JP6061924B2 - Oral dispersible formulation - Google Patents

Description

The present invention relates to a preparation with improved disintegration, a preparation with improved bioavailability of a drug, a method for producing the same, and the like.
(Background of the Invention)

Patent Document 1 discloses a tablet containing a sugar alcohol or saccharide having an average particle size of 30 μm or less, an active ingredient and a disintegrant, and a mixture containing a sugar alcohol or saccharide having an average particle diameter of 30 μm or less, an active ingredient and a disintegrant. A method for producing a tablet characterized by compression molding is disclosed.
Patent Document 2 discloses a solid oral dispersible pharmaceutical composition of agomelatine, which comprises agomelatine and granules of lactose and starch that have been simultaneously dried.
Patent Document 3 discloses a core or core layer of agomelatine, a coated solid orally dispersible pharmaceutical composition comprising an excipient that makes it possible to obtain agomelatine and an orally dispersible formulation, and Disclosed is a pharmaceutical composition comprising an orally dispersible coating.

International Publication No. 1997/047287 Pamphlet JP-T-2005-523253 JP 2007-182440 A

The objective of this invention is providing the formulation which can accelerate | stimulate the chemical | medical agent absorption from an intraoral mucosa by disintegrating rapidly after sublingual or buccal administration. Such a formulation improves bioavailability, decreases the ratio of metabolites to drug, increases Cmax, for oral (not sublingual or buccal) administration of the same drug, There are benefits including decreasing Tmax, increasing AUC (0-tlqc), and increasing the coefficient of variation of Cmax and AUC (0-tlqc). Such formulations are also generally useful for the treatment of bipolar disorder and for the remission and depression phases of the disease.
Another object of the present invention is to provide a novel formulation technique that can improve disintegration. Another object of the present invention is to provide a preparation useful as an intraoral rapidly disintegrating preparation. Such objects are not intended to limit the invention, but are merely exemplary.

Formulation: Fast disintegrating formulation As a result of intensive studies to solve the above problems, the present inventors internally added a component that prevents disintegration (masking agent, binder, etc.) as a granulating component in the grain, After coating the surface of the grain with sugar or sugar alcohol, it was found that the disintegration of the drug was improved by formulating and the bioavailability was improved, and the present invention was completed. .

That is, the present invention is as follows.
[1] A rapidly disintegrating preparation containing granules containing a drug coated with a coating layer containing sugar or sugar alcohol; and a disintegrant.
(Hereinafter, it may be abbreviated as formulation [1], and the same applies to [2] to [18] and [37] to [69] below)
[2] The rapidly disintegrating preparation according to the above [1], wherein the granule containing a drug further contains a binder.
[3] The rapidly disintegrating preparation according to [1], wherein the drug-containing granule further contains a masking agent.
[4] The rapidly disintegrating preparation according to [1], wherein the drug-containing granule further contains a solubilizer.
[4-1] The rapidly disintegrating preparation according to any one of [1] to [4], wherein the disintegration time is 30 seconds or less.
[4-2] The rapidly disintegrating preparation according to any one of [1] to [4], wherein the disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.

The “fast disintegrating preparation” of the present invention is also excellent as a preparation for absorbing a drug from the oral mucosa. Specifically, it is as follows.
[5] The preparation according to any one of [1] to [4], which is a preparation for intraoral mucosal absorption. As used herein, the terms “oral-mucosal” and “oral-mucosa” in the context of drug delivery include, for example, a drug that enters the systemic circulation and is substantially Administration of the drug directly into the mucosal lining of the oral cavity by sublingual or buccal routes to avoid hepatic first-pass metabolism. As used herein, the term “oral” in the context of drug delivery includes administration of a drug to the oral cavity but does not include administration of the drug directly to the oral mucosal lining. Drugs delivered by the oral route (as opposed to the buccal mucosal route) enter the systemic circulation after absorption in the gastrointestinal tract.
[6] The drug is (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (generic name ramelteon; The preparation according to [5] above, which may be abbreviated as compound A hereinafter).
[7] The preparation according to [5] or [6] above, which is a tablet.
[8] A step of producing granules containing a drug,
Forming a coating layer containing sugar or sugar alcohol on the obtained granules;
The coated granules are mixed with a disintegrant and then molded.
A method for producing a rapidly disintegrating preparation.

Formulation: Formulation for Absorption of Oral Mucosa of Compound A In addition to the above-mentioned formulation [6], the present inventors have formulated a formulation with excellent absorption from the oral mucosa and improved bioavailability of Compound A. We studied diligently.
[9] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide as a drug;
The ratio of unchanged drug and metabolite of the drug after blood transfer (ie, unchanged drug / metabolite) is greater than the ratio when administered orally.
For oral mucosal absorption,
Formulation.
(Here and below, "drug metabolites" are specifically (2S) -2-hydroxy-N- {2-[(8S) -1, known as M-II. (6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl] ethyl} propanamide)
[10] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide as a drug;
The ratio of unchanged drug and metabolite of the drug after blood transfer is greater than the ratio when administered orally,
Collapse time is 30 seconds or less,
For oral mucosal absorption,
Formulation.
[11] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide as a drug;
The ratio of unchanged drug and metabolite of the drug after blood transfer is greater than the ratio when administered orally,
The disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
For oral mucosal absorption,
Formulation.
[12] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and a masking agent;
Biology of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide compared to oral administration The general availability has improved by more than 10 times,
For oral mucosal absorption,
Formulation.
[13] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and a masking agent;
Biology of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide compared to oral administration The general availability has been improved by more than 10 times,
Collapse time is 30 seconds or less,
For oral mucosal absorption,
Formulation.
[14] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide and a masking agent;
Biology of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide compared to oral administration The general availability has been improved by more than 10 times,
The disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
For oral mucosal absorption,
Formulation.
[15] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, sugar or sugar alcohol, and Contains a disintegrant;
Biology of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide compared to oral administration The general availability has been improved by more than 10 times,
Collapse time is 30 seconds or less,
For oral mucosal absorption,
Formulation.
[16] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, sugar or sugar alcohol, and Contains a disintegrant;
Biology of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide compared to oral administration The general availability has been improved by more than 10 times,
The disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
For oral mucosal absorption,
Formulation.
[17] The preparation according to any of [9] to [16], which is a tablet.
[18] The preparation according to [9] or [12] above, which is in the form of a film, troche, solution, suspension, lyophilized preparation, chewing gum, or spray.

Method of Use of Compound A: Prevention and / or Treatment of Bipolar Disorder (1)
The invention also relates to a method of using Compound A for the prevention and / or treatment of bipolar disorder by intraoral mucosal administration to a human in need thereof.
[19] Oral mucosal administration of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide to humans A method of preventing and / or treating bipolar disorder.
(Hereafter, it may be abbreviated as the method [19], and the same applies to the following [20] to [23], [28], [34] and [70] to [110]).
[20] The prevention and / or treatment method according to the above [19], wherein the oral mucosal administration is sublingual administration or buccal administration (more preferably sublingual administration).
[21] 0.05 to 1.0 mg (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) per day [Ethyl] propionamide is administered according to the above [19].
[22] The prevention and / or treatment method according to the above [19], wherein the bipolar disorder is type I bipolar disorder.
[23] The prevention and / or treatment method according to [19] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[24] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is intraoral for humans (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide for active administration to mucosa A prophylactic and / or therapeutic drug for bipolar disorder contained as
(Hereafter, it may be abbreviated as a drug [24], and the same applies to the following [25] to [27] and [35]).
[25] The prophylactic and / or therapeutic agent according to the above [24], wherein the oral mucosal administration is sublingual administration or buccal administration (more preferably sublingual administration).
[26] 0.05-1.0 mg (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) per day Ethyl] propionamide is administered, the prophylactic and / or therapeutic agent according to [24] above.
[27] The prophylactic and / or therapeutic agent according to [24] above, wherein the bipolar disorder is type I bipolar disorder.
[28] The prophylactic and / or therapeutic agent according to [24] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[29] (S) -N- [2- (1,6,7,8-tetrahydro-2H-] for the prevention and / or treatment of bipolar disorder by oral mucosal administration to humans Indeno [5,4-b] furan-8-yl) ethyl] propionamide.
(Hereinafter, it may be abbreviated as compound [29], and the same applies to the following [30] to [33] and [36]).
[30] (S) -N- [2- (1,6,7,8-] according to [29] above, wherein the oral mucosal administration is sublingual administration or buccal administration (more preferably sublingual administration). Tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide.
[31] 0.05 to 1.0 mg (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) per day (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-] according to [29] above, wherein ethyl] propionamide is administered. Yl) ethyl] propionamide.
[32] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-] described in [29] above, wherein the bipolar disorder is a type I bipolar disorder. b] furan-8-yl) ethyl] propionamide.
[33] (S) -N- [2- described in [29] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder. (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide.
[34] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is the above [5]- [7] or the prophylactic and / or therapeutic method according to the above [19] to [23], which is administered as a preparation according to [9] to [18].
[35] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is the above [5]- [7] or the prophylactic and / or therapeutic agent according to [24] to [28], which is administered as a preparation according to [9] to [18].
[36] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is the above [5]- [7] or (S) -N- [2- (1,6,7,8-tetrahydro] according to the above [29] to [33] administered as a preparation according to [9] to [18] -2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide.

Formulation: Formulation for absorption of oral mucosa of Compound A (2)
Another aspect of the present invention relates to the following “formulation limited by dose and / or PK profile”.

[37] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) A preparation for oral mucosal absorption; (1) the dose of Compound A is 0.1 mg per day; and (2) the preparation is about 0.43 in a fasted state for a human subject. Cmax of Compound A within the range of about ~ 3.13 ng / ml and about 0.48 to about 2.26 ng. A formulation that yields an AUC (0-tlqc) of Compound A in the hr / ml range.
[37-1] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) (1) the dosage of Compound A is 0.1 mg per day, and (2) the formulation is about 0. 0 in a fasted state for human subjects. Compound C Cmax in the range of 43 to about 3.13 ng / ml and about 0.48 to about 2.26 ng. resulting in an AUC (0-tlqc) of compound A in the hr / ml range, and (3) an average Tmax value of plasma concentration of compound A after administration to humans of about 0.4 hours or less, preferably about A formulation that is 0.3 hours or less, and more preferably, about 0.25 hours or less.
[38] (1) The dose of Compound A is 0.1 mg per day, and (2) the formulation is about 0.66 to about 2.05 ng / ml in a fasted state for human subjects. Cmax of Compound A within the range and from about 0.67 to about 1.62 ng. The formulation of [37] above which results in an AUC (0-tlqc) of Compound A in the range of hr / ml.
[38-1] (1) The dose of Compound A is 0.1 mg per day, and (2) the preparation is about 0.66 to about 2.05 ng / ml in a fasted state for human subjects. Of compound A within the range of about 0.67 to about 1.62 ng. resulting in an AUC (0-tlqc) of compound A in the hr / ml range, and (3) an average Tmax value of plasma concentration of compound A after administration to humans of about 0.4 hours or less, preferably about The formulation according to [37-1] above, which is not longer than 0.3 hours, and more preferably not longer than about 0.25 hours.
[39] Contains (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A). A preparation for oral mucosal absorption; (1) the dose of Compound A is 0.4 mg per day; and (2) the preparation is about 2.04 in a fasted state for a human subject. To about 6.89 ng / ml and a Cmax of about 1.52 to about 6.68 ng. A formulation that yields an AUC (0-tlqc) of Compound A in the hr / ml range.
[39-1] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) (1) the dose of Compound A is 0.4 mg per day, and (2) the formulation is about 2. Compound C Cmax in the range of 04 to about 6.89 ng / ml and about 1.52 to about 6.68 ng. resulting in an AUC (0-tlqc) of compound A in the hr / ml range, and (3) an average Tmax value of plasma concentration of compound A after administration to humans of about 0.4 hours or less, preferably about A formulation that is 0.3 hours or less, and more preferably, about 0.25 hours or less.
[40] (1) The dose of Compound A is 0.4 mg per day, and (2) the formulation is about 2.54 to about 5.54 ng / ml in a fasted state for human subjects. Cmax of Compound A within the range and from about 1.98 to about 5.12 ng. The formulation of [39] above, which provides an AUC (0-tlqc) of Compound A in the range of hr / ml.
[40-1] (1) The dose of Compound A is 0.4 mg per day, and (2) the preparation is about 2.54 to about 5.54 ng / ml in a fasted state for human subjects. Of compound A within the range of about 1.98 to about 5.12 ng. resulting in an AUC (0-tlqc) of Compound A in the hr / ml range, and (3) (S) -N- [2- (1,6,7,8-tetrahydro-2H- after administration to humans] The mean Tmax value of plasma concentration of indeno [5,4-b] furan-8-yl) ethyl] propionamide is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about The preparation according to [39-1] above, which is not longer than 0.25 hours.
[41] Contains (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A). A formulation for oral mucosal absorption; (1) the dose of Compound A is 0.8 mg per day, and (2) the formulation is about 3.63 in a fasted state for a human subject. To about 14.06 ng / ml of Compound A and about 2.48 to about 14.43 ng. A formulation that yields an AUC (0-tlqc) of Compound A in the hr / ml range.
[41-1] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) A formulation for oral mucosal absorption containing; (1) the dose of Compound A is 0.8 mg per day; and (2) the formulation is about 3. Cmax of Compound A in the range of 63 to about 14.06 ng / ml and about 2.48 to about 14.43 ng. resulting in an AUC (0-tlqc) of Compound A in the hr / ml range, and (3) (S) -N- [2- (1,6,7,8-tetrahydro-2H- after administration to humans] The mean Tmax value of plasma concentration of indeno [5,4-b] furan-8-yl) ethyl] propionamide is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about Formulation that is 0.25 hours or less.
[42] (1) The dose of Compound A is 0.8 mg per day, and (2) the formulation is about 4.85 to about 10.54 ng / ml in a fasted state for human subjects. Cmax of Compound A within the range and from about 3.60 to about 9.91 ng. The formulation of [41] above which results in an AUC (0-tlqc) of Compound A in the range of hr / ml.
[42-1] (1) The dose of Compound A is 0.8 mg per day, and (2) the formulation is about 4.85 to about 10.54 ng / ml in a fasted state for human subjects. Of compound A within the range of about 3.60 to about 9.91 ng. resulting in an AUC (0-tlqc) of Compound A in the hr / ml range, and (3) (S) -N- [2- (1,6,7,8-tetrahydro-2H- after administration to humans] The mean Tmax value of plasma concentration of indeno [5,4-b] furan-8-yl) ethyl] propionamide is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about The preparation according to [41-1] above, which is not longer than 0.25 hours.

[43] contains (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A). (1) the dose of Compound A is 0.05-1.0 mg per day; and (2) of the metabolite of Compound A (M-II) relative to the unchanged form of Compound A after administration to humans A preparation for intraoral mucosal absorption having an AUC ratio of about 20 or less.
[44] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A). (1) the dose of Compound A is 0.1-0.8 mg per day; and (2) of the metabolite of Compound A (M-II) relative to the unchanged form of Compound A after administration to humans A preparation for intraoral mucosal absorption having an AUC ratio of about 20 or less.
[45] The preparation of the above-mentioned [43], wherein the AUC ratio is about 10 or less.
[46] The preparation according to [44] above, wherein the AUC ratio is about 10 or less.

[47] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide; administration to humans Later (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide metabolite (M-II) AUC ratio of the unchanged form of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide with respect to A preparation for absorption in the oral mucosa, which is about 5 times or more when orally administered.
[48] The preparation according to [47] above, wherein the AUC ratio is about 10 times or more when orally administered.
[49] The preparation according to any of [47] or [48] above, wherein the AUC ratio is about 30 times or less, preferably about 20 times or less.

[50] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide; administration to humans (S) for the unchanged form of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide The AUC ratio of the metabolite (M-II) of —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is about A preparation for intraoral mucosal absorption which is 20 or less.
[51] The preparation according to [50], wherein the AUC ratio is about 10 or less, more preferably about 5 or less.

[52] containing (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide; The bioavailability of —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is For oral mucosal absorption that improves bioavailability by about 10 times or more, and more specifically improves bioavailability by oral administration to about 10 times to about 30 times Formulation.

Administration of humans comprising [53] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide Mean Tmax value of plasma concentration of later (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide For oral mucosal absorption wherein is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0.25 hours or less.
[54] Plasma of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans The average Tmax value of the medium concentration is about 0.4 hours or less, preferably about 0.3 hours or less, more preferably about 0.25 hours or less, according to any one of [47] to [52] above Preparations

Administration of humans comprising [55] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide Pharmacokinetics including Cmax and AUC of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide Formulation for oral mucosal absorption having a coefficient of variation (CV) of parameter of about 45% or less, preferably about 35% or less, and more preferably about 30% or less.
[56] Cmax of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans The coefficient of variation (CV) of pharmacokinetic parameters including AUC and AUC is about 45% or less, preferably about 35% or less, and more preferably about 30% or less. 54].

[57] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide; The dose of -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is 0.05 to 1 per day. A preparation for oral mucosal absorption of 0 mg.
[58] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide dose per day The preparation according to [57] above, which is 0.1 to 0.8 mg.

[59] Metabolism of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans Of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide relative to product (M-II) The preparation according to any one of [57] or [58] above, wherein the AUC ratio of the body is about 5 times or more when administered orally.

[60] The preparation according to [59] above, wherein the AUC ratio is about 10 times or more when orally administered.
[61] The preparation of the above-mentioned [60], wherein the AUC ratio is about 10 times or more when orally administered.
[62] The preparation according to any of [59] to [61] above, wherein the AUC ratio is about 30 times or less, preferably about 20 times or less.

[63] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans Metabolite of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (M-II) ), The preparation according to [57] or [58] above.
[64] The preparation of the above-mentioned [63], wherein the AUC ratio is about 10 or less.
[65] The preparation according to any of [63] or [64] above, wherein the AUC ratio is about 5 or more.

[66] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide bioavailability , Improving bioavailability by about 10 times or more when administered orally, more specifically, improving bioavailability by orally administered to about 10 times or more and about 30 times or less, The preparation according to [57] or [58] above.

[67] Plasma of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans Any of the above [57] to [66], wherein the average Tmax value of the medium concentration is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0.25 hours or less. The formulation described.

[68] Cmax of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration to humans The coefficient of variation (CV) of pharmacokinetic parameters including AUC and AUC is about 45% or less, preferably about 35% or less, and more preferably about 30% or less. 67].
[69] The preparation according to any of [57] to [68], wherein the preparation further contains a disintegrant.

Method of Use of Compound A: Prevention and / or Treatment of Bipolar Disorder (2)
Another aspect of the invention relates to the following “Method of Use of Compound A Limited by Dose and / or PK Profile”.

[70] A method for preventing and / or treating bipolar disorder, wherein 0.05 to 1.0 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H- Administering indeno [5,4-b] furan-8-yl) ethyl] propionamide to the oral mucosa of a human in need thereof.
[71] 0.1-0.8 mg (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) per day The method according to [70] above, wherein ethyl] propionamide is administered.
[72] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is a sublingual route or buccal The method according to any of [70] or [71] above, which is administered by a route of administration.

[73] A method for preventing and / or treating bipolar disorder, wherein 0.1 mg (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide (Compound A) is administered to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 0.43. To about 3.13 ng / ml and the AUC (0-tlqc) of Compound A is about 0.48 to about 2.26 ng. A method that is within the range of hr / ml.
[73-1] A method for preventing and / or treating bipolar disorder, wherein 0.1 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [ Administration of 5,4-b] furan-8-yl) ethyl] propionamide (Compound A) to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 0. .43 to about 3.13 ng / ml and the AUC (0-tlqc) of Compound A is about 0.48 to about 2.26 ng. hr / ml; and mean Tmax value of plasma concentration of Compound A after administration to humans is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0 The method is 25 hours or less.
[74] The method according to any of [73] or [73-1] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[75] The method according to any of [73] or [73-1] above, wherein the bipolar disorder is a type I bipolar disorder.
[76] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of a phase of remission of bipolar disorder, according to any of [73] or [73-1] above. the method of.
[77] In the fasted state, the Cmax of Compound A is in the range of about 0.66 to about 2.05 ng / ml and the AUC (0-tlqc) of Compound A is about 0.67 to about 1.62 ng. The method according to any one of [73] or [73-1] above, which is in a range of hr / ml.
[78] The method described in [77] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[79] The method described in [77] above, wherein the bipolar disorder is a type I bipolar disorder.
[80] The method of the above-mentioned [77], wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[81] A method for preventing and / or treating bipolar disorder, wherein 0.4 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide (Compound A) is administered to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 2.04. To about 6.89 ng / ml and the AUC (0-tlqc) of Compound A is about 1.52 to about 6.68 ng. A method that is within the range of hr / ml.
[81-1] A method of preventing and / or treating bipolar disorder, wherein 0.4 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [ Administration of 5,4-b] furan-8-yl) ethyl] propionamide (Compound A) to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 2 0.04 to about 6.89 ng / ml and the AUC (0-tlqc) of Compound A is about 1.52 to about 6.68 ng. hr / ml; and mean Tmax value of plasma concentration of Compound A after administration to humans is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0 The method is 25 hours or less.
[82] The method according to any of [81] or [81-1] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[83] The method described in [82] above, wherein the bipolar disorder is type I bipolar disorder.
[84] The method of [82] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[85] In the fasted state, the Cmax of Compound A is in the range of about 2.54 to about 5.54 ng / ml and the AUC (0-tlqc) of Compound A is about 1.98 to about 5.12 ng. The method according to any one of [81] or [81-1] above, which is within a range of hr / ml.
[86] The method described in [85] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[87] The method described in [85] above, wherein the bipolar disorder is type I bipolar disorder.
[88] The method of [85] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[89] A method for preventing and / or treating bipolar disorder, wherein 0.8 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5, 4-b] furan-8-yl) ethyl] propionamide (Compound A) is administered to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 3.63. To about 14.06 ng / ml and the AUC (0-tlqc) of Compound A is about 2.48 to about 14.43 ng. A method that is within the range of hr / ml.
[89-1] A method for preventing and / or treating bipolar disorder, wherein 0.8 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [ Administration of 5,4-b] furan-8-yl) ethyl] propionamide (Compound A) to the oral mucosa of a human in need thereof, and in a fasted state, the Cmax of Compound A is about 3 .63 to about 14.06 ng / ml and Compound A has an AUC (0-tlqc) of about 2.48 to about 14.43 ng. hr / ml; and mean Tmax value of plasma concentration of Compound A after administration to humans is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0 The method is 25 hours or less.
[90] The method according to any of [89] or [89-1] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[91] The method described in [90] above, wherein the bipolar disorder is type I bipolar disorder.
[92] The method of [90] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[93] In the fasted state, the Cmax of Compound A is in the range of about 4.85 to about 10.54 ng / ml and the AUC (0-tlqc) of Compound A is 3.60 to about 9.91 ng. The method according to any one of [89] or [89-1] above, which is within a range of hr / ml.
[94] The method described in [93] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[95] The method described in [93] above, wherein the bipolar disorder is a type I bipolar disorder.
[96] The method according to [93] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.

[97] A method for preventing and / or treating bipolar disorder, wherein 0.05 to 1.0 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H- Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) comprising administering to the oral mucosa of a human in need thereof, an unchanged form of Compound A after administration The AUC ratio of the metabolite of compound A (M-II) to 20 or less.
[98] A method for preventing and / or treating bipolar disorder, wherein 0.1 to 0.8 mg of (S) -N- [2- (1,6,7,8-tetrahydro-2H- Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A) comprising administering to the oral mucosa of a human in need thereof, an unchanged form of Compound A after administration The AUC ratio of the metabolite of compound A (M-II) to 20 or less.
[99] The method according to [97] above, wherein the AUC ratio is 10 or less.
[100] The method according to [98] above, wherein the AUC ratio is 10 or less.

[101] Metabolite of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration ( (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide relative to M-II) The method according to any one of [70] to [72] above, wherein the AUC ratio is about 5 times or more when administered orally.
[102] The method according to any one of [101] above, wherein the AUC ratio is about 10 times or more when administered orally.

[103] The method according to any one of [102] above, wherein the AUC ratio is about 30 times or less, preferably about 20 times or less.
[104] unchanged form of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide after administration Of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide metabolite (M-II) The method according to any one of [70] to [72] above, wherein the AUC ratio is about 20 or less.
[105] The method of [104] above, wherein the AUC ratio is about 10 or less, more preferably about 5 or less.

[106] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is represented by (S) -N The bioavailability of [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide when administered orally Administered to improve the bioavailability by about 10 times or more, and more specifically, improve the bioavailability in the range of about 10 times or more to about 30 times or less of the bioavailability when orally administered. [70] The method according to any one of [72].

[107] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is administered (S ) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide has an average plasma Tmax value of about 0. [70]-[72] and [101]-[106] above administered for 4 hours or less, preferably about 0.3 hours or less, and more preferably about 0.25 hours or less. The method according to any one.

[108] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide is administered (S ) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide coefficient of variation of pharmacokinetic parameters including Cmax and AUC [70] to [72] and [101] to [107], wherein (CV) is administered to be about 45% or less, preferably about 35% or less, and more preferably about 30% or less. The method in any one of.

[109] The method according to any one of [70] to [72] and [101] to 108 above, wherein the bipolar disorder is type I bipolar disorder.
[110] The method according to [109] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.
[111] 0.1 mg of (S) -N- [2- (1,1) per day administered to the oral mucosa of a human in need and for the prevention and / or treatment of bipolar disorder 6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in the fasted state, the Cmax of Compound A is about 0.43 to Within the range of about 3.13 ng / ml and AUC (0-tlqc) of Compound A is about 0.48 to about 2.26 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.
[112] The prophylactic and / or therapeutic agent according to [111] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[113] The prophylactic and / or therapeutic agent according to any of [111] and [112] above, wherein the bipolar disorder is type I bipolar disorder.
[114] The prevention according to any one of [111] to [113] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder. And / or therapeutic agent.
[115] In the fasted state, the Cmax of Compound A is in the range of about 0.66 to about 2.05 ng / ml and the AUC (0-tlqc) of Compound A is about 0.67 to about 1.62 ng. The prophylactic and / or therapeutic agent according to [111] above, which is in the range of hr / ml.
[116] The prophylactic and / or therapeutic agent according to [115] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[117] The prophylactic and / or therapeutic agent according to any of [115] and [116] above, wherein the bipolar disorder is type I bipolar disorder.
[118] Prevention according to any of [115] to [117] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder And / or therapeutic agent.
[119] 0.4 mg of (S) -N- [2- (1,1) per day administered to the oral mucosa of a human in need and for prevention and / or treatment of bipolar disorder 6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in a fasted state, the Cmax of Compound A is about 2.04 to Within the range of about 6.89 ng / ml and the AUC (0-tlqc) of Compound A is about 1.52 to about 6.68 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.
[120] The prophylactic and / or therapeutic agent according to [119] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[121] The prophylactic and / or therapeutic agent according to any one of [119] and [120] above, wherein the bipolar disorder is type I bipolar disorder.
[122] Prevention according to any one of [119] to [121] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder And / or therapeutic agent.
[123] In the fasted state, the Cmax of Compound A is in the range of about 2.54 to about 5.54 ng / ml and the AUC (0-tlqc) of Compound A is about 1.98 to about 5.12 ng. The prophylactic and / or therapeutic agent according to [119] above, which is in the range of hr / ml.
[124] The prophylactic and / or therapeutic agent according to [123] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[125] The prophylactic and / or therapeutic agent according to any of [123] and [124] above, wherein the bipolar disorder is type I bipolar disorder.
[126] Prevention according to any one of [123] to [125] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder And / or therapeutic agent.
[127] 0.8 mg of (S) -N- [2- (1, per day, a drug for the prevention and / or treatment of bipolar disorder, which is administered to the oral mucosa of a human in need thereof 6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in the fasted state, the Cmax of Compound A is about 3.63 to Within the range of about 14.06 ng / ml and the AUC (0-tlqc) of Compound A is about 2.48 to about 14.43 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.
[128] The prophylactic and / or therapeutic agent according to [127] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[129] The prophylactic and / or therapeutic agent according to any one of [127] and [128] above, wherein the bipolar disorder is type I bipolar disorder.
[130] Prevention according to any of [127] to [129] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder And / or therapeutic agent.
[131] In the fasted state, the Cmax of Compound A is in the range of about 4.85 to about 10.54 ng / ml and the AUC (0-tlqc) of Compound A is 3.60 to about 9.91 ng. The prophylactic and / or therapeutic agent according to the above [127], which is in the range of hr / ml.
[132] The prophylactic and / or therapeutic agent according to [131] above, wherein the oral mucosal administration is sublingual administration or buccal administration.
[133] The prophylactic and / or therapeutic agent according to any of [131] and [132] above, wherein the bipolar disorder is type I bipolar disorder.
[134] The prevention according to any of [131] to [133] above, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder And / or therapeutic agent.
[135] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) for prevention and / or treatment of bipolar disorder Ethyl] propionamide (Compound A), 1) 0.1 mg of Compound A per day is administered to the oral mucosa of a human in need thereof, and 2) Cmax of Compound A in the fasted state In the range of about 0.43 to about 3.13 ng / ml and the AUC (0-tlqc) of Compound A is about 0.48 to about 2.26 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (within hr / ml) Compound A).
[136] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [135] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[137] The (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of the above [135] and [136], wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[138] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any of [135] to [137] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[139] In a fasted state, the Cmax of Compound A is in the range of about 0.66 to about 2.05 ng / ml and the AUC (0-tlqc) of Compound A is about 0.67 to about 1.62 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8- according to [135], which is in the range of hr / ml. Yl) ethyl] propionamide (Compound A).
[140] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [139] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[141] (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of the above [139] and [140], wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[142] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any one of [139] to [141] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[143] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) for prevention and / or treatment of bipolar disorder Ethyl] propionamide (Compound A), 1) 0.4 mg of Compound A per day is administered to the oral mucosa of a human in need thereof, and 2) in the fasted state, the Cmax of Compound A In the range of about 2.04 to about 6.89 ng / ml and the AUC (0-tlqc) of Compound A is about 1.52 to about 6.68 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (within hr / ml) Compound A).
[144] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [143] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[145] (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of [143] and [144] above, wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[146] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any one of [143] to [145] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[147] In the fasted state, the Cmax of Compound A is in the range of about 2.54 to about 5.54 ng / ml and the AUC (0-tlqc) of Compound A is about 1.98 to about 5.12 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8- according to [143] above, which is in the range of hr / ml. Yl) ethyl] propionamide (Compound A).
[148] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [147] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[149] (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of [147] and [148] above, wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[150] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any one of [147] to [149] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[151] (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) for prevention and / or treatment of bipolar disorder Ethyl] propionamide (compound A), 1) 0.8 mg of compound A per day is administered to the oral mucosa of a human in need thereof, and 2) in the fasted state, Cmax of compound A In the range of about 3.63 to about 14.06 ng / ml and the AUC (0-tlqc) of Compound A is about 2.48 to about 14.43 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (within hr / ml) Compound A).
[152] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [151] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[153] (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of [151] and [152] above, wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[154] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any of [151] to [153] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[155] In a fasted state, the Cmax of Compound A is in the range of about 4.85 to about 10.54 ng / ml and the AUC (0-tlqc) of Compound A is 3.60 to about 9.91 ng. (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8- according to [151], which is in the range of hr / ml. Yl) ethyl] propionamide (Compound A).
[156] The (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5] described in [155] above, wherein the oral mucosal administration is sublingual administration or buccal administration. 4-b] furan-8-yl) ethyl] propionamide (Compound A).
[157] The (S) -N- [2- (1,6,7,8-tetrahydro-2H] according to any one of the above [155] and [156], wherein the bipolar disorder is a type I bipolar disorder Indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
[158] The prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder, according to any one of [155] to [157] above ( S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A).
(Detailed description of the invention)

ADVANTAGE OF THE INVENTION According to this invention, the quick disintegrating formulation excellent in the disintegration, the formulation with improved bioavailability of a chemical | medical agent, its manufacturing method, etc. can be provided.
The rapidly disintegrating preparations [1] to [7] of the present invention contain a drug in a granule and mix the disintegrant as an extragranular component, whereby a drug having poor compoundability with the disintegrant (for example, Compound A) Etc.), since the influence of the disintegrant on the drug can be reduced, the stability of the drug can be improved.
The rapidly disintegrating preparation of the present invention can improve the disintegrating property by encapsulating components (for example, a masking agent, a binder, etc.) that prevent disintegration in the granules. Moreover, fast disintegration can be achieved by ensuring the invasion route of water into the preparation by coating a component that prevents disintegration with sugar or sugar alcohol. In addition, since the rapidly disintegrating preparation of the present invention is characterized in that the drug is coated with sugar or sugar alcohol, even if the drug has a high surface hydrophobicity, the drug from the preparation can be obtained by modifying the surface to be hydrophilic. Can be improved.
According to the fast disintegrating preparation of the present invention, both good disintegration and good preparation hardness can be achieved.
Among the rapidly disintegrating preparations [1] to [7] of the present invention, the rapidly disintegrating preparations [5] to [7] for absorption of the oral mucosa of the present invention are obtained by absorbing the drug from the oral mucosa, Immediate effect can be expected.
The rapidly disintegrating preparation for intraoral mucosal absorption of the present invention can improve bioavailability by improving the blood concentration of a drug (for example, Compound A etc.) that greatly receives the first-pass effect upon oral administration. it can. In addition, the rapidly disintegrating preparation for intraoral mucosal absorption of the present invention can suppress the dispersion of the absorption of such a drug, and thus can control the dispersion of the effectiveness as a medicine. Furthermore, the rapidly disintegrating preparation for intraoral mucosal absorption of the present invention can achieve a reduction in the dose of the drug and a reduction in the size of the preparation by improving the bioavailability of such a drug.
According to the production method of the present invention, the rapidly disintegrating preparation [1] to [7] of the present invention having the above effects can be produced.

FIG. 1 shows the mean serum concentration of Compound A after intraoral mucosal delivery at different concentrations. FIG. 2 shows the mean serum concentration of Compound A after buccal mucosal delivery compared to the mean serum concentration of Compound A after oral delivery. FIG. 3 shows the mean serum concentration of metabolite M-II after intraoral mucosal delivery at different concentrations. FIG. 4 shows the mean serum concentration of metabolite M-II after buccal mucosal delivery compared to the mean serum concentration of metabolite M-II after oral delivery.

Formulation: Fast disintegrating preparation The quick disintegrating preparation of the present invention is described in detail below.
The rapidly disintegrating preparation of the present invention contains a granule containing a drug coated with a coating layer containing sugar or sugar alcohol, and a disintegrant.
The drug used in the present invention is not particularly limited. For example, antipyretic analgesic / anti-inflammatory drug, psychotropic drug, anxiolytic drug, antidepressant drug, hypnotic sedative drug, gastrointestinal drug, antacid, antitussive expectorant, blood pressure lowering Agent, antidiabetic agent, osteoporosis agent, skeletal muscle relaxant or anticancer agent.
In the rapidly disintegrating preparation of the present invention, the content of the drug is usually 0.03 to 50% by weight, preferably 0.03 to 20% by weight, more preferably 0.03 to 3% by weight based on the total weight of the preparation. %.

The rapid disintegrating preparation of the present invention can reduce the influence of the disintegrating agent on the drug even when using a disintegrant having a poor compounding property by using the disintegrating agent as an extragranular component. Therefore, the stability of the drug can be improved. Thus, in the present invention, the effect is particularly exerted when a drug (for example, Compound A) having a poor compounding property with a disintegrant is used as the drug.
Compound A is a known sleep disorder therapeutic agent disclosed in US Pat. No. 6,034,239 and can be produced by a known method such as the method described in the document.

The rapidly disintegrating preparation of the present invention contains an excipient in granules containing a drug coated with a coating layer containing sugar or sugar alcohol.
Examples of the excipient include starches such as corn starch; lactose, fructose, glucose, mannitol (eg, D-mannitol), sorbitol (eg, D-sorbitol), erythritol (eg, D-erythritol), sucrose Sugars or sugar alcohols such as: anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice powder, sodium bicarbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate, etc., corn starch, D-mannitol, Crystalline cellulose is preferred.
The content of the excipient is usually 13 to 94% by weight, preferably 54 to 94% by weight, more preferably 81 to 93% by weight, based on the total weight of the preparation.

In the rapidly disintegrating preparation of the present invention, an additive may be further contained in the granule containing the drug as necessary.
As an additive which may be contained in the granule containing a chemical | medical agent, a binder, a masking agent, a solubilizer, etc. are mentioned, for example, You may use in combination as needed.
Examples of the binder include potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, starch, Arabic Examples thereof include gum powder, tragacanth, carmellose, sodium alginate, pullulan, glycerin and the like, and partially pregelatinized starch, hydroxypropylcellulose and pregelatinized starch are preferred.
The content of the binder is usually 0.5 to 20% by weight, preferably 0.5 to 15% by weight, and more preferably 1 to 10% by weight with respect to the total weight of the preparation.
Examples of the masking agent include various flavoring agents (thaumatin, sucralose, saccharin, aspartame, xylitol, citric acid, sodium L-glutamate, etc.), various receptor antagonists (benecoat, sodium chloride, etc.), various cation channel antagonists. Agents (L-arginine, etc.), various inclusion agents (α-cyclodextrin, β-cyclodextrin, etc.), various flavors (strawberry flavor, mint flavor, orange flavor, vanillin, etc.), etc. Two or more may be used in combination.
The content of the masking agent is usually 0.01 to 10% by weight, preferably 0.01 to 5% by weight, more preferably 0.01 to 1% by weight, based on the total weight of the preparation.
Examples of the solubilizer include various aqueous solvents (polyethylene glycol, propylene glycol, glycerin, etc.), various inclusion agents (α-cyclodextrin, β-cyclodextrin, etc.), various surfactants (sodium lauryl sulfate, Polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, etc.) and the like, and two or more may be used in combination as required.
The content of the solubilizer is usually 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or less, based on the total weight of the preparation.
In the rapidly disintegrating preparation of the present invention, the disintegration property can be improved by encapsulating in the granule a component that prevents disintegration (for example, a masking agent, a binder, a solubilizing agent, etc.). Moreover, fast disintegration can be achieved by ensuring the invasion route of water into the preparation by coating a component that prevents disintegration with sugar or sugar alcohol as described later.

The rapidly disintegrating preparation of the present invention contains sugar or sugar alcohol in the coating layer formed on the granule containing the drug.
Examples of the sugar or sugar alcohol include lactose, fructose, glucose, mannitol (eg, D-mannitol), sorbitol (eg, D-sorbitol), erythritol (eg, D-erythritol), sucrose, and the like. D-mannitol is preferred.
Fast disintegration can be achieved by securing the infiltration route of water into the preparation by coating the granules containing the drug with sugar or sugar alcohol. Moreover, the elution property of the drug from the preparation can be improved.
The content of sugar contained in the coating layer is usually 5 to 20% by weight, preferably 5 to 15% by weight, and more preferably 5 to 10% by weight, based on the total weight of the preparation.
The content of the sugar alcohol contained in the coating layer is usually 5 to 20% by weight, preferably 5 to 15% by weight, more preferably 5 to 10% by weight, based on the total weight of the preparation.
The total content of sugar and sugar alcohol contained in the coating layer is usually 5 to 20% by weight, preferably 5 to 15% by weight, more preferably 5 to 10% by weight, based on the total weight of the preparation. is there.

In the rapidly disintegrating preparation of the present invention, the coating layer may further contain an additive as necessary.
Examples of the additive that may be contained in the coating layer include an excipient and a disintegrant, and they may be used in combination as necessary.
Examples of the excipient include starches such as corn starch; anhydrous calcium phosphate, crystalline cellulose, microcrystalline cellulose, licorice powder, sodium hydrogen carbonate, calcium phosphate, calcium sulfate, calcium carbonate, precipitated calcium carbonate, calcium silicate and the like. Corn starch and crystalline cellulose are preferred.
Examples of the disintegrant include amino acids, starch, corn starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, carboxymethyl starch sodium and the like. Crospovidone and carmellose are preferred.

In the rapidly disintegrating preparation of the present invention, the average particle diameter of the “granules containing a drug coated with a coating layer containing sugar or sugar alcohol” is usually 50 μm to 500 μm, preferably 50 μm to 355 μm, more preferably 50 μm. ~ 150 μm.
In the present specification, the average particle size is a value measured by a laser diffraction particle size distribution analyzer, SYMPATEC: HELOS & RODOS.

In the rapidly disintegrating preparation of the present invention, examples of the disintegrant contained as an extragranular component include amino acids, starch, corn starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxy Examples thereof include propylcellulose, hydroxypropyl starch, carboxymethyl starch sodium, and crospovidone and carmellose are preferable.
The content of the disintegrant is usually 0.5 to 15% by weight, preferably 1 to 10% by weight, more preferably 2 to 5% by weight, based on the total weight of the preparation.

Examples of the lubricant that may be contained as an extragranular component in the quick disintegrating preparation of the present invention include magnesium stearate, stearic acid, calcium stearate, talc (purified talc), sucrose fatty acid ester, sodium stearyl fumarate. And sodium stearyl fumarate is preferred.
The content of the lubricant is usually 0.5 to 2% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.5 to 1% by weight, based on the total weight of the preparation.

The quick disintegrating preparation of the present invention may further contain an additive as an extragranular component, if necessary.
Examples of the additive include the masking agents and solubilizers described above, and may be used in combination as necessary.

The rapidly disintegrating preparation of the present invention is not only useful as a so-called “orally disintegrating preparation” for oral administration of drugs, but also as a preparation for oral mucosal absorption (particularly a sublingual preparation, a buccal preparation). Is preferred.
The rapid disintegrating preparation for oral mucosal absorption of the present invention can be expected to have immediate effect by being absorbed from the oral mucosa.

  The dosage form of the rapidly disintegrating preparation of the present invention is not particularly limited, but a tablet is preferred.

  When the rapidly disintegrating preparation of the present invention is a tablet, the weight of the preparation is preferably about 20 to 200 mg.

If rapidly disintegrating preparation of the present invention is a tablet, the absolute hardness is usually 1.0 N / mm ² or more, preferably 1.5 N / mm ² or more, more preferably 2.0 N / mm ² or more. When the rapidly disintegrating preparation of the present invention is a tablet, the absolute hardness is usually 5.0 N / mm ² or less.

  When the rapidly disintegrating preparation of the present invention is a tablet, the disintegration time is usually 30 seconds or shorter, preferably 15 seconds or shorter, more preferably 10 seconds or shorter. When the rapidly disintegrating preparation of the present invention is a tablet, the disintegration time is usually 1 second or longer.

In the rapidly disintegrating preparation of the present invention, as described above, the disintegration property can be improved by encapsulating the component that prevents disintegration in the granules, and the component that prevents disintegration is coated with sugar or sugar alcohol. Fast disintegration can be achieved by securing a water infiltration route into the formulation. Therefore, the rapidly disintegrating preparation of the present invention has a good disintegrating property even when molded to the high absolute hardness as described above. Thus, according to the fast disintegrating preparation of the present invention, both good disintegration and good preparation hardness can be achieved.
In the rapidly disintegrating preparation of the present invention, the disintegration time is preferably 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.

The rapidly disintegrating preparation of the present invention can be produced by a method commonly used in the pharmaceutical technical field. For example, it can be suitably produced by the method for producing a rapidly disintegrating preparation of the present invention shown below.
The method for producing the rapidly disintegrating preparation of the present invention comprises:
Step (1): a step of producing granules containing a drug,
Step (2): forming a coating layer containing sugar or sugar alcohol on the obtained granule,
Step (3): A step of forming the coated granule after mixing with a disintegrant is included.

In steps (1) to (3), an additive may be further added as necessary. As types and amounts of “drug”, “sugar”, “sugar alcohol”, “disintegrant”, and “additive” used in steps (1) to (3), the types exemplified for the rapidly disintegrating preparation, Amount. The particle diameter of the coated granule obtained by the step (2) has a range exemplified for the particle diameter of the “granule containing a drug coated with a coating layer containing a sugar or a sugar alcohol” of the rapidly disintegrating preparation. Can be mentioned.
The production of the granules in the step (1) and the formation of the coating layer in the step (2) can also be performed simultaneously.

For example, it can be specifically manufactured as follows.
Sugar or sugar alcohol (for example, D-mannitol) is dissolved in an appropriate solvent (for example, water) to obtain a coating solution.
A drug (for example, compound A etc.) and optional additives (for example, excipients such as D-mannitol, crystalline cellulose, binders such as partially pregelatinized starch, etc.) are mixed to obtain a mixture. The resulting mixture is granulated while spraying the coating liquid, and dried to obtain a granulated powder (coated granules). The obtained granulated powder (coated granules) may be sized as necessary.
The obtained coated granules, a disintegrant (for example, crospovidone, etc.) and an optional additive (for example, a lubricant such as sodium stearyl fumarate) are mixed to obtain a mixed powder. The obtained mixed powder is compression molded to obtain a tablet.

Here, the mixing (including granulation, drying, sizing, etc.) is, for example, a V-type mixer, a tumbler mixer (TM-30, TM-15S; Showa Chemical Machine Works: TM20-0-0; Suehiro) Kako Koki Co., Ltd.), high-speed agitation granulator (FM-VG-10; Paulek), universal kneader (Hatateko), fluidized bed granulator / dryer (LAB-1, FD-3S, FD-3SN, FD-5S; Paulek, Inc.), box-type vacuum dryer (Kakigi machine), power mill crusher (P-3; Showa Chemical Machinery Co., Ltd.), centrifugal rolling granulator (CF-mini, CF-260, CF- 360; Freund Sangyo Co., Ltd.), dry granulator, spray drying granulator, tumbling granulator (MP-10; Paulek) and the like.
The coating is, for example, a centrifugal rolling granulator (CF-mini, CF-260, CF-360; Freund Sangyo Co., Ltd.), a rolling granulator (MP-10; Paulek), a general fluidized bed coating. It is carried out using a pharmaceutical machine such as a device or a Wurster type coating device.
For compression molding, for example, a single tablet machine (Kikusui Seisakusho), a rotary tableting machine (Aquarius 36K, Aquarius 2L; Kikusui Seisakusho), an autograph (AG-5000B, Shimadzu Corporation), etc. are used. It is done by tableting with.

Formulation: Formulation for Intraoral Mucosal Absorption of Compound A The fast disintegrating formulation for intraoral mucosal absorption of the present invention is used when a drug (for example, Compound A etc.) that greatly receives the first-pass metabolic effect upon oral administration is used. , Especially effective. The rapid disintegrating preparation for intraoral mucosal absorption of the present invention can improve bioavailability by improving the blood concentration of such a drug. In addition, the rapidly disintegrating preparation for intraoral mucosal absorption of the present invention can suppress the dispersion of the absorption of such a drug, and thus can control the dispersion of the effectiveness as a medicine. In addition, the rapidly disintegrating formulation for oral mucosal absorption of the present invention can have side effects (eg, residual daytime sleepiness and / or fatigue) when used to treat bipolar disorder. Etc.) can be achieved, and the dosage of the drug can be reduced, and the drug can be miniaturized by improving the bioavailability of the drug.
The rapidly disintegrating preparation for oral mucosal absorption according to the present invention, particularly when using Compound A as a drug, the ratio of the drug after unchanged into the unchanged metabolite is higher than the ratio when orally administered. It has the effect of becoming larger. In addition, the rapidly disintegrating preparation for intraoral mucosal absorption of the present invention improves the bioavailability of Compound A by about 10 times or more compared with oral administration.

i. Formulation (A)
That is, the present invention contains Compound A as a drug; the ratio of unchanged drug and metabolite (especially M-II) after transfer to blood is larger than the ratio when orally administered. The present invention also relates to a preparation for oral mucosal absorption (formulations [9] to [11], [17] and [18]) (hereinafter sometimes referred to as the preparation (A) of the present invention).
When the dosage form is a tablet in the preparation (A), the disintegration time is preferably 30 seconds or less. In the case where the dosage form of the preparation (A) is a tablet, it is more preferable that the disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
The above-mentioned preparations [5] to [7] are also included in the “preparation (A)”.

ii. Formulation (B) and Bioavailability The present invention comprises Compound A, wherein the bioavailability of Compound A is improved by about 10 times or more compared to oral administration. The present invention also relates to preparations (formulations [12] to [18]) (hereinafter sometimes abbreviated as the preparation (B) of the present invention). Here, “about” means an error range of 5%. Bioavailability is usually in the range of about 30 times or less, more specifically, about 25 times or less. In other words, the bioavailability is improved in the range of about 10 times to about 30 times, more specifically in the range of about 10 times to 25 times.
When the dosage form is a tablet in the preparation (B), the disintegration time is preferably 30 seconds or less. When the dosage form is a tablet in the preparation (B), it is more preferable that the disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
The above-mentioned preparations [5] to [7] are also included in the “preparation (B)”.

Here, whether or not “the bioavailability of Compound A is improved by about 10 times or more compared with oral administration” is evaluated as follows.
Each preparation is administered to the intravenous, oral, and oral mucosa, the plasma concentration after each elapsed time is measured, and the area under plasma concentration (AUC) is calculated by a method known in this technical field. There are two types of AUC values, one is AUC (0-tlqc) and one is AUC (0-inf). AUC (0-tlqc) is the area under the serum concentration from 0 hour to the final concentration quantifiable time point (tlqc), calculated using the linear trapezoidal formula. AUC (0-inf) is the area under the serum concentration from 0 hour to infinity, and AUC (0-inf) = AUC (0-tlqc) + lqc / λz (where tlqc is the final point at which concentration can be determined, lqc is the final quantifiable concentration, and λz is the final phase disappearance rate constant, calculated by the negative slope of the logarithmic linear regression of the terminal phase of the natural log concentration-time curve. Both AUC values can be used for assessment of improved bioavailability, but in principle the assessment is based on AUC (0-inf).
(A) Bioavailability ratio calculation method A
The bioavailability (BA) is calculated by the following formula (absolute bioavailability).

BA (%) = ((oral or buccal mucosal administration AUC / oral or buccal mucosal administration dose) / (intravenous administration AUC / intravenous administration dose)) × 100

The ratio of the calculated oral mucosal administration BA to the calculated oral administration BA (that is, oral mucosal administration BA / oral administration BA) is calculated. This ratio is “BA ratio” (method A).
At this time, when the “ratio of oral mucosal BA to absolute oral BA” (absolute BA ratio) was 10 or more, the preparation had “the bioavailability of Compound A was lower than that of oral administration. It has been improved by 10 times or more. "
For specific preparations and test methods used for the test, Test Example 3 described later may be referred to. However, the method of Test Example 3 is not limited as long as substantially the same evaluation is possible.

(B) Bioavailability ratio calculation method B
As another evaluation method of the bioavailability ratio, that is, the “ratio of oral mucosa-administered BA to orally-administered BA” herein, it can be calculated by the following formula (Method B; relative BA ratio).

Relative BA ratio = A / B x 100
(Wherein “A” means the oral mucosal dose AUC / Compound A dose in the oral mucosal formulation administered to the human subject; and “B” is administered to the human subject. Means the dose of AUC / Compound A administered orally)

For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible. This test example shows that the bioavailability of oral mucosal administration is greater than oral administration.
At this time, when the “ratio of the oral mucosal BA to the oral BA” (relative BA ratio) is 10 or more, the formulation is “the bioavailability of the compound A is lower than that of the oral administration”. It has been improved by 10 times or more. "

iii. The ratio of the unchanged form of the drug to the preparation C and the metabolite of the drug The present invention contains compound A, and the ratio of the unchanged form of the drug to the metabolite after transfer into blood is greater than the ratio when administered orally. The present invention also relates to a preparation for oral mucosal absorption (formulations [9] to [11]) (hereinafter sometimes abbreviated as the preparation (C) of the present invention).
“To be greater than the ratio” specifically means that the ratio is about 5 times or more, preferably about 10 times or more. In general, it is about 30 times or less, more specifically, about 20 times or less. Here, “about” means an error range of 5%.

In the preparation (C), when the dosage form is a tablet, the disintegration time is preferably 30 seconds or less. In the case where the dosage form of the preparation (C) is a tablet, it is more preferable that the disintegration time is 30 seconds or less and the absolute hardness is 1.0 N / mm ² or more.
The preparations [5] to [7] described above are also included in the “preparation (C)”.
Here, whether or not “the ratio of the unchanged drug and the metabolite of the drug after transfer into the blood is greater than the ratio when orally administered” is evaluated as follows.
Each preparation is administered to the oral and buccal mucosa, and the plasma concentrations of both unchanged substance and metabolite are measured after each elapsed time. Both areas under the plasma concentration (AUC) are measured by a method known in this technical field. Calculate There are two types of AUC values, one is AUC (0-tlqc) and one is AUC (0-inf). AUC (0-tlqc) is the area under the serum concentration from 0 hour to the final concentration quantifiable time point (tlqc), calculated using the linear trapezoidal formula. AUC (0-inf) is the area under the serum concentration from 0 hour to infinity, and AUC (0-inf) = AUC (0-tlqc) + lqc / λz (where tlqc is the final point at which concentration can be determined, lqc is the final quantifiable concentration, and λz is the final phase disappearance rate constant, calculated by the negative slope of the logarithmic linear regression of the terminal phase of the natural log concentration-time curve. Both AUC values can be used for assessment of improved bioavailability, but in principle the assessment is based on AUC (0-inf).
The ratio of unchanged form to metabolite in each preparation (ie, unchanged form AUC / metabolite AUC) is calculated.
At this time, when the ratio at the oral mucosal administration is larger than the ratio at the oral administration, the ratio of the unchanged drug and the metabolite of the drug after moving into the blood is larger than the ratio at the oral administration. Be evaluated.
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible. Those skilled in the art will recognize that the level of metabolites (especially the specific metabolite M-II among the many metabolites of Compound A) from oral mucosal administration will be low as shown in this study. You will not be able to expect.

The dosage form of the preparation (A), the preparation (B) and the preparation (C) is not particularly limited as long as it is a dosage form that can be administered from the oral mucosa. For example, tablets (eg, sublingual tablets, buccals) Tablets), films, troches, solutions, suspensions, freeze-dried preparations, chewing gums, sprays, and the like, among which tablets are preferred.
The types and amounts of the “compound A”, “masking agent”, “sugar”, “sugar alcohol”, and “disintegrant” used in the preparation (A), preparation (B) and preparation (C) are as described above. The types and amounts exemplified for the sex preparation are mentioned.

In the present specification, the absolute hardness is a hardness per unit area and is defined by the following formula.
Absolute hardness (N / mm ² ) = Hardness (N) / (Thickness (mm) × Diameter (mm))
In the present invention, the tablet hardness can be measured using a tablet breaking strength measuring machine (TH-303MP, Toyama Sangyo Co., Ltd.).

  In the present specification, the disintegration time is a value measured using a disintegration tester (ODT-101, Toyama Sangyo Co., Ltd.) for intraoral quick disintegrating tablets.

Formulation: Formulation for absorption of oral mucosa of Compound A (2)
iv. Formulation D
The present invention also relates to a preparation for absorption in the oral mucosa (formulations [37] to [59]) (hereinafter sometimes abbreviated as the preparation (D) of the present invention).
Regarding the formulation (D), in principle, the definitions and specific examples of the terms specified in the respective formulations [37] to [59] can be referred to those exemplified for the above formulations (A) to (C).

Regarding the formulations [37] to [39], “(S) —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propion” (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide for the amide metabolite (M-II) The unchanged AUC ratio of
The unchanged AUC / (S of “(S) —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide” ) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide metabolite (MUC) AUC]
Means the value calculated by.
Here, the term “AUC” and the calculation method thereof can refer to those exemplified for the preparations (A) to (C).
The AUC ratio is about 5 times or more when administered orally, preferably about 10 times or more when administered orally. Generally, the AUC ratio is about 30 times or less when administered orally, more specifically, about 25 times or less when administered orally. Here, “about” means an error range of 5%.
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible.

(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide for formulations [40] and [41] Of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (M) -II) is the AUC ratio:
Of (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide metabolite (M-II) AUC / (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide unchanged AUC "
Means the value calculated by.
Here, the term “AUC” and the calculation method thereof can refer to those exemplified for the preparations (A) to (C).
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible.
The AUC ratio is about 25 or less, preferably about 10 or less, and more preferably about 5 or less. Generally, the AUC ratio is about 1 or greater. Here, “about” means an error range of 5%.

With respect to formulation [42], the biology of “(S) —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide. “Availability” can be calculated according to the calculation method (method B) described above for the preparation (B).
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible.
The bioavailability is improved about 10 times or more compared to oral administration. Here, “about” means an error range of 5%. In general, the bioavailability ranges from about 10 times to about 30 times the bioavailability when administered orally, more specifically, from about 10 times to about 25 times the bioavailability. To improve.

Regarding formulations [43] and [44], “(S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8- after administration to humans” In the term “I) ethyl] propionamide plasma concentration Tmax value”, Tmax means the time to reach Cmax, Cmax means the highest observed serum concentration after the formulation is administered to humans .
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible.
The average Tmax value is about 0.4 hours or less, preferably about 0.3 hours or less, and more preferably about 0.25 hours or less.

Regarding the formulations [45] and [46], the term “(S) —N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8 after administration to humans” -Il) ethyl] propionamide (unmodified) individual variability in pharmacokinetic parameters including Cmax and AUC "
Standard deviation / mean value of each target pharmacokinetic parameter x 100
It is expressed by the term “variation coefficient (%)” calculated by
For specific preparations and test methods used for the test, Test Example 4 described later may be referred to. However, the method of Test Example 4 is not limited as long as substantially the same evaluation is possible.
Individual variation is about 45% or less, more preferably about 35% or less, and most preferably about 30% or less. Here, “about” means an error range of 5%.

Dosage Forms The preparations (A) to (D) can be produced, for example, according to the production method described for the “fast disintegrating preparation of the present invention”. In particular, when the dosage forms of the preparations (A) to (D) are tablets, the production method is preferable. It is also possible to apply other techniques for orally disintegrating preparations.
In the preparations (A) to (D), when the dosage form is a film, it may be produced according to the following conventional method. For example, a coating solution (solution or suspension, solvent is purified water, for example) containing a drug, a film carrier, and other film carriers used as necessary is applied or sprayed on the holding substrate surface. After that, it can be produced by drying (Japanese Patent No. 3460538).
When the dosage form is a freeze-dried preparation in the preparations (A) to (D), it may be produced according to the following conventional method. For example, it can be produced by blending a drug, polymer, saccharide, etc., dissolving and then lyophilizing (Manufacturing Chemist, Feb. 36 (1990)).
In the preparations (A) to (D), when the dosage form is chewing gum, it may be produced according to the following conventional method. For example, a gum base resin is the main ingredient, and additives such as drugs, sweeteners, fragrances, coloring agents, softeners, and corrigents are added to a gum base consisting of wax, emulsifier and filler, and kneaded uniformly using a kneader. After that, it can be manufactured by processing such as a plate shape or a block shape (Japanese Patent Laid-Open No. 2009-136240).
In the preparations (A) to (D), when the dosage form is a troche, it may be produced according to the usual method for producing tablets.
In the preparations (A) to (D), when the dosage form is a solution or a suspension, the preparation may be produced according to a normal method for producing a liquid.
In the preparations (A) to (D), when the dosage form is a spray, it may be produced according to the usual method for producing a spray.

  The preparation of the present invention can be safely administered to mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys), particularly humans.

  The dosage of the preparation of the present invention varies depending on the administration subject, administration route, disease and the like. For example, when an oral mucosal absorption preparation containing Compound A as a drug is administered to an adult, the dose of Compound A is about 0.0002 to about 0.02 mg / kg body weight, preferably about 0.0002 to About 0.01 mg / kg body weight, more preferably about 0.0002 to about 0.005 mg / kg body weight, most preferably about 0.0002 to about 0.004 mg / kg body weight, one to several times a day Can be administered separately. Preferably, it is once a day. In other words, as will be described later, the dose of Compound A is 0.05 to 1.5 mg per day (preferably 0.05 to 1.0 mg, more preferably 0.1 to 1.0 mg, even more preferably Is 0.1-0.8 mg and most preferably 0.1 mg, 0.4 mg and 0.8 mg) and can be administered once a day.

  The solubility of Compound A is about 0.2 mg / ml regardless of pH. In order for this compound to be absorbed into the oral mucosa, the compound must first be dissolved in saliva. Considering that the amount of saliva in the oral cavity is about 1 ml, the reduction in the amount of Compound A provided by the present invention is very advantageous from a practical point of view.

  According to the preparation of the present invention, as described above, the dose of Compound A can be reduced while maintaining its effectiveness. Therefore, the size of the formulation can be reduced if necessary. This feature is one of the advantages of the present invention.

Methods of using Compound A: Prevention and / or treatment of bipolar disorder It is known that in patients with bipolar disorder, melatonin secretion is reduced and circadian rhythm is impaired. Neuroscience Letters, 475: 169-173 (2010); Journal of Psychiatric Research, 44: 69-74 (2010).
When Compound A is administered to the human oral mucosa, it is surprisingly observed that the pharmacokinetics (early onset and disappearance) of Compound A are almost the same as endogenous melatonin. With a good pharmacokinetic profile, Compound A can better tune circadian rhythms that are thought to be disturbed in patients with bipolar disorder than existing drugs for bipolar disorder. Thus, in the case of intraoral mucosal administration, Compound A is expected to show an effect superior to existing drugs for bipolar disorder. This circadian rhythm adjustment effect can also lead to better normalization of circadian rhythm and / or sleep / wake cycle in bipolar disorder patients.
As mentioned above, the present invention provides a formulation that exhibits excellent absorption from the oral mucosa for Compound A and improved bioavailability and a characteristic pharmacokinetic profile. For example, when Compound A is administered to the oral mucosa, there is less variation in Cmax and AUC between different individuals than when Compound A is administered orally.
For example, in Table 4, the Cmax of unchanged Compound A and the active metabolite M-II for sublingual administration are 4.74 + 1.52 and 4.18 ± 1.26, respectively, unchanged form / metabolism The ratio of objects is 1.13. On the other hand, the corresponding unchanged / metabolite Cmax and ratio for oral administration are 4.76 ± 5.19, 68.1 ± 23.2 and 0.07. The relevant AUC (0-inf) unchanged / metabolite ratio for sublingual and oral administration is 0.30 and 0.03, respectively. Thus, Table 4 shows that the ratio of unchanged Compound A to metabolite is higher with sublingual administration than with oral administration. Thus, sublingual or buccal administration is believed to avoid first-pass metabolism and, as a result, reduce the variability that exists between patients in Compound A metabolism. Therefore, a more effective method for preventing and / or treating bipolar disorder and a more effective drug for preventing and / or treating bipolar disorder will be provided.
That is, it becomes possible to prevent and / or treat bipolar disorder by administering Compound A to the oral mucosa to a patient suffering from bipolar disorder. Specifically, in the forms of the preparations of the present invention (formulations (A) to (D)), the prophylaxis and / or treatment can be performed by appropriately administering Compound A to humans. For example, the various types of PK profiles mentioned in methods [59]-[71] can be achieved by administering Compound A to humans in the form of formulations [37]-[58].
Here, as the administration route of Compound A, sublingual administration or buccal administration is preferable, and sublingual administration is particularly preferable.
Sublingual and buccal administration is advantageous for providing rapid onset of therapeutic effect and rapid loss. This is the opposite of oral administration where onset and disappearance is slow due to gastrointestinal transit time. Compared to oral administration, the ratio of metabolite M-II to compound A is lower in sublingual and buccal administration. By realizing the rapid disappearance, patients suffering from bipolar disorder benefit from the effects of Compound A without experiencing the protracted sleepiness associated with the presence of metabolites.
The early onset / early disappearance characteristics of sublingual and buccal administration are thought to be similar to the effects of endogenous melatonin. In one embodiment, the formulation provides a therapeutic effect by achieving a blood concentration above a certain therapeutic level for a period of time. It is desirable to match the duration and blood levels to endogenous melatonin levels in healthy individuals who are not affected by bipolar disorder.
The dose of Compound A is in the above-mentioned range. For example, when administered as a sublingual tablet or buccal tablet, 0.05 to 1.5 mg (preferably 0.05 to 1.0 mg, more preferably 0.1-1.0 mg, even more preferably 0.1-0.8 mg and most preferably 0.1 mg, 0.4 mg and 0.8 mg) It is preferred to administer the tablets to be administered (preferably once a day) to the patient.
As subject diseases, the present invention includes type I bipolar disorder, type II bipolar disorder (recurrent major depressive episodes with hypomanic episodes) (296.89), and specific It is effective for bipolar disorder, including impossible bipolar disorder (296.80). The numbers in parentheses after the above listed diseases are the Psychiatric Diagnosis and Statistical Manual published by the American Psychiatric Association, 4th edition (DSM-IV) and / or International Disease Classification, 10th edition (ICD- Refer to the classification code of 10). However, the present invention is intended to be used for the treatment of diseases associated with or similar to those described in this classification code system and, of course, may vary as more is elucidated for those diseases Should be understood. The present invention is particularly effective in the treatment of type I bipolar disorder. In particular, it is effective for “treatment of depressive symptoms (particularly acute depressive symptoms) associated with bipolar disorder” and “maintenance of remission phase of bipolar disorder”.
When performing “prevention and / or treatment of bipolar disorder by intraoral mucosal administration of Compound A”, it may be used in combination with other drugs for the prevention and / or treatment of bipolar disorder. Examples of other drugs for preventing and / or treating bipolar disorder used in combination with “Compound A” (hereinafter referred to as “concomitant drugs”) include mood stabilizers (eg, lithium, valproic acid). , Carbamazepine, lamotrigine, etc.), antipsychotics (eg, quetiapine, olanzapine, etc.), and combinations of one or more drugs selected therefrom. In addition to these, one or more SSRIs (selective serotonin reuptake inhibitors) (for example, fluvoxamine, paroxetine, escitalopram, fluoxetine, citalopram, etc.) are combined with “Compound A” and the aforementioned “concomitant drug”. It can also be administered in combination.
The administration form of the “concomitant drug” is not particularly limited, and it is sufficient that “compound A” and “concomitant drug” are combined at the time of administration. Examples of such dosage forms include: :
(1) administration of a single preparation obtained by simultaneously formulating “compound A” and “concomitant drug”;
(2) Simultaneous administration of two compounds obtained by separately formulating “Compound A” and “Concomitant drug” by the same administration route,
(3) Administration of two types of preparations obtained by separately formulating “compound A” and “concomitant drug” with a time difference in the same administration route,
(4) Simultaneous administration of two types of preparations obtained by separately formulating “compound A” and “concomitant drug” through different administration routes,
(5) Administration of two types of preparations obtained by separately formulating “compound A” and “concomitant drug” at different time intervals in different administration routes (for example, “compound A” → “combination drug” Administration in the order, or administration in the reverse order).
The dose of the “concomitant drug” can be determined based on the clinically used dose, and can be appropriately selected depending on the administration subject, administration route, disease severity, combination, and the like.
The “concomitant drug” can be administered in the same dosage form used clinically or in different dosage forms suitable for this combination therapy.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited thereto. In the following Examples and Comparative Examples, as a formulation additive (eg, D-mannitol, crystalline cellulose, etc.), a Japanese Pharmacopoeia (15th revision) or a pharmaceutical additive standard 2003 compliant product was used.

Example 1
(1) A coating liquid was prepared by dissolving 450.0 g of D-mannitol (PEARLITOL 50C, Rocket) in 2550 g of purified water. In a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A (150.5 g), D-mannitol (3068 g), crystalline cellulose (Theolas PH-101, Asahi Kasei Co., Ltd.) (112.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After 450.0 g was uniformly mixed, it was granulated while spraying 3000 g of the coating liquid, and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) 90 g of crospovidone (Kollidon CL-F, BASF Corporation) and 18 g of sodium stearyl fumarate (PRUV, JRS PHARMA) are added to 1692 g of the obtained sized powder, and a tumbler mixer (TM-30, Showa Chemical Machinery Co., Ltd.). A mixed powder was obtained by mixing at a workshop.
(3) The mixed powder was tableted using a rotary tableting machine (Aqua 08242L2JI, Kikusui Seisakusho) with a 4 mmφ punch (tablet pressure: 4 kN, weight per tablet: 30 mg) to obtain tablets.

Formulation compound A (per 30 mg) Compound A 1.0 mg
D-mannitol (in granules) 20.45 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
30 mg total

Comparative Example 1
A PEG400 solution was prepared by dissolving 15 g of polyethylene glycol 400 (PEG400) (Wako Pure Chemical Industries, Ltd.) in 35 g of purified water. 12.5 mg of Compound A was added to 50 ml of PEG400 solution, stirred and subjected to ultrasonic irradiation, and then filtered through an aqueous filter (0.45 μm). The obtained compound A solution was divided into 1 ml portions.

Formulation (per ml) Compound A A 0.25 mg
PEG400 300.0 mg
Purified water 700.0 mg
1000.25 mg total

Comparative Example 2
(1) A binding solution was prepared by dissolving 40 g of hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.) in 627 g of purified water. In a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), Compound A 2.5 g, Lactose (DMV Co., Ltd.) 1053.5 g, and Corn Starch (Japan Corn Starch Co., Ltd.) 160 g were uniformly mixed. Granulation was carried out while spraying 667 g of the binding liquid, followed by drying to obtain a granulated powder. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder.
(2) 17 g of corn starch and 5 g of magnesium stearate were added to 628 g of the obtained sized powder, and mixed into a bag to obtain a mixed powder.
(3) The mixed powder is tableted (tablet pressure: 7 kN, weight per tablet: 130 mg) with a rotary tableting machine (small tableting machine, Kikusui Seisakusho) using 4 mmφ punches, and tablets (plain tablets) )
(4) Dispersion I was obtained by dissolving and dispersing 22.44 g of hydroxypropylmethylcellulose (TC-5R) and 4.5 g of Copovidone in 198 g of purified water. Dispersion II was prepared by dispersing 25 g of titanium oxide and 0.5 g of yellow ferric oxide in 450 g of purified water. Dispersion II was added to Dispersion I and mixed by stirring to obtain a coating solution. Using a coating machine (Hi-Coater HC-LAB0, Freund Sangyo Co., Ltd.), spraying the coating solution on the uncoated tablets obtained in (3) until the weight of the uncoated tablets increases by 5 mg per tablet, the following composition Film tablets were obtained.

Formulation compound A (per 135 mg) Compound A 0.25 mg
Lactose 105.35 mg
Corn starch 19.4 mg
Hydroxypropylcellulose 4.0 mg
Magnesium stearate 1.0 mg
Hydroxypropyl methylcellulose 3.74 mg
Copovidone 0.75 mg
Titanium oxide 0.5 mg
Yellow iron sesquioxide 0.01 mg
135 mg total

Example 2
(1) A coating solution was prepared by dissolving 120 g of D-mannitol (PEARITOL 50C, Rocket) in 680 g of purified water. In a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), Compound A (10 g), D-mannitol (848 g), crystalline cellulose (Theolas PH-101, Asahi Kasei Corporation), and partially pregelatinized starch (PCS, Asahi Kasei) After mixing 120 g uniformly, the mixture was granulated while spraying with 800 g of coating solution, and then dried to obtain a granulated powder. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder.
(2) 28.2 g of the obtained sized powder, 1.5 g of crospovidone (Kollidon CL-F, BASF Corporation) and 0.3 g of sodium stearyl fumarate were mixed in a glass bottle. The resulting mixture was tableted with a 4 mmφ punch using an autograph (manufactured by Shimadzu Corp., AG-5000B) (tablet pressure: 3 KN / kg, weight per tablet: 30 mg), and a plain tablet having the following composition Got.

Formulation (per 30 mg) Composition Compound A 0.25 mg
D-mannitol (in granules) 21.2 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
30 mg total

Comparative Example 3
A PEG400 solution was prepared by dissolving 60 g of PEG400 (Wako Pure Chemical Industries, Ltd.) in 110 g of purified water. 100.0 mg of compound A was added to 100 ml of PEG400 solution, stirred and subjected to ultrasonic irradiation, and then filtered through an aqueous filter (0.45 μm). The obtained compound A solution was divided into 1 ml portions.

Formulation compound A (1.0 ml) 1.0 mg
PEG400 352.9 mg
Purified water 647.1 mg
1001 mg total

Comparative Example 4
(1) A binding solution was prepared by dissolving 660 g of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) in 10230 g of purified water. In a fluidized bed granulator / dryer (FD-S2, POWREC Co., Ltd.), Compound A (165.3 g), lactose (DMV Co., Ltd.) (17260 g), and corn starch (Nippon Corn Starch Co., Ltd.) (2640 g) were uniformly mixed, and then the binding solution. Granulation was carried out while spraying 10890 g, followed by drying to obtain a granulated powder. This granulation process was performed twice. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) 1037 g of corn starch and 298 g of magnesium stearate were added to 37430 g of the obtained sized powder, and mixed with a tumbler mixer (TM20-0-0, Suehiro Koki Co., Ltd.) to obtain a mixed powder.
(3) The mixed powder is compressed with a rotary tableting machine (Aquarius 36K, Kikusui Seisakusho) using a 7 mmφ punch (tablet pressure: 7 kN, weight per tablet: 130 mg), and tablets (plain tablets) are obtained. Obtained.
(4) 1548 g of hydroxypropyl methylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and 310.5 g of Copovidone were dissolved and dispersed in 16150 g of purified water to obtain a dispersion I. Dispersion II was prepared by dispersing 207 g of titanium oxide and 4.14 g of yellow ferric oxide in 1822 g of purified water. Dispersion II was added to Dispersion I and mixed by stirring to obtain a coating solution. Using a coating machine (Hi-Coater HCF-100N, Freund Sangyo Co., Ltd.), spraying the coating solution on the uncoated tablets obtained in (3) until the weight of the uncoated tablets increases by 5 mg per tablet, the following composition Film tablets were obtained.

Formulation (per 135 mg) Composition Compound A 1.0 mg
Lactose 104.6 mg
Corn starch 19.4 mg
Hydroxypropylcellulose 4.0 mg
Magnesium stearate 1.0 mg
Hydroxypropyl methylcellulose 3.74 mg
Copovidone 0.75 mg
Titanium oxide 0.5 mg
Yellow iron sesquioxide 0.01 mg
135 mg total

Example 3
(1) A coating solution was prepared by dissolving 120 g of D-mannitol (PEARITOL 50C, Rocket) in 680 g of purified water. In a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), Compound A 40 g, D-mannitol 818 g, crystalline cellulose (Theolas PH-101, Asahi Kasei) 30 g, and partially pregelatinized starch (PCS, Asahi Kasei) 120 g After uniformly mixing, the mixture was granulated while spraying with 800 g of the coating liquid, and then dried to obtain a granulated powder. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder.
(2) 28.2 g of the obtained sized powder, 1.5 g of crospovidone (Kollidon CL-F, BASF Corporation) and 0.3 g of sodium stearyl fumarate were mixed in a glass bottle. The resulting mixture was tableted with a 4 mmφ punch using an autograph (manufactured by Shimadzu Corp., AG-5000B) (tablet pressure: 3 KN / kg, weight per tablet: 30 mg), and a plain tablet having the following composition Got.

Formulation compound A (per 30 mg) Compound A 1.0 mg
D-mannitol (in granules) 20.45 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
30 mg total

Example 4
5 g of Compound A and 20 g of CMEC were dissolved in 500 ml of a mixture of acetone: ethanol = 3: 2, and then prepared by spray drying using a spray dryer (Pulvis Mini Spray, Yamato Scientific Co., Ltd.). The obtained solid dispersion powder was vacuum-dried at 40 ° C. for 16 hours. To 1.5 g of the solid dispersion powder, 11.5 g of D-mannitol (PEARITOL 100SD, Rocket) was added and mixed with the bottle. The obtained mixed powder was divided into 120 mg portions.

Formulation (per 120 mg) Composition Compound A 1.0 mg
CMEC 4.0 mg
D-mannitol 115.0 mg
120 mg total

Example 5
75 g of hydroxypropyl-β-cyclodextrin (hereinafter also referred to as HP-β-CyD) (KLEPTOSE HPB, Rocket) is dissolved in 422.5 g of purified water. In the obtained HP-β-CyD aqueous solution, 2.5 g of Compound A was dissolved to prepare a coating solution. In a fluidized bed granulator / dryer (MP-01, POWREC Co., Ltd.), 200 g of D-mannitol (PEARLITOL50C, Rocket) and 7.5 g of crystalline cellulose (Theolas PH-101, Asahi Kasei) are uniformly mixed and then coated. While spraying 500 g of the liquid, it was granulated and then dried to obtain a granulated powder. The obtained granulated product was sieved with a sieve of 16 mesh (aperture 1.0 mm) to obtain a sized powder. The obtained sized powder was divided into 114 mg portions.

Formulation (per 114 mg) Composition Compound A 1.0 mg
HP-β-CyD 30.0 mg
D-mannitol 80.0 mg
Crystalline cellulose 3.0 mg
114 mg total

Example 6
(1) 450 g of D-mannitol (PEARITOL 50C, Rocket) was dissolved in 2550 g of purified water to prepare a coating solution. In a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A (37.6 g), D-mannitol (3180 g), crystalline cellulose (Theolas PH-101, Asahi Kasei Co., Ltd.) (112.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After mixing 450 g uniformly, it was granulated while spraying 3000 g of coating liquid, and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) 90 g of crospovidone (Kollidon CL-F, BASF Corporation) and 18 g of sodium stearyl fumarate are added to 1692 g of the obtained sized powder, and mixed with a tumbler mixer (TM-15S, Showa Chemical Machinery Co., Ltd.). As a result, a mixed powder was obtained.
(3) The mixed powder is compressed with a rotary tableting machine (Aquarius 2L, Kikusui Seisakusho) using a 4 mmφ punch (tablet pressure: 4 kN, weight per tablet: 30 mg), and an uncoated tablet having the following composition is prepared. Obtained.

Formulation (per 30 mg) Composition Compound A 0.25 mg
D-mannitol (in granules) 21.2 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
30 mg total

Example 7
(1) 450 g of D-mannitol (PEARLITOL 50C, Rocket) was dissolved in 2550 g of purified water to prepare a coating solution. In a fluidized bed granulator / dryer (FD-5S, Powrec Co., Ltd.), Compound A (150.5 g), D-mannitol (3068 g), crystalline cellulose (Theolas PH-101, Asahi Kasei Co., Ltd.) (112.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After mixing 450 g uniformly, it was granulated while spraying 3000 g of coating liquid, and then dried to obtain a granulated powder. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) 90 g of crospovidone (Kollidon CL-F, BASF Corporation) and 18 g of sodium stearyl fumarate are added to 1692 g of the obtained sized powder, and mixed with a tumbler mixer (TM-15S, Showa Chemical Machinery Co., Ltd.). As a result, a mixed powder was obtained.
(3) The mixed powder is compressed with a rotary tableting machine (Aquarius 2L, Kikusui Seisakusho) using a 4 mmφ punch (tablet pressure: 4 kN, weight per tablet: 30 mg), and an uncoated tablet having the following composition is prepared. Obtained.

Formulation compound A (per 30 mg) Compound A 1.0 mg
D-mannitol (in granules) 20.45 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
30 mg total

Comparative Example 5
(1) A binding solution was prepared by dissolving 660 g of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) in 10230 g of purified water. In a fluidized bed granulator / dryer (FD-S2, POWREC Co., Ltd.), 1320 g of Compound A, 16104 g of lactose (DMV Co., Ltd.), and 2640 g of corn starch (Nippon Corn Starch Co., Ltd.) were uniformly mixed. While spraying, it was granulated and then dried to obtain a granulated powder. This granulation process was performed twice. Part of the obtained granulated powder was crushed with a 1.5 mmφ punching screen using a power mill grinder (P-3, Showa Chemical Machinery Co., Ltd.) to obtain a sized powder.
(2) 1037 g of corn starch and 298 g of magnesium stearate were added to 37430 g of the obtained sized powder, and mixed with a tumbler mixer (TM20-0-0, Suehiro Koki Co., Ltd.) to obtain a mixed powder.
(3) The mixed powder is compressed with a rotary tableting machine (Aquarius 36K, Kikusui Seisakusho) using a 7 mmφ punch (tablet pressure: 7 kN, weight per tablet: 130 mg), and tablets (plain tablets) are obtained. Obtained.
(4) 1548 g of hydroxypropyl methylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and 310.5 g of Copovidone were dissolved and dispersed in 16150 g of purified water to obtain a dispersion I. Dispersion II was prepared by dispersing 207 g of titanium oxide and 4.14 g of yellow ferric oxide in 1822 g of purified water. Dispersion II was added to Dispersion I and mixed by stirring to obtain a coating solution. Using a coating machine (Hi-Coater HCF-100N, Freund Sangyo Co., Ltd.), spraying the coating solution on the uncoated tablets obtained in (3) until the weight of the uncoated tablets increases by 5 mg per tablet, the following composition Film tablets were obtained.

Formulation compound A (per 135 mg) Compound A 8.0 mg
Lactose 97.6 mg
Corn starch 19.4 mg
Hydroxypropylcellulose 4.0 mg
Magnesium stearate 1.0 mg
Hydroxypropyl methylcellulose 3.74 mg
Copovidone 0.75 mg
Titanium oxide 0.5 mg
Yellow iron sesquioxide 0.01 mg
135 mg total

Example 8
(1) A coating solution was prepared by dissolving 510 g of D-mannitol (PEARITOL 50C, Rocket) in 2890 g of purified water. In a fluidized bed granulator / dryer (FD-5S, Pauleck Co., Ltd.), Compound A (17.05 g), D-mannitol (3114 g), crystalline cellulose (Theolas PH-101, Asahi Kasei Co., Ltd.) (127.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After uniformly mixing 510 g, the mixture was granulated while spraying 3400 g of coating solution, and then dried to obtain a granulated powder. A part of the obtained granulated powder was sieved using a round sieve (mesh size 1.0 mmφ), and sieved powder A was obtained.
(2) The same process as (1) was performed, and sieved powder B was obtained.
(3) To the obtained sieved powder A3146.5g and sieved powder B3146.5g, 375.0g of crospovidone (Kollidon CL-F, BASF Corporation), 750g of aspartame, 7.5g of vanillin and 75g of sodium stearyl fumarate were added. In addition, mixing powder was obtained by mixing with a tumbler mixer (TM-60S, Showa Chemical Machine Works).
(4) Tablet the mixed powder with a rotary tableting machine (Aquarius 2L, Kikusui Seisakusho) using a 4mmφ punch (tablet pressure: 4kN, weight per tablet: 30mg) Obtained.

Formulation compound A (per 30 mg) Compound A 0.1 mg
D-mannitol (in granules) 18.32 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
Aspartame 3.0 mg
Vanillin 0.03 mg
30 mg total

Example 9
(1) A coating solution was prepared by dissolving 510 g of D-mannitol (PEARITOL 50C, Rocket) in 2890 g of purified water. In a fluidized bed granulator / dryer (FD-5S, Paulek, Inc.), Compound A (68.20 g), D-mannitol (3063 g), crystalline cellulose (Theorus PH-101, Asahi Kasei Co., Ltd.) (127.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After uniformly mixing 510 g, the mixture was granulated while spraying 3400 g of coating solution, and then dried to obtain a granulated powder. A part of the obtained granulated powder was sieved using a round sieve (mesh size 1.0 mmφ), and sieved powder A was obtained.
(2) The same process as (1) was performed, and sieved powder B was obtained.
(3) To the obtained sieved powder A3146.5g and sieved powder B3146.5g, 375.0g of crospovidone (Kollidon CL-F, BASF Corporation), 750g of aspartame, 7.5g of vanillin and 75g of sodium stearyl fumarate were added. In addition, mixing powder was obtained by mixing with a tumbler mixer (TM-60S, Showa Chemical Machine Works).
(4) Tablet the mixed powder with a rotary tableting machine (Aquarius 2L, Kikusui Seisakusho) using a 4mmφ punch (tablet pressure: 4kN, weight per tablet: 30mg) Obtained.

Compound (A) of formulation (per 30 mg) 0.4 mg
D-mannitol (in granules) 18.02 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
Aspartame 3.0 mg
Vanillin 0.03 mg
30 mg total

Example 10
(1) A coating solution was prepared by dissolving 510 g of D-mannitol (PEARITOL 50C, Rocket) in 2890 g of purified water. In a fluidized bed granulator / dryer (FD-5S, Paulek, Inc.), Compound A (136.4 g), D-mannitol (2995 g), crystalline cellulose (Theorus PH-101, Asahi Kasei Co., Ltd.) (127.5 g), and partially pregelatinized starch (PCS, Asahi Kasei Co., Ltd.) After uniformly mixing 510 g, the mixture was granulated while spraying 3400 g of coating solution, and then dried to obtain a granulated powder. A part of the obtained granulated powder was sieved using a round sieve (mesh size 1.0 mmφ), and sieved powder A was obtained.
(2) The same process as (1) was performed, and sieved powder B was obtained.
(3) To the obtained sieved powder A3146.5g and sieved powder B3146.5g, 375.0g of crospovidone (Kollidon CL-F, BASF Corporation), 750g of aspartame, 7.5g of vanillin and 75g of sodium stearyl fumarate were added. In addition, mixing powder was obtained by mixing with a tumbler mixer (TM-60S, Showa Chemical Machine Works).
(4) Tablet the mixed powder with a rotary tableting machine (Aquarius 2L, Kikusui Seisakusho) using a 4mmφ punch (tablet pressure: 4kN, weight per tablet: 30mg) Obtained.

Formulation compound A (per 30 mg) Compound A 0.8 mg
D-mannitol (in granules) 17.62 mg
D-mannitol (in coating layer) 3.0 mg
Crystalline cellulose 0.75 mg
Partially pregelatinized starch 3.0 mg
Crospovidone 1.5 mg
Sodium stearyl fumarate 0.3 mg
Aspartame 3.0 mg
Vanillin 0.03 mg
30 mg total

Test example 1
About the tablet obtained in Example 1, tablet hardness and disintegration time were measured. Tablet hardness was measured using a tablet breaking strength measuring machine (TH-303MP, Toyama Sangyo Co., Ltd.) (n = 10). The disintegration time was measured using a disintegration tester (ODT-101, Toyama Sangyo Co., Ltd.) (n = 6). The results are shown in Table 1.

Disintegration tester condition rotation speed: 50rpm
Weight: 15mmφ, 10g

Test example 2
For the mixed powder obtained in Example 1, the dissolution property was measured. 15 g (corresponding to 500 mg of Compound A) was added to 500 mL of JP 2nd liquid, and evaluated by the paddle method, rotation speed 25 rpm, 37 ° C. After loading the sample, sample the eluate over time (0.25 min, 0.5 min, 0.75 min, 1 min, 5 min, 15 min, 30 min) and filter with an aqueous filter (0.45 μm) The sample was diluted 10-fold with an extract (water / acetonitrile mixture (1: 1)) and dissolved, and quantified by high performance liquid column chromatography (HPLC) under the following conditions to calculate solubility. The results are shown in Table 2.

HPLC condition detector: UV absorption photometer, measurement wavelength: 240 nm
Column: YMC-Pack ODS-AM AM-307, 5 μm, inner diameter: 4.6 mm, length: 75 mm
Column temperature: 25 ° C
Mobile phase: 0.01 mol / L phosphate buffer / acetonitrile mixture (5: 3)
Flow rate: 1.2 mL / min

Test example 3
About the injection obtained in Comparative Examples 1 and 3, the oral tablet obtained in Comparative Examples 2 and 4, the oral mucosal absorption preparation obtained in Examples 2 to 5, intravenous injection to cynomolgus monkeys under fasting conditions, Blood kinetics were measured after oral, sublingual and buccal administration. The plasma concentration was measured before administration, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes and 360 minutes, and the area under plasma concentration (AUC) was calculated by the trapezoidal formula. In addition, bioavailability (BA) was calculated by calculating the ratio of oral, sublingual and buccal AUC to intravenous AUC. The results are shown in Table 3.

Test example 4
Regarding oral preparations and oral mucosal absorption preparations, blood kinetics of unchanged substance and active metabolite M-II after oral and sublingual administration to humans were measured. Before administration, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 360 minutes, 480 minutes, 600 minutes, 720 minutes and 1440 minutes Later plasma concentrations were measured.
The results are shown in Table 4. Specifically, the symbols / terms in this table and their definitions are explained below. The experiment was performed by the crossover method in an open-label condition.
AUC (0-tlqc): Area under the serum concentration from 0 hours to the final concentration quantifiable time point (tlqc), calculated using the linear trapezoidal formula.
AUC (0-inf): calculated from AUC (0-inf) = AUC (0-tlqc) + lqc / λz (where tlqc is the final concentration quantifiable time point and lqc is the final quantifiable concentration), starting from 0 hour Area under serum concentration to infinity.
λz: the disappearance rate constant of the final phase, calculated by the negative slope of the logarithmic linear regression of the terminal phase of the natural log concentration-time curve.
Cmax: the highest serum concentration observed.
Tmax: Time to reach Cmax.
Active metabolite M-II: (2S) -2-hydroxy-N- {2-[(8S) -1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl ] Ethyl} propanamide

Example 11
In 99.5 g of water, 0.5 g of methylcellulose powder was dissolved under ice-cooling, and 100 mg of compound A was added to 10 mL of the resulting solution and stirred to uniformly disperse. The obtained suspension was filled in a spraying device (amount of spraying: 100 μL / time) to obtain an oral spray formulation.

Example 12
40 g of hydroxypropyl-β-cyclodextrin (HP-β-CyD) was dissolved in 60 g of water, and 100 mg of compound A was added to 10 mL of the resulting solution and dissolved by stirring. The obtained solution was filled in a spraying device (spraying amount: 100 μL / time) to obtain an oral spray formulation.

Example 13
To 100 mL of ethanol, 100 mg of Compound A, 1 g of polyvinylpyrrolidone and 18 g of hydroxypropylcellulose were added and dissolved with stirring. 1 mL of the obtained solution was spread and dried on a plastic sheet to obtain an intraoral fast-dissolving film preparation.

Example 14
In 100 mL of a mixed solution of water and ethanol (4: 1), 100 mg of Compound A, 5 g of D-mannitol and 100 mg of hydroxypropylcellulose were added and dissolved by stirring. 1 mL of the resulting solution is dispensed into a pocket of a blister pack having a vinyl chloride resin as an inner membrane, frozen at −30 ° C., dried using a vacuum dryer, and rapidly dissolved in the oral cavity. Got.

表５で示すように、化合物Ａを投与した緩解期における双極性患者群は、プラセボを投与した患者よりも再発を免れた割合が高かった。これは、化合物Ａが双極性障害患者の治療および緩解期におけるそれらの維持に有効であることを示す。 Test Example 5: Therapeutic effect of maintaining remission in patients with bipolar disorder Test tablet Oral 8 mg formulation containing compound A2. Test Method Test tablets were administered once daily at bedtime to a group of patients suffering from bipolar disorder and in remission for 6 months. Placebo was administered once daily at bedtime to another control group of patients with remission of bipolar disorder for 6 months. This study was conducted as a double-blind, randomized, placebo-controlled study. The time from randomization to recurrence within 6 months of treatment is determined by the investigator (PI) or defined by one of the following criteria: Depression [Montgomery-Asberg Depression Rating Scale ( Montgomery-Asberg Depression Rating Scale (MADRS) score ≧ 16]; Gonorrhea / hypomania [Young Mania Rating Scale (YMRS) total score ≧ 14]; global impressions bipolar version (CGI-BP); cumulative proportion of participants (placebo or compound) in each treatment group that escaped relapse [MADRS score ≧ 16 and YMRS total score ≧ 14], mania / depression / mixed symptoms For hospitalization due to start or change of medication, mania / depression / mixed symptoms and suicide risk or imminent suicide risk.
3. Test results The test results are shown in Table 5.

As shown in Table 5, the bipolar patient group in remission phase to which Compound A was administered had a higher rate of escape from recurrence than the patient to which placebo was administered. This indicates that Compound A is effective in treating patients with bipolar disorder and maintaining them in remission.

Test Example 6: Therapeutic effect on acute depression in patients with bipolar disorder Test tablet Oral 8 mg formulation containing compound A2. Test Method Test tablets were administered once a day for up to 8 weeks to a group of patients suffering from bipolar disorder and in the mania phase. Placebo was administered for up to 8 weeks to another control group of patients with bipolar disorder mania. This study was conducted as a double-blind, randomized, placebo-controlled study. The time from randomization to recurrence within 6 months of treatment is determined by the investigator (PI) or defined by one of the following criteria: Clinical Global Impression-Bipolar Disorder Scale (clinical global impressions scale for bipolar disorder (CGI-BP).
3. Test Results Long-term analysis of changes in outcomes indicates that the CGI-BP severity of depression is -0.1 (-0.16 to -0.05), with values below 0 supporting Compound A (95% CL; N = 9; P value = 0.001). This result indicates that Compound A can reduce depressive symptoms.

Test Example 7: Pharmacokinetic parameters Test Protocol A randomized, open-label study was conducted to assess the pharmacokinetic parameters of buccal mucosal tablets containing Compound A and bioavailability compared to oral 8 mg tablets containing Compound A.
The test consists of two parts. :
(1) Parallel group design to evaluate pharmacokinetic parameters of three doses of Compound A (0.25, 0.5 and 1 mg) in buccal mucosal tablets and (2) biological of oral 8 mg tablets 18 patients for an open-label, randomized, second-stage crossover design (1) to evaluate the relative bioavailability (pharmacokinetic profile) of oral mucosal 0.5 mg tablets compared to availability Subjects were randomly assigned to three dose regimens (ie, 0.25, 0.5, and 1 mg each; 6 subjects), and each subject received a single dose of Compound A at the assigned dose. I received it.
For (2), 24 subjects were randomly assigned to receive a single dose of either an oral mucosal 0.5 mg tablet or an oral 8 mg tablet during each of the two phases.
To assess the test, include the highest observed serum concentration (Cmax) of Compound A and M-II and the area under serum concentration (AUC (0-tlqc)) from 0 hour to the final concentration quantifiable time point Pharmacokinetic parameters were measured.
2. Test results The test results are shown in the following two tables and in FIGS.
For (1), the mean Cmax and AUC (0-tlqc) values of Compound A increase with the oral mucosal dose in proportion to the dose between 0.25 and 0.5 mg, 0.5 And 1.0 mg increased less than the dose ratio.
M-II values increased with oral mucosal dose in proportion to dose between 0.25 and 1.0 mg. The variability between subjects for both Compound A and M-II ranged from 11% to 66%.
For (2), much more in oral 8 mg tablets (% CV range 104% -109%) than in oral mucosal tablets (% CV range 30% -32%) with respect to Cmax and AUC (0-tlqc) Large variability between subjects was observed. Although the geometric mean of Cmax and AUC (0-tlqc) was considered more appropriate than the arithmetic mean for comparative purposes, the mean Cmax value of Compound A after buccal mucosal administration was 8 mg tablets orally. It was clarified that it was big compared with. The geometric mean of AUC (0-tlqc) of Compound A was similar between oral mucosa and oral administration. Also, the geometric mean of M-II Cmax and AUC (0-tlqc) was much lower after buccal mucosal administration compared to M-II after oral tablet administration. The variation between subjects with M-II was similar between both oral mucosa and oral therapy and ranged from 18% to 47%.
Thus, a 0.5 mg buccal mucosal dose increases the maximum exposure to Compound A (as measured by Cmax) and Compound A (as measured by AUC) compared to oral 8 mg tablets. For the same total total exposure. Correspondingly, buccal mucosal administration resulted in a lower rate of exposure (<7%) to M-II compared to approved oral 8 mg tablets.

Based on the data shown in Table 4 and the above data, predicted pharmacokinetic parameters for 0.1 mg, 0.4 mg and 0.8 mg sublingual tablets were calculated using the following method.
A two-compartment model for unchanged form of Compound A and a one-compartment model for its metabolite M-II were used to fit post-dose PK profiles of 0.25 mg, 0.5 mg, and 1 mg, respectively. . Subsequently, Bayesian parameter estimates were obtained, with individual parameter estimates for 0.25 mg, 0.5 mg and 1 mg doses being 0.1 mg, 0.4 mg and 0.8 mg, respectively, during the simulation. Was mapped to correspond to the dose of. Descriptive statistics were calculated based on individual simulated Cmax and AUC values, including geometric mean and corresponding 95% and 80% lower and upper geometric mean confidence intervals (CI).
The predicted geometric mean value and the geometric mean confidence interval thus obtained are shown below.

Test Example 8: Treatment effect on maintenance (maintenance of remission period of bipolar disorder) Test tablet Sublingual formulation of Example 8, Example 9 and Example 10. Test Method Test tablets are administered sublingually once a night at bedtime for up to 9 months to patients with remission of bipolar disorder. Primary outcomes can be assessed as a function of time from randomization to recurrent events. The time from randomization to recurrence in the 9-month treatment period is determined by the investigator (PI) or defined by one of the following criteria: Depression [Montgomery-Asberg Depression Rating Scale ( Montgomery-Asberg Depression Rating Scale (MADRS) score ≧ 16]; Gonorrhea / Minor Depression [Young Mania Rating Scale (YMRS) total score ≧ 14]; Mixed episodes [MADRS score ≧ 16 and YMRS sum Score ≧ 14]; or whether the participant has received psychiatric hospitalization for bipolar disorder, electroconvulsive therapy, or any psychotropic for the treatment of depression, mania / hypomania or mixed episodes Whether the medicine has been changed.
3. Test Results Compound A is expected to be very effective for maintenance treatment of bipolar disorder at all doses.

Test Example 9: Treatment effect for acute depression (depressive symptoms associated with bipolar disorder) Test tablet Sublingual formulation of Example 8, Example 9 and Example 10. Test Method Test tablets are administered sublingually once a day for up to 8 weeks to patients suffering from bipolar disorder. The primary outcome can be assessed as a function of the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline at 8 weeks. MADRS is a 10-item clinical rating scale for measuring the overall severity of depressive symptoms (i.e., sadness expressed in appearance, verbal sadness, internal tension, etc.) Are evaluated on a 7-point Likert scale from 0 (normal) to 6 (most abnormal). A high score indicates that the symptom is more severe.
3. Test Results Compound A is expected to be very effective against acute depression at all doses.

ADVANTAGE OF THE INVENTION According to this invention, the novel formulation with which the bioavailability of the chemical | medical agent was improved, its manufacturing method, etc. can be provided.
When Compound A is administered nasally (through the nasal mucosa) to a human subject, it is effective for the prevention and / or treatment of bipolar disorder as in the case of oral mucosal administration as disclosed above. Can be expected. Compound A can be administered in the form of a formulation as disclosed, for example, in WO 01/15735.
When Compound A is administered to a human subject, it can also be administered in a dosage form suitable for inhalation (eg, a nebulizer, etc.) for the prevention and / or treatment of bipolar disorder. The dosage form can be manufactured according to the usual manufacturing method in this technical field. The dose of Compound A can be determined with reference to, for example, the preparations (A) to (D) in the present application.

  This application is based on Japanese Patent Application No. 2011-227333 for which it applied in Japan, The content is altogether included in this specification.

Claims (24)

  0.1 mg of (S) -N- [2- (1,6,7) per day administered to the oral mucosa of a human in need and for prevention and / or treatment of bipolar disorder , 8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in the fasted state, the Cmax of Compound A is about 0.43 to about 3. Within the range of 13 ng / ml and the AUC (0-tlqc) of Compound A is about 0.48 to about 2.26 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.   The preventive and / or therapeutic agent according to claim 1, wherein the oral mucosal administration is sublingual administration or buccal administration.   The preventive and / or therapeutic agent according to claim 1 or 2, wherein the bipolar disorder is type I bipolar disorder.   The preventive and / or therapeutic agent according to any one of claims 1 to 3, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.   In the fasted state, Compound A has a Cmax in the range of about 0.66 to about 2.05 ng / ml and Compound A has an AUC (0-tlqc) of about 0.67 to about 1.62 ng. The prophylactic and / or therapeutic agent according to claim 1, which is in the range of hr / ml.   The prophylactic and / or therapeutic agent according to claim 5, wherein the oral mucosal administration is sublingual administration or buccal administration.   The preventive and / or therapeutic agent according to claim 5 or 6, wherein the bipolar disorder is type I bipolar disorder.   The prophylactic and / or therapeutic agent according to any one of claims 5 to 7, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.   0.4 mg of (S) -N- [2- (1,6,7) per day administered to the oral mucosa of humans in need and for the prevention and / or treatment of bipolar disorder , 8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in a fasted state, the Cmax of Compound A is about 2.04 to about 6. Within the range of 89 ng / ml and the AUC (0-tlqc) of Compound A is about 1.52 to about 6.68 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.   The prophylactic and / or therapeutic agent according to claim 9, wherein the oral mucosal administration is sublingual administration or buccal administration.   The prophylactic and / or therapeutic agent according to claim 9 or 10, wherein the bipolar disorder is type I bipolar disorder.   The prophylactic and / or therapeutic agent according to any one of claims 9 to 11, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.   In a fasted state, Compound A has a Cmax in the range of about 2.54 to about 5.54 ng / ml and Compound A has an AUC (0-tlqc) of about 1.98 to about 5.12 ng. The prophylactic and / or therapeutic agent according to claim 9, which is in the range of hr / ml.   The prophylactic and / or therapeutic agent according to claim 13, wherein the oral mucosal administration is sublingual administration or buccal administration.   The prophylactic and / or therapeutic agent according to claim 13 or 14, wherein the bipolar disorder is a type I bipolar disorder.   The prophylactic and / or therapeutic agent according to any one of claims 13 to 15, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.   0.8 mg of (S) -N- [2- (1,6,7) per day administered to the oral mucosa of a human in need and for prevention and / or treatment of bipolar disorder , 8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (Compound A), and in the fasted state, Compound A has a Cmax of about 3.63 to about 14.3. In the range of 06 ng / ml and the AUC (0-tlqc) of Compound A is about 2.48 to about 14.43 ng. Prophylactic and / or therapeutic agents that are in the hr / ml range.   The preventive and / or therapeutic agent according to claim 17, wherein the oral mucosal administration is sublingual administration or buccal administration.   The prophylactic and / or therapeutic agent according to claim 17 or 18, wherein the bipolar disorder is type I bipolar disorder.   The preventive and / or therapeutic agent according to any one of claims 17 to 19, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.   In the fasted state, Compound A has a Cmax in the range of about 4.85 to about 10.54 ng / ml and Compound A has an AUC (0-tlqc) of 3.60 to about 9.91 ng. The prophylactic and / or therapeutic agent according to claim 17, which is in the range of hr / ml.   The preventive and / or therapeutic agent according to claim 21, wherein the oral mucosal administration is sublingual administration or buccal administration.   23. The preventive and / or therapeutic agent according to claim 21 or 22, wherein the bipolar disorder is type I bipolar disorder.   24. The preventive and / or therapeutic agent according to any of claims 21 to 23, wherein the prevention and / or treatment of bipolar disorder is treatment of depressive symptoms associated with bipolar disorder or maintenance of remission phase of bipolar disorder.

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