JPH0491020A - Composition for rectal administration - Google Patents

Abstract

PURPOSE:To provide a rectal administration composition capable of avoiding the first liver-passage effect of drugs as much as possible and having high absorbability by adding a thickening agent to a rectal administration composition containing a drug highly transformable by hepativmetabolic function due to the first liver-passage effect so as to give a specific viscosity. CONSTITUTION:A rectal administration composition containing a drug apt to receive the first liver passage effect, such as cytarabine (malignant tumor drug), and a base material (fat usually employed in the preparation of ointments, suppositories), especially hard fat, is mixed with a thickening agent such as light silicic acid anhydride or methyl cellulose preferably in an amount of 0.1-10% so as to give a viscosity of 50-800cp, preferably 60-150cp, at 37 deg.C, thereby permitting to avoid the first liver passage effect as much as possible, improve the absorbability of the drug and heighten the bioavailability of the composition.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention comprises a drug, a base and a thickener, and the viscosity is 3.
50~80ocP preferably 6O-150 at 7°
The present invention relates to a composition for rectal administration prepared to be cP. More specifically, 1III11 improves absorption by avoiding the hepatic first-pass effect as much as possible.
The present invention relates to compositions for administration.

[Prior Art] Many features of the rectal administration route are known compared to other routes such as injection and oral administration.

Among these, it is said that one of the major characteristics of the route from the lower U intestine is that it directly enters the vena cava, thereby avoiding the hepatic first-pass effect. However, in conventional antidepressants, the administered antidepressant dissolves I! After that, it is known to spread in a relatively short period of time and reach the upper rectum or colon.

A method to suppress this spread is disclosed in Japanese Patent Application Laid-Open No. 61-57513.
゜The former, found in Tokuko Sho 60-1281,
Heibilogoroit.

By adding (k+) o-svolimer),
The latter is one score! Adhesive properties are imparted by adding metal salts of lli acid.6 These inhibitors are intended for local action and are intended to last in one local area.

[Problem to be solved by 51 Ming] When preparing a rectally administered drug for a drug that is likely to be metabolized by the hepatic first-pass effect, the hepatic first-pass effect can be avoided by imparting adhesive properties as in the above patent; It has been desired to develop a composition for rectal administration that has improved absorption by avoiding as much as possible the liver first-pass effect, which is insufficient in terms of release and does not lead to improved absorption.

[Means for solving the problem] The present inventors have proposed a method for rectally administering preparations of drugs that are likely to be metabolized due to the anal first-pass effect, and to increase the viscosity after administration. We focused on and conducted intensive research.

As a result, at a certain viscosity, i.e. when the viscosity of the composition is 37°, 5O-800cP#T or 6O-150cP#T
It has been discovered that when a J11 composition for rectal administration prepared to have a viscosity of , completed the invention. As shown in Experimental Example 3 below, the results of an experiment in which three kinds of dye-containing inhibitors with different viscosities were administered 1r1@ to a pegle-sized amount and their spread was observed. When the administration composition is administered, il! It is thought that it remains in the middle to lower part of the intestine and is absorbed into the body from the rectum without passing through the portal vein, resulting in high plasma concentrations.

In addition, if the viscosity is lower than these, the converted product will spread from the upper rectum to the descending colon, resulting in a hepatic first-pass effect, while if it is higher, the spread will be less, so the mucosal surface that comes into contact with it will be smaller, and the release property will also be poor. It is thought that this resulted in poor absorbency.

The gist of the present invention is 5 normal i]! The viscosity can be adjusted to an appropriate level by adding a thickener to the composition for intestinal administration.

Drugs used in the present invention include acetaminophen, acetylsalicylic acid, oxyphenbutacin, pentazocine, salicylamide, and aminovirine, which are susceptible to hepatic first-pass effects; antipyretic, analgesic, and antiinflammatory agents; and antiarrhythmic agents, such as alprenolol and pindolol. ; Neuropsychiatric drugs such as imipramine and nortributyrin; Antiepileptic drugs such as diphenylhydantoin; Cardiac drugs such as isoproterenol and dopamine; Antitussive sputum drugs such as salbutamol and terbutaline; #X convulsive drugs such as butyl scopolamine bromide ; Anticancer agents such as cytarabine, fluorouracil, tegafur, mitomycin C, and pleomycin; Antibiotics such as kanamycin, fradiomycin, cephaloridine, and cephalexin, but are not limited to these II-In the present invention The bases used are oils and fats commonly used in the preparation of ointments, antiseptics, etc. Typical examples include peanut oil, coconut oil, olive oil, and soybean oil, which are derived from natural products.1. Sesame oil, corn oil, camellia oil,
Fats such as cacao fat, lard, wool fat, beef tallow, etc. are hydrogenated.

Those modified by acetylation, one-part extraction, etc., those derived from synthesis and semi-synthesis include esters of fatty acids with 12 to 22 carbon atoms and glycerol (e.g. 1 hard fat), fatty acids with 6 to 30 aI carbon atoms, etc. Examples include esters with alcohols having 2 to 8 carbon atoms, such as isopropyl myristate, glycerogelatin, and macrogols.

Particularly suitable bases include non-standard hard phantoms.

These bases may be used alone or in combination of two or more.

Thickeners used in the present invention include inorganic fine powders, such as light anhydrous silicic acid, hydrated silicon dioxide, synthetic aluminum silicate, magnesium aluminum silicate, kaolin, bentonite, calcium phosphate, calcium hydrogen phosphate, apatite, precipitated calcium carbonate,
Talc, etc.; Cellulose pile conductor 1 such as carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxyethyl cellulose, hydroxyethyl cellulose,
Hydroxypropylcellulose, Methylcellulose,
Hydroxypropyl methylcellulose, etc.; Vinyl rust conductors, such as polyvinyl alcohol, polyvinylpyrrolidone, hydroxyvinyl polymer, etc.; Metal soaps, such as aluminum, calcium, and magnesium salts of stearic acid; Naturally derived thickeners, such as pectin, sodium alginate etc. can be mentioned. The amount to be added is not particularly limited, but preferably 0.1 to 10
% Fi! If the viscosity at 37' is 3.83 s using a suitable viscosity needle, e.g.
It is added in such a way that it becomes 50 to 800 cp, preferably 60 to 150 cp, as measured by ec'□I.

In the present invention, an absorption enhancer, an antioxidant, an inorganic powder, a preservative, an excipient, a buffer, and the like may be added as appropriate.

The dosage form obtained in the present invention may be in the form of anal analgesics that remain solid at room temperature and melt at body temperature, or may be in the form of a suspension or ointment dispersed in a wavy oily base. Fill soft capsules for administration or
Alternatively, it may be in a dosage form that is administered at the time of use using a syringe for rectal administration.

These methods are based on the well-known manufacturing method for ointments, antiseptics, etc., in which a base is heated and melted, a drug is added to it, mixed and stirred, a thickener is added to the base, the mixture is dispersed uniformly, and the mixture is filled or molded. It can be prepared.

[Effect of the invention] iI of the present invention! When the composition for intestinal administration was administered rectally, the melt spread moderately, ie, stayed in the middle to lower part of the rectum, thereby improving absorption by avoiding the first-pass effect of the liver.

[Example] Examples of the present invention are shown below.

Example 1 Wif Sole 11-15 (!am mark, Mitsuba'y
es7 hard fat) 92.8+: 45℃
Add 5 g of molten cytarabine and polyoxyethylene lauryl ether BL-9EX (registered trademark 0 Nikko Chemicals; diurnal lauromacrogol) and mix. 3. Next, add Erosil 200 (registered trademark, Nippon Aerosil; diurnal). Light anhydrous silicon!1) Add O-2K and disperse uniformly. This was dispensed into approximately 2 L suppository molds while stirring, and after being left to cool, a cytarabine inhibitor was obtained.

Viscosity: 110.9 cp, (37°) Example 2 After melting Witepsol 11-15 (registered trademark, Mitsuba Boeki: Hard Fat) 92x at 45°C.

Add 5 g of cytarabine and BL-9EX (registered trademark 0 Nikko Chemicals; diurnal lauromacrogol) 2z, which is polyoxyethylene lauryl ether, and mix and stir. !!Ri 1: was added and dispersed uniformly. This was dispensed into a suppository mold for about 2 g while stirring, and after being allowed to cool, a cytarabine inhibitor was obtained.

Viscosity: 763 cp, (37°) Example 3 Cytarabine 5 and [1L-9EX 2C were dissolved in a separately prepared 2,5z Metro1s 5M100 (registered trademark, Shin-Etsu Chemical; diurnal methylcellulose) PBS aqueous solution. The volume was then adjusted to 100 μl to obtain a cytarabine MC aqueous solution. Viscosity: 9f3.4cp, (37') Example 4 Cytarabine 5g and BL-9EX 2. 3.25% Metrose 5M100 (registered Oa
, Shin-Etsu Chemical; Diurnal Methyl Cellulose) After dissolving in PBS aqueous solution, the volume was adjusted to 100 ml to obtain a cytarabine MC aqueous solution. Viscosity: 198.5cp, (37°
) Comparative Example 1 Witepsol 11-15 (registered trademark, Mitsuba Trading; Hard Fats) 93.0. After melting at 45° C., 2 g of ether BL-9EX (Uroku Trademark 1 Nikko Chemicals; diurnal lauromacrogol) was added and mixed with stirring. After uniformly dispersing the mixture, the mixture was poured into a mold for about 20 minutes with stirring, and after being allowed to cool, a cytarabine inhibitor was obtained. Viscosity: 37.6 cp, (37°) Comparative Example 2 Cytarabine 5 and BL-9EX 2 were added to P[lS?
After dissolving in 8 waves, the volume was adjusted to 100 ml to obtain an aqueous cytarabine solution. Viscosity: 8.8 cp, (37°) Experimental Example 1 Example 1, 2 and Comparative Example 100 B/doc was applied to 4 male peagles weighing 10 to 12 kg, which were exposed to the cytarabine inhibitor prepared according to I for 36 hours. Blood was collected from the vein of the forelimb over time, and the plasma obtained by a conventional method was subjected to deproteinization with 4:1 trichloroacetic acid.
Cytarabine in plasma was quantified by LC method. From the obtained plasma concentration, the area under the hemostatic concentration curve [^UC0-8h
r (μg-hr/ml)] was determined. The results are shown in Table 1.3 and Figure 1.

Cytarabine 5 and Polyoxyethylene Lauryl Experimental Example 2 The cytarabine solutions prepared according to Example 3.4 and Comparative Example 2 were counterfeited according to Experimental Example 1. The results are shown in Table 2.
Shown in 3.

HPLC conditions Column: Nucleosyl 10SA 4.6x250 Mobile phase: 0.05M ammonium formate (PI+4.
5) Column temperature: 40°C Flow Ek: 1. Oml/sin Detection wavelength: tlV280 Table 1 Change in plasma concentration of cytarabine after ill intestinal administration (
μr/wear]) Time aσ Comparative Example 1 Example 1 Example 2 15 minutes
153 30 minutes 1,71 1 hour 1.51 2 o'clock 11fl 1.08 2.25 2. (15 3,102,35 3,102,07 2,171,88 3 hours 4 hours 6 hours 8 hours 0.73 0.35 0.09 n, d.

1.28 0.66 0.19 0.02 1.05 0.60 0.14 0.06 Table 2 Changes in plasma concentration of cytarabine after rectal administration (μ/ml 1 hour 15 minutes 30 minutes 1 hour 2 Time 3 o'clock til1 4 hours 6#lIO 3 hours Comparative example 2 2.03 2.12 1.72 0.98 0.50 0.26 0.08 n, d.

Example 3 3.35 3.41 2.69 1.62 0.84 0.50 0.15 0.05 Example 4 2.16 2.49 2.11 1.24 0.75 0.41 0. 14 0.02 Table 3 Pharmacodynamic parameters after rectal administration of cytarabine Example N.

C++ax (1 to μl) T-en asu (h ``) ^1c [o-8hr co (μ g-hr/ugly l) It turned out to be a special composition.

Experimental Example 3 The following three types of iA-containing suppositories with different viscosities were prepared, and one suppository of each was administered rectally into a Pegle-sized amount, and 45 minutes later, the suppositories were dissected and the portion from the rectum to the descending colon was removed and incised. The spread of the dye was observed.

Comparative example 1 1.711 0.58 4.70
Example 1 3.36 0.63 8.87 Example 2 2.66 0.88 6.92 Comparative Example 2 2.15 0.44 4.61 Example 3 3.48 0.38 7.71 Example
4 2.54 0.75 5.951
L M
H color lA (Blue No. 2) 5m to 5 stirrups
Erojil 200 - 4++ (20+
+ (As shown in Tables j-3, cytarabine, an absorption enhancer and a base with the addition of a thickener (composition for rectal administration according to the invention 7 Examples 1.2 and 3-4) The displacement +111w1 from the rectal injection part to the upper part, which shows better absorption from the rectum than those without adhesive (Comparative Examples 1 and 2), was determined and shown in FIG.

Claims (1)

[Claims] The composition contains a drug, a base and a thickener, and the viscosity at 37° is 50 to 800 cP, preferably 60 to 150 cP.
1. A composition for rectal administration, characterized in that it is prepared to have the following properties.