(12) United States Patent (10) Patent No.: US 8,673,360 B2 Nagata Et Al

USOO867336OB2

(12) United States Patent (10) Patent No.: US 8,673,360 B2 Nagata et al. (45) Date of Patent: Mar. 18, 2014

(54) COMPOSITIONS THAT ENABLE (58) Field of Classification Search RAPID-ACTING AND HIGHILY ABSORPTIVE USPC ...... 424/499, 434; 514/2, 417 INTRANASALADMINISTRATION See application file for complete search history. (75) Inventors: Ryoichi Nagata, Kagoshima (JP); (56) References Cited Shunji Haruta, Kagoshima (JP) U.S. PATENT DOCUMENTS (73) Assignee: Shin Nippon Biomedical Laboratories, 3,906,950 A 9, 1975 Cocozza Ltd., Kagoshima (JP) 4,013,075 A 3, 1977 Cocozza 4,159,345 A 6, 1979 Takeo et al. (*) Notice: Subject to any disclaimer, the term of this 4,226,233 A 10, 1980 Kritzer patent is extended or adjusted under 35 4,300,545 A 11/1981 Goodnow et al. 4,613,500 A 9, 1986 Suzuki et al...... 429.85 U.S.C. 154(b) by 792 days. 4,889,114 A 12/1989 Kladders 5,098,907 A 3, 1992 Kondo et al. (21) Appl. No.: 11/660,131 (Continued) PCT Fled: Aug. 5, 2005 (22) FOREIGN PATENT DOCUMENTS PCT NO.: PCT/UP2005/014389 (86) EP O122036 A1 10, 1984 S371 (c)(1), EP O 147755 A2 7, 1985 (2), (4) Date: Nov. 5, 2007 (Continued) (87) PCT Pub. No.: WO2O06/O1653O OTHER PUBLICATIONS PCT Pub. Date: Feb. 16, 2006 Rowe, et al (Eds). Handbook of Pharmaceutical Excipients. Phar maceutical Press. 2003. p. 108-109. (65) Prior Publication Data (Continued) US 2008/O260848A1 Oct. 23, 2008 Primary Examiner — Ernst Arnold (30) Foreign Application Priority Data Assistant Examiner — Hong Yu (74) Attorney, Agent, or Firm — Wilson, Sonsini, Goodrich Aug. 10, 2004 (JP) ...... 2004-233660 & Rosati, P.C. (51) Int. C. (57) ABSTRACT A6 IK 9/14 (2006.01) Powdery compositions for intranasal administration, which A6 IK38/00 (2006.01) comprise non-peptide/non-protein drugs and as a carrier, A6 IK3I/4035 (2006.01) crystalline cellulose aggregates having aparticular cribriform A6DF 3/00 (2006.01) particle diameter, yield rapid action and high absorbability of A 6LX 9/50 (2006.01) the drugs. (52) U.S. C. USPC ...... 424/499: 424/434: 514/2: 514/417 8 Claims, 4 Drawing Sheets

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(56) References Cited Office action dated Apr. 20, 2012 for U.S. Appl. No. 12/780,433. Office action dated Jun. 4, 2012 for U.S. Appl. No. 12/521,116. OTHER PUBLICATIONS Office action dated Jun. 10, 2013 for U.S. Appl. No. 12/576.219. Office action dated Jun. 25, 2012 for U.S. Appl. No. 12/346,537. Merriam-Webster's Collegiate Dictionary, 10th edition, Merriam Office action dated Sep. 6, 2011 for U.S. Appl. No. 12/346,537. Webster Incorporated: Springfield, Massachusetts, 1993, pp. 41. Office action dated Sep. 6, 2011 for U.S. Appl. No. 12/576.219. International search report (partial) dated Dec. 21, 2010 for PCT Application No. IB2010/02168. Office action dated Sep. 20, 2013 for U.S. Appl. No. 13/827,859. UK combined office action and search report dated Nov. 10, 2010 for Office action dated Sep. 24, 2008 for U.S. Appl. No. 10/545,764. Application No. GB10 12959. 1. Office action dated Oct. 10, 2012 for U.S. Appl. No. 12/780,433. U.S. Appl. No. 12/576.219, filed Oct. 8, 2009, Tsutsui et al. Office action dated Oct. 15, 2012 for U.S. Appl. No. 12/848,850. International search report and written opinion dated Jun. 28, 2011 Office action dated Dec. 5, 2011 for U.S. Appl. No. 12/346,537. for PCT Application No. IB2010/02168. U.S. Appl. No. 10/512,857, filed May 13, 2003, in the name of Tatsuo U.S. Appl. No. 13/649,515, filed Oct. 11, 2012, Nagata et al. TSuisui. U.S. Appl. No. 13/827,859, filed Mar. 14, 2013, Oki et al. International search report dated May 7, 2003 for PCT Application Advisory action dated Sep. 13, 2013 for U.S. Appl. No. 12/848,850. No.JP2003/001948. Hibberd, et al. Immunization strategies for the immunocompromised International search report dated Feb. 5, 2008 for PCT Application host: the need for immunoadjuvants. Ann Intern Med. Jun. 15, No.JP2007/074787. 1989; 110(12):955-6. International search report Jun. 8, 2010 for PCT Application No. Ishikawa, et al. Improved nasal bioavailability of elcatonin by JP2010.003285. insoluble powder formulation. Int J Pharm. Aug. 14, 2001:224(1- Kleinebudde, et al. Influence of degree of polymerization on behavior 2):105-14. of cellulose during homogenization and extrusion/spheronization. Office action dated Jan. 13, 2011 for U.S. Appl. No. 12/346,537. AAPS Pharmasci 2000, 2(2) Article 21, 1-10. Office action dated Jan. 20, 2011 for U.S. Appl. No. 12/576.219. European search report and opinion mailed Dec. 20, 2013 for Appli Office action dated Jan. 29, 2008 for U.S. Appl. No. 10/545,764. cation No. 10774745.3. Office action dated Mar. 4, 2013 for U.S. Appl. No. 12/848,850. Office action dated Apr. 12, 2012 for U.S. Appl. No. 12/576.219. * cited by examiner U.S. Patent Mar. 18, 2014 Sheet 1 of 4 US 8,673,360 B2

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60 120 130 20 TME (min) US 8,673,360 B2 1. 2 COMPOSITIONS THAT ENABLE Patent Document 2 JP-AH10-59841 (corresponding to RAPID-ACTING AND HIGHILY ABSORPTIVE EP-A1-943326) INTRANASALADMINISTRATION Patent Document 3 WO 03/004.048A1 (corresponding to EP-A1-1413311) TECHNICAL FIELD DISCLOSURE OF THE INVENTION The present invention relates to powder form pharmaceu tical compositions delivered via nasal mucosa. More specifi Problems to be Solved by the Invention cally, the present invention relates to powdery compositions 10 As described above, it is known that intranasal composi for intranasal administration which enable both rapid action tions for particular drugs using a given carrier can achieve and high absorbability of non-peptide/non-protein drugs. specific objectives. Nonetheless, the present inventors pre dicted that among Such drugs, some that are particularly BACKGROUND ART expected to have systemic effects can have enhanced drug 15 efficacy and utility value when used as intranasal composi The nasal route of drug administration has long been used tions. where local action of drug is anticipated Such as in rhinitis First, the present inventors focused on opioid analgesic treatments. Recently, various studies were carried out on agents such as morphine. Morphine plays a central role in the intranasal drug administration that is expected to have sys pain treatment of cancer patients. Various types of morphine temic effects because a) the nasal mucosa has a well devel preparations, such as Sustained-release oral preparations oped vascular network and is thus histologically advanta which continuously relieve pain, are commercially available. geous for drug absorption; b) drugs absorbed through the However, most of those preparations are long-acting prepa nasal mucosa can avoid first-pass metabolism in the gas rations for alleviating constant or continuous pain. Besides trointestinal tract and liver; c) it is self-administrable and injections, the only rapid-acting preparations for acute pain painless. 25 that Suddenly strikes the patients are Suppositories, oral solu Interesting results obtained by those studies include a par tions, and the like. Thus, there are strong demands for admin ticularly preferred embodiment of a rapid-acting and pro istration methods that are rapid-acting, effective, simple and longed-acting intranasal composition, which combines a base convenient and which can be self-administered. Further, that is water-absorbing and water-insoluble and has 90% opioid analgesic agents such as morphine are problematic in (w/w) or more of particles with a diameter in the range of 10 30 that they have decreased bioavailability because they are sig to 100 um, and a base that is water-absorbing and gel-forming nificantly affected by the first-pass metabolism in liver and and has 90% (w.fw) or more of particles with a diameter in the mucosal epithelia of the gastrointestinal tract after oral range of 50 to 350 Lim (see Patent Document 1). It is clear administration. Accordingly, the oral dosage is gradually from the Examples of Patent Document 1 that the formulation increased and as a result, patients suffer from frequent occur of 60 to 95% (w/w) hydroxypropyl cellulose (a water-absorb 35 rence of the adverse effects (in contrast to analgesic effects) of ing and gel-forming base) and crystalline cellulose (a water morphine Such as constipation, nausea, vomiting, thirst, loss absorbing and water-insoluble base) does not change drug of appetite and the like. In view of the above circumstances, if persistence, but shows immediate drug absorption as com Successfully developed, a rapid-acting intranasal preparation pared with crystalline cellulose base alone. that can avoid first-pass metabolism and be administered by a In another particularly preferred embodiment, an intrana 40 simple and convenient procedure, can be used as an admin sal composition with improved drug absorbance is proposed. istration method to improve patient’s QOL and thus to con The composition is a combination of a water-absorbing and tribute to the advancement of the technical field. water-insoluble base that has 90% (w/w) or more of particles Meanwhile, the present inventors focused on antiemetic with a diameter in the range of 10 to 250 lum, and a water agents such as tropisetron, as a drug that is expected to have absorbing and gel-forming base that has 90% (w/w) or more 45 systemic effects. Tropisetron plays an important role in pre of particles with a diameter in the range of 10 to 50 um. Patent venting nausea and Vomiting which are adverse effects of Document 2 states that particles of 150 um or more shall be cancer chemotherapy. Oral tropisetron preparations are used actively used as a water-absorbing and water-insoluble base routinely. However, Such oral preparations take a long time to Such as crystalline cellulose or the like. According to the exert their effect, and therefore it is difficult to immediately Examples of Patent Document 2, when compared with crys 50 alleviate the troubling nausea and Vomiting. Furthermore, talline cellulose base alone, a higher maximum drug level in since symptoms of nausea and vomiting impair patients’ abil blood is achieved if crystalline cellulose (a water-absorbing ity to Swallow oral drugs, there are demands for non-oral, and water-insoluble base) is combined with 5 to 40% (w/w) rapid-acting parenteral self-administrable administration hydroxypropyl cellulose (a water-absorbing and gel-forming methods. base). 55 For example, Patent Documents 1 and 2 shown above teach Furthermore, an intranasal insulin preparation proposed by how to achieve rapid action. The present inventors examined the present applicants is also known. The preparation uses as if the methods described in these documents can provide a carrier, a crystalline cellulose aggregate in which 85% intranasal compositions comprising morphine, tropisetron, or (w/w) or more of the particles have a cribriform particle the like, but could not find satisfactory compositions. diameter within the entire or partial range of 20 to 60 um. The 60 Through further investigations, the present inventors discov particles are substantially the same as those used in the ered that the use of a carrier, which is substantially the same present invention. The present applicants Succeeded in as the crystalline cellulose specified in Patent Document 3 improving insulin absorption with the preparation (see Patent that enables high intranasal absorbability of insulin, a pep Document 3). tide?protein drug, enables high absorbability as well as rapid Patent Document 1 Japanese Patent Application Kokai 65 action of non-peptide? non-protein drug comparable to that of Publication No. (JP-A) H9-291026 (unexamined, published parenteral administration, thereby completed the present Japanese patent application) invention. US 8,673,360 B2 3 4 Thus, the present invention provides powdery composi sedative drugs such as midazolam, psychotherapeutic agents tions for intranasal administration which comprise a non Such as chlorpromazine, haloperidol, tryptanol, imipramine, peptide/non-protein drug, and crystalline cellulose aggregate clomipramine, etizolam, oxazolam, and diazepam, muscle as a carrier thereof. 85% (w/w) or more of the crystalline relaxants such as eperisone, tizanidine, baclofen, suxametho cellulose aggregate are particles that have a cribriform par nium chloride, pancuronium bromide, and dantrolene; anti ticle diameter within the entire range of 20 to 60 m or a allergic agents such as chlorpheniramine, cyproheptadine, partial range thereof. meduitazine, diphenhydramine, and Sodium cromoglycate; In other words, the present invention provides powdery anti-rheumatic drugs such as auranofin, bucillamine, and compositions for intranasal administration that comprise a D-penicillamine; cardiotonic drugs such as digoxin and digi non-peptide/non-protein drug and crystalline cellulose 10 toxin; antiarrhythmic agents and antihypertensive agents aggregate as a carrier, in which 85% (w/w) (ratio in terms of Such as atenolol, propranolol, metoprolol, amiodarone, qui the total crystalline cellulose aggregate) or more of the crys nidine, procainamide, mexiletine, nicardipine, enalapril, cap talline cellulose aggregate have a cribriform particle diameter topril, prazosin, hydralazine, reserpine, and clonidine; within the entire range of 20 to 60 um or a partial range diuretic agents such as hydrochlorothiazide, potassium can thereof. 15 renoate, Spironolactone, mannitol, acetazolamide, and furo Furthermore, in a preferred embodiment, the present semide; coronary vasodilators such as diltiazem, nifedipine, invention provides the above-described compositions using a Verapamil, and dipyridamole; antidementia drugs such as crystalline cellulose aggregate of which, donepezil hydrochloride, galanthamine, and memantine; 25% (w/w) or less are particles with a cribriform particle brain activators such as citicoline and tiapride; brain circula diameter of less than 25um; tion ameliorating agents such as ATP, isosorbide, and nicer 20 to 60% (w/w) are particles with a cribriform particle goline; antiparkinsonian agents such as trihexyphenidyl, diameter of 25 to 38 um; biperiden, levodopa, dopamine, and amantadine; antihyper 20 to 60% (w/w) are particles with a cribriform particle lipidemic drugs such as clofibrate and pravastatin; antitumor diameter of 38 to 53 um; and agents such as cimetidine, famotidine, omeprazole, lanSopra the remainder are particles with a cribriform particle diam 25 Zole, pirenzepine, aldioxa, Sofalcone, and teprenone; anti eter of 53 um or greater, emetic agents such as granisetron, ondansetron, tropisetron, wherein the ratio of the total crystalline cellulose aggregate cisapride, domperidone, and metoclopramide, obesity drugs is taken as 100% (w/w). Such as mazindol; diabetic drugs such as pioglitaZone hydro One or more of the non polypeptide/non-protein drug used chloride, Voglibose, gliclazide, acarbose, ciglitaZone, Sorbi for the intranasal compositions provided in the present inven 30 nil, glimepiride, epalrestat, ganglioside, midaglizole hydro tion can be selected from the following examples without chloride, and ponalrestat; hemostatic drugs such as being construed as limiting: antibiotics, antifungal agents, cabazochrome and tranexamic acid; antithrombotic agents Sulfa drugs, antituberculosis drugs, antimicrobial agents, Such as heparin, low-molecular-weight heparin, warfarin, cil antiviral agents, hypnotic sedatives, antiepileptic agents, nar ostaZol, ticlopidine, ethyl icosapentate, andberaprost; cotic analgesics, nonnarcotic analgesics, sedative drugs, psy 35 migraine drugs such as ergotamine, dihydroergotamine, and chotherapeutic agents, muscle relaxants, antiallergic agents, Sumatriptan; antitussive drugs and expectorants such as anti-rheumatic drugs, cardiotonic drugs, antiarrhythmic codeine, tipepidine, dextromethorphan, acetylcysteine, car agents and antihypertensive agents, diuretic agents, coronary bocysteine, and bromhexine; respiratory stimulants, such vasodilators, antidementia drugs, brain activators, brain cir dimorpholamine, doxapram, and naloxone; asthma drugs culation ameliorating agents, antiparkinsonian agents, anti 40 Such as Salbutamol, terbutaline, procaterol, theophylline, hyperlipidemic drugs, antiulcer drugs, antiemetic agents, ephedrine, ibudilast, ketotifen, terfenadine, tranilast, and obesity drugs, diabetic drugs, hemostatic drugs, antithrom beclomethasone; antidiarrheal drugs such as loperamide; botic agents, migraine drugs, antitussive drugs and expecto nonsteroidal antiinflammatory agents such as mefenamic rants, respiratory stimulants, asthma drugs, antidiarrheal acid, indomethacin, ibuprofen, ketoprofen, loxoprofen, and drugs, nonsteroidal antiinflammatory agents, antipodagrics, 45 diclofenac; antipodagrics such as allopurinol, colchicine, and therapeutic agents for urinary diseases, drugs for improving benzbromarone; therapeutic agents for urinary diseases Such sexual function, agents for the uterus, Steroids, prostaglan as estramustine, chlormadinone, flavoxate, and oxybutynin, dins, vitamins, histamines, antidotes, therapeutic agents for drugs for improvement in sexual function Such as sildenafil. heavy metal toxification, quit Smoking agents, antianaphy Vardenafil, and apomorphine; uterus acting drugs such lactic agents, and antitumor agents. 50 asisoXSuprine, dinoprost, ritodrine, oestriol, and econazole; Specifically, Such non-peptide/non-protein drugs include, steroids Such as dexamethasone, triamcinolone, hydrocorti for example, antibiotics Such as penicillins, carbapenems, Sone, prednisolone, testosterone, estradiol, and chlormadi cephems, aminoglycosides, macrollides, tetracyclines, and none; prostaglandins such as alprostadil, limaprost, and dino chloramphenicols; antifungal agents such as amphotericin B, prost; Vitamins such as retinol, thiamine, riboflavin, griseofulvin, nystatin, fluconazole, flucytosine, and micona 55 pyridoxal, cobalamine, and pantothenic acid; antidotes Such Zole; Sulfa drugs such as Salazosulfapyridine and Sul as pralidoxime iodide methyl, protamine, and leucovorin; famethoxazole; antituberculosis drugs such as isoniazid, therapeutic agents for heavy metal toxification Such as dimer ethambutol, and rifampicin; antimicrobial agents such as caproland sodium thiosulfate; quit Smoking aid Such as nico enoxacin, ofloxacin, ciproflaxacin, toSufloxacin, and nor tine; antianaphylactic agents such as epinephrine; antitumor floxacin; antiviral agents such as Vidarabine, aciclovir, 60 agents such as cyclophosphamide, dacarbazine, cytarabine, didanosine, Zidovudine, oseltamivir, Zanamivir, and Valgan tegafur, 5-FU, methotrexate, mercaptopurine, epirubicin, ciclovir; sleep aids such as brotizolam, triazolam, and Zopi doxorubicin, mitomycin, and etoposide. clone; antiepileptic agents such as carbamazepine, clon Furthermore, non-peptide/non-protein drugs that require azepam, Zonisamide, Valproic acid, phenytoin, rapid-acting ability in therapy include the following: phenobarbital, and primidone; narcotic analgesics such mor 65 didanosine, Zidovudine, lamivudine, atazanavir, nelfenavir, phine, fentanyl, and pethidine; nonnarcotic analgesics Such as sanilvudine, emitricitabine, oseltamivir, Zanamivir, Valganci buprenorphine, pentazocine, and tramadol hydrochloride; clovir, amantadine, ketamine, pentobarbital Sodium, US 8,673,360 B2 5 6 lidocaine, estazolam, midazolam, triazolam, nitrazepam, range thereof. Crystalline cellulose aggregates used in the flunitrazepam, rilmazafone, Zopiclone, brotizolam, chloral present invention have a particular range of cribriform par hydrate, carbamazepine, clonazepam, Zonisamide, sodium ticle diameters. In the present invention, the powdery com valproate, phenytoin, phenobarbital, primidone, gabapentin, positions for intranasal administration exert high absorbabil opium, morphine, ethylmorphine, oxycodone, codeine, dihy ity and excellent rapid-acting ability for non-peptide/non drocodeine, fentanyl, droperidol, levorphanol, methadone, protein drugs. meperidine, pethidine, buprenorphine, butorphanol, trama Hereinafter, particle diameter refers to “cribriform particle dol, malfurafine, pentazocine, Sulpyrine, aspirin, acetami diameter' unless otherwise stated. nophen, ergotamine, dihydroergotamine, Sumatriptan, elet Such aggregates can be used in combination with non riptan, Zolmitriptan, rizatriptan, naratriptan, donepezil, 10 peptide/non-protein drugs. The phrase “within the entire suxamethonium, pancuronium, sildenafil. Vardenafil, apo range or a partial range thereof is intended to mean, for morphine, tadalafil. atropine, Scopolamine, digitoxin, example, a particle distribution where 90% (w/w) of particles digoxin, methyldigoxin, isosorbide, nitroglycerin, quinidine, or more have a particle size within the entire range of 10 to disopyramide, dopamine, dobutamine, epinephrine, etile 100 um, or a partial range thereof, for example, 20 to 60 lum. frine, norepinephrine, phenylephrine, dimorpholamine, dox 15 According to the present invention, the above-described par apram, naloxone, flumazenil, tipepidine, dextromethorphan, ticle diameter range is preferably the entire range of 20 to 60 ambroXol, bromhexine, salbutamol, terbutaline, procaterol, um or a partial range thereof. theophylline, ephedrine, sodium cromoglycate, ketotifen, Specifically, such crystalline cellulose aggregates include, oXatomide, tranilast, granisetron, aZasetron, ramosetron, tro for example, crystalline cellulose products which are avail pisetron, indisetron, palonosetron, cisapride, domperidone, able as AviceITM PH-105 and PH-F20 at FMC corp. (US) and metoclopramide, trimebutine, loperamide, mefenamic acid, Asahi Kasei, respectively, in an intact form or in a sorted indomethacin, Sulindac, ibuprofen, ketoprofen, naproxen, form. Although the preferred embodiments of the composi pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiara tions in JP-AH10-59841 (or EP-A-943326) above use crys mide, carbazochrome Sulfonic acid, tranexamic acid, prali talline cellulose aggregates having such a particle diameter doXime iodide methyl, protamine, leucovorin, dimercaprol, 25 range in combination with a water-absorbing and gel-forming deferoxamine, and Sodium thiosulfate. base, the document also describes the use of crystalline cel Furthermore, such non-peptide/non-protein drugs include, lulose having a particle diameter range of 10 to 250 um, as for example, the existing drugs that are administered by non well as the use of crystalline cellulose having a particle diam injection means, such as oral drugs and nasal drops, but eter of 100 to 250 um or 50 to 350 um for low-molecular cannot obtain satisfactory absorbability or rapid-acting abil 30 weight drugs in the Examples. Thus, the compositions of the ity. present invention can be said to be unique in using crystalline Herein, the term "crystalline cellulose aggregate” gener cellulose aggregates having the above-described diameter ally includes purified water-insoluble fractions of partial ranges independently. acid-depolymerized C-cellulose, where the O.-cellulose is More specifically, particularly preferred crystalline cellu obtained as pulp from fibrous plants. The crystalline cellulose 35 lose aggregates that can be used to exert Such effects include, aggregate obtained from rayon fibers or the like can also be but are not limited to, crystalline cellulose aggregates of used as long as it serves the purpose of the present invention. which More specifically, AviceITM and the like, and derivatives 25% (w/w) or less are particles with a cribriform particle thereof, as described in, for example, Japanese Patent Appli diameter of less than 25um; cation Kokoku Publication No. (JP-B) S39-12469 (examined, 40 20 to 60% (w/w) are particles with a cribriform particle approved Japanese patent application published for opposi diameter of 25 to 38 um; tion), JP-B S56-38.128, JP-B S61-21201, and JP-B 20 to 60% (w/w) are particles with a cribriform particle H5-38732, can be used as needed to obtain crystalline cellu diameter of 38 to 53 um; and lose aggregates for use in the present invention, by reducing the remainder are particles with a cribriform particle diam the particle size with a high-speed rotating impact mill or air 45 eter of 53 um or greater, mill to increase the bulk density, finely grinding the particles, wherein the ratio of the total crystalline cellulose aggregate and then sifting or sorting the particles into aggregates of is taken as 100% (w/w). particles with desirable size. With such cribriform particle diameter range, the powdery Such crystalline cellulose aggregates can usually be compositions for intranasal administration in the present obtained by depolymerization as described above; however, 50 invention can exert high absorbability and excellent rapid the average polymerization degree is not particularly limited acting ability for non-peptide/non-protein drugs. as long as it serves the purpose of the present invention. The compositions of the present invention can be prepared Generally, crystalline cellulose aggregates that have an aver using a conventional means for homogeneously combining age polymerization degree of 15 to 400, preferably of 80 to powdery drugs with a solid carrier (for example, an automatic 350, more preferably of 100 to 300 can be selected in the 55 mortar, mixing device, or mixer). Steps for removing par present invention. Such crystalline cellulose aggregates ticles with a diameter less than 10um may be added; however, include those whose bulk density is 0.13 to 0.65 g/cm and from the inventors’ experiences. Such removal steps were preferably 0.18 to 0.35 g/cm, without being limited thereto. unnecessary in most cases. The bulk densities shown above are values determined by In other methods or embodiments, the compositions of the using Scott Volumeter for measurement. 60 present invention may comprise other carriers or bases, pH Factors that are important for determining whether a crys adjustors, excipients, preservatives, stabilizers, lubricants, talline cellulose aggregate can be used in the present inven absorbefacients and Such in addition to the ingredients tion are size and distribution patterns of the crystalline cellu described above, as long as they do not adversely affect the lose particles constituting the aggregate. In terms of the purpose of the present invention. Such carriers and bases cibriform particle diameter, 85% (w/w) (ratio in terms of the 65 include, for example, hydroxypropyl cellulose, alginic acid, total crystalline cellulose aggregate) or more of the particles polyvinylpyrrolidone, chitosan, gamma-polyglutamic acid, are required to be in the entire range of 20 to 60 um, or apartial and arabic gum. Such preservatives include benzalkonium US 8,673,360 B2 7 8 chloride and the like. Such lubricants include magnesium BEST MODE FOR CARRYING OUT THE stearate and the like. Such absorbefacients include Angelica INVENTION essential oil (main ingredient: cyclopentadecanolide) as described in U.S. Pat. No. 5,731,303. Herein below, the present invention will be described in In the present invention, the powdery compositions for 5 more detail with reference to specific test examples of com intranasal administration also enable effective treatment of positions for the intranasal delivery of various drugs in the patients with a disease that particularly requires rapid-acting present invention, but is not construed as being limited ability and high absorbability of drugs through intranasal thereto. A single dose of an intranasal delivery composition administration. 10 was nasally administered to cynomolgus monkeys (body Any devices may be used to perform an intranasal admin weight: 4.3 to 7.2 kg). Each composition was encapsulated istration, as long as the device can efficiently deliver the and administered nasally using a device for nasal administra powder intranasal compositions of the present invention to tion (Bioactis Co. Ltd.). the nasal mucosa through intranasal administration. For example, Jetlizer (Unisia Jecs Co.) can be used. (1) Experiment of the Intranasal Administration of Morphine The optimal dosage or required dosage for disease treat 15 in Cynomolgus Monkeys ment cannot be specified, as it varies depending on the type of disease, patient’s condition, severity of the disease, adminis EXAMPLE 1. tration schedule and the like. Experts can readily determine the dosage as necessary, by referring to the results described 20 65 mg of morphine hydrochloride (equivalent to 50 mg of in the Examples herein, and considering the blood concentra morphine free base) (Takeda Pharmaceutical Company), tion, efficacy of the drug, and other factors after a standard which is a narcotic analgesic, and 135 mg of crystalline Subcutaneous injection. cellulose (Asahi Kasei: AviceITM PH-F20) were mixed thor The type of diseases which particularly require rapid-act oughly in a mortar. The obtained morphine composition was ing ability and high absorbability of drugs for treatment is not 25 prepared and 5.2 mg morphine hydrochloride (equivalent to particularly limited, and may be any diseases to which the 4.0 mg of morphine free base) per head was administered above-described non-peptide/non-protein drugs are appli nasally to male cynomolgus monkeys weighing from 5.5 to cable. Such diseases include all diseases where patients are under a condition that requires particularly rapid-acting abil 6.2 kg (n=3). ity and high absorbability in treatment. 30 The above-described crystalline cellulose used in the Thus, the present invention also relates to methods for Examples herein is a crystalline cellulose aggregate, in which treating diseases that require rapid-acting ability and high 90% (w/w) or more are particles that have a cribriform par absorbability in therapy, by administering effective doses of ticle diameter within the range of 20 to 60 um, more specifi the above-described powdery compositions for intranasal cally, in which administration into patients nasal cavity. Furthermore, the 35 6.8% (w/w) are particles with a cribriform particle diam present invention relates to the use of the above-described eter of less than 25 um; powdery compositions for intranasal administration in pro ducing pharmaceuticals for diseases that particularly require 49.7% (w/w) are particles with a cribriform particle diam rapid-acting ability and high absorbability in treatment. eter of 25 to 38 um; All the prior art documents cited herein are incorporated by 40 36.9% (w/w) are particles with a cribriform particle diam reference. eter of 38 to 53 atm; and 6.6% (w/w) are particles with a cribriform particle diam Effects of the Invention eter of 53-um or greater. Meanwhile, the bulk density of the crystalline cellulose The present invention provides rapid-acting, highly 45 aggregate was 0.21 g/cm, and the average polymerization absorptive powdery compositions for intranasal administra degree of the aggregate was 100 to 300. Herein below, the tion that enable rapid increase of drug concentration in blood parameters for crystalline cellulose used in the Examples are immediately after administration. the same as the above. BRIEF DESCRIPTION OF THE DRAWINGS 50 CONTROL, EXAMPLE1 FIG. 1 shows a time course of the plasma concentration of morphine in cynomolgus monkeys. Open circle and closed Morphine hydrochloride (Takeda Pharmaceutical Com triangle correspond to the results described in Example 1 and pany) was dissolved in purified water to prepare a morphine Control example 1 (average), respectively. 55 injection solution (morphine concentration: 4 mg/ml). The FIG. 2 shows a time course of the plasma concentration of preparation was administered Subcutaneously to male cyno tropisetron in cynomolgus monkeys. Open circle and closed molgus monkeys weighing 5.4 and 6.1 kg (n=2), at 0.52 mg triangle correspond to the results described in Example 2 and morphine hydrochloride (equivalent to 0.4 mg of morphine Control example 2 (average), respectively. free base) per kg body weight. FIG.3 shows a time course of the plasma concentration of 60 oxycodone in cynomolgus monkeys. Open circle and closed The plasma concentration of morphine free base after triangle correspond to the results described in Example 3 and administration was determined by the HPLC method. Control example 3 (average), respectively. The time course of plasma morphine concentration for the FIG. 4 shows a time course of the plasma concentration of above-described composition is shown in FIG. 1 and the fentanyl in cynomolgus monkeys. Open circle and closed 65 corresponding raw data are shown in Tables 1 and 2. Pharma triangle correspond to the results described in Example 4 and cokinetic parameters calculated based on the data are shown Control example 4 (average), respectively. in Table 3. US 8,673,360 B2 9 10 TABLE 1. (2) Experiment of the Intranasal Administration of Tro pisetronin Cynomolgus Monkeys Example 1: Morphine composition Plasma morphine concentration (ng/mL EXAMPLE 2 Time Animal No. 27.5 mg of tropisetron hydrochloride (equivalent to 25 mg of tropisetron free base) (Sigma), which is an antiemetic (min) No. 1 No. 2 No. 3 Average agent, and 72.5 mg of crystalline cellulose (Asahi Kasei: 5 172.4 1816 1418 165.2 AviceITM PH-F20) were mixed thoroughly in a mortar. The 10 295.6 205.3 1SO.8 217.2 obtained tropisetron composition was prepared and 4.4 mg 30 123.3 117.6 1116 117.5 10 tropisetron hydrochloride (equivalent to 4.0 mg of tropisetron 60 94.4 80.7 85.4 86.8 90 8O.S 65.1 68.8 71.5 free base) per head was administered nasally to male cyno 120 59.4 58.6 SS.4 57.8 molgus monkeys weighing from 6.3 to 7.2 kg (n=3). 240 29.4 21.5 26.1 25.7 CONTROL, EXAMPLE 2 480 6.8 6.5 8.1 7.1 15 The same tropisetron hydrochloride as described in Example 2 was dissolved in purified water to prepare a tro pisetron injection solution (tropisetron concentration: 2 TABLE 2 mg/ml). The injection was given intravenously to male cyno Control example 1: Morphine injection molgus monkeys weighing 6.9 and 7.2 kg (n=2), at 0.22 mg Plasma morphine concentration (ng/mL tropisetron hydrochloride (equivalent to 0.20 mg of tro pisetron free base) per kg weight. Time Animal No. The plasma concentration of tropisetron free base after (min) No. 1 No. 2 Average administration was determined by the HPLC method. The time course of plasma tropisetron concentration for the 2 175.3 1410 158.1 5 277.5 24S.O 261.3 25 above-described composition is shown in FIG. 2 and the 10 232.8 295.2 264.O corresponding raw data are shown in Tables 4 and 5. Pharma 30 151.4 1496 150.5 cokinetic parameters calculated based on the data are shown 60 104.5 82.4 93.5 in Table 6. The time course of plasma tropisetron concentra 90 68.8 63.7 66.3 tion after intravenous injection was subjected to a 2-compart 120 46.2 48.8 47.5 240 15.1 13.3 14.2 30 ment model analysis using the linear least-square method. 480 6.2 4.3 5.2 The area under the theoretical plasma concentration vs. time curve (AUC) was determined based on the theoretical plasma tropisetron concentration calculated. TABLE 3 Pharmacokinetic parameters of morphine Cmax Tmax AUCo-Aso Composition Dose l (ng/mL) (min) (ng min/mL) BA (%) Example 1 4 mg/body 3 217.2 1O.O 21038.5 63.6 (0.66 mg/kg) Control 0.4 mg/kg 2 286.4 7.5 20040.7 example 1 Note) Cmax: Maximal plasma concentration Tmax: Time required to reach the maximal plasma concentration AUC: Area under plasma concentration vs. time curve BA: Bioavailability

The results in FIG. 1 and Tables 1 to 3 show that over the 50 TABLE 4 time course of average plasma concentrations of morphine, the post-intranasal administration plasma concentration of Example 2: Tropisetron composition morphine reached 76% of the maximum plasma concentra Plasma tropisetron concentration (ng mL) tion 5 minutes after administration, and the maximum plasma 55 Time Animal No. concentration was achieved 10 minutes after administration. This post-intranasal administration plasma concentration (min) No. 1 No. 2 No. 3 Average pattern closely resembled the post-Subcutaneous administra 5 43.1 104.8 47.1 6S.O tion pattern. This shows that the intranasal administration of 60 10 42.2 846 38.0 S4.9 morphine was effective for acute pain in cancer patients 30 48.5 86.6 S8.9 64.7 immediately upon administration. Furthermore, the bioavail 60 32.3 SO.8 46.0 43.1 120 22.3 33.0 31.1 28.8 ability of the intranasal composition was as high as 63.6% 240 13.3 21.7 20.1 18.4 when compared with that of the Subcutaneous administration. 65 480 5.7 9.4 11.5 8.9 It was thus confirmed that the intranasal composition demon strates high absorbability as well as rapid-acting ability. US 8,673,360 B2 11 12 TABLE 5 tion was given Subcutaneously to male cynomolgus monkeys weighing 4.8 and 4.9 kg (n=2), at 2.8 mg oxycodone hydro Control example 2: Tropisetron injection Plasma tropisetron concentration (ng/mL chloride (equivalent to 2.5 mg of oxycodone free base) per kg weight. Time Animal No. (min) No. 1 No. 2 Average The plasma concentration of oxycodone free base after 2 95.7 81.0 88.4 administration was determined by the HPLC method. 5 49.5 79.8 64.6 10 35.2 59.4 47.3 10 30 3S.O 39.7 37.3 The time course of plasma oxycodone concentration for 60 26.5 32.O 29.2 the above-described composition is shown in FIG.3 and the 120 14.1 20.8 17.4 240 9.6 12.3 10.9 corresponding raw data are shown in Tables 7 and 8. Pharma cokinetic parameters calculated based on the data are shown in Table 9. TABLE 6 Pharmacokinetic parameters of tropisetron Cmax Tmax AUCo-Aso Composition Dose l (ng/mL) (min) (ng min/mL) BA (%) Example 2 4 mg/body 3 70.7 21.7 157046 73.4 (0.59 mg/kg) Control 0.2 mg/kg 2 7392.0 example 2 Note) Cmax: Maximal plasma concentration Tmax: Time required to reach the maximal plasma concentration AUC: Area under plasma concentration vs. time curve BA: Bioavailability

The results in FIG. 2 and Tables 4 to 6 show that over the TABLE 7 time course of average plasma concentrations of tropisetron, the maximum plasma concentration was already achieved 5 Example 3: Oxycodone composition minutes after intranasal administration. This post-intranasal 35 Plasma Oxycodone concentration (ng mL) administration plasma concentration pattern, which Suggests immediate absorption, demonstrates that tropisetron became Time Animal No. immediately effective for nausea and Vomiting caused by chemotherapy in cancer patients. Furthermore, the bioavail (min) No. 1 No. 2 No. 3 Average ability of the intranasal composition was as high as 73.4% 40 when compared with that of the intravenous injection. It was 5 215.3 197.3 241.4 218.0 thus confirmed that the intranasal composition demonstrates 10 283.0 294.5 447.1 341.5 high absorbability as well as rapid-acting ability. 2O 493.9 415.9 585.4 498.4 30 480.7 440.2 573.9 498.3 45 (3) Experiment of the Intranasal Administration of Oxyc 60 402.3 33S.O 391.7 376.3 odone in Cynomolgus Monkeys 120 251.2 2OS.O 217.5 224.6 240 * * * *

EXAMPLE 3 50 Below detection limits 100 mg of oxycodone hydrochloride (equivalent to 90 mg of oxycodone free base) (Mallinckrodt Inc.), which is a nar TABLE 8 cotic analgesic, and 200 mg of crystalline cellulose (Asahi Control example 3: Oxycodone injection Kasei: AvicelTMPH-F20) were mixed thoroughly in a mortar. 55 Plasma Oxycodone concentration (ng/mL. The obtained oxycodone composition was prepared and 16.7 mg oxycodone hydrochloride (equivalent to 15.0 mg of oxy Time Animal No. codone free base) perhead was administered nasally to male (min) No. 1 No. 2 Average cynomolgus monkeys weighing from 4.9 to 5.2 kg (n=3). 5 48O2 517.9 499.O 60 10 705.5 743.2 724.3 2O 730.3 768.5 749.4 30 598.5 612.3 605.4 COMPARATIVE EXAMPLE 3 60 4102 402.1 4O6.2 120 2O6.1 229.9 218.0 240 * * * Oxycodone hydrochloride (Mallinckrodt Inc.) was dis 65 Solved in purified water to prepare an oxycodone injection Below detection limits Solution (oxycodone concentration: 25.0 mg/ml). The injec US 8,673,360 B2 13 14 TABLE 9 Pharmacokinetic parameters of Oxycodone Cmax Tmax AUCo-Aso Composition Dose l (ng/mL) (min) (ng min/mL) BA (%) Example 3 15 mg/body 3 506.5 23.3 929.1 71.7 (2.96 mg/kg) Control 2.5 mg/kg 2 749.4 2O.O 1088.8 example 3 Note) Cmax: Maximal plasma concentration Tmax: Time required to reach the maximal plasma concentration AUC: Area under plasma concentration vs. time curve BA: Bioavailability 15 The results in FIG. 3 and Tables 7 to 9 show that over the The time course of plasma fentanyl concentration for the time course of plasma concentrations of oxycodone, the post above-described composition is shown in FIG. 4 and the intranasal administration concentration immediately corresponding raw data are shown in Tables 10 and 11. Phar increased and reached the maximum plasma concentration 20 macokinetic parameters calculated based on the data are minutes after administration. The post-intranasal administra 2O shown in Table 12. tion plasma concentration pattern shows that the time required for achieving the maximal concentration is compa TABLE 10 rable to that for the subcutaneous administration. It demon strates that immediately after intranasal administration, oxy Example 4: Fentanyl composition codone became effective to acute pain in cancer patients. 25 Plasma ?entanyl concentration (ng/mL. Furthermore, the bioavailability of the intranasal composition was as high as 71.7% when compared with that of the subcu- Time Animal No. taneous administration. It was thus confirmed that the intra- (min) No. 1 No. 2 No. 3 Average nasal composition demonstrates high absorbability as well as 30 rapid-acting ability. 5 4.2 4.8 2.1 3.7 (4) Experiment of the Intranasal Administration of Fentanyl 2. 3. . s in Cynomolgus Monkeys 30 4.1 5.3 4.8 4.7 60 3.2 3.6 3.6 3.5 EXAMPLE 4 120 2.4 2.3 2.7 2.5 35 240 * * * : 2.8 mg offentanyl citrate (equivalent to 1.8 mg offentanyl free base) (Fine Chemical Corp.), which is a narcotic analge- Below detection limits sic, and 297.2 mg of crystalline cellulose (Asahi Kasei: AviceITM PH-F20) were mixed thoroughly in a mortar. The TABLE 11 obtained fentanyl composition was prepared and 0.47 mg " fentanyl citrate (equivalent to 0.30 mg offentanyl free base) Control example 4: Fentanyl injection perhead was administered nasally to male cynomolgus mon- - Plasma ?entally concentration (ngin)- keys weighing from 4.3 to 6.1 kg (n=3). Time Animal No.

CONTROL, EXAMPLE 4 45 (min) No. 1 No. 2 Average The same fentanyl citrate as described in Example 4 was i. i. 3. dissolved in purified water to prepare a fentanyl injection 2O 6.2 6.7 6.5 Solution (fentanyl concentration: 0.5 mg/ml). The injection 30 4.3 4.6 4.4 was given subcutaneously to male cynomolgus monkeys 50 60 2.8 3.0 2.9 weighing 4.7 and 5.4 kg (n=2) at 0.079 mg fentanyl citrate 2. 2. 2. 2. (equivalent to 0.05 mg offentanyl free base) per kg weight. The plasma concentration of fentanyl free base after Below detection limits administration were determined by the HPLC method. TABLE 12

Pharmacokinetic parameters offentanyl

Cmax Tmax AUCo-Aso Composition Dose l (ng mL) (min) (ng min/mL) BA (%)

Example 4 0.30 mg/body 3 6.8 10 9.9 98.9 (0.06 mg/kg) US 8,673,360 B2 15 16 TABLE 12-continued Pharmacokinetic parameters offentanyl Cmax Tmax AUCo-Aso Composition Dose l (ng/mL) (min) (ng min/mL) BA (%) Control 0.05 mg/kg 2 6.5 2O 8.5 example 4 Note) Cmax: Maximal plasma concentration Tmax: Time required to reach the maximal plasma concentration AUC: Area under plasma concentration vs. time curve BA: Bioavailability

The results in FIG. 4 and Tables 10 to 12 show that over the 15 cellulose aggregate has a particle size distribution of 20 time course of average plasma concentrations offentanyl, the to 60 Lum and wherein when administered to a primate maximum plasma concentration was already reached 10 min intranasally, the time to maximal blood concentration utes after administration. This post-intranasal administration (Tmax) in said primate is achieved within 20 minutes. plasma concentration pattern shows that the time required to 2. The composition of claim 1, wherein Tmax is achieved reach the maximal plasma concentration was shorter than that within 10 minutes. for the Subcutaneous administration. It was thus demon 3. A powdery composition for intranasal administration strated that when administered nasally, fentanyl became comprising: immediately effective for acute pain in cancer patients. Fur i) a non-peptide/non-protein drug, wherein the drug is an thermore, the bioavailability of the intranasal composition opioid receptor agonist, or a 5-hydroxytryptaminel was as high as 98.9% as compared with the subcutaneous 25 administration. It was thus confirmed that the intranasal com (5-HT) receptor agonist; and position demonstrates high absorbability as well as rapid ii) a carrier consisting essentially of crystalline cellulose acting ability. aggregate, wherein 85% (w/w) or more of the crystalline cellulose aggregate has a particle size distribution of 20 to 60 Lum and wherein when administered to a primate INDUSTRIAL APPLICABILITY 30 intranasally, the absolute bioavailability (BA) of the drug is between 64% to 99%. As described above, the intranasal compositions of the 4. The powdery composition of claim 1 or 3, wherein the present invention exhibit high absorbability as well as rapid non-peptide/non-protein drug is Sumatriptan, Zolmitriptan, acting ability, and thus can be used to provide preparations of morphine or oxycodone. particular drugs to be administered in a new way of adminis 35 tration. 5. The powdery composition of claim 1 or claim3, wherein The invention claimed is: the non-peptide/non-protein drug is morphine. 1. A powdery composition for intranasal administration 6. The powdery composition of claim 1 or claim3, wherein comprising: the non-peptide/non-protein drug is oxycodone. i) a non-peptide/non-protein drug, wherein the drug is an 7. The powdery composition of claim 1 or claim3, wherein opioid receptor agonist, or a 5-hydroxytryptaminel 40 the non-peptide/non-protein drug is Sumatriptan. (5-HT) receptor agonist; and 8. The powdery composition of claim 1 or claim3, wherein ii) a carrier consisting essentially of crystalline cellulose the non-peptide/non-protein drug is Zolmitriptan. aggregate, wherein 85% (w/w) or more of the crystalline k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,673,360 B2 Page 1 of 1 APPLICATIONNO. : 1 1/6601.31 DATED : March 18, 2014 INVENTOR(S) : Ryoichi Nagata et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In the Claims

COLUMN 15, LINE 41: “5-hydroxytryptaminel should read --5-hydroxytryptamine1--.

COLUMN 16, LINE 24: “5-hydroxytryptaminel should read --5-hydroxytryptamine1--.

Signed and Sealed this Twelfth Day of August, 2014 74-4-04- 2% 4 Michelle K. Lee Deputy Director of the United States Patent and Trademark Office UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,673,360 B2 Page 1 of 1 APPLICATIONNO. : 1 1/6601.31 DATED : March 18, 2014 INVENTOR(S) : Nagata et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title Page:

The first or Sole Notice should read --

Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 1247 days.

Signed and Sealed this Eleventh Day of August, 2015 74-4-04- 2% 4 Michelle K. Lee Director of the United States Patent and Trademark Office