WO2011023734A1

WO2011023734A1 - Process for the precipitation of inhalable pharmaceutical agents in the propellant

Info

Publication number: WO2011023734A1
Application number: PCT/EP2010/062430
Authority: WO
Inventors: John Robertson; Christopher Edmund Valder
Original assignee: Glaxo Group Limited
Priority date: 2009-08-28
Filing date: 2010-08-26
Publication date: 2011-03-03
Also published as: GB0915106D0

Abstract

A process for providing a dispersion of a pharmaceutical product in a liquefied gas propellant in a metered dose inhaler comprising preparing a supercritical solution of the pharmaceutical product dissolved in the propellant in a supercritical fluid state then reducing the temperature and pressure of the supercritical solution to respectively below T _c and below p _c to precipitate the pharmaceutical product and provide a dispersion of the pharmaceutical product in the liquefied propellant; then charging the dispersion to the canister of an MDI.

Description

PROCESS FOR THE PRECIPITATION OF INHALABLE PHARMACEUTICAL AGENTS IN THE PROPELLANT

Field of the Invention

The present invention relates to a process for the delivery of an inhaled

pharmaceutical product into a metered dose inhaler (MDI) canister.

Introduction

An MDI is a device that delivers a predetermined dose of a pharmaceutical product to the lungs. The MDI includes an aerosol canister in which the pharmaceutical product is dispersed in a liquefied gas propellant. On activation of the device, a

predetermined amount of propellant is ejected from the canister under pressure together with a dose of the pharmaceutical product, and the propellant vaporises to dispense the pharmaceutical product as an aerosol spray. Typically, the

pharmaceutical product is prepared as a finely divided powder, for example by a micronisation procedure, and then dispersed in the liquefied gas propellant in a separate procedure to provide a suspension which is then charged to an MDI canister.

In the supercritical fluid (SCF) state, a material is simultaneously above its critical temperature (7_C) and critical pressure (p_c). In the SCF state many materials have remarkable solvent, or sometimes antisolvent, properties which they lose when they revert to the normal liquid or gas states below T_c and p_c. The solubility of substances in an SCF can, in many cases, be adjusted or "tuned" by control of temperature and pressure of the SCF in which the substance is dissolved. In some cases substances are soluble in materials in their SCF state, but are much less soluble or insoluble in the same material in its liquid state.

Reversion of an SCF to the liquid state is called "expansion" as it is normally achieved by allowing the SCF to vent through a small orifice such as a nozzle into a region at a temperature and pressure simultaneously below its critical temperature (T₀) and/or critical pressure (p_c) in a technique known as the Rapid Expansion of Supercritical Solutions (RESS) technique as described, for example, in Matson, D. W. et al, Journal of Materials Science, 1987, vol. 22(2), 1919-1928. When the SCF reverts to a liquid (or vaporises) the solid dissolved in it precipitates as fine particles, typically having a narrow size distribution, because the solid is much less soluble or insoluble in the liquid (or vapour).

It has been recognised that SCF technologies may be used in particle engineering processes for manufacturing particulate products with control over specific physical characteristics such as particle size and morphology. Particle formation processes involving SCF technology have the potential to provide alternative means of preparing fine particles of active pharmaceutical ingredients to standard approaches such as micronisation.

Processes for making particles using supercritical fluids are for known, for example in the following patent publications. In EP-A-O 627 910 a solution of a pharmaceutically active substance in a supercritical fluid is allowed to expand into a sub-critical region to form particles. In US-A-6,095,134 a solution of a substance is converted into a fine spray by expansion of an immiscible second phase of a supercritical fluid, and the spray evaporates to form particles. In WO-A-01/24917 a solution of a substance in a supercritical fluid is passed into a receiving fluid to form particles. In WO-A- 02/059184 a monomer is converted into a fine spray using supercritical fluid expansion, and the monomer is polymerised to form particles. In EP-A-1 169 117 a mixture of a solution and a supercritical fluid is passed along a conduit to form particles in the conduit.

Previously the problem has been that particles are prepared in a first step using a supercritical fluid process, and then in a second step the prepared particles are transferred to an MDI. It is an object of this invention to simplify this two-step process.

Summary of Invention

The present inventors have developed a particle formation process which produces a drug substance with the desired physical properties in a material that is suitable for use as the aerosol propellant, thereby enabling a drug substance to be particulated and then delivered directed to a pressurised MDI canister in the same material. The invention provides a process for the delivery of inhaled products, in particular inhaled pharmaceutical products, into an MDI canister in which the product is particulated using SCF technique in a solvent that is also suitable for use as an MDI propellant.

In one aspect, the invention provides a process of providing a suspension of a pharmaceutical product in a liquefied gas propellant in a metered dose inhaler (MDI) comprising the steps of:

a) preparing a supercritical solution comprising the pharmaceutical product dissolved in the propellant in a supercritical fluid (SCF) state, wherein the propellant is at or above its critical temperature (7_C) and at or above its critical pressure (p_c); then

b) reducing the temperature of the supercritical solution to below T_c and the pressure of the supercritical solution to below p_c to precipitate the pharmaceutical product and provide a dispersion of the pharmaceutical product in the liquefied propellant; then

c) optionally adjusting concentration of the dispersion; and then

d) charging the suspension to the canister of an MDI. The process of the invention advantageously enables a pharmaceutical product to be particulated and charged directly to an MDI canister without the need to switch solvents. Thus, the process of the invention provides a reduction in the complexity of conventional processes by reducing the number of unit operations between particle formation and filling of the MDI device.

In one embodiment, the supercritical solution of step (a) is prepared by: firstly providing the propellant as a supercritical fluid (SCF), which is simultaneously at or above its critical temperature (7_C) and at or above its critical pressure (p_c); then secondly dissolving the pharmaceutical product in the SCF to form a supercritical solution.

Typically, the pressure of the supercritical solution is reduced to below p_c in step (b) at the same time as the temperature of the supercritical solution is reduced to below T_c. In one aspect of the invention, step (b) involves a RESS technique. In a further aspect, step (b) involves a RESS technique in which the supercritical solution is allowed to vent through into a chamber in which both the temperature and pressure are maintained below T_c and p_c for the propellant, and at which the temperature and pressure are such that the propellant is in the liquid state.

The propellant is a liquefied gas propellant suitable for use in an MDI. Examples of such propellants include a chlorofluorocarbon (CFC) propellant. A general formula for such CFC propellants is C_nH_xF_yCl_z, where each of x, y and z is 0 or an integer and x + y + z = 2n + 2, and where n = 1-3, for example, trichlorofluromethane,

dichlorodifluromethane or dichlorotetrafluoroethane. Examples of such propellants also include a hydrofluoroalkane (HFA) propellant. A general formula for such HFA propellants is C_mH_aF_b, where each of a and b is 1or an integer and a + b = 2m + 2, and where m = 1-3, for example pentafluroethane, difluoromethane,

heptafluoropropane or tetrafluoroethane. Such propellants are well known to be liquid at temperatures of ambient or up to ca. 6O⁰C, and at pressures of typically around 5 barg. Such conditions are easy to handle.

Suitable propellants must be non-toxic and otherwise safe for inhalation by humans. In one aspect the propellant is Generally Regarded As Safe (GRAS) for use as an aerosol propellant. For example, the propellant may meet the requirements of sections 201 (s) and 409 of the United States Federal Food, Drug, and Cosmetic Act. Due to the environmental impact of CFC propellants, HFA propellants are generally preferred.

In one aspect the propellant has a boiling point (bp) of below 25⁰C, for example, below 2O⁰C, such as below 15⁰C. In some embodiments the propellant may have a boiling point of below 5⁰C, for example below O⁰C, such as below -5⁰C. In one aspect the propellant has a boiling point of above -15O⁰C, for example, above -100⁰C. A boiling point of slightly below room temperature is advantageous as the propellant exists in the pressurised canister as its vapour state in equilibrium with its gaseous state. In one aspect the propellant has a vapour pressure at 25⁰C of at least 50 kPa, for example, at least 80 kPa, such as at least 200 kPa. In one aspect the propellant has a vapour pressure at 25⁰C of less than 3000 kPa, for example less than 2000 kPa, such as less than 1700 kPa. A propellant with a vapour pressure at 25⁰C of 50 kPa or higher is advantageous for use in an MDI as the propellant is sufficiently volatile to vaporise rapidly in use. However, a vapour pressure at 25⁰C of 3000 kPa or less is advantageous to enable the propellant to be held as a liquid at room temperature in a pressurised canister at a relatively low pressure.

In one aspect the propellant has a critical temperature (7_C) of below 300⁰C, for example below 28O⁰C, such as below 25O⁰C. In some embodiments the propellant may have a critical temperature of below 22O⁰C, for example below 200⁰C. In one aspect the propellant has a critical temperature (7_C) of above -15O⁰C, for example, above -100⁰C. In one aspect the propellant has a critical pressure of less than 5000 kPa, for example, less than 4600 kPa, such as less than 4500 kPa. In some embodiments the propellant may have a critical pressure of less than 4300 kPa.

Particularly suitable liquefied gas propellants include 1 ,1 ,1 ,2-tetrafluoroethane (7_C 101⁰C, P_c 4060 kPa), trichlorofluoromethane (7_C 198⁰C, p_c 4410 kPa),

dichlorodifluoromethane (7_C 112⁰C, p_c 4270 kPa), 1 ,2-dichlorotetrafluoroethane (7_C 146⁰C, Pc 3260 kPa) and 1 ,1 ,1 ,2,3,3,3- heptafluoropropane (also known as HFC-227 or HFC-227ea). In one aspect of the invention the liquefied gas propellant is 1 ,1 ,1 ,2- tetrafluoroethane (also known as 134a, R134a, P134a, HFA 134 or SUVA).

In one aspect of the invention, in step (c) the concentration of the pharmaceutical product dispersed in the liquefied gas propellant after step (b) is adjusted. For example in this aspect of the invention, the volume of the propellant may be increased or reduced thereby adjusting the concentration of the dispersion. In one embodiment, the dispersion is diluted or thinned by the addition of further propellant to the suspension. The further propellant may, for example, be provided by condensing gaseous propellant. In one embodiment, the dispersion is concentrated or thickened by removing some of the propellant from the dispersion, for example, by evaporation.

In one aspect of the invention, the dispersion is a suspension or a colloid or a mixture of colloidal particles and suspended particles dispersed in the liquid. In one aspect, the dispersion is a colloid.

If required, the dispersion of the pharmaceutical product may be subjected to a dispersion step to break up any agglomerates and disperse the discreet primary particles within the bulk liquid propellant. Suitable dispersion processes include for example sonication or homogenisation.

The dispersion is then passed to the filling device and into the canister in the correct ratio of drug substance: liquefied propellant.

The pharmaceutical product may include any active pharmaceutical ingredient that is suitable for absorption through the lungs. In one aspect of the invention, the pharmaceutical product is suitable for the treatment of a respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD). In one aspect of the invention, the pharmaceutical product includes a bronchodilator, corticosteroid or a combination thereof. In a further aspect of the invention, the pharmaceutical product includes fluticasone propionate (FP). In some embodiments, the pharmaceutical product may include a pharmaceutically acceptable excipient. In some

embodiments, the pharmaceutical product may include a combination of more than one active pharmaceutical ingredient.

Suitable apparatus to perform the process of the invention will be apparent to those skilled in the arts of SCF manipulation and MDI container filling. Such apparatus generally comprises a source of a propellant, means such as a pump and heat exchanger to provide the propellant in a supercritical state, means such as a dissolution or extraction vessel in which to prepare the supercritical solution, and a means for reducing the temperature and pressure of the supercritical solution to respectively below T_c and p_c to precipitate the pharmaceutical product and provide a dispersion of the pharmaceutical product in the liquefied propellant. Such last means, typical in the supercritical fluid field, may comprise a conduit, typically a spray nozzle, by means of which the solution may be passed into a particle collection vessel at the temperature below T_c and below p_c. The apparatus also comprises means to charge the formed dispersion of particles into an MDI, which may be conventional. The optional means to adjust concentration of the dispersion may comprise pipework etc. to add additional propellant, and or means to evaporate excess propellant. Typically the apparatus may additionally comprise a filter for the solution, a view cell so the presence of particles may be seen, and pipework, valves, meters, sampling means etc. conventional in the art.

As a further aspect, the invention provides a suspension of a pharmaceutical product in a liquefied gas propellant in a metered dose inhaler (MDI) as a product of the process herein.

As a further aspect, the invention provides a metered dose inhaler (MDI) containing a suspension of a pharmaceutical product in a liquefied gas propellant as a product of the process herein. Brief Description of the Drawings

An example of the process of the invention involving an SCF RESS technique is described below with reference to the following figures:

Figure 1 shows a schematic diagram of an SCF RESS system suitable for use in the process of the invention;

Figure 2 shows a schematic block diagram of a combined RESS and canister filling process;

Figure 3 shows size distribution overlay of Fluticasone Propionate produced by a micronisation process and produced by an RESS technique.

Detailed Description

The invention will now be illustrated by means of the following example.

With all the heaters H1 , H2 and the condenser C1 of the supercritical fluid rapid expansion of supercritical solutions (SCF RESS) system of Figure 1 at the desired temperature, the drug substance, for example Fluticasone Propionate (FP), is charged to the extraction vessel V1 and the system filled with propellant, for example R-134a, from the supply cylinder SP and brought to cylinder pressure. Pump P1 is then started and flow through the system commences. The compressed propellant leaving P1 passes through a flow meter F1 where instantaneous and total flow can be recorded prior to being brought to the desired operating temperature in heater H1, such that the propellant is above both its critical temperature and pressure, and consequently in its supercritical fluid (SCF) state.

The propellant can now either be passed through the extraction vessel V1 (to form a solution of FP in the SCF R134a) or diverted through a by-pass via valve V4. The propellant is then passed through filter F1 , brought to the desired pre-expansion temperature H2 prior to undergoing the RESS process in expansion device N1. As the expansion device/nozzle N1 is generally of fixed geometry, any fluctuations in solute concentration, pre-expansion temperature etc. result in simultaneous fluctuations in flow rate through the expansion device/nozzle N1. This in turn can result in pressure fluctuations in the system which eventually leads to the whole process becoming unstable. To prevent this from occurring and to keep the process operating smoothly throughout start-up, extraction and shutdown, a pressure limiter PL1 is used. This effectively vents back any excess fluid delivered by the pump to the pump inlet. The physical characteristics of the drug can be manipulated and controlled by adjusting the process parameters such as temperature, pressure, nozzle geometry etc. when using the SCF RESS system equipment in the manner described above. When operating the system illustrated in Figure 1 in a conventional manner, the particles formed during the RESS process would be retained in a filter basket (not shown) inside the particle collection vessel PCV1. The expanded propellant in its liquid state is then passed through a view cell VC1 where a visual check of the fluid phase(s) present is made. Following filtration of the expanded propellant in filter F2 the fluid is either vented via valve V6 or recycled back through the system via valve V7. Thus, the drug substance is precipitated via the RESS process is separated from the propellant by filtration in the particle collection vessel PCV1.

When the system of Figure 1 is operated in accordance with the process of the present invention, some or all of the propellant is condensed to a liquid phase and this liquid phase is used to transport the drug substance in suspension, for example, as a slurry, from the expansion device N1. The suspension of the drug substance in the propellant is discharged from the RESS system and, following an optional concentration adjustment procedure, is dosed into MDI canisters.

Figure 2 describes an example of a concentration adjustment procedure and canister filling process in which the propellant is 1 ,1 ,1 ,2-tetrafluoroethane (R-134a) and the drug substance is Fluticasone Propionate (FP). The propellant / drug substance mixture leaving the RESS nozzle is in the range of 0.04-0.7 g FP/kg R-134a. The required ratio of drug substance : R-134a is 0.67-3.33 g FP/kg of R-134a (depending on the dose). Therefore a thickening step is required to bring the ratio of drug : R- 134a leaving the RESS process to the desired concentration prior to filling the canister. The gaseous R-134a/FP mixture leaving the expansion device N1 is fed to a partial condenser (not shown) instead of being filtered in PCV1 , which liquefies the desired proportion of R-134a with respect to the amount of FP present. The partial condenser is a direct or indirect contact heat exchanger. This liquid phase is used to scrub out and retain the FP particles in the R-134a slurry. The excess R-134a vapour is separated and re-cycled. If required, the liquid R-134a / FP slurry then undergoes a dispersion step to break up any agglomerates and disperse the now discreet primary particles within the bulk liquid, for example, using sonication or

homogenisation. The dispersion is passed to the filling device and into the canister in the correct ratio of drug substance: liquefied propellant.

In embodiments where the ratio of drug : fluid leaving the RESS step is higher than that required for the MDI canister, then a dilution step will be required as opposed to the thickening step outlined above.

In the embodiment of the process of the invention described above with reference to Figures 1 to 3, the propellant R-134a is used as the supercritical fluid and the pharmaceutical product is Fluticasone Propionate (FP). It will be appreciated that other liquefied gas propellants could be employed as the fluid and similar operating principles applied. Similarly, other pharmaceutical product for inhalation could be particulated and charged into an MDI canister using this process.

Table 1 gives examples of the typical operating parameters used for an R-134a RESS process for FP.

Table 1 Example RESS operating parameters used to produce FP.

Particle sizes at 10%, 50% and 90% of the sample distribution and the volume- weighted mean particle size (d 4,3) are shown in Table 2.

Table 2. Example sizing data of FP produced by RESS and micronisation.

The sizing data presented in Table 2 demonstrates that when the operating prameters of the RESS process are adjusted as set out in Table 1 , the physical properties of the particulate produced are effected and, thus, RESS may be used to tune the physical properties of a product. An overlay of the size distribution overlay of FP produced by micronisation (batch 8003940) and by RESS in experiment run 10 is provided in Figure 3. This overlay demonstrates that a 134a RESS process could potentially be used to produce material with size properties which match those of the micronised drug.

Claims

Claims.

1. A process for providing a dispersion of a pharmaceutical product in a liquefied gas propellant in a metered dose inhaler (MDI) comprising the steps of:

b) reducing the temperature of the supercritical solution to below T_c and the pressure of the supercritical solution to below p_c to precipitate the

pharmaceutical product and provide a dispersion of the pharmaceutical product in the liquefied propellant; then

c) optionally adjusting concentration of the dispersion; and then

d) charging the dispersion to the canister of an MDI.

2. The process according to claim 1 , wherein step (b) involves a rapid expansion of a supercritical solution (RESS) technique in which the supercritical solution is allowed to vent through into a chamber in which both the temperature and pressure are below T_c and p_c for the propellant.

3. The process according to claim 1 or 2 wherein the propellant has a critical

temperature of less than 250 ⁰C.

4. The process according to claim 1 , 2 or 3 wherein the propellant is a

chlorofluorocarbon (CFC) propellant.

5. The process according to claim 4 wherein the propellant is selected from

trichlorofluromethane, dichlorodifluromethane and dichlorotetrafluoroethane.

6. The process according to claim 1 , 2 or 3 wherein the propellant is a

hydrofluoroalkane (HFA) propellant suitable for use in an MDI.

7. The process according to claim 6 wherein the propellant is selected from

pentafluroethane, difluoromethane, heptafluoropropane and tetrafluoroethane.

8. The process according to any one of the preceding claims wherein step (c) is used and the volume of the propellant is increased or reduced thereby adjusting the concentration of the dispersion.

9. The process according to claim 8 wherein in step (c) the dispersion is diluted or thinned by the addition of further propellant to the suspension.

10. The process of claim 9 wherein further propellant is provided by condensing

gaseous propellant into the dispersion.

11. The process of claim 8 wherein in step (c) the dispersion is concentrated or thickened by removing some of the propellant from the dispersion by evaporation.

12. The process according to any preceding claim wherein the pharmaceutical

product is for the treatment of a respiratory disease.

13. The process according to claim 12 wherein the pharmaceutical product is

Fluticasone Propionate.

14. The process according to claim 13 wherein the propellant 1 ,1 ,1 ,2- tetrafluoroethane is used as the supercritical fluid.

15. A metered dose inhaler (MDI) containing a suspension of a pharmaceutical

product in a liquefied gas propellant as a product of the process of any one of claims 1-14.