USOO96428OOB2

(12) United States Patent (10) Patent No.: US 9,642,800 B2 Morton (45) Date of Patent: May 9, 2017

(54) DRY POWDER INHALER FORMULATIONS (56) References Cited COMPRISING SURFACE-MODIFIED PARTICLES WITH ANT-ADHERENT U.S. PATENT DOCUMENTS ADDITIVES 4,687,773. A 8/1987 Neumeyer 5,292,520 A 3, 1994 De Haan et al. (71) Applicant: VECTURA LIMITED, Chippenham 5,441,747 A 8, 1995 De Haan et al. 5,655,523 A 8, 1997 Hodson et al. (GB) 6,029,662 A 2/2000 Marcon 6,045,828 A 4/2000 Bystrom et al. (72) Inventor: David Morton, Chippenham (GB) 6,051,257 A 4/2000 Kodas et al. 6,475,523 B1 11/2002 Staniforth (73) Assignee: VECTURA LIMITED, Chippenham, 6,528,096 B1 3/2003 Musa et al. 6,528,521 B2 3/2003 Ruffet al. Wiltshire (GB) 6,989,155 B1 1/2006 Ganderton et al. 2002fOOO2176 A1 1/2002 Gupta et al. (*) Notice: Subject to any disclaimer, the term of this 2002.0035993 A1 3/2002 Edwards et al. patent is extended or adjusted under 35 2002fOO71871 A1 6/2002 Snyder et al. U.S.C. 154(b) by 0 days. 2002fOO86876 A1 7, 2002 Ruff et al. 2002/O127188 A1 9, 2002 Platz et al. 2003/0017115 A1 1/2003 Rabinowitz et al. (21) Appl. No.: 14/823,484 2003/0055034 A1 3/2003 Mongomery 2003/0113272 A1 6/2003 Staniforth (22) Filed: Aug. 11, 2015 2003. O157182 A1 8, 2003 Staniforth et al. 2003,0162835 A1 8, 2003 Staniforth et al. (65) Prior Publication Data 2003. O165436 A1 9, 2003 Staniforth et al. 2003/0175214 A1 9, 2003 Staniforth et al. US 2016/OOOO709 A1 Jan. 7, 2016 2003/0175355 A1 9/2003 Tobyn et al. 2003.0185764 A1 10/2003 Staniforth et al. 2003. O186843 A1 10/2003 Staniforth et al. Related U.S. Application Data (Continued) (63) Continuation of application No. 13/085,200, filed on FOREIGN PATENT DOCUMENTS Apr. 12, 2011, which is a continuation of application AU 2001291122 4/2002 No. 1 1/791,385, filed as application No. CN 1179097 4f1998 PCT/GB2005/0502.11 on Nov. 23, 2005, now CN 1326341 12/2001 abandoned. CN 197273O 5/2007 EP O931595 7, 1999 EP O954.282 11, 1999 (30) Foreign Application Priority Data EP 1159955 12/2001 EP 1213012 6, 2002 Nov. 23, 2004 (GB) ...... O425758.0 GB 2353222 2, 2001 JP 2001072586 3, 2001 (51) Int. Cl. (Continued) A6 IK3I/55 (2006.01) A6M I5/00 (2006.01) OTHER PUBLICATIONS A6 IK 3/473 (2006.01) A6 IK3I/35 (2006.01) Peart J. et al. “Multicomponent Particle Interactions in Dry Powder Aerosols.” Pharmaceutical Research, Spring New York LLC, US, A6 IK 47/26 (2006.01) vol. 14, No. 11-S, Jan. 1, 1997, pp. S142-S143, XPO01030455. A6 IK 47/12 (2006.01) A6 IK 9/14 (2006.01) (Continued) A6 IK3I/522 (2006.01) Primary Examiner — Suzanne Ziska A6 IK 9/00 (2006.01) Assistant Examiner — Thurman Wheeler A6 IK3I/58 (2006.01) (74) Attorney, Agent, or Firm — Matthew S. Gibson; (52) U.S. Cl. Reed Smith LLP CPC ...... A61K 9/0075 (2013.01); A61K 9/145 (2013.01); A61K 31/135 (2013.01); A61 K (57) ABSTRACT 3 1/473 (2013.01); A61 K3I/522 (2013.01); The present invention is concerned with a refinement of the A6 IK3I/55 (2013.01); A61 K3I/58 (2013.01); processing of particles that are to form a dry powder A61K 47/12 (2013.01); A61K 47/26 (2013.01); formulation which is to be administered to the lung using a A61M 15/0028 (2013.01); A61M 2202/064 dry powder inhaler (DPI) device. In particular, the present (2013.01) invention provides the processing of particles of active (58) Field of Classification Search material and particles of carrier material in the presence of CPC ...... A61 K9/0075; A61 K 9/145; A61K 31/58: additive material to provide a powder composition which A61K 3 1/55; A61K 3 1/522: A61 K exhibits excellent powder properties and which is economi 31/473; A61K 31/135; A61K 47/26; cal to produce. A61K 47/12: A61M 15/0028 See application file for complete search history. 16 Claims, 7 Drawing Sheets US 9,642,800 B2 Page 2

(56) References Cited WO O2O8988O 11 2002 WO 0208.9881 11 2002 U.S. PATENT DOCUMENTS WO 2004089374 10, 2004 WO 2004O93848 11 2004 2004/0028613 A1 2/2004 Quay WO 2005O25541 3, 2005 2004/0037785 A1 2, 2004 Stanforth et al. W. SS: 1858. 2004/004781.0 A1 3, 2004 Staniforth et al. WO 2005105043 11/2005 2004/OO52733 A1 3, 2004 Staniforth et al. WO 2006059.152 6, 2006 2004f0071635 A1 4/2004 Staniforth et al. 2004/0204439 A1 10, 2004 Stanforth 2004/0204440 A1 10, 2004 Staniforth OTHER PUBLICATIONS 2005, OO13862 A1 1/2005 Tobyn et al. 2005. O152849 A1 7/2005 Staniforth Kawaskima et al. “Design of inhalation dry powder of pranlukast 2005/0261163 A1 11/2005 Tobyn et al. hydrate to improve dispersibility by the surface modification with 2006, O127480 A1 6/2006 Tobyn et al. light anhydrous silicic acid (Aerosil 200).” International Journal of 2006/0147389 A1 7/2006 Staniforth et al. Pharmaceutics, vol. 173, No. 1-2, Oct. 1, 1998, pp. 243-251, 2006/0257491 A1 11/2006 Morton et al. XPO55190978O. 2006/0292081 A1 12/2006 Morton et al. Amendment and Response to Office Action filed in U.S. Appl. No. 2007, OO65373 A1 3, 2007 Morton et al. 13,464,445 on Nov. 10, 2014. 2007/0081948 A1 4/2007 Morton et al. Final Rejection issued in U.S. Appl. No. 13,464.445 on Jul. 8, 2014. 2010/0209358 A1 8, 2010 Staniforth Wennerstrum, et al. “Size Reduction Solutions for Hard-to-Reduce Materials.” Powder and Bulk Engineering. Jan. 2002. Kodas et al., “Aerosol Processing of Materials.” Chapter 13, pp. FOREIGN PATENT DOCUMENTS 436-491 (1999). Amann et al., “Comprehensive Pharmacy Review.” Pharmaceutical JP 2001151673 6, 2001 Sciences, Part 1, Chapter I, Drug Product Development in the JP 2003530344 10, 2003 Pharmaceutical Industry. pp. 1-6, 3rd Edition, (1997). JP 200353O425 10, 2003 Lucas et al., “Enhancement of Small Particle Size Dry Powder JP 2004.509 141 3, 2004 Aerosol Formulations. Using an Ultra-Low Density Additive.” Phar JP 2004514.504 5, 2004 maceutical Research, vol. 16, No. 10, pp. 1643-1647 (1999). WO 9116038 10, 1991 "Ensuring Patient Care, The Role of the HFC MIDI.” International W. SE: $3. Pharmaceutical Aerosol Consortium, 2nd Edition, pp. 1-56 (Jun. 1999). W. Wo: 88: ...... A61K 9.00 Ashurst et al., “Latest Advances in the Development of Dry Powder WO 9703649 2/1997 Inhalers.” Pharm. Science Technology Today, vol. 3, No. 7, pp. WO 983.1346 7, 1998 246-256 (2000). WO OO27363 5, 2000 R. Pfeffer et al. Synthesis of engineered particulates with tailed WO OO33811 6, 2000 properties using dry particle coating.” Powder Technology 117 WO OO72827 12/2000 (2001) 40-67. WO 010O262 1, 2001 Translation of Chinese Office Action dated Feb. 1, 2016 for Chinese WO O113893 3, 2001 Patent Application No. 2014 10314552.X. WO O149263 T 2001 Translation of Chinese Search Report dated Feb. 1, 2016 for WO O1765.75 10, 2001 Chinese Patent Application No. 201410314552.X. WO O178693 10, 2001 Zhenwang, “Analysis of the Research Progress of Dry Powder WO O1786.94 10, 2001 Inhalant from List Product.” Herald of Medicine, vol. 26, No. 3, WO O178695 10, 2001 Mar. 31, 2007. WO O1786.96 1939: Zeng et al., “Particulate interactions in dry powder formulations for W. 9:29, I299; inhalation” Taylor & Francis, 2001, London, p. 240-244. WO O2001.97 1, 2002 Zhenwang, “Analysis of the Study Progress of Dry Powder Inha WO O2O7805 1, 2002 lations from Commercial Available Products.” Herald of Medicine, WO O243693 6, 2002 vol. 26. No. 3, Mar. 31, 2007. WO O243701 6, 2002 WO O2O67902 9, 2002 * cited by examiner U.S. Patent May 9, 2017 Sheet 1 of 7 US 9,642,800 B2

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A 2 US 9,642,800 B2 1. 2 DRY POWDER INHALER FORMULATIONS FIG. 4, also noted as Table 3, shows the Hosokawa COMPRISING SURFACE-MODIFIED Powder Tester Results for Sorbolac 400 (Cyclomixed). PARTICLES WITH ANT-ADHERENT FIG. 5, also noted as Table 4, shows the Hosokawa ADDITIVES Powder Tester Results for Micronised Lactose (Model Drug). RELATED APPLICATIONS FIG. 6, also noted as Table 5, shows the Hosokawa Powder Tester Results for SU003 (Conventional “Large” This application is a continuation of U.S. application Ser. Carrier). No. 13/085,200 filed Apr. 12, 2011, which is a continuation FIG. 7 shows the Zeta potential of Lactose. Lactose/ of U.S. application Ser. No. 11/791,385 filed Jul. 5, 2007, 10 Magnesium Stearate that has been Turbula-blended and now abandoned which is a United States national stage of Lactose/Magnesium Stearate that has been mechanofused. International Application No. PCT/GB2005/050211, filed Nov. 23, 2005, which was published as International Pub DETAILED DESCRIPTION OF THE lication No. WO 2006/056812, and which claims benefit of INVENTION United Kingdom Application No. 0425758.0 filed, Nov. 23, 15 2004, the entire contents of which are hereby expressly The drug particles or particles of pharmaceutically active incorporated herein by reference thereto. material (also referred to herein as “active' particles) in the resuspended powder must aerosolise into an ultra-fine aero FIELD OF THE INVENTION Sol So that they can be transported to the appropriate target 2O area within the lung. Typically, for lung deposition, the The present invention is concerned with a refinement of active particles have a diameter of less than 10 Lums, fre the processing of particles that are to form a dry powder quently 0.1 to 7 um, 0.1 to 5 um, or 0.5 to 5 um. formulation which is to be administered to the lung, for For formulations to reach the deep lung or the blood example using a dry powder inhaler (DPI) device. In par stream via inhalation, the active agent in the formulation ticular, the present invention provides the processing of 25 must be in the form of very fine particles, for example, particles of active material and particles of carrier material having a mass median aerodynamic diameter (MMAD) of in the presence of additive material to provide a powder less than 10 um. It is well established that particles having composition which exhibits excellent powder properties and an MMAD of greater than 10 um are likely to impact on the which is economical to produce. walls of the throat and generally do not reach the lung. 30 Particles having an MMAD in the region of 5 to 2 Lim will BACKGROUND OF THE INVENTION generally be deposited in the respiratory bronchioles whereas particles having an MMAD in the range of 3 to 0.05 Inhalation represents a very attractive, rapid and patient um are likely to be deposited in the alveoli and to be friendly route for the delivery of systemically acting drugs, absorbed into the bloodstream. as well as for drugs that are designed to act locally on the 35 Preferably, for delivery to the lower respiratory tract or lungs themselves. It is particularly desirable and advanta deep lung, the MMAD of the active particles is not more geous to develop technologies for delivering drugs to the than 10 um, and preferably not more than more preferably lungs in a predictable and reproducible manner. not more than 3 Jum, and may be less than 2 Jum, less than 1.5 The key features which make inhalation an exciting drug um or less than 1 Lum. Especially for deep lung or systemic delivery route are: rapid speed of onset; improved patient 40 delivery, the active particles may have a size of 0.1 to 3 um acceptance and compliance for a non-invasive systemic or 0.1 to 2 um. route; reduction of side effects; product life cycle extension; Ideally, at least 90% by weight of the active particles in improved consistency of delivery; access to new forms of a dry powder formulation should have an aerodynamic therapy, including higher doses, greater efficiency and accu diameter of not more than 10 um, preferably not more than racy of targeting; and direct targeting of the site of action for 45 5um, more preferably not more than 3 Jum, not more than 2.5 locally administered drugs, such as those used to treat lung um, not more than 2.0 um, not more than 1.5 um, or even not diseases such as asthma, COPD, CF or lung infections. more than 1.0 um. However, the powder technology behind successful dry When dry powders are produced using conventional pro powders and DPI products remains a significant technical cesses, the active particles will vary in size, and often this hurdle to those wishing to succeed with this route of 50 variation can be considerable. This can make it difficult to administration and to exploit the significant product oppor ensure that a high enough proportion of the active particles tunities. Any formulation must have suitable flow properties, are of the appropriate size for administration to the correct not only to assist in the manufacture and metering of the site. It is therefore desirable to have a dry powder formu powders, but also to provide reliable and predictable resus lation wherein the size distribution of the active particles is pension and fluidisation, and to avoid excessive retention of 55 as narrow as possible. For example, the geometric standard the powder within the dispensing device. deviation of the active particle aerodynamic or volumetric size distribution (Og), is preferably not more than 2, more BRIEF DESCRIPTION OF THE DRAWINGS preferably not more than 1.8, not more than 1.6, not more than 1.5, not more than 1.4, or even not more than 1.2. This FIG. 1 shows the microporosity of various types of lactose 60 will improve dose efficiency and reproducibility. particles as measured using the Cooker SA 3100 BET Fine particles, that is, those with an MMAD of less than system as defined by pore diameter (nm) versus cumulative 101. Lum and Smaller, tend to be increasingly thermodynami percentage. cally unstable as their surface area to Volume ratio increases, FIG. 2, also noted as Table 1, shows the Hosokawa which provides an increasing Surface free energy with this Powder Tester Results for Sorbolac 400 (Mechanofused). 65 decreasing particle size, and consequently increases the FIG. 3, also noted as Table 2, shows the Hosokawa tendency of particles to agglomerate and the strength of the Powder Tester Results for Extra Fine Lactose. agglomerate. In the inhaler, agglomeration of fine particles US 9,642,800 B2 3 4 and adherence of such particles to the walls of the inhaler are Even in highly regular, crystalline powders, the short problems that result in the fine particles leaving the inhaler range van der Waals forces (which include fixed dipole and as large, stable agglomerates, or being unable to leave the similar fixed charge related forces and which depend on the inhaler and remaining adhered to the interior of the inhaler, chemistry of the functional groups exposed on the Surface of or even clogging or blocking the inhaler. the particles) can lead to highly cohesive and adhesive The uncertainty as to the extent of formation of stable powders. agglomerates of the particles between each actuation of the Solutions to some of the problems touched upon above inhaler, and also between different inhalers and different are already known. For example, flow problems associated batches of particles, leads to poor dose reproducibility. with larger amounts offine material (for example, in powder Furthermore, the formation of agglomerates means that the 10 formulations including relatively high proportions (such as MMAD of the active particles can be vastly increased, with up to from 5 to 20% by total weight of the formulation) of agglomerates of the active particles not reaching the fine lactose or drug and fine lactose) may be overcome by required part of the lung. use of a large fissured lactose as carrier particles, as dis These micron to Submicron particle sizes required for 15 cussed in earlier patent applications published as WO deep lung or systemic delivery lead to the problem that the 01/78694, WO 01/78695 and WO 01/78696. respirable active particles tend to be highly cohesive, which In order to improve the properties of powder formula means they generally exhibit poor flowability and poor tions, and in particular to improve the flowability and aerosolisation. dispersibility of the formulation, dry powder formulations To overcome the highly cohesive nature of such respirable often include additive materials which are intended to active particles, formulators have, in the past, included reduce the cohesion between the fine particles in the dry larger carrier particles of an inert excipient in powder powder formulation. It is thought that the additive material formulations, in order to aid both flowability and drug interferes with the weak bonding forces between the small aerosolisation. Relatively large carrier particles have a ben particles, helping to keep the particles separated and reduc eficial effect on the powder formulations because, rather 25 ing the adhesion of Such particles to one another, to other than Sticking to one another, the fine active particles tend to particles in the formulation if present and to the internal adhere to the surfaces of the larger carrier particles whilst in surfaces of the inhaler device. Where agglomerates of par the inhaler device. The active particles are supposed to ticles are formed, the addition of particles of additive release from the carrier particle Surfaces and become dis material decreases the stability of those agglomerates So that persed upon actuation of the dispensing device, to give a fine 30 they are more likely to break up in the turbulent air stream Suspension which may be inhaled into the respiratory tract. created on actuation of the inhaler device, where upon the In general, it has been considered that the carrier particles particles are expelled from the device and inhaled. should preferably have a mass median aerodynamic diam In the prior art, dry powder formulations are discussed eter (MMAD) of at least about 90 um, and in general terms which include additive material (for example in the form of should preferably have a mass median aerodynamic diam 35 distinct particles of a size comparable to that of the fine eter (MMAD) of greater than 40 um, and not less than 20 active particles). In some embodiments, the additive mate lm. rial may be applied to and form a coating, generally a However, whilst the addition of relatively large carrier discontinuous coating, on the active particles or on any particles does tend to improve the powder properties, it also carrier particles. has the effect of diluting the drug, usually to Such an extent 40 Preferably, the additive material is an anti-adherent mate that 95% or more by total weight of the formulation is rial and it will tend to reduce the cohesion between particles carrier. Relatively large amounts of carrier are required in and will also prevent fine particles becoming attached to order to have the desired effect on the powder properties Surfaces within the inhaler device. Advantageously, the because the majority of the fine or ultra-fine active particles additive material is an anti-friction agent or glidant and will need to adhere to the surfaces of the carrier particles, 45 give the powder formulation better flow properties in the otherwise the cohesive nature of the active particles still inhaler. The additive materials used in this way may not dominates the powder and results in poor flowability. The necessarily be usually referred to as anti-adherents or anti surface area of the carrier particles available for the fine friction agents, but they will have the effect of decreasing the particles to adhere to decreases with increasing diameter of cohesion between the particles or improving the flow of the the carrier particles. However, the flow properties tend to 50 powder. As such, the additive materials are sometimes become worse with decreasing diameter. Hence, there is a referred to as force control agents (FCAs) and they usually need to find a suitable balance in order to obtain a satisfac lead to better dose reproducibility and higher fine particle tory carrier powder. An additional consideration is that one fractions (FPFs). can get segregation if too few carrier particles are included, Therefore, an additive material or FCA, as used herein, is which is extremely undesirable. 55 a material whose presence on the Surface of a particle can An additional major problem experienced by formulators modify the adhesive and cohesive surface forces experi is the variability in Surface properties of drug and excipient enced by that particle, in the presence of other particles and particles. Each active agent powder has its own unique in relation to the Surfaces that the particles are exposed to. inherent stickiness or Surface energy, which can range In general, its function is to reduce both the adhesive and tremendously from compound to compound. Further, the 60 cohesive forces. nature of the Surface energies can change for a given The reduced tendency of the particles to bond strongly, compound depending upon how it is processed. For either to each other or to the device itself, not only reduces example, jet milling is notorious for generating significant powder cohesion and adhesion, but can also promote better variations in Surface properties because of the aggressive flow characteristics. This leads to improvements in the dose nature of the collisions it employs. Such variations can lead 65 reproducibility because it reduces the variation in the to increased Surface energy and increased cohesiveness and amount of powder metered out for each dose and improves adhesiveness. the release of the powder from the device. It also increases US 9,642,800 B2 5 6 the likelihood that the active material which does leave the improved flow, and improved aerosolisation due to the device will reach the lower lung of the patient. individually tailored surface conditioning of the respective It is favourable for unstable agglomerates of particles to drug and carrier particles. be present in the powder when it is in the inhaler device. For It has been found that the most advantageous powder a powder to leave an inhaler device efficiently and repro system incorporates one or more additives or force control ducibly, it is generally accepted that the particles should agents on the Surface of the both the drug particles and the ideally be large, preferably larger than about 40 um. Such a carrier particles, in order to maximise the potential for flow powder may be in the form of either individual particles and aerosolisation. having a size of about 40 um or larger and/or agglomerates In the prior art, it is generally not suggested to attach the of finer particles, the agglomerates having a size of about 40 10 additive to both the active particles and carrier or excipient um or larger. The agglomerates formed can have a size of as particles to obtain the advantages outlined here. much as about 1000 um and, with the addition of the additive The minimum amount of the additive or FCA necessary to material, those agglomerates are more likely to be broken improve powder properties is preferably used, for toxicol down efficiently in the turbulent airstream created on inha 15 ogy and dosing reasons. What is more, the ideal incorpora lation. Therefore, the formation of unstable or “soft' tion of the additive is in the form of at least an approximate agglomerates of particles in the powder may be favoured single minimum layer of additive material as a coating compared with a powder in which there is substantially no around each powder component, that is around both the agglomeration. Such unstable agglomerates are retained active particles and any carrier particles present. As the drug whilst the powder is inside the device but are then disrupted particles are generally Smaller (i.e. less than 5um), they will and broken up when the powder is dispensed. have a correspondingly higher Surface area to Volume ratio The use of additive materials in this manner is disclosed than the generally larger (>5um) carrier particles. in two earlier patent applications, published as WO According to a first aspect of the present invention, a 96/23485 and WO 97/03649. method of preparing a powder formulation is provided, the It is also known that intensive co-milling of micronised 25 method comprising co-milling active particles with an addi drug particles with additive material may be carried out in tive material, separately co-milling carrier particles with an order to produce composite particles. This co-micronisation additive material, and then combining the co-milled active can improve dispersibility, as disclosed in the earlier patent and carrier particles. application published as WO 02/43701. In addition, the The co-milling steps preferably produce composite par earlier application published as WO 02/00197 discloses the 30 ticles of active and additive material or carrier and additive intensive co-milling of fine particles of excipient material material. with additive material, to create composite excipient par The powder formulations prepared according to the meth ticles to which fine active particles and, optionally, coarse ods of the present invention exhibit excellent powder prop carrier particles may be added. This co-micronisation of fine erties that may be tailored to the active agent, the dispensing excipient particles and additive material has also been 35 device to be used and/or various other factors. In particular, shown to improve dispersibility. the co-milling of active and carrier particles in separate steps Whilst the various disclosures in the prior art of the use of allows different types of additive material and different additive materials as force control agents do indicate quantities of additive material to be milled with the active improvements in powder properties (such as the dispersibil and carrier particles. Consequently, the additive material can ity and flow) as a result of the addition of the additive 40 be selected to match its desired function, and the minimum material, the known powders and processing methods fail to amount of additive material can be used to match the relative provide the maximum effect possible with the optimum Surface area of the particles to which it is being applied. combination of Small carrier and drug, and do not provide In one embodiment, the active particles and the carrier the maximum effect possible from the least necessary particles are both co-milled with the same additive material amount of additive material. The optimisation of the use of 45 or additive materials. In an alternative embodiment, the the additive material is important for several reasons. Firstly, active and carrier particles are co-milled with different it is clearly desirable to provide a dry powder formulation additive materials. with the best possible powder properties in order to ensure In one embodiment of the invention, active particles of efficient, reliable and accurate dosing. Secondly, it is also less than about 5 um diameter are co-milled with an appro desirable to minimise the amount of the additive material (or 50 priate amount of an additive or force control agent, whilst indeed of any material) administered to the lung. This will carrier particles with a median diameter in the range of about reduce the risk of adverse effects that may be caused by the 3 um to about 40 um are separately co-milled with an material. Thirdly, it is desirable to be able to deliver the appropriate amount of an additive. maximum dose with optimum efficiency from a minimum Generally, the amount of additive co-milled with the powder payload, especially for high dose drugs. Finally, the 55 carrier particles will be less, by weight, than that co-milled use of as little additive material as possible will also be more with the active particles. Nevertheless, the amount of addi economical. These features will also help to keep the device tive used is kept to a minimum whilst being Sufficient to size Small, maximise number of doses per device and reduce have the desired effect on the powder properties. The treated device complexity. drug and carrier particles are then combined to provide a The present invention seeks to improve upon the powder 60 formulation with the desired features. formulations provided in the prior art, to ensure that their The additive material is preferably in the form of a coating powder properties are optimised and the powder preparation on the surfaces of the active and carrier particles. The is simple and economical. coating may be a discontinuous coating. In another embodi It is also an object of the present invention to permit an ment, the additive material may be in the form of particles increased percentage of ultra-fine drug to be used in a 65 adhering to the Surfaces of the active and carrier particles. formulation, optionally with a fine carrier component, whilst Preferably, the additive material actually becomes fused to still providing a powder formulation which exhibits the surfaces of the active and carrier particles US 9,642,800 B2 7 8 It is advantageous for carrier particles to be used in the tame or acesulfame K. Preferably, the additive consists size range having a median diameter of about 3 to about 40 Substantially of an amino acid, more preferably of leucine, um, preferably about 5 to about 30 Lum, more preferably advantageously L-leucine. The D- and DL-forms may also about 5 to about 20 um, and most preferably about 5 to about be used. As indicated above, leucine has been found to give 15 lum. Such particles, if untreated with an additive are particularly efficient dispersal of the active particles on unable to provide suitable flow properties when incorporated inhalation. in a powder formulation comprising ultra-fine active par The additive may include one or more water soluble ticles. Indeed, previously, particles in these size ranges substances. This helps absorption of the additive by the body would not have been regarded as suitable for use as carrier if it reaches the lower lung. The additive may include dipolar particles, and instead would have been added in Small 10 ions, which may be Zwitterions. It is also advantageous to quantities as a fine component. Such fine components are include a spreading agent as an additive, to assist with the known to increase the aerosolisation properties of formula dispersal of the composition in the lungs. Suitable spreading tions containing a drug and a larger carrier, typically with agents include Surfactants such as known lung Surfactants median diameter 40 um to 100 um or greater. However, the (e.g. ALECTM) which comprise phospholipids, for example, amount of the fine components that may be included in Such 15 mixtures of DPPC (dipalmitoyl phosphatidylcholine) and formulations is limited, and formulations including more PG (phosphatidylglycerol). Other suitable surfactants than about 10% fines tend to exhibit poor properties unless include, for example, dipalmitoyl phosphatidylethanolamine special carrier particles are included, such as the large (DPPE), dipalmitoyl phosphatidylinositol (DPPI). fissured lactose carrier particles mentioned above. The additive may comprise a metal Stearate, or a deriva Alternatively, compositions of micronised drug and tive thereof, for example, Sodium Stearyl fumarate or sodium micronised lactose are known, but only where this blend has Stearyl lactylate. Advantageously, it comprises a metal Stear Subsequently been Successfully compressed and granulated ate, for example, Zinc Stearate, magnesium Stearate, calcium into pellets. This process is generally very difficult to control stearate, sodium stearate or lithium stearate. Preferably, the and pellets are prone to destruction, resulting in powders additive material comprises magnesium Stearate, for with poor flow properties. 25 example vegetable magnesium Stearate, or any form of However, following treatment with additive materials, commercially available metal stearate, which may be of Substantial changes in the powder characteristics of our fine vegetable or animal origin and may also contain other fatty carrier powders are seen. Powder density is increased, even acid components such as palmitates or oleates. doubled, for example from 0.3 g/cc to over 0.5 g/cc. Other The additive may include or consist of one or more powder characteristics are changed, for example, the angle 30 Surface active materials, in particular materials that are of repose is reduced and contact angle increased. surface active in the solid state, which may be water soluble Carrier particles having a median diameter of 3 to 40 um or water dispersible, for example lecithin, in particular soya are advantageous as their relatively small size means that lecithin, or substantially water insoluble, for example solid they have a reduced tendency to segregate from the drug state fatty acids such as oleic acid, lauric acid, palmitic acid, component, even when they have been treated with an 35 Stearic acid, erucic acid, behenic acid, or derivatives (such as additive, which will reduce cohesion. This is because the esters and salts) thereof Such as glyceryl behenate. Specific size differential between the carrier and drug is relatively examples of Such materials are phosphatidylcholines, phos Small compared to that in conventional formulations which phatidylethanolamines, phosphatidylglycerols and other include ultra-fine active particles and much lager carrier examples of natural and synthetic lung Surfactants; lauric particles. The surface area to volume ratio presented by the 40 acid and its salts, for example, Sodium lauryl Sulphate, fine carrier particles is correspondingly greater than that of magnesium lauryl Sulphate; triglycerides such as Dynsan conventional large carrier particles. This higher Surface area, 118 and Cutina HR; and Sugar esters in general. Alterna allows the carrier to be successfully associated with higher tively, the additive may be cholesterol. levels of drug than for conventional larger carrier particles. Other possible additive materials include sodium benzo Carrier particles may be of any acceptable inert excipient 45 ate, hydrogenated oils which are solid at room temperature, material or combination of materials. For example, carrier talc, titanium dioxide, aluminium dioxide, silicon dioxide particles frequently used in the prior art may be composed and starch. Also useful as additives are film-forming agents, of one or more materials selected from Sugar alcohols, fatty acids and their derivatives, as well as lipids and polyols and crystalline Sugars. Other suitable carriers lipid-like materials. include inorganic salts such as Sodium chloride and calcium 50 In one embodiment of the invention, the additive com carbonate, organic salts such as sodium lactate and other prises an amino acid, a derivative of an amino acid, a metal organic compounds such as polysaccharides and oligosac stearate or a phospholipid. Preferably, the additive com charides. Advantageously, the carrier particles comprise a prises one or more of L-, D- or DL-forms of leucine, polyol. In particular, the carrier particles may be particles of isoleucine, lysine, Valine, methionine, phenylalanine, or crystalline Sugar, for example mannitol, dextrose or lactose. 55 AerocineTM, lecithin or magnesium stearate. In another Preferably, the carrier particles are composed of lactose. embodiment, the additive comprises leucine and preferably Advantageously, the additive material or FCA includes L-leucine. one or more compounds selected from amino acids and In some embodiments, a plurality of different additive derivatives thereof, and peptides and derivatives thereof. materials can be used. Amino acids, peptides and derivatives of peptides are physi 60 The present invention can be carried out with any phar ologically acceptable and give acceptable release of the maceutically active agent. The terms “active particles' and active particles on inhalation. “particles of active material and the like are used inter It is particularly advantageous for the additive to comprise changeably herein. The active particles comprise one or an amino acid. The additive may comprise one or more of more pharmaceutically active agents. The preferred active any of the following amino acids: leucine, isoleucine, lysine, 65 agents include: valine, methionine, and phenylalanine. The additive may be 1) Steroid drugs such as alcometaSone, beclomethasone, a salt or a derivative of an amino acid, for example aspar beclomethasone dipropionate, betamethasone, budesonide, US 9,642,800 B2 10 ciclesonide, clobetasol, deflazacort, diflucortolone, des 19) phosphodiesterase inhibitors such as non-specific oxymethasone, dexamethasone, fludrocortisone, flunisolide, phosphodiesterase inhibitors including theophylline, theo fluocinolone, fluometholone, fluticasone, fluticasone propri bromine, IBMX, pentoxifylline and papaverine; phosphodi onate, hydrocortisone, triamcinolone, nandrolone decano esterase type 3 inhibitors including bipyridines Such as ate, neomycin Sulphate, rimexolone, methylprednisolone milrinone, amrinone and olprinone; imidazolones Such as and prednisolone; piroXimone and enoXimone; imidazolines such as imaZodan 2) bronchodilators such as B2-agonists including salbu and 5-methyl-imaZodan; imidazo-quinoxalines; and dihy tamol, formoterol, salmeterol, fenoterol, bambuterol, bitolt dropyridazinones such as indolidan and LY181512 (5-(6- erol, sibenadet, metaproterenol, epinephrine, isoproterenol, oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-1,3-dihydro-indo1 10 2-one); dihydroquinolinone compounds such as cilostamide, pirbuterol, procaterol, terbutaline and isoetharine antimus cilostazol, and Vesnarinone; phosphodiesterase type 4 carinics including ipratropium and tiotropium, and Xanthines inhibitors such as cilomilast, etazolate, rolipram, roflumilast including aminophylline and theophylline; and Zardaverine, and including quinazolinediones such as 3) nitrates such as isosorbide mononitrate, isosorbide nitraquaZone and nitraduaZone analogs; Xanthine derivatives dinitrate and glyceryl trinitrate; 15 such as denbufylline and arofylline; tetrahydropyrimidones 4) antihistamines such as azelastine, chlorpheniramine, Such as atizoram; and oxime carbamates Such as filaminast; astemizole, cetirizine, cinnarizine, desloratadine, loratadine, and phosphodiesterase type 5 inhibitors including sildenafil. hydroxy Zine, diphenhydramine, fexofenadine, ketotifen, Zaprinast, Vardenafil, tadalafil, dipyridamole, and the com promethazine, trimeprazine and terfenadine; pounds described in WO 01/19802, particularly (S)-2-(2- 5) anti-inflammatory agents such as piroXicam, nedocro hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy mil, benzydamine, diclofenac sodium, ketoprofen, ibupro benzylamino)-5-N (2-pyrimidinylmethyl)carbamoyl fen, heparinoid, cromoglycate, fasafungine, iodoxamide and pyrimidine, 2-(5,6,7,8-tetrahydro-1, 7-naphthyridin 7-yl)- p38 MAP kinase inhibitors; 4-(3-chloro-4-methoxybenzylamino)-5-N-(2-morpho 6) anticholinergic agents such as atropine, benzatropine, linoethyl)carbamoyl-pyrimidine, and (S)-2-(2-hydroxym biperiden, cyclopentolate, oxybutinin, orphenadine, glyco 25 ethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzy pyrronium, glycopyrrolate, procyclidine, propantheline, lamino)-5N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl-py propiverine, tiotropium, trihexyphenidyl, tropicamide, tros rimidine); pium, ipratropium bromide and oxitroprium bromide; 20) antidepressants such as tricyclic and tetracyclic anti 7) leukotriene receptor antagonists such as montelukast depressants including amineptine, amitriptyline, amoxapine, and Zafirlukast; 30 butriptyline, cianopramine, clomipramine, dosulepin, dox 8) anti-allergics such as ketotifen; epin, trimipramine, clomipramine, lofepramine, nortrip 9) anti-emetics such as bestahistine, dolasetron, nabilone, tyline, tricyclic and tetracyclic amitryptiline, amoxapine, prochlorperazine, ondansetron, trifluoperazine, tropisetron, butriptyline, clomipramine, demexiptiline, desipramine, domperidone, hyoscine, cinnarizine, metoclopramide, cycl dibenzepin, dimetacrine, dothiepin, doxepin, imipramine, izine, dimenhydrinate and promethazine; 35 iprindole, levoprotiline, lofepramine, maprotiline, meli 10) hormonal drugs (including hormone analogues) Such tracen, metapramine, mianserin, mirtazapine, nortryptiline, as lanreotide, octreotide, insulin, pegvisomant, protirelin, opipramol, propizepine, protriptyline, quinupramine, Setip thyroxine, Salcotonin, Somatropin, tetracosactide, vasopres tiline, tianeptine and trimipramine; selective serotonin and sin and desmopressin; noradrenaline reuptake inhibitors (SNRIs) including clovox 11) sympathomimetic drugs such as adrenaline, nora 40 amine, dulloxetine, milnacipran and Venlafaxine; selective drenaline, dexamfetamine, dipirefin, dobutamine, dopexam serotonin reuptake inhibitors (SSRIs) including citalopram, ine, phenylephrine, isoprenaline, dopamine, pseudoephed escitalopram, femoxetine, fluoxetine, fluvoxamine, ifox rine, tramaZoline and Xylometazoline; etine, milnacipran, nomifensine, Oxaprotiline, paroxetine, 12) opioids, preferably for pain management, such as Sertraline, Sibutramine, Venlafaxine, Vicqualine and buprenorphine, dextromoramide, dextropropoxypene, 45 Zimeldine; selective noradrenaline reuptake inhibitors (NA diamorphine, codeine, dextropropoxyphene, dihydroco RIS) including demexiptiline, desipramine, Oxaprotiline and deine, hydromorphone, papaveretum, pholcodeine, loper reboxetine; noradrenaline and selective serotonin reuptake amide, fentanyl, methadone, morphine, oxycodone, inhibitors (NASSAs) including mirtazapine; monoamine phenazocine, pethidine, tramadol and combinations thereof oxidase inhibitors (MAOIs) including amiflamine, bro with an anti-emetic; 50 faromine, clorgyline, C.-ethyltryptamine, etoperidone, ipro 13) analgesics such as aspirin and other salicylates, par clozide, iproniazid, isocarboxazid, mebanazine, medifoXam acetamol, clonidine, codine, coproxamol, ergotamine, gaba ine, moclobemide, nialamide, pargyline, phenelzine, pentin, pregabalin, Sumatriptan, and non-steroidal anti-in pheniprazine, pirlindole, procarbazine, rasagiline, Safrazine, flammatory drugs (NSAIDs) including celecoxib, etodolac, Selegiline, toloxatone and tranylcypromine; muscarinic etoricoxib and meloxicam, 55 antagonists including benactyzine and dibenzepin; 14) acetylcholinesterase inhibitors such as donepezil, aZaspirones including buspirone, gepirone, ipsapirone, tan galantamine and rivastigmine; doSpirone and tiaspirone; and other antidepressants includ 15) immunomodulators such as interferon (e.g. interferon ing ameSergide, amineptine, benactyzine, bupropion, car beta-la and interferon beta-1b) and glatiramer; bamazepine, fezolamine, flupentiXol, levoprotiline, 16) NMDA receptor antagonists such as mementine; 60 maprotiline, medifoxamine, methylphenidate, minaprine, 17) hypoglycaemics Such as Sulphonylureas including nefazodone, nomifensine, oxafloZane, oxitriptan, rolipram, glibenclamide, gliclazide, glimepiride, glipizide and gliqui Sibutramine, teniloxazine, tianeptine, tofenacin, traZadone, done, biguanides including metformin, thiazolidinediones tryptophan, Viloxazine, and lithium salts; including pioglitaZone, rosiglitaZone, nateglinide, repaglin 21) serotonin agonists such as 2-methyl serotonin, bus ide and acarbose; 65 pirone, ipsaperone, tiaspirone, gepirone, lysergic acid dieth 18) narcotic agonists and opiate antidotes such as nalox ylamide, ergot alkaloids, 8-hydroxy-(2-N,N-dipropy one, and pentazocine; lamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2- US 9,642,800 B2 11 12 aminopropane, cisapride, Sumatriptan, lorazepam, clonazepam, clobazam, primidone, lamotrigine, m-chlorophenylpiperazine, traZodone, Zacopride and meza levetiracetam, topiramate, gabapentin, pregabalin, copride; vigabatrin, tiagabine, acetazolamide, ethoSuximide and 22) serotonin antagonists including ondansetron, granis piracetam; etron, metoclopramide, tropisetron, dolasetron, 35) angiotensin converting enzyme inhibitors such as trimethobenzamide, methysergide, risperidone, ketanserin, captopril, cilaZapril, enalapril, fosinopril, imidapril hydro ritanserin, clozapine, amitryptiline, R(+)-O-(2,3-dimethoxy chloride, lisinopril, moexipril hydrochloride, perindopril, phenyl)-12-(4-fluorophenyl)ethyl-4-piperidine-methanol, quinapril, ramipril and trandolapril; aZatadine, cyproheptadine, fenclonine, dexfenfluramine, 36) angiotension II receptor blockers, such as candesar fenfluramine, chlorpromazine and mianserin; 10 23) adrenergic agonists including methoxamine, meth tan, cilexetil, eprosartan, irbesartan, losartan, olmesartan pentermine, metaraminol, mitodrine, clonidine, apracloni medoxomil, telmisartan and Valsartan; dine, guanfacine, guanabenZ, methyldopa, amphetamine, 37) calcium channel blockers such as amlodipine, bepri methamphetamine, epinephrine, norepinephrine, ethylnor dil, diltiazem, felodipine, flunarizine, isradipine, lacidipine, epinephrine, phenylephrine, ephedrine, pseudo-ephedrine, 15 lercanidipine, nicardipine, nifedipine, nimodipine and Vera methylphenidate, pemoline, naphazoline, tetrahydrozoline, pamil; oxymetazoline, Xylometazoline, phenylpropanolamine, phe 38) alpha-blockers such as indoramin, doxazosin, pra nylethylamine, dopamine, dobutamine, colterol, isoprotere Zosin, teraZosin and moxisylate; nol, isotharine, metaproterenol, terbutaline, metaraminol, 39) antiarrhythmics Such as adenosine, propafenone, ami tyramine, hydroxyamphetamine, ritodrine, prenalterol, dodarone, flecainide acetate, quinidine, lidocaine hydrochlo albuterol, isoetharine, pirbuterol, bitolterol, fenoterol, for ride, mexiletine, procainamide and disopyramide; moterol, procaterol, Salmeterol, mephenterine and propyl 40) anti-clotting agents such as aspirin, heparin and low hexedrine; molecular weight heparin, epoprostenol, dipyridamole, 24) adrenergic antagonists such as phenoxybenzamine, clopidogrel, alteplase, reteplase, Streptokinase, tenecteplase, phentolamine, tolazoline, prazosin, teraZosin, doxazosin, 25 certoparin, heparin calcium, enoxaparin, dalteparin, danap trimaZosin, yohimbine, ergot alkaloids, labetalol, ketanserin, aroid, fondaparin, lepirudin, bivalirudin, abciximab, eptifi urapidil, alfuzosin, bunaZosin, tamsulosin, chlorpromazine, batide, tirofiban, tinzaparin, warfarin, lepirudin, phenindi haloperidol, phenothiazines, butyrophenones, propranolol. one and acenocoumarol; nadolol, timolol, pindolol, metoprolol, atenolol, esmolol. 41) potassium channel modulators such as nicorandil, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, 30 cromakalim, diaZOxide, glibenclamide, levcromakalim, carvedilol, medroxalol, naftopidil, bucindolol, levobunolol, minoxidil and pinacidil; metipranolol, bisoprolol, nebivolol, betaxolol, carteolol. 42) cholesterol-lowering drugs such as colestipol, celiprolol, Sotalol, propafenone and indoramin; colestyramine, bezafibrate, fenofibrate, gemfibrozil, ciprofi 25) adrenergic neurone blockers such as bethanidine, brate, rosuvastatin, simvastatin, fluvastatin, atorvastatin, debrisoquine, guabenXan, guanadrel, guanaZodine, 35 pravastatin, eZetimibe, ispaghula, nictotinic acid, acipimox guanethidine, guanoclor and guanoxan; and omega-3 triglycerides; 26) benzodiazepines Such as alprazolam, bromazepam, 43) diuretics Such as bumetanide, furosemide, torasemide, brotizolam, chlordiazepoxide, clobazam, clonazepam, clo spironolactone, amiloride, bendroflumethiazide, chlortali razepate, demoxepam, diazepam, estazolam, flunitrazepam, done, metolaZone, indapamide and cyclopenthiazide; flurazepam, halazepam, ketazolam, loprazolam, lorazepam, 40 44) Smoking cessation drugs such as nicotine and bupro lormetazepam, medazepam, midazolam, nitrazepam, nor pion; dazepam, oxazepam, praZepam, quaZepam, temazepam and 45) bisphosphonates such as alendronate sodium, Sodium triazolam; clodronate, etidronate disodium, ibandronic acid, pamidro 27) mucolytic agents such as N-acetylcysteine, recombi nate disodium, isedronate Sodium, tiludronic acid and Zole nant human DNase, amiloride, dextrans, heparin, desul 45 dronic acid; phated heparin and low molecular weight heparin; 46) dopamine agonists Such as amantadine, bromocrip 28) antibiotic and antibacterial agents such as metronida tine, pergolide, cabergoline, lisuride, ropinerole, pramipex Zole, Sulphadiazine, triclosan, neomycin, amoxicillin, ole and apomorphine; amphotericin, clindamycin, aclarubicin, dactinomycin, nys 47) nucleic-acid medicines Such as oligonucleotides, tatin, mupirocin and chlorhexidine; 50 decoy nucleotides, antisense nucleotides and other gene 29) anti-fungal drugs such as caspofungin, Voriconazole, based medicine molecules; polyene antibiotics including amphotericin, and nystatin, 48) antipsychotics Such as: dopamine antagonists includ imidazoles and triazoles including clotrimazole, econazole ing chlorpromazine, prochlorperazine, fluiphenazine, triflu nitrate, fluconazole, ketoconazole, itraconazole, terbinafine operazine and thioridazine; phenothiazines including ali and miconazole; 55 phatic compounds, piperidines and piperazines; 30) antivirals such as oseltamivir, Zanamivir, amantadine, thioxanthenes, butyrophenones and Substituted benzamides; inosine pranobex and palivizumab, DNA polymerase inhibi atypical antipsychotics including clozapine, risperidone, tors including aciclovir, adefovir and Valaciclovir, nucleo olanzapine, quetiapine, Ziprasidone, Zotepine, amisulpride side analogues including famiciclovir, penciclovir and and aripiprazole; and idoxuridine and interferons; 60 49) pharmaceutically acceptable salts or derivatives of 31) vaccines: any of the foregoing. 32) immunoglobulins; In preferred embodiments of the present invention, the 33) local anaesthetics such as amethocaine, bupivacaine, active agent is heparin (fractionated and unfractionated), hydrocortisone, methylprednisolone, prilocaine, proxymeta apomorphine, clobazam, clomipramine or glycopyrrolate. caine, ropivacaine, tyrothricin, benzocaine and lignocaine; 65 In addition, the active agents used in the present invention 34) anticonvulsants such as Sodium valproate, carbam may be small molecules, proteins, carbohydrates or mixtures azepine, oXcarbazepine, phenytoin, fosphenytoin, diazepam, thereof. US 9,642,800 B2 13 14 The term co-milling is used herein to refer to a range of micronised form (i.e. <10 Lum). The only physical change methods, including co-micronising methods, some examples which may be observed is a plastic deformation of the of which are outlined below. In the prior art, co-milling or particles to a rounder shape. co-micronising active agents or excipients with additive However the most preferred milling techniques include materials has been suggested. 5 those described in R. Pfeffer et al. “Synthesis of engineered It is stated that milling can be used to Substantially particulates with tailored properties using dig particle coat decrease the size of particles of active agent. However, if the ing, Powder Technology 117 (2001) 40-67. These include particles of active agent are already fine, for example have processes using the MechanoFusion(R) machine, the a MMAD of less than 20 um prior to the milling step, the Hybidizer(R) machine, the Theta Composer R, magnetically size of those particles may not be significantly reduced 10 assisted impaction processes and rotating fluidised bed coat where the milling of these active particles takes place in the ers. Cyclomix methods may also be used. presence of an additive material. Rather, milling of fine Preferably, the technique employed to apply the required active particles with additive particles using the methods mechanical energy involves the compression of a mixture of described in the prior art (for example, in the earlier patent particles of the dispersing agent and particles of the phar application published as WO 02/43701) will result in the 15 maceutically active agent in a nip formed between two additive material becoming deformed and being Smeared portions of a milling machine, as is the case in the Mecha over or fused to the surfaces of the active particles. The noFusion(R) and Cyclomix devices. Some preferred milling resultant composite active particles have been found to be methods will now be described in greater detail: less cohesive following the milling treatment. MechanoFusion(R): The prior art mentions two types of processes in the As the name Suggests, this dry coating process is designed context of co-milling or co-micronising active and additive to mechanically fuse a first material onto a second material. particles. First, there is the compressive type process, Such The first material is generally smaller and/or softer than the as Mechanofusion and the Cyclomix and related methods second. The MechanoFusion and Cyclomix working prin such as the Hybridiser or the Nobilta. As the name suggests, ciples are distinct from alternative milling techniques in Mechanofusion is a dry coating process designed to 25 having a particular interaction between inner element and mechanically fuse a first material onto a second material. vessel wall, and are based on providing energy by a con The first material is generally smaller and/or softer than the trolled and substantial compressive force. second. The principles behind the Mechanofusion and The fine active particles and the particles of dispersing Cyclomix processes are distinct from those of alternative agent are fed into the MechanoFusion driven vessel, where milling techniques in that they have a particular interaction 30 they are subject to a centrifugal force and are pressed against between an inner element and a vessel wall, and in that they the vessel inner wall. The powder is compressed between the are based on providing energy by a controlled and substan fixed clearance of the drum wall and a curved inner element tial compressive force. with high relative speed between drum and element. The The fine active particles and the additive particles are fed inner wall and the curved element together form a gap or nip into the Mechanofusion driven vessel (such as a Mechano 35 in which the particles are pressed together. As a result the fusion system (Hosokawa Micron Ltd)), where they are particles experience very high shear forces and very strong Subject to a centrifugal force which presses them against the compressive stresses as they are trapped between the inner vessel inner wall. The inner wall and a curved inner element drum wall and the inner element (which has a greater together form a gap or nip in which the particles are pressed curvature than the inner drum wall). The particles violently together. The powder is compressed between the fixed 40 collide against each other with enough energy to locally heat clearance of the drum wall and a curved inner element with and soften, break, distort, flatten and wrap the particles of high relative speed between drum and element. As a result, dispersing agent around the core particle to form a coating. the particles experience very high shear forces and very The energy is generally Sufficient to break up agglomerates strong compressive stresses as they are trapped between the and some degree of size reduction of both components may inner drum wall and the inner element (which has a greater 45 occur. Embedding and fusion of additive particles of dis curvature than the inner drum wall). The particles are persing agent onto the active particles may occur, and may pressed against each other with enough energy to locally be facilitated by the relative differences in hardness (and heat and soften, break, distort, flatten and wrap the additive optionally size) of the two components. Either the outer particles around the active particles to form coatings. The vessel or the inner element may rotate to provide the relative energy is generally sufficient to break up agglomerates and 50 movement. The gap between these surfaces is relatively Some degree of size reduction of both components may Small, and is typically less than 10 mm and is preferably less occur. Whilst the coating may not be complete, the than 5 mm, more preferably less than 3 mm. This gap is deagglomeration of the particles during the process ensures fixed, and consequently leads to a better control of the that the coating may be substantially complete, covering the compressive energy than is provided in Some other forms of majority of the surfaces of the particles. 55 mill such as ball and media mills. Also, in general, no These Mechanofusion and Cyclomix processes apply a impaction of milling media Surfaces is present so that wear high enough degree of force to separate the individual and consequently contamination are minimised. The speed particles of active material and to break up tightly bound of rotation may be in the range of 200 to 10,000 rpm. A agglomerates of the active particles Such that effective scraper may also be present to break up any caked material mixing and effective application of the additive material to 60 building up on the vessel Surface. This is particularly advan the surfaces of those particles is achieved. tageous when using fine cohesive starting materials. The An especially desirable aspect of the described co-milling local temperature may be controlled by use of a heating/ processes is that the additive material becomes deformed cooling hacked built into the drum vessel walls. The powder during the milling and may be Smeared over or fused to the may be re-circulated through the vessel. surfaces of the active particles. However, in practice, this 65 Cyclomix Method (Hosokawa Microm): compression process produces little or no size reduction of The cyclomix comprises a stationary conical vessel with the drug particles, especially where they are already in a a fast rotating shaft with paddles which move close to the US 9,642,800 B2 15 16 wall. Due to the high rotational speed of the paddles, the that are similar or related to all of those methods described powder is propelled towards the wall, and as a result the above. For example, methods similar to Mechanofusion are mixture experiences very high shear forces and compressive encompassed, such as those utilizing one or more very stresses between wall and paddle. Such effects are similar to high-speed rotors (i.e. 2000 to 50000 rpm) with blades or those in MechanoFusion as described above and may be 5 other elements Sweeping the internal Surfaces of the vessels sufficient to locally heat and soften, to break, distort, flatten with small gaps between wall and blade (i.e. 0.1 mm to 20 and wrap the particles of dispersing agent around the active mm). Conventional methods comprising co-milling active particles to form a coating. The energy is sufficient to break material with additive materials (as described in WO up agglomerates and some degree of size reduction of both 02/43701) are also encompassed. These methods result in components may also occur depending on the conditions and 10 composite active particles comprising ultra-fine active par upon the size and nature of the particles. ticles with an amount of the additive material on their Hybridiser R. Method: Surfaces. This is a dry process which can be described as a product Thus, the milling methods used in the present invention embedding or filming of one powder onto another. The fine are simple and cheap compared to the complex previous active particles and fine or ultra fine particles of dispersing 15 attempts to engineer particles, providing practical as well as agent are fed into a conventional high shear mixer pre-mix cost benefits. A further benefit associated with the present system to form an ordered mixture. This powder is then fed invention is that the powder processing steps do not have to into the Hybridiser. The powder is subjected to ultra-high involve organic solvents. Such organic solvents are common speed impact, compression and shear as it is impacted by to many of the known approaches to powder processing and blades on a high speed rotor inside a stator vessel, and is are known to be undesirable for a variety of reasons. re-circulated within the vessel. The active and additive In the past, jet milling has been considered less attractive particles collide with each other. Typical speeds of rotation for co-milling active and additive particles in the preparation are in the range of 5,000 to 20,000 rpm. The relatively soft of powder formulations to be dispensed using passive fine particles of dispersing agent experience Sufficient devices, with compressive processes like or related to impact force to soften, break, distort, flatten and wrap 25 Mechanofusion and Cyclomixing being preferred. The col around the active particle to form a coating. There may also lisions between the particles in a jet mill are somewhat be some degree of embedding into the surface of the active uncontrolled and those skilled in the art, therefore, consid particles. ered it unlikely that this technique would be able to provide The second of the types of processes mentioned in the the desired deposition of a coating of additive material on prior art is the impact milling processes. Such impact milling 30 the surface of the active particles. is involved, for example, in ball milling, jet milling and the Moreover, it was believed that, unlike the situation with use of a homogeniser. compressive type processes such as Mechanofusion and Ball milling is a milling method used in many of the prior Cyclomixing, segregation of the powder constituents art co-milling processes. Centrifugal and planetary ball occurred in jet mills, such that the finer particles, that were milling are especially preferred methods. 35 believed to be the most effective, could escape from the Jet mills are capable of reducing Solids to particle sizes in process. In contrast, it could be clearly envisaged how the low-micron to Submicron range. The grinding energy is techniques such as Mechanofusion would result in the created by gas streams from horizontal grinding air nozzles. desired coating. Particles in the fluidised bed created by the gas streams are However, more recently, jet milling has been shown to be accelerated towards the centre of the mill, colliding with 40 an attractive process for co-milling active and additive slower moving particles. The gas streams and the particles particles, especially for preparing powder formulations that carried in them create a violent turbulence and, as the are to be used in active devices (see the disclosure in the particles collide with one another, they are pulverized. earlier patent application published as WO 2004/001628). High pressure homogenisers involve a fluid containing the It should also be noted that it was also previously believed particles being forced through a valve at high pressure, 45 that the compressive or impact milling processes must be producing conditions of high shear and turbulence. Suitable carried out in a closed system, in order to prevent segrega homogenisers include EmulsiFlex high pressure homoge tion of the different particles. This has also been found to be nisers which are capable of pressures up to 4000 bar, Niro untrue and the co-milling processes used in the present Soavi high pressure homogenisers (capable of pressures up invention do not need to be carried out in a closed system. to 2000 bar) and Micro fluidics Microfluidisers (maximum 50 In an open system, the co-jet milling has Surprisingly been pressure 2750 bar). found not to result in the loss of the small particles, even Milling may, alternatively, involve a high energy media when using leucine as the additive material. Leucine was mill or an agitator bead mill, for example, the Netzsch high previously considered to present something of a problem energy media mill, or the DYNO-mill (Willy A. Bachofen when co-jet milled. AG, Switzerland). 55 Further, co-jet milling at lower pressures can produce All of these processes create high-energy impacts powders which perform well in passive devices whilst between media and particles or between particles. In prac powders milled at higher pressures may perform better in tice, while these processes are good at making very small active devices, such as AspirairTM. particles, it has been found that the ball mill, jet mill and the The co-milling processes can be specifically selected for homogenizer were not as effective in producing dispersion 60 the active and carrier particles. For example, the active improvements in resultant drug powders as the compressive particles may be co-jet milled or homogenized with the type processes. It is believed that the impact processes additive, whilst the carrier particles may be mechanofused discussed above are not as effective in producing a coating with the additive. of additive material on each particle as the compressive type The co-milling processes according to the present inven processes. 65 tion may be carried out in two or more stages, to provide For the purposes of this invention, all forms of co-milling beneficial effects. Various combinations of types of co and co-micronisation are encompassed, including methods milling and/or additive material may be used, in order to US 9,642,800 B2 17 18 obtain advantages. Within each step, multiple combinations solisation efficiency. However, this powder had poor flow of co-milling and other processing steps may be used. properties, and was not easily handled, giving high device For example, milling at different pressures and/or differ retention. ent types of milling or blending processes may be combined. The use of multiple steps allows one to tailor the properties of the milled particles to suit a particular inhaler device, a FPF FPD ED particular drug and/or to target particular parts of the lung. Formulation (ED) (mg) (mg) Method In one embodiment of the present invention, the milling Budesonide:magnesium 7396 1.32 1.84 MSLI process is a two-step process comprising first jet milling the stearate (5% w/w) 10 Budesonide:magnesium 80% 1.30 1.63 TSI drug on its own at Suitable grinding pressure to obtain the stearate (10% w/w) required particle sizes. Next, the milled drug is co-milled with an additive material. Preferably, this second step is carried out at a lower grinding pressure, so that the effect Example 2 achieved is the coating of the small active particles with the 15 additive material. This two-step process may produce better Mechanofused Budesonide with Fine Lactose and results than simply co-milling the active material and addi tive material at a high grinding pressure. Magnesium Stearate The same type of two-step milling process can be carried A further study was conducted to look at the Mechano out with the carrier particles, although these particles, as a fusion of a drug with both a force control agent and fine rule, do not have to be milled to such small particle sizes. lactose particles. The additive or force control agent used In another embodiment of the present invention, the was magnesium Stearate (AVocado) and the fine lactose was composite particles, which may optionally have been pro Sorbolac 400 (Meggle). The drug used was micronised duced using the two-step co-milling process discussed budesonide. above, Subsequently undergo Mechanofusion. This final 25 The blends were prepared by Mechanofusion of all three Mechanofusion step may “polish the composite particles, components together using the Hosokawa AMS-MINI, further rubbing the additive material into the particles. This blending was carried out for 60 minutes at approximately provides beneficial properties afforded by Mechanofusion, 4000 rpm. in combination with the very Small particles sizes made Formulations were prepared using the following concen possible by the co jet milling. Such an additional Mecha 30 trations of budesonide, magnesium Stearate and Sorbolac nofusion step is particularly attractive for composite active 400: particles, especially where they are very Small. 5% w/w budesonide, 6% w/w magnesium stearate, 89% The reduction in particle size may be increased by car w/w Sorbolac 400; and rying out the co-jet milling at lower temperatures. Whilst the 35 20% w/w budesonide, 6% w/w magnesium stearate, 74% co jet milling process may be carried out at temperatures w/w Sorbolac 400. between -20° C. and 40° C., the particles will tend to be TSIs and MSLIs were performed on the blends. The more brittle at lower temperatures and they therefore frac results, which are Summarised below, indicate that, as the ture more readily so that the milled particles tend to be even amount of budesonide in the blends increased, the FPF smaller. Therefore, in another embodiment of the present 40 results increased. Device and capsule retention were notably invention, the jet milling is carried out attemperatures below low in these dispersion tests (<5%), however a relatively room temperature, preferably at a temperature below 10°C., large level of magnesium Stearate was used and this was more preferably at a temperature below 0°C. applied over the entire composition. The benefits of the methods according to the present 45 invention are illustrated by the experimental data set out FPF(ED) FPF(ED) below. Formulation (TSI) (MSLI) COMPARATIVE EXAMPLES 5:6:89 66.0% 70.1% 20:6:74 75.8% Example 1 50 As an extension to this work, different blending methods Mechanofused Budesonide with Magnesium of budesonide, magnesium stearate and Sorbolac 400 were Stearate investigated further. Two formulations were prepared in the Glen Creston Grindomix. This mixer is a conventional This example studied magnesium Stearate processed with 55 food-processor style bladed mixer, with 2 parallel blades. budesonide. The blends were prepared by Mechanofusion The first of these formulations was a 5% w/w budesonide, using the Hosokawa AMS-MINI, with blending being car 6% w/w magnesium stearate, 89% w/w Sorbolac 400 blend ried out for 60 minutes at approximately 4000 rpm. prepared by mixing all components together at 2000 rpm for The magnesium Stearate used was a standard grade Sup 20 minutes. The formulation was tested by TSI and the plied by Avocado Research Chemicals Ltd. The drug used 60 results, when compared to those for the mechanofused was micronised budesonide. The powder properties were blends, showed the Grindomix blend to give lower FPF tested using the Miat Monohaler. results (see table below). Blends of budesonide and magnesium Stearate were pre The second formulation was a blend of 90% w/w of pared at different weight percentages of magnesium Stearate. mechanofused magnesium stearate:Sorbolac 400 (5:95) pre Blends of 5% w/w and 10% w/w, were prepared and then 65 blend and 10% w/w budesonide blended in the Grindomix tested. MSLIs and TSIs were carried out on the blends. The for 20 minutes. The formulation was tested by TSI and results, which are summarised below, indicate a high aero MSLI. US 9,642,800 B2 19 20 It was also observed that this formulation had notably EXAMPLES OF THE INVENTION good flow properties for a material comprising such fine particles. This is believed to be associated with the Mecha Example 5 nofusion process. Mechanofused Apomorphine and Mechanofused Fine Lactose FPF (ED) FPF Formulation (TSI) (MSLI) Firstly, 15 g of micronised apomorphine and 0.75 g. leucine are weighed into the Hosokawa AMS-MINI Mecha Grindomix 5:6:89% 57.7 nofusion system via a funnel attached to the largest port in Grindomix 10% budesonide 65.9 69.1 10 the lid with the equipment running at 3.5%. The port is (Mechanofused pre-blend) sealed and the cooling water Switched on. The equipment is run at 20% for 5 minutes followed by 80% for 10 minutes. The equipment is then switched off, dismantled and the Example 3 resulting formulation recovered mechanically. 15 Next, 19 g of Sorbolac 400 lactose and 1 g leucine are Mechanofused Salbutamol with Fine Lactose and weighed into the Hosokawa AMS-MINI Mechanofusion Magnesium Stearate system via a funnel attached to the largest port in the lid with the equipment running at 3.5%. The port is sealed and the cooling water switched on. The equipment is run at 20% for A further study was conducted to look at the Mechano 5 minutes followed by 80% for 10 minutes. The equipment fusion of an alternative drug with both a force control agent is switched off, dismantled and the resulting formulation and fine lactose particles. The additive or force control agent recovered mechanically. used was magnesium Stearate and the fine lactose was 4.2 g of the apomorphine-based material and 15.8g of the Sorbolac 400 (Meggle). The drug used was micronised Sorbolac-based material are combined in a high shear mixer salbutamol sulphate. The blends were prepared by Mecha 25 for 5 minutes, and the resulting powder is then passed nofusion using the Hosokawa AMS-MINI, blending for 10 through a 300 micron sieve to form the final formulation. 2 minutes at approximately 4000 rpm. mg of the powder formulation are filled into blisters and Formulations prepared were: fired from an Aspirair device into an NGI. An FPF of over 20% w/w salbutamol, 5% w/w magnesium stearate, 75% 50% was obtained with MMAD 1.5 microns, illustrating this w/w Sorbolac 400; and system gave a very good dispersion. The device retention 20% w/w salbutamol, 2% w/w magnesium stearate, 78% 30 was also very low, with only—1% left in the device and 7% w/w Sorbolac 400. in the blister. NGIs were performed on the blends and the results are set out below. Device and capsule retention were again low in Example 6 these dispersion tests (<10%). 35 Mechanofused Clomipramine and Mechanofused Fine Lactose Formulation FPF (ED) FPF (ED) Firstly, 20 g of a mix comprising 95% micronised clo 20:5:75 80% 74% mipramine and 5% magnesium Stearate are weighed into the 20:2:78 78% 70% 40 Hosokawa AMS-MINI Mechanofusion system via a funnel attached to the largest port in the lid with the equipment running at 3.5%. The port is sealed and the cooling water Example 4 switched on. The equipment is run at 20% for 5 minutes followed by 80% for 10 minutes. The equipment is then Preparation of Mechanofused Formulation for Use 45 switched off, dismantled and the resulting formulation in a Passive Device recovered mechanically. Next, 20g of a mix comprising 99% Sorbolac 400 lactose 20 g of a mix comprising 20% micronised clomipramine, and 1% magnesium Stearate are weighed into the Hosokawa 78% Sorbolac 400 (fine lactose) and 2% magnesium stearate AMS-MINI Mechanofusion system via a funnel attached to were weighed into the Hosokawa AMS-MINI Mechanofu 50 the largest port in the lid with the equipment running at sion system via a funnel attached to the largest port in the lid 3.5%. The port is sealed and the cooling water switched on. with the equipment running at 3.5%. The port was sealed The equipment is run at 20% for 5 minutes followed by 80% and the cooling water Switched on. The equipment was run for 10 minutes. The equipment is switched off, dismantled at 20% for 5 minutes followed by 80% for 10 minutes. The and the resulting formulation recovered mechanically. equipment was Switched off, dismantled and the resulting 55 4 g of the clomipramine-based material and 16 g of the formulation recovered mechanically. Sorbolac-based material are combined in a high shear mixer 20 mg of the collected powder formulation was filled into for 10 minutes, to form the final formulation. 20 mg of the size 3 capsules and fired from a Miat Monohaler into an powder formulation are filled into size 3 capsules and fired NGI. The FPF measured was good, being greater than 70%. from a Miat Monohaler into an NGI. The data above Suggest that magnesium Stearate content 60 in the region 5-20% yielded the greatest dispersibility. Example 7 Above these levels, experience Suggests significant sticking inside the device could occur, and the quantities used Mechanofused Theophylline and Mechanofused became unnecessary for further performance improvement. Fine Lactose Fine particle fraction values were consistently obtained in 65 the range 50 to 60%, and doubled in comparison with Firstly, 20 g of a mix comprising 95% micronised the controls containing no magnesium Stearate. ophylline and 5% magnesium Stearate are weighed into the US 9,642,800 B2 21 22 Hosokawa AMS-MINI Mechanofusion system via a funnel The equipment is run at 20% for 5 minutes followed by 80% attached to the largest port in the lid with the equipment for 10 minutes. The equipment is switched off, dismantled running at 3.5%. The port is sealed and the cooling water and the resulting formulation recovered mechanically. switched on. The equipment is run at 20% for 5 minutes 4 g of the drug based material and 16 g of the Sorbolac followed by 80% for 10 minutes. The equipment is then based material are combined in a high shear mixer for 10 switched off, dismantled and the resulting formulation minutes, to form the final formulation. recovered mechanically. 20 mg of the powder formulation is filled into size 3 Next, 20g of a mix comprising 99% Sorbolac 400 lactose capsules and fired from a Miat Monohaler into an NGI. and 1% magnesium Stearate are weighed into the Hosokawa The results of these experiments are expected to show that AMS-MINI Mechanofusion system via a funnel attached to 10 the powder formulations prepared using the method accord the largest port in the lid with the equipment running at ing to the present invention exhibit further improved prop 3.5%. The port is sealed and the cooling water switched on. erties such as FPD, FPF, as well as good flow and reduced The equipment is run at 20% for 5 minutes followed by 80% device retention and throat deposition. for 10 minutes. The equipment is switched off, dismantled In accordance with the present invention, the '% w/w of and the resulting formulation recovered mechanically. 15 additive material will typically vary. Firstly, when the addi 4 g of the theophylline-based material and 16 g of the tive material is added to the drug, the amount used is Sorbolac-based material are combined in a high shear mixer preferably in the range of 0.1% to 50%, more preferably 1% for 10 minutes, to form the final formulation. 20 mg of the to 20%, more preferably 2% to 10%, and most preferably 3 powder formulation are filled into size 3 capsules and fired to 8%. Secondly, when the additive material is added to the from a Miat Monohaler into an NGI. carrier particles, the amount used is preferably in the range The active agent used in this example, theophylline, may of 0.01% to 30%, more preferably of 0.1% to 10%, prefer be replaced by other phosphodiesterase inhibitors, including ably 0.2% to 5%, and most preferably 0.5% to 2%. The phosphodiesterase type 3, 4 or 5 inhibitors, as well as other non-specific ones. amount of additive material preferably used in connection 25 with the carrier particles will be heavily dependant upon the Example 8 size and hence Surface area of these particles. Example 10 Jet Milled Clomipramine and Mechanofused Fine Lactose Lactose Study 30 20 g of a mix comprising 95% micronised clomipramine A study was conducted to characterize the changes in the and 5% magnesium Stearate are co-jet milled in a Hosokawa properties of fine carrier particles, and of ultra-fine drug AS50 jet mill. particles, when they are co-milled with an additive material. 20g of a mix comprising 99% Sorbolac 400 (fine lactose) Micronised ultra-fine lactose was selected as a model for and 1% magnesium Stearate are weighed into the Hosokawa 35 a drug, as it is readily available in a micronised form and it AMS-MINI Mechanofusion system via a funnel attached to carries a reduced hazard compared to handling pharmaceu the largest port in the lid with the equipment running at tically active Substances. Ultra-fine lactose is also regarded 3.5%. The port is sealed and the cooling water switched on. as a particularly cohesive material, hence improving its The equipment is run at 20% for 5 minutes followed by 80% dispersibility represents a severe challenge. for 10 minutes. The equipment is switched off, dismantled 40 Meggle Sorbolac 400 and Meggle Extra Fine were and the resulting formulation recovered mechanically. selected as the fine carrier grades, as these are readily 4 g of the clomipramine-based material and 16 g of the available. However other lactose grades can be used, such as Sorbolac-based material are combined in a high shear mixer those produced by DMV. Borculo, Foremost and other for 10 minutes, to form the final formulation. 20 mg of the Suppliers, or a grade custom-made for the purpose, as long powder formulation are filled into size 3 capsules and fired 45 as it conforms to the size range indicated. from a Miat Monohaler into an NGI. The literature reveals various possible types of tests, A number of micronised drugs were co-jet milled with including measuring powder flow, powder cohesion, powder magnesium Stearate for the purposes of replacing the clo shear and powder dustiness. mipramine in this example. These micronised drugs In the first instance, several basic powder characteristics included budesonide, formoterol, Salbutamol, glycopyrro 50 were tested. These were porosity and Surface area using the late, heparin, insulin and clobazam. Further compounds are Coulter SA 3100 BET system, and particle size, which was considered Suitable, including the classes of active agents measured using a Mastersizer 2000, manufactured by and the specific examples listed above. Malvern Instruments, Ltd. (Malvern, UK). This was fol lowed by examining several standard powder properties Example 9 55 using the Hosokawa Powder Tester. Porosity Jet Milled Bronchodilator and Mechanofused Fine The powder porosity was measured using the Coulter SA Lactose 3100 BET system, with the following results. 20g of a mix comprising 95% micronised bronchodilator 60 drug and 5% magnesium Stearate are co jet milled in a Total pore volume Hosokawa AS50 jet mill. Sample (ml/g) 20 g of a mix comprising 99% Sorbolac 400 lactose and Sorbolac O.OO27 1% magnesium Stearate are weighed into the Hosokawa Mechanofused Sorbolac (60 mins) O.OO44 AMS-MINI Mechanofusion system via a funnel attached to 65 Mechanofused Sorbolac and magnesium O.OOS6 the largest port in the lid with the equipment running at stearate (98:2) (60 mins) 3.5%. The port is sealed and the cooling water switched on. US 9,642,800 B2 23 24 -continued carrier according to the present invention, the powders mechnofused with magnesium Stearate show very consider Total pore volume able drops in the angle of repose and the angle of fall, as well Sample (ml/g) as increases in aerated bulk, compared to the raw material Mechanofused Sorbolac and magnesium O.OOS2 (see Tables 1 and 2). Where the powder is mixed using a low stearate (95:5) (60 mins) shear mix, in this study a Turbula mixer was used, none of these changes are observed (see Table 1). Table 3 shows Sorbolac 400 Cyclomixed with magnesium The microporosity of the lactose particles is also shown in Stearate. In these examples, considerable drops in the angle the graph of FIG. 1. Whilst the total pore volume does 10 of repose and the angle of fall are observed, as well as increase significantly upon processing, insufficient differ increases in aerated bulk density. However, these changes ences are seen in the different pore sizes to use porosity are generally slightly less than those observed when the testing as a measure of the process. Therefore, Malvern Sorbolac 400 and magnesium Stearate are mechanofused. particle sizing of a wet powder dispersion was also con This is consistent with the increasing intensity of the pro ducted. The results are summarised below. 15 cessing methods producing increasing levels of effect. Table 4 shows micronised lactose, which in these tests is used to represent a model micronised drug. Unfortunately, Surface Malvern the variability of the results was higher and the data pro Sample Area (m’/g) dso (gm) vided, especially for the angle of repose, the angle of fall for Sorbolac 1.023 8.760 the raw material, was regarded as unreliable. The density Magnesium Stearate 13.404 9.145 increased but was still relatively low. These powders were Mechanofused Sorbolac (60 mins) 1.1.89 7.525 Mechanofused Sorbolac and magnesium 1.562 8.191 observed as being highly cohesive. Even after Mechanofu stearate (98:2) (0 mins) sion only slight improvements were seen, in contrast to the Mechanofused Sorbolac and magnesium 1496 9.112 dramatic visible powder changes for Sorbolac 400 and the stearate (98:2) (60 mins) 25 ultra-fine lactose. Mechanofused Sorbolac and magnesium 2.028 8.281 stearate (95:5) (O mins) Table 5 shows SVO03, a traditional large lactose carrier Mechanofused Sorbolac and magnesium O.961 8.551 material. In this case, the powder mechanofused with mag stearate (95:5) (60 mins) nesium Stearate shows Smaller drops in the angle of repose Extra fine lactose O.798 16.523 and no change in the angle of fall (where it remains at an Mechanofused Extra fine lactose (60 mins) O.714 18.139 30 Mechanofused Extra fine lactose and 195 17.703 already low level in its original state). Similarly, the aerated magnesium stearate (98:2) (60 mins) bulk density increased slightly, but from an already high Cyclomixed Sorbolac (60 mins) 1629 7.894 level. Cyclomixed Sorbolac and magnesium stearate 617 Thus, the results indicate that the co-milled carrier par (98:2) (0 mins) Cyclomixed Sorbolac and magnesium stearate 473 ticles within the preferred size range for the present inven (98:2) (5 mins) 35 tion and co-milled model drug particles showed a tendency Cyclomixed Sorbolac and magnesium stearate 442 to decrease in angle of repose, to increase in bulk density and (98:2) (10 mins) to increase in dispersibility. These properties would be Cyclomixed Sorbolac and magnesium stearate 383 (98:2) (20 mins) anticipated in conjunction with reduced cohesion. This Cyclomixed Sorbolac and magnesium stearate .404 improvement was observed to increase with increasing (98:2) (40 mins) 40 intensity of the co-milling methods and with increasing Cyclomixed Sorbolac and magnesium stearate 425 levels of additive material (magnesium stearate). The result (98:2) (60 mins) Cyclomixed Sorbolac and magnesium stearate 779 is an improvement in performance of a formulation contain (95:5) (O mins) ing this carrier in an inhaler, in terms of improved emitted dose and in terms of improved fine particle dose, especially 45 the fine particle dose of metered dose. Whilst the Surface area does decrease as the processing The metered dose (MD) of a dry powder formulation is time increased, this can probably be explained as being due the total mass of active agent present in the metered form to the magnesium Stearate becoming Smeared over the presented by the inhaler device in question. For example, the Surface. MD might be the mass of active agent present in a capsule Hosokawa Powder Tester 50 for a CyclohalerTM, or in a foil blister in a GyrohalerTM This system measures several different parameters, device. including: angle of repose; aerated bulk density; packed bulk The emitted dose (ED) is the total mass of the active agent density; angle of spatula before and after impact; angle of emitted from the device following actuation. It does not fall; and dispersibility. include the material left on the internal or external surfaces The system then calculates further parameters/indices, 55 of the device, or in the metering system including, for including: angle of difference (repose-fall); compressibility example, the capsule or blister. The ED is measured by (Cans index); average angle of spatula; and uniformity collecting the total emitted mass from the device in an (based on do and do). apparatus frequently identified as a dose uniformity Sam Various powders were tested using this system and the pling apparatus (DUSA), and recovering this by a validated resulting data are Summarised in Tables 1 to 5, shown in 60 quantitative wet chemical assay (a gravimetric method is FIGS. 2 to 6 respectively. possible, but this is less precise). As can be seen from the data, on processing with mag The fine particle dose (FPD) is the total mass of active nesium stearate (MgSt), virtually all of the powders showed agent which is emitted from the device following actuation a tendency to decrease the angle of repose and the angle of which is present in an aerodynamic particle size Smaller than fall, and to increase in bulk density and dispersibility. 65 a defined limit. This limit is generally taken to be 5 um if not For the Sorbolac 400 and the ultra-fine lactose, which are expressly stated to be an alternative limit. Such as 3 um, 2 um within the size range considered suitable for use as the or 1 um, etc. The FPD is measured using an impactor or US 9,642,800 B2 25 26 impinger, Such as a twin stage impinger (TSI), multi-stage an impactor or impinger, using the methods as defined in the impinger (MSI), Andersen Cascade Impactor (ACI) or a European or US Pharmacopoeias. Next Generation Impactor (NGI). Each impactor or SEM impinger has a pre-determined aerodynamic particle size This is a potentially useful method which may be used to collection cut points for each stage. The FPD value is identify powders exhibiting low cohesion, large magnesium obtained by interpretation of the stage-by-stage active agent Stearate agglomerates, and changes in Surface morphology recovery quantified by a validated quantitative wet chemical following processing and/or segregation. assay (a gravimetric method is possible, but this is less Differential Scanning Calorimetry (DSC) & Inverse Gas precise) where either a simple stage cut is used to determine Chromatography (IGC) FPD or a more complex mathematical interpolation of the 10 These techniques may be useful for quantifying the Sur stage-by-stage deposition is used. face energy and production of amorphous material during The fine particle fraction (FPF) is normally defined as the the processing of the powder particles. Amorphous material FPD divided by the ED and expressed as a percentage. is regarded as potentially harmful to the long-term stability Herein, the FPF of ED is referred to as FPF(ED) and is of powder formulations, making them prone to recrystalli calculated as FPF(ED)=(FPD/ED)x100%. 15 sation. The fine particle fraction (FPF) may also be defined as the Powder characterisation parameters such as flowability FPD divided by the MD and expressed as a percentage. indices or forms of Surface characterisation have been Herein, the FPF of MD is referred to as FPF(MD), and is considered. The Hosokawa Powder Tester provided a good calculated as FPF(MD)=(FPD/MD)x100%. test to qualify changes in powder properties. The mechano Flodex Measurement fused powders showed a tendency to decrease in angle of A means of assessing powder flow is to use the FlodexTM repose, increase in bulk density and increase in dispersibil powder tester (Hansen Research). ity. However, as the particles approach the micron size, these The Flodex provides an index, over a scale of 4 to 40 mm, Hosokawa Powder Tester tests were less equivocal. Also, of flowability of powders. The analysis may be conducted by these parameters may not be directly linked to performance placing 50 g of a formulation into the holding chamber of the 25 during aerosolisation. Flodex via a funnel, allowing the formulation to stand for 1 As well as characterizing the drug and fine carrier com minutes, and then releasing the trap door of the Flodex to ponent powders, these Hosokawa Powder Tester tests are open an orifice at the base of the holding chamber. Orifice also helpful in characterizing the final combined formula diameters of 4 to 34 mm can be used to measure the index tion, where the final formulation properties are advanta of flowability. The flowability of a given formulation is 30 geously similar to the properties of the co-milled fine carrier. determined as the smallest orifice diameter through which Consequently, the combined formulation will have good flow of the formulation is smooth. flow properties and provide low device retention. Carr's Index Further, the good dispersibility of the drug component is A formulation may be characterised by its density/ retained, providing high levels of fine particle fraction and flowability parameters and uniformity of distribution of the 35 fine particle dose, as measured by standard in vitro tests. active ingredient. The apparent Volume and apparent density Such improvements are also consistent, providing less vari can be tested according to the method described in the ability in the test results obtained than for traditional for European Pharmacopoeia (Eur, Ph.). mulation approaches. Powder mixtures (100 g) are poured into a glass graduated Another very important advantage of the system of the cylinder and the unsettled apparent volume Vo is read; the 40 present invention is the consistency of the high performance. apparent density before settling (dv) was calculated dividing One of the many benefits of consistency is that it can also the weight of the sample by the volume V. After 1250 taps lead to reduction in adverse side effects experienced, as it with the described apparatus, the apparent Volume after will allow one to administer a smaller total dose than is settling (Viso) is read and the apparent density after settling possible when relying upon conventional levels of inhaler (ds) was calculated. The flowability properties were tested 45 efficiency or other routes of administration. In particular, it according to the method described in the Eur, Ph. allows one to target specific dosing windows wherein the Powder mixtures (about 110 g) are then poured into a dry therapeutic effect is maximised whilst causing the minimum funnel equipped with an orifice of suitable diameter that is side effects. blocked by suitable means. The bottom opening of the According to a second aspect of the present invention, funnel is unblocked and the time needed for the entire 50 formulations which are obtainable by the methods according sample to flow out of the funnel recorded. The flowability is to the first aspect of the invention are provided. expressed in seconds and tenths of seconds related to 100 g In powder compositions of the present invention, at least of sample. Some of the composite particles may be in the form of The flowability can also be evaluated from the Carr's agglomerates, preferably unstable agglomerates. However, index calculated according to the following formula: Carr's 55 when the composite active particles are included in a phar index (%)=((ds-dv)/ds)x100 maceutical composition, the additive material promotes the A Carr index of less than 25 is usually considered indica dispersal of the composite active particles on administration tive of good flowability characteristics. of that composition to a patient, via actuation of an inhaler. The uniformity of distribution of the active ingredient In the turbulence created upon actuation of the inhaler may be evaluated by withdrawing 10 samples, each equiva 60 device, the agglomerates break up, releasing the composite lent to about a single dose, from different parts of the blend. particles of respirable size. The amount of active ingredient of each sample can be The powder particles according to the present invention, determined by High-Performance Liquid Chromatography which may be prepared as described herein, are not “low (HPLC). density' particles, as tend to be favoured in the prior art. Determination of the Aerosol Performances 65 Such low density particles can be difficult and expensive to An amount of powder for inhalation may be tested by prepare. Indeed, previously, those skilled in the art have only loading it into a dry powder inhaler and firing the dose into reported high performance in connection with powder par US 9,642,800 B2 27 28 ticles that have been prepared using fancy processing tech mass resolution and mass range compared to conventional niques such as complex spray drying, which result in low SIMS techniques. SIMS operating in static mode was used density particles. In contrast, the particles of the present to determine the chemical composition of the top monolayer invention are made using very simple and economical of the surface. Under static SIMS conditions, the primary processes. ion dose is limited so that statistically the sample area In contrast to the Suggestion in the prior art, it may be analysed by the rastered ion beam is exposed to the beam advantageous not to produce severely dimpled or wrinkled once only, and that the spectrum generated is representative particles as these can yield low density powders, with very of a pristine Surface. high voidage between particles. Such powders have been TOF-SIMS analysis of the Turbula mixed sample (Lac reported as having good flow and dispersion characteristics, 10 tose/Magnesium Stearate 1971 mixed by Turbula) indicated but they occupy a large Volume relative to their mass as a the presence of both lactose and magnesium Stearate in both consequence of their shape and can result in packaging positive and negative mass spectra, as shown in the table problems, i.e. require much larger blisters or capsules to below. The presence of lactose in the spectra indicates that hold a given mass of powder. the Surface coverage of magnesium Stearate is incomplete. In one embodiment of the present invention, the powders 15 TOF-SIMS analysis of the Mechanofusion mixed sample have a tapped density of at least 0.1 g/cc, at least 0.2 g/cc, (Lactose/Magnesium Stearate 1971 co-milled by Mechano at least 0.3 g/cc, at least 0.4 g/cc or at least 0.5 g/cc. fusion) also indicated the presence of both lactose and magnesium Stearate in both positive and negative mass Example 11 spectra. The presence of lactose in the spectra indicates that the Surface coverage of magnesium Stearate is incomplete. Surface Chemical Analysis of Powders It is important to note that SIMS spectra are not quanti tative and so the intensities of the peaks cannot be taken to The aim of the analysis is to identify the presence of reflect the degree of Surface coverage. magnesium Stearate on the Surface of a model co-micronised XPS powder. The model powders were processed in two different XPS is a Surface analytical technique that can quantify the ways, with one representing a conventional pharmaceutical 25 amount of different chemical species in the outermost 10 nm blending process, and the other being the intensive Mecha of a surface. In the simplest form of analysis, XPS measures nofusion process which is the subject of the invention. The the relative amount of each element present. Quantitative aim was to show the contrast in Surface coating efficiency. In elemental identification can be achieved down to 1 atom in this case the model material was micronised lactose, which 1000. All elements present can be detected with the excep could represent a micronised drug or a fine carrier. 30 tion of hydrogen. Elemental analysis may be essential in The powders have been analyzed using both TOF-SIMS determining the amount of a Surface contaminant or to and XPS. TOF-SIMS provides a mass spectrum of the quantify any surface species with a unique elemental type. outermost 1 nm of the Surface, and is used here to assess whether the magnesium Stearate coverage of the lactose is complete or in patches. XPS provides a spectrum represen 35 Relative Atomic Percentage tative of the outermost 10 nm of the surface of the sample Composition (% and is used here in comparison to the TOF-SIMS data to assess the depth of coverage of the magnesium Stearate on Sample C O Mg the lactose Surface. Lactose In addition, the powders were studied using the Zetasizer 40 3000HS instrument (Malvern Instruments Ltd, UK.) Each Measurement 1 S447 45.43 Nd: sample was tested in cyclohexane, and Zeta potential mea Measurement 2 55.29 44.71 Nd: Surements were obtained. Mean S4.9 45.1 <0.1 The following powder samples were prepared for testing: Lactose/Magnesium Lactose; Stearate (Turbula) 45 Lactose/Magnesium Stearate 1971 mixed by Turbula Measurement 1 61.23 38.00 0.44 mixer, and Measurement 2 60.40 39.02 O.SO Lactose/Magnesium Stearate 1971 mixed by Mechanofu Mean 60.8 38.5 O.S sion. Lactose/Magnesium TOF-SIMS Stearate (Mechanofusion) SIMS is a qualitative surface analytical technique that is 50 Measurement 1 81.39 17.07 1.51 capable of producing a high-resolution mass spectrum of the Measurement 2 80.72 17.8O 1.49 outermost 1 nm of a Surface. Mean 81.1 17.4 1.5 In brief, the SIMS process involves bombarding the sample surface with a beam of primary ions (for example *Nd = not detected (<0.1 atomic %) caesium or gallium). Collision of these ions with atoms and 55 XPS analysis of the Lactose/Magnesium Stearate 1971 molecules in the Surface results in the transfer of energy to them, causing their emission from the Surface. The types of sample mixed by Turbula revealed the presence of magne particles emitted from the surface include positive and sium on the Surface of the lactose indicating the presence of negative ions (termed secondary ions), neutral species and magnesium Stearate. Using the percentage presence of mag electrons. Only secondary ions are measured in SIMS. nesium on the Surface it is calculated that the magnesium Depending on the type of bias applied to the sample, either 60 stearate contributes 20% of the overall signal from the positive or negative ions are directed towards a mass spec outermost 10 nm of the sample surface. Peak fitting the trometer. These ions are then analysed in terms of their carbon 1 S envelope enables the identification and quantifi mass-to-charge ratio (m/ ) yielding a positive or negative cation of the functionalities present at the surface. The clear ion mass spectrum of counts detected versus m/. Different increase in C H C C carbon centres at the surface is fragments will be diagnostic of different components of the 65 ascribed to the coverage of magnesium Stearate and dem surface. TOF-SIMS is an advanced technique that has onstrates a similar degree of signal intensity to that predicted increased sensitivity (