CN107929257B - A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof - Google Patents
A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof Download PDFInfo
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- CN107929257B CN107929257B CN201711250965.6A CN201711250965A CN107929257B CN 107929257 B CN107929257 B CN 107929257B CN 201711250965 A CN201711250965 A CN 201711250965A CN 107929257 B CN107929257 B CN 107929257B
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- 239000002775 capsule Substances 0.000 title claims abstract description 160
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 121
- 235000002906 tartaric acid Nutrition 0.000 title claims abstract description 120
- 239000011975 tartaric acid Substances 0.000 title claims abstract description 120
- 239000000843 powder Substances 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229920001661 Chitosan Polymers 0.000 claims abstract description 51
- 239000002245 particle Substances 0.000 claims abstract description 41
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 37
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 235000004298 Tamarindus indica Nutrition 0.000 claims abstract description 19
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 32
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 25
- 229960001375 lactose Drugs 0.000 claims description 25
- 239000008101 lactose Substances 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 21
- 238000009826 distribution Methods 0.000 claims description 19
- 241000596504 Tamarindus Species 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 8
- 102220042174 rs141655687 Human genes 0.000 claims description 8
- 102220076495 rs200649587 Human genes 0.000 claims description 8
- 102220043159 rs587780996 Human genes 0.000 claims description 8
- -1 hydroxypropyl methyl Chemical group 0.000 claims description 7
- 239000003292 glue Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims 1
- 230000008021 deposition Effects 0.000 abstract description 7
- OBRNDARFFFHCGE-PERKLWIXSA-N (S,S)-formoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-PERKLWIXSA-N 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 5
- 229960000193 formoterol fumarate Drugs 0.000 abstract description 5
- 239000007921 spray Substances 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 240000004584 Tamarindus indica Species 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 47
- 238000012360 testing method Methods 0.000 description 32
- 239000000126 substance Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 14
- 229940098458 powder spray Drugs 0.000 description 13
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- FCSXYHUNDAXDRH-OKMNHOJOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 FCSXYHUNDAXDRH-OKMNHOJOSA-N 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000012372 quality testing Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 5
- 231100000037 inhalation toxicity test Toxicity 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 229940031472 brovana Drugs 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000000813 microbial effect Effects 0.000 description 4
- 239000003595 mist Substances 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- 206010014561 Emphysema Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- RQFQJYYMBWVMQG-IXDPLRRUSA-N chitotriose Chemical compound O[C@@H]1[C@@H](N)[C@H](O)O[C@H](CO)[C@H]1O[C@H]1[C@H](N)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)[C@@H](CO)O1 RQFQJYYMBWVMQG-IXDPLRRUSA-N 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 229960003728 ciclesonide Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical class C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 2
- 229960002848 formoterol Drugs 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000009700 powder processing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- BPZSYCZIITTYBL-ORAYPTAESA-N S-formoterol Chemical compound C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-ORAYPTAESA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 229960000612 arformoterol tartrate Drugs 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000009658 destructive testing Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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
- A61K9/4816—Wall or shell material
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to pharmaceutical technology fields, and in particular to a kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof.Tartaric acid Afromoterol powders for inhalation capsule provided by the invention includes capsule 's content and capsule shells, the capsule 's content is mainly made of tartaric acid Afromoterol and lactose monohydrate, and the capsule shells are mainly made of hydroxypropyl methyl cellulose, chitosan oligomer, tamarind gum, sorb alcohol and water.Tartaric acid Afromoterol powders for inhalation capsule provided by the invention has mobility of particle good, draw moist small, uniformity of dosage units and the high advantage of deposition ratio in the effective position, meet the related request of 7.0 formoterol fumarate quality standard of European Pharmacopoeia and the Chinese Pharmacopoeia two annex IL powder sprays of version in 2010.And the tartaric acid Afromoterol powders for inhalation capsule that is prepared of the present invention also advantage high with stability with high security, it is more advantageous to large-scale promotion and application.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of tartaric acid Afromoterol powders for inhalation capsule and its preparation
Method.
Background technique
Tartaric acid Afromoterol (chemical name: N- [2- hydroxyl -5- [(1R) -1- hydroxyl -2- [[(1R) -2- (4- methoxy benzene
Base) -1- Methylethyl] amino] ethyl] phenyl] formamide；No. CAS: 200815-49-2；English name:
ArformoterolTartrate it is) the correspondence isomers of Formoterol, is a kind of long-acting selective ' beta '3 adrenergic beta 2 receptor
Hormone drug, drug effect are 2 times of Formoterol raceme, are 1000 times of (S, S) corresponding isomers, and tartaric acid Afromoterol
Reinforce the side effect that acetylcholine causes bronchoconstriction to be reacted without (S, S)-Formoterol, internal adenyl cyclase can be activated
The enzyme can make ATP be converted into cAMP, the increase of intracellular cAMP can relax bronchial smooth muscle and can be reduced allergic mediators from
Cell, which is especially in hypertrophy cell, to be discharged, and can be played bronchiectatic activity with diastole bronchial smooth muscle, be can be used for controlling
Treat airway obstructives tuberculosis (the Chronic Obstructive such as chronic bronchitis, asthma type brochitis, pulmonary emphysema
Pulmonary Diseases, COPD) caused by the symptoms such as expiratory dyspnea.
Tartaric acid Afromoterol foreign countries' commercialized product is Neulized inhalation liquid, and it is poor that there are stability, when use medical fluid need through
Device atomizer sucks after being atomized into mist drop, and device is expensive, using with defect inconvenient to carry.For air flues such as pulmonary emphysema
The treatment of obstructive lung disease, inhalation are ideal administration modes.Exist to the research of Afromoterol powder spray at present more
In the research of compound preparation.
Patent document CN102000089A discloses a kind of using ciclesonide and Afromoterol as the compound system of active constituent
Agent, it is the active constituent that ciclesonide and Afromoterol are formed, medicinal group be mixed to form with pharmaceutically acceptable auxiliary material
Close object.Inhalation powder spray is made in the Pharmaceutical composition, is to be by weight by medicinal active ingredient and glycine or lactose
After 1:50-1:1000 mixing, through micronization processes, their particle size distribution range is between 0.02-200 microns, preferably 1-
Between 100 microns.The inhalation powder spray being prepared have absorb, utilizing status it is good, section be used for a variety of causes caused by asthma,
The treatment of COPD.
Patent document CN102000090A discloses a kind of using budesonide and Afromoterol as the compound system of active constituent
Agent, it is the active constituent that budesonide and Afromoterol are formed, medicinal group be mixed to form with pharmaceutically acceptable auxiliary material
Close object.Inhalation powder spray is made in the Pharmaceutical composition, is to be by weight by medicinal active ingredient and glycine or lactose
After 1:50-1:1000 mixing, through micronization processes, their particle size distribution range is between 0.02-200 microns, preferably 1-
Between 100 microns.The inhalation powder spray being prepared have absorb, utilizing status it is good, section be used for a variety of causes caused by asthma,
The treatment of COPD.
However the induction type powder spray of compound preparation is made in Afromoterol at present there are poor fluidities, hygroscopicity is big, contains
The amount uniformity is low, and deposition ratio in the effective position is low, is unfavorable for the airway obstructions such as chronic bronchitis, asthma type brochitis, pulmonary emphysema
The treatment of dyspnea caused by property tuberculosis.
Summary of the invention
In order to solve defect existing for Afromoterol induction type powder spray in the prior art, the purpose of the present invention is to provide
A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof.Tartaric acid Afromoterol powders for inhalation provided by the invention
Capsules preparation technique is simple, and good fluidity, hygroscopicity is small, and uniformity of dosage units is high, and deposition ratio in the effective position is high, is that one kind is more managed
The tartaric acid Afromoterol powders for inhalation capsule thought.
The present invention provides a kind of tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, institutes
Capsule 's content is stated to be made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；
10000~11000 parts of lactose monohydrate；
The size distribution of the lactose monohydrate are as follows: D10=20.702 μm, D50=79.027 μm, D90=140.413
μm。
Further, the capsule 's content is made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；
10978 parts of lactose monohydrate；
The size distribution of the lactose monohydrate are as follows: D10=20.702 μm, D50=79.027 μm, D90=140.413
μm。
Further, the capsule shells are made of following component and its parts by weight:
15~20 parts of hydroxypropyl methyl cellulose, 4~6 parts of chitosan oligomer, 1~3 part of tamarind gum, 1~2 part of sorbierite
With 65~75 parts of water.
Further, the capsule shells are made of following component and its parts by weight:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of tamarind gum, 2 parts of sorbierite and 70 parts of water.
Further, the chitosan oligomer by molecular weight be 5000~6500Da chitosan and molecular weight be 1000~
3000Da chitosan is by weight (4~6): (1~3) composition.
Further, the chitosan oligomer by molecular weight be 5000~6500Da chitosan and molecular weight be 1000~
3000Da chitosan is formed by weight 5:2.
In addition, the present invention also provides the preparation methods of the tartaric acid Afromoterol powders for inhalation capsule, including with
Lower step:
S1 weighs the lactose monohydrate of capsule contents composition formula total amount 10%, is crushed with airslide disintegrating mill, obtains grain
Lactose particles of the diameter less than 10 μm；
Tartaric acid Afromoterol and lactose monohydrate with mass ratio 1:10 mixing, are obtained mixture, then use air-flow by S2
Pulverizer crushes said mixture, obtains drug containing particle of the partial size less than 10 μm；
The lactose monohydrate of the lactose particles that rapid S1 is obtained, the drug containing particle that step S2 is obtained and surplus is added S3
Mixers with Multi-direction Movement mixes 55~65min, obtains content；
S4 prepare capsule shells, fill capsule, packaging to get.
Further, the pulverization conditions of the step S1 and the airslide disintegrating mill in step S2 are as follows: crushing pressure is
0.4MPa, charging rate 0.5g/min, ambient humidity≤40%.
Further, the preparation step of the capsule shells of the step S4 are as follows:
It takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl methyl
Cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned mixed
Close liquid and sorbierite, stir 10~15min under conditions of temperature is 40~50 DEG C, film forming to get.
The content of Afromoterol is 15 μ g/, every in tartaric acid Afromoterol powders for inhalation capsule provided by the invention
Containing 15 μ g of Afromoterol, it is equivalent to 22 μ g of tartaric acid Afromoterol.That is 22 μ g of tartaric acid Afromoterol, lactose monohydrate
10978 μ g are made 1, and tartaric acid Afromoterol 0.22g, lactose monohydrate 109.78g are made 10000.
Lactose monohydrate is divided into the powder and tartaric acid Afromoterol powder of 3 parts of specific dosages and specified particle diameter by the present invention
It is mixed, wherein drug can sufficiently be adsorbed by carrying out the lactose monohydrate of Ultramicro-powder after mixing with tartaric acid Afromoterol powder
Particle, then absorption drug microparticles are wrapped up further with 10% Ultramicro-powder lactose monohydrate particle being always formulated, it is ensured that medicine
The medicament contg of object, while it can also promote the flowing of micro mist, finally further improve with lactose monohydrate as carrier
The mobility of powder.
The present invention is with lactose monohydrate by tartaric acid Afromoterol with the mass ratio 1:10 mixture mixed and formula
10% lactose monohydrate of total amount carries out airslide disintegrating mill crushing respectively, and crushing pressure is 0.4MPa, and charging rate is
0.5g/min, ambient humidity≤40% obtain particle of the partial size less than 10 μm, then mix with remaining lactose monohydrate, mix
Be filled into after even model 3# self-control plant hollow capsule to get.The tartaric acid Afromoterol powder sucking that the present invention is prepared
Agent capsules have mobility of particle good, draw moist small, and uniformity of dosage units and the high advantage of deposition ratio in the effective position comply fully with Europe
The related request of 7.0 formoterol fumarate quality standard of continent pharmacopeia and the Chinese Pharmacopoeia two annex IL powder sprays of version in 2010.
It is found through experiment that 22 parts of tartaric acid Afromoterol provided by the invention, 10000~11000 parts of lactose monohydrate,
And tartaric acid Afromoterol and lactose monohydrate with the mass ratio 1:10 mixture mixed and are formulated 10% cream of total amount
After sugared monohydrate carries out airslide disintegrating mill crushing respectively, obtain particle of the partial size less than 10 μm, then with remaining one water of lactose
Object mixing is closed, 3# self-control plant hollow capsule is filled into after mixing.The tartaric acid Afromoterol powder sucking that the present invention is prepared
Agent capsules are influenced in the configuration of production process and the not chiral drug of transporting procedures, are identified by HPLC, be not detected (S,
S-), (R, S-), (S, R-) isomers, appearance, Afromoterol identify, and microbial limit, uniformity of dosage units very content meets photograph
Related the wanting of 7.0 formoterol fumarate quality standard of European Pharmacopoeia and the Chinese Pharmacopoeia two annex IL powder sprays of version in 2010
It asks.
Further, the tartaric acid Afromoterol powders for inhalation capsule Emptying Rate that the present invention is prepared is greater than 94.57%,
Droplet distribution is greater than 15.60%, and moisture is lower than 5.34%, and impurity A is lower than 0.09%, and total impurities are lower than 0.09%.And lactose one
Hydrate is higher or lower than 10000~11000 parts, and is mixed without carrying out substep progress specified particle diameter and dosage, flows
Dynamic property, draws moist, and Emptying Rate and deposition ratio in the effective position effect are greatly reduced.
Further, the tartaric acid Afromoterol powders for inhalation capsule that the present invention is prepared is in powder spray inhalation test
When, softgel shell is generated without fragment substantially, and body weight increase rate is lower than 5%, and softgel shell is not in ruckbildung, avoids fragment with trouble
Person's air-flow is inhaled into the danger of tracheae, greatly improves the safety of tartaric acid Afromoterol powders for inhalation capsule.
In addition, tartaric acid Afromoterol powders for inhalation capsule prepared by the present invention 60 DEG C of high temperature, high humidity (RH 75%),
It places 10 days, accelerated test 6 months (40 DEG C, RH 75% under the conditions of) and is kept sample under conditions of Qiang Guang (4500lx) for a long time
It investigates 18 months (25 DEG C ± 2 DEG C, relative humidity 60%) and finds afterwards, tartaric acid Afromoterol powders for inhalation glue prepared by the present invention
The appearance of capsule has no significant change in relation to the distribution of substance, content, Emptying Rate and droplet, illustrates that tartaric acid is prepared in the present invention
Afromoterol powders for inhalation capsule stability with higher.
Compared with prior art, tartaric acid Afromoterol powders for inhalation capsule provided by the invention has the advantage that
(1) tartaric acid Afromoterol powders for inhalation capsule provided by the invention has mobility of particle good, draws moist small, contains
It measures the uniformity and deposition ratio in the effective position is high, meet 7.0 formoterol fumarate quality standard of European Pharmacopoeia and Chinese Pharmacopoeia
The related request of the two annex IL powder sprays of version in 2010；
(2) the tartaric acid Afromoterol powders for inhalation capsule that the present invention is prepared is high with stability with high security
Advantage is generated without fragment substantially in powder spray inhalation test, and body weight increase rate is lower than 5%, and softgel shell is not in ruckbildung, is kept away
Fragment is exempted from as patient air flow is inhaled into the danger of tracheae.
Specific embodiment:
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Embodiment 1, a kind of tartaric acid Afromoterol powders for inhalation capsule
The tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, the capsule 's content
It is made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；10000 parts of lactose monohydrate；The size distribution of the lactose monohydrate are as follows:
D10=20.702 μm, D50=79.027 μm, D90=140.413 μm.
The capsule shells are made of following component and its parts by weight:
15 parts of hydroxypropyl methyl cellulose, 4 parts of chitosan oligomer, 1 part of tamarind gum, 1 part of sorbierite and 65 parts of water；It is described
Chitosan oligomer is 5000~6500Da chitosan by molecular weight and molecular weight is 1000~3000Da chitosan by weight (4
~6): (1~3) composition.
Preparation method:
S1 weighs 1002.2 parts of lactose monohydrates, is crushed with airslide disintegrating mill, and crushing pressure is 0.4MPa, charging
Speed is 0.5g/min, and ambient humidity≤40% obtains lactose particles of the partial size less than 10 μm；
S2 mixes 22 parts of tartaric acid Afromoterols and 220 parts of lactose monohydrates, obtains mixture, then uses air-flow crushing
Machine crushes said mixture, and crushings pressure is 0.4MPa, charging rate 0.5g/min, and it is small to obtain partial size ambient humidity≤40%
In 10 μm of drug containing particle；
The drug containing particle and one water of remaining 8777.8 parts of lactose that S3 obtains the lactose particles that step S1 is obtained, step S2
It closes object and Mixers with Multi-direction Movement is added, mix 55min, obtain content；
S4 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 10min under conditions of temperature is 40 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
Embodiment 2, a kind of tartaric acid Afromoterol powders for inhalation capsule
The tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, the capsule 's content
It is made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；10978 parts of lactose monohydrate；The size distribution of the lactose monohydrate are as follows:
D10=20.702 μm, D50=79.027 μm, D90=140.413 μm.
The capsule shells are made of following component and its parts by weight:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of tamarind gum, 2 parts of sorbierite and 70 parts of water；It is described
Chitosan oligomer is 5000~6500Da chitosan by molecular weight and molecular weight is 1000~3000Da chitosan by weight 5:2
Composition.
Preparation method:
S1 weighs 1100 parts of lactose monohydrates, is crushed with airslide disintegrating mill, and crushing pressure is 0.4MPa, charging speed
Degree is 0.5g/min, and ambient humidity≤40% obtains lactose particles of the partial size less than 10 μm；
S2 mixes 22 parts of tartaric acid Afromoterols and 220 parts of lactose monohydrates, obtains mixture, then uses air-flow crushing
Machine crushes said mixture, and crushings pressure is 0.4MPa, charging rate 0.5g/min, and it is small to obtain partial size ambient humidity≤40%
In 10 μm of drug containing particle；
The drug containing particle and remaining 9658 parts of lactose monohydrates that S3 obtains the lactose particles that step S1 is obtained, step S2
Mixers with Multi-direction Movement is added, mixes 60min, obtains content；
S4 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 12min under conditions of temperature is 45 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
Embodiment 3, a kind of tartaric acid Afromoterol powders for inhalation capsule
The tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, the capsule 's content
It is made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；11000 parts of lactose monohydrate；The size distribution of the lactose monohydrate are as follows:
D10=20.702 μm, D50=79.027 μm, D90=140.413 μm.
The capsule shells are made of following component and its parts by weight:
20 parts of hydroxypropyl methyl cellulose, 6 parts of chitosan oligomer, 3 parts of tamarind gum, 2 parts of sorbierite and 75 parts of water；It is described
Chitosan oligomer is 5000~6500Da chitosan by molecular weight and molecular weight is 1000~3000Da chitosan by weight (4
~6): (1~3) composition.
Preparation method:
S1 weighs 1102.2 parts of lactose monohydrates, is crushed with airslide disintegrating mill, and crushing pressure is 0.4MPa, charging
Speed is 0.5g/min, and ambient humidity≤40% obtains lactose particles of the partial size less than 10 μm；
S2 mixes 22 parts of tartaric acid Afromoterols and 220 parts of lactose monohydrates, obtains mixture, then uses air-flow crushing
Machine crushes said mixture, and crushings pressure is 0.4MPa, charging rate 0.5g/min, and it is small to obtain partial size ambient humidity≤40%
In 10 μm of drug containing particle；
The drug containing particle that the lactose particles that step S1 is obtained, step S2 are obtained is hydrated by S3 with remaining 9677.8 parts of lactose one
Mixers with Multi-direction Movement is added in object, mixes 65min, obtains content；
S4 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 15min under conditions of temperature is 50 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
Comparative example 1, a kind of tartaric acid Afromoterol powders for inhalation capsule
The capsule 's content of the tartaric acid Afromoterol powders for inhalation capsule and the component and its parts by weight of capsule shells
Composition is such as
Embodiment 2.
Preparation method:
S1 mixes 22 parts of tartaric acid Afromoterols and 220 parts of lactose monohydrates, obtains mixture, then uses air-flow crushing
Machine crushes said mixture, and crushings pressure is 0.4MPa, charging rate 0.5g/min, and it is small to obtain partial size ambient humidity≤40%
In 10 μm of drug containing particle；
S2 is crushed remaining 10758 parts of lactose monohydrates with airslide disintegrating mill, and crushing pressure is 0.4MPa, into
Material speed is 0.5g/min, and ambient humidity≤40% obtains lactose particles of the partial size less than 10 μm；
Mixers with Multi-direction Movement, mixing is added in the drug containing particle that step S1 is obtained and the lactose particles that step S2 is obtained by S3
60min obtains content；
S4 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 12min under conditions of temperature is 45 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
The difference from example 2 is that: lactose monohydrate is subjected to Ultramicro-powder processing.
Comparative example 2, a kind of tartaric acid Afromoterol powders for inhalation capsule
The capsule 's content of the tartaric acid Afromoterol powders for inhalation capsule and the component and its parts by weight of capsule shells
Composition is such as
Embodiment 2.
Preparation method:
S1 mixes 22 parts of tartaric acid Afromoterols and 220 parts of lactose monohydrates, obtains mixture, then uses air-flow crushing
Machine crushes said mixture, and crushings pressure is 0.4MPa, charging rate 0.5g/min, and it is small to obtain partial size ambient humidity≤40%
In 10 μm of drug containing particle；
Mixers with Multi-direction Movement is added in 10758 parts of lactose monohydrates of drug containing particle and surplus that S2 obtains S1,
60min is mixed, content is obtained；
S3 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 12min under conditions of temperature is 45 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
The difference from example 2 is that: carrier lactose monohydrate does not carry out Ultramicro-powder processing.
Comparative example 3, a kind of tartaric acid Afromoterol powders for inhalation capsule
The tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, the capsule contents packet
It is made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol, 220 parts of lactose monohydrate, 9658 parts of lactose of 1100 parts of crystalline lactose and grinding；
The size distribution of the lactose monohydrate are as follows: D10=20.702 μm, D50=79.027 μm, D90=140.413 μm.
The ingredient and its parts by weight of the capsule shells such as embodiment 2.
Preparation method:
S1 crushes crystalline lactose, crushing pressure be 0.4MPa, charging rate 0.5g/min, ambient humidity≤
40%, obtain lactose particles of the partial size less than 10 μm；
S2 mixes tartaric acid Afromoterol and lactose monohydrate, obtains mixture, is then crushed with airslide disintegrating mill
State mixture, crushing pressure is 0.4MPa, charging rate 0.5g/min, and ambient humidity≤40% obtains partial size less than 10 μm
Drug containing particle；
The drug containing particle that the lactose particles that step S1 is obtained, step S2 are obtained is added Multidirectional motion with grinding lactose and mixed by S3
Conjunction machine mixes 60min, obtains content；
S4 takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl first
Base cellulose is added to while stirring in the water of surplus, when the thick liquid of transparence is presented in stirring to solution, is added above-mentioned
Mixed liquor and sorbierite stir 12min under conditions of temperature is 45 DEG C, form a film, and 3# capsule shells are made, and fill capsule, pack,
To obtain the final product.
The difference from example 2 is that: the type of lactose is different.
Comparative example 4, a kind of tartaric acid Afromoterol powders for inhalation capsule
The component and its parts by weight such as embodiment of the capsule 's content of the tartaric acid Afromoterol powders for inhalation capsule
2。
The capsule shells are made of following component and its parts by weight:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of tamarind gum, 2 parts of sorbierite and 70 parts of water；It is described
Chitosan oligomer chitosan oligosaccharide.
Preparation method is similar to Example 2.
The difference from example 2 is that: the chitosan oligomer is chitosan oligosaccharide.
Comparative example 5, a kind of tartaric acid Afromoterol powders for inhalation capsule
The component and its parts by weight such as embodiment of the capsule 's content of the tartaric acid Afromoterol powders for inhalation capsule
2。
The capsule shells are made of following component and its parts by weight:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of tamarind gum, 2 parts of sorbierite and 70 parts of water；It is described
Chitosan oligomer is 5000~6500Da chitosan by molecular weight and molecular weight is 1000~3000Da chitosan by weight 1:1
Composition.
Preparation method is similar to Example 2.
The difference from example 2 is that: the chitosan oligomer is 5000~6500Da chitosan and molecule by molecular weight
Amount is that 1000~3000Da chitosan is formed by weight 1:1.
Comparative example 6, a kind of tartaric acid Afromoterol powders for inhalation capsule
The component and its parts by weight such as embodiment of the capsule 's content of the tartaric acid Afromoterol powders for inhalation capsule
2。
The capsule shells are made of following component and its parts by weight:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of guar gum, 2 parts of sorbierite and 70 parts of water；It is described
Chitosan oligomer is 5000~6500Da chitosan by molecular weight and molecular weight is 1000~3000Da chitosan by weight 5:2
Composition.
Preparation method is similar to Example 2.
The difference from example 2 is that: tamarind gum is replaced with into guar gum.
The quality testing test of test example one, tartaric acid Afromoterol powders for inhalation capsule
1, test material:
Tartaric acid Afromoterol powders for inhalation capsule prepared by embodiment 1, embodiment 2 and embodiment 3.
2, test method:
To embodiment 1, embodiment 2 and embodiment 3 preparation tartaric acid Afromoterol powders for inhalation capsule carry out character, Ah
Ford sieve, optical isomer, microbial limit, uniformity of dosage units and content (%) measurement, in which: Afromoterol and optical siomerism
Body identification is detected using HPLC method, the limit test of microbe of 2010 editions two annex XIJ of microbial limit Chinese Pharmacopoeia
Method is measured, and Determination of Content Uniformity is measured referring to Content uniformity test (annex XE), and content is with reference to European Pharmacopoeia
The quality standard of formoterol fumarate bulk pharmaceutical chemicals is measured.
3, test result:
Test result is as shown in table 1.
The quality testing of 1 tartaric acid Afromoterol powders for inhalation capsule of table is tested
As shown in Table 1, the tartaric acid Afromoterol powders for inhalation capsule that the present invention is prepared is in production process and storing
The configuration of the not chiral drug of process influences, and is identified by HPLC, (S, S-) is not detected, (R, S-), (S, R-) isomery
Body, appearance, Afromoterol identify, and microbial limit, uniformity of dosage units and content meet 7.0 fumaric acid Fu Mote of European Pharmacopoeia
The related request of sieve quality standard and the Chinese Pharmacopoeia two annex IL powder sprays of version in 2010.
The quality testing test of test example two, tartaric acid Afromoterol powders for inhalation capsule
1, test material:
Tartaric acid Afromoterol prepared by embodiment 1, embodiment 2, embodiment 3, comparative example 1, comparative example 2 and comparative example 3
Powders for inhalation capsule.
2, test method:
To the tartaric acid A Fute of embodiment 1, embodiment 2, embodiment 3, comparative example 1, comparative example 2 and comparative example 3 preparation
The Emptying Rate of sieve powders for inhalation capsule, droplet distribution, moisture and related substance are measured, in which: Emptying Rate measurement is referring to row
Empty rate inspection technique (Chinese Pharmacopoeia version annex I L in 2010) is measured；The measurement of droplet distribution is referring to Chinese Pharmacopoeia 2010 editions
Inhalation powder spray droplet (grain) distribution analysis (Chinese Pharmacopoeia version annex X H in 2010) and 7.0 powder spray of European Pharmacopoeia deposition
Quantity measuring method is measured；Moisture is measured using moisture inspection technique；Related substance-measuring uses HPLC method, with reference to raw material
Measuring method of the medicine in relation to substance.
3, test result:
The results are shown in Table 2 for test result.
The quality testing of 2 tartaric acid Afromoterol powders for inhalation capsule of table is tested
As known from Table 2, the tartaric acid Afromoterol powders for inhalation capsule Emptying Rate that the embodiment of the present invention 1~3 is prepared
Greater than 94.57%, droplet distribution is greater than 15.60%, and moisture is lower than 5.34%, and impurity A is lower than 0.09%, and total impurities are lower than
0.09%, and the tartaric acid Afromoterol powders for inhalation capsule Emptying Rate that comparative example 1~3 is prepared, droplet distribution, moisture and
In relation to content of material effect than difference of the invention, illustrate the partial size, supplementary product kind, auxiliary material partial size paratartaric acid of capsule 's content
The quality of Afromoterol powders for inhalation capsule has large effect.
Test example three, tartaric acid Afromoterol powders for inhalation capsule softgel shell quality testing test
1, test material:
Tartaric acid Afromoterol prepared by embodiment 1, embodiment 2, embodiment 3, comparative example 4, comparative example 5 and comparative example 6
Powders for inhalation capsule.
2, test method:
Measure tartaric acid A Fu prepared by embodiment 1, embodiment 2, embodiment 3, comparative example 4, comparative example 5 and comparative example 6
Special sieve powders for inhalation capsule percentage of damage and hygroscopicity, in which: the measuring method of percentage of damage are as follows: by embodiment 1, embodiment 2,
The sky of tartaric acid Afromoterol powders for inhalation capsule prepared by embodiment 3, comparative example 4, comparative example 5 and comparative example 6
Heart-soothing capsule each 10, powder spray inhalation test is carried out respectively, and observation punctures phenomenon, calculates the percentage of damage of capsule shells；Hygroscopicity: essence
The close tartaric acid Afromoterol powder for weighing embodiment 1, embodiment 2, embodiment 3, comparative example 4, comparative example 5 and comparative example 6 and preparing
Sucking agent capsules each 10, be placed in 20 DEG C, relative humidity be respectively 92.5% closed container in opposite increase is detected after 24 hours
Weight.
3, test result:
Test result is as shown in table 3.
The softgel shell quality testing of 3 tartaric acid Afromoterol powders for inhalation capsule of table is tested
| Percentage of damage (%) | The relative weight gain (%) | |
| Embodiment 1 | 0 | 4.6 |
| Embodiment 2 | 0 | 3.4 |
| Embodiment 3 | 0 | 4.9 |
| Comparative example 4 | 35 | 10.5 |
| Comparative example 5 | 10 | 6.6 |
| Comparative example 6 | 25 | 8.7 |
As shown in Table 3, the tartaric acid Afromoterol powders for inhalation capsule shells that the embodiment of the present invention 1~3 is prepared are in powder
Mist agent inhalation test is generated without fragment substantially, and body weight increase rate is lower than 5%, and softgel shell is not in ruckbildung, avoids fragment
As patient air flow is inhaled into the danger of tracheae, and the tartaric acid Afromoterol powders for inhalation capsule that comparative example 1~3 is prepared
Shell is broken in powder spray inhalation test is greater than 10% to rate, and body weight increase rate is greater than 5%, seriously affects tartaric acid Afromoterol
The soakage and effect of powder.
The comparative test of test example four, tartaric acid Afromoterol product
1, test material:
Tartaric acid Afromoterol powders for inhalation capsule prepared by embodiment 1, embodiment 2 and embodiment 3, tartaric acid A Fute
Sieve sucks liquid (trade name Brovana), ratifies to be listed a company by Sunovion in 7 Nikkei U.S. FDA October in 2006.
2, test method:
Tartaric acid Afromoterol powders for inhalation capsule prepared by embodiment 1, embodiment 2 and embodiment 3 and purchase
Comprehensive quality versus has been carried out according to quality standard draft between Brovana, and has carried out acid, alkali, high temperature, oxidation, illumination
Destructive testing comparison.
3, test result:
Test result is as shown in table 4.
The comparative test of 4 tartaric acid Afromoterol product of table
As shown in Table 4, the tartaric acid Afromoterol powders for inhalation capsule that prepared by the embodiment of the present invention 1~3 and purchase
Brovana meets the quality standard draft, exists without optical isomer；BROVANA product during transport and storage,
The amido bond of Afromoterol easily hydrolyzes, and the content of impurity A is caused to rise；And tartaric acid Afromoterol powder prepared by the present invention
Sucking agent capsules are then relatively stable, and after storing 24 months under long-term conditions, each impurity content is all in limits；And this
The tartaric acid Afromoterol powders for inhalation capsule for inventing preparation is easy to use, and without atomization, suction apparatus is small in size, convenient for taking
Band.
The stability test of test example five, tartaric acid Afromoterol powders for inhalation capsule
1, test material:
Embodiment 1, embodiment 2, embodiment 3, comparative example 1, comparative example 2, comparative example 3, comparative example 4, comparative example 5 and comparison
Tartaric acid Afromoterol powders for inhalation capsule prepared by example 6.
2, test method:
To embodiment 1, embodiment 2, embodiment 3, comparative example 1, comparative example 2, comparative example 3, comparative example 4, comparative example 5 and right
Tartaric acid Afromoterol powders for inhalation capsule prepared by ratio 6 is encapsulated with aluminium foil bag again after carrying out PVC blister package, is carried out strong
Light, high temperature, high humidity test, and accelerated test 6 months (40 DEG C, RH 75% under the conditions of) and 18 months (25 DEG C ± 2 DEG C, relative humidity
60%) it tests, investigates related substance, Emptying Rate, droplet distribution and content.
3, test result is as follows:
(1) it is placed 10 days under conditions of 60 DEG C of high temperature, high humidity (RH 75%), Qiang Guang (4500lx), the embodiment of the present invention
1~3 tartaric acid Afromoterol powders for inhalation capsule appearance, equal in relation to substance, content, Emptying Rate and Pcnten-1 yne-4 being prepared
Without significant change；Tartaric acid Afromoterol powders for inhalation capsule appearance, content, Emptying Rate and the mist that comparative example 1~3 is prepared
Drop distribution has decline, and related substance is increased slightly but still in limits；Comparative example 4~6 be prepared tartaric acid Ah
The appearance capsule softgel shell of Ford sieve powders for inhalation capsule softens, and 5% or more moisture absorption weight gain, content, Emptying Rate and Pcnten-1 yne-4 are equal
It slightly decreasing, related substance increase is more, but still in limits.
(2) accelerated test 6 months (40 DEG C, RH 75% under the conditions of), the embodiment of the present invention 1~3 prepare tartaric acid Ah
Ford sieve powders for inhalation capsule appearance has no significant change in relation to substance, content, Emptying Rate and Pcnten-1 yne-4；Comparative example 1~3
The related substance of tartaric acid Afromoterol powders for inhalation capsule being prepared has increase and overrun range, appearance, related object
Decline is distributed in matter, Emptying Rate, content, droplet；The tartaric acid Afromoterol powders for inhalation capsule that comparative example 4~6 is prepared
Appearance capsule softgel shell soften, 5% or more moisture absorption weight gain, content, Emptying Rate and Pcnten-1 yne-4 decline, the increase of related substance compared with
Mostly and beyond in limits.
(3) kept sample for a long time after investigation 18 months (25 DEG C ± 2 DEG C, relative humidity 60%), the embodiment of the present invention 1~3 is made
Standby tartaric acid Afromoterol powders for inhalation capsule appearance becomes without obvious in relation to substance, content, Emptying Rate and Pcnten-1 yne-4
Change；The related substance of tartaric acid Afromoterol powders for inhalation capsule that comparative example 1~3 is prepared has increase and overrun model
It encloses, decline is distributed in appearance, related substance, Emptying Rate, content, droplet；The tartaric acid A Fute that comparative example 4~6 is prepared
The appearance capsule softgel shell of sieve powders for inhalation capsule softens, and 5% or more moisture absorption weight gain, content, Emptying Rate and Pcnten-1 yne-4 decline,
Related substance increases more and exceeds in limits.
Test result shows: tartaric acid Afromoterol powders for inhalation capsule stabilization with higher is prepared in the present invention
Property, and the partial size of capsule 's content, supplementary product kind, auxiliary material partial size and capsule shells quality will affect tartaric acid Afromoterol powder
Suck the stability of agent capsules.
Claims (7)
1. a kind of tartaric acid Afromoterol powders for inhalation capsule, including capsule 's content and capsule shells, which is characterized in that the glue
It is intracapsular tolerant to be made of following components and its parts by weight:
22 parts of tartaric acid Afromoterol；
10000 ~ 11000 parts of lactose monohydrate；
The size distribution of the lactose monohydrate are as follows: D10=20.702 μm, D50=79.027 μm, D90=140.413 μm；
The capsule shells are made of following component and its parts by weight:
15 ~ 20 parts of hydroxypropyl methyl cellulose, 4 ~ 6 parts of chitosan oligomer, 1 ~ 3 part of tamarind gum, 1 ~ 2 part of sorbierite and water 65 ~
75 parts；
The preparation method of the tartaric acid Afromoterol powders for inhalation capsule, comprising the following steps:
S1 weighs the lactose monohydrate of capsule contents composition formula total amount 10%, is crushed with airslide disintegrating mill, obtains partial size and is less than
10 μm of lactose particles；
Tartaric acid Afromoterol and lactose monohydrate with mass ratio 1:10 mixing, are obtained mixture, then use air-flow crushing by S2
Machine crushes said mixture, obtains drug containing particle of the partial size less than 10 μm；
S3 the lactose monohydrate of the lactose particles that step S1 is obtained, the drug containing particle that step S2 is obtained and surplus is added more
To movement mixer, 55 ~ 65min is mixed, content is obtained；
S4 prepare capsule shells, fill capsule, packaging to get.
2. tartaric acid Afromoterol powders for inhalation capsule as described in claim 1, which is characterized in that the capsule 's content by
Following components and its parts by weight composition:
22 parts of tartaric acid Afromoterol；
10978 parts of lactose monohydrate；
The size distribution of the lactose monohydrate are as follows: D10=20.702 μm, D50=79.027 μm, D90=140.413 μm.
3. tartaric acid Afromoterol powders for inhalation capsule as described in claim 1, which is characterized in that the capsule shells are by following
Ingredient and its parts by weight composition:
18 parts of hydroxypropyl methyl cellulose, 5 parts of chitosan oligomer, 2 parts of tamarind gum, 2 parts of sorbierite and 70 parts of water.
4. tartaric acid Afromoterol powders for inhalation capsule as claimed in claim 1 or 3, which is characterized in that the oligopolymerization chitosan
Sugar is 5000 ~ 6500Da chitosan by molecular weight and molecular weight is 1000 ~ 3000Da chitosan by weight (4 ~ 6): (1 ~ 3) group
At.
5. tartaric acid Afromoterol powders for inhalation capsule as claimed in claim 4, which is characterized in that the chitosan oligomer by
Molecular weight is 5000 ~ 6500Da chitosan and molecular weight is that 1000 ~ 3000Da chitosan is formed by weight 5:2.
6. the preparation method of tartaric acid Afromoterol powders for inhalation capsule as described in claim 1, which is characterized in that the step
The pulverization conditions of rapid S1 and the airslide disintegrating mill in step S2 are as follows: crushing pressure is 0.4MPa, charging rate 0.5g/min, ring
Border humidity≤40%.
7. the preparation method of tartaric acid Afromoterol powders for inhalation capsule as described in claim 1, which is characterized in that the step
The preparation step of the capsule shells of rapid S4 are as follows:
It takes the water of half amount to stir evenly chitosan oligomer and tamarind gum, obtains mixed liquor；Then by hydroxypropyl methyl fiber
Element is added to while stirring in the water of surplus, and when the thick liquid of transparence is presented in stirring to solution, above-mentioned mixed liquor is added
And sorbierite, temperature be 40 ~ 50 DEG C under conditions of stir 10 ~ 15min, film forming to get.
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| CN201711250965.6A CN107929257B (en) | 2017-12-01 | 2017-12-01 | A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000089A (en) * | 2009-09-01 | 2011-04-06 | 北京利乐生制药科技有限公司 | Compound preparation with ciclesonide and Arformoterol as active constituents |
| CN102451173A (en) * | 2010-10-22 | 2012-05-16 | 山东新时代药业有限公司 | Tiotropium bromide capsule type inhalation aerosol powder |
| EP2682098A2 (en) * | 2012-07-05 | 2014-01-08 | Arven Ilac Sanayi Ve Ticaret A.S. | Inhalation Compositions |
| EP2821061A1 (en) * | 2013-07-01 | 2015-01-07 | Arven Ilac Sanayi Ve Ticaret A.S. | Novel inhalation formulations |
-
2017
- 2017-12-01 CN CN201711250965.6A patent/CN107929257B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000089A (en) * | 2009-09-01 | 2011-04-06 | 北京利乐生制药科技有限公司 | Compound preparation with ciclesonide and Arformoterol as active constituents |
| CN102451173A (en) * | 2010-10-22 | 2012-05-16 | 山东新时代药业有限公司 | Tiotropium bromide capsule type inhalation aerosol powder |
| EP2682098A2 (en) * | 2012-07-05 | 2014-01-08 | Arven Ilac Sanayi Ve Ticaret A.S. | Inhalation Compositions |
| EP2821061A1 (en) * | 2013-07-01 | 2015-01-07 | Arven Ilac Sanayi Ve Ticaret A.S. | Novel inhalation formulations |
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Address after: 526200 Fengshan Road, Dongcheng District, Sihui City, Guangdong, Zhaoqing Patentee after: Yili Pharmaceutical Co., Ltd Address before: No. 88, Fengshan Road, Dongcheng District, Sihui City, Guangzhou, Guangdong Patentee before: GUANGDONG YILI GROUP PHARMACEUTICAL Co.,Ltd. |