JPH0780069A - Aerosol pharmaceutical containing procatherol - Google Patents

Abstract

PURPOSE:To prepare the aerosol pharmeceutical with which effective particles at the time of injecting are sufficiently obtd., redispersibility after long-term preservation is good and a change in grain size after the long-term preservation hardly arises by incorporating procatherol or its salt, 1, 1, 1, 2-tetrafluoroethane, isopentane, n-butane and lecithin therein. CONSTITUTION:The procatherol or its salt, 1, 1, 1, 2-tetrafluoroethane, isopentane, n-butane and lecithin are incorporated into this aerosol pharmeceutical. The injecting agents constituting the aerosol pharmeceutical are the 1, 1, 1, 2-tetrafluoroethane, isopentane and n-butane and, therefore, there is no possibility of destroying the ozone stratosphere and the effective particles at the time of injecting the procatherol or its salt are sufficiently obtd., the dispersibility is good and the redispersibility after long-term preservation is also good. The change in the grain size after the long-term preservation hardly arises.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aerosol preparation containing procaterol.

[0002]

BACKGROUND OF THE INVENTION Procaterol and its salts are known compounds as bronchodilators and the like (JP-A-60-
No. 120864), which has already been used in the form of an aerosol preparation. Currently used aerosol formulations include liquefied chlorofluorocarbon (CF) as a propellant.
C) is used, but this CFC reacts with the atmospheric ozone layer and destroys the ozone layer, which causes a serious problem such as skin damage due to ultraviolet rays.

Therefore, there is an urgent need to replace CFCs involved in ozone depletion with other propellants that are more environmentally acceptable.

The present inventor has conducted various studies on aerosol preparations containing procaterol. JP-A-2
-2006267 discloses a drug, 1,1,1,2-tetrafluoroethane, a surfactant and 1,1,1,2-
Aerosol formulations are disclosed that include at least one compound that is more polar than tetrafluoroethane. However, in this publication, there is no disclosure of procaterol or a salt thereof as a medicine, and it may be difficult to formulate with the formulations specifically shown as examples in the publication,
It has been found that the use of procaterol or a salt thereof as a drug in these formulations causes the following inconvenience, and the desired aerosol formulation cannot be produced at all. That is, Example 1, Example 7, Example 9, and Example 1 of the publication
In the formulations of 3, Example 15 and Examples 19-22, the solubility of sorbitan trioleate (surfactant, Span 85) or lecithin (Lipoid S100) in 1,1,1,2-tetrafluoroethane (P134a) was determined. Due to the low level, formulation was difficult. Further, in the formulations of Example 2, Example 8 and Example 14 of the publication, when procaterol hydrochloride is used as a medicine, it is unavoidable that procaterol hydrochloride aggregates, and the deposition rate in the lung decreases. There was a problem. Further, in the formulations of Examples 4 to 6, Example 10 to 12 and Examples 16 to 18 of the publication, since ethanol is contained, it is difficult to control the particle size of procaterol hydrochloride when procaterol hydrochloride is used as a drug. There was a problem. Further, the formulation of Example 23 of the publication had a safety problem because it required an extremely high pressure. As described above, all the formulations disclosed in the above publications have problems, and it was considered that the technique of the publication cannot be applied to aerosol preparations containing procaterol.

[0005]

The present inventor, while repeating the above research, uses a mixture of 1,1,1,2-tetrafluoroethane, isopentane and n-butane as a propellant, and further blends lecithin. By doing so, not only the above problems are solved, but effective particles at the time of injection of procaterol or a salt thereof are sufficiently obtained, the dispersibility is good, and the redispersibility after long-term storage is good. It has been found that an excellent aerosol preparation can be obtained in which changes in particle size distribution after long-term storage hardly occur. The present invention has been completed based on such knowledge.

That is, the present invention relates to an aerosol preparation containing procaterol or a salt thereof, 1,1,1,2-tetrafluoroethane, isopentane, n-butane and lecithin.

In the aerosol preparation of the present invention, the compounding amount of procaterol or its salt is not particularly limited as long as it can exert its effect, but it is usually 0.00
2 to 0.08% by weight, preferably 0.01 to 0.05% by weight. In addition, 1 of the aerosol formulation of the present invention
Procaterol or its salt is usually 1 to 40μ during spraying.
g, preferably 5 to 20 μg. The salts of procaterol include usual pharmaceutically acceptable acid addition salts such as salts of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid and lactic acid. It

In the present invention, 1, 1, 1, 2 are used as the propellant.
It is essential to use a mixture of tetrafluoroethane, isopentane and n-butane. When a high boiling point compound is used as a propellant, (1) the vapor pressure becomes low and the injection force becomes small, (2) the non-volatile component (high boiling point compound) surrounds the procaterol or its salt immediately after injection, However, there is a problem that the particle size is larger than that of procaterol, etc., and the deposition rate in the lung is extremely small. In the present invention,
It has been found that the combination of 1,1,1,2-tetrafluoroethane / isopentane / n-butane is the most effective as a propellant having an appropriate vapor pressure and volatilizing immediately after injection. is there.

In the present invention, 1,1,1,2-tetrafluoroethane is preferably present in the aerosol preparation in an amount of 40 to 60% by weight, preferably about 50% by weight. The mixing ratio of 1,1,1,2-tetrafluoroethane, isopentane and n-butane is usually 1,1,
Isopentane is usually used in an amount of about 30 to 70 parts by weight, preferably 50 parts by weight, based on 100 parts by weight of 1,2-tetrafluoroethane.
About 30 parts by weight of n-butane, and preferably about 50 parts by weight of n-butane, respectively, may be added. If the blending ratio of 1,1,1,2-tetrafluoroethane is too large, a stable suspension system cannot be obtained, and conversely, if it is too small, the vapor pressure becomes low and the injection force becomes small. . If the blending ratio of isopentane and n-butane is too large or too small, an appropriate vapor pressure cannot be obtained, and neither is preferable.

As the lecithin to be added to the aerosol preparation of the present invention, conventionally known ones can be widely used, and examples thereof include those derived from plants such as soybean, those derived from animals such as egg yolk, and hydrogenated lecithin. it can. The content of lecithin is usually 0.01 to 0.1% by weight, preferably 0.02 to 0.06% by weight in the preparation. If the amount of lecithin compounded is too large, insoluble lecithin will be precipitated, and if it is too small, a stable suspension system will not be obtained.

In the aerosol preparation of the present invention, various components conventionally used such as nonionic surfactants, oils, seasonings, etc. are added within a range that does not reduce the stability or the ratio of effective particles of the aerosol preparation of the present invention. Can be added appropriately.

In preparing the aerosol preparation of the present invention, there is no particular limitation, and conventional methods can be widely applied. For example, (1) Add a propellant, a dispersant, and finely ground bulk powder into an airtight preparation tank to obtain a uniform dispersion system under pressure.
Cool the preparation tank, put it in a liquid state at normal pressure, and (3) cool it,
Fill the aerosol container with a small amount of the prepared liquid, (4) attach a metering valve, crimp it, (5) perform a weight inspection with a weight checker, then perform a leakage inspection with a water bath, and (6) package after injection inspection. Good.

There is no particular limitation in using the aerosol preparation of the present invention, and it may be used in the same manner as the conventional aerosol preparation. For example, it is good to hold the actuator in your mouth, inhale the sprayed drug while inhaling a lot, hold your breath for a few seconds, and then exhale slowly.

The aerosol preparation of the present invention is preferably administered at 1 to 2 injections per adult. The daily dose of the aerosol preparation of the present invention is not particularly limited and may be appropriately selected depending on the age, sex, weight of the patient, degree of disease and the like.

[0015]

Since the propellants constituting the aerosol preparation of the present invention are 1,1,1,2-tetrafluoroethane, isopentane and n-butane, there is no risk of depleting the ozone layer. It has no environmental problems. Further, in the aerosol formulation of the present invention, effective particles at the time of injection of procaterol or a salt thereof are sufficiently obtained, the dispersibility is good, and the redispersibility after long-term storage is good, and the particle size distribution after long-term storage. It has excellent performance that has never existed and that changes are unlikely to occur.

[0016]

[Examples] The present invention is further clarified by listing formulation examples and test examples below.

Formulation Example 1 Procaterol Hydrochloride 0.220 g 1,1,1,2-Tetrafluoroethane 500 g Isopentane 250 g n-Butane 250 g Soybean lecithin 0.300 g The above-mentioned various components were blended to prepare an aerosol formulation according to a conventional method.

Formulation Example 2 Procaterol Hydrochloride 0.220 g 1,1,1,2-Tetrafluoroethane 500 g Isopentane 250 g n-Butane 250 g Soybean lecithin 0.400 g The above-mentioned various components were blended to prepare an aerosol formulation according to a conventional method.

Formulation Example 3 Procaterol Hydrochloride 0.220 g 1,1,1,2-Tetrafluoroethane 500 g Isopentane 250 g n-Butane 250 g Soybean lecithin 0.500 g The above-mentioned various components were blended to prepare an aerosol formulation according to a conventional method.

Formulation Example 4 Procaterol Hydrochloride 0.220 g 1,1,1,2-Tetrafluoroethane 500 g Isopentane 250 g n-Butane 250 g Soybean lecithin 0.600 g The above-mentioned various components were blended to prepare an aerosol formulation according to a conventional method.

Test Example 1 With respect to the aerosol preparations obtained in the above Preparation Examples 1, 3 and 4, the ratio (%) of effective particles (4.7 μm or less) at the time of production and when stored at 37 ° C. for 1 month was determined according to the Andersen method. It was measured. The results are shown in Table 1.

[0022]

[Table 1]

Test Example 2 The aerosol preparation obtained in the above Preparation Example 2 was stored at room temperature for 3 months, 6 months, 9 months and 12 months, and at 37 ° C. for 1 month, 3 months, 6 months and 9 months at the time of production. The ratio (%) of effective particles (4.7 μm or less) at that time was measured in the same manner as in Test Example 1. The results are shown in Table 2.

[0024]

[Table 2]

Claims (1)

[Claims] 1. Procaterol or a salt thereof, 1,1,
An aerosol formulation containing 1,2-tetrafluoroethane, isopentane, n-butane and lecithin.