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(19) TZZ _T

(11) EP 2 884 962 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 9/16 (2006.01) 01.05.2019 Bulletin 2019/18 A61K 9/19 (2006.01) A61K 9/20 (2006.01)

(21) Application number: 13829914.4 (86) International application number: PCT/US2013/055258 (22) Date of filing: 16.08.2013 (87) International publication number: WO 2014/028796 (20.02.2014 Gazette 2014/08)

(54) PREPARATION OF DESICCATED FOR USE IN COMPRESSIBLE DELIVERY SYSTEMS PRÄPARAT AUS ENTWÄSSERTEN LIPOSOMEN ZUR VERWENDUNG IN KOMPRIMIERBAREN ABGABESYSTEMEN PRÉPARATION DE LIPOSOMES DESSÉCHÉS UTILISABLE DANS DES SYSTÈMES D’ADMINISTRATION COMPRESSIBLES

(84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB EP-A1- 1 484 055 EP-A1- 1 952 818 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO WO-A1-96/19199 US-A- 4 830 858 PL PT RO RS SE SI SK SM TR US-A1- 2009 215 810 US-A1- 2010 104 518 US-A1- 2010 166 673 US-B2- 7 939 106 (30) Priority: 17.08.2012 US 201261684631 P • SHAH S P ET AL: "Development of liposomal (43) Date of publication of application: amphotericin B dry formulation.", 24.06.2015 Bulletin 2015/26 2004 JUL-AUG, vol. 11, no. 4, July 2004 (2004-07), pages 247-253, XP9188638, (73) Proprietor: Smartek International LLC ISSN: 1071-7544 Livingston, NJ 07039 (US) • MARIANECCI, C ET AL.: ’A New Vesicle-loaded System Suitable for Topical (72) Inventor: FARBER, Michael Applications: Preparation and Characterization.’ Livingston, NJ 07039 (US) J PHARM PHARMACEUT SCI vol. 14, no. 3, 05 September 2011, pages 336 - 346, XP055187057 (74) Representative: Wittmann, Günther Patentanwaltskanzlei Wittmann Frans-Hals-Straße 31 81479 München (DE)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 884 962 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 884 962 B1 2

Description long term stability is experimentally challenging. Often, the encapsulated nutritional supplements fall out of the FIELD OF THE DISCLOSED TECHNOLOGY components and therefore are no longer en- capsulated. Storage conditions must be rigorously con- [0001] The subject matter disclosed generally relates 5 trolled. Additionally, attempts to improve the stability of to a formulation and method for delivery of an active in- such liposome encapsulated nutritional supplement gredient and a process of making the same. More spe- combinations have often proven to be specific to the cifically, the subject matter disclosed relates to a formu- types of nutritional supplements to be delivered and re- lation containing desiccated liposomes for transmucosal quires considerable formulating expertise. delivery of an active ingredient, and a process of making 10 [0005] Consequently, a need exists for improved prod- the same. ucts and methods for delivering an effective quantity of one or more nutritional supplements (or pharmaceutically BACKGROUND OF THE DISCLOSED TECHNOLOGY active ingredients), wherein the one or more nutritional supplements reach their targeted location prior to any [0002] The technology of producing liposomes is fairly 15 significant degradation. Of course, any appropriate lipo- mature. Indeed, various nutritional supplements have some delivery pharmacokinetic method may also provide been formulated in conjunction with liposomes to provide improvedproducts and methods for targeting appropriate for improved ways of delivering effective doses of the locations of the immune system too. nutritional supplements. Many nutritional supplements [0006] The enteral is one of the may be degraded when taken orally so that their delivery 20 most common routes of admistration for pharmaceutical is not be therapeutically effective, encapsulating nutri- compounds, and food or nutritional supplements. How- tional supplements with one or more to ever, not all substances ingested through the enteral form liposomes provides a measure of protection for the route are equally metabolized, and a lot of these sub- nutritional supplements and may enhance their thera- stances are heavily metabolized in the gastrointestinal peutic effect. Other and forms of protecting 25 tract. This effect is commonly referred to the first-pass nutritional supplements exist, but when the capsules or effect (also known as first-pass metabolism or presys- tablets disintegrate in the digestive system, the nutritional temic metabolism). First-pass effect causes the concen- supplements may not be as well received and delivered tration of a drug to be greatly reduced before it reaches to target organs as are encapsulated liposome nutritional the systemic circulation. It is the fraction of lost drug dur- supplements combinations. These combinations may be 30 ing the process of absorption which is generally related in or aerosol forms too depending on the best de- to the liver and gut wall. Notable drugs that experience sired method of introducing such pharmaceutically active a significant first-pass effect are imipramine, morphine, ingredients. propranolol, buprenorphine, diazepam, midazolam, de- [0003] Furthermore, such active pharmaceutical ingre- merol, cimetidine, and . dients may also enter the bodily system by passing35 [0007] After a drug is swallowed, it is absorbed by the through skin, and thus enter the systemic circulation, digestive system and enters the hepatic portal system. where in time targeted organs may benefit from yet an- It is carried through the portal vein into the liver before it other way of introducing active pharmaceutical ingredi- reaches the rest of the body. The liver metabolizes many ents. As is understood in the art skin is generally consid- drugs, sometimes to such an extent that only a small ered to be fairly impermeable to water. However, under 40 amount of active drug emerges from the liver to the rest appropriate conditions, as is understood in the art, some of the . This first pass through the liver pharmaceutically active ingredients actually are able to thus greatly reduces the bioavailability of the drug. Alter- penetrate the skin and enter into muscles tissues and native routes of administration like , intrave- the blood stream to relieve conditions such as arthritis nous, intramuscular, inhalational aerosol and sublingual and even muscle soreness due to overuse of such tissue. 45 avoid the first-pass effect because they allow drugs to Appropriate exercise and appropriate foods and bever- be absorbed directly into the systemic circulation. ages have also been considered to be important compo- [0008] Therefore, there is a need for formulations for nents of maintaining good health in immune compro- the transmucosal delivery of active ingredients directly mised individuals. Indeed, even when an individual’s into systemic circulation. Furthermore, there is a need health is not poor, their immune system may be under 50 for processes for the preparation of formulation for the attack at all times. Thus a healthy life style plus appro- transmucosal delivery of active ingredients into the sys- priate liposome nutritional supplements combinations temic circulation. comprising pharmaceutically active ingredients may be [0009] Shah et al, "Development of liposomal ampho- highly desirable to continue to remain in good overall tericin B dry powder inhaler formulation", DRUG DELIV- health. 55 ERY 2004 July-August, Vol. 11, no. 4, July 2004, pages [0004] It has proven to be difficult to provide stable 247-253) discloses delivery formulation for transmucosal forms of liposome encapsulated nutritional supplements delivery. because the technology of making stable liposomes with [0010] EP 1 952 818 A1 discloses preventing or treat-

2 3 EP 2 884 962 B1 4 inga bone disease by administering liposomal lactoferrin. erol, hydrogenated starch hydrolysates, inulin, isomalt, [0011] WO 96/19199 A1 discloses a proliposome pow- lactitol, Luo han guo, mabinlin, maltitol, malto-oligosac- der comprising in a single phase discrete particles of a charide, mannitol, miraculin, monatin, monellin, osladin, biologically active component together with a lipid or mix- pentadin, , tagatose, thaumatin, , acesul- ture of lipids. 5 fame potassium, alitame, of aspartame-acesulfame, [0012] EP 1 484 055 A1 relates to a dry composition dulcin, glucin, neohesperidin dihydrochalcone, neotame which allows delivery of active agents with good bioavail- and combinations thereof. ability. [0018] The at least one active ingredient may be cho- [0013] U.S. 4,830,858 discloses a method for prepar- sen from a pharmaceutical drug, a nutritional supple- ing a stable liposome precursor in the form of a mixture 10 ment, a phenylethylamine, a metabolism booster, a plant of spray-dried liposomal components. extract, an herbal medicine, an enzyme, a peptide or combinations thereof. The formulation may further com- SUMMARY OF THE DISCLOSED TECHNOLOGY prise at least one second active ingredient. The at least one second active ingredient may be chosen from a phar- [0014] According to an embodiment, there is provided 15 maceutical drug, a nutritional supplement, a phenylethyl- a compressible delivery formulation for transmucosal de- amine, a metabolism booster, a plant extract, an herbal livery of at least one compound comprising: a micronized medicine, an enzyme, a peptide or combinations thereof. or milled powder base; and a dessicated liposome for- [0019] The pharmaceutical drug may be chosen from mulation comprising at least one liposome 85 containing a nitric oxide donor, an aldosterone antagonist, an alpha- at least one compound in an amount sufficient to form a 20 adrenergic receptor antagonist, an angiotensin II, antag- unitary containing about 10 mg to about 500 onist, an angiotensin-converting enzyme inhibitor, an an- mg of the compound, depending on the molecule. The tidiabetic compound, an anti-hyperlipidemic compound, compound may be an active ingredient, a mucosal ab- an antioxidant, an antithrombotic and vasodilator com- sorption enhancer, or combinations thereof. The com- pound, a β-adrenergic antagonist, a channel pound may be an active ingredient, a mucosal absorption 25 blocker, a digitalis, a diuretic, an endothelin antagonist, enhancer, or combinations thereof. a hydralazine compound, a H2 receptor antagonist, a [0015] The micronized or milled powder base may be monoamine oxidase activity inhibitor, a neutral en- chosen from an inert powdered base, an active powdered dopeptidase inhibitor, a nonsteroidal antiinflammatory base having improvedtransmucosal permeation, or com- compound, a phosphodiesterase inhibitor, a potassium binations thereof. The inert powdered base may be cho- 30 channelblocker, a plateletreducing agent, a protonpump sen from a maltodextrin, a microcrystalline cellulose, lac- inhibitor, a renin inhibitor, a selective cyclooxygenase-2 tose, sucrose, xylitol, sorbitol, mannitol, compressible inhibitor, a psychoactive drug, a stimulant, or combina- gum base or combinations thereof. The active powdered tions thereof. The nutritional supplement may be chosen base may be chosen from a caffeine, theobromine, the- from a vitamin, a coenzyme, a cofactor, or combinations ophylline, a plant extract with bioavailable components, 35 thereof. creatine and/or drug base. The plant extract with bioa- [0020] The phenylethylamine may be chosen from vailable components may be chosen from a green coffee phenylethylamine, β-methylphenethylamine, β-keto-am- extract, guarana extract, Yerba mate extract, a tea ex- phetamine, β-hydroxy-amphetamine, β,4-dihydroxy- tract, a citrus aurantium extract, or or other botanicals phenethylamine, β,4-dihydroxy-3-hydroxymethyl-N-tert- with nutritional or health effects. The active powdered 40 butylphenethylamine, β,3-dihydroxyphenethylamine, base may be chosen from a caffeine, theobromine, cre- β,3-dihydroxy-N-methylphenethylamine, β,3,4-trihy- atine, and/or drug base. The caffeine may be a salt of droxyphenethylamine, β,3,4-trihydroxy-Nmethyl- caffeine, and the salt of caffeine may be chosen from phenethylamine, α-methylphenethylamine, α,α-dimeth- dicaffeine malate, caffeine citrate, caffeine hydrochlo- ylphenethylamine, N-methylcathinone, N-methylam- ride, or combinations thereof. 45 phetamine, N-methyl-β-hydroxyamphetamine, Nethyl- [0016] The formulation may further comprise a - cathinone,4-methylmethcathinone, 4-hydroxy- ing agent, and the flavoring agent may be chosen from phenethylamine, 3-trifluoromethyl-N-ethyl-ampheta- flavor, lemon flavor, grapefruit flavor, blueberry mine, 3-trifluoromethyl-amphetamine, 3-hydroxy- flavor, raspberry flavor, strawberry flavor, peach flavor, phenethylamine, 3-chloro-N-tert-butyl-β-ketoampheta- grape flavor, apple flavor, mango flavor, banana flavor, 50 mine, 3,4-dihydroxyphenethylamine, 3,4,5- mint flavor, flavor, flavor, butterscotch trimethoxyphenethylamine, 2,5-dimethoxy-4-tertbutylth- flavor, caramel flavor chocolate flavor, and combinations io-phenethylamine, 2,5-dimethoxy-4-propylthio- thereof. The mint flavor may be chosen from phenethylamine, 2,5-dimethoxy-4-propylphenethyl- flavor and flavor, and combinations thereof. amine, 2,5-dimethoxy-4-nitrophenethylamine, 2,5- [0017] The formulation may further comprise a sweet- 55 dimethoxy-4-nitroamphetamine, 2,5-dimethoxy-4-meth- ener and the sweetener may be chosen from glucose, ylphenethylamine, 2,5-dimethoxy-4-methylampheta- fructose, aspartame, cyclamate, saccharin, stevia, su- mine, 2,5-dimethoxy-4-isopropylthiophenethylamine, cralose, brazzein, curculin, erythritol, glycyrrhizin, glyc- 2,5-dimethoxy-4-iodophenethylamine, 2,5-dimethoxy-4-

3 5 EP 2 884 962 B1 6 iodoamphetamine, 2,5-dimethoxy-4-fluorophenethyl- process for the preparation of a dosage form com- amine, 2,5-dimethoxy-4-ethylthio-phenethylamine, 2,5- prising: a) compressing a formulation of the present in- dimethoxy-4-ethylphenethylamine, 2,5-dimethoxy-4-cy- vention in combination with a pharmaceutically accept- clopropylmethylthio-phenethylamine, 2,5-dimethoxy-4- able carrier, without a heat treatment capable of causing chlorophenethylamine, 2,5-dimethoxy-4-chloroamphet- 5 degradation of the formulation. amine, 2,5-dimethoxy-4-bromophenethylamine, 2,5- [0026] According to another embodiment, there is pro- dimethoxy-4-bromoamphetamine, 2,5-dimethoxy-4-(2- vided a process for the preparation of a formulation for fluoroethylthio)-phenethylamine, 2,4,5-trihydroxy- transmucosal delivery of at least one compound com- phenethylamine, 3,4-methylenedioxymethcathinone, prising: a) spraying a liposome formulation suspended 3,4-methylenedioxy-N-methylamphetamine, N,α-buty- 10 in a water based solvent on a micronized powder base, lene-β-methoxycarbonylphenethylamine, 3,4-methylen- the liposome formulation comprising at least one lipo- edioxy-Nethylamphetamine, 3,4-methylenedioxyam- some containing at least one compound in an amount phetamine. sufficient to form a unitary dosage form containing from [0021] The phenylethylamine may be chosen from 10 mg to about 500 mg of the compound, at a temperature phenylethylamine, β- phenylethylamine, β-methyl- 15 at a nozzle head aperture of about 60°C or less to evap- phenethylamine, β,4-dihydroxyphenethylamine, β-chlo- oratethe water basedsolvent and desiccate theliposome ro-N-tert-butyl-β-ketoamphetamine, phenelzine, and tra- wherein the liposome formulation comprises the com- nylcypromine. pound. [0022] The metabolism booster may be at least one of [0027] The compound may be an active ingredient, a ephedra, an ephedra extract, ephedrine, synephrine, a 20 mucosal absorption enhancer, or combinations thereof. Citrus aurantium extract, a Pausinystalia Yohimbe ex- The micronized powder base may be chosen from an tract, and yohimbine. The monoamine oxidase activity inert powdered base, an active powdered base having inhibitor may be at least one of Piperine, methyl piperate, improved transmucosal permeation, or combinations a piperine derivative, a methyl piperate derivative, St. thereof. The inert powdered base may be chosen from John’s Wort, American Ginseng, Asian Ginseng, 5 - hy- 25 a maltodextrin, a microcrystalline cellulose, sucrose, xy- droxy tryptophan, Bitter Orange, Brewer’s Yeast, Vitamin litol, sorbitol, mannitol, or combinations thereof. The ac- B6, L - Tyrosine and Yohimbe. tive powdered base may be chosen from a caffeine, the- [0023] The formulation may be further comprising a obromine, theophylline, a plant extract with bioavailable mucosal absorption enhancer for improved transmucos- components, and creatine. The plant extract with bioa- al permeation. The mucosal absorption enhancer may 30 vailable components may be chosen from a green coffee comprise at least one of 23-lauryl ether, aprotinin, azone, extract, guarana extract, Yerba mate extract, a tea ex- benzalkonium chloride, , cetyltri- tract, a citrus aurantium extract, or combinations thereof. methylammonium bromide, cyclodextrin, dextran sul- The active powdered base may be chosen from a caf- fate, lauric acid, lauric acid/, lysophos- feine, theobromine, and creatine. The caffeine may be a phatidylcholine, , methoxysalicylate, methyl-35 salt of caffeine. The salt of caffeine may be chosen from oleate, oleic acid, piperine, phosphatidylcholine, polyox- dicaffeine malate, caffeine citrate, caffeine hydrochlo- yethylene, polysorbate 80, sodium EDTA, sodium glyco- ride, or combinations thereof. cholate, sodium glycodeoxycholate, sodium lauryl sul- [0028] The water based solvent may further comprise fate, sodium salicylate, sodium taurocholate, sodium tau- a flavoring agent and the flavoring agent may be chosen rodeoxycholate, sodium deoxycholate, a sulfoxide, bile 40 from orange flavor, lemon flavor, grapefruit flavor, blue- , and an alkyl glycoside. According to another em- berry flavor, raspberry flavor, strawberry flavor, peach bodiment, there is provided a dosage form for transmu- flavor, grape flavor, apple flavor, mango flavor, banana cosal delivery of at least one compound comprising: a flavor, mint flavor, cinnamon flavor, vanilla flavor, butter- formulation of the present invention in combination with scotch flavor, caramel flavor chocolate flavor, and com- a pharmaceutically acceptable carrier. 45 binations thereof. The water based solvent may further [0024] The dosage form may be chosen from a chew- comprise a sweetener, and the sweetener may be cho- able tablet, a fast disintegrating tablet, a , sen from glucose, fructose, aspartame, cyclamate, sac- a granule, and a suppository. The dosage form may be charin, stevia, sucralose, brazzein, curculin, erythritol, chosen from a jelly, a , a film, a lozenge, a , glycyrrhizin, , hydrogenated starch hydrolysates, an ointment, a liquid and a spray. 50 inulin, isomalt, lactitol, Luo han guo, mabinlin, maltitol, [0025] The pharmaceutically acceptable carrier may malto-oligosaccharide, mannitol, miraculin, monatin, be a hydrocolloid, and the hydrocolloid may be chosen monellin, osladin, pentadin, sorbitol, tagatose, thauma- from agar, agarose, alginates, carrageenan (iota, kappa, tin, xylitol, acesulfame potassium, alitame, salt of aspar- lambda), cellulosics, , gelatin, gellan gum, guar tame-acesulfame, dulcin, glucin, neohesperidin dihydro- gum, gum arabic, locust bean gum, pectin, soybean gel, 55 chalcone, neotame and combinations thereof. The water starch, whey protein, xanthan gum, chewing gum, a base based solvent may be a mixture of water and alcohol and gum and derivatives thereof and combinations thereof. the alcohol may be ethanol. According to another embodiment, there is provided a [0029] The at least one active ingredient may be cho-

4 7 EP 2 884 962 B1 8 sen from a pharmaceutical drug, a nutritional supple- amine, 2,4,5-trihydroxyphenethylamine, 3,4-methylene- ment, a phenylethylamine, a metabolism booster, a plant dioxymethcathinone, 3,4-methylenedioxy-N-methylam- extract, an herbal medicine, an enzyme, a peptide or phetamine, N,α-butylene-β methoxycarbonylphenethyl- combinations thereof. amine, 3,4-methylenedioxy-Nethylamphetamine, 3,4- [0030] The process may further comprise at least one 5 methylenedioxyamphetamine. second active ingredient. The at least one second active [0033] The phenylethylamine may be chosen from ingredient may be chosen from a pharmaceutical drug, phenylethylamine, β-phenylethylamine, β-methyl- a nutritional supplement, a phenylethylamine, a metab- phenethylamine, β,4-dihydroxyphenethylamine, 3-chlo- olism booster, a plant extract, an herbal medicine, an ro-N-tert-butyl-β-ketoamphetamine, phenelzine, and tra- enzyme, a peptide or combinations thereof. 10 nylcypromine. The monoamine oxidase activity inhibitor [0031] The pharmaceutical drug may be chosen from may be at least one of Piperine, methyl piperate, pepper a nitric oxide donor, an aldosterone antagonist, an alpha- extracts, a piperine derivative, a methyl piperate deriva- adrenergic receptor antagonist, an angiotensin II, antag- tive, St. John’s Wort, American Ginseng, Asian Ginseng, onist, an angiotensin-converting enzyme inhibitor, an an- 5 - hydroxy tryptophan, Bitter Orange, Brewer’s Yeast, tidiabetic compound, an anti-hyperlipidemic compound, 15 Vitamin B6, L - Tyrosine and Yohimbe. The metabolism an antioxidant, an antithrombotic and vasodilator com- booster may be at least one of ephedra, an ephedra ex- pound, a β-adrenergic antagonist, a calcium channel tract, ephedrine, synephrine, a Citrus aurantium extract, blocker, a digitalis, a diuretic, an endothelin antagonist, a Pausinystalia Yohimbe extract, and yohimbine. The a hydralazine compound, a H2 receptor antagonist, a process may further comprise a mucosal absorption en- monoamine oxidase activity inhibitor, a neutral en-20 hancer for improved transmucosal permeation. dopeptidase inhibitor, a nonsteroidal antiinflammatory [0034] The mucosal absorption enhancer may com- compound, a phosphodiesterase inhibitor, a potassium prise at least one of 23-lauryl ether, aprotinin, azone, channel blocker,a platelet reducing agent, a proton pump benzalkonium chloride, cetylpyridinium chloride, cetyltri- inhibitor, a renin inhibitor, a selective cyclooxygenase-2 methylammonium bromide, cyclodextrin, dextran sul- inhibitor, a psychoactive drug, a stimulant, or combina- 25 fate, lauric acid, lauric acid/Propylene glycol, lysophos- tions thereof. The nutritional supplement may be chosen phatidylcholine, menthol, methoxysalicylate, methyl- from a vitamin, a coenzyme, a cofactor, or combinations oleate, oleic acid, piperine, methyl piperate, pepper ex- thereof. tracts phosphatidylcholine, polyoxyethylene, polysorb- [0032] The phenylethylamine may be chosen from ate 80, sodium EDTA, sodium glycocholate, sodium gly- phenylethylamine, β-methylphenethylamine, β-keto-am- 30 codeoxycholate, sodium lauryl sulfate,sodium salicylate, phetamine, β-hydroxy-amphetamine, β,4-dihydroxy- sodium taurocholate, sodium taurodeoxycholate, sodi- phenethylamine, β,4-dihydroxy-3-hydroxymethyl-N-tert- um deoxycholate, a sulfoxide, bile salts, and an alkyl gly- butylphenethylamine, β,3-dihydroxyphenethylamine, coside. β,3-dihydroxy-Nmethylphenethylamine, β,3,4-trihydrox- [0035] According to another embodiment, there is pro- yphenethylamine, β,3,4-trihydroxy-Nmethylphenethyl- 35 vided a compressible delivery formulation for transmu- amine, α-methylphenethylamine, α,α-dimethyl- cosal delivery of at least one active ingredient prepared phenethylamine, N-methylcathinone, N-methylamphet- by the process of the present invention. According to an- amine, N-methyl-β-hydroxyamphetamine, Nethylcathi- other embodiment, there is provided a solid dosage form none, 4-methylmethcathinone, 4-hydroxyphenethyl- prepared by compressing a formulation of the present amine, 3-trifluoromethyl-N-ethyl-amphetamine, 3-trif-40 invention, without a heat treatment capable of causing luoromethyl-amphetamine, 3-hydroxyphenethylamine, degradation of the formulation. 3-chloro-N-tert-butyl-β-ketoamphetamine, 3,4-dihydrox- [0036] The following terms are hereinafter defined. yphenethylamine, 3,4,5-trimethoxyphenethylamine, 2,5- The term "micronized" or "micronization" are intended to dimethoxy-4 tertbutylthio-phenethylamine, 2,5-dimeth- mean the process of reducing the average diameter of a oxy-4-propylthio-phenethylamine, 2,5-dimethoxy-4-pro- 45 solid material’s particles to produce particles that are only pylphenethylamine, 2,5-dimethoxy-4-nitrophenethyl- a few micrometers in diameter. amine, 2,5-dimethoxy-4-nitroamphetamine, 2,5-dimeth- [0037] The term "liposome" is intended to mean an ar- oxy-4-methylphenethylamine, 2,5-dimethoxy-4-methyl- tificially-prepared vesicle composed of a lipid bilayer. The amphetamine, 2,5-dimethoxy-4-isopropylthiophenethyl- liposome can be used as a vehicle for administration of amine, 2,5-dimethoxy-4-iodophenethylamine, 2,5-50 nutrients and pharmaceutical drugs, and it can be pre- dimethoxy-4-iodoamphetamine, 2,5 dimethoxy-4-fluor- pared by disrupting biological membranes (such as by ophenethylamine, 2,5-dimethoxy-4-ethylthio-phenethyl- sonication). Liposomes are composed of natural phos- amine, 2,5-dimethoxy-4-ethylphenethylamine, 2,5- pholipids, and may also contain mixed lipid chains with dimethoxy-4-cyclopropylmethylthio-phenethylamine, properties (e.g., egg phosphatidyleth- 2,5-dimethoxy-4-chlorophenethylamine, 2,5-dimethoxy- 55 anolamine). The major types of liposomes are the multi- 4 chloroamphetamine, 2,5-dimethoxy-4-lamellar vesicle (MLV), the small unilamellar vesicle bromophenethylamine, 2,5-dimethoxy-4-bromoamphet- (SUV), and the large unilamellar vesicle (LUV). amine, 2,5-dimethoxy-4-(2-fluoroethylthio)-phenethyl- [0038] It should be understood that the use of "and/or"

5 9 EP 2 884 962 B1 10 is defined inclusively such that the term "a and/or b" [0042] According to an embodiment, the micronized should be read to include the sets: "a and b," "a or b," powder base may be an inert powdered base, an active "a," "b." Features and advantages of the subject matter powdered base having improved transmucosal permea- hereof will become more apparent in light of the following tion, or combinations thereof. Examples of inert pow- detailed description of selected embodiments, as illus- 5 dered base include without limitations maltodextrins, mi- trated in the accompanying figures. As will be realized, crocrystalline cellulose, sucrose, xylitol, sorbitol, and the subject matter disclosed and claimed is capable of mannitol. As used herein, the term inert is intended to modifications in various respects, all without departing mean that the powdered base does not illicit any thera- from the scope of the claims. Accordingly, the drawings peutic physiological effect in organism consuming the and the description are to be regarded as illustrative in 10 formulation. nature, and not as restrictive and the full scope of the [0043] Maltodextrins are polysaccharides that are subject matter is set forth in the claims. used as a food additive. They are produced from starch by partial hydrolysis and are usually found as a white DETAILED DESCRIPTION OF EMBODIMENTS OF hygroscopic spraydried . Maltodextrins are eas- THE DISCLOSED TECHNOLOGY 15 ily digestible, being absorbed as rapidly as glucose, and might be either moderately sweet or almost flavorless. [0039] In a first embodiment, there is disclosed a com- They are commonly used for the production of sodas and pressible delivery formulation for transmucosal delivery candy and can also be found as an ingredient in a variety of at least one compound comprising: a micronized pow- of other processed foods. der base; a dessicated liposome formulation comprising 20 [0044] Microcrystalline cellulose is a term for refined at least one liposome containing at least one compound. wood pulp and is used as a texturizer, an anti-caking In a second embodiment, there is disclosed a dosage agent, a fat substitute, an emulsifier, an extender, and a form for transmucosal delivery of at least one compound bulking agent in food production. The most common form comprising a formulation of the present invention in com- is used in vitamin supplements or tablets. Sucrose is the bination with a pharmaceutically acceptable carrier, and 25 organic compound commonly known as table sugar and the dosage form may contain from about 10 mg to about sometimes called saccharose. A white, odorless, crys- 500 mg of the compound. In a third embodiment, there talline powder with a sweet taste, it is best known for its is disclosed a process for the preparation of solid dosage nutritional role. Xylitol, sorbitol, and mannitol are sugar form by compressing a formulation of the present inven- alcohol sweetener used as a naturally occurring sugar tion in combination with a pharmaceutically acceptable 30 substitute. carrier, without a heat treatment capable of causing deg- [0045] As used herein, the term "active" is intended to radation of the formulation. mean that the powdered base does have a therapeutic [0040] In a fourth embodiment, there is disclosed a physiological effect in organism consuming the formula- process for the preparation of a formulation for transmu- tion. Non limiting examples of active powdered base are cosal delivery of at least one compound comprising35 caffeine, theobromine, theophylline, a plant extract with spraying a liposome formulation suspended in a water bioavailable components, and creatine. Examples of based solvent on a micronized powder base. The lipo- plant extract with bioavailable components include green some formulation comprises at least one liposome con- coffee extract, guarana extracts, Yerba mate extracts, taining at least one compound. The spraying is effected tea extract, citrus aurantium extracts, and combinations at a temperature at a nozzle head aperture of about 60°C 40 thereof. Preferred active powdered base are include caf- or less, to desiccate the liposomes. In a fifth embodiment, feine, theobromine, and creatine. Preferably, the caffeine there is disclosed a formulation for transmucosal delivery is a salt of caffeine, such as for example dicaffeine of at least one compound prepared by the process of the malate, caffeine citrate, caffeine hydrochloride, or com- present invention. In a sixth embodiment, there is dis- binations thereof. closed a solid dosage form prepared by compressing a 45 [0046] According to another embodiment, the formu- formulation of the present invention, without a heat treat- lation of the present invention may comprise dessicated ment capable of causing degradation of the formulation. liposome formulation that comprising at least one lipo- [0041] According to the first embodiment, there is dis- some containing at least one compound. The liposome closed a formulation for transmucosal delivery of at least formulation may contain more than one type of liposome, one compound comprising: a micronized powder base; 50 each of which may be loaded with one or more different a desiccated liposome formulation comprising at least compound. According to an embodiment, the lipo- one liposome containing at least one compound. Accord- some(s) are loaded with the compound(s) with sufficient ing to an embodiment, the dessicated liposome formu- amounts of compounds to achieve unitary doses (dosage lation comprises the compound in an amount sufficient forms) capable of delivering from about 10 mg to about to form a unitary dosage form containing from about 10 55 500 mg of the compound(s), or from about 100m g to mg to about 500 mg of the compound. The compound about 500 mg, , or from about 200 mg to about 500 mg, , may be an active ingredient, a mucosal absorption en- or from about 300 mg to about 500 mg, or from about 400 hancer, or combinations thereof. mg to about 500 mg, or from about 500 mg to about 500

6 11 EP 2 884 962 B1 12 mg, or from about 600 mg to about 500 mg, or from about voring and sweetening agents. The flavoring and sweet- 700 mg to about 500 mg, or from about 800 mg to about ening agents further improve the palatability and mouth 500 mg, or from about 900 mg to about 500 mg, or from feel of the formulation of the present invention. For ex- about 1 mg to about 500 mg, or from about 10 mg to ample, the flavoring agent may be chosen from orange about 500 mg, or from about 10 mg to about 400 mg, or 5 flavor, lemon flavor, grapefruit flavor, blueberry flavor, from about 10 mg to about 300 mg, or from about 10 mg raspberry flavor, strawberry flavor, peach flavor, grape to about 200 mg, or from about 10 mg to about 100 mg, flavor, apple flavor, mango flavor, banana flavor, mint or from about 10 mg to about 50 mg, or from about 10 flavor, cinnamon flavor, vanilla flavor, butterscotch flavor, mg to about 25 mg, or from about 25 mg to about 500 caramel flavor chocolate flavor, and combinations there- mg, or from about 25 mg to about 400 mg, or from about 10 of. Preferably, the flavoring may be a mint flavor. Most 25 mg to about 300 mg, or from about 25 mg to about preferably, the flavoring may be chosen from spearmint 200 mg, or from about 25 mg to about 100 mg, or from flavor and peppermint flavor, and combinations thereof. about 25 mg to about 50 mg, or from about 50 mg to [0050] Examples of sweeteners include but are not lim- about 500 mg, or from about 50 mg to about 400 mg, or ited to glucose, fructose, aspartame, cyclamate, saccha- from about 50 mg to about 300 mg, or from about 50 mg 15 rin, stevia, sucralose, brazzein, curculin, erythritol, gly- to about 200 mg, or from about 50 mg to about 100 mg, cyrrhizin, glycerol, hydrogenated starch hydrolysates, in- or from about 100 mg to about 500 mg, or from about ulin, isomalt, lactitol, Luo han guo, mabinlin, maltitol, mal- 100 mg to about 400 mg, or from about 100 mg to about to-oligosaccharide, mannitol, miraculin, monatin, monel- 300 mg, or from about 100 mg to about 200 mg, or from lin, osladin, pentadin, sorbitol, tagatose, thaumatin, xyl- about 200 mg to about 500 mg, or from about 200 mg to 20 itol, acesulfame potassium, alitame, salt of aspartame- about 400 mg, or from about 200 mg to about 300 mg, acesulfame, dulcin, glucin, neohesperidin dihydrochal- or from about 300 mg to about 500 mg, or from about cone, neotame and combinations thereof. 300 mg to about 400 mg, or from about 400 mg to about [0051] According to another embodiment, the formu- 500 mg. Without wishing to be bound by theory, the lation of the present invention may further comprise a amount of compound will vary according to the com-25 mucosal absorption enhancer for improved transmucos- pound selected, and the desired dosage required to ob- al permeation. According to an embodiment, the mucosal tain the desired health beneficial effect or therapeutic ef- absorption enhancer may be one of the compounds in- fect. The person skilled in the art is capable of determin- cluded in one of the liposome formulation used in the ing the amount of compound necessary to be loaded into present invention. According to another embodiment, the the liposomes in order to achieve the desired amounts 30 mucosal absorption enhancer may be added as a further in the final dosage forms. ingredient of the formulation of the present invention, [0047] The use of desiccated liposomes in the formu- without the benefit of liposome encapsulation. lation of the present invention allows for the preparation [0052] Limited examples of mucosal absorption en- of formulations having low water content that have long hancer include but are not to 23-lauryl ether, aprotinin, shelf life. Furthermore, upon contact with the bodily fluids 35 azone, benzalkonium chloride, cetylpyridinium chloride, in the body cavity in proximity to the target mucosa (e.g. cetyltrimethylammonium bromide, cyclodextrin, dextran buccal, vaginal or anal), the desiccated liposomes sulfate, lauric acid, lauric acid/Propylene glycol, lyso- present in the formulation of the present invention rehy- phosphatidylcholine, menthol methoxysalicylate, methy- drate and the liposomes are shown under microscope to loleate, oleic acid, piperine, phosphatidylcholine, polyox- be normal sphericals (i.e filled with water) to provide one 40 yethylene, polysorbate 80, sodium EDTA, sodium glyco- or more liposome encapsulated compounds in situ. With- cholate, sodium glycodeoxycholate, sodium lauryl sul- out wishing to be bound by theory, it is believed that upon fate, sodium salicylate, sodium taurocholate, sodium tau- contact with the mucosa, the content of the liposome is rodeoxycholate, sodium deoxycholate, a sulfoxide, bile delivered transmucosally directly into the systemic circu- salts, and an alkyl glycoside. Preferably, the mucosal ab- lation. Furthermore, the use of desiccated liposomes also 45 sorption enhancer is piperine. Most preferably, the mu- contributes to masking of the taste of some of the com- cosal absorption enhancer is liposome encapsulated pip- pounds that they contain, thereby helping to provide a erine. Most preferable, liposome encapsulated piperine more palatable delivery system. is used in about 100 mg to about 200 mg per dosage form. [0048] According to an embodiment, unilamellar lipo- [0053] According to another embodiment, the desic- somes may be used to contain water soluble compounds 50 cated liposomes may be loaded with an active ingredient. for higher bioavailability and faster absorption. For ex- According to another embodiment, an active ingredient ample, such liposomes could be used to encapsulate may also be added to the formulation of the present in- phenylethylamine salts. According to another embodi- vention without the benefit of liposomal encapsulation. ment, bilamellar (i.e. multilamellar) liposomes may also According to an embodiment, the active ingredient may be used for lipid soluble compounds such as ecdyster- 55 have good bioavailability after first-pass metabolism. ones, or coenzyme Q10. However, the formulation of the present invention accel- [0049] According to another embodiment, the formu- erates the rate at which the active ingredient reaches lation of the present invention may further comprise fla- systemic circulation over .

7 13 EP 2 884 962 B1 14

[0054] According to another embodiment, the active ing gum, a base gum and derivatives thereof and com- ingredient is an active ingredient having a low bioavail- binations thereof. ability. In such as case, it is believed that the formulation [0058] According to another embodiment, there is dis- of the present invention may accelerate the rate at which closed a process for the preparation of a formulation for the activeingredient reaches systemic circulation over 5 transmucosal delivery of at least one active ingredient enteral administration, and increase the amount of the by spraying a liposome formulation suspended in a water active ingredient which is bioavailable over enteral ad- based solvent on a micronized powder base (as de- ministration. Examples of compounds having low bioa- scrived above). The liposome formulation comprises at vailability include but are not limited to coenzyme Q10, least one liposome containing at least one compound (as glutathione, steroids, sterols, sapponins, etc. 10 descrived above). Spraying is effected preferably in a [0055] The active ingredient may be any one of a phar- fluidized bed, or any suitable apparatus. Spraying is ef- maceutical drug, a nutritional supplement, a plant extract, fected at a temperature at a nozzle head aperture of an herbal medicine, an enzyme, a peptide or combina- about 60°C or less. Spraying of the liposome formulation tions thereof. Non limiting examples of pharmaceutical in this fashion causes the water based solvent to evap- drugs include nitric oxide aldosterone antagonists, alpha- 15 orate, as well as dissipate the heat present in the water adrenergic receptor antagonists, angiotensin II, antago- based solvent, and results in desiccation of the liposome nists, angiotensin-converting enzyme inhibitors, antidia- without damaging them. betic compounds, anti-hyperlipidemic compounds, anti- [0059] According to an embodiment, about 0.4 L to oxidants, antithrombotic and vasodilator compounds, β- about 1.0 L of the liposome formulation suspended in a adrenergic antagonists, calcium channel blockers, digi- 20 water based solvent is sprayed for each 1 kg of the mi- talis, diuretic, endothelin antagonists, hydralazine com- cronized powder base. Therefore, the volume of lipo- pounds, H2 receptor antagonists, neutral endopeptidase some formulation suspended in a water based solvent inhibitors, nonsteroidal antiinflammatory compounds, sprayed for each 1 kg of the micronized powder base phosphodiesterase inhibitors, potassium channel block- may be from about 0.4 L to about 0.5 L, or from about ers, platelet reducing agents, proton pump inhibitors, ren- 25 0.4 L to about 0.6 L, or from about 0.4 L to about 0.7 L, in inhibitors, selective cyclooxygenase-2 inhibitors, psy- or from about 0.4 L to about 0.8 L, or from about 0.4 L to choactive drugs, stimulants, or combinations thereof. about 0.9 L, or from about 0.4 L to about 1.0 L, or from Non limiting examples of nutritional supplements include about 0.5 L to about 0.6 L, or from about 0.5 L to about vitamins, coenzymes, cofactors, or combinations there- 0.7 L, or from about 0.5 L to about 0.8 L, or from about of. 30 0.5 L to about 0.9 L, or from about 0.5 L to about 1.0 L, [0056] According to the second embodiment, the for- or from about 0.6 L to about 0.7 L, or from about 0.6 L to mulations of the present inventions may be included into about 0.8 L, or from about 0.6 L to about 0.9 L, or from dosage forms, along with suitable pharmaceutically ac- about 0.6 L to about 1.0 L, or from about 0.7 L to about ceptable carriers, and the dosage form contains from 0.8 L, or from about 0.7 L to about 0.9 L, or from about about 10 mg to about 500 mg of the compound. Examples 35 0.7 L to about 1.0 L, or from about 0.8 L to about 0.9 L, of suitable dosage forms for transmucosal delivery in- or from about 0.8 L to about 1.0 L, or from about 0.9 L to clude but are not limited to chewable tablets, fast disin- about 1.0 L. Preferably, the volume is from about 0.4 L tegrating tablets, jellies, , chewing gum, granules, to about 0.7 L for each 1 kg of the micronized powder films, lozenges, and (e.g. mouth- base. washes), which may be administered buccally (i.e.40 [0060] According to an embodiment, the liposome for- through the buccal mucosa), as well as ointments, and mulation comprises the compound in an amount suffi- , which may be administered through the cientto formunitary dosage forms that contain fromabout vaginal and anal mucosa. Preferred dosage forms are 10 mg to about 500 mg of compound. Without wishing to chosen from chewable tablets, fast disintegrating tablets, be bound by theory, the amount of compound will vary chewing gums, granules, and suppositories. Other suit- 45 according to the compound selected, and the desired able dosage forms include a jelly, a gel, a film, a lozenge, dosage required to obtain the desired health beneficial a toothpaste, an ointment, a liquid and a spray. effect or therapeutic effect. The person skilled in the art [0057] According to an embodiment, the dosage form is capable of determining the amount of compound nec- of the present invention may contain any suitable phar- essary to be loaded into the liposomes in order to achieve maceutically acceptable carriers as known in the art. Ac- 50 the desired amounts in the final dosage forms. cording to an embodiment, a preferred pharmaceutically [0061] According to an embodiment, the water based acceptable carrier is a hydrocolloid. As used herein, hy- solvent may be water, or a mixture of water and alcohol. drocolloids aresubstances that form a gelin thepresence For example, the alcohol may be ethanol. According to of water. Examples of hydrocolloids include but are not another embodiment, the water based solvent may fur- limited to agar, agarose, alginates, carrageenan (iota, 55 ther comprise flavoring agents, sweetening agent, or kappa, lambda), cellulosics, chitosan, gelatin, gellan combinationsthereof. According toanother embodiment, gum, , gum arabic, locust bean gum, pectin, the water based solvent may further comprise second soybean gel, starch, whey protein, xanthan gum, chew- active ingredients, mucosal absorption enhancer, or

8 15 EP 2 884 962 B1 16 combinations thereof. Alternatively, according to another a dessicated liposome formulation comprising embodiment, the second active ingredients, mucosal ab- at least one liposome containing at least one sorption enhancer, or combinations thereof may be in- compound in an amount sufficient to form a uni- cluded with the micronized powder base, and sprayed tary dosage form containing from 10 mg to 500 with the liposome formulations. 5 mg of said compound; [0062] According to another embodiment, there is pro- wherein said compound is an active ingredient, vided a process for the preparation of a solid dosage form a mucosal absorption enhancer, or combina- by compressing a formulation of the present invention as tions thereof; described above, in combination with a pharmaceutically wherein said micronized powder base is chosen acceptable carrier as described above, without a heat 10 from an inert powdered base, an active pow- treatment capable of causing degradation of the formu- dered base having improved transmucosal per- lation. As used herein, without a heat treatment capable meation, or combinations thereof; of causing degradation of the formulation is intended to wherein said inert powdered base is chosen mean that only compression is used during the prepara- from a maltodextrin, a microcrystalline cellulose, tion of the dosage form. No heat treatment that would 15 sucrose, xylitol, sorbitol, mannitol, or combina- damage the liposome present in the formulation of the tions thereof; and present invention should be used. Liposomes are noto- wherein said active powdered base is chosen riously sensitive to increased temperatures that damage from a caffeine, theobromine, theophylline, a the phospholipids constituting their bilayers; and hence plant extract with bioavailable components, and temperature should be kept as low as possible and not 20 creatine, exceeding 60°C when preparing the dosage form from characterized by the dessicated liposome for- the formulation of the present invention. mulation being formed by spraying a liposome [0063] The present invention will be more readily un- formulation suspended in a water based solvent derstood by referring to the following example which is on said micronized powder base at a tempera- given to illustrate the invention rather than to limit its25 ture at a nozzle head aperture of about 60°C or scope. EXAMPLE 1: 7-methoxiflavone formulation. 7- less to evaporate said water based solvent and methoxiflavone has poor bioavailab ility of approximately desiccate said liposome, wherein about 0.4 L to 5%. Liposome containing 7-methoxiflavone are mixed about 1.0 L of said liposome formulation sus- with liposome containing piperine, and the mixture is pended in a water based solvent is sprayed per sprayed onto microcrystalline cellulose or maltodextrine 30 about 1 kg of said micronized powder base. in a fluid bed. The resulting powder is mixed with addi- tional bulking agents and compressed into tablets. 2. The formulation of claim 1, wherein said at least one [0064] While the disclosed technology has been taught active ingredient is chosen from a pharmaceutical with specific reference to the above embodiments, a per- drug, a nutritional supplement, a phenylethylamine, son having ordinary skill in the art will recognize that35 a metabolism booster, a plant extract, an herbal changescan be made in formand detailwithout departing medicine, an enzyme, a peptide or combinations from the spirit and the scope of the disclosed technology. thereof. The described embodiments are to be considered in all respects only as illustrative and not restrictive. All chang- 3. The formulation of claim 2, wherein at least one sec- es that come within the meaning and range of equiva- 40 ond active ingredient is chosen from a pharmaceu- lency of the claims are to be embraced within their scope. tical drug, a nutritional supplement, a phenylethyl- Combinations of any of the methods and apparatuses amine, a metabolism booster, a plant extract, an described hereinabove are also contemplated and within herbal medicine, an enzyme, a peptide or combina- the scope of the invention. It should be further understood tions thereof. that the term "about" is defined to be within a standard 45 tolerance level known in the art, or if such a definition is 4. The formulation of claim 2 or claim 3, wherein said considered imprecise, then within 5% of the amount for pharmaceutical drug is chosen from a nitric oxide which "about" is modifying. All terms listed with the mod- donor, an aldosterone antagonist, an alpha-adren- ifier "about" may also be claimed and considered to be ergic receptor antagonist, an angiotensin II, antag- disclosed in the exact amount specified. 50 onist, an angiotensin-converting enzyme inhibitor, an antidiabetic compound, an anti hyperlipidemic compound, an antioxidant, an antithrombotic and va- Claims sodilator compound, a β-adrenergic antagonist, a , a digitalis, a diuretic, an 1. A compressible delivery formulation for transmucos- 55 endothelin antagonist, a hydralazine compound, a al delivery of at least one compound comprising: H2 receptor antagonist, a monoamine oxidase ac- tivity inhibitor, a neutral endopeptidase inhibitor, a a micronized powder base; and nonsteroidal antiinflammatory compound, a phos-

9 17 EP 2 884 962 B1 18

phodiesterase inhibitor, a potassium channel block- 8. A dosage form for transmucosal delivery of at least er, a platelet reducing agent, a proton pump inhibitor, one compound comprising: a renin inhibitor, a selective cyclooxygenase-2 inhib- a formulation as claimed in claim 1, wherein said itor, a psychoactive drug, a stimulant, or combina- dosage form is chosen from a chewable tablet, a fast tions thereof. 5 disintegrating tablet, a chewing gum, a granule, and a suppository. 5. The formulation of claim 2 or claim 3, wherein said phenylethylamine is chosen from phenylethylamine, 9. A dosage form for transmucosal delivery of at least β-methylphenethylamine, β-keto-amphetamine, β- one compound comprising: hydroxy-amphetamine, β,4-dihydroxyphenethyl- 10 a formulation as claimed in claim 1, wherein said amine, β,4-dihydroxy-3-hydroxymethyl-N-tert-butyl- dosage form is chosen from a jelly, a gel, a film, a phenethylamine, β,3-dihydroxyphenethylamine, lozenge, a toothpaste, an ointment, a liquid and a β,3-dihydroxy-N-methylphenethylamine, β,3,4-tri- spray. hydroxyphenethylamine, β,3,4-trihydroxy-Nmethyl- phenethylamine, α-methylphenethylamine, α,α- 15 10. The dosage form of claim 7, wherein said pharma- dimethylphenethylamine, N-methylcathinone, N- ceutically acceptable carrier is a hydrocolloid. methylamphetamine, N-methyl-β-hydroxyampheta- mine, Nethylcathinone,4-methylmethcathinone, 4- 11. A process for the preparation of a formulation for hydroxyphenethylamine, 3-trifluoromethyl-N-ethyl- transmucosal delivery of at least one compound amphetamine, 3-trifluoromethyl-amphetamine, 3- 20 comprising: hydroxyphenethylamine, 3-chloro-N-tert-butyl-(3- ketoamphetamine, 3,4-dihydroxyphenethylamine, a) spraying a liposome formulation suspended 3,4,5-trimethoxyphenethylamine, 2,5-dimethoxy-4- in a water based solvent on a micronized powder tertbutylthio-phenethylamine, 2,5-dimethoxy-4-pro- base, said liposome formulation comprising at pylthio-phenethylamine, 2,5-dimethoxy-4-propyl-25 least one liposome containing at least one com- phenethylamine, 2,5-dimethoxy-4-nitrophenethyl- pound in an amount sufficient to form a unitary amine, 2,5-dimethoxy-4-nitroamphetamine, 2,5- dosage form containing from about 10m g to dimethoxy-4-methylphenethylamine, 2,5-dimeth- about 500 mg of said compound, at a tempera- oxy-4-methylamphetamine, 2,5-dimethoxy-4-iso- ture at a nozzle head aperture of about 60°C or propylthiophenethylamine, 2,5-dimethoxy-4-iodo- 30 less to evaporate said water based solvent and phenethylamine, 2,5-dimethoxy-4-iodoampheta- desiccate said liposome, wherein about 0.4 L to mine, 2,5-dimethoxy-4-fluorophenethylamine, 2,5- about 1.0 L of said liposome formulation sus- dimethoxy-4-ethylthio-phenethylamine, 2,5-dimeth- pended in a water based solvent is sprayed per oxy-4-ethylphenethylamine, 2,5-dimethoxy-4-cyclo- about 1 kg of said micronized powder base. propylmethylthio-phenethylamine, 2,5-dimethoxy- 35 4-chlorophenethylamine, 2,5-dimethoxy-4-chloro- 12. The process of claim 11, wherein said compound is amphetamine, 2,5-dimethoxy-4-bromophenethyl- an active ingredient, a mucosal absorption enhanc- amine, 2,5-dimethoxy-4-bromoamphetamine, 2,5- er, or combinations thereof. dimethoxy-4-(2-fluoroethylthio)-phenethylamine, 2,4,5-trihydroxyphenethylamine, 3,4-methylenedi- 40 13. The process of claim 11, wherein said micronized oxymethcathinone, 3,4-methylenedioxy-N-methyl- powder base is chosen from an inert powdered base, amphetamine, α N,-butylene-β-methoxycarbonyl- an active powdered base having improved transmu- phenethylamine, 3,4-methylenedioxy-Nethylam- cosal permeation, or combinations thereof. phetamine, 3,4-methylenedioxyamphetamine. 45 14. The process of claim 12, comprising a second active 6. The formulation of claim 4, wherein said monoamine ingredient, wherein said second active incredient is oxidase activity inhibitor is at least one of Piperine, a phenylethylamine chosen from phenylethylamine, methyl piperate, a piperine derivative, a methyl pip- β-phenylethylamine, β-methylphenethylamine, β,4- erate derivative, St. John’s Wort, American Ginseng, dihydroxyphenethylamine, 3-chloro-N-tert-butyl-β- AsianGinseng, 5-hydroxy tryptophan,Bitter Orange, 50 ketoamphetamine, phenelzine, and tranylcy- Brewer’s Yeast, Vitamin B6, L - Tyrosine and Yo- promine. himbe. 15. The process of claim 12, wherein said active ingre- 7. A dosage form for transmucosal delivery of at least dient is a monoamine oxidase activity inhibitor com- one compound comprising: 55 prising at least one of Piperine, methyl piperate, a a formulation as claimed in claim 1 in combination piperine derivative, a methyl piperate derivative, St. with a pharmaceutically acceptable carrier, wherein John’s Wort, American Ginseng, Asian Ginseng, 5 - said dosage form is a spray. hydroxy tryptophan, Bitter Orange, Brewer’s Yeast,

10 19 EP 2 884 962 B1 20

Vitamin B6, L - Tyrosine and Yohimbe. lichen Arzneimittel, einem Enzym, einem Peptid oder Kombinationen davon.

Patentansprüche 4. Formulierung nach Anspruch 2 oder Anspruch 3, wo- 5 bei das pharmazeutische Medikament ausgewählt 1. Komprimierbare Abgabeformulierung zur transmu- ist aus einem Stickoxid-Donor, einem Aldosteron- kosalen Abgabe von mindestens einer Verbindung, Antagonisten, einem alpha-adrenergischen Rezep- umfassend: torantagonisten, einem Angiotensin II, einem Anta- gonist, ein Angiotensin-umwandelnden Enzym-Inhi- eine mikronisierte Pulverbasis; und 10 bitor, einer antidiabetischen Verbindung, einer anti- eine getrocknete Liposomenformulierung, die hyperlipidämischenVerbindung, einemAntioxidans, mindestens ein Liposom umfasst, enthaltend einerantithrombotischen und vasodilatorischen Ver- mindestens eine Verbindung in einer Menge, die bindung, einem β-adrenergischen Antagonisten, ei- ausreicht, um eine einheitliche Dosierungsform nem Kalziumkanalblocker, einem Digitalis, einem zu bilden, enthaltend 10 mg bis 500 mg der Ver- 15 Diuretikum, einem Endothelin-Antagonisten, einer bindung; Hydralazin-Verbindung, einem H2-Rezeptor-Anta- wobeidie Verbindung ein Wirkstoff,ein Schleim- gonist, einem Monoaminoxidase-Aktivitätsinhibitor, hautabsorptions-Verstärker oder Kombinatio- einem neutralen Endopeptidase-Inhibitor, einer nen davon, ist; nichtsteroidalen entzündungshemmenden Verbin- wobei die mikronisierte Pulverbasis ausgewählt 20 dung, einem Phosphodiesteraseinhibitor, einem Ka- ist aus einer inerten Pulverbasis, einer aktiven liumkanal-Blocker, einem Plättchen-reduzierenden Pulverbasis mit verbesserter transmukosaler Mittel, einem Protonenpumpeninhibitor, einem Re- Permeation, oder Kombinationen davon; nin-inhibitor, einem selektiven Cyclooxygenase-2- wobei die inerte Pulverbasis ausgewählt ist aus Inhibitor, einem psychoaktiven Medikament, einem einem Maltodextrin, einer mikrokristallinen Zel- 25 Stimulans oder Kombinationen davon. lulose, Saccharose, Xylit, Sorbit, Mannit oder Kombinationen davon; und 5. Formulierung nach Anspruch 2 oder Anspruch 3, wo- wobei die aktive Pulverbasis ausgewählt ist aus bei das Phenylethylamin ausgewählt ist aus Phenyl- einem Koffein, Theobromin, Theophyllin, einem ethylamin, β-Methylphenethylamin, β-Ketoamphet- Pflanzenextrakt mit bioverfügbaren Komponen- 30 amin, β-hydroxyamphetamin, β,4-Dihydroxyphene- ten und Kreatin, tylamin, β,4-Dihydroxy-3-hydroxymethyl-N-tert-bu- dadurchgekennzeichnet, dass die getrockne- tylphenethylamin, β,3-Dihydroxyphenethylamin, te Liposomenformulierung gebildet wird durch β,3-Dihydroxy-N-methylphenethylamin, β,3,4-Trihy- Sprühen einerLiposomenformulierung, die in ei- droxyphenethylamin, β,3,4-Trihydroxy-N-methyl- nem auf Wasser-basierenden Lösungsmittel35 phenethylamin, α-methylphenethylamin, α,α-Dime- suspendiert ist, auf die mikronisierte Pulverba- thylphenethylamin, N-Methylcathinon, N-Methylam- sis bei einer Temperatur an einer Düsenkopföff- phetamin, N-Methyl-β-hydroxyamphetamin, N- nung von etwa 60 °C oder weniger, um das auf Ethylcathinon, 4-Methylmethcathinon, 4-Hydrox- Wasser-basierende Lösungsmittel zu verdamp- phenetylamin, 3-Trifluormethyl-N-ethylampheta- fen und das Liposom zu trocknen, wobei etwa 40 min, 3-Trifluormethylamphetamin, 3-Hydroxyphen- 0,4 l bis etwa 1,0 l der Liposomenformulierung, ethylamin, 3-Chlor-N-tert-butyl-β-Ketoamphetamin, die in einem auf Wasser-basierenden Lösungs- 3,4-Dihydroxyphenethylamin, 3,4,5-Trimethoxy- mittel suspendiert ist, pro etwa 1 kg der genann- phenethylamin, 2,5-Dimethoxy-4-tert-butylthiophe- ten mikronisierten Pulverbasis versprüht wird. nethylamin, 2,5-Dimethoxy-4-propylthiophenethyla- 45 min, 2,5-Dimethoxy-4-propylphenethylamin, 2,5-Di- 2. Formulierung nach Anspruch 1, wobei der mindes- methoxy-4-Nitrophenethylamin, 2,5-Dimethoxy-4- tens eine Wirkstoff ausgewählt ist aus einem phar- nitroamphetamin, 2,5-Dimethoxy-4-Methylphene- mazeutischen Medikament, einem Nahrungsergän- thylamin, 2,5-Dimethoxy-4-methylamphetamin, 2,5- zungsmittel, einem Phenylethylamin, ein Stoffwech- Dimethoxy-4-Isopropylthiophenethylamin, 2,5-Di- selverstärker, einem Pflanzenextrakt, einem pflanz- 50 methoxy-4-iodphenethylamin, 2,5-Dimethoxy-4-io- lichen Arzneimittel, einem Enzym, einem Peptid damphetamin, 2,5-Dimethoxy-4-fluorphenethyla- oder Kombinationen davon. min, 2,5-Dimethoxy-4-ethylthiophenethylamin, 2,5- Dimethoxy-4-ethylphenethylamin, 2,5-Dimethoxy- 3. Formulierung nach Anspruch 2, wobei mindestens 4-cyclopropylmethylthio-phenethylamin, 2,5-Dime- ein zweiter Wirkstoff ausgewählt ist aus einem phar- 55 thoxy-4-Chlorphenethylamin, 2,5-Dimethoxy-4-chl- mazeutischen Medikament, einem Nahrungsergän- oramphetamin, 2,5-Dimethoxy-4-Bromphenethyla- zungsmittel, einem Phenylethylamin, ein Stoffwech- min, 2,5-Dimethoxy-4-bromamphetamin, 2,5-Dime- selverstärker, einem Pflanzenextrakt, einem pflanz- thoxy-4-(2-flourethylthio)-phenethylamin, 2,4,5-tri-

11 21 EP 2 884 962 B1 22

hydroxyphenethylamin, 3,4-Methylendioxymethca- 12. Verfahren nach Anspruch 11, wobei die Verbindung thinon, 3,4-Methylendioxy-N-methylamphetamin, ein Wirkstoff, ein Schleimhautabsorptions-Verstär- N,α-butylen-β-methoxycarbonylphenethylamin,3,4- ker oder Kombinationen davon, ist. Methylendioxy-N -ethylamphetamin,3,4-Methylen- dioxyamphetamin. 5 13. Verfahren nach Anspruch 11, wobei die mikronisier- te Pulverbasis ausgewählt ist aus einer inerten Pul- 6. Formulierung nach Anspruch 4, worin die Monoami- verbasis, einer aktiven Pulverbasis mit verbesserter noxidase-Aktivität zumindest eine von Piperin, Me- transmucosaler Permeation oder Kombinationen thylpiperat, einem Piperinderivat und einem Methyl- davon. Piperatderivat, Johanniskraut, amerikanischer Gin- 10 seng, asiatischer Ginseng, 5-Hydroxy Tryptophan, 14. Verfahren nach Anspruch 12, umfassend einen Bitterorange, Bierhefe, Vitamin B6, L-Tyrosin und zweiten Wirkstoff, wobei der zweiter Wirkstoff ist Yohimbe ist. Phenylethylamin ist, welches ausgewählt ist aus Phenylethylamin, β-Phenylethylamin, β-Methylphe- 7. Dosierungsform zur transmukosalen Abgabe von 15 nethylamin, β,4-Dihydroxyphenethylamin, 3-chlor- mindestens einer Verbindung umfassend: N-tert-butyl-β-ketoamphetamin, Phenelzin und Tra- eine Formulierung nach Anspruch 1 in Kombination nylcypromin. mit einem pharmazeutisch akzeptablen Träger, wo- bei die Dosierungsform ein Spray ist. 15. Verfahren nach Anspruch 12, wobei die Monoamin- 20 oxidase-Aktivität zumindest eine von Piperin, Me- 8. Dosierungsform zur transmukosalen Abgabe von thylpiperat, einem Piperinderivat und einem Methyl- mindestens einer Verbindung umfassend: Piperatderivat, Johanniskraut, amerikanischer Gin- eine Formulierung nach Anspruch 1, wobei die Do- seng, asiatischer Ginseng, 5-Hydroxy Tryptophan, sierungsform ausgewählt ist aus einer kaubaren Ta- Bitterorange, Bierhefe, Vitamin B6, L-Tyrosin und blette, einer schnell zerfallenden Tablette, einem 25 Yohimbe ist. Kaugummi, einem Granulat und einem Zäpfchen.

9. Dosierungsform zur transmukosalen Abgabe von Revendications mindestens einer Verbindung umfassend: eine Formulierung nach Anspruch 1, wobei die Do- 30 1. Formulation d’administration compressible pour une sierungsform ausgewählt ist aus einem Gelee, ei- administration par voie transmucosale d’au moins nem Gel, einem Film, einem Dragee, einer Zahnpas- un composé comprenant : ta, einer Salbe, einer Flüssigkeit und einem Spray. une base constituée par une poudre 10. Dosierungsform nach Anspruch 7, wobei der phar- 35 micronisée ; et mazeutisch akzeptable Träger ein Hydrokolloid ist. une formulation de liposome(s) desséché(s) qui comprend au moins un liposome qui contient au 11. Verfahren zur Herstellung einer Formulierung zur moins un composé selon une quantité suffisante transmukosalen Abgabe von zumindest einer Ver- pour former une forme de dosage unitaire qui bindung umfassend: 40 contient une quantité de 10 mg à 500 mg dudit composé ; dans laquelle : a) Sprühen einer Liposomenformulierung, wel- ledit composé est un ingrédient actif, un agent che in einem auf Wasser-basierenden Lösungs- favorisant l’absorption par voie mucosale ou des mittel suspendiert ist, auf eine mikronisierte Pul- combinaisons afférentes ; dans laquelle : verbasis, wobei die Liposomenformulierung zu- 45 ladite base constituée par une poudre microni- mindest ein Liposom umfasst, das zumindest ei- sée est choisie parmi une base pulvérulente ne Verbindung in einer Menge enthält, die aus- inerte, une base pulvérulente active qui présen- reicht, um eine Einheitsdosisform zu bilden mit te une perméation par voie transmucosale amé- etwa 10 mg bis etwa 500 mg der Verbindung bei liorée ou des combinaisons afférentes ; dans einer Temperatur an einer Düsenkopföffnung 50 laquelle : von etwa 60 ° C oder weniger, um das auf Was- ladite base pulvérulente inerte est choisie parmi ser-basierende Lösungsmittel zu verdampfen une maltodextrine, une cellulose microcristalli- und das Liposom trocknen, wobei etwa 0,4 l bis ne, le sucrose, le xylitol, le sorbitol, le mannitol etwa 1,0 l der Liposomenformulierung, welche ou des combinaisons afférentes ; et dans in einem auf Wasser-basierenden Lösungsmit- 55 laquelle : tel suspendiert ist, pro etwa 1 kg der genannten mikronisierten Pulverbasis gesprüht wird. ladite base pulvérulente active est choisie parmi une caféine, une théobromine, une

12 23 EP 2 884 962 B1 24

théophylline, un extrait de plante compor- 5. Formulation selon la revendication 2 ou la revendi- tant des composants bio-disponibles et la cation 3, dans laquelle ladite phényléthylamine est créatine ; choisie parmi phényléthylamine, β-méthylphénéthy- caractérisée en ce que la formulation de lamine, β-céto-amphétamine, β-hydroxy-amphéta- liposome(s) desséché(s) est formée en pul- 5 mine, β,4-dihydroxyphénéthylamine, β,4-dihydroxy- vérisant une formulation de liposome(s) qui 3-hydroxyméthyl-N-tert-butylphénéthylamine, β,3- est en dans un solvant à base dihydroxyphénéthylamine, β,3-dihydroxy-N-méthyl- d’eau sur ladite base constituée par une phénéthylamine, β,3,4-trihydroxyphénéthylamine, poudre micronisée à une température au ni- β,3,4-trihydroxy-N-méthylphénéthylamine, α-mé- veau d’une ouverture de tête d’éjecteur10 thylphénéthylamine, α,α-diméthylphénéthylamine, d’environ 60 °C ou moins de manière à faire N-méthylcathinone, N-méthylamphétamine, N-mé- évaporer ledit solvant à base d’eau et à des- thyl-β-hydroxyamphétamine, N-éthylcathinone, 4- sécher ledit liposome, dans laquelle une méthylméthcathinone, 4-hydroxyphénéthylamine, quantité d’environ 0,4 L à environ 1,0 L de 3-trifluorométhyl-N-éthyl-amphétamine, 3-trifluoro- ladite formulation de liposome(s) qui est en 15 méthyl-amphétamine, 3-hydroxyphénéthylamine, 3- suspension dans un solvant à base d’eau chloro-N-tert-butyl-β-cétoamphétamine, 3,4-dihy- est pulvérisée pour environ 1 kg de ladite droxyphénéthylamine, 3,4,5-triméthoxyphénéthyla- baseconstituée par une poudre micronisée. mine, 2,5-diméthoxy-4-tertbutylthio-phénéthylami- ne, 2,5-diméthoxy-4-propylthio-phénéthylamine, 2. Formulation selon la revendication 1, dans laquelle 20 2,5-diméthoxy-4-propylphénéthylamine, 2,5-dimé- ledit au moins un ingrédient actif est choisi parmi un thoxy-4-nitrophénéthylamine, 2,5-diméthoxy-4-ni- médicament pharmaceutique, un complément nutri- troamphétamine, 2,5-diméthoxy-4-méthylphénéthy- tionnel, une phényléthylamine, un booster de méta- lamine, 2,5-diméthoxy-4-méthylamphétamine, 2,5- bolisme, un extrait de plante, une plante médicinale, diméthoxy-4-isopropylthiophénéthylamine, 2,5-di- une enzyme, un peptide ou des combinaisons affé- 25 méthoxy-4-iodophénéthylamine, 2,5-diméthoxy-4- rentes. iodoamphétamine, 2,5-diméthoxy-4-fluorophéné- thylamine, 2,5-diméthoxy-4-éthylthio-phénéthylami- 3. Formulation selon la revendication 2, dans laquelle ne, 2,5-diméthoxy-4-éthylphénéthylamine, 2,5-di- au moins un second ingrédient actif est choisi parmi méthoxy-4-cyclopropylméthylthio-phénéthylamine, un médicament pharmaceutique, un complément 30 2,5-diméthoxy-4-chlorophénéthylamine, 2,5-dimé- nutritionnel, une phényléthylamine, un booster de thoxy-4-chloroamphétamine, 2,5-diméthoxy-4-bro- métabolisme, un extrait de plante, une plante médi- mophénéthylamine, 2,5-diméthoxy-4-bromoam- cinale,une enzyme, un peptide ou des combinaisons phétamine, 2,5-diméthoxy-4-(2-fluoroéthyl- afférentes. thio)-phénéthylamine, 2,4,5-trihydroxyphénéthyla- 35 mine, 3,4-méthylènedioxyméthcathinone, 3,4-mé- 4. Formulation selon la revendication 2 ou la revendi- thylènedioxy-N-méthylamphétamine, N,α-butylène- cation 3, dans laquelle ledit médicament pharma- β-méthoxycarbonylphénéthylamine, 3,4-méthylè- ceutique est choisi parmi un donneur d’oxyde nitri- nedioxy-N-éthylamphétamine, 3,4-méthylè- que, un antagoniste de l’aldostérone, un antagoniste nedioxyamphétamine. des récepteurs alpha-adrénergiques, une angioten- 40 sine II, un antagoniste, un inhibiteur de l’enzyme de 6. Formulation selon la revendication 4, dans laquelle conversion de l’angiotensine, un composé antidia- ledit inhibiteur de l’activité de la monoamine oxydase bétique, un composé anti-hyperlipidémique, un an- est au moins un corps chimique pris parmi la pipé- tioxydant, un composé antithrombotique et vasodi- rine, le pipérate de méthyle, un dérivé de pipérine, latateur, un antagoniste β-adrénergique, un blo- 45 un dérivé de pipérate de méthyle, le millepertuis, le queur des canaux calciques, la digitaline, un diuré- ginseng américain, le ginseng asiatique, le 5-hy- tique, un antagoniste de l’endothéline, un composé droxytryptophane, l’orange amère, la levure de biè- d’hydralazine, un antagoniste des récepteurs H2, un re, la vitamine B6, la L-tyrosine et l’yohimbe. inhibiteur de l’activité de la monoamine oxydase, un inhibiteur de l’endopeptidase neutre, un composé 50 7. Forme de dosage pour une administration par voie anti-inflammatoire non stéroïdien, un inhibiteur de la transmucosale d’au moins un composé phosphodiestérase, un bloqueur des canaux potas- comprenant : siques, un agent de réduction des plaquettes, un in- une formulation telle que revendiquée selon la re- hibiteur de la pompe à protons, un inhibiteur de la vendication 1 en combinaison avec un excipient- rénine, un inhibiteur sélectif de la cyclooxygénase- 55 vecteur pharmaceutiquement acceptable, dans la- 2, un médicament psychoactif, un stimulant ou des quelle ladite forme de dosage est un spray/produit combinaisons afférentes. délivré par pulvérisation.

13 25 EP 2 884 962 B1 26

8. Forme de dosage pour une administration par voie 14. Procédé selon la revendication 12, comprenant un transmucosale d’au moins un composésecond ingrédient actif, dans lequel ledit second in- comprenant : grédient actif est une phényléthylamine qui est choi- une formulation telle que revendiquée selon la re- sie parmi phényléthylamine, β-phényléthylamine, β- vendication 1, dans laquelle ladite forme de dosage 5 méthylphénéthylamine, β,4-dihydroxyphénéthyla- est choisie parmi un comprimé à croquer ou à mâ- mine, 3-chloro-N-tert-butyl-β-cétoamphétamine, cher,un comprimé à désintégration rapide,une gom- phénelzine et tranylcypromine. me à mâcher ou chewing-gum, un granule et un sup- positoire. 15. Procédé selon la revendication 12, dans lequel ledit 10 ingrédient actif est un inhibiteur de l’activité de la 9. Forme de dosage pour une administration par voie monoamine oxydase qui comprend au moins un transmucosale d’au moins un composécorps chimique pris parmi la pipérine, le pipérate de comprenant : méthyle, un dérivé de pipérine, un dérivé de pipérate une formulation telle que revendiquée selon la re- de méthyle, le millepertuis, le ginseng américain, le vendication 1, dans laquelle ladite forme de dosage 15 ginseng asiatique, le 5-hydroxytryptophane, l’oran- est choisie parmi une gelée formant vaseline, un gel, ge amère, la levure de bière, la vitamine B6, la L- un film, un losange pharmaceutique, une pâte den- tyrosine et l’yohimbe. tifrice, un onguent, un liquide et un spray/produit dé- livré par pulvérisation. 20 10. Forme de dosage selon la revendication 7, dans la- quelle ledit excipient-vecteur pharmaceutiquement acceptable est un hydrocolloïde.

11. Procédé pour la préparation d’une formulation pour 25 une administration par voie transmucosale d’au moins un composé comprenant :

a) la pulvérisation d’une formulation de liposo- me(s) qui est en suspension dans un solvant à 30 based’eau sur une baseconstituée par unepou- dre micronisée, ladite formulation de liposo- me(s) comprenant au moins un liposome qui contient au moins un composé selon une quan- tité suffisante pour former une forme de dosage 35 unitaire qui contient une quantité d’environ 10 mg à environ 500 mg dudit composé, à une tem- pérature au niveau d’une ouverture de tête d’éjecteur d’environ 60 °C ou moins de manière à faire évaporer ledit solvant à base d’eau et à 40 dessécherledit liposome, danslequel une quan- tité d’environ 0,4 L à environ 1,0 L de ladite for- mulation de liposome(s) qui est en suspension dansun solvant à based’eau est pulvérisée pour environ 1 kg de ladite base constituée par une 45 poudre micronisée.

12. Procédé selon la revendication 11, dans lequel ledit composé est un ingrédient actif, un agent favorisant l’absorption par voie mucosale ou des combinaisons 50 afférentes.

13. Procédé selon la revendication 11, dans lequel ladite base constituée par une poudre micronisée est choi- sie parmi une base pulvérulente inerte, une base 55 pulvérulente active qui présente une perméation par voie transmucosale améliorée ou des combinaisons afférentes.

14 EP 2 884 962 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• EP 1952818 A1 [0010] • EP 1484055 A1 [0012] • WO 9619199 A1 [0011] • US 4830858 A [0013]

Non-patent literature cited in the description

• SHAH et al. Development of liposomal amphotericin B dry powder inhaler formulation. DRUG DELIVERY, July 2004, vol. 11 (4), 247-253 [0009]

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