JPS60188330A - Preparation of oral drug containing 1,3-dioxane derivative - Google Patents

Abstract

PURPOSE:The titled preparation for oral purpose that is made using a 1,3-dioxane derivative and a basic diluent, thus showing improved chemical stability. CONSTITUTION:A compound of the formula (R1 is H, methyl; R2 is H, methyl, ethyl) which gives an expectation of an antiulcerative such as 2-(4-methyl-3- pentenyl)-4,6-dimethyl-1,3-dioxane is pulverized together with a diluent which has been previously made basic with inorganic base and/or basic aminoacid such as synthetic aluminum silicate, Avicel, Neusilin, beta-cyclodextrin or L-glutamin to give the objective oral preparation free from decomposition with the passage of time. The treatment for making the diluent basic is carried out by mixing a basic amino acid so that its content becomes 5-50% or by adding 0.05-0.5N solution of the base to the diluent to adjust the pH to over 8 and drying.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for preparing an oral drug containing a novel 1,6-dioxane derivative as an active ingredient.

The 1,6-dioxane derivative of the present application has the general formula: (In the formula, 1 is H or CH3, and 2 is ■.

CkI3 or 02H, respectively. ), which was previously disclosed in Patent No. 58-1447
This is a novel compound disclosed by the applicant as No. 09. In particular, in general formula (1), fLl is n
, 2-(4-methyl-
BACKGROUND ART 6-pentenyl)-2,4-dimethyl-1,6-dioxane (hereinafter abbreviated as MPDD) and its close derivatives are compounds that are expected to have therapeutic effects as novel anti-ulcer drugs.

In addition to the above-mentioned MPDD, the following compounds can be exemplified as compounds belonging to general formula I.

2-(4-dimethyl-6-pentenyl)-4,6-dimethyl-1,6-dioxane 2-(4-methyl-6-pentenyl)-6-methyl-1
,3-dioxane 2-(4-methyl-6-pentenyl)-2,6-dimethyl-1,6-dioxane 2-(4-methyl-6-pentenyl)-2-ethyl-4
-Methyl-1,6-dioxane By the way, this M P D D and its related compounds are:
Since it is a liquid product, when used clinically as an oral drug, it can be used as is, except for soft capsules that can be filled with liquid.
Therefore, in order to use it as a powder or granule, it is necessary to adsorb it on an excipient that is acceptable for use in pharmaceutical production and to make it powder. However, the present application M
It has been found that when PDD and its close derivatives are powdered using currently commonly used excipients, their decomposition progresses over time, making it difficult to formulate them into formulations. The inventors of the present application have conducted various studies with the aim of creating a stable formulation of this compound. As a result, the M P D D and its approximate derivatives can be prepared using excipients that have been made alkaline by treatment with a base in advance. The present invention was completed based on the discovery that no decomposition occurs over time when the powder is pulverized using the following method.

The present invention uses generally accepted excipients such as synthetic aluminum silicates.

Avicel, Neusilin, Arkamatsu, Thyroid, β
- Cyclodextrin and L-glutamine alone,
Alternatively, any mixture of these can be treated with a basic substance that is allowed for pharmaceutical use, such as a basic amino acid or an inorganic base, and the resulting basic excipient can be used. The MPDD of the present application and its approximate derivatives are powdered and formulated using a conventional method. Examples of the above-mentioned basic amino acids include lysine and arginine, and examples of inorganic salts that are allowed to be used in pharmaceutical production include Na
f(003, Na2003, Na0L(, KOH.

Examples include KHCO3 and 2CO3.

As a specific example of the basic treatment method, in the case of the above-mentioned basic amino acid, it is excipiented so that the abrasive content of the amino acid is in the range of about 5 to 50%, depending on the properties of the excipient used. Alternatively, when an inorganic base is used, a suitable solution of the inorganic base of about 0.05 to 0.5 N, such as an aqueous solution, is prepared, and this solution is mixed into an appropriate excipient. In addition to the above, methods include 1) drying after increasing the H value to approximately 8 or higher.

The oral preparation containing MPDD or a close derivative thereof produced by the method of the present application hardly causes decomposition over time,
Moreover, the effectiveness as a drug is not impaired even if it is delayed. Table 1 shows the results of measuring the residual rate (%) of hIP 1) 1) immediately after formulation and one week after formulation for each of the oral preparations 1 to 5 obtained in Examples 1 to 5 below. be. As a control, in Example 1, the formulation was prepared using synthetic aluminum silicate without L-arginine treatment'> M P D D residual rate (%)
It is.

Table 1 Examples of the present method are listed below.

[Example 1] 1 g of L-arginine and 150 ml of purified water were added to 6 g of synthetic aluminum silicate, mixed for 1 hour, distilled off under reduced pressure, and the residue was crushed and dried at 40°C for 2 to 6 hours. A product whose drying loss met the specifications was obtained. This basic-treated synthetic aluminum silicate was mixed in the following barrel method to form a powder.

M F' D -1) ・・・・・・・・・・・・・・・
・ 400 da km rationally synthesized aluminum silicate ・
・・・・・・609tsu milk Kinuta ・・・・・・・・・−・・・＋
@1209 Avisel ・・・・・・・・・・・・・・・
- 180i1v [Fruit bait example 2] In Example 1, 2.0 g of thyroid was used instead of the synthetic aluminum silicate, and 450 da of L-arginine was used for the basic treatment in the same manner as in Example 1. Formulated into powder.

MI'DD 400M1 Basic treated thyroid 627mg milk Moe 400 Da [Example 6] Example 10 Alkamatsukuro, Og instead of synthetic aluminum silicate Using Alkamac, which had been subjected to basic treatment according to the method of Example 1, the following formulation was mixed to form a powder.

MPDD 400q Salt 4-treated Alkamatsu ・・・・・・・・・ 154
Milk Tong 500q Abyssel ・・・・・・・・・・・・ 180 ■ [Fruit (
f+Ii Example 4] Example 10 Using 2.0 g of neusilin instead of synthetic aluminum silicate, L-arginine 450! The mixture was subjected to basic treatment according to '4 and mixed into powder according to the following formulation.

M P D D ・・・・・・・・・ 400 dabasically treated neucilin ・・・・・・ 1574 Lactose ・・
550 mg [Example 5] Synthetic aluminum silicate, 6 g, o, 1N Naf (C
Add 16 ml of O3 aqueous solution and stir for 1 hour. This is suction filtered and the residue is dried at 50°C for 2 to 3 hours.

This powder was mixed according to the following formulation to form a powder.

tvfP D D-・-・・・400my Salt-treated synthetic aluminum silicate... 6609″j4J Sugar 120q Avicel ・・・・・・・・・ 180q Patent consultant
Kotobuki Pharmaceutical Co., Ltd.

Claims (1)

[Claims] and 1 (wherein, R1 is ■ or CH3, and 2 is H9OH3
or C2H5, respectively. 1,3-dioxane derivative represented by ) is prepared into an oral preparation by a conventional method using an excipient made basic with a pharmaceutically acceptable inorganic base and/or a basic amino acid. Methods for formulating stable oral drugs. 1