CN110200933A - It is used to prepare the composition and its preparation method and application for treating phthisical three compound preparation - Google Patents
It is used to prepare the composition and its preparation method and application for treating phthisical three compound preparation Download PDFInfo
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- CN110200933A CN110200933A CN201910624255.8A CN201910624255A CN110200933A CN 110200933 A CN110200933 A CN 110200933A CN 201910624255 A CN201910624255 A CN 201910624255A CN 110200933 A CN110200933 A CN 110200933A
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- ethambutol
- compound preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 76
- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 41
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims abstract description 32
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 18
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims abstract description 16
- 229960000285 ethambutol Drugs 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 206010045104 Tuberculous pleurisy Diseases 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 201000010098 pleural tuberculosis Diseases 0.000 claims abstract description 7
- 239000003826 tablet Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 239000000853 adhesive Substances 0.000 claims description 11
- 230000001070 adhesive effect Effects 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 11
- 229960003350 isoniazid Drugs 0.000 claims description 11
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 229960001225 rifampicin Drugs 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 230000003078 antioxidant effect Effects 0.000 claims description 9
- 235000006708 antioxidants Nutrition 0.000 claims description 9
- 238000009104 chemotherapy regimen Methods 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 238000011255 standard chemotherapy Methods 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 5
- AUAHHJJRFHRVPV-BZDVOYDHSA-N ethambutol dihydrochloride Chemical group [Cl-].[Cl-].CC[C@@H](CO)[NH2+]CC[NH2+][C@@H](CC)CO AUAHHJJRFHRVPV-BZDVOYDHSA-N 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 239000000814 tuberculostatic agent Substances 0.000 claims description 5
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 229940099112 cornstarch Drugs 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical group [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000007935 oral tablet Substances 0.000 claims description 2
- 229940096978 oral tablet Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000010384 tocopherol Nutrition 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- 229960001295 tocopherol Drugs 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 240000008042 Zea mays Species 0.000 claims 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- OPQCEZJIHDNSLT-UHFFFAOYSA-N butan-1-ol;n-ethylethanamine Chemical compound CCCCO.CCNCC OPQCEZJIHDNSLT-UHFFFAOYSA-N 0.000 claims 1
- 229960004106 citric acid Drugs 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- 235000005822 corn Nutrition 0.000 claims 1
- 238000005243 fluidization Methods 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 1
- 238000010422 painting Methods 0.000 claims 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 206010059866 Drug resistance Diseases 0.000 abstract description 6
- 239000002131 composite material Substances 0.000 abstract 1
- 239000007916 tablet composition Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 229960005206 pyrazinamide Drugs 0.000 description 6
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 6
- 235000020985 whole grains Nutrition 0.000 description 6
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SMNGQGWPUVVORF-UHFFFAOYSA-N 3,5-ditert-butyl-4-methylphenol Chemical compound CC1=C(C(C)(C)C)C=C(O)C=C1C(C)(C)C SMNGQGWPUVVORF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 208000036981 active tuberculosis Diseases 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to technical field of medicine, and in particular to a kind of to be used to prepare the composition and its preparation method and application for treating phthisical three compound preparation, and the drug being prepared.The composition includes Rimactazid, ethambutol or pharmaceutically acceptable ethambutol salt and the like.Compared with tetrad compound preparation, the size of three composite tablet of the present invention is small, is easier to swallow and sliver risk is small, easily facilitates patient's intake；Suitable for the whole cycle of Category II tuberculosis and tuberculous pleurisy patients, and using the intracorporal tablet quantity of intake and pharmaceutic adjuvant total amount can be substantially reduced after said preparation, so as to improve patient's compliance and reduce the generation of drug resistance.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to one kind is used to prepare the phthisical three compound system for the treatment of
Composition of agent and its preparation method and application, and the drug being prepared.
Background technique
Tuberculosis be it is a kind of seriously endanger health chronic infectious disease, newly occur every year tuberculosis patient about 800~
10000000, African and Asia developing country accounts for the most of of number of the infected, and China is that global 22 TB endemics are serious
One of country, while being also one of popular serious country of 27, whole world multi-drug resistance tuberculosis.Fall ill in China's tuberculosis year people
Number about 1,300,000, annual tuberculosis death toll is up to 130,000.Tuberculosis is mainly caused by tubercle bacillus, can invade human body many
Internal organs, it is most commonly seen with pulmonary tuberculosis.
Tuberculosis standard chemotherapy regimen are as follows: 1, just control active tuberculosis chemotherapy regimen: (1) 2H3R3Z3E3/4H3R3,
(2)2HRZE/4HR；2, one of Category II tuberculosis chemotherapy regimen: 2HRZES/6HRE；3, tuberculous pleurisy chemotherapy regimen
One of: 2HRZE/10HRE.The recommended dose of each active constituent is rifampin (R) 150mg, isoniazid in the standard chemotherapy regimen
(H) 75mg, pyrazinamide (Z) 400mg, ethambutol (E) 275mg.It follows that antituberculotic dosage is more, dosage form is big,
Instructions of taking is cumbersome, this is also to be difficult to obtain patient's hand-in-glove, be not readily accomplished one of regular chemotherapy and cannot be neglected factor.
And the drug resistance of tubercular is mainly caused by the compliance difference of patient for treatment.
When using single drug composition treatment pulmonary tuberculosis, patient needs to take daily 6~8 tablets of tablets.If cannot
Set treatment method is abided by completely, will lead to the development of multiple antibiotic resistant strain lungy.In order to control drug resistant M
The fixed dosage composition (FDC) of tablet form is suggested using by the appearance of disease, the World Health Organization (WHO), wherein active constituent
Tetrad compound preparation for isoniazid, rifampin, pyrazinamide and ethambutol is most common preparation compositions, because
The advantages such as the compound preparation has sterilization potent, and cure rate is high, drug resistance is low.
But there is also following disadvantages during making and using by this FDC: (1) size of tablet is very big, patient
It is difficult to swallow, the single tablet weight of tetrad compound preparation is substantially in 1000mg or more；(2) pyrazinamide is pulmonary tuberculosis short distance
One of drug in treatment, service life is only first 2 months in tuberculosis standard chemotherapy regimen, therefore presently the most common tetrad
Compound preparation is no longer appropriate for the therapeutic process after 2 months, and the treatment time in later period is up to 4 months or more, accounts for entirely treating
(Fig. 1 in chemotherapy regimen is especially recommended in Category II tuberculosis chemotherapy regimen and tuberculous pleurisy in 2/3 or more of period
It is shown).
Therefore, a kind of anti-tubercular drug of compound preparation form that can overcome the above tetrad compound preparation disadvantage very well is needed
Compositions and operable preparation method and therapeutic scheme.
Summary of the invention
In view of this, the present invention provides a kind of are used to prepare to treat the composition of phthisical three compound preparation, institute
Stating composition can be used for preparing phthisical three compound preparation for the treatment of, and the composition is suitable for Category II tuberculosis and tuberculosis
Property pleurisy treatment whole cycle, and using the intracorporal tablet quantity of intake and pharmaceutic adjuvant can be substantially reduced after said preparation
Total amount improves patient's compliance and reduces the generation of drug resistance；Slice weight can be obviously reduced simultaneously to increase complying with for patient
Property.
To achieve the above object, the present invention uses following scheme:
It is a kind of to be used to prepare the composition for treating phthisical three compound preparation, it include Rimactazid and ethamine
The mass ratio of butanol, the Rimactazid and ethambutol or pharmaceutically acceptable ethambutol salt and the like
For 150:75:275.
In certain embodiments, in three compound preparation, the scale point of the Rimactazid and ethambutol
It Wei not 150mg, 75mg and 275mg.
Further, the ethambutol salt is ebutol or hydrobromic acid ethambutol.
Further, the composition also includes excipient, and the excipient is diluent, disintegrating agent, adhesive, lubricant
One or more of with antioxidant.
Further, the diluent is microcrystalline cellulose or pregelatinized starch.
Preferably, the diluent is microcrystalline cellulose.
Further, the disintegrating agent is croscarmellose sodium, hands over poly- povidone, pregelatinized starch, cornstarch
With one of low-substituted hydroxypropyl cellulose or a variety of.
Preferably, the disintegrating agent is croscarmellose sodium.
Further, described adhesive is one of povidone, polyvinyl alcohol, cornstarch and pregelatinized starch or more
Kind.
Preferably, described adhesive is povidone.
Further, the lubricant is in magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid and zinc stearate
It is one or more.
Preferably, the lubricant is magnesium stearate.
Further, the antioxidant be sodium ascorbate, 2,6- di-t-butyl -4- hydroxy-methylbenzene, citric acid, tocopherol and
One of sodium metabisulfite is a variety of.
Preferably, the antioxidant is sodium ascorbate.
Further, the excipient is made of the following components by weight percentage: the disintegration of 7-15% diluent, 1-5%
Agent, the adhesive of 0.5-3%, the lubricant of 0.2-2%, 0.1-1.5% antioxidant.
Preferably, the excipient is made of the following components by weight percentage: the disintegration of 8-10% diluent, 2-4%
Agent, the adhesive of 1-1.5%, the lubricant of 0.3-1%, 0.2-1% antioxidant.
The second object of the present invention is to provide the group for being used to prepare described in one kind and treating phthisical three compound preparation
Close a kind of application of object.
To achieve the above object, the present invention uses following scheme:
The composition for treating phthisical three compound preparation that is used to prepare is in preparation tuberculosis standard chemotherapy regimen
Application in drug.
Further, the tuberculosis standard chemotherapy regimen is Category II tuberculosis chemotherapy regimen and/or Tuberculous pleura
Scorching chemotherapy regimen.
For Category II tuberculosis patient and tuberculous pleurisy patient, therapeutic scheme can are as follows: the period 1 is
First 2 months, take the additional pyrazinamide tablet of three compound preparation of this product and strepto- plain piece；Second round is 6 months later periods or 8
Month, three compound preparations need to be only taken by scheme.
The third object of the present invention is to provide a kind of preparation method of composition, and the preparation method has a simple process,
And economical and effective.
To achieve the above object, the present invention uses following scheme:
It is described be used to prepare the preparation method for treating the composition of phthisical three compound preparation the following steps are included:
1) wet granulation is carried out after being mixed isoniazid, ethambutol, diluent, adhesive and disintegrating agent, it is rear to use
Fluidized bed drying simultaneously obtains particle；
2) rifampin powder, disintegrating agent, lubricant and antioxidant are added again and carries out tabletting, and then obtain the composition.
Inventor it is creative the study found that by the way that isoniazid and ethambutol are pelletized together, benefit is added outside particle
Good fortune is flat, and by the dosage of excipient in control granular size and reduction particle, can get the composition.Meanwhile the compound
Preparation can solve the rifampin variation of crystalline form and itself and other two kinds of active materials in tableting processes for rifampin is additional,
Especially with isoniazid incompatibility the problem of.
Further, the method for the wet granulation be after isoniazid and ethambutol sieving with diluent, adhesive and suitable
Amount disintegrating agent is mixed, then uses fluidized bed drying.
Further, the rotating speed of agitator of the wet granulator is 1-8 revolutions per seconds, and cutter rotating velocity is 10-50 revolutions per seconds.
Preferably, the rotating speed of agitator of the wet granulator is 2-5 revolutions per seconds, and cutter rotating velocity is 25-40 revolutions per seconds.
Further, the time of the wet granulation is 30-150 seconds.
Preferably, the time of the wet granulation is 45-90 seconds.
Further, the temperature of charge of the step 1) drying is 30-65 DEG C, and inlet air temperature when fluidized bed is dried is
40-100℃。
Preferably, the temperature of charge of the step 1) drying is 40-55 DEG C, and inlet air temperature when fluidized bed is dried is set
It is set to 65-90 DEG C.
Further, air quantity when fluidized bed drying is 5-50m3/h。
Preferably, air quantity when fluidized bed drying is 10-40m3/h。
The fourth object of the present invention be to provide it is a kind of treat phthisical three compound preparation, the compound preparation slice weight
It is small, the intracorporal tablet quantity of intake and pharmaceutic adjuvant dosage in treatment cycle can be substantially reduced, applies positive lung particularly with controlling again
Tubercular and tuberculous pleurisy patient, so as to significantly improve patient's compliance and reduce the generation of drug resistance.
To achieve the above object, the present invention uses following scheme:
Three compound preparations are prepared by the method that phthisical three compound preparations composition is treated in the preparation.
Further, the preparation is oral tablet.
Further, the tablet is individual layer tablet, weight 565-650mg.
Preferably, weight 580-615mg.
The beneficial effects of the present invention are:
1) size of three compound preparation is small, is easier to swallow and sliver risk is small, absorbs convenient for patient；
2) three compound preparation is suitable for the whole cycle of Category II tuberculosis and tuberculous pleurisy patients, and
The intracorporal tablet quantity of intake and pharmaceutic adjuvant total amount can be substantially reduced using said preparation, so as to improve patient's compliance
With the generation for reducing drug resistance；
3) preparation process is simple, economical and effective.
Detailed description of the invention
Fig. 1 is the dosage comparison of tetrad compound preparation and three compound preparations in pulmonary tuberculosis standard chemotherapy regimen, wherein H
In generation, refers to isoniazid, and R generation refers to rifampin, and Z generation refers to pyrazinamide, and E is for ethambutol, and s is for streptomysin.
Specific embodiment
Illustrated embodiment is in order to which preferably the present invention will be described, but is not that the contents of the present invention are limited only to institute
For embodiment.So those skilled in the art according to foregoing invention content to embodiment carry out it is nonessential improvement and
Adjustment, still falls within protection scope of the present invention.
Embodiment 1 treats phthisical three compound preparation
1. (1000, tablet is made) in preparation prescription
2. preparation process
1) isoniazid, ebutol, microcrystalline cellulose and croscarmellose sodium are first mixed, to
With；
2) mixed material is crossed into 60 mesh standard sieves, and povidone is dissolved in the water, solution is made；
3) grain made parameter are as follows: rotating speed of agitator is 2 revolutions per seconds, and cutter rotating velocity is 25 revolutions per seconds, and Granulation time is 45 seconds；
4) it obtained particle is crossed into 24 mesh standard sieves is placed in fluidized bed and be dried；
5) drying parameter are as follows: temperature of charge are as follows: 30-65 DEG C；Inlet air temperature are as follows: 40-100 DEG C；Air quantity is 5-40m3/ h, to
Temperature of charge discharges after reaching 60-65 DEG C；
4) after the completion of dry, whole grain is carried out to dry particl using 24 meshes；
5) to particle addition rifampin, ascorbic acid and the magnesium stearate after whole grain, tabletting after 10min is mixed, institute is made
State three compound preparations.
Embodiment 2 treats phthisical three compound preparation
1. (1000, tablet is made) in preparation prescription
2. preparation process
1) isoniazid, ebutol, microcrystalline cellulose and croscarmellose sodium are mixed, for use；
2) mixed material is crossed into 60 mesh standard sieves, and povidone is dissolved in the water, solution is made；
3) grain made parameter are as follows: rotating speed of agitator is 5 revolutions per seconds, and cutter rotating velocity is 40 revolutions per seconds, and Granulation time is 90 seconds；
4) it obtained particle is crossed into 24 mesh standard sieves is placed in fluidized bed and be dried；
5) drying parameter are as follows: temperature of charge are as follows: 30-65 DEG C；Inlet air temperature are as follows: 40-100 DEG C；Air quantity is 10-40m3/ h,
It discharges after temperature of charge reaches 60-65 DEG C；
4) after the completion of dry, whole grain is carried out to dry particl using 24 meshes；
5) to particle addition rifampin, ascorbic acid and the magnesium stearate after whole grain, tabletting after 10min is mixed, institute is made
State three compound preparations.
1 tetrad compound preparation of comparative example
1. (1000, tablet is made) in preparation prescription
2. preparation process
1) pyrazinamide, isoniazid, ebutol, microcrystalline cellulose and croscarmellose sodium are first carried out
Mixing, for use；
2) mixed material is crossed into 60 mesh standard sieves, and povidone is dissolved in the water, solution is made；
3) grain made parameter are as follows: rotating speed of agitator is 5 revolutions per seconds, and cutter rotating velocity is 40 revolutions per seconds, and Granulation time is 90 seconds；
4) it obtained particle is crossed into 24 mesh standard sieves is placed in fluidized bed and be dried；
5) drying parameter are as follows: temperature of charge are as follows: 30-65 DEG C；Inlet air temperature are as follows: 40-100 DEG C；Air quantity is 10-40m3/ h,
It discharges after temperature of charge reaches 60-65 DEG C；
4) after the completion of dry, whole grain is carried out to dry particl using 24 meshes；
5) to particle addition rifampin, ascorbic acid and the magnesium stearate after whole grain, tabletting after 10min is mixed, is made four
Join compound preparation.
The comparative analysis of tetrad compound preparation and three compound preparations described in embodiment 3
By the mobility of particle, weight, hardness and the friability of tablet composition, disintegration time are as inspection target to reality
The preparation for applying a 1-2 and comparative example 1 compares research.
1. mobility and compressibility
Because carr index can be with reaction particles mobility and compressibility, therefore comparative study is carried out to above embodiments.
It takes total mix particle appropriate, is measured in powder densitometer, and calculate its carr index.
Table 1: total mix particle carr index value
| Embodiment 1 | Embodiment 2 | Comparative example 1 | |
| Carr index (%) | 18.4 | 19.0 | 27.8 |
Note: the calculation method of carr index is real density/heap density * 100；Carr index is smaller, and mobility is more superior.
2. slice weight and piece are thick
It takes tablet composition appropriate, at room temperature, measures slice weight in electronic balance, and thick with vernier caliper measurement piece
(diameter is 13.0mm), each embodiment take 10 respectively and are averaged.
Table 2: preparation compositions slice weight and piece are thick
| Embodiment 1 | Embodiment 2 | Comparative example 1 | |
| Slice weight (mg) | 564 | 642 | 1042 |
| Piece thickness (mm) | 5.6 | 5.9 | 8.6 |
Combination of the above object measures piece thickness and slice weight, piece type (piece is thick) smaller product under the conditions of fixinig plate diameter (13.0mm)
Compliance is higher.
3. hardness and friability
It takes tablet composition appropriate, at room temperature, the hardness of tablet composition is measured in Yu Zhineng tablet hardness instrument,
And grope the maximum value (Max) of tablet composition in every group of embodiment respectively.Separately take tablet composition appropriate simultaneously, according to " in
State's pharmacopeia " measurement tablet composition friability.
Table 3: preparation compositions hardness and friability
As shown in Table 3, composition hardness is not obviously increased as slice weight increases.
4. dissolution rate
Take tablet composition appropriate, according to dissolution method, using 900ml purified water as dissolution medium, rotating speed of agitator
It 50 revs/min, operates according to methods, the time for respectively taking 10 observation tablet compositions to be disintegrated completely.
Table 4: preparation compositions disintegration time
| Number | Embodiment 1 (min) | Embodiment 2 (min) | Comparative example 1 (min) |
| 1 | 4.3 | 4.0 | 3.5 |
| 2 | 5.0 | 4.9 | 4.7 |
| 3 | 5.0 | 4.8 | 5.5 |
| 4 | 2.4 | 5.6 | 4.2 |
| 5 | 2.9 | 6.1 | 5.9 |
| 6 | 3.7 | 4.2 | 6.3 |
| 7 | 3.9 | 3.8 | 3.2 |
| 8 | 3.8 | 2.9 | 3.0 |
| 9 | 4.2 | 4.5 | 2.8 |
| 10 | 4.0 | 5.1 | 3.6 |
| Average | 3.9 | 4.6 | 4.3 |
| RSD (%) | 0.81 | 0.92 | 1.27 |
As shown in Table 4, the disintegration time limited of three compound preparations does not substantially change, and has been disintegrated substantially in 4min or so
Entirely.
Finally, it is stated that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to compared with
Good embodiment describes the invention in detail, those skilled in the art should understand that, it can be to skill of the invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the scope of the claims of invention.
Claims (17)
1. a kind of be used to prepare the composition for treating phthisical three compound preparation, which is characterized in that the composition includes
Rimactazid, ethambutol or pharmaceutically acceptable ethambutol salt and the like, the Rimactazid
Mass ratio with ethambutol or pharmaceutically acceptable ethambutol salt and the like is 150:75:275.
2. composition according to claim 1, which is characterized in that the composition also includes excipient, the excipient
For one or more of diluent, disintegrating agent, adhesive, lubricant and antioxidant.
3. composition according to claim 1, which is characterized in that the ethambutol salt is ebutol or hydrogen bromine
Acid diethylamide butanol.
4. composition according to claim 2, which is characterized in that the diluent is that microcrystalline cellulose or pregelatinated form sediment
Powder.
5. composition according to claim 2, which is characterized in that the disintegrating agent is croscarmellose sodium, hands over
One of poly- povidone, pregelatinized starch, cornstarch and low-substituted hydroxypropyl cellulose are a variety of.
6. composition according to claim 2, which is characterized in that described adhesive is povidone, polyvinyl alcohol, corn shallow lake
One of powder and pregelatinized starch are a variety of.
7. composition according to claim 2, which is characterized in that the lubricant be magnesium stearate, sodium stearyl fumarate,
One of calcium stearate, stearic acid and zinc stearate are a variety of.
8. composition according to claim 2, which is characterized in that the antioxidant is sodium ascorbate, the tertiary fourth of 2,6- bis-
One of base -4- hydroxy-methylbenzene, citric acid, tocopherol and sodium metabisulfite are a variety of.
9. composition according to claim 2, which is characterized in that the excipient is by weight percentage by following component group
At: 7-15% diluent, the disintegrating agent of 1-5%, the adhesive of 0.5-3%, the lubricant of 0.2-2%, 0.1-1.5% antioxygen
Agent.
10. claim 1-9 is described in any item to be used to prepare the preparation for treating the composition of phthisical three compound preparation
Method, which is characterized in that the preparation method comprises the following steps:
1) wet granulation is carried out after being mixed isoniazid, ethambutol, diluent, adhesive and disintegrating agent, rear fluidisation
Bed is dry and obtains particle；
2) rifampin powder, disintegrating agent, lubricant and antioxidant are added again and carries out tabletting, and then obtain the composition.
11. preparation method according to claim 10, which is characterized in that the rotating speed of agitator of the wet granulator is 1-
8 revolutions per seconds, cutter rotating velocity is 10-50 revolutions per seconds, and the time of the wet granulation is 30-150 seconds.
12. preparation method according to claim 10, which is characterized in that the temperature of the step 1) drying is 30-65 DEG C,
Inlet air temperature when fluidized bed is dried is 40-100 DEG C, air quantity 5-50m3/h。
13. claim 10-12 is described in any item to be used to prepare the system for treating the composition of phthisical three compound preparation
Three compound preparations that Preparation Method is prepared.
14. three compound preparation according to claim 13, which is characterized in that the preparation is oral tablet.
15. three compound preparation according to claim 14, which is characterized in that the tablet is individual layer tablet, and weight is
565-650mg。
16. application of the described in any item compositions of claim 1-9 in preparation tuberculosis standard chemotherapy regimen drug.
17. application according to claim 16, which is characterized in that the tuberculosis standard chemotherapy regimen is to control the positive lung of painting again
Tuberculosis chemotherapy regimen and/or tuberculous pleurisy chemotherapy regimen.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298704A (en) * | 1999-12-29 | 2001-06-13 | 国家药品监督管理局四川抗菌素工业研究所 | Composite lifuding and preparing process |
| WO2002087547A1 (en) * | 2001-04-27 | 2002-11-07 | Lupin Limited | An improved process for preparation of four-drug anti-tubercular fixed dose combination |
| CN1611218A (en) * | 2003-10-31 | 2005-05-04 | 沈阳药科大学 | Fixed dose compound preparation of antitubercular drug and its preparing method |
| CN1864681A (en) * | 2006-06-09 | 2006-11-22 | 高华 | Preparation method of composite rifampicin micro-tablet capsule |
| CN102552204A (en) * | 2011-12-30 | 2012-07-11 | 沈阳药科大学 | Compound antituberculous coating core tablet and preparing method |
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2019
- 2019-07-11 CN CN201910624255.8A patent/CN110200933A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298704A (en) * | 1999-12-29 | 2001-06-13 | 国家药品监督管理局四川抗菌素工业研究所 | Composite lifuding and preparing process |
| WO2002087547A1 (en) * | 2001-04-27 | 2002-11-07 | Lupin Limited | An improved process for preparation of four-drug anti-tubercular fixed dose combination |
| CN1611218A (en) * | 2003-10-31 | 2005-05-04 | 沈阳药科大学 | Fixed dose compound preparation of antitubercular drug and its preparing method |
| CN1864681A (en) * | 2006-06-09 | 2006-11-22 | 高华 | Preparation method of composite rifampicin micro-tablet capsule |
| CN102552204A (en) * | 2011-12-30 | 2012-07-11 | 沈阳药科大学 | Compound antituberculous coating core tablet and preparing method |
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Application publication date: 20190906 |