MXPA99010646A - Medicinal aerosol products - Google Patents

Abstract

A pharmaceutical aerosol formulation suitable for oral and/or nasal inhalation including the anti-inflammatory drug ciclesonide, hydrofluorocarbon propellants such as HFC 134a and/or 227, and ethanol in an amount sufficient to solubilize the ciclesonide (and various optional ingredients, such as surfactant). The formulations exhibit very desirable physical and chemical stability, as well as excellent delivery characteristics.

Description

AEROSOL MEDICINE PRODUCTS DESCRIPTION OF THE INVENTION This invention relates to aerosol medicinal products and in particular to medicinal products containing an ester of pregna-1,4-diene-3, 20-dione-16-17-acetal-21 , suitable for administration by inhalation. GB-2247680 describes esters pregna-1, 4-diene-3, 20-diene-16-17-acetal-21 and its use in the treatment of inflammatory conditions. The compound has the general structure: - wherein Ri is 2-propyl, 1-butyl, 2-butyl, cyclohexyl or phenyl; and R2 is acetyl or isobutanoyl. Cyclosonide is 11β, 16α, 1,4-diene-3, 20-diene of 17, 21-tetrahydroxypregna, 16, 17-acetalicyclic with cyclohexanecarboxaldehyde, 21-isobutyrate having the structure of formula (I) without atoms of fluorine and in which Ri is cyclohexyl and R 2 is isobutanoyl. This compound has an experienced evaluation as an antiasthmatic and pharmacokinetic study showing that it would be useful in an inhaler formulation. Cyclosonide is absorbed only moderately after oral administration and has low systemic activity. The concentration of the drug in the lungs is high and the metabolism by the oxidases of the liver is very high, giving the drug a half life of low plasma. The systemic activity of cyclosonide is three times lower than that of budasonide but the anti-inflammatory activity is high for the trainer. GB-2247680 proposes a specific pressurized aerosol formulation to release cyclosonide by oral and nasal inhalation. The described formulation consists of cyclosonide as a micronized suspension of particles, sorbitan trioleate surfactant and a mixture of three CFC propellants: trichloro-fluoromethane, dichlorotetra-fluoromethane, and dichlorofluoromethane. However, these CFC propellants are now considered to cause the degradation of stratospheric ozone and there is a need to provide aerosol formulations for medicaments employing so-called "ozone-favorable" propellants. * A class of propellants that are considered to have minimal effects of decreased ozone compared to conventional chlorofluorocarbons comprise hydrofluorocarbons and a number of medicinal aerosol formulations using such propellant systems are described in, for example, EP 0372777, O91 / 04011 , W091 / 11173, W091 / 11495, 091/14422, 093/11743, and EP-0553298. These applications are all concerned with the preparation of pressurized aerosols for the administration of medicaments and seek to overcome the problems associated with the use of this new class of propellants, in particular the stability problems associated with the pharmaceutical formulations prepared. The applications propose, for example, the addition of one or more of the adjuvants such as alcohols, alkanes, dimethyl esters, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates etc.). However, despite several methods used in drugs formulated for use in aerosol inhalation, there are still many serious difficulties and uncertainties often involved in the attempt to develop a stable CFC-free physical and chemical formulation that confidently sends a dose correct drug that has the proper particle size range. In particular, there is a need for a CFC-free medicinal aerosol product "containing cyclosonide (or similar molecules) that is chemically and physically stable and that is suitable for delivery to a patient's respiratory system. better than the prior art methodology of formulating cyclosonide as a suspension the cyclosonide can be very beneficially formulated, as a physically and chemically stable solution in formulations including hydrofluorocarbon propellants In accordance with the present invention there is provided a pharmaceutical composition comprising a Therapeutically effective amount of a compound of the formula: wherein: Ri is 1-butyl, 2-butyl, cyclohexyl or phenyl and R 2 is acetyl or isobutanoyl, and a hydrofluorocarbon propellant, propellant preferably selected from 1,1,1,1-tetrafluoroethane, 1,1,1,3,3,3-heptafluoropropane and a mixture thereof, and co-solvent, preferably ethanol, ethanol in an amount effective to solubilize the compound of the formula I) and optionally a surfactant. The compound of the formula (I) is preferably cyclosonide and is generally present in a concentration of 1 to 8 mg / ml, preferably 1 to 5 mg / ml. The formulation generally comprises from 3 to 25%, preferably from 5 to 20%, more preferably from 7 to 12% by weight of ethanol. The propellant preferably includes a hydrofluoroalkane, in particular Propellant 134a, Propellant 227 or a mixture thereof, generally about 50: 50 p / p. More preferably the propellant consists of Propellan 134a. 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 of cyclosonide, 8% by weight of ethanol and Propellan 134a. The formulations can be prepared by adding the required amount of the drug in an aerosol bottle, crimping a valve in the flask and introducing a premixed emulsion of propellants and ethanol through the valve. The bottle is placed in an ultrasonic bath to ensure solubilization of the drug.

Alternatively, the formulations can be prepared by preparing a concentrate drug with ethanol and adding this concentrate to the propellant pre-cooled in a dosing container. The resulting formulation is filled into jars. The formulations can be filled in plastic, metal or glass jars. Suitable plastic materials include polyethylene sterephthalate; a preferred metal is aluminum. The bottles are equipped with a metered dose distribution valve, for example, 50 μl dispersion with each operation. A suitable metered dose dispersion valve comprises a valve clamp having a flange and associated flange gasket for interconnecting the aerosol canister and an opening therethrough; a measuring tank having walls that define an internal, external measuring chamber, an inlet orifice, an inlet end and an outlet end; an elongated 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 sealed engagement with the valve clamp, the discharge end of the valve stem passes through both of the valve clamp opening and the outlet end of the metering tank and it is in sliding seal coupling with the valve clamp; wherein the filling end of the valve stem passes through and is in slidable engagement with the inlet of the metering tank and a canister void surrounding the metering tank and the filling end of the elongate valve stem and that defines a passage between the measuring tank and the emptying of the can allows communication between the internal hole of the measuring tank and the aerosol can; . Where the valve stem is movable between a closed extended position where the filling channel of the valve stem allows communication to be opened, by means of the internal orifice, between the inside and the outside of the measuring chamber, and where the end The outlet of the metering tank is closed, and a compressed open position where the internal orifice of the metering tank is in sealed engagement with the filling end of the valve stem and the discharge port of the valve stem allowing communication between the inside and outside of the measuring chamber. A suitable valve is commercially available under the brand name SPRAYMISER.

The invention will now be described with reference to the accompanying drawings in which: Figure 1 depicts a cross section through a metered dose dispersing the valve suitable for use in the invention, Figure 2 depicts a cross section longitudinally through an adapter for accommodating an aerosol canister equipped with a metered dose distribution valve, according to the invention, Figure 3 represents a front view of the adapter shown in Figure 2, and, Figure 4 represents a detailed section of the area X shown in Figure 2. The valve illustrated in Figure 1 comprises a valve clamp (2) and an associated flange gasket (4) for coupling an aerosol canister. The flange packing (4) may conveniently comprise an ethylene-butylene copolymer, for example the copolymer commercially available from Union Carbide under the tradename FLEXOMER GERS 1085NT. A metering tank (6) has walls defining a metering chamber (8) having an inner end associated with a seal (10) and an output end associated with a diaphragm (12). An elongated valve stem (14) having a filling channel (16), a discharge end (18) and a discharge orifice (20) extending through the valve clamp and the measurement chamber in sealed engagement with the diaphragm ( 12) and the tank seal (10). The tank seal and the diaphragm may conveniently comprise a butadiene-acrylonitrile copolymer, for example Type DB-218 commercially available from American Gasket & Rubber Company. A canister vacuum (22) surrounding the measuring tank (6) and the valve stem such that a capillary channel (24) is defined between the measuring tank and the canister vacuum to allow passage of the aerosol formulation from the aerosol bottle to the inner end of the measuring chamber. The valve stem (14) is movable between a closed extended position where the filling channel (16) of the valve stem allows communication to be opened, through the internal orifice, between the inside and the outside of the measuring chamber, and in where the outlet end of the metering tank is closed, and a compressed open position where the internal orifice of the metering tank is in sealed engagement with the filling end or the "valve stem and discharge port of the valve stem" it allows to open communication between the inside and outside of the measuring chamber The valve stem (14) is rearranged to the extended position closed by the spring (15) Figures 2 to 4 illustrate a pressure and relief adapter for a aerosol flask equipped with the dispersion valve suitable for use in the invention The adapter comprises a body portion (30) and a nozzle (32) A plurality of flanges (3) 4) are positioned within the body portion (30) to place and support the aerosol can (not shown) in the correct position. The dispersion end of the elongate valve stem of the metered dose that disperses the valve that is positioned within the nozzle block (36). The adapter is made of polypropylene or high density polyethylene. However, to ensure a good seal between the valve stem (14) and the central opening (38) high density polyethylene is preferred. As shown in Figure 4, the nozzle block "(36) comprises a central opening (38) having a flashing aperture (40) to accommodate the valve stem.The valve head is inserted until it is contiguous with the flange. (42) In use, the patient inserts the nozzle in the mouth and presses the base of the aerosol canister while aspirating.The relative movement between the elongate valve stem and the measuring tank causes the discharge orifice to enter the tank. of measurement and the contents of it are distributed under pressure through the discharge end of the elongated valve stem to the internal chamber (44) in the nozzle block (36) and an outlet through the orifice (46). A pen of droplets of respirable dimension is directed from the orifice (46) in the mouthpiece (32) for inhalation by the patient. It has been found that the dimensions of the orifice (46) can have a profound effect on the respirable fraction of the formulation distributed from the adapter nozzle. Both of * the length of the pressure jet "1" and the diameter "d" of the orifice (46) affect the discharge of the lung from the formulation. This is sometimes evaluated by an "in vitro" test using an Andersen Cascade Impactor, as described in the U.S. Pharmacopoiea. An Andersen Breathable Dose is defined as the weight of the deliberate drug to plates 3 to 7 and the impactor filter for simple activation of the inhaler. The optimum dimensions also depend on the particular formulation to be dispensed. In general, the distribution of the drug increases with the increased orifice diameter "d" and with the increased pressure jet length "1" however, the Anderson Breathable Dose increases with the decrease in the diameter of the orifice "d" the selection of the particular dimensions of the nozzle orifice allows an Anderson Breathing Dose greater than 120 micrograms to be achieved through a product that delivers 200 micrograms of cyclosonide per ex-valve operation, without significant impairment of the Delivery of the Drug. Thus, the "patient" potentially deducts the benefit of an increase that the usual portion of the dispersed drug reaches the lungs without excessive drug increase in the actuator or the product falls short of the regulatory stipulations. 10% by weight of ethanol, particularly 8% by weight of ethanol, has to be found that the good respirable dose is achieved with an orifice diameter of "d" within the range of 0.20 to 0.33 mm, preferably around 0.28 mm and a jet stream length of "1" in the range of 0.30 to 0.60 mm preferably 0.50 mmf. The invention will be illustrated by the following examples: In each Example, the percentage of ethanol in the propellant / ethanol emulsion is named in parentheses. Example 1 Example 2 Example 4 Example 5 Example 6 Example 8 Example 9 Example 13 All of the formulations of Examples 1 to 15 are clear, colorless solutions, in which the cyclosonide was completely solubilized. Examples 13 to 15 are the subject of stability tests over different months and prove to be physically and chemically stable. Although the invention has been described in terms of preferred formulations and ingredients, it will be understood that those are not intended to be limiting. On the contrary, those skilled in the art will understand that various optional ingredients may be included, such as flavoring agents, preservatives, additional active ingredients, and the like, while still containing the present invention.

Claims (20)

1. CLAIMS 1. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula: wherein: Ri is 1-butyl, 2-butyl, cyclohexyl, or phenyl; and R2 is acetyl or isobutanoyl, and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof, and ethanol in an amount effective to solubilize the compound of the formula
2. (I) and optionally a surfactant. 2. The pharmaceutical composition according to claim 1, characterized in that the compound of the formula (I) is cyclosonide.
3. 3. The pharmaceutical composition according to claim 1, characterized in that it is free of surfactant.
4. 4. The pharmaceutical composition according to claim 1, characterized in that the composition comprises from 3 to 25% by weight of ethanol.
5. 5. The pharmaceutical composition according to claim 4, characterized in that the composition comprises from 5 to 20% by weight of ethanol.
6. 6. The pharmaceutical composition according to claim 5, characterized in that the composition comprises from 7 to 12% by weight of ethanol.
7. 7. The pharmaceutical composition according to claim 6, characterized in that the composition comprises 8% by weight of ethanol.
8. 8. The pharmaceutical composition according to claim 2, characterized in that it comprises from 1 to 8 mg / ml of cyclosonide.
9. 9. The pharmaceutical composition according to claim 1, characterized in that the propellant is 1,1,1,2-tetrafluoroethane.
10. 10. The pharmaceutical composition according to claim 1, characterized in that the propellant is 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical composition according to claim 9, characterized in that it consists of cyclosonide in a concentration of 1 to 5 mg / ml in an ethanol emulsion: 1,1,1,2-tetrafluoroethane with a ratio of 8:92 per weight. 12. The pharmaceutical product characterized in that it comprises an aerosol bottle equipped with a dispersion valve and containing a formulation according to claim 1. 13. The pharmaceutical composition according to claim 12, characterized in that the valve is a valve of dispersion of measurement dose. The pharmaceutical composition according to claim 13, characterized in that the valve comprises a valve clamp having a flange and associated flange gasket for employing the aerosol can and an opening therethrough; a measuring tank having walls defining an internal measuring chamber, an external one, an internal hole and an internal end and an external end; an elongated valve stem having a filling channel, a filling end and a discharge end and a discharge orifice; wherein the outlet end of the metering tank is in sealing engagement with the valve clamp, the discharge end of the valve stem passes through both of the valve clamp opening and the outer end of the metering tank and is in sliding seal coupled with the valve clamp; wherein the filling end of the valve stem passes through and is in sliding engagement with the internal orifice of the measuring tank and a canister void surrounding the measuring tank and the filling end of the elongated valve stem and defines a passage between the measuring tank and the canister vacuum allowing communication between the internal hole of the measuring tank and the aerosol can; wherein the valve stem is movable between an extended closed position where the valve trunk filling channel allows communication to be opened, through the internal orifice, between the inside and the outside of the measuring chamber, and where the end of the output of the measuring tank is closed, and an open compressed position where the internal orifice of the measuring tank is in sealing engagement with the filling end of the valve stem and the discharge opening of the valve stem allows communication between the interior and the outside of the measuring chamber. 15. The pharmaceutical product according to claim 14, characterized in that it additionally comprises an adapter having a body for containing the aerosol canister, - a nozzle block accommodating the discharge end of the valve stem and a nozzle. 16. The pharmaceutical product according to claim 15, characterized in that the nozzle block has an outlet orifice directed towards the nozzle, the outlet orifice has a diameter in the range of 0.20 to 0.33 mm. 17. The pharmaceutical product according to claim 16, characterized in that the outlet orifice has a diameter of approximately 0.28 mm. 18. The pharmaceutical product according to claim 17, characterized in that the outlet orifice has a pressure jet length in the range of 0.30 to 0.60 mm. 19. The pharmaceutical product according to claim 18, characterized in that the outlet orifice has a pressure jet length of 0.50 mm. 20. A pharmaceutical aerosol formulation contained in an aerosol canister equipped with a dispersion valve, the formulation characterized in that it comprises: a compound of the formula: wherein: Ri is 1-butyl, 2-butyl, cyclohexyl or phenyl and R2 is acetyl or isobutanoyl; a hydrofluorocarbon propellant; and the cosolvent in an amount effective to solubilize the compound of the formula (I).