CN111202724A

CN111202724A - Arbidol inhalation dry powder pharmaceutical composition and preparation method thereof

Info

Publication number: CN111202724A
Application number: CN202010094477.6A
Authority: CN
Inventors: 宋敏; 舒欣; 陈磊; 高超; 陆平波; 董海红
Original assignee: Jiangsu Alicorn Pharmaceutical Co ltd
Current assignee: Jiangsu Alicorn Pharmaceutical Co ltd
Priority date: 2020-02-16
Filing date: 2020-02-16
Publication date: 2020-05-29

Abstract

The invention belongs to the technical field of medicines, and discloses an arbidol inhalation dry powder pharmaceutical composition, a preparation method of the composition and medical application of the composition.

Description

Arbidol inhalation dry powder pharmaceutical composition and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to a preparation method of an inhaled dry powder medicinal composition.

Background

Aiming at 2019-nCoV, no specific antiviral drug exists at present all over the world, the specific antiviral drug is mainly used for symptomatic treatment of symptoms of patients, no effective antiviral drug exists, and a proper antiviral drug needs to be quickly found according to the current epidemic situation, so that the medicine has important significance for treating infectors, controlling epidemic spread and reducing fatality rate at a reasonable medicine application time.

2019-nCoV virus and SARS coronavirus have similar receptor binding path, and through the molecular mechanism of the binding interaction of S-protein and human ACE2 receptor, ACE2 exists in pulmonary alveoli and small intestine epithelial cells, and is expressed on the surfaces of arteriovenous epithelial cells and arterial smooth muscle cells of all organs, wherein the respiratory tract epithelial cells are distributed most, so that the respiratory tract and the lung are most susceptible to infection.

2019-nCoV virus can be detected in the excrement of severe patients, and no virus is detected in the urine, which indicates that the virus is gathered in alveoli after invading from respiratory tract and exists in large amount in digestive tract at later stage. However, the literature reports that the serum detection of 2019-nCoV of the American patient is negative, the detection result of the plasma of the 2019-nCoV of the Wuhan patient in China is corresponding to the detection result, the positive rate is only (6/41) 15%, and compared with the detection rate of SARS-CoV plasma virus being 79%, the detection rate of the SARS-CoV plasma virus is 79%, so that the antiviral drug for treating SARS-CoV can be absorbed into the blood from the gastrointestinal tract after oral administration, and the 2019-nCoV virus with very low concentration in the blood can not be killed.

By analyzing the symptoms of patients, the symptoms of upper respiratory tract such as nasal obstruction, nasal discharge, sore throat and the like are not obvious, and the 2019-nCoV virus of the upper respiratory tract (including nasopharynx part and oropharynx part) of most patients is negative in detection, and the 2019-nCoV virus can be detected only by collecting alveolar lavage fluid, which shows that the virus has extremely high affinity to lung, so that the medicine needs to directly reach a target point, namely alveolus.

Abidol is a double-effect anti-influenza virus drug developed by the chemical research center of the former Soviet Union drug, and is firstly marketed in Russia in 1993 for preventing and treating influenza and other acute respiratory virus infections. Arbidol is a non-nucleoside broad-spectrum antiviral drug, has main indications of influenza caused by A-type and B-type influenza viruses, and also has antiviral activity on other respiratory virus infections; in 2019, arbidol is first brought into the national medical insurance catalogue and into the clinical recommended drug list for resisting virus influenza issued by the national Weijian Commission. On day 2 and 4 of 2020, the Lianjuan team, a member of academicians of the Chinese institute of Engineers and the high-level expert of the national health Commission, published in Wuhan's latest research results for the treatment of pneumonia infected with the novel coronavirus. Li-lan juanji showed, according to preliminary tests, that: compared with a control group which is not treated with the medicament, the arbidol can effectively inhibit the coronavirus by 60 times under the condition of 10-30 micromolar concentration, and obviously inhibit the pathological change effect of the virus on cells.

Arbidol is a white-like crystalline powder, has no hygroscopicity, is readily soluble in methanol, is slightly soluble in glacial acetic acid, is almost insoluble in water, dilute hydrochloric acid and sodium hydroxide test solutions, has a solubility of only 0.024mg/ml (25 ℃) in water, and its water-insolubility limits the development of liquid preparations such as injections. The preparation sold on the market is mainly tablets, capsules and dry suspension, has two specifications of 100mg and 200mg, and belongs to a large-dose composition. Although arbidol has good safety, bitter taste and poor patient compliance, the problem of taste masking is faced when developing oral preparations for adults and children, the main drug is sensitive to high temperature, illumination and alkaline environment, and can be degraded after long-term lofting, so that the impurities are increased, the dissolution rate is reduced, the curative effect is influenced, and the improvement of the stability of the main drug is also an important aspect of research. According to the in vitro antiviral screening result, the arbidol has good efficiency of inhibiting the novel coronavirus, has the advantages of preventing the fusion and the replication of the virus, inducing interferon, obviously improving the autoimmunity, obviously relieving the influenza symptom, shortening the influenza course, preventing the occurrence and the development of the later-stage influenza syndrome, effectively preventing the influenza by being taken in the influenza epidemic period and the like, and the inhalant of the arbidol can possibly become a first micromolecule compound inhalant for treating the novel coronavirus, and has the following advantages: the preparation targets the focus, has accurate dosage and quick response, can quickly improve the pulmonary infection condition, is beneficial to improving the adaptability of an infected person, has good safety and can be used for administration of children; the medicine is not contacted with the tongue, so that the uncomfortable feeling of taking medicine caused by bitter taste is avoided; the medicament is stored in the inhalation device, protected from light and other environmental exposure, and can maintain stability.

The Pulmonary Drug Delivery System (PDDS) refers to a drug delivery system in which a drug is delivered directly into the respiratory tract via a special drug delivery device to perform local or systemic therapeutic action. Current pulmonary delivery systems include Metered Dose Inhalation (MDI), inhalation spray (inhalation), Dry Powder Inhalation (DPI), and Dry Powder Inhaler (DPI). Wherein, the aerosol needs a propellant, can destroy the atmospheric ozone layer, and requires the synergistic action of patients when in use. The spraying device of the spraying agent is too large, inconvenient to carry, low in efficiency, poor in repeatability, large in individual difference and long in inhalation process. Compared with aerosol and spray, the dry powder inhalation has no requirement of synergistic effect, does not need a propellant, has larger delivery dose and is more suitable for macromolecular drugs.

The dry powder inhalant is a new dosage form developed on the basis of quantitative inhalation aerosol and by integrating the knowledge of powder engineering, and is a drug delivery system which disperses micronized drugs alone or after being sheared and mixed with a carrier into mist to enter respiratory tracts through the active inhalation of patients by a special drug delivery device and plays a local or systemic role.

The physiological structure of the lung requires that the drug particles of the dry powder inhalant are very fine, generally, the ideal drug particle size is 1-5 μm, particles larger than the range can not enter the bronchioles, and smaller particles are easy to breathe and exhale. The drug carrier is mainly used for adsorbing drug particles, enhancing the stability of the drug during storage and keeping the drug in an amorphous glass state. When the patient inhales, the shear forces created by the turbulent air flow separate the drug from the carrier, with particles smaller than 5 μm entering the lower respiratory tract, and large particles of carrier or drug falling into the mouth and throat. The greater the shear force generated by the air turbulence, the higher the proportion of particulate drug successfully separated from the carrier, and the higher the lung deposition rate.

Arbidol is hardly dissolved in water, has the solubility of only 0.024mg/ml (25 ℃), has the defects of low bioavailability, bitter main medicine taste, poor patient compliance, sensitivity to high temperature, light and alkaline environment, poor stability and the like, and still becomes a technical bottleneck for developing other administration routes, particularly administration through respiratory tracts. Chinese patent CN1535680A provides a new molecular inclusion compound of arbidol and cyclodextrin or derivatives thereof, which improves water solubility and stability, but the required cyclodextrin dosage is large, the process is complex, and mass production is not facilitated.

The invention adopts the spray drying method to prepare the amorphous arbidol, greatly increases the solubility and the bioavailability, reduces the administration dosage, simultaneously considers that the stability enhancer and the dispersion auxiliary agent are added into the spray drying solution, thereby improving the stability of the main drug, improving the physicochemical property and the inhalation performance of the drug particles, being convenient for being uniformly mixed with an external carrier, and leading the drug to directly reach the lung without contacting the tongue and generating bitter taste when the drug is inhaled and administered.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a novel inhalation dry powder pharmaceutical composition and a preparation method thereof, the inhalation dry powder pharmaceutical composition comprises arbidol, a dispersibility aid, a stability enhancer and a medicinal carrier, and can be used for pulmonary administration through a dry powder inhalation device.

The active component is arbidol which is used for treating viral diseases and is in an amorphous state, and accounts for 5-50% of the total weight of the composition, preferably 10-30%.

The medicinal auxiliary materials in the dry powder inhalant comprise a dispersing auxiliary agent, a stability reinforcing agent and a large-particle-size carrier according to functional division.

The dispersing auxiliary agent can make the granules have proper dispersity, and can prevent the granules from agglomerating and adhering, and is selected from one or more of sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, sorbitol and the like, preferably mannitol. The dispersibility aid is small molecular amino acids, and can be one or more selected from alanine, valine, leucine, isoleucine and phenylalanine, preferably leucine.

The stability enhancer can be selected from an antioxidant and an acidic regulator, preferably the acidic regulator, including but not limited to one or more of fumaric acid, malic acid, citric acid, tartaric acid and the like, preferably malic acid.

The large particle size carrier serves to aid in the transport of the drug particles from the site of administration to the throat. Arbidol dry powder inhalers, which are suitable for airway delivery from the throat region to the lung when the particles are of small size and highly dispersed, are not suitable for delivery from the site of administration to the throat region, require the addition of a large particle size carrier.

The carrier with large particle size is selected from one or more of saccharides and sugar alcohols, preferably one or more of lactose, mannitol, trehalose, sucrose, sorbitol, glucose, β -cyclodextrin, dimethyl β -cyclodextrin, erythritol and the like, and preferably one or more of lactose monohydrate or lactose.

The carrier with large particle size is characterized in that the particle size of more than 50 percent of particles is 25-300 mu m, preferably the particle size of more than 70 percent of particles is 50-200 mu m, and more preferably the particle size of more than 90 percent of particles is 50-100 mu m. The mixing ratio of the drug particles and the large-particle-size carrier is 100: 1-1: 100, preferably 50: 1-1: 50, and more preferably 20: 1-1: 20 by weight.

It is another object of the present invention to provide a process for the preparation of a dry powder pharmaceutical composition for inhalation comprising the steps of:

(a) dissolving the active ingredient arbidol, the dispersing auxiliary agent and the stability reinforcing agent in an organic solvent, and performing spray drying to prepare amorphous drug particles;

(b) shearing and mixing the drug particles obtained in the step (a) and the large-particle-size carrier to obtain the drug.

The particle size of more than 50% of the amorphous arbidol particles is 0.1-10 mu m, preferably more than 70% of the amorphous arbidol particles is 1-5 mu m, and more preferably more than 90% of the amorphous arbidol particles is 2-4 mu m. Typically, the particle size of a particle is determined quantitatively by measuring the characteristic equivalent sphere diameter (referred to as the volume diameter) by laser diffraction, for example by a laser particle size tester.

The amorphous arbidol particles can be prepared by one or more of spray drying, hot-melt extrusion, grinding method, coprecipitation method and the like, and the spray drying method is preferred. When preparing arbidol particles by a spray drying method, a solution for spray drying is firstly prepared, namely, an active ingredient, a dispersing aid and a stability enhancer are respectively dissolved and then combined or uniformly dissolved into a solution state, and then the solution is used for subsequent spray drying. The solvent is selected from ethanol, methanol, propylene glycol or aqueous solutions thereof, preferably aqueous methanol, more preferably 50% methanol, in terms of arbidol solubility characteristics.

The solids content of the solution for spray drying affects the efficiency of spray drying and the particle size and properties of the spray-dried particles and should generally be between 0.5 and 10% (w/v), preferably between 1 and 5% (w/v), more preferably between 1 and 3% (w/v).

In spray drying, the main process parameters that affect the performance of the produced particles include the spray drying gas inlet temperature, the spray gas flow rate, the spray liquid flow rate, and the like. The higher the inlet temperature of the spray drying gas is, the faster the drying speed is, the higher the material processing capacity is, but the more easily the main drug and the pharmaceutical excipients are chemically degraded/reacted, so the suitable inlet temperature is 80-140 ℃, preferably 90-130 ℃, and more preferably 100-120 ℃.

The higher the spray gas flow is, the faster the drying speed is, the higher the material processing capacity is, but the higher the power consumption is, the more easily the main medicine and the pharmaceutic adjuvant are subjected to chemical degradation/reaction, so that the suitable gas flow is 0.2-1.0 m³Min, preferably 0.3-0.8 m³Min, and more preferably 0.5 to 0.7 m³/min。

The lower the liquid spraying flow is, the higher the gas-liquid flow ratio is, the faster the drying speed is, the smaller the particle size of the obtained particles is, but the treatment amount can be obviously reduced, the treatment time can be obviously prolonged, and the longer the treatment time is, the more easily the main drug and the pharmaceutic adjuvant are caused to be chemically degraded/reacted, so the suitable liquid spraying flow is 1-10ml/min, preferably 2-8ml/min, and more preferably 5-7 ml/min.

In other spray drying conditions, the type of spray drying gas is not particularly limited, and air may be used, but nitrogen or an inert gas may be selected as the spray drying gas in order to further reduce the chemical reaction.

Because the fluidity of the prepared particles is reduced due to too high moisture content, the stability is poor or/and the particle size of the particles is increased in the storage process, the particles are controlled by the operating parameters in the spray drying process, and it is noted that once the solution is sprayed, the inlet temperature is adjusted to keep the outlet temperature at 70-80 ℃ for about 10-15 min, so that the residual moisture of the obtained particles is further reduced by secondary drying. The water content in the granules is controlled to be 5% or less, preferably 3% or less, more preferably 2% or less.

The shearing mixing of the invention refers to that the particles in the material group are subjected to the external force from a cutter, a stirring paddle or a screen mesh, and the particles mutually form the sliding and collision action of a shearing surface, so that the local mixing is caused. The shear mixing means a device generally used for material dispersion and pulverization, and includes a disk mill, a knife mill, a ball mill, a high-speed mixer, a high-speed pulverizer, etc., preferably a high-speed mixer. The aggregate can be broken up by adopting high-speed shearing and mixing, so that the acting force between the main drug particles and the carrier is greater than that between the main drug particles, and a highly uniform drug composition is obtained, but the particle size distribution and stability of the mixed powder can be influenced by a high-energy shearing and mixing mode, poor sequence, overlong time and the like, so that all influencing factors are comprehensively considered, and a proper and time-saving shearing and mixing process is selected.

The dry powder formulations obtained by the process of the present invention, which are uniformly dispersed, can be administered by dosing in single-dose or multi-dose containers, which can be capsules or blisters, preferably capsules, more preferably HPMC capsules, by appropriate packaging to provide chemical and physical protection, by active or passive inhalation devices. The capsule can be used for inhalation preparation, and also can be used for oral administration.

The invention amorphizes the active ingredient by a spray drying technology, improves the dissolubility and bioavailability and reduces the administration dosage, in order to improve the inhalation characteristic of the particles obtained by spray drying, a dispersing auxiliary agent is added to ensure that the particles with proper particle size distribution have good dispersity and low hygroscopicity, and finally, the particles and a carrier with large particle size are sheared and mixed, thereby providing a preparation method of the dry powder pharmaceutical composition for inhalation. The composition can be administered to lung by dry powder inhalation device, has high aerodynamic Fine Particle Fraction (FPF), and has the advantages of good inhalation property, good stability and high safety.

The invention also provides application of the pharmaceutical composition in preparing medicaments for treating viral diseases, wherein the viral diseases comprise viral pneumonia, hepatitis B and AIDS, and the viral pneumonia is pneumonia caused by viruses such as influenza virus, SARS virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, 2019 novel coronavirus, coxsackie, echovirus, herpes simplex, varicella-zoster, rubella, measles and the like.

Detailed Description

Example 1: preparation of amorphous arbidol

Dissolving arbidol in 50% methanol solution with solid content of 3% (w/v), spray drying according to the following process parameters, collecting the obtained particles, calculating the yield,

inlet temperature: 120 ℃;

liquid spraying flow rate: 6 ml/min;

atomization pressure: 180 KPa;

flow rate of spray gas: 0.6 m³/min。

Example 2: preparation of amorphous arbidol particles

Weighing arbidol according to the ratio of 6:2:1:1 (w/w): mannitol: leucine: malic acid was dissolved in 50% methanol solution at a solids content of 3% (w/v), spray dried according to the process parameters in example 1 and the resulting granules were collected.

Example 3: preparation of amorphous arbidol particles

Weighing arbidol according to the ratio of 6:2:1:1 (w/w): mannitol: leucine: fumaric acid was dissolved in 50% methanol solution with a solid content of 3% (w/v), spray-dried according to the process parameters in example 1, and the resulting particles were collected.

Example 4: preparation of amorphous arbidol particles

Weighing arbidol according to the ratio of 5:2:1:2 (w/w/w): mannitol: leucine: malic acid was dissolved in 50% methanol solution at a solids content of 3% (w/v), spray dried according to the process parameters in example 1 and the resulting granules were collected.

Example 5: arbidol composition preparation for dry powder inhalation by using lactose monohydrate as large-particle-size carrier

Lactose monohydrate was weighed according to the following table and mixed with the granulate of example 4 in a high speed mixer with shear for 10 min.

Drug particle saturation solubility determination

Adding excessive particles in the embodiments 1-4 into purified water, oscillating for 24 hours at the rotating speed of 200 rpm, centrifuging, taking supernate and determining the saturated solubility, wherein the results are as follows:

	raw material for non-treatment	Example 1
			Saturated solubility (mg/ml)	0.024	1.02

The saturation solubility of arbidol alone in example 1 was greatly increased after spray drying compared to the untreated base.

Yield, angle of repose, particle size D₉₀And evaluation of moisture absorption

"particle size (D90)" according to the invention: the laser particle size tester measures the percentage of particles with different particle sizes in the powder sample to the total amount of the particles, and D90 indicates the corresponding particle size when the cumulative particle size distribution percentage of one sample reaches 90%.

The angle of repose of the powder is measured by a fixed funnel method, also known as a residual cone method. Injecting sample powder into the center of a disc with a certain limited diameter through a funnel until the material on the inclined edge of the powder accumulation layer automatically flows out along the edge of the disc, stopping injecting, measuring the height of a cone formed on the disc, and comparing the height with the radius of the disc to obtain the tangent value of the repose angle, thereby obtaining the repose angle. It is considered that the smaller the angle of repose, the smaller the friction force, the better the fluidity, and the easier the filling.

The "hygroscopicity" of the present invention: the method is carried out according to the guideline of the drug hygroscopicity test in the appendix of the second part of Chinese pharmacopoeia 2015 edition.

	Yield (%)	Angle of repose: (^。）	D₉₀（μm）	Moisture absorption (%)
					Example 1	56	62	6.78	38.5
Example 2	66	41	4.78	28.2
					Example 3	62	45	4.47	30.1
Example 4	63	40	4.02	27.5

From the above results, it can be seen that the addition of the dispersibility aid increases the yield of the drug particles, and the particles attain smaller angles of repose and particle size, indicating better flowability, more uniform particle size distribution, and less hygroscopicity. Comparative examples 2 to 4, the kind and amount of the stability enhancer had no influence on the yield, angle of repose, particle size distribution and hygroscopicity

Stability study of the composition

The purpose of this study was to investigate the effect of examples 2-4 on stability.

The drug particles of the examples 2-4 are placed under the conditions of long-term conditions (25 ℃/RH 60%) and accelerated conditions (40 ℃/75% RH) for 1 month, then samples are taken and tested, the content of impurities is counted, and the change trend of the impurities is judged.

	At 0 time	Accelerated condition of 1 month	Long term conditions of 1 month
				Example 2	0.11	0.27	0.19
Example 3	0.20	0.39	0.26
				Example 4	0.10	0.22	0.15

In comparative examples 2 to 4, the stability enhancing effect of malic acid was stronger than that of fumaric acid, and the larger the amount thereof, the better the stability.

The "fog particle distribution", namely the fine particle dose (FPF), is an important parameter for evaluating the quality of an inhaled preparation, and refers to the percentage of the fine drug particle dose of the inhaled powder aerosol in a labeled amount, which can be measured by an in vitro device (refer to "0951 inhalation preparation fine particle aerodynamic property measurement method" in the fourth part of the chinese pharmacopoeia 2015), and the numerical value of the "fog particle distribution", which can reflect the deposition rate of an active ingredient in the lung, for example, when the gas flow reaches 60L/min, the ratio of the fog particle distribution in 2-7 grades is equivalent to the deposition rate of the active ingredient in the lung.

The test instrument: the New Generation of Impactors (NGI) are equipment available from COPLEY, united kingdom.

The dry powder mixture of example 5 was loaded in an aliquot of 25mg into HPMC capsule No. 3, the fogging distribution and the emitted dose of the dry powder in each capsule were measured using a New Generation Impactor (NGI) at a flow rate of 60L/min for 4s per inhalation time, and the amount of the 2 nd to 7 th (aerodynamic particle size range: 0.34 to 4.46 μm) collecting pan was counted as the total amount of fogging distribution.

	At 0 time	Accelerated condition of 1 month	Long term conditions of 1 month
				FPF value (%)	40.3	46.5	42.8

Claims

1. An arbidol inhalation dry powder pharmaceutical composition comprises arbidol and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise:

(1) large particle size carrier selected from sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, trehalose, sucrose, sorbitol, glucose, β -cyclodextrin and dimethyl β -cyclodextrin, erythritol and one or more of them, preferably lactose monohydrate or anhydrous lactose;

(2) the dispersing auxiliary agent can be selected from sugar and sugar alcohol compounds, including but not limited to lactose, mannitol, sorbitol and the like, and also can be selected from one or more of micromolecular amino acids, alanine, valine, leucine, isoleucine, phenylalanine and the like, and mannitol and leucine are preferred;

(3) the stability enhancer can be selected from acid regulators, including but not limited to one or more of fumaric acid, malic acid, citric acid, tartaric acid, etc., preferably malic acid.

2. Composition according to claim 1, characterized in that the active ingredient arbidol is in an amorphous state, representing between 5% and 50% of the total weight of the composition, preferably between 10% and 30%.

3. The pharmaceutical composition of claim 1 or 2, wherein the amorphous arbidol has a particle size of 0.1 to 10 μm for more than 50%, preferably 1 to 5 μm for more than 70%, and more preferably 2 to 4 μm for more than 90%.

4. A dry powder pharmaceutical composition for inhalation according to claim 3, wherein said large particle size carrier comprises more than 50% of the particles having a size of between 25 and 300 μm, preferably more than 70% of the particles having a size of between 50 and 200 μm, more preferably more than 90% of the particles having a size of between 50 and 100 μm.

5. A process for the preparation of a dry powder pharmaceutical composition for inhalation according to claim 1 comprising the steps of:

(a) dissolving arbidol, a dispersing auxiliary agent and a stability reinforcing agent in an organic solvent, and performing spray drying to prepare amorphous drug particles;

6. The preparation method of claim 5, wherein the amorphous arbidol is prepared by one or more of spray drying, hot-melt extrusion, grinding and coprecipitation, preferably by spray drying.

7. The process according to claim 5 or 6, characterized in that the organic solvent is selected from ethanol, methanol, propylene glycol, and the like or aqueous solutions thereof, preferably aqueous methanol solution; the solid content of the solution is 0.5-10% (w/v), preferably 1-5% (w/v), and more preferably 1-3% (w/v).

8. The method according to claim 5 or 6, wherein the step (b) is shear mixing using a disk mill, a knife mill, a ball mill, a high-speed pulverizer, and a high-speed mixer, preferably a high-speed mixer.

9. The dry powder pharmaceutical composition of claim 1, 2 or 4 for use in preparing a medicament for treating respiratory viral diseases, wherein the viral diseases comprise viral pneumonia, hepatitis b and aids, and the viral pneumonia is pneumonia caused by viruses such as influenza virus, SARS virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, 2019 novel coronavirus, coxsackie, echovirus, herpes simplex, varicella-zoster, rubella, measles and the like.

10. Use according to claim 9, characterized in that the medicament can be a dry powder inhalation formulation.