Title:  Powdery nasal compositions

United States Patent:  6,428,805

Issued:  August 6, 2002

Inventors:  Dohi; Masahiko (Hino, JP); Uejima; Yasuhide (Hino, JP); Fujii; Takao (Hino, JP)

Assignee:  Teijin Limited (Osaka, JP)

Appl. No.:  530203

Filed:  April 26, 2000

PCT Filed:  August 24, 1999

PCT NO:  PCT/JP99/04560

371 Date:  April 26, 2000

102(e) Date:  April 26, 2000

PCT PUB.NO.:  WO00/12136

PCT PUB. Date:  March 9, 2000

A powdery nasal composition comprising a drug and colloidal cellulose is provided. The composition is a nasal composition providing a superior absorption activity for the drug.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide compositions for nasal administration that have excellent absorptivity of drugs.

It is also an object of the present invention to provide compositions for nasal administration that exhibit excellent absorptivity, in particular much higher maximum blood concentrations.

It is a further object of the present invention to provide compositions for nasal administration that exhibit excellent absorptivity, in particular much higher maximum blood concentrations, of highly water-soluble drugs, highly fat-soluble drugs, and peptidyl and proteinaceous drugs having high molecular weights.

It is a still further object of the present invention to provide compositions for nasal administration that exhibit excellent absorptivity, in particular much higher maximum blood concentrations, of drugs that originally have good nasal absorptivity such as highly water-soluble drugs, highly fat-soluble drugs, and nonpeptidyl and nonproteinaceous drugs having high molecular weights.

Furthermore, it is an object of the present invention to provide safe compositions for nasal administrations in these compositions for nasal administrations.

In intensive efforts to solve the above problems, the present inventors have found that by using a drug and colloidal cellulose, it is possible to provide a novel powdery composition for nasal administration having excellent absorptivity for those drugs and nonpeptidyl and nonproteinaceous drugs that had low nasal absorptivity, in particular a novel powdery composition for nasal administration with which a significantly high maximum blood concentration can be obtained, and thereby have accomplished the present invention.

Thus, the present invention provides a powdery composition for nasal administration comprising a drug and colloidal cellulose.

Embodiment for Carrying Out the Invention

Preferred examples of the drugs of the present invention preferably include nonpeptidyl and nonproteinaceous drugs and peptidyl and proteinaceous drugs.

As nonpeptidyl and nonproteinaceous drugs, a wide range of nonpeptidyl and nonproteinaceous drugs are available. Specific examples include anti-inflammatory steroids or non-steroidal anti-inflammatory drugs, analgesic anti-inflammatory drugs, sedatives, anti-depressants, antitussive expectant drugs, anti-histamine drugs, anti-allergic drugs, antiemetic drugs, hypnotic drugs, vitamins, sex steroid hormones, anti-cancer drugs, anti-arrhythmic drugs, anti-hypertensive drugs, anti-anxiety drugs, psychomimetics, anti-ulcer drugs, cardiac stimulants, analgesics, bronchodilatiors, anti-obesity drugs, platelet aggregation suppressive drugs, antidiabetic drugs, muscle relaxants, anti-migraine drugs, antirheumatic drugs, and the like. As nonpeptidyl and nonproteinaceous drugs, one or more of those selected from the group consisting of the above can be used. Among them, preferred examples include antiemetic drugs, hypnotic drugs, vitamins, sex steroid hormones, anti-migraine drugs, analgesics, and the like.

More specifically, examples of such nonpeptidyl and proteinaceous drugs include: anti-inflammatory steroids or non-steroidal anti-inflammatory drugs such as hydrocortisone, prednisolone, triamcilnolone, dexamethasone, betamethasone, beclomeithasone, fluticasone, mometasone, fluocortin, budesonide, salbutamol, and salmeterol; analgesic anti-inflammatory drugs such as acetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine, phenylbutasone, mefenamic acid, flufenamic acid, ibufenac, ibuprofen, alclofenac, diclofenac, and indometacin; sedatives such as scopolamine; anti-depressants such as imipramine; antitussive expectrant drugs such as sodium cromoglycate, codeine phosphate, and isoproterenol,hydrochloride; anti-histamine drugs such as diphenhydramline, triprolidine, isothipendyl, and chlorpheniramine; anti-allergic drugs such as amlexanox, azelastine, ozagrel, tranilast, and ketotifen; anti-emetic drugs such as; ondansetron, granisetron, metoclopramide, cisapride, and domperidone; hypnotic drugs such as brotizolam and melatonine; vitamins such as cyanocobalamine and mecobalamine; sexual steroid hormones such as estradiol, estritol, progesterone, and testosterone; anti-cancer drugs such as tamoxiphene and tegafur; anti-arrhythmic drugs such as propranolol and atenolol; anti-hypertensive drugs such as nicardipine; anti-anxiety drugs such as diazepam; psychomimetics such as nitrazepam; anti-ulcer drugs such as cimetidine and ranitidine; cardiac stimulants such as dopamine; analgesics such as morphine and buprenorphine; bronchodilators such as oxitropium and ozagrel; anti-obesity drugs such as mazindol; platelet aggregation suppressive drugs such as beraprost, and carbacyclin;, antidiabetic drugs such as acarbose and sorbitol; muscle relaxants such as pinaverium and inaperisone; anti-migraine drugs such as ergotamine, imigran, and alniditan; antirheumatic drugs such as actarit and platonin.

The peptidyl and proteinaceous drugs of the present invention are preferably those of which molecular weight does not exceed 30,000. As peptidyl and proteinaceous drugs of which molecular weight does not exceed 30,000, there may be mentioned, for example, luteinizing hormone-releasing hormones, growth hormone-releasing factors, somatostatin derivatives, vasopressins, oxytocins, hirudin derivatives, enkephalins, adrenocorticotrophic hormone derivatives, bradykinin derivatives, calcitonins, insulins, glucagon derivatives, growth hormones, growth hormone-releasing hormones, luteinizing hormones, insulin-like growth hormones, calcitonin gene-related peptides, atrial natriuretic peptide derivatives, interferons, interleukins, erythropoietins, granulocyte colony-stimmulating factor, macrophage forming stimulating factor, parathyroid hormones, parathyroid hormone-releasing hormone, prolactin, thyroid stimulating hormone-releasing hormone, and angiotensins. As the peptidyl and proteinaceous drugs of the present invention, one or more of those selected from the group consisting of these specific examples can be used.

According to the present invention, the particle diameter of the drugs is preferably less than 150 .mu.m. More preferably the diameter is less than 50 .mu.m wherein the effects are further enhanced. However, drugs which are too finely pulverized, though showing enhanced absorption promoting effects, pose a problem of pharmaceutical handling due to scattering, etc., and a more preferred diameter of the drugs is 0.5 .mu.m or greater and less than 10 .mu.m.

As a method of rendering the diameter of particles of the drugs 10 .mu.m, there can be mentioned the pressurized type of pulverization by mortars etc., the rotating impact type of pulverization by centrifugation etc., recrystalization by a spray drier, a lyophilizer etc.

The colloidal cellulose of the present invention is a colloidal cellulose obtained by, for example, spray-drying one or more of viscosity-increasing agents and crystalline cellulose, said viscosity-increasing agents comprising carboxymethylcellulose, sodium salts of carboxymethylcellulose, calcium salts of carboxymethylcellulose, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic acid starch, and the like. Among them, colloidal celluloses comprising crystalline cellulose and a sodium salt of carboxymethylcellulose or xanthan gum are commercially available from Asahi Chemical Industry Co., Ltd. as Avicel RC-581, Avicel RC-591, and Avicel CL-611, Avicel RC-N81, etc., which are preferred since they have already been put into practical use in pharmaceutical formulations.

Avicel RC-581 and Avicel RC-591 are each composed of crystalline cellulose and CMCNa at a mixed weight ratio of 89/11, and AvicelCL-611- at a ratio of 85/15, which are trade marks of products of Asahi Chemical Industry Co., Ltd. Similarly, AvicelRC-N81 is a!special mixture of crystalline cellulose and a natural polysaccharide and is a trade mark of products of Asahi Chemical Industry Co., Ltd. These are colloidal cellulose made by the production method as described above, and have distinct properties different from those of physical mixtures of cellulose and CMCNa. For example, according to technical documents of Asahi Chemical Industry Co., Ltd., colloidal cellulose has features that: (1) it has excellent suspension stability, (2) it has excellent emulsion stability, (3) the dispersion solution thereof exhibits thixotropy, and the like. It is clear to a person skilled in the art that these features are evidently different from those of crystalline cellulose itself or physical mixtures of cellulose and CMCNa.

The composition of the present, invention may be prepared by, for example, a method of mechanically mixing colloidal cellulose and a drug.

Mechanical mixing as used herein refers to mixing with a mixer of the fixed vessel type such as a high speed mixer or a mixer of the rotary type such as a V-type mixer. Specifically, mixing with the fixed vessel type is preferred since. it significantly enhances the effects of the present invention.

As used herein, mixers of the fixed vessel type include universal mixers, ribbon mixers, automatic mortars, ball mills, and other mixers such as high speed mixers, power fully automatic mixers, etc., as well as manual pressurized mixing with mortars. Mixers of the rotary vessel type are V-shaped mixers, cross rotary mixers, double-coned mixers, and the like.

The amount of the drug for use in the present invention is a therapeutically effective amount, and may be decided depending on the drug administered, the kind and degree of the disease to be treated, the age and weight of the patient, and the like. Generally, the amount is equal to 20 times that used for injection administration, and more preferably equal to 10 times.

Since the amount of the powder that can be applied to the nasal cavity is limited and depends on the amount required for treatment, the amount of colloidal cellulose cannot be generally specified, but it is preferably an equal amount to one weight part of the drug, most preferably 5 or more weight parts and more preferably 10 or more weight parts per weight part of the drug.

In order to improve the physical property, appearance, or smell etc. as a pharmaceutical formulation of the composition of the present invention, known lubricants, binders, diluents, colorants, preservatives, antiseptics, corrigents, and the like can be added as desired. As lubricants, there can be mentioned, for example, talc, stearic acid and salts thereof, wax, and the like; as binders, starch, dextrin, and the like; as diluents, starch, lactase, and the like; as colorants, Red No. 2 and the like; as preservatives, ascorbic acid and the like; as antiseptics, paraoxybenzoic acid esters and the like; as corrigents, menthol and the like.

The composition of the present invention may be formulated into a suitable dosage form in order to be administered as a pharmaceutical formulation. An example of such a dosage form is a capsule in which the present invention has been filled by each dosage unit, which is sprayed into the nasal cavity using a suitable dispenser. The composition of the present invention at an amount for unit dosage or at an amount for multiple doses is dispensed in a suitable container, and the composition of the present invention may be administered at an amount for unit dosage given at one time or in divided doses.

Thus, in accordance with the present invention, a powdery composition for nasal administration having excellent absorptivity via the nasal cavity and a significantly higher maximum blood concentration than the conventional compositions for nasal administrations can be provided for highly water-soluble drugs, highly fat-soluble drugs, and peptidyl and proteinaceous drugs having high molecular weight.

According to the powdery composition for nasal administration of the present invention, it is possible to obtain significantly-higher maximum blood concentration at an amount equal to the conventional amount for nonpeptidyl and nonproteinaceous drugs as well as expensive peptidyl and proteinaceous drugs. Accordingly, the amount used of the drug can be reduced. Furthermore, it is possible to stably obtain the desired therapeutic effect by minimizing variation in blood concentrations.

Furthermore, the powdery composition for nasal administration of the present invention has an excellent absorptivity (sustained blood concentration) similarly to the conventional powdery compositions for nasal administrations, and it obviates the need of using specifically absorption-promoting agents that have an irritating nature and therefore it is safe, and it is expected that the desired therapeutic effect can be stably obtained.

Therefore, it is believed that the present invention is highly valuable for drug therapy by the administration of non-injection type drugs.

Claim 1 of 5 Claims

What is claimed is:

1. A powdery nasal composition comprising a drug and colloidal cellulose, wherein said colloidal cellulose is obtained by spray-drying crystalline cellulose and one or more viscosity-increasing polymers selected from the group consisting of carboxymethylcellulose, a sodium salt of carboxymethylcellulose, a calcium salt of carboxymethylcellulose, xantha gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and acrylic acid starch.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.