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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D83/00—Containers or packages with special means for dispensing contents
  • B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
  • B65D83/75—Aerosol containers not provided for in groups B65D83/16 - B65D83/74

Definitions

• a pharmaceutical product comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or substance mixture.
• Propellant-containing metered dose aerosols have long been used for the treatment of patients. Especially in the treatment of respiratory diseases, these metered dose inhalers have proven to be effective with the corresponding active ingredients.
• chlorofluorohydrocarbons CFCs
• hydrofluorocarbons HFCs
• HFC-134 (a) 1,1,1,2-tetrafluoroethane
• the propellant-containing metered dose aerosols are sealed in a package that serves the drug safety.
• the packaging consists - as known from the prior art - for example, aluminum composite foil or polyethylene films or other tightly closed containers, such as glass bottles or aluminum cans with screw caps.
• this packaging is intended to guarantee that the pharmaceutical substance, substance formulation or substance mixture does not lose water or absorb water or moisture from the environment.
• the water diffusion through the rubber components of the metered dose aerosols has a negative impact on the stability of the pharmaceutical product and may therefore affect the quality.
• the propellant gas contained in the metered dose inhaler can escape from the metered dose aerosol over a relatively long period of time and escapes into the surrounding packaging. This then partially inflates. The amount of escaped propellant gas is so low that it does not affect the quality of the pharmaceutical product.
• the inflated packaging may present a problem with the storage of the pharmaceutical product. In addition, this effect may lead to the uncertainty of patients who may find the product defective and no longer effective.
• a pharmaceutical product comprising a propellant-containing metered dose inhaler, an effective amount of adsorbent, a pharmaceutically active substance, substance formulation or substance mixture and a packaging which encloses the adsorbent and the metered dose inhaler with the pharmaceutically active substance, substance formulation or mixture of substances the adsorbent is in addition to the propellant-containing metered dose inhaler in the package.
• the invention particularly relates to pharmaceutical products containing a pharmaceutically active substance, substance formulation or substance mixture, wherein the pharmaceutically active substance, substance formulation or substance mixture is used for the treatment of respiratory diseases.
• the adsorbent absorbs the propellant gas and the package no longer inflates. At the same time it is surprisingly found that the adsorbent does not affect the water content of the pharmaceutically active substance, substance formulation or substance mixture of the propellant-containing metered dose inhaler.
• Suitable adsorbents are the following substances available on the market: activated carbon, silica gels, molecular sieves, ion exchangers, alumina, zeolites and / or magnesium sulfate.
• activated carbon silica gels, molecular sieves, ion exchangers, alumina, zeolites and / or magnesium sulfate.
• a mixture of two or more adsorbents may be used.
• charcoal tablets are used, as they are available in pharmacies for the treatment of diarrheal diseases. Most preferably, one charcoal tablet per metered dose inhaler is enclosed by the package.
• HFCs CFCs 11, 12, 114, nitrous oxide (N 2 O nitrous oxide) or carbon dioxide (CO 2 ) or HFCs, preferably HFC 134a or HFC 227, are used as propellant gases in the dosing aerosol.
• HFC propellants are HFC-32 (difluoromethane), HFC-143 (a) (1,1,1-trifluoroethane), HFC 134 (1,1,2,2-tetrafluoroethane) and HFC-152a (1,1 - difluoroethane)
• W is a pharmacologically active agent and (for example) selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HI antihistamines, P AF - antagonists and PI3-kinase inhibitors. Furthermore, two- or three-fold combinations of W can be combined and used for application in the device according to the invention.
• W represents a betamimetics combined with anticholinergics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
• W represents an anticholinergic agent combined with a betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors or LTD4 antagonists
• W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
• W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist
• W represents an EGFR inhibitor combined with a LTD4 antagonist.
• Preferred betamimetics for this purpose are compounds selected from the group consisting of albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharines, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol , Orciprenaline, Pirbuterol, Procaterol, Reproterol, Rimiterol, Ritodrine, Salmefamol, Salmeterol, Soterenol, Sulphone terol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and
• the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
• Preferred anticholinergic compounds are compounds which are selected from the group consisting of 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 the chloride salt, tolterodine.
• the cations are the pharmacologically active ones
• the abovementioned salts may preferably contain Chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate as counterions are preferred.
• the chlorides, bromides, iodides and methanesulfonates are particularly preferred.
• anticholinergics are selected from the salts of the formula AC-I
• X is a single negatively charged anion, preferably an anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-Toluenesulfonate, preferably a singly negatively charged anion, more preferably an anion selected from the group consisting of fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, most preferably bromide, optionally in the form of their racemates, enantiomers or hydrates Significance are those drug combinations that contain the enantiomers of the formula AC-l-en
• R is either methyl or ethyl and in which X ⁇ may have the abovementioned meanings.
• the compound of the formula AC-2 may also be present in the form of the free base AC-2-base.
• Preferred corticosteroids are compounds selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR - 106541, NS-126, ST-26 and
• any reference to steroids includes reference to their optionally existing salts or derivatives, hydrates or solvates
• Examples of possible salts and derivatives of Steroids may be: alkali metal salts such as sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• Preferred PDE4 inhibitors here are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, 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
• the acid addition salts of the PDE4 inhibitors are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
• Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and - l - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2- hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid,
• these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• salts or derivatives whose formation the LTD4 antagonists are capable of are understood to be: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• Preferred EGFR inhibitors are compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
• these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozan, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
• these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• HI-antihistamines here preferably compounds are used, which are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, Cexchlorpheniramin, pheniramine, doxylamine, chlorphenoxamine , Dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
• these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
• inhalable macromolecules can be used as disclosed in EP 1 003 478.
• the compound may be derived from the group of derivatives of ergot alkaloids, the triptans, the CGRP inhibitors, the phosphodiesterase V inhibitors, optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.
• the substances, substance formulations or substance mixtures are preferably in the form of suspension or solution aerosols.
• Suitable packaging materials are all tight-closing foils (for example polyethylene foils), preferably aluminum composite foils.
• the packaging of the metered dose aerosols (with the substance, substance formulation or substance mixture) and the adsorbent is carried out by standard methods, as known from the literature.
• Aluminum composite foil neutral, from Tscheulin-Rothal GmbH, Friedrich-Meyer-Str. 23, 79331 Teningen, Germany, according to DIN 1784.
• the film thickness is 50 ⁇ m ⁇ 10%.
• the metered dose inhalers used contained HFC 227.
• the metered dose inhalers did not contain a pharmaceutical product but were so-called placebo metered dose inhalers.
• the samples were stored at 5O 0 C and weighed after different periods of storage.
• the aluminum bags were cut open and the aerosol containers weighed alone, as well as the flattened aluminum bags with charcoal tablets.
• charcoal tablets prevents bloating aluminum bags.

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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• General Health & Medical Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2006
  • 2006-03-02 DE DE102006009599A patent/DE102006009599A1/de not_active Withdrawn
  • 2006-10-20 US US12/091,105 patent/US20080279788A1/en not_active Abandoned
  • 2006-10-20 JP JP2008537066A patent/JP2009516648A/ja active Pending
  • 2006-10-20 EP EP06807454A patent/EP1942867A2/de not_active Withdrawn
  • 2006-10-20 WO PCT/EP2006/067642 patent/WO2007048764A2/de active Application Filing
  • 2006-10-20 CA CA002626298A patent/CA2626298A1/en not_active Abandoned
• 2011
  • 2011-05-19 US US13/111,248 patent/US20110223113A1/en not_active Abandoned

Non-Patent Citations (1)

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