Medicinal aerosol formulations

Details Medicinal aerosol formulations Medicinal aerosol formulations

2001-04-20

2002-11-05

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S046000, C424S489000, C128S200140, C128S200240

Reexamination Certificate

active

06475467

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to medicinal suspension aerosol formulations and to a novel use of cromoglycic acid and nedocromil salts.
BACKGROUND OF THE INVENTION
For the preparation of medicinal metered-dose aerosols, as a rule suitable propellants are only those which can be liquefied at room temperature and which lead on successive spraying of the contents to no or only in any case to a slight decrease in the internal pressure in the container. In the past, customarily chlorofluorocarbons (CFCs), such as trichloro-trifluoromethane (F11), dichlorodifluoromethane (F12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114), and occasionally also short-chain alkanes, such as propane, butane and isobutane, were used.
On account of the ozone problem, caused by the elimination of free-radical chlorine atoms from CFCs, in the Montreal Agreement many countries have come to an understanding that they will no longer use CFCs as propellants in future. Gases, such as carbon dioxide, nitrogen and the like, can admittedly be liquefied under pressure, but are not utilizable as propellants for metered-dose aerosols, because the internal pressure in the container very greatly decreases with increasing emptying. However, fluorinated alkanes, in particular hydrofluoroalkanes (in the context of the present invention also designated “HFA”) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), have proved suitable CFC substitutes for the medicinal area, as they are inert and have a very low toxicity. On account of their physical properties, such as pressure, density etc., they are particularly suitable for replacing CFCs such as F11, F12 and F114 as propellants in metered-dose aerosols.
However, it has been shown that the customary excipients used in CFC-containing metered-dose aerosols, such as lecithin, sorbitan trioleate and oleic acid, are only inadequately soluble in hydrofluoroalkanes, such as HFA 134 and HFA 227. It has therefore been proposed either to improve the solubility in a manner known per se by use of a cosolvent such as ethanol or to coat the active compound particles with the surface-active agent or—instead of this—to dispense with a surface-active agent or to use special, propellant-soluble surface-active agents. These proposals are found, for example, in U.S. Pat. Nos. 2,868,691, 3,014 844, DE-A-2 736 500, EP-A-0 372 777, WO-A-91/11495, EP-A-0 504 112, EP-B-0 550 031, WO-A-91/04011, EP-A-0 504 112 and WO-A-92/00 061.
It is generally known that in the case of suspension formulations only active compound particles which are smaller than 6 &mgr;m are respirable. For the desired deposition of the active compounds in the lungs, these must therefore be comminuted or micronized by means of specific processes, such as pinned-disk, ball or air-jet mills. A grinding process, however, as a rule leads to an increase in surface area, which is accompanied by an increase in the electrostatic charge of the micronized active compound, whereby the flow behaviour and the active compound dispersion is then usually impaired. As a result of the interfacial and charge activities, there is frequently an agglomeration of active compound particles or alternatively adsorption of active compound at interfaces, which becomes conspicuous, for example, in the accumulation on equipment or container surfaces.
In aerosol preparations in which the active compound is present suspended in liquefied propellant, deposition or ring formation can occur in the container at the position where the liquid phase changes into the gas phase. Without wetting the micronized active compound particles or conducting away charges and modifying their surface properties, suspensions can only be inadequately stabilized or kept in a dispersed state. The lack of wetting or dispersion of the active compound particles also has the result that these in many cases have a high tendency for adsorption and stick to surfaces, such as the container inner wall or the valve, which then leads to an underdosage and to a poor dosage accuracy from puff of spray to puff of spray. In the case of suspensions, it is therefore as a rule necessary to add a surface-active excipient or a lubricant in order to lower the adsorption on interfaces and to achieve an acceptable dosage accuracy. A change or reduction in the proportion of the inhalable, respirable particles, the so-called fine particle dose (FPD), occurring in the course of storage, which leads to a decrease in the activity of the aerosol formulation, is particularly problematical.
To overcome these problems, as a rule permitted surface-active substances are added, as have already been used earlier in the CFC-containing formulations. Alternatively to this, in certain cases a modification of the surface properties by means of various measures (e.g. coating) can help to minimize these undesired effects. Because, however, surface-active agents such as oleic acid, sorbitan trioleate and lecithin only dissolve inadequately in hydrofluoroalkanes such as HFA 134a and/or HFA 227, a polar cosolvent such as ethanol is or must be added so that the pharmaceutical technology problems can be controlled better.
If, however, ethanol is added in a higher concentration, the density of the propellant mixture decreases, which can lead to an undesired demixing, especially in the case of suspensions. Moreover, a “wet spray” can undesirably be obtained, because the propellant evaporates much more rapidly than ethanol. In addition, however, as a result of the increase in the solubility during storage, dissolving effects can occur which then lead to crystal growth and in turn to a reduction in the amount of inhalable, respirable particles, the so-called fine particle dose (FPD).
It is additionally disadvantageous that in the case of ethanol concentrations of, for example, 10% or more, the proportion of inhalable particles (<6 &mgr;m) decreases, because the spray can produce particles having a greater aerodynamic diameter on account of the different evaporation properties of ethanol and the propellant. As a result of this, there is a reduction in the fine particle dose (FPD) crucial for the activity. This may explain why most commercially available metered-dose aerosols have been formulated as suspensions.
In the case of ethanol-containing aerosols, there are moreover also occasionally problems of active compound stability in the case of suspension formulations. In addition, the active compound stability, the active compound dispersion and the fine particle dose can also be adversely affected by moisture.
To measure the aerodynamic particle size distribution or the FPD or fine particle fraction (FPF), impactors, such as the 5-stage multistage liquid impinger (MSLI) or 8-stage Andersen cascade impactor (ACI), which are described in Chapter <601> of the United States Pharmacopeia (USP) or in the inhalants monograph of the European Pharmacopeia (Ph. Eur.) are suitable. By means of the aerodynamic particle distribution, it is possible by means of a so-called “log-probability plot” (logarithmic representation of the probability distribution) to calculate the mean aerodynamic particle diameter (median mass aerodynamic diameter (MMAD)) of aerosol preparations. Using this information on particle distribution, information is obtained as to whether the active compound is more easily deposited in the upper or lower area of the lungs.
As follows from the preceding text, adherence to a high dosage accuracy, i.e. the constant release of active compound from puff of spray to puff of spray, is a fundamental problem of suspension metered-dose aerosols, which is made additionally difficult by the replacement of CFCs. In addition to the valve and actuator, the dosage accuracy essentially depends on the suspension properties, i.e. on how easily and homogeneously the active compound is dispersed in the propellant and how long the suspension remains in this labile equilibrium state without change in its physical properties. The maintenance of a high dosage accuracy in the case

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