US009381189B2

(12) United States Patent (10) Patent No.: US 9,381,189 B2 Green et al. (45) Date of Patent: Jul. 5, 2016

(54) INGREDIENTS FOR INHALATION AND (56) References Cited METHODS FOR MAKING THE SAME U.S. PATENT DOCUMENTS (75) Inventors: Matthew Michael James Green, 4,582,265 A * 4/1986 Petronelli ...... 241.95 Wiltshire (GB); Richard Michael Poole, 6,257,233 B1 7/2001 Burr et al. 2004/01 18007 A1* 6/2004 Chickering et al...... 34/360

Wiltshire (GB) 2006, O257491 A1* 11, 2006 Morton et al. ... 424/489 (73) Assignee: VECTURA LIMITED, Wiltshire (GB) 2008/0063719 A1 3/2008 Morton et al...... 424/489 (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 EP O709086 A2 5, 1996 U.S.C. 154(b) by 641 days. EP 14981 16 A1 1, 2005 GB 2387781 A 10, 2003 JP 2005298.347 10/2005 (21) Appl. No.: 13/514,672 JP 200954.1393 11, 2009 JP 2012,542618 6, 2012 (22) PCT Fled: Dec. 8, 2010 WO 96.23485 A1 8, 1996 WO 9703649 A1 2, 1997 (86) PCT NO.: PCT/GB2O10/052053 WO O2OO197 A1 1, 2002 WO O243701 A2 6, 2002 S371 (c)(1), WO 2005105043 A2 11/2005 Aug. 20, 2012 WO 2007053904 A1 5/2007 (2), (4) Date: WO 2008.000482 1, 2008 (87) PCT Pub. No.: WO2O11AO70361 WO 2009095684 A1 8, 2009 OTHER PUBLICATIONS PCT Pub. Date: Jun. 16, 2011 Brunauer et al. "Adsorption of Gases in Multimolecular Layers'. J. (65) Prior Publication Data Am. Chem. Soc., vol. 60, (Feb. 1938) pp. 309-319. Nagai, et al. “Improvement in Dissolution Property of Poorly Water US 2012/0309809 A1 Dec. 6, 2012 Soluble Drugs by Using Mechanofusion System.” J. Soc. Powder Technol. Japan, 43, 640-647 (2006). (30) Foreign Application Priority Data Japanese Pharmaceutical Additives Directory 2007, p. 138. Dec. 8, 2009 (GB) ...... O921481.8 * cited by examiner (51) Int. C. Primary Examiner — Bethany Barham A6 IK 9/14 (2006.01) Assistant Examiner — Melissa Javier A6 IK3I/404 (2006.01) (74) Attorney, Agent, or Firm — Matthew S. Gibson; Reed B2C 23/00 (2006.01) Smith LLP CO7D 209/6 (2006.01) A6 IK3I/4045 (2006.01) (57) ABSTRACT A61 K9/00 (2006.01) A method of processing an active ingredient, the method (52) U.S. C. comprising Submitting a pharmaceutically active ingredient CPC ...... A6 IK3I/4045 (2013.01); A61 K9/141 in the absence of excipients and/or additives to compression (2013.01); A61 K9/0073 (2013.01) and shearing forces. The invention also relates to composi (58) Field of Classification Search tions comprising an active prepared by the method. None See application file for complete search history. 16 Claims, 5 Drawing Sheets U.S. Patent Jul. 5, 2016 Sheet 1 of 5 US 9,381,189 B2

Fig 1

Circularity of succinate blends over time at 25/60 storage conditions

---.S.--Sysa-as --Jetmilled

--&-sto MCB or Hum MCB

Time (months)

Fig 2

Circularity of sumatriptan succinate blends over time at 40/75 storage conditions 1.00 ys

fS-0-Jetmilled rostd MCB so Hum MCB

Time (months) U.S. Patent Jul. 5, 2016 Sheet 2 of 5 US 9,381,189 B2

Fig 3

Convexity of sumatriptan succinate blends over time at 25/60 storage conditions

s |-0- Jetmilled ic-sc std MCB 3 as Hum MCB

Time (months)

Fig. 4

Convexity of Sumatriptan succinate blends over time at 40/75 storage conditions

i --Jetmilled --S-a Std MCB 3 as Hum MCB

Time (months) U.S. Patent Jul. 5, 2016 Sheet 3 of 5 US 9,381,189 B2

Fig 5

CE d(50) of Sumatriptan succinate blends over time at 25/60 storage conditions 3.50 as 3.00 s Š E 2.50 aga Jetmilled \SYYYYYY stic micb c 2.OO Hum M CB O 150 1.OO O 2 4 6 Time (months)

Fig 6

CE d(50) of Sumatriptan succinate blends over time at 40/75 storage conditions 3.50 s 3.00 Es 2.50 -- Jetmilled

Š \Six stc. mCb O 2.OO r Hum MCB O 150 1.OO s O 2 4. 6 Time (months) U.S. Patent Jul. 5, 2016 Sheet 4 of 5 US 9,381,189 B2

Fig 7

Amorphous content of processed sumatriptan blends Over time

S. O.O2OO

--Jet milled 25/60 Š 0.0150 esse Jet milled 40/75 S ...S. Std MCB 25/60 & ... 3: ... Std MCB 40/75 5 0.01.00 – -8- Hum MCB 25/60 -- Hum MCB 40/75

0.0050 -

OOOOO - O 2 4 6 Timepoint (months) U.S. Patent Jul. 5, 2016 Sheet 5 of 5 US 9,381,189 B2

Fig 8

Stabiliy of Sumatriptan Succinate blends. (25/60 storage, F1, 12.29mg dose) 10.0 9. O & cere -' -8-DD Jetmilled 8.0 a s ...s--- DD MCB 5 7.0 a? Sas re-DD Hum MCB --- "--, -o-FPD Jetmilled 5. 6.O ...X.... FPDMCB 5. O --&- FPD Hum MCB E D

O 3 5 6 Time (months)

Fig 9

Stability of sumatriptan succinate blends. (40775 storage, F1, 12.29mg dose) 10.0

-- DD Jetmilled G ...&... DD MCB 5 ~&- DD Hum MCB s -----. FPD Jetmilled S. ...&... FPD MCB as a FPD Hum MCB S C Of

O 1 2 3 4 5 6 Time (months) US 9,381,189 B2 1. 2 INGREDIENTS FOR INHALATION AND The reduced tendency of the particles to bond strongly, METHODS FOR MAKING THE SAME either to each other or to the device itself, not only reduces powder cohesion and adhesion, but can also promote better RELATED APPLICATIONS flow characteristics. These effects lead to improvements in the dose reproducibility because it reduces the variation in the This application is the United States National Stage Appli amount of powder metered out for each dose and improves the cation of International Application No. PCT/GB2010/ release of the powder from the device. It also increases the 052053, filed Dec. 8, 2010, which was published as Interna likelihood that the active material which does leave the device tional Publication No, WO 2011/070361 A1, and which will reach the lower lung of the patient. claims benefit of Great Britain Patent Application No. 10 The use of additive materials in this manner is disclosed in O921481.8 filed Dec. 8, 2009. Both applications are incorpo WO 96/23485 and WO 97/03649. It is also known that intensive co-milling of micronised rated by reference in their entirety herewith. drug particles with additive material may be carried out in The present invention relates to active ingredients for inha order to produce composite active particles. This co-microni lation and methods for making Such active ingredients. 15 sation can improve dispersibility, as disclosed in WO Inhalation represents a very attractive, rapid and patient 02/43701. In addition, WO 02/00197 discloses the intensive friendly route for the delivery of systemically acting drugs, as co-milling offine particles of excipient material with additive well as for drugs that are designed to act locally on the lungs material, to create composite excipient particles to which fine themselves. It is particularly desirable and advantageous to active particles and, optionally, coarse carrier particles may develop technologies for delivering drugs to the lungs in a be added. This co-micronisation of fine excipient particles predictable and reproducible manner. and additive material has also been shown to improve dispers The key features which make inhalation a useful drug ibility. delivery route are: rapid speed of onset; improved patient There is still a need for improved dry powderformulations. acceptance and compliance for a non-invasive systemic route; In one aspect the invention relates to a method of process reduction of side effects; product life cycle extension; 25 ing an active ingredient, the method comprising Submitting a improved consistency of delivery; access to new forms of pharmaceutically active ingredient or ingredients in the therapy, including higher doses, greater efficiency and accu absence of excipients (e.g. carrier particles) and/or additives racy of targeting; and direct targeting of the site of action for to compression and shearing forces. locally administered drugs, such as those used to treat lung In one aspect the invention relates to a method of process diseases. 30 ing an active ingredient, the method comprising Submitting a However, the powder technology behind successful dry pharmaceutically active ingredient or ingredients alone to powders and dry powder inhaler (DPI) or pressured metered compression and shearing forces. dose inhalers (pMDI) products remains a significant technical In one aspect the active is a micronised active. hurdle to those wishing to succeed with this route of admin The invention further relates to an active ingredient obtain istration and to exploit the significant product opportunities. 35 able or obtained using the above method. Any formulation suitably has properties that allow for the The invention further relates to an inhaler device compris manufacture and metering of the powders, provide reliable ing an active ingredient obtainable or obtained by the method and predictable resuspension and fluidisation, and avoid of the invention, or an active ingredient which has been fur excessive retention of the powder within the dispensing ther processed where necessary into a suitable pharmaceuti device. 40 cally acceptable form. A major problem experienced by formulators is the vari The invention further relates to a receptacle. Such as a ability in Surface properties of drug particles. Each active blister or capsule, comprising a dose of a active ingredient, agent powder has its own unique inherent Stickiness or Sur obtainable or obtained by the method of the invention, or an face energy, which can range tremendously from compound active ingredient which has been further processed where to compound. Further, the nature of the Surface energies can 45 necessary into a suitable pharmaceutically acceptable form. change for a given compound depending upon how it is pro cessed. For example, jet milling is notorious for generating BRIEF DESCRIPTION OF THE significant variations in Surface properties because of the DRAWINGS/FIGURES aggressive nature of the collisions it employs. Such variations can lead to increased surface energy, increased cohesiveness, 50 FIG. 1 discloses circularity of Sumatriptan succinate over adhesiveness and process induced disorder. time under different processing conditions and 25/60 storage In order to improve the properties of powder formulations, conditions; and in particular to improve the flowability and dispersibility FIG. 2 discloses circularity of Sumatriptan succinate over of the formulation, dry powder formulations can include time under different processing conditions and 40/75 storage additive materials which are intended to reduce the cohesion 55 conditions; between the fine particles in the dry powderformulation. It is FIG. 3 discloses convexity of Sumatriptan succinate over thought that the additive material interferes with the bonding time under different processing conditions and 25/60 storage forces between the Small particles, helping to keep the par conditions; ticles separated and reducing the adhesion and cohesion of FIG. 4 discloses convexity of Sumatriptan Succinate over Such particles to one another, to other particles in the formu 60 time under different processing conditions and 40/75 storage lation if present and to the internal surfaces of the inhaler conditions; device. Where agglomerates of particles are formed, the addi FIG. 5 discloses CE (circle equivalent) diameter of tion of particles of additive material decreases the stability of Sumatriptan Succinate over time under different processing those agglomerates so that they are more likely to break up in conditions and 25/60 storage conditions; the turbulent air stream created on actuation of the inhaler 65 FIG. 6 discloses CE (circle equivalent) diameter of device, whereupon the particles are expelled from the device Sumatriptan Succinate over time under different processing and inhaled. conditions and 40/75 storage conditions; US 9,381,189 B2 3 4 FIG. 7 discloses amorphous content of Sumatriptan Succi ent. The invention relates, in one particular aspect, to a nate over time after processing (wherein the line describing method of processing an active ingredient, the method com the Std MCB 25/60 experiment starts between 0.015 and prising Submitting an active ingredient or ingredients alone to 0.010 dm, is greater than 0.000 at 3 months and the dm rises compression and shearing forces in the absence of magne at 6 months and the line describing the Hum MCB 40/75 sium Stearate. experiment starts between 0.015 and 0.010 dm and is 0.000 at In one aspect the processing of an active alone may be 3 months); carried out in the presence of a gas or gases that are Suitable FIG. 8 discloses stability of Sumatriptan succinate blends for, or facilitate or improve the processing step. Such as air at under different processing conditions and 25/60 storage con room temperature, or at a higher or lower relative humidity ditions, wherein the stability is measured by the delivered and 10 fine particle doses provided via an inhaler device, based upon than ambient conditions, or gaseous solvents. Gases in this a nominal dose of 12.29 mg (wherein DD jetmilled starts at context are not considered to represent a pharmaceutically 3.6 mg, rises to about 6.6 mg at 1 and 2 months, falls to 5.5 mg acceptable material and are not excluded from the processing at 3 months and rises to 6.4 mg at 6 months; DD MCB starts step. at over 6.5 mg, falls slightly to 6.4 at 1 month, rises to 7.6 mg 15 Without wishing to be bound by theory, subjecting an at 2 months, falls to 5.9 mg at 3 months and rises to 6.9 mg at active agent or agents to compression and shearing forces is 6 months: DD Hum MCB starts at 5.4 mg, rises to 6.3 mg at thought to reduce the amorphous content of an active ingre 1 month, rises further to 7.6 mg at 2 months, rises yet further dient, and may also increase circularity of an active, which to 9.1 mg at 3 months and rises yet further to 9.5 mg at 6 properties of the active may lead to improvements in the months; FPD jetmilled starts at 2 mg, rises to 2.9 mg at 1 properties of the particle for inhalation delivery, such as month, falls to 2.7 mg at 2 months, falls to 2.6 mg at 3 months improved stability, flowability and dispersability. and remains the same at 6 months; FPDMCB starts at 3.5 mg. The active ingredient is Subjected to a compressive and falls to 3.4 mg at 1 month, rises to 3.5 mg at 2 months, falls to shearing force. 3.0 mg at 3 months and rises to 3.1 mg at 6 months; and FPD Suitably the active ingredient is located in a vessel and the Hum MCB starts at 3.2 mg, rises to 3.3 mg at 1 months, rises 25 force is exerted on the active ingredient between the wall of further to 3.5 at 2 months and further to 3.9 mg at 3 months, the vessel and the face of an inner element within the vessel before falling to 3.3 mg at 6 months); which rotates within the vessel. In one aspect rotation of the FIG. 9 discloses stability of Sumatriptan succinate blends inner element results in a compression and shearing force under different processing conditions and 40/75 storage con being applied to the active ingredient in the space between the ditions, wherein the stability is measured by the delivered and 30 wall and the face of the inner element. fine particle doses provided via an inhaler device, based upon In one aspecta compressive and shearing force is applied in a nominal dose of 12.29 mg (wherein DD jetmilled starts at a gap of predetermined width, suitably between the wall of 3.6 mg, rises to 7.1 mg at 1 month, falls to 5.2 mg at 2 months, the vessel and an inner element. rises to 6.0 mg at 3 months and rises to 7.7 mg at 6 months; In one aspect the compressive and shearing force is DD MCB starts at over 6.5 mg, falls to 5.52 mg at 1 month, 35 achieved by Subjecting the active ingredient to mechanofu rises to 7.7 mg at 2 months, falls to 5.2 mg at 3 months and sion (also known as mechanochemical bonding (MCB)), rises to 7.9 mg at 6 months: DD Hum MCB starts at 5.4 mg. Cyclomix or Hybridiser processes, as described below. In one rises to 6.5 mg at 1 month, falls to 5.9 mg at 2 months, rises to preferred aspect the compressive and shearing force is 6.7 mg at 3 months and rises yet further to 8.7 mg at 6 months; achieved by use of mechanofusion technique as described FPDjetmilled starts at 2 mg, rises to 2.9 mg at 1 month, falls 40 herein. to 2.2 mg at 2 months, rises to 2.4 mg at 3 months and rises to In one aspect the active ingredient treated in the present 2.9 mg at 6 months; FPDMCB starts at 3.5 mg, falls to 2.8 mg invention has a reduced amorphous content, when compared at 1 month, rises to 2.9 mg at 2 months, falls to just below 2.4 to untreated active ingredient or micronised active ingredient, mg at 3 months and rises to 2.4 mg.at 6 months; and FPD Hum for example as measured by, Dynamic Vapour Sorption MCB starts at 3.2 mg, rises to 3.3 mg at 1 months, falls to 2.7 45 (DVS) analysis as described herein. In one aspect the active mg at 2 months and maintains this value at 3 months, before ingredient treated in the present invention has reduced amor falling to 2.4 mg at 6 months). phous content when compared to the same active ingredient When used herein, the term “circle equivalent diameter', when micronised by jet milling, or when compared to mate refers to the diameter of a circle that has the same area as a rial which has not undergone an MCB step, suitably a reduc 2-dimensional image of the particle. Further details of circle 50 tion of amorphous content of up to 10%, up to 20%, up to equivalent diameter may be found at: 30%, up to 40%, up to 50% or even up to 60%, 70%, 80%, http://www.fei.com/uploadedFiles/Documents/Content/ 90% or more, when compared to jet milling, for example as particle morphology.pdf. measured by DVS as disclosed herein. In one aspect the The invention relates, in one aspect, to a method of pro amorphous content is not detectable. cessing an active ingredient, the method comprising Submit 55 In one aspect the active ingredient is in the form of particles ting an active ingredient or ingredients alone to compression prior to processing. and shearing forces. Reference to processing of an active The following processes, which are not limiting, are Suit ingredient alone herein includes reference to processing of able to provide a compressive and shearing force. two or more actives alone, unless otherwise clear from the Mechanofusion has previously been described as a dry COInteXt. 60 process designed to mechanically fuse a first material onto a In one aspect, processing of the active ingredient alone second material. It should be noted that the use of the terms indicates that the active is not mixed or coated with any other "mechanofusion' and “mechanofused are supposed to be Substance, Such as any other Solid material, during process interpreted as a reference to a particular type of milling pro ing. In one aspect processing of an active alone indicates cess, but not a milling process performed in a particular processing in the absence of other materials that might be 65 apparatus. The compressive milling processes work accord Suitable for inclusion in a pharmaceutical product. For ing to a different principle to other milling techniques (Com example, processing is carried out in the absence of an excipi minution techniques), relying on a particular interaction US 9,381,189 B2 5 6 between an inner element and a vessel wall, and they are vessel, and is re-circulated within the vessel. Typical speeds based on providing energy by a controlled and Substantial of rotation are in the range of 5,000 to 20,000 rpm. compressive force. The above processes suitably apply a high enough degree The active ingredient is fed into the vessel of a mechano of force to separate individual particles of active ingredient fusion apparatus (such as a Mechano-Fusion system and to break up tightly bound agglomerates of the active (Hosokawa Micron Ltd)) or the Nobilta (Hosokawa Micron ingredient. Ltd) or Nanocular (Hosokawa Micron Ltd) apparatus, where In general, no impaction of milling media Surfaces is it is Subject to a centrifugal force and is pressed against the present so that wear and consequently contamination are vessel inner wall. The active ingredient is compressed minimised. 10 The speed of rotation may vary between the ranges of 200 between the fixed clearance of the drum wall and a curved to 10,000 rpm through out processing. Typical processing inner element with high relative speed between drum and capacity is between 4000-5000 rpm, which equates to 80% element. The inner wall and the curved element togetherform engine capacity. It is, however, preferable to introduce pow a gap or nip in which the particles are pressed together. As a der into the processing chambers at slower speeds. Introduc result, the active ingredient experiences very high shear 15 tion of powder at slower speeds prevents clogging because it forces and very strong compressive stresses as they are is easier to process an already moving powder. A scraper may trapped between the inner drum wall and the inner element also be present to break up any caked material building up on (which has a greater curvature than the inner drum wall). The the vessel Surface. This is particularly advantageous when particles are pressed against each other with enough energy to using fine cohesive starting materials. locally increase the temperature and soften, break, distort, The local temperature may be controlled by use of a heat flatten and thereby reduce the amount of amorphous/disor ing/cooling jacked built into the drum vessel walls. dered material in the sample. The active ingredient may be re-circulated through the Either the outer vessel or the inner element may rotate to vessel. provide the relative movement. In an alternate embodiment The pressure and shearing force are exerted for a suitable the outer vessel and the inner element may rotate with respect 25 time to achieve a reduction in the amorphous content of the to each other. active ingredient, for example as measured by DVS as dis The gap between the outer vessel and the inner element closed herein. Suitably the time is between 1 minute and 24 Surfaces is relatively small, and is typically less than 10 mm hours, such as between 5 minutes and 12 hours, such as and is preferably less than 5 mm, more preferably less than 3 between 10 minutes and 2 hours. mm, more preferably less than 2 mm, preferably less than 1 30 Suitably these compression milling processes produce mm or preferably less than 0.5 mm. This gap is fixed, and little or no size reduction of the active ingredient, especially consequently leads to a better control of the compressive where they are already in a micronised form (suitably <10um energy than is provided in some other forms of mill such as MMAD). One physical change which may be observed is a ball and media mills. Alternatively, a sequential use of rotors plastic deformation of the particles to a rounder shape. with Smaller gaps throughout the blending process may be 35 The active ingredient may be micronised prior to compres used. Such an approach lends itself to providing control over sion and shearing. Micronisation may be by any Suitable initial powder processing permitting gentler forces before method. Micronization is the process of reducing the average using rotors with Smaller gaps to impart a milling process of diameter of a solid materials particles, for example by mill greater intensity. ing or grinding. In one aspect a micronised active is an active Another compressive milling process that may be used in 40 ingredient that has been subjected to a mechanical process the present invention is the Cyclomix method. The Cyclomix which applies sufficient force to the active ingredient that the comprises a stationary conical vessel with a fast rotating shaft process is capable of breaking coarse particles down to fine with paddles which move close to the wall. Due to the high particles of mass median aerodynamic diameter of not more rotational speed of the paddles, the active ingredient is pro than 50 Lum MMAD as discussed below. pelled towards the wall, and as a result it experiences very 45 In one aspect micronisation of the active ingredient may be high shear forces and compressive stresses between wall and achieved using one or a combination of the following meth paddle. Such effects are similar to those in Mechanofusion as ods: ball milling, jet milling, jet blending, high-pressure described above and may be sufficient to increase the tem homogenation, or any other milling method. perature and soften, to break, distort, and flatten the active Ball milling is a milling method used in many of the prior ingredient particles. 50 art co-milling processes. Centrifugal and planetary ball mill The device used is preferably capable of exerting a force of ing may also be used. greater than 1 N. It will be appreciated by the skilled person, Jet mills are capable of reducing Solids to particle sizes in that pressure force that is exerted upon the active will be the low-micron to Submicron range. The grinding energy is affected by multiple factors including the force imparted by created by gas streams from horizontal grinding air nozzles. the rotor on the powder when compressed against the drum 55 Particles in the fluidised bed created by the gas streams are wall, the volume of powder within the processing chamber, accelerated towards the centre of the mill, colliding within. weight of the powder, density of the powder and the inherent The gas streams and the particles carried in them create a cohesiveness of the powder components which dictate the violent turbulence and, as the particles collide with one resistance to flow. In addition to these, the speed, temperature, another, they are pulverized. humidity, amount of powder and type of machine can be 60 High pressure homogenisers involve a fluid containing the varied independently to achieve a suitable form of an active particles being forced through a valve at high pressure, pro according to the present invention. ducing conditions of high shear and turbulence. Suitable In another aspect the compressive and shearing forces may homogenisers include EmulsiFlex high pressure homogenis be carried out by the Hybridiser R. Method. The active ingre ers which are capable of pressures up to 4000 bar, Niro Soavi dient is fed into the Hybridiser. The powder is subjected to 65 high pressure homogenisers (capable of pressures up to 2000 ultra-high speed impact, compression and shear as it is bar) and Microfluidics Microfluidisers (maximum pressure impacted by blades on a high speed rotor inside a stator 2750 bar). US 9,381,189 B2 7 8 Alternatively micronised active ingredient may be pro In another aspect the active ingredient is conditioned at a duced by using a high energy media mill or an agitator bead minimum temperature. Preferably, the temperature is at least mill, for example, the Netzsch high energy media mill, or the 30°C., in one aspect 35°C., in one aspect 40°C., in one aspect DYNO-mill (Willy A. Bachofen AG, Switzerland). 50° C., or higher than 50° C. Processing temperatures may be In one aspect the present invention relates to a method of 5 controlled via an external or integrated cooling jacket. Alter processing an active ingredient whereinan (optionally micro natively, the processing temperature may also be controlled nised) active ingredient is Subjected to a compressive and via a suitably heated or cooled atmosphere. Alternatively, shearing force, in the absence of another powder material. temperature may also be varied over time during the treat Various compression methods of the prior art have been ment of the active ingredient. For example the heated atmo used to combine two different powders. Thus the active ingre 10 sphere may be introduced by increasing temperature with dient of the prior art, such as in EP14981 16, is used in com processing time until the desired temperature is achieved. bination with materials such as diluting agents, lubricants and Alternatively, once a steady heated State is achieved the tem coating agents. In contrast the present invention is carried out perature may be decreased within the vessel with processing in the absence of other powders, and thus the effect is time. obtained on the active ingredient in the absence of powdered 15 The particles of the invention may suitably be character excipients, lubricants and coating agents, for example. ized by their solid state stability. Solid state stability can be In one aspect the processing of the active ingredient is assessed using techniques well known in the art. Particular carried out in the absence of any other active ingredient. In techniques such as DVS may be used. Another method used to one aspect the processing of the active ingredient is carried characterize the aerosol performance of a powder is by deter out in the absence of any excipient. In one aspect the process mining the fine particle fraction. The fine particle fraction ing of the active ingredient is carried out in the absence of any describes the size distribution of airborne particles. One other lubricant or coating agent. method of measuring the size distribution, or fine particle In a further aspect of the present invention the active ingre fraction, of airborne particles is by impactor testing, for dient is conditioned during the compression and shearing example using a Casacade impactor. One particular technique step. 25 that may be used is the ACI (Andersen Cascade Impactor). The term “conditioning is used herein involves treating The size cut-off of each stage is dependent on the flow rate at the active ingredient by Subjecting it to compressive and which the ACI is operated. shearing forces under conditions of controlled relative Atomic force microscopy (AFM) may be used to deter humidity, temperature, speed of rotation and/or gap width. mine the surface properties of the product either in Surface In one aspect the active ingredient may be conditioned 30 Topography Analysis or Solid-Solid Interaction Measure under conditions of low relative humidity. Preferably, the mentS. active is treated under conditions of less than 10% relative Surface Topography Analysis uses a scanning probe humidity. method that requires continuous contact between the probing In one aspect the active ingredient may be conditioned tip and the Substrate. Upon encountering protrusions or Sur under a humid atmosphere. Preferably, the active ingredient is 35 face deformations the probe reacts causing a cantilever to conditioned under a relative humidity ranging from 5 to 90%. bend. This is identified by a laser deflection on the photodiode When intending to process under conditions of higher humid detector. The varying signal is digitally interpreted and the ity, relative humidity ranges from 50 to 90%, 55 to 87%, 60 to Surface Substrate is reconstructed as a 3 dimensional image. 84%. 65 to 80% and 70 to 75% are preferred. When intending It is also possible to employ an intermittent contact mode, to process under conditions of reduced humidity, ranges are 40 commonly known as Tapping mode, wherein the AFM tip from 5 to 50%, 7.5 to 40%, 10 to 30%, 12.5 to 20% and most engages with the sample surface thereby reducing the lateral preferably less than 15% relative humidity are preferred. In forces which disrupt fragile Surfaces. This mode measures a the case of cryogenic preparation, for example liquid nitro change in amplitude of an oscillating tip. When the tip gen, reduced humidity ranges will be less than 5%. encounters underlying Substrate Surfaces, variations in the The active ingredient may be conditioned under a solvent 45 amplitude of the oscillating tip are recorded by deflection of containing atmosphere. Such as an organic Solvent. Solvents the laser. include and/or acetone. The skilled artisan would Solid-Solid Interaction Measurements fix a particle of appreciate the nature of risk associated with processing under interest on the apex of a cantilever. Under Such an arrange such environments. Suitable environments include ethanol/ ment, it is possible to determine the forces between the sub nitrogen in ratios of 5:95% (w/w), or more preferably 2.5: 50 ject particle and a substrate. By plotting the measured deflec 97.5% (w/w) or most preferably 1: 99% (w/w). Alternatively tion of the cantilever as a function of displacement, a picture methanol/nitrogen in ratios of 5:95% (w/w), or more prefer of the interaction between the subject particle and substrate ably 2.5:97.5% (w/w) or most preferably 1: 99% (w/w) may can be determined. be used. Alternatively acetone/nitrogen in ratios of 5: 95% The particle morphology may be assessed by a microscope (w/w), or more preferably 2.5:97.5% (w/w) or most prefer 55 such as Morphologi G3 (Malvern Instruments) which can ably 1: 99% (w/w) may be used. The solvent may be intro measure particle circularity and convexity. duced as a vapour within the gas lines. The solvent may be The mass median aerodynamic diameter (MMAD) of par introduced as a vapour in increasing amounts, from 0%, for ticles comprising the active ingredient generated using the example, increasing to 5% (w/w) with processing time. Alter method of this invention is preferably not more than 10 um, natively, once a steady Vapour state is achieved the Solvent 60 and advantageously it is not more than 5um, more preferably vapour may be decreased within the vessel with processing not more than 3 um and most preferably not more than 1 Jum. time. Accordingly, advantageously at least 90% by weight of Humidity may also be varied over time during the treat particles comprising the active ingredient have a diameter of ment of the active ingredient. The length of time to which the not more than 10 um MMAD, advantageously not more than particles are exposed to this humidity may also be varied. 65 5um, preferably not more than 3 um and more preferably not When used herein, “water is neither an excipient or an more than 1 lum. In one aspect at least 90% by weight of additive material. particles comprising the active ingredient have a mass median US 9,381,189 B2 10 aerodynamic diameter in the range of 10 to 2 um, preferably The present invention can be carried out with any suitable in the range of 5 to 1 um, advantageously in the range of 3 to pharmaceutically active agent. Specific active agents that 0.5 um, and especially advantageously in the range of 2 to may be used include, but are not limited to, agents of one or 0.05um. more of the following classes listed below. Particles comprising the active ingredient may be of a 5 1) Adrenergic such as, for example, , suitable size for inhalation to the desired part of the lung, for , , , , , example, having an MMAD in the range of 3 to 0.1 um for , , epinephrine, ethylnorepinephrine, absorption in the deep lung, 5 to 0.5um for absorption in the , , , , respiratory bronchioles, 10 to 2 um for delivery to the higher hydroxyamphetamine, isoetharine, isoproterenol, respiratory system and 2 to 0.05um for delivery to the alveoli. 10 isotharine, mephenterine, , methamphet Additionally, the active particles discussed above may be amine, , methpentermine, , formulated with excipient particles that have a geometric , metaproterenol, metaraminol, mito diameter in the range of 5 to 250 um, preferably 10 to 100 um, drine, , , , pemo advantageously 20 to 75 Lim, and especially advantageously line, , phenylethylamine, phenylpropanola 40 to 50 lum. The geometric diameter of the particles will not 15 mine, , , , propylhexedrine, normally be higher than 350 um. pseudo-ephedrine, , , , terb In one aspect the product of the process of the present utaline, tetrahydrozoline, tramaZoline, tyramine and invention has a lower amorphous content immediately after . treatment when compared to the same material that has been 2) Adrenergic antagonists such as, for example, . micronized (e.g. impact milled or, more Suitably, jet milled). , , , , , In one aspect the product of the process of the present , , , . invention has a higher delivered dose and/or a higher fine , , , , ergot particle dose immediately after treatment when compared to alkaloids, esmolol, , , , the same material that has been micronized (e.g. impact , , , , meto milled or, more suitably, jet milled). 25 prolol, , , , , penb In one aspect the product of the process of the present utolol, , , , invention has a lower Surface area, Suitably as determined by , , , , , tam BET (the BET methodology and theory is discussed in S. Sulosin, , , , , Brunauer, P. H. Emmett and E. Teller, J. Am. Chem. Soc., and . 1938, 60,309 (BET is derived from the names of the papers 30 3) Adrenergic neurone blockers such as, for example, authors)) immediately after treatment when compared to the bethanidine, debrisoquine, guabenXan, guanadrel, guana same material that has been micronized (e.g. impact milled or, Zodine, guanethidine, guanoclor and guanoxan. more suitably, jet milled). “Immediately after treatment 4) Drugs for treatment of addiction, such as, for example, refers to the properties of the product on the day of treatment, . Suitably as assessed on the day of treatment or very shortly 35 5) Drugs for treatment of alcoholism, such as, for example, thereafter, in the following one or two days, or held under disulfuram, and naltrexone. storage conditions where said properties are essentially main 6) Drugs for Alzheimer's disease management, including tained. acetylcholinesterase inhibitors such as, for example, done In one aspect the product of the process of the present pezil, , rivastigmine and tacrin. invention has a higher circularity or convexity immediately 40 7) Anaesthetics Such as, for example amethocaine, ben after treatment when compared to the same material that has Zocaine, , hydrocortisone, , been micronized (e.g. impact milled or, more Suitably, jet lignocaine, methylprednisolone, , milled). , and tyrothricin. In one aspect the active ingredient produced by the method 8) Angiotensin converting enzyme inhibitors such as, for disclosed herein is stable under 25/60 storage conditions over 45 example, captopril, cilaZapril, enalapril, fosinopril, imi a six-month (e.g. a five-month, four-month, three-month, dapril hydrochloride, lisinopril, moexipril hydrochloride, two-month or, suitably, one-month) period, wherein the dif perindopril, quinapril, ramipril and trandolapril. ference in percentage FPF of the nominal dose is no more than 9) Angiotensin II receptor blockers, such as, for example, +20% (e.g. +15%, +10%, +7% or, suitably +5%) of an initial candesartan, cilexetil, eprosartan, irbesartan, losartan, percentage FPF value. For example, when the difference in 50 medoxomil, olmesartan, telmisartan and Valsartan. percentage FPF is no more than +20%, if the nominal dose is 10) Antiarrhythmics such as, for example, adenosine, amido 10 mg and the initial FPF value of the nominal dose is 50% darone, , flecamide acetate, hydro (i.e. a FPD of 5 mg), then the FPF value obtained after six chloride, , , propafenone and qui months may not be more than 70% (i.e. more than a FPD of 7 nidine. mg) or less than 30% (i.e. less than a FPD of 3 mg) of the 55 11) Antibiotic and antibacterial agents (including the beta nominal dose. The initial percentage FPF value of the nomi lactams, fluoroquinolones, ketolides, macrollides, Sulpho nal dose can be taken immediately after the active ingredient namides and tetracyclines) Such as, for example, aclarubi is prepared, but may be taken at any time thereafter and, in this cin, amoxicillin, amphotericin, azithromycin, aztreonam context, reference to the passage of time refers to the amount chlorhexidine, , clindamycin, colistime of time that has elapsed since obtaining the initial percentage 60 thate, dactinomycin, dirithromycin, doripenem, erythro FPF value. mycin, fusafungine, gentamycin, metronidazole, mupiro When used herein, the terms “25/60 storage conditions” cin, natamycin, , nystatin, oleandomycin, refers to an environment maintained at 25°C. and 60% rela , pimaricin, probenecid, , Sul tive humidity. phadiazine and triclosan. When used herein, the terms “40/75 storage conditions” 65 12) Anti-clotting agents such as, for example, abciximab, refers to an environment maintained at 40° C. and 75% rela acenocoumarol, alteplase, , bemiparin, bivalirudin, tive humidity. certoparin, clopidogrel, dalteparin, danaparoid, dipy US 9,381,189 B2 11 12 ridamole, enoxaparin, epoprostenol, eptifibatide, fonda 18) Anti-emetics Such as, for example, , aza parin, heparin (including low molecular weight heparin), setron, , bestahistine, , buclizine, heparin calcium, lepirudin, phenindione, reteplase, Strep chlorpromazine, , , , dimenhy tokinase, tenecteplase, tinzaparin, tirofiban and warfarin. drinate, , diphenidol, , dolas 13) such as, for example, GABA analogs etron, dronabinol, , , hyoscine, including tiagabine and vigabatrin; including lorazepam, , , , ; including alprazolam, , , , , chlordiazepoxide, clobazam, clonazepam, diazepam, flu , , triethylperazine, trifluopera razepam, lorazepam, midazolam, oxazepam and Zine, , and . Zolazepam; hydantoins including phenyloin, phenyltriaz 10 19) such as, for example, acrivastine, astemi ines including ; and miscellaneous anticonvul Zole, , azelastine, , carbinox sants including acetazolamide, , ethoSuX amine, cetirizine, chlorpheniramine, cinnarizine, clemas imide, fosphenyloin, , , tine, cyclizine, , , , , , primidone, , diphenhydramine, , fex 15 ofenadine, hydroxy Zine, , levocabastine, lorata , , valproic acid and . dine, mizolastine, promethazine, pyrilamine, 14) such as, for example, and tetra and trimeprazine. cyclic antidepressants including , 20) Anti-infective agents such as, for example, antivirals (in (tricyclic and amitryptiline), , cluding nucleoside and non-nucleoside reverse tran , , , , Scriptase inhibitors and protease inhibitors) including aci , , , , dothi clovir, adefovir, , cidofovir, , epin, , , , levoprotiline, famiciclovir, foScarnet, ganciclovir, idoxuridine, indinavir, , , , , inosine pranobex, lamivudine, nelfinavir, nevirapine, osel , , nortryptiline, , tamivir, palivizumab, penciclovir, pleconaril, ribavirin, , , , , 25 , ritonavir, ruprintrivir, saquinavir, stavudine, and ; selective and nora Valaciclovir, Zalcitabine, Zanamivir, Zidovudine and inter drenaline inhibitors (SNRIs) including clovox ferons: AIDS adjunct agents including dapsone; aminogly amine, dulloxetine, and ; selective cosides including tobramycin; antifungals including serotonin reuptake inhibitors (SSRIs) including citalo amphotericin, caspofungin, clotrimazole, econazole pram, , femoxetine, , , 30 nitrate, fluconazole, itraconazole, , micona ifoxetine, milnacipran, nomifensine, , paroX Zole, nystatin, terbinafine and Voriconazole; anti-malarial etine, , sibutramine, venlafaxine, vidualine and agents including quinine; antituberculosis agents includ Zimeldine; selective noradrenaline reuptake inhibitors ing capreomycin, ciprofloxacin, ethambutol, meropenem, (NARIs) including demexiptiline, desipramine, oxapro piperacillin, rifampicin and Vancomycin; beta-lactams tiline and reboxetine; noradrenaline and selective serotonin 35 including cefazolin, cefinetazole, cefoperaZone, cefoxitin, reuptake inhibitors (NASSAs) including mirtazapine; cephacetrile, cephalexin, cephaloglycin and cephalori monoamine oxidase inhibitors (MAOIs) including ami dine; cephalosporins, including cephalosporin C and flamine, brofaromine, clorgyline, O-ethyltryptamine, eto cephalothin; cephamycins such as cephamycin A, cepha peridone, iproclozide, iproniazid, isocarboxazid, mebana mycin B. cephamycin C, cephapirin and cephradine; lep Zine, , moclobemide, nialamide, pargyline, 40 rostatics Such as clofazimine; penicillins including amox phenelzine, pheniprazine, pirlindole, procarbazine, rasa icillin, ampicillin, amylpenicillin, azidocillin, giline, Safrazine, , toloxatone and tranylcyprom benzylpenicillin, carbenicillin, carfecillin, carindacillin, ine; muscarinic antagonists including and clometocillin, cloxacillin, cyclacillin, dicloxacillin, dibenzepin; azaspirones including , , diphenicillin, heptylpenicillin, hetacillin, metampicillin, , and tiaspirone; and other antide 45 methicillin, nafcillin, 2-pentenylpenicillin, penicillin N. pressants including acetaphenazine, ademetionine, S-ad penicillin O, penicillin S and penicillin V: quinolones enosylmethionine, , , amineptine, including ciprofloxacin, clinafloxacin, difloxacin, grepa , benactyzine, benmoxine, binedaline, bupro floxacin, norfloxacin, ofloxacine and temafloxacin, tetra pion, carbamazepine, caroXaZone, cericlamine, cotinine, cyclines including doxycycline and oxytetracycline; mis feZolamine, . , kitanserin, levopro 50 cellaneous anti-infectives including lineZolide, tiline, lithium salts, maprotiline, medifoxamine, meth trimethoprim and Sulfamethoxazole. ylphenidate, metralindole, minaprine, , nisoX 21) Anti-neoplastic agents such as, for example, droloxifene, etine, nomifensine, , oxitriptan, tamoxifen and toremifene. phenyhydrazine, rolipram, , Sibutramine, 22) Antiparkisonian drugs such as, for example, amantadine, , tianeptine, tofenacin, traZadone, , 55 andropinirole, , , benserazide, and . , benztropine, , , caber 15) agents such as, for example, , goline, carbidopa, , entacapone, eptastigmine, , biperiden, cyclopentolate, glycopyrrolate, , galanthamine, lazabemide, levodopa, , hyoscine, ipratropium bromide, orphenadine hydrochlo , , mofegiline, , trihex ride, OXitroprium bromide, oxybutinin, , pro 60 yphenidyl, , , , , cyclidine, propantheline, propiverine, , tiotro propentofylline, rasagiline, remacemide, ropinerole, sel pium, , tropicamide and troSpium. egiline, spheramine, and tolcapone. 16) Antidiabetic agents such as, for example, pioglitaZone, 23) such as, for example, , rosiglitaZone and troglitaZone. alizapride, , amoxapine, amperozide, aripipra 17) Antidotes such as, for example, deferoxamine, edropho 65 Zole, , benzquinamide, , buramate, nium chloride, fiumazenil, , naloxone, and nal , , carphenazine, , trexOne. chlorpromazine, , , clomac US 9,381,189 B2 13 14 ran, , clospirazine, clothiapine, , brozil, ispaghula, nictotinic acid, omega-3 triglycerides, , droperidol, flupenthixol, , pravastatin, rosuvastatin and simvastatin. , haloperidol, , , 35) Drugs for cystic fibrosis management such as, for , metofenazate, molindrone, , pen example, Pseudomonas aeruginosa infection vaccines (eg fluridol, pericyazine, perphenazine, , pipam AerugenTM), 1-anti trip sin, amikacin, cefadroxil, erone, , , prochlorperazine, pro denufosol, duramycin, , mannitol, and tobra mazine, , , , , mycin. , , , thiothixene, trifluperi 36) Diagnostic agents such as, for example, adenosine and dol, triflupromazine, , , aminohippuric acid. and ; phenothiazines including aliphatic 10 37) Dietary Supplements such as, for example, melatonin and compounds, piperidines and ; , Vitamins including vitamin E. butyrophenones and Substituted . 38) Diuretics such as, for example, , bendroflume 24) Antirheumatic agents such as, for example, diclofenac, thiazide, , chlortalidone, cyclopenthiazide, heparinoid, hydroxychloroquine and methotrexate, , indapamide, metolaZone, Spironolactone and leflunomide and teriflunomide. 15 torasemide. 25) such as, for example, adinazolam, alpidem, 39) Dopamine agonists such as, for example, amantadine, alprazolam, alseroxlon, amphenidone, , bro apomorphine, bromocriptine, , lisuride, per mazepam, bromisovalum, buspirone, captodiamine, capu golide, pramipexole and ropinerole. ride, carbcloral, carbromal, chloral betaine, chlordiazep 40) Drugs for treating erectile dysfunction, Such as, for oxide, , , , flurazepam, example, apomorphine, apomorphine diacetate, moxisy hydroxy Zine, ipsapiraone, , loprazolam, lyte, phentolamine, phosphodiesterase type 5 inhibitors, lorazepam, loxapine, mecloqualone, , meth such as sildenafil, tadalafil. Vardenafil and yohimbine. aqualone, methprylon, metomidate, midazolam, 41) Gastrointestinal agents such as, for example, atropine, oxazepam, propanolol, tandospirone, traZadone, , famotidine, lanSoprazole, , ome and . 25 prazole and rebeprazole. 26) Appetite stimulants such as, for example, dronabinol. 42) Hormones and analogues such as, for example, cortisone, 27) Appetite Suppressants such as, for example, , epinephrine, estradiol, insulin, Ostabolin-C, parathyroid phentermine and Sibutramine; and anti-obesity treatments hormone and testosterone. Such as, for example, pancreatic lipase inhibitors, serotonin 43) Hormonal drugs such as, for example, desmopressin, and norepinephrine re-uptake inhibitors, and anti-anorec 30 lanreotide, leuprolide, octreotide, pegvisomant, protirelin, tic agents. salcotonin, Somatropin, tetracosactide, thyroxine and 28) Benzodiazepines such as, for example, alprazolam, bro vasopressin. mazepam, brotizolam, chlordiazepoxide, clobazam, clon 44) Hypoglycaemics Such as, for example, Sulphonylureas azepam, cloraZepate, demoxepam, diazepam, estazolam, including , , , flunitrazepam, flurazepam, halazepam, ketazolam, lopra 35 and ; biguanides including metformin; thiazo Zolam, lorazepam, lormetazepam, medazepam, mida lidinediones including pioglitaZone, rosiglitaZone, nateg Zolam, nitrazepam, nordazepam, oxazepam, praZepam, linide, and acarbose. quazepam, temazepam and triazolam. 45) Immunoglobulins. 29) Bisphosphonates Such as, for example, alendronate 46) Immunomodulators such as, for example, interferon (e.g. Sodium, Sodium clodronate, etidronate disodium, iban 40 interferon beta-la and interferon beta-Ib) and glatiramer. dronic acid, pamidronate disodium, isedronate Sodium, 47) Immunosupressives Such as, for example, azathioprine, tiludronic acid and Zoledronic acid. cyclosporin, mycophenolic acid, rapamycin, sirolimus and 30) Blood modifiers such as, for example, cilostazol and tacrolimus. dipyridamol, and blood factors. 48) Mast cell stabilizers such as, for example, cromoglycate, 31) Cardiovascular agents such as, for example, acebutalol, 45 iodoxamide, nedocromil, ketotifen, tryptase inhibitors and adenosine, amiloride, , atenolol, benazepril, pemirolast. bisoprolol, bumetanide, candesartan, captopril, clonidine, 49) Drugs for treatment of migraine headaches such as, for , disopyramide, dolfetilide, doxazosin, enalapril, example, , alperopride, amitriptyline, amoxap esmolol, ethacrynic acid, flecanide, furosemide, gemfi ine, atenolol, clonidine, codeine, coproxamol, cyprohepta brozil, , irbesartan, labetolol, losartan, lovastatin, 50 dine, dextropropoxypene, , diltiazem, metolaZone, , mexiletine, nadolol, , doxepin, , , fluoxetine, , pindolol, prazosin, procainamide, propafenone, propra , lidocaine, lisinopril, lisuride, loxapine, nolol, quinapril, , ramipril, Sotalol, spironolac , metoclopramide, metoprolol, nadolol. tone, telmisartan, tocamide, torsemide, , Valsar , , oxycodone, paroxetine, pizo tan and . 55 tifen, pizotyline, prochlorperazine propanolol, pro 32) blockers such as, for example, amlo poxyphene, protriptyline, , Sertraline, Sumatrip dipine, , diltiazem, , , gallo tan, timolol, , , Verapamil, pamil. , , , , , and non-steroidal anti-inflammatory drugs. nifedipine, and Verapamil. 50) Drugs for treatment of motion sickness such as, for 33) Central nervous system stimulants such as, for example, 60 example, diphenhydramine, promethazine and Scopola amphetamine, brucine, caffeine, , dextro mine. amphetamine, ephedrine, fenfluramine, mazindol, methy 51) Mucolytic agents such as N-, ambroXol. phenidate, modafmil, pemoline, phentermine and Sibutra amiloride, dextrans, heparin, desulphated heparin, low mine. molecular weight heparin and recombinant human DNase. 34) Cholesterol-lowering drugs such as, for example, acipi 65 52) Drugs for multiple Sclerosis management Such as, for moX, atorvastatin, ciprofibrate, colestipol, colestyramine, example, , methylprednisolone, mitoxantrone bezafibrate, ezetimibe, fenofibrate, fluvastatin, gemfi and prednisolone. US 9,381,189 B2 15 16 53) Muscle relaxants such as, for example, baclofen, chlor rahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4- ZOXaZOne, , methocarbamol, methoxybenzylamino)-5-N-(2-morpholinoethyl) orphenadrine, quinine and . carbamoyl-pyrimidine, and (S)-2-(2-hydroxymethyl-1- 54) NMDA receptor antagonists such as, for example, pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5- mementine. 5 N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl-pyrimidine). 55) Nonsteroidal anti-inflammatory agents such as, for 63) modulators such as, for example, cro example, aceclofenac, acetaminophen, alminoprofen, makalim, , glibenclamide, levcromakalim, amfenac, aminopropylon, amiXetrine, aspirin, benoxapro , and . fen, bromfenac, bufexamac, carprofen, celecoxib, choline, 64) Prostaglandins such as, for example, alprostadil, dinopro cinchophen, cinmetacin, clometacin, clopriac, diclofenac, 10 stone, epoprostanol and misoprostol. diclofenac sodium, diflunisal, ethenZamide, etodolac, 65) Respiratory agents and agents for the treatment of respi etoricoxib, fenoprofen, flurbiprofen, , ratory diseases including bronchodilators such as, for indomethacin, indoprofen, ketoprofen, ketorolac, loxopro example, the B2-agonists , bitolterol, brox fen, maZipredone, meclofenamate, , aterol, , , fenoterol, formoterol, meloxicam, nabumetone, naproxen, , pare 15 , levalbuterol, metaproterenol, , coxib, phenylbutaZone, piroxicam, pirprofen, rofecoxib, picumeterol, pirbuterol, procaterol, , , Salicylate, Sulindac, tiaprofenic acid, tolfenamate, tolmetin salbutamol, salmeterol, and the like; inducible and Valdecoxib. synthase (iNOS) inhibitors; the antimuscarin 56) Nucleic-acid medicines Such as, for example, oligonucle ics ipratropium, ipratropium bromide, oxitropium, tiotro otides, decoy nucleotides, antisense nucleotides and other pium, glycopyrrolate and the like; the Xanthines amino gene-based medicine molecules. phylline, theophylline and the like; adenosine receptor 57) Opiates and Such as, for example, alfentanil, antagonists, cytokines such as, for example, interleukins allylprodine, alphaprodine, anilleridine, benzylmorphine, and interferons; cytokine antagonists and chemokine bezitramide, buprenorphine, , carbiphene, antagonists including cytokine synthesis inhibitors, endot cipramadol, clonitaZene, codeine, codeine phosphate, dex 25 helin receptor antagonists, elastase inhibitors, integrin tromoramide, , diamorphine, dihy inhibitors, leukotrine receptor antagonists, prostacyclin drocodeine, dihydromorphine, diphenoxylate, dipipanone, analogues, and ablukast, ephedrine, epinephrine, fenleu fentanyl, hydromorphone, L-alpha acetyl methadol, levor ton, iloprost, iralukast, isoetharine, isoproterenol, mon phanol, lofentanil, loperamide, meperidine, meptazinol, telukast, OntaZolast, pranlukast, , sibena , metopon, , , , 30 det, tepoxalin, Verlukast, Zafirlukast and Zileuton. Oxycodone, papaveretum, , , 66) Sedatives and hypnotics such as, for example, alpra , pholcodeine, remifentanil, Sufentanil, trama Zolam, butalbital, chlordiazepoxide, diazepam, estazolam, dol, and combinations thereof with an anti-emetic. flunitrazepam, flurazepam, lorazepam, midazolam, 58) Opthalmic preparations such as, for example, betaxolol temazepam, triazolam, , Zolpidem, and Zopiclone. and ketotifen. 35 67) Serotonin agonists such as, for example, I-(4-bromo-2,5- 59) Osteoporosis preparations such as, for example, alendr dimethoxyphenyl)-2-aminopropane, buspirone, m-chlo onate, estradiol, estropitate, raloxifene and risedronate. rophenylpiperazine, , ergot alkaloids, gepirone, 60) Other analgesics such as, for example, apaZone, benzpip 8-hydroxy-(2-N,N-dipropylamino)-tetraline, ipsaperone, erylon, , caffeine, , clonixin, lysergic acid diethylamide, 2-methyl serotonin, meza ethoheptazine, , , orphenadrine, penta 40 copride, Sumatriptan, tiaspirone, and . Zocine, propacetamol and propoxyphene. 68) Serotonin antagonists such as, for example, amitryptiline, 61) Other anti-inflammatory agents such as, for example, aZatadine, chlorpromazine, clozapine, cyproheptadine, B-cell inhibitors, p38 MAP kinase inhibitors and TNF dexfenfluramine, R(+)-O-(2,3-dimethoxyphenyl)-I-2-(4- inhibitors. fluorophenyl)ethyl-4-piperidine-methanol, , 62) Phosphodiesterase inhibitors such as, for example, non 45 fenclonine, fenfluramine, granisetron, ketanserin, methy specific phosphodiesterase inhibitors including theophyl Sergide, metoclopramide, mianserin, ondansetron, risperi line, theobromine, IBMX, pentoxifylline and papaverine; done, , trimethobenzamide and tropisetron. phosphodiesterase type 3 inhibitors including bipyridines 69) Steroid drugs such as, for example, alcometaSone, Such as milrinone, aminone and olprinone; imidazolones beclomethasone, beclomethasone dipropionate, Such as piroXimone and enoXimone; imidazolines such as 50 betamethasone, budesonide, butiXocort, ciclesonide, clo imaZodan and 5-methyl-imaZodan; imidazo-quinoxalines; betasol, deflazacort, diflucortolone, desoxymethasone, and dihydropyridaZinones Such as indolidan and LYI dexamethasone, fludrocortisone, flunisolide, fluocinolone, 81512 (5-(6-oxo-I, 4.5, 6-tetrahydro-pyridazin-3-yl)-1,3- fluometholone, fluticaSone, fluticasone proprionate, dihydro-indol-2-one); dihydroquinolinone compounds hydrocortisone, methylprednisolone, mometaSone, nan Such as cilostamide, cilostazol, and Vesnarinone; motapi 55 drolone decanoate, neomycin Sulphate, prednisolone, Zone; phosphodiesterase type 4 inhibitors such as cilomi rimexolone, rofileponide, triamcinolone and triamcinolone last, etazolate, rolipram, oglemilast, roflumilast, ONO acetonide. 6126, tolafentrine and Zardaverine, and including quinazo 70) Sympathomimetic drugs such as, for example, adrena linediones such as nitraquaZone and nitraduaZone analogs; line, dexamfetamine, dipirefin, dobutamine, dopamine, xanthine derivatives such as denbufylline and arofylline: 60 , , noradrenaline, phenylephrine, tetrahydropyrimidones such as atizoram; and oxime car pseudoephedrine, tramazoline and Xylometazoline. bamates such as filaminast; and phosphodiesterase type 5 71) Nitrates such as, for example, glyceryl trinitrate, isosor inhibitors including sildenafil. Zaprinast, Vardenafil, tad bide dinitrate and isosorbide mononitrate. alafil, dipyridamole, and the compounds described in WO 72) Skin and mucous membrane agents such as, for example, 01/19802, particularly (S)-2-(2-hydroxymethyl-1-pyrro 65 bergapten, isotretinoin and methoXSalen. lidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-N-(2- 73) Smoking cessation aids such as, for example, , pyrimidinylmethyl)carbamoylpyrimidine, 2-(5,6,7,8-tet nicotine and Varenicline. US 9,381,189 B2 17 18 74) Drugs for treatment of Tourette's syndrome such as, for In a further embodiment of the present invention there is example, pimozide. provided a composition, preferably a pharmaceutical compo 75) Drugs for treatment of urinary tract infections such as, for sition, comprising an active ingredient made by a method example, darifenicin, , propantheline bromide according to the present invention in combination with an and tolteridine. additional ingredient Such as an additive, carrier and/or fla 76) Vaccines (e.g. solid vaccines). vouring agent or other excipient. 77) Drugs for treating vertigo Such as, for example, betahis In one aspect the additive material is an anti-adherent mate tine and . rial that will tend to decrease the cohesion between the active 78) Therapeutic proteins and peptides such as acylated insu ingredient, and between the active ingredient and other par lin, glucagon, glucagon-like peptides, exendins, insulin, 10 ticles present in the pharmaceutical composition. insulin analogues, insulin aspart, insulin detemir, insulin The additive material may be an anti-friction agent (gl glargine, insulin glulisine, insulin lispro, insulin , idant), suitably to give better flow of the pharmaceutical com isophane insulins, neutral, regular and insoluble insulins, position in, for example, a dry powder inhaler which will lead and protamine Zinc insulin. Suitable proteins are solid pro to a better dose reproducibility. teins. 15 Where reference is made to an anti-adherent material, or to 79) Anticancer agents such as, for example, anthracyclines, an anti-friction agent, the reference is to include those mate doxorubicin, idarubicin, epirubicin, methotrexate, taxanes, rials which are able to decrease the cohesion between the paclitaxel, docetaxel, cisplatin, Vinca alkaloids, Vincristine particles, or which will tend to improve the flow of powder in and 5-fluorouracil. an inhaler, even though they may not usually be referred to as 80) Pharmaceutically acceptable salts or derivatives of any of anti-adherent material or an anti-friction agent. For example, the foregoing. leucine is an anti-adherent material as herein defined and is In addition, the active ingredient used in the present inven generally thought of as an anti-adherent material but lecithin tion may be small molecules, proteins, carbohydrates or mix is also an anti-adherent material as herein defined, even tures thereof. though it is not generally thought of as being anti-adherent, It should be noted that drugs listed above under a particular 25 because it will tend to decrease the cohesion between the indication or class may also find utility in other indications. A active ingredient and between the active ingredient and other plurality of active agents can be employed in the practice of particles present in the pharmaceutical composition. the present invention. Active ingredients made in the present The additive material may be in the form of particles which invention may be combined with other active ingredients, tend to adhere to the Surfaces of active ingredient, as disclosed optionally also be made by processes of the present invention, 30 in WO1997/03649. Alternatively, the additive material may Suitably to form a drug for inhalation. be coated on the surface of the active ingredient by a co Specific combinations of two medicaments which may be milling method, as disclosed in WO 2002/43701. Therefore, mentioned include combinations of steroids and B2-agonists. in one aspect of the invention, the method may further com Examples of Such combinations are beclomethasone and for prise and additional step of coating the Surface of the active moterol; beclomethasone and salmeterol; fluticaSone and for 35 ingredient with an additive material (e.g. by a co-milling moterol; fluticasone and Salmeterol; budesonide and formot method). erol; budesonide and salmeterol; flunisolide and formoterol; The additive material may include one or more compounds flunisolide and salmeterol, ciclesonide and formoterol; selected from amino acids and derivatives thereof, and pep ciclesonide and salmeterol; mometaSone and formoterol; and tides and derivatives thereof. Amino acids, peptides and mometasone and salmeterol. Other combinations include 40 derivatives of peptides are Suitably physiologically accept B2-agonists and antimuscarinics, as well as the combination able and give acceptable release of the active ingredient on of steroid, LAMA (long-acting ) and inhalation. LABA (Long-acting beta2-). Such as a steroid, tiotro The additive may comprise one or more of any of the pium (LAMA) and formoterol (LABA). following amino acids: leucine, isoleucine, , Valine, In one aspect, APIs for use in the invention are able to be 45 methionine, and . The additive may be a salt or micronised by impact milling or, more Suitably, by jet milling. a derivative of an amino acid, for example aspartame or The skilled person will also appreciate those physical acesulfame K. Preferably, the additive consists substantially parameters, such as indentation hardness, will assist in the of an amino acid, more preferably of leucine, advantageously identification of those actives (also called active pharmaceu L-leucine. The L-, D- and DL-forms of an amino acid may tical ingredients or APIs herein) suitable for working accord 50 also be used. As indicated above, leucine has been found to ing to the teachings of the invention. Furthermore, the skilled give particularly efficient dispersal of the active ingredient on person would understand what processes are required to inhalation. modify unsuitable APIs in order to make them suitable for The additive may include one or more water soluble sub working according to the invention. For example, Vickers stances. A water Soluble Substance may be a substance that hardness test, Brinell hardness test, Knoop hardness test, 55 may be capable of dissolving wholly or partly in water and Meyer hardness test, Rockwell hardness test, Shore durom which is not entirely insoluble in water. This may help absorp eter hardness or the Barcol hardness test, may be used to tion of the additive by the body if it reaches the lower lung. assess the suitability of the target API. Those APIs initially The additive may include dipolar ions, which may be Zwitte found unsuitable for working according to the present inven rions. It is also advantageous to include a spreading agent as tion, may be, for example, cryogenically treated prior to or 60 an additive, to assist with the dispersal of the composition in during working. the lungs. Suitable spreading agents include Surfactants such In one embodiment of the present invention, there is pro as known lung surfactants (e.g. ALECTM) which comprise vided an active ingredient obtainable or obtained using any of phospholipids, for example, mixtures of DPPC (dipalmitoyl the methods described in the specification, suitably in the phosphatidylcholine) and PG (phosphatidylglycerol). Other form of a powder such as a dry powder, the latter suitably 65 Suitable Surfactants include, for example, dipalmitoyl phos containing less than 10%, more preferably less than 7% or phatidyl than olamine (DPPE), dipalmitoyl phosphatidyli most preferably less that 5% (w/w) water or other fluid. nositol (DPPI). US 9,381,189 B2 19 20 The additive may comprise a metal Stearate, or a derivative of a powder material and then combining the active ingredi thereof, for example, Sodium Stearyl fumarate or sodium ents or, more Suitably, active ingredient with another agent, Stearyl lactylate. Advantageously, it comprises a metal Stear Such as another active ingredient, an excipient or additive. ate, for example, Zinc Stearate, Stearate, calcium The invention further relates to a method of processing an stearate, sodium stearate or lithium stearate. Preferably, the active ingredient, the method comprising Submitting micro additive material comprises magnesium Stearate, for example nised active ingredients or, more Suitably, a micronised active Vegetable magnesium Stearate, or any form of commercially ingredient alone to compression and shearing forces and then available metal stearate, which may be of vegetable or animal combining the active ingredients or, more Suitably, active origin and may also contain other fatty acid components such ingredient with another agent. Such as another active ingre as palmitates or oleates. 10 dient, an excipient or additive. The invention provides an active ingredient for use in a The additive may include or consist of one or more surface pharmaceutical composition, preferably a pharmaceutical active materials. A surface active material may be a substance composition for inhalation, more preferably a powder for a capable reducing the Surface tension of a liquid in which it is dry powder inhaler. Preferably, the active ingredient may be dissolved. Surface active materials may in particular be mate for use in a pharmaceutical composition for a pressurized rials that are surface active in the solid state, which may be 15 water soluble or water dispersible, for example lecithin, in metered dose inhaler (pMDI). particular soya lecithin, or substantially water insoluble, for The invention further provides an active ingredient example solid state fatty acids such as oleic acid, lauric acid, obtained by the method of the present invention for use in palmitic acid, Stearic acid, erucic acid, behenic acid, or medicine, and use of an active ingredient obtained by the derivatives (such as esters and salts) thereof Such as glyceryl method of the present invention in the preparation of a medi behenate. Specific examples of such materials are phosphati cament for prevention or treatment of disease, for example, dylcholines, phosphatidylethanolamines, phosphatidylglyc including diseases approved for treatment with known active erols and other examples of natural and synthetic lung Sur ingredients listed above. factants; lauric acid and its salts, for example, Sodium lauryl In another embodiment of the present invention, powders Sulphate, magnesium lauryl Sulphate; triglycerides Such as in accordance with the present invention may be administered Dynsan 118 and Cutina HR; and Sugar esters in general. 25 using active or passive devices. Alternatively, the additive may be cholesterol. In one embodiment of the invention, the inhaler device is an Other possible additive materials include sodium benzoate, active device, in which a source of compressed gas or alter hydrogenated oils which are solid at room temperature, talc, native energy source is used. Examples of Suitable active titanium dioxide, aluminium dioxide, silicon dioxide and devices include AspirairTM (Vectura), MicrodoseTM and the starch. Also useful as additives are film-forming agents, fatty 30 active inhaler device produced by Nektar Therapeutics (as acids and their derivatives, as well as lipids and lipid-like covered by U.S. Pat. No. 6,257.233). materials. In an alternative embodiment, the inhaler device is a pas In one aspect additive particles are composed of lactose. sive device, in which the patient’s breath is the only source of The additive particles may be lactose fines. The additive gas which provides a motive force in the device. Examples of lactose may be added a various stages of the formulation “passive dry powder inhaler devices include the RotahalerTM assembly or the additive lactose may be formed as a result of and DiskhalerTM (GlaxoSmithKline) and the TurbohalerTM processing of a larger lactose carrier particle. Said processing (Astra-Draco), MonohalerTM (Miat), GyroHalerTM (Vectura) produces Smaller lactose particles that may adhere to the and NovolizerTM (Viatris GmbH). larger carrier particles or combine with different components The size of the doses can vary from micrograms to milli of the composition. grams, depending upon the active ingredient, the delivery In one aspect a plurality of different additive materials can 40 device and disease to be treated. Suitably the dose will range be used. from 1 ng to 50mg of active ingredient, more preferably 10ug Carrier particles may be of any acceptable inert excipient to 20 mg being preferred and most preferably 100 ug to 10 mg material or combination of materials. For example, carrier being more preferred. The skilled artisan will appreciate that particles frequently used in the prior art may be composed of dose of the active will depend on the nature of the active one or more materials selected from Sugar alcohols, polyols 45 pharmaceutical ingredient, therefore a dose of 1 mg to 10 mg. and crystalline Sugars. Other Suitable carriers include inor more preferably 2 mg to 8 mg, more preferably 3 mg to 7 mg ganic salts such as Sodium chloride and calcium carbonate, and most preferably 4 mg to 5 mg is required. Alternatively a organic salts such as Sodium lactate and other organic com dose of 5 mg to 15 mg, more preferably 6 mg to 14 mg., more pounds Such as polysaccharides and oligosaccharides. preferably 7 mg to 13 mg and most preferably 8 mg to 12 mg Advantageously, the carrier particles comprise a polyol. In 50 is required. Alternatively a dose of 10 mg to 20 mg, more particular, the carrier particles may be particles of crystalline preferably 12 mg to 18 mg, more preferably 14 mg to 16 mg Sugar, for example mannitol, dextrose or lactose. Preferably, and most preferably 14.5 mg to 15.5 mg is required. Alterna the carrier particles are composed of lactose. Suitable tively a dose of 20 mg to 25 mg, more preferably 21 mg to 24 examples of such excipient include LactoHale 300 (Friesland mg, more preferably 22 mg to 23 mg and most preferably 22.5 Foods Domo), LactoHale 200 (Friesland Foods Domo), Lac mg is required. Doses referred to above are nominal doses. toHale 100 (Friesland Foods Domo), Prismallac 40 55 Reference to doses herein is generally a reference to (Meggle). Inhallac 70 (Meggle). metered doses (MD) (or nominal doses (ND), the two terms The ratio in which the carrier particles (if present) and may be used interchangeably). The MD is the dose of active active ingredient are mixed will depend on the type of inhaler pharmaceutical ingredient in the blister or capsule or formu device used, the type of active particle used and the required lation holding receptacle. dose. The carrier particles may be present in an amount of at 60 The emitted dose (ED) or delivered dose (DD) (the two least 50%, more preferably 70%, advantageously 90% and terms may be used interchangeably) is the total mass of the most preferably 95% based on the combined weight of the active agent emitted from the device following actuation. It active ingredient and the carrier particle. does not include the material left on the internal or external The invention also relates to a method of processing an Surfaces of the device, or in the metering system including, active ingredient, the method comprising Submitting micro 65 for example, the capsule or blister. The ED is measured by nised active ingredients or, more Suitably, a micronised active collecting the total emitted mass from the device in an appa ingredient to compression and shearing forces in the absence ratus frequently identified as a dose uniformity sampling US 9,381,189 B2 21 22 apparatus (DUSA), and recovering this by a validated quan replaced with references to processing of other pharmaceuti titative wet chemical assay (a gravimetric method is possible, cally acceptable ingredients, as appropriate. but this is less precise). The ingredient may be combined with other components of The fine particle dose (FPD) is the total mass of active a pharmaceutical composition, such as an active ingredient or agent which is emitted from the device following actuation 5 excipient. In one aspect such other components may also have which is present in an aerodynamic particle size Smaller than been Subjected to compression and shearing forces in the a defined limit. This limit is generally taken to be 5 um absence of another powder material. MMAD if not expressly stated to be an alternative limit, such It will be understood that particular embodiments as 3 Lum, 2 Lim or 1 Lum, etc. described herein are shown by way of illustration and not as The fine particle fraction (FPF) is normally defined as the 10 limitations of the invention. The principal features of this FPD (the dose that is <5 um MMAD) divided by the delivered invention can be employed in various embodiments without Dose (DD) which is the dose that leaves the device. The FPF departing from the scope of the invention. Those skilled in the is expressed as a percentage. Herein, the FPF of DD is art will recognize, or be able to ascertain using no more than referred to as FPF (DD) and is calculated as FPF (DD)=(FPD/ 15 routine study, numerous equivalents to the specific proce DD)x100%. dures described herein. Such equivalents are considered to be The fine particle fraction (FPF) may also be defined as the within the scope of this invention and are covered by the FPD divided by the Metered Dose (MD) which is the dose in claims. All publications and patent applications mentioned in the blister or capsule, and expressed as a percentage. Herein, the specification are indicative of the level of skill of those the FPF of MD is referred to as FPF (MD), and may be skilled in the art to which this invention pertains. All publi calculated as FPF (MD)=(FPD/MD)x100%. cations and patent applications are herein incorporated by According to an embodiment of the present invention, a reference to the same extent as if each individual publication receptacle is provided, holding a dose of the active ingredient or patent application was specifically and individually indi prepared according to the present invention. The receptacle cated to be incorporated by reference. The use of the word “a” may be a capsule or blister, preferably a foil blister. 25 or “an' when used in conjunction with the term “comprising Active ingredient, Suitably in the form of a powder, in in the claims and/or the specification may mean "one.” but it accordance with the present invention may be pre-metered. is also consistent with the meaning of “one or more.” “at least The powders may be kept infoil blisters which offer chemical one, and "one or more than one.” The use of the term 'or' in and physical protection whilst not being detrimental to the the claims is used to mean “and/or unless explicitly indicated overall performance. Indeed, the formulations thus packaged 30 tend to be stable over long periods of time, which is very to refer to alternatives only or the alternatives are mutually beneficial, especially from a commercial and economic point exclusive, although the disclosure supports a definition that of view. refers to only alternatives and “and/or.” Throughout this In one embodiment, the composition according to the application, the term “about is used to indicate that a value present invention is held in a receptacle containing a single 35 includes the inherent variation of error for the measurement, dose of the powder, the contents of which may be dispensed the method being employed to determine the value, or the using one of the aforementioned devices. variation that exists among the study Subjects. Reservoir devices may also be used. As used in this specification and claim(s), the words "com The invention also relates to a method of processing an prising (and any form of comprising. Such as “comprise' and active ingredient, the method comprising Submitting an active 40 “comprises”), “having (and any form of having, such as ingredient to compression and shearing forces in the absence “have” and “has'), “including (and any form of including, of another powder material, optionally then combining the such as “includes and “include’) or “containing (and any active ingredient with another agent, Such as another active form of containing, Such as “contains and “contain’) are ingredient, an excipient or additive, and then packaging the inclusive or open-ended and do not exclude additional, unre active ingredient into a receptacle or drug delivery device. 45 cited elements or method steps. In one aspect the invention relates to a method of process The term “or combinations thereofas used herein refers to ing an ingredient for use in a pharmaceutical composition, the all permutations and combinations of the listed items preced method comprising Submitting the ingredient to compression ing the term. For example, A, B, C, or combinations thereof and shearing forces in the absence of another powder mate is intended to include at least one of A, B, C, AB, AC, BC, or rial. 50 ABC, and if order is important in a particular context, also In the embodiments discussed above, the ingredient is an BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing active agent, such as a drug, capable of having a prophylactic with this example, expressly included are combinations that or therapeutic effect. However, alternatively, the ingredient is contain repeats of one or more item or term, such as BB, a pharmaceutically acceptable component other than an AAA, BBC, AAABCCCC, CBBAAA, CABABB, and so active, for example, an excipient Such as an additive, carrier 55 forth. The skilled artisan will understand that typically there and/or flavouring agents and/or taste masking agent as is no limit on the number of items or terms in any combina described above, which then may optionally be used in com tion, unless otherwise apparent from the context. bination with an active to provide a pharmaceutical compo All of the compositions and/or methods disclosed and sition. claimed herein can be made and executed without undue The above disclosure made in relation to the processing of 60 experimentation in light of the present disclosure. While the active ingredients applies equally to a method for processing compositions and methods of this invention have been other pharmaceutically acceptable ingredients, such as described interms of preferred embodiments, it will be appar excipients, and to pharmaceutical compositions comprising ent to those of skill in the art that variations may be applied to the ingredient, delivery devices comprising the ingredient the compositions and/or methods and in the steps or in the and packaged doses of the pharmaceutical composition com 65 sequence of steps of the method described herein without prising the ingredient, unless otherwise apparent from the departing from the concept, spirit and scope of the invention. context, and references to processing of active may be All Such similar Substitutes and modifications apparent to US 9,381,189 B2 23 24 those skilled in the art are deemed to be within the spirit, (powder addition), 5 mins (a) 20% speed, stepped up to 80% Scope and concept of the invention as defined by the appended speed (10% increments) for 10 minutes. Closed loop chilling claims. unit 19°C. setpoint. The present invention is illustrated by the by the experi Results mental data set out below, which is not limiting upon the Convexity, (table 1) invention: Circularity, (table 1) DVS, (table 2 & 3) EXAMPLES ACI, (table 2) Surface area, (table 4) In the experiments, the active ingredient used was 10 Particle Size, (table 1) Sumatriptan succinate. Different treatments of the active were compared for different physical properties, as listed below: Example 1.3 Example 1.1 Jet Milled and MCB Processed Sumatriptan 15 Succinate with Elevated Humidity Jet Milled Sumatriptan Succinate Jet Milling, Convexity, Circularity, DVS, ACI, Surface This example studied the disordered/amorphous content of area, Particle Size, circular equivalent diameter, were carried jet milled Sumatriptan Succinate. out as in example 1. The same Jet milled batch as example 1.1 Methods was used. Jet Milling, of blend CSS090120RPA, was carried out MCB processing was carried out on blend using AS50 spiraljet mill (Hosokawa), Sumatriptan Succinate CSSO90121KCA, Hosokawa minikit, 1 mm rotor gap, 20 g (Natco), feed rate (first pass) 3.2 g/min, feed rate (second batch size, elevated humidity Supplied by humidifying an pass) 4 g/min, compressed air Supply, Venturi 5 bar, grind 3 25 external chamber and transferred via tubing, Solenoid and bar, on a 100 g batch size. pump (2 l/min), humidity measured by thermohygrom Convexity, (number distribution), circularity (number dis eter 81.6% RH. Powder processing: 5 minutes (a) 5% speed tribution) and circular equivalent diameter (number distribu (powder addition), 5 mins (a) 20% speed, stepped up to 80% tion) were measured by Morphologi G3 optical microscope speed (10% increments) for 10 minutes. Closed loop chilling on a dry dispersion of 1 mm of material using 25um foil. The 30 unit setpoint 19°C. parameters were 4 bar injection pressure, injection time 10 Results ms, settling time 120 seconds. X20 magnification. Trash size Convexity, (table 1) 10 pixels. Approx 5000 particles measured. Circularity, (table 1) DVS, sample size approximately 100 mg. The sample was DVS, (table 2 & 3) then analysed using a Surface Measurement Systems DVS1 35 with the following programme: % RH: 0, 20, 40, 50, 60, 70, ACI, (table 2) 80, 90 two symmetrical cycles at 40°C. with a set step time Surface area, (table 4) of 90 minutes. Particle Size, (table 1) ACI, Device (F1), Blister 17.2 mg fill weight (nominal Example 1.4 dose of Sumatriptan=12.29 mg). Flow rate and time adjusted 40 to achieve a 4 kPa pressure drop and 4 liters of air (in the region of 60.1/min and 4 seconds). Jet Milled and MCB Processed Sumatriptan Surface area, BET by Beckman Coulter SA3100 Gas Succinate with Reduced Humidity Adsorption Apparatus 3-10 hr outgas at 60° C. max. BET profile. 60°C. max during analysis. Sample size 160 mg-860 45 Jet Milling, blend CSS080828RPA, was carried out using ng. AS 50 spiral jet mill (Hosokawa), Sumatriptan succinate The results of analysis is listed below: (Natco), feed rate (first pass)3 g/min, feed rate (second pass) Convexity, (table 1) 3 g/min, compressed air Supply, Venturi 5 bar, grind 3 bar. 80 Circularity, (table 1) g batch size. DVS, (table 2 & 3) 50 MCB processing was carried out on blend ACI, (table 2) CSS080829RPA, using a Hosokawa minikit, 1 mm rotor gap, Surface area, (table 4) 20g batch size, reduced humidity Supplied by compressed air Particle Size, (table 1) via tubing, Solenoid and pump (2 l/min), humidity measured by thermohygrometer-LT 10% RH. Powder processing: 5 Example 1.2 55 minutes (a) 5% speed (powder addition), 5 mins (a 20% speed, stepped up to 80% speed (10% increments) for 10 Jet Milled Sumatriptan Succinate which is Processed minutes. Mains water cooled at 19°C. by MCB DVS and ACI analysis was carried out according to Example 1.1. Methodology 60 Particle Size was assessed using a Malvern Mastersizer Jet Milling, Convexity, Circularity, DVS, ACI, Surface 200, with a dry cell dispersion. area, Particle Size and circular equivalent diameter, were all Results carried out as in example 1.1 The same jet milled batch as DVS, see (table 2) example 1.1 was used. ACI, see (table 2) MCB processing was carried out using blend 65 Surface area, 4.28 m/g CSSO90121 RPA and a Hosokawa minikit, 1 mm rotor gap, 20 Particle Size, d0.1 um=0.761, d0.5 um=1.787, d0.9 g batch size, Powder processing: 5 minutes (a) 5% speed um=3.692

US 9,381,189 B2 27 28 TABLE 1-continued

Morphologi G3 data table - circularity, convexity and particle size for: i) jet milled Sumatriptan Succinate. ii) jet milled and MCB processed Sumatriptan Succinate in ambient conditions. iii) jet milled and MCB processed in raised humidity.

Con Combined Cir Combined Con- Rep- vex convexity cular circularity CE Mean CE CE Mean CE CE Mean CE Time di- li- ity le:8 ity (8. diameter diameter diameter diameter diameter diameter point tions Sample cate Mean (of 3 reps) mean (of 3 reps) D(0.1) Im D(0.1) Im D(0.5) Im D(0.5) Im D(0.9) Im D(0.9) Im

CSSO9012 2 O.986 O.934 1.09 2.04 3.69 1KCA 3 O.990 O.942 1.01 1.93 3.56 40.75 Jet milled 1 O.988 O.987 O.935 0.931 O.99 O.94 1.97 1.91 3.92 3.92 CSSO9012 2 O.987 O.931 O.94 1.87 3.94 ORPA 3 O.986 O.926 O.88 1.90 3.90 St MCB 1 O.977 O.982 O.911 O.922 1.00 1.OS 2.35 2.26 4.61 4.44 CSSO9012 2 O.98S O.930 120 2.34 4.6O 1RPA 3 O.983 O924 O.94 2.09 4.10 Hum MCB 1 O.983 O.986 O928 0.934 1.11 1.10 2.18 2.14 4.13 4.O3 CSSO9012 2 O.987 O.935 1.13 2.17 4.09 1KCA 3 O.989 O.938 1.06 2.08 3.88

TABLE 2 ACI and DVS results for: i) jet milled Sumatriptan succinate. Ii) jet milled and MCB processed Sumatriptan Succinate in ambient conditions. Iii) jet milled and MCB processed in raised humidity. Iii) jet milled and MCB processed in reduced humidity. 25.60 40.75 Amorphous phase Amorphous phase DD FPD FPF FPF as % content dim, 9% dry FPD FPF as % of content dim, % dry (mg) (mg) (%) of nominal (%) DD (mg) (mg) FPF (%) nominal (%) JetMilled

O 3.60 1.97 SS3 16.0 O.O213 3.60 1.97 55.3 16.0 O.O213 1 6.57 2.90 44.4 23.6 na 7.07 2.86 40.4 23.3 na 2 6.67 2.68 40.9 21.8 na 5.17 2.16 41.3 17.6 na 3 S.S4 2.58 46.70 21.0 O.OO12 5.95 2.37 40.30 19.30 ND 6 6.4O 2.61 41.2O 21.2 O.OO28 7.68 2.87 37.8 23.4 ND St MCB

O 6.52 3.45 S3.6 28.1 O.O120 6.52 3.45 S3.6 28.1 O.O12 1 6.41 3.37 S2.8 27.4 na 5.52 2.78 SO.8 22.6 na 2 7.62 3.51, 46.1 28.6 na 7.66 2.89 38.1 23.5 na 3 5.90 3.OO SO.7 24.4 O.OOO8 5.23 2.35 4S.OO 1910 ND 6 6.85 3.07 45.7 2SO O.OO21 7.90 2.40 30.40 19.50 ND Humid MCB

O 5.39 3.16 6.O.O 25.7 O.O120 5.39 3.16 6O.O 25.7 O.O12 1 6.26 3.26 52.6 26.5 na 6.51 3.25 51.1 26.4 na 2 7.57 3.46 45.9 28.2 na 5.89 2.66 45.8 21.6 na 3 9. OS 3.94 44.O 32.1 O.OO14 6.68 2.66 40.13 21.60 ND 6 9.46 3.33 35.2 27.1 ND 8.73 2.43 27.90 1980 ND

Reduced Humidity MCB Prototype F1 device Amorphous phase DD FPD FPF FPF as % content dim, % dry (mg) (mg) (%) of nominal (%)

O 7.29 3.92 53.77 31.90 O.O121 nia = test not performed. ND = amorphous phase Not Detected. US 9,381,189 B2 29 30 TABLE 3 sion and shearing forces has a less variable profile from T-0 months to T=1 month, in a period where profile of the jet ACI and DVS results for: i) jet milled Sumatriptan succinate. milled product is highly variable, for example, as assessed by ii) jet milled and MCB processed Sumatriptan Succinate in ambient delivered dose. Thus the process of the present invention conditions. iii) iet milled and MCB processed in raised humidity. provides an active with enhanced properties in comparison Mass Loss (% with a jet milled product. Further, as shown by Table 3, the variability of the FPF Process Condition Initial 3 months 6 months (when based upon nominal dose) is less for the mechanofused Jet mill 25 C.60% RH O.O213 O.OO12 O.OO28 active ingredient compared to the active ingredient that has Jet mill 40° C.;75% RH ND ND 10 undergone jetmilling only. Jet mill, MCB 25 C.60% RH O.O12O O.OOO8 O.OO21 What is claimed: Jet mill, MCB 40° C.;75% RH ND ND 1. A method of processing an active ingredient, the method Jet mill, humid 25 C.60% RH O.O12O O.OO14 ND MCB consisting offeeding a pharmaceutically active ingredient to Jet mill, humid 40° C.;75% RH ND ND a mechanofusion apparatus and Subjecting the pharmaceuti MCB 15 cally active ingredient to compression and shearing forces, wherein the active ingredient is micronized prior to compres sion and shearing forces and wherein the active ingredient is glycopyrrolate. TABLE 4 2. The method of claim 1, wherein the active is conditioned BET surface area measurements for: i) jet milled Sumatriptan during compression and shearing. Succinate. ii) jet milled and MCB processed Sumatriptan 3. The method of claim 2, wherein the active is conditioned succinate in ambient conditions. iii) jet milled and MCB by an elevated level of relative humidity compared to ambient processed Sumatriptan Succinate in raised humidity. conditions. T = 6 T = 6 4. The method of claim3, wherein the active is conditioned months (a) months (c) 25 by increasing the relative humidity over time to 70%. T = O 25.60 40.75 BET BET BET 5. The method of claim 1, wherein the active ingredient is Sample Surface Surface Surface conditioned at a minimum temperature. Blend BN description area m/g area m/g area mg 6. The method of claim 2, wherein the active ingredient is CSSO9012ORPA Sumatriptan 4.736 3.944 3.380 conditioned at a minimum temperature. Succinate 30 7. The method of claim 3, wherein the active ingredient is jetmilled conditioned at a minimum temperature. CSSO90121RPA Sumatriptan 3.735 3.311 2.88O 8. The method of claim 4, wherein the active ingredient is Succinate MCB processed conditioned at a minimum temperature. CSSO90121KCA Sumatriptan na 3.237 2.421 9. The method of claim 5, wherein the minimum tempera Succinate 35 ture is at least 50° C. humid MCB 10. The method of claim 6, wherein the minimum tempera processed ture is at least 50° C. 11. The method of claim 7, wherein the minimum tempera ture is at least 50° C. CONCLUSIONS 40 12. The method of claim 8, wherein the minimum tempera ture is at least 50° C. Examples 1-4 13. The method of claim 1, wherein the micronization is impact milling or jet milling. DVS analysis points to the formation of surface disordered 14. The method of claim 13, whereinanamorphous content (amorphous) structure as a result of jet milling technique. The 45 of the active is reduced with respect to the micronised active amorphous content of the same starting material when pro starting material, suitably as measured by DVS. cessed by a process involving compression and shearing, 15. A method of processing an active ingredient according under both humid (82% RH) and dry (10% RH) conditions, to claim 1, wherein the active material is combined after results in a product with less amorphous product after pro compression and shearing with another material, wherein the cessing than jet milling. That product demonstrated higher 50 another material is selected from a group consisting of levels of delivered dose and fine particle fraction, interalia, another active, carrier and additive; or further processed. than a jet milled product. The product of the invention pro 16. A method according to claim 1, wherein the active duced by compression and shearing forces has a greater cir ingredient is packaged after processing into a receptacle or cularity and convexity after treatment than the same jet milled delivery device. product. The product of the invention produced by compres