JPH06239746A - Sustained release preparation of morphine - Google Patents

Abstract

PURPOSE:To obtain a sustained release preparation capable of stably maintaining concentration of morphine for a long period of time by changing kinds and thickness of coating of each microcapsule and successively dissolving microcapsules. CONSTITUTION:This sustained release preparation of morphine is obtained by coating a solution of morphine with a contrast medium, an amino acid, a starch or a higher alcohol to give microcapsules, blending the microcapsules with a sodium chloride injection, an artificial spinal fluid or a local anesthetic solution and is injected to spinal subarachnoid cavity or epidural space. This preparation is applicable even to a patient incapable of taking orally.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for persistent pain, that is, a morphine sustained-release preparation which is administered to eliminate persistent severe pain mainly found in end-stage cancer patients.

[0002]

2. Description of the Related Art Intense pain that appears in many end-stage cancer patients lasts for a long period of time and, in addition, disturbs sleep of the patient, lowers appetite, and promotes weakness. Therefore, morphine has been conventionally used as a pain killer in patients. However, if the dose of this morphine is small, a sufficient analgesic effect cannot be obtained, or even if it is obtained, it disappears in a short time. Conversely, if the dose is increased too much, the analgesic effect increases, and the duration of the effect is 6-.
Although it can be extended to 8 hours or longer, it has effects other than the analgesic effect of morphine and increases side effects such as drowsiness and respiratory depression. For this reason, many clinical experiments have
It was revealed that hourly oral administration had the best balance.

However, the patient and his / her family should take it every 4 hours.
In addition, it is quite inconvenient for medical staff, and the administration at night is extremely burdensome. Therefore, 12
An oral sustained-release agent for morphine sulfate has been developed that can maintain the plasma concentration of morphine over time (eg, Shionogi Pharmaceutical MS
Contin tablets etc.). This sustained-release tablet is a mechanism in which when hydrated water is absorbed in the digestive organs, morphine sulfate is dissolved inside the tablet and gradually released outside the tablet. Three times the dose of the above-mentioned morphine aqueous solution is administered every 12 hours. However, since the maximum blood concentration thereof is slightly higher than that of the single administration of the morphine hydrochloride aqueous solution once, and the decrease thereafter is gradual, the effective blood concentration is maintained for 12 hours. As a result, there are advantages that not only restrictions on patients are reduced, good night sleep is obtained, but also a burden on medical staff is reduced.

[0004]

However, the oral morphine sulfate sustained-release agent has a drawback that it has a duration of only 12 hours and cannot be used in patients who cannot take it orally.
In view of the above problems, it is an object of the present invention to provide a morphine sustained-release preparation that can maintain a stable morphine plasma concentration for a long period of time, for example, about 100 days by a single injection.

[0005]

To achieve the above object, the morphine sustained-release preparation of the present invention comprises a microcapsule coated with a morphine solution, and the microcapsule is placed in the spinal subarachnoid space or epidural space. And a solution for injection. This morphine solution may be of any kind as long as it is a solution containing morphine sulfate, morphine hydrochloride, and other morphine, and the coating containing the morphine solution is a contrast agent or an amino acid or starch or higher alcohol or the like. Is physiological saline, artificial spinal fluid, local anesthetic solution, or the like. The microcapsules have a size of 100 μm or less, and contain morphine sulfate in an amount of 1.5 to 4.5 mg, and are coated with a nonionic contrast agent, iofendilate, or the like. It is mixed in a solution such as saline and administered to the spinal subarachnoid space using a 25 gauge (0.5 mm diameter) Rumbal needle (for spinal anesthesia).

At this time, for example, by changing the coating thickness (iofendrate, etc.) of each capsule, or by changing the type, the time until each capsule is dissolved in the solution is changed, and the capsules are immediately dissolved. It is possible to provide sustained release of morphine at a constant concentration for a long period of time as a whole by preparing various capsules from various types to capsules that dissolve after a long time. It has been known in the anesthesiology area that this subarachnoid administration of morphine is effective for pain relief after surgery, but the present inventor has found that subarachnoid administration of sustained release morphine is also useful for cancer pain. Therefore, compared to conventional intravenous administration, intramuscular administration, and oral administration, it has been proved by long-term studies and experiments that a single dose can be significantly reduced by matching with the receptor in the dorsal horn of the spinal cord. Applying this,
By administering microcapsules containing morphine to the subarachnoid space, a morphine sustained-release preparation for an extremely long period was completed.

[0007]

The morphine sustained-release preparation according to the present invention is injected into the spinal subarachnoid space. Among the microcapsules of this sustained-release morphine preparation, the microcapsules covered with a coating with the thinnest coating or the material that dissolves the fastest dissolves first, and the morphine in them dissolves after the spinal cord. It acts on the horns and also on the central nervous system to exert an analgesic effect. When the effect decreases, the next capsule dissolves and morphine acts, etc.Since the capsules dissolve sequentially and the time of onset of morphine action can be adjusted, a stable concentration of morphine in the cerebrospinal fluid can be maintained. Be drunk

[0008]

INDUSTRIAL APPLICABILITY According to the present invention, conventional oral morphine sustained-release preparations can be given at most 12 hours at a time due to action or excretion of gastric juice, whereas in spinal fluid, a certain type of coating is given. Focusing on the fact that the speed at which the agent dissolves is always constant, the morphine has a different thickness and type.
By forming various microcapsules by mixing, mixing the capsules in a solution, and injecting the solution into spinal fluid, the morphine concentration can be stably maintained for an extremely long period of time. This greatly reduces the constraints on the patient,
The burden of medical staff can be reduced while being relieved of taking medication every short time. Further, the range of living activities of patients such as traveling and going out is remarkably widened, and unlike the oral preparation, it is directly injected into the spinal subarachnoid space and the like, so that there is an advantage that it can be used, for example, even for patients who cannot take oral intake.

Claims (4)

[Claims] 1. A morphine sustained-release preparation comprising a microcapsule coated with a morphine solution and a solution for injecting the microcapsule into the spinal subarachnoid space or the epidural space. 2. The sustained-release morphine preparation according to claim 1, wherein the coating is a contrast medium, an amino acid, starch or higher alcohol. 3. The sustained-release morphine preparation according to claim 1, wherein the solution is physiological saline, artificial spinal fluid, or local anesthetic solution. 4. The morphine sustained-release preparation according to claim 1, wherein the microcapsules are 100 microns or less.