Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-08-29
2001-10-30
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000
Reexamination Certificate
active
06309624
ABSTRACT:
This invention relates to aerosol formulations of use in the administration of medicaments by inhalation.
The use of aerosols to administer medicaments has been known for several decades. Such aerosols generally comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol.
The most commonly used aerosol propellants for medicaments have been CCl
3
F (propellant 11) in admixture with CCl
2
F
2
(propellant 12) and CF
2
Cl.CF
2
Cl (propellant 114). However these propellants are now believed to provoke the degradation of stratospheric azone and there is thus a need to provide aerosol formulations for medicaments which employ so called “ozone-friendly” propellants.
A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise hydrogen-containing chlorofluorocarbons and fluorocarbons and a number of medicinal aerosol formulations using such propellant systems have been disclosed in, for example, EP 0372777, WO91/04011, WO91/11173, WO91/11495, WO91/14422, WO92/00061, WO92/00062 and WO92/00107.
These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. These applications all propose the addition of a wide range of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and nonfluorinated surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants in small amounts to minimise potential ozone damage.
Surprisingly, we have now found that mixtures of a non ozone-depleting propellant and a specific fluorinated hydrocarbon may be employed as propellant systems suitable for use in pharmaceutical aerosol compositions.
There is thus provided in one aspect of the invention an aerosol formulation comprising:
(a) 1,1,1,2-tetrafluoroethane (CF
3
CH
2
F), 1,1,1,2,3,3,3-heptafluoro-n-propane (CF
3
CHFCF
3
) or mixtures thereof as propellant;
(b) 1,1,2,2,3-pentafluoropropane as co-propellant; and
(c) particulate medicament
Generally, the ratio of propellant:copropellant is in the range of about 30:70 to about 95:5, preferably 50:50 to 90:10 by weight, especially 50:50 to 80:20, for example 75:25 (w/w).
Medicaments which may be administered in aerosol formulations according to the invention include any drugs useful in inhalation therapy which may be presented in a form which is substantially completely insoluble in the selected propellant system. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. dilitiazem; antiallergics, e.g. cromolyn, cromogylcate or nedocromil; antibiotics, e.g. cephalosporins, penicillins, streptomycin, sulphonamides or tetacyclines; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, fluticasone, tipredane, budesonide, triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, epinephrine, fenoterol, formoterol, isoprenaline, isoproterenol, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, repoterol, rimiterol, salbutamol, salmeterol, terbutaline or (−)-4-amino-3,5-dichloro-&agr;[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium bromide; hormones, e.g. cortisone, hydrocortisone or prednisolone; and therapeutic proteins and peptides, e.g. glucagon or insulin. It will be clear to a person skilled in the art that, where appropriate, the medicaments will be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (eg hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include bronchodilators and anti-inflammatory steroids of use in the treatment of asthma by inhalation to, for example salbutamol (e.g. as the sulphate), salmeterol (e.g. as the hydroxynaphthoate known as salmeterol xinafoate), beclomethasone dipropionate or a solvate thereof, fluticasone propionate or (−)-4-amino-3,5-dichloro-&agr;-[[[6-[2-(2pyridinyl)ethoxy]hexyl]amino]methyl] benzenemethanol.
The particle size of the particulate medicament should be such as to permit inhalation of substantially all of the medicament into the lungs upon administration of the aerosol formulation and will thus desirably be less than 20 microns, preferably in the range 1 to 10 microns, e.g. 1 to 5 microns. The particle size of the medicament may be reduced by conventional means, for example by milling or micronisation.
The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.
It is desirable that the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone. In particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CCl
3
F, CCl
2
F
2
and CF
3
CCl
3
. As used herein “substantially free” means less than 1% w/w based upon the propellant system, in particular less than 0.5%, for example 0.1% or less.
The propellant may optionally contain an adjuvant having a higher polarity and/or a higher boiling point than the propellant. Polar adjuvants which may be used include (e.g. C
2-6
) aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol, preferably ethanol. In general only small quantities of polar adjuvants (e.g. 0.05-3.0% w/w) may be required to improve the stability of the dispersion—the use of quantities in excess of 5% w/w may tend to dissolve the medicament. Formulations in accordance with the invention may preferably contain less than 1% w/w, e.g. about 0.1% w/w, of polar adjuvant. However, the formulations of the invention are preferably substantially free of polar adjuvants, especially ethanol. Suitable volatile adjuvants include saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane and alkyl ethers such as dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C
1-6
hydrocarbon.
Optionally, the aerosol formulations according to the invention may further comprise one or more surfactants. The surfactants must be physiologically acceptable upon administration by inhalation. Within this category are included surfactants such as oleic acid, sorbitan trioleate (Span
R
85), sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceyl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil and sunflower seed oil. Preferred surfactants are lecithin, oleic acid and sorbitan trioleate.
An alternative class of surfactants are described in EP 0478686, especially surfactants of formula (I)
wherein n is an integer of 1 to 18, especially 2 to 12; m is an integer of 0 to 17, especially 0 to 11; and R
1
, R
2
and R
3
are each independently a hydrogen atom or a C
1-4
alkyl
Sapsford Andrew
Savage Andrew Patrick
Bacon & Thomas
Bawa Raj
Glaxco Group Limited
LandOfFree
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