WO1994025017A1 - PERNASAL PREPARATION COMPRISING threo-3-(3,4-DIHYDROXYPHENYL)SERINE - Google Patents

Abstract

A pernasal preparation is produced in liquid form (in an amount of 10 ml) by adding 200 mg of L-threo-3-(3,4-dihydroxyphenyl)serine, 200 mg of disodium glycyrrhetic acid 3-0-monohemiphthalate and 100 mg of sodium ascorbate to a tris hydrochloride solution to adjust the pH to 4.5. This preparation is lowly irritant for the nasal mucosa and suitable for administering a clinically effective amount of L-threo-3-(3,4-dihydroxyphenyl)serine through the nasal mucosa.

Description

 Nasal preparations 3-(3, 4-dihydroxy phenyl) serine Nasal formulation

 The present invention relates to a preparation for intranasal administration of threo-3- (3,4-dihydroxyphenyl) serine (hereinafter abbreviated as threo-DOPS). Background art

 L-Threo-D-PS is a non-in vivo precursor of norupinephrine, and when administered orally, acts on the action of aromatic L-amino acid decarboxylase in the blood It is converted to norepinephrine by the enzyme and acts on peripheral norepinephrine receptors to enhance the action of sympathetic neurons.

In addition, low-leose DOPS is a lipid-soluble low molecular weight compound with a molecular weight of 23.1.19.When administered orally, part of it passes through the blood-brain barrier and is also taken up by the central nervous system. And enhances the action of Norupinefline activator. Therefore, L-Threau DOPS is a therapeutic agent for essential hypotension and orthostatic hypotension, utilizing the potentiating effect of sympathomimetic neurons, as well as for norepinefrin. Utilizing the potentiating effect of activated neurons, it was found in patients with Parkinson's disease. It has been widely used as a therapeutic agent for freezing feet (USP4330558 and USP4497826). Furthermore, when L-threo-DOPS is administered to patients with familial amyloid polyuropathy (FAP), there is some degree of orthostatic hypotension and diarrhea caused by autonomic nervous disorder. It has been reported to show efficacy (USP4330558).

 However, in a group of patients with severe diarrhea, such as FAP patients, oral administration of L-Threo-DOPS did not increase blood norepinefrin levels at all, In some cases, subsequent pharmacological effects are difficult to achieve. Not only in these patients, but also in patients with essential hypotension, orthostatic hypotension, or Parkinson's disease, oral administration of L-slo-D0PS This suggests that pharmacological effects may be affected by digestive conditions.

 Therefore, it is desired to develop nasal drops of L-Threo-D OPS as a route of administration that does not depend on the digestive condition of the patient.

 Accordingly, an object of the present invention is to provide a new nasal administration preparation of threo-D OPS.

Disclosure of the invention

 The present invention

 1) Threo-D OPS or a pharmaceutically acceptable acid addition salt thereof;

2) phospholipids, saponins, bile acids or their salts, At least one component selected from the group consisting of lysyl retinoic acid or a salt thereof and a derivative of glycyl retinoic acid; and

 3) at least one component selected from the group consisting of ascorbic acid, tartaric acid, citric acid, ascorbic acid and salts thereof;

 And wherein the pH is adjusted to 4.0 to 6.0 when in a liquid form.

 Furthermore, the present invention

 1) Threo 3-(3, 4-dihydroxyphenyl) serine or a pharmaceutically acceptable acid addition salt thereof;

 2) At least one member selected from the group consisting of phospholipids, saponins, bile acids or salts thereof, glycyl retinoic acid or salts thereof, and derivatives of glycyl retinoic acid. component

; and

 3) at least one ingredient selected from the group consisting of ascorbic acid, tartaric acid, cunic acid, aspartic acid and salts thereof;

 And administering to the human nasal cavity a preparation in a liquid form whose pH has been adjusted to 4.0 to 6.0. (Hydroxyphenyl) Serine administration method.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of intranasal administration of the preparation of the present invention in normal subjects. Shows the relationship between time and blood norepine frin level.

 FIG. 2 shows the relationship between the time after intranasal administration of the preparation of the present invention and blood norepinephrine levels in FAP patients showing diarrhea symptoms. In FIG. 2,。 indicates the case of intranasal administration of the preparation of the present invention, and · indicates the case of oral administration.

 FIG. 3 shows the elevation of cerebrospinal fluid norepinephrine levels in normal subjects at 1 and 2 hours after nasal administration of the preparation of the present invention.

 FIG. 4 shows the effect of intranasal administration of the preparation of the present invention on the number of diarrhea observed in FAP patients. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

 The threo-D OPS used as the active ingredient of the nasal administration preparation of the present invention is represented by the following formula:

で表わされる公知の化合物であり、 例えば特公平 1 一 4 9 1 3 9 号公報及び U S P 4 4 8 0 1 0 9 記載の方法に よ り製造する こ とができ る。 ス レオー D O P S には光学 活性体の L体および D体があ り、 またそのラセ ミ 体であ る D L体が存在する。 本発明では L体である L ース レオ — D 〇 P S が好ま しい。

And can be produced, for example, by the methods described in Japanese Patent Publication No. 114913/19 and US Pat. No. 4,480,109. Sleo DOPS has an L-form and an D-form of the optically active form, and a DL-form which is a racemic form thereof. In the present invention, the L-form L — D 〇 PS is preferred.

 Threo D OPS can also be used in the form of a pharmaceutically acceptable acid addition salt. Examples of the acid used to form the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as fumaric acid, citric acid, tartaric acid, and succinic acid. Can be

 In the preparation for nasal administration of the present invention, phospholipid, saponin, bile acid or a salt thereof, glycyl retinoic acid or a salt thereof and a derivative of glycyl retinoic acid are used. Use at least one component selected from the group. Examples of phospholipids include phosphatidylcholine, phosphatidylserine, lysophosphatidylcholine, phosphatidylethanolamine, and phosphatidylamine. Glycerin lipids such as diluinositol or sphingolin lipids such as sphingomyelin and ceramide phosphonoethylamine No.

 Examples of the saponin include steroid saponins such as dichitonin, gitonin, and tigonin, and triterdinoids such as hederin and glycyllithin. And so on. Examples of the sugar component of saponin include glucose, galactose, pentose, methylpentose, arabinose, and glucuronic acid.

The bile acids include, for example, cholate, glycocholate, taurocholate, deoxycholate or dehydrocholate. Further, alkali metal salts such as sodium salts thereof may be used. Examples of the derivative of glycyl retinoic acid include those in which the hydroxyl group is ester-bonded to another carboxylic acid, and preferably, glycyl retinoic acid represented by the following formula: One-to-one copy

ま たはその塩、 さ らに好ま し く はグ リ シル レ チ ン酸 3 — 〇 一 モ ノ へ ミ フ 夕 レ ー ト ニナ ト リ ウ ム塩が挙げ られ る。

Or a salt thereof, and more preferably, glycyl retinoic acid 3-monomonohemihydroquinone latenium salt.

 Further, in the nasal administration preparation of the present invention, at least one selected from the group consisting of ascorbic acid, tartaric acid, citric acid, aspartic acid and salts thereof is used. Ingredients are used. Of these components, sodium ascorbinate is preferred.

The nasal administration preparation of the present invention contains the above-mentioned two components together with Threo-DOPS, and is adjusted to a pH of 4.0 to 6.0 when in a liquid form. You. Therefore, according to the present invention, in addition to the preparation in a liquid form whose pH is adjusted to 4.0 to 6.0, both Sloe D and PS are increased. It also includes solid preparations consisting of the two components described above, which are dissolved in an appropriate solvent at the time of use and adjusted to a pH of 4.0 to 6.0. To prepare the preparation of the present invention in a liquid form, a commonly used buffer such as a tris-hydrochloric acid solution is used, and the pH is adjusted by hydrochloric acid or sodium hydroxide. It is performed using a pharmaceutically acceptable pH regulator. The intranasal preparation of the present invention may contain, if necessary, commonly used suspending agents, emulsifiers, solubilizing agents, isotonic agents and the like.

 The content of threo-DOPS in the intranasal preparation of the present invention is not particularly limited, but is preferably 50 to 400 mg per 10 ml of the preparation in a liquid form, and more preferably. The range is 200 to 30 O mg.

 At least one component selected from the group consisting of phospholipids, saponins, bile acids or salts thereof, glycyl retinoic acid or salts thereof, and derivatives of glycyl retinoic acid The content of the drug is not particularly limited, but is preferably 50 to 40 mg per 10 ml of the preparation in a liquid form, and more preferably 200 to 30 mg. O mg.

 The content of at least one component selected from the group consisting of ascorbic acid, tartaric acid, cuenic acid, aspartic acid and salts thereof is not particularly limited, but is preferably in a liquid form. It is 25 to 200 mg per 100 m1, more preferably 100 to 200 mg.

The preparation for nasal administration of the present invention can be prepared by a known method or Manufactured by similar means. For example, a stereo —

D0PS and the two kinds of components are mixed in an arbitrary order and, for example, dissolved, suspended or emulsified in a buffer solution to produce a preparation in a liquid form. At this time, pharmaceutically acceptable additives such as a buffer, a stabilizer, a tonicity agent, a solubilizer, a disintegrant, a suspending agent, and a preservative may be added as necessary. it can. It can also be prepared as a solid preparation containing threo-D-PS and other two components. Such a solid preparation is dissolved in the above-mentioned buffer solution, distilled water or the like at the time of use, and adjusted to pH 4.0 to 6.0 by adding a pH adjuster as necessary. Is done. Such solid dosage forms may be in the form of a kit, in combination with buffers, pH adjusters and the like.

 The dose and the number of times of administration of the intranasal preparation of Sloe D0PS in the present invention may be appropriately selected according to the patient's symptoms and the like. For example, the dose of Sleo D0PS per adult per day may be 20 to 200 mg, preferably 40 to 100 mg.

 In order to actually administer the preparation of the present invention, the method of instillation into the nasal cavity is preferred, and the method of intranasal administration using a sprayer usually used for nasal administration is adopted. ^) O

Next, the nasal administration preparation of the present invention will be described in more detail with reference to Examples and Test Examples, but it should not be construed that the invention is limited thereto. Example

 L-threate DOPS 200 mg, glycyrrhetinic acid 3 — 0—Mono hemi-fuitinite sodium salt 20 O mg, Askolbin Add 1 OO mg of sodium acid to a solution of tris-HC1 (tris-HC1), adjust the pH to 4.5 with hydrochloric acid and sodium hydroxide, and form an aqueous solution. A sodium chloride-dosage formulation for intranasal administration of DOPS (1 O ml) was obtained.

Test example 1

 Fluctuations in blood norepinephrine levels after nasal administration of L-threo-D OPS preparation in normal subjects

 To five normal subjects, the invented preparation obtained in the Example was administered to the right and left nasal cavities by 4 drops each (total amount, 8 mg Z 0.4 ml), and the increase in blood The measured Norwepine fringe level was measured. Figure 1 shows the measurement results. As can be seen from Fig. 1, L-threo-D〇PS showed a transient rise 15 minutes after nasal administration, and then significant blood levels for 2 hours after nasal administration. Additives that show elevated levels of norepine frin only (glycyl retinoic acid 3 — 0— No significant increase in norupinephrine levels was observed in sodium nitrate.

Test example 2

Norepine in the blood after oral L-threo-D〇PS administration and after administration of the preparation of the present invention in FAP patients with diarrhea symptoms Fluctuations in fly level

 In three FAP patients, the formulation of the present invention obtained in the Example was applied after nasal instillation (administered 4 drops in the left and right nasal cavities: 8 mg ZO. 4 ml in total), and increased norepinephrine in the blood. The ring level was measured. Figure 2 shows the measurement results. As can be seen from Fig. 2, as in normal subjects, L-Sleo-D-PS PS showed a transient rise 15 minutes after nasal instillation, and was significant for 2 hours after nasal instillation. The level of blood norepine frin increased. Additives only (glycyl retinoic acid 3 — mono-monophosphate, sodium salt of sodium and sodium ascorbinate) have significant levels of No increase in Pineflin level was confirmed. In these patient groups, due to diarrhea, oral administration (100 mg) did not produce a significant increase in norupinephrine level. Test example 3

 Elevated Cerebrospinal Fluid Norepnefin Level in Normal Subjects Three normal subjects were administered the preparation of the present invention in the same manner as in Test Example 1, and the level of norepinefrine in the cerebrospinal fluid was measured. Figure 3 shows the measurement results. As can be seen from FIG. 3, a significant increase in the level of norepinephrine in the cerebrospinal fluid was obtained at 1 and 2 hours after administration.

Test example 4

 Improvement effect of the preparation of the present invention on orthostatic hypotension and diarrhea observed in FAP patients

Formulation of the present invention obtained in Examples in 3 FAP patients Was administered to the left and right nasal cavities three times a day (total dose: 8 mg / 0.4 ml) four times a week for one week. Thereafter, the number of diarrhea per day was examined and compared with the number of diarrhea at the time of non-administration, oral administration of L-threo-D0PS, and administration of the additive alone. The results are shown in Fig. 4. As can be seen from FIG. 4, the number of diarrhea was significantly reduced by administration of the preparation of the present invention. Orthostatic hypotension was also significantly improved after nasal administration. Industrial applicability

 The preparation for nasal administration of the present invention has low irritation to the nasal mucosa, and can cause damage to the nasal mucosa even if a clinically effective amount of L-threo-DOPS is repeatedly administered for a long period of time. It is expected that there will be no. Therefore, the preparation of the present invention is extremely suitable for nasal mucosal administration, and can be used for a long period of time by a painless and simple method of spraying or dripping into the nasal cavity by the patient. It has the advantage that it can be supplied to the blood without causing adverse reactions and without being affected by the condition of the digestive tract.

In recent years, a route by which drugs administered into the nasal cavity are transported into the cerebrospinal fluid via a route from the olfactory nerve has been proposed. CJ. Pharm, Pharmacol, 43, 449-9-4 51 (1991) and Chem, Pharm, Bull. 39 (9): 2456-2458 (1991)], and the preparation of the present invention Not effectively in the cerebrospinal fluid It was confirmed from Test Example 3 above that the compound had an effect of increasing the concentration of norepinephrine. Nasal administration of the preparation of the present invention raises the level of norepinephrine in the cerebrospinal fluid, so that treatment of Parkinson's disease by nasal administration is a step further. It is also expected to move forward. In addition, the dose is smaller than that of oral administration, and can exert the same effect as the pharmacological action of oral administration.

Claims

1. 1) Threo-3 — (3,4-dihydroxyphenyl) serine or a pharmaceutically acceptable acid addition salt thereof;  2) At least at least one selected from the blue group consisting of phospholipids, saponins, bile acids or their salts, glycyrrhetic acid or its salts, and derivatives of glycyrrhetic acid. One component; and  3) A small fist selected from the group consisting of ascorbic acid, tartaric acid, citric acid, aspartic acid and their salts At least one ingredient  A nasal administration preparation, wherein ρ 時 に is adjusted to 4.0 to 6.0 when in a liquid form.  2. The pharmaceutical composition for nasal administration according to claim 1, wherein the stereo 3- (3,4-dihydroxyphenyl) serine is in L-form.  3. Nasal formulation as claimed in Claims 1 or 2, which contains glycinoleretinic acid 3 — 0 — monohemiphthalate sodium salt ο 4. The preparation for nasal administration according to any one of claims 1 to 3, which comprises sodium ascorbylate. 5. The preparation for nasal administration according to any one of claims 1 to 4, which is in a liquid form adjusted to a ρ output of 4.0 to 6.0. 6. 1) SLEO — 3 — (3, 4 — J G) serine or a pharmaceutically acceptable acid addition salt thereof; 2) selected from the group consisting of phospholipids, saponins, bile acids or their salts, glycyrrhetinic acid or its salts, and derivatives of glycyrrhetic acid At least one component; and  3) at least one component selected from the group consisting of ascorbic acid, tartaric acid, citric acid, aspartic acid and salts thereof;  Claims 1 to 4 which are in the form of a solid preparation for use after being adjusted to a liquid pH of 4.0 to 6.0 at the time of use. Or the nasal administration preparation according to item 1.  7.1) threo-3- (3,4-dihydroxyphenyl) serine or a pharmaceutically acceptable acid addition salt thereof;  2) selected from the group consisting of phospholipids, saponins, bile acids or their salts, glycyl retinate or its salts, and derivatives of glycyl retinate At least one component; and  3) at least one component selected from the group consisting of ascorbic acid, tartaric acid, citric acid, aspartic acid and salts thereof;  And administering to the human nasal cavity a preparation in the form of a liquid whose pH has been adjusted to 4.0 to 6.0. Dihydroxyphenyl) Serine administration method.