JP3197221B2 - Powdery nasal composition having improved absorption - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a powdery composition for nasal administration having improved drug absorption. More specifically, the present invention relates to a powdery composition for nasal administration having improved absorption of a drug from the nasal mucosa using a base having a specific type, composition and particle size.

[0002]

BACKGROUND OF THE INVENTION Some non-peptide and protein drugs,
For example, anti-inflammatory steroids, analgesics and anti-inflammatory drugs, antitussives, antihistamines, anti-allergics, anti-emetics, sleep-inducing drugs, vitamins, sex steroid hormones, anti-tumor drugs, anti-arrhythmic / hypertensive drugs, anti-anxiety / psychotropic Drugs such as drugs, anti-ulcer drugs, inotropic drugs, analgesics, etc. 1. The site of action is local to the nasal mucosa. 2. A quick effect is desired; Development of a transnasal drug has been desired for reasons such as a low absorption rate by oral administration. In addition, many peptide / protein drugs are not easily absorbed into the body even when administered orally, for example, because they are degraded by proteolytic enzymes in the gastrointestinal tract. Therefore, it is often necessary to administer by injection in order to use it for treatment. However, injections place a burden on patients due to pain, necessity of going to hospital, and the like. Therefore, development of a non-invasive administration method which replaces injection, such as a nasal administration agent, is desired.

[0003] Nasal administration is a method of administering a drug to the circulating blood through the nasal mucosa, and vigorously removes the drug along with other routes, such as transdermal administration, ophthalmic administration, rectal administration and pulmonary administration. It has been studied as an injection-type administration method. Among these administration methods, the nasal mucosa has a developed vasculature compared to the skin, ocular mucosa, rectal mucosa, etc., and is easy to administer, and some drugs have been put into practical use as nasal administration preparations. Some are. In addition, the drug is absorbed into the blood faster than oral administration, and it can be expected to be as effective as injection administration. However, the absorption of the drug from the nasal mucosa
It depends on the physical properties such as the lipid solubility of the drug and the molecular weight, etc., and it has been pointed out that, for a highly water-soluble drug, a fat-soluble drug, and a peptide / protein drug having a large molecular weight, the absorption is low. ing. Therefore, a device for improving the absorption of these drugs from the nasal mucosa has been proposed.

For example, Suzuki et al. (JP-B-60-34925)
Discloses a continuous nasal formulation that efficiently supplies a drug with a nasal composition composed of cellulose ether at a concentration sufficient to obtain a therapeutic effect. Also Nolte
(Hormone Metabolic Research Vol. 22, 170-174,
1991), Bruice et al. (Diabetic Medicine Vol. 8, 366-37)
0, 1991) report an intranasal insulin formulation containing an absorption enhancer, sodium glycolate or sodium taurofusidate. However, these absorption promoters have a problem of irritation to the nasal mucosa and have not been put to practical use. On the other hand, Suzuki et al. (JP-B-62-42888) have disclosed that a powdery nasal administration composition comprising a water-absorbing and poorly water-soluble base can convert polypeptides without using irritating additives. A method for nasal absorption is disclosed. It has been reported that polypeptides such as insulin and calcitonin are remarkably efficiently absorbed by this method as compared with conventional liquid intranasal compositions.

Further, the same publication discloses that a water-absorptive and poorly water-soluble base is provided with a water-absorptive and water-soluble base in an amount of 0.1 to 0.1% relative to the water-absorbable and poorly water-soluble base. It is disclosed that when used in combination with 60% by weight, particularly preferably 1 to 50% by weight, a powdery intranasal composition having sustained release properties is provided. For example, 80% by weight of the crystalline cellulose of Example 2 (a water-absorbing and poorly water-soluble base)
The combination of water-absorbable and sodium polyacrylate (water-absorbable and water-soluble base) has no difference in the blood glucose lowering rate compared to the crystalline cellulose alone ( Although there is no difference in the medium concentration), a sustained effect of the blood concentration based on sustained release is suggested. Also, in the case of using the crystalline cellulose of Example 14 in combination with 25% by weight of hydroxypropylcellulose (a water-absorbing and water-soluble base), the maximum blood concentration was higher than that of the crystalline cellulose alone. Inferior, but sustainability is described. Further, in Example 4, the preparation of hydroxypropylcellulose alone and the preparation of crystalline cellulose alone were compared, and hydroxypropylcellulose could delay the disappearance of insulin from the blood more than crystalline cellulose, but at the highest blood concentration It is described as being significantly inferior.

[0006] The same publication discloses a method for producing a composition comprising such a water-absorbing and poorly water-soluble base and a water-absorbing and easily water-soluble base, comprising a polypeptide and a water-absorbing and poorly water-soluble base. A method of simultaneously adding and mixing a water-absorptive and water-soluble base at the same time as mechanically mixing a base with a polypeptide, adding a polypeptide and a water-absorbable and poorly water-soluble base to water A method of simultaneously adding and mixing a water-absorptive and water-soluble base during kneading, freeze-drying a water-absorptive and water-soluble base with a polypeptide to obtain a water-absorptive and poorly water-soluble base Are mechanically mixed. For example, in Example 1 (b) of the publication, Carbopol 934 (a water-absorbing and water-soluble base) was added to an aqueous hydrochloric acid solution of insulin.
Is dissolved and freeze-dried, and then mixed with crystalline cellulose (a water-absorptive and poorly water-soluble base) to obtain a composition having a particle size of 90% by weight or more and a particle size of 75 to 149 microns. This is evaluated in Example 2 above. Furthermore, the publication also describes the particle size of the composition,
Particles smaller than 10 microns are likely to escape from the nasal cavity or reach the lungs at the time of administration, and particles greater than 250 microns have poor retention on mucous membranes, and therefore have a particle size of 90% by weight of the composition. Is preferably in the range of 20 to 150 microns.

[0007] The absorbability of a drug is usually evaluated as a temporal change in the amount of the drug that has passed through a biological membrane and transferred to the blood. More specifically, the maximum blood concentration (maximum blood concentration) is used.
It will be evaluated in two aspects: the duration of the blood concentration above a certain value (duration). In general, it is obviously desirable that both the maximum blood concentration and the duration are simultaneously large from the viewpoint of both therapeutic effect and therapeutic efficiency.
It should be recognized that for drugs that are inherently poorly absorbed, such as proteinaceous drugs, it is first necessary to raise the blood concentration as much as possible, that is, to have a high maximum blood concentration.

[0008]

SUMMARY OF THE INVENTION Peptide-protein drugs are generally expensive. In addition, when the absorption rate is low, the blood concentration varies widely, and the expected therapeutic effect is often not obtained stably. Therefore, there is a need to provide a method for nasal administration of a peptide / protein drug having a higher absorption rate. In particular, there is a strong need to provide a safe and more absorbable nasal administration method. Especially also
Even with a high absorption rate, there is a need for a nasal administration method that can provide a higher maximum blood concentration as described above. This is the same for non-peptide and protein drugs.

By the way, the above-mentioned method of Suzuki et al.
According to JP-A-34925, it is possible to release an effective amount of a drug continuously or absorb a drug-effective amount of a drug that originally exhibits good nasal absorption. According to the publication, it is disclosed that an effective amount of the anti-inflammatory steroid can be continuously released by using a combination of an anti-inflammatory steroid and a base such as cellulose ether. Specifically, according to Examples 5 and 6 of the publication, when nasal administration of triamcinolone acetonide, which is one of the anti-inflammatory steroids, together with hydroxypropylcellulose or methylcellulose, a longer duration of the therapeutic effect can be obtained as compared with the control aqueous solution. It is disclosed. However, the technology disclosed in the publication discloses that the base administered into the nasal cavity together with the drug gels on the nasal mucosa and stays on the nasal mucosa with the drug, whereby the drug is gradually released from the base and absorbed. Therefore, the function of promoting the absorption of the drug is not sufficiently provided, and the water-soluble drug, the lipid-soluble drug, and the peptide / protein Drugs do not exhibit a high absorption rate, and there is a strong demand for the development of a nasal administration method that can effectively utilize these drugs from the viewpoint of therapeutic effect and therapeutic efficiency.

The method of Suzuki et al. (Japanese Patent Publication No. 62-4288)
No. 8), in Example 6 of the publication, when calcitonin was intranasally administered together with crystalline cellulose, a preparation having a higher maximum blood concentration and a longer sustained blood concentration was obtained as compared with a nasal solution as a control. ing. However, even in this case, the nasal absorption rate of the peptide / protein drug (the area under the blood concentration / time curve of the drug after nasal administration (AUC)) should exceed 10 to 20% of that after injection. There is no. In addition, the combined effect of the water-absorbing and poorly water-soluble base and the water-absorbing and easily water-soluble base is the sustained-release effect as compared to the water-absorbing and poorly water-soluble base alone ( (Sustained release or sustained release) only (according to the description in the publication, "Polypeptides are gradually absorbed"), and effects other than the sustained release effect, including the examples. Is not suggested at all. That is, in the same publication, when a water-absorbing and sparingly water-soluble base is used in combination with a water-absorbing and sparingly water-soluble base, peptide /
No increase in the maximum blood concentration of proteinaceous drugs is described. Further, there is no description that the maximum blood concentration of a non-peptide / protein drug is increased when such two kinds of base materials are used in combination. Moreover,
The publication exemplifies a large number of water-absorbable and poorly water-soluble bases including crystalline cellulose and a large number of water-absorbable and easily soluble waters including hydroxypropylcellulose. No mention is made of the fact that a specific type of base combination can provide an intranasal formulation exhibiting excellent peak blood concentrations for peptide-proteinaceous drugs and non-peptide-proteinaceous drugs.

[0011] That is, an object of the present invention is to provide a composition for nasal administration having excellent drug absorbability. Another object of the present invention is to provide a composition for nasal administration having a higher drug absorbability, especially the highest blood concentration. Furthermore, an object of the present invention is to provide a composition for nasal administration which is excellent in the absorbability of a highly water-soluble drug, a highly fat-soluble drug, and a peptide / proteinaceous drug having a large molecular weight. To provide things. Further, the object of the present invention is to provide a highly water-soluble drug, a drug other than a fat-soluble drug, and a drug exhibiting good nasal absorption, such as a non-peptide / protein drug, which is more excellent in absorbability. Another object of the present invention is to provide a composition for nasal administration having a higher maximum blood concentration.

In Japanese Patent Publication No. Sho 62-42888, 90% by weight of the powdery composition for nasal administration has a particle size of 20 to 20%.
It is preferably in the range of 150 microns. However, if the particle size distribution of the particles of this composition was further finely classified, it was unknown how the deposition distribution of the particles in the nasal cavity would be or could be controlled. The present inventors have intensively examined this point, and the powder of 10 to 50 microns is mainly deposited and distributed in the nasal cavity, near the pharynx and in the posterior inferior turbinate.
The powder of 0 micron is deposited and distributed in the middle part of the nasal cavity centering on the middle turbinate, and the powder of 100 to 350 microns is mainly distributed in the front of the nasal cavity, the vestibule of the nose, the upper turbinate, and the front of the middle turbinate. Deposition distribution was found. Of these 100 to 350 microns, particles of 150 microns or more are said to have poor deposition on the nose, and powder having such a relatively large particle size was distributed in the front of the nasal cavity after spraying. That was surprising. At the same time, the present inventors have also intensively studied the ciliary movement of the nasal mucosa, and found that the clearance due to the ciliary movement of the posterior nasal mucosa is relatively faster than that of the nasal cavity. Furthermore, by combining a water-absorbing and poorly water-soluble base with a specific amount of a water-absorbing and gel-forming base, surprisingly, the maximum blood concentration can be increased in Japanese Patent Publication No. Sho 62-42888. It has been found that it can be further improved. Based on these findings, based on these findings, the particle size of the water-absorbing and gel-forming base material of 90% by weight or more is 10 to 100 microns, and the water-absorbing and poorly water-soluble base material is 90% by weight or more. By limiting the particle size of the particles to 10 to 350 microns, they have found that the maximum blood concentration, which was not recognized in Japanese Patent Publication No. Sho 62-42888, can be significantly improved.

It is presumed that this is because the distribution in the nasal cavity after spraying was changed by changing the particle size of the two types of bases. The cause of this is currently being studied intensively, but it is expected that the difference in the distribution of the base material due to the small difference in the particle diameter described above is brought about. That is, the water-absorbable and gel-forming base of 10 to 100 microns is distributed together with the drug from the middle part to the deep part of the nasal cavity centering on the middle turbinate and is administered to the whole nasal cavity by gelling there. The retained composition is retained while 10
The water-absorbing and poorly water-soluble base of ~ 350 microns is
The drug is distributed in the middle of the nasal cavity from the front of the nasal cavity, especially the nasal vestibule and the upper nasal turbinate, resulting in high absorption of the drug, resulting in the effect of increasing the maximum blood concentration of the drug and increasing the therapeutic effect. Is considered to occur.

In addition to these findings, the present inventors have combined a certain water-absorbing and poorly water-soluble base with a water-absorbing and gel-forming base in a specific composition, By setting the particle size of the base material to a specific particle size, the maximum blood concentration of the drug absorbed from the nasal mucosa is significantly increased as compared with the conventional composition for nasal administration, that is, the absorbability of the drug is increased. It has been discovered that an improved powdery nasal administration composition can be provided, and that a powdery nasal administration composition having improved absorption of a drug, which has been conventionally poorly absorbed from the nasal mucosa, can be provided. Moreover, Japanese Patent Publication No. Sho 62-428
In the case of sodium polyacrylate, potassium polyacrylate, polyethylene glycol, polyvinylpyrrolidone, amylose, pullulan and the like which are mentioned as the same water-absorbing and gel-forming base in JP-A-88, the water absorption It could not be expected that such an effect would not be exhibited at all even when used in combination with a water-soluble and poorly water-soluble base. Hydroxypropyl starch, carboxymethyl starch, amylose, amylopectin, pectin, sodium caseinate, gum arabic, glucomannan, crosslinked polyacrylic acid and its salts, which are also listed as the same water-absorbing and poorly water-soluble base,
Even in the case of a crosslinked polyvinyl alcohol, polyhydroxyethyl methacrylate, etc., it cannot be expected that such an effect is not exhibited at all even when used in combination with the above-mentioned water-absorbing and gel-forming base. Was.

Furthermore, it has been found that in such a powdery composition for nasal administration, the maximum blood concentration of not only peptide / protein drugs but also non-peptide / protein drugs at the same time is increased as compared with the prior art. Furthermore, the present inventors have determined that the maximum blood concentration of each drug is the water absorption relative to the sum of the water-absorbable and poorly water-soluble base and the water-absorbable and gel-forming base in the base. And the ratio changes depending on the amount of the gel-forming base, and the ratio depends on the molecular weight of the drug, for example, when the drug is a peptide-protein drug,
It has been found that there is a preferable base compounding ratio depending on the molecular weight. Based on these findings, the present inventors have diligently studied the limitations of the prior art described above and have found that a powdered nasal administration composition that provides a significantly higher maximum blood concentration compared to a conventional powdered nasal administration composition. Are provided, and the present invention has been achieved.

[0016]

Means for Solving the Problems That is, the present invention provides: Drugs and a. At least one water-absorbable and gel-forming base selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose; c. Crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth gum, polyvinylpyrrolidone, chitin, containing at least one water-absorbable and poorly water-soluble base selected from the group consisting of chitosan. A powdery nasal administration composition comprising: (1) the amount of the water-absorbable and gel-forming base is the same as that of the water-absorbable and poorly water-soluble base; About 5 to 5 times the sum of the amounts of the forming base
(2) a particle size of 90% by weight or more of the water-absorptive and poorly water-soluble base has a particle size of 10 μm or more;
(3) The water-absorbable and gel-forming base material having a particle size of 90% by weight or more has a particle size of 10%.
A powdered nasal composition ranging from microns to 100 microns.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The drugs of the present invention include, for example, non-peptide / protein drugs and peptide / protein drugs having a molecular weight of not more than 30,000. As non-peptide / protein drugs, it is widely available for non-peptide / protein drugs, such as anti-inflammatory steroid drugs, analgesic / anti-inflammatory drugs, antitussive expectorants, antihistamine drugs, anti-allergic drugs, antiemetic drugs, sleep-inducing drugs , Vitamins, sex steroid hormones, anti-tumor drugs, anti-arrhythmic / hypertensive drugs, anti-anxiety / psychotropic drugs, anti-ulcer drugs, inotropic drugs, analgesics, bronchodilators, obesity drugs, platelet aggregation inhibitors, diabetes Examples include one or more non-peptide / protein drugs selected from the group consisting of drugs, muscle relaxants, and antirheumatic drugs.

Examples of such non-peptide / protein drugs include, for example, anti-inflammatory steroids or non-steroidal anti-inflammatory drugs such as hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, fluticasone, mometasone, fluocortin, budesonide, salbutamol, salmeterol and the like. Acetaminophen, phenacetin, aspirin,
Analgesic and anti-inflammatory drugs such as aminopyrine, sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, ibuprofen, alclofenac, diclofenac, indomethacin; antitussive expectorants such as sodium cromoglycate, codeine phosphate, isoproterenol hydrochloride; diphenhydramine , Triprolidine, isotipendyl, chlorpheniramine and the like; antihistamines such as amlexanox, azelastine, ozacrel, tranilast, and ketotifen; anti-allergic drugs such as ondansetron, granisetron, metoclopramide, cisapride, domperidone; Hypnotic-inducing drugs; vitamins such as cyanocobalamin and mecobalamin; estradiol, estriol, progesterone, testosterone, etc. Steroid hormone drugs; tamoxifen, an anti-tumor drugs such as tegafur; propranolol, atenolol, anti-arrhythmia, high blood pressure drugs such as nicardipine; diazepam, an anti-anxiety-psychotropic drugs such as nitrazepam;
Antiulcer drugs such as cimetidine and ranitidine; cardiotonic drugs such as dopamine; analgesics such as buprenorphine; bronchodilators such as oxytropium and ozacrel; therapeutic agents for obesity such as mazindol; platelet aggregation inhibitors such as beraprost and carbacycline; acarbose Diabetic drugs, such as, sol vinyl, etc .;
Muscle relaxants such as binaperum and inaperizone; and antirheumatic drugs such as actarit and platonin.

The peptide-proteinaceous drug of the present invention preferably has a molecular weight of not more than 30,000, and preferably has a molecular weight of not more than 30,000.
Proteinaceous drugs include, for example, luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, vasopressins, oxytocins, hirudin derivatives, enkephalins, adrenocorticotropin derivatives, bradykinin derivatives, calcitonins , Insulins, glucagon derivatives, growth hormones, growth hormone-releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferons, erythropoietin, granulocytes It consists of colony formation stimulating factor, macrophage formation stimulating factor, parathyroid hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone, and angiotensin. It includes one or more peptide proteinaceous drug selected from the group.

In the present invention, one or more water-absorbable and gel-forming bases selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose are used as the water-absorbable and gel-forming base. A gel-forming base is used. Among these, the water-absorbable and gel-forming base of the present invention includes one or more water-absorbable and gel-forming bases selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and sodium carboxymethylcellulose. A forming base is preferred, and among them, hydroxypropyl cellulose is particularly preferred. Still further, in the present invention, hydroxypropylcellulose used as a water-absorbing and gel-forming base has a 2% aqueous solution having a viscosity of 150 to 4,
It is preferably 000 cps. Although some hydroxypropyl celluloses have lower viscosities,
When a substance having a viscosity lower than cps is used, the effect of increasing the maximum blood concentration of the present invention may not always be sufficient.

In the present invention, the water-absorbing and poorly water-soluble base is selected from the group consisting of crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth gum, polyvinylpyrrolidone, chitin and chitosan. One or more water-absorptive and poorly water-soluble bases are used. Among these, the water-absorbing and poorly water-soluble base of the present invention includes crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth gum, polyvinylpyrrolidone, chitin, and chitosan. 1 selected from
More than one type of water-absorbing and hardly water-soluble base is preferable, and among them, crystalline cellulose is particularly preferable. Preferred combinations of the water-absorptive and gel-forming base and the water-absorptive and poorly water-soluble base include combinations of the above-described preferred examples, and a particularly preferred combination is water. Hydroxypropylcellulose as an absorbent and gel-forming base and crystalline cellulose as a water-absorbable and poorly water-soluble base can be mentioned.

The amount of the water-absorbing and gel-forming base used in the present invention is determined by the sum of the water-absorbing and poorly water-soluble base and the water-absorbing and gel-forming base. It is about 5 to 40% by weight, preferably 30 to 40% by weight. The amount of the water-absorbing and gel-forming base also depends on the type of the drug of the present invention, and when the drug of the present invention is a non-peptide / protein drug, 5 to 40% by weight as described above. In particular, when the content is 30 to 40% by weight, the effect of increasing the maximum blood concentration is remarkable, which is preferable. Further, when the drug of the present invention is a peptide / protein drug, it is further subdivided depending on the molecular weight, and when the molecular weight is 500 to 1,500, the amount of the water-absorbable and gel-forming base is reduced. When the content is 5 to 30% by weight, the effect of increasing the maximum blood concentration is remarkable, and it is particularly preferable to be 20 to 30% by weight. Further, the molecular weight of the peptide / protein drug is from 1,500 to 3,
In the case of 000, the effect of increasing the maximum blood concentration is remarkable when the amount of the water-absorbing and gel-forming base is 5 to 20% by weight, particularly preferably 10 to 20%.
% By weight. In such a case, the molecular weight is 500 to 1,
500 peptide / protein drugs include vasopressins, luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, oxytocins, hirudin derivatives, enkephalins, adrenocorticotropic hormone derivatives, bradykinin derivatives And at least one peptide / protein drug selected from the group consisting of: calcitonins, insulins, glucagon derivatives, calcitonins, insulins, and glucagon derivatives. Hormones,
Growth hormone releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferons, erythropoietin, granulocyte colony stimulating factor, macrophage stimulating factor, parathyroid gland Examples include one or more peptide / protein drugs selected from the group consisting of hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone, and angiotensin.

The composition of the present invention has a particle size of 90% by weight or more of a water-absorptive and poorly water-soluble base, a particle size of 10 to 350 microns, and a water-absorptive gel. Particles having a particle size of 90% by weight or more of the forming base have a particle size of 1
0-100 microns. Above all, a particle size of 90% by weight or more of the water-absorptive and poorly water-soluble base is 10%.
Particles having a particle size of 10 to 100 microns, and 90% by weight of a water-absorbing and poorly water-soluble base, The particle size of the above particles is 10 to 250 microns, and 90% by weight of the water-absorbing and gel-forming base
When the particle diameter of the above particles is 10 to 50 microns, it is preferable since a further increase in the maximum blood concentration can be obtained. That is, a particularly preferred particle diameter of the composition of the present invention is 90% by weight of a water-absorbable and poorly water-soluble base.
The above particles have a particle size of 10 to 250 microns, and the particles of 90% by weight or more of the water-absorbing and gel-forming base have a particle size of 10 to 50 microns.

In order to produce the composition of the present invention, the following method is preferred. That is, 1. 90% by weight or more of the particles have a particle size of 10 to 350.
After mechanically mixing a drug with a water-absorbable and poorly water-soluble base in the range of 10 microns, 90% by weight or more of the water-absorbable base having a particle size in the range of 10 to 100 microns and 1. a method of mechanically mixing a gel-forming base; After the drug is attached to the water-absorbing and poorly water-soluble base by freeze-drying, 90% by weight or more of the particles are pulverized and sieved so that the particle size becomes 10 to 350 microns, and then the 90% by weight is added. % Or more of the particles have a particle size of 10 to 100.
2. mechanically mixing a water-absorbing and gel-forming base in the micron range, or 90% by weight or more of the particles have a particle size of 10 to 350.
Water-absorbing and poorly water-soluble base in the micron range,
In this method, a water-absorbable and gel-forming base and a drug whose 90% by weight or more particles have a particle size in the range of 10 to 100 microns are simultaneously mechanically mixed. When producing the composition of the present invention, the drug is also prepared by a method other than freeze-drying the drug with a water-absorptive and poorly water-soluble base. It is desirable to keep it.

The amount of drug used in the present invention is an effective therapeutic amount and is specific to each drug. Usually, the amount of each drug is the same amount to 20 times, more preferably the same amount to 10 times the amount used for injection administration. The ratio of the drug of the composition of the present invention to the base (the sum of a water-absorbing and poorly water-soluble base and a water-absorbing and gel-forming base) is determined by the amount of powder applicable to the nasal cavity. Since there is a limit to the amount of the drug, it cannot be unconditionally limited because it depends on the therapeutic amount of the drug. However, the amount is preferably equal to or more than 1 weight of the drug, particularly preferably 5 weight or more, more preferably 1 weight of the drug. 10 weight or more.

The composition of the present invention may contain, if necessary, a known lubricant, binder, diluent, coloring agent, preservative,
Preservatives, flavoring agents and the like may be added. As a lubricant,
For example, talc, stearic acid and its salts, waxes, etc., as binders, for example, starch, dextrin, etc., as diluents, for example, starch, lactose, etc., as coloring agents, for example, red No. 2, etc. Examples of the agent include ascorbic acid, examples of the preservative include paraoxybenzoic acid esters, and examples of the flavoring agent include menthol. In addition, the composition of the present invention is in an appropriate dosage form to be administered as a preparation. Such forms include capsules filled with the present invention in dosage units, which are sprayed intranasally with a suitable dosage device. Alternatively, the composition of the present invention may be contained in an appropriate container for each dosage unit or in a plurality of unit amounts, and the dosage unit may be administered or dividedly administered during the administration operation.

Thus, according to the present invention, even a highly water-soluble drug, a highly fat-soluble drug, and a peptide or protein drug having a large molecular weight are excellent in absorption from the nasal cavity and have the highest blood concentration in conventional nasal administration. It provides a novel powdered nasal composition which is significantly increased over the composition. As a result, not only for expensive peptide / protein drugs, but also for non-peptide / protein drugs, it is possible to obtain a significantly higher maximum blood concentration even with the same amount as before, thereby reducing the amount of drug used. In addition to the above, it is expected that the desired therapeutic effect can be stably obtained by reducing the variation in blood concentration. Further, the present invention not only provides a higher maximum blood concentration, but also has excellent drug absorption (persistence of blood concentration) as well as a conventional powdered nasal administration composition, and has an irritating absorption. There is no need to use an accelerator or the like, and it is expected that the desired therapeutic effect can be stably obtained with safety. The fact that the present invention achieves a higher maximum blood concentration by nasal administration of a drug than in the past can be said to have extremely high significance for drug therapy by administration of a non-injectable drug.

[0028]

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but these do not limit the present invention in any way.

[Examples 1 to 4] As Examples 1 to 4 and Comparative Examples 1 to 5, various bases shown in Table 1 were added to 10 mg of beclomethasone propionate (manufactured by SICOR), which is one of anti-inflammatory steroids. Are mixed in an amount of 150 mg each, and 0.16 m of magnesium stearate is used as a lubricant.
g was added to prepare a powder composition. At this time, microcrystalline cellulose (Avicel PH101 manufactured by Asahi Kasei Corporation)
Means that the particle size of 90% by weight or more of the particles is 100 to 25%.
Hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) having a particle diameter of 90% by weight or more having a particle diameter of 10 to 100 microns was used. In Table 1, microcrystalline cellulose is described as crystalline cellulose, but has the same meaning as "crystalline cellulose" (the same applies hereinafter).

[0030]

[Table 1]

These compositions (Examples 1-4 and Control Examples 1-5) were used as white native male rabbits (body weight 2.5-3.0 k).
g) Intranasal powder administration device (manufactured by Teijin Limited: Publizer)
Was administered such that the dose of the composition was 2 mg / kg. After a certain period of time, blood was collected from the ear vein, and beclomethasone propionate in the blood was measured by RIA. Table 2 shows the results. When the proportion of hydroxypropylcellulose in the whole base is 5 to 40% by weight, the maximum blood concentration is higher than 0% (Comparative Example 1), and further 30 to 4%.
The case of 0% (Examples 3 and 4) shows a higher maximum blood concentration, which indicates that the composition of the present invention has remarkably improved absorption and increased the maximum blood concentration.

[0032]

[Table 2]

[Examples 5 to 8] As Examples 5 to 8 and Comparative Examples 6 to 10, 100 mg of metoclopramide (manufactured by SIGMA), one of the antiemetic drugs, was mixed with various bases described in Table 3 respectively. The powder composition was adjusted by mixing 200 mg each and adding 0.30 mg of magnesium stearate as a lubricant. At this time, microcrystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Corporation) having 90% by weight or more of particles having a particle diameter of 50 to 350 microns, hydroxypropylcellulose (manufactured by Nippon Soda: H
PC-H) has a particle size of 90% by weight or more of the particles.
Each having a size of 0 to 100 microns was used.

[0034]

[Table 3]

These compositions (Examples 5 to 8 and Control Examples 6 to 10) were used as white native male rabbits (body weight 2.5 to 3.0).
kg) into the nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 3 mg / kg. After a certain period of time, blood was collected from the ear vein, and metoclopramide in the blood was measured by the HPLC method. Table 4 shows the results
Shown in When the proportion of hydroxypropylcellulose in the whole base is 5 to 40% by weight, the maximum blood concentration is higher than 0% (Comparative Example 5), and further 30 to 40%.
% (Examples 7 and 8) show a higher maximum blood concentration, indicating that the composition of the present invention significantly improved the absorption and increased the maximum blood concentration.

[0036]

[Table 4]

[Examples 9 to 11] As Examples 9 to 11 and Comparative Examples 11 to 15, 10 mg of leuprolide acetate (manufactured by Bachem), one of luteinizing hormones, was used.
Each of the bases described in Table 5 was mixed in an amount of 200 mg, and magnesium stearate was added as a lubricant.
21 mg was added to adjust the powder composition. At this time, as for leuprolide acetate, a freeze-dried product is pulverized in a mortar, and 90% by weight or more of particles having a particle size of 10 to 150 microns is converted to microcrystalline cellulose (Avic Chemical Co., Ltd .: Avic).
el PH101) has a particle diameter of 50 to 350 microns of 90% by weight or more of the particles, and hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H)
Particles having a particle diameter of 90% by weight or more of 10 to 100 microns were used.

[0038]

[Table 5]

These compositions (Examples 9 to 11 and Control Examples 11 to 15) were used to prepare white native male rabbits (body weight 2.5 to
(3.0 kg) into a nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 2.5 mg / kg. After a certain period of time, blood was collected from the ear vein, and leuprolide acetate in the blood was measured by the RIA method.
Further, as a control example 16, an aqueous solution of leuprolide acetate was simultaneously administered. Table 6 shows the results. When the proportion of hydroxypropylcellulose in the whole base is 5 to 30% by weight, the maximum blood concentration is higher than 0% (Comparative Example 11), and when the proportion is 20 to 30% (Example 10,
11) shows a higher maximum blood concentration, indicating that the compositions of the Examples significantly improved the absorbability and increased the maximum blood concentration.

[0040]

[Table 6]

[Examples 12 to 14] As Examples 12 to 14 and Controls 17 to 22, salmon calcitonin (manufactured by Bachem), which is one of calcitonins, was 0.10 m.
g of each of the bases described in Table 7 in an amount of 150 mg.
Each was mixed, and 0.16 mg of magnesium stearate was added as a lubricant to prepare a powder composition. At this time, the salmon calcitonin was obtained by pulverizing a freeze-dried product in a mortar and crushing 90% by weight or more of particles having a particle size of 10 to 150 microns into microcrystalline cellulose (Avi Kasei Co., Ltd .: Avi
Cel PH101) is a hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) obtained by adjusting the particle size of 90% by weight or more of the particles to 50 to 350 microns.
Means that the particle size of 90% by weight or more of the particles is 10 to 100.
Each having a micron size was used.

[0042]

[Table 7]

These compositions (Examples 12 to 14 and Controls 17 to 22) were used as white native male rabbits (weighing 2.5 to
(3.0 kg) into a nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 0.6 mg / kg. After a certain time, blood was collected from the ear vein, and salmon calcitonin in the blood was measured by the RIA method. As a control 23, an aqueous solution of salmon calcitonin was simultaneously administered. Table 8 shows the results. When the proportion of hydroxypropylcellulose in the whole base is 5 to 20% by weight, the maximum blood concentration is higher than 0% (Control Example 17), and when the proportion is 10 to 20% (Examples 13 and 14). ) Shows a higher maximum blood concentration, which indicates that the compositions of the examples significantly improved the absorbability and increased the maximum blood concentration.

[0044]

[Table 8]

[Examples 15 to 17] As Examples 15 to 17 and Controls 24 to 30, 10 mg of human growth hormone (manufactured by Bachem), which is one of the growth hormones, was used.
Each of the bases described in Table 9 was mixed in an amount of 240 mg each, and magnesium stearate was added as a lubricant in a mixture of 0.1 mg and 0.2 mg of magnesium stearate.
25 mg was added to prepare a powder composition. At this time, human growth hormone is obtained by crushing the freeze-dried product in a mortar,
Particles having a particle size of 10% to 150 μm by weight or more are converted into microcrystalline cellulose (Avicel manufactured by Asahi Kasei Corporation).
PH101) has a particle diameter of 50 to 350 microns of 90% by weight or more of the particles, and hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) has a particle diameter of 90% or more of the particles. Each having a size of 10 to 100 microns was used.

[0046]

[Table 9]

These compositions (Examples 15 to 17 and Control Examples 23 to 29) were used as white native male rabbits (body weight 2.5 to 2.5).
(3.0 kg) into a nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 2.5 mg / kg. After a certain period of time, blood was collected from the ear vein, and human growth hormone in the blood was measured by the RIA method. As a control example 30, an aqueous solution of human growth hormone was simultaneously administered. Table 10 shows the results. When the proportion of hydroxypropylcellulose in the whole base is 5 to 20% by weight, the maximum blood concentration is higher than 0% (Comparative Example 24), and when the proportion is 10 to 20% (Examples 16 and 17). )
Indicates higher peak blood levels, indicating that the compositions of the Examples significantly improved the absorption and increased the peak blood levels.

[0048]

[Table 10]

[Examples 18 to 26] A water-absorbing and poorly water-soluble base containing leuprolide acetate (manufactured by Bachem) as a main ingredient using the two bases listed in Table 11 below. A composition having a weight ratio of water-absorbable and gel-forming base of 80:20 was prepared and administered to rabbits under the same conditions as in Example 10. In addition, compositions were prepared in the same manner as in Examples 18 to 26 using the bases shown in Table 11 as Control Examples 31 to 39 and administered to rabbits. Here, 90% by weight of the water-absorbable and poorly water-soluble base shown in Table 11
The above particles had a particle size of 50 to 350 microns, and the particles having a water-absorbing and gel-forming base material of 90% by weight or more had a particle size of 10 to 100 microns.

[0050]

[Table 11]

Table 12 shows the obtained maximum blood concentrations and their times. It can be seen that Examples 18-26 give significantly higher peak blood concentrations, whereas Control Examples 31-39 absorb but have lower peak blood concentrations compared to the Examples.

[0052]

[Table 12]

[Examples 27 to 30] A water-absorbing and poorly water-soluble base containing leuprolide acetate (manufactured by Bachem) as a main ingredient using the two bases listed in Table 13 below. A composition having a weight ratio of water-absorbable and gel-forming base of 80:20 was prepared and administered to rabbits under the same conditions as in Example 10. In addition, compositions were prepared in the same manner as in Examples 27 to 30 using the bases shown in Table 13 as Control Examples 40 to 45 and administered to rabbits. Here, 90% by weight of the water-absorbable and poorly water-soluble base shown in Table 13
The above particles had a particle size of 50 to 350 microns, and the particles having a water-absorbing and gel-forming base material of 90% by weight or more had a particle size of 10 to 100 microns.

[0054]

[Table 13]

Table 14 shows the obtained maximum blood concentration and the time. It can be seen that Examples 27-30 give significantly higher peak blood concentrations, whereas Controls 40-45 absorb but have lower peak blood concentrations compared to the Examples.

[0056]

[Table 14]

[Examples 31 to 58] The ratio of the weight of hydroxypropylcellulose to the sum of the weights of hydroxypropylcellulose and microcrystalline cellulose was 5, 10, 20, 30, 30 for the various drugs listed in Table 15 below.
A powdery composition was prepared using a base at 40 and 50% by weight and administered to rabbits in the same manner as in the previous example, and the blood concentration was measured by radioactivity.

[0058]

[Table 15]

Similarly, powdery compositions consisting only of microcrystalline cellulose of various drugs were prepared and administered to rabbits. Here, microcrystalline cellulose has a particle diameter of 50 to 350 microns of particles of 90% by weight or more, and hydroxypropyl cellulose has a particle diameter of 10 to 100 microns of particles of 90% or more. did. Table 16 shows relative values of the respective maximum blood concentrations when the maximum blood concentration of microcrystalline cellulose alone was set to 1.0.
Thus, in the case of a non-peptide proteinaceous drug, the maximum blood concentration increases remarkably when hydroxypropylcellulose is 5 to 40% by weight, particularly when the concentration is 30 to 40% by weight. Is even more pronounced and has a molecular weight of 5
In the case of the peptide-proteinaceous drug of 00 to 1,500, the maximum blood concentration increases remarkably when hydroxypropylcellulose is 5 to 30% by weight, particularly when the concentration is 20 to 30% by weight. In the case of peptide-proteinaceous drugs having a molecular weight of 1,500 to 30,000, hydroxypropylcellulose is increased by 5%.
It can be seen that the increase in the maximum blood concentration is remarkable when it is 重量 20% by weight, and the increase in the maximum blood concentration is particularly remarkable when it is 10-20% by weight.

[0060]

[Table 16]

Examples 59-61 Examples 59-61 and Control Examples 46-49 (Control Example 48 was omitted) were estradiol dipropionate, one of the sex steroid hormones (Wako Pure Chemical Industries, Ltd.) Crystalline cellulose (Avicel PH101 from Asahi Kasei Corporation) and hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-) prepared in advance to the particle size shown in Table 17 to 10 mg.
H) was mixed in an amount of 140 mg and 60 mg each, and 0.21 m of magnesium stearate was used as a lubricant.
g was added to prepare a powder composition. Controls 50 to 5
200 mg of crystalline cellulose having the particle size shown in the table as 2
And estradiol dipropionate (10 mg) to prepare a composition.

[0062]

[Table 17]

These compositions (Examples 59 to 61 and Control Examples 46 to 52) were used as white native male rabbits (body weight 2.5 to 2.5).
(3.0 kg) in a nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 2 mg / kg. After a certain period of time, blood was collected from the ear vein, and estradiol dipropionate in the blood was measured by the RIA method. The results are shown in Table 18. The particle size of crystalline cellulose, which is a water-absorbing and poorly water-soluble base, is 90% by weight of 50 to 350 microns, and the particle size of hydroxypropylcellulose, a water-absorbing and gel-forming base, is as follows: When 90% by weight thereof is 10 to 100 microns (Example 59), the crystals exhibit a higher maximum blood concentration than the others (Control Examples 46 to 52), and are water-absorbable and poorly water-soluble bases. The particle size of cellulose is 90% by weight of 10
Hydroxypropylcellulose, which is a water-absorbing and gel-forming base at 0-250 microns, has a particle size of
When 90% by weight thereof is 10 to 100 microns (Example 60), the particle size of the crystalline cellulose as a water-absorbing and poorly water-soluble base is 100 to 25% by weight.
Hydroxypropylcellulose, which is a water-absorbing and gel-forming base at 0 microns, has a particle size of 90%.
When the weight% is 20 to 50 microns (Example 61), it shows a further remarkable peak blood concentration, which indicates that the composition has significantly improved absorption and increased the peak blood concentration.

[0064]

[Table 18]

[Examples 62 to 64] Salmon calcitonin (Bach), one of calcitonins, was used as Examples 62 to 64 and Control Examples 53 to 56 (Control Example 55 was omitted).
em) (0.10 mg) and crystalline cellulose (Avi Kasei: Avi) prepared in advance to the particle size shown in Table 19.
cel PH101) and hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) are each 120 m.
g and 30 mg each, and 0.16 mg of magnesium stearate was added as a lubricant to prepare a powder composition. In addition, 150 mg of crystalline cellulose and salmon calcitonin 0.1 having the particle sizes shown in the same table as Comparative Examples 57 to 59 were used.
0 mg was mixed to prepare a composition.

[0066]

[Table 19]

These compositions (Examples 62 to 64, Control Examples 53 to 59) were used as white native male rabbits (body weight 2.5 to
(3.0 kg) into a nasal cavity with a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 0.6 mg / kg. After a certain time, blood was collected from the ear vein, and salmon calcitonin in the blood was measured by the RIA method. The results are shown in Table 20. In the case where crystalline cellulose has a particle size of 90% by weight or more of particles of 10 to 100 microns, and hydroxypropyl cellulose has a particle size of 90% by weight or more of particles of 50 to 350 microns (Example 6)
2) shows a higher maximum blood concentration than the others (Control Examples 53 to 59), and furthermore, crystalline cellulose has a particle size of 90% by weight or more of the particles in 100 to 250 microns, and hydroxypropyl cellulose has When the particle diameter of 90% by weight or more of the particles is 10 to 100 microns (Example 6)
3) and in the case where crystalline cellulose has a particle size of at least 90% by weight of 100 to 250 microns and hydroxypropylcellulose has a particle size of at least 90% by weight of 20 to 50 microns ( Example 6
4), further showing a remarkable maximum blood concentration, which shows that the compositions of the Examples significantly improved the absorbability and increased the maximum blood concentration.

Further, the particle size of particles of 90% by weight or more of crystalline cellulose and hydroxypropyl cellulose is 20 to
In the case of 150 microns (Control Example 53), there was no difference in the maximum blood concentration compared with the case of crystalline cellulose alone (Control Example 59), and some persistence was observed. In addition, the particle size of 90% by weight or more of the crystalline cellulose is 10 to 10%.
When the composition was prepared with the particle diameter of 0 micron and 90% by weight or more of hydroxypropylcellulose being 50 to 350 microns (Control Example 56), a remarkable decrease in the maximum blood concentration was confirmed as compared with crystalline cellulose alone. .

[0069]

[Table 20]

Examples 65-66 As Examples 65-66 and Control Examples 60-62, leuprolide (Bachem), one of the luteinizing hormone releasing hormones, was used.
Crystalline cellulose (Avicel PH101 manufactured by Asahi Kasei Co., Ltd.) in which the particle size of particles of 90% by weight or more is adjusted to 50 to 350 microns in 10 mg and 90% by weight thereof.
Hydroxypropylcellulose prepared by adjusting the particle size of the particles by weight to at least 10 to 100 microns (manufactured by Nippon Soda Co., Ltd .:
HPC) was mixed with 160 mg and 40 mg each, and 0.21 magnesium stearate was used as a lubricant.
mg was added to adjust the powder composition. However, the viscosity of the used hydroxypropylcellulose was 2.0 to 2.9 cps in a 2% aqueous solution (Comparative Example 60), and 3.0 to 3.0.
5.9 cps (Control Example 61), 6.0 to 10.0
cps (Control Example 62), 150-400 cps (Example 65), and 1000-4000 cps
(Example 66) was used. These compositions (Examples 65 to 66, Control Examples 60 to 62) were administered to a nasal cavity of a white native male rabbit (body weight: 2.5 to 3.0 kg) by a powder dispenser (Publicizer manufactured by Teijin Limited). At the dose of the composition,
The dose was 2.5 mg / kg. After a certain period of time, blood was collected from the ear vein, and leuprolide in the blood was measured by the RIA method. The results are shown in Table 21. It can be seen that when the viscosity of hydroxypropylcellulose is 150 cps or more, the absorbability is remarkably improved and the maximum blood concentration is increased.

[0071]

[Table 21]

Example 67 Example 67 and Comparative Example 63
-65, FITC-dextran (S), a hydrophilic polysaccharide that can be a model compound for peptide / protein drugs
Sigma, average molecular weight 4400)
Hydroxypropyl cellulose (Nippon Soda Co., Ltd .: HPC), crystalline cellulose (Asahi Kasei Co., Ltd .: Avic) having 90% by weight or more of the particles having a particle size as described in No. 2
el PH101) in a mixture of 19 mg and 171 mg respectively (Example 67, Control Examples 63 and 64), or
Crystalline cellulose (Avicel PH10 manufactured by Asahi Kasei Corporation)
1) Only 190 mg was mixed (Control Example 65) to prepare a powdery composition. These compositions were administered into the nasal cavity of a white native male rabbit (body weight 3 kg) using a powder administration device (manufactured by Teijin Limited: Publyzer) so that the dose of the composition was 4 mg / kg. After a certain period of time, blood was collected from the ear vein, and the concentration of FITC-dextran (FD4) in the blood was measured by HPLC. The results are shown in FIG. By combining 11% by weight of hydroxypropylcellulose, a water-absorbable and gel-forming base, with crystalline cellulose, which is a water-absorbable and poorly water-soluble base, the maximum blood level is higher than that of crystalline cellulose alone. Concentration can be improved,
Further, the particle diameter of hydroxypropyl cellulose is adjusted to 38.
It can be seen that the composition of the present invention having a size of ５０50 microns can further significantly increase the maximum blood concentration.

[0073]

[Table 22]

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a powdery nasal administration composition of the present invention having improved absorbability (Example 67: -O- and a control nasal powder composition (Control Examples 63 to 65). :-□-,-, respectively
FITC-dex when Δ- and-×-were administered to rabbits
The tran concentration (ng / ml) is shown.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 38/11 A61K 47/36 38/17 47/38 38/21 47/42 38/22 37/02 38/23 37/24 38/26 37/26 38/27 37/28 38/28 37/30 38/55 37/34 45/00 37/36 47/32 37/42 47/36 37/43 47/38 37/64 47 / 42 37/66 H (72) Inventor Takao Fujii 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Limited Tokyo Research Center (56) References JP-A-60-224616 (JP, A) Hei 7-507303 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 47/30-47/42

Claims (14)

(57) [Claims] Claims 1. Drugs and a. At least one water-absorbable and gel-forming base selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose; c. Crystalline cellulose, alpha-cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked starch, gelatin, casein, tragacanth gum, Oyo
A powdery nasal composition comprising at least one water-absorbable and poorly water-soluble base selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone, wherein (1) said water-absorbable and gel-forming composition The water-soluble base is 5 to 40% by weight of the sum of the water-absorbable and poorly water-soluble base and the water-absorbable and gel-forming base. (3) 90% by weight of the water-absorbable and gel-forming base, wherein the particle size of the particles of at least 90% by weight of the base which is absorptive and poorly water-soluble is in the range of 10 to 350 microns;
A powdery composition for nasal administration wherein the particles have a particle size in the range of 10 microns to 100 microns. 2. The water-absorbable and poorly water-soluble base of 90
Weight percent or more of the particles have a particle size in the range of 38-250 microns, and 90% or more of the water-absorbable and gel-forming base particles have a particle size in the range of 10-65 microns. A composition for nasal administration according to claim 1. 3. The powdery powder according to claim 1, wherein the drug is a drug selected from the group consisting of non-peptide / proteinaceous drugs and peptide / proteinaceous drugs having a molecular weight of not more than 30,000. Nasal composition. 4. The non-peptide / proteinaceous drug includes an anti-inflammatory steroid, an analgesic / anti-inflammatory, an antitussive expectorant, an antihistamine, an antiallergic, an antiemetic, a sleep-inducing drug, a vitamin, a sex steroid hormone, an antitumor Drugs, antiarrhythmic / hypertensive, anti-anxiety / psychotropic, anti-ulcer, inotropic, analgesic, bronchodilator, obesity, platelet aggregation inhibitor, diabetes, muscle relaxant, and antirheumatic The powdery composition for nasal administration according to claim 3, which is at least one non-peptide / protein drug selected from the group consisting of: 5. The method according to claim 1, wherein the peptide / protein drug is a luteinizing hormone-releasing hormone, a growth hormone-releasing factor, a somatostatin derivative, a vasopressin, an oxytocin, a hirudin derivative, an enkephalin, an adrenocorticotropic hormone derivative, Bradykinin derivatives, calcitonins, insulins, glucagon derivatives, growth hormones, growth hormone releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferon Erythropoietin, granulocyte colony stimulating factor, macrophage stimulating factor, parathyroid hormones, parathyroid hormone releasing hormone, prolactin, thyroid stimulating hormone releasing hormone,
The powdery nasal administration composition according to claim 3, which is at least one peptide / protein drug selected from the group consisting of and angiotensin. 6. The method according to claim 1, wherein the drug has a molecular weight of 500 to 1,50.
0, wherein the amount of the water-absorbing and gel-forming base is the same as the water-absorbing and poorly water-soluble base and the water-absorbing and gel-forming base. The nasal powder composition according to claim 1, which is about 5 to 30% by weight of the sum of the amounts of the compounds. 7. The peptide / proteinaceous drug may be a vasopressin, a luteinizing hormone releasing hormone, a growth hormone releasing factor, a somatostatin derivative, an oxytocin, a hirudin derivative, an enkephalin, an adrenocorticotropic hormone derivative, The powdery composition for nasal administration according to claim 6, wherein the composition is at least one peptide / protein drug selected from the group consisting of bradykinin derivatives. 8. The method according to claim 1, wherein the drug has a molecular weight of 1,500 to 3,
000 peptide-proteinaceous drugs, wherein the amount of the water-absorbable and gel-forming base is the same as that of the water-absorbable and poorly water-soluble base. The powdered nasal composition according to claim 1, wherein the composition is about 5 to 20% by weight of the total amount of the base. 9. The peptide / proteinaceous drug may be a calcitonin, an insulin, a glucagon derivative, a growth hormone, a growth hormone releasing hormone, a luteinizing hormone, an insulin-like growth factor, a calcitonin gene-related peptide, Atrial natriuretic peptide derivatives, interferons, erythropoietin, granulocyte colony stimulating factor, macrophage stimulating factor,
Parathyroid hormones, parathyroid hormone releasing hormone,
The powdery composition for nasal administration according to claim 8, which is at least one peptide / protein drug selected from the group consisting of prolactin, thyroid-stimulating hormone-releasing hormone, and angiotensin. 10. The water-absorptive and poorly water-soluble base,
Microcrystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth, and at least one water-absorbing and poorly water-soluble base selected from the group consisting of polyvinylpyrrolidone. 10. A powdery nasal administration composition according to any one of claims 9 to 9. 11. The water-absorptive and poorly water-soluble base,
The powdery nasal administration composition according to any one of claims 1 to 9, which is crystalline cellulose. 12. The water-absorbing and gel-forming base is at least one water-absorbing and gel-forming base selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and sodium carboxymethylcellulose. The base of claim 1
12. The composition for nasal administration in powder form according to any one of claims 11 to 11. 13. The water-absorbable and gel-forming base is hydroxypropylcellulose.
The powdery composition for nasal administration according to any one of claims 1 to 10. 14. The method of claim 14, wherein the hydroxypropyl cellulose is
The powdery composition for nasal administration according to claim 13, which is a hydroxypropylcellulose having a viscosity of 150 to 4,000 cps in a 2% aqueous solution.