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EP2001536A1 - Emballage pour inhalateur de poudre multidose avec proprietes optimisees de purge - Google Patents

Emballage pour inhalateur de poudre multidose avec proprietes optimisees de purge

Info

Publication number
EP2001536A1
EP2001536A1 EP07727327A EP07727327A EP2001536A1 EP 2001536 A1 EP2001536 A1 EP 2001536A1 EP 07727327 A EP07727327 A EP 07727327A EP 07727327 A EP07727327 A EP 07727327A EP 2001536 A1 EP2001536 A1 EP 2001536A1
Authority
EP
European Patent Office
Prior art keywords
amino
phenyl
quinazoline
chloro
fluoro
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.)
Withdrawn
Application number
EP07727327A
Other languages
German (de)
English (en)
Inventor
Herbert Wachtel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2001536A1 publication Critical patent/EP2001536A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0048—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged in a plane, e.g. on diskettes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/0045—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters
    • A61M15/0046—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier
    • A61M15/0051—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using multiple prepacked dosages on a same carrier, e.g. blisters characterized by the type of carrier the dosages being arranged on a tape, e.g. strips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the invention relates to a package for pharmaceutical compositions, blends or formulations for use in a powder inhaler.
  • the multi-dose powder inhalers contain the drug, mixture or formulation either in the form of a powder supply from which a single unit dose is withdrawn from a cavity by a built-in dosing unit or pre-dosed, packaged unit doses that are either stored together in the device ( eg in the form of packaging in blisters) or when used individually in the device (eg in the form of capsules).
  • Powder formulation packaged in the device for the product quality and thus the suitability for inhalation application, crucial.
  • one of the main purposes of the package is to keep the chemical composition of the atmosphere inside the package constant to prevent or stabilize physical or chemical changes in the drug, mixture or formulation.
  • fine particle dose is understood to mean the dose that reaches the lungs of the patient.
  • the fine particle dose is influenced by the interactions of the micronized drug particles with each other as well as the interactions with the excipients.
  • a packaging has a shape and an opening pattern (ie, the locations of the packaging, which allow the opening of the blister by piercing or cutting), the optimized air flow and thus an optimized application of the drug, the mixture or allow formulation.
  • EP 0 703 800 B1 or EP 0 911 047 A1 disclose a powder inhaler consisting of a cup-shaped lower part and a likewise cup-shaped lid.
  • the patient can press an actuator which is displaceable from a rest position into a movement and cooperates with at least one injectable into the capsule holder needle. With the help of the needle or the needles, the capsule is pierced and the drug released.
  • DE 3348370 and DE 3336486 disclose inhalers containing a disc-shaped blister pack having a plurality of circularly arranged cavities.
  • the individual cavities each contain a dose of a medicament powder intended for inhalation.
  • the cavities are closed on both sides, eg by a sealing foil.
  • the cavitate is opened to expose the medicament powder.
  • An air channel connects the opened cavity with the mouthpiece of the inhaler.
  • the inhaler of DE 3336486 is described more closely by way of example.
  • This housing has a housing in which a chamber (storage chamber) is located which has an air inlet and in which is a disc-shaped, round blister with packaged drug pockets
  • the blister is loosely connected to a round, rotatable disc on the disc holes are formed circumferentially, which have in the axial direction contact with the medicine bags, ie the pockets and holes are above or below each other
  • the chamber has an air outlet.
  • the inhaler also has a piston arranged so that it can open in each case a medicament pocket pierceable so that the medicament is released into the chamber and can be inhaled via a mouthpiece.
  • the package packaging is characterized in that it is in direct contact with the inhalation formulation.
  • the package packaging may be surrounded by a second external protection, the secondary packaging means
  • Capsule a solid or flexible blister with cavities or a disc with cavities
  • the secondary packaging may be a blister, a bag, a bag or other container.
  • the secondary packaging generally encloses the packaging material completely. Secondary packaging is used in particular when the packaging material does not provide adequate protection against moisture
  • the P ⁇ marpackstoff and optionally the secondary packaging have the task to protect the drug and the entire inhalation formulation from chemical or physical change, so that it remains stable in the long term.
  • physical changes include changes that may alter the application of the predetermined fine particle dose.
  • the choice of a suitable material for the packaging material is determined by two factors: Firstly, the material must be able to fulfill the mentioned protective function. On the other hand, the material must be such that the package can be given the necessary form for use in the powder inhaler and that can fulfill its intended function.
  • the present invention therefore relates to packaging for inhalable powders, which are optimized in their shape, in their piercing pattern, as well as in the level of a drug, a mixture or formulation.
  • the invention relates to optimized packaging means, as described above, which due to the shape of their opening pattern in their piercing pattern, as well as the level of a drug, a mixture or formulation allow improved air flow and thus improved application of the drug, the mixture or formulation ,
  • the packaging means are preferably a capsule, a blister, a blister disc, a blister screw or a blister band.
  • blisters these various forms are collectively referred to as blisters (with the exception of the capsule).
  • the capsule usually consists of two parts, a capsule body (body) and a capsule cap (cap), which are telescoped into one another. But also multi-part capsules are known.
  • capsules of size 2-4, most preferably size 3 are used.
  • the capsule material is made of non-digestible plastic or gelatin, in particular hard gelatin.
  • the blister disk can be, for example, a cylinder-like disk of up to 5 mm in height and a diameter of up to 15 cm. Holes or holes are formed in the disk perpendicular to the disk plane (cavities).
  • a disk can be used for example in an inhaler according to DE 3348370 or DE 3336486.
  • Such an inhaler has a housing in which the disc-shaped, round blister with packaged medicine bags is located.
  • the inhaler has u.a. a pen which is arranged so that it can each open a medicine bag, so that the drug is released into the chamber and can be inhaled via a mouthpiece.
  • the shape of the packaging material according to the invention is fundamentally predetermined by the powder inhaler to be used.
  • the packaging has a teardrop-shaped or oval shape or the shape of an eight.
  • the inflow surfaces and the outflow surface or surfaces are at a maximum distance from each other.
  • the packaging material which is a blister, initially has a base element which consists of a thermoplastic and at least two cavities separated from one another by a web.
  • the cavities are open at least to one side, possibly also after two, opposite sides. These openings are closed in the ready-to-use packaging, for example, a firmly bonded to the base element sealing film.
  • the packaging may consist of the commercially available materials. Preferably, it consists of a plastic. Very particular preference is given to plastics from the group of thermoplastic polymers, for example polystyrenes, polyolefins, polyamides, polyvinyl chlorides, polyethylene, polycarbonate, polyesters, polypropylene,
  • Polyethylene terephthalate or polyurethanes used. These have the necessary stiffness or mobility to fulfill the mechanical tasks of the primary packaging. Also suitable, for example, natural products such as gelatin or composite materials of plastic and metals, such as aluminum.
  • all walls of the cavity consist of the same material.
  • at least the wall closing the opening may be of a different material than the remaining walls.
  • the level of the drug, formulation or mixture in the packaging can be optimized and depends on the fluidity of the drug, formulation or mixture.
  • Flowability refers to the ability of the drug, formulation or
  • ⁇ i is the solidification stress and ⁇ c is the bulk solids strength.
  • the flowability is determined by means of ring shear device.
  • the flowability is 4> ff c > 1.
  • you use packaging that is partially filled are, in the way that a free air passage between at least one inlet opening and an outlet opening exists.
  • the flowability is 4 ⁇ ff c .
  • packaging means which are partially filled, such that a free air passage between at least one inlet opening and an outlet opening or which are filled, so that an advantageous filling method (simple and inexpensive) can be applied.
  • the filling volume is determined by the shape of the packaging and a special dosing can be omitted.
  • inhalable compounds are used, e.g. also inhalable macromolecules, as disclosed in EP 1 003 478.
  • 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, HIV antihistamines, P AF antagonists and PI3 kinase inhibitors.
  • a pharmacologically active agent selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, HIV antihistamines, P AF antagonists and PI3 kinase inhibitors.
  • two- or three-fold combinations of W can be combined and used for application in the device according to the invention. Exemplary combinations of W would be:
  • W represents a betamimetics combined with an anticholinergic, 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
  • W represents a PDE4 Inhibitors 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, Sulphoneterol, Terbutaline, Tiaramide, Tolubuterol, Zinterol, CHF-1035, HOKU-81, KUL-1248 and 3- (4- ⁇ 6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -hexy
  • 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 ,
  • anticholinergic compounds are preferably used here, which are selected from the group consisting of tiotropium salts, preferably the
  • the cations are the pharmacologically active ingredients.
  • the aforementioned 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 being preferred as counterions.
  • 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-Toluene sulfonate, 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.
  • anion selected from the group consisting of fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, cit
  • 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
  • Reference to steroids includes a reference to their possibly existing ones Salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even 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
  • these acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
  • salts or derivatives which the LTD4-antagonists are capable of forming include: 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 1CR-62 and - 4 - [(3-Ch] or-4-fluoro-phenyl) -amino] -6- ⁇ [4- (morpholin-4-yl) -l-oxo-2-buten-1-yl] -amino ⁇ -7-cyclopropylmethoxy -quinazoline
  • 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, if appropriate in the form of their pharmacologically acceptable acid addition salts, their solvates and / or hydrates.
  • FIGS. 1-10 show, by way of example, the various forms of a capsule or a single cavity of a blister (called packaging in its entirety) and the corresponding piercing positions.
  • Fig. 1 Ball or hemisphere, 5 hole-shaped inlet openings, 1 outlet Fig. 2: Ball or hemisphere, 4 hole-shaped inlet openings, 1 outlet Fig. 3: Oval shape, 6 hole-shaped inlet openings, 1 outlet Fig.
  • Figure 10 Shape of the number "eight”, 2x2 hole-shaped inlet openings, asymmetric, 1
  • FIG. 11 Drop shape, 3 hole-shaped inlet openings, 1 outlet
  • FIG. 12 Drop shape, 4 hole-shaped inlet openings, 1 outlet
  • FIG. 13 Drop shape, sickle cut inlet, 1 outlet Example:
  • the emptying properties were determined with a model powder (glass beads) in such a way that the time until emptying was measured at a given, constant volume flow (corresponding to 10 L / min air).
  • Table 1 gives the results of the various forms for capsules or blisters.
  • the inlet openings are illustrated as small circles, the outlet openings are shown as large circles.
  • Table 1 shows that the emptying characteristics of a package depend substantially on its shape and opening or openings.
  • the flow rate of the air through the packaging in commercial size 10 liters / minute
  • the active ingredient in micronized form has a particle size of 1-5 microns.
  • the powder mixture also contains lactose 200 m.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un emballage pour médicament, mélanges de médicaments ou formulations de médicaments pour utilisation dans un inhalateur de poudre.
EP07727327A 2006-03-27 2007-03-26 Emballage pour inhalateur de poudre multidose avec proprietes optimisees de purge Withdrawn EP2001536A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006014434A DE102006014434A1 (de) 2006-03-27 2006-03-27 Packmittel für Mehrdosispulverinhalatoren mit optimierten Entleerungseigenschaften
PCT/EP2007/052854 WO2007110402A1 (fr) 2006-03-27 2007-03-26 Emballage pour inhalateur de poudre multidose avec proprietes optimisees de purge

Publications (1)

Publication Number Publication Date
EP2001536A1 true EP2001536A1 (fr) 2008-12-17

Family

ID=38117438

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07727327A Withdrawn EP2001536A1 (fr) 2006-03-27 2007-03-26 Emballage pour inhalateur de poudre multidose avec proprietes optimisees de purge

Country Status (19)

Country Link
US (1) US20070221535A1 (fr)
EP (1) EP2001536A1 (fr)
JP (1) JP2009531238A (fr)
KR (1) KR20080110866A (fr)
CN (1) CN101410147A (fr)
AR (1) AR060073A1 (fr)
AU (1) AU2007229530A1 (fr)
BR (1) BRPI0710106A2 (fr)
CA (1) CA2646337A1 (fr)
DE (1) DE102006014434A1 (fr)
EA (1) EA200801917A1 (fr)
EC (1) ECSP088768A (fr)
MX (1) MX2008011694A (fr)
NO (1) NO20083890L (fr)
PE (1) PE20071301A1 (fr)
TW (1) TW200803933A (fr)
UY (1) UY30234A1 (fr)
WO (1) WO2007110402A1 (fr)
ZA (1) ZA200807579B (fr)

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CA2936301C (fr) * 2013-10-15 2021-06-08 Mystic Pharmaceuticals, Inc. Buse a turbulences a debit controlable

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PE20071301A1 (es) 2008-02-04
EA200801917A1 (ru) 2009-04-28
CA2646337A1 (fr) 2007-10-04
BRPI0710106A2 (pt) 2011-08-02
US20070221535A1 (en) 2007-09-27
CN101410147A (zh) 2009-04-15
JP2009531238A (ja) 2009-09-03
ZA200807579B (en) 2009-10-28
DE102006014434A1 (de) 2007-10-04
WO2007110402A1 (fr) 2007-10-04
NO20083890L (no) 2008-11-17
MX2008011694A (es) 2008-09-24
AR060073A1 (es) 2008-05-21
AU2007229530A8 (en) 2008-11-13
TW200803933A (en) 2008-01-16
ECSP088768A (es) 2008-10-31
AU2007229530A1 (en) 2007-10-04
KR20080110866A (ko) 2008-12-19
UY30234A1 (es) 2007-10-31

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