KR100496512B1 - Medicament component of berberine for the use of preventing and treating of analgesic tolerance to morphine - Google Patents

Abstract

The present invention relates to a drug containing berberine as an active ingredient, and in particular, a drug containing berberine as an active ingredient, which inhibits and prevents the formation of morphine resistance caused by several repeated administrations of morphine used as an analgesic agent. It is about.

Description

Medicine component of berberine for the use of preventing and treating of analgesic tolerance to morphine}

Analgesic is a medicine used for the purpose of suppressing or alleviating pain. It is usually divided into narcotic analgesics and non-narcotic analgesics. Narcotic analgesics have excellent analgesic effects on visceral pain and the like, and thus are used clinically for the treatment of pain in terminal cancer patients. However, such narcotic analgesics are addictive and indulgent when used in relatively large doses or repeatedly for long periods of time, and when they are repeatedly exposed to a constant dose of drugs, resistance to analgesic activity occurs quickly, reducing the efficacy of analgesics. In order to achieve the desired or expected effect, there is a problem of increasing the amount of drug to be used.

Morphine, a typical narcotic analgesic, belongs to an addictive drug along with cocaine and methamphetamine, and is known to have the best analgesic effect among painkillers developed to date. However, repeated administration of morphine leads to a gradual decrease in analgesic action and eventually toleration of analgesic action, which is clinically limited in its use despite its excellent efficacy. Therefore, in order to utilize morphine as an analgesic agent, it is very important to maintain the initial analgesic action without attenuation of analgesic effect, which can be achieved by inhibiting the formation of resistance to morphine.

2- (1-pyrrolidinyl) acetamide of Korean Patent Application Publication No. 1999-0036248 (Application No.:10-1998-0700916) as a drug that prevents or inhibits the formation of resistance to the analgesic action of narcotic analgesics such as morphine. Dependent and / or resistance-forming inhibitors for narcotic analgesics comprising derivatives as active ingredients have been disclosed, the composition differs from the berberine-containing medicament of the present invention and relates to a medicament containing berberine. There is an antidepressant comprising a portoberberine alkaloid compound having a monoamine oxidase inhibitory activity of -0281003 as an active ingredient, but it is related to the use as an antidepressant, not related to the inhibition of morphine resistance formation of berberine.

The present inventors have conducted research to develop a drug that has the effect of inhibiting the formation of resistance to analgesic action by repeated morphine administration, the result that berberine, a major component of natural product, yellow lotus, yellow white, small wall has a strong inhibitory effect on morphine resistance. It confirmed and led to this invention. Therefore, an object of the present invention is to provide a medicament for use in the prevention and inhibition of morphine resistance formation containing berberine as an active ingredient.

The present invention provides novel uses of berberine and medicaments containing berberine. More specifically, as a drug containing berberine as an active ingredient, it provides a drug for preventing and inhibiting the formation of resistance to morphine to prevent or inhibit the formation of resistance to the analgesic action of morphine.

According to another embodiment of the present invention, there is provided a medicament for preventing and inhibiting the formation of resistance to morphine, which is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier together with the active ingredient.

 According to another embodiment of the present invention there is provided the use of berberine for the manufacture of a medicament for preventing or inhibiting the formation of resistance to the analgesic action of morphine.

In the medicament according to the present invention, berberine (7, 8, 13, 13a-tetradihydro-9,10-dimethoxy-2,3- (methylenedioxy) verbinium) as an active ingredient is an isoquinoline alkaloid. It can be extracted from various kinds of plants such as roots of coptis japonica, a barberry vulgaris, and bark of phellodendron amurense. In the past, it was used as a dye for wool, silk, leather, etc., and is currently known as a general medicine with bactericidal effect, suit effect, and anti-ulcer effect. Safety doses of berberine are already known in the literature, and the LD ₅₀ value in berberine rats is known to be 90 mg / kg (intraperitoneal) (Tang, W. and Eisenbrand, G., Chinese Drugs of Plant). Origin, pp. 362-371, Springer Verlag, Berlin, Heidelberg, New York). As the medicament of the present invention, berberine can be used commercially available.

The dose of berberine used as a medicament for preventing and inhibiting the formation of resistance of morphine of the present invention varies depending on the age, weight and degree of disease of the patient, but usually 20 to 100 mg (peritoneal injection) or 50 to 400 mg ( Oral administration). On the other hand, the electrical dosage may be appropriately determined by the experience of those skilled in the art.

In the present invention, the narcotic analgesic is limited to morphine, but is not particularly limited to morphine as long as the resistance to analgesic action is substantially formed by single administration or repeated administration over a short or long term. The narcotic analgesics include, for example, morphine and its semisynthetic compounds obtained from opium, non-natural compounds such as pettidine having a morphine-like action, and salts thereof. More specifically, for example, alkaloids obtained from opium and its semisynthetic phenanthrenes (morphine, oxymolphone, hydromorphone, codeine, hydrocodine, heroin, thebain, bufurenol, etc.); Phenyl piperidines (meperidine, fentanyl, etc.); Phenylheptylamines (mesasone, propoxyphene, etc.); Morphinanes (revolpanol, metholpan, revolpan, etc.); And benzomoalpanes (phenazocin, pentazocin, etc.).

A medicament containing berberine of the present invention may further contain a pharmaceutically acceptable carrier which is usually widely used in the art depending on the formulation. Specifically, the berberine-containing drug of the present invention may be administered orally or in the form of an injection. Oral compositions include tablets and gelatin capsules, which include diluents (eg, lactose, dextrose, sucrose, Mannitol, sorbitol, cellulose and / or glycine), a lubricant (e.g. silica, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol) and tablets also contain a binder (e.g. magnesium aluminum silicate, starch) Paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally disintegrating agents (e.g. starch, agar, alginic acid or its sodium salt) or boiling mixtures and It is preferred to contain absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably isotonic aqueous solutions or suspensions, and the compositions mentioned are sterile or contain auxiliaries such as preservatives, stabilizers, wetting or emulsifier solution promoters, salts and / or buffers for controlling osmotic pressure. In addition, they may contain other therapeutically valuable substances.

Berberine, an active ingredient of the medicament of the present invention, has a significant effect on the analgesic effect caused by the repeated administration of morphine without affecting the analgesic action by single administration of morphine, to the same extent as the initial administration and analgesic effect. The inhibitory effect was confirmed. Therefore, the medicament of the present invention can generally be used in combination with the administration of morphine, thereby preventing the formation of resistance to the analgesic action of morphine, and consequently the medicament of the present invention is prophylactically for the purpose of preventing the formation of such resistance. It is possible to use. In addition, the medicament of the present invention has the effect of inhibiting and alleviating the resistance to analgesic action already formed by repeated administration of morphine, and as a result, the medicament of the present invention is generally aimed at suppressing the resistance already formed. May continue to be used with morphine and used therapeutically.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention more specifically, but the scope of the present invention is not limited to these examples.

Example 1

Effect of berberine on analgesic effect by single administration of morphine

ICR male mice weighing 18 to 25 g were used as experimental animals. Animals were reared for at least one week in a control room where temperature and humidity were constantly controlled, and 10 animals per group were used for each experiment. In addition, the morphine used in the Example was purchased from Kukdong Pharmaceutical (Incheon), berberine (berberine hemisulfate) was purchased from Sigma (USA) was used by dissolving in distilled water.

The effect of morphine on analgesic action and resistance formation was examined by hot plate test, one of the analgesic tests using heat stimulation in mice. To this end, the basic reaction time for the high temperature pain of the mice was measured on a 52 ° C. hot plate, and the response of the mice was based on the reaction time by licking or jumping the hind legs. Mice were removed after a cut-off time of measurement, i.e. a maximum of 30 seconds, when no pain response was seen for more than 30 seconds. Distilled water and berberine 1, 3 and 10 mg / kg were pretreated by intraperitoneal injection, respectively, and 30 minutes later, physiological saline and morphine 5 mg / kg were administered by subcutaneous injection. 30, 60 and 90 minutes after injection, the measurement was carried out with the maximum response time of 30 seconds in the same manner as the default measurement on a hot plate. Analyzes of the response to pain obtained the values of the following maximum possible effects (M.P.E.) and expressed the intensity of analgesic activity as AUC (Area Under the Curve).

M.P.E. (%) = (Tt-To) / (Tc-To) X 100

  (Tc: maximum allowable time, Tt: reaction time during test, To: basic reaction time)

As shown in FIG. 1 (significance compared to the physiological saline administration group: *** P <0.001), the morphine-only group was found to significantly increase the analgesic effect of the mice compared to the saline administration group. Could. It was also observed that the groups pretreated with berberine 1, 3 and 10 mg / kg prior to morphine administration had little effect on the analgesic effect of morphine.

Example 2

Effect of berberine on the formation of resistance to analgesic effects caused by repeated administration of morphine

To create a model for the formation of resistance to the analgesic action of morphine by repeated administration of morphine, distilled water and berberine 1, 3, 10 mg / kg were pretreated by intraperitoneal injection method, and after 30 minutes, physiological saline and morphine 10 mg / kg Subcutaneous injections were repeated once for 6 days. The next day, ie on day 7, the baseline response time for pain at high temperatures in mice on a hot plate was measured. Analysis of the formation of resistance to analgesic action induced by morphine was calculated by calculating the value of the maximum possible effect in the same manner as in Example 1.

As shown in FIG. 2 (significance compared with physiological saline administration group: ** P <0.01, compared with morphine administration group: + P <0.05, significance compared with resistance forming group: # # P <0.01), morphine Continuous repeated administration significantly reduced the initial analgesic effect of morphine. In other words, although the formation of resistance to the analgesic action of morphine was recognized, it was confirmed that the formation of morphine resistance was significantly inhibited in the group pretreated with berberine 10 mg / kg.

As described above, the present invention provides a drug for preventing and inhibiting the formation of resistance to morphine containing berberine as an active ingredient. The medicament of the present invention can contribute to effectively maintaining the analgesic action by the first administration of morphine even in the repeated administration, and since it significantly prevents and suppresses the formation of resistance to the analgesic action caused by the repeated administration of morphine, morphine It can be effectively used to prevent or alleviate the formation of resistance to.

1 is a graph showing the effect of berberine on the analgesic effect of morphine upon a single administration of morphine to mice.

Figure 2 is a graph showing the effect of berberine inhibits the formation of the resistance of the analgesic morphine upon repeated administration of morphine to the mouse.

Claims (2)

Prevention of inhibitor formation, resistant to the analgesic action of morphine, containing berberine as an active ingredient. The method of claim 1, Characterized in that in the form of a pharmaceutical composition comprising a berberine and a pharmaceutically acceptable carrier, Prevention of the formation of resistance to the analgesic action of morphine, inhibitors.