JP2008273899A - Sleep-inducing agent for pernasal absorption use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sleep-inducing agent for pernasal absorption use, enabling early efficacy of its own, and promising reduction of its dose owing to its improved bioavailability. <P>SOLUTION: The sleep-inducing agent for pernasal absorption use is characterized by being prepared by spraying a saccharide charged in powdery form into a fluidized-bed granulator with a suspension obtained by adding an effective amount of a sleep-inducing substance to an aqueous solution of one or more cellulose ethers to effect fluidized-bed granulation, or prepared by spraying such a saccharide and an effective amount of a sleep-inducing substance with such an aqueous solution to effect fluidized-bed granulation. In this case, it is preferable that the saccharide be lactose and the cellulose ether be hydroxypropyl cellulose. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a nasal absorption sleep-inducing or sleeping agent comprising a drug-containing fine powder. More specifically, the present invention relates to a nasal absorption sleep-inducing or sleep-inducing agent that can be easily prepared by using a drug and hydroxypropylcellulose, and that quickly shows a high maximum blood concentration by nasal administration.

A drug used as a sleep inducer, for example, brotizolam, which is a thienotriazolodiazepine-based sleep inducer, is taken as a tablet or an orally disintegrating tablet. Sleep induction drugs are intended to have a rapid onset of action for their intended purpose, but when administered orally, they may not be absorbed into the body due to degradation in the gastrointestinal tract, etc. It has been pointed out that there are variations in the expression of.
Therefore, it is desired to develop a drug design for a sleep-introducing drug that is reliably absorbed into a living body, has a rapid onset of action effects, and does not vary in its expression.

  By the way, the nasal administration method is an administration method in which a drug is absorbed in vivo via a nasal mucosa and transferred to a circulating blood stream. In nasal administration, administration of a drug is simple, and since the nasal mucosa has a vascular system, the absorbability of the drug is superior to that of skin, ocular mucosa, rectal mucosa and the like. Furthermore, since the drug is rapidly transferred into the blood by nasal administration, it can be expected to have an immediate effect equivalent to that of injection administration.

According to previous studies, the absorbability of drugs from the nasal mucosa depends on the physical properties and molecular weight of the drug. Generally, drugs with high water solubility and drugs with high fat solubility have low absorbability. It has been reported.
From this point, various nasal administration means for improving the absorbability of a drug in the nasal mucosa have been proposed. For example, Patent Document 1 discloses a continuous intranasal administration comprising a cellulose ester and a drug. A preparation has been reported (Patent Document 1).

  This formulation is a formulation that, when administered intranasally, adheres to the nasal mucosa and gradually releases the drug on the spot, allowing the drug to be absorbed from the nasal mucosa and releasing its effective amount continuously. It is possible. However, it has been considered that the function of promoting the absorption of a drug is not necessarily sufficiently provided. Preferred drugs that can be administered are anti-inflammatory steroid drugs, analgesic anti-inflammatory drugs, antihistamine drugs, drugs with antiallergic action, etc., and maintenance of local drug concentration rather than absorption to systemic blood is desirable. It was an important drug.

  In addition to the above, various nasal administrations of various drugs including brotizolam, which is a sleep inducer, have been studied. For example, (1) a drug, a water-absorbing and gel-forming base such as hydroxypropylcellulose and hydroxypropylmethylcellulose, and a water-absorbing and poorly water-soluble base such as crystalline cellulose and α-cellulose. (2) The amount of the water-absorbing and gel-forming base is about 5 to 40 of the sum of the water-absorbing and gel-forming base and the water-absorbing and poorly water-soluble base. (3) A powdered nasal administration composition in which the drug is unevenly distributed in a water-absorbing and poorly water-soluble base than a water-absorbing and gel-forming base is proposed. (Patent Document 2).

  In addition, a powdery nasal solution containing a drug, a water-absorbing and gel-forming base such as hydroxypropylcellulose and hydroxypropylmethylcellulose, and a water-absorbing and poorly water-soluble base such as crystalline cellulose and α-cellulose. Administration composition (Patent Document 3) or drug, water-absorbing and gel-forming base such as hydroxypropylcellulose and hydroxypropylmethylcellulose, water-absorbing and poorly water-soluble such as crystalline cellulose and α-cellulose A powdery nasal administration composition (Patent Document 4) comprising the above-mentioned base has been proposed.

  Further, a powder comprising a drug, a water-absorbing and gel-forming base such as hydroxypropylcellulose and hydroxypropylmethylcellulose, and a water-absorbing and poorly water-soluble base such as crystalline cellulose and α-cellulose. In the form of nasal administration, the amount of the water-absorbing and poorly water-soluble base comprises the water-absorbing and poorly water-soluble base and the water-absorbing and gel-forming base. Powdered nasal administration composition (Patent Document 5) that is about 5 to 40% by weight of the sum of the amount, Powdered nasal composition comprising drug and colloidal cellulose (Patent Document 6), particle size of 10 μm A composition for powdery nasal administration comprising a drug that is less than or a freeze-dried drug, a water-absorbing and poorly water-soluble base, and a water-absorbing and gel-forming base (Patent Document 7) From drug and hydrogel-forming bases A powdery composition for nasal administration (Patent Document 8), a method for producing a powdered composition in which a liquid containing a drug is sprayed and adhered to a water-soluble polymer (Patent Document 9) and the like have been reported.

  However, the composition of these compositions and the production method thereof are complicated, and although a sleep inducer is exemplified as a drug, a specific composition for nasal administration and the composition of the composition are used. There is no disclosure regarding the administration method, dosage, effective blood concentration, pharmacological action / effect as a nasal sleep inducer.

Japanese Patent Publication No. 60-34925 Republished 97-31626 Japanese Patent Laid-Open No. 10-59841 JP-A-9-291015 JP-A-9-291026 No. 00-121366 Republication No. 00-12063 JP 2001-2589 A JP 2002-348252 A

  The present invention provides a nasal absorption sleep-inducing or sleep-inducing agent that can exhibit early efficacy as a sleep-inducing agent or a sleep-inducing agent, and is expected to reduce the dose by improving bioavailability. Is an issue.

  As a result of intensive studies in order to solve the above-mentioned object, the present inventors have introduced an effective amount of sleep into an aqueous solution of one or more cellulose ethers into a saccharide powdered in a fluidized bed granulator. Powder formulation obtained by spraying fluidized bed granulation while spraying a suspension obtained by adding an agent or a sleeping agent, or sugar introduced in a fluidized bed granulator and an effective amount of sleep introduction Confirmed that the powder formulation prepared by fluidized bed granulation while spraying an aqueous solution of one or more cellulose ethers on the active substance or the sleep-active substance solves the above-mentioned problems. The present invention has been completed.

That is, the present invention specifically includes the following configuration.
(1) Spraying a suspension obtained by adding an effective amount of a sleep-inducing agent or a sleep-inducing agent to an aqueous solution of one or more cellulose ethers into a saccharide powdered in a fluid bed granulator While spraying fluidized bed granulation, spray one or more aqueous solutions of cellulose ether onto the saccharide and the effective amount of sleep-inducing agent or sleep-inducing agent charged in the fluidized bed granulator. Nasal absorption sleep-inducing or sleep-inducing agent, characterized by being prepared by fluidized bed granulation while;
(2) The nasal absorption sleep-inducing or sleep-inducing agent according to 1 above, wherein the saccharide is lactose;
(3) The nasal absorption sleep-inducing or sleep-inducing agent according to 1 or 2 above, wherein the cellulose ether is hydroxypropylcellulose;
(4) A nasal absorption sleep-inducing or sleep-inducing agent according to any one of 1 to 3 obtained by performing fluidized bed granulation under the following conditions:
Supply air temperature 60-80 ° C,
Supply air volume 40-50m ³ / hr,
Spray air pressure 0.11 to 0.13 MPa,
Spray air flow rate 27-33L / min,
Liquid feeding speed 9 to 11 g / min, nozzle hole diameter 1.0 to 1.4 mm;
(5) The nasal absorption sleep-inducing or sleep-inducing agent according to any one of 1 to 4 above, wherein the average particle size is 80 to 100 μm;
(6) The nasal absorption sleep-inducing or sleep-inducing agent according to 1 to 5 above, wherein the powder has a specific volume (Lose value) of 2.1 to 3.6 (mL / g);
(7) The sleep-inducing or sleep-inducing agent for nasal absorption according to 1 to 6 above, wherein the sleep-inducing agent is brotizolam and the hypnotic agent is zolpidem tartrate;
It is.

The nasal absorption sleep-inducing agent or sleep-inducing agent provided by the present invention (hereinafter referred to as “the nasal absorption sleep-inducing agent” in the present specification is interpreted as including the sleep-inducing agent and the sleep-inducing agent). The active ingredient sleep-inducing agent or sleep-inducing agent (hereinafter referred to as “sleep-inducing agent” unless otherwise specified) is well absorbed into the living body via the nasal mucosa. Therefore, it is a preparation that exhibits a rapid effect and can exert a purposeful effect as a sleep inducer.
Moreover, it is a formulation that can be administered to patients who are difficult to administer orally due to various diseases.

  Furthermore, the sleep-inducing agent for nasal absorption provided by the present invention has a uniform content of the sleep-inducing agent, which is an active ingredient in terms of formulation, and nasal absorption in which the drug-containing particles do not reach the lungs when nasally inhaled. Is a formulation suitable for intranasal administration, having low irritation to the nasal mucosa and almost no unpleasant odor. In addition, after adhering to the intranasal mucosa, it can swell while absorbing the nasal secretions and release the active ingredient, so it has the advantage of being able to efficiently supply the drug at a concentration that provides a therapeutic effect ing.

In the present invention, as described above, as one basic embodiment, an effective amount of sleep-introducing agent is added to an aqueous solution of one or more cellulose ethers in a saccharide powdered in a fluidized bed granulator. A sleep-inducing agent for nasal absorption, which is prepared by fluidized bed granulation while spraying a suspension obtained by addition.
In addition, the present invention provides, as another basic aspect, an aqueous solution of one or more cellulose ethers in a saccharide charged in a fluidized bed granulator and an effective amount of a sleep-inducing agent or a sleeping agent. A sleep-inducing or sleep-inducing agent for nasal absorption, characterized by being prepared by fluidized bed granulation while spraying.

Hypnotic-introducing agents as active ingredients used in the present invention include, for example, benzodiazepine ultra-short-acting sleep-inducing agents such as triazolam, mitazolam, etc. And the like, long-acting sleep induction agents such as quazepam, flurazepam, haloxazolam, and the like can be mentioned.
Among these, in the present invention, brotizolam, which is a short-acting sleep induction agent, is particularly preferable.
Examples of the sleeping agent include zolpidem tartrate, haloperidol, zopiclone, and the like.

  On the other hand, examples of the saccharide used in the present invention include lactose, mannitol, sorbitol and the like, and lactose is preferably used.

  Examples of the cellulose ether used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, and the like, preferably hydroxypropylcellulose.

  Hereinafter, the preparation of the sleep-inducing agent for nasal absorption of the present invention will be described by taking brotizolam as an example of the sleep-inducing agent.

As described above, the preparation of the nasal absorption sleep-inducing agent of the present invention is performed by spraying a suspension of cellulose ether containing the sleep-inducing agent onto the saccharide powdered in a fluid bed granulator, thereby This is done by adhering an introducing agent to the surface. Spraying can also be performed using a drug solution or drug suspension.
Examples of the solvent to be used include water, ethanol, acetone, isopropyl alcohol, and the like, preferably water.

  As the fluidized bed granulator to be used, for example, a fluidized bed, a stirred fluidized bed, or a granulator such as vacuum rolling can be used. In order to avoid an increase in the particle size of the powder during granulation, a method of setting a small spray amount or intermittently spraying the liquid is preferable.

  The powder of the powder formulation charged into the fluidized bed granulator means a powder or finely divided composition. In addition to sugars, this powdery composition contains commonly used additives such as starches such as corn starch and sodium carboxymethyl starch; crystalline cellulose; gelatin; lubricants such as magnesium stearate An agent; a fragrance; a colorant; and a fluidizing agent may be blended within a range that does not hinder the uniformity of drug content.

The amount of the cellulose ether constituting the suspension to be sprayed is, for example, 100 parts by weight of the solid content to be used (the total weight of hydroxypropylcellulose, brotizolam and lactose) in the case of hydroxypropylcellulose in the examples described later. Is 0.1 to 5% by weight, preferably 0.1 to 3% by weight, and more preferably about 2% by weight.
For example, in the case of water, the amount of the solvent to be used varies depending on the amount of hydroxypropylcellulose and brotizolam used, and is not particularly limited. However, the concentration of hydroxypropylcellulose is usually 1 to 5% by weight, preferably 2 to 4%. It is recommended to use an amount in the range of%.

The amount of brotizolam as an active ingredient is not particularly limited, but is usually in the range of 20 to 70% by weight, preferably 20 to 60% by weight, based on 100 parts by weight of the total weight of hydroxypropylcellulose and brotizolam.
For example, since approximately 12 mg of the powder composition is sprayed at a time when spraying into the nasal cavity, examples of the dosage form include those containing 0.25 mg in 12 mg of the powder composition.

The conditions for fluidized bed granulation are shown below, for example, when brotizolam is used.
Supply temperature, supply air volume, spray air pressure, spray air flow rate, liquid feeding speed, nozzle hole diameter, etc. vary depending on the amount of hydroxypropyl cellulose, water, brotizolam, etc. used for granulation, but usually the supply temperature 60-80 ° C., preferably 70 ° C., the supply air flow rate 40 to 50 m ³ / hr preferably ^{45 m} 3 / hr, spray air pressure 0.11～0.13MPa, preferably 0.12 MPa, sprayed air flow rate 27～33L / Min, preferably 30 L / min, liquid feeding speed 9 to 11 g / min, preferably 10 g / min, nozzle hole diameter 1.0 to 1.4 mm, preferably 1.2 mm.

The specific volume (Loose value) of the powder, which is a sleep-inducing agent for nasal absorption obtained by the production method of the present invention, varies depending on the type of drug used, the amount used, etc., but is not particularly limited, but is 2 to 3.6 (mL / g), for example, in the case of brotizolam, preferably 2.1 to 2.4 (mL / g), in the case of zolpidem tartrate, preferably 2.9 to 2.5, specific volume (Pat value) Is 1.6 to 2.5 (mL / g), for example, in the case of brotizolam, preferably 1.6 to 1.8 (mL / g), and in the case of zolpidem tartrate, preferably 2.2 to 2.4. (ML / g).
The angle of repose is in the range of 31 to 39 (°), preferably 34 to 37 (°).
Furthermore, the moisture value is preferably 0.2% or less.

  Hereinafter, the present invention will be described in detail with reference to the production method, test examples, and examples of brotizolam-containing nasal absorption sleep-inducing agents, but the present invention is the same for other sleep-inducing agents or sleep-inducing agents. However, the present invention is not limited to this.

Example 1: A bronzolam 0.25 mg / 12 mg formulation-containing sleep-introducing agent for intranasal absorption, hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) (7.2 g) was dissolved in water (223.8 g), and brotizolam (Sanyo Chemical Research Laboratories) was dissolved therein. A solution obtained by adding 7.5 g of a suspension is used as a spray solution.
Using 355.3 g of lactose (Watanabe Chemical Co., Ltd.) as the powder preparation, spraying the spray liquid using a fluidized bed granulator (Multiplex MP01 type, manufactured by Paulek), fluidized bed granulation conditions; Fluidized bed granulation at 70 ° C., supply air volume 45 m ³ / hr, spray air pressure 0.12 MPa, spray air flow rate 30 L / min, liquid feed rate 10 g / min, nozzle hole diameter 1.2 mm, and containing nasal absorption containing brotizolam 360 g of a sleep induction agent for use was obtained.

Example 2: Brochizolam 0.15 mg / 12 mg formulation containing content of nasal absorption sleep introducing agent 7.2 g of hydroxypropyl cellulose was dissolved in 223.8 g of water, and 4.5 g of brotizolam was added and suspended. Let the solution be the spray solution. 345.3 g of the lactose was used as a powder preparation, and 360 g of a sleep induction agent for nasal absorption containing brotizolam was obtained by the same treatment as in Example 1 below.

Example 3: Brotizolam 0.1 mg / 12 mg formulation-containing content of nasal absorption sleep-introducing agent 7.2 g of hydroxypropyl cellulose was dissolved in 223.8 g of water, and 3.0 g of brotizolam was added and suspended. Let the solution be the spray solution. 345.3 g of the lactose was used as a powder preparation, and 360 g of a sleep induction agent for nasal absorption containing brotizolam was obtained by the same treatment as in Example 1 below.

  The physical properties of the nasal absorption sleep-inducing agent obtained by the production methods of Examples 1 to 3 are shown in Table 1 below.

Example 4: A solution obtained by dissolving 7.2 g of a nasal absorption hypnotic agent hydroxypropylmethyl cellulose (manufactured by Nippon Soda Co., Ltd.) containing zolpidem tartrate 5 mg / 30 mg in 232.8 g of water is used as a spray solution. As powder preparation, 60.0 g of zolpidem tartrate (manufactured by Sanyo Chemical Research Co., Ltd.) and 292.8 g of lactose (manufactured by Watanabe Chemical Co., Ltd.) were used, and sprayed using a fluidized bed granulator (multiplex MP01 type, manufactured by POWREC). Sprayed liquid, fluidized bed granulation conditions: air supply temperature 70 ° C., air supply air volume 40 m ³ / hr, spray air pressure 0.12 MPa, spray air flow rate 30 L / min, liquid feed rate 10 g / min, nozzle hole diameter 1. Fluidized bed granulation was performed at 2 mm to obtain 360 g of a nasal absorption hypnotic agent containing zolpidem tartrate.

Example 5: Nasal absorption hypnotic agent containing zolpidem tartrate 3 mg / 30 mg formulation A solution obtained by dissolving 7.2 g of the above hydroxypropyl cellulose in 232.8 g of water is used as a spray solution. The powder was charged with 36.0 g of zolpidem tartrate and 316.8 g of lactose, and then treated in the same manner as in Example 1 to obtain 360 g of a nasal absorption hypnotic agent containing zolpidem tartrate.

Example 6: Zolpidem tartrate 2 mg / 30 mg formulation-containing nasal absorption hypnotic agent A solution obtained by dissolving 7.2 g of the hydroxypropyl cellulose in 232.8 g of water is used as a spray solution. The powder was charged with 24.0 g of zolpidem tartrate and 328.8 g of lactose, and then treated in the same manner as in Example 1 to obtain 360 g of a nasal absorption hypnotic agent containing zolpidem tartrate.
The amount of zolpidem tartrate, which is an active ingredient, is not particularly limited, but is preferably in the range of 20 to 95% by weight, preferably 70 to 95% by weight, based on 100 parts by weight of the total weight of hydroxypropylcellulose and zolpidem tartrate. It is.

As a comparative example, a pulverized particle formulation described below was prepared.
As a pulverized preparation, a pulverized particle preparation was prepared by pulverizing brotizolam as an active ingredient together with lactose as a carrier and a lubricant as another additive.

Comparative Example 1: Preparation of pulverized particle preparation containing brotizolam 0.25 mg / 17 mg formulation A: Preparation of each pulverized product A-1: Preparation of crushed product (particle) of brotizolam Brotizolam (average particle size: 0.88 μm) Using a desktop lab jet mill (AO-JET-MILL, manufactured by Seishin Co., Ltd.), pulverized under conditions of nozzle air pressure: 0.5 to 0.6 MPa, powder feed rate: 5 to 10 g / hour, and attached to a classification device Both particles of a sample (average particle size: 2.17 μm, yield: 64.7%) and a final collection bottle collection sample (average particle size: 0.88 μm; yield: 16.5%) were obtained.
A-2: Preparation of pulverized product (particles) of lactose As a carrier particle, a sieve shaker (ES-65, manufactured by Iida Seisakusho Co., Ltd.) was used with Dialactos R (manufactured by Freund Sangyo Co., Ltd.) having openings of 150 μm and 75 μm. After shaking for 15 minutes, what remained on the 75 μm sieve (sized to 75 to 150 μm) was used.

B: Preparation of pulverized particle preparation containing 0.25 mg of brotizolam Unbroken brotizolam (average particle size: 0.88 μm), and brotizolam prepared above [ground product 1 (average particle size: 2.17 μm); (Average particle diameter: 0.88 μm)], 0.053 g of each of them was used, 3.33 g of carrier particles prepared by pulverization as described above, magnesium stearate as a lubricant (manufactured by Taihei Chemical Industrial Co., Ltd.) ) 0.017 g was weighed into a 10 mL centrifuge tube with a stopper, and mixed for 3 minutes with a test tube mixer (NS-80, manufactured by Inoue Seieido Co., Ltd.) to obtain 3.4 g of each of three types of pulverized particle formulations. .

Comparative Example 2: Preparation of pulverized particle preparation containing brotizolam 0.15 mg / 17 mg preparation and 0.1 mg / 12 mg preparation In accordance with the production method of Comparative Example 1, unmilled brotizolam (average particle size: 10.3 μm) Using the three types of pulverized product of brotizolam 1 (average particle size: 2.17 μm) and pulverized product 2 (average particle size: 0.88 μm) prepared above, carrier particles prepared by pulverization and lubricant The mixture was mixed with magnesium stearate as an agent to obtain 3.4 g each of three kinds of crushed preparations containing 0.15 mg of brotizolam and 3 crushed preparations containing 0.1 mg of brotizolam.

Test Example 1: Content Test A content test using the powder formulation of the nasal absorption sleep introduction agent obtained in Examples 1 to 3 and the pulverized particle formulation obtained in Comparative Example 1 was examined.

[Method]
12 mg powder formulation of the nasal absorption sleep induction agent obtained in Example 1 or 17 mg of three kinds of pulverized particle formulations obtained in Comparative Example 1 (0.25 mg, 0.15 mg and 0.1 mg as brotizolam, respectively) The amount of the active ingredient brotizolam was extracted, and the resulting extract was extracted with an HPLC system [interface; D-7000, autosampler; D-7200, pump; D-7100, column. Oven; D-7300 type, detector; D-7400 type, PC; FLORA 370 (manufactured by Hitachi, Ltd.)], and the content value of brotizolam was determined. Ten measurements were performed, and an average value and a relative standard deviation were calculated.

[HPLC operating conditions]
Column: YMC-Pack Pro C18: inner diameter 4.6 mm, length 15 cm, particle diameter 5 μm (manufactured by YMC Corporation),
Column temperature: 40 ° C
Mobile phase: Water / acetonitrile (for LC, Wako Pure Chemical Industries, Ltd.) (57:43) mixed solution,
Flow rate: 0.8 mL / min Measurement wavelength: 240 nm

  As a result, there was no particular problem with the content.

Test Example 2: Single injection weight from multi-dose device for nasal inhalation, and content during single injection test example Powder formulation of sleep introduction agent for nasal absorption of the present invention prepared in Example 1 and Comparative Example Using the pulverized particle formulation obtained in 1 above, a single injection weight and a single injection content test from a multi-dose device for nasal inhalation were performed.

[Method]
In a multi-dose device for nasal inhalation, about 0.96 g of the powder formulation of the sleep-inducing agent for nasal absorption of the present invention prepared in Example 1, or about 1.36 g of the pulverized particle formulation prepared in Comparative Example 1 (each about Equivalent to 80 spray particles) and the weight of each device was measured.
The weight of the device was measured for each injection, and the difference was obtained as the single injection weight.
In addition, the sprayed preparation was coated with 100 mL Erlenmeyer flask [methanol (special grade, manufactured by Wako Pure Chemical Industries) / glycerin (special grade, manufactured by Wako Pure Chemical Industries)] / water mixture (16: 2: 1) on the inner surface. It was collected by extraction and analyzed by extraction and HPLC system (same conditions as described above) to determine the content value of brotizolam during one injection.
The operation was repeated 10 times, and the average value and relative standard deviation of the single injection weight and brotizolam content during the single injection were calculated.

[result]
The results are shown in Table 2 below. In the table, A represents a preparation containing 0.25 mg of brotizolam, B represents a preparation containing 0.15 mg, and C represents a preparation containing 0.1 mg.

As can be seen from the results shown in the table, the sleep-inducing agent for nasal absorption of the present invention, which is the powder formulation of Example 1, has a stable spray weight from the device and a drug content in the propellant, There was little variation.
On the other hand, in the pulverized particle formulation of Comparative Example 1, the spray weight from the device was not stable and varied greatly, and the spray weight was sprayed only about 80% of the prescribed amount. In addition, there was a large variation in the drug content in the propellant.

Test Example 3: In Vitro Inhalation Test Example Using the powder formulation of the nasal absorption sleep-inducing agent of the present invention prepared in Example 1 above and the pulverized particle formulation prepared in Comparative Example 1, the following in In vitro inhalation studies were performed.

[Method]
A human nasal cavity model (manufactured by Hitachi, Ltd.) [1% Hibiswako 105 (manufactured by Wako Pure Chemical Industries, Ltd.) aqueous solution on the 0th to 7th filters of the cascade impactor (Andersen type, manufactured by COPLEY) Set to apply].
The nasal absorption sleep of the present invention prepared in Example 1 was applied to the nasal cavity of the human nasal cavity model while sucking for 8.5 seconds at an air flow rate of 28.3 L / min with a suction pump (manufactured by GAST Manufacturing Corporation). The nozzle part of the multi-dose device for nasal inhalation filled with the powder preparation of the introduction agent or the pulverized particle preparation prepared in Comparative Example 1 was inserted, and the preparation was sprayed.
(1) Human nasal cavity model, (2) Throat, (3) 0th order filter, (4) Primary filter, (5) 2nd to 5th order filter, (6) 6th to 7th order filter Brotizolam was extracted from the preparation adhering to, and analyzed by the HPLC system (under the above conditions) to determine the adhesion (deposition) ratio of brotizolam to each part (1) to (6).

[result]
Both the preparation of Example 1 and the preparation of Comparative Example 1 were carried out using a preparation containing 0.25 mg of brotizolam.
The results are shown in Table 3.

As can be seen from the results shown in the table, the powder formulation of the nasal absorption sleep introduction agent of Example 1 has no deposition from the primary filter to the seventh filter, and avoids reaching the lung of the formulation. Was done. Moreover, the favorable result was obtained also about the uniformity of content.
The powder preparation of the sleep-inducing agent for nasal absorption of Example 1 does not contain a lubricant, but has a good fluidity and has a stable injection amount even when no lubricant is added. It was possible to put out. It seemed to be possible by controlling the particle size.

  On the other hand, in the pulverized particle preparation of Comparative Example 1, deposition of the preparation particles was confirmed up to the 2nd to 7th filters (corresponding to aerodynamic particle diameter of about 0.4 to 6 μm) which are said to reach the lungs. It was.

  Similarly, the in vitro inhalation test was conducted for the preparation containing 0.15 mg of brotizolam and the preparation containing 0.1 mg. The results were the same for the preparation of Example 1 of the present invention and the preparation of Comparative Example 1. It was.

Test Example 4: In vitro inhalation test using a single dose device for nasal inhalation [Method]
Hydroxypropylmethylcellulose (HPMC) hard capsules (capsule size 2) were filled with a single dose (12 mg) of the test preparation and then set in a single dose device for nasal inhalation. The capsule was punctured by operating the device and sprayed onto the nostrils of the nasal cavity model with compressed air.
The inhalation evaluation test apparatus was used under the same conditions as the multi-tank type evaluation similar to Test Example 3, and sprayed to the right and left nasal cavities once (that is, two sprays per test).
Capsules were collected after each spray and the amount of brotizolam in the formulation remaining in the capsules was measured. In addition, after spraying on both nasal cavities, the amount of brotizolam in the formulation remaining in the device was measured. Evaluation of deposition on the nasal cavity model, throat, and each stage was performed in the same manner as described above.
As a test preparation, the powder preparation of the nasal absorption sleep introduction agent prepared in Examples 1, 2, and 3 of the present invention was used.

[result]
The results are shown in Table 4 below.

  As can be seen from the results shown in the table, the powder formulation of the nasal absorption sleep-inducing agent of the present invention has no deposition from the primary filter to the seventh filter even in a single administration, and the formulation lung Was able to avoid reaching.

Test Example 5: Pharmacokinetic test Brotizolam was administered nasally or orally to rats under pentobarbital anesthesia, and changes in plasma drug concentration were compared.
[Method]
To a 9-week-old male SD rat fasted overnight, about 0.42 mg / kg brotizolam was administered nasally or orally. For nasal administration, a powder formulation of the sleep-inducing agent for nasal absorption of the present invention prepared according to Example 1 was used.
Blood was collected from the femoral artery at 15, 30, 60, and 120 minutes after each administration, and the brotizolam concentration in the blood was measured by HPLC-MS / MS method according to the method of Tarai et al. (Pharmacology and Clinical Practice, Vol. 10, No. 11, pages 513-524). did.

[result]
The results are shown in FIG.
As can be seen from the results shown in the figure, the blood concentration by nasal administration was 4 in comparison with the case of oral administration at the time 15 minutes after the administration when the blood concentration was highest in both administration routes. The blood concentration was 6 times higher, and this concentration ratio was observed throughout the measurement period, confirming the high bioavailability of the nasal preparation compared to oral administration.

Test Example 6: Test by nasal administration to humans A sleep inducing drug obtained in each of the above examples of the present invention was applied to a commercially available spray device capable of spraying a certain amount of powder under informed consent. Were filled with a powder preparation containing an effective amount showing an action, and sprayed into the nasal cavity of one subject (adult male).
As a result, for example, brotizolam has low irritation and almost no unpleasant odor. In addition, the sleep-sleeping action was quickly manifested.
Although the effective amount of brotizolam for sleep induction is not particularly limited, it is said to be 0.01 mg to 10 mg / adult / once, preferably 0.01 mg to 1 mg / adult / once. If the dose increases, sleep induction The time was short and the sleep duration was long.

As described above, the present invention provides a sleep-inducing agent for nasal absorption that exhibits a high maximum blood concentration rapidly by nasal administration.
The sleep-inducing agent for nasal absorption provided by the present invention has a sleep-inducing agent as an active ingredient that is well absorbed into the living body via the nasal mucosa, and thus has a rapid onset of effects and is suitable as a sleep-inducing agent. Since it is a preparation that can exert an effect and can be administered even to patients who are difficult to administer orally due to various diseases, its medical contribution is great.

It is not shown that the blood concentration when the formulation of Example 1 was administered nasally and orally was compared. In the figure, ● represents nasal administration, and x represents changes in blood concentration after oral administration.

Claims (7)

  While spraying a suspension obtained by adding an effective amount of a sleep-inducing agent or a sleeping agent to an aqueous solution of one or more cellulose ethers into a saccharide powdered in a fluid bed granulator Fluidized bed while spraying aqueous solution of one or more kinds of cellulose ether on sugars and effective amount of sleep-inducing agent or sleep-inducing agent charged in powder in a fluidized bed granulator A sleep-inducing or sleep-inducing agent for nasal absorption, characterized by being prepared by granulation.   The nasal absorption sleep-inducing or sleep-inducing agent according to claim 1, wherein the saccharide is lactose.   The sleep-inducing or sleep-inducing agent for nasal absorption according to claim 1 or 2, wherein the cellulose ether is hydroxypropylcellulose. The sleep-inducing or sleep-inducing agent for nasal absorption according to any one of claims 1 to 3, obtained by fluidized bed granulation under the following conditions.
Supply air temperature 60-80 ° C,
Supply air volume 40-50m ³ / hr,
Spray air pressure 0.11 to 0.13 MPa,
Spray air flow rate 27-33L / min,
Liquid feeding speed 9-11g / min, nozzle hole diameter 1.0-1.4mm   The average particle diameter is 80-100 micrometers, The sleep introduction | transduction or sleep agent for nasal absorption of Claims 1-4.   The nasal absorption sleep-inducing or sleep-inducing agent according to claim 1, wherein the powder has a specific volume (Lose value) of 2.1 to 3.6 (mL / g).   The sleep-inducing or sleeping agent for nasal absorption according to claim 1, wherein the sleep-inducing agent is brotizolam and the sleeping agent is zolpidem tartrate.

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