CA2062854A1 - Pharmaceutical aerosol formulations - Google Patents
Pharmaceutical aerosol formulationsInfo
- Publication number
- CA2062854A1 CA2062854A1 CA002062854A CA2062854A CA2062854A1 CA 2062854 A1 CA2062854 A1 CA 2062854A1 CA 002062854 A CA002062854 A CA 002062854A CA 2062854 A CA2062854 A CA 2062854A CA 2062854 A1 CA2062854 A1 CA 2062854A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- group
- propellant gas
- pharmaceutical
- aerosol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/124—Aerosols; Foams characterised by the propellant
Abstract
Pharmaceutical Aerosol Formulations Abstract The present invention relates to an aerosol formulation comprising:
a) a liquefied propellant gas or propellant gas mixture from the group of the alternative propellant gases that do not have removable chlorine atoms;
b) a non-ionic surfactant from the group of the monoacetylated or diacetylated monoglyc-erides of the MYVACET series;
c) a pharmaceutical active ingredient or active ingredient combination and, if necessary, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
The aerosol formulation can be used especially in inhalation therapy for the treatment of disorders of the upper respiratory tract, such as asthma or rhinitis.
a) a liquefied propellant gas or propellant gas mixture from the group of the alternative propellant gases that do not have removable chlorine atoms;
b) a non-ionic surfactant from the group of the monoacetylated or diacetylated monoglyc-erides of the MYVACET series;
c) a pharmaceutical active ingredient or active ingredient combination and, if necessary, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
The aerosol formulation can be used especially in inhalation therapy for the treatment of disorders of the upper respiratory tract, such as asthma or rhinitis.
Description
s~
4-185~2/A
Pharmaceutical Aerosol Formulation The invention relates to a pharmaceutical composition comprising chlorine-free propellant gases for use as an aerosol formulation, to a process for the preparation of that pharma-ceutical composition and to its use in a method of therapy, especially in inhalation therapy.
The administration of active ingredients using aerosols is becoming increasingly impor-tant, especially using inhalation dosing aerosols, for the treatment of disorders of the respiratory tract, for example asthma or allergic rhinitis (hay fever). By means of such an aerosol the active ingredient is able to reach the actual target site, for example the bronchioles, in an effective dose without burdening the entire organism to the extent that occurs, for example, with peroral administration.
An aerosol is a mixture of substances consisting of a gaseous dispersant and liquid or solid, disperse constituents (ABC Chemie, vol. 1, page 23, 2nd edition 1974, Verlag Harri Deutsch, D-6000 Frankfurt/Main).
The gaseous dispersant is called propellant gas, and may also consist of a mixture of several propellant gases. For pharmaceutical applications, the disperse constituents consist of liquid or solid active ingredients, a distinction being made between powder or suspension aerosols (solid/gaseous) and emulsion or liquid aerosols (liquid/gaseous).
Aerosols may additionally comprise other excipients, such as surfactants.
The term "aerosols" is used especially for mixtures of substances in pressure-tight vessels (spray cans) that contain the gaseous dispersant under pressure in the liquid state at room temperature. The pressure-tight vessels are closed by a metering or pressure valve. Upon administration after operating the metering valve, the actual aerosol, comprising s~olid particles or droplets dispersed in the propellant gas, escapes from the pressurlsed vessel.
Discussions and hlvestigations concerning the cause of damage ~o the atmosphertc ozone layer by chlorolluorocarbons (CFCs) have limited lhe industrial use as propellant gases in ,5~L
4-185~2/A
Pharmaceutical Aerosol Formulation The invention relates to a pharmaceutical composition comprising chlorine-free propellant gases for use as an aerosol formulation, to a process for the preparation of that pharma-ceutical composition and to its use in a method of therapy, especially in inhalation therapy.
The administration of active ingredients using aerosols is becoming increasingly impor-tant, especially using inhalation dosing aerosols, for the treatment of disorders of the respiratory tract, for example asthma or allergic rhinitis (hay fever). By means of such an aerosol the active ingredient is able to reach the actual target site, for example the bronchioles, in an effective dose without burdening the entire organism to the extent that occurs, for example, with peroral administration.
An aerosol is a mixture of substances consisting of a gaseous dispersant and liquid or solid, disperse constituents (ABC Chemie, vol. 1, page 23, 2nd edition 1974, Verlag Harri Deutsch, D-6000 Frankfurt/Main).
The gaseous dispersant is called propellant gas, and may also consist of a mixture of several propellant gases. For pharmaceutical applications, the disperse constituents consist of liquid or solid active ingredients, a distinction being made between powder or suspension aerosols (solid/gaseous) and emulsion or liquid aerosols (liquid/gaseous).
Aerosols may additionally comprise other excipients, such as surfactants.
The term "aerosols" is used especially for mixtures of substances in pressure-tight vessels (spray cans) that contain the gaseous dispersant under pressure in the liquid state at room temperature. The pressure-tight vessels are closed by a metering or pressure valve. Upon administration after operating the metering valve, the actual aerosol, comprising s~olid particles or droplets dispersed in the propellant gas, escapes from the pressurlsed vessel.
Discussions and hlvestigations concerning the cause of damage ~o the atmosphertc ozone layer by chlorolluorocarbons (CFCs) have limited lhe industrial use as propellant gases in ,5~L
spray cans by regulations of the legislature in many countries. It is known from various research works that only the chlorine atoms in the CFCs and the reactive radicals resulting therefrom are responsible for the damage to the ozone layer.
For industrial, non-pharmaceutical applications, therefore, so-called alternative propellant gases or propellants, for example saturated hydrocarbons, such as propane or n-butane, or chlorine-free fluorohydrocarbons (HFCs or F~s), for example tetrafluoroethane, or mix-tures of those propellant gases are increasingly being used. From the ecological stand-point alone there is an urgent need to replace also for pharmaceutical applications all CFCs, which are potentially damaging to the ozone layer, by environmentally moreacceptable, alternative propellant gases.
Suitable propellant gases for pharmaceutical applications and also suitable propellant gases or propellants for pharmaceutical aerosols are those that can be liquefied under pressure at room temperature and that are toxicologically safe and do not exhibit side-effects upon inhalation or topical administration.
For inhalation therapy in particular, there is a need for aerosols in which the solid particles or droplets dispersed in the propellant gas have a preferred diameter of about 0.5 - 6 llm.
It is desirable that suspension aerosols comprise the active ingredient distributed as homogeneously as possible so that, after shaking, it remains in the finely dispersed state for as long as possible. It is also desirable that the particle size distribution remains unchanged caused by solubility effects of the solid active ingredient suspended in the propellant composition.
European Patent Application 372 777 discloses aerosol formulations comprising the "alternative" propellant tetrafluoroethane (134a). In order to increase the stability of suspensions in that liquefied propellant, it is proposed that a suspension aid in the form of a non-ionic surfactant, for example a sorbitan fatty acid ester of the SPAN type, for example SPAN 85 (sorbitan trioleate), be used. Owing to the insufficient solubility of such surfactants in the liquefied propellant 134a, a solvent, for example ethanol, that has a higher polarity than does the propellant itself is added.
The problem underlying the present invention is to determine a specific suspension aid for active ingredients in aerosol formulations that dissolves rnore readily in liquefied`
"alternative" propellant gases than do the known suspension aids hitherLo used for that purpose. In solving this problem, it has surprisingly been found that non-ionic surfactants from the group consisting of monoacetylated and diacetylated monoglycerides are readily soluble in the "alternative" propellant gases mentioned, especially in heptafluoropropane (227), and promote the production of homogeneous suspensions while additionally exhibiting outstanding lubricating properties for the dosing valve.
The present invention relates to a pharmaceutical composition for use as an aerosol comprising:
a) a liquefied propellant gas or propellant gas mixture having a vapour pressure of more than 1 bar ~md less than 6 bar (20C) from the group consisting of unsubstitutedhydrocarbons and partially to completely fluorinated hydrocarbons;
b) a non-ionic surfactant from the group consisiting of monoacetylated and diacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination and, optionally, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
In an especially preferred embodiment of the invention, the aerosol comprises the alternative propellant gas heptafluoropropane (227). This propellant gas has the advantage of a lower vapour pressure of approximately 4 bar compared with the higher vapour pressure of approximately 5.7 bar exhibited at the same temperature by the alternative propellant gas tetrafluoroethane (134a).
The term "pharmaceutical composition" defines a mixture of substances that is suitable for various applications as an aerosol, preferably for inhalation, but also topically, in humans and animals, preferably in humans, and can be used for the treatment of various disorders, for example asthma or allergic rhinitis.
The term "aerosol" is defined hereinbefore. The pressure vessel for producing the aerosol itself may contain the active ingredient or active ingredient combination either in solid form as a suspension or in liquid form as an emulsion or solution in the propellant gas or propellant gas mixture compressed to a liquid. In the technical literature, the pressure vessel together with its contents and the metering valve are occasionally referred to as a dosing aerosol. Within the scope of the description of this invention, the term "dosing aerosol" is intended to refer only to thc contents of the pressure vessels.
For industrial, non-pharmaceutical applications, therefore, so-called alternative propellant gases or propellants, for example saturated hydrocarbons, such as propane or n-butane, or chlorine-free fluorohydrocarbons (HFCs or F~s), for example tetrafluoroethane, or mix-tures of those propellant gases are increasingly being used. From the ecological stand-point alone there is an urgent need to replace also for pharmaceutical applications all CFCs, which are potentially damaging to the ozone layer, by environmentally moreacceptable, alternative propellant gases.
Suitable propellant gases for pharmaceutical applications and also suitable propellant gases or propellants for pharmaceutical aerosols are those that can be liquefied under pressure at room temperature and that are toxicologically safe and do not exhibit side-effects upon inhalation or topical administration.
For inhalation therapy in particular, there is a need for aerosols in which the solid particles or droplets dispersed in the propellant gas have a preferred diameter of about 0.5 - 6 llm.
It is desirable that suspension aerosols comprise the active ingredient distributed as homogeneously as possible so that, after shaking, it remains in the finely dispersed state for as long as possible. It is also desirable that the particle size distribution remains unchanged caused by solubility effects of the solid active ingredient suspended in the propellant composition.
European Patent Application 372 777 discloses aerosol formulations comprising the "alternative" propellant tetrafluoroethane (134a). In order to increase the stability of suspensions in that liquefied propellant, it is proposed that a suspension aid in the form of a non-ionic surfactant, for example a sorbitan fatty acid ester of the SPAN type, for example SPAN 85 (sorbitan trioleate), be used. Owing to the insufficient solubility of such surfactants in the liquefied propellant 134a, a solvent, for example ethanol, that has a higher polarity than does the propellant itself is added.
The problem underlying the present invention is to determine a specific suspension aid for active ingredients in aerosol formulations that dissolves rnore readily in liquefied`
"alternative" propellant gases than do the known suspension aids hitherLo used for that purpose. In solving this problem, it has surprisingly been found that non-ionic surfactants from the group consisting of monoacetylated and diacetylated monoglycerides are readily soluble in the "alternative" propellant gases mentioned, especially in heptafluoropropane (227), and promote the production of homogeneous suspensions while additionally exhibiting outstanding lubricating properties for the dosing valve.
The present invention relates to a pharmaceutical composition for use as an aerosol comprising:
a) a liquefied propellant gas or propellant gas mixture having a vapour pressure of more than 1 bar ~md less than 6 bar (20C) from the group consisting of unsubstitutedhydrocarbons and partially to completely fluorinated hydrocarbons;
b) a non-ionic surfactant from the group consisiting of monoacetylated and diacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination and, optionally, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
In an especially preferred embodiment of the invention, the aerosol comprises the alternative propellant gas heptafluoropropane (227). This propellant gas has the advantage of a lower vapour pressure of approximately 4 bar compared with the higher vapour pressure of approximately 5.7 bar exhibited at the same temperature by the alternative propellant gas tetrafluoroethane (134a).
The term "pharmaceutical composition" defines a mixture of substances that is suitable for various applications as an aerosol, preferably for inhalation, but also topically, in humans and animals, preferably in humans, and can be used for the treatment of various disorders, for example asthma or allergic rhinitis.
The term "aerosol" is defined hereinbefore. The pressure vessel for producing the aerosol itself may contain the active ingredient or active ingredient combination either in solid form as a suspension or in liquid form as an emulsion or solution in the propellant gas or propellant gas mixture compressed to a liquid. In the technical literature, the pressure vessel together with its contents and the metering valve are occasionally referred to as a dosing aerosol. Within the scope of the description of this invention, the term "dosing aerosol" is intended to refer only to thc contents of the pressure vessels.
The propellant gas or propellant gas mixture is so selected that, at a temperature of approximately 20C, it is in a liquid state of aggregation and has a minimum pressure higher than approximately 1 bar up to a maximum pressure of approximately 6 bar. Suit-able propellant gases or propellant gas mixtures are, therefore, those that exhibit a constant internal pressure in the dosing vessel until the latter is completely empty and that, in view of the environmental problems mentioned hereinbefore, do not have any removable chlorine atoms.
Such propellant gases or propellant gas mixtures are known per se for the preparation of pharmaceutical aerosols, for example unsubstituted saturated hydrocarbons, for example n-propane, n-butane or isobutane or mixtures thereof, or partially fluorinated or completely fluorinated (perfluorinated) hydrocarbons.
Partially l:luorinated hydrocarbons are derived from aliphatic hydrocarbons having prefer-ably from 1 to 4 carbon atoms, for example methane, ethane, propane, n-butane or iso-butane, or from cycloaliphatic hydrocarbons having preferably 3 and 4 carbon atoms, for example cyclopropane or cyclobutane, by replacing the hydrogen atom(s) with at least one fluorine atom and preferably at least two fluorine atoms in such a manner that at least one hydrogen atom, and accordingly one hydrocarbon bond, remains in the molecule.
Completely fluorinated (perfluorinated) hydrocarbons are derived from the mentioned aliphatic hydrocarbons having from I to 4 carbon atoms and from the mentioned cyclo-aliphatic hydrocarbons having 3 and 4 carbon atoms by replacement of the hydrogen atoms with corresponding fluorine atoms.
Suitable partially or completely fluorinated hydrocarbons are, for example, methane derivatives having from 1 to 4 fluorine atoms, ethane derivatives having from 1 to 6 fluorine atoms, propane derivatives having from 1 to 8 fluorine atoms, n-butane deriva-tives having from 1 to 10 fluorine atoms, cyclopropane derivatives having from 1 to 6 fluorine atoms and cyclobutane derivatives having from 1 to 8 fluorine atoms. In these partially or completely fluorinated hydrocarbons, the hydrogen atom or atoms may be located at different places in the hydrocarbon structure. For partially fluorinated hydrocarbons the following cases of isomerism are possible:
If only one hydrogen atom is present, in the propanc and butane derivatives it may be terminal or located at an intermediatc member of the carbon chain.
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If there is more than one hydrogen atom, then still further cases of isomerism are possible for the ethane, propane, n-butane, cyclopropane and cyclobutane derivatives and for hydrocarbons having an even higher number of carbon atoms. Some or all of the hydr-ogen atoms may be terminal and some or all may be located at one or at different inter-mediate members of the carbon chains. "Mixed" cases of isomerism are also possible, in which the hydrogen atoms are located, in varying distribution, at the terminal carbon atoms and at the same or at different carbon intermediate members in the case of aliphatic derivatives, or at the same or at different ring carbon members in the case of cyclo-aliphatic derivatives.
In order to shorten the usual nomenclature and to differentiate the partially fluorinated hydrocarbons mentioned and also the completely fluorinated hydrocarbons mentioned hereinafter, code names are commonly used; these are explained in "Pharmazeutische Technologie", H. Sucker, P. Fuchs, P. Speiser (editor), Thieme Verlag, D-7000 Stuttgart 1978, on page 735 and can also be applied to CFCs. For the numerous cases of isomerism mentioned, suffixes using the letters a, b ... are customary.
Preferred partially fluorinated hydrocarbons are pentafluoroethane (125), tetrafluoroethane (134 and 134a), trifluoroethane (143a), difluoroethane (152 and 152a) and heptafluoropropane (227).
A non-ionic surfactant from the group of the monoacetylated and diacetylated monoglyc-erides is a monoglyceride (glycerol esterified by a saturated or unsaturated fatty acid) that contains, in addition to the acyl radical of a fatty acid, preferably one or even two acetyl radicals. The acyl radical is preferably derived from an unsaturated fatty acid having more than ten, and an even number of carbon atoms. A monoglyceride that is obtainable from a mixture of monoacetylated or diacetylated monoglycerides using the customary separation methods, for example fractional distillation, is preferred.
The acetylated monoglyceride contains as the acyl radical of a saturated fatty acid, for example a ~l0 20alkanoyl radical having an even number of carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl or n-icosanoyl.
The acetylated monoglyceride contains as the acyl radical of an unsaturated fatty~acid preferably a C~0 20alkenoyl radical having an even number of carbon atoms, for cxample - 6 - ;Z~?~ r~ ~
9-cis-dodecenoyl, -tetradecenoyl or -hexadecenoyl, 6-cis- or 6-trans-octadecenoyl, 9-cis-or 9-trans-octadecenoyl or 1 l-cis-octadecenoyl.
Especially preferred are acetylated monoglycerides ~hat are obtainable commercially under the Trademark MYVACET (Eastman) and authorised by health authorities, e.g. the FDA in the USA, for use as additives for processed foods. Acetylated monoglycerides of the MYVACET series are used as lubricants, plasticisers, non-ionic emulsifiers and solubilisers. The products obtainable commercially under the name MYVACET 5-07, 7-00, 7-07, 9-08, ~-40 and 9-45 are especially preferred.
Most especially suitable are the liquid acetylated monoglycerides, for example MYVACET 9-40 and MYVACET 9-45 K, that can be characterised as follows:
solidification point: 7-8C
density at 20C: 0.98-0.99 [g/cm3]
hydroxyl number: 15 acid number: 3 iodine number: ~0-51 saponification value: 370-380 Surprisingly, it has now been found that it is possible to prepare especially homogeneous and stable suspensions using liquid MYVACET types, especially with active ingredients from the group of betasympathomimetics, e.g. salbutamol or formoterol fumarate, in the mentioned alternative liquefied propellant gases or propellant gas mixtures of component a) which do not damage the ozone layer. Surprisingly, it was also found that undesirable adhesion to the wall of the pressure vessel can be prevented by the addition of a polar solvent such as ethanol. Furthermore, it was found that, using the combination MYVACET and ethanol, other active ingredients from chemically different classes of substances also can be converted, together with propellant gases such as 2~7 or 13~a and n-butane, into homogeneous and readily re-dispersible suspensions that can be used as aerosol formulations.
The non-ionic surfactant b) is present in the pharmaceutical composition in a conccntra-tion of approximately from 0.0001 to 5.0, preferably approximately from 0.001 to 0.5, %
by weight.
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In principle, there are suitable for the aerosol formulation all active ingredients or active ingredient combinations c) that are inert towards the propellant gas component a) and component b), the non-ionic surfactant, and to any additional excipients present. The choice of active ingredients is governed by the diagnosis and subject to the limitation of being able to administer the chosen active ingredient or active ingredient combination as an aerosol formulation, preferably by inhalation, but also topically.
Suitable active ingredients are, for example:
Alkaloids: bromocriptine, ergotamine, atropine;
Anti-allergics: azelastin, cetirizin, epinastin, nedocromil, disodium cromoglycate, ketotifen, pemirolast, traxanox, amlexanox, protopine, tepoxalin, midaglizole, picumast, quazolast, repirinast, suplatast;
Antibiotics: fusafungine, gentamycin, neomycin, minccycline, erythromycin, streptomycin, ofloxacin, ciprofloxacin, cephalexin, cefatrizine, cefaclor, ceftriaxone;
Andmycotics: clotrimazole, ketoconazole, amorolfin, bifonazole;
Betasympathomimetics: bambuterol, salbutamol, formoterol, salmeterol, pirbuterol, carbuterol, clenbuterol, reproterol, rimiterol, hexprenaline, fenoterol, bitolterol, terbutaline, mabuterol, tulobuterol;
Anticholinergics: ipratropium, oxitropium, telenzepine, troventol;
Potassium channel openers: cromakalim, lemakalim;
Corticoids: budesonide, flunisolide, beclomethasone, fluticasone, triamcinolone,fluocortinbutyl, butixocort, cloprednol, fluticason, mometason, tipredane;
Mucolytics: acetylcysteine, ambroxole, carbocysteine, furosemide, amiloride;
Phosphodiesterase-inhibitors: theophylline, isbuphylUne, zandaverine, enprophylline;
Thromboxane inhibitors, e.g. vapiprost, ozagrel; Leucotriene inhibitors, e.g. bunaprolast, ibudilast;
Platelet aggregation factor(PAF) antagonists, e.g. ginkgolides or mequitamium;
Antiinfective agents: pentamidin, hydroxychloroquine; and cytostatic agents such as methotrexate.
Especially preferred are active ingredients that are used in inhalation therapy for the prophylactic and/or acute treatment of bronchial obstructions, such as asthma, for example salbutamol, formoterol, salmeterol, disodium cromoglycate, nedocromil, oxitropium, ipra-tropium, budesonide, beclomethasone, flunisolide and triamcinolone.
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If they contain a salt-forming group, the mentioned active ingredients may be present in the aerosol in the form of the free compounds or in the form of their pharmaceutically acceptable salts.
The aerosol comprises the active ingredient or active ingredient combination in a proportion of approximately from 0.0001 to 5.0 % by weight, preferably approximately from 0.001 to 2.5 % by weight.
It is possible to admix with the pharmacéutical composition, for example, customary pharmaceutical excipients that are suitable for aerosol formulations. For example, a solvent having a higher polarity than that of the liquefied propellant gas component a) can be added. Since the propellant gases or propellant gas mixtures of component a) have little polarity, numerous other, more polar solvents, such as ethanol, isopropanol, propylene glycol, dimethyl ether and mixtures of those solvents, which may be added in any desired concentrations, for example from approximately 0.1 to 30 % by weight, are suitable as additives.
As additional excipients there may be added, in addition to component b), other non-ionic surfactants that increase the wetting and dispersibility of pharmaceutical active ingredients still further and/or, as lubricants, improve the mechanical valve functions and prevent the deposition of solids by adsorption onto the inside of the pressure vessel.
Such additional non-ionic surfactants are, for example, sorbitan fatty acid esters, for example sorbitan trioleate, sesquioleate, monooleate or monolaurate, which are commer-cially obtainable, for example, under the Trademark SPAN, for example SPAN 85, 80 and 20, polyoxyethylenesorbitan esters, for example polyoxyethylene(20)sorbitan monolaurate or monooleate, for example esters that are obtainable commercially under the Trademark TWEEN, for example TWEEN 20, 40, 60 and 80, oleyl, stearyl or lauryl polyoxyethylene esters that are obtainable commercially under the Trademarks BRIJ or GENAPOL, for example BRIJ 92, 72, 30 or GENAPOL 0-020, and block copolymers that are commercially obtainable under the Trademarks SYNPERONIC.
Other excipients are, for example, pharmaceutically approved oils, for example oils of vegetable origin, for example from corn, olives, cotton seeds, rape or sunflowers, phospholipids, for example synthetic lecithin or natural lecithin dervivatives that àre commercially obtainable under the Tradcmark EPIKURON, diethylene glycol dioleate, ~?~ 5 tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, monooleate or monoricinoleate, cetyl alcohol, polyethylene glycol 400, polyol fatty acid esters or cetylpyridinium chloride. Taste correctives, such as saccharin, aspartames and flavourings, for example dentomint, can also be added.
The mentioned excipients of component d) may be added in a proportion of approximately from 0.0001 to 10 % by weight, preferably approximately from 0.001 to 1 % by weight, based on the entire weight of the pharmaceutical formulation.
The present invention relates preferably to a pharmaceutical composition comprising:
a) a propellant gas or propellant gas mixture selected from the group consisting of propane, n-butane, isobutane, di-, tri-, or tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from ~he group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of the antiallergics, e.g. disodium cromoglycate or nedocromil, betasympatho-mimetics, e.g. salbutamol, salmeterol or formoterol, anticholinergics, e.g. oxilropiurn- or ipratropium bromide, and corticoids, e.g. budesonide, Qunisolide, beclomethasone or triamcinolone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present invention relates preferably to a pharmaceutical composition comprising:
a) a propellant gas or propellant gas mixture from ihe group consisting of propane, n-butane, isobutane, tetraQuoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromoglycate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcino-lone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present in~ention relates especially to a pharmaceutical composition comprisin~:
a) the propellant gas heptaQuoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylatcd monoglycerides;
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2~ f'o6~3 - 10- .
e) a pharmaceutical active ingredient or active ingredient combination from the group disodium cromoglyeate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcinolone and, optionally, d) further eonventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present invention also relates to a process for the preparation of the pharmaceutical composition which is carried out in a manner known per se and is described, for example, in the aforementioned "Pharma~eutische Technologie" on pages 736-737.
The pharmaceutical composition can be prepared by placing the pharmaceutical active ingredient or active ingredient combination c) in a pressure-tight vessel and introducing, in any desired sequence of the steps, the non-ionic surfactant b), where appropriate the conventional pharmaceutical excipients d), and introducing the propellant gas orpropellant gas mixture a), homogenising, and introducing the homogeneous mixture into dosing vessels suitable for aerosol formulations.
If the active ingredient or ingredients is/are in solid, for example crystalline, form, they are to be comminuted, preferably by micronisation. The upper limit for the average particle size in the case of topical formulations is considered to be an average partiele diameter of less than 100 and, in the ease of inhalation formulations for the purpose of deposition in the respiratory tract, less than 10 micrometers. A particle size of approximately from 0.1 to 5 micrometers is preferred for inhalation formulations, which can be achieved by the use of conventional comminution methods, for example grinding in an air jet mill.
Component c) is weighed into an open batch pressure vessel equipped with a stirring and homogenising apparatus, and there are added, according to the formulation instructions, in the desired sequence, components b) - surfactant- and, where appropriate, d) other excipients, for example ethanol. The pressure vessel is closed and the propellant gas or propellant gas mixture is introduced. The active ingredient is homogenised in the propellant gas/excipient mixture in the customary manner, for example by stirring, shaking or treatment with ultrasound. Using known filling techniques, the contents of the pressure vessel are introduced through the valve into dosing vessels, for example pres-sure-tight vessels consisting of tinplate or aluminium whieh are referred to in eornmon parlanee as spray cans and are provided with the customary dosing valves. The pres-sure-tight valves release approximately from 25 to 100 microlitres in the case of inhalation dosing aerosols.
The invention also relates to the use of the pharmaceutical aerosol composition in a therapeutic method, for which a need exists depending on the therapeutic category of the active ingredient or active ingredient combination present in the claimed composition. The pharmaceutical aerosol composition is especially useful for the treatment by inhalation of allergic diseases of the respiratory tract such as asthma or allergic rhinitis, especially in the event that the composition contains active agents such as formoterol, disodium cromoglycate or salbutamol.
The invention also relates to the use of a non-ionic surfactant from the group of the monoacetylated or diacetylated monoglycerides for the preparation of a pharmaceutical composition that can be used as an aerosol. Especially preferred is the use of a liquid, non-ionic acetylated monoglyceride that is known under the name MYVACET.
The following Examples illustrate the invention:
The active ingredient, micronised to a particle size of less than 6 micrometers, is weighed according to the Recipe into a previously dried batch pressure vessel, and the propellant gas or propellant gas mixture, comprising, in the respective concentrations according to the Recipe Example, the excipient ethanol, the non-ionic surfactant MYVACET and,where appropriate, other excipients, is added. After stirring and homogenising, the pressurised suspension is diluted with propellant gas where appropriate, and introduced by the customary pressure fill techni~que into aluminium or glass vessels of approximately 20 ml volume which are closed by a dosing valve. In the Recipe Examples, the amounts weighed in are each given in % by weight:
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Recipe Example No. 1 2 3 4 5 6 7 . _ formoterol fumarate 0.017 0.017 0.017 0.017 0.017 0.017 0.017 ipratropium bromide 0.086 0.086 0.086 MYVACET 9-40 0.030 0.030 0.043 0.086 0.0152 MYVACET 9-45 0.017 0.034 SPAN 85 0.019 ethanol 5.0 5.0 n-butane 69.953 69.946 69.745 tetrafluoroethane 30.0 30.0 30.0 heptafluoropropane 99.953 99.810 94.947 94.949 Recipe Example No. 8 9 10 11 12 formoterol fumarate 0.017 0.017 0.03 0.017 0.03 ipratropium bromide 0.086 0.154 MYVACET 9-40 0.03 MYVACET 9-45 0.008 0.034 0.017 0.153 ethanol 2.6 n-butane 69.0 tetrafluoroethane 99.949 30.94 69.7 heptafluoropropane 97.375 99.88 29.963 i r~
Recipe Example No. 13 14 15 16 17 . . _ _ salbutamol base 0.143 0.143 0.143 disodium cromoglycate 1.5 1.5 budesonide MYVACET 9-40 0.014 0.014 0.15 0.1 MYVACET 9-45 0.14 ethanol 5.0 5.0 1.0 5.0 5.0 n-butane 64.843 65.1 tetrafluoroethane 30.0 33.3 heptafluoropropane 94.843 98.843 98 35 Recipe Example No. 18 19 20 21 22 23 _ ~ __ salbutamol base 0.142 salbutamol sulfate 0.142 disodium cromoglycate 1.587 ipratropium bromide 0.029 beclomethasone dipropionc Ite 0.367 budesonide 0.312 MYVACET 9-45 0.021 0.021 0.001 0.039 0.001 0.039 TWEEN 60 0.142 0.142 0.158 1.171 ethanol 5.642 5.642 0.735 11.00 0.183 11.50 n-butane heptafluoropropane 94.053 94 053 99.235 87.216 99.449 85.975 The Examples of above illustrate the preparation of suspension aerosols which are easily redispersed. In order to achieve better homogenisation of the mix~ures ancl to avoid adsorptive effects, the addition of 0.5 - 20 %, especially 0.5 - 12 % ethanol isrecommended.
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Such propellant gases or propellant gas mixtures are known per se for the preparation of pharmaceutical aerosols, for example unsubstituted saturated hydrocarbons, for example n-propane, n-butane or isobutane or mixtures thereof, or partially fluorinated or completely fluorinated (perfluorinated) hydrocarbons.
Partially l:luorinated hydrocarbons are derived from aliphatic hydrocarbons having prefer-ably from 1 to 4 carbon atoms, for example methane, ethane, propane, n-butane or iso-butane, or from cycloaliphatic hydrocarbons having preferably 3 and 4 carbon atoms, for example cyclopropane or cyclobutane, by replacing the hydrogen atom(s) with at least one fluorine atom and preferably at least two fluorine atoms in such a manner that at least one hydrogen atom, and accordingly one hydrocarbon bond, remains in the molecule.
Completely fluorinated (perfluorinated) hydrocarbons are derived from the mentioned aliphatic hydrocarbons having from I to 4 carbon atoms and from the mentioned cyclo-aliphatic hydrocarbons having 3 and 4 carbon atoms by replacement of the hydrogen atoms with corresponding fluorine atoms.
Suitable partially or completely fluorinated hydrocarbons are, for example, methane derivatives having from 1 to 4 fluorine atoms, ethane derivatives having from 1 to 6 fluorine atoms, propane derivatives having from 1 to 8 fluorine atoms, n-butane deriva-tives having from 1 to 10 fluorine atoms, cyclopropane derivatives having from 1 to 6 fluorine atoms and cyclobutane derivatives having from 1 to 8 fluorine atoms. In these partially or completely fluorinated hydrocarbons, the hydrogen atom or atoms may be located at different places in the hydrocarbon structure. For partially fluorinated hydrocarbons the following cases of isomerism are possible:
If only one hydrogen atom is present, in the propanc and butane derivatives it may be terminal or located at an intermediatc member of the carbon chain.
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If there is more than one hydrogen atom, then still further cases of isomerism are possible for the ethane, propane, n-butane, cyclopropane and cyclobutane derivatives and for hydrocarbons having an even higher number of carbon atoms. Some or all of the hydr-ogen atoms may be terminal and some or all may be located at one or at different inter-mediate members of the carbon chains. "Mixed" cases of isomerism are also possible, in which the hydrogen atoms are located, in varying distribution, at the terminal carbon atoms and at the same or at different carbon intermediate members in the case of aliphatic derivatives, or at the same or at different ring carbon members in the case of cyclo-aliphatic derivatives.
In order to shorten the usual nomenclature and to differentiate the partially fluorinated hydrocarbons mentioned and also the completely fluorinated hydrocarbons mentioned hereinafter, code names are commonly used; these are explained in "Pharmazeutische Technologie", H. Sucker, P. Fuchs, P. Speiser (editor), Thieme Verlag, D-7000 Stuttgart 1978, on page 735 and can also be applied to CFCs. For the numerous cases of isomerism mentioned, suffixes using the letters a, b ... are customary.
Preferred partially fluorinated hydrocarbons are pentafluoroethane (125), tetrafluoroethane (134 and 134a), trifluoroethane (143a), difluoroethane (152 and 152a) and heptafluoropropane (227).
A non-ionic surfactant from the group of the monoacetylated and diacetylated monoglyc-erides is a monoglyceride (glycerol esterified by a saturated or unsaturated fatty acid) that contains, in addition to the acyl radical of a fatty acid, preferably one or even two acetyl radicals. The acyl radical is preferably derived from an unsaturated fatty acid having more than ten, and an even number of carbon atoms. A monoglyceride that is obtainable from a mixture of monoacetylated or diacetylated monoglycerides using the customary separation methods, for example fractional distillation, is preferred.
The acetylated monoglyceride contains as the acyl radical of a saturated fatty acid, for example a ~l0 20alkanoyl radical having an even number of carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl or n-icosanoyl.
The acetylated monoglyceride contains as the acyl radical of an unsaturated fatty~acid preferably a C~0 20alkenoyl radical having an even number of carbon atoms, for cxample - 6 - ;Z~?~ r~ ~
9-cis-dodecenoyl, -tetradecenoyl or -hexadecenoyl, 6-cis- or 6-trans-octadecenoyl, 9-cis-or 9-trans-octadecenoyl or 1 l-cis-octadecenoyl.
Especially preferred are acetylated monoglycerides ~hat are obtainable commercially under the Trademark MYVACET (Eastman) and authorised by health authorities, e.g. the FDA in the USA, for use as additives for processed foods. Acetylated monoglycerides of the MYVACET series are used as lubricants, plasticisers, non-ionic emulsifiers and solubilisers. The products obtainable commercially under the name MYVACET 5-07, 7-00, 7-07, 9-08, ~-40 and 9-45 are especially preferred.
Most especially suitable are the liquid acetylated monoglycerides, for example MYVACET 9-40 and MYVACET 9-45 K, that can be characterised as follows:
solidification point: 7-8C
density at 20C: 0.98-0.99 [g/cm3]
hydroxyl number: 15 acid number: 3 iodine number: ~0-51 saponification value: 370-380 Surprisingly, it has now been found that it is possible to prepare especially homogeneous and stable suspensions using liquid MYVACET types, especially with active ingredients from the group of betasympathomimetics, e.g. salbutamol or formoterol fumarate, in the mentioned alternative liquefied propellant gases or propellant gas mixtures of component a) which do not damage the ozone layer. Surprisingly, it was also found that undesirable adhesion to the wall of the pressure vessel can be prevented by the addition of a polar solvent such as ethanol. Furthermore, it was found that, using the combination MYVACET and ethanol, other active ingredients from chemically different classes of substances also can be converted, together with propellant gases such as 2~7 or 13~a and n-butane, into homogeneous and readily re-dispersible suspensions that can be used as aerosol formulations.
The non-ionic surfactant b) is present in the pharmaceutical composition in a conccntra-tion of approximately from 0.0001 to 5.0, preferably approximately from 0.001 to 0.5, %
by weight.
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In principle, there are suitable for the aerosol formulation all active ingredients or active ingredient combinations c) that are inert towards the propellant gas component a) and component b), the non-ionic surfactant, and to any additional excipients present. The choice of active ingredients is governed by the diagnosis and subject to the limitation of being able to administer the chosen active ingredient or active ingredient combination as an aerosol formulation, preferably by inhalation, but also topically.
Suitable active ingredients are, for example:
Alkaloids: bromocriptine, ergotamine, atropine;
Anti-allergics: azelastin, cetirizin, epinastin, nedocromil, disodium cromoglycate, ketotifen, pemirolast, traxanox, amlexanox, protopine, tepoxalin, midaglizole, picumast, quazolast, repirinast, suplatast;
Antibiotics: fusafungine, gentamycin, neomycin, minccycline, erythromycin, streptomycin, ofloxacin, ciprofloxacin, cephalexin, cefatrizine, cefaclor, ceftriaxone;
Andmycotics: clotrimazole, ketoconazole, amorolfin, bifonazole;
Betasympathomimetics: bambuterol, salbutamol, formoterol, salmeterol, pirbuterol, carbuterol, clenbuterol, reproterol, rimiterol, hexprenaline, fenoterol, bitolterol, terbutaline, mabuterol, tulobuterol;
Anticholinergics: ipratropium, oxitropium, telenzepine, troventol;
Potassium channel openers: cromakalim, lemakalim;
Corticoids: budesonide, flunisolide, beclomethasone, fluticasone, triamcinolone,fluocortinbutyl, butixocort, cloprednol, fluticason, mometason, tipredane;
Mucolytics: acetylcysteine, ambroxole, carbocysteine, furosemide, amiloride;
Phosphodiesterase-inhibitors: theophylline, isbuphylUne, zandaverine, enprophylline;
Thromboxane inhibitors, e.g. vapiprost, ozagrel; Leucotriene inhibitors, e.g. bunaprolast, ibudilast;
Platelet aggregation factor(PAF) antagonists, e.g. ginkgolides or mequitamium;
Antiinfective agents: pentamidin, hydroxychloroquine; and cytostatic agents such as methotrexate.
Especially preferred are active ingredients that are used in inhalation therapy for the prophylactic and/or acute treatment of bronchial obstructions, such as asthma, for example salbutamol, formoterol, salmeterol, disodium cromoglycate, nedocromil, oxitropium, ipra-tropium, budesonide, beclomethasone, flunisolide and triamcinolone.
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If they contain a salt-forming group, the mentioned active ingredients may be present in the aerosol in the form of the free compounds or in the form of their pharmaceutically acceptable salts.
The aerosol comprises the active ingredient or active ingredient combination in a proportion of approximately from 0.0001 to 5.0 % by weight, preferably approximately from 0.001 to 2.5 % by weight.
It is possible to admix with the pharmacéutical composition, for example, customary pharmaceutical excipients that are suitable for aerosol formulations. For example, a solvent having a higher polarity than that of the liquefied propellant gas component a) can be added. Since the propellant gases or propellant gas mixtures of component a) have little polarity, numerous other, more polar solvents, such as ethanol, isopropanol, propylene glycol, dimethyl ether and mixtures of those solvents, which may be added in any desired concentrations, for example from approximately 0.1 to 30 % by weight, are suitable as additives.
As additional excipients there may be added, in addition to component b), other non-ionic surfactants that increase the wetting and dispersibility of pharmaceutical active ingredients still further and/or, as lubricants, improve the mechanical valve functions and prevent the deposition of solids by adsorption onto the inside of the pressure vessel.
Such additional non-ionic surfactants are, for example, sorbitan fatty acid esters, for example sorbitan trioleate, sesquioleate, monooleate or monolaurate, which are commer-cially obtainable, for example, under the Trademark SPAN, for example SPAN 85, 80 and 20, polyoxyethylenesorbitan esters, for example polyoxyethylene(20)sorbitan monolaurate or monooleate, for example esters that are obtainable commercially under the Trademark TWEEN, for example TWEEN 20, 40, 60 and 80, oleyl, stearyl or lauryl polyoxyethylene esters that are obtainable commercially under the Trademarks BRIJ or GENAPOL, for example BRIJ 92, 72, 30 or GENAPOL 0-020, and block copolymers that are commercially obtainable under the Trademarks SYNPERONIC.
Other excipients are, for example, pharmaceutically approved oils, for example oils of vegetable origin, for example from corn, olives, cotton seeds, rape or sunflowers, phospholipids, for example synthetic lecithin or natural lecithin dervivatives that àre commercially obtainable under the Tradcmark EPIKURON, diethylene glycol dioleate, ~?~ 5 tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, monooleate or monoricinoleate, cetyl alcohol, polyethylene glycol 400, polyol fatty acid esters or cetylpyridinium chloride. Taste correctives, such as saccharin, aspartames and flavourings, for example dentomint, can also be added.
The mentioned excipients of component d) may be added in a proportion of approximately from 0.0001 to 10 % by weight, preferably approximately from 0.001 to 1 % by weight, based on the entire weight of the pharmaceutical formulation.
The present invention relates preferably to a pharmaceutical composition comprising:
a) a propellant gas or propellant gas mixture selected from the group consisting of propane, n-butane, isobutane, di-, tri-, or tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from ~he group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of the antiallergics, e.g. disodium cromoglycate or nedocromil, betasympatho-mimetics, e.g. salbutamol, salmeterol or formoterol, anticholinergics, e.g. oxilropiurn- or ipratropium bromide, and corticoids, e.g. budesonide, Qunisolide, beclomethasone or triamcinolone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present invention relates preferably to a pharmaceutical composition comprising:
a) a propellant gas or propellant gas mixture from ihe group consisting of propane, n-butane, isobutane, tetraQuoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromoglycate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcino-lone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present in~ention relates especially to a pharmaceutical composition comprisin~:
a) the propellant gas heptaQuoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylatcd monoglycerides;
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e) a pharmaceutical active ingredient or active ingredient combination from the group disodium cromoglyeate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcinolone and, optionally, d) further eonventional pharmaceutical excipients that are suitable for aerosol formula-tions.
The present invention also relates to a process for the preparation of the pharmaceutical composition which is carried out in a manner known per se and is described, for example, in the aforementioned "Pharma~eutische Technologie" on pages 736-737.
The pharmaceutical composition can be prepared by placing the pharmaceutical active ingredient or active ingredient combination c) in a pressure-tight vessel and introducing, in any desired sequence of the steps, the non-ionic surfactant b), where appropriate the conventional pharmaceutical excipients d), and introducing the propellant gas orpropellant gas mixture a), homogenising, and introducing the homogeneous mixture into dosing vessels suitable for aerosol formulations.
If the active ingredient or ingredients is/are in solid, for example crystalline, form, they are to be comminuted, preferably by micronisation. The upper limit for the average particle size in the case of topical formulations is considered to be an average partiele diameter of less than 100 and, in the ease of inhalation formulations for the purpose of deposition in the respiratory tract, less than 10 micrometers. A particle size of approximately from 0.1 to 5 micrometers is preferred for inhalation formulations, which can be achieved by the use of conventional comminution methods, for example grinding in an air jet mill.
Component c) is weighed into an open batch pressure vessel equipped with a stirring and homogenising apparatus, and there are added, according to the formulation instructions, in the desired sequence, components b) - surfactant- and, where appropriate, d) other excipients, for example ethanol. The pressure vessel is closed and the propellant gas or propellant gas mixture is introduced. The active ingredient is homogenised in the propellant gas/excipient mixture in the customary manner, for example by stirring, shaking or treatment with ultrasound. Using known filling techniques, the contents of the pressure vessel are introduced through the valve into dosing vessels, for example pres-sure-tight vessels consisting of tinplate or aluminium whieh are referred to in eornmon parlanee as spray cans and are provided with the customary dosing valves. The pres-sure-tight valves release approximately from 25 to 100 microlitres in the case of inhalation dosing aerosols.
The invention also relates to the use of the pharmaceutical aerosol composition in a therapeutic method, for which a need exists depending on the therapeutic category of the active ingredient or active ingredient combination present in the claimed composition. The pharmaceutical aerosol composition is especially useful for the treatment by inhalation of allergic diseases of the respiratory tract such as asthma or allergic rhinitis, especially in the event that the composition contains active agents such as formoterol, disodium cromoglycate or salbutamol.
The invention also relates to the use of a non-ionic surfactant from the group of the monoacetylated or diacetylated monoglycerides for the preparation of a pharmaceutical composition that can be used as an aerosol. Especially preferred is the use of a liquid, non-ionic acetylated monoglyceride that is known under the name MYVACET.
The following Examples illustrate the invention:
The active ingredient, micronised to a particle size of less than 6 micrometers, is weighed according to the Recipe into a previously dried batch pressure vessel, and the propellant gas or propellant gas mixture, comprising, in the respective concentrations according to the Recipe Example, the excipient ethanol, the non-ionic surfactant MYVACET and,where appropriate, other excipients, is added. After stirring and homogenising, the pressurised suspension is diluted with propellant gas where appropriate, and introduced by the customary pressure fill techni~que into aluminium or glass vessels of approximately 20 ml volume which are closed by a dosing valve. In the Recipe Examples, the amounts weighed in are each given in % by weight:
;' :, ' ' 2~?~ 5~
Recipe Example No. 1 2 3 4 5 6 7 . _ formoterol fumarate 0.017 0.017 0.017 0.017 0.017 0.017 0.017 ipratropium bromide 0.086 0.086 0.086 MYVACET 9-40 0.030 0.030 0.043 0.086 0.0152 MYVACET 9-45 0.017 0.034 SPAN 85 0.019 ethanol 5.0 5.0 n-butane 69.953 69.946 69.745 tetrafluoroethane 30.0 30.0 30.0 heptafluoropropane 99.953 99.810 94.947 94.949 Recipe Example No. 8 9 10 11 12 formoterol fumarate 0.017 0.017 0.03 0.017 0.03 ipratropium bromide 0.086 0.154 MYVACET 9-40 0.03 MYVACET 9-45 0.008 0.034 0.017 0.153 ethanol 2.6 n-butane 69.0 tetrafluoroethane 99.949 30.94 69.7 heptafluoropropane 97.375 99.88 29.963 i r~
Recipe Example No. 13 14 15 16 17 . . _ _ salbutamol base 0.143 0.143 0.143 disodium cromoglycate 1.5 1.5 budesonide MYVACET 9-40 0.014 0.014 0.15 0.1 MYVACET 9-45 0.14 ethanol 5.0 5.0 1.0 5.0 5.0 n-butane 64.843 65.1 tetrafluoroethane 30.0 33.3 heptafluoropropane 94.843 98.843 98 35 Recipe Example No. 18 19 20 21 22 23 _ ~ __ salbutamol base 0.142 salbutamol sulfate 0.142 disodium cromoglycate 1.587 ipratropium bromide 0.029 beclomethasone dipropionc Ite 0.367 budesonide 0.312 MYVACET 9-45 0.021 0.021 0.001 0.039 0.001 0.039 TWEEN 60 0.142 0.142 0.158 1.171 ethanol 5.642 5.642 0.735 11.00 0.183 11.50 n-butane heptafluoropropane 94.053 94 053 99.235 87.216 99.449 85.975 The Examples of above illustrate the preparation of suspension aerosols which are easily redispersed. In order to achieve better homogenisation of the mix~ures ancl to avoid adsorptive effects, the addition of 0.5 - 20 %, especially 0.5 - 12 % ethanol isrecommended.
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Claims (8)
1. A pharmaceutical composition for use as an aerosol comprising:
a) a liquefied propellant gas or propellant gas mixture having a vapour pressure of more than 1 bar and less than 6 bar (20°C) from the group consisting of unsubstituted hydrocarbons and partially to completely fluorinated hydrocarbons;
b) a non-ionic surfactant from the group consisting of monoacetylated or diacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination and, optionally, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
a) a liquefied propellant gas or propellant gas mixture having a vapour pressure of more than 1 bar and less than 6 bar (20°C) from the group consisting of unsubstituted hydrocarbons and partially to completely fluorinated hydrocarbons;
b) a non-ionic surfactant from the group consisting of monoacetylated or diacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination and, optionally, d) other conventional pharmaceutical excipients that are suitable for aerosol formulations.
2. A pharmaceutical composition according to claim 1 comprising:
a) a propellant gas or propellant gas mixture from the group consisting of propane, n-butane, isobutane, di-, tri-, or tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of antiallergics, betasympathomimetics, anticholinergics and corticoids, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
a) a propellant gas or propellant gas mixture from the group consisting of propane, n-butane, isobutane, di-, tri-, or tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of antiallergics, betasympathomimetics, anticholinergics and corticoids, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
3. A pharmaceutical composition according to claim 1 comprising:
a) a propellant gas or propellant gas mixture from the group consisting of propane, n-butane, isobutane, tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group of the monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromoglycate, salbutamol, salmeterol, formoterol, oxitropiurn bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcino-lone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
a) a propellant gas or propellant gas mixture from the group consisting of propane, n-butane, isobutane, tetrafluoroethane (134a) and heptafluoropropane (227);
b) a non-ionic surfactant from the group of the monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromoglycate, salbutamol, salmeterol, formoterol, oxitropiurn bromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcino-lone, and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
4. A pharmaceutical composition according to claim 1 comprising:
a) the propellant gas heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromnglycate, salbutamol, salmeterol formoterol, oxitropiumbromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcinolone and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
a) the propellant gas heptafluoropropane (227);
b) a non-ionic surfactant from the group consisting of monoacetylated monoglycerides;
c) a pharmaceutical active ingredient or active ingredient combination from the group consisting of disodium cromnglycate, salbutamol, salmeterol formoterol, oxitropiumbromide, ipratropium bromide, budesonide, flunisolide, beclomethasone and triamcinolone and, optionally, d) further conventional pharmaceutical excipients that are suitable for aerosol formula-tions.
5. A process for the preparation of the pharmaceutical composition according to claim 1 which comprises placing the pharmaceutical active ingredient or active ingredient combi-nation c) in a pressure-tight vessel and introducing, in any desired sequence of the steps, the non-ionic surfactant b), where appropriate the conventional pharmaceutical excipi-ents d), and introducing the propellant gas or propellant gas mixture a), homogenising, and introducing the homogeneous mixture into dosing vessels suitable for aerosol formula-tions.
6. A pharmaceutical composition according to claim 1 for use as an aerosol formulation in a therapeutic method of treatment of on the human or animal body.
7. A pharmaceutical composition according to claim 1 for use as an aerosol formulation in nasal or oral inhalation therapy for the treatment of disorders of the respiratory tract.
8. The use of a non-ionic surfactant from the group of the monoacetylated or diacetylated monoglycerides for the preparation of a pharmaceutical composition that can be used as an aerosol formulation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH781/91-2 | 1991-03-14 | ||
| CH78191 | 1991-03-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2062854A1 true CA2062854A1 (en) | 1992-09-15 |
Family
ID=4195038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002062854A Abandoned CA2062854A1 (en) | 1991-03-14 | 1992-03-12 | Pharmaceutical aerosol formulations |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0504112A3 (en) |
| JP (1) | JPH04327527A (en) |
| KR (1) | KR920017643A (en) |
| AU (1) | AU646723B2 (en) |
| CA (1) | CA2062854A1 (en) |
| FI (1) | FI921060A (en) |
| HU (1) | HU208398B (en) |
| IE (1) | IE920826A1 (en) |
| IL (1) | IL101169A0 (en) |
| MX (1) | MX9201082A (en) |
| NO (1) | NO920987L (en) |
| NZ (1) | NZ241938A (en) |
| ZA (1) | ZA921877B (en) |
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| US5837699A (en) * | 1994-01-27 | 1998-11-17 | Schering Corporation | Use of mometasone furoate for treating upper airway passage diseases |
| US6461591B1 (en) | 1997-02-05 | 2002-10-08 | Jago Research Ag | Medical aerosol formulations |
| US6475467B1 (en) | 1998-08-04 | 2002-11-05 | Jago Research Ag | Medicinal aerosol formulations |
| US6585958B1 (en) | 1998-07-24 | 2003-07-01 | Jago Research Ag | Medicinal aerosol formulations |
| US6737044B1 (en) | 1998-04-03 | 2004-05-18 | University College Cardiff Consultants Limited | Aerosol composition |
| US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
| US7994197B2 (en) | 2007-02-11 | 2011-08-09 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
| US8080236B2 (en) | 2002-04-17 | 2011-12-20 | Nektar Therapeutics Uk, Ltd | Particulate materials |
| US8513279B2 (en) | 1999-07-14 | 2013-08-20 | Almirall, S.A. | Quinuclidine derivatives and medicinal compositions containing the same |
| US9254262B2 (en) | 2008-03-13 | 2016-02-09 | Almirall, S.A. | Dosage and formulation |
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| US10085974B2 (en) | 2008-03-13 | 2018-10-02 | Almirall, S.A. | Dosage and formulation |
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-
1992
- 1992-03-05 EP EP19920810171 patent/EP0504112A3/en not_active Withdrawn
- 1992-03-06 IL IL101169A patent/IL101169A0/en unknown
- 1992-03-10 AU AU12188/92A patent/AU646723B2/en not_active Ceased
- 1992-03-10 JP JP4051853A patent/JPH04327527A/en active Pending
- 1992-03-11 FI FI921060A patent/FI921060A/en not_active Application Discontinuation
- 1992-03-12 CA CA002062854A patent/CA2062854A1/en not_active Abandoned
- 1992-03-12 NZ NZ241938A patent/NZ241938A/en unknown
- 1992-03-12 MX MX9201082A patent/MX9201082A/en unknown
- 1992-03-13 NO NO92920987A patent/NO920987L/en unknown
- 1992-03-13 HU HU9200850A patent/HU208398B/en not_active IP Right Cessation
- 1992-03-13 KR KR1019920004118A patent/KR920017643A/en not_active Application Discontinuation
- 1992-03-13 ZA ZA921877A patent/ZA921877B/en unknown
- 1992-03-13 IE IE082692A patent/IE920826A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| HU9200850D0 (en) | 1992-05-28 |
| EP0504112A3 (en) | 1993-04-21 |
| HUT60430A (en) | 1992-09-28 |
| AU646723B2 (en) | 1994-03-03 |
| HU208398B (en) | 1993-10-28 |
| JPH04327527A (en) | 1992-11-17 |
| NO920987L (en) | 1992-09-15 |
| ZA921877B (en) | 1992-10-28 |
| IE920826A1 (en) | 1992-09-23 |
| NO920987D0 (en) | 1992-03-13 |
| AU1218892A (en) | 1992-09-17 |
| IL101169A0 (en) | 1992-11-15 |
| NZ241938A (en) | 1993-06-25 |
| FI921060A0 (en) | 1992-03-11 |
| FI921060A (en) | 1992-09-15 |
| EP0504112A2 (en) | 1992-09-16 |
| KR920017643A (en) | 1992-10-21 |
| MX9201082A (en) | 1992-09-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |