CN107184555B - A kind of Procaterol Hydrochloride granule - Google Patents
A kind of Procaterol Hydrochloride granule Download PDFInfo
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- CN107184555B CN107184555B CN201710409682.5A CN201710409682A CN107184555B CN 107184555 B CN107184555 B CN 107184555B CN 201710409682 A CN201710409682 A CN 201710409682A CN 107184555 B CN107184555 B CN 107184555B
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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, are related to a kind of Procaterol Hydrochloride granule and preparation method thereof.The auxiliary material that Procaterol Hydrochloride granule is made of by Procaterol Hydrochloride and at least lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, 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, croscarmellose sodium and palmityl aspartic acid diethylester is sprayed onto calcium chloride master batch surface and is prepared.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 is simple for process, relatively low to equipment requirement, energy consumption is low is convenient for industrialized production.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of Procaterol Hydrochloride granule.
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 that beta 2 adrenoreceptor agonists are imitated in one kind, on 2 kidneys of β of bronchial smooth muscle
Adrenoceptor has higher selectivity, can diastole bronchial smooth muscle, and with certain anti-allergic effects and promote breathe
Ciliary movement effect in road has been approved in bronchial asthma, asthmatic bronchitis, has increased with bronchial reactivity
The treatment of the diseases such as acute bronchitis, chronic obstructive pulmonary disease.It is used to treat the clinic of pneumonia alone or in combination on Procaterol Hydrochloride
Experiment also has shown that good effect（Chou Lihua, Li Na ambroxol hydrochlorides add Procaterol Hydrochloride treatment infantile pneumonia
Clinical observation on the therapeutic effect [J] modern diagnosis and treatment, 2014, (5): 1061-1062）.China's approved Sichuan great Zhong at present
Procaterol Hydrochloride and its drug product formulation listing of 14 enterprises such as pharmaceutical Co. Ltd.Its most pharmaceutical dosage form is piece
Agent, in addition there is also capsules and oral solution dosage form.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 related substance [J]
Journal of Chinese Hospital Pharmacy, 2007,27（05）：703-704.）.
Procaterol Hydrochloride belongs to the drug of denier administration, is administered daily 1~2 time, and 25 μ g, adult are each every time by children
50μg.Dosage is very few to cause to lack drug effect, medication excess may then cause cardiac arrhythmia, tachycardia, blood pressure to reduce,
Many adverse reactions such as chatter, neuroticism, hypopotassaemia, hyperglycaemia.The methods of needing to pass through gastric lavage if necessary, removes drug,
And it needs according to adverse reaction symptom emergent management.There is cardiac arrhythmia when adverse reactions, using the beta-blockers 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 one of principal element for influencing patient medication safety.Good content uniformity not only contributes to the maintenance of drug effect, also favorably
In the unnecessary toxic side effect of reduction.
On the other hand, asthma attack often has the characteristics that acute attack, and the patient that the systems such as children and old age are weaker
It is relatively more.Often compliance is poor for children, not only needs to solve the problems, such as taste through adding in sweetener etc. in oral formulations,
Also need to solve the problems, such as the card larynx of children, i.e., oral solid formulation enter in children mouthful after due to cannot rapid water swelling
The problem of generating disintegration and absorbing, cause dysphagia.And gerontal patient equally exists this and asks since salivary secretion is reduced
Topic.
In addition, Procaterol Hydrochloride easily aoxidizes 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 the problems, such as its be easy to oxidation, the term of validity it is short.Pharmacy
Company Parke-Davis/Warner-Lambert had studied early in 1984 it is a kind of prevent Procaterol Hydrochloride aoxidize
Stabilizer, the stabilizer are made 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 process, 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 grain size of Procaterol Hydrochloride particle is reduced by spray-on process dispersion method（The scattered particle diameter of spraying
Generally 40~80 μm）, passed through porous destructing formed in freeze-drying Procaterol Hydrochloride particle, and in granule
More disintegrant and hygroscopic agent are added in prescription.By reducing grain size, improving preparation specific surface area can expand this method
The contact area of drug and moisture, while using hygroscopicity auxiliary material enhancing water absorbing capacity, using disintegrant and freeze the more of formation
Pore structure accelerates the disintegration solution rate of drug granule, so as to which the agent dissolving time is made to foreshorten to 8~14 s, so as to effectively
Solve the problems, such as the card larynx of Procaterol Hydrochloride oral solid formulation.Simultaneously, the technical solution is molten by configuring drug
The scattered method of spraying is carried out after liquid, by the stable homogeneous liquid-phase system of solution, improves Procaterol Hydrochloride oral administration solid
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 relevant technical solution of Procaterol granule.
However, though the technical solution of CN105232470A can reach acceleration using the preparation process of spraying joint freeze-drying
Drug 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 energy consumption is high, and cold drying equipment needs freon that can cause environmental pollution as refrigerant.
On the other hand, the technical solution of CN105232470A employs the higher auxiliary material of viscosity, is prepared into thick liquid and is then sprayed
Mist disperses thick liquid and easily blocks the smaller atomizing nozzle of bore, and heavy caliber atomizing nozzle is then difficult to prepare the smaller particle of particle
Agent, so as to significantly reduce the melting speed of Procaterol Hydrochloride particle.The third aspect is as cold as the third Ka Te of hydrochloric acid of seasoning preparation
Sieve grain structure is loose, is conducive to quickly water suction disintegration, but brittleness is higher, and the thinner powder of easily broken grain size causes particle
Grain size difference is excessive, and needs to add in a large amount of lubricants and just can ensure that drug mobility, solves drug and is difficult to pour out from the package
The problem of.Fourth aspect, the technical solution of CN105232470A have used more hygroscopicity auxiliary material, and specific grain surface product compared with
Greatly, although being conducive to that drug is accelerated to dissolve disintegration in mouth, card larynx is prevented, since its hygroscopicity is stronger, easy moisture absorption hair
Raw deliquescence, causes medicine stability to reduce.
In conclusion granule can reduce solid pharmaceutical preparation grain size, Procaterol Hydrochloride melting speed is improved；By drug
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 there are still the problems such as stability is low, hygroscopicity is high, friability is high and preparation process is higher to equipment requirement,
And the solution of hygroscopicity, friability problem often extends Procaterol Hydrochloride granule and dissolves disintegration rate, technically
In the presence of the problem to condition 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 problems, such as that its stability is low, hygroscopicity is high, friability is high and preparation process is higher to equipment requirement.
The content of the invention
The technical issues of for above-mentioned complexity in the prior art, the object of the present invention is 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 of Procaterol Hydrochloride and pharmaceutically acceptable pharmaceutic adjuvant,
It is wherein described
Pharmaceutically acceptable pharmaceutic adjuvant includes at least：Lactose, hydroxypropyl methyl cellulose, cross-linked carboxymethyl fiber
Plain sodium, calcium chloride and palmityl aspartic acid diethylester.
Preferably, 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：1~4 weight of Procaterol Hydrochloride
Measure part, 12000~14000 parts by weight of lactose, 600~800 parts by weight of hydroxypropyl methyl cellulose, croscarmellose sodium
400~700 parts by weight of parts by weight, 3900~5100 parts by weight of calcium chloride, 1~5 parts by weight of palmityl aspartic acid diethylester..
Preferably, 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：2 weight of Procaterol Hydrochloride
Part, 13970 parts by weight of lactose, 620 parts by weight of hydroxypropyl methyl cellulose, 550 weight of croscarmellose sodium parts by weight
Part, 5080 parts by weight of calcium chloride, 2 parts by weight of palmityl aspartic acid diethylester.
Preferably, 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：3 weight of Procaterol Hydrochloride
Part, 12650 parts by weight of lactose, 750 parts by weight of hydroxypropyl methyl cellulose, 650 weight of croscarmellose sodium parts by weight
Part, 3940 parts by weight of calcium chloride, 4 parts by weight of palmityl aspartic acid diethylester.
Preferably, 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：2 weight of Procaterol Hydrochloride
Part, 12800 parts by weight of lactose, 700 parts by weight of hydroxypropyl methyl cellulose, 600 weight of croscarmellose sodium parts by weight
Part, 4500 parts by weight of calcium chloride, 3 parts by weight of palmityl aspartic acid diethylester.
Preferably, the pharmaceutically acceptable pharmaceutic adjuvant further includes corrigent and colorant.
Another aspect of the present invention additionally provides a kind of preparation process of above-mentioned Procaterol Hydrochloride granule, including following
Step：
1）Recipe quantity calcium chloride is taken to crush, the mesh sieve of 280 mesh~400 is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl
Aspartic acid diethylester, ball milling mixing, the ratio that 3~6ml water is added according to every 1g powder add into mixed-powder
Enter sterilized water for injection, 600~1000rpm stirs 0.15~0.45h and obtains suspension；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion
Spraying granulation, fluidized bed atomization 1.8~2.4BAR of pressure, inlet air temperature are 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 inlet air temperature for 65~75 DEG C of 1~3h of fluidized drying to get.
Preferably, above-mentioned steps 1）Middle calcium chloride crosses 300 mesh sieves；Step 2）Middle amount of water is to add in 5ml water per 1g powder,
Mixing speed is 800~900rpm, mixing time 0.3h；Step 3）Middle fluidized bed atomization pressure be 2.1 BAR, inlet air temperature
For 82 DEG C, intake velocity is 95 m3/ h, peristaltic pump hydrojet speed are 15ml/min, and nozzle diameter is 0.7 mm；Step 4）In
Inlet air temperature is 70 DEG C, and drying time is 1.5 h.
Lactose CAS described in technical scheme is 10039-26-6, and 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 quality standard is recorded in Chinese Pharmacopoeia four in 2015；The skill of the present invention
Croscarmellose sodium CAS described in art scheme is 74811-65-7, and 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 remarkably promote
Procaterol Hydrochloride granule is dissolved and is disintegrated, and still is able to preferably solve Procaterol Hydrochloride granule under greater particle size
Card larynx problem；Using the calcium chloride powder of certain grain size 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 contains
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 used preparation process can realize a step
Granulation, step is simple, energy consumption is relatively low, relatively low to equipment requirement, suitable for large-scale industrial production.In addition, the present invention
Procaterol Hydrochloride granule supplementary product consumption remains to reach required considerably less than the Procaterol Hydrochloride granule of the prior art
Uniform content degree.
Specific embodiment
Below in conjunction with the detailed explanation present invention of specific embodiment, which 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.
1 Procaterol Hydrochloride granule of embodiment and its preparation process
Prescription：Procaterol Hydrochloride 2g, lactose 13970g, 620 g of hydroxypropyl methyl cellulose, cross-linked carboxymethyl cellulose
Sodium parts by weight 550g, calcium chloride 5080g, 2 g of palmityl aspartic acid diethylester.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 5ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 900rpm stirrings 0.3h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
2 Procaterol Hydrochloride granule of embodiment and its preparation process
Prescription：3 g of Procaterol Hydrochloride, 12650 g of lactose, 750 g of hydroxypropyl methyl cellulose, cross-linked carboxymethyl fiber
Plain 650 g of sodium parts by weight, calcium chloride 3940g, 4 g of palmityl aspartic acid diethylester.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 5ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 850rpm stirrings 0.3h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
3 Procaterol Hydrochloride granule of embodiment and its preparation process
Prescription：2 g of Procaterol Hydrochloride, lactose 12800g, 700 g of hydroxypropyl methyl cellulose, cross-linked carboxymethyl fiber
Plain sodium parts by weight 600g, 4500 g of calcium chloride, 3 g of palmityl aspartic acid diethylester.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 5ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 800rpm stirrings 0.3h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
4 Procaterol Hydrochloride granule of embodiment and its preparation process
Prescription：4 g of Procaterol Hydrochloride, 12050 g of lactose, 610 g of hydroxypropyl methyl cellulose, cross-linked carboxymethyl fiber
Plain 410 g of sodium parts by weight, calcium chloride 4900g, palmityl aspartic acid diethylester 1g.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 5ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 800rpm stirrings 0.3h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
5 Procaterol Hydrochloride granule of embodiment and its preparation process
Prescription：1 g of Procaterol Hydrochloride, 13528 g of lactose, hydroxypropyl methyl cellulose 790g, cross-linked carboxymethyl fiber
Plain sodium parts by weight 680g, calcium chloride 5000g, palmityl aspartic acid diethylester 1g.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 5ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 820rpm stirrings 0.3h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
The galenic pharmacy of 6 Procaterol Hydrochloride granule of embodiment is investigated
Respectively using granule prepared by embodiment 1-5 as investigation object.To investigate different prescriptions and preparation process to hydrochloric acid
The influence of Procaterol granular preparation feature, special standby comparative example once：
Comparative example 1 (is prepared) using the prescription and preparation process of patent document CN105232470A embodiments 1:
Prescription：Procaterol Hydrochloride 2g, lactose 12000g, mannitol 24000g, fructose 720g, trehalose 640g, malt
Dextrin 2400g, superfine silica gel powder 8g, xanthans 160g, PVP K30 40g.
Preparation process：Above-mentioned former, auxiliary material, adds water 320L to dissolve, atomizing freeze drying, nozzle diameter 1.5mm, atomizing pressure
0.2MPa, -45 DEG C of initial freezing temperature, vacuum degree 7Pa, low-temperature distillation drying 8 it is small when to get.
Comparative example 2:Prescription（With embodiment 1）：Procaterol Hydrochloride 2g, lactose 13970g, hydroxypropyl methyl cellulose
620 g, 55 0g of croscarmellose sodium parts by weight, 5080 g of calcium chloride, 2 g of palmityl aspartic acid diethylester.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 500 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palm
Acyl aspartic acid diethylester, ball milling mixing, the ratio that 8ml water is added according to every 1g powder add in sterile injection into mixed-powder
Suspension is obtained with water 1200rpm stirrings 0.5h；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.0BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
Comparative example 3:Prescription (no palmityl aspartic acid diethylester)：Procaterol Hydrochloride 1g, lactose 14000g, hydroxypropyl
Ylmethyl cellulose 800g, 700 g of croscarmellose sodium parts by weight, calcium chloride 5000g.
Preparation process：
1）Recipe quantity calcium chloride is taken to crush, 300 mesh sieves is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, ball milling
Mixing adds in sterilized water for injection 900rpm stirrings 0.3h into mixed-powder according to the ratio of every 1g powder addition 5ml water and obtains
Suspension；
3）With step 1）Gained calcium chloride fine powder be excipient, step 2）Gained suspension is hydrojet, using fluid bed top
Portion's spraying granulation, fluidized bed atomization pressure 2.1BAR, inlet air temperature are 82 DEG C, intake velocity 95m3/ h, peristaltic pump hydrojet speed
15ml/min, nozzle diameter 0.7mm；
4）After hydrojet has been sprayed, adjustment inlet air temperature for 70 DEG C of fluidized drying 1.5h to get.
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, passes through laser particle size analysis
Instrument measures
The average grain diameter of each group granule sample, median, peak diameter, D10（Grain size accounts for particle less than its particle
The 10% of sum）、D90（Grain size accounts for the 90% of total number of particles less than its particle）Wait relevant parameters.As a result 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 quickly dissolving and disperses, but granularity
Distributional difference is maximum.The granule average grain diameter of comparative example 2 is higher than embodiment 1, since 2 prescription of comparative example is same as Example 1
But preparation process is different, therefore process variations may be the reason for causing its grain size different.Granule prepared by comparative example 3 is averaged
Grain size is close with embodiment 3,4, and size distribution difference and embodiment 1-5 illustrate to remove palmityl in prescription without significant difference
Aspartic acid diethylester does not make significant difference to granule size distribution and average grain diameter.
Granule grain size prepared by embodiment 1-5 is larger compared with 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 to simulating oral cavity environment, difference Example 1-5 and comparative example
Prepared by 1-3
Each 0.5g of Procaterol Hydrochloride granule, water was added dropwise in the ratio that 37 DEG C of water of 5ml are added according to every g particles, at 30 seconds
Inside drip off.The timing since be added dropwise, metering granule leach the required time completely.As a result 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, shorter than the granule of comparative example 1
Required leaches the time, and the granule of comparative example 3 leached the time limit more than 29 seconds, far above embodiment 1-5 and comparative example 1 and 2
The time is leached needed for granule, shows that palmityl aspartic acid diethylester dissolves disintegration tool to Procaterol Hydrochloride granule
Remarkably promote effect.The time is leached higher than embodiment 1-5 needed for the granule of comparative example 2, illustrates to prepare less than comparative example 3
Process variations can also influence granule and leach the time.Result is investigated as it can be seen that palmityl aspartic acid with reference to granularity and size distribution
Diethylester 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：
Hydrochloric acid third in the high effective liquid chromatography for measuring granule announced using Chinese ministry standard WS1- (X-114) -96Z
The content of Quattro.It is filler with octadecylsilane chemically bonded silica, with sodium dihydrogen phosphate (sodium dihydrogen phosphate
11.04g with water dissolution and is diluted to 1000ml, with phosphorus acid for adjusting pH value 3.10 ± 0.05)-methanol (83:17) it is mobile phase；
Detection wavelength is 259nm.
Each 6 batches of the Procaterol Hydrochloride particle that respectively prepared by Example 1-5 and comparative example 1-3, every batch of 10g；Efficiently
Liquid chromatogram
Method measures the Procaterol Hydrochloride content of every batch of sample, and calculates its relative standard deviation.As a result 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%,
One property is poor；The relative standard deviation of Procaterol Hydrochloride content in granule prepared by embodiment 1-5（%）It is below 1.5%,
And less than 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 process 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
In dry conical flask, the accurate total weight for weighing sample+conical flask, is then placed in climatic chamber, 25 DEG C of design temperature is wet again
Degree 75%, opening place the total weight of accurate determination sample+conical flask after 168h, calculate Moisture percentage.
Moisture percentage (%)=[（The gross weight of sample and conical flask before total weight-moisture absorption of sample and conical flask after moisture absorption
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 after the granule 168h that prepared by embodiment 1-5 and comparative example 2
With comparative example 3, illustrating the granule prescription of the present invention just has the advantages of 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 powders
The characteristic integrated tester Procaterol Hydrochloride particulate samples that respectively prepared by testing example 1-5 and comparative example 1-3 stop
Angle, tablet angle, apparent density, tap density, dispersion degree obtain Carr ' the s slamp values of sample, evaluate its mobility.As a result
It see the table below：
As seen from the above table, granule Carr ' the s slamp values that prepared by embodiment 1-5 are above comparative example 1, illustrate this
The granule mobility that the granule prescription and its preparation process of invention are worth is 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 is weighed after crossing 300 mesh sieves,
Respectively
Friability tester is put into, the bead for adding in a diameter of 7mm rotates 100 times, collects sample, crosses 300 mesh again
It weighs after sieve.Calculate particle percentage loss of weight.Particle percentage loss of weight=[（Weigh before friability-friability after weigh）Claim before/friability
Weight] × 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 leaches the galenic pharmacies such as time limit, uniform content degree, hygroscopicity, mobility and friability and refers to
Mark is as it can be seen that granular preparation index prepared by embodiment 1-5 is significantly better than the granule of comparative example 1-3.
The safety research of 7 Procaterol Hydrochloride granule of embodiment
Male SD rat 30,300~400g of weight is removed, is randomly divided into 5 groups, every group 6, gavage gives embodiment respectively
1st, 2,4,5 and comparative example prepare granule（Aqueous solution）, calculated according to Procaterol Hydrochloride, dosage 1mg/kg/day
（The maximum safe dose of SD Oral Administration in Rats Procaterol Hydrochlorides is 1mg/kg/day）, it is administered daily 1 time, successive administration 30 days.
The cavities secretion such as daily observation activities in rats state, hair color, stool and urine, breathing, nasal cavity and urethra.Locate for 24 hours after the last administration
Dead rat, core, liver, spleen, lung, kidney, pancreas, brain tissue, 10% formaldehyde fixes, graded ethanol dehydration, paraffin embedding, and 4 μm are thin
Piece, 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 visually observes, has no different
Often, rat tissue's pathological observation is showed no apparent pathological change.The result shows that Procaterol Hydrochloride granule mouth of the invention
Take good security.Outside demineralizing acid Procaterol, other auxiliary materials are under test dose in granule（SD Oral Administration in Rats hydrochloric acid third blocks
The maximum safe dose of special sieve is 1mg/kg/day）With good security.
Claims (5)
1. a kind of Procaterol Hydrochloride granule, is made of Procaterol Hydrochloride and pharmaceutically acceptable pharmaceutic adjuvant,
It is characterized in that, the pharmaceutically acceptable pharmaceutic adjuvant includes at least：Lactose, hydroxypropyl methyl cellulose, crosslinking carboxylic first
Base sodium cellulosate, calcium chloride and palmityl aspartic acid diethylester；Procaterol Hydrochloride in the Procaterol Hydrochloride granule
With the weight of lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, calcium chloride and palmityl aspartic acid diethylester
Part ratio is：1~4 parts by weight of Procaterol Hydrochloride, 12000~14000 parts by weight of lactose, hydroxypropyl methyl cellulose 600~800
Parts by weight, 400~700 parts by weight of croscarmellose sodium parts by weight, 3900~5100 parts by weight of calcium chloride, palmityl
1~5 parts by weight of aspartic acid diethylester；The preparation method of the Procaterol Hydrochloride granule comprises the following steps：
1）Recipe quantity calcium chloride is taken to crush, the mesh sieve of 280 mesh~400 is crossed, it is spare to obtain calcium chloride fine powder；
2）Take recipe quantity Procaterol Hydrochloride, lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, palmityl day
Winter propylhomoserin diethylester, ball milling mixing, the ratio that 3~6ml water is added according to every 1g powder add in 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 be 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 inlet air temperature is 74~92 DEG C, 86~107 m of intake velocity3/ 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 inlet air temperature is 65~75 DEG C of 1~3h of fluidized drying, both.
A kind of 2. Procaterol Hydrochloride granule according to claim 1, which is characterized in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：2 parts by weight of Procaterol Hydrochloride, 13970 parts by weight of lactose, hydroxypropyl methyl cellulose
620 parts by weight, 550 parts by weight of croscarmellose sodium parts by weight, 5080 parts by weight of calcium chloride, palmityl aspartic acid two
2 parts by weight of ethyl ester.
A kind of 3. Procaterol Hydrochloride granule according to claim 1, which is characterized in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：3 parts by weight of Procaterol Hydrochloride, 12650 parts by weight of lactose, hydroxypropyl methyl cellulose
750 parts by weight, 650 parts by weight of croscarmellose sodium parts by weight, 3940 parts by weight of calcium chloride, palmityl aspartic acid two
4 parts by weight of ethyl ester.
A kind of 4. Procaterol Hydrochloride granule according to claim 1, which is characterized in that the Procaterol Hydrochloride
Procaterol Hydrochloride and lactose, hydroxypropyl methyl cellulose, croscarmellose sodium, calcium chloride and palmityl day in granula
The winter weight part ratio of propylhomoserin diethylester is：2 parts by weight of Procaterol Hydrochloride, 12800 parts by weight of lactose, hydroxypropyl methyl cellulose
700 parts by weight, 600 parts by weight of croscarmellose sodium parts by weight, 4500 parts by weight of calcium chloride, palmityl aspartic acid two
3 parts by weight of ethyl ester.
A kind of 5. Procaterol Hydrochloride granule according to claim 1, which is characterized in that step 1）Middle calcium chloride mistake
300 mesh sieves；Step 2）Middle amount of water is that 5ml water is added in per 1g powder, and mixing speed is 800~900rpm, and mixing time is
0.3h；Step 3）Middle fluidized bed atomization pressure is 2.1 BAR, and inlet air temperature 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 inlet air temperature is 70 DEG C, and drying time is 1.5 h.
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