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US 2003O124191A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0124191A1 Besse et al. (43) Pub. Date: Jul. 3, 2003

(54) USE OF AN IMMEDIATE-RELEASE Publication Classification POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS (51) Int. Cl." ...... A61K 31/7048; A61K 31/56; A61K 31/522; A61K 31/4965; A61K 31/445; A61K 31/573; (76) Inventors: Jerome Besse, Listrac Medoc (FR); A61K 31/496; A61K 31/4178; Laurence Besse, Listrac Medoc (FR) A61K 31/135 (52) U.S. Cl...... 424/489; 514/182; 514/177; 514/178; 514/29; 514/649; Correspondence Address: 514/317; 514/343; 514/263.35; Michael L. Kenaga 514/554; 514/629; 514/263.33; Piper Marbury Rudnick & Wolfe 514/397; 514/255.04 P.O. Box 64807 Chicago, IL 60664-0807 (US) (57) ABSTRACT (21) Appl. No.: 10/106,923 The present invention relates to the use of a powder com (22) Filed: Mar. 25, 2002 prising at least one active Substance, at least one Surfactant, at least one wetting agent and at least one diluent, for (30) Foreign Application Priority Data preparing a pharmaceutical or nutraceutical composition, this composition allowing rapid and immediate release of Dec. 27, 2001 (FR)...... O116934 the active Substance. US 2003/O124191A1 Jul. 3, 2003

USE OF AN IMMEDIATE-RELEASE POWDER IN 0011. The active substances of the powder used accord PHARMACEUTICAL AND NUTRACEUTICAL ing to the invention may be selected from those convention COMPOSITIONS ally used in the following pharmacotherapeutic families: allergology, anaesthesia/reanimation, cancerology and hae 0001. The present invention relates to the use of an matology, cardiology and angiology, contraception and immediate-release powder for buccal application, intended interruption of pregnancy, dermatology, endocrinology, gas for the preparation of pharmaceutical or nutraceutical com troenterohepatology, gynaecology, immunology, infectiol positions. ogy, metabolism and nutrition, neurology/psychiatry, oph 0002 The use according to the invention of a powder for thalmology, otorhinolaryngology, pneumology, preparing a pharmaceutical or nutraceutical composition rheumatology, Stomatology, toxicology, and urology/neph allows a rapid release (or “flash”) of the active substance rology, and also from analgesics and antispasmodics, anti when the composition comprising it is administered mucos inflammatory agents, contrast products used in radiology, ally. haemostatics, and blood treatment products and derivatives. 0.003 Pharmaceutical forms which allow rapid release of 0012 Advantageously, the active substances may be an active Substance are already known. They are tablets of Selected from the group consisting of the active Substances the “lyoc' type or tablets which disintegrate rapidly in the which cross the mucosal barrier and reach the Systemic mouth, such as for example the FLASHTABOR (ETHYP circulation, Such as acetate, A-4-androstenedi HARM) or SOBLET(R) technology, or film-type systems one, 3-keto-, desogeStrel, , Oestradiol provided in the form of a “wafer', i.e. films for buccal and derivatives thereof, norethisterone acetate, progester application which allow more or less rapid dissolution of the one, testosterone, dihydrotestosterone, trinitrine, fentanyl, active Substances. nitroglycerine, nicotine (nicotine S(-)), Scopolamine, cloni dine, isosorbide dinitrate, laevonorgestrel in combination 0004. This being so, these two pharmaceutical forms with ethinyl Oestradiol or with Oestradiol, androstanolone, have several drawbacks. The tablets suffer from a significant dipropionate, phloroglucinol, molsidomine, friability, which makes them delicate to handle, and, more and combinations thereof. over, their disintegration time is very often longer than 10 seconds. The films are difficult to apply due to their very 0013 They may also be selected from the active sub Small thickness. In addition, the two pharmaceutical forms stances which croSS the mucosal barrier and have a localized suffer from a major drawback in that they allow only a action, Such as: acetazolamide, acyclovir, adapalene, relatively low load of active Substance, diverse and varied alclomethasone dipropionate, , ameline, bam excipients being required for their Structural integrity. ethan Sulphate--escin, Valerate, betametha Sone dipropionate, bufeXamac, caffeine, calcipotriol mono 0005 The Applicant Companies have therefore sought to hydrate, cetrimonium bromide, propionate, develop a pharmaceutical form which can overcome the crilanomer, , dexpanthenol, diclofenac, diflucor drawbacks encountered by the prior formulations. tolone, Valerate, , diphenydramine hydrochlo ride, econazole nitrate, erythromicin, pivalate, 0006 They have thus succeeded in developing a powder, fluocinolon acetonide, fluocinodine, fluocortolone, fluocor the use of which in a pharmaceutical or nutraceutical com tolone hexanoate, fluocortolone pivalate, , position allows rapid and immediate release of the active hydrocortison acetate, ibacitabine, ibuprofen, imiquimod, Substance alone or in combination, when said composition is , ketoprofen, , metronidazole, administered buccally. nitrate, minoxidil, nifluminic acid, penciclovir, 0007 For the purpose of the present invention, the benzoyl peroxide, piroxam, iodinated povidone, expression “rapid and immediate release' is intended to promestriene, pyrazinobutaZone, roXithromycin, Sulphaceta mean release of all of the active substance(s) in less than 30 mide, , tazaroteine, tretinoin and isotretinoin, Seconds, preferably leSS than 15 Seconds and even more triclocarban, Vidarabine monophosphate and combinations preferentially in less than 10 Seconds. thereof. 0008. The powder used according to the invention, unlike 0014. They may also be selected from the following the tablets and films of the prior art, is delicate neither in active Substances: B-3-adrenergic agonist, growth hormone, terms of its handling nor in its application. It also allows a Oxybutinin, buprenorphine, pergolide, nestorone, 7C.-me considerable active Substance load. Specifically, the load of thyl-19-nortesterone, mecamylamine, Salbutamol, Sel active Substances per dose unit can be considerably greater egiline, buSpirone, ketotifen, lidocaine, ketorolac, eptaZo than the 20 mg imposed in particular by the technology of cine, insulin, C.-interferon, prostaglandins, 5-aminolevulinic the films of the “wafer type or equivalent. acid, benzodiazepine alproZolam, diclofenac, fenoprofen, flubiprofen, ketoprofen, methyl phenidate, miconazole, 0009. The use of the powder according to the present piroXicam, bruprenorphine, dexmedetomidine, praZOsin invention therefore has many advantages compared to the (C.-adrenergic antagonist), alproStadil, tulobuterol (B-adren known pharmaceutical forms in the prior art. ergic agonist), ethinyl Oestradiol--norelgestromin, physostig mine, medindolol (C.-adrenergic agonist), rotigotine 0.010 Thus, the present invention relates to the use of a (dopamine D2 antagonist), thiatolserine and combinations powder comprising at least one active Substance, at least one thereof. Surfactant, at least one wetting agent and at least one diluent, for preparing a pharmaceutical or nutraceutical composition, 0015 They may also be selected from the following this composition allowing rapid and immediate release of active Substances: Esomeprazole, Melagatran (in the case of the active Substance when it is administered mucosally. thrombosis), Rosuvastatin, EZetimide, Pitavastatin (hyper US 2003/O124191A1 Jul. 3, 2003 lipidaemia), Mitiglinide (type II diabetes), Cilomilast, Vio line, menthol, methoxySalicylate, methyl oleate, oleic acid, Zan (asthma), Aripipazole (psychiatry), Omapatrilat (hyper phosphatidylcholine, polyoxyethylene, polySorbate 80, tensive), Orzel (cancerology), Caspofongin acetate, Sodium EDTA, Sodium glycocholate, Sodium glycodeoxy Voriconazole (infections), new COX inhibitors such as cholate, Sodium lauryl Sulphate, Sodium Salicylate, Sodium Etoricoxib (inflammation), Valdecoxib (arthritis) and Pare taurocholate, Sodium taurodeoxycholate, Sulphoxides and coxib, Substance P antagonist (depression), Darifenacin alkyl glycosides. (urology), Eletriptan (migraine), Alosetron, Tegaserod, 0024. According to a preferential embodiment of the Capravirine (HIV) and combinations thereof. powder used according to the invention, it has a particle size 0016. The powder used according to the invention may of between 0.01 um and 1000 um, preferably between 0.1 contain one or more active principles in combination with tim and 100 um, and even more preferentially between 1 um one another. and 50 lum. 0017 For nutraceutical applications, the active substance 0025 The composition containing the powder used may be chosen from the list of raw materials authorized as according to the invention is administered mucosally. It may food Supplements, Such as, for example, from the group be applied, for example, on the buccal mucous membrane, consisting of Vitamins, mineral Salts, brewer's yeast, etc. the nasal mucous membrane or the vaginal mucous mem brane, and also Sublingually. 0.018. According to a preferential embodiment of the powder according to the invention, the active Substances are 0026 Advantageously, the composition comprising the micronized before being mixed with other ingredients. It is powder used according to the invention is in a dry form also possible to mix the non-micronized active Substance packaged in a spray or in the form of a Sachet. These with the other ingredients of the powder and then to micron formulations allow a precise dose of active material to be ize the final mixture. This promotes rapid (by increasing the delivered easily. Surface area of contact with the buccal cavity) and homo 0027 All the methods known to those skilled in the art geneous release of the active Substance. Moreover, Systems may be used in the context of producing the powder used for Spraying powder are particularly Suitable for Spraying according to the invention. micronized products. 0028. As an example of a method for preparing a powder, 0019. The powder used according to the invention may mention may be made of wet or dry granulation, preferen also comprise one or more Surfactants, preferably non-ionic tially followed by micronization. Surfactants, such as polyoxyethylene Sorbitan (fatty acid ester), polyoxyethylene alkyl ether, the polyoxyethylene 0029. Alternatively, according to another embodiment, derived from castor oil, and mixtures thereof. the active Substance is micronized and then mixed with the excipients in the form of powder, and the mixture thus 0020 When needed, this powder may also comprise a obtained is granulated, by wet or dry granulation. wetting agent Selected from the group consisting of polyols 0030. According to another embodiment, the powder such as Sorbitol, glycerol or PEG, and mixtures thereof. used according to the invention may be prepared by Spray 0021. The powder used according to the invention may drying. The raw materials are Solubilized in a Solvent and also comprise a binding agent Selected from the group then the resulting Solution or Suspension is spray-dried. The consisting of acacia, alginic acid, Sodium carboxymethyl grain thus obtained may be used directly, or after microni cellulose, microcrystalline cellulose, dextrins, ethylcellu Zation, for preparing the pharmaceutical or nutraceutical lose, gelatin, glucose, guar gum, hydroxypropylmethylcel composition administered according to the invention. lulose, methylcellulose, polyethylene oxide, povidone, 0031. The active substance on its own or the final mixture pregelatinized Starch, and mixtures thereof. of ingredients may be micronized. 0022. The powder used according to the invention may also comprise a diluent Selected from the group consisting of 0032. The invention will be more clearly understood Sodium or calcium carbonate or bicarbonate, Sucrose, man using the non-limiting examples described below. nitol, Xylitol, Sorbitol, lactose, microcrystalline cellulose or EXAMPLE 1. cellulose powder, Starch and derivatives thereof, dibasic calcium phosphate, tribasic calcium phosphate, calcium Powders To Be Used According To The Invention Sulphate, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol and mixtures thereof. 0033 Four powders each having the following weight composition are prepared: 0023 The powder used according to the invention may also comprise a penetration enhancer which may be Selected from the group consisting of aliphatic fatty acid esterS Such as isopropyl myristate, fatty acids Such as oleic acid; alco Composition Quantity in % hols or polyols, Such as ethanol, propylene glycol or poly Phloroglucinol 1O ethylene glycol; the components of essential oils and terpene Sorbitol 89 derivatives (such as eugenol, geraniol, nerol, eucalyptol or Propylene glycol 1. Testosterone 1O menthol); Surfactants, moisturizers Such as glycerol or urea; Sorbitol 88 keratolytic agents, Such as alpha-hydroxy acids, 23-lauryl Cremophor RH40 2 ether, aprotinin, azone, benzalkonium chloride, cetylpyri Dihydrotestosterone 5 dinium chloride, cetyltrimethylammonium bromide, cyclo Xylitol 90 dextrins, dextran Sulphate, lauric acid, lySophosphatidylcho US 2003/O124191A1 Jul. 3, 2003

acetate, 5-aminolevulinic acid, the benzodiazepine alproZo -continued lam, diclofenac, fenoprofen, flubiprofen, ketoprofen, methyl phenidate, miconazole, piroXicam, bruprenorphine, dexme Composition Quantity in % detomidine, prazosin (C.-adrenergic antagonist), gestodene + Glycerol 3 ethinyl Oestradiol, alproStadil, tulobuterol (B-adrenergic Tween 80 2 agonist), ethinyl Oestradiol--norelgestromin, physostigmine, Molsidomine 1O Xylitol 83 lidocaine, medindolol (C.-adrenergic agonist), rotigotine Propylene glycol 5 (dopamine D2 antagonist), ethinyl Oestradiol--norethindrone Montanox 80 2 acetate, thiatolserine, phlorglucinol, molsidomine, esome prazole, melagatran (in the case of thrombosis), rosuvasta tin, eZetimide, pitavastatin (hyperlipidaemia), mitiglinide 0034. The various components are mixed in a mixer/ (type II diabetes), cilomilast, Viozan (asthma), aripipazole granulator such as ZANCHETTA ROTOLAB mixer/granu (psychiatry), Omapatrilat (hypertensive), orzel (cancerol lator/drier under vacuum, or equivalent, until the mixture is ogy), caspofongin acetate, Voriconazole (infections), new homogenized. A wetting Solution or Suspension is then COX inhibitors such as etoricoxib (inflammation), Valde incorporated with Stirring in order to obtain a wet granule. coxib (arthritis) and parecoxib, Substance P antagonist (depression), darifenacin (urology), eletriptan (migraine), 0035. This granule is then dried under Suitable conditions alosetron, tegaserod, capravirine (HIV) and combinations in order to evaporate the granulation Solvent. This granule is thereof. then dried and calibrated, and then micronized using an 5. Method according to claim 1, wherein the active airjet micronization machine of the ALPINE or JETMIL Substance is Selected from the group consisting of Vitamins, type (or equivalent). mineral Salts and brewer's yeast. 1. Method for administering a pharmaceutical or nutra 6. Method according to claim 1, wherein the Surfactant is ceutical composition to a Subject, Said method comprising Selected from the group consisting of non-ionic Surfactants, contacting Said pharmaceutical or nutraceutical composition Such as polyoxyethylene Sorbitan (fatty acid ester), poly with a mucosal Surface, Said pharmaceutical or nutraceutical oxyethylene alkyl ether, the polyoxyethylene derived from composition containing a powder comprising at least one castor oil, and mixtures thereof. active Substance, at least one Surfactant, at least one wetting 7. Method according to claim 1, wherein the wetting agent agent and at least one diluent, whereby rapid and immediate is Selected from the group consisting of polyols Such as release of the active Substance is obtained. Sorbitol, glycerol or polyethylene glycol, and mixtures 2. Method according to claim 1, wherein at least the active thereof. Substance is in micronized form. 8. Method according to claim 1, wherein the diluent is 3. Method according to claim 1, wherein the powder is in Selected from the group consisting of Sodium, calcium micronized form. carbonate or bicarbonate, Sucrose, mannitol, Xylitol, Sorbi 4. Method according to claim 1, wherein the active tol, lactose, microcrystalline cellulose or cellulose powder, Substance is Selected from the group consisting of oestradiol Starch and derivatives thereof, dibasic calcium phosphate, and derivatives thereof, norethisterone acetate, progester tribasic calcium phosphate, calcium Sulphate, dextrates, one, testosterone, dihydrotestosterone, trinitrine, fentanyl, dextrins, dextrose excipients, fructose, kaolin, lactitol and nitroglycerine, nicotine (nicotine S(-)), Scopolamine, cloni mixtures thereof. dine, isosorbide dinitrate, laevonorgestrel in combination 9. Method according to claim 1, wherein the powder with ethinyl Oestradiol or with oestradiol, androstanolone, comprises a binding agent Selected from the group consist alclometasone dipropionate, acetazolamide, acyclovir, ada ing of acacia, alginic acid, Sodium carboxymethylcellulose, palene, alclomethasone dipropionate, amcinonide, ameline, microcrystalline cellulose, dextrins, ethylcellulose, gelatin, bamethan Sulphate--escin, , glucose, guar gum, hydroxypropylmethylcellulose, methyl betamethasone dipropionate, bufeXamac, caffeine, calcipot cellulose, polyethylene oxide, povidone, pregelatinized riol monohydrate, cetrimonium bromide, clobetasol propi Starch, and mixtures thereof. onate, crilanomer, desonide, dexpanthenol, diclofenac, 10. Method according to claim 1, wherein the powder , Valerate, difluprednate, diphenydramine comprises a penetration enhancer Selected from the group hydrochloride, econazole nitrate, erythromicin, flumetaSone consisting of aliphatic fatty acid esterS Such as isopropyl pivalate, fluocinolon acetonide, fluocinodine, fluocortolone, myristate; fatty acids Such as oleic acid; alcohols or polyols, fluocortolone hexanoate, fluocortolone pivalate, hydrocorti Such as ethanol, propylene glycol or polyethylene glycol; the Sone, hydrocortison acetate, ibacitabine, ibuprofen, imiqui components of essential oils and terpene derivatives (Such as mod, ketoconazole, ketoprofen, lidocaine, metronidazole, eugenol, geraniol, nerol, eucalyptol or menthol); Surfactants; miconazole nitrate, minoxidil, nifluminic acid, penciclovir, moisturizerS Such as glycerol or urea; keratolytic agents, benzoyl peroxide, piroxam, iodinated povidone, Such as alpha-hydroxy acids, 23-lauryl ether, aprotinin, promestriene, pyrazinobutaZone, roXithromycin, Sulphaceta aZone, benzalkonium chloride, cetylpyridinium chloride, mide, triamcinolone, tazarotene, tretinoin and isotretinoin, cetyltrimethylammonium bromide, cyclodextrins, dextran triclocarban, Vidarabine monophosphate, P-3-adrenergic Sulphate, lauric acid, lysophosphatidylcholine, menthol, agonist, growth hormone, oxybutinin, buprenorphine, per methoxySalicylate, methyl oleate, oleic acid, phosphatidyl golide, oestradiol--nestorone, nestorone, 7C.-methyl-19-nort choline, polyoxyethylene, polysorbate 80, sodium EDTA, esterone, mecamylamine (nicotine antagonist)+nicotine, Sodium glycocholate, Sodium glycodeoxycholate, Sodium Salbutamol, Selegiline, buSpirone, ketotifen, lidocaine, test lauryl Sulphate, Sodium Salicylate, Sodium taurocholate, osterone--Oestradiol, ketorolac, eptazocine, insulin, a-inter Sodium taurodeoxycholate, Sulphoxides, alkyl glycosides, feron, prostaglandins, 17-p-Oestradiol--norethindrone and mixtures thereof. US 2003/O124191A1 Jul. 3, 2003

11. Method according to claim 1, wherein the powder has 15. Method according to claim 14, wherein the compo a particle size of between 0.01 um and 1000 um. Sition is applied to the buccal mucous membrane Sublin 12. Method according to claim 11, wherein the powder gually. has a particle size between 0.1 um and 100 um. 13. Method according to claim 12, wherein the powder 16. Method according to claim 1, wherein the composi has a particle size between 1 um and 50 lim. tion is in a sprayable form. 14. Method according to claim 1, wherein the pharma 17. Method according to claim 1, wherein the composi ceutical or nutraceutical composition is applied on the tion is contained in a Sachet. buccal mucous membrane, the nasal mucous membrane or the Vaginal mucous membrane.