Title:  Propellant mixtures and aerosols for micronizing medicaments with compressed gas

United States Patent:  6,228,346

Assignee:  Pari GmbH Spezialisten fur Effektive Inhalation (Starnberg, DE)

Filed:  December 9, 1998

PCT NO:  PCT/EP97/02149

102(e) Date:  December 9, 1998

PCT PUB. Date:  November 6, 1997

Foreign Application Priority Data:  Apr 25, 1996[DE] (196 16 573)

Propellant mixtures and medicament aerosols which contain them are described for micronizing medicaments for pulmonary use. The propellant mixture is in a subcritical state and contains at least one component from a first class of propellant gasses and at least one component from a second class of propellant gasses. The first class includes propellant gasses with an evaporation enthalpy of 200 kJ/kg or less at 25^oC. and a vapor pressure of 20 bars or more at 25^oC., and the second class includes propellant gasses with an evaporation enthalpy of 300 kJ/kg or more at 25^oC. and a vapor pressure of 10 bars or less at 25^oC. By using this propellant mixture in a medicament aerosol, micronized medicaments are obtained in which approximately 80% by weight of the generated particles have less than 8 .mu.m diameter.

DETAILED DESCRIPTION OF THE INVENTION

Key characteristics of representatives of the two propellant gas classes used according to the invention are as follows.

Propellant gas class 1:

At room temperature (25^oC.), these gases exhibit a high vapor pressure of 20 bar or more, preferably 20 to 70 bar, and a small evaporation enthalpy of 200 kJ/kg or less, preferably 180 to 50 kJ/kg. Such gases include sulfur hexafluoride, carbon dioxide and ethane. Their poor dissolving capacity as regards the majority of organic substances, particularly pharmaceuticals, is typical.

Propellant gas class 2:

These gases have, on the other hand, a relatively low vapor pressure at room temperature (25^oC.) of 10 bar or less, preferably 2 to 10 bar, and a high evaporation enthalpy at 25^oC. of 300 kJ/kg or more, preferably 340 to 450 kJ/kg. Preferred agents are dimethyl ether, propane, butane and pentane. These gases frequently exhibit a good dissolving capacity for a great many organic substances.

The invention also relates to a pharmaceutical aerosol for pulmonary application; in addition to one or more pharmaceutical substances, this aerosol contains the aforementioned propellant mixture.

The propellant mixtures according to the invention preferably contain one or more propellant gases from the 1st propellant gas class having a percentage content, relative to the propellant mixture, of 10 to 80 wt. %, with particular preference for 15 to 60 wt. %, and one or more propellant gases from the 2nd propellant gas class having a percentage content ranging from 20 to 90 wt. %, with particular preference for 40 to 85 wt. %. The propellant mixture may also contain other propellant gases, though it preferably comprises just those from Classes 1 and 2. The pharmaceutical may be present in the aerosol composition in a dissolved state (solution aerosol) or in a suspended state (suspension aerosol).

As far as a suspension aerosol is concerned, what is also of consequence is the original particle size of the pharmaceutical to be suspended in the propellant mixture. Since the particle size is indeed (undesirably) increased during the spraying process, but virtually cannot be reduced in size, the pharmaceutical should already be present in a sufficiently fine form before being introduced into the propellant, i.e. reduced to a particle diameter of less than 8 .mu.m. The fine particles can also be more easily suspended.

On account of their physical properties, such as vapor pressure and evaporation enthalpy, the propellant combinations of sulfur hexafluoride and butane, sulfur hexafluoride and dimethyl ether, ethane and butane, and ethane and dimethyl ether are particularly suitable for a suspension aerosol. Due to the excellent dissolving capacity of dimethyl ether, the propellant combinations of sulfur hexafluoride and dimethyl ether, and ethane and dimethyl ether are particularly suitable for a solution aerosol.

Many drugs are easily soluble in lower alcohols such as ethanol, propanol or isopropanol, as well as water, acetone and several other solvents. To improve the solubility of pharmaceuticals in a propellant gas mixture used according to the invention in a solution aerosol, compounds such as solubilizers or entrainers can be added thereto.

Surfactants are frequently added in a suspension aerosol for enhanced suspension of the pharmaceutical. A suspension aerosol formulation requires the surfactant used to be soluble in the propellant mixture. The conventional surfactants, such as oleic acid, lecithin and sorbitan trioleate, are easily soluble in the 2nd propellant gas class and are also soluble in the propellant gas mixture used here. In consequence, such surfactants can be used without difficulty in the production of a suspension aerosol formulation.

The propellant mixture according to the invention is used in the subcritical state in a pharmaceutical aerosol for pulmonary application so as to micronize the pharmaceutical, with about 80 wt. %, preferably about 90 wt. % and particularly preferably about 100 wt. % of the micronized pharmaceutical particles, i.e. those generated by spraying, having a diameter of less than 8 .mu.m. In another preferred embodiment, about 80 wt. %, preferably about 90 wt. % and particularly preferably about 100 wt. % of the micronized pharmaceutical particles have a diameter of less than 5 .mu.m. The percentages each relate to the total mass of the produced pharmaceutical particles "dried" after evaporating the propellant. These particles therefore have a smaller mass and are not so easily precipitated in the mouthpiece of the metered dose aerosol or in the spacer. Improved respirability means that not only the bronchial or upper pulmonary region, but also more deeply lying sections of the lungs and pulmonary alveoli are reached. This is not only a decisive advantage when the lung itself represents the affected organ to be treated, the resorption of systemic-action pharmaceuticals is also improved.

According to the invention, the propellant mixture is used in a pharmaceutical composition, viz. a pharmaceutical aerosol, for pulmonary application. The amount of propellant mixture in the finished pharmaceutical aerosol is preferably 80 to 99.99 wt. %, with particular preference for 90 to 99.99 wt. %. In addition to the pharmaceutical, this composition contains the above-described propellant mixture and optionally other common, pharmaceutically compatible diluents, excipients, entrainers, solubilizers and surfactants. The pharmaceutical may be present in the aerosol composition as a solution or suspension with a percentage content of 0.01 to 5 wt. %, preferably 0.03 to 1 wt. %. The operating pressure of the composition is 2 to 100, preferably 3 to 50 bar, with particular preference for 5 to 20 bar. For micronization, a spray nozzle common for this purpose is used.

In a preferred embodiment of the newly developed pharmaceutical aerosol, the propellant mixture solely comprises one or more components from the above two classes. The aforementioned solubilizers and/or surfactants can also be optionally present.

To achieve specific or improved effects, a combination of different active ingredients with varying percentage contents can be used in an aerosol formulation, e.g. combinations of ipratropium bromide and fenoterol, salbutamol and disodium cromoglicinic acid, and salbutamol and beclometason-17,21-dipropionate.

In all those instances in which a surfactant is used, the weight ratio of pharmaceutical to surfactant ranges from 100:1 to 1:100, preferably from 20:1 to 1:10.

According to the invention, the pharmaceutical aerosol formulations, each relative to the total formulation, preferably have the following compositions unless otherwise indicated:

Propellant gas class 1: 10 to 80 wt. %, particularly preferred 15 to 60 wt. %

Propellant gas class 2: 20 to 90 wt. %, particularly preferred 40 to 85 wt. %

(each relative to the propellant mixture)

Propellant mixture: 80 to 99.99 wt. %, particularly preferred 90 to 99.99 wt. %

Pharmaceuticals: 0.01 to 5 wt. %, particularly preferred 0.03 to 1 wt. %

Surfactants: up to S wt. %, particularly preferred up to 1 wt. %

Solubilizers (entrainers): up to 10 wt. %, particularly preferred up to 2 wt. %.

(each relative to finished pharmaceutical aerosols)

Claim 1 of 31 Claims

What is claimed is:

1. A propellant mixture for pharmaceutical aerosols for micronizing the pharmaceuticals for pulmonary application, wherein

said propellant mixture exists in a subcritical state and includes at least one component from a first class of propellant gases and at least one component from a second class of propellant gases,

said first class comprising propellant gases having an evaporation enthalpy at 25^oC. of 200 kJ/kg or less and a vapor pressure at 25^oC. of 20 bar or more, and

said second class comprising propellant gases having an evaporation enthalpy at 25^oC. of 300 kJ/kg or more and a vapor pressure at 25^oC. of 10 bar or less,

wherein at least about 80 wt. % of the micronized pharmaceuticals have a diameter of less than 8 .mu.m.

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