PT106094A - ADMINISTRATION BY INHALATION OF FORMULATIONS WITH HIGH DOSE - Google Patents
ADMINISTRATION BY INHALATION OF FORMULATIONS WITH HIGH DOSE Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 93
- 238000009472 formulation Methods 0.000 claims abstract description 69
- 239000002775 capsule Substances 0.000 claims abstract description 16
- 239000000843 powder Substances 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 28
- 239000000872 buffer Substances 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 229960003722 doxycycline Drugs 0.000 claims description 8
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000002685 pulmonary effect Effects 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 239000007979 citrate buffer Substances 0.000 claims description 3
- 229940112141 dry powder inhaler Drugs 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 238000009413 insulation Methods 0.000 claims 2
- 239000004280 Sodium formate Substances 0.000 claims 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims 1
- 235000019254 sodium formate Nutrition 0.000 claims 1
- 239000012064 sodium phosphate buffer Substances 0.000 claims 1
- 239000010959 steel Substances 0.000 claims 1
- 230000008961 swelling Effects 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 10
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
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- 230000003115 biocidal effect Effects 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000003172 expectorant agent Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 229940066491 mucolytics Drugs 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- OMDMTHRBGUBUCO-IUCAKERBSA-N (1s,5s)-5-(2-hydroxypropan-2-yl)-2-methylcyclohex-2-en-1-ol Chemical compound CC1=CC[C@H](C(C)(C)O)C[C@@H]1O OMDMTHRBGUBUCO-IUCAKERBSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
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- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
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- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960003870 bromhexine Drugs 0.000 description 1
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical compound C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000003562 lightweight material Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003016 pheromone Substances 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 229960000230 sobrerol Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 229910021654 trace metal Inorganic materials 0.000 description 1
- OMDMTHRBGUBUCO-UHFFFAOYSA-N trans-sobrerol Natural products CC1=CCC(C(C)(C)O)CC1O OMDMTHRBGUBUCO-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ESTA INVENÇÃO É REFERENTE À ADMINISTRAÇÃO DE FORMULAÇÕES COM DOSES ELEVADAS DE COMPOSTOS ACTIVOS FARMACÊUTICOS POR INALAÇÃO. A PRESENTE INVENÇÃO DESCREVE FORMULAÇÕES EM PÓ ADEQUADAS PARA INALAÇÃO CONSISTINDO DE COMPOSTOS ACTIVOS FARMACÊUTICOS E UM AGENTE MUCOLITICO E / OU UM TAMPÃO, OU OUTROS, QUE POSSAM TER UMA FUNÇÃO PARA ALÉM DO TRANSPORTE DO API, BEM COMO A SUA UTILIZAÇÃO NO TRATAMENTO DE CONDIÇÕES MÉDICAS.This invention relates to the administration of high dosage formulations of pharmaceutical active compounds by inhalation. The present invention describes suitable powder formulations for inhalation comprising active pharmaceutical compounds and a pharmaceutical agent and / or a capsule, or others, which may have a function in addition to the transport of the API, as well as its use in the treatment of medical conditions .
Description
Administracio por Inalação de formulações com dose elevadaAdministration by Inhalation of high dose formulations
Introdução % muitos anos, o mercado do tratamento por inalação da pò seco (QPIJ tifo sido dominado por formulações de Çdiloosteréides efõo; à base de agentes anlçotinêrglcos para o tratamento da asma e da doença pulmonar obstrutiva crónica (tlEClS). Estes ednapos acllvos farmaesqiiòos (:AFÍ| sio gerãlmente administrados em quantidades baixam na gama do micrograma. Na formulação destes agentes tem sido utilizada urna estratégia através da qual o APf è misturado oem #m exeipieníe, geraimante lactose, auxiliando a administração e dispersão do API e tornando-o rnais proeessâvel. Estão disponíveis no mercado pemplos de tais formulações.Introduction In many years, the market for dry powder inhalation (QPIJ) has been dominated by formulations of phosphate dehydrogenase, based on ancillary agents for the treatment of asthma and chronic obstructive pulmonary disease (TCLEC). In the formulation of these agents a strategy has been used whereby the APf is mixed in the same way as the lactose generator, aiding the administration and dispersion of the API and making it more effective Examples of such formulations are available on the market.
Aetuaimenie está a emergtr oro çppfunto de tratamentos que requer a ãdmldsffaçle dedoses iledbdos, tia gama dd miligrama e em alguns desos des dezenas do Estes tratamentos emergentes incluem, entre outros, antibióticos pera o tfãtamedfç da flbrosé idlstica, e ubiizam AF(s menos potentes* mas talvez mals eficazes do que anteriormente. A mudança de patamar na dose exigida per estes agentes, significa que para uma administração eficaz é neoessâna uma abordagem fundamenfalrnente diferente para o dáserwolvimeeto di fbrmuiãçáo. Melhorar as estratégias existentes de combinação API í transportador não é suficiente. !rn vez: disso, estas novas formulações tem de ter concentrações de API elevadas, e possivelmente outras substâncias sem afeito aofivo que promovam a penetração do AP! até ao tocil da aotuaçlq, e preferencialniente sem de traaspertaderes £pu, peio menos, ter baixa concentração dos mesmosl, a fim de alcançar as doses: de API requeridas. Ã eíímirrafão ©u rrtrgiò dos exoipíentes tmospertsdores Wff&m novos desafios para a dispersio; efláente dos APis num sistema de inalação de pó seco. A SsiibÇlP apropriada «ia técnica de: processamento das partículas è oxlramameeie Importante pois a dispersão efelente requer uma distribuição de limando de partícula que proporcione espaço suficiente entre as partículas para aumentar a permeaóidade ao ar e propemionar propriedades de voo. 0: controle: n|óroso de: morfologia de supdíde: des partículas á Ifuilmente necessário pera que; as partículas em; contacta umas com as outras durenle a amiazenágem, se possam separar eficazmente quando o fluxo de ar para Inalação fór apicado. A patente americana US 6.868.199 descreve um método eiciente pare a admmisÍraçlo de umi grande massa de aerossol féripêuticd. Este roèfedo compreende a administração de pelo menos 58% da massa de pa^lcuias: %er Ddmamlcamente leves'' possuindo urna densidade balida Interior a 0,4 g&m^ que incluem, pelo menos, 16 miligramas de eginle ictlvo sonido num recipiente que tem um vblume de peio menos 0.37 cm"', sendo este volume maior que os existentes nos diapositivos comuns. Este documento mostra que atè agora para atingir uma dose elevada de aclive administrado as partículas eram obrigadas a ter uma densidade muito baixa e a formulação tinha que compreender transportadores pois de outro modo poderia ocorrer a agregação. Devido â baixa densidade e necessidade de excipiente a formulação tem de ser administrada a partir de: um; mepente de grande volume legeivalente a çipeulas # ã e maior). A combinação de um ARI com outras substâncias como um agente muoeifico ou um tampão pode melhorar a acçle do mesmo. Tal como para as formuiaçoes anteriormeníe referidas as tormulaçães de combinação de agentes antibióticos e agentes mucoiiticós requerem também o uso de um transportador para proporcioner a formulação (ver, pm exempio. WG2012/2080700 e GB 1242211), o que limita a quantidade de AP! que pode ser administrada. k administração feftoftffitflr 4b·. clmmm M miligrama: cia grande concentração 44 >4IS| requer- aio sd uma estrada de formulação fundamentalmenie diferente tnas tambérn em: Inalador à& pê seco capai 4b conter e alctentementa dispersar orna grande massa de mafaditThese emerging treatments include, but are not limited to, antibiotics for the treatment of idiopathic lupus erythematosus, and include AF (s) less potent * but rather may be more effective than before.changing the dose level required by these agents means that for an effective delivery there is a fundamentally different approach to the formulation of the formulation. Improving the existing strategies of the carrier combination is not sufficient. In addition, these new formulations must have high API concentrations, and possibly other non-phytoactive substances which promote AP penetration to the top of the pack, and preferably without any permeability, at least have low concentration, in order to achieve the required doses of APIs. the challenge of the new exporters and new challenges for dispersion; effective in a dry powder inhalation system. Suitable technique of particle processing is oxidation. Important because the efficient dispersion requires a particle filing distribution that provides sufficient space between the particles to increase air permeability and propel flight properties. 0: control: nodes of: morphology of suppose: des particles is If necessary, but; the particles in; contact with each other during the breakdown, can be effectively separated when the air flow to the Inhalation is vitiated. U.S. Patent 6,868,199 describes a method suitable for admixing a large mass of feedstock aerosol. This composition comprises administering at least 58% of the mass of lightweight materials having an inner bleaching density to 0.4 gm and which includes at least 16 milligrams of trace metal in a container which has a vblume of less than 0.37 cm ', and this volume is larger than those on ordinary slides. This document shows that until now to achieve a high dose of accler administered the particles were required to have a very low density and the formulation had to comprise carriers since otherwise aggregation could occur. Due to the low density and need for excipient the formulation has to be administered from: one; large-volume mega-legeivalent to appendages # ã and greater). The combination of an ARI with other substances as a muoid agent or a buffer may improve the action thereof. As for the above formulations, combinations of antibiotic agents and mucoiitic agents also require the use of a carrier to provide the formulation (see, eg, WG2012 / 2080700 and GB 1242211), which limits the amount of AP! which can be administered. k administration feftoftffitflr 4b ·. ml M milligram: high concentration 44> 4IS | It is also necessary to have a formulation route which is fundamentally different in: Inhaler to & dry cape 4b contain and warmly disperse large mass of mafadit
Breve descrição da invençãoBRIEF DESCRIPTION OF THE INVENTION
De adenfo com um aspecto dá presente Invenpcv é apresentada uma formulação findSOlMlsa na forma de um pó adequado pira inalação, pua compreende ura ou mals princípios acftvos fonnaoieticos: a em agente ηιροοίΐρρ e/oe um tampão, èrrr pua i formulação ê Me de eaêsfoncsas Iransporfadoras;, P# apprda com oeM aspeofo da invenção & apresentido m processo para a produção de uma formulação do acordo com a Invenção, compreendendo o passo do suspensão^ dd principio; aettve farmacêutico numa solução do um tampão 0m m agente mucoliííco, D pê pode então ser obtido a partir da suspedslp pdf epmgto; pr seoa|em< rMforenelalmente por secagem por atdmianpo. fdum outro; aipeofo da invenção,: ê. apresentado oro rnèfodode administração de uma: formulação1 de acorde com a; Invaoçio, em goe a formulação é administrada através de um inalador possuindo od podendo conter em rpepiáeufo, A mvençãe apreaenta tampem uma cápsula comproandendó a formulação da acorde com a Invenção,In an aspect of the invention there is provided a pharmaceutical formulation in the form of a suitable powder for inhalation, which comprises one or more of the following principles: a) in the form of an agent and / or a buffer, and in the form of a disintegrating agent According to the present invention, The present invention relates to a process for the production of a formulation according to the invention, comprising the step of suspending the principle; in a solution of a buffer of a mucolytic agent, D may then be obtained from the following suppository; pr seoa | in < rMore usually by drying at different times. fdum other; of the invention. A method according to any of the preceding claims, wherein: In one embodiment, the formulation is administered via an inhaler having the ability to contain the drug in a sterile form. The composition comprises a capsule which matches the formulation according to the invention,
Também ;i apresentado um Inalador contendo a fOrmuiaçlo de acordo com a Invenção, A Invenção também apresenta um btister ou Meter sirip compreendendo a ilação do .acerbo com a lavenção.Also shown is an Inhaler containing the formulation according to the Invention, the Invention also features a bistler or a Meter comprising the composition of the invention with the invention.
Num outro aspecto, a invenção ãpeaenia uma formulação farmacêutica para uso mm® m< A presente invenção: apnsserttá um pmdíito étn pé óã ffosa elevada, adequado pare inalação em que um principio aotivo fármáoiutloo ou uma mistura d* pu mais princípios actlvos farmacêuticos é famaíMo domo uma formulação que consiste num principio aotivo farmacêutico ou uma mistura de bois ou mais princípios ãçtiêos: firmaoêufioos o um tampão efou um agente mucolilícc ;py: um tampão que pmferpneiaí mente aotua como um agente nmeoliíee, pode: o tampão controla o pH para aviar danos no pulmio e o agente rnueqltloo facilita a penetração do APi até ap Ipcaído datamente. iPtil formulações são adequadas para saram .giiiistfliip p$f «m matador de pé seep, Inaiadares de pé seco incluem os que usam cápsulas, reservatório, Motors pu putros, 0 vqfeme léerne total da: reciplante deve ser em qualquer caso Igual ou irláner á Í,,3I cnrs.In another aspect, the invention relates to a pharmaceutical formulation for use mm® m < The present invention provides a high pharmaceutical composition suitable for inhalation in which a pharmaceutically active ingredient or a mixture of pharmaceutically active principles is a formulation consisting of a pharmaceutical active principle or a mixture of steers or more The capsule comprises a capsule containing a buffer and a mucolytic agent; a buffer which is administered as a polymeric agent, the buffer controls the pH to cause damage to the lung and the reducing agent facilitates the penetration of the APi to apcaitally . Suitable formulations are suitable for use in the manufacture of dry foot dressings. Dry foot blades include those which use capsules, reservoir, motors, putty, etc. The total weight of the recloser must be equal to or equal to .
As vantagens dá prasente invenção incluem ofornecimenío por inalação de uma formulação cie dose elevada contida num rea pi ente de tamanho normal incluindo w: tampão e/du um agente muoôiitloo, sem necessidade de transperiader, p que implica uma menor Quantidade da pi m ser administrado a em consequência menos ou meneres efeitos secundádes.Advantages of the invention include administration by inhalation of a high dose formulation contained in a normal sized area including a buffer and / or a mutagenic agent, without the need for a transporter, implying a smaller amount of the drug to be administered resulting in fewer or more side effects.
Por livre de substâncias transportadoras, queremos dizer que a formulação desta invenção è livre de transportadores fannaeêutloos convencionais do tipoi usado corno ãansportadoree cónvermiónaia de API em formulações de pó seco. Úm trãnspotiador convenciona! è #. lactose* As fonnuíaçóss desta invenção ião livres ou fêssenciaimenie livres de lactose. As formulações da ίηνΜφο aioBy free of carrier substances, we mean that the formulation of this invention is free of conventional carrier type carriers used as carriers and API powder in dry powder formulations. More information is available! and #. lactose. The compositions of this invention are free or lactose free. The formulations of ίηνΜφο
também livres ou essencial mente livros de API outras substâncias transportadorasalso free or essentially mind books of other API substances
Descrição detaiaácia Φ InvençãoDescription detaiaácia Φ Invención
AflVêbçio apresenta uma formulação livre de Ipnsedrtadprds compreerídendd dm principio activo farmacêutico m uma mistura de dois ou mais pnnetpios activos farmacêuticos: e um agente mucoNtleo e / ou çm tampão,. Quando é usado um tampão sem um agente mucoitiçc é prelêrivel que o tampão actue como agente maçóííico,:The present invention provides a free formulation of pharmaceutical compositions comprising a mixture of two or more pharmaceutical active compounds and a mucofluoride agent and / or a buffer. When a buffer is used without a mucocidal agent, it is predictable that the buffer acts as an agent,
Praferencialmenta a formulação consiste essenoiãlrnenfe em ura m mais princípios activos e um agente mucolliloo e/ um tampão.Preferably the formulation consists essentially of one or more active principles and a mucolytic agent and / or a buffer.
Preferendalmente, a formulação consiste num pnheipio activo farmacêutico ou uma mistura de dois ou rnais princípios activos farmacêuticos e um tampão. E desejável que o próprio fimpie tenha propriedades mucolltlcas, Por agente mucolltlcp entendemos um agente que promove a dissolução do muco no aparelho respiratório.Preferably, the formulation consists of a pharmaceutical active pantene or a mixture of two or more pharmaceutical active ingredients and a buffer. It is desirable that the fimpy itself has mucopolytic properties. By mucopolytic agent we mean an agent which promotes the dissolution of mucus in the respiratory tract.
Uma formulação de acordo com a invenção pariicularrnente preferida compreende um tampio que è um citrato, tal como o citrato de sódioA formulation according to the invention particularly preferred comprises a buffer which is a citrate, such as sodium citrate
Numa formulação preferida de acordo com a invenção o princípio ou princípios activo farmecêutico é a doxiciollna ou um dos seus sets teonaceuficãmente aceitáveis.In a preferred formulation according to the invention the pharmaceutical active principle or principles is doxycycline or one of its sets is suitably acceptable.
Assim, uma formulação pmfanda è aquele gue consiste esseneialmepe em doxiciollna e um tampão de citrato.Thus, a pheromone formulation is that which consists essentially of doxycycline and a citrate buffer.
As fòímuiaçdes <|u iitwptçld sio formulaçfã# d#: modo a ierem capazes: de administrar ume dose elevada da API ad paciente, Preforenciatmenie, a formulação è capaz de administrar uma dose de 5 mg ou mais cie um ou rnaís API. O princípio ou princípios activos farmacêuticos podem ser escolhidos de entre quaisquer princípios ãotivos fermaeêutioes adequados para administração por Inalação, tais como ahtlOiitócos, antlvírais, estorcidos, bronco-dilatadores, anti-coílnergicos, animai, hormonas, proteínas, pèptldos e analgésicos. D tampão podo ser qualquer composto adequado para tamponar uma formulação de pé seco e é peferenclalm^te om saí de citrato ou fosfato. Além disso, o tampão é de preferência um ag^íe mucoiitico. O citrato de sódio é um tampão preferido que, em adição às suas propriedades de tampão tem a vantagem de autuar corno um agente mucoiitico. Alternativamente um agente muooiltico quo não é um tampão;, ou um tampão que oio é um agente mucotlioo podem ser usados, 'Φ tampão controla o pH para evitar danos no pulmão o o a|ente muoóíitíeo fapiíía a penetração do API até ao local: de tfefimehío, D agente mucoiitico pode Sir qualquer agonfe com as propriedades mucoillcas reífuendas, adequado par uso numa formulação de pó seco e que mp compatível com os rostinfes componentes da formulaflo, fã pedfo m matéria conhecerá os agentes mueotiíoos adequados. Exemplos de agentes mucolltlcos incluem a acaprofina, a acetttcisteioa, o ambroxei, a bromexlna, o seu derivado Irovanexina, a earhoolstema, o ddídroí e o sobrerol. A formulaçio pode ser utilizada para d tratamenfo de problemas de saúde, em particular das doenças pulmonares que respondem a antibióticos, tais como a fibrose cística e infeeçães pulmonares. De preferência, o principio eu prlneiplos acíivo farmacêutico è orn antibiótico, mals preferenciaíroenfe doxiaeíina. & tohramidna, amoxicitin^ varmemloipi m thsíemiofna m uai dm -.mm. uri* ou misturas dos mesmos. & formulação pode ser obtida por qualquer método de redução de pdfoutas adequado que reduza o tamanho da partícula dos componentei da: fbrniulação para am tamanho da partícula apfapdado para inaiaçlo, Oa pneoipios aelvos slo,. em seguida, isospensos numa solução do agente moooilep i í m tampão e mem por exemplo por secagem per atomização oíi qualquer potra têeníea usual deisaoapom, Álidi dlssO:, salas fbrmuiaçdes de ddsá elevada, per serem administradas per Inalaple dírddladiahfo no pulmio fépmeihfam a administração dá: uma quaptldadê Ihfsdor de API do qm a q» é oormalmente administrada; gor via oral, e eopsiqqebtemente são espetados menos m menores efeitos sêeendlnos adversos, Á formulação pode ser eoléoada mm eapssJaa adequadas para em inalador de cápsulas, nos réservaiirlos de um inalador de mservatbrio ou noa Msfersde um inalador da biktw ou outro recipiente apropriado para ser usado mm inalador, indapendentamente do tipo de recipiente, qualquer dose individual estará preferedolaimente oondda num volume Igual ou inferior a Õ,3S orãm A fomiulafâo ê eotãp administrada por Inalação para o tratamento de problemas do saede em espeelai doenças do pulmão tais como Ibroae ofstloa e Infecções pulmonares., entre outros..The formulations are capable of administering a high dose of the API to the patient. Preformattively, the formulation is capable of delivering a dose of 5 mg or more to one or more APIs. The pharmaceutical active principle (s) may be chosen from any pharmaceutical functional principles suitable for administration by Inhalation, such as ethoxylated, anthelmintic, anesthetized, bronchodilators, anti-allergenic, animal, hormones, proteins, peptides and analgesics. The buffer may be any suitable compound for buffering a dry foot formulation and is preferably from citrate or phosphate. In addition, the buffer is preferably a muco-otic agonist. Sodium citrate is a preferred buffer which, in addition to its buffer properties, has the advantage of being a muco acid agent. Alternatively a muleoylating agent which is not a buffer, or a buffer which is a mucociliary agent, may be used, the buffer controls the pH to prevent damage to the lung or mucoid, and may interfere with the penetration of the API to the site of: The mucoactive agent may be agonizing with suitable mucocilic properties suitable for use in a dry powder formulation and which is compatible with the components of the formulation, the compositions of which will be suitable for use in preparing the compositions. Examples of mucopolysaccharide agents include acaprophin, acetonecysteine, ambroxel, bromhexine, its derivative Irovanexin, acryloheterase, dioxan and sobrerol. The formulation may be used for treating health problems, in particular for lung diseases that respond to antibiotics, such as cystic fibrosis and pulmonary infections. Preferably, the pharmaceutical active ingredient is an antibiotic, most preferably a doxycycline. & tohramidna, amoxicillin, varmemloipine, thiememiofna m uai dm-.mm. uri * or mixtures thereof. & formulation may be obtained by any suitable method of reducing the size of the particles of the composition: the formulation is suitable for the size of the particle prepared for inhalation. then they are suspended in a solution of the mole fractionating agent and for example by spray drying or any usual filament of deodorant such as sodium, potassium and magnesium, and they are administered at a low dose in the lung. : a quaptlder of the API that is normally administered; The formulation may be used in suitable amounts for capsule inhalers, in the reservoirs of a syringe inhaler or in the form of a bikini inhaler or other suitable container to be used mm inhaler, indifferently of the type of container, any individual dose will preferably be in the range of a volume equal to or less than 1%. The formulation is administered by Inhalation for the treatment of bleeding problems in lung diseases such as esophagus and Infections pulmonary, among others ..
Um processo para a produçlo de urna formulação de acordo com a invenção compreende o passo de suspender o ingrediente actlvo farmacêutico mmm solução de um tampão efeu agente mueolltloo. O processo podo ainda compreender o passo de isolar a formulação: na fornia do pê por secagem, Preterenokbmenta uimzame a secagem por aiomizaçlo. •cio preferido da invenção o pô após o moiamento mantém a forma :poli;motftoe e pureza pufmlop fdêndoa: a antóâdo isolamento. Λ invenção Incidi nm. método para a adminiafrapia de uma formulação cio m mm a invenção,: em que a fomldlãçlo # administrada a parir la um inalador com ou capaz do conter um reoepiâcutO> O Inalador é preíereneiaimeníe um Inalador de cta cápsulas ou da mservatddo, Λ: fermiUiaçlSP é administrada: a um paoianta que pode beneficiar do um ou maisA process for the production of a formulation according to the invention comprises the step of suspending the pharmaceutical active ingredient in a solution of a chemotactic agent buffer. The process may further comprise the step of isolating the formulation: in the form of powder upon drying, the drying is carried out by wetting. The preferred powder of the invention after the milling has the shape: polypropylene and purity of the powder. Λ invention Incidi nm. the method of administering a formulation in accordance with the invention, wherein the preparation is administered in the form of an inhaler with or capable of containing a reuptake inhibitor. The Inhaler is preferably a capsule or an inhaler inhaler, the medicament is administered to a patient who may benefit from one or more
No método: acima, o receptáoulo tam pmlareneialmente um volanw igual ou Inferior a 0.35 cm;‘.In the above method, the receptacle also typically has a volume equal to or less than 0.35 cm;
No método acima e na invenção em geral, a dose administrada edua-se na gania cia miligrama: isto ê» é administrado 1 mg ou mais de APS. Pmloranoialmento sio adrninSsmadas pelo menos Sm§ de APS» se adequado 1b nid ou mais de APS > A invenção também apresenta cápsulas compreendendo a formulação de áoordp com a Invenção. Será claro para o perito na matéria que a cápsula pode ser qualquer cápsuía adequada pa?a um inalador de pó (DPI). A invenção também apresenta um inalador compreendendo a formulação de acordo eqm a invenção, que e pteferenolalmenie um inalador de pó seco. Inaladores adequados incluem inaladores de básieoç inaladores: d# cápsulas e inaladores de mservaiddo.In the above method and in the invention in general, the dose administered is produced in mg milligram: ie 1 mg or more of APS is administered. Polymorphonylation is preferably at least 10 mM APS, if appropriate 1 nid or more APS > The invention also features capsules comprising the oral tablet formulation of the invention. It will be clear to the person skilled in the art that the capsule may be any capsule suitable for a powder inhaler (DPI). The invention also features an inhaler comprising the formulation according to the invention, which is a dry powder inhaler. Suitable inhalers include basic inhaler inhalers: d # capsules and inhalers.
Um inalador de acordo com a Invenção preferemáeimente administra uma doseAn inhaler according to the invention preferably administers a dose
ámblfo da invenção,of the invention,
Exemplo:Example:
Para avaliar o oooeeio da admlnistraçad da uma dosa elevada da DPI o antibiótico ddlfeicílaa mdnoiidfatada foi peado como molécula modelo pua depois de formulada foi administrada usando o inalador TwInCaps# (Hovione) A estratégia de formulação eroprepa elimina o transportador e damblna o antibiótico com citrato de sódi%: um tampao e oonbáctdb agente fodCPtiílco para ipotanclalmonfo aumaritar a capacidade de permtraçao do antibiótico através das camadas da pteteoção da mucosa spe inibam a acfNdade antibiótica contra paaddPmonaa %&nigmosa e potras bactenas nos pulrttlaa dá pabiánfás mM-fprose cística, A formulação dá dose elevada produzida por mlcronização, emTo evaluate the administration of a high dosage of DPI, the methylated difluylated antibiotic was used as the template molecule after formulation was administered using the TwInCaps # (Hovione) inhaler. The formulation strategy eliminates the carrier and gives the antibiotic with citrate The composition of claim 1, further comprising administering to a patient a medicament suitable for administration to the patient to increase the antibiotic permeability of the antibiotic through the layers of the mucosal ptothesis to inhibit the antibiotic activity against the mucous membranes and the bacteria in the lungs of the cystic fibrosis. high dose produced by
contém doxiosdina monohidratada (80%), ombinaçio com citrato de sódio (20%). O 9 citrato $$$& foi incorporado utilizando secagem por temisaçle do urdo auspensio de doxicioiina numa solução do citrato do sódio. & formaíagio de pó resultante foi colocada em TwinCapstf? toado sido tostados duas massas de enchimento diferentes mm pesos d e pó de §i mg e ?i mg em cada uma das duas cavidades do Inalador que têm volume inferior a δ,^, Λ dosa administrada (OD), a dosa de partículas finas f FPO| e íracoio de pafiiouías finas (FPF) foram então determinadas usando um Fasf Scremsng impactar (Fli| A FPD foi classificada como a quantidada de APt com tamanho de partlculalufénora 5 μηι.contains doxiosdine monohydrate (80%), ombination with sodium citrate (20%). The citrate 9 & was incorporated using drying by reason of the auspiciousness of doxycycline in a solution of sodium citrate. & The resulting powder formation was placed in TwinCapstf? two different filling weights mm powder weights of æl mg and æl mg in each of the two Inhaler wells having volume less than δ,,, Λ administered dose (OD) have been roasted, the fine particle dose f FPO | (FPF) were then determined using a Fasf Scremsng impact. The FPD was classified as the amount of APt with a particle size of 5 μηι.
Corno se pode observar aAs one can observe the
dos resultados a na «« mesmo com formulações que compreendem 80% de doxiclcllne: é possiVei obter doses superiores a 41 mg de adf vd administrados por cavidade e FPO superior a 20 mg de AP! por cavidade, As íracções: de parficuias finas, uma medida da eficiência de dispersio, são da ordem de 50%, e semelhantes para os dois pesos dd: enchimento. Mós dados pfeviamaote relatados por tdishra fd e Mlshra & WmfàtMãm opdmtelfoo and chamteotedon <É spm% éiaã mirnspartlaím fer mhteboo âBimrf'φχγ^-im $0$$ 131(12} i8i3~W2&i§mm$a doteioiiriai hiclato numa formulaglo com mistura de fictese, a taogac de paticuias luas doou um pouco abate de WM,of the results even with formulations comprising 80% of doxycycline: doses greater than 41 mg of administered adva per well and FPO greater than 20 mg of AP can be obtained. The fractions of fine particles, a measure of the dispersion efficiency, are of the order of 50%, and the like for the two weights dd: filler. Data reported by tdishra fd and Mlshra & In contrast to the present invention, the present invention provides a process for the preparation of a compound of formula (I) in the form of a compound of formula (I) in which the moiety of moieties donated or a little slaughter of WM,
Foi portento pessive! conseguir assegurar uma boa emissio de dose e uma boa dispersão, expressas nos valores de FPD e FPF, mesmo na ausência de lactose somo agente transportador.It was pessive portent! ensure good dose delivery and good dispersion expressed in the FPD and FPF values, even in the absence of lactose as the carrier.
Em conclusão, a formulação com 80% de doxieídina administrada peio dispositivo laíinOaps^ demonstmo a capacidade de administrar mals do que 40In conclusion, the 80% doxycycline formulation administered by the laparoscopic device demonstrated the ability to administer more than 40
Soas maior do que 20 mg. da dose do aotlvo com· a respsottva dose do párdeuias mg,Soas greater than 20 mg. of the dose of the substance with the respsottva dose of the infants mg,
Oascrfpio da figura A Figura mostra os resultados de DO o FPD do dexícietina por 4om para as duas dosagens analisadas, 11 de Janeiro £013 1 " Uma formulação farmacêutica, na forma, di |jô5 adequada para inalaçle caracterlzada por compreender ura ou mata princípios activos farmacêuticos e um agente rttycolicç a I ou um tampão e sem agente transportador. .2 * lima temufmtmàò. tom 1 reivindicação 1 spBdfenpada por çerttpreendar dois pbnoipios aclives fsnnacêutioos. a - Uma át mxRfo mm :à; r#píiiw#i' i Íif2 caracimzada pwmmMf essencmlmente num ou mãis princípios acllvos farmacêuticos e um; agente mucoliflco e f ou um tampão. 4 - Uma formulação de acordo com d reivindicação 1, I oy 3 earaofariaady; por consisti em um pdoclplo aotfvo fefmseêytioo m. uma mistura dt dóis m ftwfe pdtictqios: acives famtaciuticos ê um tampão. 5 - Uma formulação do acordo com qualquer uma das reivindicações precedentes oaradfer&ada por o tamplo Sr pmpdedadss; mucoiittdãs. 6 ·> Uma formulação de acordo com qualquer uma das mivindlcações precedentes caraotetiiada por o tamplo ser um fosfato ou um citrato. 7 ~ Uma lormuiaçio de acorde com a reivindicação i caractenzada por o tampao ser o cifras da sódio. § ™; Uma formatação de acordo com qualquer uma; das reivindicações precedentes, caraoferizada por o principio ou principies acllvos farmacêuticos ser um antibiótico. 9 - Uma formuiição de acordo com a reivindicação 8. caraoierilada por o principio m mmpm activos faonaclytloos ser mmmm dosiciciina, ou umúmmm sais farmaceutieamenfe aceitáveis:.The figure shows the results of the OD of the dexicillin FPD by 4 μm for the two dosages analyzed, January 11 £ 013 1 " A pharmaceutical formulation in the form suitable for inhalation characterized in that it comprises a pharmaceutical active ingredient and a conventional agent or a buffer and without carrier. .2 * lima temufmtmàò. tone 1 claim 1 spBdfpwnbypreparing two phoenopsis fsnnacêutioos. a - one at least mm; A pharmaceutical composition comprising at least one pharmaceutical composition comprising at least one pharmaceutical composition comprising at least one pharmaceutically acceptable carrier. mucolytic agent and f or a buffer. A formulation according to claim 1, 1 and 3, characterized in that it comprises: because it consisted of a pdoclplo aotfvo fefmseêytioo m. a mixture of two of these compounds: famciic acid is a buffer. A formulation according to any one of the preceding claims, characterized in that the compound of the formula: mucotiditans. 6 · > A formulation according to any one of the preceding claims characterized in that the compound is a phosphate or a citrate. A conversion according to claim 1 wherein the cap is sodium ciphers. § ™; A formatting according to any one; of the preceding claims, wherein the pharmaceutical principle or principles are an antibiotic. 9. A process according to claim 8, characterized in that the active ingredient is in the form of a pharmaceutically acceptable salt.
Claims (15)
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| PT106094A PT106094A (en) | 2012-01-13 | 2012-01-13 | ADMINISTRATION BY INHALATION OF FORMULATIONS WITH HIGH DOSE |
| PCT/GB2013/000015 WO2013104892A1 (en) | 2012-01-13 | 2013-01-14 | Application of high dose compounds via inhalation |
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| PT106094A PT106094A (en) | 2012-01-13 | 2012-01-13 | ADMINISTRATION BY INHALATION OF FORMULATIONS WITH HIGH DOSE |
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| AU2010229668C1 (en) | 2009-03-26 | 2016-09-15 | Pulmatrix Operating Co., Inc. | Dry powder formulations and methods for treating pulmonary diseases |
| EP2611438B1 (en) | 2010-08-30 | 2020-04-01 | Pulmatrix Operating Company, Inc. | Dry powder formulations and methods for treating pulmonary diseases |
| DK3470057T3 (en) | 2010-09-29 | 2021-11-22 | Pulmatrix Operating Co Inc | CATIONIC DRY POWDER INCLUDING MAGNESIUM SALT |
| CN107096014B (en) | 2010-09-29 | 2022-07-15 | 普马特里克斯营业公司 | Monovalent metal cation dry powder for inhalation |
| NZ629722A (en) | 2012-02-29 | 2017-03-31 | Pulmatrix Operating Co Inc | Inhalable dry powders |
| RU2015146871A (en) | 2013-04-01 | 2017-05-10 | Пулматрикс, Инк. | DRY POWDERS WITH THIOTROPY |
| WO2016013986A1 (en) | 2014-07-25 | 2016-01-28 | Agency For Science, Technology And Research | Antibiotic compositions for treating bacterial infections |
| CN109745301A (en) * | 2017-11-08 | 2019-05-14 | 北京盈科瑞创新药物研究有限公司 | A kind of carbocisteine nebulized inhalation solution preparation and preparation method thereof |
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| WO2007061454A1 (en) * | 2005-11-22 | 2007-05-31 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
| TW201141557A (en) * | 2010-04-26 | 2011-12-01 | Hovione Int Ltd | A simple capsule-based inhaler |
| WO2011135327A1 (en) * | 2010-04-26 | 2011-11-03 | Hovione International Ltd. | A simple capsule-based inhaler |
| CA2791149A1 (en) * | 2010-04-26 | 2011-11-03 | Hovione International Ltd. | Two piece capsule-based inhaler having capsule cutting means |
| US20110259328A1 (en) * | 2010-04-26 | 2011-10-27 | Hovione International Ltd. | Simple capsule-based inhaler |
| AR080968A1 (en) * | 2010-04-26 | 2012-05-23 | Hovione Int Ltd | INDIVIDUAL INHALER WITH CAPSULA |
| PT105065B (en) * | 2010-04-26 | 2012-07-31 | Hovione Farmaciencia S A | A SIMPLE INHALER OF CAPSULES |
| AU2011247073A1 (en) * | 2010-04-26 | 2012-08-30 | Hovione Technology Limited | A simple capsule-based inhaler |
| SG183307A1 (en) * | 2010-04-26 | 2012-09-27 | Hovione Int Ltd | A simple capsule-based inhaler |
| CO6561767A2 (en) * | 2010-04-26 | 2012-11-15 | Hovione Int Ltd | INDIVIDUAL INHALER WITH CAPSULE |
| EP2536460A1 (en) * | 2010-04-26 | 2012-12-26 | Hovione International Ltd. | A simple capsule-based inhaler |
| CN102933244A (en) * | 2010-04-26 | 2013-02-13 | 霍维翁国际有限公司 | Simple Capsule-Based Inhaler |
| KR20130028722A (en) * | 2010-04-26 | 2013-03-19 | 호비온 인터내셔날 리미티드 | A simple capsule-based inhaler |
| AU2011247073B2 (en) * | 2010-04-26 | 2013-03-21 | Hovione Technology Limited | A simple capsule-based inhaler |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013104892A8 (en) | 2013-09-19 |
| WO2013104892A1 (en) | 2013-07-18 |
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