JPH04187636A - Narcotic preparation - Google Patents

Abstract

PURPOSE:To provide a hollow suppository narcotic preparation containing a sustained-release narcotic preparation and powdery morphine and having quick activity as well as sustained activity. CONSTITUTION:A sustained-release narcotic preparation is mixed to a base for the preparation of suppository and powdery morphine free from particular sustained-release treatment is sealed in the hollow part of a hollow sustained- release preparation. The sustained-release preparation is formed to a desired pharmaceutical form. The sustained-release preparation is preferably a morphine- containing preparation effective as an analgesic for terminal cancer. The weight ratio of the sustained-release preparation to the powdery morphine is 1:(1-10), preferably 1.0:(1.0-2.0).

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to narcotic preparations, and more particularly, to a hollow powder containing a sustained-release narcotic preparation and powdered morphine, which has an immediate effect and a long-lasting effect. Concerning narcotic preparations having both properties.

[Prior art and inventions or problems to be solved] It is one of the important duties of medical care to relieve patients from various diseases and the pain that accompanies them. The biggest challenge in terminal medical care is to alleviate the symptoms and make the life of the patient as easy as possible. Various types of narcotic preparations are most commonly used to alleviate such pain or severe pain. Nowadays, sustained release oral narcotic formulations are provided to reduce the burden on victims associated with drug administration. However, depending on the location of the lesion, oral administration may not be possible. In addition, they are often in a difficult state to grieve. Moreover, in most cases, the pain is unbearable, so a drug with immediate effects is required. Thus, the ideal formulation for analgesic treatment, such as for terminally ill patients, is an immediate and long-acting narcotic formulation that can be administered to patients in all situations.

"Means for Solving the Problems" The present inventors have worked diligently with the aim of developing a narcotic formulation that can be administered to patients who have difficulty in administering it orally, and that has both immediate and long-lasting effects. As a result of repeated research, we have found that by incorporating a sustained-release narcotic preparation and powdered morphine into a hollow powder, the blood concentration increases extremely quickly and the blood concentration remains constant over a long period of time. The present invention has been completed based on the discovery that a narcotic preparation can be obtained that provides the following effects.

That is, the present invention provides a hollow skewered narcotic formulation containing a sustained release narcotic formulation and powdered morphine.

In the present invention, powdered morphine means morphine that has not been subjected to any special sustained release treatment, and also includes its salts, such as hydrochloride, sulfate, and acetate.

The preparation of the present invention may contain any sustained-release narcotic preparation, and most preferably a preparation containing morphine, which is effective as an analgesic for terminal illness. Various sustained-release morphine formulations are commercially available, and as long as rectal administration is possible, they can be used as such in the formulations of the present invention. The ratio of morphine to powdered morphine in the sustained release narcotic preparation used for formulation is in the range of 1:1 to 110 by weight;
．． 0: It is preferable that it is 1.0-20.

When preparing the second formulation of the present invention, a sustained-release preparation was mixed into the J base for making the powder, and powdered morphine was poured into the hollow part of the hollow powder. (eg, the formulation shown in FIG. 1).

The base can be selected from those commonly used in the production of powders]
There are many choices; for example, cocoa butter can be cited. Semi-synthetic tricrycerite is particularly preferred. In addition, a method for producing a hollow-type powder is known, and has been reported by Matsumoto et al. The formulation of the present invention has an oleaginous base W as described in the Examples below.
It was prepared according to the method of Matsumoto et al. using equivalent amounts of i tepsol (witenopzole) H-1,5 and Witepsol E-75 (Maruishi Pharmaceutical). However, it will be understood by those skilled in the art that the present invention is not limited to a specific manufacturing method, but also includes preparations prepared by other hollow-type powder manufacturing methods. .

[Effect] The narcotic preparation of the present invention contains a sustained-release narcotic preparation and powdered morphine, so it shows a rapid effect with a single administration to the rectum and remains effective for a long period of time.

The present invention will be explained in more detail with reference to Examples below.

Example 1 Morphine-containing powder Witepsol H-15 (Maruishi Pharmaceutical)] Oy and Wi
tepsoIE-75 (Maruishi Pharmaceutical) 109 and 40-4
Heat and melt at 5°C. A portion of the obtained /fl liquid was approx.
711IC was injected into a plastic container with a volume of 12.25IQ, and the morphine-containing sustained release preparation "MS Contin,"
Shionogi & Co.] Inject 1 tablet (morphine sulfate: 10 myy) and immediately attach a hollow skewer plug. After leaving for about 1 hour at room temperature, the plug is pulled out and the formed hollow part is filled with 10 m9 of morphine hydrochloride powder. Next, a cloudy lawn-like base is filled so that the total volume of the powder is 2.25 rrlQ, and the mixture is left to stand at room temperature for about 1 hour to solidify and mold (FIG. 1C).

Changes in blood morphine concentration over time when the morphine-containing powder obtained in the Examples was administered to domestic rabbits were investigated using the method described in the Experimental Examples below.

1) Preparation of the formulation a) HE (immediate-release planing containing powdered morphine) WiLepsol H-] 5 and Witepsol E
-75 were respectively heated and melted at 49.40-45°C, and pulverized morphine hydrochloride 100Q was added thereto and the mixture was uniformly mixed to form a suspension. This was dispensed into a plastic container with a volume of fjL0.9vrQ, and left to stand at room temperature for about 1 hour to solidify and form 10 HE suppositories (Figure 1a).
. One powder (081 g) contains 10 mg of morphine hydrochloride.

b) MSC (sustained release powder containing sustained release morphine formulation) Witepsol H-15109 and Witepso
1 Melt E-75109 by heating to 40-45°C. The volume of the resulting mixed liquid was 1.8m12! ! 2.25mC
Pour into a plastic container and leave at room temperature for 10 minutes.

Next, 1 tablet of MS Contin (Shionogi & Co., Ltd.) (10 mq of morphine sulfate) was added, and a cloudy wax/container base was added to make the total amount 2.25 ffQ, and the mixture was left for about 1 hour on the island. Then, solidify and mold (Fig. 1b).

c) MSC-) 1 (Formulation containing powdered morphine and sustained release morphine formulation) Prepared according to the method described in Example I above.

2) Comparative Experiment Using male domestic rabbits (Japanese white breed, weight 2.6 kg), intravenous administration and rectal administration of the three types of skewers prepared in I) above were performed. Each administration experiment was separated by at least one week.

Intravenous administration: 10 mg/m2 to rabbits fasted for 48 hours
A one-shot administration of 1 mc of Q morphine hydrochloride solution into one ear vein was performed.

For rectal administration, insert 1 skewer into a rabbit that has been fasted for 48 hours.
The skewer was inserted and the anus was immediately clamped with a clip to prevent the skewer from leaking.

In either case, IWQ of blood was collected from the ear vein before and at each hour after administration, and immediately incubated at 13,000 r.m. at 4°C.
Plasma was separated by centrifugation for pmTI 0 minutes, stored frozen at -40°C, and used for analysis.

Morphine'tRW in 1 m plasma was determined by high performance liquid chromatography (HPLC) after an extraction operation was performed by adding the internal standard substance naloxoxy to 05 rn plasma as shown in the analysis steps below.

Analysis process Plasma O65 tail Q Extrelut R1 column, 3 minutes eluent HPLC HPLC conditions + (r-'LC rule 1- C-6A D Punorum TO5O1-101) S-80TM inner diameter 4 6HHX length 150 items 7 quality 40 °C Mobile phase 0015M phosphate buffer (pH 3,5) methanol (928) Flow rate ], 2 mQ/min Internal standard (I, S,): Naloquinone hydrochloride Obtained HP
An example of an LC chromatogram is shown in FIG. Figure 3 shows the time course of plasma morphine concentration when three types of skewers were administered. From the plasma concentration take, the maximum blood concentration (Cmax), Cm
The time to reach ax (T max), the in vivo half-life at the terminal part of the blood concentration (t+zz), the average residence time (
M RT ), area under the plasma concentration curve (AUG), and hyperability (BA) were determined. The results are shown in Table 1 and Figure 3 below. In Figure 3, △ is HE
,・represents MSC1○ represents MS(, -H skewer.

Table - ↓ Straw kinetic parameters of morphine after rectal administration to domestic rabbits Skewer type parameters HE M S CM S
C-H dose (IIHj/- animals) 10 1
0 20Cmax (ng/mQ) 4
6.0 59.7 142.6Tmax (m
in) 15 120 10
t1z2 (min) 288.7 276
,0 3g8.6MRT (min) 4
22.7 517.2 545.4A 'J C
Cu9・mIn/Hρ) 12.638.3 43.
98A (%) 24.8 75.3
43.2 The results in Table 1 and Figure 3 show that the MS of the present invention
Compared to the other two suppositories, the C-H skewer has been shown to provide a rapid increase in blood concentration and a frugal administration, resulting in a high blood concentration that lasts for 12 hours.

[Effects of the Invention] The narcotic preparation of the present invention causes an immediate increase in blood concentration with a single rectal administration, and maintains the high blood concentration for approximately 12 hours thereafter, and therefore is effective against cancer in terminally ill cancer patients. Very useful for the purpose of alleviating sexual pain. Usually, a single dose for an adult patient (well, the amount of morphine hydrochloride is 1O
~100m@.

[Brief explanation of the drawing]

Figures 1(a) and (b) show a conventional powder; Figure 1(c)
) shows a longitudinal sectional front view of the powder of the present invention. FIG. 2 is an HPLC chromatogram of morphine (M) using naloxosi (X) as an internal standard after extraction from plasma. FIG. 3 is a chart 7 showing the time course of the plasma concentration of morphine after administration of three types of powder to domestic rabbits. Patent applicant Isamu Horikoshi (1 other person) Representative patent attorney Aoyama Aoyama (2 others) Figure 1 Figure 2 ↓ Σ Figure 3

Claims (1)

[Scope of Claims] 1. A hollow suppository narcotic formulation containing a sustained-release narcotic formulation and powdered morphine. 2. The preparation according to claim 1, wherein the active ingredient in the sustained release narcotic preparation is morphine. 3. The formulation according to claim 2, wherein the sustained release narcotic formulation contains morphine and powdered morphine in a weight ratio of 1:1 to 1:10.