IE47128B1

IE47128B1 - Pressurised aerosol formulation

Info

Publication number: IE47128B1
Application number: IE1432/78A
Authority: IE
Inventors: Buraun Kennesu
Original assignee: Fisons Ltd
Priority date: 1977-07-19
Filing date: 1978-07-17
Publication date: 1983-12-28
Also published as: FR2397833A1; SE7807934L; JPS6411615B2; DE2831419A1; BE869055A; CH627075A5; IT7825845A0; CA1112567A; IE781432L; DE2831419C2; NL7807625A; IL55161A0; AU522792B2; MY8400252A; SE443087B; JPS5435209A; NZ187894A; HK51585A; IT1158890B; IL55161A

Abstract

A dispersion or suspension of lecithin or of a sorbitan ester or of sorbitol in a propellant of dichlorodifluoromethane is free of trichloromonofluoromethane propellant. The surfactants are used in pressurised packaged compsns. particularly finely divided medicaments. The surfactants form stable dispersions in the propellant, avoiding the use of propellant which has certain undesirable properties. The compsn. pref. contains less than 0.2-2% surfactant. It pref. contains a finely divided medicament, esp. of dia. 0.01-10 mu, in an amt. of 1-5%.

Description

This invention relates to novel pressure pack formulations of fine powders.

Lecithin and various esters, notably sorbitan esters, e.g. sorbitan oleates such as sorbitan sesquioleate ('Arlacel C') sorbitan mono-oleate ('Span 80’) and sorbitan trioleate (’Span 85’), sorbitan monolaurate, polyoxyethylene sorbitol pentaoleate and polyoxyethylene sorbitol tetraoleate, have for some time been known as surfactants for use in pressure pack formulations of 1° materials and in particular for use in pressure pack formulations of finely divided medicaments. The formulation of these surfactants has involved the use of propellant 11 (trichloromonofluoromethane). Propellant 11 has however certain undesirable properties. The common practice in pressure pack manufacture is to make a so called 'concentrate' or 'nucleus suspension' of the conpound to be dispensed, e.g. the medicament, and one of the above surfactants in either propellant 11 or propellant 114 (1,2-dichloro-l,1,2,2tetrafluoroethahe). These concentrates may, because of the relatively high boiling point of the propellants, be handled at, or just below, room temperature. It·has however been found that lecithin and the esters mentioned above are extremely difficult to disperse in propellant 114 and these surfactants have therefore been dispersed in propellant 11. Other propellants of lower boiling point have not been used because these surfactants would not dissolve in these other propellants at the low temperatures - 2 47128 involved and furthermore would be solid at these low temperatures.

We have now found that lecithin and the above esters can be made into stable dispersions in propellant 12 (dichlorodifluoromethane).

According to our invention we provide a dispersion or suspension of lecithin or a sorbitan or sorbitol ester in propellant 12, the dispersion or suspension containing substantially no propellant 11. The dispersion may, if desired contain up to 25% by weight of propellant 114, but preferably contains no propellants other than propellant 12.

The dispersion may be made by adding the lecithin or the sorbitan or sorbitol ester to the propellant 12 (or to a mixture of propellants 12 and 114) at a temperature of below about -30°C, e.g. at -40°C, using a high dispersion mixer. The dispersion preferably emprises less than 4.0ί, e.g. from 0,2 to 2,01 w/w of the leicithin or of the sorbitan or sorbitol ester. In making the suspension the surfactant solidifies, but is readily dispersed as small discrete particles in the propellant 12 (or the mixture of propellants 12 and 114). The resulting dispersions are usually stable for at least 30 minutes.

The dispersion of the surfactant in the propellant 12 (or the mixture of propellants 12 and 114) can be mixed with the finely divided material which it is desired to dispense from the pressure pack. Suitable finely divided materials include medicaments and notably inhalation medicaments, e.g. bronchodilators such as - 3 47128 isoprenaline, orciprenaline, terbutalene, rimiterol, fenoterol, carbuterol or salbutamol or a pharmaceutically acceptable salt o£ any one thereof; topical steroids such as bedomethasone dipropionate, betamethasone valerate or triamcinolone acetonide; and compounds which prevent the release of mediators of anaphylaxis such as disodium cromoglycate. When disodium cromoglycate is used we prefer it to be dried before use. When the medicament is to be inhaled we prefer that it has a mass median diameter in the range 0.01 to 10 microns. We prefer the finely divided material to comprise from 0.05 to 15., preferably from 0.1 to 10.0 and most preferably from 1 to 5$ of the dispersion. Further propellant 12 and/or propellant 114 (appropriately cooled, e.g. to -50°C) may be added to the original dispersion or the original dispersion containing the finely divided material which it is desired to dispense.

According to our invention we also provide a dispersion or suspension of lecithin or a sorbitan or sorbitol ester in a mixture of propellant 12 and propellant 114, the dispersion or suspension containing no propellant 11, and preferably containing no other propellants whatsoever.

We prefer the ratio of propellant 12 to propellant 114 in the final mixture to be in the range 2 to 1:1, and preferably about 1,5:1 by weight; i.e. we prefer an excess of propellant 12 over propellant 114.

We prefer the dispersion or suspension of the surfactant in the final mixture of propellants 12 and 114 to contain from 0.15 to - 4 47128 2.04, preferably 0.2 to 1.2% by weight of lecithin or of the sorbitan or sorbitol ester. We also prefer such dispersions or suspensions to contain from 0.05 to 2.04, and preferably from 0.2 to 2.04, by weight of medicament, e.g. disodium cromoglycate.

Dispersions of from 0.2 to 2 parts by weight of sorbitan ester in a mixture of from 50 to 70 parts by weight of propellant 12 and from 50 to 30 parts by weight of propellant 114 are stable for at least 16 hours at a temperature of -60°C.

We particularly prefer dispersions in which the surfactant is a sorbitan ester, e.g. sorbitan trioleate ('Span 80'). When lecithin is used we prefer it to be vegetable, e.g. soya, lecithin The expositions according to the invention preferably contain less than 1.04, more preferably less than 0.54 and most preferably less than 0.24 by weight of water.

As a particular facet of our invention we provide a mixture comprising a sorbitan ester, e.g. sorbitan trioleate, disodium cromoglycate, propellant 12, propellant 114 and no propellant 11.

Certain expositions according to the invention are advantageous in that they either give a higher proportion of fine particles in the aerosol cloud produced, or that they can be used to produce such formulations, as compared to equivalent compositions containing propellant 11. A suitable method of determining the proportion of fine particles produced in an aerosol cloud is described in J Pharm, Pharmac. 1973, 25, Suppl. 32P-36P. - 5 47128 The invention is illustrated, but in no way limited, by the following Examples.

Example 1 Method.

The sorbitan ester is dispersed in up to half the propellant 12 at -40°C while stirring with a high dispersion mixer. The drydrug is added to the resulting dispersion and disperses in it very readily. The balance of the propellant 12 is then added at -50°C, followed by the propellant 114 also cooled to -50°C. The resulting mixtures are then filled into vials onto which valves, e.g. metering valves, are subsequently crimped.

Ingredients t Table i w/w I w/w Dried micronised disodium cromoglycate O.36OS 1.4420 Sorbitan trioleate 0.2500 1.0000 Propellant 114 39.7558 39..0232 Propellant 12 59.6337 58.5348 Stability Batches of vials fitted with metering valves and containing the above formulations were stored at 5°C, 25°C and 37°C respectively for a period of 12 months. Two further batches of vials were stored at respectively (a) temperatures which varied from 1S°C th 37°C, and (b) at a temperature of 45°C for a period - 6 47138 ' of 6 months. No change in (a) the amount of disodium cromoglycate dispersed per shot, (b) the content of fine particles in the cloud or (c) the crystal size of the sodium cromoglycate was observed over the period of observation.

Example 2 Using the method described in Example 1 the following compositions were made and filled into vials. (a) Beclomethasone dipropionate, SO^g/dose t w/w 10 Beclomethasone dipropionate, micronised 0.0729 Sorbitan monolaurate 0.2187 Propellant 114 29.9125 Propellant 12 69.7959 Cb) Betamethasone valerate, 100 ^g/dose 15 I w/w Betamethasone valerate, micronised 0.1442 Sorbitan sesquioleate; 0.3605 Propellant 114 39.7981 Propellant 12 59.6972 20 Cc) Orciprenaline sulphate, 750 ztg/dose t w/w Orciprenaline sulphate, micronised 1.0707 Sorbitan monolaurate 1.9935 Propellant 114 48.4654 25 Propellant 12 48.4654 - 7 4 7128 (d) Terbutalene sulphate, 200 ^.g/dose 5 w/w Terbulatene sulphate, micronised 0.2869 Sorbitan monooleate . 0.5739 Propellant 114 44.6126 Propellant 12 54.5266 (β) Rimiterol hydrobromide, 200 zig/dose 4 w/w Rimiterol hydrobromide, micronised 0.2900 Sorbitan trioleate 0.7252 Propellant 114 34.6447 Propellant 12 64.3401 Cf) Salbutamol sulphate, 120.5 ^-g/dose (equivalent to 100/c g/dose / salbutamol) 4 w/w Salbutamol sulphate, micronised 0.1738 Sorbitan monooleate 0.3309 Propellant 114 39.7981 Propellant 12 59.6972 fe) Fenoterol hydrobromide, 200 ug/dose 4 w/w Fenoterol hydrobromide, micronised 0.2869 Sorbitan sesquioleate 0.7174 Propellant 114 44.5481 Propellant 12 54.4476 - 8 47128 (h) Isoprenaline hydrochloride 160 g/dose and phenylephrine bitatrate 240^g/dose Isoprenaline hydrochloride, micronised Phenylephrine bitatrate, micronised Sorbitan trioleate

Claims

1. CLAIMS:1. A dispersion or suspension of a finely divided medicament which prevents the release of mediators of anaphylaxis, and lecithin or a sorbitan or sorbitol ester in propellant 12, 5 the dispersion or suspension containing no propellant 11.

2. A dispersion or suspension according to Claim 1 containing no propellant other than propellant 12.

3. A dispersion or suspension according to Claim 1 or Claim 2 comprising less than 4.0% by weight of lecithin or of the 10 sorbitan or sorbitol ester.

4. A dispersion or suspension according to Claim 3 comprising from 0.2 to 2.0% by weight of the lecithin or of the sorbitan or sorbitol ester.

5. A dispersion or suspension according to any one of the 15 preceding claims wherein the finely divided medicament is disodium cromoglycate.

6. A dispersion or suspension according to any one of the preceding claims, wherein the medicament is of mass median diameter of 0.01 to 10 microns. 20

7. A dispersion or suspension according to any one of the preceding claims comprising from 0.05 to 15% by weight of finely divided medicament. 4712 - 11

8. A dispersion or suspension according to Claim 7 comprising from 0.1 to 10.0% by weight of finely divided medicament.

9. A dispersion or suspension according to Claim 8 5 comprising from 1 to 5% by weight of finely divided medicames

10. A dispersion or suspension according to any one of the preceding claims comprising propellant 114.

11. A dispersion or suspension according to Claim 10, wherein there is an excess of propellant 12 over propellant 10 114.

12. A dispersion or suspension according to Claim 11, wherein the ratio of propellant 12 to propellant 114 is in the range 2 to 1:1 by weight.

13. A dispersion or suspension according to Claim 12, 15 wherein the ratio is 1.5:1.

14. A dispersion or suspension according to any one of Claims 10 to 13 comprising from 0.15 to 2.0% by weight of lecithin or of the sorbitan or sorbitol ester.

15. A dispersion or suspension according to Claim 14 47138 - 12 comprising from 0.2 to 1.2% by weight of lecithin or of the sorbitan or sorbitol ester.

16. A dispersion or suspension according to any one of Claims 10 to 15 comprising from 0.05 to 2.0% by weight of 5 medicament,

17. A dispersion or suspension according to any one of the preceding claims comprising a sorbitan ester.

18. A dispersion or suspension according to Claim 17, wherein the ester is a sorbitan oleate. 10

19. A dispersion or suspension according to Claim 17, wherein the ester is sorbitan sesguioleate, sorbitan monooleate, or sorbitan monolaurate.

20. A dispersion or suspension according to Claim 18, wherein the ester is sorbitan trioleate. 15

21. A dispersion or suspension according to any one of the preceding claims comprising less than 1% by weight of water.

22. A dispersion or suspension according to Claim 1 and substantially.as hereinbefore described in Example 1.