CN101032484A - Capsule type tiotropium bromide inhalation powder - Google Patents

Abstract

The present invention discloses one kind of tiotropium bromide capsule atomized powder preparation, which includes tiotropium bromide or tiotropium bromide monohydrate in 0.04-1.5 wt% and fine lactose powder of size smaller than 15 microns for adsorbing tiotropium bromide or tiotropium bromide monohydrate. The present invention also provides the preparation process of the atomized powder preparation. The tiotropium bromide capsule atomized powder preparation has simple preparation process, excellent flowability and homogeneously distributed active component.

Description

A kind of capsule type tiotropium bromide inhalation powder

Technical field

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

Background technology

Tiotropium bromide is a kind of anticholinergic agents, and its chemistry is by name: and bromination (1R, 2R, 4S, 5S, 7S)-and 7-[2-hydroxyl-2,2-two (2-thienyl) acetoxyl group]-9,9-dimethyl-3-epoxy-9-nitrogen secocubane [3.3.1.0. ^2.4] the nonane monohydrate, its chemical constitution is as follows:

Boehringer Ingelheim company and Pfizer 2002 are in Holland and the Philippine tiotropium bromide inhalant that gone on the market, trade name: Spiriva ^TMTiotropium bromide is a kind of long lasting Antimuscarinic drugs, and the hypotype M1 to M5 of M-ChR is had similar affinity.For respiratory tract, it brings into play pharmacological action by the M3 receptor that suppresses on the smooth muscle, thus the diastole bronchus.Test shows that this antagonist is competitive and reversible, is used for the treatment of chronic obstructive pulmonary disease (COPD).Be administered once in one day (sucking 18 μ g/ days) can significantly improve the respiratory function of patients with chronic obstructive pulmonary diseases, act on sustainable more than 24 hours.Tiotropium bromide is a quaternary ammonium salt, and oral absorption is poor, be fit to inhalation, and the whole body cholinolytic effect is not remarkable behind the inhalation, so side effect is little, toxicity low (Drugs of the Future, 2000.25 (7): 693-699).

At present, developed the multiple method for preparing capsule type tiotropium bromide inhalation powder: for example, Boehringer Ingelheim company discloses a kind of sucked powder agent that contains tiotropium bromide in Chinese patent CN1210017C (day for announcing is on July 13rd, 2005), at first will mix the mixture that obtains excipient than coarse grain excipient (200M) with than particulate excipient (5 μ m) lactose monohydrate, and then with the micronization tiotropium bromide monohydrate, obtain the powder spray that can suck.

In addition, the said firm discloses another preparation method in Chinese patent application (publication number CN1717225A, open day on January 4th, 2006), and the lactose monohydrate of mean diameter 10-50 μ m is mixed with the micronization tiotropium bromide.The tiotropium bromide dust cloud preparation of above-mentioned two application preparations has all adopted the blended method of a plurality of alternating layers, complicated process of preparation.

Nanchang Hongyi Science Co., Ltd discloses a kind of Ammonium suction powder dose and its preparation method in Chinese patent application publication number CN1439362A (open day: on JIUYUE 3rd, 2003), said preparation is to be that 10 μ g to 30 μ g, particle diameter are that thiatro bromoaminium anhydrous compound superfine powder and 10mg to 30mg, the mean diameter of 1 μ m to 5 μ m is the medicinal carrier micropowder of amino acids of 30 μ m to 80 μ m with single dose content, and for example filled capsules is prepared from behind the abundant mixing of glycine.

Fudan University also discloses a kind of inhaled tiotropium bromide powder preparation and preparation method thereof in Chinese patent application CN1557308A (open day: on December 29th, 2004), it contains medicine tiotropium bromide and carrier aminoacid and recrystallization lactose, by following method preparation, the dry micronization of tiotropium bromide and aminoacid mixing solution spray is formed micropowder, again with recrystallization lactose mixing filled capsules or make other preparation.

Shanghai Huatuo Medicine Sci-Tech Development Co., Ltd is in Chinese patent application CN1593414A (open day: also disclose a kind of capsule type tiotropium bromide inhalation powder and preparation method thereof on March 16th, 2005); this capsule type inhalation aerosol powder is made up of tiotropium bromide medicine carrying micropowder and excipient; wherein tiotropium bromide medicine carrying micropowder adopts the spray drying process preparation; the particle diameter of tiotropium bromide medicine carrying micropowder be 80% diameter of particle in 0.5 μ m-5 mu m range, 90% diameter of particle is less than 10 μ m.

At present, no matter be listing or the tiotropium bromide of above bibliographical information can suck powder spray, in order to make a spot of tiotropium bromide uniform distribution, their preparation technology is more complicated, all be to carry out micronization, and then prepare with mixed with excipients with tiotropium bromide or its monohydrate or with amino acid whose mixture.

Summary of the invention

The present invention has overcome the deficiency that above-mentioned prior art exists, and provides a kind of preparation technology's novelty, simple and tiotropium bromide distributed uniform, stable tiotropium bromide capsule type in powder spray can suck powder spray.

The purpose of this invention is to provide a kind of tiotropium bromide capsule type and can suck powder spray.

Another object of the present invention provides the preparation method that this tiotropium bromide capsule type can suck powder spray.

The inventor can suck in the experiment of powder spray at the research tiotropium bromide, is surprisingly found out that lactose micropowder absorption tiotropium bromide and the tiotropium bromide for preparing can suck powder spray, advantage such as it has active ingredient and is evenly distributed, and is stable, and preparation technology is simple.

The invention provides a kind of tiotropium bromide and can suck powder spray, wherein, 0.04 tiotropium bromide or tiotropium bromide monohydrate to 1.5% weight ratio are adsorbed on the lactose micropowder, the lactose micropowder particle diameter is all less than 15 μ m, and about 90% less than 8 μ m, and preferred lactose micropowder particle diameter is all less than 12 μ m, and about 90% less than 7 μ m, more preferably the lactose micropowder particle diameter is all less than 10 μ m, and about 90% less than 5 μ m; The weight ratio of tiotropium bromide or tiotropium bromide monohydrate is preferred 0.09 to 1.2%, more preferably, and 0.3 to 0.9%, preferred especially 0.5 to 0.8%.

The present invention also provides a kind of preparation method that above-mentioned tiotropium bromide capsule type can suck powder spray for preparing, and it comprises:

1. preparation lactose micropowder.Take by weighing lactose, add 0.5-3.0 (with the weight ratio of lactose) doubly, preferred 0.8-2.0 doubly, preferred especially 1.0-1.8 water doubly, heating is dissolved above-mentioned lactose fully; Put coldly, filter; Stir to make in right amount to the preferred anhydrous isopropyl alcohol of filtrate adding isopropyl alcohol lentamente down and separate out crystallization, filter; Filtering layer places aqueous isopropanol, and preferred 95% aqueous isopropanol more preferably washs in the anhydrous isopropyl alcohol, sieves, and can select 200 orders, preferred 240 orders, and more preferably 300 mesh sieves filter; Drying is pulverized the lactose micropowder that promptly obtains, its particle diameter is all less than 15 μ m, and about 90% less than 8 μ m, and preferred lactose micropowder particle diameter is all less than 12 μ m, and about 90% less than 7 μ m, and more preferably the lactose micropowder particle diameter is all less than 10 μ m, and about 90% less than 5 μ m;

2. tiotropium bromide is adsorbed on the lactose micropowder that step 1 obtains.Take by weighing tiotropium bromide anhydrous powder or tiotropium bromide 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 preferred 0.09 to 1.2%, more preferably, and 0.3 to 0.9%, preferred especially 0.5 to 0.8%; The system soft material, 140 orders, 120 mesh sieve system granules preferably, drying, 100 orders, preferably 80 orders, more preferably 60 mesh sieve granulate, filled capsules.

The inventor has prepared the lactose micropowder that meets requirement of the present invention with reference to the document about lactose crystn

Adopt solvent crystallization to prepare lactose micropowder, solvent is meant the solvent that ethanol, acetone, isopropyl alcohol etc. are pharmaceutically commonly used, preferred isopropyl alcohol, more preferably anhydrous isopropyl alcohol.

Result of the test shows that solvent crystallization can be used to prepare lactose micropowder, and particle diameter meets the requirements, and through lactose micropowder preparation technology's checking, feasible process can obtain particle diameter all less than 10 μ m, and about 90% particle diameter is less than the lactose micropowder of 5 μ m.

Prepare three batches of carrier mass lactose micropowders (first, second batch, the 3rd batch) by solvent crystallization, the particle diameter that the following method in back is checked the lactose micropowder particle is pulverized in crystallization, and the result shows, feasible process.Check result is as follows:

The distribution (first) of table 1 lactose micropowder particle

Particle size range (μ m)
											The visual field	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	22	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
Meansigma methods					2.23

The distribution of table 2 lactose micropowder particle (second batch)

Particle size range (μ m)
											The visual field	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	21	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
Meansigma methods					2.22

The distribution of table 3 lactose micropowder particle (the 3rd batch)

Particle size range (μ m)
											The visual field	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
Meansigma methods					2.23

Particle diameter inspection method (10 * 40)

It is an amount of to get the carrier mass lactose micropowder, adds dehydrated alcohol, after the powerful jolting, draws an amount of (being equivalent to lactose 1 μ g) with micropipette immediately, places on the microscope slide, checks according to granulometry (two appendix IX of Chinese Pharmacopoeia version in 2000 E, first method).

The number (Ni) of the carrier mass lactose micropowder particle of (0～2.5,2.5～5,5～7.5,7.5～10,10～15,15～20,20～30,30～50,＞50 μ m) in the different-grain diameter scope in each visual field is write down in 10 visuals field of casual inspection respectively.The mean diameter of above-mentioned each particle size range (Di) is respectively 1.25,3.75,6.25,8.75,12.5,17.5,15,40,50 μ m.Calculate the number average bead diameter (D) of carrier mass lactose micropowder by following formula:

$D=\frac{\underset{i=1}{\overset{n}{\mathrm{\Σ}}}{N}_i{D}_i}{\underset{i=1}{\overset{n}{\mathrm{\Σ}}}{N}_i}$

In addition, by detecting Emptying Rate that the present invention can suck particulate flowability (angle of repose), filled capsules in the powder spray, deposition ratio in the effective position, uniformity of dosage units etc., the result shows that the tiotropium bromide granule in the powder spray of the present invention has good flowability; Particle size distribution, moisture and character, and capsule 's content Emptying Rate, deposition ratio in the effective position and uniformity of dosage units etc. meet relevant regulation.

Capsule type tiotropium bromide inhalation powder of the present invention, through high temperature (40 ℃, 60 ℃), high light (under 4500 ± 5001x) irradiations, high humility (RH75% ± 5%) condition 5,10 days influence factors' test, the result shows, except 60 ℃ of capsule shells hardening of high temperature, becomes fragile--can not measure its deposition ratio in the effective position, high humidity 92.5% moisture absorption serious (can not detect), under high humidity 75% condition, sample is moisture absorption slightly, outside deposition ratio in the effective position slightly descends; Under other condition, physical and chemical indexs such as the character of sample, moisture, deposition ratio in the effective position, Emptying Rate and content with comparison in 0 day, have no significant change, and meet relevant regulation.

Because of tiotropium bromide is lower at the content of powder spray, principal agent is difficult to mixing with micropowder state and mixed with excipients, perhaps hybrid technique is very complicated, and these have all limited the application of this product.Tiotropium bromide of the present invention can suck powder spray, adopts wet method system granule in the technology, after principal agent is dissolved with solvent, with the micronization mixed with excipients, principal agent is adsorbed on the carrier mass lactose, guaranteed uniformity of dosage units, and technology is simple, is more suitable for the needs of large-scale production.

The specific embodiment

Specify technical scheme of the present invention below by example; for a person skilled in the art; should be understood to this is not restriction to embodiment of the present invention; it is conspicuous according to prior art the technical characterictic in the embodiment being replaced, and still belongs to protection scope of the present invention.

Embodiment 1. tiotropium bromide capsule type powder sprays

1. lactose micropowderization

Get lactose 100g, add water 120ml, heating makes fully dissolving, puts coldly, filters, stir the slow down isopropyl alcohol 300ml that adds, make and separate out crystallization, filter, filtering layer is put and is washed among the 95% aqueous isopropanol 200ml, crosses 200 mesh sieves, filter, put 105 ℃ of aeration-dryings 5 hours, pulverize, promptly.

2. prepare the tiotropium bromide powder spray

1. take by weighing tiotropium bromide monohydrate 22.5mg, add dehydrated alcohol 10ml, heating makes dissolving fully, and is standby.

2. take by weighing lactose micropowder 30.0g, with above-mentioned 1. solution mixing, system soft material, 120 mesh sieve system granules, 60 ℃ of aeration-drying 3 hours, 80 mesh sieve granulate.

3. measure tiotropium bromide (C in the granule ₁₉H ₂₀NO ₃S ₂) content, adjusting loading amount, to make every capsules contain tiotropium bromide be 100.0% of labelled amount.

4. filled capsules.

5. pack.

6. check.

Embodiment 2. tiotropium bromide capsule type powder sprays

1. lactose micropowderization

Get lactose 100g, add water 180ml, heating makes fully dissolving, puts coldly, filters, stir the slow down isopropyl alcohol 200ml that adds, make and separate out crystallization, filter, filtering layer is put and is washed among the anhydrous isopropyl alcohol 400ml, crosses 300 mesh sieves, filter, put 105 ℃ of aeration-dryings 5 hours, pulverize, promptly.

2. prepare the tiotropium bromide powder spray

1. take by weighing tiotropium bromide monohydrate 22.5mg, add dehydrated alcohol 10ml, heating makes dissolving fully, and is standby.

2. take by weighing lactose micropowder 30.0g, with above-mentioned 1. solution mixing, system soft material, 140 mesh sieve system granules, 60 ℃ of aeration-drying 3 hours, 100 mesh sieve granulate.

3. measure tiotropium bromide (C in the granule ₁₉H ₂₀NO ₃S ₂) content, adjusting loading amount, to make every capsules contain tiotropium bromide be 100.0% of labelled amount.

4. filled capsules.

5. pack.

6. check.

Embodiment 3. tiotropium bromide capsule type powder sprays

Preparation method is with reference to embodiment 1, and the sieve of just granulating is 100 orders, and granulate sieve 60.

Investigate the foregoing description 1～3 and make particulate flowability (angle of repose) and deposition ratio in the effective position etc., and the powder spray result of the test, specifically see the following form.

Table 4 mobility of particle assay

	The end (centimetre)	High (centimetre)	Angle of repose (degree)
				Embodiment 3	5.84	1.26	28.7°
Embodiment 1	5.84	1.72	36.7°
				Embodiment 2	5.84	3.25	52.3°

The particulate deposition ratio in the effective position result of table 5

	Embodiment 3	Embodiment 1	Embodiment 2
				Deposition ratio in the effective position	11.30％	19.68％	21.22％

Table 6 powder spray content check result

The investigation project	Embodiment 3	Embodiment 1	Embodiment 2
				Character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.21	3.09	3.12
				Number average bead diameter (μ m)	2.25	2.24	2.26

The Emptying Rate of table 7 powder spray

The investigation project	Embodiment 3	Embodiment 1	Embodiment 2
				Emptying Rate %	97.24	97.31	97.52

In addition, the powder spray of embodiment 1 preparation through high temperature (40 ℃, 60 ℃), high light (5,10 days influence factors' result of the test under 4500 ± 5001x) irradiations, high humility (RH75% ± 5%) condition:

40 ℃ of result of the tests of table 8 inhaled tiotropium bromide powder preparation high temperature

Time (my god)	0	5	10
				The content character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.05	2.98	2.97
				Deposition ratio in the effective position %	19.22	17.55	18.81
Emptying Rate %	97.0	97.0	98.2
				Content %	100.21	98.59	101.15

60 ℃ of result of the tests of table 9 inhaled tiotropium bromide powder preparation high temperature

Time (my god)	0	5	10
				The content character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.05	2.95	2.93
				Deposition ratio in the effective position %	19.22	/	/
Emptying Rate %	97.0	/	/
				Content %	100.21	100.37	100.21

Table 10 inhaled tiotropium bromide powder preparation exposure experiments to light result

Time (my god)	0	5	10
				The content character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.05	3.12	3.23
				Deposition ratio in the effective position %	19.22	20.33	20.62
Emptying Rate %	97.0	95.3	95.3
				Content %	100.21	99.96	100.13

Table 11 inhaled tiotropium bromide powder preparation relative humidity 75% ± 5% result of the test

Time (my god)	0	5	10
				The content character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.05	3.31	3.47
				Deposition ratio in the effective position %	19.22	13.68	/
Emptying Rate %	97.0	93.1	92.8
				Content %	100.21	100.03	100.10
Draw wet rate	/	1.28	1.31

Table 12 inhaled tiotropium bromide powder preparation air at room temperature result of the test

Time (my god)	0	5	10
				The content character	Off-white powder	Off-white powder	Off-white powder
Moisture %	3.05	3.17	3.19
				Deposition ratio in the effective position %	19.22	16.19	16.64
Emptying Rate %	97.0	96.3	96.5
				Content %	100.21	99.58	100.47
Draw wet 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.