JP2000290184A - Pernasally administrable preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation affording high cerebral migration tendency compared to the case with intravenous administration, therefore useful as a medicament for the brain as a target, for example, a therapeutic agent for Alzheimer's disease by including a specific compound (K252a derivative). SOLUTION: This preparation is obtained by including pref. 0.01-10 mg, more pref. 1-1.5 mg, of a compound of the formula [R1 and R2 are each H, hydroxymethyl, mercaptomethyl, a (substituted) alkoxymethyl, (substituted) alkylthiomethyl, (substituted) alkenyloxymethyl or (substituted) alkenylthiomethyl; R3 is an alkyl] (K252a derivative). Additionally, this preparation may also contain a solubilizing agent (e.g. phospholipid, specifically lysophosphatidylcholine). The dosage form of this preparation may be any, e.g. aqueous solution, lyophilized agent, powder, its administration mode being e.g. droplet or powder spray.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for nasal administration containing a K252a derivative.

[0002]

2. Description of the Related Art The general formula (I)

[0003]

Embedded image

(Wherein R ¹ and R ² are the same or different and each represents hydrogen, hydroxylmethyl group, mercaptomethyl group, substituted or unsubstituted alkoxymethyl group, substituted or unsubstituted alkylthiomethyl group, substituted or unsubstituted Represents a substituted alkenyloxymethyl group or a substituted or unsubstituted alkenylthiomethyl group, and R ³ represents an alkyl group) (K252a derivative)
[Hereinafter, a compound represented by the general formula (I) is converted to a compound (I)
That. The same applies to compounds of other formula numbers.]
Are useful compounds for neurodegenerative diseases such as Alzheimer's disease [J. Med. Chem. , 40 , 1863-
1869 (1997), Tokuhyo Hei 6-504731, WO
96/13506].

Compound (I) is hardly soluble in water and therefore difficult to prepare as an injection, and has a first-pass effect in the liver (metabolism, etc.).
Therefore, there is a demand for an administration route which is an alternative to an injection or an oral preparation. In recent years, as a new administration route of drugs that are expected to have systemic effects instead of injections or oral drugs,
Nasal mucosal absorption has been noted [J. Pharm. Sc
i. , 75 , 1085 (1986), Int. J. Ph
arm. , 9 , 165 (1987)]. This is because the vascular system of the nasal mucosa is significantly developed and is suitable as a drug absorption site. On the other hand, it is considered that not all drugs can be applied as a nasal agent due to physical properties such as molecular weight and solubility.

[0006]

SUMMARY OF THE INVENTION The object of the present invention is to provide K2
An object of the present invention is to provide a nasal administration preparation containing a 52a derivative.

[0007]

Means for Solving the Problems As a result of intensive studies on the nasal administration of a drug, the present inventors have found that when the compound (I) or a pharmacologically acceptable salt thereof is administered nasally, it is administered intravenously. It has been found that higher brain translocation is obtained in comparison. In particular, when used as a drug targeting the brain, for example, a therapeutic drug for Alzheimer's disease, the effect is considered to be remarkable.

[0008] The present invention relates to an intranasal preparation containing Compound (I) or a pharmaceutically acceptable salt thereof. Hereinafter, the present invention will be described in detail.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of the general formula (I), the alkyl group and the alkyl moiety in the alkoxymethyl group and the alkylthiomethyl group are linear or branched and have 1 to 10 carbon atoms, for example, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Examples of the alkenyl moiety in the alkenyloxymethyl group and the alkenylthiomethyl group include linear or branched C 2-10 carbon atoms such as vinyl, allyl, 1-propenyl,
Butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like.

The substituent in the substituted or unsubstituted alkoxymethyl group, substituted or unsubstituted alkylthiomethyl group, substituted or unsubstituted alkenyloxymethyl group, and substituted or unsubstituted alkenylthiomethyl group is as follows. 3 to, for example, a hydroxyl group,
Examples include a halogen atom, an alkoxy group, an amino group, a mono- or dialkylamino group, and the like. The halogen atom means each atom of fluorine, chlorine, bromine and iodine. The alkyl moiety in the alkoxy group and the mono- or dialkylamino group has the same meaning as the above-mentioned alkyl moiety.

As the compound (I), for example, the compounds shown in Table 1 can be mentioned.

[0012]

[Table 1]

Compound (I) is described in J. Med. Che
m. , 40 , 1863-1869 (1997), Japanese Translation of PCT International Publication No. 6-504731, WO96 / 13506, or the like, or according to them. The amount of compound (I) used in the intranasal preparation of the present invention is 0.0
It may be in the range of 1 to 10 mg, preferably 1 to 10 mg.
1.5 mg.

The preparation of the present invention may contain a solubilizing agent. Examples of the solubilizer include phospholipids, polyethylene glycol, propylene glycol, polyvinylpyrrolidone, and the like. The phospholipid is not particularly limited, for example, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, egg yolk lecithin,
Soy lecithin and the like, preferably lysophosphatidylcholine.

The amount of the solubilizer used in the intranasal preparation of the present invention may be in the range of 5 to 1,000 mg per 1 mg of the drug, but is preferably 20 to 200 mg.
The preparations of the present invention may contain pharmaceutically acceptable stabilizers, excipients, pH adjusters, buffers, preservatives, antioxidants, solubilizing agents, isotonic agents, depending on the purpose of the preparation. Agents, surfactants, soothing agents, thickeners and the like can be included. Examples of the stabilizer include mannitol and the like.
Excipients include mannitol, sucrose, glucose and the like. Examples of the pH adjuster include hydrochloric acid, sodium hydroxide and the like. Examples of the buffer include citric acid, phosphoric acid, acetic acid, lactic acid and the like, and pharmacologically acceptable salts thereof. Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate and the like. Examples of antioxidants include ascorbic acid and vitamin E. Examples of the solubilizer include polyethylene glycol, propylene glycol, and polyvinylpyrrolidone. Examples of the tonicity agent include glycerin, glucose, sodium chloride and the like. Examples of the surfactant include polysorbate 80 (Kao), Pluronic F68 (Asahi Denka Kogyo) and the like. Examples of the soothing agent include benzyl alcohol and lidocaine. Examples of the thickener include carboxyvinyl polymer, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, chitosan and the like.

The dosage form of the preparation of the present invention may be any of an aqueous solution, a lyophilized agent and a powder, and the administration form includes a droplet spray, a powder spray and the like. For example, in the case of an aqueous solution, compound (I) or a pharmaceutically acceptable salt thereof and a solubilizer, and if necessary, a stabilizer, an excipient, a pH adjuster, a buffer, a preservative, an antioxidant, and a dissolution agent. Prepared by dissolving adjuvants, isotonic agents, surfactants, soothing agents, thickeners, etc. in water for injection or buffer, sterile filtration, dispensing into containers and, if necessary, final sterilization. can do. In the case of a freeze-dried agent, compound (I) or a pharmaceutically acceptable salt thereof and a solubilizer, and if necessary, a stabilizer, an excipient, a pH adjuster, a buffer, a preservative, an antioxidant, Dissolution aids, isotonic agents, surfactants, soothing agents, thickeners, etc. are dissolved in water for injection or buffer, sterile filtered, dispensed into vials, freeze-dried and stoppered with rubber stoppers. And
It can be prepared by winding the cap. In the case of powder, compound (I) or a pharmaceutically acceptable salt thereof and a solubilizing agent, which are produced aseptically,
If necessary, after mixing stabilizers, excipients, pH adjusters, buffers, preservatives, antioxidants, dissolution aids, tonicity agents, surfactants, soothing agents, thickeners, etc. It can be prepared by dispensing into a container.

The pH at the time of preparing the chemical solution of the present invention is preferably from 3 to 10, and more preferably from 5 to 8. Next, the effects of the intranasal preparation of the present invention will be described with reference to test examples.

Test Example 1 Male SD rats (200-350 g, SLC Japan) were anesthetized with urethane (1.2 g / kg), and then the trachea was cannulated to secure the airway. 25 μL of the preparation for nasal administration obtained in Examples 1 and 2 and Comparative Example 1 described later was administered into the left nasal cavity, and after a certain period of time, the blood was exsanguinated from the abdominal aorta and the whole brain was extracted. After washing the removed brain,
Equivalent weight of water for injection was added, and under ice-cooling, using a Polytron homogenizer (BT-10-20, BIOTRON),
A homogenate was prepared. 5 mL of ethyl acetate is added to 1 mL of the homogenate, shaken for 10 minutes, and then 3,000 at 4 ° C.
Centrifugation was performed at rpm / min for 10 minutes. After separating the supernatant and evaporating the solvent, high performance liquid chromatography (HP
It was dissolved in a mobile phase for LC) and the concentration of compound 4 in the brain was measured using HPLC. The area under the obtained brain drug amount-time curve (AUC) was calculated. AUC is
It was calculated by the time when the amount of drug in the brain returned to the baseline.

Test Example 2 Male SD rats (200-350 g, SLC Japan) were anesthetized with urethane (1.2 g / kg). 250 μL of the preparation for intravenous administration obtained in Comparative Example 2 described below was intravenously injected into the tail, and after a certain period of time, the blood was exsanguinated from the abdominal aorta and the whole brain was removed. After washing the extracted brain, add an equal weight of water for injection,
Under ice cooling, a polytron homogenizer (BT-10-2)
0, BIOTRON) to prepare a homogenate. 5 mL of ethyl acetate is added to 1 mL of the homogenate, and 1
After shaking for 0 minutes, centrifugation was performed at 3000 rpm / min at 4 ° C for 10 minutes. After separating the supernatant and distilling off the solvent,
It was dissolved in a mobile phase for PLC, and the concentration of Compound 4 in the brain was measured using HPLC. The area under the obtained brain drug amount-time curve (AUC) was calculated. AUC is
It was calculated by the time when the amount of drug in the brain returned to the baseline.

The HPLC conditions are shown below. Column: YMC-Pack ODS-AM AM-312 (manufactured by YMC Corporation) Mobile phase: 20 mM ammonium acetate-acetic acid (pH 4.0): acetonitrile (30:70, V / V) Flow rate: 1.0 mL / min Detection Wavelength: UV: 295 nm Fluorescence: excitation wavelength 295 nm, fluorescence wavelength 378 nm The results are shown in Table-2.

[0021]

[Table 2]

From these results, it has been clarified that when the compound (I) or a pharmaceutically acceptable salt thereof is administered nasally, a higher brain-localizing property can be obtained than when intravenous administration is performed. Hereinafter, examples and comparative examples of the present invention will be described, but the present invention is not limited to these examples.

[0023]

Example 1 150 mg of lysophosphatidylcholine was added to chloroform /
It was dissolved in 10 mL of a mixture of ethanol (50:50, V / V). Separately, compound 3 and 3 mg were dissolved in chloroform / ethanol (50:50, V / V) mixed solution 10 mL.
These were mixed in a flask and stirred, and then the solvent was distilled off under reduced pressure to form a thin film. 2 mL of water for injection in this thin film
Was added and stirred with a vortex mixer to prepare a preparation for nasal administration.

Example 2 400 mg of phosphatidylcholine was dissolved in 10 mL of a chloroform / ethanol (50:50, V / V) mixed solution. Separately, 8 mg of Compound 4 was dissolved in 10 mL of a chloroform / ethanol (50:50, V / V) mixed solution. These were mixed in a flask and stirred, and then the solvent was distilled off under reduced pressure to form a thin film. 2 mL of water for injection in this thin film
Was added and stirred with a vortex mixer to prepare a preparation for nasal administration.

Comparative Example 1 150 mg of lysophosphatidylcholine was added to chloroform /
It was dissolved in 10 mL of a mixture of ethanol (50:50, V / V). Separately, compound 3 and 3 mg were dissolved in chloroform / ethanol (50:50, V / V) mixed solution 10 mL.
These were mixed in a flask and stirred, and then the solvent was distilled off under reduced pressure to form a thin film. 2 mL of water for injection in this thin film
Was added and stirred with a vortex mixer, and then diluted 10-fold with water for injection to prepare a preparation for intravenous administration.

[0026]

According to the present invention, there is provided a nasal administration preparation containing a K252a derivative.

Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court II (Reference) // C07D 498/22 C07D 498/22 (72) Inventor Masaji Nakakura 1188 Shimodomekari, Nagaizumi-cho, Sunto-gun, Shizuoka Kyowa Hakko Kogyo Kogyo Co., Ltd. Within the Pharmaceutical Research Institute (72) Inventor Eiji Hayakawa 1188 Shimotsukari, Nagaizumi-cho, Sunto-gun, Shizuoka Pref. 4C086 AA01 CB22 MA01 MA02 MA04 MA05 MA59 NA02 NA10 ZA16

Claims (4)

[Claims] 1. A compound of the general formula (I) (In the formula, R ¹ and R ² are the same or different and each is hydrogen, hydroxylmethyl group, mercaptomethyl group, substituted or unsubstituted alkoxymethyl group, substituted or unsubstituted alkylthiomethyl group, substituted or unsubstituted alkenyl Represents an oxymethyl group or a substituted or unsubstituted alkenylthiomethyl group, and R ³ represents an alkyl group)
Or a pharmaceutically acceptable salt thereof. 2. The preparation according to claim 1, which comprises a solubilizing agent. 3. The preparation according to claim 2, wherein the solubilizing agent is a phospholipid. 4. The preparation according to claim 3, wherein the phospholipid is lysophosphatidylcholine.