CN109745565B - Dry powder composition for inhalation and preparation method thereof - Google Patents
Dry powder composition for inhalation and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a dry powder composition for inhalation and a preparation method thereof, the dry powder composition comprises a long-acting cholinergic receptor blocker, a long-acting beta receptor agonist, a stabilizer and a medicinal carrier, wherein a part of the stabilizer and the long-acting beta receptor agonist form a coating, and the dosage of the part of the stabilizer is the dosage which enables the long-acting beta receptor agonist to be completely coated. The dry powder composition of the invention has good chemical stability and can be targeted for pulmonary administration through a dry powder inhalation device.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dry powder composition for inhalation and a preparation method thereof.
Background
Both long-acting cholinergic receptor blockers and long-acting beta receptor agonists are common drugs used to treat chronic obstructive pulmonary disease. The long-acting cholinergic receptor blocker can combine with acetylcholine receptor and beta receptor, thereby inhibiting the bronchotonic property mediated by choline transmitter and blocking the bronchoconstriction reflex mediated by vagus nerve. Long-acting beta receptor agonists bind to the beta receptor, elevate cyclic adenosine monophosphate (cAMP) levels, relax airway smooth muscle, and may also reduce mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte responses, and increase mucociliary transport. The combination of the two can relieve the dyspnea symptom of patients with chronic obstructive pulmonary disease, and the drug effect is stronger than that of single administration. The medicament can be atomized by the administration device and deposited in the lung for absorption after the two are prepared into the dry powder inhalant, the targeting property of the medicament is further enhanced, the toxic and side effects are obviously reduced, the onset speed is also obviously increased, and the clinical test verifies that the medicament has good safety and tolerance.
The long-acting cholinergic receptor blocking agent belongs to tropane medicines, most of which are alkaloids formed by condensing derivative amino alcohols such as tropane and the like with different organic acids into esters, and the molecular structure of the long-acting cholinergic receptor blocking agent is easy to hydrolyze and is unstable due to ester bonds. The long-acting beta receptor stimulant (adrenomimetic drug) has a basic structure of phenethylamine in a molecular structure, and a benzene ring has phenolic hydroxyl which is sensitive to alkali and is easily oxidized when meeting light or heat in the air. The dry powder inhalant is a solid preparation, and the powder particles (containing effective components and other auxiliary materials), the moisture on the surface of the particles and the air in the gaps among the particles form a system with coexistence of solid, liquid and gas phases. Because the dry powder inhalant has stronger targeting property, the dosage of the two active ingredients of the medicine is usually lower, and the ratio of the active ingredients in the prescription is usually 0.05-5.0 percent, even lower than the content of water or impurities in main auxiliary materials (such as lactose). In order to enable the active ingredients of the dry powder inhalant to reach the lung, the active ingredients are usually micronized, and the particle size of the active ingredients is usually less than 5 microns, so that the specific surface area of the powder is greatly improved, and the powder is more easily contacted with moisture and impurities adsorbed on the surface of a filler with larger particles to react. There is also a potential risk of compatibility between the two active ingredients of a compound dry powder inhaler. These factors make the long-acting cholinergic receptor blocker and long-acting beta receptor agonist form a compound preparation after being mixed with proper fillers and additives, the chemical stability is poor, and the active ingredients are easy to degrade in the placement process, thereby affecting the safety and effectiveness of the medicament.
The patent CN105125542 discloses that a medicinal composition of tiotropium bromide and formoterol can treat respiratory tract and lung inflammatory diseases, wherein tiotropium bromide and formoterol are in the form of powder spray, but the powder spray only comprises tiotropium bromide, formoterol and lactose, and the preparation process adopts a co-mixing mode, so that the prepared product has low stability, the impurity content of the product is increased after the product is placed for a period of time, and the shelf life of the product is reduced.
The raw materials and auxiliary materials are difficult to coat or form a stable inclusion compound method due to the requirement of atomization during drug delivery. On the other hand, from the viewpoint of safety of inhalation administration, common stabilizers, antioxidants and the like cannot be added to the dry powder inhalation preparation, and the use of a desiccant is often limited due to the fact that the moisture content is too low to generate static electricity or cause the property change of a packaging system (such as a capsule or a plastic material). There is therefore a great need to develop means for improving the chemical stability of the product in inhalation formulations.
Disclosure of Invention
In order to overcome the product stability problem in the prior art, the invention provides a dry powder composition for inhalation and a preparation method thereof.
The invention adopts the following technical scheme to solve the problem.
In one aspect, the present invention provides a dry powder composition for inhalation comprising a long-acting cholinergic receptor blocker, a long-acting beta agonist, a stabilizer, and a pharmaceutically acceptable carrier, wherein a portion of the stabilizer forms a coating with the long-acting beta agonist, and the portion of the stabilizer is present in an amount such that the long-acting beta agonist is completely encapsulated.
Preferably, the long-acting cholinergic receptor blocker is selected from tiotropium, glycopyrronium, aclidinium, umeclidinium in the form of a pharmaceutically acceptable bromide, chloride, iodide or monohydrate thereof, preferably tiotropium bromide or monohydrate thereof.
Preferably, D of the long-acting cholinergic receptor blocker50Less than 5 μm.
Preferably, the stabilizing agent is selected from one or more of stearate, amino acid and derivatives thereof, and polyethylene glycol, and is preferably magnesium stearate or leucine.
Preferably, the long-acting beta receptor agonist is selected from indacaterol, formoterol, vilanterol, salmeterol, oloterol and pharmaceutically acceptable salts thereof, preferably formoterol, a fumarate thereof or a dihydrate of a fumarate thereof.
Preferably, D of said long-acting beta receptor agonist50Less than 5 μm.
Preferably, the pharmaceutically acceptable carrier is selected from one or more of saccharides, sugar alcohols, preferably lactose monohydrate, lactose anhydrous or a mixture thereof.
In the present invention, the carrier for the Chinese medicine of the inhaled dry powder composition refers to a component serving as a filler in the preparation. The active ingredient or the compound containing the active ingredient can be combined on the surface of the carrier in the preparation process of the preparation so as to meet the processing requirements of the working procedures of dispersion, mixing, quantitative filling and the like. To achieve this, the proportion of pharmaceutically acceptable carrier in the inhaled dry powder composition generally needs to be significantly greater than the active ingredient or the active ingredient complex.
The active ingredient or its complex containing the active ingredient can be dissociated from the surface of the carrier under the action of airflow during inhalation administration to reach the lung, thereby exerting therapeutic effect.
Preferably, the weight ratio of the long-acting cholinergic receptor blocker to the medicinal carrier is 1: 20-1: 2000.
Preferably, the weight ratio of the long-acting beta receptor agonist to the pharmaceutically acceptable carrier is 1: 20-1: 2000.
Preferably, the weight ratio of the stabilizer to the medicinal carrier is 1: 20-1: 2000.
Preferably, the weight ratio of the stabilizer forming a coating with the long-acting beta receptor agonist to the long-acting beta receptor agonist is 1: 10-10: 1.
In another aspect, the present invention also provides a method of preparing the above dry powder composition for inhalation, comprising the steps of: a) co-grinding and mixing the long-acting beta receptor agonist and a part of stabilizer to form a compound; b) and c) stirring and mixing the compound formed in the step a) with the long-acting cholinergic receptor blocker, the rest stabilizer and the medicinal carrier at a high speed to obtain the compound.
Preferably, in step a), the co-grinding mixture is carried out using a grinding apparatus selected from the group consisting of a ball mill, a disk mill, a planetary ball mill, a mechanical fusion machine and a jet mill.
Preferably, in step a), the weight ratio of the stabilizer forming a coating with the long-acting beta receptor agonist to the long-acting beta receptor agonist is 1: 10-10: 1.
Co-mulled mixing refers to the local mixing of a long-acting beta receptor agonist and a stabilizer by a suitable device under the push of an external force. The grinding intensity of these devices is generally significantly higher than high speed mixing. Common grinding equipment comprises a ball mill, a disc mill, a mechanical fusion machine, a jet mill and the like, and the equipment can drive particles in a container to mutually extrude, collide and rub through air flow, stirring paddles, grinding rods, grinding balls, container walls and the like to break loose active ingredients and stabilizer component agglomerates into particles with proper particle size, uniformly disperse the stabilizer and the active ingredients, and then form loose powder aggregates through the acting force among the particles. The crystal particles of the active ingredient of the long-acting beta receptor stimulant in the powder and the particles of the stabilizing agent have larger specific surface area and stronger mutual binding force, and the contact area of the crystal particles of the active ingredient of the long-acting beta receptor stimulant and the long-acting cholinergic receptor blocker or other medicinal carriers (and moisture or impurities on the surface of the crystal particles) can be effectively reduced in the subsequent preparation processing and storage processes, so that the stability of the medicament is improved.
For co-micronization by using a jet mill, the pulverization pressure of more than 0.2MPa is generally adopted; for the co-grinding by adopting a high-speed ball mill, the rotating speed of more than 300r/min is generally adopted; for co-grinding by adopting a planetary ball mill, the rotating speed of a sun wheel is generally above 30 r/min; for a disc grinder, the rotating speed of a vibration chassis is generally above 700 r/min.
The high-speed stirring and mixing means that the particles in the material group are subjected to external force from a cutter, a stirring paddle or a screen mesh and the like, and the inside of the powder generates a stirring effect due to flowing, so that the materials are mixed. The stirring and mixing equipment includes a high-speed stirrer, a high-speed mixer and the like, and besides the flowing, loose active ingredients or loose lumps of the active ingredients and the stabilizer can be broken up into smaller lumps by the high-speed rotation of a cutter or a stirring paddle, and the small lumps are uniformly dispersed and combined on the carrier, the mixing intensity of the equipment is generally lower than that of a co-grinding equipment, and in order to not generate a grinding effect on the basic particles and not to damage the combination of the stabilizer and the active ingredients, the linear speed of the stirring paddle (or the cutter) is 1-100m/s, preferably 10-60 m/s.
The process may be suitably mixed in other ways to enhance the uniformity of dispersion of the stabilizer and active ingredient in the carrier, including V-mixers, three-dimensional mixers, wet-mix granulators, universal mixers, and the like.
The resulting powder composition may be pre-dosed in single-or multi-dose containers, which may be capsules or blisters, preferably capsules, through appropriate packaging to provide chemical and physical protection, and administered by active or passive inhalation devices.
The invention has the beneficial effects that:
on one hand, the invention adds the stabilizing agent on the basis of the prescription of the existing compound dry powder inhalant, and obtains the compound by co-grinding and mixing partial stabilizing agent and the long-acting beta receptor stimulant, thereby obviously reducing the contact among the long-acting beta receptor stimulant, the long-acting cholinergic receptor blocker and the medicinal carrier particles, and improving the chemical stability of the long-acting beta receptor stimulant and the long-acting cholinergic receptor blocker in the composition.
On the other hand, through the screening design of process procedures and parameters, a compound obtained by co-grinding and mixing part of the stabilizing agent and the long-acting beta receptor stimulant is mixed with the long-acting cholinergic receptor blocker and the medicinal carrier through high-speed stirring, so that the stability reduction of active ingredients caused by the excessive mixing of the long-acting cholinergic receptor blocker and the stabilizing agent is avoided, the compound dry powder preparation with better chemical stability and uniform dispersion is obtained, and the compound dry powder preparation can be quantitatively filled in a single-dose or multi-dose dry powder inhalation device for administration to the lung. The technical problem of poor chemical compatibility among the long-acting cholinergic receptor blocker, the long-acting beta receptor agonist and the filler particles in the prior art is solved, and the shelf life of the product is greatly prolonged.
Drawings
FIG. 1 is a graph showing the trend of the total amount of tiotropium bromide impurity in some examples of the stability studies of example 16 according to the present invention; and
fig. 2 is a graph showing the trend of the increase in the total amount of formoterol as an impurity in some of the examples of the stability studies of example 16 of the present invention.
Detailed Description
Example 1: preparation of micronized tiotropium bromide
Micronizing tiotropium bromide monohydrate and tiotropium bromide anhydride respectively in a jet mill under the crushing pressure of 0.6MPa to obtain product with particle diameter D50To 5 μm or less.
Example 2: preparation of micronized formoterol fumarate
Micronizing formoterol fumarate dihydrate and formoterol fumarate in an air flow pulverizer respectively, wherein the pulverizing pressure is 0.6Mpa, and the particle diameter D of the obtained product50To 5 μm or less.
Example 3: tiotropium bromide formoterol for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
The magnesium stearate with the prescription amount of 1/10 was weighed according to the following table and mixed with the micronized formoterol dihydrate obtained in example 2 for 2min under stirring, transferred to a planetary ball mill, mixed for 10min at a sun rotation speed of 500r/min, and left to stand to prepare a powder composite (D)502.23 μm) and then micronized tiotropium bromide monohydrate (D) prepared in example 1 was added502.65 μm), lactose monohydrate, and the remainder of the prescription magnesium stearate were mixed in a high speed mixer for 2min at a paddle speed of 10 m/s.
Example 4: tiotropium bromide formoterol dry powder for inhalation by using mannitol as carrier and leucine as stabilizer
Preparation of
Leucine in a prescribed amount of 1/10 was weighed according to the following table and mixed with the micronized formoterol obtained in example 2 with stirring for 2min, transferred to a planetary ball mill, mixed at a sun rotation speed of 500r/min for 10min, and left to stand appropriately to prepare a powder composite (D)502.4 μm) and then micronized tiotropium bromide (D) prepared in example 1 was added502.7 μm), mannitol and the remainder of the formulaLeucineMixing in a high-speed stirrer for 2min at a linear speed of a stirring paddle of 60m/s, and finally mixing in a three-dimensional mixer for 10-20 min.
Example 5: tiotropium bromide formoterol for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.5g of magnesium stearate and 0.5g of formoterol fumarate dihydrate were weighed according to the following table, mixed for 2min with stirring, transferred to a jet mill, and co-micronized at a pulverizing pressure of 0.4MPa to prepare a powder composite (D)502.3 μm, formoterol fumarate dihydrate content 48.2%), appropriate amount of powder complex, where formoterol corresponds to the prescribed amount, was added to micronized tiotropium bromide monohydrate (D) prepared in example 1502.65 μm), lactose monohydrate and the rest of the magnesium stearate in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 100m/s, and finally, the mixture is mixed in a three-dimensional mixer for 10-20 min.
Example 6: tiotropium bromide formoterol for inhalation with anhydrous lactose as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.5g of magnesium stearate and 0.5g of formoterol fumarate dihydrate were weighed according to the following table, mixed for 2min with stirring, transferred to a jet mill, and co-micronized at a pulverizing pressure of 0.4MPa to prepare a powder composite (D)502.3 μm, formoterol fumarate dihydrate content 48.2%), appropriate amount of powder complex, where formoterol corresponds to the prescribed amount, was added to micronized tiotropium bromide monohydrate (D) prepared in example 1502.65 μm), anhydrous lactose and the rest of the prescribed amount of magnesium stearate were mixed in a high speed mixer for 2min, with a paddle speed of 10m/s, and finally mixed in a three-dimensional mixer for 10-20 min.
Example 7: tiotropium bromide formol for inhalation by using lactose monohydrate as carrier and polyethylene glycol 6000 as stabilizer
Preparation of dried Terro powder
0.05g of polyethylene glycol 6000 and 0.2g of formoterol fumarate dihydrate were weighed according to the following table, stirred and mixed for 2min, transferred to a jet mill, co-micronized at a pulverizing pressure of 0.4MPa, and a powder complex (D) was prepared502.3 μm, formoterol fumarate dihydrate content 82.4%), appropriate amount of powder complex, where formoterol corresponds to the prescribed amount, was added to micronized tiotropium bromide monohydrate (D) prepared in example 1502.65 μm), lactose monohydrate and the rest of polyethylene glycol 6000 according to the prescription are mixed in a high-speed stirrer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Example 8: preparation of micronized Wumei ammonium bromide
Micronizing ammonium Bromide in jet mill under 0.8MPa to obtain product with particle diameter D50To 5 μm or less.
Example 9: preparation of micronized aclidinium bromide
Will be provided withAclidinium bromideMicronizing in jet mill under 1.2MPa to obtain product with particle diameter D50To 5 μm or less.
Example 10: preparation of micronized glycopyrronium bromide
Will be provided withGlycopyrrolateMicronizing in jet mill under 0.6MPa to obtain product with particle diameter D50To 5 μm or less.
Example 11: ultramonium bromide for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.2g of magnesium stearate and 0.2g of vilanterol trifluoromethanesulfonate were weighed according to the following table, mixed for 2min with stirring, transferred to a jet mill, co-micronized at a crushing pressure of 0.4MPa to prepare a powder complex (D50 ═ 1.88 μm, vilanterol trifluoromethanesulfonate content 50.5%), an appropriate amount of the powder complex was taken, wherein vilanterol corresponds to the prescribed amount, and then micronized umetramonium bromide (D) prepared in example 8 was added502.05 μm), lactose monohydrate and the rest of the magnesium stearate in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Example 12: adodiammonium-oldacterol for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.2g of magnesium stearate and 0.2g of olodaterol hydrochloride are weighed out according to the table below, mixed for 2min with stirring, transferred to a jet mill, co-micronized at a crushing pressure of 0.4MPa to prepare a powder complex (D50 ═ 2.28 μm, olodaterol hydrochloride content 51.9%), a suitable amount of the powder complex is taken, wherein the amount of olodaterol corresponds to the prescribed amount, and then micronized aclidinium bromide (D) prepared in example 9 is added502.02 μm), lactose monohydrate and the rest of the magnesium stearate in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Example 13: glycopyrrolate indacaterol for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.4g of magnesium stearate and 4g of indacaterol maleate were weighed according to the table below, mixed for 2min with stirring, transferred to a jet mill, co-micronized at a crushing pressure of 0.4MPa to prepare a powder complex (D50 ═ 1.81 μm, indacaterol maleate content 91.5%), an appropriate amount of the powder complex was taken, wherein the indacaterol was in the amount prescribed, and then micronized glycopyrronium bromide (D) prepared in example 10 was added (D501.76 μm), lactose monohydrate and the rest of the magnesium stearate in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Example 14: tiotropium bromide salmeterol for inhalation with lactose monohydrate as carrier and magnesium stearate as stabilizer
Preparation of Dry powders
0.2g of magnesium stearate and 2.0g of salmeterol xinafoate are weighed according to the following table, stirred and mixed for 2min, transferred to air flow powderIn a crusher, co-micronizing at 0.4MPa of pulverizing pressure to prepare powder compound (the particle diameter of the product is 1.81 μm, salmeterol xinafoate content is 91.5%), taking a proper amount of the powder compound, wherein the amount of salmeterol is equivalent to the amount prescribed, and adding micronized tiotropium bromide (D) prepared in example 1502.65 μm), lactose monohydrate and the rest of the magnesium stearate in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Example 15: tiotropium bromide Samamizumab for inhalation with lactose monohydrate as carrier and acetylcysteine as stabilizer
Preparation of dried Terro powder
0.2g of acetylcysteine and 2.0g of salmeterol xinafoate are weighed according to the following table, stirred and mixed for 2min, transferred to a jet mill, co-micronized at a crushing pressure of 0.4MPa to prepare a powder compound (the particle size of the product is 1.99 μm, the content of salmeterol xinafoate is 91.5%), a proper amount of the powder compound is taken, wherein the amount of salmeterol is equivalent to the prescribed amount, and then micronized tiotropium bromide (D) prepared in example 1 is added502.65 μm), lactose monohydrate and the rest of acetylcysteine in the prescription are mixed in a high-speed mixer for 2min, the linear speed of a stirring paddle is 50m/s, and finally, the mixture is mixed in a three-dimensional mixer for 5-10 min.
Comparative example 1
Weighing micronized tiotropium bromide monohydrate prepared in example 1 according to the ratio of 200:1 in the following table, uniformly mixing with an appropriate amount of magnesium stearate, transferring to a jet mill, co-micronizing under the crushing pressure of 0.4MPa to prepare a powder compound (the particle size of the product is 2.11 μm, and the content of the tiotropium bromide monohydrate is 99.1%), weighing an appropriate amount of the powder compound according to the following table, adding micronized formoterol fumarate dihydrate prepared in example 2, the rest of magnesium stearate and lactose monohydrate according to the prescription amount, mixing for 3min in a high-speed mixer, and finally transferring to a three-dimensional mixer for mixing for 5-10min, wherein the linear speed of a stirring paddle is 50 m/s.
Comparative example 2
The micronized tiotropium bromide monohydrate prepared in example 1, the micronized formoterol fumarate dihydrate prepared in example 2 and magnesium stearate were weighed according to the following table, mixed with stirring for 2min, transferred to a planetary ball mill, mixed for 10min with a sun rotation speed of 500r/min, left to stand to prepare a powder mixture, then added with lactose monohydrate, mixed for 3min in a high-speed mixer with a paddle speed of 50m/s, and transferred to a three-dimensional mixer for 5-10 min. .
Comparative example 3
The micronized tiotropium bromide monohydrate prepared in example 1 and the micronized formoterol fumarate dihydrate prepared in example 2 were weighed according to the following table, stirred and mixed for 2min, then transferred to a planetary ball mill, mixed for 10min with a sun gear rotating speed of 500r/min, appropriately left to stand, a powder mixture was prepared, lactose monohydrate was added, mixed for 3min in a high-speed mixer with a stirring paddle linear speed of 50m/s, and finally transferred to a three-dimensional mixer for 5-10 min.
Comparative example 4
Weighing the wumei ammonium bromide and the vilanterol trifluoromethanesulfonate, stirring and mixing for 2min, transferring the mixture into a jet mill, carrying out co-micronization at the crushing pressure of 0.4MPa to prepare a powder compound, taking a proper amount of a powder mixture, wherein the wumei ammonium bromide and the vilanterol are basically equivalent to the formula amount, then adding magnesium stearate and lactose monohydrate, mixing for 2min in a high-speed mixer, stirring at the linear speed of a stirring paddle of 50m/s, and finally mixing for 5-10min in a three-dimensional mixer.
Comparative example 5
Weighing proper amounts of tiotropium bromide, salmeterol xinafoate and magnesium stearate, and respectively carrying out air current grinding on the tiotropium bromide, the salmeterol xinafoate and the magnesium stearate to obtain powder D50Transferring 0.4g of the powder to a planetary ball mill at a ratio of 1:1:1 below 5 μm, mixing at a sun rotation speed of 500r/min for 10min, and standing to obtain a powder composite. Taking a proper amount of the powder mixture, wherein the amount of the tiotropium bromide and the salmeterol xinafoate is basically equal to the amount of the prescription, then adding the lactose monohydrate and the rest magnesium stearate according to the amount of the prescription, mixing for 2min in a high-speed mixer with the linear velocity of a stirring paddle of 50m/s, and finally mixing for 5-10min in a three-dimensional mixer.
Example 16: long-acting cholinergic receptor blockers and long-acting beta receptor agonist stability studies for inhalation
The purpose of this study was to simulate the stability changes of the produced product during storage.
Taking the powders of examples 3 to 7 and comparative examples 1 to 3, filling a capsule at 25 mg/capsule to prepare a dry powder inhalation formulation of tiotropium bromide formoterol which can be administered to the lung by a dry powder inhalation device; taking the powders of example 11 and comparative example 4, 12.5 mg/capsule filling to prepare a dry powder inhalation formulation of wumei ammonium bromide vilanterol which can be administered to the lung by a dry powder inhalation device; the powders of example 14 and comparative example 5, filled into capsules at 5.5 mg/capsule, produced a dry powder inhalation formulation of salmeterol tiotropium bromide that can be administered to the lung by a dry powder inhalation device. Each group of capsules was sealed with an aluminum foil bag, and then placed at 40 ℃ in an RH 75% environment, and the content and the change of related substances were measured at regular intervals, and the results are shown below,
TABLE 1 variation of impurity levels of formoterol and tiotropium bromide
TABLE 2 Vilantelo and Umamizium bromide impurity content variation table
TABLE 3 Salmeterol and tiotropium bromide impurity content variation table
The stability data studies of examples 3-7 and comparative examples 1, 2, 3, example 11 and comparative example 4, and example 14 and comparative example 5 show that the addition of stabilizers and the mixing process together affect the stability of the product, and that the stability of the product is greatly improved only when the stabilizers and long-acting beta-agonists are first mixed to form a complex and then mixed with other formulation ingredients. The stability of the two components can be improved simultaneously by adding the stabilizer into the formula, grinding and mixing the compound and stirring at a high speed. The obtained powder can be filled into capsule and administered together with special medicinal powder inhaler for treating chronic obstructive pulmonary disease.
Claims (12)
1. A dry powder composition for inhalation comprising a long-acting cholinergic receptor blocker, a long-acting beta agonist, a stabilizer, and a pharmaceutically acceptable carrier, wherein a portion of the stabilizer forms a coating with the long-acting beta agonist, the portion of the stabilizer is in an amount such that the long-acting beta agonist is completely encapsulated, and the coating is mixed with the long-acting cholinergic receptor blocker, the remaining stabilizer, and the pharmaceutically acceptable carrier to form a dry powder composition;
wherein the stabilizing agent is selected from one or more of stearate, amino acid and derivatives thereof, and polyethylene glycol;
the medicinal carrier is selected from one or more of saccharides and sugar alcohols;
d of the long-acting cholinergic receptor blocker50Less than 5 μm;
d of said long-acting beta receptor agonist50Less than 5 μm;
the long-acting cholinergic receptor blocker is selected from the group consisting of tiotropium, glycopyrronium, aclidinium, umeclidinium, pharmaceutically acceptable bromides, chlorides, iodides and monohydrate forms thereof;
the long-acting beta receptor agonist is selected from indacaterol, formoterol, vilanterol, salmeterol, and oldacterol and pharmaceutically acceptable salts thereof.
2. A dry powder composition according to claim 1, wherein the long-acting cholinergic receptor blocker is tiotropium bromide or a monohydrate thereof.
3. The dry powder composition according to claim 1, wherein the stabilizer is magnesium stearate or leucine.
4. A dry powder composition according to claim 1, wherein the long-acting beta receptor agonist is formoterol, a fumarate salt thereof or a dihydrate of the fumarate salt thereof.
5. The dry powder composition according to claim 1, wherein the pharmaceutically acceptable carrier is lactose monohydrate, lactose anhydrous or a mixture thereof.
6. The dry powder composition according to claim 1, wherein the weight ratio of the long-acting cholinergic receptor blocker to the pharmaceutically acceptable carrier is 1: 20-1: 2000.
7. The dry powder composition according to claim 1, wherein the weight ratio of the long-acting beta receptor agonist to the pharmaceutically acceptable carrier is 1:20 to 1: 2000.
8. The dry powder composition according to claim 1, wherein the weight ratio of the stabilizer to the pharmaceutically acceptable carrier is 1:20 to 1: 2000.
9. The dry powder composition according to claim 1, wherein the weight ratio of the stabilizer forming a coating with the long-acting beta-receptor agonist to the long-acting beta-receptor agonist is 1:10 to 10: 1.
10. A method of preparing a dry powder composition according to any one of claims 1 to 9, comprising the steps of: a) co-grinding and mixing the long-acting beta receptor agonist and a part of stabilizer to form a compound; b) and c) stirring and mixing the compound formed in the step a) with the long-acting cholinergic receptor blocker, the rest stabilizer and the medicinal carrier at a high speed to obtain the compound.
11. The process according to claim 10, characterized in that in step a), the co-grinding mixture is carried out using a grinding apparatus selected from the group consisting of ball mills, disk mills, planetary ball mills, mechanical fusion machines or jet mills; in the step b), the linear speed of the high-speed stirring mixer is 1-100 m/s.
12. The method as claimed in claim 11, wherein in step b), the linear speed of the high speed stirring mixer is 10-60 m/s.
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| GB2614901A (en) * | 2022-01-21 | 2023-07-26 | Nanopharm Ltd | Inhalable formulations |
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| CN116194087A (en) * | 2020-01-15 | 2023-05-30 | 四川海思科制药有限公司 | Indanterol-containing inhalation aerosol pharmaceutical composition and preparation method thereof |
| CN111297837B (en) * | 2020-03-26 | 2022-02-22 | 上海方予健康医药科技有限公司 | Preparation method of dry powder inhalant |
| CN114515280B (en) * | 2020-11-18 | 2023-08-11 | 云南汉盟制药有限公司 | Pharmaceutical composition and application thereof |
| CN115364075B (en) * | 2022-09-16 | 2023-11-10 | 苏州易合医药有限公司 | Inhalation particle composition and preparation method thereof |
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