US 2005O181054A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0181054A1 Nishibe et al. (43) Pub. Date: Aug. 18, 2005

(54) PHARMACEUTICAL COMPOSITION FOR (30) Foreign Application Priority Data APPLICATION TO MUCOSA Apr. 21, 1998 (JP)...... 10-110887(PAT) (75) Inventors: Yoshihisa Nishibe, Tokyo (JP); Wataru Apr. 21, 1998 (JP)...... 10-110888(PAT) Kinoshita, Tokyo (JP); Hiroyuki Kawabe, Tokyo (JP) Publication Classification (51) Int. Cl." ...... A61K 9/24; A61K 31/56; Correspondence Address: A61K 31/70; A61K 31/205 SUGHRUE MION, PLLC (52) U.S. Cl...... 424/473; 514/23: 514/169; 2100 PENNSYLVANIAAVENUE, N.W. 514/554 SUTE 800 WASHINGTON, DC 20037 (US) (57) ABSTRACT (73) Assignee: TEIJIN LIMITED The present invention provides a pharmaceutical composi tion for application to the mucosa to be used in drug therapy (21) Appl. No.: 11/102,760 comprising a water-insoluble and/or water-low Soluble Sub stance, a medicament, and an aqueous medium, and having (22) Filed: Apr. 11, 2005 an osmotic pressure of less than 290 mOsm. This compo Sition is Superior over conventional pharmaceutical compo Related U.S. Application Data Sitions for application to the mucosa, due to efficient and high permeability to the blood at the mucosa. The present (63) Continuation of application No. 10/201,303, filed on invention further provides a pharmaceutical composition for Jul. 24, 2002, which is a continuation of application application to the mucosa comprising a hemostatic agent and No. 09/446,276, filed on Dec. 21, 1999, filed as 371 a medicament. This composition is Superior over conven of international application No. PCT/JP99/02126, tional pharmaceutical compositions for application to the filed on Sep. 28, 1999. mucosa, due to permeability and retentivity at the mucosa. Patent Application Publication Aug. 18, 2005 Sheet 1 of 4 US 2005/0181054A1

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PHARMACEUTICAL COMPOSITION FOR (Japanese Unexamined Patent Publication (Kokai) No. 63 APPLICATION TO MUCOSA (1988)-303931), for example, provides a method of applying to the nasal cavity a growth hormone-releasing factor at the TECHNICAL FIELD liquid form having an osmotic pressure ratio of 1 (an osmotic pressure of 290 mOsm) or lower as a method for 0001. The present invention relates to a pharmaceutical enabling quick and efficient absorption of the a growth composition for application to the mucosa to be used in drug hormone-releasing factor through the nasal mucosa to the therapy comprising a water-insoluble and/or water-low blood circulation. Furthermore, Ohwaki et al. (Japanese Soluble Substance, a medicament, and an aqueous medium, Unexamined Patent Publication (Kokai) No. 60 (1985)- and having an OSmotic pressure of less than 290 mOsm. 123426) provides a method of applying to the nasal cavity More specifically, the present invention relates to a phar a Solution of Secretin having an OSmotic preSSure ratio of 1 maceutical composition for application to the mucosa com to 5 (an osmotic pressure of 290-1450 mOsm) and a pH of prising a water-insoluble and/or water-low Soluble Sub 2 to 5 as a method for enabling quick absorption of Secretin stance, a medicament, and an aqueous medium, and having through the nasal mucosa to blood circulation. Furthermore, an osmotic pressure of less than 290 mOsm, that is Superior Awatsu et al. (Pharm. Res. Vol. 10, No. 9, 1372-1377, 1993) to conventional pharmaceutical compositions for application provides a method of applying to the nasal mucosa a to the mucosa, due to efficient and high permeability to the pharmaceutical Solution to which polyoxyethylene 9-lau blood at the mucosa. rylether was added as an absorption enhancer as a method 0002 The present invention also relates to a pharmaceu for enabling efficient absorption of a granulocyte colony tical composition for application to the mucosa comprising Stimulating factor through the nasal mucosa to blood circu a hemostatic agent and a medicament. More specifically, the lation. present invention relates to a pharmaceutical composition 0006. However, when these pharmaceutical preparations for application to the mucosa in which a medicament has are given to the mucosa, liquid-dripping can occur, or the been mixed with a hemostatic agent and that is Superior over pharmaceutical preparations are quickly excreted to the conventional pharmaceutical compositions for application to outside of the mucus tissue due to a mucociliary clearance the mucosa due to high permeability and retention at the function etc. before being adequately transported or perme COS. ated to the mucosa tissue. Because of this, the transport of an adequate amount of drug into the blood cannot be effected BACKGROUND ART when systemic administration through transport to the blood 0003) Application to the mucosa as a method of drug circulation is attempted. Furthermore, the method of using therapy has been recognized as a useful means of medication an absorption enhancer is yet to be realized because the for Such reasons as (1) it permits direct application to the absorption enhancer has the problem of irritating the nasal affected area for diseases of local areas Such as nasal mucosa. On the other hand, when local administration is mucosa, oral mucosa, and vaginal mucosa, (2) its immediate attempted through retention of the drug in the mucosa tissue, effects for Systemic diseases can be expected as in the case an adequate amount of the drug cannot be retained at the of a nasal Spray to the nasal mucosa and a Suppository to the tissue. In addition, even if the problem of retentivity has rectal mucosa, and (3) its application is easy compared to been Solved, permeation into the mucosa tissue is not injection, as represented by an oral drug targeted at the adequate. intestinal mucosa, and the like. For example, pharmaceutical 0007 Thus, it is strongly desired to develop a pharma preparations for application to the mucosa have already been ceutical preparation for application to the mucosa, that commercially available due to reason (1) in the case of nasal allows the transport of an adequate amount of the drug sprays for treatment of allergic rhinitis, and due to reason (2) through the mucosa to the blood circulation after the appli in the case of Suppositories to alleviate pain. cation to the mucosa. Alternatively, it is Strongly desired to 0004 AS pharmaceutical preparations for local mucus develop a pharmaceutical preparation for application to the diseases, Saunders et al., (WO 92-14473), for example, mucosa that enables the transport to and retention in the provides a Suspension preparation containing Tipredane as mucosa tissue of an adequate amount of the drug when the main drug as the pharmaceutical preparation for treat applied to the mucosa. ment of allergic rhinitis. Also, Helzner (WO 97-01337) provides a pharmaceutical preparation comprising an anti DISCLOSURE OF THE INVENTION histamic drug, a Steroid and water as the pharmaceutical 0008 Thus, the first object of the present invention is to preparation for treatment of allergic rhinitis. AS the phar provide a pharmaceutical composition for application to the maceutical preparation for local mucus diseases, further more, Kim et al., (WO 98-00178) provides a suspension mucosa, that has efficient and high permeability through the preparation having a thixotropic property as the pharmaceu mucosa to the blood when applied to the mucosa. tical preparation for application to the nasal mucosa. Suzuki 0009. The second object of the present invention is to et al. (Japanese Examined Patent Publication (Kokoku) No. provide a pharmaceutical composition for application to the 60 (1985)-34925) also provides a sustained release pharma mucosa, that has efficient and high permeability to the ceutical preparation for administration to the nasal cavity mucosa and retentivity at the mucosa when applied to the that permits the efficient Supply of the drug at a concentra COS. tion Sufficient to obtain a therapeutic effect. 0010. After intensive studies to attain the above first 0005. As the pharmaceutical preparations for systemic object, the present inventors have found that it is possible to diseases, Several methods have been provided that enhance provide a pharmaceutical preparation for application to the the absorption of drugs through the mucosa. Nagata et al. mucosa that is Superior over conventional liquid composi US 2005/0181054A1 Aug. 18, 2005 tion due to efficient and high permeability through the over conventional pharmaceutical compositions for applica mucosa to the blood, by formulating a drug that contains a tion to the mucosa, due to markedly efficient and high water-insoluble and/or water-low soluble Substance and that permeability to the blood at the mucosa. has an osmotic pressure of less than 290 mOsm, and thereby 0015. After intensive studies to attain the above second have reached the present invention. object, the present inventors have found that by formulating 0.011) An enhanced absorption of a drug through the a pharmaceutical preparation in which a hemoStatic agent mucosa by controlling the osmotic pressure of a pharma has been added to a pharmaceutical preparation containing ceutical preparation is disclosed in a patent to Ohwaki and a medicament, a pharmaceutical composition for application has been reported in a paper by AwaZu et al. (Pharm. Res. to the mucosa having efficient and high permeability to and Vol. 10, No. 9, 1372-1377, 1993). However, these phenom retentivity at the mucosa can be provided, and thereby have ena are only observed in aqueous Solution preparations that attained the present invention. do not contain a water-insoluble and/or water-low Soluble 0016. Thus, in the second aspect, the present invention Substance, and thereby are essentially different from the provides a pharmaceutical composition for application to the pharmaceutical preparation of the present invention in which mucosa comprising one or more hemostatic agent and one or the inclusion of a water-insoluble and/or water-low soluble more medicament, and more specifically, an aqueous phar Substance is essential. Furthermore, it has been shown in maceutical composition for application to the mucosa com Osada's patent that absorption through the rat nasal mucosa prising one or more hemostatic agent, one or more water of growth hormone releasing factor is higher when the insoluble Substance and/or water-low Soluble Substance and preparation has an osmotic pressure ratio of 1 (osmotic one or more medicament, and having an osmotic pressure of pressure of 290 mOsm) or lower, and in Ohwaki's patent it less than 290 mOsm. The composition is a pharmaceutical is higher when Secretin has an osmotic pressure ratio of 1 composition for application to the mucosa, that is Superior (osmotic pressure of 290 mOsm) or greater, and in Awazu's over conventional pharmaceutical compositions for applica patent the absorption of granulocyte colony-stimulating fac tion to the mucosa, due to markedly efficient and high tor is higher when the preparation has an osmotic pressure permeability and retentivity at the mucosa. of 285 mC)sm than 174 mosm. These observations thereby Suggest that it is not easy to think of the present invention BRIEF DESCRIPTION OF DRAWINGS that permits enhanced absorption regardless of the type of drug used. In these aqueous Solution preparations the degree 0017 FIG. 1 is a graph showing the relationship between of enhancement in absorption by controlling osmotic pres osmotic pressure and bioavailability in the result that com Sure is at most about 3-fold compared to the isotonic pares the absorptivity of fluorescein in working example 1 pharmaceutical preparations, and therefore the degree of 10 and Comparative example 1. to 20-fold of the present invention is Surprising. 0018 FIG. 2 is a graph showing the relationship between 0012 The patent application by Saunders (WO oSmotic pressure and bioavailability in the result that com 92-14473) and Helzner (WO 97-01337) described above pares the absorptivity of 5-carboxy fluorescein in Working describe pharmaceutical preparations containing a water example 2 and Comparative example 2. insoluble and/or water-low soluble Substance. However, 0019 FIG. 3 is a graph showing the relationship between Saunders patent application (WO 92-11473) makes no oSmotic pressure and bioavailability in the result that com description of OSmotic pressure of pharmaceutical prepara pares the absorptivity of Salmon calcitonin in working tions in general, in its claim, and merely describes in the example 3 and Comparative example 3. Specification that isotonicity is preferred, and Helzner's patent application makes no description of OSmotic pressure 0020 FIG. 4 is a photograph showing the expansion of of pharmaceutical preparations in general, and merely the composition when the composition of the present inven describes in the Specification that the addition of an isotonic tion having an osmotic pressure of 10 mosm (A) or a agent is preferred. From these patents, therefore, one cannot composition having an OSmotic pressure of 290 mOsm expect a drastic enhancement in the absorption at low (isotonic pressure) was added to a physiological Saline oSmotic pressures. having the same osmotic pressure as the mucus (thereby Simulating the mucus) on the mucosa. 0013. It is surprising therefore that the effect of enhanc ing drug absorption through the mucosa is drastic when a EMBODIMENTS FOR CARRYING OUT THE water-insoluble or water-low Soluble Substance is coexist INVENTION ent. That is, although there are reports that the effect of low oSmotic pressure is observed in Some aqueous Solution 0021. As the medicament of the present invention, any preparations, we have found, Surprisingly, that the effect can agent can be applied including, for example, one for Sedative be observed by adding a water-insoluble or water-low hypnotics, one for antianxiety drugs, one for anticonvul Soluble Substance and the effect does not depend on the type Sants, one for analgesic antipyretics, one for local anesthet of the drug used. ics, one for antispasmodics, one for cardiac Stimulants, one for diuretics, one for vasoconstrictors, one for vasodilators, 0.014 Thus, in the first aspect, the present invention one for bronchodilators, one for peptic ulcer drugs, one for provides an aqueous pharmaceutical composition for appli analgesics, one for hormone preparations, one for antidotes, cation to the mucosa comprising one or more water-in one for vaccines, one for antibiotics, one for chemothera Soluble Substance and/or water-low Soluble Substance and peutics, one for anti-Parkinson drugs, one for psychoneurot one or more medicament, and having an OSmotic pressure of ics, one for muscle relaxants, one for antiarrhythmic drugs, less than 290 mOsm. The composition is a pharmaceutical one for antihypertensive drugs, one for hypolipidemic drugs, composition for application to the mucosa that is Superior one for respiratory Stimulants, one for expectorants, one for US 2005/0181054A1 Aug. 18, 2005

antiflatuents, one for Vitamins, one for antiallergic drugs, can be mentioned crystalline cellulose carmellose Sodium and the like. Among them, relatively lipoSoluble agents are that is a mixture of carboxymethyl cellulose Sodium and preferred and Specific examples include lipoSoluble Vita crystalline cellulose. Preferably the concentration of these mins, Steroids, and prostaglandins. Among the highly water water-soluble polymers, when added, is 1% w/w to 30% Soluble agents, those having a high molecular weight are w/w relative to the water-insoluble and/or water-low soluble preferred, and Specific examples include proteins, and pep Substance. tides. 0027. It is an essential requirement in the first aspect of 0022 Agents that develop beneficial effects when present the present invention that the osmotic pressure of the phar in the mucosa include, for example, antiallergic drugS Such maceutical preparation is less than 290 mOsm, and prefer as tranilast, amlexanox, repirinast, ibudilast, tazanolast, ably it is 150 mCsm or lower, more preferably 60 mOsm or pemirolast, OXatomide, azelastine hydrochloride, terfena lower, more preferably 30 mC)sm or lower, and most pref dine, astemizole, Sodium cromoglicate, ketotifen fumarate, erably 10 mC)sm or lower. The control of osmotic pressure emedastine fumarate, epinastine hydrochloride, meduita is not required in the Second aspect of the present invention, Zine, Suplatast tosilate, OZagrel, Seratorodast, pranlukast, but it is preferably lower than the osmotic pressure of the 5-lipoxygenase inhibitors, and platelet activating antago mucus at the mucosa of the targeted administration site, and nists, Steroids for rhinitis and asthma Such as beclometaSone specifically it is less than 290 mOsm, preferably 150 mC)sm dipropionate, fluticaSone propionate, flunisolide, and or lower, more preferably 60 mCsm or lower, more prefer mometasone; VaccineS Such as influenza HA vaccine, and; ably 30 mOsm or lower, and most preferably 10 mosm or agents for genetic therapy Such as antisense, ribozyme, and lower. VectOrS. 0028. In the present invention, the addition of a substance 0023. In the first aspect of the present invention, the for controlling osmotic pressure (osmotic pressure-control water-insoluble and/or water-low Soluble Substance is an ling agent) is not particularly required, but when it is added essential component, and in the Second aspect of the present any Substance can be used. Specific examples include Salts invention, the composition preferably contains a water Such as Sodium chloride, and water-Soluble SugarS Such as insoluble and/or water-low soluble Substance. Such a water glucose, and among them SaltS Such as Sodium chloride are insoluble or water-low soluble substance may be any sub preferred. stance, and preferred examples include celluloses and more 0029. The hemostatic agent for use in the second aspect preferably crystalline celluloses. of the present invention may be any agent, and specific 0024. The concentration of the water-insoluble and/or examples include tranexamic acid, epsilon aminocaproic water-low Soluble Substance, that is present as Solid particles acid, carbazochrome, carbazochrome Sulfonate, carbazo in an aqueous medium in the first aspect of the present chrome Sodium Sulfonate, phytonadione, etamsylate, mono invention, is preferably 0.1% w/w or greater relative to the ethanol amine oleate, thrombin, hemocoaglase, adreno total amount of the preparation, and more preferably 1% to chrome monoaminoguanidine mesilate, and the like. When 10% w/w. The concentration of the water-insoluble and/or the above water-Soluble polymer is added, the hemostatic water-low Soluble Substance that is present as Solid particles agent or the medicament is preferably highly lipoSoluble, in an aqueous medium in the Second aspect of the present and Specific examples include carbazochrome, carbazo invention is preferably 0.1% w/w or greater relative to the chrome Sulfonate, and carbazochrome Sodium Sulfonate as total amount of the preparation, and more preferably 1% to the hemostatic agent, and lipoSoluble vitamins, Steroids, and 10% w/w. prostaglandins as the medicament. AS the highly water Soluble medicament, a high molecular weight compound is 0.025 In any of the aspects of the present invention, preferred and Specific examples include proteins and pep preferably the water-insoluble or water-low soluble Sub stance that is present as Solid particles in an aqueous medium tides. is homogeneously dispersed in the aqueous medium. 0030. In the present invention, a known surfactant can be added and Specific examples include polySorbate 80, glyc 0026. In any of the aspects of the present invention, erin monoStearate, polyoxyl Stearate, Lauromacrogol, Sor preferably a water-soluble polymer is further added to the composition. Specifically, alginic acid, propylene glycol, bitan oleate, Sucrose fatty acid esters, and the like. Among polyethylene glycol, glycerin, polyoxyethylene polyoxypro them, polysorbate 80 is most preferred. pylene glycol, pectin, low methoxyl pectin, guar gum, gum 0031. The amount of the medicament for use in the arabic, carrageenan, methyl cellulose, carboxymethyl cellu present invention is a therapeutically effective amount and lose Sodium, Xanthan gum, hydroxypropyl cellulose, can be determined depending on the type of drug adminis hydroxypropyl methyl cellulose, and the like can be men tered, the type and the degree of the disease, the age and the tioned, and preferably carboxymethyl cellulose Sodium, weight of the patient, and the like. It is usually from the same Xanthan gum, and hydroxypropyl cellulose can be men to 20 times as much as the amount of each drug commonly tioned. The above polyoxyethylene polyoxypropylene gly used for injection, more preferably from the Same to 10 col is a Series of polymers in which ethylene oxide has been times as much. addition-polymerized to a polypropylene glycol obtained by polymerization of propylene oxide, and are classified into 0032. The concentration of the medicament of the present Several types by the difference in the mean degree of invention is preferably 0.01% w/w to 1% w/w relative to the polymerization of propylene oxide and ethylene oxide, with total amount of the pharmaceutical preparation, and most any type being usable in the present invention. In addition, preferably 0.05% w/w to 0.5% w/w. as preferred combinations of a water-Soluble polymers and 0033. In order to improve the physical properties, appear water-insoluble and/or water-low soluble Substance, there ances, or Smells of the composition of the present invention, US 2005/0181054A1 Aug. 18, 2005

a known antiseptic, a pH controlling agent, a preservative, a Micro-Osmometer Model 3MO from Advance Instruments, buffer, a colorant, a Smell corrigent, and the like may be Inc. The result is shown in Table 1. added, as desired. For example, benzalkonium chloride as the antiseptic, hydrochloric acid as the pH controlling agent, 0039. One hundred ul each of the compositions 1 to 10 ascorbic acid as the preservative, citric acid and Salts thereof for application to the nasal mucosa was sprayed to the as the buffer, Red No. 2 as the colorant, menthol as the Smell unilateral nasal cavity of rabbits (Japanese White, male, corrigent may be mentioned. weighing 3 kg) using a commercially available Suspension device. At 5, 10, 15, 30, 60, and 120 minutes after the 0034. The mucosa to which the present invention is administration, 0.5 ml of the blood was taken from the ear applied may be any mucosa. Specific examples include vein and the plasma level of fluorescein was determined by intestinal mucosa, gastric mucosa, nasal mucosa, tracheal/ HPLC. From the time-concentration curve till 120 minutes bronchial/pulmonary mucosa, mucosa of oral cavity, rectal after the Spraying, AUCoo was determined and bio mucosa, Vaginal mucosa, and the like, and nasal mucosa is availability (B.A.) for the intravenous injection was calcu most preferred. lated. The mean values of three rabbits are shown in Table 0035. The composition of the present invention may be 1. formulated in a dosage form Suitable for administration as a pharmaceutical preparation. It may contain an indirect doS TABLE 1. age form Such as an oral formulation for administration to Osmotic the gastric and intestinal mucosa, but the composition of the Composition pressure B.A. present invention is preferably administered directly to the No. Composition (mCsm) (%) mucosa, and most preferably it takes a dosage form that can 1. Fluorescein: 0.1% wiw 5 63 be sprayed as a mist. In this case, the composition of the Crystalline cellulose carmellose present invention may be filled in a gastric or enteric sodium: 1.7% wiw capsule, for example, and the composition is exposed at the Polysorbate 80: 0.1% w/w desired site of mucosa. AS another dosage form, when given Benzalkonium chloride: 0.03% ww. 2 Fluorescein: 0.1% wiw 3O 47 to the rectal mucosa, the present invention may be filled in Crystalline cellulose carmellose a capsule in a unit dosage form, which is administered as a sodium: 1.7% wiw Suppository. When given to the oral mucosa, nasal mucosa, Polysorbate 80: 0.1% w/w or vaginal mucosa, the composition of the present invention Benzalkonium chloride: 0.03% w/w Sodium chloride: 0.08% wiw may be filled in a Spray-type container, a fixed amount of 3 Fluorescein: 0.1% wiw 72 16 which is sprayed to the oral cavity, nose, or vagina. When Crystalline cellulose carmellose given to the tracheal/bronchial/pulmonary mucosa, the sodium: 1.7% wiw present invention may be filled to an inhalation-type con Polysorbate 80: 0.1% w/w Benzalkonium chloride: 0.03% ww. tainer, which is allowed to be inhaled into the trachea, Sodium chloride: 0.2% wiw bronchus, or lung. 4 Fluorescein: 0.1% wiw 128 13 Crystalline cellulose carmellose EXAMPLES sodium: 1.7% wiw Polysorbate 80: 0.1% w/w Benzalkonium chloride: 0.03% ww. 0.036 The present invention will now be explained with Sodium chloride: 0.4% wiw reference to the following examples. 5 Fluorescein: 0.1% wiw 3O 29 Crystalline cellulose carmellose 0037 Fluorescein and carboxy fluorescein used in the sodium: 1.7% wiw present invention are Substances generally used as a model Polysorbate 80: 0.1% w/w drug of the lipoSoluble low molecular weight drug and of the Benzalkonium chloride: 0.03% ww. Glucose: 0.5% w/w water-Soluble low molecular weight drug, respectively. AS 6 Fluorescein: 0.1% wiw 72 1O an example of the water-Soluble high molecular weight drug, Crystalline cellulose carmellose Salmon calcitonin was used. Fluorescein was obtained from sodium: 1.7% wiw Wako Pure Chemicals, 5-carboxy fluorescein was from Polysorbate 80: 0.1% w/w Benzalkonium chloride: 0.03% ww. Molecular Probes, Salmon calcitonin was from Bachem, Glucose: 1.2% w/w crystalline cellulose carmellose sodium was from AvielTM 7 Fluorescein: 0.1% wiw 128 9 RC-591 NF manufactured by Asahi Chemical Industry, Co., Crystalline cellulose carmellose sodium: 1.7% wiw Ltd., Polysorbate 80 was from Wako Pure Chemicals, ben Polysorbate 80: 0.1% w/w Zalkonium chloride was from Nakalai Tesque, glucose was Benzalkonium chloride: 0.03% ww. from Wako Pure Chemicals, Sodium chloride was from Glucose: 2.1% w/w Wako Pure Chemicals, caroboxymethyl cellulose sodium 8 Fluorescein: 0.1% wiw O 22 was from Wako Pure Chemicals, carbazochrome was from Crystalline cellulose carmellose sodium: 0.1% wiw Wako Pure Chemicals, tranexamic acid was from Wako Pure Polysorbate 80: 0.1% w/w Chemicals. Benzalkonium chloride: 0.03% ww. 9 Fluorescein: 0.1% wiw O 37 Example 1 Crystalline cellulose carmellose sodium: 0.5% wiw Polysorbate 80: 0.1% w/w 0.038 Fluorescein composition Nos. 1 to 10 for applica Benzalkonium chloride: 0.03% ww. tion to the mucosa comprising the components described in 1O Fluorescein: 0.1% wiw 7 53 the following Table 1 were prepared. For each pharmaceu Crystalline cellulose carmellose tical preparation, OSmotic pressure was measured using the US 2005/0181054A1 Aug. 18, 2005

Instruments, Inc. The result is shown in Table 3. Bioavail TABLE 1-continued ability (B.A.) of the compositions 17 to 18 determined by the method described in Working example 1 is also shown in Osmotic Table 3. Composition pressure B.A. No. Composition (mCsm) (%) TABLE 3 sodium: 3.0% w/w Polysorbate 80: 0.1% w/w Osmotic Benzalkonium chloride: 0.03% ww. Composition pressure B.A. No. Composition (mCsm) (%) 17 5-carboxy fluorescein: 0.1% w/w 6 52 Comparative Example 1 Crystalline cellulose carmellose sodium: 1.7% wiw Polysorbate 80: 0.1% w/w 0040 Fluorescein composition Nos. 11 to 16 for appli Benzalkonium chloride: 0.03% ww. cation to the mucosa comprising the components described 18 5-carboxy fluorescein: 0.1% w/w 3O 47 in the following Table 2 were prepared. For each pharma Crystalline cellulose carmellose ceutical preparation, OSmotic pressure was measured using sodium: 1.7% wiw the Micro-Osmometer Model 3MO from Advance Instru Polysorbate 80: 0.1% w/w ments, Inc. The result is shown in Table 2. Bioavailability Benzalkonium chloride: 0.03% ww. (B.A.) of the compositions 11 to 16 determined by the Glucose: 0.4% w/w method described in Working example 1 is also shown in Table 2. Comparative Example 2 TABLE 2 0042. 5-Carboxy fluorescein composition Nos. 19 to 22 Osmotic for application to the mucosa comprising the components Composition pressure B.A. described in the following Table 4 were prepared. For each No. Composition (mCsm) (%) pharmaceutical preparation, osmotic pressure was measured 11 Fluorescein: 0.1% ww. 290 7 using the Micro-Osmometer Model 3MO from Advance Crystalline cellulose carmellose Instruments, Inc. The result is shown in Table 4. Bioavail sodium: 1.7% w/w ability (B.A.) of the compositions 19 to 22 determined by the Polysorbate 80: 0.1% w/w Benzalkonium chloride: 0.03% ww. method described in working example 1 is also shown in Sodium chloride: 0.9% ww. Table 4. 12 Fluorescein: 0.1% ww. 340 7 Crystalline cellulose carmellose TABLE 4 sodium: 1.7% w/w Polysorbate 80: 0.1% w/w Osmotic Benzalkonium chloride: 0.03% ww. Composition pressure B.A. Glucose: 5% ww. No. Composition (mCsm) (%) 13 Fluorescein: 0.1% ww. 4OOO 4 Crystalline cellulose carmellose 19 5-carboxy fluorescein: 0.1% w/w 340 5 sodium: 1.7% w/w Crystalline cellulose carmellose Polysorbate 80: 0.1% w/w sodium: 1.7% wiw Benzalkonium chloride: 0.03% ww. Polysorbate 80: 0.1% w/w Glucose: 67% w/w Benzalkonium chloride: 0.03% ww. 14 Fluorescein: 0.1% ww. 5 7 Glucose: 5% ww. Carboxy methyl cellulose sodium: 2O 5-carboxy fluorescein: 0.1% w/w 4OOO 3 0.2% w/w Crystalline cellulose carmellose Polysorbate 80: 0.1% w/w sodium: 1.7% wiw Benzalkonium chloride: 0.03% ww. Polysorbate 80: 0.1% w/w 15 Fluorescein: 0.1% ww. 3O 5 Benzalkonium chloride: 0.03% ww. Carboxy methyl cellulose sodium: Glucose: 67% w/w 0.2% w/w 21 5-carboxy fluorescein: 0.1% w/w 6 7 Polysorbate 80: 0.1% w/w Carboxy methyl cellulose sodium: Benzalkonium chloride: 0.03% ww. 0.2% w/w Sodium chloride: 0.08% wiw Polysorbate 80: 0.1% w/w 16 Fluorescein: 0.1% ww. 3O 5 Benzalkonium chloride: 0.03% ww. Carboxy methyl cellulose sodium: 22 5-carboxy fluorescein: 0.1% w/w 3O 3 0.2% w/w Carboxy methyl cellulose sodium: Polysorbate 80: 0.1% w/w 0.2% w/w Benzalkonium chloride: 0.03% ww. Polysorbate 80: 0.1% w/w Glucose: 0.5% w/w Benzalkonium chloride: 0.03% ww. Glucose: 0.4% w/w

Example 2 Example 3 0041 5-Carboxy fluorescein composition Nos. 17 to 18 for application to the mucosa comprising the components 0043 Salmon calcitonin composition Nos. 23 to 24 for described in the following Table 3 were prepared. For each application to the mucosa comprising the components pharmaceutical preparation, OSmotic pressure was measured described in the following Table 5 were prepared. For each using the Micro-Osmometer Model 3MO from Advance pharmaceutical preparation, osmotic pressure was measured US 2005/0181054A1 Aug. 18, 2005

using the Micro-Osmometer Model 3MO from Advance pharmaceutical preparation having an almost isotonic Instruments, Inc. The result is shown in Table 5. Bioavail osmotic pressure of 340 mOsm (Composition Nos. 11 and ability (B.A.) of the compositions 23 to 24 determined by the 12) or with a pharmaceutical preparation having a high method described in working example 1 is also shown in osmotic pressure of 4000 mOsm (Composition No. 13), and, Table 5. as shown in Table 1, the bioavailability is increased by 8 to 15 fold. Bioavailability decreases with increased osmotic TABLE 5 pressure, and at 30 mOsm (Composition No. 2) it is three fourth that of 5 mosm (Composition No. 1) and at a higher Osmotic 72 mOsm (Composition No. 3) it decreases to a great extent. Composition pressure B.A. Even at 128 mC)sm (Composition No. 4) it exhibits a No. Composition (mCsm) (%) bioavailability about twice as high as that of the pharma 23 Salmon calcitonin: 0.008% wiw 1O 52 ceutical preparation having 290 mOsm or greater (Compo Crystalline cellulose carmellose sodium: 1.7% w/w sition Nos. 11 to 13). It has been also shown that even when Polysorbate 80: 0.1% w/w isotonic at low osmotic preSSure, Salts. Such as Sodium Benzalkonium chloride: 0.03% ww. chloride (Composition Nos. 2 to 4) have higher bioavail 24 Salmon calcitonin: 0.008% wiw 3O 47 ability than water-Soluble salts Such as glucose (Composi Crystalline cellulose carmellose sodium: 1.7% w/w tion Nos. 5 to 7). Furthermore, it indicates that up to about Polysorbate 80: 0.1% w/w 1.5%, the higher the concentration of the water-insoluble or Benzalkonium chloride: 0.03% ww. water-low soluble substances is, the higher the bioavailabil Glucose: 0.4% w/w ity is (comparison between Composition Nos. 8 and 9 and Composition No. 1). Even for the pharmaceutical prepara tions having a low osmotic preSSure, plasma levels were Comparative Example 3 almost equal to the pharmaceutical preparations having 0044 Salmon calcitonin composition Nos. 25 to 28 for isotonic or high OSmotic pressure when they do not contain application to the mucosa comprising the components water-insoluble or water-low Soluble Substances (Composi described in the following Table 6 were prepared. For each tion Nos. 14 to 16). These results indicate that the effect of pharmaceutical preparation, OSmotic pressure was measured oSmotic pressure of the pharmaceutical preparation which is using the Micro-Osmometer Model 3MO from Advance isotonic or lower on the permeability of the water-low Instruments, Inc. The result is shown in Table 6. Bioavail Soluble Substance to the blood at the mucosa is markedly ability (B.A.) of the compositions 25 to 28 determined by the exhibited only when a water-insoluble or water-low soluble method described in working example 1 is also shown in Substance is included, and thereby the effect of the aqueous Table 6. pharmaceutical composition of the present invention for application to the mucosa was demonstrated. TABLE 6 0046) When the model drug is a water-soluble low Osmotic molecular weight Substance, 5-carboxy fluorescein, plasma Composition pressure B.A. levels of 5-carboxy fluorescein in rabbits that were sprayed No. Composition (mCsm) (%) with a pharmaceutical preparation having a low Osmotic pressure of 6 mosm (Composition No. 17) to the nasal 25 Salmon calcitonin: 0.008% wiw 340 3 Crystalline cellulose carmellose mucosa were markedly higher than those in rabbits that were sodium: 1.7% w/w Sprayed with a pharmaceutical preparation having an almost Polysorbate 80: 0.1% w/w isotonic osmotic pressure of 340 mOsm (Composition Nos. Benzalkonium chloride: 0.03% ww. 19) or with a pharmaceutical preparation having a high Glucose: 5% ww. 26 Salmon calcitonin: 0.008% wiw 4OOO 2 osmotic pressure of 4000 mOsm (Composition No. 20), and, Crystalline cellulose carmellose as shown in Table 3, the bioavailability is increased by 9 to sodium: 1.7% w/w 17 fold. Furthermore, even for the pharmaceutical prepara Polysorbate 80: 0.1% w/w tions having a low osmotic preSSure, plasma levels were Benzalkonium chloride: 0.03% ww. Glucose: 67% w/w almost equal to the pharmaceutical preparations having 27 Salmon calcitonin: 0.008% wiw 6 5 isotonic or high OSmotic pressure when they do not contain Caroboxymethyl cellulose sodium: a water-insoluble or water-low Soluble Substance (Compo 0.2% w/w Polysorbate 80: 0.1% w/w sition Nos. 21 to 22). Benzalkonium chloride: 0.03% ww. 0047 These results indicate that the effect of osmotic 28 Salmon calcitonin: 0.008% wiw 3O 5 Caroboxymethyl cellulose sodium: preSSure of the pharmaceutical preparation which is isotonic 0.2% w/w or lower on the permeability of the water-low soluble Polysorbate 80: 0.1% w/w substance to the blood at the mucosa is markedly exhibited Benzalkonium chloride: 0.03% ww. only when a water-insoluble or water-low soluble substance Glucose: 0.4% w/w is included, and thereby the effect of the aqueous pharma ceutical composition of the present invention for application 0.045 When the model drug is a liposoluble low molecu to the mucosa was demonstrated. lar weight Substance, fluorescein, plasma levels of fluores 0048 When the drug is a water-soluble high molecular cein in rabbits that were sprayed with a pharmaceutical weight Salmon calcitonin, plasma levels of Salmon calcito preparation having a low osmotic pressure of 5 mOsm nin in rabbits that were sprayed with a pharmaceutical (Composition No. 1) to the nasal mucosa were markedly preparation having a low Osmotic pressure of 10 m0Sm higher than those in rabbits that were sprayed with a (Composition No. 23) to the nasal mucosa were markedly US 2005/0181054A1 Aug. 18, 2005

higher than those in rabbits that were sprayed with a nasal cavity, and the mean residual ratio in the nasal cavity pharmaceutical preparation having an almost isotonic for three rabbits is shown in Table 7. osmotic pressure of 340 mOsm (Composition Nos. 25) or with a pharmaceutical preparation having a high osmotic TABLE 7 pressure of 4000 mOsm (Composition No. 26), and, as residual shown in Table 5, the bioavailability is increased by 13 to 19 ratio in fold. Osmotic nasal Composition pressure cavity B.A. 0049 Even for the pharmaceutical preparations having a No. Composition (mCsm) (%) (%) low Osmotic pressure, plasma levels were almost equal to the 29 Fluorescein: 0.1% wiw 5 49 3O pharmaceutical preparations having isotonic or high osmotic Carbazochrome: 0.1% w/w preSSure when they do not contain a water-insoluble or Crystalline cellulose water-low soluble substance (Composition Nos. 27 and 28). carmellose sodium: 1.7% wiw Polysorbate 80: 0.1% w/w 0050. These results indicate that the effect of osmotic Benzalkonium chloride: preSSure of the pharmaceutical preparation which is isotonic 0.03% w/w 3O Fluorescein: 0.1% wiw 3O 32 22 or lower on the permeability of the water-low soluble Carbazochrome: 0.1% w/w substance to the blood at the mucosa is markedly exhibited Crystalline cellulose only when a water-insoluble or water-low soluble substance carmellose sodium: 1.7% wiw Polysorbate 80: 0.1% w/w is included, and thereby the effect of the aqueous pharma Benzalkonium chloride: ceutical composition of the present invention for application 0.03% w/w to the mucosa was demonstrated. Sodium chloride: 0.08% wiw 31 Fluorescein: 0.1% wiw 72 1O 1O 0051. With regard to the result that compares the absorp Carbazochrome: 0.1% w/w tivity of fluorescein in Example 1 and Comparative example Crystalline cellulose 1, the relationship between the osmotic pressure and bio carmellose sodium: 1.7% wiw Polysorbate 80: 0.1% w/w availability is shown in FIG. 1. Also, with regard to the Benzalkonium chloride: result that compares the absorptivity of 5-carboxy fluores 0.03% w/w cein in Example 2 and Comparative example 2, the rela Sodium chloride: 0.2% wiw tionship between the OSmotic pressure and bioavailability is 32 Fluorescein: 0.1% wiw 128 9 7 Carbazochrome: 0.1% w/w shown in FIG. 2. Also, with regard to the result that Crystalline cellulose compares the absorptivity of Salmon calcitonin in Example carmellose sodium: 1.7% wiw 3 and Comparative example 3, the relationship between the Polysorbate 80: 0.1% w/w osmotic pressure and bioavailability is shown in FIG. 3. It Benzalkonium chloride: 0.03% w/w is apparent that in any of the drugs, bioavailability increases Sodium chloride: 0.4% wiw with decreased OSmotic pressure and that a water-insoluble 33 Fluorescein: 0.1% wiw 7 51 28 and/or water-low Soluble Substance represented by crystal Tranexamic acid: 0.1% ww. line cellulose carmelloSe Sodium is required to obtain a high Crystalline cellulose carmellose sodium: 1.7% wiw bioavailability. Polysorbate 80: 0.1% w/w 0.052 FIG. 4 is a photograph that shows the expansion of Benzalkonium chloride: the composition when the composition of the present inven 0.03% w/w tion having an osmotic pressure of 10 m0Sm and that having an osmotic pressure of 290 mOsm (isotonic) were added to Comparative Example 4 the physiological Saline having the same OSmotic preSSure as 0054 Fluorescein composition Nos. 34 to 38 for appli the mucus on the mucosa (thus, Simulating mucus). The cation to the mucosa comprising the components described figure shows that the composition of the present invention in the following Table 8 were prepared. For each pharma having a low Osmotic preSSure remain at the addition site ceutical preparation, OSmotic pressure was measured using whereas the isotonic compositions easily disperse. the Micro-Osmometer Model 3MO from Advance Instru ments, Inc. Bioavailability (B.A.) and the residual ratio in Example 4 the nasal cavity of the composition Nos. 34 to 38 determined 0053 Fluorescein composition Nos. 29 to 33 for appli by the method described in Working example 4 are also cation to the mucosa comprising the components described shown in Table 8. in the following Table 7 were prepared. For each pharma ceutical preparation, OSmotic pressure was measured using TABLE 8 the Micro-Osmometer Model 3MO from Advance Instru residual ments, Inc. The result is shown in Table 7. Bioavailability ratio in Compo- Osmotic nasal (B.A.) of the composition Nos. 29 to 33 determined by the sition pressure cavity B.A. method described in Working example 1 is also shown in No. Composition (mCsm) (%) (%) Table 7. 120 minutes after this, blood was drawn from the rabbits, the nasal cavity was washed with 500 ml of 4 mM 34 Fluorescein: 0.1% ww. 5 23 63 Crystalline cellulose NaOH solution in water, and then the concentration of carmellose sodium: 1.7% ww. fluorescein in the wash solution was determined by HPLC. Polysorbate 80: 0.1% w/w The amount of fluorescein in the wash Solution relative to Benzalkonium chloride: 0.03% w/w the amount given was calculated as a residual ratio in the US 2005/0181054A1 Aug. 18, 2005

greater than those obtained with the conventional composi TABLE 8-continued tions can be obtained even at Smaller doses or lower admin istration frequencies than the conventional methods. This residual can lead to reduction in Side effects. ratio in Compo- Osmotic nasal 0058. Thus, the present invention extremely useful in sition pressure cavity B.A. terms of therapeutic and economic effects for drug therapies No. Composition (mosm) (%) (%) that employ application to the mucosa. 35 Fluorescein: 0.1% wiw 3O 15 47 Crystalline cellulose carmellose sodium: 1.7% wiw 1. An acqueous pharmaceutical nasal composition for Polysorbate 80: 0.1% w/w application to the mucosa, comprising one or more water Benzalkonium chloride: 0.03% ww. insoluble and/or low water Soluble Substance, and one or Sodium chloride: 0.08% wiw 36 Fluorescein: 0.1% wiw 72 5 16 more medicament, and having an osmotic preSSure of leSS Crystalline cellulose than 290 mOsm. carmellose sodium: 1.7% wiw 2. (canceled) Polysorbate 80: 0.1% w/w 3. An acqueous pharmaceutical nasal composition for Benzalkonium chloride: 0.03% ww. Sodium chloride: 0.2% wiw application to the mucosa, comprising one or more hemo 37 Fluorescein: 0.1% w/w 128 4 13 Static agent, one or more water-insoluble and/or low water Crystalline cellulose Soluble Substance, and one or more medicament, and having carmellose sodium: 1.7% wiw an osmotic pressure of less than 290 mOsm. Polysorbate 80: 0.1% w/w Benzalkonium chloride: 0.03% ww. 4. (canceled) Sodium chloride: 0.4% wiw 5. The pharmaceutical composition for application to the mucosa according to claim 1 or 3, wherein Said OSmotic pressure 90 mOsm or less. 0.055 The residual ratio in the nasal cavity and retentivity 6. (canceled) in the nasal mucosa of the model drug fluorescein are higher 7. (canceled) by 2 to 3-fold in the Examples of the present invention 8. The pharmaceutical composition for application to the (composition Nos. 29 to 33) containing a hemostatic agent mucosa according to claim 1, further comprising an OSmotic (carbazochrome or tranexamic acid) than the in the Com preSSure-controlling agent. parative examples (composition Nos. 34 to 37) containing 9. The pharmaceutical composition for application to the no hemoStatic agent. In particular, when OSmotic pressure is mucosa according to claim 8, wherein Said OSmotic pres as low as 5 mOsm (composition No. 29) or 7 mosm Sure-controlling agent is a Salt. (composition No. 33), residual ratio in the nasal cavity is 10. The pharmaceutical composition for application to the very high at about 50%. The result indicates that a drug, that mucosa according to claim 8, wherein Said OSmotic pres permeates into the blood after a single administration of the Sure-controlling agent is Sodium chloride. drug, Stays at the mucosa without permeating into the blood 11. The pharmaceutical composition for application to the when coadministered with a hemostatic agent, and thereby mucosa according to claim 8, wherein Said OSmotic-pressure the usefulness of the present invention has been shown for controlling agent is a water-Soluble Sugar. the drugs of which efficacy depends on the amount of the 12. The pharmaceutical composition for application to the drug and on the time of retention at the local mucosa which mucosa according to claim 8, wherein Said OSmotic pres may lead to side effects. Furthermore, it has been shown that Sure-controlling agent is glucose. the amount remaining in the mucosa is greater for the 13. The pharmaceutical composition for application to the pharmaceutical preparations having low osmotic pressure mucosa according to claim 1, wherein Said water-insoluble for which the amount permeated to the blood is greater, and and/or low water Soluble Substance is a cellulose. therefore the usefulness of the present invention becomes 14. The pharmaceutical composition for application to the even greater when the pharmaceutical preparation has a low mucosa according to claim 13, wherein Said cellulose is oSmotic pressure. crystalline cellulose. 15. The pharmaceutical composition for application to the INDUSTRIAL APPLICABILITY mucosa according to claim 1 or 3, wherein Said one or more 0056 Thus, the first aspect of the present invention water-insoluble and/or low water Soluble Substance is provides a composition for application to the mucosa which present as Solid particles in an aqueous medium. has efficient and high permeability of the drug through the 16. The pharmaceutical composition for application to the mucosa to the blood. By using Such a composition of the mucosa according to claim 1 or, wherein Said one or more present invention for application to the mucosa, effects equal water-insoluble and/or low water Soluble Substance is dis to or greater than those obtained with the conventional persed as Solid particles in an aqueous medium. compositions can be obtained even at Smaller doses or 17. The pharmaceutical composition for application to the Smaller administration frequencies than the conventional mucosa according to claim 1 or 3 further comprising a methods. This can lead to reduction in Side effects. water-Soluble polymer Substance. 18. The pharmaceutical composition for application to the 0057 The second aspect of the present invention pro mucosa according to claim 17, wherein Said water-Soluble vides a composition for application to the mucosa which has polymer is one or more Selected from the group consisting efficient and high permeability to the blood and retentivity at of alginic acid, polyethylene glycol, glycerin, polyoxyeth the mucosa. By using Such a composition of the present ylene polyoxypropylene glycol, propylene glycol, pectin, invention for application to the mucosa, effects equal to or low methoxyl pectin, guar gum, gum Arabic, carrageenan, US 2005/0181054A1 Aug. 18, 2005 methyl cellulose, carboxymethyl celleulose Sodium, Xanthan 26. The pharmaceutical composition for application to the gum, hydroxypropyl cellulose, and hydroxypropyl methyl mucosa according to any of claims 1 or 3, wherein Said cellulose. medicament is a lipoSoluble medicament. 19. The pharmaceutical composition for application to the 27. The pharmaceutical composition for application to the mucosa according to claim 17, wherein Said water-Soluble mucosa according to claim 1 or 3, wherein Said mucosa is polymer is carboxymethyl cellulose Sodium. nasal mucosa. 20. The pharmaceutical composition for application to the 28. The pharmaceutical composition for application to the mucosa according to claim 17 wherein Said water-Soluble mucosa according to claim 3, wherein Said hemostatic agent polymer is Xanthan gum. is one or more Selected from the group consisting of tran 21. The pharmaceutical composition for application to the examic acid, epsilon aminocaproic acid, carbazochrome, mucosa according to claim 17, wherein Said water-Soluble carbazochrome Sulfonate, carbazochrome Sodium Sulfonate, polymer is hydroxypropyl methyl cellulose. phytonadione, etamsylate, monoethanol amine oleate, 22. The pharmaceutical composition for application to the thrombin, hemocoaglase, and adrenochrome monoami mucosa according to claim 17, wherein the combination of noguanidine mesilate. Said water-insoluble Substance and water Soluble polymer is 29. The pharmaceutical composition for application to the crystalline cellulose carmellose Sodium. mucosa according to claim 3, wherein the agent other than 23. The pharmaceutical composition for application to the Said hemostatic agent is one or more Selected from the group mucosa according to claim 1 or 3, further comprising a consisting of an antiallergic agent, an antihistamic agent, an Surfactant. anticholinergic agent, a Steroid, a vaccine, and a Substance 24. The pharmaceutical composition for application to the for gene therapy, and the mucosa is nasal mucosa. mucosa according to claim 23, wherein Said Surfactant is 30. The pharmaceutical composition for application to polysorbate 80. nasal mucosa according to claim 29, wherein the agent other 25. The pharmaceutical composition for application to the than Said hemostatic agent is a Steroid. mucosa according to any of claims 1 or 3, wherein Said medicament is a water-Soluble medicament. k k k k k