KR20140003976A

KR20140003976A - Compositions comprising etanercept for the treatment of recurrent pregnancy loss

Info

Publication number: KR20140003976A
Application number: KR1020120071977A
Authority: KR
Inventors: 김정훈
Original assignee: 울산대학교 산학협력단
Priority date: 2012-07-02
Filing date: 2012-07-02
Publication date: 2014-01-10

Abstract

The present invention relates to a composition containing etanercept for treating protopathic recurrent pregnancy loss, more specifically, to a composition containing therapeutically effective amount of etanercept which is an active component for the treatment of habitual abortion, and a habitual abortion treatment containing the composition. The composition and the treatment are injected to patients with protopathic habitual abortion of unknown causes to effectively prevent and treat habitual abortion without toxicity and side effects, and increase the rate of live births. [Reference numerals] (AA) Registering and randomly allocating 96 female patients; (BB) Registering 48 people in an etanercept injection group and performing assigned treatment; (CC) 16 people: clinical pregnancy failure; (DD) 6 people: abandonment; (EE) Registering 48 people in an IVIG (immunoglobulin) injection group and performing assigned treatment; (FF) 17 people: clinical pregnancy failure; (GG) 3 people: abandonment; (HH) 1 person: ectopic pregnancy; (II,JJ) Analyzing the results of 27 clinically normal pregnancy patients

Description

Compositions comprising etanercept for the treatment of recurrent pregnancy loss}

The present invention relates to a composition for the treatment of habitual miscarriage (recurrent pregnancy loss, RPL) comprising an itanercept, specifically, a composition for treating the habitual miscarriage comprising a therapeutically effective amount of the active ingredient iterceptor and The habitual miscarriage treatment agent prepared by formulating the composition can be administered to patients with primary RPL of unknown cause to effectively prevent and treat the habitual miscarriage without toxicity and side effects, as well as to significantly increase the live birth rate. .

Etanercept (trade name: Enbrel) is a therapeutic agent for autoimmune diseases that inhibit tumor necrosis factor (TNF), a water-soluble inflammatory cytokine. It is a fusion protein having a molecular weight of 150 kDa that fuses the soluble fragment and the Fc region of immunoglobulin (Ig) G1. Itanercept inhibits its activity through binding to TNFα, which causes a number of diseases associated with excessive inflammatory responses in mammals, including humans, such as rheumatoid arthritis, juvenile rheumatoid, and psoriatic arthritis. It is known to have therapeutic effects on autoimmune diseases such as arthritis, plaque psoriasis and ankylosing spondylitis.

Meanwhile, maternal abnormal immune responses to the fetus are known to be associated with unexplained recurrent pregnancy loss (RPL). Immunotherapies, including intravenous immunoglobulin (IVIG), are mainly used for the treatment of patients with these diseases, but clinical studies have shown conflicting results. .

Therefore, the present inventors studied an effective treatment method for primary RPL patients, and compared with IVIG, which is an inhibitor of tumor necrosis factor (TNF) -α The present invention has been completed by discovering a remarkably good therapeutic effect.

Accordingly, it is an object of the present invention to provide a therapeutic composition that can effectively treat habitual miscarriage.

It is another object of the present invention to provide a habitual lactic acid therapeutic prepared by formulating the composition.

In order to achieve the above object, the present invention provides a composition for the treatment of recurrent pregnancy loss (RPL) comprising a therapeutically effective amount of itneret (etanercept).

In order to achieve the above another object, the present invention provides a habitual lactic acid therapeutic agent prepared by formulating the composition.

The present invention relates to a composition for treating habitual miscarriage (recurrent pregnancy loss, RPL) containing itanercept, specifically, a composition for treating habitual miscarriage comprising a therapeutically effective amount of iterceptor, the active ingredient, and The habitual miscarriage treatment comprising the composition is administered to patients with primary RPL of unknown cause compared to the immunoglobulin (IVIG), which is a conventional treatment, to effectively prevent and treat habitual miscarriage without toxicity and side effects, can significantly increase live birth rates.

FIG. 1 is a randomized screening, test, and analysis of Etanercept and immunoglobulin (IVIG) test groups, which are conventional primary RPL therapeutic agents, in 96 primary RPL patients according to an embodiment of the present invention. This is a flow chart showing the process.

Hereinafter, the present invention will be described in detail.

According to one embodiment of the present invention, in 96 patients with primary unexplained primary recurrent pregnancy loss (RPL) identified as having suffered at least three unexplained miscarriages without prior birth, as shown in FIG. As a result, 48 patients were divided into the etanercept group and the remaining 48 patients into the immunoglobulin (IVIG) group, which was treated with iterceptor and IVIG, respectively. In the case of 25 mg of Etanercept once a week until the 12th week of reappointment, the same amount was administered subcutaneously once every 2 weeks in the relocation parking, and in the IVIG group, 10 mg of IVIG once a week until the 12th week of reappointment, Subsequent doses were administered subcutaneously in biweekly parking sessions, followed by 27 patients in each group selected for clinical intrauterine pregnancy. As a result, the live birth rate (85.2%) and the birth rate (88.5%) in clinical pregnancy without the brighted ovum were excluded from the primary RPL. Compared to IVIG group (55.6% surviving infants, 60.0% surviving infants in clinical pregnancies without blighted ovum), it was found to be significantly higher but without any side effects or toxicity.

Therefore, the therapeutic composition for treating RPL comprising Etanercept according to the present invention in a therapeutically effective amount can significantly improve the prevention and treatment of abortion disease as well as the survival rate of surviving infants when administered to primary RPL patients compared to conventional IVIG administration. It can be seen.

The dosage of Etanercept, the active ingredient in the composition of the present invention may vary depending on age, sex, weight, symptoms, degree of disease, drug form, route of administration and duration, and according to an embodiment of the present invention Mammalian mammals may be administered parenterally, preferably subcutaneously, in the form of 0.01 to 10 mg / kg body weight, preferably 0.1 to 1 mg / kg body weight, once every 1 to 3 weeks. It is not limited. Also in some cases, dosage values below the above-mentioned range may be more suitable, and more dosages may be used without causing harmful side effects, and in larger dosages, several smaller dosages may be dispensed. Can be administered.

The therapeutic compositions of the present invention can be used in any form suitable for pharmaceutical formulations in accordance with conventional methods, for example, various oral, including tablets, pills, powders, capsules, syrups, emulsions, microemulsions and the like. It may be formulated in dosage forms or in various parenteral dosage forms including, but not limited to, sterile injectable solutions for intramuscular, intravenous or subcutaneous injection, or external preparations such as ointments, creams, or suppositories. .

In addition, the therapeutic composition containing the itanercept of the present invention may further include appropriate carriers, excipients and diluents commonly used in the formulation of pharmaceutical compositions according to the dosage form thereof, and the therapeutic compositions of the present invention. When prepared in the form of this oral formulation, examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate and stearic acid, magnesium stearate, calcium stearate, gelatin, talc, interface Active agents, suspending agents, emulsifiers, diluents, and the like, and when prepared in the form of injectables, examples of carriers include water, saline, aqueous glucose solutions, pseudoglucose solutions, alcohols, glycols, ethers (e.g. polyethylene glycol 200), oils , Fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers and the like.

Pharmaceutical dosage forms of the compositions of the invention may also be used in the form of their pharmaceutically acceptable salts, or may be used alone or in combination with other pharmaceutically active drugs or in the form of a suitable combination.

The therapeutic composition containing a therapeutically effective amount of the itanercept of the present invention can be administered to patients with primary RPL of unknown cause to effectively treat the disease without increasing serious toxicity and side effects and increase the rate of birth of surviving infants. have. Accordingly, the present invention provides a habitual lactic acid therapeutic prepared by formulating the composition.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.

Example : For unexplained primary habitual abortion Italycept effect

1) Test method

The following tests were performed on 96 patients with unexplained primary recurrent pregnancy loss (RPL) who were found to have had an unexplained miscarriage more than three times without previous birth experience. Random distributions were made using pre-packaged envelopes and computer-generated lists. The 48 patients thus allocated were divided into the etanercept group and the remaining 48 patients into the immunoglobulin (IVIG) group. Treatment in each group started from the early luteal phase of the conception cycle and continued until week 32. For the Etanercept group, 25 mg of Etanercept until week 12 Was administered every week by subcutaneous injection and then every 2 weeks in the reapartment parking lot. IVIG was administered weekly subcutaneously and then once every two weeks in the reparatory parking, a flow chart for the distribution, testing and analysis of the randomized screening process for each test group is shown in FIG. Twenty seven patients in each group selected for clinical intrauterine pregnancy were analyzed as follows.

2) Result

The characteristics of the two groups of subjects are shown in Table 1 below. Statistical analysis in Table 1 confirmed that there was no significant difference in significance probability using the independent t-test, and each value represents the mean ± standard deviation.

Etanercept County IVIG County Number of patients 27 27 Patient age (years) 36.1 ± 2.4 35.7 ± 2.3 Spouse age (years) 39.6 ± 4.2 38.7 ± 4.5 BMI (Body Mass Index) (kg / m ² ) 21.3 ± 1.5 21.1 ± 1.4 Non-smokers (percentage) 25/27 (88.9%) 26/27 (92.6%) Number of smokers (%) 3/27 (11.1%) 2/27 (7.4%) Follicle 9.0 ± 3.4 9.3 ± 4.0 Abortion Count Before Test 4.0 ± 1.0 3.7 ± 1.0 Number of Pregnancy More Than 20 Weeks Before the Test 0.2 ± 0.5 0.1 ± 0.4

As can be seen in Table 1, no significant difference was found in the characteristics of the patients in both test groups, and the average number of abortions before the test was 4.0 ± 1.0 in the Itanercept group and 3.7 ± 1.0 in the IVIG group. It was. Of the 27 pregnant women in the Itanercept family, 15 are through planned timed coitus in the natural cycle, 8 are through IVF-ET (in vitro baby procedure), and 4 are controlled Pregnant by performing intrauterine insemination (IUI) via ovarian stimulation (COS). In the IVIG group, 16 of 27 were planned marital relationships in the natural cycle, 6 were IVF-ET, and 5 Two were pregnant through the UI with COS.

After performing a therapeutic effect test in accordance with the test method for these two groups of patients and analyzed the therapeutic effect of each drug based on the results are shown in Table 2 below. Statistical analysis in Table 2 confirmed that there was no significant difference in the probability using the Chi-square test or the Fishers exact test.

Etanercept County IVIG County Number of patients 27 27 Abortion Rate (Percent) 4/27 (14.8%) 12/27 (44.4%) Surviving birth rate (percent) 23/27 (85.2%) 15/27 (55.6%) Birth rate of surviving infants excluding dead persons (percent) 23/26 (88.5%) 15/25 (60.0%) Abortion Regeneration Parking Lot (Note) 9.0 ± 1.0 9.6 ± 3.5 Survival premature birth rate (percent)
Premature birth 1/23 (4.3%)
Week 34 2/15 (13.3%)
30 and 35 weeks each

As a result, as shown in Table 2, the live birth rate of the Itanercept group was 85.2% (23/27), which was significantly higher than that of the IVIG group (55.6% (15/27)). (P (significance probability) = 0.035). In addition, the birth rate of surviving infants in clinical pregnancy without the blighted ovum in the Itanercept group was 88.5% (23/26), compared with 60.0% (15/25) in the IVIG group. (P = 0.027). At this time, one mother in the Itanercept group had a preterm birth at 34 meetings, and two mothers in the IVIG group had preterm births at 30 and 35 meetings, respectively. Congenital anomalies of newborns were not observed in either group, and no adverse effects from administration of Etanercept or IVIG were identified in all patients.

Thus, the composition comprising the itancept according to the present invention, when administered to patients with primary cause of unknown RPL compared with conventional IVIG administration, significantly improves the survival rate of the infant as well as the prevention and treatment of habitual miscarriage without toxicity or side effects. It can be seen that.

So far I looked at the center of the preferred embodiment for the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims

A composition for the treatment of recurrent pregnancy loss (RPL) comprising a therapeutically effective amount of itanercept (etanercept).

The method of claim 1,
The itanercept is a composition for the treatment of habitual miscarriage, characterized in that administered once every 1 to 3 weeks in an amount of 0.1 to 1 mg / kg body weight.

The method of claim 1,
The itanercept is administered in a subcutaneous injection form, characterized in that the composition for the treatment of habitual miscarriage.

A habitual lactic acid therapeutic prepared by formulating the composition of claim 1.