According to the present invention, a powdery preparation for nasal administration comprising a physiologically active substance, a non-water-absorbing and hardly water-soluble powder(s) and one or two selected from the group consisting of a mucolytic agent and a nonionic surfactant is provided.

Description of the Invention

The present invention is to provide a powdery preparation for nasal administration which comprises a physiologically active substance, a non-water-absorbing and hardly water-soluble powder(s), and one or two selected from the group consisting of a mucolytic agent(s) and a nonionic surfactant(s), and by the nasal administration, a sufficient concentration in blood stream for the activity of the physiologically active substance in a living body can be accomplished.

The present inventors have found that a non-water-absorbing and hardly water-soluble powder(s) and at least one selected from the group consisting of a mucolytic agent(s) and a nonionic surfactant(s) are added to the physiologically active substance, and the resulting product is administered nasally, then, the nasal absorption of the physiologically active substance can be markedly improved whereby the present invention has been accomplished.

That is, the present invention relates to a powdery preparation for nasal administration which comprises a physiologically active substance, a non-water-absorbing and hardly water-soluble powder(s), and one or two selected from a mucolytic agent(s) and a nonionic surfactant(s).

When the powdery preparation for nasal administration of the present invention is sprayed/inhaled into nasal cavity, due to the presence of the non-water-absorbing and hardly water-soluble powder(s), the physiologically active substance and the mucolytic agent and/or the nonionic surfactant are attached to mucous membrane of the nasal cavity and retained, and yet the non-water-absorbing and hardly water-soluble powder(s) does/do not absorb mucus of the nasal mucous membrane, so that the physiologically active substance and the mucolytic agent- and/or the nonionic surfactant are dissolved in a minute amount of the mucus, whereby the physiologically active substance and the mucolytic agent- and/or the nonionic surfactant cause locally high concentration solution. In such a state, by utilizing concentration gradient of the physiologically active substance, and according to the action of the mucolytic agent- and/or the nonionic surfactant dissolved at a high concentration, absorption property itself through the nasal mucous membrane is locally improved and the physiologically active substance can reach from the nasal mucous membrane the blood vessel system existing under the membrane with good efficiency, whereby nasal absorption of the physiologically active substance can be promoted.

Also, a non-water-absorbing and hardly water-soluble powder(s) does/do not itself absorb a medicine dissolved in the nasal cavity, so that an availability of the medicine for absorption is not lowered.

And yet, the powdery preparation for nasal administration of the present invention acts on the nasal mucous membrane locally and scatteringly, so that it does not act on the whole nasal mucous membrane as in the liquid preparation for nasal administration, whereby it causes less adverse effects on the nasal mucous membrane.

BEST MODE FOR CARRYING OUT THE INVENTION

In the non-water-absorbing and hardly water-soluble powder(s) to be used for the powdery preparation for nasal administration of the present invention, as a non-water-absorbing and hardly water-soluble substance, there may be mentioned a substance preferably having a water absorption rate of 5 mm/min or less, and a solubility in water (25.degree. C., hereinafter the same) of 100 mg/L or less, more preferably a substance having a water absorption rate of 1 mm/min or less, and a solubility in water of 50 mg/L or less, most preferably a substance having a water absorption rate of 0.5 mm/min or less, and a solubility in water of 20 mg/L or less.

The water absorption rate means a value in which, according to the method described in summary collection of 16th Symposium on Particulate Preparations and Designs (1999), pp. 163 to 167, powder is filled in a glass tube having an inner diameter of 2.1 cm, while the glass tube is maintained at a vertical state and a bottom end thereof is dipped in pure water, a distance from the bottom end of the glass tube to the upper end of water absorbed upward from the bottom end of the glass tube is measured.

Also, the powdery preparation for nasal administration of the present invention is to be administered by spraying into nasal cavity using a gas, so that it is in a powdery form as a whole, preferably containing a solvent such as water, etc. as little as possible.

Specific examples of the non-water-absorbing and hardly water-soluble substances may include various kinds of materials such as non-water-absorbing and hardly water-soluble cellulose derivatives (for example, ethyl cellulose, cellulose acetate, nitro cellulose, cellulose triacetate, cellulose acetate phthalate, hydroxypropyl-methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, etc.), non-water-absorbing and hardly water-soluble higher fatty acid and its ester or salt (hardened oil, hydrogenated soybean oil, carnauba wax, bleached beeswax, sucrose fatty acid ester, stearic acid, a salt of stearic acid, etc.), non-water-absorbing and hardly water-soluble biodegradable polymers (polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, etc.), non-water-absorbing and hardly water-soluble synthetic polymers (polyethylene terephthalate, polyethylene, polyvinyl chloride, etc.), non-water-absorbing and hardly water-soluble polyvalent metal salt (calcium carbonate, barium sulfate, hydroxy-apatite, etc.), non-water-absorbing and hardly water-soluble metal oxides (talc, silicon dioxide, titanium oxide, etc.), and the non-water-absorbing and hardly water-soluble cellulose derivatives are preferably used, in particular, ethyl cellulose and/or cellulose acetate is/are preferably used, and from the view point of non-water-absorbing property, ethyl cellulose and/or cellulose acetate of a high substitution degree is/are particularly preferred.

Here, the high substitution degree means that among the hydroxyl groups of L-glucose constituting the cellulose molecule, hydrogen atoms of the hydroxyl groups which are not used for bonds between L-glucoses are substituted by a substituent(s) on an average of 70% or more, preferably on an average of 80% or more, particularly preferably on an average of 85% or more.

Also, as the non-water-absorbing and hardly water-soluble powder(s), it is preferred that mucus of the nasal mucous membrane, etc. are hardly attached to the surface of the powder particles, so that the powder particles having no cavity on their surface are preferred. Though an average diameter of the powder particles may vary depending on the kinds of the physiologically active substance, and the mucolytic agent- and/or the nonionic surfactant to be contained in the powdery preparation for nasal administration, form of use, etc., it may be usually in the range of 5 to 200 .mu.m, preferably in the range of 20 to 150 .mu.m, more preferably in the range of 30 to 120 .mu.m, most preferably in the range of 40 to 100 .mu.m.

Though the non-water-absorbing and hardly water-soluble powder(s) may be those which are commercially available powder product(s) as such, the non-water-absorbing and hardly water-soluble solid substance may be processed or the commercially available powder product may be further processed to prepare a desired particle diameter and shape and the processed product is used.

Also, the non-water-absorbing and hardly water-soluble powder(s) may be one non-water-absorbing and hardly water-soluble powder, or a plural number of non-water-absorbing and hardly water-soluble powders.

As a method of processing the non-water-absorbing and hardly water-soluble substance, any conventional fine particle-formation method can be optionally used and there may be employed, for example, a physically pulverizing method such as jet-mill pulverization, hummer mill pulverization, rotary type ball mill pulverization, vibration ball mill pulverization, beads mill pulverization, shaker mill pulverization, rod mill pulverization, tube mill pulverization, etc.; a crystallization method in which the non-water-absorbing and hardly water-soluble substance is once dissolved in a solvent, then crystallized by changing temperature, changing a composition of the solvents, etc., and recovering by the method of centrifugation or filtration, etc.; a spray drying method in which the non-water-absorbing and hardly water-soluble substance is once dissolved in a solvent, and spraying the solution into a drying room of a spray dryer using a spray nozzle to volatilize the solvent in the sprayed solution within a short period of time, and the like.

Also, the non-water-absorbing and hardly water-soluble powder(s) may be subjected to a treatment so that the particle diameter falls within a predetermined range by suppressing the fluctuation of the particle diameter by means of the method such as sieving, fractioning due to sedimentation by gravity, fractioning by centrifugation, fractioning by inertia force due to gas flow, etc.

One or two selected from the group consisting of a mucolytic agent(s) and a nonionic surfactant(s) mean either of (a) a mucolytic agent(s), (b) a nonionic surfactant(s) or (c) a mucolytic agent(s) and a nonionic surfactant(s), and in either of (a) to (c), the mucolytic agent(s), and the nonionic surfactant(s) may comprise only one component or may comprise a plural number of components.

Though as the mucolytic agent- and/or the nonionic surfactant, any material which can promote absorption of the physiologically active substance to the mucous membrane may be used, a material which has less adverse effects on the nasal mucous membrane such as stimulating property, etc., and which can markedly improve absorption from the nasal mucous membrane in a small amount may be preferably used. The mucolytic agent alone, or a combination of the mucolytic agent and the nonionic surfactant are preferably used, and in view of stimulating property to the nasal mucous membrane, the mucolytic agent is most preferably used.

As preferred examples of the mucolytic agents, there may be mentioned cysteine derivatives, and active SH group-containing alcohols. As the cysteine derivatives, there may be mentioned, for example, N-(C.sub.2-5 alkanoyl)cysteine such as N-acetylcysteine, etc., S-(C.sub.1-4 alkyl)cysteine such as S-methylcysteine, S-ethylcysteine, etc., and S-(C.sub.2-5 carboxyalkyl)cysteine such as S-carboxymethylcysteine, etc.

Also, as the cysteine derivatives, cysteine-containing peptides are included, and there may be mentioned, for example, glutathiones which are a kind of tripeptides. Examples of the glutathiones may include, in addition to glutathione, glutathione esters such as a glutathione C.sub.1-8 alkyl ester (see U.S. Pat. No. 4,784,685), etc.

As the cysteine of these cysteine derivatives, DL-form, L-form and D-form are included, and in particular, L-cysteine is preferred.

As the active SH group-containing alcohol, there may be mentioned a C.sub.3-6 active SH group-containing alcohol, more specifically 1,4-dithiothreitol.

As the nonionic surfactant, a nonionic surfactant which has low protein-denaturing ability and has low membrane solubilizing property is preferred.

As such a nonionic surfactant may be mentioned a polyoxyethylene-C.sub.10-14 alkyl ether, a polyoxyethylene-(C.sub.6-10 alkyl-phenyl) ether, a C.sub.6-10 alkyl-glucose ether and an N-(C.sub.6-10 alkyl)carbamoyl-C.sub.1-4 alkyl-glucose ether, etc.

As the polyoxyethylene-C.sub.10-14 alkyl ether and the polyoxyethylene-(C.sub.6-10 alkyl-phenyl) ether, those having a polyoxyethylene portion in the range of 65 to 90% by weight based on the whole molecule are preferred, and there may be specifically mentioned polyoxyethylene-lauryl ether having an average molecular weight of 560 to 1300 [for example, BL-9 available from Nikkol: polyoxyethylene(9) lauryl ether; BL-25: polyoxyethylene(25) lauryl ether]; polyoxy-ethylene-octylphenyl ether having an average molecular weight of 600 to 800, particularly polyoxyethylene-tert-octylphenyl ether having an average molecular weight of 600 to 800 [for example, Triton X-100 available from Nacalai: polyoxyethylene (9-10) p-tert-octylphenyl ether, Triton X-102: polyoxyethylene (12-13) p-tert-octylphenyl ether]; polyoxyethylene-nonylphenyl ether having an average molecular weight of 600 to 700, particularly polyoxyethylene-n-nonylphenyl ether having an average molecular weight of 600 to 700 [for example, NP-10 available from Nikkol: polyoxyethylene (10) p-n-nonylphenyl ether].

As the C.sub.6-10 alkyl-glucose ether and N-(C.sub.6-10 alkyl)-carbamoyl-C.sub.1-4 alkyl-glucose ether, those having a glucose portion in the range of 50 to 65% by weight based on the whole molecule is preferred, and there may be specifically mentioned 1-O-octyl-.beta.-D-glucopyranoside, particularly 1-O-n-octyl-.beta.-D-glucopyranoside; 6-O-(N-heptylcarbamoyl)methyl-.alpha.-D-glucopyranoside, particularly 6-O-(N-n-heptylcarbamoyl)methyl-.alpha.-D-glucopyranoside.

Moreover, as the nonionic surfactant, a nonionic surfactant whose concentration in an aqueous solution at which 50% of red blood cells are hemolysed is 1% by weight or more, particularly 5% by weight or more, is preferred since it causes less adverse effects on the nasal mucous membrane.

Here, the concentration of the nonionic surfactant in an aqueous solution at which 50% of red blood cells are hemolysed can be estimated by the following method. Red blood cells are added in a ratio of 0.2% by weight to physiological salines containing the nonionic surfactant which had been adjusted to various concentrations, the mixtures are allowed to stand at 37.degree. C. for 10 minutes, and the absorbance (540 nm) of hemoglobin in the supernatant is measured. On the other hand, when red blood cells are added to purified water with the same ratio and are completely hemolysed, the absorbance is considered to be 100%. Hemolysis ratios of the red blood cells at the respective concentrations of the nonionic surfactant are calculated, whereby the concentration of the nonionic surfactant at which the hemolysis ratio becomes 50% is estimated by an interpolation method.

As the physiologically active substance, it is not particularly limited so long as it is a medicine having less stimulation to nasal mucous membrane, but a physiologically active substance which shows medicinal effect with a small dose is preferred since a large amount of medicine cannot be administered by nasal administration.

Also, when the powdery preparation for nasal administration of the present invention is applied to a physiologically active substance which can be hardly absorbed by nasal route, improvement in nasal absorption of the physiologically active substance becomes remarkable, so that a hydrophilic hardly-absorbable substance is preferably used as the physiologically active substance.

Incidentally, the term hardly-absorbable means that when an aqueous solution of a physiologically active substance is nasally administered to human by spraying, 5% or less of the sprayed amount is absorbed.

As such a physiologically active substance may be mentioned those used as antibiotics, blood-forming agents, infectious diseases treating agents, anti-dementia, antiviral agents, anti-tumor agent, antipyretic agents, analgesic, anti-inflammatory, antiulcer, antiallergic agent, antipsychotic medicine, cardiotonic agent, cardiac dysrhythmia treating agent, vasodilators, hypotensive agent, diabetes treating agent, anticoagulant, cholesterol lowering agent, osteoporosis treating agent, hormone agent, vaccine, etc.

As these substances, in addition to the low molecular weight physiologically active substance, peptidic physiologically active substance, polysaccharide physiologically active substance, etc. are included, and the powdery preparation for nasal administration of the present invention shows marked effects when it is applied to the peptidic physiologically active substance and/or polysaccharide physiologically active substance, and it is particularly preferably applied to the peptidic physiologically active substance.

As the peptidic physiologically active substances, there may be mentioned an antagonist, agonist or soluble receptors thereof and derivatives thereof, and with regard to a substance having sugar chain, those which have a different structure in chain are also included. If necessary, these substances may be modified by a synthetic polymer such as polyethylene glycol, etc., or a natural polymer such as hyaluronic acid, etc., or else, may be modified by an optional sugar such as galactose, mannose, etc., or may be modified by a sugar chain or non-peptidic compound. Also, they may be a substance which provides a lipid-soluble property to the peptidic physiologically active substance, such as phospholipids, fatty acids, etc. These peptidic physiologically active substances have a molecular weight of 200 to 200000, preferably have a molecular weight of 200 to 50000, more preferably have a molecular weight of 200 to 25000, and most preferably have a molecular weight of 200 to 10000.

Preferred peptidic physiologically active substances may include cytokine, peptide hormone, growth factor, a factor which acts on cardiac vessel system, a factor which acts on central and peripheral nerve systems, etc., and specific examples are as mentioned below.

As the cytokine, there may be mentioned interferons (for example, interferon-.alpha., -.beta., -.gamma.), interleukins (for example, interleukin-1 to 11), tumor necrosis factor (for example, TNF-.alpha., -.beta.), leukemia inhibitory factor (LIF), blood-forming factor [for example, erythropoietin, thrombopoietin, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF)], etc.

As the peptide hormone, there may be mentioned insulin, growth hormone, gonadotropic hormone, melanocyto-stimulating hormone, luteotropic hormone, leuteinizing hormone, leuteinizing hormone-releasing hormone (LH-RH) and its derivatives (goserelin, buserelin, leuprorelin), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH) and its derivatives (taltirelin), calcitonin, etc.

As the growth factor, there may be mentioned nerve growth factors (for example, NGF, NGF-2/NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), hepatocytes growth factor (HGF), etc.

As the factor which acts on cardiac vessel system, there may be mentioned endothelin, endothelin inhibitor, endothelin antagonist, endothelin formation enzyme inhibitor, desmopressin, renin, angiotensin I to III, atrial natriumuretic peptide (ANP), etc.

As the factor which acts on central and peripheral nerve systems, there may be mentioned enkephalin, endorphin, dynorphin, neoendorphin, etc.

In these peptidic physiologically active substances, a soluble receptor of the polypeptide is included in the concept. In these peptidic physiologically active substance, those which are chemically modified by a polymer such as polyethylene glycol, or by a natural polymer such as chondroitin, polysaccharides, or by a non-peptidic substance may be respectively included. The non-peptidic substance herein mentioned may be a ligand to a receptor, or an antigen to an antibody. Moreover, the above-mentioned peptidic physiologically active substance may include those in which a plural number of peptides are bound by a chemical method or a genetic recombinant technique.

As the physiologically active polysaccharide substance, there may be mentioned a low molecular weight heparin, a heparin-like substance, etc.

Also, in the powdery preparation for nasal administration of the present invention, the physiologically active substance can be taken into a body from a blood vessel system under the mucous membrane of the nasal cavity immediately after administration, and a time interval from the administration to the generation of the medicinal effects is short. Therefore, it can also be suitably employed for a physiologically active substance with which a short onset time (a time interval between the administration of a medicine and the generation of the medicinal effects) produces therapeutic advantages.

Thus, the powdery preparation for nasal administration of the present invention can be suitably applied to a physiologically active substance, for example, narcotic analgesic (for example, alkaloid type narcotic), migraine treating agent [for example, 5-hydroxytryptamine (HT) 1 receptor agonist, neurokinin (NK) 1 receptor antagonist, iGluR5 receptor antagonist, .beta. adrenergic blocking agent], preventive for travel sickness [for example, central anti-cholinergic agent, anti-histaminic agent, 5-hydroxytryptamine (HT) 1 receptor agonist], antiemetic [for example, neurokinin (NK) 1 receptor antagonist, 5-hydroxytryptamine (HT) 3 receptor antagonist], sexual function improving agent [for example, phosphodiesterase (PDE) 5 inhibitor, .alpha.-melanin cell stimulating hormone (MSH) analogue, dopamine D2 receptor agonist, non-steroidal androgen receptor modulator], diabetes treating agent (for example, insulin), first aid medicine at the time of low blood sugar (for example, glucagon), etc.

Though a formulation ratio of the powdery preparation for nasal administration of the present invention may vary depending on various factors such as a kind of the physiologically active substance, kinds of the mucolytic agent- and/or the nonionic surfactant, used form thereof, etc., the physiologically active substance may be used in an amount of 0.1 to 80% by weight based on the whole preparation, the non-water-absorbing and hardly water-soluble powder(s) may be used in the amount of 15 to 99.4% by weight based on the same, and the mucolytic agent- and/or the nonionic surfactant may be used in the amount of 0.5 to 5% by weight based on the same.

A (spraying/inhalation) dose of the powdery preparation for nasal administration of the present invention is generally 3 to 50 mg/ time, preferably 5 to 20 mg/each time. Even in such a small amount of (spraying/inhalation) dose, the powdery preparation for nasal administration of the present invention can give an excellent nasal absorption promoting effect by using a small amount of the non-water-absorbing and hardly water-soluble powder(s), and the mucolytic agent- and/or the nonionic surfactant. Thus, a physiologically active substance which is required to be absorbed in a living body at a relatively large dose (1 mg/person/time or so) for generating a physiological activity can be nasally absorbed.

Also, the non-water-absorbing and hardly water-soluble powder(s) does/do not itself show any physiological activity at the nasal mucous membrane, so that when a physiologically active substance which shows sufficient physiological activity with a small (spraying/inhalation) dose is to be nasally administered, an amount of the non-water-absorbing and hardly water-soluble powder(s) may be intentionally increased to control fluctuation of a dose of the physiologically active substance to be administered per one spraying/inhalation.

The physiologically active substance, and the mucolytic agent- and/or the nonionic surfactant to be contained in the powdery preparation for nasal administration of the present invention can be mixed in a powder state with the non-water-absorbing and hardly water-soluble powder(s) to give the powdery preparation for nasal administration of the present invention, and the preparation can be used as such. However, in this case, it is preferred to regulate a density and particle diameter of the powder particles in order to prevent the respective components from separation at the time of administration into nasal cavity by spraying/inhalation.

For example, it is preferred that densities calculated from the outer shape of the physiologically active substance, and the mucolytic agent- and/or the nonionic surfactant are in the range of 0.7 to 1.5-fold to the density calculated from the outer shape of the non-water-absorbing and hardly water-soluble powder(s), preferably in the range of 0.8 to 1.3-fold, and the particle diameters of the powder of the physiologically active substance, and the mucolytic agent- and/or the nonionic surfactant are in the range of 0.3 to 1.2-fold to the particle diameter of the non-water-absorbing and hardly water-soluble powder(s), preferably in the range of 0.4 to 1.1-fold.

Preparation of powder and designing of the particle diameter of the physiologically active substance, and the mucolytic agent- and/or the nonionic surfactant can be also carried out by using the means useful for forming the non-water-absorbing and hardly water-soluble powder(s). When the physiologically active substance is a peptidic substance, preparation of powder can be carried out with maintaining physiological activity thereof by lyophilizing an aqueous mixed solution of the peptidic physiologically active substance and polyethylene glycol, and adding an organic solvent which does not dissolve the polypeptide but dissolves polyethylene glycol to the resulting solid material (Japanese Unexamined Patent Publication No. Hei. 11-302156), or by adding an organic solvent which does not dissolve a peptide and is water-miscible to a frozen product of an aqueous mixed solution containing a peptidic physiologically active substance and a phase-separation inducing agent (WO 02/30449), and recovering powder of the peptidic physiologically active substance from the formed suspension.

Also, the physiologically active substance and/or the mucolytic agent- and/or the nonionic surfactant can be used by fixing on the surface of the non-water-absorbing and hardly water-soluble powder(s) to prepare a powdery preparation for nasal administration of the present invention, and can be used in this form.

For example, the physiologically active substance and/or the mucolytic agent- and/or the nonionic surfactant is/are dissolved in an aqueous solvent (for example, water, aqueous ethanol, aqueous acetone, aqueous methanol, aqueous acetonitrile), the solution is added to the non-water-absorbing and hardly water-soluble powder(s), the mixture is dried by the method such as drying under reduced pressure, drying at normal temperature, lyophilization, etc., and if necessary, the resulting product is sieved, to fix the physiologically active substance and/or the mucolytic agent- and/or the nonionic surfactant on the surface of the non-water-absorbing and hardly water-soluble powder(s).

Alternatively, an aqueous solvent (for example, water, aqueous ethanol, aqueous acetone, aqueous methanol, aqueous acetonitrile) is added to a mixture of the powder of a non-water-absorbing and hardly water-soluble substance, the physiologically active substance and/or the mucolytic agent- and/or the nonionic surfactant. The resulting mixture is kneaded, dried, again pulverized and sieved to have a desired particle diameter, whereby the physiologically active substance and/or the mucolytic agent- and/or the nonionic surfactant is/are fixed on the non-water-absorbing and hardly water-soluble powder(s) to prepare the powdery preparation for nasal administration of the present invention.

Incidentally, the powdery preparation for nasal administration of the present invention is administered in a dry state, and no solvent is added to the preparation. However, when the other powder solid components do not exert any adverse effects on the nasal mucous membrane, and do not inhibit nasal absorption, other additional components may be added in a small amount to increase the total amount of the preparation so that an administration (spraying/inhalation) dose of the physiologically active substance per one time becomes constant and the stability of the physiologically active substance is improved.

As such a component to be added in a small amount may be mentioned, for example, a lubricant [talc, stearic acid and its salt (sodium salt, calcium salt), Carplex, etc.], a binder (starch, dextrin, etc.), a pH adjusting agent (citric acid, glycine, etc.), a preserver (ascorbic acid, etc.), an antiseptic agent (paraoxybenzoates, benzalkonium chloride, phenol, chlorobutanol, etc.), odor masking agent (menthol, citrus flavoring, etc.).

The powdery preparation for nasal administration of the present invention can be administered into nasal cavity by spraying, and a predetermined amount of the powdery preparation for nasal administration can be sprayed into the nasal cavity with air or a gas (air, nitrogen gas, argon gas, carbon dioxide gas, substitute flon gas, etc.) which does not cause any adverse effect to human body.

As a method of spraying, any conventionally used devices for nasal administration can be used, and for example, there may be considered a method in which the powdery preparation for nasal administration of the present invention is filled in a device for pressure administration with a predetermined dose spraying system, and is sprayed into nasal cavity with each predetermined dose, a method in which the powdery preparation for nasal administration of the present invention is filled in a capsule, etc. in a predetermined amount, and when necessity arises, the capsule, etc. is mounted as such on the device for pressure administration and is made by perforation, etc. in a state wherein the powdery preparation for nasal administration can be sprayed, and the powdery preparation is sprayed with air or a gas which does not exert any adverse effects on the human body into nasal cavity, and the like.

Further, a spraying speed of air or a gas which does not exert any adverse effects on the human body at the time of spraying is preferably controlled so that almost all the constitutional components of the powdery preparation for nasal administration reaches mucous membranes of concha nasalis superior, concha nasalis media, concha nasalis inferior which have the most efficient absorption ratio among the mucous membranes of the nasal cavity, and in addition to the spraying speed of the gas, the powdery preparation for nasal administration is sprayed synchronized with the inhalation of air through the nose of the patient to be nasally administered to give more efficient delivery thereof to the absorption site.

Moreover, the powdery preparation for nasal administration of the present invention can be nasally absorbed only by inhalation without spraying it into the nasal cavity. The powdery preparation for nasal administration of the present invention is filled in a blister pack, etc. with a predetermined dose, and when necessity arises, it is mounted as such on a inhalation device, and is converted to a state that the powdery preparation for nasal administration can be taken out by pressure, etc., and the preparation is subjected to inhalation whereby the powdery preparation for nasal administration can reach the nasal cavity.

Concomitantly, the powdery preparation for nasal administration of the present invention can be used for administration through lung, administration through pharynx mucous membrane, etc., or may be administered to a patient by using a conventionally used administration device (spraying/inhalation device for administration through lung, spraying device for administration through pharynx mucous membrane, etc.) according to the administration method.
 

Claim 1 of 17 Claims

1. A powdery preparation for nasal administration which comprises a physiologically active substance, a non-water-absorbing and hardly water-soluble cellulose derivative powder(s) and a mucolytic cysteine derivative(s) or a combination of a mucolytic cysteine derivative(s) and a nonionic surfactant(s).

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