HK1022271B - Pharmaceutical aerosol composition - Google Patents

Description

Medicinal aerosol composition

The present invention relates to pharmaceutical aerosol compositions. In particular, the present invention relates to aerosol compositions for use in pressurised Metered Dose Inhalers (MDIs). The invention also relates to the use of certain components in aerosol compositions, to a process for their preparation and to their use for administering active substances by inhalation.

Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.

Active agents commonly delivered by inhalation include bronchodilators and β 2 agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergic agents and other agents that can be effectively administered by inhalation, thus increasing the therapeutic index and reducing the side effects of the active agent.

There are several types of inhalers that are currently available. One of the most widely used is the pressurized Metered Dose Inhaler (MDI), which uses a propellant to deliver droplets of a pharmaceutical-containing product as an aerosol to the respiratory tract. Formulations for MDIs (aerosol formulations) typically include an active, one or more liquefied propellants, and a surfactant or solvent.

For many years, for medicinal aerosolsPreferred propellants are a group of chlorofluorocarbons, commonly known as freons or CFCs, e.g. CCl₃F (Freon 11 or CFC-11), CCl₂F₂(Freon 12 or CFC-12), and CClF₂-CClF₂(Freon 114 or CFC-114). Chlorofluorocarbons have properties particularly suited for use in aerosols, including high vapor pressure to produce a mist of droplets of suitable particle size from the inhaler.

Recently, chlorofluorocarbon (CFC) propellants such as freon 11 and freon 12 have been implicated in the destruction of the ozone layer, and their production is gradually being stopped.

In 1987, the montreal grass treaty, which was drawn for ozone depleting substances, was initiated by the United nations environmental programming, to gradually reduce the use of CFCs until its elimination.

Aerosol pharmaceutical products for the treatment of asthma and bronchopulmonary diseases are considered indispensable and therefore are temporarily left out. It is believed that the pharmaceutical use of CFCs will be discontinued in the near future. The ozone destruction capacity of CFCs is proportional to the chlorine content.

Given that chlorine-free Hydrofluorocarbons (HFAs), also known as Hydrofluorocarbons (HFCs), are less ozone-damaging, these materials have been proposed as replacements for CFCs.

HFAs, in particular 1, 1, 1, 2-tetrafluoroethane (HFA 134a) and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA227) have been recognized as the best candidates for CFC-free propellants, and several patent applications disclose some pharmaceutical aerosol formulations employing such HFA propellant systems.

In many of these applications where HFAs are used as propellants, it has been proposed to add one or more of adjuvants (including compounds that act as co-solvents), surfactants (including fluorinated and non-fluorinated surfactants), dispersants (including alkyl polyethoxylates), and stabilizers.

Cosolvents that may be used in these formulations include alcohols (e.g., ethanol) and polyols (e.g., propylene glycol).

Pharmaceutical aerosol formulations using such propellant systems are disclosed, for example, in EP 0372777. EP0372777 requires the use of HFA134a as a propellant in combination with both a surfactant and an adjuvant which is more polar than the propellant.

For aerosol suspension compositions, surfactants are often added to improve the physical stability of the suspension. EP0372777 describes that the presence of a surfactant helps to prepare a stable, homogeneous suspension and may also help to prepare a stable solution formulation.

The surfactant also lubricates the valve assembly in the inhaler device.

Several other patent applications have mentioned the use of propylene glycol as a solvent with higher polarity than the propellant in HFA pressurized metered dose inhaler formulations, such as in the following patents:

EP504112 relates to a pharmaceutical aerosol formulation free of CFCs comprising: propellant (hydrocarbon, HFA or a mixture), one or more pharmaceutically active ingredients, non-ionic surfactant and optionally other conventional pharmaceutical adjuvants suitable for aerosol formulations, including solvents with higher polarity than the propellant, other non-ionic surfactants as valve lubricants, vegetable oils, phospholipids, taste-masking agents.

DE 4123663 describes a pharmaceutical aerosol composition comprising a dispersion or suspension of an active agent in combination with a compound having surface active or lipophilic properties, heptafluoropropane as propellant and an alcohol such as ethanol and/or propylene glycol.

U.S.5,534,242 describes an aerosol-dispensable pharmaceutical composition comprising a lidocaine base and a vasoconstrictor dissolved in an HFA propellant and optionally an organic solvent.

Other applications propose the addition of dispersants to the composition. U.S.5,502,076 relates to compositions for inhalation of aerosols comprising HFA, a leukotriene antagonist and a dispersant comprising a 3C-bonded triester, vitamin E acetate, glycerol, tert-butanol or a transesterified oil/polyethylene glycol.

EP 384371 describes a propellant for aerosols comprising pressure-liquefied HFA227 mixed with pressure-liquefied propane and/or n-butane and/or isobutane and/or dimethyl ether and/or 1, 1-difluoroethane. This document also discloses foam formulations (shave foams and shower foams) comprising glycerol as an additive.

The efficiency of aerosol devices such as MDIs is a function of the dose deposited in place in the lungs. Deposition is affected by several factors, the most important of which is aerodynamic particle size. Solid particles and/or droplets in aerosol formulations can be identified by their mass median aerodynamic diameter (MMAD, around which the mass aerodynamic diameter is equally distributed).

Particle deposition in the lung depends primarily on three physical mechanisms: (1) collision, a function of particle inertia; (2) sedimentation by gravity; and (3) diffusion resulting from brownian motion of fine submicron (< 1 μm) particles. The mass of the particles determines which of the three main mechanisms dominates.

The effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of the forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacement due to diffusion decreases. In fact, diffusion plays a minor role in the deposition of medicinal aerosols. Collision and sedimentation can be estimated from the determination of the mass median diameter (MMAD), which determines the displacement through the flow line under the influence of inertia and gravity, respectively.

Aerosol particles with an equivalent MMAD and GSD (geometric standard deviation) have a similar deposition in the lungs regardless of their composition. GSD is a measure of the variability of the diameter of the pneumatic particles.

For inhalation therapy, the preferred aerosol is inhaled with particles of about 0.8 to 5 μm in diameter. Particles with a diameter of more than 5 μm are deposited in the oropharynx mainly by inertial collision, particles with a diameter of 0.5-5 μm are mainly influenced by gravity and are ideal particles for deposition in the conducting airways, and particles with a diameter of 0.5-3 μm are ideal particles for aerosol delivery to the periphery of the lungs. Particles smaller than 0.5 μm can be exhaled.

Particles suitable for respiration are generally considered to be particles having an aerodynamic diameter of less than 5 μm. These particles, especially those of about 3 μm in diameter, are effectively deposited in the lower respiratory tract by sedimentation.

It has recently been demonstrated for beta in patients with mild and severe airflow obstruction₂The selected particle size of the stimulant or anticholinergic aerosol should be about 3 μm (Zaanen P et al, J.International Pharm 1994, 107: 211-7; J.International 1995, 114: 111-5; thoracic (Thorax)1996, 51: 977-980).

In addition to therapeutic purposes, the size of the aerosol particles is also important in terms of side effects of the drug. For example, it is well known that aerosol formulations of oropharyngeal deposition of steroids can lead to side effects such as oral and laryngeal candidiasis.

On the other hand, high systemic exposure to aerosol particles due to deep lung penetration can enhance the undesirable effects of the drug system. For example, systemic exposure to steroids can have adverse effects on bone metabolism and growth.

It has been reported that the particle size characteristics of prior art HFA aerosol formulations are often quite different from the product to be replaced.

EP 0553298 describes an aerosol formulation comprising: a therapeutically effective amount of beclomethasone 17, 21 dipropionate (BDP); a propellant comprising a hydrofluorocarbon selected from the group consisting of HFA134a, HFA227, and mixtures thereof, and ethanol in an amount effective to solubilize the 17, 21 beclomethasone dipropionate in the propellant. The formulation is further characterized in that substantially all of the beclometasone 17, 21 dipropionate is soluble in the formulation and the formulation contains no more than 0.0005 wt% of any surfactant.

These formulations of Beclomethasone Dipropionate (BDP) as a solution in HFA134a have been reported in the literature to deliver particles with a MMAD size distribution of 1.1 μm. This indicates that there is increased peripulmonary deposition of very small particles, and that submicron particles can be readily absorbed directly into the blood stream from the alveoli. The rate and extent of absorption by the system is significantly increased with consequent increase in undesirable effects such as certain side effects. The greater part of the dose is exhaled. This has great significance for clinical efficacy and toxic effects. This is because the composition of the formulations using HFAs may alter the physical form of the respiratory mist.

The present invention provides a composition for use in an aerosol inhaler, the composition comprising: an active substance, a propellant comprising a Hydrofluoroalkane (HFA), a cosolvent, and further comprising a low volatility component to increase the Mass Median Aerodynamic Diameter (MMAD) of aerosol particles upon actuation of the inhaler.

The nature and concentration of the low volatility component can be selected to affect, for example, the size and/or density of the particles, both of which affect MMAD.

It is an object of the present invention to provide aerosol formulations which avoid or mitigate the problems indicated above, and in particular to provide aerosol compositions comprising HFA as propellant which have similar dimensional characteristics to the CFC compositions they replace. That would help provide HFAs propellant-containing MDIs that are pharmaceutically and clinically equivalent to MDIs using CFCs.

Although most commonly used in formulations wherein the active agent is in solution, the ingredients can also be applied in suspension formulations and mixed formulations wherein only one component is present in solution.

The invention thus makes it possible to design formulations using HFAs having particle size characteristics similar to those of the CFC formulations they replace. This has allowed the development of products which are pharmaceutically and clinically comparable to CFC formulations.

Examples of low volatility components that can be included in aerosol formulations to increase the MMAD of the aerosol particles include: high density components such as glycerol and propylene glycol, and low density compounds such as oleic acid and certain vegetable oils.

Glycerol and propylene glycol have previously been investigated as additives in aqueous systems relating to the spraying of fluids by means of jet sprayers or ultrasonic sprayers. The content of propylene glycol or glycerol in these systems is very high (10-50% v/v). The results were ambiguous.

Davis SS examined the atomization characteristics of two common sprayers using a propylene glycol-water system in International journal of pharmacy 1(2), 71-83, 1978. An output of aerosol solution droplets through a maximum amount at 30% vol./vol. The increased output is parallel to the increased particle size.

Davis SS examined the output of aerosol droplets from a conventional nebulizer using a water-propylene glycol-ethanol system in International journal of pharmacy 1(2), 85-93, 1978.

In summary, increasing the alcohol content results in an increase in the total output of the nebulizer. However, much of this output is in the form of solvent vapor, and there is only a small increase in the output of therapeutically effective aerosol droplets.

Miller WC and Mason JW used the radiosolor technique in journal of Aerosol medicine (J Aerosol Med)4(4), 293-4, 1991 to determine whether the addition of propylene glycol would improve Aerosol delivery by a jet nebulizer in normal human subjects with spontaneous respiration. They found no significant difference in deposition or permeability between the saline control and the 20% propylene glycol solution.

McCallion et al, in pharmaceutical research (Pharm Res)12(11), 1682-7, 1995, attempted to estimate the effect of three jet nebulizers and two ultrasonic devices on aerosol size and output characteristics of a fluid system comprising: water, ethanol, 10-50% (v/v) glycerol solution, 10-50% (v/v) propylene glycol solution and 200/0.65 cs-200/100 cs siloxane fluid. The parameters considered are viscosity and surface tension.

Oleic acid has been used in aerosol formulations to improve the physical stability of drug suspensions, as a dispersant suitable for keeping suspended particles from agglomeration.

It has now been unexpectedly found that oleic acid can be used as a solubilizer and/or as a stabilizer or low volatility component of active ingredients in the solution formulations of the present application.

When used as a solubilizer/stabilizer, the amount of oleic acid may vary depending on the concentration and characteristics of the active. When used as a low volatility component, the percentage concentration of oleic acid should preferably be no less than 0.5% w/w.

In general terms, the low volatility component can be any compound that is safe, compatible with the propellant system of the present invention, and capable of affecting the size or density of the aerosol particles and thus the MMAD.

As can be seen from the results reported in the table, the effect of the low volatility component on the MMAD of the particles is related to its density. The higher the density of the low volatility component, the higher the MMAD of the aerosol particles increases upon actuation of the inhaler.

Known prior art published applications relating to aerosol formulations employing new propellant systems have attempted to overcome the stability problems of the formulations. The present application seeks to address both the stability problems of the formulation and the therapeutic problems associated with new drug aerosols, as the presence of low volatile components in the formulation affects the most important factors contributing to aerosol delivery to the lungs: the aerodynamic mass of the particles.

It has been surprisingly found that by adding a low volatility component to the composition, the MMAD of the aerosol particles on actuation of the inhaler can be increased and the composition can then be formulated such that the aerodynamic particle size characteristics are similar to those of CFC-propellant compositions.

Advantageously, the low volatility component has a vapour pressure at 25 ℃ of no more than 0.1kPa, preferably no more than 0.05 kPa. We have found that by adding components having such low vapor pressures, control of MMAD can be achieved.

It is believed that the addition of a component having a low vapor pressure inhibits the aerosolizable nature of the HFA propellant, giving larger particles upon actuation of the inhaler and after evaporation of the propellant.

The low vapor pressure of the low volatility component is in contrast to the vapor pressure of the co-solvent, which is preferably not less than 3kPa, more preferably not less than 5kPa, at 25 ℃.

The co-solvent advantageously has a higher polarity than the propellant and is used to increase the solubility of the active substance in the propellant.

The co-solvent is advantageously an alcohol. The co-solvent is preferably ethanol. The co-solvent may comprise one or more substances.

The low volatility component may be one species or a mixture of two or more species.

We have found that glycols are particularly suitable for use as low volatility components, particularly propylene glycol, polyethylene glycol and glycerol.

Other materials believed to be particularly suitable include other alcohols and glycols, for example alkanols such as decanol, sugar alcohols including sorbitol, mannitol, lactitol and maltitol, tetrahydrofurfuryl alcohol and dipropylene glycol.

It is also contemplated that a variety of other materials may be suitable for use as the low volatility component including vegetable oils, organic acids such as saturated carboxylic acids including lauric, myristic and stearic acid; unsaturated carboxylic acids, including sorbic acid, and especially oleic acid; saccharin, ascorbic acid, cyclamic acid, amino acids, or aspartame may also be used.

The low volatility component may include esters such as ascorbyl palmitate and tocopherols; alkanes such as dodecane and octadecane; terpenes, such as menthol, eucalyptol, limonene; sugars, such as lactose, glucose, sucrose; polysaccharides, such as ethyl cellulose, dextran; antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole; polymers, such as polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone; amines, such as ethanolamine, diethanolamine, triethanolamine; steroids, e.g. cholesterol, cholesterol esters.

The amount of low volatile component in the composition will depend to some extent on its density and the amount of active and co-solvent in the composition. The composition advantageously comprises no more than 20 wt% of low volatility components. Preferably, the composition comprises no more than 10 wt% of low volatility components.

Upon actuation of the inhaler, the propellant and ethanol vaporize, but the low volatility component is generally not vaporized due to its low vapor pressure.

It is believed that the composition preferably contains at least 0.2 wt%, preferably at least 1 wt% of low volatility components. The composition may comprise 1 wt% to 2 wt%.

The composition most advantageously should be such that the MMAD of the aerosol particles is not less than 2 μm when the aerosol inhaler is actuated in use. For some actives, the MMAD is preferably no less than 2.5 μm, while for some formulations the preferred MMAD should be greater than 3 μm or even greater than 4 μm. As shown in the examples below, the MMAD of the aerosol particles is about 2.8 μm for a corresponding inhaler formulation using a CFC propellant (see Table 4 below).

Preferred HFA propellants are HFA134a and HFA 227. The propellant may comprise a mixture of more than one component.

The composition may be in the form of a solution or suspension or an ultra-fine suspension or a colloidal solution. The invention relates in particular to the case where the composition is a solution, but also to suspensions, in particular those of small particle size. Preferably, the composition is a solution.

In some cases a small amount of water may be added to the composition to improve the dissolution of the active and/or low volatility components in the co-solvent.

The active substance may be any biologically active substance or substances that can be administered by inhalation. Actives commonly administered in that manner include: beta is a₂Stimulants, such as salbutamol and its salts, steroids, such as beclomethasone dipropionate, or anticholinergics (anti-choleergics), such as ipratropium bromide.

The invention further provides the use of a low volatility component in a composition for an aerosol inhaler, the composition comprising an active material, a propellant comprising a Hydrofluoroalkane (HFA) and a co-solvent, the low volatility component being used to increase the Mass Median Aerodynamic Diameter (MMAD) of aerosol particles on actuation of the inhaler.

As previously mentioned, upon actuation of the inhaler, the aerosol particles advantageously have an MMAD of not less than 2 μm, more preferably not less than 2.5 μm for many formulations.

As mentioned previously, the low volatility component advantageously has a vapor pressure at 25 ℃ of no greater than 0.1 kPa.

The invention also provides an inhaler containing the composition of the invention.

There is also provided a method of filling an aerosol inhaler with a composition, the method comprising filling the inhaler with:

(a) one or more active substances selected from the group consisting of,

(b) one or more low-volatility components, which are,

(c) one or more of a plurality of cosolvent,

followed by the addition of a propellant containing Hydrofluoroalkane (HFA).

The invention further provides aerosol particles emitted from an aerosol inhaler containing a composition comprising an active ingredient, a propellant comprising a Hydrofluoroalkane (HFA), a cosolvent and a low volatility component, wherein the Mass Median Aerodynamic Diameter (MMAD) of the aerosol particles is not less than 2 μm.

For certain compositions, as indicated previously, it is preferred that the MMAD of the particles be not less than 2.5 μm.

The particles will generally be in the form of droplets.

Embodiments of the present invention will now be described by way of example.

The aerosol compositions of the present invention described below are prepared by the following method. The desired components of the composition were added to the tank in the following order: medicine, non-volatile additive and absolute ethyl alcohol. After pressing the valve on the can, propellant is added through the valve. The weight gain of the cans was recorded after each component was added to calculate the weight percent of each component in the formulation.

The aerodynamic particle size distribution of each formulation was identified using a Multistage grid Impactor (Multistage Cascade Impactor) according to the method described in the European pharmacopoeia 2 nd edition, 1995, part V.5.9.1, pages 15-17. In this particular case, an Andersen grille Impactor (ACI) was used. Results are given from ten cumulative actuations of the formulation. Drug deposition on each ACI plate was determined by high pressure liquid chromatography. Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) were calculated from plots of cumulative percent undersize drug collected on each ACI plate (probability unit scale) versus upper cutoff diameter for each ACI plate (log10 scale). The fine particle dose of each formulation was determined from the mass of drug collected on a 2-stage filter (< 5.8 μm) divided by the number of actuations per trial.

Tables 1 and 2 show comparative examples which show the characteristics of aerosol formulations containing HFA134a, different amounts of Beclomethasone Dipropionate (BDP) (active substance) and different concentrations of ethanol. These formulations do not contain low volatility components. It can be seen that MMAD is not significantly affected by the cosolvent to propellant ratio.

An increase in the concentration of the active ingredient gives a small change in MMAD, which is now related to the BDP content.

For an equivalent concentration of BDP, the content of ethanol and addition of up to 0.5% water did not significantly affect MMAD.

Table 3 compares the properties of CFC ipratropium bromide (IPBr) standard formulations with HFA134a, ethanol, ipratropium bromide solution formulations containing 0-1% glycerol.

It can be seen that the MMAD of the HFA-based propellant formulation is significantly lower than that of the conventional CFC formulation.

The MMAD of the HFA/ethanol-IPBr formulation was 1.2. + -. 1.9 or 1.3. + -. 0.1. mu.m, depending on the ethanol content (12.9. + -. 0.1% w/w and 25% w/w, respectively), compared to the MMAD (2.8. + -. 0.1 μm) of the CFC-IPBr formulation.

The addition of low volatility additives (such as glycerin) increases the particle MMAD of HFA solution formulations; the increase is related to the glycerol concentration.

The results of tables 1 and 2 are confirmed, i.e., MMAD is not significantly affected by the cosolvent to propellant ratio.

In other studies, the effects of increasing concentrations of propylene glycol, glycerol and polyethylene glycol (PEG) in formulations of HFA134a and Beclomethasone Dipropionate (BDP) ethanolate were determined.

The "%" used for the components of the composition is "wt%", unless otherwise indicated.

The results are reported in tables 4, 5, 6, 7 and 8.

The results show a direct relationship between the percentage of low volatility component and the particulate MMAD. We can see that the actuator pores have a slight effect on MMAD, but still maintain the relationship between the concentration of the low volatile component and the particulate MMAD. These findings demonstrate that the addition of a defined amount of a low volatility additive to an HFA formulation can increase the MMAD of the particles to values comparable to previously known CFC formulations that HFA formulations are attempting to replace.

Advantageously, the addition of the low volatility component does not significantly alter the GSD. In particular, when glycerol was used as the low volatility component, tables 6 and 7 show that the addition of glycerol did not significantly alter GSD. Glycerol is a particularly preferred material for the low volatility component.

The increase in MMAD of the particles by adding a defined amount of glycerol to the HFA solution formulation was also observed from the flunisolide formulation in the presence of an appropriate concentration of a flavoring agent (e.g. menthol) (table 9).

As can be seen from table 10, similar results were obtained with salbutamol. A small amount of oleic acid (0.3%) was added to the formulation to improve the physical stability of the solution. At this concentration, oleic acid did not significantly alter the particulate MMAD of the active.

In table 11, formulations of HFA134a, ethanol 15.4 ± 0.2%, BDP in combination with salbutamol in the absence and presence of 1.2% glycerol and oleic acid in an amount of 0-1.3% are compared.

The results show that:

a) the MMAD of both actives in the solution combination without the low volatility component is virtually the same as the individual compounds;

b) oleic acid at a concentration of 1.3% acts as a low density, low volatile compound and significantly increases the MMAD of the particles;

c) the effect of low volatility components on MMAD is related to its density; oleic acid at a concentration of 1.3% did cause an increase in MMAD less than 1.2% glycerol with higher density.

d) The presence of the two active substances, the low-volatility component and the stabilizer in the formulation does not cause any interference between the components.

Oleic acid is another preferred material for low density, low volatility components.

Finally, table 12 shows that the addition of low volatility components makes it possible to adjust the MMAD of the active formulated as a solution in the HFA 227/ethanol system.

Thus, the formulations of the invention can improve the delivery characteristics of the drug to the lung by adjusting the aerodynamic particle size and size distribution, so that the deposition pattern gives equivalent clinical effect.

Table 1: BDP formulation in HFA134a and ethanol-actuator orifice 0.25mm

	BDP 10mg/10ml ethanol 7.9%	BDP 10mg/10ml ethanol 12.9-13.0%	BDP 20mg/10ml ethanol 7.9%	BDP 20mg/10ml ethanol 13.0%
					Average spray dose (μ g)	44.7	45.1	84.8	87.6
Dose of fine particles (μ g)	31.1	24.5	63.1	46.2
					MMAD±GSD	0.8±1.8	0.9±2.0	1.0±1.8	1.0±1.9
Spray weight (mg)	59.0	58.7	59.1	57.6
					Number of repetitions	6	2	6	2

Table 2: BDP formulation in HFA134a, ethanol and small amount of water (up to 0.5%) -actuator

Small hole 0.33mm

	BDP 10mg/10ml ethanol 13.7% H2O 0.1％	BDP 10mg/10ml ethanol 13.6% H2O 0.5％	BDP 50mg/10ml ethanol 14.9% H2O 0.1％	BDP 50mg/10ml ethanol 14.9% H2O 0.5％
					Average spray dose (μ g)	43.2	42.9	222.1	215.1
Dose of fine particles (μ g)	14.9	12.7	67.4	60.2
					MMAD(μm)±GSD	1.0±2.2	1.0±2.1	1.8±2.2	1.7±2.2
Spray weight (mg)	58.1	58.0	59.0	57.5
					Number of repetitions	6	6	6	6

Table 3: comparison of a Standard CFC ipratropium Bromide formulation (4mg/10ml IPBr) with HFA134 a/EtOH-ipratropium Bromide solutions in the absence and presence of increasing amounts of Glycerol

Preparation	CFC-IPBr	HFA134 a/ethanol 25% -IPBr**	HFA 134a-IPBr*
						Content of Glycerol (%)		0	0	0.5	1.0
Average spray dose (μ g)	18.8	17.1	16.1	18.7	18.8
						Dose of fine particles (μ g)	6.1	2.6	3.9	6.9	5.6
MMAD(μm)±GSD	2.8±1.8	1.3±2.0	1.2±1.9	1.9±2.0	2.5±2.1
						Spray weight (mg)	75.4	55.7	58.0	59.0	58.3
Number of repetitions	3	4	6	6	6

^*HFA formulations: 4mg/10ml IPBr; 12.9 +/-0.1% (w/w) of ethanol; HFA134a was filled to 12 ml.^**IPBr 4mg/10 ml; HFA134a was filled to 12 ml. Actuator orifice: 0.33mm table 4: comparison of BDP formulations in HFA134a and ethanol in the Presence of increasing amounts of propylene glycol

	Propylene glycol content
					0.0％(w/w)	1.1％(w/w)	3.2％(w/w)	6.8％(w/w)
	Average ejected dose(μg)	41.8	44.0	43.6					44.9
Dose of fine particles (μ g)					10.3	9.3	7.3	4.9
	MMAD(μm)±GSD	1.1±2.3	1.6±3.4	2.9±4.1					4.6±3.9
Number of repetitions					2	6	6	6

Preparation: BDP 10mg/10 ml; 12.9 +/-0.1% (w/w) of ethanol; HFA134a was filled to 12 ml.

Actuator orifice: 0.42mm table 5: comparison of BDP formulations in HFA134a and ethanol in the Presence of increasing amounts of propylene glycol

	Propylene glycol content
					0.0％(w/w)	0.7％(w/w)	2.8％(w/w)	6.3％(w/w)
	Average spray dose (μ g)	209.1	218.4	204.2					242.6
Dose of fine particles (μ g)					41.6	41.1	32.1	25.2
	MMAD(μm)±GSD	1.7±2.3	2.1±2.7	3.3±3.2					4.4±3.8
Number of repetitions					3	3	3	3

Preparation: BDP 50mg/10 ml; ethanol 15.2 +/-0.4% (w/w); HFA134a was filled to 12 ml.

Actuator orifice: 0.42mm table 6: comparison of BDP formulations in HFA134a and ethanol in the Presence of increasing amounts of Glycerol

	Content of Glycerol
					0.0％(w/w)	1.0％(w/w)	1.3％(w/w)	1.6％(w/w)
	Average spray dose (μ g)	205.8	218.3	220.8					228.0
Dose of fine particles (μ g)					105.9	94.4	100.3	96.6
	MMAD(μm)±GSD	1.4±1.9	2.4±2.0	2.6±2.0					2.7±2.0
Number of repetitions					6	3	3	2

Preparation: BDP 50mg/10 ml; ethanol 15.0 +/-0.2% (w/w); HFA134a was filled to 12 ml.

Actuator orifice: 0.25mm table 7: comparison of BDP formulations in HFA134a and ethanol in the Presence of increasing amounts of Glycerol

	Content of Glycerol
					0.0％(w/w)	1.0％(w/w)	1.3％(w/w)	1.6％(w/w)
	Average spray dose (μ g)	222.1	227.9	228.4					231.7
Dose of fine particles (μ g)					67.4	55.9	54.3	50.9
	MMAD(μm)±GSD	1.8±2.2	2.8±2.2	3.1±2.3					3.1±2.3
Number of repetitions					6	4	3	2

Preparation: BDP 50mg/10 ml; ethanol 15.0 +/-0.2% (w/w); HFA134a was filled to 12 ml.

Actuator orifice: 0.33mm

Table 8: comparison of BDP formulations in HFA134a and ethanol in the Presence of polyethylene glycol (PEG)400 or 8000

	PEG 400	PEG8000
				1.1％(w/w)	1.0％(w/w)	0.0％(w/w)
	Average spray dose (μ g)	218.9	215.0				222.1
Dose of fine particles (μ g)				55.6	55.6	67.4
	MMAD(μm)±GSD	2.5±2.2	2.5±2.2				1.8±2.2
Number of repetitions				2	1	6

Preparation: BDP 50mg/10 ml; 14.9 +/-0.1% (w/w) of ethanol; HFA134a was filled to 12 ml.

Actuator orifice: 0.33mm

Table 9: comparison of the formulation of solutions of flunisolide in HFA134a and ethanol in the absence and presence of Glycerol

Menthol% (w/w)	Glycerol% (w/w)	Fine Particle Dose (FPD) (μ g)	MMAD	GSD	Dose of spray (μ g)	Number of repetitions (n)
							0	0	76.85	1.8	2.15	217.1	2
0.4	0.9	77.84	2.9	2.1	221.6	5

Preparation: flunisolide 50mg/10 ml; 15.0 percent of ethanol plus or minus 0.1 percent; HFA134a was filled to 12 ml.

Actuator orifice: 0.30mm

Table 10: comparison of the preparation of an alkaline solution of HFA134a and salbutamol in ethanol in the absence and presence of Glycerol

Glycerol% (w/w)	Oleic acid% (w/w)	Dose of spray (μ g)	FPD(μg)	MMAD(μm)	GSD	Number of repetitions (n)
							0	0.35	85.8	29.1	1.7	2.3	1
1.3	0.36	92.0	25.2	2.8	2.4	1

Preparation: salbutamol base 20mg/10 ml; ethanol 15% (w/w); HFA134a was filled to 12 ml.

Actuator orifice: 0.30mm

Table 11: solution formulations of a combination of BDP and salbutamol base in HFA134a and ethanol in the absence and presence of glycerol, oleic acid, and combinations thereof

Glycerol% (w/w)	Oleic acid% (w/w)	BDP				Salbutamol base				Actuator nozzle (mm)	(n)
												Dose of spray (μ g)	FPD(μg)	MMAD(μm)	GSD	Dose of spray (μ g)	FPD(μg)	MMAD(μm)	GSD
		0	0	208.9	67.8	1.7	2.4	82.5	26.9											1.7	2.2	0.33	2
0	0.3									212.7	60.6	2.2	2.3	84.8	24.0	2.0	2.6	0.33	2
		0	1.3	212.5	58.5	2.4	2.2	85.9	23.9											2.4	2.1	0.30	1
1.2	0.3									210.8	63.3	2.9	2.1	85.3	25.1	3.0	2.0	0.30	1

Preparation: BDP 50mg/10 ml; salbutamol base 20mg/10 ml; ethanol 15.4 +/-0.2% (w/w); HFA134a was filled to 12 ml.

Table 12: 50mg/10ml BDP in HFA227 and ethanol 15.0 + -0.2% (w/w) in the presence and absence of glycerol as a non-volatile additive. HFA227 was filled to 12 ml; actuator orifice 0.33mm

	HFA 227
			0% (w/w) Glycerol	1.42% (w/w) Glycerol
	FPD(μg)	62.1			43.5
MMAD(μm)			2.2	4.1
	GSD	2.6			2.4
Average spray dose (μ g)			221.25	230.5
	Number of repetitions	2			2

Claims (13)

1. A composition in the form of a solution for use in an aerosol inhaler, the composition comprising an active substance, a propellant comprising a hydrofluoroalkane, a cosolvent and further comprising a low volatility component comprising glycerol or a glycol or oleic acid in an amount of from 0.2 to 10% by weight of the composition to increase the mass median aerodynamic diameter of the aerosol particles on actuation of the inhaler.

2. The composition of claim 1 wherein the low volatility component has a vapor pressure at 25 ℃ of no greater than 0.1 kPa.

3. The composition of claim 2 wherein the low volatility component has a vapor pressure at 25 ℃ of no greater than 0.05 kPa.

4. A composition according to any preceding claim, wherein the co-solvent has a vapour pressure at 25 ℃ of not less than 3 kPa.

5. A composition according to claim 1, 2 or 3, wherein the co-solvent has a vapour pressure at 25 ℃ of not less than 5 kPa.

6. A composition according to claim 1, 2 or 3, wherein the co-solvent is an alcohol.

7. A composition as claimed in claim 1, 2 or 3 wherein the propellant comprises one or more hydrofluoroalkanes selected from the group consisting of HFA134a and HFA 227.

8. A composition according to claim 1, 2 or 3 which is such that, on actuation of the aerosol inhaler in use, the mass median aerodynamic diameter of the aerosol particles is not less than 2 μm.

9. A composition according to claim 1, 2 or 3 wherein the active substance is beclomethasone dipropionate, the co-solvent is ethanol and the low volatility component is glycerol.

10. Use of a low volatility component comprising an active material, a propellant comprising a hydrofluoroalkane and a co-solvent in an amount of from 0.2 to 10% by weight of the composition, in a composition for an aerosol inhaler for increasing the mass median aerodynamic diameter of aerosol particles on actuation of the inhaler, said low volatility component comprising glycerol or a glycol or oleic acid.

11. Use of the low volatility component of claim 10 to give a mass median aerodynamic diameter of aerosol particles of not less than 2 μm.

12. Use of a low volatility component as claimed in claim 10 or 11 wherein the low volatility component has a vapour pressure at 25 ℃ of no more than 0.1 kPa.

13. Use of a low volatility component according to claim 10 or 11 in a composition as claimed in any one of claims 1 to 9.