Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1996-04-05
2003-02-25
Dees, José C. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S045000
Reexamination Certificate
active
06524557
ABSTRACT:
This invention relates to drug formulations containing medically useful peptides and proteins, for inhalation from an aerosol inhaler.
BACKGROUND OF THE INVENTION
A range of drugs are administered in aerosol formulations through the mouth or nose. One widely used method for dispensing such an aerosol formulation involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. Pressurised metered dose inhalers, or pMDI's, are normally used to dispense such formulations to a patient. Surface active agents, or surfactants, are commonly included in order to aid dispersion of the drug in the propellant and to prevent aggregation of the micronised drug particles.
Until recently, chlorofluorocarbon-containing propellants (CFC's) were accepted for use in all pharmaceutical aerosol formulations. Typical surfactant dispersing agents used in the CFC formulations were for example sorbitantrioleate, oleic acid, lecithines, and ethanol. Since CFC's have been implicated in the destruction of the ozone layer, a new generation of propellants has emerged to take their place.
Hydrofluoroalkane (HFA) propellants such as 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and 1,1-difluoroethane (P152a) are considered to be the most promising new propellants. Not only are they environmentally acceptable, but they also have low toxicity and vapour pressures suitable for use in aerosols. However the surfactants normally used in CFC-aerosol formulations are not particularly suitable for use with the new generation of propellants and therefore in recent years a number of alternative surfactants have been suggested for use specifically with the HFA propellants, among them polyethoxylated surfactants and fluorinated surfactants.
Peptide-based drugs have not traditionally been among those drugs which are administered from aerosol formulations, although various aerosol formulations have been suggested.
For example U.S. Pat. No. 5,284,656 discloses a formulation of granulocyte colony stimulating factor (G-SCF) comprising a finely divided powder containing G-SCF suspended in a propellant, with the aid of a surfactant such as sorbitan trioleate, soya lecithin or oleic acid. U.S. Pat. No. 5,364,838 discloses an insulin formulation wherein a dry powder of insulin is suspended within a low boiling point propellant with an excipient such as oleic acid.
SUMMARY OF THE INVENTION
We have now surprisingly found that various substances which enhance the absorption of polypeptides in the respiratory tract are also particularly suitable as surfactants for use with HFA propellants.
The invention thus provides a pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C
8
-C
16
fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract.
The surfactants employed in the present invention are surprisingly suitable for use with HFA propellants; their capabilities for enhancement of the absorption of polypeptide give them a dual function which makes them especially beneficial for use in the present polypeptide aerosol formulations.
Of the fatty acids and salts thereof, C
8
-C
16
fatty acids salts are preferred. Examples of preferred fatty acid salts are sodium, potassium and lysine salts of caprylate (C
8
), caprate (C
10
), laurate (C
12
) and myristate (C
14
). As the nature of the counterion is not of special significance, any of the salts of the fatty acids are potentially useful. A particularly preferred fatty acid salt is sodium caprate.
Suitable bile salts may be for example salts of cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid.
Of the bile salts, trihydroxy bile salts are preferred. More preferred are the salts of cholic, glycocholic and taurocholic acids, especially the sodium and potassium salts thereof. The most preferred bile salt is sodium taurocholate.
Suitable phospholipids may be for example single-chain phospholipids, for example lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylethanolamine, lysophosphatidylinositol and lysophosphatidylserine or double-chain phospholipids, for example diacylphosphatidylcholines, diacylphosphatidylglycerols, diacylphosphatidylethanolamines, diacylphosphatidylinositols and diacylphosphatidylserines.
Of the phospholipids, diacylphosphatidylglycerols and diacylphosphatidylcholines are preferred, for example dioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine.
Suitable alkyl saccharides may be for example alkyl glucosides or alkyl maltosides, such as decyl glucoside and dodecyl maltoside.
The most preferred surfactants are bile salts.
The propellant may comprise one or more of 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane (P227) and 1,1-difluoroethane (P152a), for example, optionally in admixture with one or more other propellants. Preferably the propellant comprises P134a or P227, or a mixture of P134a and P227, for example a density-matched mixture of p134a and P227.
The polypeptide may be any medically or diagnostically useful peptide or protein of small to medium size, i.e. up to about 40 kD molecular weight (MW), for which systemic delivery is desired. The mechanisms of improved polypeptide absorption according to the present invention are generally applicable and should apply to all such polypeptides, although the degree to which their absorption is improved may vary according to the MW and the physico-chemical properties of the polypeptide, and the particular surfactant used. It is expected that polypeptides having a molecular weight of up to 30 kD will be most useful in the present invention, such as polypeptides having a molecular weight of up to 25 kD or up to 20 kD, and especially up to 15 kD or up to 10 kD.
The polypeptide is preferably a peptide hormone such as insulin, glucagon, C-peptide of insulin, vasopressin, desmopressin, corticotropin (ACTH), corticotropin releasing hormone (CRH), gonadotropin releasing hormone (GnRH), gonadotropin releasing hormone agonists and antagonists, gonadotrophin (luteinizing hormone, or LHRH), is calcitonin, parathyroid hormone (PTH), bioactive fragments of PTH such as PTH(34) and PTH(38), growth hormone (GH) (for example human growth hormone (hGH)), growth hormone releasing hormone (GHRH), somatostatin, oxytocin, atrial natriuretic factor (ANF), thyrotropin releasing hormone (TRH), prolactin, and follicle stimulating hormone (FSH), and analogues of any of the above.
Other possible polypeptides include growth factors, interleukins, polypeptide vaccines, enzymes such as deoxyribonuclease (DNase), endorphins, glycoproteins, lipoproteins, and polypeptides involved in the blood coagulation cascade, that exert their pharmacological effect systemically. It is expected that most if not all polypeptides of small to medium size can be effectively delivered by the methods of the invention.
The preferred polypeptide is insulin.
In addition to drug, propellant and surfactant, a small amount of ethanol (normally up to 5% but possibly up to 20%, by weight) may be included in the formulations of the present invention. Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion.
The composition may of course contain other additives as needed, including other pharmaceutically active agents, adjuvents, carriers, flavouring agents, buffers, antioxidants, chemical stabilisers and the like. As examples of suitable additives may be mentioned for exanple lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinit
Bäckström Kjell
Dahlbäck Magnus
Johansson Ann
Källstrand Göran
Lindqvist Elisabet
AstraZeneca AB
Dees Jose C.
Fish & Richardson P.C.
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