JPH03106822A - Injection for remedy of skin wound and dermatic disease - Google Patents

Abstract

PURPOSE:To obtain an injection effective in actively and directly promoting the cure of skin wound and dermatic diseases without giving pain to the patient by using epidermal growth factor(EGF) as an active component. CONSTITUTION:The active component of the subject injection is a beta-urogastrone having an amino acid sequence of formula (dotted line is disulfide bond), gamma- urogastrone having a structure produced by depleting one amino acid from the C-terminal of betaurogastrone, a compound having a structure produced by depleting 2-7 amino acids from the beta-urogastrone, etc. The daily dose of EGF is preferably about 0.01-100mug/kg. EGF can be produced e.g. by the purification of human urine extract, the gene recombination technique, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides epithelial cell growth factor (EpiderIIIal).
The present invention relates to an injection containing GrotgthFactor (hereinafter referred to as EGF) or a pharmaceutically acceptable salt thereof as an active ingredient for treating skin wounds such as burns and cuts, and skin diseases such as bedsores and skin ulcers.

[Conventional technology]

In 1975, H. Gregory purified a peptide factor that strongly suppresses gastric acid secretion from human urine (named it β-urogastrone) and determined the entire 53 amino acid sequence (Nature, Vol. 257). ，
325-327, 1975).

On the other hand, apart from Gregory's research, S. Cohen et al. investigated a peptide that promotes eyelid cleavage in newborn mice, which is abundantly contained in mouse submandibular glands, from the perspective of a factor that promotes the proliferation of epithelial cells. He named it EGF, studied its physiological effects and structure, and in 1972 elucidated the entire amino acid sequence (53 amino acids) of mouse EGF (J. Biol.
Chem. 2 4 Volume 7, pp. 7612-762l, 1
972). Furthermore, they discovered that human EGF (hereinafter abbreviated as hEOF), which has the same physiological effects as mouse EGF, was also present in the urine of pregnant women, and demonstrated its amino acid composition (Proc. Nat. Acad. Sci. S
A, Vol. 72, pp. 1317-1321, 1975).

Today, hEGF and β-urogastrone are the same substance.
The amino acid sequence of the following formula (r) determined by Gregory is widely accepted as the correct structure.

The following margin (in the formula, -1---- indicates a disulfide bond) EG
The physiological effects of F include suppressing gastric acid secretion and promoting cell proliferation as mentioned above, as well as promoting corneal repair (Sav
age, C. , et al.: Expt-Eye Res,,
Volume 15, page 361, 1973; Japanese Patent Publication No. 59-6502
No. 0), bone repair promoting effect (Kumagawa,
II. , et al., Calcif. Tissue In
t. 3 vol. 5, p. 542, 1983; Unexamined Japanese Patent Publication No. 1983-
293925) etc. are known.

Since EGF has the above-mentioned physiological effects, attempts have been made to use EGF to promote the recovery of the epithelium when the epithelium is damaged due to skin wounds, skin ulcers, etc. For example, JP-A-62-27 proposes a cream-like drug containing EGF.

In addition, as other treatments for these skin wounds and skin diseases, methods using anti-inflammatory agents, antibiotics, skin surface protectants, etc. are used.

[Problem to be solved by the invention]

However, when EGF is used as an external preparation such as a cream or ointment,
EGF, which has a relatively large molecular weight of about 6,000, is difficult to be taken up by cells, and EGF in the drug has difficulty coming into contact with the diseased area due to infiltration of body fluids from the diseased area.Furthermore, it is difficult to apply external preparations to the affected area. - It was found that there are problems such as the spread of the disease inflicting unbearable pain on the patient.

Furthermore, anti-inflammatory agents, antibiotics, skin surface protectants, and the like do not actively promote the healing of the disease itself, but indirectly promote the healing of the disease by alleviating symptoms and preventing infection.

Therefore, there has been a desire for a drug that does not cause unbearable pain to patients and actively and directly promotes healing of diseases. The present invention provides an injection that actively and directly promotes healing of skin wounds such as burns and cuts, and skin diseases such as bedsores and skin ulcers without causing pain to patients.

[Means to solve the problem]

Skin wounds such as burns and cuts, and skin diseases such as bedsores and skin ulcers are extremely localized diseases, and conventional wisdom has held that systemic administration such as intravenous injection is not expected to be highly effective. However, the present inventors unexpectedly discovered that systemic administration of EGF exerts excellent effects on the above-mentioned diseases, and completed the present invention.

That is, the present invention relates to an injection for treating skin wounds and skin diseases that contains epidermal growth factor (EGF) or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition to β-urogastrone (hEGF1.3) shown by the formula (!), the EGF used in the present invention may be one having the same physiological activity, albeit to a different degree. As such, β-urogas? γ-urogastrone (hEGF1-
．． ■) and h E G F1-n (n
is an integer from 5 to 46), some of these constituent amino acids are substituted with other natural or unnatural amino acids, some of these constituent amino acids are deleted or added, etc., and mixtures of these But that's fine.

These EOFs can be produced by various methods, such as extraction and purification from human urine (Gregory +
H. l et al., Hoppe Seyler's Z+
Physiol, Chen. , 3 5 6 volumes, 17
65-1774, 1975; Gregory, t{
．． , Nature, 257, 325-327
Page, 1975; Japanese Unexamined Patent Publication No. 58-99418;
Publication No. 8-219124; Publication No. 60-161923, etc.);
No. 22096: No. 58-216697; No. 5
9-132892, etc.).

The preparation of the present invention is an injection. Injections can be administered by intravenous, intramuscular, subcutaneous, or drip administration.

Although injections can be made into solution formulations, freeze-dried formulations are preferred to ensure long-term storage stability. EG
To stabilize F, human albumin, human globulin,
It may also be a lyophilized preparation to which proteins, amino acids, etc. that do not have antigenicity to humans, such as gelatin, are added. Distilled water for injection, physiological saline for injection, aqueous sugar solution, etc. are used to dissolve the freeze-dried preparation.

The dose of EGF can be adjusted appropriately depending on the patient's age, body weight, symptoms, etc., but the dose in the case of an injection is preferably about 0.01 to 100 μg/kg per day.

[Effect]

There are several possible mechanisms of action by which FGF promotes the healing of skin wounds such as burns and cuts, and skin diseases such as pressure sores and skin ulcers, including the action of EGF on epithelial cell proliferation and the promotion of epithelial keratinization, and these mechanisms are complex. It is thought that the healing of the above-mentioned diseases is promoted as a result of their combined effects.The detailed mechanism of action must be elucidated in the future.

? Examples] The present invention will be explained in more detail with reference to the following examples. The test drug, EGF, was isolated and purified from the urine of healthy human men, and was derived from β-urogastrone (hEG
F■-53)↓4%, γ-urogastrone (hEGF
,, ■) 67%, and hEGF-A in addition. , h E G
A sample containing small amounts of F, 5o and hEGF1-s1 was used.

(Example 1) After the hair on the back of a Wista strain male rat weighing 230 to 240 g was shaved, the hair was removed using a hair removal cream. Under bentobarbital anesthesia, stainless steel cylinders (diameter Sun, weight 3.1 g) heated to 300° C. were placed on two locations under bentobarbital anesthesia for 10 seconds under their own weight to create burns. The burn injury model rats thus obtained were divided into three groups (10 rats in each group) and treated.

Group 1: Physiological saline administered once a day (control group) Group 2:
Group 3 in which 20 μg/kg of EGF was administered once a day through the tail vein. 20 μg/kg of EGF was administered through the tail vein every 2 days, 3 days a week. The day when the skin peeled off due to the burn was considered as healing, and the number of days for healing was determined. The results of the comparison are shown in Table 1.

From Table 1, it can be seen that the EGF administration group significantly promoted the healing of burn wounds in rats compared to the control group administering physiological saline.

Table 1 shows that burn treatment experiments are progressing. Group 1 Physiological saline once a day administration group (control group) Group 2 Human EGF 20 μg/kg once a day administration group 3 Human EGF 50 μg/kg once a day administration group Table 2 Burn injury using submandibular gland removed rats Treatment experiment tree: There was a significant difference at P<0.05 compared to the engineering group (control) (Example 2) To further confirm the effect of EGF administration, we used rats whose left and right submandibular glands had been removed one week earlier. A burn treatment experiment similar to that in Example 1 was conducted (Table 2). From the results in Table 2, EG
The F administration group significantly promoted the healing of burn wounds in submandibular gland removed rats compared to the physiological saline administration group*=P<0.0 compared to the I group (control)
[Effect of the invention] The present invention provides a drug that actively and directly promotes the healing of skin wounds such as burns and cuts, and skin diseases such as bedsores and skin ulcers without causing pain to patients. Provide (Ichino)

Claims (1)

[Claims] 1. An injection for treating skin wounds and skin diseases containing epidermal growth factor or a pharmaceutically acceptable salt thereof as an active ingredient.