JPH06305952A - Threo-3-(3,4-dihydroxyphenyl)serine nasotracheal administration pharmaceutical preparation - Google Patents

Abstract

(57) [Summary] [Object] To provide a nasal preparation of DL or L-threo-3- (3,4-dihydroxyphenyl) serine. [Structure] L-threo-3- (3,4-dihydroxyphenyl) serine 200 mg, glycyrrhetinic acid 3-O-
A tris-hydrochloric acid solution was added to 200 mg of monohemiphthalate disodium salt and 100 mg of sodium ascorbate to adjust the pH to 4.5 to obtain a liquid nasal preparation (10 ml).

Description

Detailed Description of the Invention

[0001]

The present invention relates to threo-3- (3,4-
Dihydroxyphenyl) serine (hereinafter, threo-DOP
Abbreviated as S. ).

[0002]

L-threo-DOPS is a non-living precursor of norepinephrine, and when orally administered, it produces aromatic L-amino acid decarboxylase in blood. It is converted into norepinephrine by the action of decarboxylase), acts on peripheral norepinephrine receptors, and enhances the action of sympathomimetic neurons. Also, L-Threo-DOP
S is a lipophilic low molecular weight compound having a molecular weight of 213.19, and a part thereof passes through the blood-brain barrier and is also taken up by the central nervous system to enhance the action of norepinephrine-operated neurons. Therefore, L-threo-DOPS utilizes the former action, as a therapeutic drug for essential hypotension and orthostatic hypotension, and also utilizes the latter action, and Parkinson (Parkinso)
n) It has been widely used as a remedy for the freezing feet found in patients with Fever disease. Furthermore, it has been reported that administration to familial amyloid polyneuropathy (FAP) patients shows some effectiveness on orthostatic hypotension and diarrhea symptoms caused by autonomic neuropathy.

[0003]

However, in a group of patients with severe diarrhea, such as familial amyloid polyneuropathy patients, even when L-threo-DOPS is orally administered, the blood norepinephrine level is completely elevated. No
In some cases, it is difficult to exert the pharmacological effect after administration. Not only in these patient groups, but also in patients with essential hypotension, orthostatic hypotension or Parkinson's disease, oral administration suggests that the pharmacological effects may depend on the condition of the digestive system. . Therefore, L-threo-as an administration route that does not depend on the symptom state of the digestive organs of the administration patient.
Development of nasal drops for DOPS is desired.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that 1) phospholipids, saponins, bile acids, glycyrrhetinic acid or glycyrrhetinic acid derivatives, and 2) ascorbic acid, By adding tartaric acid, citric acid, aspartic acid or salts thereof, and adjusting the pH to 4.0 to 6.0, excellent D
It has been found that a nasal formulation of L or L-threo-DOPS can be obtained, and the present invention has been completed.

The present invention will be described in detail below. The threo-DOPS in the present invention is preferably L-form. Examples of the phospholipid include glycerophospholipids such as phosphatidylcholine, phosphatidylserine, lysophosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, and sphingolipids such as sphingomyelin and ceramidephosphonoethylamine. Examples of saponins include steroid saponins such as digitonin, gitonin and tigonine, and triterpenoids such as hederin and glycyrrhizin. Examples of the sugar component of saponin include glucose, galactose, pentose, methylpentose, arabinose and glucuronic acid. Examples of the bile acid include cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid and dehydrocholic acid, and may be alkali metal salts such as sodium salts thereof.

Examples of the derivative of glycyrrhetinic acid include those in which the hydroxyl group is ester-bonded with another carboxylic acid, preferably glycyrrhetinic acid 3 represented by the following formula:
-O-monohemiphthalate (Glycyrrhetinic acid 3-O-
monohemiphthalate)

[Chemical 1] Or a salt thereof, more preferably glycyrrhetinic acid 3
-O-monohemiphthalate disodium salt may be mentioned. Among the ascorbic acid, tartaric acid, citric acid, aspartic acid or salts thereof used in the present invention, sodium ascorbate is preferable. The preparation of the present invention has a pH of 4.0 to 6.0 depending on a pharmaceutically acceptable pH adjusting agent.
It was prepared in. Threo-DO in the formulation of the present invention
The content of PS is not particularly limited, but is preferably 50 to 400 mg, more preferably 200, per 10 ml of the preparation.
mg. Glycyrrhetinic acid 3-O- in the present invention
The content of monohemiphthalate or its salt is not particularly limited, but is preferably 50 to 400 per 10 ml of the preparation.
mg, more preferably 200 mg. The content of sodium ascorbate in the present invention is not particularly limited, but it is preferably 25 to 200 mg, more preferably 100 mg per 10 ml of the preparation.

The preparation for nasal administration of threo-DOPS of the present invention is produced by a known method or a method analogous thereto. For example, mixing, dissolving the required ingredients in any order,
It is produced by suspending or emulsifying. At this time, additives such as pharmaceutically acceptable buffering agents, stabilizers, tonicity agents, solubilizing agents, disintegrating agents, suspending agents and preservatives can be added as necessary. . The dose and frequency of administration of the threo-DOPS nasal preparation in the present invention may be appropriately selected depending on the patient's symptoms and the like. The starting compound, threo-DOPS, is a known compound and can be produced, for example, by the method described in JP-B-1-49139.

[0008]

INDUSTRIAL APPLICABILITY The preparation of the present invention has low irritation to the nasal mucosa, and even if a nasally administered preparation of L-threo-DOPS in a clinically effective amount is repeatedly administered over a long period of time, it does not damage the nasal mucosa. Expected not to give. Therefore, the preparation of the present invention is extremely suitable for nasal mucosal administration, and L-threo-DOPS is administered over a long period of time by a simple method that does not require the pain of spraying or dripping into the nasal cavity by the patient himself, and adverse reaction It has the advantage that it can be stably fed into the blood without being caused by the condition of the digestive tract. Furthermore, in recent years, a route in which a drug administered into the nasal cavity is carried into the cerebrospinal fluid via a route from the olfactory nerve has been proposed, but the preparation of the present invention is effective not only in blood but also in cerebrospinal fluid. It was confirmed by the test examples described later that it has an effect of increasing the norepinephrine concentration. Since nasal administration of this drug raises the level of norepinephrine in the cerebrospinal fluid, it is expected that the treatment method for Parkinson's disease by nasal administration will advance one step further. Further, the dose is smaller than that of oral administration, and the same effect as the pharmacological action of oral administration can be exhibited.

[0009]

EXAMPLES Next, the formulations of the present invention will be specifically described by way of Examples and Test Examples, but the invention is not limited thereto. Example L-threo-DOPS 200 mg, glycyrrhetinic acid
3-O-monohemiphthalate disodium salt 200 m
g, a tris-HCl solution was added to 100 mg of sodium ascorbate and adjusted to pH 4.5 with hydrochloric acid and sodium hydroxide to obtain a liquid L-threo-DOPS nasal preparation (10 ml).

Test Example 1 Fluctuations in blood norepinephrine level after intranasal administration of L-threo-DOPS formulation in normal subjects The formulation of the present invention obtained in the examples was applied to the left and right nasal cavities of 5 subjects in 5 subjects. It was administered dropwise (total amount, 8 mg / 0.4 ml) and the increased norepinephrine level was measured. L-
Threo-DOPS showed a transient increase 15 minutes after nasal drip and then a significant increase in blood norepinephrine level for 2 hours after nasal drip (FIG. 1). No significant increase in norepinephrine level was confirmed with the additives alone (glycyrrhetinic acid 3-O-monohemiphthalate disodium salt and sodium ascorbate).

Test Example 2 Oral L-threo-D in FAP patients showing diarrhea
Changes in blood norepinephrine level after administration of OPS and administration of the preparation of the present invention In three FAP patients, the preparation of the present invention was applied postnasally (4 drops each to the left and right nasal cavities: total amount 8 mg)
/0.4 ml) and increased norepinephrine levels were measured. As in the normal subjects, a transient increase in L-threo-DOPS was observed 15 minutes after nasal instillation, followed by a significant increase in blood norepinephrine level for 2 hours after nasal instillation (FIG. 2). No significant increase in norepinephrine level was confirmed with the additives alone (glycyrrhetinic acid 3-O-monohemiphthalate disodium salt and sodium ascorbate). In addition, due to diarrhea in these patient groups, no significant increase in norepinephrine level was obtained by oral administration (100 mg) (FIG. 2).

Test Example 3 Elevation of cerebrospinal fluid norepinephrine level in normal subjects When the same amount of the preparation of the present invention was administered to 3 normal subjects, norepinephrine levels in the cerebrospinal fluid were significant at 1 and 2 hours after administration. A significant increase was obtained (Fig. 3).

Test Example 4 Improvement effect of the preparation of the present invention on orthostatic hypotension and diarrhea observed in FAP patients. For 3 FAP patients, the preparation of the present invention obtained in the examples was applied to the left and right nasal cavities, 4 drops each in 1 drop. 3 times a day (8 mg total once)
/0.4 ml) for 1 week. When the number of subsequent diarrhea was compared with the number of diarrhea when not administered, when L-threo-DOPS was orally administered, and when the additive alone was administered,
Administration of the preparation of the present invention significantly reduced the number of diarrhea (Fig. 4). Orthostatic hypotension was also significantly improved after nasal administration.

[0014]

[Brief description of drawings]

FIG. 1 shows the relationship between time after nasal administration of the preparation of the present invention and blood norepinephrine level in normal subjects.

FIG. 2 shows L in FAP patients with diarrhea.
-Shows the relationship between time after threo-DOPS administration and blood norepinephrine level. ○ indicates the case of administration of the preparation of the present invention
Indicates the case of oral administration.

FIG. 3 shows an increase in cerebrospinal fluid norepinephrine level at 1 and 2 hours after administration of the preparation of the present invention in normal subjects.

FIG. 4 shows the effect of the formulation of the present invention on the number of diarrhea observed in FAP patients.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toshiomi Goto 1-1, Honjo, Kumamoto City Department of Internal Medicine, Kumamoto University School of Medicine

Claims (2)

[Claims] 1. A DL or L-threo-3- (3,4-)
Dihydroxyphenyl) serine, 2) phospholipids, saponins, bile acids, glycyrrhetinic acid or derivatives of glycyrrhetinic acid, and 3) ascorbic acid, tartaric acid, citric acid, aspartic acid or salts thereof, and a pH of 4.0. A nasal preparation which is adjusted to 6.0. 2. The nasal preparation according to claim 1, wherein threo-3- (3,4-dihydroxyphenyl) serine is L-form.