GB2434098A - Process for the preparation of an inhalable dry powder formulation - Google Patents
Process for the preparation of an inhalable dry powder formulation Download PDFInfo
- Publication number
- GB2434098A GB2434098A GB0526446A GB0526446A GB2434098A GB 2434098 A GB2434098 A GB 2434098A GB 0526446 A GB0526446 A GB 0526446A GB 0526446 A GB0526446 A GB 0526446A GB 2434098 A GB2434098 A GB 2434098A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dry powder
- process according
- active pharmaceutical
- carrier particles
- inhalation
- 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- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 34
- 239000000843 powder Substances 0.000 title claims abstract description 30
- 238000009472 formulation Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000008569 process Effects 0.000 title claims abstract description 10
- 239000002245 particle Substances 0.000 claims abstract description 35
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 34
- 235000019359 magnesium stearate Nutrition 0.000 claims description 17
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 8
- IREJFXIHXRZFER-PCBAQXHCSA-N indacaterol maleate Chemical compound OC(=O)\C=C/C(O)=O.N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 IREJFXIHXRZFER-PCBAQXHCSA-N 0.000 claims description 7
- 229960004735 indacaterol maleate Drugs 0.000 claims description 7
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 4
- 239000008116 calcium stearate Substances 0.000 claims description 4
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- 150000003431 steroids Chemical class 0.000 claims description 3
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- 235000000346 sugar Nutrition 0.000 claims description 3
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- 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 8
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- IHOXNOQMRZISPV-YJYMSZOUSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]azaniumyl]ethyl]-2-oxo-1h-quinolin-8-olate Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 IHOXNOQMRZISPV-YJYMSZOUSA-N 0.000 description 3
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- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 229940112141 dry powder inhaler Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- OKFDRAHPFKMAJH-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-(methanesulfonamido)dibenzofuran-1-carboxamide Chemical compound C=12C3=CC(NS(=O)(=O)C)=CC=C3OC2=C(OC(F)F)C=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl OKFDRAHPFKMAJH-UHFFFAOYSA-N 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- KHICUSAUSRBPJT-UHFFFAOYSA-N 2-(2-octadecanoyloxypropanoyloxy)propanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C(O)=O KHICUSAUSRBPJT-UHFFFAOYSA-N 0.000 description 1
- DDYUBCCTNHWSQM-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound COC1=CC=C(C(CC(N)=O)N2C(C3=CC=CC=C3C2=O)=O)C=C1OC1CCCC1 DDYUBCCTNHWSQM-UHFFFAOYSA-N 0.000 description 1
- KGVIJLMNQNSQHB-UHFFFAOYSA-N 5,6-diethyl-2,3-dihydro-1h-inden-2-amine Chemical compound C1=C(CC)C(CC)=CC2=C1CC(N)C2 KGVIJLMNQNSQHB-UHFFFAOYSA-N 0.000 description 1
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 1
- OTINTMLHLKCOBW-NDEPHWFRSA-N 5-[(1r)-2-[(5,6-diethyl-2,3-dihydro-1h-inden-2-yl)amino]-1-hydroxyethyl]-8-phenylmethoxy-1h-quinolin-2-one Chemical compound C1=2NC(=O)C=CC=2C([C@@H](O)CNC2CC=3C=C(C(=CC=3C2)CC)CC)=CC=C1OCC1=CC=CC=C1 OTINTMLHLKCOBW-NDEPHWFRSA-N 0.000 description 1
- IHJYYLJZVBVLEK-INIZCTEOSA-N 5-[(2r)-oxiran-2-yl]-8-phenylmethoxy-1h-quinolin-2-one Chemical compound C=12NC(=O)C=CC2=C([C@H]2OC2)C=CC=1OCC1=CC=CC=C1 IHJYYLJZVBVLEK-INIZCTEOSA-N 0.000 description 1
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- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
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- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
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- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 1
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- 230000000877 morphologic effect Effects 0.000 description 1
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- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 229960002657 orciprenaline Drugs 0.000 description 1
- 229960001609 oxitropium bromide Drugs 0.000 description 1
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
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- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Classifications
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- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
-
- 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
- A61P11/06—Antiasthmatics
-
- 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
- A61P11/08—Bronchodilators
-
- 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
- A61P11/12—Mucolytics
-
- 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
- A61P11/14—Antitussive agents
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Abstract
A process for preparing dry powder formulations for inhalation. The process comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents and then admixing carrier particles.
Description
<p>Case PRI4-34779P1/HO 161 2434098</p>
<p>ORGANIC COMPOUNDS</p>
<p>This invention relates to organic compounds and their use as pharmaceuticals, in particular a process for preparing inhalable dry powder formulations containing one or more active pharmaceutical ingredients.</p>
<p>Dry powder formulations for inhalation in the treatment of respiratory diseases are generally formulated by mixing a micronised active pharmaceutical ingredient with coarse carrier particles to give to an ordered mixture. The carrier particles, which are most commonly lactose, make the micronised active pharmaceutical ingredient less cohesive and improve its flowability. This makes the powder easier to handle during the manufacturing process. The micronised active particles tend to adhere to the surface of the carrier particles whilst stored in a dry powder inhaler device but are dispersed from the surfaces of the carrier particles on inhalation into the respiratory tract to give a fine suspension. The larger carrier particles are mostly deposited in the oropharyngeal cavity.</p>
<p>In recent years ternary agents such as magnesium stearate are often included in dry powder formulations for inhalation. For example, Unites States patent US 6645466 discloses the use of magnesium stearate in dry powder formulations for inhalation to improve moisture resistance and storage stability, and United States patent US 6,528,096 discloses the use of a lubricant such as magnesium stearate in dry powder formulations for inhalation to provide ordered stable mixtures without segregation of the active particles during handling and before use. Such dry powder formulations for inhalation are commonly prepared by mixing carrier particles and magnesium stearate to give a preliminary mixture or blend of magnesium stearate coated carrier particles, then admixing active particles to give the desired formulation.</p>
<p>It has now been found, surprisingly, that it is advantageous to mix active particles with a ternary agent such as magnesium stearate to give a preliminary mixture or blend, then admix carrier particles to give the desired formulation.</p>
<p>Accordingly in broad terms the present invention provides a process for preparing dry powder formulations for inhalation that comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents, then admixing carrier particles.</p>
<p>Case PRJ4-34779P1/HO 161 The or each active pharmaceutical ingredient may be an active pharmaceutical ingredient or drug substance that is suitable for administration by inhalation, for example for the treatment of a respiratory disease. Suitable active pharmaceutical ingredients include anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances. Preferred active pharmaceutical ingredients include beta-2 adrenoceptor agonists, antimuscarinic agents, steroids and PDE4 inhibitors. Suitable beta-2 adrenoceptor agonists include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, indacaterol, procaterol, formoterol, carmoterol, TA-2005, GSK 159797 and pharmaceutically acceptable salts thereof.</p>
<p>Suitable antimuscarinic agents include ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi). Suitable steroids include budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide and mometasone furoate. Suitable PDE4 inhibitors include cilomilast (Ariflo GlaxoSmithKline), Roflumilast (Byk Gulden),V- 1 1294A (Napp), BAY1 9-8004 (Bayer), SCH-35 1591 (Schering-Plough), Arofylline (Almirall), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VMSS4/UMS6S (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo) and GRC 3886 (Oglemilast, Glenmark).</p>
<p>The or each active pharmaceutical ingredient active ingredient suitably has an average particle diameter of up to about 10 Jim, for example 0.1 to S p.m, preferably 1 to 5 pm. The particle size of the or each active pharmaceutical ingredient can be reduced to the desired level by conventional methods, for example by grinding in an air-jet mill, ball mill or vibrator mill, sieving, microprecipitation, spray-drying, lyophilisation or controlled crystallisation from conventional solvents or from supercritical media.</p>
<p>The or each ternary agent is preferably a surface active material, in particular a material that is surface active in the solid state, which may be water soluble, for example lecithin, in particular soya lecithin, or substantially water insoluble, for example solid state fatty acids such as lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof. Specific examples of such materials include magnesium stearate; calcium stearate; sodium stearyl fumarate; sodium stearyl lactylate; phospatidylcholines, phosphatidylglycerols and other examples of natural and synthetic lung surfactants; Liposomal formulations; lauric acid and its salts, for example, sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general. Preferably the ternary agent is magnesium stearate or calcium stearate, especially magnesium stearate.</p>
<p>Case PRJ4-34779P1/HO 161 Magnesium stearate is highly surface active and should therefore be added in particularly small amounts, for example 0.1 to 2% by weight or more preferably 0.25 to 1% by weight, based on the total formulation, of magnesium stearate.</p>
<p>The use of magnesium stearate leads to a general improvement in the inhalable fine particle fraction, and also stabilizes the carrier materials and active compounds by suppressing or slowing down undesirable morphological phase transitions. Magnesium stearate enhances the dosing efficiency of dry powder formulations administered by pulmonary inhalation by improvement of powder flowability.</p>
<p>The ternary agent is preferably in particulate form but it may be added in liquid or solid form and for some materials, especially where it may not be easy to form particles of the material and/or where those particles should be especially small, it may be preferred to add the material in a liquid, for example as a suspension or a solution.</p>
<p>The carrier particles may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. They are suitably composed of one or more crystalline sugars including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol or sorbitol. An especially preferred carrier is lactose, for example lactose monohydrate or anhydrous lactose.</p>
<p>Preferably substantially all (by weight) of the carrier particles have a diameter of 20 to 1000 jim, more preferably SO to 500 jim, but especially 20 to 250 jim. The diameter of substantially all (by weight) of the carrier particles is suitably less than 355 jim. This provides good flow and entrainment characteristics and improved release of the active particles in the airways to increase deposition of the active particles in the lower lung. It will be understood that, throughout, the diameter of the particles referred to is the aerodynamic diameter of the particles.</p>
<p>The active pharmaceutical ingredient(s) may be mixed with the ternary agent(s) using any suitable method, for example a high or low shear mixing method. The active pharmaceutical ingredient(s) and/or the ternary agent(s) may be sieved prior to mixing.</p>
<p>Pre-mixing the ternary agent with the active pharmaceutical ingredient in this way serves to maximize the extent to which the surface of the active particles are covered by the ternary Case PR/4-34779P11H0 161 agent. It enhances the interaction between the active particles and the ternary agent significantly. Particles of the ternary agent form a layer on the active particles that reinforce the desired effects of the ternary agent, e.g. by minimizing the negative effects of moisture on the chemical stability of the active particles.</p>
<p>In a preferred low shear mixing method an active pharmaceutical ingredient and a ternary agent are mixed in a low shear mixer such as a Turbula powder blender for 1 to 60 minutes at 1 to 60 revolutions per minutes. In a preferred high-shear mixing method an active pharmaceutical ingredient and a ternary agent are mixed in a high shear mixer such as a MiPro powder blender for 1 to 60 minutes at 100-4000 rpm.</p>
<p>The carrier particles may be mixed with the pre-mixed active pharmaceutical ingredient(s) and ternary agent(s) using any suitable method, for example a high or low shear mixing method as described above.</p>
<p>Where necessary or useful, the mixture of active pharmaceutical ingredient(s), ternary agent(s) and carrier particles is subjected to a final size reduction or blending step so that the dry powder formulation meets desired physical properties.</p>
<p>The dry powder may be contained as unit doses in capsules of, for example, gelatin or plastic, or in blisters (e.g. of aluminium or plastic), for use in a dry powder inhalation device, which may be a single dose or multiple dose device. Preferably the total weight of powder per capsule is from S mg to SO mg. Alternatively, the dry powder may be contained in a reservoir in a multi-dose dry powder inhalation (MDDPI) device adapted to deliver, for example, 3-25 mg of dry powder per actuation. A suitable device for delivery of dry powder in encapsulated form is described in US 3991761, while suitable MDDPI devices include those described in WO 97/20589 and WO 97/30743.</p>
<p>The invention is illustrated by the following Examples.</p>
<p>EXAMPLES</p>
<p>The following formulations are prepared to deliver 200 tg doses of indacaterol maleate in the multi-dose dry powder inhalation dry powder inhaler device described in WO 97/20589.</p>
<p>Case PRJ4-34779P111-JO 161</p>
<p>S</p>
<p>Example 1</p>
<p>Indacaterol maleate and magnesium stearate are mixed in a high shearing MiPro powder blender for 20 minutes at 250 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed for 20 minutes at 250 rpm. FPF(DD) = 29.7%, where FPF means fine particle fraction and DD means delivered dose, and BU = 94.0%</p>
<p>Example 2</p>
<p>Indacaterol maleate and magnesium stearate are mixed in a high shearing MiPro powder blender for 5 minutes at 500 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed (at low-shear) for 10 minutes at 220 rpm. FPF(DD) = 16.7%, BU = 99.3%</p>
<p>Example 3</p>
<p>Indacaterol maleate and calcium stearate are mixed in a low shearing a Turbula powder blender for 30 minutes at 44 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed in a high shearing MiPro powder blender for 10 minutes at 22 rpm. FPF(DD) = 24.9%, BU = 95.1%</p>
<p>Example 4</p>
<p>Indacaterol maleate and magnesium stearate are mixed in a low shearing a Turbula powder blender for 10 minutes at 22 rpm to form a pre-blend. Lactose is added to the pre-blend then mixed for 10 minutes at 22 rpm. FPF(DD) 18.3%, BU = 99.5% In these Examples, indacaterol maleate, (R)-S-[2-(S,6-diethyl-indan-2-ylamino)1-hydroxy ethyll -8 -hydroxy-1 H-quinolin-2-one maleate, is prepared by reacting (R)-8-benzyloxy-5-oxiranyl-ca rbostyril with 5,6-diethyl-indan-2-ylamine to give 8 -benzyloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino) -1 -hydroxy-ethyl] -IH-quinolin-2-one, subjecting the latter to a deprotecting reaction to replace the benzyl group by hydrogen, and recovering the resultant compound as a maleate salt. Such a process is described in detail in WO 2004/76422, the contents of which is incorporated herein by reference. (R)-8-benzyloxy-5-oxiranylcarbostyril may he prepared as described in WO 1995/25104. S,6-Diethyl-indan-2ylamine may be prepared as described in WO 2003/76387.</p>
Claims (1)
- <p>Case PRI4-34779P11H0 161</p><p>CLAIMS</p><p>1. A process for preparing dry powder formulations for inhalation that comprises mixing one or more active pharmaceutical ingredients with one or more ternary agents, then admixing carrier particles.</p><p>2. A process according to claim I wherein the ternary agent is a water-soluble surface-active agent.</p><p>3. A process according to claim 2 wherein the ternary agent is magnesium stearate or calcium stearate.</p><p>4. A process according to claim 1 in which the or each active pharmaceutical ingredient is selected from the group consisting of anti-inflammatory, bronchodilatory, antihistamine, decongestant or anti-tussive drug substances.</p><p>S. A process according to claim 1 in which the or each active pharmaceutical ingredient is selected from the group consisting of beta-2 adrenoceptor agonists, antimuscarinic agents, steroids or PDE4 inhibitors.</p><p>6 A process according to claim S in which the formulation'contains indacaterol maleate.</p><p>7. A process according to claim 1 wherein the carrier particles are crystalline sugars.</p><p>8. A process according to claim 7 wherein the carrier particles are lactose monohydrate or anhydrous lactose.</p><p>9. A process for preparing dry powder formulations for inhalation substantially as herein defined with reference to any one or more of the Examples.</p>
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150202297A1 (en) * | 2012-07-05 | 2015-07-23 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | Dry powder inhalers comprising a carrier other than lactose and a ternary component |
US10022323B2 (en) | 2013-03-28 | 2018-07-17 | Vectura Limited | Use of stearate in an inhalable formulation |
US10105316B2 (en) | 2012-07-05 | 2018-10-23 | Arven llac Sanayi Ve Ticaret A.S. | Inhalation compositions comprising muscarinic receptor antagonist |
US10111957B2 (en) | 2012-07-05 | 2018-10-30 | Arven Ilac Snayi ve Ticaret A.S. | Inhalation compositions comprising glucose anhydrous |
Citations (1)
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WO2001076575A2 (en) * | 2000-04-07 | 2001-10-18 | Arakis Ltd. | The treatment of respiratory diseases |
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WO2001076575A2 (en) * | 2000-04-07 | 2001-10-18 | Arakis Ltd. | The treatment of respiratory diseases |
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Title |
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KONA, 2005, Vol. 23, BEGAT P. ET. AL., see pages 109-121, note particularly pages 116-118. * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150202297A1 (en) * | 2012-07-05 | 2015-07-23 | Arven Ilac Sanayi Ve Ticaret Anonim Sirketi | Dry powder inhalers comprising a carrier other than lactose and a ternary component |
US10105316B2 (en) | 2012-07-05 | 2018-10-23 | Arven llac Sanayi Ve Ticaret A.S. | Inhalation compositions comprising muscarinic receptor antagonist |
US10111957B2 (en) | 2012-07-05 | 2018-10-30 | Arven Ilac Snayi ve Ticaret A.S. | Inhalation compositions comprising glucose anhydrous |
US10022323B2 (en) | 2013-03-28 | 2018-07-17 | Vectura Limited | Use of stearate in an inhalable formulation |
US10729647B2 (en) | 2013-03-28 | 2020-08-04 | Vectura Limited | Use of stearate in an inhalable formulation |
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