NZ624161B2 - An inhalable medicament comprising tiotropium - Google Patents

Abstract

Disclosed is an inhalable solution formulation comprising a tiotropium salt (Spiriva®), 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% citric acid (or other organic acid) and an hydrofluoroalkane (HFA) propellant, wherein the percentages are percentages by weight based on the total weight of the formulation. Also disclosed is a pressurised metered dose Inhaler (pMDI) comprising a canister containing the formulation, wherein the formulation is chemically stable and which does not adversely react with the internal surfaces of the inhaler. ulation. Also disclosed is a pressurised metered dose Inhaler (pMDI) comprising a canister containing the formulation, wherein the formulation is chemically stable and which does not adversely react with the internal surfaces of the inhaler.

Description

wo 2013/092237 AN INHALABLE MEDICAMENT COMPRISING TIOTROPIUM The present invention relates to an inhalable medicament and more specifically to a on formulation of tiotropium.

Tiotropium is an anticholinergic agent and is indicated as a maintenance bronchodilator treatment to relieve symptoms of patients with chronic obstructive pulmonary disease (COPD). Tiotropium is marketed as Spiriva® in the form of an inhalation powder or solution for inhalation.

The present invention is directed to a ation of tiotropium. Tiotropium contains a quaternary ammonium cation and is typically used as the bromide salt which has the following structure: \fi/ Br’ The two most common approaches for formulating inhalable medicaments for use outside of the emergency room are the dry powder inhaler (DPI) and the pressurised metered dose inhaler (pMDl). An example of the DPI is the marketed inhalation powder. The inhalation powder contains tiotropium bromide monohydrate and lactose stored in a hard capsule and is 2O administered using the HandiHaler® dry powder inhaler. However, the pMDl is an alternative approach to delivering pium e to the lungs. Typically patient compliance is greater with a pMDl as they tend to be easier to use. Moreover, the DPI suffers from the drawback that only a small n of the powdered active ingredient is actually inhaled into the lungs. pMDl formulations may be ted as suspensions or ons. WO 03/082252 provides an example of tiotropium bromide monohydrate in HFA 134a or 227 formulated as a suspension. In a solution formulation, the active ingredient is dissolved in the lant system and hence avoids problems such as ial blockage of the pMDl dispensing nozzle orifice, physical instability of the suspended particles and the requirement to use suspending agents such as tants. on formulations are also easier to cture. However, a significant m associated with formulating tiotropium salts as a solution formulation is that the active ingredient is chemically unstable in the presence of the co-solvents, such as ethanol, required to solubilise the active ingredient in the HFA propellant.

The marketed solution for inhalation circumvents this problem by avoiding the pMDl altogether. Instead, the product employs the Respimat® “soft-mist inhaler”. The formulation contains tiotropium bromide, benzalkonium chloride, disodium edentate, purified water and hydrochloric acid 3.6% (for pH adjustment). Instead of using a ied lant, the Respimat® r produces a mist by the action of a spring within the inhaler. r, the pMDI is a preferred approach and a number of attempts have been made to formulate 1O tiotropium as a pMDl formulation.

WO 94/13262 discloses the use of inorganic or organic acids to stabilise solution formulations. However, the disclosure therein is principally directed to opium bromide and it is not apparent how the ch should be modified to apply to tiotropium.

US 2005/0058606 addresses the problem of stabilising a tiotropium bromide solution formulation also using inorganic or organic acids.

However, significant concerns have arisen over the use of acids to stabilise solution formulations as the acids themselves can react with the metallic e of the canister leading to the ng of metal salts into the formulation which can lead to r instability of the active ingredient and/or contamination of the formulation. For example, EP 1 666 029 discloses pMDI solution ations in which the internal surfaces of the inhaler consist of stainless steel or ed aluminium, or in which the internal surfaces are lined with an inert organic coating, in order to minimise the effects of the canister on the chemical instability of the active ingredient. In addition, EP 2 201 934 describes a pMDI formulation containing a tiotropium salt, an HFA propellant, one or more co-solvents and a l acid. This document teaches the importance of using an aerosol can fitted with sealing rings and gaskets which are in contact with the formulation, made of a butyl or halo-butyl rubber, in order to avoid adverse interactions of the acid-containing formulation with the als of the rings and gaskets.

There remains, therefore, a need in the art for pMDl solution formulations of tiotropium salts which are chemically stable and which do not ely react with the internal surfaces of the inhaler.

Accordingly, the present invention provides a solution ation comprising a tiotropium salt, 12-20% ethanol, 01-15% of water, ODS-0.10% citric acid and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the 40 formulation.

This formulation provides a precise limitation in the absolute and relative amounts of the ethanol, water and citric acid in order to e a high degree of chemical stability to the active ingredient without ely affecting the material of the inhaler.

The formulation of the t invention is a solution formulation and hence the formulation is a single homogeneous phase. The tiotropium salt and the citric acid are thus dissolved in the propellant/ethanol/water phase. The formulation can be cooled to 490 and then re—heated to ambient temperature without precipitation of the active ingredient.

As the formulation is a solution, the formulation does not require the presence of surfactants (which are used to stabilise suspended particles of the active ingredient in a suspension formulation). Accordingly, it is not necessary to add surfactant to the formulation and hence the ation of the present invention is preferably substantially free of surfactant (e.g. the formulation contains less than 0.0001% by weight of surfactant based on the total weight of the formulation).

The formulation contains the tiotropium salt, 12-20% l, 0.1-1.5% of water, ODS-0.10% citric acid and an HFA propellant. All of the percentages are tages by weight based on the total weight of the formulation, i.e. the total weight of the active ingredient and all excipients present. Preferably, the formulation contains 0.15 to 0.75% water.

The present invention is applicable to tiotropium salts generally, but preferably the present ation contains tiotropium bromide which is the most commonly used salt and the salt presently on the market. The preferred quantities of excipients set out herein are particularly, but not exclusively, designed for use with tiotropium bromide as the tiotropium salt.

The amount of tiotropium salt present will vary depending on the dose of pium which is required for the particular product. Typically, the tiotropium salt (preferably the bromide) is present in an amount to provide 1-10 micrograms of tiotropium base, ex valve, per actuation.

Preferably, 2-6 micrograms of tiotropium base, ex valve, per actuation. That is, the amount of free base equivalent in the metered dose as measured as it leaves the valve. This corresponds to a preferred amount of tiotropium bromide of 0.00422-0.02110 wt%.

The l is preferably dehydrated ethanol according to the USP. The ethanol is principally present to lise the tiotropium salt. In a preferred embodiment, the amount of ethanol is 12-15%. The water is preferably purified water, ing to the USP. The water is preferably present at 0.30-0.60%. The citric acid is preferably anhydrous citric acid according to the USP. In another red ment, the amount of citric acid is 08%. It is 40 believed that the relatively high concentration of citric acid es the required chemical stability to the tiotropium salt. However, retaining a relatively low level of water prevents the citric acid from degrading the canister.

It is particularly preferred that the amounts are simultaneously 12-15% ethanol, 0.30—0.60% water and 0.05-0.08% citric acid. More preferably, the components are present at about 15% ethanol, about 0.5% of water and about 0.06% citric acid.

The formulation also contains a hydrofluoroalkane (HFA) propellant. Such propellants are well known in the art. The preferred HFAs of the present invention are HFA 134a and/or HFA 1O 227. Preferably HFA 134a is used.

On actuation of the inhaler, a metered dose of the formulation is released from the inhaler.

The d dose of the formulation passes through the valve stem and stem block where it is discharged via an orifice in the dispensing nozzle of the stem block into the mouthpiece and hence to the patient. On release, the propellant rapidly evaporates g the active ingredient dissolved in small droplets of ethanol and water which will in turn evaporate to some extent. The particle size of the droplets will depend on a number of factors, including the precise amounts of ethanol and water used, the size of the orifice in the dispensing nozzle, the spray force, the plume geometry, etc. Typically, however, the droplets will be less than 5 s in er. For some applications, the droplet sizes will be too small for optimal lung deposition. In such cases, ol may be added to the formulation. Glycerol is less volatile than l and hence experiences less ation on actuation, thereby providing larger droplets (by larger is meant that they have a higher mass median aerodynamic er as measured by an NGI). ingly, in a red embodiment, the formulation of the present invention further comprises glycerol. In a particularly preferred embodiment, the formulation of the present invention consists of a tiotropium salt rably the bromide), 12-20% ethanol, 01-15% of water, 0.05—0.10°/o citric acid, an HFA propellant and optionally glycerol, in a preferred amount of 0.56%. The preferred amounts of the excipients set out hereinabove apply y to this embodiment.

The solution formulation of the present ion is intended to be administered using a pressurised metered dose inhaler (pMDl). pMDls are well known in the art; see, for example, Drug Delivery to the Respiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987, pages 87—88, or Pharmaceutics — The Science of Dosage Form Design, Second Edition, Ed. M.E. Aulton, Churchill Livingstone, 2002, page 476 et seq for s). pMDls typically have a medicament-containing canister and an actuator housing having a mouthpiece. The canister is usually formed from an ium cup having a crimped lid which carries a metering valve assembly. The metering valve assembly is provided with a 40 protruding valve stem which is inserted as a push fit into a stem block in the or housing.

To actuate, the user applies a compressive force to the closed end of the canister. The internal components of the metering valve assembly are spring loaded so that, typically, a compressive force of 15 to 30 N is required to activate the device. In response to this compressive force, the er moves axially with respect to the valve stem by an amount varying between about 2 and 4 mm. This degree of axial movement is sufficient to actuate the metering valve and cause a metered quantity of the formulation to be expelled h the valve stem. This is then released into the iece via an orifice in the dispensing nozzle of the stem block. A user inhaling through the mouthpiece of the device at this point will thus receive a dose of the active ingredient.

An inhalation-actuated inhaler (also known as -actuated r) is particularly preferred in order to prevent inadvertent actuation into the eye(s) of the patient. Suitable inhalers are disclosed in WO 92/09323, GB 2 264 238 and WO 01/93933. The present invention most preferably employs the r as described with reference to Figs. 3-5 of WO 92/09323.

The present invention further provides a pressurised metered dose inhaler sing a canister, wherein the canister contains the solution formulation as described herein. The canister is located in the actuator housing as discussed hereinabove. The canister preferably contains 100 actuations or fewer, preferably about 60 actuations (Le. a one-month supply, based on two actuations per dose). This is a relatively low quantity and hence the head space in the canister tends to be r than with conventional pMDls which provides an increased tendency for the tiotropium salt to degrade chemically. However, even in this more challenging nment, the formulation of the present invention is able to provide the required level of al ity. For example, a 10 mL brim-full-capacity canister may have a fill volume of 2.5—6.3 mL and a corresponding headspace volume of 7.5-3.7 mL. The valve is ably a 25-63 microlitre valve, more preferably a 25 or 50 microlitre valve.

It has surprisingly been found that the formulation of the t invention is not only capable of reducing or ting al degradation of the active ingredient, but also does not icantly affect the material of the canister (see Examples 2 and 3 set out hereinbelow).

This provides the significant advantage that an uncoated aluminium canister may be used, thereby reducing the costs of the pMDl without adversely affecting the formulation. Thus, ing to a preferred embodiment of the present invention, the pMDl comprises a canister composed of aluminium in which the internal surfaces are uncoated. It is envisaged that similar stabilising properties may be achieved using similar ations of tiotropium bromide using other organic acids, such as ascorbic acid.

Accordingly, in a further aspect, the t invention provides a solution formulation comprising a tiotropium salt, 12—20% ethanol, 0.1—1.5% of water, 0.05-0.10°/o of an organic acid, preferably ascorbic acid, and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the formulation.

Preferably, the formulation contains 0.15 to 0.75% water. Other preferred embodiments of this aspect are identified in the dependent claims.

The present invention will now be described with reference to the following examples which are not intended to be ng.

‘IO Example 1 ence example) Tiotropium bromide on formulations were prepared using HFA 134a and ethanol only with ethanol concentrations of 8-15%. One such formulation consists of 0.08%w/w pium bromide, 12%w/w ethanol and 88%w/w HFA 134a. The solution was cooled to 4°C and then re-heated to CRT without precipitation of the drug. A rapid chemical degradation of the tiotropium bromide was observed.

Example 2 s of solution formulations were prepared by combining tiotropium bromide, ethanol, water and citric acid and mixing the components until a solution was . All ations contained 0.0071°/ow/w tiotropium bromide and HFA 134a to 100%w/w. The solution was charged into an aluminium canister which was then sealed with a 50 microlitre valve and filled with HFA 134a. All but batch H used an aluminium canister coated with FEP. The amounts of the excipients are set out in the following table.

Formulation Target (% w/w) 0.0035 0.0035 0.0035 After 3 months only s A, l, C, E and H were subjected to continued testing. The s are shown the following table (in which CRT represents controlled room temperature, i.e. 0% relative humidity and ACC represents accelerated stability testing ions, i.e. 409C, 75% relative humidity).

Composition (%) Citric acid, water, ethanol 0 06, 0 25 12 97.5% 98.0% 98.8% 92.6% 102.5% 91.7% IIIIIII0 06, 0 512 95.7% 97.2% 96.8% 91.0% 96.6% 85.1% 0.06 0.25, 15 98 0% 97 5% 97.9% 95.8% 106.1% 95.2% Coated1 IIIIIII0.06 0515 97 5% 100.1% 97.5% 92.7% 103.5% 94.0% H IIIIIII0.06, 0.515 99.3% 101.7% 101.0% 97.4% 104.6% 96.5% FEP coated can.

The results show an acceptably low level of chemical degradation after 6 . Batches E and H also show essentially the same results indicating that the formulation of the present invention can be tolerated in uncoated canisters.

Example 3 Given the significant risk that acidic formulation might corrode the aluminium canister, the uncoated canisters from batch H were igated further. Firstly, the aluminium content of the formulation after 3 months was ined. The concentration was recorded as 1.59 ppm which does not represent a toxicological hazard. Secondly, the er were subjected to surface analysis by SEM. Strips of 25mm x 15mm dimensions were cut from the canister and their surfaces were examined using JEOL 840 SEM. Images were taken at three different locations (top, middle and bottom end of strip) using two magnifications (100x and 250x) and compared to the results obtained with an unused canister. No damage to the canisters used with the tiotropium bromide formulation were observed.

Example 4 Three suitable commercial formulations are as follows: Ingredient Concentration Concentration Concentration (% w/w) (% w/w) (% w/w) Tiotropium bromide 0.01107 0.01107 0.00716% ———— —-Im-Imm They deliver 5.25 pg pium as 6.3 pg tiotropium bromide (ex-valve) per actuation from a 50 uL metering valve.

A le mixing process for the concentrate sub-batch is as follows: nse the citric acid into a mixing container Add the purified water to the mixing container and thoroughly dissolve the citric acid. Stir until ved and visually clear.

Add the ethanol to the container and continue to mix for about 5 minutes.

Add thetIotropIum bromIde to the mixing container, cap, and thoroughly mix until visibly dissolved. Then mix for additional 10 minutes.

A suitable process for filling the concentrate sub—batch into pMDI canisters is as follows: Place empty canisters into vial racks capable of holding 60 canisters each.

Dispense target ox 3.51 mL) of the drug concentrate into aluminium pMDI canisters -Place a pMDI metering valve on each filled canister p the valve to the canister using a suitable pMDI valve _5Add target amount of HFA 134a through the valve using 6 Verify that the net fill weights are achieved using a balance or check weigher.

Print product and batch information on each er. (e.g. product ID, lot number, date and serial number) Assay and related substances Assay and related substances are critical indicators of the chemical stability of the drug product and have been monitored for the first and third formulations in Example 4 under ACC and CRT storage ions.

‘IO Assay data (%w/w) at initials and on stability for the third formulation in Example 4 were determined (average of n = 3 units at each time-point). The formulations were tested in a valve upright orientation (“VU”) and a valve down ation (“VD”). The target concentration for this batch was 0.0071%. The results are set out in the following table: 0.0071 % CTR 0.0071% 0.0068% 0.0073% 0.0067% -3C 0.0068% 0.0067% 1 0.0068% Five lots of the first formulation in Example 4 were also tested. The results are set out in the following table: Lot no. I-120103 I-120201 I-120301 I-120401 I-120502 Time Point Condition VD VU VD/VU VD/VU VD/VU (months) 0.011% 0.011% 0.011% 0.011% 0.011% _————— N/A: the stability time—points had not been d when the data were compiled.

The assay data demonstrated that there was no change in the formulation concentration.

Related substances data confirmed these findings.

Example 6 Delivered dose uniformity Delivered dose uniformity was measured on the five batches of the first formulation from Example 4 at initials and on stability. The target delivered dose is 4.5 mcg/actuation 0f tiotropium, ex-actuator. Three canisters were measured for h-life DDU at each time- point for each stability condition. For each canister, ten ex—actuator doses were determined, three at the beginning (BOL), four at middle (MOL) and three at the end of canister life (EOL).

The numerical averages for each time-point are summarised in the following table (average of n = 30 at each oint): Time Point (months) —————— —————— —————— The data demonstrate that the delivered dose is consistent through tage at all e conditions and time-points tested with very little ility.

Example 7 Aerodynamic particle size distribution Aerodynamic particle size distribution (aPSD) was measured using the next generation 1O impactor (NGI — apparatus E, Ph. Eur.) on the five batches of the first ation from Example 4 at initials and on stability. These measurements were conducted at the beginning and end of canister life. The method used 20 actuations into the NGI per determination. The method used 20 actuations into the NGI per determination. The results were as follows (average of n = 6 at each time-point): WWWWW nun-mn- i—flfl-flfi- The results show a consistent aPSD profile of tiotropium HFA BAI irrespective of the batches, their storage times and conditions. This is consistent with the mance of a solution formulation.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the ce of the stated features but not to de the ce or addition of further features in various embodiments of the invention. 6659557_1 (GHMatters) P96913.NZ JOSHUAF

Claims (22)

Claims

1. A solution formulation comprising a tiotropium salt, 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% citric acid and an HFA propellant, wherein the percentages are 5 percentages by weight based on the total weight of the formulation.

2. A formulation as claimed in claim 1, wherein the tiotropium salt is tiotropium bromide.

3. A formulation as claimed in claims 1 or 2, wherein the tiotropium salt is present in an 10 amount to provide 1-10 micrograms of pium base, ex valve, per actuation.

4. A formulation as claimed in claims 1 or 2, wherein the tiotropium salt is present in an amount to provide 2-6 micrograms of tiotropium base, ex valve, per ion. 15

5. A formulation as claimed in any one of the ing claims, wherein the HFA propellant is HFA 134a and/or HFA 227.

6. A formulation as claimed in any one of the preceding claims, wherein the formulation further comprises glycerol.

7. A formulation as claimed in any one of the preceding claims, wherein the amount of ethanol is 12-15%.

8. A formulation as claimed in any one of the preceding claims, n the amount of 25 water is 0.30-0.60%.

9. A formulation as claimed in any one of the ing claims, wherein the amount of citric acid is 0.05-0.08%. 30

10. A formulation as claimed in any one of the preceding claims, sing about 15% 7_1 (GHMatters) P96913.NZ JOSHUAF l, about 0.5% of water and about 0.06% citric acid and an HFA propellant.

11. A formulation as claimed in any one of the preceding claims, consisting of a tiotropium salt, 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% citric acid, an HFA propellant 5 and optionally 0.5-5% glycerol.

12. A pressurised metered dose inhaler comprising a canister, wherein the er contains the solution formulation as claimed in any one of the preceding claims, or any one of claims 14 to 19.

13. A pressurised d dose inhaler as claimed in claim 12, wherein the canister is composed of aluminium in which the internal surfaces are uncoated.

14. A solution formulation comprising a tiotropium salt, 12-20% ethanol, 5% of 15 water, 0.05-0.10% of an organic acid and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the formulation.

15. A formulation as claimed in claim 14, wherein the acid is ascorbic acid. 20

16. A formulation as claimed in claim 14 or 15, including one or more of the features of claims 2 to 8.

17. A formulation as d in any one of claims 14 to 16, wherein the amount of organic acid is 0.05-0.08%.

18. A formulation as d in any one of claims 14 to 17 comprising about 15% ethanol, about 0.5% of water and about 0.06% organic acid and an HFA propellant.

19. A formulation as claimed in any one of claims 14 to 18 ting of a tiotropium salt, 30 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% organic acid, an HFA propellant and ally 0.5-5% glycerol. 6659557_1 (GHMatters) P96913.NZ JOSHUAF

20. A formulation as claimed in any one of the ing claims for use in the treatment of chronic obstructive pulmonary disease (COPD). 5 21. Use of a solution formulation comprising 12-20% ethanol, 0.1-1.5% of water, 0.05-

0.10% citric acid and an HFA propellant for ising a tiotropium salt, wherein the percentages are percentages by weight based on the total weight of the formulation.

22. A formulation as claimed in any one of claims 1 to 11 or 14 to 19, a rized 10 metered dose inhaler as claimed in claim 12 or 13, or the use as claimed in claim 21, substantially as herein described with reference to the Examples. 6659557_1 (GHMatters) P96913.NZ JOSHUAF