US009381189B2 (12) United States Patent (10) Patent No.: US 9,381,189 B2 Green et al. (45) Date of Patent: Jul. 5, 2016 (54) INGREDIENTS FOR INHALATION AND (56) References Cited METHODS FOR MAKING THE SAME U.S. PATENT DOCUMENTS (75) Inventors: Matthew Michael James Green, 4,582,265 A * 4/1986 Petronelli ....................... 241.95 Wiltshire (GB); Richard Michael Poole, 6,257,233 B1 7/2001 Burr et al. 2004/01 18007 A1* 6/2004 Chickering et al. ............ 34/360 Wiltshire (GB) 2006, O257491 A1* 11, 2006 Morton et al. ... 424/489 (73) Assignee: VECTURA LIMITED, Wiltshire (GB) 2008/0063719 A1 3/2008 Morton et al. ................ 424/489 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP O709086 A2 5, 1996 U.S.C. 154(b) by 641 days. EP 14981 16 A1 1, 2005 GB 2387781 A 10, 2003 JP 2005298.347 10/2005 (21) Appl. No.: 13/514,672 JP 200954.1393 11, 2009 JP 2012,542618 6, 2012 (22) PCT Fled: Dec. 8, 2010 WO 96.23485 A1 8, 1996 WO 9703649 A1 2, 1997 (86) PCT NO.: PCT/GB2O10/052053 WO O2OO197 A1 1, 2002 WO O243701 A2 6, 2002 S371 (c)(1), WO 2005105043 A2 11/2005 Aug. 20, 2012 WO 2007053904 A1 5/2007 (2), (4) Date: WO 2008.000482 1, 2008 (87) PCT Pub. No.: WO2O11AO70361 WO 2009095684 A1 8, 2009 OTHER PUBLICATIONS PCT Pub. Date: Jun. 16, 2011 Brunauer et al. "Adsorption of Gases in Multimolecular Layers'. J. (65) Prior Publication Data Am. Chem. Soc., vol. 60, (Feb. 1938) pp. 309-319. Nagai, et al. “Improvement in Dissolution Property of Poorly Water US 2012/0309809 A1 Dec. 6, 2012 Soluble Drugs by Using Mechanofusion System.” J. Soc. Powder Technol. Japan, 43, 640-647 (2006). (30) Foreign Application Priority Data Japanese Pharmaceutical Additives Directory 2007, p. 138. Dec. 8, 2009 (GB) ................................... O921481.8 * cited by examiner (51) Int. C. Primary Examiner — Bethany Barham A6 IK 9/14 (2006.01) Assistant Examiner — Melissa Javier A6 IK3I/404 (2006.01) (74) Attorney, Agent, or Firm — Matthew S. Gibson; Reed B2C 23/00 (2006.01) Smith LLP CO7D 209/6 (2006.01) A6 IK3I/4045 (2006.01) (57) ABSTRACT A61 K9/00 (2006.01) A method of processing an active ingredient, the method (52) U.S. C. comprising Submitting a pharmaceutically active ingredient CPC ............. A6 IK3I/4045 (2013.01); A61 K9/141 in the absence of excipients and/or additives to compression (2013.01); A61 K9/0073 (2013.01) and shearing forces. The invention also relates to composi (58) Field of Classification Search tions comprising an active prepared by the method. None See application file for complete search history. 16 Claims, 5 Drawing Sheets U.S. Patent Jul. 5, 2016 Sheet 1 of 5 US 9,381,189 B2 Fig 1 Circularity of sumatriptan succinate blends over time at 25/60 storage conditions ---.S.--Sysa-as --Jetmilled --&-sto MCB or Hum MCB Time (months) Fig 2 Circularity of sumatriptan succinate blends over time at 40/75 storage conditions 1.00 ys fS-0-Jetmilled rostd MCB so Hum MCB Time (months) U.S. Patent Jul. 5, 2016 Sheet 2 of 5 US 9,381,189 B2 Fig 3 Convexity of sumatriptan succinate blends over time at 25/60 storage conditions s |-0- Jetmilled ic-sc std MCB 3 as Hum MCB Time (months) Fig. 4 Convexity of Sumatriptan succinate blends over time at 40/75 storage conditions i --Jetmilled --S-a Std MCB 3 as Hum MCB Time (months) U.S. Patent Jul. 5, 2016 Sheet 3 of 5 US 9,381,189 B2 Fig 5 CE d(50) of Sumatriptan succinate blends over time at 25/60 storage conditions 3.50 as 3.00 s Š E 2.50 aga Jetmilled \SYYYYYY stic micb c 2.OO Hum M CB O 150 1.OO O 2 4 6 Time (months) Fig 6 CE d(50) of Sumatriptan succinate blends over time at 40/75 storage conditions 3.50 s 3.00 Es 2.50 -- Jetmilled Š \Six stc. mCb O 2.OO r Hum MCB O 150 1.OO s O 2 4. 6 Time (months) U.S. Patent Jul. 5, 2016 Sheet 4 of 5 US 9,381,189 B2 Fig 7 Amorphous content of processed sumatriptan blends Over time S. O.O2OO --Jet milled 25/60 Š 0.0150 esse Jet milled 40/75 S ...S. Std MCB 25/60 & ... 3: ... Std MCB 40/75 5 0.01.00 – -8- Hum MCB 25/60 -- Hum MCB 40/75 0.0050 - OOOOO - O 2 4 6 Timepoint (months) U.S. Patent Jul. 5, 2016 Sheet 5 of 5 US 9,381,189 B2 Fig 8 Stabiliy of Sumatriptan Succinate blends. (25/60 storage, F1, 12.29mg dose) 10.0 9. O & cere -' -8-DD Jetmilled 8.0 a s ...s--- DD MCB 5 7.0 a? Sas re-DD Hum MCB --- "--, -o-FPD Jetmilled 5. 6.O ...X.... FPDMCB 5. O --&- FPD Hum MCB E D O 3 5 6 Time (months) Fig 9 Stability of sumatriptan succinate blends. (40775 storage, F1, 12.29mg dose) 10.0 -- DD Jetmilled G ...&... DD MCB 5 ~&- DD Hum MCB s -----. FPD Jetmilled S. ...&... FPD MCB as a FPD Hum MCB S C Of O 1 2 3 4 5 6 Time (months) US 9,381,189 B2 1. 2 INGREDIENTS FOR INHALATION AND The reduced tendency of the particles to bond strongly, METHODS FOR MAKING THE SAME either to each other or to the device itself, not only reduces powder cohesion and adhesion, but can also promote better RELATED APPLICATIONS flow characteristics. These effects lead to improvements in the dose reproducibility because it reduces the variation in the This application is the United States National Stage Appli amount of powder metered out for each dose and improves the cation of International Application No. PCT/GB2010/ release of the powder from the device. It also increases the 052053, filed Dec. 8, 2010, which was published as Interna likelihood that the active material which does leave the device tional Publication No, WO 2011/070361 A1, and which will reach the lower lung of the patient. claims benefit of Great Britain Patent Application No. 10 The use of additive materials in this manner is disclosed in O921481.8 filed Dec. 8, 2009. Both applications are incorpo WO 96/23485 and WO 97/03649. It is also known that intensive co-milling of micronised rated by reference in their entirety herewith. drug particles with additive material may be carried out in The present invention relates to active ingredients for inha order to produce composite active particles. This co-microni lation and methods for making Such active ingredients. 15 sation can improve dispersibility, as disclosed in WO Inhalation represents a very attractive, rapid and patient 02/43701. In addition, WO 02/00197 discloses the intensive friendly route for the delivery of systemically acting drugs, as co-milling offine particles of excipient material with additive well as for drugs that are designed to act locally on the lungs material, to create composite excipient particles to which fine themselves. It is particularly desirable and advantageous to active particles and, optionally, coarse carrier particles may develop technologies for delivering drugs to the lungs in a be added. This co-micronisation of fine excipient particles predictable and reproducible manner. and additive material has also been shown to improve dispers The key features which make inhalation a useful drug ibility. delivery route are: rapid speed of onset; improved patient There is still a need for improved dry powderformulations. acceptance and compliance for a non-invasive systemic route; In one aspect the invention relates to a method of process reduction of side effects; product life cycle extension; 25 ing an active ingredient, the method comprising Submitting a improved consistency of delivery; access to new forms of pharmaceutically active ingredient or ingredients in the therapy, including higher doses, greater efficiency and accu absence of excipients (e.g. carrier particles) and/or additives racy of targeting; and direct targeting of the site of action for to compression and shearing forces. locally administered drugs, such as those used to treat lung In one aspect the invention relates to a method of process diseases. 30 ing an active ingredient, the method comprising Submitting a However, the powder technology behind successful dry pharmaceutically active ingredient or ingredients alone to powders and dry powder inhaler (DPI) or pressured metered compression and shearing forces. dose inhalers (pMDI) products remains a significant technical In one aspect the active is a micronised active. hurdle to those wishing to succeed with this route of admin The invention further relates to an active ingredient obtain istration and to exploit the significant product opportunities. 35 able or obtained using the above method. Any formulation suitably has properties that allow for the The invention further relates to an inhaler device compris manufacture and metering of the powders, provide reliable ing an active ingredient obtainable or obtained by the method and predictable resuspension and fluidisation, and avoid of the invention, or an active ingredient which has been fur excessive retention of the powder within the dispensing ther processed where necessary into a suitable pharmaceuti device. 40 cally acceptable form. A major problem experienced by formulators is the vari The invention further relates to a receptacle. Such as a ability in Surface properties of drug particles. Each active blister or capsule, comprising a dose of a active ingredient, agent powder has its own unique inherent Stickiness or Sur obtainable or obtained by the method of the invention, or an face energy, which can range tremendously from compound active ingredient which has been further processed where to compound.