JPS6411615B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to new finely divided pressure pack formulations. Lecithin and various esters, especially sorbitan esters, such as sorbitan sesquioleate ["Arlacel" C], sorbitan monooleate ["Span" 80] and sorbitan trioleate ("Span") Sorbitan oleate, sorbitan monolaurate, polyoxyethylene sorbitol pentaoleate, and polyoxyethylene sorbitol tetraoleate, such as ``85), have traditionally been used for pressure-filling formulations of substances, especially for pressure-filling finely divided pharmaceuticals. Known as a surfactant for use in formulations. Propellant 11 (trichloromonofluoromethane) is used in formulations containing these surfactants. However, this propellant 11 has certain undesirable properties. In a common method for producing pressure-filled formulations, the compound to be formulated, e.g. a drug, and one of the surfactants mentioned above are combined in a mixture of propellant 11 or propellant 114 (1,2-dichloro-1 , 1,2,2-tetrafluoroethane), so-called "concentrates" or "nucleus suspensions" are produced. These concentrates can be handled at room temperature or slightly below room temperature because the propellant has a relatively high boiling point. However, lecithin and the aforementioned esters are known to be extremely difficult to disperse in propellant 114, so these surfactants are dispersed in propellant 11. Other propellants with lower boiling points have not been used because the surfactants do not dissolve in the other propellants at low temperatures and are solid at such low temperatures. be. The present inventors have now discovered that lecithin and the aforementioned esters can be stably dispersed in a mixture of propellant 12 (dichlorodifluoromethane) and propellant 114. According to the invention, therefore, lecithin or sorbitan or sorbitol ester is used as a propellant.
12 and propellant 114, the dispersion or suspension contains propellant 12 in excess of propellant 114. , and does not contain propellant 11, and the dispersion or suspension is mixed with a finely divided medicament, and the medicament is disodium cromoglycate, lecithin or Inhalable dispersions or suspensions of sorbitan or sorbitol esters are provided. The dispersion or suspension of the present invention contains lecithin, sorbitan ester or sorbitol ester,
Propellant 12 and propellant at a temperature below about -30℃, e.g. -40℃ using a high dispersion mixer.
It can be adjusted by adding it to a mixture with 114.
Preferably, the dispersion contains less than 4.0% by weight of lecithin or sorbitan or sorbitol ester, for example from 0.2 to 2.0%. Although the surfactant solidifies during preparation of the dispersion or suspension, it is readily dispersed as fine, discrete particles in the mixture of propellant 12 and propellant 114. The resulting dispersion or suspension is usually stable for at least 30 minutes. The dispersion or suspension obtained by dispersing the surfactant in a mixture of propellant 12 and propellant 114 can be mixed with the finely divided disodium cromoglycate to be administered from a pressure-filled container. . Preferably, the disodium cromoglycate is dried before use. Preferably, the disodium cromoglycate has a mass median diameter of 0.01 to 10 microns. Finely divided disodium cromoglycate accounts for 0.05-15% of the dispersion, preferably 0.1-10.0%, most preferably 1-5%
It is preferable that the Additionally, propellant 12 and/or propellant 114 (cooled to a suitable temperature, e.g. -50°C) may be added to the original dispersion or finely divided material desired to be administered. It can be added to the original dispersion containing. The weight ratio of propellant 12 to propellant 114 in the final mixture is between 2 and 1.5:1, preferably about
The ratio is 1.5:1. That is, propellant 12 is used in excess of propellant 114. In the dispersion or suspension of the surfactant in the final mixture of propellant 12 and propellant 114, lecithin or sorbitan or sorbitol ester is present in an amount of 0.15 to 2.0% by weight, preferably 0.2 to 1.2% by weight. It is preferable that the content is % by weight. In such a dispersion or suspension
Preferably, 0.05 to 2.0% by weight, preferably 0.2 to 2.0% by weight, of disodium cromoglycate is contained. 60 to 2 parts by weight of sorbitan ester
A dispersion or suspension dispersed in a mixture of 70 parts by weight of propellant 12 and 40 to 30 parts by weight of propellant 114 is stable at a temperature of -60°C for at least 16 hours. Particularly preferred are dispersions in which the surfactant is a sorbitan ester, such as sorbitan trioleate ("Span 80"). When using lecithin, it is preferable to use a vegetable one, such as soya lecithin. The composition of the present invention is preferably 1.0% by weight or less, more preferably 0.5% by weight or less, most preferably 0.2% by weight.
It is preferable that the following water is contained. A particular composition of the invention consists of a sorbitan ester, such as sorbitan trioleate, disodium cromoglycate, propellant 12 and propellant 114, and propellant 11
An inhalable composition is provided that is free of. Certain of the compositions of the present invention have the advantage of having a greater proportion of fine particles in the aerosol cloud than comparable compositions containing propellant 11 or the preparation of such formulations. It has the advantage that it can be used for A suitable method for determining the proportion of fine particles in an aerosol spray is described in J.Pharm.Pharmac.1973.25. Expanded Edition,
It is described on pages 32-36. Examples and comparative examples of the present invention are shown below. Preparation method of example composition: Add sorbitan ester to up to half of the amount of propellant 12 at -40°C while stirring using a high dispersion mixer.
dispersed inside. Dry disodium chromoglycate was added to the resulting dispersion and it was easily dispersed. Then add the remaining propellant 12 to -
Propellant 114, which was added at 50°C and also cooled to -50°C, was added. The mixture thus obtained is filled into a medicine bottle, which is then fitted with a valve, e.g. a metering valve, at the top of the bottle.

[Table] Stability Three vials fitted with metering valves and filled with the above formulation were each stored at 5°C, 25°C and 37°C for 12 months. Separately, two similar vials were stored for 6 months at (a) a temperature of 15-37°C and (b) a temperature of 45°C, respectively. As a result, during the test period, (a) the amount of disodium cromoglycate per shot, (b) the content of fine particles in the spray, or (c) the particle size of disodium cromoglycate No change was observed. Comparative Example Aerosol formulations A and B of disodium cromoglycate were prepared according to the following formulations.

[Table] Sorbitan ester was dispersed in half the amount of propellant 12 at -40°C while stirring with a high dispersion mixer. When dry disodium chromoglycate was added to the resulting dispersion, it was very easily dispersed. The remainder of propellant 12 was then added at -50°C, followed by propellant 114, which had also been cooled to -50°C. The resulting mixture was filled into a vial and the vial was fitted with a metering valve. Exactly the same preparation method, vial and metering valve were used for each batch. The above unit was tested in the following manner - 2 months after manufacture and 3.5 months after manufacture (stored at room temperature) 1 Appearance of Suspension The unit was cooled to -55°C and opened. Transfer the contents to a small glass container, seal the container,
After warming to room temperature, shaking and standing for 10 minutes, it was visually inspected.

Aggregates also remain in [Table].

Claims (1)

[Claims] 1. Lecithin or sorbitan or sorbitol ester as propellant 12 and propellant 114
an inhalable dispersion or suspension comprising propellant 12 in excess of propellant 114 and containing propellant 11 in excess of propellant 114. and that the dispersion or suspension is mixed with a finely divided medicament and the medicament is disodium cromoglycate.
Inhalable dispersions or suspensions of lecithin or sorbitan or sorbitol esters. 2. The inhalable dispersion or suspension according to claim 1, wherein the medicament has a mass average diameter of 0.01 to 10 microns. 3 Contains 0.05 to 15% by weight of finely ground pharmaceuticals,
An inhalable dispersion or suspension according to claim 2. 4 Contains 0.1 to 10% by weight of finely ground pharmaceuticals,
An inhalable dispersion or suspension according to claim 3. 5. The inhalable dispersion or suspension according to claim 4, which contains 1 to 5% by weight of a finely ground medicament. 6. An inhalable dispersion or suspension according to any one of claims 1 to 5, wherein the ratio of propellant 12:propellant 114 is from 2:1 to 1.5:1. 7 The ratio of propellant 12:propellant 114 is
An inhalable dispersion or suspension according to claim 6, wherein the ratio is 1.5:1. 8. The inhalable dispersion or suspension according to any one of claims 1 to 7, containing 0.15 to 2.0 parts by weight of lecithin or sorbitan or sorbitol ester. 9. An inhalable dispersion or suspension according to claim 8, containing from 0.2 to 1.2 parts by weight of lecithin or sorbitan or sorbitol ester. 10. The inhalable dispersion or suspension according to any one of claims 3 to 9, containing 0.05 to 2.0 parts by weight of a medicament. 11. The inhalable dispersion or suspension according to any one of claims 1 to 10, which contains a sorbitan ester. 12 The ester is sorbitan oleate,
An inhalable dispersion or suspension according to claim 11. 13 The ester is sorbitan sesquioleate,
13. An inhalable dispersion or suspension according to claim 12, which is sorbitan monooleate or sorbitan monolaurate. 14. The inhalable dispersion or suspension according to claim 12, wherein the ester is sorbitan trioleate. 15. An inhalable dispersion or suspension according to any one of claims 1 to 14, containing less than 1% by weight of water.