JPH03236328A - Medicine composition for psoriasis therapy - Google Patents

Abstract

PURPOSE:To provide a new medicine composition effective for psoriasis therapy, containing an interleukin I having excellent anti-psoriatic effect and a carrier, diluent or excipient capable of administration as a medicine. CONSTITUTION:The objective new composition containing (A) interleukin I at an amount effective for psoriasis therapy and (B) at least one kind of carrier, diluent or excipient capable of administration as a medicine. The interleukin I (IL-1) is human IL-1 of natural origin, recombinant-type human IL-1 or a polypeptide with its anti-psoriatically active site. The present composition can be administered as an intravenous, intramuscular, subcutaneous or intracutaneous injection, or a peroral preparation, external preparation, suppository or instillation.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to interleukin 1 (Interlen
The present invention relates to a pharmaceutical composition for mineral treatment containing IL-1 (hereinafter referred to as IL-1) as an active ingredient.

BACKGROUND OF THE INVENTION Minerals are chronic skin diseases that have long been known for their distinctive clinical symptoms, characterized by localized erythema covered with white scales, often accompanied by varying degrees of discomfort. It is. Although it has been shown that this disease is not contagious, the cause and mechanism of this disease have not yet been fully elucidated [Krueger, G., G.
ger, G, G, )r ``Psoriasis: Recent concepts of its etiology and pathogenesis''
Concepts of its Etiology
y and Pathogenesis”), The Year Book on Dermatology
of Dermatology) (1981),
Dobson, R,L
,) and Sears, B, H, (Thiers,
B, H,) [Collection.

Minerals form distinctive skin lesions and rashes that psychologically impair the social life of the patient. In Western countries, approximately 2% of the total population is affected by mineralogy.

The onset of mineral lesions and their remission are often experienced alternately over several years. Mineral formations have two characteristic symptoms.

Namely, it is an inflammatory reaction common to other superficial skin diseases and a tendency for abnormal proliferation of the epidermis. Many researchers have endeavored to elucidate the mechanism of this inflammatory response from an immunological perspective, and the mechanism of abnormal proliferation of the epidermis from a cellular physiological perspective, but these mechanisms are still poorly understood. Unexplained [Beutner, E, H, (Beutner+
E, H.), “Autoimmunity in Mineral Diseases” (“Auto
CRC Press, Boca Raton, 1982.

Mineralization is a typical disease associated with inflammatory keratosis of the skin, and the number of patients suffering from mineralization is increasing.

Various classifications have been made for minerals, but generally,
It is classified into vulgaris mineral deposits, purulent mineral deposits, arthritic mineral deposits, drip mineral deposits, etc. Among these disease types, vulgaris is the main type, accounting for 80% to 90% of the gold side of the disease.

When infected with mineralogy, erythematous macules or red papules with clear boundaries appear on areas of the body that are susceptible to external inflammatory stimuli.
For example, it occurs on areas such as the head, elbows, knees, buttocks, and hairy areas where bacteria and fungi can grow.

Typical granular therapy methods traditionally used by physicians are to control hyperactive proliferation of epidermal cells, suppress inflammatory responses, promote immune regulation, and prevent bacterial and fungal infections. That's true. For example, the following treatment methods have traditionally been used: (1) External and internal use of adrenocortical hormones. (2) Photochemotherapy. (3) Phototherapy (UV irradiation). (4) External treatment with coal tar. (5)
Administration of methotrexate. (6) Administration of retinoid.

Although corticosteroids have an immediate effect in alleviating mineral symptoms to some extent, the susceptibility to tachyphylaxis makes continuous administration of this hormone difficult and, more undesirably, the dose has to be increased. . In such cases, when administration of this hormone is discontinued to administer the drug or to avoid side effects, dermatitis often occurs as a rebound phenomenon, further worsening the symptoms.

Therefore, it is difficult to effectively treat carbonization with corticosteroids alone. Photochemotherapy and therapies using epidermal cell growth inhibitors such as coal tar, anthralin, and retinoids in combination with corticosteroids may achieve some therapeutic effect, but do not completely cure mineralization. It is not possible. [Renique, naughty, naughty. Roenigk+
H,H,, Jr.) and Meinbach, H.I.
(Mainbach, H, 1,), “Soraiasis (P
soriasis) J, Marcel Deckker (Marc)
el Dekker Inc.), New York, 19
1985].

Therefore, it is an object of the present invention to provide a new pharmaceutical composition effective for treatment of mineral deposits.

(Means for Solving the Problems) The present inventors continued intensive research into the pharmacological effects of IL-1, and unexpectedly found that IL-1
They discovered that it has an anti-carbonization effect, and based on this knowledge, they continued their research and completed the present invention.

IL-1 has been reported as a factor with mitogenic activity on mouse thymocytes [Gery, 1. , Ge
r-shon, R., and Waksman, B.
,H,,J,Exp,Med,, 136128-13
8. (1972)]. Since then, its isolation and purification have progressed, and so far, I
The chemical structures of L-1 have been clarified [A
uron+P,E,,Webb+A,C,,Rosen
wa-sser, Lj, et al, Pro
c, Natl, Acad, Sci, USA, +81+7
907-791L (1984); March
+C,J, +Mo5ley+B, +Larsen,A,
et al, + Nature, 315.641-6
47+ (1985); Lomendico,
P, T, + Gubler, U, + Helman.

C.P. et al., Nature, 312.
458-462+ (1984);Furutani,
Y, + Notake + M- + Yamayosh
i, M,,et al,+Nucleic Ac1d
Res,, 13.5869-5882. (1985
Year)].

IL-1 is divided into two different groups with isoelectric points p15 and pI = 7 to 8, the former is called α type and the latter β type, but both of them are located on the same cell surface. It has been shown that it binds to a specific receptor [Do
wer, S, ni, + Kronl>eim+s, R,
+ Hopp+T, P, et al,, Nature
, 324.266-268° (1986)].

IL-1 induces the proliferation and differentiation of T lymphocytes, B lymphocytes, and natural killer (NK) cells, promotes the production of lymphokines, and has the effect of enhancing the tumor cytotoxic activity of monocytes and NK cells. It is considered to be one of the factors that plays an important role in regulating antibody production and cell-mediated immunity. On the other hand, as a mediator of acute-phase inflammatory reactions, IL-1 has a thermogenic effect and an effect of inducing the production of acute inflammatory proteins in hepatocytes, as well as a proliferation-promoting effect on fibroblasts and an inhibitory effect on collagenase and prostaglandin. It has been reported that it promotes the production of [D
inarello, C.A., FASEB J.l.
2+108~115. (1988) 1゜The active ingredient IL-1 of the pharmaceutical composition of the present invention includes naturally derived human IL-1 and recombinant human IL-1 produced by recombinant gene technology, and its anti-mineralization active site. Contains polypeptides. Also included are aggregates and mixtures of these polypeptides.

The human IL-1 mentioned above is, for example, Gu
ler, U.) et al. [J, Immuno
l.

136, 2492-2497. (1986) 1
Tossi, M.

The method by Tocci, Mu, et al. [J, I
mmunol.

For Yu, 1109-1114. (1987)].

The anti-mineralization effect of human IL-1 will be specifically explained below using experimental examples.

The human IL-1 used in the following experimental examples was Kikumoto,
Y, (Kikumoto, Y,) et al. Bioch
e+m.

Biophys, Res, Comn+un, + 14
1, pp. 315-321, 1987. The prepared IL-1 standard was SO
3 showed unity on electrophoresis.

(Experimental example) Mouse tail epidermis model [Wrench+RandBritt
n, A, Z,, Br, J, Dermatol,, 9
2+ 569-574+ (1975); Blad
on+P, T, +Taylor, M, +Wood+E,
J, + et al, Arch, Dermatol,
Res, + 277+ 121~12.5+ (1985
We investigated the effects of human IL-1 on human IL-1.

Human IL-1 was added to the tail of a 5-week-old male BALB/C mouse.
Phosphate buffer containing (0.1% bovine blood serum Alpha 2
50 μl (containing μH dithiothreitol and 0.15M NaC1) was administered subcutaneously, and 4 days later, histological examination of the tail epidermis was performed by hemadoxylin and eosin staining.
The presence or absence of the granular layer in each of the 5 cale regions was observed. The results are 5cale reg of the epidermis of the entire mouse tail.
ion, 5cale re-gio with granular layer
The proportion of n is expressed as a percentage. Further, as a control, a phosphate buffer solution containing no human IL-1 was used. The results are shown in Table 1.

Drug Table 1 Dose Cut into mouse tail epidermis Human) Effect of IL-1 Number of granular layer positive 5kale regions Number of mice Number of mice Total number of 5kale regions Vehicle
50 μm Human IL-10, 25 ng 2.5 ng 5 ng 2.6 a) 1.6 0 2.9 1.1 H a) Standard error above the mean b) Significant difference from the vehicle administration group (*: p< Q, 05;
#: p<0.0Ql) xioo (%) (blank below) As is clear from Table 1, human IL-1 was administered by administering the proportion of the 5 cale region containing the granular layer out of the 5 cale region of the epidermis of the entire mouse tail. This caused a significant increase in the dependence of
Wrench+R-) et al. [Br, J, Dermatol
,, 92.569-574° (1975) 1 and Brighton, P.T. (Bladon, P.T.)
[Arch, Dermatol, Res, 277
, 121-125. (1985)], which indicates the effectiveness of the drug screening system for treating dryness, indicating that human IL-1 has anti-desiccation activity.

The pharmaceutical composition for treating mineral deposits of the present invention can be administered as intravenous, intramuscular, subcutaneous, or subcutaneous injections, or as oral preparations, external preparations, suppositories,
It can be administered as eye drops.

Examples of formulations include solutions or lyophilized products.

In its formulation, excipients include potato starch, corn starch, dextrin, wheat,
Starches such as starch, starch derivatives such as hydroxypropyl starch, te's such as lactose, glucose, siglla, mantonitol, and sorbitol, celluloses such as methylcellulose, carboxymethylcellulose, and hydroxypropylcellulose, sodium chloride, boric acid, Inorganic substances such as calcium sulfate, calcium phosphates, precipitated calcium carbonate, and fluidizing agents include heavy magnesium oxide, synthetic magnesium aluminate silicate, hydrous silicic acid, talc, magnesium stearate, silicic anhydride, and kaolin. etc., as a binder,
Synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and derivatives thereof,
Natural products such as gum arabic, tragacanth, sodium alginate, gelatin, and gluten; stabilizers include proteins such as albumin, gelatin, globulin, protamine, and protamine salt; and amino acids; pH regulators include hydrochloric acid and hydroxylation. Sodium, phosphates, citrate,
Carbonates etc. can be used.

Additionally, IL-1 can be administered by a topical route, such as by application to or penetration into the skin in an ointment or gel base. These formulations use surfactants such as sodium lauryl sulfate, Tween surfactants, and Spa
n) type surfactants, and adhesives include natural rubber, butyl rubber, polyisobutylene, polyalkyl acrylate, polyterpene resin, etc., and oil bases include aliphatic higher alcohols, higher fatty acid esters, waxes, Triglycerides, monoglycerides, liquid paraffin, Isopar, petrolatum, silicone oil and lanolin, improved vegetable oils
castor oil), castor oil
Natural products such as oil) can be used. In these dosage forms, dosage forms well known to those skilled in the art can also be used.

According to another aspect of the invention, an effective amount of IL
A method of treating psoriasis is provided comprising administering -1 to a patient suffering from psoriasis.

The pharmaceutical compositions of the invention generally provide a daily dosage of about 0.01 to 10,000 μg of IL-1 for troughing.
Preferably, for topical administration, at a dose of about 0.0
In doses of 1 to 100 μg, for typical administrations such as intravenous or intramuscular administration, approximately 0.1 to 1000 μg.
g, and for oral administration, about 1 to 10 g.
．． A dose of 000 μg can be administered to xerosis patients. - The daily dosage varies depending on the patient's age and symptoms.

As mentioned above, the pharmaceutical compositions of the present invention can be administered at doses of 0.01 to 10.000 μg per day, typically over a period of several days to several weeks. This daily dose can be administered to the patient in multiple doses or in divided doses.

The pharmaceutical composition of the present invention can be administered daily or at intervals. Examples of typical administration methods are shown below.

a) Daily administration for 1 to 4 weeks b) Daily administration for 6 days, followed by intermittent administration with body medications in between for 7 days to several weeks c) Once a week administration d) Daily administration for 5 days, then 1 Intermittent administration with a period of several months of physical therapy.

As described above, according to the present invention, it is possible to provide a pharmaceutical composition for treating mineral minerals that does not substantially have the drawbacks of currently known dry treatment methods.

An embodiment of the present invention will be specifically described below in Examples.

(Example) Human 1-IL-1 is prepared by recombinant DNA technology according to the above experimental example, and the obtained recombinant human IL-1 is used to prepare a lyophilized preparation for injection having the following composition.

composition human IL-1 D-mannitol Normal serum albumin (human) sodium chloride Sodium dihydrogen phosphate (pH 8.0 with sodium hydroxide) 50μg 0 mg 0 mg 2.0 mg 3.9 mg (prepared to)

Claims (1)

[Claims] A pharmaceutical composition for treating psoriasis, comprising an amount of interleukin-1 effective for treating psoriasis and at least one pharmaceutically administrable carrier, diluent or excipient.