Patent 6,881,423

A powdery composition for nasal administration, where (1) the composition contains (i) a drug, (ii) a water-absorbing and gel-forming base material such as hydroxyprophyl cellulose or hydroxpropylmethyl cellulose and (iii) a water-absorbing and water-insoluble base material such as crystalline cellulose or .alpha.-cellulose, (2) wherein the amount of water-absorbing and gel-forming base material is about 5-40 wt. % based on the total of the water-absorbing and gel-forming base material and the water-absorbing and water-insoluble base material, and (3) wherein the drug is unevenly dispersed more on/in the water-absorbing and water-insoluble base material than on/in the water-absorbing and gel-forming base material.

Description of the Invention

TECHNICAL FIELD

The present invention relates to a powdery composition for nasal administration, in which the absorption of a drug through the nasal mucosa is improved. More specifically, the present invention provides a powdery composition for nasal administration which can exhibit a high maximum blood concentration by compounding a pair of base materials of specific kinds and having a specific composition to specify the state of the existence of the drug in the base materials.

BACKGROUND ARTS

For instance, in a non-peptide/non-proteinaceous drug such as an anti-inflammatory steroid, the development of a pharmaceutical preparation for nasal administration is desired because of the fact that (1) the topical nasal mucosa can be an objective site of action, (2) rapid action can be expected in the pharmaceutical preparation for nasal administration, (3) on the other hand, the absorption through oral administration is low in some drug, and others.

Further, many of peptide/proteinaceous drugs are not readily absorbed into body mainly because it is readily decomposed by proteolytic enzymes in the gastrointestinal tract when orally administered. Therefore, it is often forced to administer such a drug by injection in order to use it for therapy. Unfortunately, injection imposes burden such as pain, attendance to the hospital, etc., to a patient. Accordingly, it is desired to develop a pharmaceutical preparation for noninvasive administration such as nasal administration which can substitute injection.

Nasal administration, by which a drug is transferred into circulating blood through the nasal mucosa, is being energetically studied as a method for non-injection type administration together with transdermal administration, transocular administration, transrectal administration, transpulmonary administration, etc. Among these non-injection type administration methods, the nasal administration is easy to administer a drug. Moreover, nasal administration is considered to be superior in the absorption of a drug among the non-injection type administration methods since the blood vessel system in the nasal mucous membrane is more developed compared with the skin, the ocular mucous membrane, the rectal mucous membrane, etc. Therefore, a pharmaceutical preparation for nasal administration has been put into practice in some drugs. Further, the transfer of a drug into blood in nasal administration is faster than that in oral administration, and it can be expected that nasal administration has immediate effect similar to injection. On the other hand, the absorption of a drug through the nasal mucosa depends on physical properties such as lipophilicity of the drug and also on the molecular weight, etc. It is pointed out that a drug having a high solubility in water, a drug having a high lipophilicity, a peptide/proteinaceous drug having a large molecular weight, etc., is generally low in absorption trough the nasal mucosa. Under these circumstances, some contrivances to improve the absorption of such a drug through the nasal mucosa has been proposed.

For instance, Suzuki, et al., [Japanese Patent Publication (Examined) 60(1985)-34925] disclosed a long acting pharmaceutical preparation for nasal cavity comprising a cellulose ether and a drug.

The long acting pharmaceutical preparation for nasal cavity of the patent publication is aimed to allow a drug to adhere on the nasal mucosa and to slowly release the drug over a long period of time. Some of the objects, i.e. the drug is absorbed through the nasal mucosa and the effective amount of the drug is released in a sustained state, have been achieved. However, the main object of a long acting pharmaceutical preparation of said patent is put on the slow releasing of the drug, and accordingly the enhancement of absorption of the drug appears to be not always sufficient. The drugs concretely cited as preferable examples in said patent include an anti-inflammatory steroid, an analgesic anti-inflammatory agent, an antihistaminic agent, a drug having anti-allergic effect, etc., for which the keeping of topical concentration rather than systemic absorption is important.

In a long acting pharmaceutical preparation for nasal cavity of said patent publication, it is assumed that a high pernasal absorption ratio is hardly achieved for a drug having a high solubility in water, a drug having a high lipophilicity or a peptide/proteinaceous drug having a large molecular weight. Under these circumstances, the development of a pharmaceutical preparation for administering such a drug on the nasal mucosa, which can utilize it effectively in terms of curing effect and curing efficiency, is strongly desired.

Nolte, et al., (Hormone Metabolic Research Vol. 22, 170-174, 1990) and Bruice et al., (Diabetic Medicine Vol. 8, 366-370, 1991) reported insulin preparations for nasal administration containing sodium glycolate or sodium taurofusidate as an absorption promoter. However, these absorption promoters have problems in irritation on the nasal mucosa, and the preparations have not been put in practice yet.

On the other hand, Suzuki, et al., [Japanese Patent Publication (Examined), 62(1987)-42888] disclosed a powdery composition for nasal administration excellent in absorption through the nasal mucosa comprising a polypeptide and a water-absorbing and water-insoluble base material. They reported that the nasal absorption of the polypeptide without using an absorption promoter had been achieved in the composition.

However, even in the composition of the above patent publication, none of the nasal absorption ratios of polypeptides [the area under blood concentration-time curve (AUC) after nasal administration] exceeds 10-20% of AUC in injection. For instance, in Example 4 of the patent publication, the maximum blood concentration of insulin was less than 200 .mu.U/ml when 10 units of insulin had been administered to a rabbit, and it was about 20% of the maximum blood concentration obtained in injection with same amount of insulin. The absorption ratio of the nasal preparation determined from AUC is estimated to be less than 10% of the absorption ratio of injection.

The patent publication describes the combined use of a water-absorbing and water-insoluble base material with a water-absorbing and water-soluble base material in an amount of 0.1-60 wt % based on the water-absorbing and water-insoluble base material, especially preferably 1-50 wt %.

However, concerning the objects and the effects of the combined use, only the slow releasing effect (slow releasability or sustainability) comparing the single use of a water-absorbing and water-insoluble base material is described.

Further, there is no description about the use of a non-peptide/non-proteinaceous drug instead of a polypeptide.

Furthermore, in spite that the patent publication cites a number of water-absorbing and water-insoluble base materials including crystalline cellulose and a number of water-absorbing and water-soluble base materials including hydroxypropyl cellulose, it does not mention at all that a combination of base materials having specific kinds, specific compositions and specific particle sizes among these base materials can provide a powdery composition for nasal administration which can exhibit an excellent maximum blood concentration for a peptide/proteinaceous drug or a non-peptide/non-proteinaceous drug.

Generally, a peptide/proteinaceous drug is expensive, and further when an absorbing ratio is low, its blood concentration tends to vary largely and an expected curing effect is not stably obtained in many cases. Therefore, it is desired to provide a composition of a peptide/proteinaceous drug for nasal administration capable of giving a higher rate of absorption. Further, it is strongly desired to provide a composition for nasal administration which is safe and capable of giving a higher rate of absorption at the same time. Furthermore, it is desired to provide a composition for nasal administration capable of giving a higher maximum blood concentration. The situations are same in a non-peptide/non-proteinaceous drug.

One of the objects of the present invention is to provide a composition for nasal administration excellent in absorption of a drug.

Another object of the present invention is to provide a composition for nasal administration capable of exhibiting high absorption of a drug, especially a higher maximum blood concentration.

A further object of the present invention is to provide a composition for nasal administration capable of exhibiting high absorption, especially a higher maximum blood concentration, even for a drug having a high water solubility, a drug having a high lipophilicity or a peptide/proteinaceous drug having a larger molecular weight.

Still another object of the present invention is to provide a composition for nasal administration capable of exhibiting more excellent absorption, especially capable of exhibiting a higher maximum blood concentration, also for a drug which can exhibit excellent nasal absorption by nature, that is, a drug which is not high in water solubility nor high in lipophilicity, a drug which is a non-peptide/non-proteinaceous drug, etc.

Yet another object of the present invention is to provide a composition for nasal administration which is described in the above objects and at the same time excellent in safety.

The inventors of the present invention have zealously pursued studies for achieving the above-mentioned tasks and completed the present invention by finding that one can provide a new powdery composition for nasal administration excellent in absorption through the nasal mucosa by using a pair of base materials of specific kinds and having a specific composition and by specifying the state of existence of a main drug in the base materials, even for the drug having low absorption through the nasal mucosa or a non-peptide/non-proteinaceous drug.

DISCLOSURE OF THE INVENTION

The present invention is a powdery composition for nasal administration, which is characterized in that

(1) the composition contains (i) a drug, (ii) a water-absorbing and gel-forming base material of one kind or more selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose and (iii) a water-absorbing and water-insoluble base material of one kind or more selected from the group comprising crystalline cellulose, .alpha.-cellulose, cross-linked sodium carboxy-methyl cellulose, cross-linked starch, gelatin, casein, tragacanth gum, polyvinyl pyrrolidone, chitin and chitosan,

(2) the content of the water-soluble and gel-forming base material is about 5-40 wt % based on the total of the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material, and

(3) the drug is unevenly dispersed more on/in the water-absorbing and water-insoluble base material than on/in the water-absorbing and gel-forming base material.

BEST MODE FOR CARRYING OUT THE INVENTION

Preferred examples of a drug of the present invention include non-peptide/non-proteinaceous drugs and peptide/proteinaceous drugs.

A variety of non-peptide/non-proteinaceous drugs are usable as the non-peptide/non-proteinaceous drug of the present invention. The concrete examples of the non-peptide/non-proteinaceous drug include anti-inflammatory steroids or nonsteroidal anti-inflammatory drugs, analgesic anti-inflammatory agents, sedatives, treating agents for depression, antitussive expectorants, antihistaminic agents, antiallergic drugs, antiemetic drugs, hypnotics, vitamin preparations, sex steroid hormones, antineoplastic drugs, antiarrhythmic drugs, antihypertensive drugs, antianxiety drugs, psychotropic drugs, antiulcer drugs, cardiotonics, analgesics, bronchodilators, treating agents for obesity, antithrombotic drugs, antidiabetic drugs, muscle relaxants, anti-rheumatics, etc. One kind or more selected from the group comprising the above drugs can be used as the non-peptide/non-proteinaceous drug. Among them, one kind or more selected from the group comprising antiemetic drugs, hypnotics, vitamin preparations, sex steroid hormones and analgesics are preferable.

Precisely, examples of the non-peptide/non-proteinaceous drug include one kind or more selected from the group comprising the followings: anti-inflammatory steroids or nonsteroidal anti-inflammatory drugs such as hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclometasone, fluticasone, mometasone, fluocortin, budesonide, salbutamol and salmeterol; analgesic anti-inflammatory agents such as acetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, ibuprofen, alclofenac, diclofenac and indomethacin; sedatives such as scopolamine; treating agents for depression such as imipramine; antitussive expectorants such as sodium cromoglycate, codeine phosphate and isoproterenol hydrochloride; antihistaminic agents such as diphenhydramine, triprolidine, isothipendyl and chlorpheniramine; antiallergic drugs such as amlexanox, azelastine, ozagrel, tranilast and ketotifen; antiemetic drugs such as ondansetron, granisetron, metoclopramide, cisapride and domperidone; hypnotics such as brotizolam and melatonin; vitamin preparations such as cyanocobalamin and mecobalamin; sex steroid hormones such as estradiol, estriol, progesterone and testosterone; antineoplastic drugs such as tamoxifen and tegafur; antiarrhythmic drugs such as propranolol and atenolol; antihypertensive drugs such as nicardipine; antianxiety drugs such as diazepam; psychotropic drugs such as nitrazepam; antiulcer drugs such as cimetidine and ranitidine; cardiotonics such as dopamine; analgesics such as morphine and buprenorphine; bronchodilators such as oxitropium and ozagrel; treating agents for obesity such as mazindol; antithrombotic drugs such as beraprost and carbacyclin; antidiabetic drugs such as acarbose and sorbinil; muscle relaxants such as pinaverium and inaperisone; anti-rheumatics such as actarit and platonin; etc.

Further, a peptide/proteinaceous drug of the present invention preferably has a molecular weight of less than 30,000. The peptide/proteinaceous drug having a molecular weight of less than 30,000 is exemplified in the following: luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, vasopressins, oxytocins, hirudin derivatives, enkephalins, adrenocorticotropic hormone 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 polypeptide derivatives, interferons, interleukins, erythropoietin, granulocyte colony forming-stimulating factor, macrophage forming-stimulating factor, parathyroid hormones, parathyroid hormone-releasing hormone, prolactin, thyroid-stimulating hormone-releasing hormone and angiotensins. As the peptide/proteinaceous drug of the present invention, one kind or more selected from the group comprising the substances shown above as concrete examples can be used.

A water-absorbing and gel-forming base material of the present invention is a base material of one kind or more selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose.

Among these base materials, as the water-absorbing and gel-forming base material of the present invention, one kind or more selected from the group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and sodium carboxymethyl cellulose is preferable, and hydroxypropyl cellulose is especially preferable.

Further, as the hydroxypropyl cellulose, a hydroxypropyl cellulose having a viscosity of 2% aqueous solution in the range of 150-4000 cps is preferable. The viscosity means a kinetic viscosity and can be determined by a viscometer such as Cannon-Fenske viscometer, Cannon-Fenske reverse flow-type viscometer, Ubbellohde viscometer or Ostwald viscometer. Among them, an Ubbellohde viscometer is preferable since it gives high accuracy of measurement. The values of viscosity described in the present invention were determined at 37^oC. using an Ubbellohde viscometer produced by Shibata Kagaku Kikai Kougaku Co. Although a hydroxypropyl cellulose having a lower viscosity is available, when a hydroxypropyl cellulose having a viscosity of lower than 150 cps is used, the increasing effect on maximum blood concentration of the present invention can not always be attained in a sufficient manner.

A water-absorbing and water-insoluble base material of the present invention is one kind or more selected from the group comprising crystalline cellulose, .alpha.-cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked starch, gelatin, casein, tragacanth gum, polyvinyl pyrrolidone, chitin and chitosan.

Among them, as the water-absorbing and water-insoluble base material of the present invention, one kind or more selected from the group comprising crystalline cellulose, .alpha.-cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked starch, gelatin, casein, tragacanth gum, polyvinyl pyrrolidone, chitin and chitosan is preferable, and crystalline cellulose is especially preferable.

Examples of a preferable combination of a water-absorbing and gel-forming base material and a water-absorbing and water-insoluble base material include a combination between both the base materials cited above as preferable examples. The combination of hydroxypropyl cellulose as the water-absorbing and gel-forming base material and crystalline cellulose as the water-absorbing and water-insoluble base material is especially preferable.

A water-absorbing and gel-forming base material in the present invention is used in an amount of about 5-40 wt % based on the total of the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material.

The amount of the water-absorbing and gel-forming base material also depends on the kind of a drug of the present invention. In cases where the drug is a non-peptide/non-proteinaceous drug, the amount is preferably about 20-40 wt % since prominent increasing effect on maximum blood concentration is observed in this range.

In cases where a drug of the present invention is a peptide/proteinaceous drug, the range of the preferable amount of the water-absorbing and gel-forming base material is subdivided by the molecular weight of the drug. In cases where the molecular weight of the peptide/proteinaceous drug is not less than 500 and less than 1500, prominent increasing effect on maximum blood concentration is observed when the amount of the water-absorbing and gel-forming base material is in the range of about 5-30 wt %, and especially prominent effect is observed in the range of 20-30 wt %. Further, in cases where the molecular weight of the peptide/proteinaceous drug is not less than 1500 nor more than 30,000, prominent increasing effect on maximum blood concentration is observed when the amount of the water-absorbing and gel-forming base material is in the range of about 5-20 wt %, and especially prominent effect is observed in the range of 10-20 wt %.

Examples of the peptide/proteinaceous drug having a molecular weight of not less than 500 and less than 1500 include vasopressins, luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, oxytocins, hirudin derivatives, enkephalins, adrenocorticotropic hormone derivatives, bradykinin derivatives, etc. Further, examples of the peptide/proteinaceous drug having a molecular weight of not less than 1500 and less than 30,000 include calcitonins, insulins, glucagon derivatives, growth hormones, growth hormone-releasing hormones, luteinizing hormones, insulin-like growth factors, calcitonin gene-related peptides, atrial natriuretic polypeptide derivatives, interferons, erythropoietin, granulocyte colony forming-stimulating factor, macrophage forming-stimulating factor, parathyroid hormones, parathyroid hormone-releasing hormone, prolactin, thyroid-stimulating hormone-releasing hormone, angiotensins, etc.

A powdery composition for nasal administration of the present invention is characterized in that a drug is unevenly dispersed more on/in a water-absorbing and water-insoluble base material than on/in a water-absorbing and gel-forming base material.

The state, in which the drug is unevenly dispersed more on/in the water-absorbing and water-insoluble base material than on/in the water-absorbing and gel-forming base material, includes a state in which the drug is adhered to base materials according to the compounding ratio of the base materials. A state, in which 70 wt % or more based on the drug is adhered to both the base materials according to the compounding ratio of the base materials, is preferable. A state, in which 80 wt % or more based on the drug is adhered to both the base materials according to the compounding ratio of the base materials, is especially preferable. For instance, in a state in which 70 wt % or more based on the drug is adhered to both the base materials according to their compounding ratio, when the amount of the water-absorbing and gel-forming base material is 40 wt % based on the total of both the base materials, 42 wt % based on the drug adheres to the water-absorbing and water-insoluble base material, 28 wt % adheres to the water-absorbing and gel-forming base material, and the remaining 30 wt % is homogeneously dispersed in the composition.

Furthermore, the state, in which the drug is unevenly dispersed more on/in the water-absorbing and water-insoluble base material than on/in the water-absorbing and gel-forming base material, also includes a state in which the drug is adhered to the water-absorbing and water-insoluble base material in a larger amount than in a state in which the drug is adhered to both the base materials according to their compounding ratio. A state, in which 60 wt % or more based on the drug is adhered to the water-absorbing and water-insoluble base material, is preferable. A state, in which 70 wt % or more, especially 80 wt % or more, based on the drug is adhered to the water-absorbing and water-insoluble base material, is especially preferable. In these states, the remaining less than 30 wt % or less than 20 wt % based on the drug is homogeneously dispersed in the composition freely and/or adhered to the water-absorbing and gel-forming base material.

The adhering of a drug to a base material in the present invention indicates a state in which the drug totally exits on the surface of the base material in an adhered state, a part of the drug exits in the base material and the other part exists on the surface of the base material, or the drug totally exists in the base material.

A composition of the present invention, in which a main drug is dispersed in a specifically uneven state, can be manufactured by the following manufacturing method 1, 2 or 3.

The method 1: A drug is mechanically mixed with a water-absorbing and water-insoluble base material, in which at least 90 wt % based on the particles have an average particle diameter in the range of 10-350 .mu.m. Subsequently, a water-absorbing and gel-forming base material, in which at least 90 wt % based on the particles have an average particle diameter in the range of 10-350 .mu.m, is added to the resultant mixture, and they are mechanically mixed.

The method 2: A drug is allowed to adhere to a water-absorbing and water-insoluble base material by freeze drying to obtain a drug-adhered base material. For the freeze drying, the drug and the water-absorbing and water-insoluble base material is dissolved or dispersed in an aqueous solution and the resultant solution or dispersion may be subjected to a freeze drying process. Subsequently, the freeze dried base material is pulverized and sieved so that at least 90 wt % based on the resultant particles have an average particle diameter in the range of 10-350 .mu.m. To the obtained powder fraction, powder of a water-absorbing and gel-forming base material, in which at least 90 wt % based on the particles have an average particle diameter in the range of 10-350 .mu.m, is added, and they are mechanically mixed.

The method 3: A water-absorbing and water-insoluble base material, in which at least 90 wt % based on the particles have an average particle diameter in the range of 10-350 .mu.m, a water-absorbing and gel-forming base material, in which at least 90 wt % based on the particles have an average particle diameter in the range of 10-350 .mu.m and a drug are mechanically mixed by one step.

Among these manufacturing methods, the first and the second manufacturing methods are desirable in that they can easily obtain a composition having a state in which the drug is dispersed more on/in the water-absorbing and water-insoluble base material than on/in the water-absorbing and gel-forming base material. For instance, in the first manufacturing method, the drug can be mixed strongly with the water-absorbing and water-insoluble base material, and subsequently the obtained powdery body can be mixed weakly with the water-absorbing and gel-forming base material. In the second manufacturing method, the mechanical mixing of the obtained powdery body with the water-absorbing and gel-forming base material can be performed either strongly or weakly.

In the first manufacturing method, 60 wt % or more based on the drug in the obtained composition is dispersed in a state adhered to the water-absorbing and water-insoluble base material. In the second manufacturing method, 80 wt % or more based on the drug is dispersed in a state adhered to the water-absorbing and water-insoluble base material. The water-absorbing and gel-forming base material is homogeneously dispersed in the whole compositions.

The third manufacturing method is desirable in that it can easily produce a composition in which the drug is homogeneously dispersed on/in both the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material according to the compounding ratio. In this method, the drug and both the base materials can be mixed strongly by one step. For example, 80 wt % or more based on the drug is dispersed according to the compounding ratio of both the base materials. Herein, when the amount of the water-absorbing and water-insoluble base material is 60 wt % based on the total of both the base materials, 48 wt % or more based on the drug is dispersed in a state adhered to the water-absorbing and water-insoluble base material, and the drug which is not adhered to either of the base materials is homogeneously dispersed. In this case, the effect of the present invention is sometimes more or less lowered since the amount of the drug adhered to the water-absorbing and gel-forming base material is somewhat larger than in cases where the drug is dispersed more on/in the water-absorbing and water-insoluble base material.

As another method for manufacturing a composition of the present invention in which a drug is unevenly dispersed more on/in a water-absorbing and water-insoluble base material, the following method can be applied. That is, when a drug is lipophilic, the drug and the water-absorbing and water-insoluble base material are dissolved or dispersed in an organic solvent such as ethanol, and subsequently the resultant solution or dispersion is evaporated. The obtained powder is graded to have an average particle diameter of 10-350 .mu.m, and a water-absorbing and gel-forming base material is added to the resultant powder, and they are mechanically mixed strongly or weakly.

For performing the third manufacturing method, the drug, the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material may be dissolved or dispersed in an aqueous solution, the resultant solution or dispersion is freeze dried, and the freeze-dried body is pulverized. By using the obtained powder, one can produce an objective composition.

Further, in the first and the third manufacturing methods, it is preferable to adjust the particle diameters also of the drug to 10-350 .mu.m in at least 90 wt % based on the particles in advance.

In the present invention, the state of uneven existence of a drug can be identified by following processes.

That is, the drug, the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material are differently colored with pigments of food additive or fluorescent substances such as fluorescein, respectively.

For instance, when the drug is white powder, the water-absorbing and water-insoluble base material is colored with a pigment such as Blue No. 1, while the water-absorbing and gel forming base material is colored with a different pigment from the pigment used for coloring the water-absorbing and water-insoluble base material. That is, when the water-absorbing and water-insoluble base material is colored with Blue No. 1, the water-absorbing and gel-forming base material is colored with Red No. 3 or Yellow No. 4, and these colorings enable the differentiation of the main drug and the base materials by visual observation, from each other. For the coloring, following methods may be applied. The water-absorbing and water-insoluble base material is immersed in an aqueous solution of a pigment, the mixture is stirred and allowed to stand, and then the resultant mixture is filtered or the solvent of the mixture is evaporated to dry up to obtain the colored base material. For the water-absorbing and gel-forming base material, a pigment is dissolved in an organic solvent such as ethanol, the base material is added to the resultant solution, and the solvent is evaporated to dry up to obtain the colored base material. The obtained film-shaped base material is pulverized into adequate particle sizes.

Concretely, the water-absorbing and water-insoluble base material is colored with Blue No. 1, and the water-absorbing and gel-forming base material is colored with Red No. 3. By using a white powdery main drug and the colored base materials, a composition of the present invention is prepared according to a manufacturing method described above. A small amount of the obtained composition is placed on a slide glass, and the specimen is observed under a microscope having a lens of magnification of 100-1000 times, e.g. 500 times. Thus, it is identified that almost entire part of the white main drug is adhered to the blue-colored water-absorbing and water-insoluble base material, and scarcely adhered to the red-colored water-absorbing and gel-forming base material, i.e. the main drug is unevenly adhered more to the water-absorbing and water-insoluble base material.

Further, by the freeze drying in the second and the third manufacturing methods, one can obtain a composition in which a drug is included in base material(s).

When a composition of the present invention is manufactured by a method other than freeze drying of a drug and base materials, it is preferable to treat the drug in advance so that at least 90 wt % based on the particles have particle diameters in the range of 10-350 .mu.m.

Herein, mechanical mixing in the manufacturing of a composition of the present invention can be performed e.g. by a container rotary-type mixer such as a twin shell blender, a cross-rotary mixer or a double corn mixer, a container fixed-type mixer such as a universal mixer, a ribbon mixer, an automatic mortar or a ball mill, or another type mixer such as a high-speed mixer or a powerful automatic mixer. The mechanical mixing in the present invention also includes manual compression mixing using a mortar.

In the above mixing, strong mixing expresses manual mixing using a mortar, mechanical mixing using a container fixed-type mixer such as a universal mixer, a ribbon mixer, an automatic mortar or a ball mill, or mechanical mixing using a high-speed mixer, a powerful automatic mixer, etc. By these types of mixing, the drug mainly adheres to base materials and is homogeneously mixed in the adhered state. On the other hand, weak mixing expresses mixing using a container rotary-type mixer such as a twin shell blender, a cross-rotary mixer, a double corn mixer or a ball-free ball mill, and the main part of the drug is homogeneously dispersed and mixed without being adhered to base materials in weak mixing.

Further, besides the above-mentioned first to third manufacturing methods, a powdery composition for nasal administration of the present invention can be prepared by specifying particle diameters of base materials. For instance, it can be prepared by (i) adjusting particle diameters of at least 90 wt % based on the particles of a water-absorbing and water-insoluble base material to 10-350 .mu.m, (ii) adjusting particle diameters of at least 90 wt % based on particles of a water-absorbing and gel-forming base material to 10-105 .mu.m, and (iii) making the average particle diameter of the water-absorbing and water-insoluble base material larger than the average particle diameter of the water-absorbing and gel-forming base material.

Especially, a state, in which the average particle diameter of at least 90 wt % based on the particles of a water-absorbing and water-insoluble base material is 10-250 .mu.m and the average particle diameter of at least 90 wt % based on the particles of a water-absorbing and gel-forming base material is 10-105 .mu.m, is preferable since a composition of the state enables increasing in maximum blood concentration. A state, in which the average particle diameter of at least 90 wt % based on the particles of a water-absorbing and water-insoluble base material is 10-250 .mu.m, and the average particle diameter of at least 90 wt % based on the particles of a water-absorbing and gel forming base material is 10-65 .mu.m, is especially preferable since a composition of the state enables further increasing in maximum blood concentration. In both cases, the average particle diameters of the water-absorbing and water-insoluble base material are larger than the average particle diameter of the water-absorbing and gel-forming base material.

Herein, a state, in which the average particle diameter of at least 90 wt % based on the particles of a base material is 10-250 .mu.m, can be identified by classifying particles using testing sieves and giving vibration by hands or machine. That is, at least 90 wt % based on the particles pass through a sieve having an aperture of 250 .mu.m and remain on a sieve having an aperture of 10 .mu.m. While the sieves are being vibrated, the weight of powder on each sieve is measured at appropriate interval, and when the variation of the weight becomes 0.1% or less, the classification of the particles will be completed.

Further, a state, in which the average particle diameter of the water-absorbing and water-insoluble base material is larger than the average particle diameter of the water-absorbing and gel-forming base material, is a state in which the average particle diameters of both the base materials are in the above-mentioned ranges, and at the same time the average particle diameter of the water-absorbing and water-insoluble base material is larger than the average particle diameter of the water-absorbing and gel-forming base material.

A powdery composition for nasal administration of the present invention, in which the average particle diameter of a water-absorbing and water-insoluble base material is larger than that of a water-absorbing and gel-forming base material, can be prepared by a manufacturing method for a powdery preparation common in the art, e.g. the main drug, the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material are mechanically mixed.

However, the production of powdery compositions of the present invention by the above-mentioned first to third manufacturing methods is preferable since powdery compositions produced by them can achieve extremely high effects.

As a water-absorbing and water-insoluble base material and a water-absorbing and gel-forming base material of the present invention, as far as it does not contradict the object of the present invention, one can use microspheres having above-mentioned specific properties and comprising a specific kind of base material, e.g. starch or crystalline cellulose, which is known as a base material useful for a powdery composition for nasal administration. Herein, it is preferable to use microspheres having particle diameters in the range of above-mentioned sizes.

The amount of a drug to be used in the present invention, an effective therapeutic dose, depends on the kind of each drug, the kind and severity of disease, the age and body weight of a patient, etc. Generally, it ranges from equal amount to 20 times the amount of the drug to be used for injection, more preferably from equal to 10 times.

Further, the ratio of the amount of a drug to that of base materials (the total of a water-absorbing and water-insoluble base material and a water-absorbing and gel-forming base material) can not be defined indiscriminately since the amount applicable to the nasal cavity is limited and the amount of the drug depends on the therapeutic dose. However, the amount of the base material is preferably 1 pt. wt. or more, especially preferably 5 pts. wt. or more and further especially preferably 10 pts. wt. or more, each based on 1 pt. wt. of the drug.

In order to improve the properties, appearance, or odor of a composition of the present invention, it may optionally contain a lubricant, a binder, a diluent, a coloring agent, a preservative, an antiseptic, a corrigent, etc., known per se. Examples of these additives are cited as follows: talc, stearic acid, its salt, a wax, etc., as the lubricant; a starch, a dextrin, etc., as the binder; a starch, lactose, etc., as the diluent; Red No. 2, etc., as the coloring agent; ascorbic acid, etc., as the preservative; a p-hydroxybenzoate ester, etc., as the antiseptic; and menthol, etc., as the corrigent.

In order to administer a composition of the present invention, it is formulated into an adequate administration form. As the administration form, there is a capsule in which each administration dose of the composition is placed. The composition in the capsule is sprayed into the nasal cavities by an adequate administration device. Also, a composition of the present invention in an amount of one dose or plural doses is placed in an adequate container, and the composition in an amount of one dose may be administered by single dosage or divided dosage.

Industrial Field of Application

Thus, the present invention provides a powdery composition for nasal administration excellent in absorption from the nasal cavity and capable of exhibiting extreme increase in maximum blood concentration compared with a conventional composition for nasal administration even for a drug having a high solubility in water, a drug having a high lipophilicity or a peptide/proteinaceous drug having a large molecular weight.

Not only for an expensive peptide/proteinaceous drug but also for a non-peptide/non-proteinaceous drug, a powdery composition for nasal administration of the present invention gives an extremely high maximum blood concentration even with same dose as in a conventional composition, and accordingly the use of the drug can be reduced. The composition also can reduce fluctuation of blood concentration and stably obtain the objective pharmaceutical effect.

Further, a powdery composition for nasal administration of the present invention is excellent in the absorption and durability of blood concentration similarly to a conventional powdery composition for nasal administration. However, differently from the conventional composition, the composition of the present invention needs no absorption stimulator having irritation, and it is safe and expected to stably achieve the desired therapeutic effect.

Therefore, the present invention has an extremely deep meaning for medicinal therapy which is carried out by administering a non-injection type drug.

Claim 1 of 11 Claims

What is claimed is:

1. A powdery composition for nasal administration comprising

(i) a drug,

(ii) one or more of a water-absorbing and gel-forming base material selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose and

(iii) one or more of a water-absorbing and water-insoluble base material selected from the group consisting of crystalline cellulose, .alpha.-cellulose, cross-linked sodium carboxy-methyl cellulose, cross-linked starch, chitin and chitosan,

wherein the content of the water-absorbing and gel-forming base material is about 5-40 wt % based on the total of the water-absorbing and water-insoluble base material and the water-absorbing and gel-forming base material,

70 wt % or more based on the drug is dispersed on or in the water-absorbing and water-insoluble base material and on or in the water-absorbing and gel-forming base material,

the water-absorbing and water-insoluble base material and water-absorbing and gel-forming base material comprise particles,

wherein the drug is dispersed more on or in the water-absorbing and water-insoluble base material than on or in the water-absorbing and gel-forming base material, and

wherein the powdery composition is obtained by a method comprising adhering the drug to the water-absorbing and water-insoluble base material by freeze drying,

then, pulverizing and sieving the water-absorbing and water-insoluble base material with the adhered drug to obtain a resultant water-absorbing and water-insoluble base material comprising water-absorbing and water-insoluble particles, wherein at least 90 wt % based on the resultant water-absorbing and water-insoluble particles have an average particle diameter in the range of 10-350 .mu.m, and

subsequently, mechanically mixing the water-absorbing and gel-forming base material, in which at least 90 wt % based on the water-absorbing and gel-forming particles have an average particle diameter in the range of 10-350 .mu.m, with the resultant water-absorbing and water-insoluble base material.

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