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Suspension for oral administration comprising amorphous tolvaptan

A suspension and amorphous technology, applied in the direction of medical preparations of non-active ingredients, active ingredients of heterocyclic compounds, digestive system, etc., can solve the problems of reduced solubility and absorption, and achieve excellent absorption and high solubility , the effect of delaying crystallization

Active Publication Date: 2015-10-28
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] When tolvaptan is prepared as a solid preparation using a common preparation technology, tolvaptan becomes crystals, and there is a problem that solubility and absorption from the gastrointestinal tract are reduced

Method used

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  • Suspension for oral administration comprising amorphous tolvaptan
  • Suspension for oral administration comprising amorphous tolvaptan
  • Suspension for oral administration comprising amorphous tolvaptan

Examples

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preparation example Construction

[0123] As a preferable preparation method, for example, uniformly dispersing (suspending) particles containing amorphous tolvaptan in an aqueous suspension containing hydroxypropylmethylcellulose (HPMC) or an aqueous solution containing HPMC Methods.

[0124] Specifically, the following method can be mentioned, that is, adding HPMC to purified water, and sweeteners, suspending agents, preservatives, stabilizers and / or flavoring agents added as needed to prepare an aqueous suspension or aqueous solution, and then add the particles containing amorphous tolvaptan therein to make it uniformly dispersed (suspended).

[0125] More specifically, a method comprising the steps of:

[0126] (1) Disperse the sweetener and suspending agent in purified water, stir at 79-85°C for 0.5-3 hours to obtain a uniform solution, and then cool to 27-33°C;

[0127] (2) Add preservative and stabilizer respectively and dissolve in purified water;

[0128] (3) Hydroxypropyl methylcellulose (HPMC) and...

preparation example 1A

[0147] Preparation Example 1A (suspension: purified water only)

[0148] Add 0.15 g of amorphous tolvaptan-containing granules (spray-dried product; tolvaptan SD (spray-dried) powder) to 100 g of purified water, and disperse by sufficiently stirring, the amorphous tolvaptan-containing granules Tolvaptan and hydroxypropylcellulose (HPC; HPC-SL, manufactured by Nippon Soda Co., Ltd., the same below) were contained at a weight ratio of 2:1.

preparation example 1B

[0149] Preparation Example 1B (suspension: 20% xylitol)

[0150] 20 g of xylitol was added to 80 g of purified water, dissolved by sufficient stirring, and then 0.15 g of granules containing amorphous tolvaptan (spray-dried product; tolvaptan SD powder; 2:1 by weight) were added thereto. than containing tolvaptan and hydroxypropyl cellulose (HPC; HPC-SL)), dispersion is carried out by thorough stirring.

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Abstract

This invention provides a suspension for oral administration comprising particles containing amorphous tolvaptan that can inhibit or delay crystallization of amorphous tolvaptan over time in the suspension, and stably maintain high solubility of tolvaptan and excellent absorbability of tolvaptan from the gastrointestinal tract; and a solid formulation for oral administration that can be suspended to prepare the suspension for oral administration at the time of use. This invention relates to a suspension for oral administration, in particular, a syrup, comprising (a) particles containing amorphous tolvaptan, (b) hydroxypropyl methylcellulose (HPMC), and (c) a solvent, wherein the amount of the HPMC (b) is 0.1 to 25% by weight based on the total weight of the suspension for oral administration.

Description

technical field [0001] The present invention relates to suspensions (especially syrups) for oral administration containing amorphous tolvaptan and methods for their manufacture. Background technique [0002] Tolvaptan (tolvaptan) is 7-chloro-5-hydroxyl-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2 shown in formula (I), 3,4,5-tetrahydro-1H-benzazepine It is a vasopressin antagonist having aquaretic activity (Patent Document 1). Tolvaptan is marketed as a therapeutic drug against hyponatremia, fluid retention in heart failure, and fluid retention in cirrhosis. [0003] [0004] When tolvaptan is prepared as a solid preparation using a common preparation technique, tolvaptan becomes a crystal, and there is a problem that the solubility and the absorbability from the gastrointestinal tract are lowered. As a means to solve the above problems, Patent Document 2 reports a means of dissolving tolvaptan and hydroxypropyl cellulose in an organic solvent, and then powdering the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K47/26A61K47/38A61K9/16A61K31/55
CPCA61K9/0095A61K9/1652A61K31/55A61K47/26A61K47/38A61P1/00A61P1/16A61P13/00A61P3/12A61P7/10A61P9/00A61P9/04A61K9/0053A61K9/10
Inventor 赤木亮之铃木海中村笃哉西林彻
Owner OTSUKA PHARM CO LTD
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