JP7239981B2 - Preventive or therapeutic agent for recurrent pregnancy loss - Google Patents

Description

TECHNICAL FIELD The present invention relates to a preventive or therapeutic agent for recurrent pregnancy loss. More particularly, the present invention relates to a preventive or therapeutic agent for recurrent pregnancy loss and a pharmaceutical composition for preventing or treating recurrent pregnancy loss.

Recurrent pregnancy loss is defined as a condition in which a pregnancy is established, but a live baby cannot be obtained due to repeated miscarriage, premature birth, and stillbirth. Aspirin therapy, heparin therapy, steroid therapy, etc. are known as treatment methods for recurrent pregnancy loss (see, for example, Non-Patent Document 1).

By the way, allergic diseases such as allergic rhinitis and atopic dermatitis caused by mites are known. Hyposensitization therapy using a mite-derived antigen has been put into practical use as one of the therapeutic methods for these diseases. For example, Patent Document 1 describes a rapidly dissolving sublingual tablet containing a mite-derived antigen.

JP 2016-193929 A

Chakraborty P., et al., Aspirin and low-molecular weight heparin combination therapy effectively prevents recurrent miscarriage in hyperhomocysteinemic women., PLoS One, 8 (9), e74155, 2013.

However, conventional aspirin therapy, heparin therapy, steroid therapy, etc. may not provide sufficient therapeutic effects for recurrent pregnancy loss. In addition, there is concern about teratogenicity of these drugs, and attention should be paid to bleeding and decreased platelets. Accordingly, an object of the present invention is to provide a preventive or therapeutic agent for recurrent pregnancy loss.

The present invention includes the following aspects.
[1] A prophylactic or therapeutic agent for recurrent failure, which contains a mite-derived antigen as an active ingredient.
[2] The prophylactic or therapeutic agent according to [1], which is for subcutaneous administration.
[3] A pharmaceutical composition for preventing or treating recurrent pregnancy loss, containing the preventive or therapeutic agent according to [1] and an adjuvant.
[4] The pharmaceutical composition for prevention or treatment according to [3], which is for subcutaneous administration.

INDUSTRIAL APPLICABILITY According to the present invention, a preventive or therapeutic agent for recurrent pregnancy loss can be provided.

3 is a representative photograph of the uterus of the control group in Experimental Example 1. FIG. 4 is a graph showing the results of Experimental Example 1. FIG.

[Preventive or therapeutic agent for recurrent pregnancy loss]
In one embodiment, the present invention provides a prophylactic or therapeutic agent for recurrent failure to thrive, containing a mite-derived antigen as an active ingredient.

As used herein, "prophylactic or therapeutic agent" means a prophylactic or therapeutic agent. That is, it can be said that the present invention provides a preventive agent for recurrent pregnancy loss or a therapeutic agent for recurrent pregnancy loss.

In the present specification, "containing as an active ingredient" means containing as a main active ingredient, and the content is not particularly limited as long as it contains the tick-derived antigen as a medicinal ingredient.

A mating system of CBA/J (H-2:k)×DBA/2 (H-2:d) is known as an animal model of recurrent abortion in humans. On the other hand, the CBA/J(H-2:k)×BALB/c(H-2:d) mating system is an animal model with a low abortion rate.

As will be described later in Examples, the inventors have demonstrated that fetal mortality can be significantly reduced by administering tick-derived antigens to recurrent abortion model mice. Therefore, the prophylactic or therapeutic agent of this embodiment can prevent or treat recurrent pregnancy loss. The prophylactic or therapeutic agent of this embodiment is preferably for subcutaneous administration.

Dermatophagoides farinae (hereinafter sometimes referred to as "Derf"), Dermatophagoides pteronyssinus (hereinafter sometimes referred to as "Derp") and the like are known as mites that cause allergic diseases. .

Among the antigens (allergens) produced by these mites, the most problematic ones are Group I (DerI), which is abundantly contained in their excreta and has a molecular weight of about 25,000, and DerI, which is abundantly contained in the insect body and has a molecular weight of about 14. ,000 of proteins called croup II (DerII).

Group I and Group II proteins from Derf are called DerfI and DerfII proteins, respectively. Group I and Group II proteins derived from Derp are also referred to as DerpI and DerpII proteins, respectively.

In the preventive or therapeutic agent of the present embodiment, the tick-derived antigen includes a tick worm body extract, a tick excrement extract, a recombinant DerfI protein or a fragment thereof, a recombinant DerfII protein or a fragment thereof, a recombinant DerpI protein or fragments thereof, recombinant DerpII protein or fragments thereof, mixtures thereof, and the like can be used. In addition, mites may be used singly or in combination of two or more.

In particular, mite-derived antigens for desensitization therapy for mite-allergic rhinitis have well-established manufacturing techniques and are readily available, and thus can be suitably used as the preventive or therapeutic agent of the present embodiment.

Administration of the prophylactic or therapeutic agent of this embodiment to a patient can be performed, for example, by subcutaneous administration. Subcutaneous administration can be performed by injection or the like.

The dosage of the prophylactic or therapeutic agent of the present embodiment varies depending on the patient's symptoms, age, administration method, etc., and cannot be determined unconditionally. Dosing schedules include one or more administrations of

[Pharmaceutical composition for preventing or treating recurrent pregnancy loss]
In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating recurrent pregnancy loss, containing the preventive or therapeutic agent described above and an adjuvant. That is, the pharmaceutical composition of this embodiment contains a tick-derived antigen and an adjuvant.

As used herein, "prophylactic or therapeutic pharmaceutical composition" means a prophylactic or therapeutic pharmaceutical composition. That is, it can be said that the present invention provides a pharmaceutical composition for preventing recurrent pregnancy loss or a pharmaceutical composition for treating recurrent pregnancy loss.

By containing an adjuvant, the pharmaceutical composition of the present embodiment can improve the preventive or therapeutic effect of recurrent pregnancy loss and suppress the onset of anaphylactic shock.

As an adjuvant, the same adjuvant as used in ordinary vaccine formulations can be used. More specifically, for example, aluminum hydroxide gel, Freund's complete adjuvant, Freund's incomplete adjuvant, hemozoin and the like can be used.

The pharmaceutical composition of this embodiment is preferably for subcutaneous administration. The pharmaceutical composition of this embodiment is preferably formulated as a pharmaceutical composition containing the aforementioned prophylactic or therapeutic agent, adjuvant and pharmaceutically acceptable carrier. The pharmaceutical composition is preferably in a parenteral dosage form such as an injection.

As the pharmaceutically acceptable carrier, those that are usually used for formulation of pharmaceutical compositions can be used without particular limitation. Pharmaceutically acceptable carriers include, for example, purified water, base materials such as titanium oxide, carnauba wax, synthetic squalane, crotamiton and gelatin; binders such as ethyl cellulose, glycerin and methacrylic acid copolymer S; crystalline cellulose and croscarmellose. excipients such as sodium, magnesium stearate and hypromellose; stabilizers such as gum arabic, magnesium aluminometasilicate, povidone, benzyl alcohol, sodium acetate and magnesium stearate; plasticizers such as macrogol 400 and macrogol 6000; Dissolution aids such as benzyl benzoate and benzyl alcohol; adhesives such as rubber-based adhesives and silicone-based adhesives;

The pharmaceutical composition may further contain additives. Additives include sweeteners such as sucrose, lactose and saccharin; flavors such as peppermint and l-menthol; preservatives such as benzoic acid, salicylic acid, thimerosal and phenol.

The pharmaceutical composition is prepared by appropriately combining the above-mentioned mite-derived antigen, adjuvant, and the above-mentioned pharmaceutically acceptable carrier and additive, and mixing them in a unit dosage form generally accepted for pharmaceutical practice. can do. Administration of the pharmaceutical composition of this embodiment to a patient can be performed, for example, by subcutaneous administration. Subcutaneous administration can be performed by injection or the like.

The dosage of the pharmaceutical composition of the present embodiment varies depending on the patient's symptoms, age, administration method, etc., and cannot be determined unconditionally. Dosage schedules include single or multiple administrations.

[Other embodiments]
In one embodiment, the present invention provides a method of preventing or treating recurrent pregnancy loss comprising administering to a patient in need of treatment an effective amount of a tick-derived antigen. As the mite-derived antigen, those similar to those described above can be used.

In one embodiment, the present invention provides tick-derived antigens for the prevention or treatment of recurrent pregnancy loss. As the mite-derived antigen, those similar to those described above can be used.

In one embodiment, the present invention provides use of a tick-derived antigen for producing a preventive or therapeutic agent for recurrent pregnancy loss. As the mite-derived antigen, those similar to those described above can be used. In addition, the tick-derived antigen may be mixed with the adjuvant described above and formulated as a pharmaceutical composition.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to the following examples.

[Experimental example 1]
CBA/J (female) mice crossed with DBA/2 (male) mice, which are habitual abortion models, were given 10 μg/mouse tick-derived antigen (mite (Df) worm body extract, product number 10107, ITEA Co., Ltd. Tokyo Environmental Allergy Research Institute) was intraperitoneally administered together with 400 μg/mouse of hemozoin. Hemozoin is an adjuvant. A control female abortion model mouse was administered physiological saline as a vehicle. Subsequently, mating was performed 10 to 13 days after administration of the tick-derived antigen.

Subsequently, on the 14.5th day of pregnancy, the uterus was collected and observed under a stereomicroscope, and the fetal death rate was calculated as the number of dead fetal sites/the number of implantation sites. FIG. 1 is a representative photograph of the uterus of the control group. In FIG. 1, arrows indicate dead resorbed fetuses.

Moreover, FIG. 2 is a graph showing the measurement results of the fetal mortality rate. In FIG. 2, the "control group" indicates the results of mice to which physiological saline was administered, and the "tick-derived antigen-administered group" indicates the results of mice to which the tick-derived antigen was administered. In addition, in FIG. 2, "*" indicates that there is a significant difference from the test group at P<0.05.

As a result, a significant reduction in the fetal mortality rate was observed in the tick-derived antigen-administered group compared with the control group. These results demonstrate that the mite-derived antigen is useful as a preventive or therapeutic agent for recurrent failure to thrive.

INDUSTRIAL APPLICABILITY According to the present invention, a preventive or therapeutic agent for recurrent pregnancy loss can be provided.

Claims (4)

A prophylactic or therapeutic agent for recurrent infertility, comprising a mite-derived antigen as an active ingredient. The preventive or therapeutic agent according to claim 1, which is for subcutaneous administration. A pharmaceutical composition for preventing or treating recurrent pregnancy loss, comprising the preventive or therapeutic agent according to claim 1 and an adjuvant. The preventive or therapeutic pharmaceutical composition according to claim 3, which is for subcutaneous administration.

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