CN101032484A - Capsule type tiotropium bromide inhalation powder - Google Patents

Abstract

The invention discloses a tiotropium bromide capsule type powder spray, which comprises tiotropium bromide or tiotropium bromide monohydrate and lactose micropowder, 0.04 to 1.5% by weight of tiotropium bromide or tiotropium bromide The monohydrate is adsorbed on the lactose micropowder, and the particle size of the lactose micropowder is all less than 15 μm, and about 90% are less than 8 μm. In addition, the present invention also provides a method for preparing the above-mentioned powder spray. The tiotropium bromide capsule type powder spray of the present invention has a simple preparation process, the particles have good fluidity, and the active ingredients are evenly distributed.

Description

A kind of tiotropium bromide capsule type inhalation powder spray

technical field

The present invention relates to a kind of pharmaceutical preparation, more specifically, the present invention relates to a kind of tiotropium bromide capsule type inhalation powder and a preparation method thereof.

Background technique

Tiotropium bromide is an anticholinergic drug with the chemical name: (1R,2R,4S,5S,7S)-7-[2-hydroxy-2,2-di(2-thienyl) bromide Acetoxy]-9,9-dimethyl-3-epoxy-9-azacyclooctane[ ^3.3.1.0.2.4 ]nonane monohydrate, its chemical structure is as follows:

Boehringer Ingelheim and Pfizer launched tiotropium bromide inhalation in Netherlands and Philippines in 2002, trade name: Spiriva ^TM . Tiotropium bromide is a long-acting antimuscarinic drug with similar affinity for muscarinic receptor subtypes M1 to M5. For the respiratory tract, it acts pharmacologically by inhibiting M3 receptors on smooth muscle, thereby dilating the bronchi. Tests have shown that this antagonist is competitive and reversible for the treatment of chronic obstructive pulmonary disease (COPD). Administration once a day (inhalation of 18 μg/day) can significantly improve the respiratory function of patients with chronic obstructive pulmonary disease, and the effect can last for more than 24 hours. Tiotropium bromide is a quaternary ammonium salt, poor oral absorption, suitable for inhalation administration, and systemic anticholinergic effect is not significant after inhalation administration, so side effects are small, and toxicity is low (Drugs of the Future, 2000.25 (7): 693- 699).

At present, a variety of methods for preparing tiotropium bromide capsule-type inhalation powders have been developed: for example, Boehringer Ingelheim discloses a thiotropium-containing Inhalable powder of trotropium bromide, the mixture of excipients is obtained by first mixing the coarser excipient (200M) and the finer excipient (5μm) lactose monohydrate, and then with micronized tiotropium bromide Ammonium monohydrate, available as an inhalable powder.

In addition, the company disclosed another preparation method in the Chinese patent application (publication number CN1717225A, publication date: January 4, 2006), in which lactose monohydrate with an average particle size of 10-50 μm and micronized tiotropium bromide mix. The tiotropium bromide powder mist preparations prepared by the above two applications all adopt the method of mixing multiple alternating layers, and the preparation process is complicated.

Nanchang Hongyi Science and Technology Co., Ltd. discloses a kind of tiotropium bromide inhalation powder and its preparation technology in Chinese patent application publication number CN1439362A (disclosure date: on September 3rd, 2003), and this preparation is based on single dose content of Tiotropium bromide anhydrous superfine powder of 10 μg to 30 μg, particle size 1 μm to 5 μm and amino acid pharmaceutical carrier powder, such as glycine, fully mixed and filled with capsules become.

Fudan University also discloses a kind of tiotropium bromide inhalation powder and its preparation method in Chinese patent application CN1557308A (disclosure date: December 29, 2004), which contains medicine tiotropium bromide and carrier amino acid and recrystallized The lactose is prepared by the following method: spray drying and micronizing the mixed solution of tiotropium bromide and amino acid to form micropowder, and then mix it with recrystallized lactose to fill capsules or make other preparations.

Shanghai Huatuo Pharmaceutical Technology Development Co., Ltd. also discloses a tiotropium bromide capsule type inhalation powder and its preparation method in Chinese patent application CN1593414A (disclosure date: March 16, 2005). The spray is composed of tiotropium bromide drug-loaded superfine powder and excipients, wherein the tiotropium bromide drug-loaded superfine powder is prepared by a spray drying method, and the particle diameter of the tiotropium bromide-loaded superfine powder is 80% The particle size is in the range of 0.5 μm-5 μm, and 90% of the particle size is less than 10 μm.

At present, whether it is listed or the tiotropium bromide inhalable powder mist that is reported in the above literature, in order to make a small amount of tiotropium bromide evenly distributed, their preparation technology is all more complicated, all is to use tiotropium bromide or one of them Hydrates or mixtures with amino acids are micronized and then mixed with excipients.

Contents of the invention

The present invention overcomes the shortcomings of the above-mentioned prior art, and provides a tiotropium bromide capsule-type inhalable powder with a novel and simple preparation process and uniform and stable distribution of tiotropium bromide in the powder.

The object of the present invention is to provide a kind of tiotropium bromide capsule type inhalable powder spray.

Another object of the present invention is to provide a preparation method of the tiotropium bromide capsule type inhalable powder.

The contriver is in the experiment of researching tiotropium bromide respirable powder aerosol, surprisingly finds that the tiotropium bromide respirable powder aerosol prepared by the absorption of tiotropium bromide by lactose micropowder has the uniform distribution of active ingredients, Stable, simple preparation process and other advantages.

The invention provides an inhalable tiotropium bromide powder, wherein, 0.04 to 1.5% by weight of tiotropium bromide or tiotropium bromide monohydrate is adsorbed on lactose micropowder, and the particle size of lactose micropowder is smaller than 15 μm, and about 90% are less than 8 μm, preferably the particle size of lactose fine powder is less than 12 μm, and about 90% is less than 7 μm, more preferably the particle size of lactose fine powder is less than 10 μm, and about 90% is less than 5 μm; tiotropium bromide or tiotropium bromide The weight ratio of ammonium monohydrate is preferably 0.09 to 1.2%, more preferably, 0.3 to 0.9%, particularly preferably 0.5 to 0.8%.

The present invention also provides a preparation method for preparing the above-mentioned tiotropium bromide capsule type inhalable powder, which comprises:

1. Prepare lactose micropowder. Weigh the lactose, add 0.5-3.0 (to the weight ratio of lactose) times, preferably 0.8-2.0 times, especially preferably 1.0-1.8 times of water, heat to completely dissolve the above-mentioned lactose; let cool, filter; stir slowly to Add isopropanol, preferably anhydrous isopropanol, to the filtrate to crystallize in an appropriate amount, and filter; Select 200 mesh, preferably 240 mesh, more preferably 300 mesh sieve, filter; dry and pulverize, the obtained lactose powder has a particle size of less than 15 μm, and about 90% of it is less than 8 μm, preferably the lactose powder has a particle size of less than 12 μm. And about 90% are less than 7 μm, more preferably the particle size of the lactose micropowder is less than 10 μm, and about 90% are less than 5 μm;

2. Adsorb tiotropium bromide on the lactose micropowder that step 1 obtains. Weigh tiotropium bromide anhydrous powder or tiotropium bromide monohydrate, add dehydrated alcohol of 200 to 1000 times of weight ratio, completely dissolve, and set aside; The solution is mixed evenly, wherein the weight ratio of tiotropium bromide or tiotropium bromide monohydrate to lactose micropowder is preferably 0.09 to 1.2%, more preferably, 0.3 to 0.9%, especially preferably 0.5 to 0.8%; soft material, 140 mesh , preferably 120 mesh sieve granules, dry, 100 mesh, preferably 80 mesh, more preferably 60 mesh sieve granules, and fill capsules.

The inventor referred to the literature about lactose crystallization and prepared lactose micropowder meeting the requirements of the present invention

Lactose micropowder is prepared by a solvent crystallization method, and the solvent refers to pharmaceutically commonly used solvents such as ethanol, acetone, and isopropanol, preferably isopropanol, more preferably anhydrous isopropanol.

The test results show that the solvent crystallization method can be used to prepare lactose micropowder, and the particle size meets the requirements. After the verification of the lactose micronization preparation process, the process is feasible, and the lactose micropowder with a particle size of less than 10 μm can be obtained, and about 90% of the particle size is less than 5 μm.

Prepare three batches (the first batch, the second batch, the third batch) of carrier material lactose micropowder by solvent crystallization method, the following method checks the particle diameter of lactose micropowder particle after crystallization pulverization, the result shows, technique is feasible. The inspection results are as follows:

Table 1 Distribution of lactose micropowder particles (the first batch) Particle size range (μm) vision 0 0～2.5 2.5～5 5～7.5 7.5～10 10～15 15～20 20～30 30～50 >50 1 0 119 55 8 3 0 0 0 0 0 2 0 105 46 8 2 0 0 0 0 0 3 0 128 68 6 1 0 0 0 0 0 4 0 107 35 4 2 0 0 0 0 0 5 0 96 43 7 4 0 0 0 0 0 6 0 83 47 3 2 0 0 0 0 0 7 0 130 twenty two 7 3 0 0 0 0 0 8 0 124 59 6 1 0 0 0 0 0 9 0 85 53 3 1 0 0 0 0 0 10 0 108 41 4 2 0 0 0 0 0 Ni 0 1002 422 53 19 0 0 0 0 0 Di 0 1.25 3.75 6.25 8.75 12.5 17.5 25 40 50 Ni*Di 0 1252.5 1582.5 331.25 166.25 0 0 0 0 0 f 0 66.98 28.21 3.54 1.27 0.00 0.00 0.00 0.00 0.00 average value 2.23

Table 2 Distribution of lactose micropowder particles (second batch) Particle size range (μm) vision 0 0～2.5 2.5～5 5～7.5 7.5～10 10～15 15～20 20～30 30～50 >50 1 0 131 56 9 2 0 0 0 0 0 2 0 112 59 10 3 0 0 0 0 0 3 0 123 61 6 5 0 0 0 0 0 4 0 130 43 7 1 0 0 0 0 0 5 0 115 33 5 2 0 0 0 0 0 6 0 98 60 3 2 0 0 0 0 0 7 0 86 twenty one 8 1 0 0 0 0 0 8 0 104 44 5 3 0 0 0 0 0 9 0 118 37 4 2 0 0 0 0 0 10 0 108 57 5 1 0 0 0 0 0 Ni 0 1027 411 59 20 0 0 0 0 0 Di 0 1.25 3.75 6.25 8.75 12.5 17.5 25 40 50 Ni*Di 0 1283.75 1541.25 368.75 175 0 0 0 0 0 f 0 67.70 27.09 3.89 1.32 0.00 0.00 0.00 0.00 0.00 average value 2.22

Table 3 Distribution of lactose micropowder particles (the third batch) Particle size range (μm) vision 0 0～2.5 2.5～5 5～7.5 7.5～10 10～15 15～20 20～30 30～50 >50 1 0 125 46 8 1 0 0 0 0 0 2 0 133 65 11 4 0 0 0 0 0 3 0 111 63 7 2 0 0 0 0 0 4 0 92 59 7 2 0 0 0 0 0 5 0 129 41 6 3 0 0 0 0 0 6 0 127 66 3 1 0 0 0 0 0 7 0 87 28 5 1 0 0 0 0 0 8 0 124 43 6 2 0 0 0 0 0 9 0 118 32 5 3 0 0 0 0 0 10 0 121 55 4 1 0 0 0 0 0 Ni 0 1040 432 59 19 0 0 0 0 0 Di 0 1.25 3.75 6.25 8.75 12.5 17.5 25 40 50 Ni*Di 0 1300 1620 368.75 166.25 0 0 0 0 0 f 0 67.10 27.87 3.81 1.23 0.00 0.00 0.00 0.00 0.00 average value 2.23

Particle size inspection method (10×40)

Take an appropriate amount of lactose micropowder as a carrier substance, add absolute ethanol, shake vigorously, immediately draw an appropriate amount (equivalent to 1 μg of lactose) with a micropipette, put it on a glass slide, and measure it according to the particle size determination method (Appendix Two, Chinese Pharmacopoeia 2000 Edition) IX E first method) inspection.

Randomly inspect 10 fields of view, and record the particle size ranges in each field of view (0-2.5, 2.5-5, 5-7.5, 7.5-10, 10-15, 15-20, 20-30, 30-50, > 50 μm) the number of particles (Ni) of the carrier substance lactose powder. The average particle diameters (Di) of the above-mentioned particle size ranges are 1.25, 3.75, 6.25, 8.75, 12.5, 17.5, 15, 40, and 50 μm, respectively. Calculate the number-average particle diameter (D) of the carrier material lactose micropowder by the following formula:

$\mathrm{<span\; class="notranslate">\; D.</span>}<span\; class="notranslate">\; =</span>\frac{\underset{\mathrm{<span\; class="notranslate">\; i</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\overset{\mathrm{<span\; class="notranslate">\; no</span>}}{\mathrm{<span\; class="notranslate">\; \&Sigma;</span>}}}{\mathrm{<span\; class="notranslate">\; N</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}{\mathrm{<span\; class="notranslate">\; D.</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}}{\underset{\mathrm{<span\; class="notranslate">\; i</span>}<span\; class="notranslate">\; =</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\overset{\mathrm{<span\; class="notranslate">\; no</span>}}{\mathrm{<span\; class="notranslate">\; \&Sigma;</span>}}}{\mathrm{<span\; class="notranslate">\; N</span>}}_{\mathrm{<span\; class="notranslate">\; i</span>}}}$

In addition, by detecting the fluidity (angle of repose) of the particles in the inhalable powder aerosol of the present invention, the emptying rate of the filled capsule, the deposition amount of the effective part, the content uniformity, etc., the results show that the tiotropium in the powder aerosol of the present invention Ammonium bromide granules have good fluidity; the particle size distribution, moisture content and properties, as well as the emptying rate of the capsule content, the deposition amount of the effective part and the content uniformity, etc. meet the relevant regulations.

Tiotropium bromide capsule type inhalation powder mist of the present invention, through high temperature (40 ℃, 60 ℃), strong light (4500 ± 5001x) irradiation, high humidity (RH75% ± 5%) condition 5, 10 day influence factors The test results show that, except that the capsule shell becomes hard and brittle at a high temperature of 60°C—it is impossible to measure the deposition amount of its effective parts, the high humidity is 92.5% and the moisture absorption is serious (cannot be detected), and the sample has a slight moisture absorption under the condition of high humidity of 75% , the amount of deposition in the effective part decreased slightly; under other conditions, the physical and chemical indicators of the sample, such as the properties, moisture, deposition amount of the effective part, emptying rate and content, did not change significantly compared with the 0 day, which met the relevant regulations.

Due to the low content of tiotropium bromide in the powder aerosol, it is difficult to mix the main drug with the excipient in a fine powder state, or the mixing process is very complicated, which limits the application of this product. The tiotropium bromide inhalable powder and aerosol of the present invention adopts the wet method to prepare granules in the process, and after dissolving the solvent for the main drug, it is mixed with the micronized excipient, so that the main drug is adsorbed on the carrier substance lactose, and the content is guaranteed to be uniform Moreover, the process is simple and more suitable for the needs of mass production.

Detailed ways

The technical solution of the present invention is specifically described below by examples. For those skilled in the art, it should be understood that this is not a limitation to the embodiment of the present invention. It is obvious to replace the technical features in the embodiment according to the prior art. Still belong to the protection scope of the present invention.

Embodiment 1. Tiotropium bromide capsule type powder spray

1. Lactose micronization

Take 100g of lactose, add 120ml of water, heat to dissolve completely, let cool, filter, slowly add 300ml of isopropanol under stirring, to precipitate crystals, filter, wash the filter layer in 200ml of 95% isopropanol solution, and pass through 200 mesh Sieve, filter, ventilate and dry at 105°C for 5 hours, and pulverize to obtain.

2. Preparation of tiotropium bromide powder spray

① Weigh 22.5 mg of tiotropium bromide monohydrate, add 10 ml of absolute ethanol, heat to dissolve completely, and set aside.

②Weigh 30.0g of lactose micropowder, mix it with the solution of ① above, make a soft material, sieve 120 mesh to make granules, ventilate and dry at 60°C for 3 hours, and sieve the granules with an 80 mesh sieve.

③Measure the content of tiotropium bromide (C ₁₉ H ₂₀ NO ₃ S ₂ ) in the granules, and adjust the filling volume so that each capsule contains 100.0% of the marked amount of tiotropium bromide.

④ Fill the capsule.

⑤ Packaging.

⑥ Inspection.

Embodiment 2. Tiotropium bromide capsule type powder spray

1. Lactose micronization

Take 100g of lactose, add 180ml of water, heat to dissolve completely, let cool, filter, slowly add 200ml of isopropanol under stirring, to precipitate crystals, filter, wash the filter layer in 400ml of anhydrous isopropanol, and pass through a 300-mesh sieve , filtered, placed at 105 ℃ ventilated and dried for 5 hours, crushed, that is.

2. Preparation of tiotropium bromide powder spray

① Weigh 22.5 mg of tiotropium bromide monohydrate, add 10 ml of absolute ethanol, heat to dissolve completely, and set aside.

②Weigh 30.0g of lactose micropowder, mix it with the solution of ① above, make a soft material, sieve 140 mesh to make granules, ventilate and dry at 60°C for 3 hours, and sieve granules with a 100 mesh sieve.

③Measure the content of tiotropium bromide (C ₁₉ H ₂₀ NO ₃ S ₂ ) in the granules, and adjust the filling volume so that each capsule contains 100.0% of the marked amount of tiotropium bromide.

④ Fill the capsule.

⑤ Packaging.

⑥ Inspection.

Embodiment 3. Tiotropium bromide capsule type powder spray

The preparation method refers to Example 1, except that the granulating sieve is 100 mesh, and the sizing sieve is 60 mesh.

Investigate the fluidity (angle of repose) and the deposition amount of the effective part of the particles obtained in the above-mentioned Examples 1-3, as well as the results of the powder spray test, see the table below for details.

Table 4 Particle fluidity test results Bottom (cm) height (cm) Angle of repose (degrees) Example 3 5.84 1.26 28.7° Example 1 5.84 1.72 36.7° Example 2 5.84 3.25 52.3°

Table 5 The results of the deposition amount of the effective part of the particles Example 3 Example 1 Example 2 Effective part deposition 11.30% 19.68% 21.22%

             Table 6 Inspection results of powder aerosol contents

investigation Example 3 Example 1 Example 2 character off-white powder off-white powder off-white powder Moisture % 3.21 3.09 3.12 Number average particle size (μm) 2.25 2.24 2.26

The emptying rate of table 7 powder aerosol investigation Example 3 Example 1 Example 2 Empty rate% 97.24 97.31 97.52

In addition, the powder mist prepared in Example 1 was subjected to high temperature (40°C, 60°C), strong light (4500±5001x) irradiation, and high humidity (RH75%±5%) conditions for 5 and 10 days. Test results of influencing factors:

Table 8 Tiotropium bromide inhalation powder aerosol high temperature 40 ℃ test result time (days) 0 5 10 Content traits off-white powder off-white powder off-white powder Moisture % 3.05 2.98 2.97 Effective site deposition % 19.22 17.55 18.81 Empty rate% 97.0 97.0 98.2 content% 100.21 98.59 101.15

Table 9 Tiotropium bromide inhalation powder aerosol high temperature 60 ℃ test result time (days) 0 5 10 Content traits off-white powder off-white powder off-white powder Moisture % 3.05 2.95 2.93 Effective site deposition % 19.22 / / Empty rate% 97.0 / / content% 100.21 100.37 100.21

Table 10 tiotropium bromide inhalation powder aerosol light test result time (days) 0 5 10 Content traits off-white powder off-white powder off-white powder Moisture % 3.05 3.12 3.23 Effective site deposition % 19.22 20.33 20.62 Empty rate% 97.0 95.3 95.3 content% 100.21 99.96 100.13

Table 11 Tiotropium bromide inhalation powder aerosol relative humidity 75% ± 5% test result time (days) 0 5 10 Content traits off-white powder off-white powder off-white powder Moisture % 3.05 3.31 3.47 Effective site deposition % 19.22 13.68 / Empty rate% 97.0 93.1 92.8 content% 100.21 100.03 100.10 Moisture rate / 1.28 1.31

Table 12 Tiotropium bromide inhalation powder aerosol room temperature air test result time (days) 0 5 10 Content traits off-white powder off-white powder off-white powder Moisture % 3.05 3.17 3.19 Effective site deposition % 19.22 16.19 16.64 Empty rate% 97.0 96.3 96.5 content% 100.21 99.58 100.47 Moisture rate / 0.23 0.24

Claims (10)

1. a tiotropium bromide can suck powder spray, it is characterized in that it comprises tiotropium bromide or the tiotropium bromide monohydrate and the lactose micropowder of 0.04 to 1.5% weight ratio.

2. powder spray according to claim 1, wherein, tiotropium bromide or tiotropium bromide monohydrate are adsorbed on the lactose micropowder, and the lactose micropowder particle diameter is all less than 15 μ m, and about 90% less than 8 μ m.

3. powder spray according to claim 1, wherein, the weight ratio of tiotropium bromide or tiotropium bromide monohydrate is 0.09 to 1.2%, the lactose micropowder particle diameter is all less than 12 μ m, and about 90% less than 7 μ m.

4. powder spray according to claim 1, wherein, the weight ratio of tiotropium bromide or tiotropium bromide monohydrate is 0.3 to 0.9%, the lactose micropowder particle diameter is all less than 10 μ m, and about 90% less than 5 μ m.

5. method for preparing the described powder spray of the arbitrary claim of claim 1 to 4, it comprises:

(1) preparation lactose micropowder;

(2) tiotropium bromide is adsorbed on the lactose micropowder that step 1 obtains;

Perhaps, this method only comprises tiotropium bromide is adsorbed on the lactose micropowder.

6. method according to claim 5, wherein step (1) comprising: take by weighing lactose, add 0.5-3.0 doubly with the water of the weight ratio of lactose in, heating is dissolved above-mentioned lactose fully; Put coldly, filter; Stir to make in right amount to filtrate adding solvent lentamente down and separate out crystallization, filter; Filtering layer is put in this solvent and is washed, and crosses 200 mesh sieves, filters; Drying is pulverized the lactose micropowder that promptly obtains;

7. method according to claim 6, wherein the solvent described in the step (1) is pharmaceutically acceptable solvent, is selected from ethanol, acetone, the isopropyl alcohol one or more.

8. method according to claim 7, wherein pharmaceutically acceptable solvent is an anhydrous isopropyl alcohol.

9. the method for stating according to claim 5, wherein step (2) comprising: take by weighing tiotropium bromide anhydrous powder or monohydrate, add the dehydrated alcohol of 200 to 1000 times of weight ratios, dissolving is standby fully; Take by weighing the lactose micropowder that step (1) obtains, with above-mentioned tiotropium bromide solution mixing, wherein the weight ratio of tiotropium bromide or tiotropium bromide monohydrate and lactose micropowder is 0.09 to 1.2%.

10. according to the described method of the arbitrary claim of claim 5-9, wherein step (2) further comprises: system soft material, 120 mesh sieve system granules, drying, 80 mesh sieve granulate.