HK1010737B - Novel vehicle gases and their use in medical preparations - Google Patents

Description

The invention relates to new suspensions of medicinal products in liquefied propellant gases for the production of inhalation aerosols, which typically contain 1,1,1,2,3,3,3-heptafluoropropane (TG 227).

Aerosols of powdered (micronized) medicinal products are widely used in therapy, e.g. in the treatment of obstructive respiratory diseases. Insofar as such aerosols are not produced by spraying powdered or sprayed solutions, suspensions of the medicinal products in liquefied fuel gases are used. The use of hydrochlorofluorocarbons has become a problem because of their negative effects on the earth's atmosphere (destruction of the ozone layer, greenhouse effect), and so other fuels or mixtures of fuels are being sought which do not have these negative effects or at least have them to a lesser extent. However, the search for therapeutic propellants is faced with considerable difficulties because they have to meet a number of criteria which are not easily reconciled, such as toxicity, stability, vapour pressure, density and solvent behaviour.

1,1,1,2,3,3,3-Hpetafluoropropane and its mixtures with propane and/or n-butane and/or i-butane and/or dimethyl ether are known to be propellants from the subsequent publication EP-A-234 371.

EP-A-315 783 mentions, inter alia, the use of 1,1,1,4,4,4-hexafluorobutan as a propellant and its suitability for sprays for asthmatics. However, the hexafluorobutan is not suitable as a propellant in itself, since it boils at a standard pressure of about 25 to 30°C and therefore does not provide the pressure required for the delivery of the medicinal product in a propellant. TG 227, on the other hand, has a boiling point of -17,4°C at normal pressure and therefore provides the necessary pressure of several bars at normal application temperatures.

Err1:Expecting ',' delimiter: line 1 column 107 (char 106)

Research Disclosure May 1989 (30161) reports that it has now been found that hydrocarbons, such as butane and pentane, carbon dioxide, dimethyl ether, nitrogen and hydrocarbons can be used as fuel gases for drugs, these drugs being applied directly to the lye.

TG 227 (1,1,1,2,3,3,3-heptafluoropropane) has been found to be particularly suitable for use in combination with one or more propane, butane, pentane and DME (dimethyl ether) propellant suspensions, where appropriate.

The components to be used in addition to TG 227 are added when the properties of the propellant are to be modified, e.g. when a different density of the liquefied propellant, a different pressure or a different solvent behaviour is to be adjusted. Pharmaceutical preparations based on the new propellant contain an active substance in finely distributed form, as a suspension, and generally surface active substances, such as a phospholipid (such as lecithin), an ester of a polyalcohol (such as sorbitol) with higher saturated or unsaturated fatty acids (e.g. stearin, antimethyl, palm oil), e.g. sorbitol, a polyolethyl or oxorbitol, a higher ester, as a suspension. Such substances can be dispersed unevenly in the new propellant, but can be easily removed by the newly manufactured suspension.

The proportions of the individual components of the mixture of the fuel gas (if TG 227 is not used alone) can vary widely. The proportion (percentage by weight) is 10 to 100% for TG 227. The mixture may also contain up to 50% propane and/or butane and/or pentane and/or DME. Within these limits, the components are selected so that a total of 100% is obtained.

The proportion of the suspended medicinal product in the finished preparation is between 0.001 and 5%, preferably 0.005 to 3%, and in particular 0.01 to 2%. The surfactants are added in amounts of 0.01 to 10%, preferably 0.05 to 5%, in particular 0.1 to 3% (here as in the case of medicinal products, the percentage by weight of the finished preparation is indicated). All substances suitable for inhalation or intranasal use may be used as medicinal products in the new preparations. These substances are in particular betamimetics, anticholinergics, steroids, antiallergics, PAF antagonists and combinations of such active substances.

The following examples are given in detail: It is a beta-imitator of:BambuterolBitolterolCarbuterolClenbuterolFenoterolHexoprenalinIbuterolPirbuterolProcaterolReproterolSalbutamolSalmeterolSulfonterolTerbutalinTulobuterol 1-(2-Fluor-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, which is a substance which is used in the manufacture of chemicals. The term 'sodium nitrate' means any organic compound containing more than one of the following:

As an anticholinergic: Ipratropium bromideOxitropium bromideTrospium chlorideBenzyl N-β-fluorethylnortropinestermethobromide

As a steroid: The following substances are to be classified in the additive:

As an antiallergic: It is not intended to be used in the manufacture of other medicinal products.

As PAF antagonists: The Commission has decided to initiate the procedure laid down in Article 108 (2) of the Treaty.

The active substances may also be combined, e.g. betamimetics plus anticholinergics or betamimetics plus antiallergics.

Examples of drug suspensions (indicated as % by weight): Other

1.)	0,10 % Oxitropiumbromid	2.)	0,3 % Fenoterol
	0,01 % Sojalecithin		0,1 % Sojalecithin
	4,0 % Pentan		10,0 % Pentan
	95,89 % TG 227		70,0 % TG 227
			19,6 % TG 12
3.)	0,1 % Ipratropiumbromid	4.)	0,3 % Fenoterol
	0,1 % Sojalecithin		0,1 % Sojalecithin
	20,0 % Propan		30,0 % TG 11
	20,0 % Butan		69,6 % TG 227
	49,8 % TG 11
5.)	1,5 % Dinatrium	6.)	0,3 % Salbutamol
	cromoglicat		0,2 % Span 85
	0,1 % Tween 20		20,0 % Pentan
	98.4 % TG 227		60,0 % TG 227
			19,5 % TG 12
7.)	0,15 % Fenoterol	8.)	0,1 % Ipratropium-
	0,06 % Ipratropium-		bromid
	bromid		0,1 % Sojalecithin
	0,10 % Sojalecithin		15,3 % Propan
	40,00 % TG 11		30,5 % TG 11
	19,69 % Propan		54,0 % TG 227
	40,00 % TG 227

Claims (10)

1. Pharmaceutical suspensions in liquefied propellant gases for the production of aerosols for inhalation, characterised in that they contain 1,1,1,2,3,3,3-heptafluoropropane as propellant, optionally in admixture with one or more propellant gases selected from the group comprising propane, butane, pentane or dimethyl ether, the content of 1,1,1,2,3,3,3-heptafluoropropane being between 10 and 100 % by weight, based on the propellant.
2. Pharmaceutical suspension according to claim 1, characterised in that a surfactant substance selected from the group comprising the phospholipids, sorbitan esters with a higher saturated or unsaturated fatty acid or polyethoxysorbitan esters of a higher, preferably unsaturated fatty acid is added.
3. Pharmaceutical suspension according to claim 2, characterised in that the surfactant substance is a lecithin, a polyoxyethylene sorbitan oleate or sorbitan trioleate.
4. Pharmaceutical suspension according to claim 1, 2 or 3, characterised in that it contains as active substance a beta-mimetic, an anticholinergic, a steroid, an antiallergic or a PAF antagonist or a combination of such compounds.
5. Pharmaceutical suspension according to claim 4, characterised in that the beta-mimetic used is:

   bambuterol

   bitolterol

   carbuterol

   clenbuterol

   fenoterol

   hexoprenaline

   ibuterol

   pirbuterol

   procaterol

   reproterol

   salbutamol

   salmeterol

   sulfonterol

   terbutalin

   tulobuterol

   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol

   erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one

   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.butyl-amino)ethanol

   1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.butylamino)ethanol;

   the anticholinergic used is:

   ipratropium bromide

   oxitropium bromide

   trospium chloride

   benzylic acid-N-β-fluoroethylnortropinester

   methobromide

   the steroid used is:

   budesonide

   beclomethasone (or the 17,21-dipropionate)

   dexamethasone-21-isonicotinate

   flunisolide;

   the antiallergic used is:

   disodium cromoglycate

   nedocromil

   the PAF antagonists used are:

   4-(2-chlorophenyl)-9-methyl-2-[3-(4-morpholinyl)-3-propanon-1-yl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[4-morpholinyl)carbonyl]-4H-7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[N,N-dipropylaminocarbonyl)-4H-7H-cyclopenta[4,5]thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepine.
6. Pharmaceutical suspension according to claim 4, characterised in that the combination of the active substances comprises one of the beta-mimetics mentioned in claim 5 and one of the anticholinergics mentioned in claim 5.
7. Pharmaceutical suspension according to claim 4, characterised in that the combination of the active substances comprises one of the beta-mimetics mentioned in claim 5 and disodium cromoglycate.
8. Pharmaceutical suspension according to claim 4, characterised in that the combination of the active substances comprises one of the beta-mimetics mentioned in claim 5 and one of the PAF antagonists mentioned in claim 5.
9. Pharmaceutical suspension according to claim 4, characterised in that the combination of the active substances comprises disodium cromoglycate and one of the PAF antagonists mentioned in claim 5.
10. Use of 1,1,1,2,3,3,3-heptafluoropropane as propellant, optionally in admixture with one or more propellant gases selected from the group comprising propane, butane, pentane or dimethyl ether, the content of 1,1,1,2,3,3,3-heptafluoropropane being between 10 and 100 % by weight, based on the propellant, in the preparation of pharmaceutical suspensions for producing aerosols for inhalation.