Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-05-26
2002-09-17
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C514S180000, C525S283000, C521S149000, C521S064000
Reexamination Certificate
active
06451287
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel surfactants, which are particularly useful in dispersing particles in an aerosol composition containing a fluorine-containing propellant. The invention also relates to pharmaceutical aerosol compositions and methods of stabilizing drugs in such compositions using these surfactants.
2. Description of the Related Art
Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. See generally P. Byron,
Respiratory Drug Delivery
, CRC Press, Boca Raton, Fla. (1990). One widely used method for dispensing such an aerosol drug formulation involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispensed by activation of a dose-metering valve affixed to the container. Further background concerning the use of surfactants in MDI's is discussed in WO 00/00181, which is incorporated herein by reference.
A metering valve may be designed to consistently release a fixed, predetermined amount of the drug formulation upon each activation. As the suspension is forced from a container through the dose-metering valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes, leaving a cloud of very fine particles of the drug formulation. This cloud is usually directed into the body of the patient by a channeling device, e.g., a cylinder-like or cone-like passage, with one of its ends attached to the outlet of the pressurized container, and the other end inserted in the mouth or nose of the patient. Concurrently with the activation of the aerosol dose-metering valve, the patient inhales the drug formulation particles into the lungs or nasal cavity. Systems for dispensing drugs in this way are known as “metered dose inhalers (MDI's).” See Byron, supra at 167-207.
Many materials, including drug formulations, have a tendency to aggregate (also referred to as “flocculate” or “clump-up”) when stored as fine particles having dimensions of a few microns in a suspension. For an aerosol delivery system to work properly the aggregation needs to be controlled so as to maximize free volume in the sedimentary layer since this type of arrangement facilitates redispersion of the particles as compared to a more tightly packed arrangement. Further, the suspension should be substantially homogenous throughout the administered dose at the time of activation of the metering valve.
To control aggregation of fine particles and, thereby, to influence the dispersability of the suspension, compounds known as surface active agents, or surfactants, are often used to coat the surfaces of the fine particles and assist in wetting the particles with an aerosol propellant. The use of surfactants in this way to maintain substantially uniform suspensions is said to “stabilize” the suspensions.
For several years, the chlorofluorocarbons (CFC's) gained wide spread acceptance as the propellants of choice for inhalation drug formulations. However, for environmental reasons, there has been a move to replace chlorofluorocarbons with hydrofluorocarbon (HFC) propellants, such as HFC-134A (1,1,1,2-tetrafluoroethane) and HFC-227 (1,1,1,2,3,3,3-heptafluoropropane). When these hydrofluorocarbon propellants are used as a propellant in a pressurized drug delivery system, various technical problems can occur with various drug formulations. It has proven particularly difficult to form stabilized compositions with such propellants. In light of the need to reduce the use of CFC propellants, there is a continuing need for the development of stabilized aerosol formulations containing HFC propellants.
Thiel in U.S. Pat. No. 4,352,789, teaches the use of insoluble perfluorinated surface-active dispersing agents in CFC and perfluorinated propellants. These agents include perfluorinated sulfonamide alcohol phosphate esters and their salts, perfluorinated alkyl sulfonamide alkylene quaternary ammonium salts and perfluorinated alcohol phosphate esters and their salts. Thiel teaches that surfactants must be insoluble in the propellant. Further, he teaches that the drug must be coated with the surfactant in an organic solvent, dried, then added to the propellant mixture.
Johnson in U.S. Pat. No. 5,126,123 teaches aerosol inhalation drug formulations using propellant 134A and surfactants which include perfluoroalconic acid, potassium, perfluoroalkyl sulfonates and ammonium perfluoroalkyl carboxylates.
Johnson in U.S. Pat. No. 5,376,359 teaches methods of stabilizing an aerosol formulation containing solid dried particles. The surfactants used in these formulations include fluoropolymers that are soluble in the HFC propellant.
PCT WO 91/11173 teaches pressurized aerosol compositions containing a hydrofluorocarbon propellant and a fluorinated surfactant. Preferred surfactants include fluorinated alcohols, esters, amides, N-oxides or sulfonamides.
PCT WO 92/00061 teaches pressurized aerosol compositions containing a medicament, a hydrofluorocarbon propellant and a polyethoxylated surfactant. Preferred surfactants include non-fluorinated block copolymers of ethylene oxide and propylene oxide.
In the art, one disadvantage of incorporating a surfactant in an MDI formulation has been introducing the need for a corresponding co-solvent. In many situations, the presence of a co-solvent has one or more disadvantages. For example, the co-solvent may have toxicological issues. Moreover, while ethanol is basically safe, it is not suitable for all patient groups. Co-solvents may also have a higher Global Warming Potential (GWP) than the propellant somewhat negating one of the primary benefits of using HFC propellants. Co-solvents (e.g., ethanol) may dissolve the drug at elevated levels resulting in particle size growth at reduced levels. In other words, co-solvents (e.g., ethanol) may cause partial solubility of drug in suspension formulations, which can cause undesired particle growth through a process known in the art as “Ostwald Ripening.” Such phenomena is very drug specific, however. Co-solvents may also lower the vapor pressure of the MDI formulation thereby reducing atomization performance, which adversely affects lung delivery performance. Such disadvantages may be exacerbated as the inhaler is operated because the concentration of co-solvent in the MDI formulation may increase.
The present invention is advantageous in that it overcomes the disadvantages discussed herein while imparting the advantages of employing the surfactants of the present invention in an MDI formulation. In the present invention, surfactants are employed without the need for a co-solvent.
SUMMARY OF THE INVENTION
The present invention, in one embodiment, relates to a pharmaceutical aerosol composition, comprising a drug, a fluorine-containing propellant, and an amphiphilic fluorinated block copolymer having at least one lyophobic block and at least one lyophilic block, wherein each of said blocks are formed from a plurality of monomeric units.
In another embodiment, the present invention relates to an aerosol composition, comprising particles, a fluorine-containing propellant, and an amphiphilic fluorinated block copolymer having at least one lyophobic block and at least one lyophilic block, wherein each of said blocks are formed from a plurality of monomeric units.
The present invention also relates to a pressurized container, such as a metered dose inhaler, containing the aerosol composition therein. The pressurized container preferably has a dispensing valve for dispensing the aerosol composition.
In a preferred embodiment of the invention, the amphiphilic fluorinated block copolymer comprises at least one lyophobic block, wherein the total molecular weight of the lyophobic block or blocks is between 500 and 5,000; and at least one lyophilic block, wherein the total molecular weight of th
Carson Terri Johnson
Desimone Joseph M.
Miller John F.
Wells Sharon
Haghighatian M.
Rogers Christopher P.
Smithkline Beecham Corporation
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