Patent Application
20110223113
A pharmaceutical product is claimed according to the invention, containing a propellant gas-containing metered dose aerosol, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or mixture of substances and packaging which encloses the adsorbent and the metered dose aerosol with the pharmaceutically active substance, substance formulation or mixture of substances.
Propellant gas-containing metered dose aerosols have long been used to treat patients. These metered dose aerosols with the corresponding active substances have proved particularly satisfactory for treating respiratory complaints.
The propellant gases used in the metered dose aerosols are either traditional chlorofluorocarbons (CFCs) or hydrofluorocarbons (HFCs). The latter are preferred for environmental reasons and have largely replaced CFCs in the mean time. These systems are described for example in U.S. Pat. No. 4.174.295.
It is known that certain HFCs are particularly suitable for medical use. European Application No. 0 372 777 describes for example the use of 1,1,1,2-tetrafluoroethane (HFC-134(a)) in the pharmaceutical field.
PCT Application No. WO91/11496 describes the use of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) in the field of metered dose aerosols.
The metered dose aerosols containing propellant gas are welded into a packaging that serves as a drug safety wrapper. As known in the prior art, the packaging consists for example of composite aluminium foil or polyethylene films or other containers that provide a tight seal, such as glass bottles or aluminium cans with screw caps.
This packaging is intended to ensure, inter alia, that the pharmaceutical substance, substance formulation or mixture of substances does not suffer any loss of water or absorb any water or moisture from the environment. The diffusion of water through the rubber components of metered dose aerosols has a negative influence on the stability of the pharmaceutical product and may therefore affect the quality.
The packaging of metered dose aerosols together with an adsorbent to absorb moisture is known from the prior art (JP 59174473). Suitable adsorbents are activated charcoal, silica gels, molecular sieves and certain ion exchangers.
It is now known that the propellant gas contained in the metered dose aerosol may escape from the metered dose aerosol over a lengthy period and escape into the surrounding packaging. This then becomes partially inflated. The quantity of propellant gas that escapes is so small that it does not impair the quality of the pharmaceutical product. However, the inflated packaging may present problems during the storage of the pharmaceutical product. Moreover, this effect may give rise to uncertainty on the part of the patients, who in some cases regard the product as damaged and no longer effective.
According to the invention a pharmaceutical product is proposed containing a propellant gas-containing metered dose aerosol, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or mixture of substances and a packaging which encloses the adsorbent and the metered dose aerosol with the pharmaceutically active substance, substance formulation or mixture of substances, the adsorbent being contained in the packaging together with the propellant gas-containing metered dose aerosol. The invention relates in particular to pharmaceutical products containing a pharmaceutically active substance, substance formulation or mixture of substances, wherein the pharmaceutically active substance, substance formulation or mixture of substances is used to treat respiratory complaints.
It has surprisingly been found that the adsorbent absorbs the propellant gas and the packaging is no longer inflated. At the same time, it has surprisingly been found that the adsorbent does not affect the water content of the pharmaceutically active substance, substance formulation or mixture of substances of the propellant gas-containing metered dose aerosol.
The following commercially available substances are suitable as adsorbents: activated charcoal, silica gels, molecular sieves, ion exchangers, aluminium oxide, zeolites and/or magnesium sulphate. It is also possible to use a mixture of two or more adsorbents. Preferably, charcoal tablets of the kind that can be obtained from pharmacies for treating diarrhoea are used. Most preferably, one charcoal tablet is enclosed in the packaging for each metered dose aerosol.
The propellant gases used in the metered dose aerosol are CFCs, FCKW 11, 12, 114, laughing gas (N2O, nitrous oxide) or carbon dioxide (CO2) or HFCs, preferably HFC 134a or HFC 227. Other examples of HFC propellant gases are HFC-32 (difluoromethane), HFC-143(a) (1,1,1-trifluoroethane), HFC 134 (1,1,2,2-tetrafluoroethane) and HFC-152a (1,1-difluoroethane).
The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the invention. Combinations of W might be, for example:
The compounds used as betamimetics are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and
optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions the above-mentioned salts may preferably contain the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
Other preferred anticholinergics are selected from among the salts of formula AC-1
wherein X− denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly preferably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceutical combinations which contain the enantiomers of formula AC-1-en
wherein X− may have the above-mentioned meanings Other preferred anticholinergics are selected from the salts of formula AC-2
wherein R denotes either methyl or ethyl and wherein X− may have the above-mentioned meanings. In an alternativen embodiment the compound of formula AC-2 may also be present in the form of the free base AC-2-base.
Other specified compounds are:
The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X may have the meanings given hereinbefore for X.
As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR-106541, NS-126, ST-26 and
optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
PDE4-inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof. According to the invention the acid addition salts of the PDE4 inhibitors are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
H1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
It is also possible to use inhalable macromolecules, as disclosed in EP 1 003 478.
In addition, the compounds may come from the groups of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.
The following substances, substance formulations or mixtures of substances are most particularly preferred: ipratropium, salbutamol, salmeterol, fenoterol, oxitropium, formoterol, budesonide, fluticasone, cyclesonide, mometasone, flunisolide, beclomethasone, while the substances, substance formulations or mixtures of substances may also be in the form of salts or esters.
The substances, substance formulations or mixtures of substances are preferably in the form of suspended or dissolved aerosols.
The packaging material used may be any tight-sealing foils or films (e.g. polyethylene films), preferably composite aluminium foils.
The packaging of the metered dose aerosols (with the substance, substance formulation or mixture of substances) and adsorbent is carried out using standard methods as known from the literature.
Tests were carried out which demonstrate that in propellant gas-containing metered dose aerosols the presence of an adsorbent absorbs the propellant gas, with the result that the packaging no longer inflates at all, or only slightly, and the water content of the medicament, formulation or mixture is not affected and thus contributes to product safety by ensuring a stable product quality.
The following samples were produced:
For the evacuation, after the metered dose aerosol has been placed in the composite aluminium bag the air is sucked out using a thin tube and the bag is sealed immediately.
The following aluminium bags (standard packaging with aluminium coating, plastic-coated aluminium) were used:
Charcoal tablets made by Hevert Sobernheim/Nahe “medicinal charcoal in 250 mg portions” Batch No. 311297 were used.
The metered dose aerosols used contained HFC 227. The metered dose aerosols contained no pharmaceutical product but were so-called placebo metered dose aerosols.
The samples were stored at 50° C. and weighed after various storage times.
After 14 months' storage the aluminium bags were cut open and the aerosol containers were weighed on their own, and the flattened aluminium bags containing charcoal tablets were also weighed.
The following results were obtained:
The following conclusions can be drawn from the data in the Table:
The addition of charcoal tablets prevents the aluminium bags from inflating.
There does not appear to be any difference between the evacuated and unevacuated aluminium bags.
The charcoal tablets absorb virtually all the losses of propellant gas from the aerosol cans. The checking of bags nos. 3 and 6 shows that the increased weight loss of bags nos. 3 and 6 can be put down to defective welding of the aluminium bags.
| Number | Date | Country | Kind |
|---|---|---|---|
| 102005052128.2 | Oct 2005 | DE | national |
| 102006009599.5 | Mar 2006 | DE | national |
This application is a continuation of U.S. patent application Ser. No. 12/091,105 filed Jun. 25, 2008 and claims the benefit of PCT/EP2006/067642 filed Oct. 20, 2006 and priority from German Applications DE 102005052128.2 filed Oct. 28, 2005 and 102006009599.5 filed Mar. 2, 2006, the entireties of which are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12091105 | Jun 2008 | US |
| Child | 13111248 | US |
