JP3197223B2 - A powdery composition for nasal administration that has both immediate effect and sustainability - 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 capable of absorbing a drug from the nasal mucosa immediately, efficiently and efficiently. More specifically, the present invention relates to a powdery composition for nasal administration capable of immediately and continuously absorbing a drug from the nasal mucosa by specifying the composition of the base.

[0002]

BACKGROUND OF THE INVENTION Some non-peptide and proteinaceous drugs, such as anti-inflammatory steroids, analgesics and anti-inflammatory drugs, antitussives, antihistamines, antiallergic drugs, antiemetic drugs, sleep-inducing drugs, vitamins, sex steroid hormones, Oncologic, antiarrhythmic
For drugs such as hypertensive drugs, anti-anxiety / psychotropic drugs, anti-ulcer drugs, inotropic drugs, analgesics, bronchodilators, obesity drugs, platelet aggregation inhibitors, diabetes drugs, muscle relaxants, anti-rheumatic drugs, etc.
The development of nasal drugs is desired in situations where oral administration is not possible, where rapid action is desired compared to oral administration, or where the absorption rate due to oral administration is low and drug efficacy is difficult to develop. ing.

[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 more developed vasculature than 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, cilia are present on cells on the surface of the nasal mucosa, and foreign substances such as drugs administered to the surface of the nasal mucosa are quickly discharged to the pharynx by the ciliary movement.
For this reason, it has been pointed out that many drugs have low absorption from the nasal mucosa and that their blood concentrations disappear quickly. Therefore, a device for improving and sustaining absorption of these drugs from the nasal mucosa has been proposed.

For example, Suzuki et al. (JP-B-60-34925)
Discloses a continuous nasal preparation comprising a nasal composition comprising cellulose ether, which efficiently supplies a drug at a concentration sufficient to obtain a therapeutic effect.

[0005] Suzuki et al. (JP-B-62-42888) disclose a powdery nasal administration composition comprising a water-absorbing and poorly water-soluble base such as crystalline cellulose without using irritating additives. However, it discloses a method for nasal absorption of polypeptides. It has been reported that polypeptides such as insulin and calcitonin can be remarkably efficiently absorbed by this method as compared with conventional liquid intranasal compositions. Specifically, in Example 6 of the publication, when calcitonin was intranasally administered together with crystalline cellulose, which is a water-absorbable and poorly water-soluble base, the maximum blood concentration and blood concentration were higher than those of a control nasal solution. Which have excellent sustainability.

Further, the publication discloses that a water-absorbing and poorly water-soluble base such as hydroxypropylcellulose is used as a water-absorbing and poorly water-soluble base. 0.1 to 60% by weight, particularly preferably 1 to 60% by weight
It is disclosed that when used in a combined amount of 50% by weight, a powdery nasal administration composition having sustained release properties is provided. For example, the crystalline cellulose of Example 2 (a water-absorbing and poorly water-soluble base) is used in combination with 80% by weight of a water-absorbing and sodium polyacrylate (a water-absorbing and water-soluble base). Compared to the crystalline cellulose alone formulation, there was no difference in the blood glucose lowering rate (no difference in the maximum blood concentration), but a sustained effect of the blood concentration based on sustained release was suggested. I have. 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.

The above water-absorbing and poorly water-soluble base is 0.1 to 60% by weight, particularly preferably 1 to 5% by weight.
The amount of the water-absorbable and water-soluble base of 0% by weight is based on the sum of the amount of the water-absorbable and poorly water-soluble base and the amount of the water-absorbable and water-soluble base. When converted again as the amount of the base material having poor solubility in water, it becomes 62.5 to 99.9% by weight, preferably 66.7 to 99.0% by weight.

[0008] 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. Has poor retention on mucous membranes, so that 90% by weight of the composition has a particle size of 20 to 1
It discloses that it is preferably in the range of 50 microns.

However, the same publication discloses that the water-absorbing and poorly water-soluble base and the water-absorbing and water-soluble base having different particle size distributions are used.
There is no description or suggestion of the effect obtained thereby.

[0010]

According to the method of Suzuki et al. (Japanese Patent Publication No. 60-34925), for a drug which originally exhibits good nasal absorption, an effective amount of the drug is continuously released. It is possible to absorb an amount showing a medicinal effect. Specifically, the publication discloses that an effective amount of a drug can be continuously released by using a drug such as an anti-inflammatory steroid and a cellulose ether in combination. That is, Examples 5 and 6 of the publication disclose that when intranasal administration of triamcinolone acetonide, which is one of the anti-inflammatory steroids, together with hydroxypropylcellulose or methylcellulose, a longer therapeutic effect can be obtained as compared with the control aqueous solution. Have been.

However, the onset of this effect was 6% after administration.
It is １２12 hours, and it is clear that the result is that although the durability is obtained, the immediate effect is obtained at the same time as the durability. The reason is that this technology is based on the phenomenon that cellulose ether administered into the nasal cavity with a drug gels on the nasal mucosa, stays with the drug, and the drug is gradually released from the base and absorbed. This is probably because the drug is not provided with the function of absorbing the drug immediately.

[0012] That is, in the case of the preparation described in the publication, the absorption of the drug is continued due to the viscosity of the base, but the absorption is not promptly recognized to that extent, and as a result, the onset of the drug effect is delayed. is there. When a liquid preparation is used to reduce the viscosity of the base in order to obtain the immediate effect of the drug, there are problems such as insufficient sustainability of absorption.

As mentioned above, Suzuki et al.
No. 42888) discloses that a powdery nasal composition comprising a water-absorptive and poorly water-soluble base allows polypeptides to be efficiently nasal-absorbed, and is water-absorbable and easily water-soluble. It is disclosed that the use of the above base at a specific blending ratio provides a powdery nasal administration composition having sustained release properties.

[0014] However, even in the method disclosed in the publication, sufficient sustainability is not always obtained.

As described above, in the prior art, the immediate effect and the sustainability are contradictory, and it is impossible to combine them, and from the viewpoint of the therapeutic effect of the drug and the treatment efficiency, both are combined. There is a strong demand for the development of new formulations. There is also a strong demand for the development of more excellent preparations in terms of sustainability.

That is, an object of the present invention is to provide a powdery composition for nasal administration which is more excellent in the sustainability of drug absorption.

It is another object of the present invention to provide a powdery composition for nasal administration which has both immediate effect and sustainability of drug absorption.

It is a further object of the present invention to provide not only peptide / protein drugs but also non-peptide / protein drugs as drugs, which have such excellent absorption continuity, or both immediate effect and continuity of absorption. To provide a powdered composition for nasal administration.

The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have determined that a specific water-absorbing and poorly water-soluble base and a specific water-absorbing and gel-forming base are specified. It has been found that a powdery composition for nasal administration can be provided which is more excellent in sustainability of a drug absorbed from the nasal mucosa, or which has both immediate effect and sustainability in combination with the compounding ratio. More specifically, by specifying the type and composition of the base, the drug can be absorbed from the nasal mucosa more sustainedly or immediately and continuously, and a powder that can provide immediate effect and sustained therapeutic effect of the drug. It has been discovered that nasal administration compositions can be provided.

Moreover, such effects are not limited to the case where a polypeptide (peptide / proteinaceous drug) is used as a drug, and the same applies to the case where a non-peptide / proteinaceous drug is used, or the effect of peptide / proteinaceous drug. It has been found that nonpeptidic and proteinaceous drugs have a better immediate and sustained absorption effect than drugs.

Further, the present inventors have conducted intensive studies on the particle size of such a powdery nasal administration composition in which the composition of the base was specified. The powder is mainly distributed near the pharynx and in the posterior lower turbinate, and the powder of 50 to 100 microns is deposited and distributed in the middle part of the nasal cavity centering on the middle turbinate.
The ~ 350 micron powder was found to be mainly deposited and distributed in the anterior part of the nasal cavity, in the nasal vestibule, in the upper turbinate and in the middle turbinate. Of these 100-350 microns, particles of 150 microns or more are said to have poor particle deposition on the nose, and powder having such a relatively large particle size is distributed in the front of the nasal cavity after spraying. What we did 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.

Based on these findings, the inventors of the present invention have found that in a powdery nasal administration composition in which the composition of such a base is specified, the particle size of particles of 90% by weight or more of both bases is further improved. Is a specific range, the particle size of 90% by weight or more of the water-absorptive and poorly water-soluble base is particularly preferred.
By providing a particle size of 50-350 microns for particles that are -100 microns, 90% by weight or more of the water-absorbable and gel-forming base, better sustained absorption, or immediate and sustained It has also been found that absorption can be obtained.

It is presumed that the reason for this is that the distribution in the nasal cavity after spraying has changed due to the change in the particle size of the two bases. That is, when a water-absorbable and poorly water-soluble base and a water-absorbable and gel-forming base are sprayed with the same particle size distribution, both bases adhere to the nasal cavity with almost the same distribution, Reduce the particle size distribution of the water-absorbing and poorly water-soluble base, or reduce the particle size distribution of the water-absorbing and poorly water-soluble base and increase the particle size distribution of the water-absorbing and gel-forming base As a result, the distribution of both bases in the nasal cavity after spraying changes, and a water-absorbable and poorly water-soluble base provides immediate absorption, while a water-absorbable and gel-forming base provides a sustained This contributes to absorption, and the effect of the present invention is further enhanced.

Based on these findings, the present inventors have conducted intensive studies on the above-mentioned limitations of the prior art, and found that they have superior sustainability, or immediate action and sustainability, as compared with conventional powder nasal administration compositions. The present invention has been found to provide a powdery composition for nasal administration having a combined function, and has arrived at the present invention.

[0025]

SUMMARY OF THE INVENTION Accordingly, 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. Comprising at least one water-absorptive and poorly water-soluble base selected from the group consisting of crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, casein, tragacanth gum, polyvinylpyrrolidone, chitin, and chitosan. A powdery composition for nasal administration, wherein the amount of the water-absorbable and poorly water-soluble base is the amount of the water-absorbable and poorly water-soluble base and the water-absorbable and gel-forming base A nasal composition in powder form which is about 5 to 40% by weight of the total amount.

[0026]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the drug of the present invention include one or more drugs selected from the group consisting of non-peptide / protein drugs and peptide / protein drugs having a molecular weight of not more than 30,000. it can.

As the non-peptide / protein drug, a wide variety of non-peptide / protein drugs can be used.
Examples include anti-inflammatory steroids, analgesic anti-inflammatory drugs, antitussive expectorants, antihistamines, antiallergics, antiemetics, sleep-inducing drugs, vitamins, sex steroid hormones, antitumor drugs, antiarrhythmic and hypertensive drugs, One selected from the group consisting of anti-anxiety / psychotropic drugs, anti-ulcer drugs, inotropic drugs, analgesics, bronchodilators, obesity drugs, platelet aggregation inhibitors, diabetes drugs, muscle relaxants, anti-rheumatic drugs, etc. The above non-peptide / protein drugs can be mentioned.

Specific examples of non-peptide / protein drugs include hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, fluticasone, mometasone, fluocortin,
Anti-inflammatory steroids or non-steroidal anti-inflammatory drugs such as budesonide, salbutamol, salmeterol; acetaminophen, phenacetin, aspirin, aminopyrine,
Analgesic and anti-inflammatory drugs such as sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, ibuprofen, alclofenac, diclofenac, indomethacin; antitussive expectorants such as sodium cromoglycate, codeine phosphate, isoproterenol hydrochloride; diphenhydramine, triproproline Antihistamines such as lysine, isotipendyl and chlorpheniramine; amlexanox,
Antiallergic drugs such as azelastine, ozacrel, tranilast, and ketotifen; antiemetic drugs such as ondansetron, granisetron, metoclopramide, cisapride, domperidone; hypnotic drugs such as brotizolam; vitamins such as cyanocobalamin and mecobalamin; Sex steroid hormone drugs such as progesterone and testosterone; antitumor drugs such as tamoxifen and tegafur; propranolol, atenolol,
Antiarrhythmic / hypertensive drugs such as nicardipine; antianxiety / psychotropic drugs such as diazepam and nitrazepam; antiulcer drugs such as cimetidine and ranitidine; inotropic drugs such as dopamine; analgesics such as buprenorphine; bronchial tubes such as oxytropium and ozacrel Dilatation drugs; antiobesity drugs such as mazindol; platelet aggregation inhibitors such as beraprost and carbcycline; diabetes drugs such as acarbose and sorbinyl; muscle relaxants such as pinaverium and inaperizone; antirheumatic drugs such as actarit and platonin; You.

The peptide / protein drug of the present invention preferably has a molecular weight of not more than 30,000, and such a peptide / protein having 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, as a water-absorbing and gel-forming base, at least one water-absorbing and / or water-absorbing base selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose. A gel-forming base is used.

Among these, the water-absorbing and gel-forming base of the present invention includes at least one water-absorbing base selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and sodium carboxymethylcellulose. And a gel-forming base. Among them, hydroxypropylcellulose is particularly preferred.

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 4,000.
It is preferably cps. Some hydroxypropyl celluloses have lower viscosities, but 150 cps
When a substance having a lower viscosity 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-absorptive and poorly water-soluble base of the present invention is selected from the group consisting of crystalline cellulose, α-cellulose, crosslinked sodium carboxymethylcellulose, crosslinked starch, gelatin, polyvinylpyrrolidone, chitin and chitosan. One or more selected water-absorptive and poorly water-soluble bases are preferred, and among them, crystalline cellulose is particularly preferred.

A preferred combination of a water-absorbing and gel-forming base and a water-absorbing and poorly water-soluble base is as follows:
Combinations of the preferred examples described above are mentioned. Particularly preferred combinations are hydroxypropylcellulose as a water-absorbing and gel-forming base and crystal as a water-absorbing and poorly water-soluble base. Cellulose can be mentioned.

The amount of the water-absorbable and poorly water-soluble base used in the present invention is about the sum of the water-absorbable and poorly water-soluble base and the water-absorbable and gel-forming base. 5-40% by weight
It is. In the present invention, by mixing the water-absorbable and poorly water-soluble base with the water-absorbable and gel-forming base in such a ratio, the sustained absorption effect of the present invention, which is superior to the conventional one, can be obtained. Or an immediate and sustained absorption effect.

The amount of the water-absorbing and poorly water-soluble 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. The amount is about 5 to 40% by weight, but this value can be appropriately adjusted depending on the physical properties of the drug, the required blood profile, and the like. For example, in the case of a highly fat-soluble drug, an ideal immediate and sustained absorption can be obtained at about 5 to 20% by weight of about 5 to 40% by weight. In the case of expensive drugs, about 20% out of about 5-40% by weight
In the case of ４０40% by weight, it is desirable because an ideal immediate and sustained absorption can be obtained.

[0038] The composition of the present invention can also enhance its effect by changing the state of the drug. For example, even when the drug is uniformly dispersed in a water-absorbable and poorly water-soluble base and a water-absorbable and gel-forming base, immediate and sustained absorption and immediate Although it is possible to obtain a sustained pharmacological effect, it is also possible to enhance the effect by unevenly distributing the drug to a water-absorbable and gel-forming base.

Here, the state in which the drug is uniformly dispersed means that
Drugs adhering to powder consisting of a water-absorbing and poorly water-soluble base and a water-absorbing and gel-forming base adhere to both bases according to the mixing ratio of both bases The state that is doing. Therefore, 80% by weight of the whole drug adheres to the powder, and the amount of the base in which the powder is water-absorbable and poorly water-soluble is the same as that of the water-absorbable and poorly water-soluble base. In the case of a compounding ratio of 40% by weight of the sum of the gel-forming bases, the water-absorbing and poorly water-soluble base contains 32% by weight of the drug, and the water-absorbing and gel-forming bases It means a state where 48% by weight of the drug is attached to the agent. on the other hand,
The state in which the drug is unevenly distributed in the water-absorbable and gel-forming base means that when the mixing ratio of both bases is the same as above, the amount of the drug exceeding 48% by weight is water-absorbable and It refers to a state of being attached to a gel-forming base.

In the above description, the expression that the drug is attached to the base means that the whole drug is attached to the surface of the base and that the drug is partly taken into the base. The term also includes a state in which a part is exposed to the outside from the surface of the base and a state in which the entire drug is taken into the base.

The presence state of the drug in the composition of the present invention can be adjusted by, for example, its production method. That is, when the drug is uniformly attached and dispersed in a water-absorbable and poorly water-soluble base and a water-absorbable and gel-forming base,
A method of mechanically mixing a drug with a water-absorbable and poorly water-soluble base and a water-absorbable and gel-forming base simultaneously, or a method of mixing a drug with a water-absorbable and poorly water-soluble base and water And a gel-forming base can be simultaneously dissolved and suspended in purified water, freeze-dried and then pulverized. When the drug is unevenly distributed on the water-absorbing and gel-forming base, the drug is first mechanically mixed with the water-absorbing and gel-forming base, and then the water-absorbing and water-hardening base is mixed. A method of mixing a soluble base, or dissolving a drug in purified water together with a water-absorbable and gel-forming base, freeze-drying and pulverizing, and mechanically mixing with a water-absorbable and poorly water-soluble base Can be obtained.

There is no particular limitation on the particle size of both bases in the composition of the present invention. Generally, the particle size of 90% by weight or more of the composition is in the range of 20 to 150 microns. However, 90% by weight or more of both the water-absorbing and poorly water-soluble base and the water-absorbing and gel-forming base have a particle size of 10 microns to 35%.
In the case where the average particle diameter is in the range of 0 micron, the particle size of 90% by weight or more of the water-absorbing and poorly water-soluble base is preferably 10%.
In the range of from 10 microns to 350 microns, especially if the particle size of more than 90% by weight of the water-absorbing and gel-forming base is in the range from 10 microns to 350 microns. 90% by weight or more of a water-absorbable and gel-forming base having a particle size of 10 to 100 microns in a particle size of 90% by weight or more of the poorly water-soluble base.
When the particle diameter of the above particles is in the range of 50 μm to 350 μm, it is preferable because more excellent continuous absorption or immediate and continuous absorption can be obtained.

In this case, as a method of adjusting the particle size, a method of mechanically mixing using a base material whose particle size has been adjusted in advance, for example, the particle size of 90% by weight or more of the particles is 10 μm to 350 μm. Crushing and sieving to be in the range of, a method combining these methods,
For example, a method known to those skilled in the art can be used.

In preparing the composition of the present invention, the drug may be prepared in advance by a method other than freeze-drying the drug with a water-absorbable and poorly water-soluble base, for example, by reducing the particle size of 90% by weight or more of the drug. It is desirable to set it to 10 to 350 microns.

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 the amount of the water-absorbing and poorly water-soluble base and the amount of the water-absorbing and gel-forming base) is determined in the nasal cavity. Since there is a limit to the amount of powder that can be applied, the amount depends on the therapeutic amount of the drug, so it cannot be limited unconditionally. However, the amount is preferably equal to or more than 1 weight of the drug, particularly preferably 5 weight per 1 weight of the drug. The weight is more preferably 10 weight or more.

The composition of the present invention may contain, if necessary, known lubricants, binders, diluents, coloring agents, preservatives, and the like, in order to improve the physical properties, appearance, and odor of the preparation.
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.

Further, the composition of the present invention is in a suitable dosage form to be administered as a pharmaceutical. 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, as described above, the present invention provides a powdery composition for nasal administration which is more excellent in the sustainability of drug absorption by specifying the type and composition of the base, and the immediate effect of drug absorption. Powdery nasal administration composition with long-lasting properties, as well as peptide / protein drugs, as well as non-peptide / protein drugs among drugs, such excellent long-lasting absorption or immediate absorption Providing a powdery composition for nasal administration having both a long lasting property and a long-lasting one has a very high significance for drug therapy by administering a non-injectable drug.

[0050]

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. In the following, the crystalline cellulose of the present invention may be described as crystalline cellulose.

[Examples 1 to 4] As Examples 1 to 4 and Comparative Examples 1 to 4, 10 mg of beclomethasone propionate (manufactured by SICOR), which is one of anti-inflammatory steroids, was prepared by adding various bases shown in Table 1 Were mechanically mixed by 150 mg each, and 0.16 mg of magnesium stearate was added as a lubricant to prepare a powder composition. At this time, microcrystalline cellulose (Avicel P, manufactured by Asahi Kasei Corporation)
H101) has a particle diameter of 90% by weight or more
Hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) having a particle diameter of 90% by weight or more and particles having a particle diameter of 10 to 350 microns was used.

[0052]

[Table 1]

These compositions (Examples 1 to 4 and Controls 1 to 4) were used as white native male rabbits (body weight 2.5 to 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. As Control Example 5, a suspension of beclomethasone propionate was similarly administered with a syringe. 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 crystalline cellulose in the whole base is 5 to 40% by weight, 0%
Compared to (Control Example 4), the absorption was immediate, although the durability was unchanged. Further, it can be seen that more immediate absorption is exhibited at 30 to 40%.

[0055]

[Table 2]

[Examples 5 to 8] As Examples 5 to 8 and Comparative Examples 6 to 9, 100 mg of metoclopramide (manufactured by SIGMA), one of the antiemetic drugs, was treated with various bases described in Table 3 respectively. 200 mg each was mixed by a ball mill, and magnesium stearate 0.30 m 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 10 to 350%.
Micron-sized hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-H) having a particle size of 90% or more by weight of 10 to 350 microns was used.

[0057]

[Table 3]

These compositions (Examples 5 to 8 and Control Examples 6 to 9) were used as white native male rabbits (body weight 2.5 to 3.0 k).
g) Intranasal powder administration device (manufactured by Teijin Limited: Publizer)
Was administered such 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. When the proportion of crystalline cellulose in the whole base is 5 to 40% by weight, 0%
As compared to (Control Example 9), the durability was unchanged, but immediate absorption was observed. Further, it can be seen that the case of 5 to 20% shows more immediate absorption.

[0060]

[Table 4]

[Examples 9 to 17] 2 shown in Table 5 below
The weight ratio of a water-absorptive and poorly water-soluble base and a water-absorptive and gel-forming base containing beclomethasone propionate (manufactured by SICOR) as a main agent using the following bases was 20: 80 compositions (Examples 9-17) were prepared,
It was administered to rabbits under the same conditions as in Examples 1-4. Also,
Compositions were prepared in the same manner as in Examples 9 to 17 using the bases shown in Table 5 as Control Examples 10 to 18 and administered to rabbits. Here, the particle size of 90% by weight or more of the water-absorbable and poorly water-soluble base shown in Table 5 is 10 to 350 microns, which is 90% by weight of the water-absorbable and gel-forming base.
Particles having a particle diameter of 10 to 350 microns were used.

[0062]

[Table 5]

Table 6 shows the change over time in the obtained blood concentration. It can be seen that Examples 9 to 17 are superior to Control Examples 10 to 18 in the immediate effect of absorption.

[0064]

[Table 6]

[Examples 18 to 21] A water-absorbing and poorly water-soluble base containing beclomethasone propionate (manufactured by SICOR) as a main ingredient using the two bases shown in Table 7 below. Compositions (Examples 18 to 21) in which the weight ratio of the water-absorbable and gel-forming base was 80:20 were prepared and administered to rabbits under the same conditions as in Examples 1 to 4. In addition, compositions were similarly prepared using the bases shown in Table 7 as Control Examples 19 to 24, and were administered to rabbits. Here, the particle diameter of particles having a weight of 90% or more of the water-absorbing and poorly water-soluble base shown in Table 7 is 10 to 350 microns, which is 90% or more of the water-absorbing and gel-forming base. The particles having a particle diameter of 10 to 350 microns were used.

[0066]

[Table 7]

Table 8 shows the change over time in the obtained blood concentration. Examples 18-21 are compared to Control Examples 19-24,
It can be seen that the absorption sustainability is excellent.

[0068]

[Table 8]

[Examples 22 to 24] As Examples 22 to 24, 10 m of estradiol dipropionate (manufactured by Wako Pure Chemical Industries, Ltd.) which is one of the sex steroid hormones was used.
g of crystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Corporation) and hydroxypropyl cellulose (H, manufactured by Nippon Soda Co., Ltd.) previously prepared to the particle sizes shown in Table 9.
PC-H) was mixed in an amount of 40 mg and 160 mg each, and 0.2% of magnesium stearate was used as a lubricant.
1 mg was added to prepare a powder composition. Comparative Example 25
Crystalline cellulose 200 having a particle size shown in the same table as No. 27
mg and 10 mg of estradiol dipropionate were mixed to prepare a composition.

[0070]

[Table 9]

These compositions (Examples 22 to 24, Control Examples 25 to 27) 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. Table 10 shows the results.

Both hydroxypropyl cellulose and crystalline cellulose have a particle size of 90% by weight or more of 10 to 3%.
It can be seen that in the case of 50 microns (Example 22), it is superior to hydroxypropylcellulose alone (Control Examples 25 to 27) in the immediate effect of absorption or in the immediate effect and sustainability of absorption.

Further, 90% by weight or more of the crystalline cellulose has a particle size of 10 to 100 μm, and 90% by weight or more of the hydroxypropyl cellulose has a particle size of 10 to 100 μm.
In the case of 350 microns (Example 23), and in the case where the particle size of crystalline cellulose is 90% by weight or more in 50 to 250 microns and the particle size of hydroxypropyl cellulose is 90% by weight or more in 10 to 50 microns (Example 23) 24) It can be seen that a more immediate absorption effect and sustainability were obtained.

[0074]

[Table 10]

Examples 25 and 26 The composition of Example 22 was prepared in the same manner. Further, as Examples 25 and 26, 10 mg of estradiol dipropionate (manufactured by Wako Pure Chemical Industries, Ltd.), which is one of the sex steroid hormones, and 90% by weight or more of the particles were reduced to 10 to 350 microns. The prepared crystalline cellulose (Asahi Kasei Co., Ltd .: Avice)
1 PH101) and hydroxypropylcellulose (HPC: manufactured by Nippon Soda Co., Ltd.) prepared by adjusting the particle size of 90% by weight or more of the particles to 10 to 350 μm by the following method. 1. Estradiol dipropionate 10 mg, crystalline cellulose 40 mg, hydroxypropyl cellulose 16
0 mg were mixed simultaneously (identical to Example 22). 2. Estradiol dipropionate 10 mg and hydroxypropyl cellulose 160 mg were mechanically mixed,
Thereafter, 40 mg of crystalline cellulose was mechanically mixed (Example 25). 3. Estradiol dipropionate (10 mg) and hydroxypropyl cellulose (160 mg) were dispersed in 100 ml of water, freeze-dried, pulverized, and sieved so that 90% by weight or more of the particles had a particle size of 10 to 350 microns.
Thereafter, 40 mg of crystalline cellulose was mechanically mixed (Example 26).

The compositions obtained by these processes (Examples 22, 25 and 26) were applied to a nasal cavity of a white native male rabbit (body weight: 2.5 to 3.0 kg) by a powder dispenser (Teijinsha). Manufactured by a publisher) and the dose of the composition is 2 mg / k.
g. After a certain period of time, blood was collected from the ear vein, and estradiol propionate in the blood was measured by the RIA method. Table 11 shows the results.

From Table 11, it was clarified that when the drug was unevenly distributed in the water-absorbing and gel-forming base, a more excellent effect could be obtained.

[0078]

[Table 11]

──────────────────────────────────────────────────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 (12)

(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 the water-absorbable and poorly water-soluble base is 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. 2. The composition according to claim 1, wherein said water-absorbing and poorly water-soluble base and said water-absorbing and gel-forming base are 9
The powdery nasal administration composition according to claim 1, wherein the particle size of 0% by weight or more of the particles is in the range of 10 to 350 microns. 3. The composition of claim 2, wherein the water-absorbable and poorly water-soluble base has a particle size of 90% by weight or more of the particles in the range of 10 to 100 microns. Particles having a particle size of 90% by weight or more
The powdered nasal composition according to claim 1, which ranges from 0 microns to 350 microns. 4. The composition of claim 1, wherein the water-absorbable and poorly water-soluble base has a particle size of 90% by weight or more of the particles in the range of 10 to 100 microns. Particles having a particle size of 90% by weight or more
The powdered nasal composition according to claim 1, which ranges from 0 microns to 350 microns. 5. The composition according to claim 1, wherein the drug is uniformly dispersed in the water-absorbable and poorly water-soluble base and the water-absorbable and gel-forming base. The powdery nasal administration composition according to claim 1, wherein the water-absorbable and gel-forming base is more unevenly dispersed than the water-absorbable and hardly water-soluble base. 6. The drug according to claim 1, wherein the drug is at least one 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. Item 14. A powdery nasal administration composition according to Item. 7. The non-peptide / proteinaceous drug may be an anti-inflammatory steroid, an analgesic / anti-inflammatory, an antitussive expectorant, an antihistamine,
Antiallergic drugs, antiemetic drugs, sleep-inducing drugs, vitamins, sex steroid hormone drugs, antitumor drugs, antiarrhythmic / hypertensive drugs, antianxiety / psychotropic drugs, antiulcer drugs, inotropic drugs, analgesics, bronchodilators, The powdery nasal administration composition according to claim 6, which is a drug selected from the group consisting of a therapeutic agent for obesity, a platelet aggregation inhibitor, a diabetic drug, a muscle relaxant, and an antirheumatic drug. 8. The peptide / proteinaceous drug may be 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,
And 1 selected from the group consisting of angiotensin and the like
The powdery intranasal composition according to claim 6, which is at least one peptide / protein drug. 9. aqueous absorbent in and sparingly water-soluble base is, crystalline cellulose, alpha-cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked starch, gelatin, Oyo
At least one water-absorptive and poorly water-soluble base selected from the group consisting of polyvinylpyrrolidone and polyvinylpyrrolidone.
A powdery nasal administration composition according to any one of the above. 10. The water-absorptive and poorly water-soluble base,
The powdery nasal administration composition according to any one of claims 1 to 8, which is crystalline cellulose. 11. 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. Claim 1 which is an acidic base
The composition for nasal administration in powder form according to any one of claims 8 to 10. 12. The water-absorbing and gel-forming base is hydroxypropylcellulose.
A powdery nasal administration composition according to any one of the above.