Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-07-13
2003-11-04
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S045000, C514S172000, C514S177000, C514S178000, C514S179000, C514S180000, C514S182000, C514S291000, C514S314000, C514S408000, C514S428000, C514S453000, C514S456000, C514S460000, C514S529000, C514S631000, C514S636000, C514S637000, C514S642000, C514S716000, C514S717000, C514S718000, C514S721000, C514S724000, C514S727000, C514S728000, C514S731000, C514S734000, C514S738000, C514S772000, C514S772300, C514S772400, C514S772500, C514S772600, C514S772700, C514S777000, C514S783000, C514S951000, C514S958000, C514S
Reexamination Certificate
active
06641800
ABSTRACT:
This invention relates to pressurised aerosol compositions, in particular compositions of inhalation medicaments.
BACKGROUND OF THE INVENTION
Pressurized aerosols for the administration of medicaments, and indeed for other applications, conventionally contain one or more liquefied chlorofluorocarbons (CFC's) as propellant. Such materials are suitable for use in such applications since they have the right vapor pressures (or can be mixed in the right proportions to achieve a vapor pressure in the right range) and are essentially taste- and odor free.
In recent years there has been increasing concern about the depletion of the ozone layer in the upper atmosphere. This is believed to be due to the release into the atmosphere of CFC's and has led to a search for alternative agents for use in all applications of CFC's. To this end, aerosols for many applications are now pressurised using pressurised gases such as nitrogen or hydrocarbons. However, such propellants are generally not suitable for use in the administration of inhalation medicaments since they are toxic and/or the pressure within the canister falls each time the device is used which leads to unreproducible dosing.
The use of hydrofluorocarbons as aerosol propellants has also been suggested. However, considerable difficulties have been encountered in finding suspending agents which are soluble in hydrofluoroalkanes and capable of stabilising medicament suspensions.
SUMMARY OF THE INVENTION
Surprisingly, we have found that certain polymers are both soluble in the aerosol propellants and capable of stablizing medicament compositions.
DETAILED DESCRIPTION OF THE INVENTION
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 is 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 trimethylammoniumethyl 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 0.0001 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 CF
3
CFH
2
(Propellant 134a), CH
3
CHF
2
(Propellant 152a) and CF
3
CHFCF
3
(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 cases 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 0 372 777, 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 polyvinylpyrrolidone 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,
Gibson Mark
Mistry Suresh N
Choi Frank
Dees Jose′ G.
Fisons Ltd.
Nixon & Vanderhye
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