{MA A 2 USO103282 «2) United States Patent 10) Patent No. US 10,328,216 B2 Boeck! et al. (4s) Date of Patent: Jun, 25, 2019 (54) ENCAPSULATION oF tarormutic 31/352 (201501), AIK 476 (20130) INGREDIENT AOLM 1500 (01301). BOLD 12.08% {Go15.01), 4616 2202064 01301) THAL-TRRE Field of Classification Seareh None (71). Applicane Flurry Poder LLC, Torpon Springs, : funy See application file for complete seach history (72) Inventors: Andrew John Bocekt, Tarpon Springs, (26) Reforen a 1 (US): David Edward Cookson, Us. PanaNT DOCUMENTS Oil. (US) (13); Assignee: larry Powtrs; LUC, Tipo Sig, disntoo A Moan Bout Haas) (Continue), (7) Notise: Subject to any disclaimer the er of this FOREIGN PATENT DOCUMENTS patent is extended or adjoied under 35 ee ape nae wo. uteose at 10194 (21) Appl No. asan17s3 OTTER PUBLICATIONS (22) Filed: San. 20,2017 Insertional Sec Rot aa Wien Opin for PETAI017 (1529 ed Na 30. 2017. 11 pase «) Prior Publication Data Caden Wis 20170232210.A1 Aug 17,2017 ae Primary Esominer — Prot V Amol Related US. Application Date assistant Examiner — Kyung § Chang. (2) Provisional apivaion No. 637290068 led ou Jou. C4) stern sgann ov Pion ape Tousen 20. 2016 Swoiton TLP (1) me 6 ABSTRACT aoa i (200601) method of mimufatoring » flowable amd dispenible AGIK 31/382 2601) Tens Inui adios oe peoder incides solubilizing 9 Hpopilic substance ia 8 GIR 916 (2006.01) terpene 10 fm a mixtre ad eating the mixture Yo fon ASK NG (2006.01) a nancemulsion dispersed in an aqueous solution. ‘The otk 9/14 (2006.01) fsuenos solu includes at Int one fanetonal exien. AGIK 9/00 (2006.01) The nanoemulsion is then spray dried, thereby evaporating, (Continued) fret the agus potion and then the pene wo For cry (2) us.cL poser formed fom solid ples comprising te lipo CPC AGIA HAR (201501); ABER AMS Pll sane (3013.01), 42m 9774 (201301); A6IK 9/1617 2013.01); AGIK 971694 (2013.01), ALK 21 Claims, 8 Drawing Sheets(51) IneeL ALM 15/00 BOLI 13M (36) sonsn asrasz arsose sar Soss37 S928 US 10,328,216 B2 Page 2 (200601) (200601) References Cited US, PATENT DOCUMENTS bast Ss02908 Tere 1w1ps0 11988 19 31980 Jn991 41998 az002 sian 33003 e206 annie Novel ta. Nowell ta Nowell ta Nevll ea Radhakrishnan. ASIK 9.007% as Plas al Wate et a Plate a Pla ta 9.452246 B2 92015. Gumuste etm, 20NOiGI391 AT 42013. Saloman eta BOWwOITVOTH ALY 9.2016 Doky ABIK 3618 OTHER PUBLICATIONS, lsh); Mahmoud A.. "Marijuana and the Cannabis” Sshoot ‘of Phannacy, The Univesity of Masissipg, 2007 Hurmna Press, Inc. NI, 333 pages. reeve om www husunapress.com, ‘Gupta, al, "Fonmilation Suatepesolnpove the Bion sabity ‘of Poorly Abuorbed, Drugs with. Special Lnphasis on Self laying Systems” ISKN Pharmagaaics, Yl 21S: Ao {3,16 pages. tive om gpd oo 10,1188 2015 S450) Jali, eal, “Nano-Eumlsion Production by Sonieation asd ‘Mizrouiiztion A Comparison." IntrationalJorsal of Fo Properties. 2006 ol 9, No.3 p. 475-485; retrieved fom ps: Govt 080 100800 10600554 * cited by examinerU.S. Patent Jun.25,2019 Sheet 1 of 8 US 10,328,216 B2 102-|__ | SOLUBILIZE A LIPOPHILIC SUBSTANCE IN A TERPENE| L ‘OR OTHER ORGANIC SOLVENT TO FORM A MbcTURE 104) | DD ATLEAST ONE FUNCTIONAL EXCIPIENT TO 7] WATER TO FORM AN AQUEOUS SOLUTION ¥ _-y | spense re wnune vo Te Aqueous 106-_| 'Snnmon use a nouocezes oR vireasonrc DewceTOFORMA COARSE EMULSION 108.) TREAT THE COURSE EMULSION WITH AN \-] ULTRASONIC OR HIGH SHEAR DEVICE TO FORM AN. EMULSION WITH NANOSIZED OIL PARTICLES ¥ SPRAY DRY THE AQUEOUS SOLUTION, THEREBY EVAPORATING THE TERPENE AND AN AQUEOUS, PORTION OF THE AQUEOUS SOLUTION TO FORM A DRY POWDER FORMED FROM SOLID PARTICLES THAT INCLUDE THE LIPOPHILIC SUBSTANCE ? FIG. 1 100U.S. Patent 202-\_} Jun. 25,2019 Sheet 2 of 8 DISSOLVE A LIPOPHILIC INGREDIENT IN AN ORGANIC SOLVENT TO FORM A LIPOPHILIC PHASE ] 204-\_ DISSOLVE A SURFACTANT AND/OR EMULSIFIER IN THE LIPOPHILIC PHASE ¥ 2067" DISSOLVE ONE OR MORE EXCIPIENTS INTO WATER| ‘TO FORM AN AQUEOUS PHASE ¥ 208 DISPERSE THE LIPOPHILIC PHASE INTO THE AQUEOUS PHASE TO FORM AN EMULSION THAT INCLUDES NANOSIZED Olt. DROPLETS. I 210-1 ‘SPRAY DRY THE EMULSION TO FORM A DRY POWDER THAT INCLUDES THE LIPOPHILIC INGREDIENT FIG. 2 US 10,328,216 B2 200U.S. Patent Jun. 25,2019 Sheet 3 of 8 3027) MIX AN OIL SOLUTION WITH A WATER SOLUTION TO FORM AN OIL-IN-WATER EMULSION COMPOSITION 304) SPRAY DRY THE OIL-IN-WATER EMULSION TO FORM A DRY POWDER COMPOSITION FIG. 3 US 10,328,216 B2U.S. Patent Jun. 25,2019 Sheet 4 of 8 US 10,328,216 B2 Part A. aqueous phase @ Part B. 0.01 - 0.3 nmoil droplets FIG. 4U.S. Patent Jun. 25, 2019 Sheet 5 of 8 US 10,328,216 B2 120 0505 10. aa, FIG. 5 DHT Gam) | Ox (50) (em). Dx (90) Gum) ] 0268 Size Classes (yen) ot aor H 3 s-| ot 134 (0) Aysuag aunyonU.S. Patent Jun, 25, 2019 Sheet 6 of 8 US 10,328,216 B2 i = S iy if. 8 1, F ga 3 if _ lee § ess sife |* i lial te it (69 sub auTionU.S. Patent Jun. 25,2019 Sheet 7 of 8 US 10,328,216 B2 FIG. 7U.S. Patent Jun, 25, 2019 Sheet 8 of 8 US 10,328,216 B2 180000 1,000 224 190 ‘Size Ciasses (um) 7000 ‘Sample Name Ox (10) (um) Ox (50) Gun) Dx (90) Gum i & eo} G frag on aot “(8 Ass BUYONUS 10,328,216 B2 1 INHALATION CROSS-REFERENCE TO RELATED APPLICATIONS This application is non-provisional of U.S. Provisional Applivation No, 62/280,968, fled on Jan, 20, 2016, the complete disclosure of which is herein incorporated by reference BACKGROUND OF THE INVENTION [Due to their hydrophobic nature and fow solubility in water, lipophilic aetive substances often exhibit poor bio availabilty via the oral gastrointestinal (Gl) delivery route Furthermore, accurate and precise dasing is poor for devas delivered via the Gl system due to inherent varibilty cased by factors such a fasting sate and fist pass metabo: lism. As an altemative, pulmonary delivery using 9 dry powder inhaler (DP!) may be used. Traditional lactose ‘carrer (lactose blend) formulations for DPIs typically offer low dag loads, commonly less than 6% (tA), and low delivery efficiencies (DE), lypically delivering <30% of the dug to the luags. Lactose blends are also highly Dow rate dependent, showing significant variability with respect to sacredynainic performace, Once formulated, lactose blends ‘ely on iater-partice forces to bind mironized drug Wo rwer lactose carrier nartcles to maintain a uniform distribution of ddivg. This enn preseot challenges during transportation and filling of powder into packages. which impast mechanical energy capable of redistdbuting or otherwise disturbing ‘lead uniformity. Engincered particles (eg splay dried) for DPIs oiler ‘Siguifican improvements in dug payload. DE, good serosol performance across a wide flow rates, and a lower risk for supregation of drug from excipients. However, lipophilic ddnig substances are challenging 10 encapsulate into dry, owable, aud dispersible powders that are compatible wil, dey powder inhalers. In alton, oils and fats exhibit poor ‘dissolution and dispersion when incoeparated into aqusons systems Which are common in the preparation of annex. solutions used to produce spray dried powders. This inven- tiom relates (© new uses for terpenes a non-ioxi, natural solubilizers for preparing vehicles (or annex. solutions) prising various drugs, agricultural chemicals, cosmetics, and foods, BRIEF SUMMARY OF THE INVENTION The present disclosare generally relates to dry powder ‘compositions and methods for administering and preparing, such compositions Finbodinents are directed to dey powder ‘compositions in which volatile terpenes are used as process ing aid 10 ereate nanoemutsions containing lipophilic active substances, which may then be stabilized in dey powder form, and to methods for preparing and using such com= pounds. One group of sue lipophilic aetive substaace are exicicis of comaabis, which are commercially avaible as Sticky, resinows cls, oF us high purity crystalline forms. The dry powder compositions may include any suitable lipo- philic substance. Por example, there may be an oil-in-water ‘nanoemulsion composition that includes eannabinesds in the oil fstion that is spray died to form a dry powder 2 ‘composition. The oil-in-ter emulsion compositions may Include « hydrophobic amino seid, e, levee, a distechs- Fide, ex trebalose, andor an oligosaccharide, e.g inulin Such dry powder compositions may he administered to a subject via polmonarytnhalaton, Inne aspect, a method of manufacturing a flowable and dispersible powder ie provided. The method may inelide solubilizing a Tipophilie substance in a terpene fo Tors mixture and treating the mixture wo form a nanoemulsion ‘dispersed in an aqueous solution. The aqueans solution may ude atleast one functional excipient. The terpene fia: tion may include at least one functional excipient. The method may also inclode spraying drying. the nanoenision ‘thereby evaporating atleast a portion ofthe terpene and the majority ofthe water to form & stable dry powder formed from solid particles that inclade the lipophilic substance. In another aspect, method of manufacturing 4 flowable ‘and’ dispersible’ powder inclades dissolving lipophilic ingredient ia an organic solvent to form a lipophilic phase ‘nc dissolving atleast one of surfactant or an emulsifier in the lipopilie phase. The method may alsa include dissoly~ ing one’ of more excipients into water to forms an aqueous phase and chillin the aqueous pase 19 hotween about 1° C. ‘and 10°C. The method may funher include dispersing the Fipophilic phase into the chilled aqueous phase to form an ‘emulsion that inchides nanosized ol droplets. Altemtively. the emulsion may be prepared by heating the organic al ‘aqueous phases 1 besvees 50 and 75° C, The metbod may include spray drying the emulsion to form a dry powder that jncludes one or more lipophilic ingredients In another aspect, a method of manufacturing & lowable and dispersible powder may include mixing an ol solution ‘with a water solution to form an vileio-water emulsion composition. The oil solution may include cannabinoid The method may also include spray drying the oil-in-water ‘emulsion composition wo form & dry powder composition, Tnanother aspect. x dry powder composition ix provided. ‘The dey powder composition may’ include a lipophilic coma portent and one oF more of a kydrophobic amino acid. a \isaecharide. «oligosaccharide surfactant, an emulsifier. 3 stabilizing additive, or a bulking ageat. The dey powder ‘composition may have bulk density between 0.05 and 0.30; ‘Bem’, tp density bowen 0,10 and 0:60 gem", and mois- Ture eoatent helow about 10% ws. The dey powder exon position ay also include between about 0.01% and 60% sw of the lipophilic component In another aspect, a method of arosolizing a dry powder Formulation is provided. The method! may include providing ‘dy powder formulation that as a lipophilic component ‘and one or more ofa hydrophobic amino acid, a disuech ride, a oligosaccharide, a surfictant, au emulsifier, 9 stabi lining additive, ora biking agen. The dry powder compo sition may include between about (101% and 50% ws oF the lipophilic component. The method may also include introducing the dry powder fomulation to sa serosolization device nd introducing the dry powder formulation to a gas furwam within the aerosolization device to disperse the dey powder formulation The features and advantages of the present invention will be apparent to those skilled in the art. While numerous clumges may be made by those skilled in the art, suel ‘humges are within the spirit of the invention. BRIEP DESCRIPTION OF THE DRAWINGS FIG. 1 isa Mowehen depicting @ process for mamalactur- ing a flowable and dispersible powder aecorting 0 embadi-US 10,328,216 B2 3 FIG. 21s 3 Mowehart depicting « process for manufactur: ing a flowable aud dispersible powder according lo enbodi- FIG, 389 Mowehaet depicting a process for mamulact ing lowable ad dispersible powder according io embo- FIG. 4 depicts a schematic of an unnex solution that was prepared for spray drying aeconting to embodimens, FIG. § depicts. griph of a droplet size disebunion after ‘processing int a nanosized oil-in-water enulion according, {o embodiments, HIG. 6484 plot of a optical particle size distnbution of powders spray dried for pulmonary delivery according 10 mbodiments FIG. 7 9 scanning electron microseopy’ image of spray dried panicles conaining cinahinoids acconling to embodiments FIG. 8 isa plot of aa optical particle size distribution of powders spray dried for pulmonary delivery secording 10 embodiments DETAILED DESCRIPTION OF THE INVENTION Embodiments of the preseat invention relate to dry pow: der compositions for improved pulmonar. topical, entra ‘or parenteral delivery of lipophilic substances, and to met ‘ods forthe preparation and use of such compositions. More particularly, volute terpenes are employed as processing, Aids 10 achieve dispersion of the lipopiliefracion(s) in a ‘nanoemlsion which is stabilized and encapsdated in func= tional eseipiens using a spy deving method. Tresment swith nano-sized units of lipophilic drug substances has shown enhanced bioavailability in vivo. as described in T Vi, J. Wan, H. Xu, X. Yang. A new solid selfmicrocmulsi- {ing formulation peepared by spay-deying ta impeove the ‘ral bioavailability of poorly water solble drugs. European Journal of Pharmaceutics and Biopharmacenties, Volume 70, Issue 2, October 2008, Pages 439-444 and in 8. Gupta R. Kesar. A. Oni, Fomnulation Strategies to Tepove the Bioavailability of Poorly Absorbed Drugs with Special Emphasis ont ScleEmolsifying Systems. ISRN Pharmiaces- tics, December 2013, te entre contents of which are hereby incomporsted by reference. The inerease in surface area 0 ‘volume with décreasing particle size resulis in greater poten tial for eficent tanspor and uptake in the human body. ‘Such lipophilic dey powder compositions may’ be adminis- {ered to a subject via pulmonary ination in an amount clletive to trea andor prevent a number of conditions. sel, as systemic and/or lang conditions An inhalable dry powder preparation for lipophilic dra substances offers adhantages over oral GI delivery. For ‘example, pilmonary delivery offers a igh surlacesrea wih ‘rapid absorption det high vascularization and cieumven- tion of the frst poss ellect, a¢ described in Sung, J. C Pulliam, Bo Lx BaWvards, D. A. Nanoparticles for drag delivery wo the lungs. Trends in Biotechnology. 2007, 25, 563-570, the entire contents of which is hereby incoeporated by reference. Rapid daug absomption muy be favorsble ia analgesic, antiometic, and other medicaments, Further, pov ‘der compositions may be engineered such tha a controlled Soetion of the dose impacts the deep lung (Line particle ffuetio) while the remainder impacts mucosa in the upper airways: Such a delivery method results in rapid uptake via the lung followed by a slo, sustained release of dig via GL and transmucosal modes. By these means, pharmacokinetics (of the proivet may be todilsted 4 AA formulation and » spray drying teliique are used to stabilize lipophilic active ingredients in a dry powder having ‘good flow properties and dispersibility- The lipophilie ingre- dents are solubilized andor dilated in carier erpene(s) and the combined mixture is wate! to form a napocmulsion dispersed in an aqueous solution. The aqueous fraction contains dissolved funetional excipients which serve as bulking. encapsulation, stabilizing. and flow enhancement ‘agents. During the spray deying process the aquoons and. {erpene cartier phases evaporate ta form solid particles. The resulting powders exhibit excellent dispersbility into nemo- ol auitable fer pulmonary delivery. Dissolution of powders Jno aqueous liquids prodiees 2 nano-sized dispersion ofthe oil phase. Such methods have proven to be very eliieal, Stable, and exhibit excellent afc to batch cousstency ipophilic ingredients, suchas cannabinoid extracts, are ‘commonly available as sticky. viscous concentrates which present processing challenges for discretization into more desirable nano-sized particles. Dissolving these challenging ‘dnig substances ia solvents reduces surface tension and feuabies their break up into nanosized droplets via high, shear mechanisms such as ulrasonies of mierofhidizers The inclusion of surfactant inthe oil phase stabilizes nano sized droplets in an emulsion by acting aw barrier apainst droplet eoslescence, therehy enhancing emulsion stability Formulating with excipients having low aqueous solbili {(€ levcine}, the nano-sized sticky oil phases encapsulated ‘within a shell which precipitates fmt ding the drying ‘event, This entrapment prodices particles having surlace cchameterstics which are dominated by the encapsulating ‘excipient. Use of eine as an encapsulating excipieat his hhoen show to impr excellent ovvahility ad dispersibility 1 powaers. Canaaoineids area class of compounas genie from Cannabis plants. At leust 113 cannabinoids have been ‘eniied ia the plaut, 2s described in O, Aizpurva-Olsizaa, U, Soydaner, E, Oztlek, et al. Evolution ofthe Cansabinoic ‘and Terpene Content during the Grawth of Canwabis sativa Ponts from Ditferem Chemotypes, J, Nat, Prod, 2016, 79 (2), pp 324331, the entire contents of which” hereby orporated by relerence. The twa primary eannabinoids contained in Cannabis are A9-tetahydracannainal (THC): on Ml nes ‘and cannabidiol (CBD): cm P fait Commonly used reeretionally, cannabinoids ane being swsed and studied for use in # number of mestical eonditions Including, but not limited to, epilepsy. refractory epilepsy,US 10,328,216 B2 5 fragile X syuidrome, osteoarthritis, anxiety, ehronic pai. Other medical uses may inchide the weatment of sleep disorders including insomnia, fibromyalgia. spinal injury. ‘hunom limbs, migraines andior other headaches, eramps, sleep apnea, esncer, muscular dystrophy, HIV/AIDS, gaa coma, hypertension, fatigue, asthma, ALS, lack of uppetite, noresia, cachexia, gatrintestioal disorders, nase, di betes, Crohn's, anxieg, ADDYADHD, stress, bipolar disor der, obsessive compulsive disonler (OCD), post-raumatic siress disorder (PTSD), depression, Tourette's, seizures (i eluding Dravet Syndroms), multiple sclerosis, Alzcimer's, Parkinson's, spasticity, osteoporosis, inflammation, airs, sexual performance and ibido enboacement, andor syznp- toms thereof ‘While largely discussed in relation to cannabinoid com. positions, i ill be appreciated that compositions containing, ‘other lipophilic drug substances may he manufactared ad (of aduinistered using the methods described here, Examples of other ipophilic/low solubility drug substances include, bur are not limited. those shown in Table } below, TABLE 1 Hows cogent a? wpe Stents Geen Dae Saft rice bors Erompcin ‘mcs anton Fein ‘Slenm shame skr Feo ‘pare is: Pec ‘in nan! Moker Fcwone fra ‘saseion Fneae pope 114 Ghee —— a dn Toles! Stan cine ‘iar shanoe beer In one embodiment, 3 composition ofthe present diselo- sure is 9 dey powder that inchides cannabinoids. As used hercin. the torn cannabinoids includes natural derivatives of ‘canmabis or hemp plat, or synthesized analogues. As used. dispersible in an inhalation device to formant aerosol, while Inger particles exhibit good flow properties. In. some ccnbodiments, this moisture conten! may be below about 6 10% by weight water helow about 796 by weight water, below about S% by weight water or below about 4% by ‘weight water Purthermore, as used tein, the tea “ahs lato powder” means a composition that inchades finely Aispersed solid particles that are capable of being readily lisperse in ination device ud subseyuenty ible by a subject so thatthe particles reach the hngs to pormit penetration into the upper and lower airways. Tins, the powder is said to be “respirable.” Ia some embodiments, a Ay power composition ofthe present dislosure may have ‘tp density aeatr than about! wea. (020 glem’ or greater than about 0.4 ple? and mass seroynamic ameter (MMAD) betwee aad 4 um. While canuabiaods may be predominately nse in the descriptions ‘nttodiced to the lipophilic faction to segregate i fom chemically incompatible active or inactive components Examples of combination products (two or more APIs) fnclide Combivent Respimat® (ahuterolsipratropiun), Advair Disks (Mlicasone+ salmeterol, Symbicon HEAR (hudesonidesformoter), Usibron™ Neobaler Ginda- Cclerolsglyeopymoniuts). as Fludform® (Matiasoae pr pionatesiamoterol fumarite). The organic solvent may include @ (erpene, such as Ulimonene, other limonene, andlor heta-myrcene. Other organic solvents may ince at faleabol such as ethanol oF methaol. Ta same embodiments, the lipophilic ingredient is combined with the organic sol ‘vent in ratio o Tess than 1,0 by weight At block 204, a least one of surfactant or an emulsifior ‘is dissolved inthe lipophilic plas. Emulsifiers may inelude ‘no-one detergents, nonionic block copolymers. onic sur- factants, and/or combinations thereof Other emulsifiers may include’ phospholipids, polysorbates, sorbitan Laurate, polyglyceryl- laura, dylauryl citrate, andor combinations thereof In some embodiments the emulsifier may'inclode a eyelicoligosaecharide, el 38 an alphadextrin and/or beta> ‘yelodextsia. At block 206, one or more excipients are dissolved into water to fon an aquoous phase, Stability of the nanoemulsion may be eabaneed by adjustments to pil by the iniroduetion excipients suchas citrate or sodium citrate The lipophilic phase ix dispersed into theaguoous phare at ‘lock 208 to form an emulsion that includes nana-sized i droplets. This dispersing may’ inchude the use of ultrasonic Ihomagenization and/or high pressurc/hiah shese homogeni- alin, In some embedlasent, dhe emulsion may be formed ina contiouots, inline manner such that emulsifiers are not required. Suc an emulsion muy be rapidly fed into a spay dryer. The nanosized droplets have a droplet size doy between about 20am and 1 um, a droplet size day between about 20 and 500 nm, oa droplet size dep benween about 50 ‘and 300 om The ewulsion may include « matrix forming excipient Mavis forming excipients may include an oligosaccharide such as inulin, In some embodiments, the matrix forming, ‘xeipientsinchide a saccharide andiors polysaccharide. The emulsion may further include an encapsulating. excipient, such ay at amino acid like levine 16 The emulsion may be spray dried wo form a dey powder that igeludes the lipophilie ingredient a1 block 240, The emulsion my also be sonified with an altresonie bom ‘operating ia pulse mode, Droplets farmed! during the speay ‘drying msy be atomized using a mult-id atomizer and at least one fuid lized by the multi stomizer may’ be a ‘compressed gis. In some embodiments, the dry powder includes berween about 0.01% and S0°% wie of te Tipo- philic ingredient FIG, 3 depiets a Nowehart of 3 process 300 of manic turing 2 Aowable und dispersible powder, similar to pro- ceetses 100 and 200) described above. Process 300 may include mixing anol solution with a water solution (or oer solvent) form an oil-in-water enmlsion composition at ‘lock 302 The oil solution may include a cannabinoid oF ‘other Fipophilie svater emilsion eo tundra oligosaceluride. The ol-in- on may be spray dried to fom ‘dry powder composition at Block 304. This dry powder ‘composition may be administered, such as by pulmonary inhalation, in the treatment of a number of systemic andor lung eanditions, To facilitate a better understanding of the present ive: tion, the following examples of certain aspects of some ‘embodiments are given. In no way should the following, ‘exunples be read to limit, or define, the entire scope ofthe invention. Additionally the processes for manufieture an administration of the dry powder compositions described hherein may include sdditional steps, have stops omitted, andlor steps combined EXAMPLE 1 An annex solution (feedstock) for spray deying into dry powder yas prepared in two portions: a lipophilic phase Preparation and an aqucous phase preparation. The propi- Taliou ofthe lipophilic phase invelved dissolving a lipophilic active ingredient (hops oil extrt) into an organi solvent (@-limonene) followed by dissolving a sueiciant (naulsi- fer) into the Rpophilie'solvent mixture. The aqueous phase preparation involved selecting excipients (eg. amino acids, carbohydrates, disaccharides, oligosuccharides, cellulose) ‘and dissolving these excipiens into water at or near 20°C. ‘or at higher temperatures depeucing on excipient solbilit ‘The lipophilic phase preparation was dispersed Hato the aqueous plsse preparation to form an emulsion 400 hat Includes nanosized oil droplets 402 distributed within aque- ‘ous phase preparation 40M as show in PIG. 4. Tho majority ‘oF vil droplets 402 ranged between about 01 am and 03 tm. The panicle size distribution fr the oil droplets 402 a8 ‘determined by Malvern Mastersizer 3000 with HydroMV is shown in FIG. . The particle size distribution ineluded the following values: Dyy (usn)-0.108: Dap (umn)-0.205; and Dig (um)-0483. The emulsion containing nano-partcles ‘was formed using common practices such as ultrasonic ‘andlor high pressure homogenizer techniques. The resultant ‘annex solution was spray dried into dry power which had. Dy (um)-10: Dy, (umn)-22; and De (um)-4.1. Capsules filled with powder (10 mg target) were aerosol tested (ACT ft 283 lpm) with the RSOI inhaler were found 1 have MMAD (um)-3., FPP=85%, and DE=73%,US 10,328,216 B2 q7 “Active substances" or “ative ingredient” ¢ described herein eludes «lipophilic agea, dug, compound, eompo- sition of mattor or mixtare thoreof which provides some phoemscological, outraeutical, o¢ mutriion EXAMPLE 2 As in Example 1, sn annex solution (feedstock) for spray drying into dry powder was prepared in two portions: a lipophilic phase preparation and an aqueous phase prepara- tion. The preparation of the lpophile phase involved dis- solvang a ipophuli active agreent ato an organ solvent followed by adding a surfactant (emulsifier) into the lipo- philicsolvent mixture. The aquecus phase preparation involved selecting excipients (e amino acids, earbohy- rates, disaccharides, oligosaccharides, cellulose, aids) and dissolving these excipients into water ator near 20° C..or at higher temperatures depending on excipient solubility. The aqueous and lipophilic preparations were bested 10 between about 60° Cand 70°C. The lipophilic phase ‘reparation was then dispersed into the aqueous phase ‘reparation to form an emulsion 400 that inclodes nanosized oil droplets 402 distibuted within aqueous phase prepara- tion 404, The majority of oil droplets 402 ringed between bout 0.01 aim and 0.3 nen. The droplet size distribution #6 measured by. Malvern Mastersizer 3000 with HydroMV included the following values: D»(us)-0.2; Dy (um)-0O3; And Day (um)°O5. The emolsion containing nano-paricles ‘was formed using common placlices sich as ultrsonic and/or high pressure homogenizer techaiyues. The resultant annex solution was spray dried into a dry powder (7.5% oil feximet content which had Dy (um)-O.8, Dy (usm)>2 0: and Day (omn)~4.0. Capsales filled with powder (10 mg target) ‘ere aerosol ested (ACI at 28.3 lpm) with the RSOV inhaler hat MMAD(um)-2.5, FPF=95%, and DE-89%, “Active substances” or “active ingredient” ax described herein includes a lipophilic auent, drug. compound, eompo- sition of mater or mixture thereof which provides some pharmacological, nuiraevtical, or mttional aetin, EXAMPLE 3 Day powder caunabinoid compositions suitable for pul- monary delivery were prodiveed using a speay dryer at high yield (80-90%) and at Sg batch sizes. These powders ‘exhibited very good verosol performance when gested Via the RSO1 intaler (Plastispe,Ialy) as evidenced by mean DE ‘of 68% and fine TPE of 83% as determined by Anderson, Caseade Impactor (ACD), Particle size distribution for two batches of spray dried powder is depicted in FIG. 6. The particle size dintnbution included the Following values for Aho frst ate: Dy (um) 499: Bag (am)-2.F2 and Dao (am) 4.6. The particle size distnbution inelnded the Fellowing values forthe second bateh: Dy. (tm)-03%; Dyy (um); and Dyy (um)-4.1. Particle size distribution was very eon ‘stent aeross the two batches. A scanning electron miero~ ‘graph showing particle appearance is shown in FIG. 7 Ingredients for producing @ dey powder composition having approsimauly 64% by weight cannabinoid active ingredient inelude leucine (2° g), inulin (1.0 a), HPMC (0.15 g), delimonene (1-1 g), Plemtamulse™ (04 g), super Critically extracted cannabis oil containing 90% THC (0.3 2) and water. The emulsion (annex solution) was prepared, in accordauce with the process of Example 1 A Production Minor (GEA Group, DE) with eustom high cficieney eyelone was used to generate and collect the powder. The equilibrium drying coneltion was established 18 using de-ionized water, When sishle operation wat achieved, the nozzle iapu was switehed vo annex (Fee Sock) solution. The sotion was fed tothe dryer unt iw: ‘depleted and then the nozzle was switched sek to water for approximately $ minutes to clear the system. The collector ‘containing dey powder was exehanged fora clean collector and the dryer was chen shut down, The filled eollectoe was rapidly eapped on removal 10 minimize exposure wo room Inuit. The filled collestor was transfered into 2 low Inmidity glove box purged with clean dry air or nitrogen where the powder was Irinsferable into other vessels for storage oF into capsules and/or other unit dose packets, EXAMPLE 4 A carbohydrate bulking agent was included in-an il cextrct-levcine formulation. The addition of trehalose as a ‘carbohydrate bulking agent can improve the chemical sto Dility of dry-powder cannabinoid compositions ofthe pres cent disclosure. Additionally. trebelose and DSPC were inverted in the powder formblaion based on their inclusion in DPI products approved by the EDA, eg TOBHM® Pod: ler" (Novartis. AG), Dry pavwder cil extract eompnitions suitable for pulmo nary delivery were produeed using a Mobile Minor ( Group, DE) spray dryer. Capsule filed with theve powders (10 mg target) had an MMAD of 2:3 jm and exhibited ‘excellent gerosol peeformance when actuated via the RSOL inhaler (Plastiape, Italy) as evidenced by FPF of 93% and DE of 90%, The particle size distribution forthe spray dred powiler is depicted ia FIG. 8, The particle size distribution Include the following valves: (um}=I-1: Dg, (umn)=22: and Dog (a) =42. Ingredients for producing dry powder composition having approximately 12% by weight active ingradient Include leucine (80%), trebalove (6.5%), DSPC (1.5%), and supercritically extracted oil (12%). Water and d-limonene ‘were used as solvents The emulsion (annex solution) was prepared in accordhnce with the process of Example 1 EXAMPLE § ‘A carbohydrate bulking agent was inlnded in @ cannabi- noideleucine formation, The adiion oF trebalose a8 a ‘carbohydrate bulking agent can improve the chemical sta- bility of dry-powder caunabinoid compositions of the pres ‘ent disclosure. Additionally, trehalose has been incorporsted. in powder for pulmonary administration products approved by the FDA, eg TORI Podhaler™ (Novartis, AG) Dry powder cannabinoid compositions eutable For pl monary delivery were produced using a Mobile Minor (GE ‘Group, DE) spray dryer Those powders exhibited very good, aerosol performance when actuated via the RSO) inhaler (Plastiape, aly) as evidenced by mean DE of 68% and fine PF of 83% as determined by Anderson Cascade Impacior (ACT operated at 28.3 Ipm). The particle size distribution for the spray dried powder is depicted in FIG. 9. The panicle size distribution included the following values: Dy, (um)= 5; Day (um)-2.7; and Day (Um)-6., Ingrelients for producing a dry powder composition ving approximately 5% by weight cannabinoid active Ingredient include leucine (47%), tehulose (47%), DSPC (19%), and supercritcally extracted camnabis erystals eon- taining 99% CHD (5%), Water and delimonene were used as solvents. The eamision (annex solution) was prepared in accordance with the process of Example 1US 10,328,216 B2 19 ‘What is claimed is 1A method of manufactur powder, the method comprising solubilizing a lipophilic substunce and a phospholipid in ‘terpene to Torin» Hpophilic misture: tedding atleast one factional excipient to water to form eons solation i which the functional excipient is Aissolved; fier the at least one Functional excipient is completely dissolved. dispersing the lipophilic mixture into the ‘aqueous solution using one or both ofa homogenizer ot ‘an trasonlc device ro form a coarse emulsion treating the coarse emulsion wih a microfludizer wo form ‘8 nanogmulsion; and spray drying the nanoemulsion to eveporste at least a ‘portion ofthe terpene anu substantially al oF the water ‘0 fom a dry powder for pulmonary administration in powder fom. the dry poser being formes! from solid panicles comprising the lipophilic sustance, the resul- ‘unt dry powder having mass median seosol diameter (MMAD) between 0.5 and 5 ym. and a fine pariele fraction (FPF) ond delivery efficiency (DE) greater than airs, 2. The method of manufucturing a Howable and dispers~ ‘ble powder of eins 1, where the dry powder has « moisture content below about 10% by weight water 3. The method of manufacturing » Nowable and dispers- ‘ble powder af elias 1, wherein: the dry powder has a tap density between about 0.1 lem? ‘od 06 sven 4, The method bf manufacturing w Rowable und dispers- ‘ble powder of els 1, wherein: the lipophilic substance comprises one oF more of a ‘cannabinoid, alpha tocopherol, ampotericin B, alor’- sitin, azithromycin, beclomethasone, budesonide, caspofungia, ciprofloxacin, elemstine. clotaviine, exelosporine, dihydroengotamine, dronabiool, teride, erytiromysin, felodipine. fentanyl, Hevainie, ‘uieasoxe firoate, Mutcasads propionate. fuser, alveopyrronim, indacaterol, iaconszale, loxapine, mometasone, simodipine, werolimus, — tretinoin, vilaterol, oF derivtives oF analogues thereof 5. The method of mamafacturing » flowable and dispers~ ible powder of claim 1. where the lipophilic substance is dispersed in an aqueous phase and the utility of lipophilic phase is 10 impatt the MMAD, the FPF, and the DE 10 the spray-dried pow- der 6. The method of manafseturing 8 Howable and disperss ible poseder af elaim 5, wherein: the lipophilic substance comprises nicotine. 7. The method of manofacturing « Rowable and dispers- ible powder of elaim 6, wherein: f plurality of emulsions containing spare drug sub- Stances are combined wit the aguetus solution and tne spy dried. produce combination products. 8. The method of manufsetring « Nowable and disper ‘ble powder of elim 1, where Separate dmg substances are contained within the aquoons ‘olution and the mixture and once spray dri, procice combination products 9. The method of manulseturing 8 Nowable und dispers- ible powder of claim 8, wherein ‘8 plurality of emulsions containing sepamite drug sub- Stances are combined with the aqueous solution and nce spriy dried. prodice combination products, flowable und dispersible 20 10, The method of manufacturing a awable seal dispers= ible povder of clan 1, wherein: 1 plurality of emulsions containing separate drug sub- tances are combined with the aqueous solution and ‘once spray dried, produce combimition proucts. 11, The method of maniacturing a flowable and dispers- ible povder of claim 1, wherein: the dry powder comprises between about I ight of » cannabinosd, 12. The methed of manufacturing a flowable and dispers- ‘ble powder of claim 11, wherein: the cannabinoid comprises at least one of tetaiydrocan- ‘oabinol (THC), tetrahydrocannabinolic acid (THC), ‘annabidiol (CBD), canmbidiolie acid (CBDs), ean ‘ahinol (CBN), exnsabichromene (CBC), or eannab- igerol (CBG) 13, The method of mamufscturing a Nowable and dispers- ‘ble povder of elaim 1, wherein: the dry powder further comprises one oF more of a hydrophobic amino acd, a disaccharide, a oligosacc ride, surfactant, an emulsifle, a stabilizing eddtive, ‘or a bulking agent 14, The method of manufacturing a flowable and dispers- ible powder of claim 13, wherein: the hydrophobic amino oid comprises one or mote of ‘ryploplias,tyraine,leveine,rleucine, or phenylal- 15. The method of manufacturing # Nowable and dispers- le powder of elaion 13, wherein ‘oon-ionie detergent, » nonionic block copolymer, an Tonic surfactant, phospholipids, citrates, sorbitan lau- ‘atc, polyglyeeryl laure, or eyclic cligosaccharis- des. sand 2048 by 16, The meio of manufacturing 4 owable and dispers- able powder of elaim 1, wherein: the dey powder contains ove ar more of hydroxypropyl ‘methylcellulose (HPMC) or methylcellulose (MC) 17. The method of mamulseturing a flowable sud dispers- ‘ble poseder of elaim 1, wherein: the dey powder comprises one oF more of lactose, man ‘tol trehalose, rffinose, of maltodextrins. 18. The method of mamafactriag a Nlowable and dispers= able powder of elaim 1, wherein: the lerpene comprises one or more of limonene, other Timonenes, oF beta-myzcene, 19. The method of manufacturing a flowable avd dispers- ible poseder of elaim 1, wherein: the dry powdar has a bull donsity of between about 0.05 ‘gem’ and 0.3 giem’ 20, The method of manucturing a fewwable and dispers- ible posider of elaim 1, wherein: the MMAD of the resultant dey powder is between about and 3 yn. 21. Amethod of manufueturing a Nowable and dispersible power, the method comprising: ‘olabiizing « lipophilic substance and » phospholipid in a terpene to form lipophilic mixture; ‘adding a lost one functional excipient Water to fort ‘an aqueous solution in which the Functional exeipieat is dissolved: talier the at least one fanctonal excipient is completely issolved, dispersing the lipophilic mixture into the aqueous solution using one or both ofa homogenizer or fa ultrasonic device to Form a coarse erulsonUS 10,328,216 B2 2 treating the coarse emulsion with one oF bot oF the tllrsonic device or a high shear device to form a ssanoetnulsion: a spray’ deying the nanoemulsion 10 evgporate at least a ‘ponion ofthe terpene an substantially allo the water " fom a dey povsder for pulmonary administration ia powder fom the dry powder being formed from solid particles comprising the lipophilic substaace, the resul- “ant dey powder having mass median aerosol diameter (MMAD) between 0.5 and 5 yn, and a fine particle fraction (FPF) und delivery efficiency (DE) greater than. 108% 2