HK1029046B - Compressed gas packagings using polyoxyethylene glyceryl oleates - Google Patents

Description

Compressed air packaging using polyoxyethylene glyceryl oleate

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Aerosol puffer packaging has been used for many years for a variety of purposes. Aerosol propellant packages are understood to be pressure-resistant containers in which a mixture of liquefied propellant gas and therapeutic substance is released under pressure by operation of a valve. Compressed air packaging is described, for example, in Pharmazeutische technology, published by Sucker, Fucks, and Speiser (Thieme, Stuttgart, P673-688 1991). Aerosol and aerosol packs are also described in List, Arzuneiformenlehre (Wissenschaftliche Verlagsgesell-schaft, Stuttgart, 1985, P8-18) and Voigt, Lehrebuch der pha-rmazeutischen technology, (VCH, Weinheim, 1987, P427-436). Aerosol by Thoma (published by the authors, Frankfurt, 1979.5) also illustrates this commonly used dosage form in great detail. For the medical sector, it is very advantageous to use them for the purpose of delivering the active substances directly to the lungs where they are deposited. Aerosol blister packs have the advantage that they can be used to produce a cloud of evenly dispersed particles which can be inhaled rapidly by the patient. The result is to make it rapidly effective at the site of action-for example in the lungs-which is of crucial importance in bronchial asthma therapy. On the other hand, this property of local administration directly to the lungs allows preventive agents to be kept at low doses in the prevention of asthma attacks. In this way, the occurrence of undesirable side effects can be minimized as compared to administration via the gastrointestinal system.

Aerosol compression packs have thus found wide use in the treatment of respiratory disorders. It is simple, safe and inexpensive. Problems associated with the possibility of absorption by the patient and the possibility of sudden spray of the aerosol can be avoided either by inserting an expansion chamber between the aerosol package and the patient's mouth, or by using a special structure of the inhaler which causes the spray of the aerosol to be absorbed by the patient.

In addition to inhalation applications for the prevention and treatment of bronchial asthma and acute asthma attacks, the formulations of the present invention can also be used for nasal or mouth sprays (tongue and mouth applications).

CFCs (chlorofluorocarbons) have hitherto been used as aerosol propellants for dispensing. For example, the following chlorofluorocarbons and hydrocarbons may be used as aerosol propellants: pentane, n-butane, isobutane, TG11, TG12, TG21, TG22, TG23, TG113, TG114, TG115, TG142b, and TG C318.

The designation of the types of chlorofluorocarbons is derived from the following code system

Number in one place ═ number of fluorine atoms

The number-1 in the ten position being the number of hydrogen atoms

Number in hundred +1 ═ number of carbon atoms

Number of valence remaining as chlorine atom

Based on the basic principle of ozone theory (as fluorochlorohydrocarbons and other chlorine-containing organic compounds destroy ozone in the stratosphere), liquefied gases have been found that can be used as aerosols, are neither combustible nor destroy ozone, and are not harmful to health.

Non-chlorinated fluorocarbons have been used for some time, for example, 1, 1, 1, 2-tetrafluoroethane (TG134a) or 2H-heptafluoropropane (TG 227).

In addition to TG134a and TG227, mention may be made of: TG152a (difluoroethane, CH)₃CHF₂) TG143a (trifluoroethane, CH)₃CF₃) And TG161 (fluoroethane, CH)₃CH₂F)。

However, one disadvantage of such aerosol propellants is that they require the use of suspension stabilizers and valve lubricants that do not dissolve sufficiently in the aerosol propellant. Thus, the use of TG134a requires the use of approximately 25% ethanol in order to solubilize the sorbitan trioleate (Span) currently used in aerosol suspensions^R85) To a sufficient extent (see EP 372777 a 2). The following compounds may also be used, for example: polyvalent alcohols such as glycerol, esters such as ethyl acetate, ketones such as acetone and hydrocarbons such as hexane and heptane, pentane and also isopropanol. One disadvantage of such high concentrations is that the active substance present in the suspension can show signs of insolubility, giving rise to the risk of particle enlargement. On the one hand, if the particle size of the active substance increases by more than 10 μm during storage of this type of suspension, the aerosol valve will be blocked, and on the other hand, the efficacy will decrease as the particles of the active substance, because of their size, can no longer reach deeper parts of the lungs until the aerosol mass loses its therapeutic effect.

Therefore, there is a great need for substances having the following properties:

-is physiologically acceptable

Technically suitable for stabilizing aerosol suspensions of TG134a and TG227 and for improving the performance of their dosage valves

Other solubilizers soluble in TG134a or TG227 and acceptable in physiological terms, either not in use or only in small amounts

-has an acceptable taste

It has been surprisingly found that polyoxyethylene-25-propanetrioleate constitutes a substance having the above-mentioned required properties (trade name "Tagat^RTO ", manufacturer: goldschmidt, Essen). The polyoxyethylene-25-propyl trioleate has the following structure

An HLB value of 11.3 and a hydroxyl number between 18 and 33; the acid value reaches the maximum value of 2; the saponification number is between 75 and 90 and the iodine number between 34 and 40.

The hydroxyl number is determined according to DGF-C-V17 a, the acid number is determined according to DGF-C-V2, the saponification number is determined according to DGF-C-V3, and the iodine number is determined according to DGF-C-V11. Polyoxyethylene-25-glyceryl trioleate is an amber liquid. The polyoxyethylene glyceryl trioleate has the following properties:

physiological acceptability (with sorbitan trioleate (Span)^R85) Comparison)

Technically suitable for stabilizing aerosol suspensions of TG134a and/or TG227 and for improving the performance of their dosage valves

Soluble in TG134a or TG227, with less than 1-2% ethanol or similar alcohols present

-has an acceptable taste

Other compounds suitable as suspension stabilizers and exhibiting the above properties are: -Tagat^RO

In chemical terms, Tagat^RO is polyoxyethylene-30-propanetriyl monooleate.

Polyoxyethylene-30-glyceryl monooleate has the following structural formula: structural formula II:here n: an HLB value of about 30 is 16.4; hydroxyl number between 50 and 65; acid valueA maximum of 2; the saponification number is between 30 and 45 and the iodine number between 15 and 19. -Tagat^RO2

In chemical terms, Tagat^RO2 is a polyoxyethylene-20-propanetriyl monooleate.

Polyoxyethylene-20-glyceryl monooleate has the following structural formula: structural formula III

Where m: about 20

HLB value is 15.0; a hydroxyl number between 70 and 85; the acid value is 2 at most; the saponification number is between 40 and 55 and the iodine number between 21 and 27.

TG134a or TG227 with 1-2% ethanol has such a low dissolving power for conventional active substances that it is not possible to play any role in the possible increase in the crystallization of the active substances. The HLB values of suspension stabilizers of hitherto commercially available formulations are less than 5 (e.g. Span 85: HLB ═ 1.8) and are in the range of water-in-oil emulsifiers. (see Voigt Lehrbuch der pharmazeutisc-hen Technologie, book P332, Weinheim, 1987). Thus, for example, polyoxyethylene-25-propanetrioleate, polyoxyethylene-30-propanetrioleate and polyoxyethylene-20-propanetrioleate, which have HLB values of from 11.3 to 16.4, are suitable for this purpose, and are surprising.

The amounts of polyoxyethylene-25-propanetrioleate, polyoxyethylene-30-propanetrioleate and polyoxyethylene-20-propanetrioleate used are between 0.3 and 8000, in particular between 5 and 4000, particularly preferably between 15 and 2500 (wt.%), relative to the amount of active substance used per unit.

The following may be used as active substances:

analgesics, antiallergics, antibiotics, anticholinergics, antihistamines, anti-inflammatory substances, antitussives, bronchodilators, diuretics, enzymes, cardiovascular substances, hormones, proteins and peptides. Examples of analgesics are codeine, diacetylmorphine, dihydromorphine, ergotamine, fentanyl citrate, morphine; examples of antiallergic agents are cromolyn, nedocromil; examples of antibiotics are cephalosporins, fusarium, neomycin, penicillins, pentamidine, streptomycin, sulfonamides, tetracyclines; examples of anticholinergics are atropine, atropine methyl nitrate, brominated antispasmodics, scopolamine bromohydrate, tolpirozole chloride; examples of antihistamines are * benthalazine, flu * statin, maxaparin; the anti-inflammatory substances include beclomethasone dipropionate, budesonide, dexamethasone, 9-defluorinated fluocinolone, fluticasone, tipredn and triamcinolone; examples of antitussives are narcotine, noscapine; examples of bronchodilators are bambuterol, metamitron, albuterol, diclofenac, ephedrine, epinephrine, formoterol, fenoterol, hexadephrine, albuterol, isoprenaline, metaproterenol, phenylephrine, norephedrine, pirbuterol, procaterol, propertisone, albuterol, terbutaline, tolbutaterol; examples of diuretics are amiloride, furosemide; an example of an enzyme is trypsin; examples of cardiovascular substances are thionitrogen * ketone and nitroglycerin; examples of hormones are cortisone, hydrocortisone, prednisolone; examples of proteins and peptides are cyclosporin, cetrorelix, glucagon, insulin. Other useful active substances include epinephrine, colchicine, heparin, and scopolamine.

Combinations of the above may also be used.

The active substances listed by way of example can be used as free bases or acids or as pharmaceutically acceptable salts. For example, physiologically acceptable alkaline earth or alkali metal species or amines, such as, again, acetate, benzenesulfonate, benzoate, bicarbonate, acid tartrate, bromide, chloride, iodide, carbonate, citrate, fumarate, malate, maleate, gluconate, lactate, pamoate, hydroxynaphthoate and sulfate, can be used as counterions. Esters, such as acetates, acetonates, propionates, dipropionates, valerates may also be used.

Tagat^RTO，Tagat^RO or Tagat^RThe amount of O2 used is, for example, from 0.01 to 5% by weight, in particular from 0.2 to 2.5% by weight, particularly preferably from 0.75 to 1.5% by weight, relative to the total amount of the mixture of active substance, aerosol propellant gas or aerosol propellant gas mixture, and optionally auxiliary substances.

Co-solvents, for example aliphatic alcohols having 2 to 6 carbon atoms or esters or ketones or polyols thereof, may be added. Examples are ethanol, isopropanol, propylene glycol, acetone, ethyl acetate, n-propanol, preferably ethanol and isopropanol.

Ethanol or isopropanol is used in an amount of 0% to 10%, in particular 0.1 to 2%, particularly preferably 0.2% to 1%, by weight, relative to the total weight of the mixture.

Of course, it is also possible to add other surface-active substances, such as those listed in EP 0372777.

The suspension of the active substance can be carried out either at normal pressure (in which case the suspension medium has to be cooled to a low temperature, for example-35 ℃ to-55 ℃) or at room temperature (15 ℃ to 25 ℃) in a pressure vessel at normal temperature.

After homogenization the suspension is filled into a pressure tank, which is closed with a dosage valve or is subsequently closed.

Example 1

1000 g of 2H-heptafluoropropane (═ aerosol propellant 227) were cooled to a temperature of about-55 ℃ and 11.7 g of polyoxyethylene-25-propanetrioleate (trade name: Tagat) dissolved in 11.7 g of absolute ethanol^RTO, Goldschmidt corporation) was stirred. Then 16.8 g micronized disodium cromoglycate and 8.4 g micronized phenformin hydrochloride were added together with 0.9 g micronized saccharin sodium and 6.75 g peppermint oil and the resulting suspension was stirred vigorously. Further stirring and cooling to prepare 11700 g of suspension with cooled aerosol 227, then filled into a metal can closed with a dosage valve, giving 50. mu.l of suspension per spray. 1 mg of disodium cromoglycate and 0.5 mg of phenprobamate per injection were released.

Example 2

1000 g of 2H-heptafluoropropane (═ aerosol propellant 227) were cooled to a temperature of about-55 ℃ and 11.7 g of absolute alcohol were dissolved 11.7 g of polyoxyethylene-30-propanetriyl monooleate (trade name: Tagat:. RTM.)^RO, Goldschmidt corporation) was stirred. Then 16.8 g micronized disodium cromoglycate and 8.4 g micronized phenprobamate hydrochloride were added, as well as 0.9 g micronized saccharin sodium and 6.75 g peppermint oil, and the resulting suspension was stirred vigorously. 1170.0 g of suspension with cooled aerosol 227 was made with further stirring and cooling and then filled into a metal can closed with a dosage valve, discharging 50 microliters of suspension per shot. 1 mg of disodium cromoglycate and 0.5 mg of phenprobamate per injection were released.

Example 3

1000 g of 2H-heptafluoropropane (═ aerosol propellant 227) were cooled to a temperature of about-55 ℃ and 11.7 g of polyoxyethylene-20-propanetriyl monooleate (trade name: Tagat) were dissolved in 11.7 g of anhydrous alcohol^RO2, Goldschmidt) was stirred. Then 16.8 g micronized disodium cromoglycate and 8.4 g micronized phenprobamate hydrochloride were added, as well as 0.9 g micronized saccharin sodium and 6.75 g peppermint oil, and the resulting suspension was stirred vigorously. 1170.0 g of suspension with cooled aerosol propellant 227 was made with further agitation and cooling and then filled into a metal can closed with a dosage valve, emitting 50 microliters of suspension per shot. 1 mg of disodium cromoglycate and 0.5 mg of phenprobamate per injection were released.

Example 4

The procedure was as in example 1 except that 16.8 g of micronized D-18024 was used in place of 16.8 g of micronized disodium cromoglycate and 8.4 g of micronized phenprobamate.

1 mg of D-18024 was emitted per injection. D-18024 has the following structural formula:the INN name of D-18024 is flezelastine hydrochloride.

Example 5

The procedure was as in example 1 except that 4.2 grams of micronized budesonide were used in place of 16.8 grams of micronized disodium cromoglycate, 8.4 grams of micronized phenprochloraz hydrochloride, 0.9 grams of micronized sodium saccharin and 6.75 grams of peppermint oil.

Each spray contained 0.25 mg budesonide.

Example 6

1000 g of 2H-heptafluoropropane (═ aerosol propellant 227) were cooled to a temperature of about-55 ℃ and admixed with 11.7 g of polyoxyethylene-25-propanetriyl trioleate (trade name: Tagat;)^RTO, Goldschmidt company) and 6.75 grams of Dentomint PH799959 (manufacturer: haarmann un-d Reimer, Holzminden) was stirred for reaction. With further stirring and cooling, 16.8 g micronized disodium cromoglycate and 8.4 g micronized phenprobamate and 0.9 g micronized saccharin sodium were added and the resulting suspension was stirred vigorously. 1170.0 g of suspension with cooled aerosol propellant 227 was made with further agitation and cooling and then filled into a metal can closed with a dosage valve, discharging 50 microliters of suspension per shot. 1 mg of disodium cromoglycate and 0.5 mg of phenprobamate per injection were released.

Claims (5)

1. Aerosol-propellant package suitable for the administration of biologically active substances by oral inhalation, characterized in that a polyoxyethylene-20-propanetrioleate of the formula III is used as suspension stabilizer and/or valve lubricant and 2H-heptafluoropropane and/or 1, 1, 1, 2-tetrafluoroethane is used as aerosol propellant,

structural formula III

Wherein m is 20.

2. Aerosol compressed gas packaging according to claim 1, characterised in that the polyoxyethylene-20-glyceryl monooleate of formula III is present in a proportion of between 0.01% and 5% relative to the total weight of the mixture.

3. Aerosol compressed gas packaging according to claim 1, characterised in that the polyoxyethylene-20-glyceryl monooleate of formula III is present in a proportion of between 0.2% and 2.5% relative to the total weight of the mixture.

4. Aerosol compressed gas packaging according to claim 1, characterised in that the polyoxyethylene-20-glyceryl monooleate of formula III is present in a proportion of between 0.75% and 1.5% relative to the total weight of the mixture.

5. A process for the preparation of aerostatic packs according to any one of claims 1 to 4, characterized in that 2H-heptafluoropropane and/or 1, 1, 1, 2-tetrafluoroethane are used as aerosol propellant.