Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-11-15
2001-07-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C514S174000
Reexamination Certificate
active
06264923
ABSTRACT:
This application claims priority under 35 U.S.C. 119 to GB 9710496.2, filed May 21, 1997, and GB 9803990.2, filed Feb. 25, 1998.
FIELD
This invention relates to medicinal aerosol products and in particular to medicinal products containing a pregna-1,4,diene-3,20-dione-16-17-acetal-21 ester suitable for administration by inhalation.
BACKGROUND
GB-2247680 discloses pregna-1,4-diene-3,20-dione-16-17-acetal-21 esters and their use in the treatment of inflammatory conditions.
The compounds have the general structure:
wherein
R
1
is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and
R
2
is acetyl or isobutanoyl.
Ciclesonide is 11&bgr;,16&agr;,17,21-tetrahydroxypregna 1,4-diene-3,20-dione, cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyrate having the structure of formula (I) without fluorine atoms and in which R
1
is cyclohexyl and R
2
is isobutanoyl. This compound has undergone evaluation as an antiasthmatic and pharmacokinetic studies show that it will be useful in an inhaler formulation. Ciclesonide is only moderately absorbed after oral administration and has low systemic activity. Concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. Systemic activity of ciclesonide is three times lower than that of budesonide but anti-inflammatory activity is higher for the former.
GB-2247680 proposes a specific pressurized aerosol formulation for delivering ciclesonide for oral and nasal inhalation. The disclosed formulation consists of ciclesonide as a micronized suspension of particles, sorbitan trioleate surfactant, and a mixture of three CFC propellants: trichloro-fluoromethane, dichlorotetrafluoromethane, and dichlorodifluoromethane. However these CFC propellants are now believed to provoke the degradation of stratospheric ozone and there is 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 hydrofluorocarbons and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777, W091/04011, W091/11173, W091/11495, W091/14422, WO93/11743, and EP-0553298 (all hereby incorporated by reference). These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome problems associated with the use of this new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared. The applications propose, for example, the addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc.).
However, despite the various approaches used in formulating drugs for use in aerosol inhalation, there are still many serious difficulties and uncertainties often encountered in attempting to develop a physically and chemically stable CFC-free formulation that reliably delivers an accurate dose of drug having the proper particle size range. In particular, there is a need for a CFC-free medicinal aerosol product containing ciclesonide (or similar molecules) that is chemically and physically stable and that is suitable for delivery to the respiratory system of a patient.
SUMMARY
It has now been surprisingly found that, rather than the prior art approach of formulating ciclesonide as a suspension, ciclesonide can be very beneficially formulated as a physically and chemically stable solution in formulations including hydrofluorocarbon propellants. According to the present invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula:
in which:
R
1
is 1-butyl, 2-butyl, cyclohexyl or phenyl and
R
2
is acetyl or isobutanoyl, and a hydrofluorocarbon propellant, preferably selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof, and cosolvent, preferably ethanol, in an amount effective to solubilize the compound of formula (I) and optionally a surfactant.
The compounds of formula (I) is preferably ciclesonide and is generally present at a concentration of from 1 to 8 mg/ml, preferably 1 to 5 mg/ml.
The formulation generally comprises from 3 to 25% preferably 5 to 20%, more preferably 7 to 12% by weight ethanol.
The propellant preferably includes a hydrofluoroalkane, in particular Propellant
134
a
, Propellant
227
or a mixture thereof, generally at about 50:50 w/w. More preferably the propellant consists of Propellant
134
a.
The formulations may contain surfactant but are preferably free of surfactant. The formulations are preferably free of other excipients.
Preferred formulations consist of from 1 to 5 mg/ml ciclesonide, 8% by weight ethanol and Propellant
134
a.
The formulations may be prepared by adding the required quantity of drug into an aerosol vial, crimping a valve on the vial and introducing a pre-mixed blend of propellant and ethanol through the valve. The vial is placed in an ultrasonic bath to ensure solubilisation of the drug.
Alternatively, the formulations may be prepared by preparing a drug concentrate with ethanol and adding this concentrate to the pre-chilled propellant in a batching vessel. The resulting formulation is filled into vials.
The formulations may be filled in plastics, metal or glass vials. Suitable plastics materials include polyethyleneterephthalate; a preferred metal is aluminium.
The vials are equipped with a metered dose dispensing valve e.g. dispensing 50 &mgr;l with each actuation. A suitable metered dose dispensing valve comprises a valve ferrule having a rim and associated rim gasket for engaging the aerosol vial and an aperture therethrough;
a metering tank having walls defining an exterior, an internal metering chamber, an inlet orifice, an inlet end, and an outlet end;
an elongate valve stem having a filling channel, a filling end, a discharge end, and a discharge orifice;
wherein the outlet end of the metering tank is in sealing engagement with the valve ferrule, the discharge end of the valve stem passes through both the valve ferrule aperture and the outlet end of the metering tank and is in slidable sealing engagement with the valve ferrule;
wherein the filling end of the valve stem passes through and is in slidable engagement with the inlet orifice of the metering tank, and a bottle emptier surrounding the metering tank and filling end of the elongate valve stem and defining a passage between the metering tank and bottle emptier allowing communication between the inlet orifice of the metering tank and the aerosol vial;
wherein the valve stem is movable between an extended closed position wherein the filling channel of the valve stem allows open communication, via the inlet orifice, between the interior and the exterior of the metering chamber, and wherein the outlet end of the metering tank is closed, and a compressed open position wherein the inlet orifice of the metering tank is in sealing engagement with the filling end of the valve stem and the discharge orifice of the valve stem allows open communication between the interior and exterior of the metering chamber.
A suitable valve is commercially available under the trade name SPRAYMISER.
REFERENCES:
patent: 5482934 (1996-01-01), Calatayud et al.
patent: 5653961 (1997-08-01), McNally et al.
patent: 5653962 (1997-08-01), Akehurst et al.
patent: 5674473 (1997-10-01), Purewal et al.
patent: 5776432 (1998-07-01), Schultz et al.
patent: 5980867 (1999-11-01), Tzou et al.
patent: 195 41 689 (1996-05-01), None
patent: 0372777 (1990-06-01), None
patent: 0553298 (1993-08-01), None
patent: 2247680 (1992-03-01), None
patent: 91/04011 (1991-04-01), None
patent: 91/11495 (1991-08-01), None
patent: 91/11173 (1991-08-01), None
patent: 91/14422 (1991-10-01), None
patent: 93/11743 (1993-06-01), None
patent: 95/17195 (1995-06-01), Non
Fatania Kanu M.
Muller Helgert
Oliver Martin J.
Scott John S.
3M Innovative Properties Company
Howard MarySusan
McQueeney P.
Page Thurman K.
Ringsred Ted K.
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