CN101744792A - Fluticasone propionate and salmeterol xinafoate compound dry powder inhalation and preparation technology thereof - Google Patents
Fluticasone propionate and salmeterol xinafoate compound dry powder inhalation and preparation technology thereof Download PDFInfo
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- CN101744792A CN101744792A CN200810204741A CN200810204741A CN101744792A CN 101744792 A CN101744792 A CN 101744792A CN 200810204741 A CN200810204741 A CN 200810204741A CN 200810204741 A CN200810204741 A CN 200810204741A CN 101744792 A CN101744792 A CN 101744792A
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- lactose
- dry powder
- fluticasone propionate
- salmaterol
- powder inhalation
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Abstract
The invention provides fluticasone propionate and salmeterol xinafoate compound dry powder inhalation, which is composed of active ingredients and a pharmaceutic auxiliary material, wherein, the active ingredients comprise 1.0%-9.0% of the fluticasone propionate and 0.5%-1.0% of the salmeterol xinafoate; and the pharmaceutic auxiliary material comprises 90.5%-98.0% of lactose, wherein, the lactose comprises lactose 1 and lactose 2, lactose 1 accounts for 10-90% of the dry powder inhalation, and lactose 2 accounts for 10-90% of the dry powder inhalation. The dry powder inhalation in the invention is used for continuous or single administration to treat inflammation or obstructive diseases of respiratory tract. The inhalation has the advantages of high bioavailability, portability, convenient administration, no pollution and the like, thus having favorable application value; and the preparation technology provided in the invention is simple and is suitable for industrial production.
Description
Technical field:
The present invention relates to pharmaceutical preparation, be specifically related to the compound dry powder inhalation and the preparation technology thereof of FLUTICASONE PROPIONATE and salmeterol xinafoate.
Background technology:
FLUTICASONE PROPIONATE is a kind of anti-inflammatory activity that has, and can be used for treating the allergic symptom of respiratory system and the corticosteroid hormone of inflammatory symptom.Salmeterol xinafoate is the long-acting beta 2 receptor promoter that is used for the treatment of asthma and chronic obstructive pulmonary disease.The The combined medication can be used for the conventional therapy of reversibility obstructive airway diseases, comprises adult and infantile asthma.
Over past ten years, Foradil Aerolizer formoterol fumarate because its targeting, efficient, quick-acting, toxic and side effects is little, advantage such as pollution-free, development is rapidly.Foradil Aerolizer formoterol fumarate belongs to a kind of of respiratory tract administration preparation.Because size of pharmaceutical particles distributes different, thereby can make particles with different sizes arrive the different zones of action.Generally, granule more than the 10 μ m is under normal person's breathing strength effect, can not enter respiratory system, the bronchus that the granule of 5-10 μ m can only enter trachea and pulmonary top, and the granule of 1-5 μ m can enter tiny bronchus and alveolar surface, granule less than 0.9 μ m then becomes aerosol, the pulmonary of can coming in and going out, and be difficult for quantitatively stopping the fixed lung areas of body.FLUTICASONE PROPIONATE and salmeterol xinafoate are made the respiratory tract administration preparation of composite dry powder inhalant dosage form, can make medicine in local absorption, the least possible blood circulation that enters whole body, thus greatly the hormone medicine that slows down of degree uses the untoward reaction that causes.
The preparation of China listing be salmaterol replace the Kazon inhalant (Ge Lansu's
).This inhalant is used is that standard is received apparatus, and the vesicle of built-in pharmaceutical need pierce through the vesicle inhalation in the use.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, sets up fluticasone and salmaterol compound dry powder preparation.
The invention provides a kind of FLUTICASONE PROPIONATE and salmaterol former times acid esters compound dry powder preparation how.
Fluticasone of the present invention and salmaterol compound dry powder preparation are become to be grouped into by following weight percent proportioning:
Active component:
FLUTICASONE PROPIONATE 1.0%-9.0%;
Salmaterol former times is acid esters 0.5%-1.0% how;
Pharmaceutic adjuvant: lactose 90.5%-98.0% is mixed by the lactose of different-grain diameter size.
Described lactose comprises lactose one and lactose two.
Lactose one: 10%-90%, described lactose granule size between 20-370 μ m, medium particle diameter 100-140 μ m;
Lactose two: 10%-90%, described lactose granule size between 10-260 μ m, medium particle diameter 60-90 μ m.
Another object of the present invention has provided above-mentioned FLUTICASONE PROPIONATE and the salmaterol former times preparation technology of acid esters compound dry powder preparation how, and this technology comprises the following steps:
(1) how acid esters mixes with lactose one and lactose two with active component FLUTICASONE PROPIONATE, salmaterol former times, mixes the mixture that obtains active component and lactose after 0.5-1 hour;
(2) with the mixture quantitative filling in multiple dose reservoir devices dry powder doser.
Wherein step (1) adopts the high speed shear mixer to mix, described high speed shear mixer, be provided with level and vertical two kinds of blades in its mixing chamber, respectively in level and movement in vertical direction, the rotating speed of horizontal direction blade is that 50-500rpm optimizes rotating speed at 300rpm, and the rotating speed of vertical direction is that 30-1000rpm optimizes rotating speed at 300rpm.
The FLUTICASONE PROPIONATE that preparation technology of the present invention makes and salmaterol former times be acid esters compound dry powder preparation how, reaches and the brand medicine
Identical curative effect of medication.Concerning Foradil Aerolizer formoterol fumarate, different dosers, owing to suck the effect difference, thus determined different content formulation and technologies.
FLUTICASONE PROPIONATE of the present invention and salmaterol former times, how the used device of acid esters compound dry powder inhalation belonged to heavy dose of storage storehouse formula powder inhaler, sucked 13mm at every turn
3The dry powder content, dosage reaches 250 μ g/ salmaterol former times of every suction FLUTICASONE PROPIONATE acid esters 50 μ g how.
The effect detection test of product of the present invention: 1, powder particle size distribution: utilize laser particle analyzer that the particles of powder size distribution is detected, it is as follows that corresponding respective instance preparation process obtains the result: guarantee that D10 is controlled at 1-10 μ m, D50 is controlled at 50-100 μ m, and D90 is controlled at 100-170 μ m particle size distribution.2, the vitro detection of pulmonary deposited dose test: adopt the medicine pulmonary deposited dose in 8 grades of impacting type samplers detections of Andersen respiratory tract administration process, the result: detect particle size distribution and ratio, the control response rate is at 90-110%.3, the uniformity to ejecta detects: utilize the Diskus sampling apparatus uniformity of dry powder formulations to be detected the result: guarantee that the ejecta quality is between 7.0 ± 0.5mg.
Foradil Aerolizer formoterol fumarate of the present invention has the bioavailability height, is easy to carry, convenient drug administration, advantage such as pollution-free.Have a good application prospect.Dry powder formulations of the present invention as carrier, makes crude drug evenly attached on the lactose granule with lactose, when keeping administering effect, has simplified preparation technology.
Foradil Aerolizer formoterol fumarate of the present invention is used for continuously or single-dose, the inflammation of treatment respiratory tract or obstruction disease.This Foradil Aerolizer formoterol fumarate has specific particle size distribution characteristic, medicine is distributed at respiratory tract reach the optimal deposition amount, thereby make drug effect reach maximum.Have the bioavailability height, be easy to carry, convenient drug administration, advantage such as pollution-free.Excellent application value is arranged.
The specific embodiment
Embodiment one,
Technology: how acid esters mixes with lactose one and lactose two with active component FLUTICASONE PROPIONATE, salmaterol former times, adopts that the high speed shear mixer mixes, the preparation intermediate powder.Described high speed shear mixer, its mixing chamber contain two kinds of mixing blades, respectively in level and movement in vertical direction.Obtain active component and pharmaceutic adjuvant powder mixture thereof.With the mixture quantitative filling for preparing in multiple dose reservoir devices dry powder doser.
Composition:
FLUTICASONE PROPIONATE 6.4g
Salmaterol former times is acid esters 1.0g how
Lactose one 152.6g
Lactose two 40.0g
During mixing:
Horizontal direction mixing speed 100rpm
Vertical direction shear rate 50rpm
Incorporation time 30min
Embodiment two,
Technology: with embodiment one.
Composition:
FLUTICASONE PROPIONATE, 6.4g
Salmaterol former times is acid esters 1.0g how
Lactose one 152.6g
Lactose two 40.0g
During mixing:
Horizontal direction mixing speed 100rpm
Vertical direction shear rate 300rpm
Incorporation time 45min
Embodiment three,
Technology: with embodiment one.
Composition:
FLUTICASONE PROPIONATE, 6.4g
Salmaterol former times is acid esters 1.0g how
Lactose one 152.6g
Lactose two 40.0g
During mixing:
Horizontal direction mixing speed 200rpm
Vertical direction shear rate 300rpm
Incorporation time 30min
Embodiment four,
Technology: with embodiment one.
Composition:
FLUTICASONE PROPIONATE, 10.0g
Salmaterol former times is acid esters 2.0g how
Lactose one 152.6g
Lactose two 40.0g
Technology:
Horizontal direction mixing speed 250rpm
Vertical direction shear rate 0rpm
Incorporation time 45min
Embodiment five,
Technology: with embodiment one.
Composition: percentage by weight (%)
FLUTICASONE PROPIONATE, 6.4g
Salmaterol former times is acid esters 2.0g how
Lactose one 152.6g
Lactose two 40.0g
Technology:
Horizontal direction mixing speed 250rpm
Vertical direction shear rate 300rpm
Incorporation time 45min
The effect detection test of embodiment of the invention product:
1, powder particle size distribution
Utilize laser particle analyzer that the particles of powder size distribution is detected, it is as follows that corresponding respective instance preparation process obtains the result: guarantee that D10 is controlled at 1-10 μ m, D50 is controlled at 50-100 μ m, and D90 is controlled at 100-170 μ m particle size distribution
Distribution of particles
Technology D10 (μ m) D50 (μ m) D90 (μ m)
Embodiment 1
Embodiment 2 2.767 0.52 149.35
Embodiment 3 2.457 4.90 149.10
Embodiment 4 3.378 6.66 154.28
Embodiment 5 2.668 0.21 151.27
D10:1.85 refers to account for 10% of all detected particle volumes less than the particle volume of 3.60 μ m.
D50:68.57 refers to account for 50% of all detected particle volumes less than the particle volume of 82.26 μ m.
D90:147.41 refers to account for 90% of all detected particle volumes less than the particle volume of 145.50 μ m.
2, the vitro detection of pulmonary deposited dose test
Adopt the medicine pulmonary deposited dose in 8 grades of impacting type samplers detections of Andersen respiratory tract administration process, it is as follows that corresponding respective instance preparation process obtains the result: detect particle size distribution and ratio, the control response rate is at 90-110%.
The response rate: by the method for 8 grades of impacting type samplers of Andersen type, or by the multistage collision sampler of pharmaceutical aerosol, multipole liquid knockout device, single-stage impinger, the ratio of the amount of the medicine that methods such as elbow formula secondary sampler record and the theoretical content of medicine.
MMAD: average air kinetics median diameter.Refer to method or the sampling of multipole liquid knockout device by 8 grades of impacting type samplers of Andersen type, the granularity that the method for the multistage collision sampler of pharmaceutical aerosol records, in logarithmic coordinates, be x axle or y axle with the granularity, with the cumulative distribution is y axle or x axle, make fitting a straight line figure, the pairing granularity of 50% cumulative distribution directly goes out data by detecting instrument among the figure.
FPF: fine grained proportion.Method by 8 grades of impacting type samplers of Andersen type or the sampling of multipole liquid knockout device, the second level that the method for the multistage collision sampler of pharmaceutical aerosol records following (not comprising the second level) or 6.5 μ m medication amount account for the ratio of premier's opinion medication amount that doser provides.
3, the uniformity to ejecta detects:
Utilize the Diskus sampling apparatus that the uniformity of dry powder formulations is detected, it is as follows that corresponding respective instance preparation process obtains the result: guarantee that the ejecta quality is between 7.0 ± 0.5mg.
| Technology | Ejecta (mg) |
| Embodiment one | ??7.3 |
| Embodiment two | ??6.7 |
| Embodiment three | ??6.9 |
| Embodiment four | ??6.9 |
| Embodiment five | ??7.1 |
Ejecta: the amount of the medicine that doser provides at every turn.
Claims (7)
- FLUTICASONE PROPIONATE and salmaterol former times acid esters compound dry powder inhalation how, it is characterized in that this compound dry powder preparation is grouped into by the one-tenth of following weight percent proportioning:Active component: FLUTICASONE PROPIONATE 1.0%-9.0%; Salmaterol former times is acid esters 0.5%-1.0% how;Pharmaceutic adjuvant: lactose 90.5%-98.0% is mixed by the lactose of different-grain diameter size.
- 2. according to described FLUTICASONE PROPIONATE of claim 1 and salmeterol xinafoate compound dry powder inhalation, it is characterized in that described pharmaceutic adjuvant lactose comprises lactose one and lactose two; Described lactose one is 10-90% at the Foradil Aerolizer formoterol fumarate proportion, and lactose two is 10-90% at the Foradil Aerolizer formoterol fumarate proportion.
- 3. inhalant according to claim 2, it is characterized in that described lactose one for the lactose granule size between 20-370 μ m, medium particle diameter 100-140 μ m; Described lactose two granular sizes between 10-260 μ m, its medium particle diameter 60-90 μ m.
- 4. the preparation technology of FLUTICASONE PROPIONATE and salmeterol xinafoate compound dry powder inhalation is characterized in that this technology comprises the following steps:Prescription:Active component: FLUTICASONE PROPIONATE 1.0%-9.0%; Salmaterol former times is acid esters 0.5%-1.0% how; Pharmaceutic adjuvant: lactose 90.5%-98.0%;Technology:(1) with active component FLUTICASONE PROPIONATE 1.0%-9.0%; Salmaterol former times, how acid esters 0.5%-1.0% mixed with the 99.3%-94.3% lactose, mixed the mixture that obtains principal agent and lactose after 0.5-1 hour;(2) with the mixture fill in multiple dose reservoir devices dry powder doser, make each 13mm of suction 3The dry powder content, dosage reaches 250 μ g/ salmaterol former times of every suction FLUTICASONE PROPIONATE acid esters 50 μ g how.
- 5. according to the preparation technology of described FLUTICASONE PROPIONATE of claim 4 and salmeterol xinafoate compound dry powder inhalation, it is characterized in that, when step (1) is mixed, in the cavity of described high speed shear mixer, horizontal direction and vertical direction blade are set.
- 6. according to the preparation technology of claim 5, it is characterized in that when step (1) was mixed, the rotating speed of described horizontal direction blade was 50-500rpm, the rotating speed of vertical direction is 30-1000rpm.
- 7. according to the preparation technology of claim 5, it is characterized in that when step (1) was mixed, the rotating speed of described horizontal direction blade was 300rpm, the rotating speed of vertical direction is 300rpm.
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|---|---|---|---|
| CN 200810204741 CN101744792B (en) | 2008-12-17 | 2008-12-17 | Fluticasone propionate and salmeterol xinafoate compound dry powder inhalation and preparation technology thereof |
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|---|---|---|---|
| CN 200810204741 CN101744792B (en) | 2008-12-17 | 2008-12-17 | Fluticasone propionate and salmeterol xinafoate compound dry powder inhalation and preparation technology thereof |
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| CN101744792A true CN101744792A (en) | 2010-06-23 |
| CN101744792B CN101744792B (en) | 2013-04-17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107095875A (en) * | 2016-02-23 | 2017-08-29 | 天津金耀集团有限公司 | A kind of how sour salmeterol fluticasone propionate compound powders for inhalation composition of former times |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL95590A (en) * | 1989-09-08 | 1996-06-18 | Glaxo Group Ltd | Pharmaceutical compositions comprising salmeterol and fluticasone propionate |
| US6503537B2 (en) * | 1997-03-20 | 2003-01-07 | Schering Corporation | Preparation of powder agglomerates |
| JP2007509941A (en) * | 2003-10-28 | 2007-04-19 | グラクソ グループ リミテッド | Inhalation pharmaceutical preparation using lactose anhydride and its administration method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107095875A (en) * | 2016-02-23 | 2017-08-29 | 天津金耀集团有限公司 | A kind of how sour salmeterol fluticasone propionate compound powders for inhalation composition of former times |
| CN107095875B (en) * | 2016-02-23 | 2022-03-18 | 天津金耀集团有限公司 | Salmeterol xinafoate and fluticasone propionate compound powder inhalant composition |
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| CN101744792B (en) | 2013-04-17 |
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Owner name: ZHANG KAI Free format text: FORMER OWNER: SHANGHAI FOSUN PUSHI PHARMACEUTICAL TECHNOLOGY CO., LTD. Effective date: 20120615 Free format text: FORMER OWNER: SHANGHAI FOSUN PHARMACEUTICAL (GROUP) CO., LTD. Effective date: 20120615 |
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Effective date of registration: 20150615 Address after: 215421 Taicang city in Jiangsu Province town of Shaxi Biomedical Park Road No. 5, Zhenhui plant No. 6 Patentee after: Suzhou Pharmaceutical Co., Ltd. Address before: Pudong Zhangjiang road 201203 Bing Shanghai No. 306 Building No. 3 2 floor Patentee before: Zhang Kai |
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Address after: No. 69, Zhen Xi Road, bio Pharmaceutical Industrial Park, Shaxi Town, Taicang, Jiangsu Patentee after: Suzhou Pharmaceutical Co., Ltd. Address before: 215421 Taicang city in Jiangsu Province town of Shaxi Biomedical Park Road No. 5, Zhenhui plant No. 6 Patentee before: Suzhou Pharmaceutical Co., Ltd. |
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