WO2013005020A1

WO2013005020A1 - Method of producing a nebuliser composition

Info

Publication number: WO2013005020A1
Application number: PCT/GB2012/051543
Authority: WO
Inventors: Abdelbary ELHISSI; Fatmohn JAMA; Waqar AHMED; Kevin Taylor
Original assignee: University Of Central Lancashire
Priority date: 2011-07-01
Filing date: 2012-07-02
Publication date: 2013-01-10
Also published as: GB201111250D0

Abstract

The present invention relates to a method of producing a nebuliser composition, particularly a nebuliser composition suitable for nebulised pulmonary delivery to a patient. The method involves a) introducing a solid dosage form of the pharmaceutically active agent into a diluent; and b) dispersing and/or dissolving the pharmaceutically active agent in the diluent to form the nebuliser composition. Solid dosage forms of pharmaceutically active agents have been found to be surprisingly effective in the nebulised pulmonary delivery of the pharmaceutically active agent, especially where the solid dosage form is dispersed and/or dissolved in situ within a nebuliser and simultaneously nebulised to deliver the pharmaceutically active agent to the patient.

Description

METHOD OF PRODUCING A NEBULISER COMPOSITION

INTRODUCTION

[0001] The present invention relates to a method of producing a nebuliser composition, in particular a nebuliser composition for the nebulised pulmonary delivery of a pharmaceutically active agent. The present invention also relates to a nebuliser composition obtained by this method, a method of nebulising a pharmaceutically active agent, a method of delivering a pharmaceutically active agent by nebulisation, a solid dosage form of a pharmaceutically active agent for use as a medicament in in situ nebulised pulmonary delivery, and a kit of parts.

BACKGROUND ART

[0002] Pharmaceutical drugs can be administered to patients via a variety of different delivery routes, including oral, parenteral, transdermal, pulmonary, intranasal, vaginal and rectal routes. Typically drugs are appropriately formulated for a pre-determined delivery route.

[0003] Under certain circumstances, pulmonary drug delivery or delivery of drugs to the lungs can offer significant therapeutic advantages over other means of drug delivery. For instance, pulmonary delivery is often preferred for drugs which act locally within the respiratory system, as faster onset of therapeutic effects can be achieved at lower doses with fewer systemic adverse effects. Moreover, pulmonary delivery can allow drugs to evade first pass hepatic effects. Such advantages are particularly marked where rapid delivery of a drug to the lungs is desirable, such as in the nebulised delivery of salbutamol to treat asthma and asthma attacks.

[0004] Nebulisers are unique in their ability to generate large volumes of aerosols from simply prepared solutions or dispersions (including suspensions) of the drug (O'Callaghan, C. and Barry, P.W., The science of nebulised drug delivery. Thorax, 52 (1997) Suppl 2, S31 -S44). A typical example of a nebuliser is the air-jet nebuliser (also known as a compressor nebuliser), which operates by passing highly compressed gas through a small "venturi" nozzle, resulting in creation of liquid filaments that are then converted into aerosol droplets. Large droplets are recycled by the nebuliser baffles whilst smaller ones are released for inhalation (O'Callaghan and Barry, 1997). [0005] The bronchodilator, salbutamol sulphate, is typically supplied as an aqueous nebuliser composition for use in nebulised pulmonary delivery. Unfortunately such nebuliser compositions degrade over time via hydrolysis (Malkki, L, Tammilehto, S., Decomposition of salbutamol in aqueous solutions. I. The effect of pH, temperature and drug concentration. International Journal of Pharmaceutics, 63 (1990) 17-22). Therefore, current nebuliser compositions suffer from storage stability problems, especially in warmer climates where storage temperatures tend to be higher. As such, drug safety problems can arise from the prolonged storage of stocks of such nebuliser compositions.

[0006] It is therefore an object of the present invention to solve the storage stability problems associated with currently available nebuliser compositions.

SUMMARY OF THE INVENTION

[0007] According to a first aspect of the present invention, there is provided a method of producing a nebuliser composition comprising a pharmaceutically active agent dispersed and/or dissolved in a pharmaceutically acceptable diluent, said method comprising:

a) introducing a solid dosage form of the pharmaceutically active agent into the diluent; and

b) dispersing and/or dissolving the pharmaceutically active agent in the diluent to form the nebuliser composition.

[0008] The inventors have found solid dosage forms of pharmaceutically active agents to be surprisingly effective for producing nebuliser compositions. In particular, the inventors found a solid dosage form to be a surprisingly useful nebulisable form of a pharmaceutically active agent. Such solid dosage forms exhibit excellent storage stability as compared to currently available nebuliser compositions which are supplied in a pre-diluted form. The solid dosage forms of the present invention are stable for prolongued periods under relatively warm storage conditions, and can be readily used to produce nebuliser compositions shortly before (or indeed simultaneously with) the nebulised pulmonary delivery thereof. In addition, solid dosage forms are more volume efficient than their currently available pre-diluted counterparts, and thus easier and cheaper to transport and store.

[0009] According to a second aspect of the present invention, there is provided a nebuliser composition obtainable by, obtained by, or directly obtained by the method of the first aspect. [0010] According to a third aspect of the present invention, there is provided a method of nebulising a pharmaceutically active agent, said method comprising nebulising the nebuliser composition obtainable by, obtained by, or directly obtained by the method of the first aspect.

[0011] According to a fourth aspect of the present invention, there is provided a method of delivering a pharmaceutically active agent by nebulisation, said method comprising nebulising the nebuliser composition obtainable by, obtained by, or directly obtained by the method of the first aspect.

[0012] According to a fifth aspect of the present invention, there is provided a use of a solid dosage form of a pharmaceutically active agent in the manufacture of a medicament for treating a medical condition via in situ nebulised pulmonary delivery.

[0013] According to a sixth aspect of the present invention, there is provided a solid dosage form of a pharmaceutically active agent for use as a medicament in in situ nebulised pulmonary delivery of the pharmaceutically active agent.

[0014] According to a seventh aspect of the present invention, there is provided a kit of parts comprising a solid dosage form of a pharmaceutically active agent, and a pharmaceutically acceptable diluent.

[0015] Features, including suitable, optional, and preferred features of one aspect are also features, including suitable, optional, and preferred features of any other aspect.

BRIEF DESCRIPTION OF THE DRA WINGS

[0016] For a better understanding of the present invention, and to show how embodiments of the same are put into effect, reference is now made, by way of example, to the following diagrammatic drawings, in which:

[0017] Figure 1 is a schematic view of a modern air-jet nebuliser showing the workings of the vent system during inhalation (left) and exhalation (right) [Source: O'Callaghan C, Barry PW, (1997). The science of nebulised drug delivery. Thorax, 52:Suppl 2, S31 -S44];

[0018] Figure 2 is a series of bar charts showing (a) Output; (b) drug delivery rate; and (c) time required to reach "dryness" of aerosols generated from salbutamol sulphate (SS) tablets dispersed within a Pari LC Sprint nebuliser as compared to salbutamol sulphate (SS) solution (n= 3±sd); and [0019] Figure 3 is a series of bar charts showing (a) Droplet size; (b) size distribution and elucidation of the fraction of aerosol droplets in various size ranges using a tablet or a conventional solution of salbutamol sulphate (SS) (n= 3±sd).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0020] Herein, a "nebuliser composition" refers to a composition that is purpose made for the nebulised delivery of a pharmaceutically active agent.

[0021] Herein, a "solid dosage form" refers to a solid form of a pharmaceutically active agent in admixture with one or more pharmaceutically acceptable excipients.

[0022] Herein, the terms "dispersed", "dispersing" or "dispersion" are, unless otherwise stated, intended to refer to a dispersion of particles in a liquid medium. This includes, by way of example, a course dispersion of particles (i.e. suspended particles), a colloidal dispersion of particles, and even a nanodispersion.

Nebuliser Composition

[0023] The present invention provides a nebuliser composition obtainable by, obtained by, or directly obtained by the methods described herein.

[0024] Suitably the nebuliser composition is a liquid composition comprising:

a) a pharmaceutically acceptable diluent; and

b) a dispersed or dissolved form of a solid dosage form of a pharmaceutically active agent.

[0025] The nebuliser composition is suitably an aqueous nebuliser composition.

[0026] In a particular embodiment, the pharmaceutically active agent is dissolved in the pharmaceutically acceptable diluent. In such cases, the nebuliser composition may comprise a solubility enhancer, for instance where the active agent is not readily soluble in the diluent. Alternatively, the nebuliser may be free of solubility enhancers, for instance, where the active agent is readily soluble in the diluent (such as where salbutamol sulphate is the active agent).

[0027] In an alternative embodiment, the pharmaceutically active agent is dispersed in the pharmaceutically acceptable diluent. In some such embodiments, the nebuliser composition is a dispersion of the pharmaceutically active agent, suitably a colloidal dispersion thereof. In an alternative embodiment, the nebuliser composition is a suspension of the pharmaceutically active agent (such as where a steroid is the active agent). In another embodiment, the nebuliser composition is a nanodispersion of the pharmaceutically active agent. Suitably such a nanodispersion comprises a nanocarrier.

[0028] In an embodiment, the nebuliser composition is an isolated composition that is ready-for-use in the nebulised pulmonary delivery thereof. In an alternative embodiment, the nebuliser composition is not isolated, but is rather generated in situ within a nebuliser.

[0029] The weight ratio of the solid dosage form to diluent is suitably between 1 :100 and 1 :10000, more suitably between 1 :1000 and 1 :5000, and most suitably between 1 :1500 and 1 :2500.

Pharmaceutically Active Agent

[0030] The active agent may be any pharmaceutically active agent suitable for pulmonary delivery via a nebuliser. Pharmaceutically active agents that are prone to degradation (especially hydrolytic degradation), such as salbutamol and salts thereof, are particularly suitable for use with the present invention. Such degradable actives benefit, in terms of storage stability, from being stored in a solid dosage form before use in the nebulised pulmonary delivery of such actives.

[0031] References herein to any particular pharmaceutically active agent are also intended to refer to the pharmaceutically acceptable salts, solvates, and/or closely- related derivatives (e.g. pro-drugs) thereof.

[0032] In a particular embodiment, the pharmaceutically active agent is an anti-asthma agent (e.g. salbutamol, beclometasone, budesonide, sodium cromoglicate, etc.). Anti- asthma agents are particularly suitable for nebulised pulmonary delivery to patients, since they typically act locally within the respiratory system. In a particular embodiment, the anti-asthma agent is for emergency relief from asthma attacks. In a particular embodiment the pharmaceutically active agent is salbutamol, or a salt thereof (e.g. salbutamol sulphate).

[0033] In a particular embodiment, the pharmaceutically active agent is an antimicrobial agent for the treatment of pulmonary bacteria (e.g. tuberculosis) or fungi (e.g. aspergillosis). [0034] In a particular embodiment, the pharmaceutically active agent is an anti-cancer agent, especially for the treatment of pulmonary cancers or breast cancers.

[0035] In a particular embodiment, the pharmaceutically active agent is a vaccine. Many liquid vaccine formulations currently require refrigeration to remain stable, and so the use of solid dosage forms, which exhibit greater storage stability, in the nebulised pulmonary delivery of vaccines is particularly advantageous.

[0036] In a particular embodiment, the pharmaceutically active agent comprises a hormone, DNA, or siRNA. In a particular embodiment, the pharmaceutically active agent is insulin (especially for the treatment of diabetes).

[0037] In a particular embodiment, the pharmaceutically active agent is a protein or a gene (e.g. DNA or siRNA). Current dosage forms of proteins and genes tend to suffer from instability problems, which creates storage issues. Solid dosage forms of proteins or genes for use in nebulised pulmonary delivery thus provide a surprising solution to these problems. In particular, solid dosage forms comprising GIT enzymes enable such macromolecules to be formulated as tablets for aerosol therapy via nebulisation in accordance with the present invention. Such treatments will considerably improve the quality of life of the relevant patients.

Pharmaceutically Acceptable Diluent

[0038] The diluent may be any diluent suitable for nebulisation.

[0039] Suitably, the diluent is an aqueous diluent, such as water or a saline solution. In a particular embodiment, the diluent is a saline solution. Suitably the saline solution comprises 0.1 to 3 wt% sodium chloride, more suitably 0.2 to 2.0 wt%, most suitably 0.5 to 1 .0 wt%. Saline solutions are particularly suitable as diluents where the pharmaceutically active agent is an anti-asthma agent such as salbutamol.

[0040] The diluent may be selected to complement the pharmaceutically active agent. For instance, in an embodiment, the diluent contains a solubility enhancer (e.g. a pH adjuster, a surfactant, a co-solvent, a co-solute, a complexing agent) to assist solubility of the pharmaceutically active agent. In another embodiment, the diluent comprises an emulsifier (e.g. a surfactant) to facilitate emulsification of the pharmaceutically active agent in the diluent.

[0041] The diluent may be selected to complement the particular solid dosage form. For instance, in an embodiment the diluent contains one or more additives to assist in the disintegration, dispersion, and/or dissolution of the solid dosage form. One suitable additive may be a solubility enhancer, such as a suitable surfactant.

Solid Dosage Form

[0042] The present invention provides a use of a solid dosage form of a pharmaceutically active agent in the manufacture of a medicament for treating a medical condition via in situ nebulised pulmonary delivery of the pharmaceutically active agent.

[0043] The present invention provides a solid dosage form of a pharmaceutically active agent for use as a medicament in in situ nebulised pulmonary delivery of the pharmaceutically active agent.

[0044] A "solid dosage form" refers to a solid form of a pharmaceutically active agent in admixture with one or more pharmaceutically acceptable excipients. Any suitable solid dosage form of the pharmaceutically active agent may be used. In particular, the solid dosage form may be a tablet, capsule, sachet, or granule formulation. In a particular embodiment, the solid dosage form is a compressed solid formulation.

[0045] In an embodiment, the solid dosage form is suitably a conventional commercially available solid dosage form of the pharmaceutically active agent, such as a tablet, capsule, sachet, or granule formulation. Such solid dosage forms comprise the pharmaceutically active agent in admixture with one or more pharmaceutically acceptable excipients. In a particular embodiment, the solid dosage form is a tablet.

[0046] The solid dosage form may be a dispersible formulation, such as a dispersible tablet, sachet or granule formulation, which is formulated to disperse and/or solubilise the drug in the diluent prior to administration. In an alternative embodiment, the solid dosage form may be a conventional formulation that is normally taken orally in solid form (i.e. without prior dispersion in a diluent), such as a tablet or capsule. In such cases, dispersion and/or dissolution of the drug can be facilitated within the nebuliser by operation of the nebuliser. In an embodiment, the solid dosage form is dispersed and dissolved in situ within the nebuliser. In an alternative embodiment, the solid dosage form may be dispersed and/or dissolved prior to being placed in the nebuliser and administered.

[0047] The person skilled in the art, which may include a pharmaceutical formulation scientist, would readily understand how to adapt the formulation of the solid dosage form to provide a solid dosage form suitable for use in the methods of the present invention. In particular, the skilled person would be able to choose appropriate pharmaceutically acceptable excipients for the solid dosage form to aid disintegration, dispersion, and/or dissolution of the solid dosage form and/or the pharmaceutically active agent comprised thereof. For instance, an anti-asthma agent such as salbutamol sulphate is a sufficiently soluble active agent to require no solubility enhancers within the solid dosage form. However, other anti-asthma agents such as beclometasone dipropionate are lipophilic and thus solid dosage forms thereof advantageously contain a solubility enhancer to improve their compatibility with the methods of the present invention. For proteins, such as insulin, excipients (e.g. lipids, surfactants) which protect their primary, secondary, and/or tertiary structure during nebulisation are particularly advantageous to mitigate against protein damage from shearing effects during nebulisation.

[0048] Solid dosage forms which lead to the formation of nanodispersions, in the methods of the present invention, advantageously comprise a nanocarrier.

[0049] Particularly suitable solid dosage forms for use with the present invention are:

• Compressed solid formulations of any of the abovementioned pharmaceutically active agents.

• Oral solid dosage forms of any of the abovementioned pharmaceutically active agents (especially compressed oral dosage forms).

• Tablets of any of the abovementioned pharmaceutically active agents.

• Tablets of an anti-asthma active agent (especially oral tablets), particularly where the anti-asthma agent is salbutamol or a pharmaceutically acceptable salt thereof.

• Tablets of salbutamol (especially oral tablets).

Method of Producing a Nebuliser Composition

[0050] The present invention provides a method of producing a nebuliser composition comprising a pharmaceutically active agent dispersed and/or dissolved in a pharmaceutically acceptable diluent, said method comprising:

b) dispersing and/or dissolving the pharmaceutically active agent in the diluent to form the nebuliser composition. [0051] Likewise, the present invention provides a method of dispersing and/or dissolving a pharmaceutically active agent in a pharmaceutically acceptable diluent, said method comprising:

[0052] In some embodiments, step b) is performed outside the nebuliser. For instance, dispersion and/or dissolution of the pharmaceutically active agent in the diluent may be effected by manual or automated agitation, ultrasonication, or other techniques known in the art.

[0053] In particular embodiments, step b) takes place within a nebuliser. In some such embodiments, step a) is performed outside the nebuliser such that an undispersed and/or undissolved mixture of the solid dosage form in the diluent (e.g. a heterogeneous slurry) is charged to a nebuliser reservoir (i.e. the reservoir arranged to receive standard pre-formed nebuliser compositions) before step b) is performed within the nebuliser. In an alternative embodiment, step a) is performed within the nebuliser before step b) is then performed within the nebuliser (e.g. the solid dosage form is charged to the nebuliser reservoir followed by the diluent, or visa versa). In a particular embodiment, step b) is facilitated by operation of the nebuliser. Suitably the nebulisation conditions within an operating nebuliser facilitates step b). Step b) may involve disintegration of the solid dosage form, for instance where the solid dosage form is a tablet.

[0054] In a particular embodiment, the nebuliser is a compressed nebuliser (e.g. an air- jet nebuliser). In such cases, dispersion and/or dissolution of the pharmaceutically active agent in the diluent is suitably aided within the nebuliser by operating the nebuliser to produce aerosols under the influence of compressed gas passed through a small nozzle (e.g. "venturi" nozzle). Step b) may also be aided by the recycling of aerosols (e.g. those which are too large for inhalation) within the nebuliser.

[0055] In another embodiment, the nebuliser is a vibrating mesh nebuliser. In such cases, step b) may be aided within the nebuliser by operating the nebuliser to produce aerosols.

[0056] In another embodiment, the nebuliser is an ultrasonic nebuliser. In such cases, step b) may be aided within the nebuliser by operating the nebuliser to expose the mixture of the solid dosage form in the diluent to ultrasonic radiation. [0057] In another embodiment, the nebuliser comprises a combination of features selected from the compressed nebuliser, the vibrating mesh nebuliser, and/or the ultrasonic nebuliser. In such cases, step b) may be aided within the nebuliser by operating some or all of this combination of features.

[0058] Suitably, step b) is performed within the nebuliser by operating the nebuliser for a period of time before the nebulised pharmaceutically active agent is released for inhalation. The period of time may suitably be at least 10 seconds, suitably at least 1 minute, suitably at least 5 minutes. The period of time may suitably be less than 30 minutes, suitably less than 20 minutes, suitably less than 10 minutes.

[0059] Solid dosage forms, especially compressed solid formulations, were found to be surprisingly effective for in situ dispersion (and/or dissolution) and simultaneous nebulisation. The nebulisation process itself was found to be a surprisingly efficient means of dispersing and/or dissolving such solid dosage forms, thereby allowing a nebuliser to serve a dual function of dispersing the solid dosage forms (which are much more stable on storage than standard nebuliser compositions) and nebulising the resulting dispersions to provide a nebulised form of the pharmaceutically active agent for pulmonary delivery to a patient.

Method of Nebulising a Pharmaceutically Active Agent

[0060] The present invention provides a method of nebulising a pharmaceutically active agent, said method comprising nebulising the nebuliser composition obtainable by, obtained by, or directly obtained by the methods described herein.

[0061] The present invention also provides a method of delivering a pharmaceutically active agent by nebulisation, said method comprising nebulising the nebuliser composition obtainable by, obtained by, or directly obtained by the methods described herein. Such a method suitably further comprises delivering the nebulised nebuliser composition to a patient via inhalation. The method suitably further comprises delivering the nebulised nebuliser composition to the lungs of a patient suffering from asthma.

[0062] In a particular embodiment, delivery of the nebuliser composition to the patient via inhalation takes place whilst the solid dosage form is still being dispersed and/or dissolved within the diluent in accordance with step b). As such, the method involves simultaneously:

• dispersing and/or dissolving the pharmaceutically active agent in the diluent to form the nebuliser composition; and • delivering the nebulised nebuliser composition to a patient via inhalation.

[0063] Suitably, the nebulised form of the nebuliser composition comprises aerosol particles having a droplet size less than 6 μηι. Suitably, the nebulised form of the nebuliser composition comprises aerosol particles having a droplet size more than 2 μηι.

Kit of Parts

[0064] The present invention provides a kit of parts comprising a solid dosage form of a pharmaceutically active agent, and a pharmaceutically acceptable diluent.

[0065] Suitably, the kit further comprises instructions on carrying out any of the methods described herein.

EXAMPLES

Materials and Methods

[0066] Salbutamol sulphate (99%), sodium chloride, glacial acetic acid and sodium 1 - hexane sulphonate were purchased from Alfa Aesar, UK. Water and methanol used in high performance liquid chromatography (HPLC) were of HPLC grade and supplied by Fisher Scientific Ltd., UK. Salbutamol sulphate tablets (2.4 mg; equivalent to 2 mg salbutamol) (Actavis, UK) were supplied by a local pharmacy via a prescription for research purposes issued by the School of Pharmacy and Biomedical Sciences, University of Central Lancashire.

[0067] The nebuliser employed in the following examples was a Pari LC Sprint nebuliser linked to a Pari TurboBoy compressor (Pari GmbH, Germany).

[0068] FIG. 1 provides a schematic view of the air-jet nebuliser showing the workings of the vent system during inhalation (left) and exhalation (right). The nebuliser 100 has:

• a compressed gas inlet 10 which is connectable to a compressor (not shown);

• a tapered nozzle 20 through which compressed gas can pass;

• two feeding tubes 30 the upper ends of which are located near the nozzle 20, whilst the bottom ends of the feeding tubes are dipped into a liquid nebuliser composition contained within a nebuliser reservoir 40; • a nebuliser reservoir 40 for initially containing the nebuliser composition (or initially an undispersed and/or undissolved mixture of a solid dosage form and a diluent);

• an aerosol outlet 50 through which the nebulised nebuliser composition is delivered to a patient;

• a first respiratory valve 60 which opens and closes respectively upon a patient's inspiration and expiration; and

• a second respiratory valve 70 which closes and opens respectively on a patient's inspiration and expiration.

[0069] Modern air-jet nebulisers convert liquids into aerosols by employing compressed gas forced at high velocity through a narrow "venturi" nozzle 20. This creates an area of negative pressure above the liquid which, by the "Bernoulli effect", draws the liquid up a feed tube 30 as fine filaments that collapse into aerosol droplets because of liquid's surface tension (McCallion ONM, Taylor KMG, Bridges PA, Thomas M, Taylor AJ, (1996a). Jet nebulisers for pulmonary drug delivery. Int. J. Pharm., 130:1 -1 1 ; O'Callaghan C, Barry PW, (1997). The science of nebulised drug delivery. Thorax, 52:Suppl 2, S31 -S44). A small proportion of the aerosol, the "secondary aerosol", is released for inhalation via the aerosol outlet 50, whilst the largest proportion, the "primary aerosol", is too large to escape the baffles of the nebuliser and hence is recycled within the device to be atomized further into smaller droplets that are suitable for inhalation (McCallion et al., 1996a; O'Callaghan and Barry, 1997). Many modern jet nebulisers are designed to be breath-actuated or breath-enhanced. Pari jet nebulisers are common examples of breath-enhanced devices which operate by employing vent systems that close during exhalation (FIG. 1 ).

Example 1 - Formulation mass output (standard nebuliser composition)

[0070] A drug solution was prepared by dissolving salbutamol sulphate (24 mg) (equivalent to 20 mg of salbutamol free-base) in NaCI (0.9%) solution (50 ml). A Pari LC Sprint nebuliser was weighed and attached to a Pari TurboBoy compressor (Pari GmbH, Germany). Salbutamol sulphate solution (5 ml) was placed in the nebuliser and the device was again weighed. Nebulisation commenced and completed to "dryness" (30 s after aerosol completely ceased) and the device weight was recorded and the aerosol output calculated.

[0071] Aerosol output (%) = (mass delivered / liquid's mass before nebulisation) X 100%. Example 2 - Formulation mass output (nebuliser compositions of the invention)

[0072] In another experiment, a salbutamol sulphate tablet (2.4 mg) was placed in the nebuliser and NaCI (0.9%) solution (5 ml) was added. The nebuliser was weighed and nebulisation was performed to "dryness" as per Example 1 . The aerosol output was calculated as per Example 1 .

Example 3 - Drug mass output

[0073] After completed nebulisation of the drug solution, the nebuliser was rinsed with deionised water and the amount of the drug in the residual volume was determined using HPLC. The drug output (i.e. percentage of the weight nebulised) was determined by subtraction from the original amount of the drug before nebulisation (i.e. 2.4 mg). For the tablet formulation the residual volume was rinsed and the rinsings passed through a 0.45 μηι GD/XP syringe filter to get rid of particulates left in the residual volume. Additional water was injected to collect the drug remaining within the filter. The collected salbutamol sulphate was analyzed using HPLC. Drug mass output was calculated by subtracting the amount in the residual volume from the original drug amount.

High performance liquid chromatography (HPLC) analysis

[0074] The mobile phase was prepared by mixing an aqueous solution of sodium 1 - hexane sulphonate hydrate (5mM) with methanol and glacial acetic acid (74:25:1 v/v/v). HPLC analysis was performed using an Agilent 1200 instrument with a UV detector (Agilent, USA), salbutamol sulphate solution (10 μΙ) was injected via the autosampler G1329A in a C-18 Phenomenex column (4.6mmx250mm, 5μηι; Waters Phenomenex, UK) after setting up the temperature of the column at 40 °C and the flow rate of the mobile phase at 1 ml /min. The amount of the drug was analyzed against a calibration curve at a UV wavelength of 276 nm.

Statistical analysis

[0075] All types of experiments were conducted three times and analysis of variance and student's Mests were performed as appropriate. P values below 0.05 indicate that difference between the groups is statistically significant. Results and Discussion - Output study and speed of nebulisation

[0076] The influence of formulation on total formulation mass output and drug output was investigated using salbutamol sulphate as a conventional solution or a tablet dispersed in NaCI (0.9%) solution (Fig.1 ). Both formulations generated high mass and drug outputs. For each formulation, there was no statistical difference (P>0.05) between formulation mass output and drug output. However, the mass output generated from the solution formulation was higher than that generated from the salbutamol sulphate tablet (P<0.05) (Fig.l a), indicating that some insoluble fragments of the tablet were left within the nebuliser reservoir after reaching the "dryness" status. Most importantly, there was no difference (P>0.05) in the drug output between the two formulations (Fig.1 ), indicating that tablet disintegration and subsequent drug release has been followed by incorporation of high drug fractions in the nebulised droplets.

[0077] When drug output rate was compared between the two formulations, no statistical significance (P>0.05) was recorded, however, the tablet formulation showed higher inconsistency between experiments (Fig.1 b). This may have been due to the erratic nebulisation at the beginning and towards the end of nebulisation, possibly due to the presence of partially dissolved particles or tablet fragments within the nebuliser reservoir and which slightly prolonged the time required to reach "dryness" (Fig.1 c).

Example 4 - Size analysis of the aerosol droplets

[0078] The nebuliser was directed towards a vacuum line and nebulisation was commenced, with the generated aerosol passing across the laser beam of the Spraytec laser diffraction size analyzer (Malvern Instruments Ltd., UK). After 5 min of commencing nebulisation, size and size distribution were analyzed and expressed as the volume median diameter (VMD, 50% undersize) and Span respectively. Span = (90% undersize - 10% undersize) / VMD. It is necessary that a particle is less than 5 or 6 μηι to be regarded as "respirable" or in "fine particle fraction (FPF)" and particles smaller than 2 μηι may deposit in the alveolar region (Stahlhofen, W., Gebhart, J. and Heyder, J., Experimental determination of the regional deposition of aerosol particles in the human respiratory tract. Am. Ind. Hyg. Assoc. J., 41 (1980) 385-398). Particles larger than 12 μηι are unsuitable for pulmonary deposition, and may rather deposit in the extrathoracic region (Heyder, J., Effect of cystic fibrosis on inhaled aerosol boluses. Am. Rev. Respir. Dis., 140 (1989) 1317-1324). Therefore, further analysis was performed by considering the size fractions of aerosol droplets smaller than 5.4 μηι, between 5.4 and 1 1 .6 μηι and those larger than 1 1 .6 μηι. These size cuts were used to represent droplets that are likely to deposit in lower respiratory airways, upper airways and extrathoracic region respectively. The drug dose in "FPF" was calculated by multiplying the drug output by the aerosol fraction below 5.4 μηι.

Statistical analysis

[0079] All types of experiments were conducted three times and analysis of variance and student's Mests were performed as appropriate. P values below 0.05 indicate that difference between the groups is statistically significant.

Results and Discussion - Droplet size analysis

[0080] The VMD of the generated droplets was below 5 μηι for both formulations with no significant difference (P>0.05) between the two formulations (Fig.2a). This suggests that both the salbutamol sulphate solution and the tablet are suitable for generating aerosols with a high "FPF" (fine particle fraction). When the 90% undersize of the aerosols was compared between the two formulations, the tablet generated droplets with more inconsistent values (Fig.2a). This was accompanied by more variable Span values for the tablet formulation, possibly indicating the occasional generation of large droplets from this formulation. The aerosol fraction larger than 1 1 .6 μηι was also more inconsistent for the tablet formulation (Fig.2c). The aerosol droplets in the other size ranges were similar between the two formulations (Fig.2c), suggesting that aerosol droplet size distribution was not dependent on formulation. It was also observed that most droplets smaller than 5.4 μηι were greater than 2.1 μηι, suggesting that droplets delivered in "FPF" would not be ideal for targeting the alveolar region in very high proportions (Fig.2c), which is appropriate for a bronchodilator drug, such as salbutamol.

[0081] The dose delivered in the "FPF" is also determined by the amount of the drug emitted from the nebuliser (i.e. drug output). When the two formulations were compared, the overall dose released from the nebuliser was similar (P>0.05). Although a trend towards a lower fine particle dose was seen using the tablet formulation, statistically there was no difference (P>0.05) between the two formulations (Table 1 ). Table 1 : Total dose and dose in "FPF" of salbutamol sulphate (SS) aerosols generated using a Pari LC Sprint air-jet nebuliser (n= 3±sd)

[0082] This study has demonstrated the principle of this method of generating nebulised aerosols, using a commercially available tablet formulation. The tablet employed had the following excipients: maize starch, lactose monohydrate, dispersed pink (erythrosine (E127), carmoisine (E122), titanium dioxide (E171 ), sodium starch glycollate, talc and magnesium stearate. It is now possible to formulate and produce our own tablets using a range of excipients and processing parameters to optimize this approach.

CONCLUSIONS

[0083] A novel and economical approach to delivering salbutamol sulphate aerosols was employed by dispersing a salbutamol sulphate tablet in an air-jet nebuliser. High drug output and "FPF" were produced and were comparable to those using a conventional salbutamol sulphate solution.

Claims

1 . A method of producing a nebuliser composition comprising a pharmaceutically active agent dispersed and/or dissolved in a pharmaceutically acceptable diluent, said method comprising:

2. The method as claimed in claim 1 , wherein step b) is performed within a nebuliser.

3. The method as claimed in claim 2, wherein step b) is facilitated by operation of the nebuliser.

4. The method as claimed in any of claims 1 to 3, wherein the solid dosage form is an oral solid dosage form.

5. The method as claimed in any of claims 1 to 4, wherein the solid dosage form is a tablet, capsule, sachet, or granule formulation.

6. The method as claimed in claim 5, wherein the solid dosage form is a tablet.

7. The method as claimed in any of claims 1 to 6, wherein the solid dosage form is a compressed solid formulation.

8. The method as claimed in any of claims 1 to 7, wherein the solid dosage form is a dispersible formulation, which is formulated to disperse and/or solubilise the pharmaceutically active agent in the diluent.

9. The method as claimed in any of claims 1 to 8, wherein the nebuliser is a compressed nebuliser (e.g. an air-jet nebuliser) or an ultrasonic nebuliser.

10. The method as claimed in any of claims 1 to 9, wherein the pharmaceutically active agent is selected from:

- an anti-asthma agent (e.g. salbutamol, beclometasone, budesonide, sodium cromoglicate, etc.);

- an antimicrobial agent for the treatment of pulmonary bacteria or fungi;

- an anti-cancer agent;

- a vaccine; - a hormone;

- a protein; or

- a gene.

1 1 . The method as claimed in any of claims 1 to 10, wherein the pharmaceutically active agent is an anti-asthma agent.

12. The method as claimed in claim 1 1 , wherein the pharmaceutically active agent is salbutamol, or a salt thereof.

13. The method as claimed in any of claims 1 to 12, wherein the pharmaceutically acceptable diluent is a saline solution.

14. A nebuliser composition obtainable by, obtained by, or directly obtained by the method as claimed in any of claims 1 to 13.

15. A method of nebulising a pharmaceutically active agent, said method comprising nebulising the nebuliser composition as claimed in claim 14.

16. A method of delivering a pharmaceutically active agent by nebulisation, said method comprising nebulising the nebuliser composition as claimed in claim 14.

17. The method as claimed in claim 16, wherein the method further comprises delivering the nebulised nebuliser composition to a patient via inhalation.

18. The method as claimed in claim 17, wherein the method involves simultaneously:

dispersing and/or dissolving the pharmaceutically active agent in the diluent to form the nebuliser composition; and

delivering the nebulised nebuliser composition to a patient via inhalation.

19. A solid dosage form of a pharmaceutically active agent for use as a medicament in in situ nebulised pulmonary delivery of the pharmaceutically active agent.

20. A kit of parts comprising a solid dosage form of a pharmaceutically active agent, and a pharmaceutically acceptable diluent.

21 . A method, a nebuliser composition, a solid dosage form, or a kit of parts, as substantially hereinbefore described with reference to the examples and figures.