555A CN 107184555 A CN107184555 A CN 107184555A CN 201710409682 A CN201710409682 A CN 201710409682A CN 107184555 A CN107184555 A CN 107184555A
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
Abstract
The invention belongs to field of medicaments, it is related to a kind of Procaterol Hydrochloride granule and preparation method thereof.The auxiliary material that Procaterol Hydrochloride granule is made up of by Procaterol Hydrochloride and at least lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, calcium chloride and palmityl aspartic acid diethylester is made.The granule is prepared using fluidization spray method, using calcium chloride as master batch, the suspension that Procaterol Hydrochloride is prepared with mannitol, hydroxypropyl methyl cellulose, Ac-Di-Sol and palmityl aspartic acid diethylester is sprayed onto calcium chloride master batch surface and is prepared from.The granule dissolves high fast not card larynx, uniform content degree, mobility height, hygroscopicity is low, friability is low, stability is high, and its preparation method technique is simple, relatively low to equipment requirement, power consumption is low is easy to industrialized production.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of Procaterol Hydrochloride granule and preparation method thereof.
Background technology
Procaterol Hydrochloride, English name Procaterol Hydrochloride, chemical name 5- (1- hydroxyl -2- isopropyls
Amido butyl) -8- carboxyquinolone hydrochloride semi-hydrates, molecular formula C16H22N2O3·HCl·1/2H20, molecular weight
335.83, CAS 62929-91-3, are to imitate beta 2 adrenoreceptor agonists in one kind, on the kidneys of β 2 of bronchial smooth muscle
Adrenoceptor has higher selectivity, can diastole bronchial smooth muscle, and with certain anti-allergic effects and promote breathe
Road ciliary movement effect, has been approved in bronchial astehma, asthmatic bronchitis, has increased with bronchial reactivity
The treatment of the diseases such as acute bronchitis, chronic obstructive pulmonary disease.It is used for the clinic for treating pneumonia alone or in combination on Procaterol Hydrochloride
Experiment also has shown that good effect（Chou Lihua, Li Na ambroxol hydrochlorides add Procaterol Hydrochloride to treat infantile pneumonia
Clinical observation on the therapeutic effect [J] modern diagnosis and treatment, 2014, (5): 1061-1062）.Current China's approved Sichuan great Zhong
Procaterol Hydrochloride and its drug product formulation listing of 14 enterprises such as pharmaceutical Co. Ltd.Its pharmaceutical dosage form majority is piece
Agent, there is also capsule and oral solution dosage form in addition.Procaterol Hydrochloride granule is on only a product goes through at present
City（Chen Aiying, Xu Shifang, Jiang Li rosy clouds high effective liquid chromatography for measuring procaterol hydrochloride dropping pill contents and relevant material [J]
Journal of Chinese Hospital Pharmacy, 2007,27（05）：703-704.）.
Procaterol Hydrochloride belongs to the medicine of denier administration, is administered daily 1~2 time, and children 25 μ g every time, adult is each
50μg.Dosage is very few to cause to lack drug effect, medication excess may then cause cardiac arrhythmia, tachycardia, blood pressure reduction,
Many adverse reactions such as chatter, neuroticism, hypopotassaemia, hyperglycaemia.Need to remove medicine by methods such as gastric lavages if necessary,
And need according to adverse reaction symptom emergent management.When there are the adverse reactions such as cardiac arrhythmia, using the beta-blocker meeting such as inderal
There is certain improvement, but airway resistance may be made to increase.Therefore, the uniform content sex chromosome mosaicism of Procaterol Hydrochloride peroral dosage form
It is to influence one of principal element of patient medication safety.Good content uniformity, not only contributes to the maintenance of drug effect, also favorably
In the toxic side effect that reduction is unnecessary.
On the other hand, the characteristics of asthma attack often has acute attack, and the weaker patient of system such as children and old age
It is relatively many.Often compliance is poor for children, not only needs to solve the problems, such as taste through adding sweetener etc. in oral formulations,
Also need to solve the problems, such as the card larynx of children, i.e. oral solid formulation into children it is intraoral after due to can not water swelling rapidly
Produce disintegration and absorb, the problem of causing dysphagia.And gerontal patient is reduced due to salivary secretion, equally exist this and ask
Topic.
In addition, Procaterol Hydrochloride is easily aoxidized in the presence of moisture and air, therefore spray inhalation administration is unfavorable for
Its medicine stability, at present foreign countries researching and developing its Foradil Aerolizer formoterol fumarate with overcome its be easy to oxidation, the term of validity is short the problem of.Pharmacy
Company Parke-Davis/Warner-Lambert had studied early in 1984 it is a kind of prevent Procaterol Hydrochloride aoxidize
Stabilizer, the stabilizer is made up of the ammonium salt of monovalent metal and Texapon Special, can be improved hydrochloric acid third under sour environment and block
The oxidation resistance of special sieve, but the stabilizer has not been put to business application so far, it may be possible to due to its human-body safety sex chromosome mosaicism or
Stablizing effect is still undesirable and is abandoned（U.S. Patent Publication No. US4616022 A, applicant Warner-Lambert
Company, 1984 applyings date August 17 days）.Therefore, how by changing pharmaceutical formulation or preparation technology, improve hydrochloric acid third and block
The oxidation resistance and stability of special sieve, are one of current Procaterol Hydrochloride preparation technique urgent problems to be solved.
For above-mentioned technical problem, Chinese patent literature CN105232470A discloses a kind of particle of Procaterol Hydrochloride
Agent and preparation method thereof.The particle diameter of Procaterol Hydrochloride particle is reduced by spray-on process dispersion method（The scattered particle diameter of spraying
Generally 40~80 μm）, passed through freeze-drying so that forming porous destructing in Procaterol Hydrochloride particle, and in granule
More disintegrant and hygroscopic agent is added in prescription.This method is by reducing particle diameter, and it is to expand to improve preparation specific surface area
The contact area of medicine and moisture, while strengthen water absorbing capacity using hygroscopicity auxiliary material, using disintegrant and it is lyophilized formed it is many
Pore structure accelerates the disintegration dissolution velocity of drug particles, so as to make the agent dissolving time foreshorten to 8~14 s, so that effectively
The card larynx for solving the problems, such as Procaterol Hydrochloride oral solid formulation.Simultaneously, the technical scheme is molten by configuring medicine
The scattered method of spraying is carried out after liquid, by the stable homogeneous liquid-phase system of solution, Procaterol Hydrochloride oral administration solid is improved
The uniform content degree of preparation.In addition to Chinese patent literature CN105232470A, have not yet to see other documents and disclose on hydrochloric acid
The related technical scheme of Procaterol granule.
However, though CN105232470A technical scheme can reach acceleration using the preparation technology of spraying joint freeze-drying
Medicine dissolves and improves the purpose of solid content uniformity, but this method is to production equipment performance requirement high technology stability
Poor with repeatability, production power consumption is high, and cold drying equipment needs freon as refrigerant, can cause environmental pollution.
On the other hand, CN105232470A technical scheme employs the higher auxiliary material of viscosity, is prepared into thick liquid and then is sprayed
Mist disperses thick liquid and easily blocks the less nozzle of bore, and heavy caliber nozzle is then difficult to prepare the less particle of particle
Agent, so as to significantly reduce the melting speed of Procaterol Hydrochloride particle.The third aspect, is as cold as the Ka Te of hydrochloric acid third of seasoning preparation
Sieve grain structure is loose, is conducive to quick water suction disintegration, but fragility is higher, easily crushes the thinner powder of particle diameter, causes particle
Particle diameter difference is excessive, and needs to add a large amount of lubricants and just can ensure that medicine mobility, solves medicine and is difficult to pour out from the package
The problem of.Fourth aspect, CN105232470A technical scheme has used more hygroscopicity auxiliary material, and specific grain surface product compared with
Greatly, although be conducive to accelerating medicine to dissolve disintegration in mouth, prevent card larynx, but because its hygroscopicity is stronger, easy moisture absorption hair
Raw deliquescence, causes medicine stability to reduce.
In summary, granule can reduce solid pharmaceutical preparation particle diameter, improve Procaterol Hydrochloride melting speed；By medicine
The spraying of solution is scattered can to improve the uniform content degree of main ingredient in the formulation；By can by desivac and disintegrant, hygroscopic agent
The melting speed for further improving Procaterol Hydrochloride particle solves the problems, such as the card larynx of its oral solid formulation.But current hydrochloric acid third
Quattro granule still suffers from the problems such as stability is low, hygroscopicity is high, friability is high and preparation technology is higher to equipment requirement,
And often extension Procaterol Hydrochloride granule dissolves disintegration rate for the solution of hygroscopicity, friability problem, technically
In the presence of the problem conditioned each other.At present need solve the problems, such as Procaterol Hydrochloride particle card larynx, uniform content degree problem it is same
When solve the problem of its stability is low, hygroscopicity is high, friability is high and preparation technology is higher to equipment requirement.
The content of the invention
For above-mentioned complicated technical problem present in prior art, it is an object of the invention to provide a kind of new hydrochloric acid
Procaterol granule.
To achieve the above object, technical scheme is as follows：
A kind of Procaterol Hydrochloride granule, is made up of Procaterol Hydrochloride and pharmaceutically acceptable pharmaceutic adjuvant, wherein
It is described
Pharmaceutically acceptable pharmaceutic adjuvant at least includes：Lactose, hydroxypropyl methyl cellulose, cross-linked carboxymethyl cellulose
Sodium, calcium chloride and palmityl aspartic acid diethylester.
It is preferred that, Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, friendship in the Procaterol Hydrochloride granule
Connection sodium carboxymethylcellulose, the weight part ratio of calcium chloride and palmityl aspartic acid diethylester are：The weight of Procaterol Hydrochloride 1~4
Measure part, the parts by weight of lactose 12000~14000, the parts by weight of hydroxypropyl methyl cellulose 600~800, Ac-Di-Sol
The parts by weight of parts by weight 400~700, the parts by weight of calcium chloride 3900~5100, the parts by weight of palmityl aspartic acid diethylester 1~5..
It is preferred that, Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, friendship in the Procaterol Hydrochloride granule
Connection sodium carboxymethylcellulose, the weight part ratio of calcium chloride and palmityl aspartic acid diethylester are：The weight of Procaterol Hydrochloride 2
Part, the parts by weight of lactose 13970, the parts by weight of hydroxypropyl methyl cellulose 620, the weight of Ac-Di-Sol parts by weight 550
Part, the parts by weight of calcium chloride 5080, the parts by weight of palmityl aspartic acid diethylester 2.
It is preferred that, Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, friendship in the Procaterol Hydrochloride granule
Connection sodium carboxymethylcellulose, the weight part ratio of calcium chloride and palmityl aspartic acid diethylester are：The weight of Procaterol Hydrochloride 3
Part, the parts by weight of lactose 12650, the parts by weight of hydroxypropyl methyl cellulose 750, the weight of Ac-Di-Sol parts by weight 650
Part, the parts by weight of calcium chloride 3940, the parts by weight of palmityl aspartic acid diethylester 4.
It is preferred that, Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, friendship in the Procaterol Hydrochloride granule
Connection sodium carboxymethylcellulose, the weight part ratio of calcium chloride and palmityl aspartic acid diethylester are：The weight of Procaterol Hydrochloride 2
Part, the parts by weight of lactose 12800, the parts by weight of hydroxypropyl methyl cellulose 700, the weight of Ac-Di-Sol parts by weight 600
Part, the parts by weight of calcium chloride 4500, the parts by weight of palmityl aspartic acid diethylester 3.
It is preferred that, the pharmaceutically acceptable pharmaceutic adjuvant also includes flavouring and colouring agent.
Another aspect of the present invention additionally provides a kind of preparation technology of above-mentioned Procaterol Hydrochloride granule, including following
Step：
1）Take recipe quantity calcium chloride to crush, cross the mesh sieve of 280 mesh~400, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl
Aspartic acid diethylester, ball milling mixing, the ratio for adding 3~6ml water according to every 1g powder is added into mixed-powder goes out
Bacterium water for injection, 600~1000rpm stirs 0.15~0.45h and obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, using at the top of fluid bed
Spraying granulation, fluidized bed atomization 1.8~2.4BAR of pressure, EAT is 74~92 DEG C, intake velocity 86~107
m3/ h, peristaltic pump hydrojet 12~18ml/min of speed, 0.5~1.0mm of nozzle diameter；
4）After hydrojet has been sprayed, adjustment EAT is 65~75 DEG C of 1~3h of fluidized drying, is produced.
It is preferred that, above-mentioned steps 1）Middle calcium chloride crosses 300 mesh sieves；Step 2）Middle amount of water is to add 5ml water per 1g powder,
Mixing speed is 800~900rpm, and mixing time is 0.3h；Step 3）Middle fluidized bed atomization pressure is 2.1 BAR, EAT
For 82 DEG C, intake velocity is 95 m3/ h, peristaltic pump hydrojet speed is 15ml/min, and nozzle diameter is 0.7 mm；Step 4）In
EAT is 70 DEG C, and drying time is 1.5 h.
Lactose CAS described in technical scheme is 10039-26-6, and its quality standard is recorded in 2015
Chinese Pharmacopoeia four；The hydroxypropyl methyl cellulose entitled Hypromellose of English described in technical scheme,
Claim hydroxypropyl methylcellulose, No. CAS is 9004-65-3, and its quality standard is recorded in Chinese Pharmacopoeia four in 2015；The skill of the present invention
Ac-Di-Sol CAS described in art scheme is 74811-65-7, and its quality standard is recorded in China in 2015
Pharmacopeia four；Calcium chloride described in technical scheme is commonly used for filler in the solid dosage forms such as tablet, granule,
Its quality standard is recorded in Chinese Pharmacopoeia four in 2015；Palmityl aspartic acid diethyl described in technical scheme
Ester, No. CAS is 3397-14-6, belongs to surfactant, this is known in those skilled in the art.
Applicant of the present invention's discovery beyond expectation in an experiment, palmityl aspartic acid diethylester can be remarkably promoted
Dissolving and being disintegrated for Procaterol Hydrochloride granule, still is able to preferably solve Procaterol Hydrochloride granule under greater particle size
Card larynx problem；Using the calcium chloride powder of certain particle diameter as master batch, by Procaterol and filler, adhesive, disintegrant
Prepare suspension, the Procaterol Hydrochloride granule that spray-fluidized method is sprayed onto the preparation of calcium chloride master batch surface both has and preferably contained
Measure homogeneity, it may have preferable mobility, relatively low friability and relatively low hygroscopicity, prepared Procaterol Hydrochloride
The preparation stability of granula and the stability of main ingredient Procaterol Hydrochloride are higher.And the preparation technology used can realize a step
Granulation, step is simple, it is relatively low, relatively low to equipment requirement to consume energy, it is adaptable to large-scale industrial production.In addition, the present invention
Procaterol Hydrochloride granule supplementary product consumption is remained to needed for reaching considerably less than the Procaterol Hydrochloride granule of prior art
Uniform content degree.
Embodiment
Below in conjunction with the explanation present invention of specific embodiment in detail, the embodiment is only used for explaining the technical side of the present invention
Case, it is impossible to be interpreted as limiting protection scope of the present invention.
The Procaterol Hydrochloride granule of embodiment 1 and its preparation technology
Prescription：Procaterol Hydrochloride 2g, lactose 13970g, the g of hydroxypropyl methyl cellulose 620, Ac-Di-Sol weight
Measure part 550g, calcium chloride 5080g, the g of palmityl aspartic acid diethylester 2.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 5ml water according to every 1g powder adds sterilized water for injection into mixed-powder
900rpm stirrings 0.3h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The Procaterol Hydrochloride granule of embodiment 2 and its preparation technology
Prescription：The g of Procaterol Hydrochloride 3, the g of lactose 12650, the g of hydroxypropyl methyl cellulose 750, Ac-Di-Sol
The g of parts by weight 650, calcium chloride 3940g, the g of palmityl aspartic acid diethylester 4.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 5ml water according to every 1g powder adds sterilized water for injection into mixed-powder
850rpm stirrings 0.3h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The Procaterol Hydrochloride granule of embodiment 3 and its preparation technology
Prescription：The g of Procaterol Hydrochloride 2, lactose 12800g, the g of hydroxypropyl methyl cellulose 700, Ac-Di-Sol
Parts by weight 600g, the g of calcium chloride 4500, the g of palmityl aspartic acid diethylester 3.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 5ml water according to every 1g powder adds sterilized water for injection into mixed-powder
800rpm stirrings 0.3h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The Procaterol Hydrochloride granule of embodiment 4 and its preparation technology
Prescription：The g of Procaterol Hydrochloride 4, the g of lactose 12050, the g of hydroxypropyl methyl cellulose 610, Ac-Di-Sol
The g of parts by weight 410, calcium chloride 4900g, palmityl aspartic acid diethylester 1g.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 5ml water according to every 1g powder adds sterilized water for injection into mixed-powder
800rpm stirrings 0.3h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The Procaterol Hydrochloride granule of embodiment 5 and its preparation technology
Prescription：The g of Procaterol Hydrochloride 1, the g of lactose 13528, hydroxypropyl methyl cellulose 790g, Ac-Di-Sol
Parts by weight 680g, calcium chloride 5000g, palmityl aspartic acid diethylester 1g.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 5ml water according to every 1g powder adds sterilized water for injection into mixed-powder
820rpm stirrings 0.3h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The galenic pharmacy of the Procaterol Hydrochloride granule of embodiment 6 is investigated
Respectively using the granule of embodiment 1-5 preparations as investigation object.Hydrochloric acid third is blocked to investigate different prescriptions and preparation technology
The influence of special sieve granular preparation feature, special standby comparative example once：
Comparative example 1 (is prepared) using the prescription and preparation technology of patent document CN105232470A embodiments 1:
Prescription：Procaterol Hydrochloride 2g, lactose 12000g, mannitol 24000g, fructose 720g, trehalose 640g, maltodextrin
2400g, superfine silica gel powder 8g, xanthans 160g, PVP K30 40g.
Preparation technology：Above-mentioned former, auxiliary material, the 320L that adds water dissolvings, atomizing freeze drying, nozzle diameter 1.5mm, atomizing pressure
0.2MPa, -45 DEG C of initial freezing temperature, vacuum 7Pa, low-temperature distillation is dried 8 hours, is produced.
Comparative example 2:Prescription（Be the same as Example 1）：Procaterol Hydrochloride 2g, lactose 13970g, hydroxypropyl methyl cellulose
620 g, the 0g of Ac-Di-Sol parts by weight 55, the g of calcium chloride 5080, the g of palmityl aspartic acid diethylester 2.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 500 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 8ml water according to every 1g powder adds sterilized water for injection into mixed-powder
1200rpm stirrings 0.5h obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.0BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
Comparative example 3:Prescription (no palmityl aspartic acid diethylester)：Procaterol Hydrochloride 1g, lactose 14000g, hydroxypropyl
Ylmethyl cellulose 800g, the g of Ac-Di-Sol parts by weight 700, calcium chloride 5000g.
Preparation technology：
1）Take recipe quantity calcium chloride to crush, cross 300 mesh sieves, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, ball milling mixing,
The ratio for adding 5ml water according to every 1g powder adds sterilized water for injection 900rpm stirrings 0.3h into mixed-powder and must be suspended
Liquid；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization pressure 2.1BAR, and EAT is 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment EAT is 70 DEG C of fluidized drying 1.5h, is produced.
The project and result that galenic pharmacy is investigated are as follows：
（1）Granularity and size distribution are investigated：
The Procaterol Hydrochloride granule that respectively prepared by Example 1-5 and comparative example 1-3, is surveyed by laser particle size analyzer
It is fixed
The average grain diameter of each group granule sample, median, peak diameter, D10（Particle diameter accounts for total number of particles less than its particle
10%）、D90（Particle diameter accounts for the 90% of total number of particles less than its particle）Deng relevant parameter.As a result it see the table below：
As seen from the above table, the granule average grain diameter that prepared by comparative example 1 is minimum, is conducive to quick dissolving scattered, but size distribution
Difference is maximum.The granule average grain diameter of comparative example 2 is higher than embodiment 1, because the prescription of comparative example 2 is same as Example 1 but system
Standby technique is different, therefore process variations are probably to cause the reason for its particle diameter is different.Granule average grain diameter prepared by comparative example 3
It is close with embodiment 3,4, and size distribution difference and embodiment 1-5 illustrate to remove palmityl asparagus fern in prescription without significant difference
Propylhomoserin diethylester does not make significant difference to granule size distribution and average grain diameter.
Granule particle diameter prepared by embodiment 1-5 is larger relative to comparative example 1, but particle diameter distribution difference is smaller.Illustrate this
The Procaterol Hydrochloride granule prescription and preparation method of invention have the advantages that particle size differences are small.
（2）Leach time limit investigation：
Electric-heated thermostatic water bath prepares 37 DEG C of warm water and is used to simulating oral cavity environment, respectively Example 1-5 and comparative example 1-3 systems
Standby
Water is added dropwise in each 0.5g of Procaterol Hydrochloride granule, the ratio for adding 37 DEG C of water of 5ml according to every g particulates, is dripped in 30 seconds
It is complete.The timing since the completion of dropping, metering granule leaches the required time completely.As a result it see the table below.
As seen from the above table, the granule that prepared by embodiment 1-5 leaches the time limit and is below 9 seconds, needed for the granule for being shorter than comparative example 1
Leach the time, the granule of comparative example 3 leached the time limit more than 29 seconds, far above embodiment 1-5 and the particle of comparative example 1 and 2
The time is leached needed for agent, shows that palmityl aspartic acid diethylester dissolves disintegration with aobvious to Procaterol Hydrochloride granule
Write facilitation.The time is leached higher than embodiment 1-5 needed for the granule of comparative example 2, illustrates preparation technology less than comparative example 3
Difference can also influence granule to leach the time.Visible, the palmityl aspartic acid diethyl with reference to granularity and size distribution investigation result
Ester is to larger Procaterol Hydrochloride particle（Average grain diameter is more than 100 μm）Still there is significant dissolution to dissipate effect.
（3）Uniform content degree is investigated：
The Ka Te of hydrochloric acid third in the high effective liquid chromatography for measuring granule announced using Chinese ministry standard WS1- (X-114) -96Z
The content of sieve.It is filler with octadecylsilane chemically bonded silica, with sodium dihydrogen phosphate, (sodium dihydrogen phosphate 11.04g is used
Water dissolves and is diluted to 1000ml, with ± the 0.05)-methanol (83 of phosphorus acid for adjusting pH value 3.10:17) it is mobile phase；Detection wavelength
For 259nm.
Each 6 batches of the Procaterol Hydrochloride particle that respectively prepared by Example 1-5 and comparative example 1-3, every crowd of 10g；Efficiently
Liquid chromatogram
Method determines the Procaterol Hydrochloride content of every batch of sample, and calculates its relative standard deviation.As a result it see the table below.
As seen from the above table, the relative standard deviation of granule uniform content degree prepared by comparative example 2（%）Higher than 2.0%, homogeneity
It is poor；The relative standard deviation of Procaterol Hydrochloride content in granule prepared by embodiment 1-5（%）1.5% is below, and it is low
In the granule of comparative example 1, illustrate that granule uniform content degree prepared by embodiment 1-5 is higher than comparative example 1,2.
The granule uniform content degree of comparative example 2 is less than granule prepared by embodiment 1-5, illustrates preparation technology difference pair
Uniform content degree has a significant impact；The granule uniform content degree of comparative example 3 is similar to granule prepared by embodiment 1-5, says
Bright palmityl aspartic acid diethylester does not make significant difference to the uniform content degree of Procaterol Hydrochloride granule.
（4）Hygroscopicity is investigated：
Precision weighs each 10g of Procaterol Hydrochloride particle prepared by embodiment 1-5 and comparative example 1-3, is respectively placed in dry cone
In shape bottle, the accurate gross weight for weighing sample+conical flask, is then placed in climatic chamber, 25 DEG C of design temperature, humidity again
75%, opening places the gross weight of accurate determination sample+conical flask after 168h, calculates Moisture percentage.
Moisture percentage (%)=[（After moisture absorption before gross weight-moisture absorption of sample and conical flask sample and conical flask gross weight
Amount）Sample particle weight before/moisture absorption] × 100%.The hydroscopicity result of each group granule see the table below.
As seen from the above table, hydroscopicity is substantially less than comparative example 1 and right after the granule 168h that prepared by embodiment 1-5 and comparative example 2
Ratio 3, illustrating the granule prescription of the present invention just has the advantages that hydroscopicity is low.
（5）Mobility is investigated：
The Procaterol Hydrochloride granule that respectively prepared by Example 1-5 and comparative example 1-3, using BT-1000 powder characteristics
Comprehensive tester is distinguished the angle of repose of Procaterol Hydrochloride particulate samples prepared by testing example 1-5 and comparative example 1-3, put down
Plate angle, apparent density, tap density, decentralization, obtain Carr ' the s slamp values of sample, evaluate its mobility.As a result see below
Table：
As seen from the above table, granule Carr ' the s slamp values that prepared by embodiment 1-5 are above comparative example 1, illustrate the present invention
Granule prescription and its granule mobility that is worth of preparation technology be better than comparative example 1.
（6）Friability is investigated：
The Procaterol Hydrochloride granule that respectively prepared by Example 1-5 and comparative example 1-3, weighs after crossing 300 mesh sieves, respectively
Friability tester is put into, the bead for adding a diameter of 7mm rotates 100 times, collects sample, crosses again after 300 mesh sieves
Weigh.Calculate particle percentage loss of weight.Particle percentage loss of weight=[（Weighed before friability-friability after weigh）Weighed before/friability]
×100%.The percentage loss of weight result of each group granule see the table below.
As seen from the above table, the granule friability that prepared by embodiment 1-5 is substantially less than comparative example 1.
Consider, size distribution, leach the galenic pharmacies such as time limit, uniform content degree, hygroscopicity, mobility and friability and refer to
Mark is visible, and granular preparation index prepared by embodiment 1-5 is significantly better than comparative example 1-3 granule.
The safety research of the Procaterol Hydrochloride granule of embodiment 7
Remove male SD rat 30,300~400g of body weight is randomly divided into 5 groups, every group 6, respectively gavage give embodiment 1,2,
4th, 5 and comparative example prepare granule（The aqueous solution）, calculated according to Procaterol Hydrochloride, dosage is 1mg/kg/day（SD
The maximum safe dose of Oral Administration in Rats Procaterol Hydrochloride is 1mg/kg/day）, it is administered daily 1 time, successive administration 30 days.Daily
Observe the cavity secretion such as activities in rats state, hair color, stool and urine, breathing, nasal cavity and urethra.24h puts to death big after last dose
Mouse, core, liver, spleen, lung, kidney, pancreas, brain tissue, 10% formaldehyde fixes, graded ethanol dehydration, FFPE, and 4 μm of thin slices,
Optical microphotograph Microscopic observation each group rat organ's pathological change situation after HE dyeing.
The secretion of the cavities such as each group activities in rats state, hair color, stool and urine, breathing, nasal cavity and urethra, which is visually observed, has no different
Often, rat tissue's pathological observation, is showed no obvious pathological change.As a result show, Procaterol Hydrochloride granule mouthful of the invention
Take security good.Outside demineralizing acid Procaterol, the auxiliary material of other in granule is under test dose（SD Oral Administration in Rats hydrochloric acid third blocks
The maximum safe dose of special sieve is 1mg/kg/day）With good security.
Claims (8)
1. a kind of Procaterol Hydrochloride granule, is made up of Procaterol Hydrochloride and pharmaceutically acceptable pharmaceutic adjuvant, its
It is characterised by, the pharmaceutically acceptable pharmaceutic adjuvant at least includes：Lactose, hydroxypropyl methyl cellulose, crosslinking carboxylic first
Base sodium cellulosate, calcium chloride and palmityl aspartic acid diethylester.
2. a kind of Procaterol Hydrochloride granule according to claim 1, it is characterised in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：The parts by weight of Procaterol Hydrochloride 1~4, the parts by weight of lactose 12000~14000, hydroxypropyl
The parts by weight of methylcellulose 600~800, the parts by weight of Ac-Di-Sol parts by weight 400~700, calcium chloride 3900~
5100 parts by weight, the parts by weight of palmityl aspartic acid diethylester 1~5.
3. a kind of Procaterol Hydrochloride granule according to claim 2, it is characterised in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：The parts by weight of Procaterol Hydrochloride 2, the parts by weight of lactose 13970, hydroxypropyl methyl cellulose
620 parts by weight, the parts by weight of Ac-Di-Sol parts by weight 550, the parts by weight of calcium chloride 5080, palmityl aspartic acid two
The parts by weight of ethyl ester 2.
4. a kind of Procaterol Hydrochloride granule according to claim 2, it is characterised in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：The parts by weight of Procaterol Hydrochloride 3, the parts by weight of lactose 12650, hydroxypropyl methyl cellulose
750 parts by weight, the parts by weight of Ac-Di-Sol parts by weight 650, the parts by weight of calcium chloride 3940, palmityl aspartic acid two
The parts by weight of ethyl ester 4.
5. a kind of Procaterol Hydrochloride granule according to claim 2, it is characterised in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：The parts by weight of Procaterol Hydrochloride 2, the parts by weight of lactose 12800, hydroxypropyl methyl cellulose
700 parts by weight, the parts by weight of Ac-Di-Sol parts by weight 600, the parts by weight of calcium chloride 4500, palmityl aspartic acid two
The parts by weight of ethyl ester 3.
6. a kind of Procaterol Hydrochloride granule according to claim 1 to 5, it is characterised in that described pharmaceutically
The pharmaceutic adjuvant of receiving also includes flavouring and colouring agent.
7. the preparation method of a kind of Procaterol Hydrochloride granule described in claim 1 to 5, it is characterised in that including following
Step：
1）Take recipe quantity calcium chloride to crush, cross the mesh sieve of 280 mesh~400, obtain calcium chloride fine powder standby；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, Ac-Di-Sol, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio for adding 3~6ml water according to every 1g powder adds sterile injection into mixed-powder
With water, 600~1000rpm stirs 0.15~0.45h and obtains suspension；
3）With step 1）Gained calcium chloride fine powder is excipient, step 2）Gained suspension is hydrojet, is sprayed using at the top of fluid bed
Mist is pelletized, fluidized bed atomization 1.8~2.4BAR of pressure, and EAT is 74~92 DEG C, the m of intake velocity 86~1073/ h, it is compacted
Dynamic pump hydrojet 12~18ml/min of speed, 0.5~1.0mm of nozzle diameter；
4）After hydrojet has been sprayed, adjustment EAT is 65~75 DEG C of 1~3h of fluidized drying, both.
8. a kind of preparation method of Procaterol Hydrochloride granule according to claim 7, it is characterised in that step 1）In
Calcium chloride crosses 300 mesh sieves；Step 2）Middle amount of water is that 5ml water is added per 1g powder, and mixing speed is 800~900rpm, stirring
Time is 0.3h；Step 3）Middle fluidized bed atomization pressure is 2.1 BAR, and EAT is 82 DEG C, and intake velocity is 95 m3/ h,
Peristaltic pump hydrojet speed is 15ml/min, and nozzle diameter is 0.7 mm；Step 4）Middle EAT is 70 DEG C,
Drying time is 1.5 h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743548A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of Cefprozil granule and preparation method thereof |
| CN113384540A (en) * | 2021-07-22 | 2021-09-14 | 北京海泰天正医药科技有限公司 | Procaterol hydrochloride particle composition and preparation method thereof |
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| CN1813734A (en) * | 2005-11-28 | 2006-08-09 | 陈茜 | Procaterol hydrochloride dropping pill and its preparing method |
| CN105232470A (en) * | 2014-07-05 | 2016-01-13 | 黑龙江龙德药业有限公司 | Procaterol hydrochloride granules and preparation process thereof |
| WO2017047586A1 (en) * | 2015-09-14 | 2017-03-23 | 日本新薬株式会社 | Tablet |
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| CN1711990A (en) * | 2004-06-25 | 2005-12-28 | 五洲制药股份有限公司 | Corpuscles with coating of bronchodilator and production thereof |
| CN1813734A (en) * | 2005-11-28 | 2006-08-09 | 陈茜 | Procaterol hydrochloride dropping pill and its preparing method |
| CN105232470A (en) * | 2014-07-05 | 2016-01-13 | 黑龙江龙德药业有限公司 | Procaterol hydrochloride granules and preparation process thereof |
| WO2017047586A1 (en) * | 2015-09-14 | 2017-03-23 | 日本新薬株式会社 | Tablet |
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| CN108743548A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of Cefprozil granule and preparation method thereof |
| CN113384540A (en) * | 2021-07-22 | 2021-09-14 | 北京海泰天正医药科技有限公司 | Procaterol hydrochloride particle composition and preparation method thereof |
| CN113384540B (en) * | 2021-07-22 | 2022-04-01 | 北京海泰天正医药科技有限公司 | Procaterol hydrochloride particle composition and preparation method thereof |
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