CN114652704A

CN114652704A - Tryprostinil soft mist inhalant

Info

Publication number: CN114652704A
Application number: CN202210464256.2A
Authority: CN
Inventors: 戴向荣; 李小羿; 殷雷; 陈林清
Original assignee: Zhaoke Pharmaceutical Guangzhou Co ltd
Current assignee: Zhaoke Pharmaceutical Guangzhou Co ltd
Priority date: 2022-04-29
Filing date: 2022-04-29
Publication date: 2022-06-24

Abstract

The present invention provides a liquid, propellant-free pharmaceutical formulation containing treprostinil that achieves better aerosolization in soft mist inhalers than existing treprostinil formulations, and in which the active substance is stable for 1, 2 or more years of storage.

Description

Tryprostinil soft mist inhalant

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a treprostinil inhalable preparation.

Background

Treprostinil, chemical name [ [ (1R,2R,3aS,9aS) -2,3,3a,4,9,9 a-hexahydro-2-hydroxy-1- [ (3S) -3-hydroxyoctyl ] -1H-benzo [ f ] inden-5-yl ] oxy ] acetic acid, having the following formula:

there are three formulations currently on the market that treprostinil has developed, subcutaneous or intravenous (ramodelin, 20 ml: 20mg), sustained release tablets (orenitiram, 0.125m/0.25mg) and inhalants nebulized by ultrasonic pulse (Tyvaso, 1.74mg/0.29 ml).

According to "Thevoiceofchoice", the FDA-issued patient-centric drug development initiative reports mention that patients seek a more convenient and effective treatment to ameliorate the spectrum of symptoms of pulmonary hypertension that affect daily life. In contrast to the administration of medication that requires immediate cessation of all activities being performed (including work, going to the toilet, bathing, etc.), it is desirable to have a way that is easy to operate and that can be used for any treatment at any time and any place.

Inhalation administration refers to an administration mode in which one or more drugs enter the deep lung of the respiratory tract via a special administration device to exert local or systemic effects. Inhalation formulations include mainly the category 3 aerosol inhalants, powder inhalants and liquid formulations for nebulizers.

Tyvaso is a liquid formulation for nebulizers and has developed a treprostinil inhalation system (see U.S. Pat. No. 6,057) by Unitedtepherepeutics, which converts a treprostinil liquid drug formulation into a nebulized form by a nebulizer and inhales into the human lungs for therapeutic purposes. However, the pulmonary hypertension patient is a chronic disease, the high-incidence period is generally 20-40 years old, the moderate and mild patients receiving treatment still can normally go out for activities and work, and the aerosol inhalation Tyvaso needs to use a specific atomization device which is large in volume and not convenient to carry according to the product requirements. When the atomizing device is used, the atomizing device is required to be used four times when being awake a day after liquid medicine is added, the atomizing device is used once every four hours, an external power supply is possibly required during use, and equipment cannot be flatly placed and toppled in the use or standby process of one day, so that the daily use of the aerosol inhalant Tyvaso for a patient going out is still inconvenient, and the quality of work and life is influenced.

According to US patent No. 10898494, the company liquidttechnologies has invented a dry powder inhalation of treprostinil, belonging to the inhalation powder aerosol, which is contained in a capsule in a dry granular formulation of 25 micrograms of treprostinil, to be inhaled into the patient by means of a dry powder inhaler. However, the particle size of the drug particles in dry powder inhalants and dry powder inhalation preparations is small (1-5 μm), the aggregation among the particles is enhanced due to strong interaction forces (van der Waals force, electrostatic force and capillary force) among the particles, and the particles are easy to agglomerate in the storage process, so that the particle size is changed and the drug effect is influenced, and carrier particles are usually required to prevent the agglomeration phenomenon of the drug powder. Generally adding carrier particles with the particle size of 70-100 mu m, mixing with the drug micro powder with the particle size of 0.5-7 mu m, so that the drug micro powder is adsorbed on the surface of the carrier particles, when in use, the drug micro powder is separated from the carrier particles in the inhalation process of a patient and enters the lung of a human body to be deposited, as described in patent US patent10076505, the prescription is 1.06% treprostinil sodium, 92.44% trehalose dihydrate, 2% polysorbate 80, 4% L leucine, 0.27% sodium citrate dihydrate and 0.23% sodium chloride, trehalose which is a macromolecular polysaccharide compound with large particle size is used as a carrier to be mixed with treprostinil sodium micropowder to prepare treprostinil inhalant, however, during inhalation, only about 20% to 30% of the drug is delivered to the lungs, and a large amount of the drug and the auxiliary materials are deposited in the mouth and throat and finally enter the stomach, possibly causing adverse side effects by the digestive system. And the patient with sensitive pharynx is easy to cause stress cough and influence inhalation feeling.

US20190030268 details a soft mist inhalation device, a propellant-free liquid drug inhalable device for metered administration. The medicinal solution in the atomizer is converted into aerosol acting on lung, and the medicinal solution is sprayed by the atomizer in a high-pressure mode in various countries. Such inhalers are particularly suitable for use with the liquid formulations of the present invention. The inhalation device has the advantages of small shape, convenient operation, and convenience for administration, and can be taken by patients to any place.

Figure 1 shows a section of the suction device in a pressurized state. The inhalation device comprises a nebulizer 1, a liquid 2, a container 3, a liquid compartment 4, a pressure generator 5, a holder 6, a drive spring 7, a delivery tube 9, a check valve 10, a nozzle 12, a mouthpiece 13, an aerosol 14, an air inlet 15, an upper housing 16, an inner part 17, a lower housing 18.

Administration of the inhalable solutions of the present invention using the inhalation device described above will result in atomization of a small quantity of liquid, less than about 70 μ l, for example less than about 30 μ l or less than about 15 μ l of the drug solution, in a single spray, such that the inhalable portion of the aerosol corresponds to a therapeutically effective amount. The mean particle size of the emitted aerosol is less than 10 μm or 15 μm. A detailed description of such a soft mist inhalation device can be seen in US 20190030268.

The soft mist inhaler disclosed in US20190030268 has a length of less than about 8cm to about 18cm and a width of about 2.5cm to about 5cm, is compact in form, easy to operate, can be carried anywhere by a patient, and provides great convenience for the patient to administer the medicament.

However, there is no soft mist inhalation available on the market for treprostinil administration. Compared with Tyvaso aerosol inhalation devices on the market, the soft aerosol inhalation device is smaller, more convenient, low in requirement on the inspiratory flow rate of a patient, prolonged in administration time and long in spraying duration, and the patient can fully deposit the medicine in the lung only through natural breathing, so that the utilization degree is improved; compared with dry powder inhalant or dry powder inhalation, the throat foreign body sensation is improved, and the administration dosage is reduced.

Disclosure of Invention

The present invention provides a liquid, propellant-free pharmaceutical formulation and a method of administering a pharmaceutical formulation by aerosolizing the pharmaceutical formulation in a soft mist inhaler. And meets the required criteria to enable optimal nebulisation of the solution in the above described inhaler. And to ensure that the active substance in the pharmaceutical preparation is stable over several years (in particular possibly 1 or 2 years) of storage.

In a first aspect of the invention, there is provided a pharmaceutical formulation comprising: (a) treprostinil and/or a pharmaceutically acceptable salt of treprostinil; (b) a solvent; (c) a pharmaceutically acceptable solubilizer; and (d) a pharmaceutically acceptable preservative.

Further, the pharmaceutical formulation is liquid.

Further, the pharmaceutical formulation is propellant free.

Further, the treprostinil or the pharmaceutically acceptable salt of treprostinil is one or more of its respective stereoisomers.

Further, the treprostinil is a mixture of one or more of the various forms of treprostinil, such as the form exemplified in US9822057B2, the form exemplified in EP2970091a1, or the various forms of treprostinil disclosed under the following U.S. patents: U.S. Pat. nos. 5153222, 5234953, 6521212, 6756033, 6803386, 7199157, 6054486, 7417070, 7384978, 7879909, 8563614, 8252839, 8536363, 8410169, 8232316, 8609728, 8350079, 8349892, 7999007, 8658694, 8653137, 9029607, 8765813, 9050311, 9,199,908, 9,278,901, 8,747,897, 9,358,240, 9,339,507, 9,255,064, 9,278, 902, 9,278,903, 9,758,465; 9,422,223, respectively; 9,878,972, respectively; 9,624,156; US published patent application Nos. 2009-0036465, 2008-0200449, 2008-0280986, 2008-024697, 2010-0275616, 2011-0184262, 2011-0184295, 2011-0323567, 2010323567, 20103-0323567, 2016-0030356, 2016-0051505, 2016-0355, 2016-3868, 2010-0328232, 2015-0148414, 2016-0045470, 201600129087, 2010-009087, 2010-0095432, 2016-0153847 and PCT publication Nos. WO00/57701, WO-2016010538, WO 38532, 201603835 058124, WO-028 358-0153847.

In some embodiments, the pharmaceutically acceptable salt of treprostinil is one or more than two of the salts of treprostinil referred to in patent US9988334B 2.

In some embodiments, the pharmaceutically acceptable salt of treprostinil is selected from one of treprostinil sodium salt, calcium salt, diethanolamine salt, triethanolamine salt, L-arginine salt, lysine salt, meglumine salt, ammonium salt, choline salt.

Further, the pharmaceutical formulation has treprostinil or a pharmaceutically acceptable salt thereof present in an amount ranging from about 0.086mg/ml to about 0.6 mg/ml; in some embodiments, the amount is in the range of 0.080 to 0.12mg/ml, in some embodiments, in the range of 0.13 to 0.18mg/ml, in some embodiments, in the range of 0.19 to 0.3mg/ml, and in some embodiments, in the range of 0.4 to 0.6 mg/ml.

Further, the solvent is selected from an organic solvent or a mixed solvent consisting of water and the organic solvent; preferably, the organic solvent is selected from one or more of alcohols, N-methyl pyrrolidone, benzyl benzoate and dimethyl sulfoxide; more preferably, the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenethyl alcohol, polyethylene glycol; particularly preferably, the solvent is selected from the group consisting of ethanol, benzyl alcohol, or a combination of ethanol, benzyl alcohol, water, or a combination of ethanol, benzyl alcohol and N-methylpyrrolidone, or a combination of ethanol, benzyl alcohol and dimethyl sulfoxide.

In some embodiments, the solvent is a mixture of water and ethanol, with ethanol having some penetration enhancing effect. In one embodiment, the amount of ethanol is from about 100mg/ml to about 300 mg/ml. In some embodiments, the amount of ethanol is from 100mg/ml to 150mg/ml, in some embodiments from 200mg/ml to 300mg/ml, in some embodiments from 160mg/ml to 200mg/ml, in some embodiments from 210mg/ml to 250mg/ml, and in some embodiments, from 250mg/ml to 300 mg/ml.

Further, in some embodiments, the pharmaceutical formulation comprises a stabilizer tromethamine, together with tromethamine as an alkaline modifier or buffer, preferably, tromethamine in an amount of about 0.05mg/ml to about 0.2 mg/ml; in other embodiments, the stabilizing agent is sodium hydroxide, sodium citrate, or tween-80.

In some embodiments, the pharmaceutical formulation may further comprise one or more osmolytes selected from one or more of sodium chloride, magnesium chloride, glucose, sodium chloride, phosphate, citrate, in some embodiments sodium chloride as an osmolyte that may be optimally osmolyte the bulk solution to 300 + -30 mOsm/kg, in one embodiment the amount of bulk sodium chloride is from about 0.1mg/ml to about 9mg/ml, such as from 0.1mg/ml, 0.5mg/ml, 2.0mg/ml, 2.5mg/ml, 3.0mg/ml, 3.5mg/ml, 4.0mg/ml, 4.5mg/ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0 mg/ml.

Further, the pharmaceutical formulation may also include one or more preservatives, which provide antimicrobial properties and may further provide stability benefits. Preferably, the preservative is an aromatic acid and a phenolic compound, or a mixture of these compounds. In some embodiments, the preservative is selected from, but not limited to, tween 80, sodium citrate, m-cresol, sodium benzoate, chlorhexidine acetate, chlorhexidine gluconate, 50% benzalkonium chloride in combination with one or more of; in some embodiments, the preservative is 50% benzalkonium chloride, which may act as both a surfactant and a solubilizer, preferably, 50% benzalkonium chloride is present in an amount of about 0.1mg/ml to about 9mg/ml, such as 0.1mg/ml, 0.5mg/ml, 2.0mg/ml, 2.5mg/ml, 3.0mg/ml, 3.5mg/ml, 4.0mg/ml, 4.5mg/ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0 mg/ml.

In some embodiments, the pharmaceutical formulation further comprises an acidity regulator, in one embodiment, the acidity regulator is hydrochloric acid, and in other embodiments, the acidity regulator may be selected from, but not limited to, citric acid, benzoic acid, acetic acid, and other pharmaceutically acceptable acidity regulators. Preferably, the pH of the pharmaceutical preparation is 6.5-8.5.

In some embodiments, the pharmaceutical formulation is an inhalable formulation.

In other embodiments, the pharmaceutical formulation is an inhalable formulation which can be administered by soft mist inhalation device nebulization or air compression nebulizer nebulization, preferably the pharmaceutical formulation is administered in combination with a soft mist inhalation device, further preferably the pharmaceutical formulation is used with a soft mist inhalation device as disclosed in US 20190030268.

Further, the present pharmaceutical formulation has low inspiratory flow requirements for the patient, and the patient need only breathe naturally to deposit the drug adequately in the lungs. And improved delivery of inhaled drugs by increasing pulmonary deposition.

The present invention provides a liquid, propellant-free pharmaceutical formulation containing treprostinil or a pharmaceutically acceptable salt thereof, to enable optimal nebulization of solutions in soft mist inhalers. And to ensure that the active substance in the pharmaceutical preparation is stable over a storage period of several years, in particular possibly 1 or 2 years.

Drawings

FIG. 1 is a sectional view of a soft mist suction device in a pressurized state;

figure 2 chemical stability of the main ingredient for 24 months.

Detailed Description

The present invention is intended to provide a liquid, propellant-free pharmaceutical formulation containing treprostinil and meeting the required criteria to enable optimal atomisation of the solution in a soft mist inhaler.

By "soft mist inhaler" is meant a propellant-free liquid drug inhalable device for metered administration as disclosed in the previously US patent US 20190030268. It is particularly suitable for use in the inhalable formulations of the invention. The aerosol particle size formed by a spray should be less than 10 microns, more preferably less than 5 microns.

The source of treprostinil used below is preferably from Guizhou scientific Co., Ltd, with the product batch number L-200-.

Tyvaso uses an inhaler device of Nebu-tec Optineb-irModel ON-100/7, an ultrasonic mesh vibratory atomizer, and used models TD-100 and TD-300.

According to the available Tyvaso inhalation preparation, the solvent content of the treprostinil inhalable preparation is set according to effective clinical data, wherein the Tyvaso inhalation preparation is required to be used for four times a day, 3 breaths are carried out, and the dosage of about 6 micrograms is breathed.

The inhalable device mentioned in US20190030268 may be used to atomize a small volume of liquid in one spray, about less than 70 μ l, e.g. less than about 30 μ l or less than about 15 μ l of drug solution, so that the product should contain about 0.086mg/ml to about 0.4mg/ml treprostinil.

Example 1 preparation of sample 1 and sample 2 inhalable solutions

The ingredients are listed in Table 1, and treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric vials according to Table 1. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 3 compositional content of 100ml inhalable solutions of sample 1 and sample 2

Components	Sample 1	Sample 2
			Treprostinil	8.6mg	60mg
Tromethamine	10mg	10mg
			Sodium chloride	500mg	500mg
50% benzalkonium chloride	20mg	20mg
			95% ethanol	20g	20g
Water for injection	Adding to 100ml	Adding to 100ml
			Adjusting the pH to	6.8	6.8

Table 2 determination of the content of inhalable solutions of sample 1 and sample 2

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample 1	Treprostinil	0.0879	98.81
Sample 2	Treprostinil	0.5972	100.20

Example 2 preparation of inhalable solutions for sample 3, sample 4 and sample 5

The ingredients are listed in Table 3, and treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric vials according to Table 3. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 3 compositional content of 100ml inhalable solutions for sample 3, sample 4 and sample 5

Table 4 determination of content of inhalable solutions for sample 3, sample 4 and sample 5

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample 3	Treprostinil	0.2977	98.02
Sample No. 4	Treprostinil	0.3062	97.47
				Sample No. 5	Treprostinil	0.2908	99.69

Example 3 preparation of inhalable solutions for sample 6 and sample 7

The ingredients are listed in Table 5, and Treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric flasks as per Table 5. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 5 compositional content of 100ml inhalable solutions of sample 6 and sample 7

Components	Sample No. 6	Sample 7
			Treprostinil	30mg	30mg
Sodium chloride	500mg	500mg
			Tromethamine	5mg	20mg
50% benzalkonium chloride	20mg	20mg
			95% ethanol	20g	20g
Water for injection	Adding to 100ml	Adding to 100ml
			Adjusting the pH with HCl to	6.8	6.8

TABLE 6 determination of the content of inhalable solutions of sample 6 and sample 7

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample No. 6	Treprostinil	0.3029	99.56
Sample 7	Treprostinil	0.3081	99.70

Example 4 preparation of inhalable solutions for sample 8 and sample 9

The ingredients are listed in Table 7, and treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric vials according to Table 7. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 7 compositional content of 100ml inhalable solutions of sample 8 and sample 9

Components	Sample	8	Sample 9
				Treprostinil	30mg	30mg
Sodium chloride	10mg	900mg
			Tromethamine	10mg	10mg
50% benzalkonium chloride	20mg	20mg
			95% ethanol	20g	20g
Water for injection	Adding to 100ml	Adding to 100ml
			Adjusting the pH to	6.8	6.8

TABLE 8 determination of the content of inhalable solutions of sample 8 and sample 9

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample 8	Treprostinil	0.2977	98.24
Sample 9	Treprostinil	0.3102	97.35

Example 5 preparation of inhalable solutions for sample 10 and sample 11

The ingredients are listed in Table 9, and Treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric flasks as per Table 9. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 9 compositional content of 100ml inhalable solutions for sample 10 and sample 11

Components	Sample	10	Sample 11
				Treprostinil	30mg	30mg
Sodium chloride	500mg	500mg
			Tromethamine	10mg	10mg
50% benzalkonium chloride	20mg	20mg
			95% ethanol	10g	30g
Water for injection	Adding to 100ml	Adding to 100ml
			Adjusting the pH to	6.8	6.8

TABLE 10 determination of the content of inhalable solutions of sample 10 and sample 11

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample 10	Treprostinil	0.2977	99.02
Sample 11	Treprostinil	0.3102	100.15

Example 6 preparation of inhalable solutions for sample 12 and sample 13

The ingredients are listed in Table 11, and Treprostinil and 50% benzalkonium chloride were placed in 100ml volumetric flasks as per Table 9. Dissolving with 95% ethanol. Adding tromethamine and sodium chloride, adding a proper amount of water for injection, and performing ultrasonic treatment to completely dissolve. Finally, the volume is determined by purified water and the pH is adjusted to the corresponding value.

TABLE 11 compositional content of 100ml inhalable solutions for sample 12 and sample 13

TABLE 12 determination of the content of inhalable solutions of sample 12 and sample 13

Sample numbering	Components	Concentration (mg/ml)	Content measurement (%)
				Sample 12	Treprostinil	0.3046	97.13
Sample 13	Treprostinil	0.2977	99.22

Example 7

Sample 3, sample 4 and sample 5 were nebulized using a soft mist inhaler, a compressed air nebulizer (PARI plus) and an ultrasonically vibrating mesh nebulizer (TD-7001), respectively. The particle size distribution of the sprayed droplets was then measured by Sprattec (STP5311, Malvern). The results are shown in Table 13, with D50 being less than 10 μm for sample 3, sample 4, and sample 5, but the particle size distribution of the soft mist inhaler varied less and was more uniform.

TABLE 13 determination of atomized particle size for sample 3, sample 4 and sample 5

Example 8 chemical stability testing of active ingredients in the pharmaceutical formulations of examples 1-7

The contents of sample 1, sample 2, sample 3, sample 5, sample 7, sample 9, sample 11, sample 12 and sample 13 in examples 1 to 7 were measured when they were left at 15 ℃ to 25 ℃ for 6 months, 12 months and 24 months, respectively, and the results are shown in Table 14 and the trends are shown in FIG. 2.

TABLE 14 results of stability studies of examples 1-7

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A liquid, propellant-free pharmaceutical formulation comprising: (a) treprostinil or a pharmaceutically acceptable salt of treprostinil; (b) a solvent; (c) a pharmaceutically acceptable solubilizer; and (d) a pharmaceutically acceptable preservative.

2. The pharmaceutical formulation of claim 1, wherein treprostinil or a pharmaceutically acceptable salt of treprostinil is present in an amount ranging from 0.086 to 0.6 mg/ml.

3. The pharmaceutical formulation of claim 1, wherein the solvent is a mixture of water and ethanol, and the ethanol is present in an amount of 100 to 300 mg/ml.

4. The pharmaceutical formulation of claim 1, wherein the solubilizer is tromethamine in an amount of 0.05 to 0.2 mg/ml.

5. The pharmaceutical formulation of claim 1, further comprising an osmolality adjusting agent having an osmolality of 300 ± 30 mOsm/kg.

6. The pharmaceutical formulation of claim 5, wherein the tonicity modifier is selected from one or more of glucose, sodium chloride, magnesium chloride, phosphate or citrate.

7. The pharmaceutical formulation of claim 1, wherein the preservative is a combination of one or more of tween 80, sodium citrate, m-cresol, sodium benzoate, chlorhexidine acetate, chlorhexidine gluconate, 50% benzalkonium chloride.

8. The pharmaceutical formulation of claim 1, further comprising an acidity regulator having a pH of 6.5 to 8.5.

9. The pharmaceutical formulation of claim 8, wherein the acidity regulator is selected from one or more of hydrochloric acid, citric acid, benzoic acid, and acetic acid.

10. A pharmaceutical formulation according to any one of claims 1 to 9, which is an inhalable formulation that can be administered by soft mist inhalation device nebulization or air compression nebulizer nebulization.