Title:  Pressurized aerosol inhalation compositions

United States Patent:  6,123,924

Inventors:  Mistry; Suresh N (Birstall, GB); Gibson; Mark (Shepshed, GB)

Appl. No.:  478338

Pressurized aerosol inhalation composition consisting essentially of a liquefied hydrofluoroalkane, a powdered medicament dispersible to form a suspension in the liquefied hydrofluoroalkane, and polyvinylpyrrolidone present in a concentration of 0.00001 to 10% w/w.

DESCRIPTION OF THE INVENTION

Surprisingly, we have found that certain polymers are both soluble in the aerosol propellants and capable of stabilising medicament compositions.

Thus, according to the invention, we provide a pressurised aerosol composition comprising a liquefied hydrofluoroalkane, a powdered medicament dispersable therein and a polymer soluble in the liquefied hydrofluoroalkane, characterised in that the polymer includes recurring structural units, the units being selected from amide containing units and carboxylic acid ester containing units.

The polymer may be a homopolymer, that is the polymer consists of the same recurring structural units, or it may be a copolymer, that is the polymer contains recurring units in addition to either amide containing units or carboxylic acid ester units. The polymer may also be a copolymer of amide containing units and carboxylic acid ester units. Such copolymers may be either block copolymers or random copolymers.

We prefer polymers which include recurring structural units containing an amide group. We particularly prefer the amide containing unit to be 1-ethylene-pyrrolidin-2-one. We especially prefer the polymer to be a homopolymer containing recurring 1-ethylene-pyrrolidin-2-one, that is polyvinylpyrrolidone.

In general, we have found that polyvinylpyrrolidones having a wide range of average molecular weights give acceptable suspensions. Although polymers can be characterised by their weight average molecular weights, viscosity average molecular weights or number average molecular weights, it is more usual to characterise polymers, in particular polymers such as polyvinylpyrrolidone, by K values, in which K is determined from viscosity measurements using the Fikentscher equation (H. Fikentscher, Cellusochemie, 1932, 13, 58-64 and 71-74). In particular we prefer the polymer to have a K value of from 10 to 150, more preferably 15 to 120; Particular K values and ranges that may be mentioned include 10-14, 15-18, 29-32, 88-100 and 115-125.

Suitable polymers containing carboxylic acid ester containing recurring structural units include polyvinylacetate and copolymers of vinyl acetate and vinyl pyrrolidone, that is polyvinylpyrrolidone/vinyl acetate copolymer. We have found that polyvinylacetate with a weight average molecular weight of 250,000 gives particularly stable suspensions.

Other polymers that may be mentioned include acrylic acid/methacrylic acid ester copolymers, especially those in which the methyl and ethyl ester groups have been replaced with a low content of trimethylammomiumethyl groups, preferably at a ratio of 1:20, especially at a ratio of 1:40. We have found that such copolymers having a weight average molecular weight of 150,000 give stable suspensions.

The amount of polymer in the composition will depend on the active ingredient to be dispersed, its concentration and the particular polymer selected. However, in general the amount of polymer is from 0.00001 to 10% w/w, more preferably 0.001 to 5% w/w and especially 0.001 to 1% w/w.

The compositions may, in addition to the polymer, contain other excipients, in particular excipients intended to improve valve lubrication and excipients to modify flavour. Particular lubricants that may be mentioned include polyethoxylated compounds, especially polyethylene glycol. We prefer polyethylene glycol having a mean molecular weight of from 200 to 3000, preferably 400 to 2000, eg 1500. Other polyethoxylated compounds that may be used as lubricants include polysorbates, eg polysorbate 80, and alkyl aryl polyether alcohols, eg tyloxapol. Other lubricating excipients that may be mentioned include high molecular weight fully halogenated chlorofluorocarbons and esters of medium chain fatty acids. The amount of lubricant in the composition will depend on the other components of the composition, the active ingredient, the nature of the valve, etc. In general, we prefer a concentration of 0.01 to 4% w/w and more preferably 0.1 to 2% w/w.

Flavour modifying excipients that may be added to the composition include peppermint oil, menthol, Dentomint (Dentomint is a tradename), saccharin and saccharin sodium. When the flavour modifying excipient is a solid, preferably it is micronised. The concentration will depend on the individual composition and the flavour modifying excipient. In general, we prefer a concentration of 0.005 to 4% w/w; more preferably 0.01 to 1% w/w.

By the term `hydrofluoroalkane` we mean a compound of general formula

C_x H_y F_z

in which x is an integer from 1 to 3, y+z=2x+2 and y and z are both at least 1.

Particular hydrofluoroalkanes of interest are CF₃ CFH₂ (Propelant 134a), CH₃ CHF₂ (Propellant 152a) and CF₃ CHFCF₃ (Propellant 227). We particularly prefer compositions including propellant 227.

In general the vapour pressure of the propellant mixture should be in the range suitable and permitted for aerosol propellants. The vapour pressure may be varied by mixing one or more hydrofluoroalkanes and/or some other suitable vapour pressure modifying agent in appropriate proportions.

We prefer the vapour pressure of the mixture to be in the range 20 to 100 psig, more preferably 40 to 80 psig, eg about 60 psig.

In certain case we have found it advantageous to add to the compositions excipients capable of increasing the solubility of the polymer or of other excipients, in the propellant. In general we have found that the polymers selected have a solubility in the propellant of at least 0.0001% w/w, preferably at least 0.001% w/w, particularly 0.01% w/w and especially 0.1% w/w. Excipients capable of increasing the solubility of the polymer include liquid excipients which are more polar than the liquefied propellant, where polarity is defined in terms of relative Kauri butanol values, as described in European patent application 0 372 777. Particular excipients that may be mentioned include alcohols eg ethanol and isopropanol. However, in contrast to the teaching of EP 0 373 777, we have found that only very small quantities of such excipients are required. In particular we have found that good compositions can be prepared in propellant 134a with a polyvinylpyrolidone as polymer with a variety of active ingredients and less than 10% w/w, preferably less than 5% w/w, more preferably less than 2% w/w, eg 0.2% w/w ethanol.

Medicaments which may be dispersed in the propellant mixture according to the invention include any medicaments which are conventionally administered to the lung and/or nose by inhalation of a pressurised aerosol formulation. Such medicaments include drugs for use in the prophylactic or remedial treatment of reversible obstructive airways disease, eg drugs such as sodium cromoglycate, nedocromil sodium, inhaled steroids, eg beclomethasone dipropionate, fluticasone propionate, budesonide and tipredane, and bronchodilators, eg salbutamol, reproterol, terbutaline, formoterol, pirbuterol, isoprenaline, salmeterol, fenoterol and salts thereof, ad anticholinergic agents such as ipratropium bromide, oxitropium bromide and atropine and combinations of two or more of these agents, eg a combination of a prophylactic agent with a bronchodilator, eg sodium cromoglycate with salbutamol.

Other medicaments that may be mentioned include antihistamines, eg clemastine, pentamidine and salts thereof, acetyl-.beta.-methylcholine bromide, peptide hormones such as insulin and amylin, bradykinin antagonists, PLA₂ inhibitors, PAF antagonists, lipoxygenase inhibitors, leukotriene antagonists, CNS active drugs, such as NMDA antagonists, glutamate antagonists, CCK agonists and antagonists; macrolide compounds including FK 506, rapamycin, cyclosporin and structurally related compounds, vitamins, vaccines, eg MMR vaccine and polio vaccine and vectors for gene therapy, eg plasmids containing genes intended to correct genetic disorders such as cystic fibrosis.

Where the medicament is intended for delivery to the lung, it preferably has a particle size distribution such that a high proportion of the particles are of a size capable of penetrating deep into the lung. In particular, the medicament is preferably in a form having a mass median diameter of from 0.01 to 10 .mu.m, more preferably from 0.1 to 4 .mu.m, eg about 2 or 3 .mu.m.

The amount of medicament in the composition will depend on the nature of the active ingredient and the condition to be treated. However, the composition preferably comprises from 0.01 to 15% w/w, preferably from 0.1 to 10% w/w, and most preferably from 0.5 to 5% w/w medicament.

According to a further aspect of the invention there is provided a method of producing a pressurised aerosol composition as herein described, which comprises dispersing the powdered medicament and the polymer in the liquefied hydrofluoroalkane.

In particular, the compositions may be produced by cold fill or pressure fill techniques. In cold filling, the ingredients are placed in a cooled mixing vessel, cooled liquefied propellant added and a dispersion produced by vigorous stirring. Alternatively, a slurry may be prepared of the ingredients in a portion of cooled liquid propellant and the remainder of the liquefied propellant added under vigorous stirring. Aliquots of the dispersed composition are then filed into cooled aerosol cans and sealed with a suitable valve, eg a metering valve.

In pressure filling, the ingredients are placed in a pressure vessel, liquefied propellant added under pressure through a valve and a dispersion of the ingredients in the liquefied dispersed composition are then filled, under pressure, through the valve into suitable cans provided with appropriate valves, eg metering valves.

The compositions according to the invention are advantageous in that the solubility of the polymer is such as to ensure good dispersion of the medicament and smooth operation of the aerosol valve.

The compositions of the present invention may also be advantageous in that they are substantially taste- and odour-free and have suitable vapour pressures for the administration of medicaments by inhalation, yet are environmentally safe and acceptable, especially when compare with compositions including chlorofluorocarbons. In addition, they may be less irritant than corresponding compositions including conventional surfactants such as oleic acid and sorbitan trioleate.

The performance of the compositions according to the present invention can be assessed using the following test procedures:

1. Settling times

A glass bottle containing the composition is gently shaken five times and then stood upright. The time interval between standing the bottle upright and the first appearance of flocculation or separation of powder in the propellant determined (S₁). Timing is continued until complete separation, defined as when three lines of standard newspaper print can be read through the propellant from the top or bottom, depending on whether the active ingredient floats or sinks (S₂). In some compositions, complete separation does not occur. For these compositions, a turbidity factor ranging from 1 to 5 is determined, 1 denoting that a small proportion of the active ingredient is suspended and 5 denoting that the majority of the active ingredient is suspended.

2. Dispersion Tests

Dispersion testing on compositions formulated in cans having a metering valve can be assessed using a glass multistage liquid impinger, eg of the type described by J. H. Bell et al, J. Pharm. Sci., 1971, 60(10), 1559.

3. Lubrication

The lubricating effects of the composition can be assessed by filling the formulation into a can and closing the can with a modified metering valve from which the return spring has been removed. The stem of the valve is subjected to a compression force and the reading recorded in Newtons. This gives a measure of the lubricating efficacy of the composition.

4. Dose uniformity

Dose uniformity is assessed by discharging a metered dose aerosol can containing the composition into a filter tube which has sufficient air flowing through it to entrain all the dose. The tube is washed out with a suitable solvent and the amount of medicament assayed. The medicament entrained on the mouthpiece is also washed off and assayed. The variation of dose evaluated throughout the life of the can is a measure of dose uniformity. In a variation of this test, dose uniformity after standing can be assessed by shaking the aerosol can, allowing to stand for a predetermined time and assessing dose in the manner described above.

5. Caking potential

Compositions to be assessed are filled into plastic coated glass bottles. The assessment is carried out by allowing the samples to be stored for a period of time in order that complete sedimentation and compaction of the powder mass can take place, eg 3 months. After that period, the glass bottles are shaken by gentle twisting of the hand to totally invert the bottles. The number of bottle inversions required to completely resuspend the drug is noted. The number gives a measure of the degree of compaction of the composition. Since ease of drug particle redispersion is essential for dose uniformity, any composition requiring more tan 5 shakes suggests possible problems in long-term storage.

Claim 1 of 16 Claims

What is claimed is:

1. A pressurized aerosol inhalation composition consisting essentially of:

a liquefied hydrofluoroalkane;

a powdered medicament dispersible to form a suspension in the liquefied hydrofluoroalkane; and

polyvinylpyrrolidone present in a concentration of 0.00001 to 10% w/w.

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