JPH11322582A - Nasal mucosal sticking and retention type carrier for pernasal absorption - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a carrier for pernasal absorption, especially a nasal mucosal sticking and retention type carrier for pernasal absorption capable of uniformly dispersing and sticking a drug and providing ultrahigh in vivo absorbability in order to absorb the drug through a mucosal membrane in the nasal cavity. SOLUTION: This carrier is the one for a drug for pernasal absorption, has sticking and retention properties for the mucosal membrane in the nasal cavity and is capable of widely distributing into the interior of the depth of the nasal cavity without migrating to the lungs when spray inhaling the drug into the nostrils and substantially has a mass and a particle diameter within the range without making the drug fall by its own weight after sticking to the nasal mucosal membrane. Many voids are formed on the surface of a primarily granulated microcrystal having many voids on the surface or on the surface of a granulated crystal prepared by secondarily aggregating and granulating the primarily granulated microcrystal to provide 0.1-0.4 m<2> /g surface area and the crystal particle diameter is further within the range of 15-300 μm when the specific gravity thereof is about 0.5-1.0.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a carrier (carrier / base) for nasal absorption, and more particularly, to spray a physiologically active substance into a nostril in order to absorb the physiologically active substance through a nasal mucosa. When inhaling, the drug is evenly dispersed
The present invention relates to a carrier of the nasal mucosa attachment / retention type for nasal absorption to be attached.

[0002]

BACKGROUND OF THE INVENTION Physiologically active peptides such as calcitonin, insulin and the like are high molecular compounds that are used in various medical applications in medical practice because of their specific physiological activities. However, these bioactive peptides are degraded by proteases in the gastrointestinal tract or have high molecular weight and high polarity, so they are hardly absorbed from the intestinal mucosa as they are, and therefore, oral administration is difficult. Is limited to injection administration. By the way, such an administration method gives pain at the injection site to the patient, which is not preferable, and when administered at regular intervals, causes significant pain to the patient. Therefore, it is desired to develop a non-injectable administration method which is simple and can be self-administered for safe and frequent administration. From such a viewpoint, for example, for calcitonin, an aerosol for nasal inhalation of a powder suspension using a fluorocarbon as a propellant has been developed, and furthermore, a nasal aerosol as a nasal administration method has been developed. An internal spray has also been developed.

[0003] On the other hand, a large number of synthetic drugs for various therapeutic purposes have been developed so far and widely used in medical practice. However, many of these synthetic drugs have only been developed as oral or parenteral administration preparations, especially in the case of drugs that cannot be administered orally, by intravenous or intramuscular injection. And other methods have been developed. By the way, recently, as one of the drug administration routes, the advantage of the nasal administration method has attracted attention. Particularly in the nasal administration method, a venous plexus has developed in the nasal mucosa lamina propria of the nasal cavity, which is the site of administration, and the drug is absorbed through this nasal mucosa and enters the systemic circulatory system. It is an excellent method for administering a physiologically active peptide, which is a drug that is difficult to administer, or for administering other physiologically active substances. Although various intranasal administration preparations utilizing such advantages have been proposed,
The preparation examples so far are not yet sufficient in terms of drug absorption or local irritation.

[0004]

SUMMARY OF THE INVENTION The present inventor has proposed a method for intranasal administration of a bioactive peptide or other bioactive substance, which has been difficult to administer orally, which has good absorbability in the body and has no irritation. Have been considering the development of
A composition for nasal absorption has been proposed in which these physiologically active substances are dispersed, adhered and bound to several specific carriers. In the course of the study, the present inventor focused on the fact that the intranasal absorption of a physiologically active substance in intranasal administration is proportional to the surface area of a carrier on which the physiologically active substance is dispersed, adhered and bound. . That is, a composition for nasal administration in which a physiologically active substance is dispersed in a carrier, adhered and bound,
At the stage of intranasal administration and contact with the nasal mucosa, the carrier constituting the composition is as fine as possible, which results in higher absorption due to a larger contact area with the nasal mucosa. .

[0005] However, if the particles of the carrier are too fine, it is difficult to spray into the nasal cavity, and even if it can be sprayed, it is inhaled to the lungs through the nostrils, which causes undesirable side effects. On the other hand, if the particle size is too large, the specific surface area is small and sufficient absorption cannot be expected, and the composition adhered to the nasal mucosa drops due to its own weight, and the intended in vivo absorption may be increased. It will not be possible. As a result of examining that point, the present inventor:
Fine crystals having a large number of voids on the surface or by agglomerating the fine crystals to form a large number of voids on the surface of the granulated crystal, having a sufficient surface area for drug adsorption It has been newly discovered that a porous carrier having a specific particle size and having a property of adhering and retaining to the mucous membrane in the nasal cavity is excellent in the adsorptivity of a physiologically active drug and is particularly preferable. It was.

[0006] Accordingly, the present invention provides a drug for uniform absorption and dispersal into a nasal cavity by spraying and inhaling the drug in order to absorb the drug through a carrier for nasal absorption, particularly a mucous membrane in the nasal cavity. It is an object of the present invention to provide a carrier of a nasal mucosa attachment / retention type for nasal absorption which makes it possible to perform the treatment.

[0007]

SUMMARY OF THE INVENTION In order to solve the above-mentioned problems, the present invention provides a drug carrier for nasal absorption, which has adhesion / retention property to a mucous membrane in a nasal cavity and is sprayed into a nostril. When inhaled, it has a mass and particle size that is widely distributed to the inside of the nasal cavity without transferring to the lungs and falls by its own weight after attaching to the nasal mucosa, and has many voids on the surface Primary granulated fine crystals having a large number of voids formed on the surface of the granulated crystals by subjecting them to secondary coagulation granulation to have a surface area of 0.1 to 0.4 m
² / g and a specific gravity of about 0.5 to 1.0
The present invention provides a porous nasal mucosa-adhering / retaining carrier for nasal absorption having a crystal particle diameter in the range of 15 μm to 300 μm in the above case.

[0008] In this case, the first feature of the carrier provided by the present invention is that the carrier itself as a drug carrier has a large number of voids formed on the surface of the carrier itself so that the carrier has a sufficient surface area. It is to have.
Therefore, since many voids (holes) are formed on the surface of the carrier, a physiologically active substance is attached and sealed in the pores (voids), and the surface area of the carrier is increased. In nasal administration, contact with the mucous membrane in the nasal cavity is further promoted, and good in vivo absorbability is obtained.

It has been found that such a carrier preferably has a surface area of 0.1 to 0.4 m ² / g. With such a surface area, as a carrier in which a number of voids are formed, a fine crystal having a number of voids formed on the surface by primary granulation, or by secondary agglomeration of such fine crystals. It may be one in which a number of voids are formed on the surface of the granulated crystal. As the carrier subjected to the secondary aggregation and granulation, for example, voids may be formed on the surface of the granulated crystal by aggregating and re-granulating fine particles having a particle diameter of less than 10 μm such as about 1 to 2 μm. . In addition, the carrier obtained by re-aggregating and granulating the fine particles, after adhering and staying on the nasal mucosa, gradually disintegrates and disperses in the original fine particles, and can increase the sustained-release absorbability. Can be.

[0010] The second characteristic is that the mass and the crystal particle diameter of the carrier itself are widely distributed throughout the nasal cavity without being transferred to the lungs when sprayed and inhaled into the nasal cavity. The carrier has a mass and a particle size within a range not falling due to the specific gravity of the carrier, and specifically, when the specific gravity of the carrier is about 0.5 to 1.0, the crystal particle size is within a range of 15 μm to 300 μm. That is. It has been found that carriers having a mass and a crystal diameter specified in such a range are efficiently and uniformly distributed to the inner part of the nasal cavity and adhere to the nasal mucosa.

Accordingly, the specific preferred embodiment of the carrier of the present invention is a specific carrier having the above-mentioned characteristics, and the specific preferred embodiment is a drug carrier for nasal absorption. It has adhesion and retention properties to the mucous membrane in the nasal cavity, and when sprayed and inhaled into the nostril, it is widely distributed inside the nasal cavity without transferring to the lungs, and within the range where it does not fall due to its own weight after attaching to the nasal mucosa It is a primary granulated fine crystal having a certain mass and particle diameter and having a large number of voids on its surface, and has a surface area of 0.1
０．４0.4 m ² / g and the specific gravity is about 0.5０．５
In the case of 1.0, the crystal particle diameter is 15 μm to 300 μm
m, a porous, nasal mucosa-adhering / retaining carrier for nasal absorption.

Still another preferred embodiment of the present invention is a drug carrier for nasal absorption, which is poorly soluble in water, has a property of adhering to and retaining on mucous membrane in the nasal cavity,
When sprayed and inhaled into the nostrils, it has a mass and particle size that is widely distributed inside the nasal cavity without transferring to the lungs and that does not fall by its own weight after adhering to the nasal mucosa, and a large number on the surface The secondary granulation of the primary granulated fine crystals having voids to form a number of voids on the surface of the granulated crystal, the surface area is 0.1 to 0.4
m is ² / g, and porosity of nasal absorption nasal muco-retentive carrier in crystal grain size in this case a specific gravity of about 0.5 to 1.0 within the range of 15μm~300μm Is provided.

Among them, particularly preferred carriers are those having a crystal grain surface area of 0.1 to 0.4 m ² / g and a specific gravity of about 0.5 to 1.0 when the crystal grain diameter is about 0.5 to 1.0. 15 μm to 180 μm, preferably 15 μm
It is a porous, nasal mucosa-adhering / retaining carrier for nasal absorption in the range of μm to 80 μm.

It has been found that these carriers provided by the present invention more preferably have a pH of the carrier itself in the range of 2.5-12. Furthermore, the carrier of the present invention has such a property that, when administered intranasally, the carrier retains the clearance time to the nasal mucosa due to the surface tension on the nasal mucosa. Furthermore, the carrier of the present invention can be administered nasally in a state of suspension in water, and such a carrier applicable to suspension use in water is also included in the scope of the present invention. But also.

In the definition of the present invention, "substantially having a mass and an average particle diameter within a range not falling by its own weight after adhering to the nasal mucosa" means that the nasal mucosa adhering to nasal mucosa of the present invention is used. -Means that the crystal particle diameter is within the above range at about 90% or more, preferably 95% or more of the stagnant carrier, and more specifically, about 90% or more, preferably 95% of the carrier. In the above, it means that the crystal particle diameter is in the range of 15 μm to 300 μm when the specific gravity of the carrier is about 0.5 to 1.0.

[0016]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As described above, the carrier provided by the present invention is basically a porous nasal mucosa-adhering / retaining carrier having a large number of voids on the carrier surface. As used herein, "having a large number of voids on the surface" means that it has only to be porous, for example, in which countless fine crystals form a lump, thereby forming pores. And a ball-shaped one in which innumerable fibers are intertwined to form holes, or a coral-shaped one having innumerable branches on the surface and having holes formed by the branches.

The substance constituting the carrier provided by the present invention is not particularly limited as long as it has a character as a carrier (carrier) applicable to nasal administration, and various substances can be mentioned. it can. For example, a carrier for nasal absorption which has been clinically used so far, a carrier which is a polyvalent metal compound already proposed by the present inventors (Japanese Patent Application No. 7-66640), and a gastric mucosal tissue Carrier which is a restoration / protection substance (Japanese Patent Application 8-
22959) and carriers such as various ceramic carriers (Japanese Patent Application No. 8-22958) have adhesion / retention properties to the mucous membrane in the nasal cavity as a carrier and migrate to the lungs when sprayed and inhaled into the nostrils. Mass and particle size within a range that does not fall down by its own weight after adhering to the nasal mucosa
That is, when the carrier has a specific gravity of about 0.5 to 1.0, a porous crystalline or powdery nasal mucosa for nasal absorption having a particle size in the range of 15 μm to 300 μm.
Any retention type carrier may be used.

Specific examples of such carriers include celluloses such as crystalline cellulose, α-cellulose, hydroxypropylcellulose, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose and derivatives thereof; hydroxypropyl starch, carboxymethyl starch, crosslinked starch; Polysaccharides such as amylose, amylopectin, pectin and derivatives thereof; gums such as gum arabic, tongarara gum, glucomannan and derivatives thereof; polyvinylpyrrolidone, cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol;
Crosslinked vinyl polymers such as polyhydroxyethyl methacrylate and derivatives thereof; taurine and the like. Furthermore, even finely pulverized products such as rice or soybeans,
Any carrier having the above mass and particle size can be used as the carrier for nasal mucosa attachment / retention of the present invention.

Further, as the carrier which is a polyvalent metal compound, a divalent or higher valent metal compound, specifically, a divalent or higher valent metal compound such as an aluminum compound, a calcium compound, a magnesium compound, a silicon compound, an iron compound, a zinc compound, etc. It is. Specific examples of such aluminum compounds include dried aluminum hydroxide gel, chlorohydroxyaluminum, synthetic aluminum silicate, light aluminum oxide, colloidal hydrous aluminum silicate, aluminum magnesium hydroxide, aluminum hydroxide,
Examples include aluminum hydroxide gel, aluminum sulfate, dihydroxyaluminum acetate, aluminum stearate, natural aluminum silicate, aluminum monostearate, and potassium aluminum sulfate.

Examples of the calcium compounds include apatite, hydroxyapatite, calcium carbonate, disodium calcium edetate, calcium chloride, calcium citrate, calcium glycerophosphate, calcium gluconate, calcium silicate, calcium oxide, calcium hydroxide, calcium hydroxide and calcium stearate. , Tricalcium phosphate, calcium lactate, calcium pantothenate, calcium oleate, calcium palmitate, calcium D-pantothenate, calcium alginate, anhydrous calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium acetate, calcium saccharate, Examples include calcium sulfate, calcium monohydrogen phosphate, calcium para-aminosalicylate, a lime compound in a living body, and the like.

Further, as the magnesium compound, L
-Magnesium aspartate, magnesium chloride, magnesium gluconate, magnesium aluminate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium stearate, magnesium carbonate, magnesium metasilicate aluminate, magnesium sulfate, sodium magnesium silicate And synthetic sodium and magnesium silicates.

Examples of the silicon compound include hydrated silicon dioxide, plasma anhydrous silicic acid, synthetic hydrotalcite, diatomaceous earth, and silicon dioxide. The iron compound includes iron sulfate. The zinc compound includes zinc chloride and stearic acid. Zinc, zinc oxide, zinc sulfate and the like can be mentioned.

Among the above-mentioned polyvalent metal compound carriers, carriers of hydroxyapatite as a calcium compound, calcium carbonate, calcium lactate, magnesium stearate as a magnesium compound, and aluminum hydroxide as an aluminum compound are particularly favorable. It turned out to show. Hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (O
H) ₂ ) is a main component of the minerals of animal bones and teeth. Although it has been used as a surface coating component of artificial bone of ceramic materials for medical use,
The application of a nasal formulation as a carrier has not been previously investigated.

As a carrier similar to the hydroxyapatite, a lime compound in a living body can be used, such as a calcium pyrophosphate crystal (Ca _{2.
P 2 O 7 · 2H 2 O} ), dicalcium phosphate crystals (C
aHPO ₄ · 2H ₂ O), octacalcium phosphate crystals _{(Ca 8 H 2 (PO 4} ) 6 · 5H 2 O), tricalcium phosphate _{(Ca 3 (PO 4) 2} ), calcium oxalate crystals (CaC ₂ O ₄ .H ₂ O) and the like.

On the other hand, the carrier provided by the present invention includes a substance for repairing / protecting mucosal tissues. Although these mucosal tissue repair / protective substances have not been examined for use as a carrier for nasal administration preparations, according to the study of the present inventors, they are unexpectedly porous. It has physical properties as polycrystalline, especially, individual fine particles are re-granulated and has porosity. When an active substance is dispersed, adhered or bonded to this, extremely good nasal It has been found that it can be a dosage formulation carrier. In particular, even if the same mucosal tissue repair / protective substance is homogenized and finely sized, the bioactive substance has poor adhesion and binding properties, and even if it is administered intranasally, it will have satisfactory bioabsorbability. I could not give it.

Therefore, such a substance for repairing and protecting mucosal tissues, which is a carrier for drugs for nasal absorption, has a property of adhering to and retaining on mucous membranes in the nasal cavity and, when sprayed and inhaled into the nostrils, absorbs into the lungs. As a mass and particle size within a range that does not fall down due to its own weight after adhering to the nasal mucosa after being attached to the nasal mucosa without shifting,
The specific gravity of the carrier obtained by granulating and aggregating fine particles is about 0.5 to
In the case of 1.0, the particle size is 15 μm to 300 μm.
μm, and the surface area is 0.1 to 0.1 μm.
A porous crystalline or powdery substance at 4 m ² / g is
It is preferred as the carrier for nasal mucosa attachment / retention of the nasal absorption of the present invention.

As such a substance for repairing / protecting mucosal tissue, a substance for repairing / protecting gastric mucosal tissue or a substance for regulating gastrointestinal function is particularly preferable, and examples thereof include drugs which have already been clinically used. Such substances include:
Gefarnate (commercial name: gefanil), aceglutamide aluminum (commercial name: glumar), sucralfate (commercial name: alsalmine), L-glutamine (commercial name: gurmin), sofacalcon (commercial name: Soron),
Teprenone (commercial name: Celvex), praunitol (commercial name: Kelnac), rebamipide (commercial name: mucosta), aldioxa (commercial name: Aranta, Isalone, Ascomp, etc.), setraxate (commercial name: Neuel),
Toloxipide (trade name: Aplace), Benexate hydrochloride betadex (trade name: Urgut), thiamine-cobalt-chlorophyllin complex compound (trade name: Gaslon N), domperidone (trade name: nauzerin), trimebutine maleate (trade name) name: Serekinon), cisapride (commercial name: Asenarin), HT ₃ antagonist, HT
₄ agonists and the like.

On the other hand, the physiologically active drugs used for nasal administration after being dispersed, adhered and bound to the nasal mucosa adherent / retentive carrier for nasal absorption provided by the present invention include physiologically active peptides and hypnotic sedatives. , Antiepileptic, minor tranquilizer, major tranquilizer, antidepressant, muscle relaxant, antiallergic, antirheumatic, inotropic, antiarrhythmic, diuretic hypotensive, α-blocker, β-blocker, calcium antagonist Agents, angiotensin conversion inhibitors (AEC inhibitors), antihypertensives, vitamins, coronary vasodilators, cerebral circulation metabolism improvers, anti-atherosclerotic agents, cardiovascular agents, bronchodilators, anti-ulcer agents, antiemetic agents, obesity Therapeutic agents, platelet aggregation inhibitors, agents for treating diabetes / diabetic complications, corticosteroids, DNA / RNA drugs, and the like. These drugs are already used in medical practice
In addition to drugs already on the market, drugs under clinical trial may be used. Such drugs include, for example, those with the following common names. It goes without saying that the following example does not mean that the present invention is limited to this.

Hypnotic sedatives include lormetazepam, quazepam, sorbidem and the like; antiepileptic agents such as sodium valproate and zabril; minor tranquilizers such as diazepam, buspirone and suriclone;
Major tranquilizers include cerretide diethylamine, emonaprid, risperidone, mosapramine hydrochloride, etc .; anti-depressants, such as trazoton hydrochloride, fluvoxamine, dimerdin, rolipram; etc .; muscle relaxants, pinaverium, inaperizone hydrochloride, simeropium bromide, bromide Cimetropium, etc .;
Pemilocast potassium, tazanolast, traxanox sodium, dolcast, emecadastin fumarate, rotatadine, ceritidine, splast tosilate, celabenast, bateplast, doquarast, butenafine hydrochloride, pentigetide, bikumasuro, levocabastine, etc .; Salazosulfapyridine,
Nuclemedone, Platonin, Actarit, etc .; Cardiotonic agents such as xamoterol, vesnarin, nitroprusside, amrinone, xamoterol, docarpamine, antap, ibopamine, enoximone, loprinone, fenoldupan, pimobendan, milrinone; antiarrhythmic agents, flecainide hydrochloride, ,
Cibenzoline succinate, beprichol, amiodarone,
Pentisomid, pyrmenol hydrochloride, molacidin and the like.

As the diuretic antihypertensive, α-hump,
Tosemide and the like; α-blocker agents such as doxazosin tosylate, harnal and bunazosin hydrochloride; and β-blocker agents such as carvedilol, bisoprolol fumarate, tilisolol, xybenolol hydrochloride, ceriprolol hydrochloride, metoprolol tartrate, carteolol hydrochloride, Bopinrol, betaxol, bevantolol hydrochloride, etc .; calcium antagonists include bepridyl hydrochloride, nisoldipine, nimodipine, nitrendipine, flomethidine, nakadipine, galopamil, manidipine hydrochloride, paronidipine, nitrendipine, mepiradipine hydrochloride, fasudil hydrochloride, silnidipine fumarate, sesadiyl fumarate Amlodipine, efonidipine hydrochloride, diltiazem hydrochloride,
Clench Azem maleate, Lacidipine, Hoshidipine,
Felodipine, nildipine, remacarim, asanidipine, pranidipine, isradipine, dalodipine, etc .; Examples of angiotensin conversion inhibitors (AEC inhibitors) include althiopril calcium, cilazapril, ramipril,
Lisinopril, temocapril, spirapril, imidapril hydrochloride, benacepril, quinapril, fosenopril, etc .; antihypertensives: ketanserin tartrate, pinacidil, diazoxide, naphtopidyl, clonidine, flosequinan, chroma potassium, etc .; vitamin B ₁₂ derivatives such as cobalamin like.

Further, coronary vasodilators such as isosorbide and molsidomine; cerebral circulatory metabolism improvers such as ademethionine tosylate sulfate, dihydroergotoxin mesylate, aniracetam, naphtidofuryl oxalate, teniloxazine maleate, minapurine hydrochloride, Buflomezil hydrochloride, oxiracetam, azetilerin, vinconade, erythritol, fasudil hydrochloride, amylizine hydrochloride, tamoraridin, nebracetam fumarate, erjiberin, etc .; as anti-atherogenic agents, bezafibrate, questran, boliceride, simvastatin, etc. Levocarnitine chloride, alinidine hydrobromide, etc .; bronchodilators such as oxitropium bromide, theophylline, ozacrel hydrochloride, salmeterol, tulobuterol hydrochloride, etc .; anti-ulcer agents Include proamipide, misoprostol, nizatidine, emprostil, albaprostil, lotraxate hydrochloride, embrostil, trimoprostil, rotraxate hydrochloride, omeprazole, beperidium iodide, ransporazole, nizatidine, leioprostil, polaprezinc, reminoprazole Anti-emetic agents such as granisetron, ondansetron, azasetron, domperidone, cisapride, etc .; anti-obesity agents, mazindol; platelet aggregation inhibitors, tederparin, argipidine, iloprost, ataprost, Beraprost, carbacicycline, isvocrell, amplag, satigrel, clopidocrel, etc .;
Therapeutic agents for diabetic complications include pioglidazone hydrochloride, botigibose, gliclazide, acarbose, cyglitazone, solvinyl, gumpyride, epalrestat, ganglioside, midaglizole hydrochloride, ponalrestat, etc .; Beclomethasone, fluorometholone, hydrocortisone succinate, paramethasone acetate, betamethasone, corticasone, etc .;
Examples include transgene RNA, DNA, antisense and the like in gene therapy.

However, in the present invention, it has been found that physiologically active peptides show particularly good results as physiologically active drugs. Such bioactive peptides include:
They are peptide hormones, bioactive proteins and enzyme proteins. Such usable bioactive peptides include, for example, peptide hormones such as calcitonin, insulin, thyrotropin releasing hormone (TRH)
For example, thyroliberin, luteinizing hormone-releasing hormone (LH-RH) such as buserelin, somatostatin, adrenocorticotropic hormone (ACTH), adrenocorticotropic hormone-releasing hormone (CRH) such as corticoliverin, growth hormone-releasing hormone (GH-RH) such as somatorelin Gonatropin (gonadotropin), gonadotropin-releasing hormone (GnRH) such as gonadoriberin, parathyroid hormone (PTH), growth hormone (G
H) For example, somatropin, prolactin (mammary stimulating hormone), follicle stimulating hormone (FSH), glucagon, vasopressin, somatostatin (growth hormone release inhibitor), paratormon (parathyroid hormone: PTH), angiotensin, gastrin, secretin, melanocyte stimulation Hormones, oxytocin, protirelin, luteinizing hormone (LH), corticotropin, somatropin, thyrotropin (thyroid stimulating hormone), somatostatin (growth hormone stimulating factor), β-endorphin,
Opioid peptides such as enkephalin, G-CSF,
Erythropoietin, superoxide dismutase (SOD) and the like. In addition, interferon, interleukin, urokinase, lysozyme, vaccine and the like can also be mentioned. These physiologically active peptides are not limited to those described above, and needless to say, the composition of the present invention can be used as long as it can be administered nasally by the specific carrier of the present invention.

Among the above-mentioned physiologically active peptides, peptide hormones are particularly preferred. Among these peptide hormones, calcitonin, insulin, somatostatin and the like are preferred, and insulin, calcitonin, parathyroid hormone (PTH), human growth hormone ( HG
H), growth hormone releasing hormone (GH-RH), gontropin (gonadotropin), gonadotropin releasing hormone (GnRH) and the like are particularly preferable. As calcitonin, salmon calcitonin, human calcitonin,
Salmon human chimeric calcitonin, porcine calcitonin, chicken calcitonin, bovine calcitonin, el (eel)
Calcitonin and the like; many of these calcitonins are naturally occurring, extractable or semi-synthesized, and are commercially available. In these calcitonins, the stability is said to be in the order of el-calcitonin-human calcitonin-salmon calcitonin, but even salmon calcitonin, which is said to be relatively inferior in stability, is special in the present invention. By dispersing in a carrier to form the composition of the present invention, it has been found that, for example, bioavailability and effective concentration in blood are extremely good. Therefore, so-called commercially available calcitonin is suitable as the bioactive peptide used in the present invention.

Dispersed in a specific carrier provided by the present invention,
The effective dose of the physiologically active substance to be attached and bound and administered intranasally includes the individual active substance to be selected (for example, relative activity titer for calcitonin, insulin unit for insulin), treatment It depends on the target disease to be treated, the desired number of administrations, the required individual therapeutic effect, and the like. In particular, the therapeutic effect of a formulation containing the active substance can be determined in comparison with bioavailability with other known formulations.

For example, taking insulin as an example,
When used for diabetes, 4 to 20 insulin units are injected subcutaneously at the initial stage, and the maintenance amount is usually 4 to 4 per day.
-100 units are used, and the maximum amount is 800 units per day. Therefore, when the composition according to the present invention is administered by nasal administration, 4 to 100 units of insulin may be used.

In the case of calcitonin, when treatment with conventional calcitonin, for example, salmon calcitonin is performed by intramuscular injection, about 50 to 100 MRC (I
U) Individual doses of units are applied at a rate of about 1 x day to about 3 x week. Thus, when the composition according to the invention is administered by the nasal route, from about 50 to about 400 MR.
C units, more preferably about 100 to about 200 MRC
Suitably, the unit dose will be administered from about 1 x day to about 3 x weekly for treatment. The dose is administered in a single application, ie, from about 50 to about 400 MRC.
Conveniently, the treatment is effected by administration of a single intranasal dose consisting of units, preferably about 100 to about 200 MRC units of calcitonin. The content of other physiologically active substances can be determined based on the same concept.

Therefore, when producing the composition of the present invention, for example, the content of the physiologically active substance is, for example, 0.0001 to 30%, preferably 0.01 to 20%, more preferably 0.01 to 20% per 100% of the weight of the preparation. 0.1-5.
It is better to mix 0%. The carrier of the present invention (typically, hydroxyapatite, calcium carbonate,
The compounding amount of a polyvalent metal compound such as calcium lactate, magnesium stearate or aluminum hydroxide: or a gastric mucosal tissue repair / protective substance such as sucralfate or sofacalcon) is, for example, 70 to 99.995% per 100% of the weight of the preparation. , Preferably 80 to 99.99
%, More preferably 95 to 99.9%, it has been found that good nasal absorption can be obtained. In this way, a physiologically active substance, which has conventionally been difficult to administer orally, can be formulated into a formulation that can be effectively absorbed in vivo by intranasal administration.

In order to obtain a composition for nasal absorption containing an effective dose of a bioactive drug proposed by the present invention, it can be obtained by mixing the special carrier of the present invention with a bioactive drug. . For example, a physiologically active peptide is selected as a physiologically active drug, and in a composition for nasal absorption when hydroxyapatite or calcium carbonate, which is a calcium compound, is used as a carrier, these carriers and the physiologically active peptide are mixed. It is done by doing. Specifically, for example, this mixing can be performed by ordinary kneading, followed by sieving to obtain a composition having a particle size suitable for nasal absorption.

In this case, the carrier used in the production of the composition for nasal absorption of the present invention, when sprayed and inhaled into the nostrils, is distributed widely to the inner part of the nasal cavity without transferring to the lungs, and Having a mass and a particle diameter substantially within a range not falling by its own weight after being attached to the carrier, that is, when the specific gravity of the carrier is about 0.5 to 1.0, the particle diameter is within a range of 15 μm to 300 μm. , Preferably 15 μm to 250 μm, more preferably 15 μm to 200 μm, more preferably 15 μm to 200 μm.
It is good that it is from μm to 80 μm. On the other hand, the physiologically active substance is preferably as fine powder as possible, and its average particle size is usually 20 μm or less, preferably 10 μm or less.

More specifically, when a physiologically active peptide such as salmon calcitonin or ercalcitonin is used as the physiologically active substance, the effective amount of calcitonin is determined by using, for example, 1% of gelatin as a stabilizer for calcitonin and 0% of aspartic acid as a stabilizer for calcitonin. 0.1 to 0.5%, preferably about 0.38%, and mixed with an aqueous solution having a pH of 4.5 to 5.5 and freeze-dried. Next, this freeze-dried powder is kneaded with the carrier of the present invention, for example, hydroxyapatite in about two to three times, and kneaded at a kneading humidity of about 55%. A homogeneously bonded fine powder (intranasal composition) is obtained.

As another example, calcitonin is used as a physiologically active substance, and gastric mucosal tissue repair is used as a carrier.
When sucralfate is used as a protective agent, for example, after mixing with a carrier and low-substituted hydroxypropylcellulose (HPC-L), stirring, and allowing it to stand for about 5 minutes, calcitonin is added thereto and further mixed. After adding a small amount of purified water and kneading, about 1
Lyophilize for 0-14 hours. After freeze-drying, warm up to 30 ° C. over 3 to 5 hours, preferably about 4 hours, and finally add calcium stearate there,
Can be kneaded.

The composition for nasal absorption thus obtained is filled into a low-grease type capsule to prevent loss of the active substance before use (for example, before administration into the nasal cavity). Packaging, preferably closed packaging. As such a closed package, a combination of a blister package and an aluminum package is preferable. In this case, the humidity in all the steps is desirably 60% or less. In addition, even for other physiologically active drugs, the desired nasal absorption composition can be obtained by performing the treatment according to the above-mentioned method in combination with the drug to be used and the carrier.

Hereinafter, the specific effects of the composition for nasal absorption using the specific carrier provided by the present invention will be described by test examples.

[Test example]

Test Example 1: Examination of Particle Size Salmon calcitonin, which is a physiologically active peptide, was selected as a physiologically active drug, and calcium carbonate, which is a calcium compound and having a mean particle size of 9.36 μm, was selected from the Japanese Pharmacopoeia. The composition was used for nasal absorption. The salmon calcitonin content is 200 MRC (IU) / 25 m
g of the composition was prepared. The calcium carbonate used had an average particle diameter of 9.36 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was intranasally administered (single dose) to three normal male subjects, and 2.5 ml of blood data was obtained.
0 hours, 5, 10, 15, 20, 30, 45, 60, 9
Blood was collected every 0, 2 hours, and 3 hours, and the blood concentration of salmon calcitonin was measured using a standard RIA assay kit. Table 1 summarizes the results.

[0045]

[Table 1]

As is clear from the results in the table, the use of calcium carbonate as a carrier shows that salmon calcitonin is absorbed into the blood by nasal administration. However, the average particle diameter of the carrier used was 9.36 μm, and it was a fine powder as a preparation for nasal administration. In actual use, scattering to the outside of the nostrils was observed, which was not very preferable.

Test Example 2: Examination of Particle Size As a bioactive drug, eel calcitonin (elcatonin), which is a bioactive peptide, was selected, and as a carrier, calcium carbonate of the Japanese Pharmacopoeia was secondarily aggregated and granulated to give an average particle size of 75.16 μm. With calcium carbonate (Sumida)
Was selected as a composition for nasal absorption. The content of elcatonin is 300 MRC (IU) / 25 mg, 200 M
RC (IU) / 25mg, 100MRC (IU) / 25
mg, 50 MRC (IU) / 25 mg and 25 MR
A total of five compositions were prepared to give a composition of C (IU) / 25 mg. The calcium carbonate (Sumida) used had an average particle diameter of 75.16 μm as observed by a particle size distribution analyzer, had a surface area of 0.12 m ² / g, and had a porous crystalline property. Was something.

Each of the above compositions was administered nasally (single dose) to six postmenopausal normal females as subjects to which each composition was to be administered, and blood samples were 2.5 ml each, for 0 hours, 5, 10, and 10 minutes. Fifteen, two
Blood was collected every 0, 30, 45, 60, 90, 2 hours, and 3 hours, and the concentration of elcatonin in the blood was measured using a standard RIA assay kit. In addition, 300 MRC (IU)
The administration example of the / 25 mg composition was performed by 5 persons. Similarly, as a control, nine normal postmenopausal women were intramuscularly injected with Elcatonin 40 MRC (IU), and blood samples were collected in the same manner.
Elcatonin blood levels were measured. The results are summarized in Tables 2 to 7.

[0049]

[Table 2]

[0050]

[Table 3]

[0051]

[Table 4]

[0052]

[Table 5]

[0053]

[Table 6]

[0054]

[Table 7]

As is evident from the results in the table, the use of calcium carbonate as a carrier shows that the absorption of elcatonin into the blood by nasal administration is observed, and particularly, the maximum blood concentration is reached within a short time. Turns out to be. The carrier used here had an average particle size of 75.16 μm, a surface area of 0.12 m ² / g, and was observed by a particle size distribution analyzer to be porous and crystalline. When used as a carrier, no scattering to the outside of the nostrils was observed, which was particularly preferable. From the comparison between Test Example 1 described above and Test Example 2, it is clear that a carrier having an average particle size of 10 μm or more used in nasal administration is more desirable. In addition, SD in the blood concentration of elcatonin in each administration group
(Standard deviation value) was lower than that in the intramuscular injection group of the control example (Table 7), indicating that it was particularly excellent for nasal administration.

Test Example 3: Salmon calcitonin, a physiologically active peptide, was selected as a physiologically active drug, and sucralfate (manufactured by Chugai Pharmaceutical Co., Ltd.), a substance for repairing and protecting gastric mucosal tissue, was selected as a carrier. did. The salmon calcitonin content is 200 MRC (IU)
/ 25 mg of a composition of the present invention was prepared. Sucralfate as a carrier has an average particle size of 17.45 in observation with a particle size distribution analyzer.
μm, and was porous and crystalline. Nasal administration of the above composition to two normal male subjects (single dose)
Then, 2.5 ml of the blood sample was added for 0 hour, 5, 10, 1
Blood was collected every 5, 20, 30, 45, 60, 90, 2 hours, and 3 hours, and salmon calcitonin blood levels were measured using a standard RIA assay kit. Table 8 summarizes the results.

[0057]

[Table 8]

As is evident from the results in the table, the use of porous crystalline sucralfate having a specific particle size as a carrier is also superior in the absorption of salmon calcitonin into blood by nasal administration. Prove. On the other hand, the same sucralfate had an average particle diameter of 19.19 μm.
Even if the product has a uniform particle size (manufactured by Fuji Chemical), it does not have a porous crystalline structure, and the adherence of salmon calcitonin after formulation for nasal administration is low. It was found to be unfavorable.

Test Example 4: Methylcyanocobalamin was selected as a physiologically active drug, and sucralfate (manufactured by Chugai Pharmaceutical Co., Ltd.) was used as a carrier to repair and protect gastric mucosal tissue.
Was selected as a composition for nasal absorption. The composition of the present invention was prepared such that the content of methylcyanocobalamin was 500 μg / 25 mg. Sucralfate as a carrier had an average particle diameter of 17.45 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was administered nasally (single dose) to two normal male subjects, and blood samples were collected at 2.5 m.
0 hours, 5, 10, 15, 20, 30, 45,
Blood is collected every 60, 90, 2 hours, 2.5 hours, 3 hours,
The blood levels of methylcyanocobalamin were measured.
Table 9 summarizes the results.

[0060]

[Table 9]

As is evident from the results in the table, the use of porous crystalline sucralfate having a specific particle size as a carrier is also superior in the absorption of methylcyanocobalamin into the blood by nasal administration. Prove.

Test Example 5: As a bioactive drug, hPTH
Select (1-34) and repair gastric mucosal tissue as carrier
Sucralfate (manufactured by Chugai Pharmaceutical Co., Ltd.), which is a protective substance, was selected as a composition for nasal absorption. hPTH (1-34)
The composition of the present invention was prepared such that the content of was 120 μg / 30 mg. Sucralfate as a carrier had an average particle diameter of 17.45 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was administered nasally (single dose) to three normal male subjects, and blood samples were 2.5 ml each for 0 hours, 5, 10, 15, 20, 30, 45, 6
Blood was collected every 0, 90, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours, and the blood concentration of hPTH (1-34) was measured using the ELISA 1-34 PTH2 antibody method. Table 10 summarizes the results.

[0063]

[Table 10]

As is evident from the results in the table, the use of porous crystalline sucralfate having a specific particle size as a carrier can also be achieved by intranasal administration of hPTH (1-3).
It turns out that 4) is excellent in absorption into blood.

Test Example 6: Buserelin, a luteinizing hormone-releasing hormone (LH-RH), was selected as a bioactive drug, and sucralfate (manufactured by Chugai Pharmaceutical Co., Ltd.), a substance for repairing and protecting gastric mucosal tissues, was selected as a carrier. The composition was used for nasal absorption. The content of buserelin is 50 μg
The composition of the present invention was prepared so as to give a composition of / 30 mg. Sucralfate as a carrier has an average particle size of 17.45 in observation with a particle size distribution analyzer.
μm, and was porous and crystalline. Nasal administration of the above composition to two normal male subjects (single dose)
Then, 2.5 ml of the blood sample was added for 0 hour, 5, 10, 1
Blood was collected every 5, 20, 30, 45, 60, 90, 2 hours, and 4 hours, and the blood concentration of buserelin was measured by the direct method. Table 11 summarizes the results.

[0066]

[Table 11]

As is evident from the results in the table, the use of porous crystalline sucralfate having a specific particle size as a carrier was also confirmed by the intranasal administration of the absorption of buserelin (LH-RH) into the blood. Turns out to be excellent.

Test Example 7 Human growth hormone (HGH) was selected as a physiologically active drug, and sucralfate (manufactured by Chugai Pharmaceutical Co., Ltd.), which is a substance for repairing and protecting gastric mucosal tissue, was selected as a carrier to give a composition for nasal absorption. . The composition of the present invention was prepared so that the composition of human growth hormone (HGH) was 12 units / 30 mg. Sucralfate as a carrier had an average particle diameter of 17.45 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was administered nasally (single dose) to two normal male subjects, and blood samples were 2.5 ml each for 0 hours, 5, 10, 15, 20, 3, and 2.
Blood is collected every 0, 45, 60, 90, 2 hours, and 3 hours, and human growth hormone (HGH) is collected from a blood growth hormone amount measurement kit based on IRMA (immunoradiometric assay) using a bead solid phase method. The blood concentration was measured. Table 12 summarizes the results.

[0069]

[Table 12]

As is evident from the results in the table, the use of porous crystalline sucralfate having a specific particle size as a carrier is also superior in the absorption of human growth hormone (HGH) into blood by nasal administration. Turns out to be. In the above Test Examples 4 to 7, even if the same sucralfate was used as the carrier,
The sized product having an average particle size of 19.19 μm (manufactured by Fuji Chemical) does not have a porous crystalline structure, and after the formulation for nasal administration, adherence of the physiologically active substance Was not preferred.

Test Example 8 Methylcyanocobalamin was selected as a physiologically active drug, and Sofalcone (manufactured by Taisho Pharmaceutical Co., Ltd.), a substance for repairing and protecting gastric mucosal tissue, was selected as a carrier to give a composition for nasal absorption. The composition of the present invention was prepared such that the content of methylcyanocobalamin was 500 μg / 25 mg. Sofalcon as a carrier had an average particle diameter of 33.19 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was intranasally administered (single dose) to two normal male subjects, and 2.5 ml of blood data was obtained.
0 hours, 5, 10, 15, 20, 30, 45, 60, 9
Blood was collected every 0, 2, 2.5 hours and every 3 hours, and the blood concentration of methylcyanocobalamin was measured. Table 13 summarizes the results.

[0072]

[Table 13]

As is evident from the results in the table, the use of porous crystalline sofacalcon having a specific particle size as a carrier also shows excellent absorption of methylcyanocobalamin into the blood by nasal administration. Turns out. The average particle size of the carrier used here is 33.19 μm,
In addition, observation by a particle size distribution meter revealed that the product was porous and crystalline, and that it was not particularly scattered outside the nostrils when used as a carrier for intranasal preparations, and was particularly preferable.

Test Example 9: Human growth hormone (HGH) was selected as a physiologically active drug, and sofacalcon (manufactured by Taisho Pharmaceutical Co., Ltd.) was used as a carrier to repair and protect gastric mucosal tissue.
Was selected as a composition for nasal absorption. The composition of the present invention was prepared so that the composition of human growth hormone (HGH) was 12 units / 30 mg. Sofalcon as a carrier had an average particle diameter of 33.19 μm as observed by a particle size distribution analyzer, and was porous and crystalline. The above composition was administered nasally (single dose) to two normal male subjects, and blood samples were collected at 2.5 m.
0 hours, 5, 10, 15, 20, 30, 45,
Blood was collected every 60, 90, 2 hours, and 3 hours, and the blood concentration of human growth hormone (HGH) was measured using a blood growth hormone amount measurement kit based on IRMA (immunoradiometric assay) using the bead solid phase method. A measurement was made. Table 14 summarizes the results.

[0075]

[Table 14]

As is evident from the results in the table, the use of porous crystalline sofacalcon having a specific particle size as a carrier can also be achieved by intranasal administration of human growth hormone (HG).
It turns out that the absorption of H) into the blood is excellent.

Test Example 10 Insulin was selected as a physiologically active peptide, and a composition for nasal absorption was prepared using two types of calcium carbonate having different surface areas of particles as carriers. Calcium carbonate as a carrier is as follows. Light calcium carbonate (Sumida B)-average particle diameter: 100 µm, and the surface area of the particles is 0.1 µm.
12 m ² / g. Heavy calcium carbonate-average particle diameter: 47 μm, and the surface area of the particles is 0.307 m
² / g. The dose of insulin was 17I.
U (unit) was used. Using three crab-eating monkeys weighing about 3 kg, the above composition was administered intranasally, and before administration and after administration.
Blood is collected at 0, 60, 120, 240 and 24 hours,
Insulin blood levels were measured. Table 15 summarizes the results.

[0078]

[Table 15]

As carriers for nasal absorption, two types of calcium carbonate (light and heavy) having a specific surface area and a specific particle size were examined. Both calcium carbonates showed good blood insulin concentrations. I have. However, as is clear from the results in the table, heavy calcium carbonate having a large surface area shows better results, and it is understood that a carrier having a large surface area is more preferable.

[0080]

As described above, according to the present invention, a physiologically active drug such as a physiologically active peptide, which has been difficult to administer orally, is absorbed by nasal administration by using a specific carrier. The present invention provides a composition for nasal absorption, which is a preparation having good properties and non-irritating properties.

Claims (9)

[Claims] 1. A carrier for drugs for nasal absorption, which adheres to and stays on the mucous membrane in the nasal cavity and, when sprayed and inhaled into the nostrils, is widely distributed inside the nasal cavity without transferring to the lungs Primary-granulated fine crystals having a mass and particle diameter substantially within a range not falling by their own weight after being attached to the nasal mucosa and having a large number of voids on the surface, or secondary-agglomerated granules thereof To form a large number of voids on the surface of the granulated crystal so that the surface area is 0.1 to 0.4 m ² / g.
And a porous carrier for nasal mucosa for nasal absorption having a crystal particle size in the range of 15 μm to 300 μm when its specific gravity is about 0.5 to 1.0. 2. The carrier according to claim 1, wherein the carrier is a primary granulated fine crystal. 3. The porous nasal mucosa-adhering / retaining carrier according to claim 1, which is a granulated crystal obtained by secondary aggregation granulation. 4. The crystal particles have a surface area of 0.1 to 0.4 m ^2.
The porous nasal absorption according to any one of claims 1 to 3, wherein the crystalline particle diameter is in a range of 15 µm to 180 µm when the specific gravity is about 0.5 to 1.0. Nasal mucosa attachment / retention type carrier. 5. The crystal particle has a surface area of 0.1 to 0.4 m ^2.
The porous nasal absorption according to any one of claims 1 to 3, wherein the crystal particle size is in the range of 15 µm to 80 µm when the specific gravity is about 0.5 to 1.0. Nasal mucosa attachment / retention type carrier. 6. The carrier according to claim 1, wherein the pH of the carrier itself is in the range of 2.5 to 12. 7. The carrier according to claim 1, which is poorly soluble in water and maintains a clearance time to the nasal mucosa by surface tension on the nasal mucosa as a carrier that adheres and stays on the nasal mucosa. A porous carrier for nasal mucosa for nasal absorption according to the above-mentioned. 8. The porous nasal mucosa-adhering / retaining carrier according to claim 1, which can be used as a suspension. 9. A composition for nasal absorption wherein a physiologically active substance is dispersed, adhered and bound to the carrier for nasal mucosa attachment / retention according to any one of claims 1 to 8.