JPH09295936A - External preparation for treating bone disease of artificial dialysis patient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject external preparation, containing a specific n-6- based unsaturated fatty acid, having sufficient treating effect on bone disease of artificial dialysis patent, effective on alleviation of pain, free from adverse effect and capable of using for a long period. SOLUTION: This external preparation contains one kind or two or more kinds of compounds selected from γ-linolenic acid, dihomo-γ-linolenic acid and their derivatives. Furthermore, γ-linolenic acid is preferably γ-linolenic acid- containing oil and fat extracted from yeast cell body of the genus Mortierella. A content (converted to an amount of γ-linolenic acid in the case of dihomo-γ- linolenic acid and each derivative) of the γ-linolenic acid is usually preferably 2-20wt.% based on the external preparation. The external preparation is preferably used by applying to a part of lesion once or twice per day, spreading the applied agent and lightly massaging the applied part. An amount of the γ-linolenic acid is preferably 0.4 to 10mg/10cm2 (skin area)/day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for treating bone diseases associated with artificial dialysis patients.

[0002]

2. Description of the Related Art With the recent development of dialysis therapy, chronic renal failure itself is now less likely to be a direct cause of death, and long-term survival of 20 years or more has become possible by selecting an appropriate treatment method. However, it is known that various complications develop due to the shift to dialysis. For an artificial dialysis patient (hereinafter referred to as a dialysis patient), who has a large mental and physical burden of receiving dialysis, these complications are more costly.
This significantly impairs the ability of life (hereinafter referred to as QOL). Therefore, at present, the measures for complications associated with long-term survival and appropriate treatment methods are being sought.

As a complication of such a dialysis patient, hyperparathyroidism, which is a major cause of the development of pruritus cutis and renal osteodystrophy, is known. It was clarified that γ-linolenic acid and dihomo-γ-linolenic acid were very effective against these complications compared with existing drugs, and there was no problem in safety by long-term administration (Japanese Patent Application No. 6-79066).

On the other hand, renal bone dystrophy (renalosteodosis) is a major bone lesion associated with renal disease in dialysis patients.
ystrophy: hereinafter referred to as ROD) and dialysis amyloidosis (hereinafter referred to as amyloidosis) are known.

ROD is a metabolic bone disease that accompanies renal disease, and is divided into fibrous osteomyelitis in which the resorption pits are replaced by fibrous tissue due to increased bone resorption and osteomalacia due to abnormal calcification of bone. Actually, it is often said that these bone lesions are mixed. Also, ectopic calcification may occur around joints and soft tissues. It is said that many factors are involved in the cause of ROD. For example, there is a decrease in active vitamin D ₃ due to renal abolition as an endocrine organ, an increase in parathyroid hormone secretion, a decrease in the number of parathyroid vitamin D ₃ receptors, a decrease in serum Ca level, an abnormality in P metabolism, and dialysis therapy. As an effect of itself, IL-1, IL-6, IL-released by complement, leukocytes, etc. activated by contact with a dialysis membrane and influx of endotoxin from perfusate
8. Involvement of inflammatory cytokines such as TNF has been pointed out.

On the other hand, bone lesions due to amyloidosis are
Β ₂ microglobulin (β ₂ M) deposited on bones and joints
Causes carpal tunnel syndrome, spring fingers, joint pain, bone cysts, etc. As the cause, the above-mentioned cytokine promotes the release of β ₂ M from cells and also enhances the protease activity of macrophages, resulting in β ₂ M locally or in blood.
Fragmente that easily decomposes and easily forms amyloid
It is said to produce dβ ₂ M.

Bone lesions associated with these renal diseases are bone pain,
It causes joint pain, limitation of the range of motion of the joint, numbness, fractures, etc., and greatly impairs the QOL of dialysis patients.

[0008] ROD and amyloidosis are frequently complicated in long-term dialysis patients, and once they occur, they are often difficult to treat, and are the most difficult complications for dialysis patients.

For such a bone disease of a dialysis patient, R
For the treatment of OD, for example, an active vitamin D agent is used, but it has a drawback that the therapeutic effect is not sufficient and that it easily causes hypercalcemia and ectopic calcification. Further, there is currently no effective therapeutic means for bone disorders caused by amyloidosis.

For pain caused by bone diseases, steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents are used, but side effects due to long-term use of these agents pose a problem.

[0011]

The present invention has been made from the above point of view and has a sufficient therapeutic effect on bone diseases of dialysis patients and also has favorable results in pain relief and side effects. It is an object of the present invention to provide an external preparation for the treatment of bone diseases of dialysis patients which can be used for a long time without adverse effects such as.

[0012]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a specific n-
It was found that 6-unsaturated fatty acids improve bone disease associated with renal disease in dialysis patients and also have good results in relieving bone pain, and thus completed the present invention.

That is, the present invention relates to γ-linolenic acid,
An external preparation for treating a bone disease of an artificial dialysis patient, which comprises one or more selected from dihomo-γ-linolenic acid and derivatives thereof.

The present invention will be described in detail below. The active ingredients γ-linolenic acid and dihomo- used in this invention
γ-linolenic acid (these and derivatives thereof are referred to as “γ
-Sometimes referred to as "linolenic acid and the like") is an endogenous substance known as an n-6 essential fatty acid. γ-Linolenic acid is converted from linoleic acid by the enzyme δ6-desaturase. However, this enzyme activity is weak, and this step is the rate-determining step of n-6 fatty acid metabolism, and it is said that it is difficult to smoothly convert linoleic acid into γ-linolenic acid. The enzyme activity is also weakened by various factors such as diabetes, alcohol intake, aging, atopic dermatitis, and zinc deficiency. For the first time, a treatment using γ-linolenic acid or the like as an active ingredient was attempted for the complication of a dialysis patient (the above-mentioned publication). These inventors
In dialysis patients with many metabolic disorders, this enzyme activity is further weakened, and active substances such as γ-linolenic acid, dihomo-γ-linolenic acid and prostaglandin E ₁ are less likely to be produced. I think that there is.
γ-Linolenic acid and the like have a function of suppressing the production of the inflammatory cytokine, and are expected to prevent the influence on the bone joint as much as possible. Also, since the conversion of γ-linolenic acid to dihomo-γ-linolenic acid is very rapid, the use of γ-linolenic acid and dihomo-γ-linolenic acid is the same for practical purposes. Become.

By the way, steroid and non-steroid anti-inflammatory agents are used for pain of bone disease.
As for the analgesic effect of these anti-inflammatory agents, steroidal anti-inflammatory agents act by the enzyme phospholipase A ₂ that releases arachidonic acid from phospholipids, and non-steroidal anti-inflammatory agents act as arachidonic acid released from phospholipids. It is exerted by inhibiting the action of the enzyme cyclooxygenase, which acts on blood plasma, to block the production of prostaglandins such as prostaglandin E ₂ that has a potent pain-enhancing effect on the pain-producing substance bradykinin in plasma. Is believed to be. The present inventors have focused on the analgesic action of such anti-inflammatory agents. That is, γ-linolenic acid and the like have a function of suppressing the enzymatic activity of phospholipase A ₂ ,
The pain-relieving effect of linolenic acid and the like is considered to be because γ-linolenic acid and the like have one aspect common to the above-mentioned actions of these anti-inflammatory agents.

[0016] In the case of long-term dialysis, it has been reported that administration of an anti-inflammatory agent reduces inflammatory cell infiltration around amyloid and that amyloid was not detected in patients with systemic lupus erythematosus (Ryuko Kawai et al. Histopathological study of anti-inflammatory therapy in dialysis amyloidosis.
Journal of Japan Society for Dialysis Therapy. Volume 26 Supplement
1,988,1993. ) The present inventors also pay attention to this case, and considering that γ-linolenic acid and the like have a common pharmacological action with these anti-inflammatory agents as described above, the effects of γ-linolenic acid and the like on amyloidosis can also be expected. I thought it might be.

The natural sources of γ-linolenic acid and the like used in the present invention are limited, and usually, genus Mortierella and Muco (Muco) are used.
r) genus, filamentous fungi such as Rhizopus (genus Rhizopus) or plants such as evening primrose, borage, etc., and oils and fats contained in algae such as spirulina, etc., extracts from these may be used as they are, You may use the refined thing. Further, γ-linolenic acid and the like can be obtained by chemical synthesis, and commercially available products may be used. Among these, Mortierella
γ-linolenic acid-containing oils and fats (manufactured by Idemitsu Material Co., Ltd.) extracted from bacterium belonging to the genus ierella) are preferred. This oil is a γ obtained from other natural products.
-In contrast to the fact that linolenic acid-containing fats and oils have a high linoleic acid content and lack oxidative stability, oleic acid is the main constituent fatty acid, so they are excellent in oxidative stability and have the characteristic that certain quality is easily obtained. are doing.

As the above-mentioned γ-linolenic acid or dihomo-γ-linolenic acid derivatives, esters obtained by reacting these with various alcohols such as ethyl ester, glycerol ester, phospholipid, etc., or inorganic or organic Examples of the salt include salts obtained by reacting the base with the base in an equimolar ratio, such as sodium salt and potassium salt.

When the content of γ-linolenic acid in the external preparation for treating bone diseases (dihomo-γ-linolenic acid and each derivative is converted into the amount of γ-linolenic acid) becomes too small, bone diseases are reduced. The therapeutic effect of is not sufficiently obtained, and even if it is too large, it causes inconveniences such as being economically expensive and having too high fluidity. Therefore, it is usually used within the range of 2 to 20% by weight. .

The external preparation for treating bone diseases of the present invention is the above-mentioned γ
-Containing linolenic acid or the like as an active ingredient, for example, a liquid, an emulsion, a cream, a gel prepared by dissolving or mixing and dispersing the above drug with a preservative, a stabilizer, a flavoring agent, a coloring agent, etc. in a base. It can be used as an external preparation in the form of gel, jelly, paste or the like, and the dosage form is not particularly limited, but it is considered that it can be absorbed from the skin, is easy to manufacture, and massage after application. If done, oil liquid (oil)
It is preferred to be in the form. If necessary, a poultice,
It is also possible to use plaster. These can be manufactured using a conventionally known technique.

The above-mentioned base may be any one which is pharmaceutically acceptable, and any of those conventionally used for preparing the above-mentioned dosage form can be optionally used. For example,
Vitamin E, lanolin, white petrolatum, squalene, paraffin, plastibase, sesame oil, soybean oil, oils and fats such as olive oil, α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, myristooleic acid, palmitooleic acid, oleic acid, Erucic acid, lauric acid,
Fatty acids such as myristic acid; surfactants such as sorbitan monostearate, polyoxyethylene glycerin monostearate, polyoxyethylene nolyl phenyl ether; sodium alginate, gelatin, methylcellulose, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, polyvinyl Examples thereof include thickeners such as alcohol; water and the like, and one or more of these are used depending on the intended formulation. Among these, vitamin E and its derivatives are preferably used. Most of vitamin E is taken in as a constituent component of cell membranes, and its antioxidant action suppresses the production of lipid peroxides, stabilizes the membrane, and contributes to exhibiting normal membrane function. Because it is considered.

So far, it has not been known to apply an external preparation containing γ-linolenic acid or the like as an active ingredient to bone diseases associated with renal diseases. For dialysis patients who are under restricted water intake, it is very convenient that the intended effect is obtained with the external preparation. As is clear from the therapeutic examples in the examples described below, it is understood that the topical γ-linolenic acid and the like of the external preparation according to the present invention are effectively permeated and absorbed through the skin.

The thus-obtained external preparation for treating bone diseases of the present invention may be applied to the lesion site once or twice a day, spread, and if possible, gently massaged.

The amount of the external preparation for treating a bone disease of the present invention to be used depends on the kind of bone disease, the degree of symptoms, the location of the affected area and its size, etc., but the amount of γ-linolenic acid is 0. 4 to 10 mg / 10 cm ² (skin area) is preferable.

[0025]

EXAMPLES Examples using the external preparation for treating bone diseases of the present invention will be described below. <Manufacturing method of external preparation> Mortierel
la) γ-linolenic acid-containing fats and oils (γ
1 part by weight of linolenic acid (containing about 8% by weight) and Vitamin E (trade name: Emix-80, manufactured by Eisai Co., Ltd.) 1
Parts by weight were mixed by a conventional method to produce the external preparation for treating bone diseases according to the present invention. Next, the following treatment was performed using the obtained external preparation.

Treatment of renal osteodystrophy.

[Therapeutic Example 1] A 48-year-old woman diagnosed with a bone disease due to renal osteodystrophy with a dialysis history of about 10 years had persistent pain in both feet and increased pain during walking. For this reason, he took two kinds of anti-inflammatory drugs twice a day. About 0.1 g of each of the external preparations for treating bone diseases of the present invention was applied once a day to both toes and lightly massaged. During that day, the pain in both toes was relieved, the use of anti-inflammatory drug could be reduced to once a day, and the pain in both toes when walking was improved. No side effects on the skin due to the use of the external preparation were observed.

[Treatment Example 2] A 59-year-old woman with a history of dialysis of about 5 years who had been diagnosed with bone disease due to renal osteodystrophy and complained of pain in both knee joints and fingers of both hands. He was unable to sit upright and had limited range of motion for both knee and finger joints. About 0.1 g of each of the external preparations for treating bone diseases of the present invention was applied twice a day to both knee joints and both fingers and lightly massaged. From the 2nd to 3rd days, the pain became less severe, and the knees and knuckles became slightly bent compared to before treatment. No side effects such as irritation caused by the use of the external preparation were observed.

Treatment of osteoarthritis due to amyloidosis.

[Treatment example 1] A 50-year-old man with 22 years of dialysis history who was diagnosed with carpal tunnel syndrome.
He was accompanied by joint pain as well as a remarkable limitation of the range of motion of his knuckles. About 0.1 g of the external preparation for treating bone diseases of the present invention was applied to the finger of the right hand twice a day, and a light massage was applied. A week later, I started to bend until my thumb and forefinger stuck together. One month later, all five fingers began to bend, and he recovered until he had a fist. As my fingers began to bend, my knuckles became less painful. Moreover, no side effects were observed due to the use of the external preparation.

[Treatment example 2] A 68-year-old woman diagnosed with carpal tunnel syndrome, who had a history of dialysis for about 17 years and had symptoms on the entire left finger, accompanied by numbness and joint pain. There were restrictions. The external preparation for the treatment of bone diseases according to the present invention is applied daily 1
Approximately 0.1 g was applied to the finger of the left hand and lightly massaged. From the day after the treatment, numbness and pain were alleviated, and the fingers became gradually bendable. There were no side effects such as irritation caused by the use of the external preparation.

[0028]

EFFECTS OF THE INVENTION As is clear from the above-mentioned treatment examples, the external preparation for treating bone diseases of artificial dialysis patients of the present invention has a sufficient therapeutic effect on bone lesions associated with renal diseases and relieves pain. It can be seen that it is also excellent in safety.

Claims (2)

[Claims] 1. An external preparation for treating a bone disease of an artificial dialysis patient, which comprises one or more selected from γ-linolenic acid, dihomo-γ-linolenic acid and derivatives thereof. 2. γ-Linolenic acid is Mortierella (Mor)
The external preparation for treating bone disease of an artificial dialysis patient according to claim 1, which is a γ-linolenic acid-containing oil or fat extracted from a bacterium belonging to the genus Tierella).