JP4794148B2 - Nephrotic syndrome therapeutic agent - Google Patents

Description

で表される（±）−〔２−〔４−（３−エトキシ−２−ヒドロキシプロポキシ）フェニルカルバモイル〕エチル〕ジメチルスルホニウム ｐ−トルエンスルホネート（一般名：トシル酸スプラタスト）を有効成分として含むネフローゼ症候群治療剤に関する。 The present invention relates to formula (1)

(±)-[2- [4- [3- (2-Ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate (generic name: suplatast tosylate) as an active ingredient It relates to a therapeutic agent.

Nephrotic syndrome is a syndrome in which protein leaks into the urine due to increased permeability of glomerular snares, resulting in severe proteinuria, hypoproteinemia, hyperlipidemia, and edema.
Nephrotic syndrome is not a single disease but a clinical syndrome of glomerular disease that develops with common symptoms from various causative diseases. In adults, urine protein is 3.5 g / day or more and serum protein is 6.0 g / dl or less. Many of them are accompanied by edema and serum cholesterol of 250 mg / dl or more.

Nephrotic syndrome is usually classified as primary (primary) or secondary (secondary), and primary nephrotic syndrome refers to the glomerular body with the main lesions, specifically microvariable. , Membranous nephropathy, focal glomerulosclerosis, membranoproliferative glomerulonephritis and the like.
Secondary nephrotic syndrome is a systemic disease that has spread to the glomeruli, such as infections (syphilis, malaria, etc.), multiple myeloma, diabetic nephropathy, lupus nephritis, rheumatoid arthritis, renal amyloidosis, malignant tumor, Examples include pregnancy toxemia and purpura nephritis.

Among these, minimal change nephritic syndrome (MCNS) is a syndrome in which no significant abnormality can be found histologically on a light microscope while exhibiting symptoms of nephrotic syndrome.
This minimal change nephrotic syndrome is most common in primary nephrotic syndrome (about 80% of children and about 30% of adults cause nephrotic syndrome), especially in the younger age group . Pediatric patients often have allergic symptoms such as asthma and skin rash.

  In pharmacotherapy for nephrotic syndrome, steroid hormone is the first-line drug, especially in the micro-change type, 90% or more of steroid drugs are effective, and proteinuria disappears in 1 to 2 weeks after the start of treatment. is there.

  However, even if the effect appears once, about 60% of recurrence cases are observed with the steroid administration stoppage or dose reduction ("Modern Physician" Vol.19, No.8, 1998, pp.985-989) : Non-patent document 1), there are also side effects of steroids such as growth disorders, pathological fractures, infectious diseases, diabetes, cataracts and glaucoma. Of these side effects, especially growth disorders are very serious for pediatric patients.

In addition, cyclosporine (immunosuppressive agent) is often used in combination with steroid-resistant cases or when the side effects of steroids are significant due to high degree of dependence. Since long-term use tends to cause drug-induced renal damage, when cyclosporine is used in combination, it is necessary to administer while monitoring the blood concentration.
Under such circumstances, development of a nephrotic syndrome therapeutic agent with few side effects and excellent effects has been desired from the medical standpoint.

  On the other hand, suplatast tosylate used as an active ingredient in the therapeutic agent for nephrotic syndrome of the present invention has an excellent inhibitory effect on IgE antibody production and is known as a therapeutic agent for bronchial asthma, atopic dermatitis and allergic rhinitis (Japanese Patent Publication No. 3-70698: Patent Document 1).

Also, suplatast tosylate is a therapeutic agent for dysuria (WO00 / 27383: Patent Document 2), a therapeutic agent for pruritus associated with renal dialysis (JP-A-11-315019: Patent Document 3), C-type or non-B non- It is also known to be useful as an agent for improving liver function abnormality due to hepatitis C virus (Japanese Patent Laid-Open No. 2002-114672: Patent Document 4).
However, it has not been known that suplatast tosylate has an excellent effect as a therapeutic agent for nephrotic syndrome.

Japanese Patent Publication No. 3-70698 WO00 / 27383 Japanese Patent Laid-Open No. 11-315019 JP 2002-114672 A `` Modern Physician '' Vol.19, No.8, 1998, pp.985-989

  An object of the present invention is to provide a therapeutic agent for nephrotic syndrome having few side effects and excellent effects.

  The present inventors have observed the therapeutic effect on nephrotic syndrome using various drugs, and found that suplatast tosilate unexpectedly exerted an excellent effect on the treatment of nephrotic syndrome, and completed the present invention. It came to.

That is, the present invention relates to (±)-[2- [4- [3- (3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate (hereinafter referred to as suplatast tosylate) represented by the formula (1). A therapeutic agent for nephrotic syndrome, which comprises an active ingredient as an active ingredient.

  The present invention also provides a therapeutic agent for primary nephrotic syndrome, comprising suplatast tosylate represented by the above formula (1) as an active ingredient.

  The present invention also provides a therapeutic agent for minute change nephrotic syndrome characterized by containing suplatast tosilate represented by the above formula (1) as an active ingredient.

  The present invention also provides a treatment for nephrotic syndrome, primary nephrotic syndrome or minimal change nephrotic syndrome, which further comprises a steroid agent as an active ingredient in addition to suplatast tosylate represented by the above formula (1). An agent is provided.

Furthermore, the present invention relates to nephrotic syndrome, primary nephrotic syndrome or minimal change nephrotic comprising a therapeutic agent containing suplatast tosylate represented by the above formula (1) as an active ingredient and a preparation containing a steroid as an active ingredient. A kit preparation for treating a syndrome is provided.
As used herein, “treatment” means prevention and treatment of disease, and maintenance therapy for symptom reduction and recurrence prevention.

  Suplatast tosylate contained as an active ingredient in the therapeutic agent for nephrotic syndrome of the present invention is a known compound and can be produced, for example, by the method described in Japanese Patent Publication No. 3-70698.

The “nephrotic syndrome” in which suplatast tosylate is effective refers to a syndrome exhibiting severe proteinuria, hypoproteinemia, hyperlipidemia, and edema.
In addition, “primary nephrotic syndrome” means that the glomerulus itself has a lesion site, such as microvariable, membranous nephropathy, focal glomerulosclerosis, membranoproliferative glomerulonephritis, etc. Say.
Among these, “minimal change nephrotic syndrome” refers to a syndrome that exhibits symptoms of nephrotic syndrome but cannot find any significant abnormality histologically on an optical microscope.

  In the present invention, when a steroid agent is used in combination with suplatast tosylate, not only the therapeutic effect of nephrotic syndrome is further improved, but also the dose of the steroid agent is compared with the case where the steroid agent is used alone for the treatment of nephrotic syndrome. Since it can reduce, it is suitable also from the surface of the side effect reduction by a steroid agent.

  Examples of the `` steroidal agent '' include prednisolone, methylprednisolone, methylprednisolone acetate, prednisolone acetate valerate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, flutamethasone pivalate, triamcinolone acetonide, dexamethasone, dexamethasone, acetic acid Dexamethasone valerate, dexamethasone propionate, fluocinolone, fluocinolone acetonide, betamethasone, betamethasone valerate, betamethasone dipropionate, beclomethasone propionate, clobetasone butyrate, fludroxycortide, fluocinonide, harcinonide, amflunonide, amflunonide Diflucortron herbate, diflorazone acetate, propionate Betazole, cortisone acetate, sodium hydrocortisone phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone sodium succinate, sodium prednisolone phosphate, halopredon acetate, sodium methylprednisolone succinate, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate , Betamethasone phosphate, parameterzone acetate, betamethasone butyrate propanoate, mometasone furanate, deprodon propionate, alcromethasone propionate, and the like.

  The therapeutic agent for nephrotic syndrome of the present invention can be administered to humans in various forms. Examples of such forms include oral preparations, injections, rectal suppositories, and external preparations (ointments, patches, etc.), and these preparations can be produced by conventional methods well known to those skilled in the art.

  Among oral preparations, solid preparations are processed by conventional methods after adding excipients, if necessary, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, and flavoring agents to suplatast tosylate. Tablet, coated tablet, granule, powder, capsule, dry syrup and the like. In addition, oral liquid preparations can be made into oral liquid preparations, syrup preparations, etc. by treating with suplatast tosylate using a corrigent, buffer, stabilizer, corrigent and the like by conventional methods.

  The injection is prepared by adding a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. to suplatast tosylate, and processing by a conventional method to produce a subcutaneous injection, an intramuscular injection, It may be an intravenous injection.

  A suppository for rectal administration can be made into a suppository by adding an excipient to suplatast tosylate and, if necessary, a surfactant or the like, and then treating it by a conventional method.

  Among external preparations, ointments such as pastes, creams, gels, etc. are formulated by adding stabilizers, wetting agents, preservatives, etc., as necessary to a base containing suplatast tosylate, and processing by conventional methods. Can be Examples of the base include white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like. Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and the like.

  In addition, a patch as an external preparation can be produced by applying the above-mentioned ointment, cream, gel, paste or the like on a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, or a film of soft vinyl chloride, polyethylene, polyurethane, or a foam sheet is suitable.

A steroid agent can also be made into the administration form similar to said suplatast tosylate.
Therefore, when both suplatast tosylate and a steroid agent are used as active ingredients, a single dosage form containing both of them or two dosage forms containing each of them may be used. When two dosage forms are used, the same dosage route form (for example, both oral preparations) may be used as a kit, or different administration route forms (for example, one is an oral dosage form and the other is the other dosage form). As an injection). Moreover, as long as the objective of this invention is achieved, the separately prepared formulation may be used for the same administration subject simultaneously or with a time difference, and the number of administrations per day of each formulation may be different.

  The amount of suplatast tosylate to be incorporated in the above-mentioned various preparations can be appropriately determined according to the symptoms of the patient to whom this is to be administered, or depending on the dosage form thereof, but generally about 5 to 5 per oral unit per dosage unit. 1000 mg, about 0.1 to 500 mg for injections, and about 5 to 1000 mg for suppositories and external preparations are desirable.

Also, the daily dose of suplatast tosylate may vary depending on the patient's symptoms, body weight, age, sex, and other conditions. 5 doses are preferred.
In addition, when a steroid is used in combination, the dosage is appropriately determined depending on the type of steroid used, but usually about 0.001 to 1000 mg per day is preferable, and the dose can be gradually reduced.

  The therapeutic agent for nephrotic syndrome of the present invention can exert an excellent therapeutic effect without side effects as in the case of a steroid agent conventionally used as a first-line drug for nephrotic syndrome. Even when a steroid is used in combination, the dose can be reduced, and the problem of side effects caused by the steroid can be avoided or reduced.

(Example)
The following examples and test examples explain the present invention in more detail, but the present invention is not limited thereto.

Example 1 (tablets)
Suplatast tosilate 50mg
Corn starch 50mg
Microcrystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Lactose 47mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Unsaturated glyceride 2mg
Titanium dioxide 2mg
The composition having the above blending ratio was processed according to a conventional method to prepare tablets containing 50 mg of suplatast tosylate per tablet.

Example 2 (Granule)
Suplatast tosilate 300mg
Lactose 540mg
Corn starch 100mg
Hydroxypropylcellulose 50mg
Talc 10mg
A composition comprising the above blending ratio was processed according to a conventional method to prepare granules containing 300 mg of suplatast tosylate per packet.

Example 3 (Capsule)
Suplatast tosilate 100mg
Lactose 30mg
Corn starch 50mg
Microcrystalline cellulose 10mg
Magnesium stearate 3mg
A composition comprising the above blending ratio was processed according to a conventional method to prepare a capsule containing 100 mg of suplatast tosylate per capsule.

Example 4 (Injection)
Suplatast tosilate 100mg
Sodium chloride 3.5mg
Distilled water for injection Appropriate amount A composition comprising the above blending ratio was treated according to a conventional method to prepare an injection containing 100 mg of suplatast tosylate per ampoule (2 ml).

Example 5 (Dry syrup)
Suplatast tosilate 50mg
Purified white sugar 949mg
Fragrance Appropriate amount A composition comprising the above blending ratio was processed according to a conventional method to prepare a dry syrup preparation containing 50 mg of suplatast tosylate per packet.

Example 6 (Syrup)
Suplatast tosilate 50mg
Refined white sugar 1000mg
1 mg ethyl parahydroxybenzoate
Fragrance Appropriate amount Colorant Appropriate amount Purified water Appropriate amount A composition consisting of the above blending ratio was treated according to a conventional method to prepare a syrup containing 2 mg of suplatast tosylate in 2 ml.

Example 7 (suppository)
Suplatast tosilate 300mg
Witepsol W-35 ^* 1400mg
(*: Registered trademark, a mixture of mono-, di- and tri-glycerides of saturated fatty acids from lauric acid to stearic acid, manufactured by Dynamit Nobel)
A composition comprising the above blending ratio was treated according to a conventional method to prepare a suppository containing 300 mg of suplatast tosylate per piece.

Example 8 (Tablets)
Suplatast tosilate 50mg
Prednisolone 5mg
Corn starch 45mg
Microcrystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Lactose 47mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Unsaturated glyceride 2mg
Titanium dioxide 2mg
The composition having the above blending ratio was processed according to a conventional method to prepare tablets containing 50 mg of suplatast tosylate and 5 mg of prednisolone per tablet.

Example 9 (kit)
<Hard capsule containing suplatast tosylate>
Suplatast tosilate 100mg
Lactose 50mg
Corn starch 47mg
Crystalline cellulose 50mg
Talc 2mg
Magnesium stearate 1mg
A composition comprising the above blending ratio was processed according to a conventional method to prepare a hard capsule containing 100 mg of suplatast tosylate per capsule.

<Tablets containing dexamethasone>
Dexamethasone 0.5mg
Lactose 45mg
Corn starch 50mg
Crystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Fatty acid glycerin ester 2mg
Titanium dioxide 2mg

The composition having the above blending ratio was processed according to a conventional method to prepare tablets containing 0.5 mg of dexamethasone per tablet.
One hard capsule containing suplatast tosylate prepared as described above and one tablet containing dexamethasone were made into a single packaging form.

Test example 1
A boy 9 years and 4 months old. Nephrosis developed due to systemic edema at the age of 4 years and 6 months.
Prednisolone was administered at a dose of 35 mg / day for 4 weeks, then reduced to 25 mg / every other day and administered for 4 weeks. After that, although complete remission was achieved by treatment with steroids, recurrence was repeated at a frequency of more than 4 times a year when the dose was reduced to about 10 mg / day (steroid-dependent recurrent microchange type nephrosis syndrome).

  When recurrence occurred at the age of 8 years and 3 months, proteinuria disappeared after complete administration of prednisolone 40 mg / day for 2 weeks. Thereafter, the dose of prednisolone was reduced by 5 mg / day every 2 weeks, and administration of suplatast tosylate (trade name: IPD dry syrup / Taiwa Pharmaceutical Co., Ltd., 6 mg / kg body weight / day) was started. There has been no recurrence of nephrosis for 9 months after discontinuing prednisolone (1 year and 1 month after complete remission).

Test example 2
5 years 3 months, girl. Nephrosis developed due to systemic edema at the age of 3 years and 7 months. As in Test Example 1, steroid-dependent frequent relapsing microchange nephrotic syndrome was diagnosed, and when prednisolone was reduced to about 5 mg / day, recurrence was repeated (3 recurrences in 8 months).

  When recurrence occurred at the age of 4 years and 3 months, proteinuria disappeared after complete administration of prednisolone 30 mg / day for 2 weeks. Thereafter, the dose of prednisolone was reduced by 5 mg / day every 2 weeks, and administration of suplatast tosylate (trade name: IPD dry syrup / Taiwa Pharmaceutical Co., Ltd., 6 mg / kg body weight / day) was started. There is no recurrence of nephrosis for 9 months after discontinuing prednisolone (1 year after complete remission).

Test example 3
7 years and 6 months old boy. At the age of 4 years and 10 months, nephrotic syndrome developed with a bronchial asthma attack. Relapsed with seizures at the age of 5 years 9 months and 6 years 1 month. The first relapse and the first relapse were spontaneously ameliorated without specific treatment for nephrosis by controlling asthma attacks, but steroid therapy was required for the second relapse. Prednisolone 2 mg / kg / day was administered, and proteinuria disappeared (complete remission) within one week. The dose of prednisolone was reduced to 1.3 mg / kg / 2 days, administration of prednisolone was discontinued after 4 weeks (6 years 3 months), and instead of suplatast tosilate (trade name: IPD Dry Syrup / Taiwa Pharmaceutical Co., Ltd.) Administration (6 mg / kg body weight / day, maximum 300 mg / day) was started. Even after the administration of prednisolone was discontinued, asthma attacks disappeared from the age of 6 years and 5 months, and no relapse of nephrosis was observed for 1 year and 3 months (1 year and 5 months from complete remission).

Test example 4
5 years, 11 months, boy. Nephrotic syndrome developed at the age of 3 years and 2 months, and steroid therapy was administered for a total of 8 weeks as in Test Example 3. Although responsiveness to steroids was good, he experienced recurrence at the age of 4 years 0 months and 4 years 7 months with upper respiratory tract inflammation. Upon recurrence at the age of 4 years and 7 months, administration of suplatast tosylate (trade name: IPD dry syrup / Taisho Pharmaceutical Co., Ltd.) (6 mg / kg body weight / day, maximum 300 mg / day) was started after complete remission. There has been no recurrence of nephrosis since the start of suplatast tosylate (1 year and 4 months from complete remission).

  The therapeutic agent for nephrotic syndrome containing suplatast tosylate as an active ingredient of the present invention is useful as a therapeutic agent for nephrotic syndrome that replaces steroidal agents.

Claims (3)

Formula (1):

(±)-[2- [4- [3- (2-ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate (generic name: suplatast tosylate) represented by the formula: A therapeutic agent for preventing recurrence of minimal change nephrotic syndrome. A therapeutic agent for minimal change nephrotic syndrome comprising suplatast tosylate and a steroid as an active ingredient. A kit preparation for the treatment of minimal change nephrotic syndrome comprising the therapeutic agent for preventing recurrence according to claim 1 containing suplatast tosylate as an active ingredient and a preparation containing a steroid agent as an active ingredient.