WO2003059344A1 - Suppositories containing indole derivative - Google Patents

Abstract

As the results of discussions aiming at develop suppositories containing (±)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, it is found out that this compound might induce an urge to defecate of a patient because of having an effect of stimulating the rectum. Since a preparation inducing an urge to defecate would exert undesirable effects on patients’ QOL, it is hardly usable for medical purposes. Thus, it is intended to provide suppositories of the above compound having an excellent COX-2 selective inhibitory effect with little stimulation on rectum. It is found out that the above object can be achieved by providing suppositories which contain (±)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid together with a fat-soluble high-melting point suppository base and a light silicic anhydride.

Description

 Specification

 Suppositories containing indole derivatives

 Book: The description is based on (Sat) -1,8-Jethyl-1,3,4,9-tetrahydropyrano [3,4-1b] indole-11-acetic acid (hereinafter referred to as Compound A) or its optical activity The present invention relates to a suppository of the body, or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter, referred to as compound A, etc.).

 Background technology

 At present, many non-steroidal analgesic * anti-inflammatory drugs (NS AIDs) are known, and not only oral preparations (eg, tablets, shellfish granules, powders) but also rectal preparations are used. Have been.

 In general, rectal administration can reduce drug degradation and metabolism compared to oral administration.

(2) It is less likely to cause side effects such as gastrointestinal disorders, (3) Suitable for infants and the elderly who have difficulty in oral administration, and (4) It is not affected by diet. It is commonly used as

 However, compound A (Biol. Pharm. Bull., 17 (1 2), 1577- 1583 (1 9), known as NSAIDs, which is characterized by selective inhibition of COX-2. 94) etc.), oral preparations (anchoring agents, capsules, etc.) are only outstanding, and rectal preparations are not on the market.

 Disclosure of the invention ·

 Investigation was conducted with the aim of developing a suppository containing Compound A, and it was found that Compound A had a rectal stimulating effect, which may cause a patient's inconvenience. Formulations that induce bowel movements have a negative impact on the patient's quality of life and are difficult to use as medicines.

 An object of the present invention is to provide a suppository having less rectal irritation, such as compound A having an excellent COX-2 selective inhibitory action.

As a result of intensive studies, the present inventors have found that, by formulating a suppository containing Compound A and the like, an oil-based high melting point suppository base and light caffeic anhydride are blended to obtain the above-mentioned compound. The inventors have found that the target can be achieved, and completed the present invention.

 As the present invention, for example,

 (1) Fatty and oily high melting point suppository base, light caffeic anhydride, and. (Sat) 1-1,8-ethyl-1,3,4,9-tetrahydropyrano [3,4-1b] indole A suppository comprising 1-acetic acid or an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate of any of them;

 (2) The suppository according to (1), wherein the oleaginous high melting point suppository base is glyceride 髙 melting point suppository base.

 (3) Glyceride-The glyceride in the melting point suppository base is a mixture of mono-, di-, and tri-glycerides, and one to three acyl portions of each such glyceride are the same. Or differently, a suppository according to (2), which is a fatty acid residue having 8 to 20 carbon atoms.

(4) The suppository according to any of (2) or (3), wherein the glycerol-melting point suppository base has an iodine value of 5 or less.

 (5) The suppository according to any one of (2) to (4), wherein the glyceride high melting point suppository base has a hydroxyl value of 50 or less.

 (6) The suppository according to any one of (1) to (5), wherein the compounding ratio of the oleaginous 髙 melting point suppository base is 5% by weight to 50% by weight.

 (7) The suppository according to any one of (1) to (6), wherein the light caffeic anhydride is a hydrophilic light caffeic anhydride.

(8) The suppository according to any one of (1) to (7), wherein the light silicic acid is light silicic acid having a specific surface area of 50 to 400 m ² Zg.

 (9) The mixing ratio of the light keic anhydride is 0.1% by weight to 5% by weight. /. (1)

A suppository according to any one of to (8),

Can be mentioned.

 Examples of the “pharmaceutically acceptable salt” according to the present invention include an alkali metal salt such as a sodium salt and a potassium salt, and an alkaline earth metal salt such as a calcium salt. Examples of the “solvate according to the present invention” include hydrates and ethanol solvates.

In the present invention, "oil-based high melting point suppository base" refers to the rectal body temperature of general healthy adults. Oil-based suppository base having a higher melting point (above about 37.0 ° C); glyceride 髙 melting-point suppository base (oil-based high-melting-point suppository base containing glyceride as a main constituent) ) Is preferred. Glycerides--Each glyceride in the melting point suppository base is a mixture of mono-, di-, and triglycerides of the same or different fatty acids having 8 to 20 (preferably 12 to 18) carbon atoms. It is desirable.

The glyceride 髙 melting point suppository base preferably has an iodine value of 5 or less, more preferably 3 or less. The glyceride high melting point suppository base preferably has a hydroxyl value of 50 or less, more preferably 30 or less. For example, Witepsol (registered trademark, the same shall apply hereinafter) E-85, Witebsol E-75, Witepsol E-76, Witebsol H-ί85, Witepsol 1-1-37, Witebzole 42-42 (above, SASOL Ge) rmany GmbH), Famasol (registered trademark) A-105 (manufactured by NOF Corporation), Novata (registered trademark, the same applies hereinafter) C, Novata D (above, manufactured by Henkee 1), Sabosia (registered trademark, hereinafter the same.) B, Saposaia BM, Sabosaia BML, Saposaia BS _2, Sabosaia BS ₂ X, Sabosaia BT, Sabosaia BP, Saposaia C, Saposaia CM, Saposaia CS _2, Saposaia CS ₂ X, Saposaia CT, Saposaia D, Sabosia DM, Saposia NB and Saposia NC (all manufactured by GATTEFOS SE).

 The “oil-based 髙 melting point suppository base” may contain a pharmaceutically acceptable additive. Examples of such additives include phospholipids (lecithin), nonionic surfactants (polysorbates), beeswax, and ethoxylated cetyl stearyl alcohol. The amount of such additives in a suppository is suitably 10% by weight or less.

The mixing ratio of the oily high melting point suppository base in one suppository varies depending on the type of suppository base used and the presence or absence of other additives, but is preferably 5% by weight to 50% by weight, and 8% by weight. % To 40% by weight is preferred. It is more preferably from 10% by weight to 35% by weight. In the present invention, the “light silicic anhydride” refers to silicic anhydride having a large specific surface area among silicon dioxides, and high purity is preferred. The light caustic anhydride may be hydrophilic or kneaded, but hydrophilic light caustic anhydride is preferred! /. Ma In addition, the specific surface area of the light acid anhydride is preferably 50 to 400 m ² / g, more preferably 100 to 300 in ² / g. For example, aerodinore (registered trademark, manufactured by Nippon Aerosil Co., Ltd.), carplex (registered trademark, manufactured by Shionogi & Co., Ltd.), siloide (registered trademark, manufactured by Fuji Siricia Chemical Co., Ltd.), Ad Solider 101 (registered trademark, Freund) Sekisui Co., Ltd.) and light caustic anhydride (manufactured by Tokuyama Corporation).

 The blending ratio of light caieic anhydride in one suppository varies depending on the type of suppository base used and the presence or absence of other additives, but it is preferably 0.1% by weight to 5% by weight. % To 3% by weight is preferred. More preferably, it is 0.5% by weight to 2% by weight. The amount of compound A and the like contained in the suppository according to the present invention is desirably set in consideration of the patient's condition such as the degree of illness, age, and body weight. Any amount can be achieved as long as it is achievable. Usually, in a suppository, 10 to 100 mg is appropriate, preferably 20 to 800 mg, and more preferably 30 to 600 mg. It is.

The suppository of the present invention can be produced by a general production method such as a melting method and a compression molding method. In other words, the raw materials such as Compound A and other oily high melting point suppository bases, light caffeic anhydride, and commonly used suppository bases should be melt-mixed in advance, put into a mold, cooled and solidified before molding. Thus, the suppository of the present invention can be produced (melting method). Raw materials such as compound A and other oily high melting point suppository bases, light caffeic anhydride, and commonly used suppository bases are mixed, and granulated to form a compact. Thereby, the suppository of the present invention can be produced (compression molding method). The shape of the suppository according to the present invention is not particularly limited as long as it can be administered as a suppository, and examples thereof include a conical shape, a spun shape, a spherical shape, and an oval shape. The suppository of the present invention may optionally contain pharmaceutically acceptable additives. Such additives include, for example, stabilizers (eg, citrate, ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole), preservatives (eg, paraoxybenzoic acid esters), emulsifiers (eg, gum arabic, Cholesterol, polyoxyl stearate 40, sonolebitan sesquioleate, polysorbate 80, sodium laurinolate sulfate, medicated soap, sucrose'fatty acid esters), suspending agents (eg, gum arabic, sodium alginate, methylcellulose, carbohydrate) Xymethylcellulose sodium, polyvinylpyrrolidone, polysorbate 80, tragacanth, aluminum monostearate, fats and oils (animal and vegetable fats and oils (eg, olive oil, corn oil, castor oil, cottonseed oil, cotton germ oil, wheat germ oil, cacao oil) , Beef tallow, lard, wool fat, turtle fat, squalane, hardened oil), mineral oils (eg, petrolatum, solid paraffin, liquid paraffin, dehydrated lanolin, silicone oil), waxes (eg, jojoba oil, carnauba wax, beeswax) , Lanolin)), solubilizers (eg, propylene glycol, benzyl alcohol), pi-I regulators (buffers), consistency improving additives or provide a homogeneous distribution of activated food in the base Auxiliaries, other, polyethylene glycol, polyoxyethylene alcohol, purified water It is possible 举Geru. The amount of the powerful additive in the suppository is suitably 20% by weight or less.

 Best form to carry out the invention

'Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples. It goes without saying that the present invention is not limited to the following examples.

Example 1

 Compound A 3 5 mg

 Dipuchi / Lehi Droxito Nolen 2 mg

 Butylhydroxydisole 0.16 mg

 Aerozil 2 0 0 2 O m g

 Huitebzonole E— 8 5 2 9 O mg

 Ui _ tebusol H-5

 2 g in total

 In accordance with the above suppository formulation, ditebsol E-85 and ditebsol H-5 were stirred and melted at about 50 ° C, then cooled to about 45 ° C, and stirred while diptylhydroxytoluene and butylhydroxyani were added. Sole, aerosil 200 and Compound A were sequentially added and mixed well in each case, and then, at about 40 ° C, suppository containers were filled in 2 g portions, cooled, and solidified to obtain the composition of the present invention. A suppository containing Compound A was obtained.

Example 2

 Compound A 3 5 mg

Diptyl hydroxytoluene 2 mg Petit Nolehi Droxyanisonore 0.16 mg

 AEROSIL 200 15mg

 Witebsol E—85 290 mg

 A _tebusol H-5

 2g in total

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Example 3

 Y Dagger Compound A 35mg

 Diptinolehi droxytonoreen 2 mg

 Butyl hydroxyanisole 0.16mg

 Akorozir 200 25mg

 Witebsol E— 85 29 Omg

 Witepzo Mono H- 5— _

 2 g in total

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Example 4.

 Compound A 35mg

 Dibutyl hydroxytruene 2mg

 Petilhi-Droxydisole 0.16 mg

 Aerodil 200 2 Omg

 Pharmazono A- 10.5 29 Omg

 Pharmazonore B— 05

 Total? g

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Example 5

Compound A 35mg Diptyl hydroxytoluene 2 mg

 Butynole hydroxyazole 0.1 "6mg

 Aerozil 200 2 Omg

 Saposir CM 65 Omg

 Saposir A IM

 2 g in total

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Example 6

 Compound A 35mg

 Dibutyl hydroxytoluene: 2mg

 Butylhydroxydisole 0.1 6mg

 Aerodil 200 2 Omg

 Witepzo Mono E-75 65 Omg

 Nopta 299

 2 g in total

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Example 7

 Compound A 20 Omg

 Diptinole hydroxytonoreen 2 mg

 0.16 mg

 Aerozil 200 2 Omg

 Huitebzonole E— 8 5 2 7 Omg

 D-Tepzonore H-5

 2 g in total

 The compound A-containing suppository according to the present invention was obtained according to the above-mentioned suppository formulation and according to Example 1 below.

Comparative Example 1 (Control) Diptyl hydroxytoluene 2 mg

 Petilhi Droxia Sonole 0.16mg

 Aerozil 200 2 Omg

 Zitebzonore E -85 29 Omg

 Quitepsol H-5.

 2 g in total

 According to the above suppository formulation, a control mouth suppository was obtained according to Example 1 below. Comparative Example 2

 Compound A 35mg

 Dibutinole hydroxytoluene 2mg

 Butinorehydroxydisole 0.16 mg

 Witebsol H— 5 qs

 2 g in total

 According to the above suppository formulation, a suppository containing Compound A was obtained according to Example 1 below. Comparative Example 3

 Y Dagger Compound A 35mg

 Diptyl hydroxytoluene 2 mg

 Puchinore hydroxyanisonore 0.16mg

 Witepzo Mono E-85 29 Omg

 Weitebsol H— 5 _

 2 g in total

 According to the above suppository formulation, a suppository containing Compound A was obtained according to Example 1 below. Comparative Example 4

 Compound A 35mg

 Dibutyl hydroxytoluene 2 mg

 Butynole Hydroxydisole 0.16mg

 Aerodil 200 2 Omg

 Witepzo Mono H- 5

2 g in total According to the above suppository formulation, a suppository containing Compound A was obtained according to Example 1 below.

Test Example 1 Irritation evaluation

 Each suppository of Example 1, Example 2, Example 3, Comparative Example 1, Comparative Example 2, and Comparative Example 3 was rectally administered to one group of 10 male beagle dogs aged 2 to 5 years fasted for 40 hours. Defecation was observed immediately after administration until 6 hours after administration, and used as an index of local irritation. In other words, a formulation with a smaller number of defecations has less local irritation. Table 1 shows the results. table 1

表 1から明らかなように、 実施例 1、 実施例 2と実施例 3の坐剤は比較例 1の プラセボ坐剤と同様な排便率を示し、 比較例 2、 比較例 3、 比較例 4の坐剤に'比 ベて排便率が低くつまり局所刺激性が少ないことがわかった。

As is clear from Table 1, the suppositories of Example 1, Example 2 and Example 3 show the same defecation rate as the placebo suppository of Comparative Example 1, and the suppositories of Comparative Example 2, Comparative Example 3, and Comparative Example 4 It was found that the defecation rate was lower than that of suppositories, that is, local irritation was less.

Test example 2 Absorption evaluation

Using a group of three 1-year-old male beagle dogs fasted for 0 hours, the suppository obtained in Example 7 was rectally administered.For comparison, one tablet orally containing a commercially available oral preparation containing 200 mg of compound A was orally administered. Blood was collected at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after each administration, and the obtained plasma was subjected to a predetermined pretreatment, and the plasma compound A was The concentration was quantified by the HPLC method. The results are shown in Table 2 and FIG. ■ Table 2

表 2及び図 1からわかるように、 本発明坐剤は錠剤に比べ Cmaxが高く、 T maxが短いことより、 臨床的にも有用であることが示唆された。

As can be seen from Table 2 and FIG. 1, the suppository of the present invention has a higher Cmax and a shorter Tmax than the tablet, suggesting that it is clinically useful.

 Industrial applicability As described above, in the formulation of suppositories containing compound A having rectal irritation, etc., the combination of an oily high melting point suppository base and light In addition, it is possible to provide a suppository containing Compound A or the like, which can reduce rectal irritation and improve QOL of patients.

 Brief explanation of drawings

 FIG. 1 shows the results of plasma concentration measurement comparing the absorbability of a suppository of the present invention and a commercially available oral preparation containing Compound A. The vertical axis represents the plasma concentration of compound A (μg / mL), and the horizontal axis represents time (hours). One and one are the test results of the suppository of the present invention. Represents the test results.

Claims

The scope of the claims 1. Fatty oil-based high melting suppository base, light caffeic anhydride, and (Sat) 1,1,8-Jethyl-1,3,4,9-tetrahydropyrano [3,4-b] indole-1-acetic acid or the like A suppository comprising an optically active substance, or a pharmaceutically acceptable salt of any of them, or a solvate of any of them.  2. The suppository according to claim 1, wherein the oleaginous high melting point suppository base is a glyceride high melting point suppository base.  3. Glyceride—Melting point suppository group The glyceride in lj is a mixture of mono-, di-, and triglycerides, wherein one to three acyl portions of each such glyceride are the same or different, 3. The suppository according to claim 2, wherein the suppository is a fatty acid residue having the number of 8 to 20. 4. The symmetric according to any one of claims 2 or 3, wherein the glyceride-melting point suppository base has an iodine value of 5 or less.  5. The suppository according to any one of claims 2 to 4, wherein the glyceride 髙 melting point suppository base has a 7j acid value of 50 or less.  6. The suppository according to any one of claims 1 to 5, wherein the compounding ratio of the oil-based 髙 melting point suppository base is 5% by weight to 50% by weight.  7. The suppository according to any one of claims 1 to 6, wherein the light caffeic anhydride is hydrophilic light caffeic anhydride. 8. light anhydrous Kei acid is light anhydrous Kei acid having a specific surface area of 50 to 400 m ² Zg, suppositories according to any of claims 1-7.  9. The suppository according to any one of claims 1 to 8, wherein the blending ratio of the light caffeic anhydride is 0.1% by weight to 5% by weight.