CN104523658A - Erdosteine powder inhalation and preparation method thereof - Google Patents
Erdosteine powder inhalation and preparation method thereof Download PDFInfo
- Publication number
- CN104523658A CN104523658A CN201410765144.6A CN201410765144A CN104523658A CN 104523658 A CN104523658 A CN 104523658A CN 201410765144 A CN201410765144 A CN 201410765144A CN 104523658 A CN104523658 A CN 104523658A
- Authority
- CN
- China
- Prior art keywords
- erdosteine
- powder
- superfine powder
- superfine
- pluronics
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QGFORSXNKQLDNO-UHFFFAOYSA-N erdosteine Chemical compound OC(=O)CSCC(=O)NC1CCSC1=O QGFORSXNKQLDNO-UHFFFAOYSA-N 0.000 title claims abstract description 169
- 229960003262 erdosteine Drugs 0.000 title claims abstract description 169
- 239000000843 powder Substances 0.000 title claims abstract description 142
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 32
- 229920001983 poloxamer Polymers 0.000 claims description 79
- 229940098458 powder spray Drugs 0.000 claims description 48
- 239000002775 capsule Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 27
- 238000010298 pulverizing process Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 abstract description 69
- 230000000694 effects Effects 0.000 abstract description 35
- 229940079593 drug Drugs 0.000 abstract description 34
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 20
- 210000004185 liver Anatomy 0.000 abstract description 18
- 230000015556 catabolic process Effects 0.000 abstract description 15
- 238000006731 degradation reaction Methods 0.000 abstract description 15
- 230000008030 elimination Effects 0.000 abstract description 12
- 238000003379 elimination reaction Methods 0.000 abstract description 12
- 238000002156 mixing Methods 0.000 abstract description 11
- 238000000227 grinding Methods 0.000 abstract description 2
- 210000004072 lung Anatomy 0.000 abstract description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 abstract 3
- 229920001993 poloxamer 188 Polymers 0.000 abstract 3
- 229940044519 poloxamer 188 Drugs 0.000 abstract 3
- 210000004369 blood Anatomy 0.000 description 19
- 239000008280 blood Substances 0.000 description 19
- 230000002685 pulmonary effect Effects 0.000 description 14
- 238000010579 first pass effect Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 11
- 230000000968 intestinal effect Effects 0.000 description 10
- 210000002784 stomach Anatomy 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 230000004087 circulation Effects 0.000 description 5
- 239000007919 dispersible tablet Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000010010 raising Methods 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 108010063045 Lactoferrin Proteins 0.000 description 1
- 102100032241 Lactotransferrin Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- FGQXHNYNPDGTKW-UHFFFAOYSA-N acetonitrile;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound CC#N.OC(=O)CC(O)(C(O)=O)CC(O)=O FGQXHNYNPDGTKW-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 1
- 229940078795 lactoferrin Drugs 0.000 description 1
- 235000021242 lactoferrin Nutrition 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to an erdosteine powder inhalation which is actively inhaled in a superfine powder mode and directly delivers a medicine to the lung to exert effect, solving the problem of low degradation effect and liver first pass elimination effect bioavailability of a medicine in gastrointestinal tracts. The erdosteine powder inhalation is prepared by mixing superfine erdosteine powder and superfine poloxamer 188 powder, wherein the average particle size of the superfine erdosteine powder at the weight ratio of 20:3-2:1 is 1-5 micrometers, and the maximum particle size is not more than 10 micrometers; the average particle size of the superfine poloxamer 188 powder is 60-80 micrometers, and the maximum particle size is not more than 100 micrometers. A preparation method comprises the following steps: grinding erdosteine, carrying out superfine crushing by using a superfine crusher to obtain the superfine powder of which the average particle size is 1-5 micrometers; carrying out superfine crushing on poloxamer 188 by using the superfine crusher to obtain the superfine powder of which the average particle size is 60-80 micrometers; and uniformly mixing the crushed superfine powder according to a proportion of 20:3-2:1, and then subpackaging.
Description
Technical field
The invention belongs to field of medicaments, in particular to a kind of erdosteine inhalation powder spray and preparation method thereof.
Background technology
Erdosteine is a kind of prodrug, in structure with non-free close sulfydryl, to local mucin inactive, after oral through metabolism produce three containing free sulfhydryl groups metabolite and play pharmacological action.Erdosteine cylinder metabolism-ure can make mucinous disulfide bonds in bronchial secretion; and change secretions composition and rheological property; reduce sputum viscosity; improve downtrod respiratory function; this product energy scavenging free radicals; the oxidation deactivation that available protecting a1-antitrypsin brings out from cigarette, dirt, prevents the damage to elastance of lung albumen and neutrophilic granulocyte.Obviously can increase IgA/ albumin, lactoferrin/albuminous ratio, weaken local inflammation, strengthen and improve the osmosis of antibiotic to bronchial mucosa, be conducive to the treatment of the various inflammation of respiratory tract.The structural formula of erdosteine is as follows:
The erdosteine of clinical middle application is oral type at present, ratio is if any oral erdosteine capsule, erdosteine dispersible tablet etc., but there is stomach, intestinal degradation effect in oral administration, and gastrointestinal tract first pass effect and liver head cross elimination effect, make medicine enter sanguimotor proto-drug and reduce.By the enzymes metabolism in gastrointestinal tract mucous or liver before medicine enters blood circulation, have influence on the curative effect of medicine, reduce the dose and the blood drug level that arrive body circulation, and the problem such as bioavailability is low.In view of this, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of erdosteine inhalation powder spray, there is good absorbability and stability, and initiatively suck with superfine powder form, directly medicine is delivered to pulmonary's onset, medicine Degradation in the gastrointestinal tract can be overcome, and the problem such as liver head crosses elimination effect and bioavailability is low, easy to use, price is also comparatively cheap.
Another object of the present invention is the preparation method providing a kind of erdosteine inhalation powder spray.
The object of the present invention is achieved like this: a kind of erdosteine inhalation powder spray, be mixed by erdosteine superfine powder and PLURONICS F87 superfine powder; The mass ratio of wherein said erdosteine superfine powder and PLURONICS F87 superfine powder is 20:3 ~ 2:1;
The mean diameter of described erdosteine superfine powder is 1 μm ~ 5 μm, and wherein maximum particle diameter is no more than 10 μm; The mean diameter of described PLURONICS F87 superfine powder is 60 μm ~ 80 μm, and maximum particle diameter is no more than 100 μm.
The erdosteine of current clinical middle application is oral type, ratio is if any oral erdosteine capsule, erdosteine dispersible tablet etc., but there is stomach, intestinal degradation effect in oral administration, and gastrointestinal tract first pass effect and liver head cross elimination effect, make medicine enter sanguimotor proto-drug and reduce.By the enzymes metabolism in gastrointestinal tract mucous or liver before medicine enters blood circulation, have influence on the curative effect of medicine, reduce the dose and the blood drug level that arrive body circulation, and the problem that bioavailability is low.
The absorbability of the therapy in dry powder form of oarse-grained erdosteine is poor simultaneously, and be all capsule or the dispersible tablet use of making the fill of erdosteine bulky grain clinically in the past, but, the present invention is found by a large amount of tests, after erdosteine dry powder and PLURONICS F87 superfine powder being mixed with special ratios, the absorbance of erdosteine dry powder can be improved.So, finally obtain erdosteine dry powder to mix the absorbance that can improve erdosteine dry powder with the mass ratio of 20:3 ~ 2:1 with PLURONICS F87 superfine powder.And with the problem that the erdosteine dry powder doses that this proportioning is made can effectively avoid the consumption of erdosteine excessive.
But, because be directly dry medicated powder is sucked from cavity to enter pulmonary, so, the erdosteine bulky grain in the past made can not be satisfied the demand, simultaneously, not only demand fulfillment patient when spraying into the acceptance of medicine, and need the sense of discomfort alleviating patient, sucking in the process of pulmonary from cavity simultaneously, in order to avoid stomach, intestinal degradation effect, and gastrointestinal tract first pass effect and liver head cross elimination effect, the present inventor adjusts again the particle diameter of erdosteine dry powder and PLURONICS F87 by a large amount of orthogonal experiments, erdosteine dry powder is made erdosteine superfine powder, its mean diameter is made to be 1 μm ~ 5 μm, maximum particle diameter is no more than 10 μm, PLURONICS F87 dry powder is made PLURONICS F87 superfine powder, and its mean diameter is 60 μm ~ 80 μm, and maximum particle diameter is no more than 100 μm.With such particle diameter, the two is mixed according to aforementioned proportion, under PLURONICS F87 superfine powder synergism, avoid stomach, intestinal degradation effect, and gastrointestinal tract first pass effect, reduce erdosteine superfine powder simultaneously and arrive the liver head elimination effect excessively produced in the process of pulmonary, and the acceptance level of patient is high, does not have sense of discomfort completely, also substantially increase service efficiency and the drug safety of erdosteine.
, proved by test, by erdosteine inhalation powder spray provided by the invention by after cavity administration, its blood drug level is far above the blood drug level after the administration of tablet or large granule meanwhile.
Erdosteine inhalation powder spray provided by the invention, patient independently initiatively can be sucked by suction apparatus, medicine is directly transported to pulmonary's onset, reduce the stomach of medicine, intestinal degradation effect, and gastrointestinal tract first pass effect and liver head cross elimination effect, the help of medical personnel is not needed independently to carry out, easy to use; And preparation cost is low, Clinical practice price is also comparatively cheap.
Meanwhile, by erdosteine inhalation powder spray provided by the invention directly to Pulmonary inhalation, also have the following advantages:
1. without gastrointestinal tract Degradation;
2. without liver first-pass effect;
3. drug absorption is rapid, rapid-action after administration;
4. macromolecular drug bioavailability can by absorption enhancer or other method should be used for improve;
5. small-molecule drug is particularly useful for respiratory tract and directly sucks or spray into administration;
6. directly enter body circulation after drug absorption, reach the object of whole body therapeutic;
7. can be used for the large medicine of water solublity that gastrointestinal tract is difficult to absorb;
8. good patient compliance, is specially adapted to the patient that former need carry out long term injections treatment;
9. play the medicine of local action, dosage obviously reduces, and toxic and side effects is little.
Further, the mass ratio of described erdosteine superfine powder and described PLURONICS F87 superfine powder is 20:5 ~ 20:7.
Further, the described erdosteine superfine powder of 200mg mixes with the described PLURONICS F87 superfine powder of 60 ~ 100mg.
Further, the described erdosteine superfine powder of 300mg mixes with the described PLURONICS F87 superfine powder of 70 ~ 90mg.
Further, the described erdosteine superfine powder of 400mg mixes with the described PLURONICS F87 superfine powder of 75 ~ 85mg.
Further, the mean diameter of described erdosteine superfine powder is 2 μm ~ 4 μm, and the mean diameter of described PLURONICS F87 superfine powder is 65 μm ~ 75 μm.Preferably, the mean diameter of described erdosteine superfine powder is 3 μm, and the mean diameter of described PLURONICS F87 superfine powder is 70 μm.
Present invention also offers the preparation method preparing erdosteine inhalation powder spray, comprise the following steps:
Step one: by erdosteine porphyrize, carries out micronizing with super micron mill, obtains the erdosteine superfine powder that average particle size is 1 μm ~ 5 μm;
Step 2: PLURONICS F87 super micron mill is carried out micronizing, obtains the PLURONICS F87 superfine powder that mean diameter is 60 μm ~ 80 μm;
Step 3: after the ratio taking mass ratio as 20:3 ~ 2:1 by the erdosteine superfine powder after pulverizing and PLURONICS F87 superfine powder mixes, use capsule subpackage.
The erdosteine inhalation powder spray made by the method effectively can improve the uniformity of the erdosteine after pulverizing and PLURONICS F87 particle diameter, the bulk density reduced therebetween is poor, the uniformity coefficient that both raisings mix and the stratification phenomenon produced in long-term standing process.
Further, in step one, the mean diameter of the described erdosteine superfine powder obtained is 2 μm ~ 4 μm;
In step 2, the mean diameter of the described PLURONICS F87 superfine powder obtained is 65 μm ~ 75 μm.
Further, in step 3, after the ratio taking mass ratio as 20:5 ~ 20:7 mixes, carry out subpackage with 0-2 capsule by the described erdosteine superfine powder after pulverizing and PLURONICS F87 superfine powder.
Using method: when using erdosteine inhalation powder spray provided by the present invention, point capsule installed is incapsulated in type powder vapor inhalator, patient uses the direct inhalation powder spray of the suction nozzle that capsule-type powder vapor inhalator is arranged, and powder spray can be taken directly pulmonary's onset.
Compared with prior art, erdosteine inhalation powder spray that the present invention relates to and preparation method thereof also has following beneficial effect:
(1) provide the unprecedented dosage form of a kind of erdosteine and pulmonary administration mode, reduce the stomach of medicine, intestinal degradation effect, and gastrointestinal tract first pass effect and liver head cross elimination effect, improve the effective rate of utilization of medicine.
(2) erdosteine raw material particle size is all less than 10 μm, improves drug safety and effectiveness, and the patient used is without sense of discomfort.
(3) its preparation process is fairly simple, easy to operate, be applicable to suitability for industrialized production, and the bulk density reduced between erdosteine superfine powder and PLURONICS F87 superfine powder is poor, the uniformity coefficient that both raisings mix and the stratification phenomenon produced in long-term standing process.
Accompanying drawing illustrates:
Fig. 1 is erdosteine superfine powder scanning electron microscope (SEM) photograph provided by the invention;
Fig. 2 is PLURONICS F87 micropowder scanning electron microscope (SEM) photograph provided by the invention;
Fig. 3 be erdosteine powder spray provided by the invention and current Clinical practice erdosteine tablet upon administration 3 hours in blood drug level variation diagram in patient's body.
Detailed description of the invention
Below by specific embodiment, the present invention is described in further detail.
A kind of erdosteine inhalation powder spray, is mixed by erdosteine superfine powder and PLURONICS F87 superfine powder; The mass ratio of wherein said erdosteine superfine powder and PLURONICS F87 superfine powder is 20:3 ~ 2:1;
Preferably, the mass ratio of described erdosteine superfine powder and described PLURONICS F87 superfine powder is 20:5 ~ 20:7.
According to the safety using amount of erdosteine, preferably, the erdosteine superfine powder of 200mg mixes with the PLURONICS F87 micropowder of 60 ~ 100mg.The erdosteine superfine powder of 300mg mixes with the PLURONICS F87 micropowder of 70 ~ 90mg.The erdosteine superfine powder of 400mg mixes with the described PLURONICS F87 micropowder of 75 ~ 85mg.More preferably, the erdosteine superfine powder of 200mg mixes with the PLURONICS F87 micropowder of 70 ~ 90mg.The erdosteine superfine powder of 300mg mixes with the PLURONICS F87 micropowder of 75 ~ 85mg.The erdosteine superfine powder of 400mg mixes with the described PLURONICS F87 micropowder of 78 ~ 82mg.
The mean diameter of described erdosteine superfine powder is 1 μm ~ 5 μm, and wherein maximum particle diameter is no more than 10 μm; The mean diameter of described PLURONICS F87 superfine powder is 60 μm ~ 80 μm, and maximum particle diameter is no more than 100 μm.
Preferably, the mean diameter of erdosteine superfine powder is 2 μm ~ 4 μm, and the mean diameter of PLURONICS F87 micropowder is 65 μm ~ 75 μm.More preferably, the mean diameter of erdosteine superfine powder is 3 μm, and the mean diameter of PLURONICS F87 micropowder is 70 μm.
It is ultra micro dry powder that erdosteine capsule type inhalation aerosol powder of the present invention can suck form; its active component is erdosteine, and chemistry is by name: (±)-N-[2-(carboxymethyl sulfydryl)-acetyl group]-homocysteine thiolactone.The mean diameter of erdosteine superfine powder is at 1 μm ~ 5 μm, and maximum particle diameter is no more than 10 μm.The erdosteine superfine powder scanning electron microscope (SEM) photograph obtained is see accompanying drawing 1.
Erdosteine inhalation powder spray pharmaceutical carrier of the present invention is PLURONICS F87, and the mean diameter after micronization 60 μm ~ 80 μm, maximum particle diameter is no more than 100 μm.The PLURONICS F87 micropowder scanning electron microscope (SEM) photograph obtained is see accompanying drawing 2.
The erdosteine of current clinical middle application is oral type, ratio is if any oral erdosteine capsule, erdosteine dispersible tablet etc., but there is stomach, intestinal degradation effect in oral administration, and gastrointestinal tract first pass effect and liver head cross elimination effect, make medicine enter sanguimotor proto-drug and reduce.By the enzymes metabolism in gastrointestinal tract mucous or liver before medicine enters blood circulation, have influence on the curative effect of medicine, reduce the dose and the blood drug level that arrive body circulation, and the problem that bioavailability is low.
The absorbability of the therapy in dry powder form of oarse-grained erdosteine is poor simultaneously, and be all capsule or the dispersible tablet use of making the fill of erdosteine bulky grain clinically in the past, but, the present invention is found by a large amount of tests, after erdosteine dry powder and PLURONICS F87 superfine powder being mixed with special ratios, the absorbance of erdosteine dry powder can be improved.So, finally obtain erdosteine dry powder to mix the absorbance that can improve erdosteine dry powder with the mass ratio of 20:3 ~ 2:1 with PLURONICS F87 superfine powder.And with the problem that the erdosteine dry powder doses that this proportioning is made can effectively avoid the consumption of erdosteine excessive.
But, because be directly dry medicated powder is sucked from cavity to enter pulmonary, so, the erdosteine bulky grain in the past made can not be satisfied the demand, simultaneously, not only demand fulfillment patient when spraying into the acceptance of medicine, and need the sense of discomfort alleviating patient, sucking in the process of pulmonary from cavity simultaneously, in order to avoid stomach, intestinal degradation effect, and gastrointestinal tract first pass effect and liver head cross elimination effect, the present inventor adjusts again the particle diameter of erdosteine dry powder and PLURONICS F87 by a large amount of orthogonal experiments, erdosteine dry powder is made erdosteine superfine powder, its mean diameter is made to be 1 μm ~ 5 μm, maximum particle diameter is no more than 10 μm, PLURONICS F87 dry powder is made PLURONICS F87 superfine powder, and its mean diameter is 60 μm ~ 80 μm, and maximum particle diameter is no more than 100 μm.With such particle diameter, the two is mixed according to aforementioned proportion, under PLURONICS F87 superfine powder synergism, avoid stomach, intestinal degradation effect, and gastrointestinal tract first pass effect, reduce erdosteine superfine powder simultaneously and arrive the liver head elimination effect excessively produced in the process of pulmonary, and the acceptance level of patient is high, does not have sense of discomfort completely, also substantially increase service efficiency and the drug safety of erdosteine.
, proved by test, by erdosteine inhalation powder spray provided by the invention by after cavity administration, its blood drug level is far above the blood drug level after the administration of tablet or large granule meanwhile.
Erdosteine inhalation powder spray provided by the invention, patient independently initiatively can be sucked by suction apparatus, medicine is directly transported to pulmonary's onset, reduce the stomach of medicine, intestinal degradation effect, and gastrointestinal tract first pass effect and liver head cross elimination effect, the help of medical personnel is not needed independently to carry out, easy to use; And preparation cost is low, Clinical practice price is also comparatively cheap.
Meanwhile, by erdosteine inhalation powder spray provided by the invention directly to Pulmonary inhalation, also have the following advantages:
1. without gastrointestinal tract Degradation;
2. without liver first-pass effect;
3. drug absorption is rapid, rapid-action after administration;
4. macromolecular drug bioavailability can by absorption enhancer or other method should be used for improve;
5. small-molecule drug is particularly useful for respiratory tract and directly sucks or spray into administration;
6. directly enter body circulation after drug absorption, reach the object of whole body therapeutic;
7. can be used for the large medicine of water solublity that gastrointestinal tract is difficult to absorb;
8. good patient compliance, is specially adapted to the patient that former need carry out long term injections treatment;
9. play the medicine of local action, dosage obviously reduces, and toxic and side effects is little.
Present invention also offers the preparation method of erdosteine inhalation powder spray, comprise the following steps:
Step one: by erdosteine porphyrize, carries out micronizing with super micron mill, obtains the erdosteine superfine powder that average particle size is 1 μm ~ 5 μm; Preferably, the mean diameter of the described erdosteine superfine powder obtained is 2 μm ~ 4 μm.
Step 2: PLURONICS F87 super micron mill is carried out micronizing, obtains the PLURONICS F87 superfine powder that mean diameter is 60 μm ~ 80 μm; Preferably, the mean diameter of the described PLURONICS F87 superfine powder obtained is 65 μm ~ 75 μm.
Step 3: after the ratio taking mass ratio as 20:3 ~ 2:1 by the erdosteine superfine powder after pulverizing and PLURONICS F87 superfine powder mixes, use capsule subpackage.In order to improve the effectiveness of proportioning, preferably, after the ratio taking mass ratio as 20:5 ~ 20:7 by the described erdosteine superfine powder after grinding and PLURONICS F87 micropowder mixes, subpackage is carried out with 0-2 capsule.
The erdosteine inhalation powder spray made by the method effectively can improve the uniformity of the erdosteine after pulverizing and PLURONICS F87 particle diameter, the bulk density reduced therebetween is poor, the uniformity coefficient that both raisings mix and the stratification phenomenon produced in long-term standing process.
Embodiment 1:
By erdosteine medicine porphyrize, carrying out micronizing with super micron mill, obtaining grain through being the erdosteine ultra micro dry powder of 1 μm ~ 5 μm: pulverized by PLURONICS F87 speed lapping pulverizer, obtaining particle diameter is 60 μm ~ 80 μm PLURONICS F87 superfine powder; Take 200g erdosteine superfine powder and 60g PLURONICS F87 micropowder, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 2 capsules, fill 260mg, make 1000 capsules, to obtain final product for every.
Embodiment 2:
By erdosteine medicine porphyrize, carrying out micronizing with super micron mill, obtaining grain through being the superfine powder of 1 μm ~ 2 μm: pulverized by PLURONICS F87 speed lapping pulverizer, obtaining particle diameter is 60 μm ~ 65 μm PLURONICS F87 superfine powder; Take 200g erdosteine superfine powder and 80g PLURONICS F87 micropowder, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 2 capsules, fill 280mg, make 1000 capsules, to obtain final product for every.
Embodiment 3:
By erdosteine medicine porphyrize, carrying out micronizing with super micron mill, obtaining grain through being the superfine powder of 1 μm ~ 3 μm: pulverized by PLURONICS F87 speed lapping pulverizer, obtain the PLURONICS F87 superfine powder that particle diameter is 60 μm ~ 70 μm; Take 200g erdosteine micropowder and 100g PLURONICS F87 micropowder, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 2 capsules, fill 300mg, make 1000 capsules, to obtain final product for every.
Embodiment 4:
By erdosteine medicine porphyrize, micronizing is carried out with super micron mill, obtain grain through being the ultra micro dry powder of 2 μm ~ 3 μm: by PLURONICS F87 speed lapping pulverizer, speed lapping is pulverized, and obtaining particle diameter is 65 μm ~ 70 μm PLURONICS F87 superfine powder; Take 300g erdosteine micropowder and 60g PLURONICS F87 superfine powder, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 1 capsule, fill 360mg, make 1000 capsules, to obtain final product for every.
Embodiment 5:
Take erdosteine medicine superfine powder 300g and PLURONICS F87 micropowder 80g, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 1 capsule, every 380 ㎎, make 1000 capsules altogether, obtain erdosteine inhalation powder spray.
Embodiment 6:
Take erdosteine medicine superfine powder 300g and PLURONICS F87 micropowder 100g, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 1 capsule, every 400 ㎎, make 1000 capsules altogether, obtain erdosteine inhalation powder spray.
Embodiment 7:
Take erdosteine medicine superfine powder 400g and PLURONICS F87 micropowder 60g, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 0 capsule, every 460 ㎎, make 1000 capsules altogether, obtain erdosteine inhalation powder spray.
Embodiment 8:
Take erdosteine medicine superfine powder 400g and PLURONICS F87 micropowder 80g, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 0 capsule, every 480 ㎎, make 1000 capsules altogether, obtain erdosteine inhalation powder spray.
Embodiment 9:
Take erdosteine medicine superfine powder 400g and PLURONICS F87 micropowder 100g, by the mixing of equal increments method, after abundant mix homogeneously, fill No. 0 capsule, every 500 ㎎, make 1000 capsules altogether, obtain erdosteine inhalation powder spray.
Experimental example 1: different way of administration is on the impact of E Duositan bioavailability
Method: rabbit 8, male and female are not limit, body weight 1.7 ~ 2.0kg.Be divided into oral commercially available E Duositan sheet group and erdosteine inhalation powder spray group, often organize 4, erdosteine inhalation powder spray used, all containing principal agent 300mg, respectively in 0.5,1.0,1.5,2.0,2.5,3.0h blood sampling after administration, is put in refrigerator to be measured for subsequent use.Adopt the concentration of high effective liquid chromatography for measuring erdosteine in whole blood.
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2000 two annex VD).Be filler with octadecylsilane chemically bonded silica; With 0.01mol/L citric acid-acetonitrile (65:35) and by triethylamine adjust ph to 3.0 for mobile phase; Determined wavelength is 254nm; Flow velocity is 1ml/min; Column temperature is room temperature, and sampling volume is 10 μ l.Often to organize the mean concentration of experiment for vertical coordinate, the time is abscissa mapping, and result as shown in Figure 3.
As can be seen from above-mentioned clinical experiment, the E Duositan tablet that erdosteine inhalation powder spray provided by the invention is compared commercially available, it is after cavity/canal drug administration, within 3 hours, its blood drug level is all far away higher than the blood drug level after tablet for administration, and instant effect, can see with reference to the accompanying drawings, erdosteine inhalation powder spray provided by the invention passes through cavity/canal drug administration, after half an hour, its blood drug level reaches 0.9mg/ml, the blood drug level of erdosteine tablet is then only 0.7mg/ml, the administration of erdosteine inhalation powder spray is after 1 hour, its blood drug level reaches more than 1.3mg/ml, and its blood drug level of erdosteine tablet is only between 0.9 ~ 1mg/ml.And, the present invention is in administration when 1.5 hours, its blood drug level reaches 1.4mg/ml, and the blood drug level of erdosteine tablet is only 1.2mg/ml, and within follow-up 2 hours, the blood drug level of erdosteine inhalation powder spray continues the blood drug level higher than erdosteine tablet, then illustrate that the effective rate of utilization of erdosteine inhalation powder spray is far away higher than existing erdosteine tablet, the effective ingredient that then can directly act on the pulmonary of disease whereabouts is higher, certainly, its cure rate is also higher.
Experimental example 2:
Erdosteine inhalation powder spray is to the clinical observation on the therapeutic effect of Chronic bronchitis during acute stage
Method: the patient 117 examples being diagnosed as clinically the acute episode of chronic bronchitis phase is divided into treatment group 58 example, matched group 59 example, treatment group: take erdosteine inhalation powder spray at random; Matched group: oral commercially available erdosteine sheet, is 7 days the course for the treatment of.
(1) criterion of therapeutical effect:
A. effective: condition of illness sign starts the effect occurred, but has little effect.
B. effective: condition of illness sign has obvious good effect.
C. invalid: condition of illness sign does not change.
(2) therapeutic outcome: two groups of clinical therapeutic efficacies see the following form 1.
Table 1 erdosteine inhalation powder spray clinical treatment observation is added up
As can be seen from two groups of upper table relatively, dosage form of the present invention, obtains good curative effect clinically, and 58 patients take preparation of the present invention and have no untoward reaction after 7 days, and its therapeutic effect is better than tablet.
Erdosteine inhalation powder spray prepared by the present invention is without gastrointestinal tract Degradation, and without liver first-pass effect, drug absorption is rapid, rapid-action after administration, can reduce its untoward reaction while ensure that product curative effect, improves drug safety; This dosage form can be carried with, medication convenient, improves the compliance of patient.Clinic is applied.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. an erdosteine inhalation powder spray, is characterized in that, is mixed by erdosteine superfine powder and PLURONICS F87 superfine powder; The mass ratio of wherein said erdosteine superfine powder and PLURONICS F87 superfine powder is 20:3 ~ 2:1;
The mean diameter of described erdosteine superfine powder is 1 μm ~ 5 μm, and wherein maximum particle diameter is no more than 10 μm; The mean diameter of described PLURONICS F87 superfine powder is 60 μm ~ 80 μm, and maximum particle diameter is no more than 100 μm.
2. a kind of erdosteine inhalation powder spray according to claim 1, is characterized in that, the mass ratio of described erdosteine superfine powder and described PLURONICS F87 superfine powder is 20:5 ~ 20:7.
3. a kind of erdosteine inhalation powder spray according to claim 1, is characterized in that, the described erdosteine superfine powder of 200mg mixes with the described PLURONICS F87 superfine powder of 60 ~ 100mg.
4. a kind of erdosteine inhalation powder spray according to claim 1, is characterized in that, the described erdosteine superfine powder of 300mg mixes with the described PLURONICS F87 superfine powder of 70 ~ 90mg.
5. a kind of erdosteine inhalation powder spray according to claim 1, is characterized in that, the described erdosteine superfine powder of 400mg mixes with the described PLURONICS F87 superfine powder of 75 ~ 85mg.
6. a kind of erdosteine inhalation powder spray according to claim 1, is characterized in that, the mean diameter of described erdosteine superfine powder is 2 μm ~ 4 μm, and the mean diameter of described PLURONICS F87 superfine powder is 65 μm ~ 75 μm.
7. prepare the method for the erdosteine inhalation powder spray described in any one of claim 1-6, it is characterized in that, comprise the following steps:
Step one: by erdosteine porphyrize, carries out micronizing with super micron mill, obtains the erdosteine superfine powder that average particle size is 1 μm ~ 5 μm;
Step 2: PLURONICS F87 super micron mill is carried out micronizing, obtains the PLURONICS F87 superfine powder that mean diameter is 60 μm ~ 80 μm;
Step 3: after the ratio taking mass ratio as 20:3 ~ 2:1 by the erdosteine superfine powder after pulverizing and PLURONICS F87 superfine powder mixes, use capsule subpackage.
8. the method preparing erdosteine inhalation powder spray according to claim 7, is characterized in that,
In step one, the mean diameter of the described erdosteine superfine powder obtained is 2 μm ~ 4 μm;
In step 2, the mean diameter of the described PLURONICS F87 superfine powder obtained is 65 μm ~ 75 μm.
9. the method preparing erdosteine inhalation powder spray according to claim 7, is characterized in that,
In step 3, after the ratio taking mass ratio as 20:5 ~ 20:7 mixes, carry out subpackage with 0-2 capsule by the described erdosteine superfine powder after pulverizing and PLURONICS F87 superfine powder.
10. the method for erdosteine inhalation powder spray according to claim 7, is characterized in that, described super micron mill is air-flow super micron mill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410765144.6A CN104523658B (en) | 2014-12-11 | 2014-12-11 | Erdosteine powder inhalation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410765144.6A CN104523658B (en) | 2014-12-11 | 2014-12-11 | Erdosteine powder inhalation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104523658A true CN104523658A (en) | 2015-04-22 |
| CN104523658B CN104523658B (en) | 2017-02-22 |
Family
ID=52839420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410765144.6A Expired - Fee Related CN104523658B (en) | 2014-12-11 | 2014-12-11 | Erdosteine powder inhalation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104523658B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101606931A (en) * | 2009-08-06 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of erdosteine composition and preparation method thereof |
| EP2281557A2 (en) * | 2008-04-29 | 2011-02-09 | HanAll Biopharma Co., Ltd. | Pharmaceutical formulation containing angiotensin-ii receptor blocker |
| CN102846633A (en) * | 2011-07-01 | 2013-01-02 | 天津金耀集团有限公司 | Inhalant containing N-acetyl-L-cysteine and ciclesonide and preparation method thereof |
-
2014
- 2014-12-11 CN CN201410765144.6A patent/CN104523658B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2281557A2 (en) * | 2008-04-29 | 2011-02-09 | HanAll Biopharma Co., Ltd. | Pharmaceutical formulation containing angiotensin-ii receptor blocker |
| CN101606931A (en) * | 2009-08-06 | 2009-12-23 | 山东罗欣药业股份有限公司 | A kind of erdosteine composition and preparation method thereof |
| CN102846633A (en) * | 2011-07-01 | 2013-01-02 | 天津金耀集团有限公司 | Inhalant containing N-acetyl-L-cysteine and ciclesonide and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 邓铁宏等: "《药剂学》", 31 August 2011 * |
| 黄秀清等: "载体对微粉型粉雾剂呼吸道沉降的影响", 《药学实践杂志》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104523658B (en) | 2017-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1025859B1 (en) | Powdery pernasal compositions | |
| ES2762806T3 (en) | Treatment using mast cell stabilizers for systemic disorders | |
| KR101763195B1 (en) | Dry powder vancomycin compositions and associated methods | |
| CN105833399B (en) | Manual Diskus | |
| CN102920683B (en) | Olanzapine oral instant membrane | |
| JP6509193B2 (en) | Composition comprising at least two dry powders obtainable by spray drying to improve the stability of the formulation | |
| RU2010141333A (en) | NEW DOSE AND PREPARATION FORM | |
| CN104784197A (en) | EGCG and beta-glucan composition, and preparation method, and medical application thereof | |
| WO2011093818A2 (en) | Pharmaceutical compositions comprising salmeterol and fluticasone | |
| CN111358773B (en) | Peramivir dry powder inhalant and preparation method thereof | |
| CN103860525B (en) | A kind of capsule type inhalation aerosol powder containing effective ingredient ambrisentan and preparation technology thereof | |
| JP2001055323A (en) | Powdery composition for nasal administration | |
| CN103462942A (en) | Suction-type ambroxol hydrochloride solution | |
| CN112438942A (en) | Pharmaceutical composition containing alkalizer and its synergist and its application | |
| CN102335132A (en) | Asarin inhalation aerosol and preparation method thereof | |
| CN104523658B (en) | Erdosteine powder inhalation and preparation method thereof | |
| CN104208047B (en) | Dry potassium sodium dehydroandrographolide succinate powder inhalation and preparation method thereof | |
| WO2018018851A1 (en) | Preparation methods for oseltamivir carboxylic acid hydrochloride and atomized agent thereof | |
| CN100515392C (en) | Dry powder composition for improvement of effective position medical deposit | |
| WO2011093811A2 (en) | Pharmaceutical preparations comprising formoterol and fluticasone | |
| JP2005298347A (en) | Inhalation preparation and method for producing the same | |
| CN111110634A (en) | Chloroquine phosphate inhalation aerosol and preparation method thereof | |
| CN102302475B (en) | Resibufogenin dry powder inhalant and preparation method and application thereof | |
| CN101057845B (en) | Bulleyaconitin A dry emulsion and its preparation method and application | |
| CN104208688A (en) | Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170317 Address after: Meilan District 570100 in Hainan province Haikou city Guilin Yang Development Zone (Guilin ocean power station on the right side) Patentee after: Hainan Yi Shun Pharmaceutical Co.,Ltd. Address before: 570208 Hainan province Haikou Haidian road two Binjiang coast 4-1701 Patentee before: Chen Changtan |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170222 |