JPH03190823A - Erythropoietin hypodermic or intramuscular administration agent - Google Patents

Abstract

PURPOSE:To obtain a hypodermic or intramuscular administration agent containing erythropoietin as an active ingredient and as necessary further analgesic and having high treating effect. CONSTITUTION:Erythropoietin having 1000-2000 IU per vial is dissolved in distilled water having pH 6-7.5 and 0.25-0.5% serum albumin and 0.5-10% analgesic (e.g. procaine hydrochloride or benzyl alcohol) are added thereto and the mixture is sterilized and as necessary subjected to freeze drying to prepare the hypodermic or intramuscular administration agent. The agent is administered normally in an amount of 1500-6000 IU per time once to three times weekly. The agent exhibits blood making effect in reduced amount, compared with intravenous injection and treating effect is remarkably improved by administering small amount of the agent in high frequency. The agent reduces danger caused in case of intravenous injection and injection by patient himself is made possible.

Description

[Detailed Description of the Invention] Eris l-1 boetin (hereinafter abbreviated as EPO) is known as a blood-enhancing hormone, and is produced in the kidneys.
It has the effect of acting on stem cells in the bone marrow and promoting their differentiation into red blood cells.

EPO is excreted in urine in trace amounts, and it is known that it is contained in particularly large amounts in the urine of patients with aplastic anemia. Substances purified and recovered from this urine are widely used as research reagents.

In recent years, genetic engineering has made it possible to produce human I-E PO.
Publication No. 1010 discloses the human EPO gene and a method for producing human EPO using this gene.

EPO is mainly used to treat anemia associated with kidney disease, but is also known to be effective for recovery from post-operative bleeding, cancerous anemia, and rheumatic anemia.

EPO is an IP:protein with a molecular weight of about 3111.000, and since it is trapped in the liver and rapidly decomposed in vivo, it has been widely administered by intravenous injection for treatment. Particularly for renal dialysis patients, it is common to administer the drug intravenously through an arteriovenous shunt after hemodialysis.

As for EPO injections, examples of stable EPO preparations are disclosed in JP-A-61-91131 and JP-A-61-97229. These are all examples of formulations intended for intravenous administration. However, in previous reports and publications, it is not known that there are differences in therapeutic effects depending on the route of administration.

The present inventors confirmed for the first time that there is a large difference in therapeutic effect depending on the route of administration of human EPO, and discovered that the more effective routes of administration are subcutaneous and intramuscular routes, and completed the present invention. It's arrived.

Therefore, it is an object of the present invention to provide a subcutaneous or intramuscular injection with high therapeutic efficacy, containing erythropoietin as an active ingredient.

A further object of the present invention is to provide a subcutaneous or intramuscular injection of erythropoietin that is easy to administer.

Section test desecration 1 叡J) Bi translation Δ hand killing.

The present invention relates to a subcutaneously or intramuscularly administered erythropoietin agent containing urithroboetin as an active ingredient, and further to a subcutaneously or intramuscularly administered erythropoietin agent containing a combination of erythropoietin and an analgesic agent.

In the present invention, EPO may be a purified product derived from urine or one produced by genetic recombination. Such purified EPO is administered subcutaneously or intramuscularly to anemic patients. The dosage varies depending on the anemia status of the patient, but usually 1500 to 6000 IU is administered subcutaneously or intramuscularly 1 to 3 times a week.

The subcutaneous or intramuscular injection may be in the form of an injection solution, or may be in the form of a lyophilized product and dissolved before use to form an injection solution. Furthermore, if necessary, isotonic agents such as carbohydrates and salts, and stabilizers such as albumin, mannitol, and dextran may be added. Since subcutaneous and intramuscular administration often causes severe pain to patients, in the present invention,
For pain relief, it is desirable to add a local anesthetic such as brocaine hydrochloride or benzyl alcohol in an amount of 0.5 to 10% of the injection volume. The addition of this local anesthetic reduces the patient's pain during subcutaneous and intramuscular injections, and also allows self-injection if necessary. Furthermore, low-dose, high-frequency administration, which is a characteristic of EPO, can be performed by subcutaneous or intramuscular injection without causing pain to the patient, and a strong hematopoietic effect can be achieved.

In the preparation of subcutaneous or intramuscular doses, 1000-20,0001 U of EPO per vial at pH 6-7.
5 in distilled water, add 0.25-0.5% serum albumin and 0.5-10% local anesthetic, and sterilize.

It can also be freeze-dried if necessary.

EXAMPLES Below, Examples and Experimental Examples will be shown to further explain the present invention in detail.

Example 1 EPO derived from human urine 6,000,000 IU Human serum albumin 2500 mg Pharmacopoeia benzyl alcohol 40 g Total amount was 1 liter with distilled water for injection. shall be.

This composition solution was filled into ampoules in an amount of 1 mfl and sterilized to prepare an EP○60001U injection solution.

Example 2 Genetically recombinant EP○ 12,000,000 1
U Human serum albumin 2500 ■ Pharmacopoeia procaine hydrochloride 40 g Adjust the total amount to 1β with distilled water for injection.

This composition solution was dispensed one by one into sterilized vials using a Millipore filter, freeze-dried, and then sealed.

A 12,000 IU injection solution was prepared by dissolving this vial in 1 mfl of physiological saline.

Experimental Example In this experimental example, the effects of the EPO subcutaneous intramuscular administration preparation will be explained.

The upper and lower 1/3 of the left kidney of a 6-week-old Wistar male rat was cut and removed, and after 1 week, the right kidney was completely resected to create a rat with renal failure. After raising the rats for an additional 3 weeks, rats with renal anemia were selected by blood analysis and used for experiments. The anemic rats were divided into 10 groups of 5 to 6 rats each, and a sham operation group in which only laparotomy was performed but no nephrectomy was also created.

EPO was administered at 3001 U/kg for 2 weeks, and the administration schedule was as shown in Table 1.

Table 1 Dose Number of administration Route of administration 300 IU 1 intravenous 1
Muscle 1 Subcutaneous 75 4 Vein 75 4 Muscle 75 4 Subcutaneous 42 7 Vein 42 7 Muscle 42 7 Subcutaneous - Physiological saline 7 times To confirm the effect after subcutaneous administration, hematocrit and hemoglobin values, which are indicators of anemia, before and after administration. , the number of red blood cells, and the number of reticulocytes were measured and are shown in FIG. Also 300 IU
/kg administration group, blood E 24 hours after administration
PO titers were measured by radioimmunoassay and are shown in FIG.

As shown in Figure 1, the anemia index was improved in both intramuscular and subcutaneous administration groups, especially when the dose was lowered.
The healing effect was significantly improved by increasing the number of sessions.

In particular, it was found that subcutaneous administration had the highest hematocrit and hemoglobin values, which are indicators of anemia, and that intramuscular administration had the highest therapeutic effects, and that subcutaneous and intramuscular administration were significantly more therapeutically effective than intravenous administration.

It was also confirmed that the titer in the blood after administration was such that subcutaneous or intramuscular administration was required for a long period of time. This experiment confirmed that the subcutaneous route of administration can maintain therapeutic levels of efficacy compared to the traditional intravenous route of administration.

By implementing the present invention, it has become possible to provide an effective EP○ formulation in a smaller amount than intravenous injection formulations. Furthermore, intravenous injection preparations must be administered by a doctor due to the risk of infection when administered to a patient. However, subcutaneous and intramuscular injections are less dangerous than intravenous injections, and patients can also self-inject the drug, as is the case with insulin.

In particular, when a pain-reducing agent is used in combination, a small amount of the preparation can be administered frequently without causing pain to the patient, and the hematopoietic effect can be significantly enhanced.

[Brief explanation of drawings]

FIG. 1 shows changes in blood analysis values when EPO was administered to rats with renal anemia. In addition, 1. V, intravenous injection, 1. M, intramuscular injection;
S, C, indicate subcutaneous injection, respectively. Furthermore, black columns indicate values before injection, and white columns indicate values after injection. Figure 2 shows blood E after administering 3001 U/kg of EPO.
The time course of PO titer is shown. In addition, M indicates intravenous injection, * indicates intramuscular injection, ■ indicates subcutaneous injection, and M indicates control. (TI)/10,000) ri, 30. ．． 2-) ~ (%) High conviction semi-■ world (%) -1"-rl 6-4, a'y (8 Tada/, 0TX) Sharing TfJT Gi 158-

Claims (3)

[Claims] (1) An erythropoietin subcutaneous or intramuscular administration agent characterized by containing erythropoietin as an active ingredient. (2) A subcutaneous or intramuscular administration agent for erythropoietin, which contains erythropoietin as an active ingredient and further contains an analgesic agent. (3) The subcutaneous or intramuscular administration agent for erythropoietin according to claim (2), wherein the analgesic agent is one or two local anesthetics selected from the group consisting of procaine hydrochloride and benzyl alcohol.