JP2023116252A - Intravaginal administration device, ovarian function control method, and kit for administering preparation into vagina of livestock - Google Patents

Abstract

An object of the present invention is to provide an intravaginal administration device that is difficult to fall out of the vagina.
A vaginal administration device (100) has a mounting part (11) for mounting a preparation (12) to be administered into the vagina of livestock, an insertion part (10) to be inserted into the vagina of the livestock, a wing portion 20 having a plurality of wings (21a) and wings (21b) connected to one end of the insertion portion (10) and extending in a direction away from the one end, wherein the wings (20) include the wings (21a); and the ends of the wings (21b) opposite to the ends connected to the insertion portion 10 are in an open state separated from each other, and when a force is applied in a direction to bring the ends closer, the ends are moved to each other. Closed state is reached.
[Selection drawing] Fig. 1

Description

TECHNICAL FIELD The present invention relates to an intravaginal administration device, a method for controlling ovarian function, and a kit for intravaginally administering a formulation to domestic animals.

In recent years, the reduction in productivity due to the prolongation of the breeding cycle associated with the extension of the open period after parturition of livestock has become a problem. As a method for shortening the open period of livestock after parturition, a method of forcibly inducing ovulation by administering GnRH preparations, progesterone preparations, etc. to livestock is known. In addition, as described in Patent Document 1, there is also a method of controlling follicle development by administering into the blood a neurokinin receptor agonist that acts on the reproductive center to promote normal ovulation.

Methods for administering the formulation to domestic animals include intravaginal administration in addition to the blood administration described above. Vaginal administration includes a method of directly inserting the formulation into the vagina by a human hand, and a method of inserting a vaginal administration tool coated or adhered with the formulation into the vagina of livestock. As an example of a vaginal administration device, Non-Patent Document 1 describes an intravaginal administration device for administering a progesterone formulation into the vagina of a goat.

JP 2017-81917

Endo et. al., Journal of Reproduction and Development, Vol.66, p.489-492, 2020

The vaginal administration device preferably remains in the vagina and does not fall off to ensure that the formulation is taken up by the livestock. The vaginal administration device described in Non-Patent Document 1 is intended for vaginal administration to goats, and administration to other livestock is not considered. Patent document 1 relates to blood administration of the formulation, and does not describe anything about vaginal administration.

One aspect of the present invention has been made to solve the above-described problems, and an object thereof is to provide an intravaginal administration tool that is less likely to fall out of the vagina of livestock.

In order to solve the above-mentioned problems, an intravaginal administration device according to an aspect of the present invention has an attachment part for attaching a formulation to be administered into the vagina of livestock, an insertion part to be inserted into the vagina of livestock, a wing portion having a plurality of wings connected to one end of the insertion portion and extending in a direction away from the one end, the wing portion having an end opposite to the end of the wing connected to the insertion portion. The ends are in an open state separated from each other, and when a force is applied in a direction to bring the ends closer together, the ends are brought into a closed state closer to each other.

A method for controlling ovarian function according to one aspect of the present invention includes the step of administering a formulation containing a neurokinin receptor agonist into the vagina of livestock using the vaginal administration device according to one aspect of the present invention.

A kit for intravaginally administering a formulation according to one aspect of the present invention to livestock includes a vaginal administration tool according to one aspect of the present invention, and a formulation.

ADVANTAGE OF THE INVENTION According to one aspect of the present invention, it is possible to provide an intravaginal administration device that does not easily fall out of the vagina.

1 is a view showing an intravaginal administration device according to Embodiment 1 of the present invention; FIG. 1 is a diagram showing a state in which a preparation is attached to the vaginal administration device according to Embodiment 1 of the present invention. FIG. Fig. 2 is a diagram showing a vaginal administration device according to Embodiment 2 of the present invention; FIG. 10 is a diagram showing a state in which a preparation is attached to the vaginal administration device according to Embodiment 2 of the present invention. 1 is a diagram showing an intravaginal administration device according to one aspect of the present invention; FIG. FIG. 3 shows changes in MUA volley intervals due to blood administration of neurokinin receptor agonists. FIG. 2 shows changes in MUA volley interval and blood LH concentration due to intravaginal administration of a neurokinin receptor agonist. FIG. 10 shows changes in MUA volley intervals due to intravaginal administration of a sustained-release formulation containing a neurokinin receptor agonist.

[Intravaginal administration device]
One aspect of the present invention relates to a vaginal administration device for administering a formulation intravaginally to domestic animals. The present invention also includes a vaginal administration method, which includes a step of administering the formulation into the vagina of domestic animals using the vaginal administration device according to one aspect of the present invention. The vaginal administration method according to one aspect of the present invention is also an ovarian function control method in which a preparation capable of regulating the ovarian function of domestic animals is administered intravaginally to domestic animals using the vaginal administration device according to one aspect of the present invention. could be.

[Embodiment 1]
A vaginal administration device according to Embodiment 1 of the present invention will be described below with reference to FIGS. FIG. 1 shows a vaginal administration device 100 according to Embodiment 1 of the present invention. FIG. 2 is a diagram showing a state in which the preparation 12 is attached to the vaginal administration device 100 according to Embodiment 1 of the present invention. In FIG. 1, 1001 indicates a front view, 1002 indicates a left side view, 1003 indicates a right side view, 1004 indicates a plan view, and 1005 indicates a bottom view. 2, 1011 indicates a front view, 1012 indicates a left side view, 1013 indicates a right side view, 1014 indicates a plan view, and 1015 indicates a bottom view. 1 and 2, the rear view of the intravaginal administration device 100 is omitted because it is the same as the front view 1001 or 1011. FIG. FIG. 5 shows a vaginal administration device according to one aspect of the present invention.

As shown in FIGS. 1 and 2, the vaginal administration device 100 includes an insertion section 10 and wings 20 . The vaginal administration device 100 is inserted into the vagina from the vaginal opening of livestock by the whole or a part of the insertion portion 10 and the wing portions 20 . The vaginal administration device 100 is safe enough to be inserted into the vagina of livestock, and is made of a flexible material that does not damage the vagina during insertion, retention, and removal from the vagina. can be At least the insertion portion 10 and the wings 20 of the vaginal administration device 100 are preferably made of medical silicone. Further, it is preferable that the wing portion 20 is manufactured so as to have a flexibility that allows opening and closing of the wing portion 20 described later to a desired extent.

(insertion section 10)
The insertion part 10 has a mounting part 11 for mounting a formulation 12 to be administered into the vagina of livestock, and is inserted into the vagina of the livestock. The insertion portion 10 is a portion that is first inserted into the livestock's body when the vaginal administration device 100 is inserted into the vagina of the livestock. The insertion portion 10 may have a size and shape that allows it to be inserted through the vaginal opening of a domestic animal and reach the vagina. From the viewpoint of facilitating insertion into the vagina of livestock, the shape of the insertion portion 10 may be, for example, a rhombus, but is not limited to this.

In the vaginal administration device 100 , the mounting portion 11 of the insertion portion 10 is grooves 11 a and 11 b provided on the outer edge of the insertion portion 10 . As an example, by inserting the drug product 12 into the grooves 11a and 11b, the side walls of the grooves 11a and 11b sandwich and hold the drug product 12 . Since the formulation 12 is, for example, a capsule having a shape and size defined by the Japanese Pharmacopoeia, the grooves 11a and 11b may have any shape that can hold such a capsule. As an example, the grooves 11a and 11b have a length of 3-5 cm and a depth of 0.5-1 cm.

The mounting part 11 only needs to be capable of mounting one or a plurality of preparations 12 . As an example, as shown in FIGS. 1 and 2, grooves 11a and 11b may be provided on the two sides of the distal end of rhomboidal insertion portion 10, respectively, and formulation 12 may be attached to each. The grooves may be provided on two sides of the lozenge-shaped insertion portion 10 on the wing portion 20 side, or may be provided on all four sides.

Since the type and size (dosage amount) of the preparation 12 to be administered can be appropriately changed according to the mounting section 11 configured in this way, it can be used for general purposes. Formulation 12 is not particularly limited as long as it can be absorbed through the vagina, but one example is a formulation used in the method for controlling ovarian function described below.

(Feather 20)
The wing portion 20 is connected to one end of the insertion portion 10 and has a plurality of wings extending away from the one end. The feather portion 20 is connected to the end of the insertion portion 10 that faces the tip that is inserted into the vaginal opening. The wing has a shape extending from the end connected to the insertion section 10 in a direction away from the insertion section 10 . The wing portion 20 may have at least two wings 21a and 21b, and may have three or more wings.

The wings 20 are in an open state in which the ends of the wings 21a and 21b facing the ends connected to the insertion portion 10 are separated from each other. When a force is applied in a direction (the Y direction in FIG. 1) to bring the distant ends of the wings 21a and 21b closer to each other, the wings 20 are brought into a closed state in which the ends are close to each other. The wing portion 20 can be easily deformed by applying a force in a direction in which the distant ends of the wings 21a and 21b are brought closer to each other, so that the ends can be brought close to each other.

In this manner, the wing portion 20 is configured to transform from an open state in which the wings 21a and 21b are open to a closed state in which the wings 21a and 21b are closed. Therefore, the vaginal administration device 100 can be easily inserted into the vagina by inserting it into the vagina with the wings 20 in the closed state. If the wings 20 are opened after the vaginal administration device 100 is inserted into the vagina, the vaginal administration device 100 is caught on the vaginal wall by the opened wings 21a and 21b, and does not easily come off.

The vaginal administration device 100 is inserted into the vagina in a state in which a force is applied to the ends of the wings 21a and 21b in a direction to bring them closer to each other, and then the vaginal administration device 100 is released. can be inserted and retained in the vagina. Further, if the wing portion 20 is made of a highly flexible material so that it can be easily opened and closed with a small force, the wing portion 20 can be opened and closed by the pulsation of the vagina. As a result, the intravaginal administration device 100 can be inserted further into the vagina, and the intravaginal administration device 100 can be made more difficult to fall out of the vagina.

A cord 30 may be connected to at least a portion of the feather portion 20 . As shown in FIG. 5, one end of the string 30 is fixed to a hole 23a provided in the wing 21a, and the other end is passed through a hole 23b provided in the wing 21b so that the string 30 can be taken in and out through the hole 23b. It has become. As a result, when the string 30 is pulled away from the wing portion 20 (especially the wing 21b), the wing 21a is pulled by the string 30 toward the wing 21b, and the wing portion 20 is deformed so that the wing 21a approaches the wing 21b. closed.

At least a part of the cord 30 is present outside the livestock when the insertion portion 10 and the wing portion 20 are present in the vagina of the livestock. Therefore, when the intravaginal administration device 100 remains in the vagina, the wings 20 are closed by pulling the string 30, and the intravaginal administration device 100 can be taken out from the vagina.

In this way, when the vaginal administration device 100 is inserted into or removed from the vagina, the wings 20 are in the closed state, so removal is easy and the vaginal wall or the like is not damaged. can be prevented. Further, when the intravaginal administration device 100 remains in the vagina, the wings 20 are in the open state, so the wings 21a and 21b are caught on the vaginal wall and the like, making it difficult for the vaginal administration device 100 to fall out of the vagina.

One end of the string 30 may be fixed to the hole 23b and connected so as to pass through the hole 23a. A ring 40 may be attached to the end of the string 30 opposite to the end fixed to the hole 23a or 23b (the end that is not fixed). Since the string 30 is pulled by pulling the ring 40, the string 30 is easily pulled.

The wing portion 20 may be provided with a notch portion 22 at a connecting portion between at least one of the wing portions 21 a and 21 b and the insertion portion 10 . Although the shape of the notch 22 is not particularly limited, it is preferably a shape having at least a portion of an arc, such as circular, semicircular, or fan-shaped. By providing the notch 22, the force required to open and close the wing 20 is reduced, making it easier to open and close. The ease of opening and closing the notch 22 varies depending on its shape and size. As an example, when the notch 22 has a semicircular shape, the larger the diameter, the easier it is to open and close the wings 20 .

The vaginal administration device 100 is used for administering a formulation to the vagina of domestic animals. Examples of livestock that use a vaginal administration device include, but are not limited to, cattle, goats, sheep, and the like. In the vaginal administration device 100, the size and shape of each part can be appropriately set according to the type of livestock to be used, the size of the livestock, the shape and size of the livestock's vagina, and the like.

For example, when the intravaginal administration device 100 is used for cows, the vaginal opening of cows is usually 6 to 9 cm, so the size may be adjusted accordingly. As an example, the long diameter of the insertion portion 10 (the longest diameter in the horizontal direction in the front view 1001 of FIG. 1) is 3 to 7 cm, and the short diameter (the longest diameter in the vertical direction in the front view 1001 of FIG. 1) is 2 to 5 cm. be. The wings 21a and 21b have a length of 10 to 15 cm, a width of 10 to 15 cm, and an angle between the wings 21a and 21b of 40 to 100 degrees. Moreover, when the notch 22 is semicircular, its diameter is 0.5 to 1.5 cm. The vaginal administration device 100 having such a size is preferable because it is less likely that an excessive load is applied to the vaginal wall, causing the cow to feel discomfort or pain, or causing inflammation.

Since the intravaginal administration device 100 does not easily fall out of the vagina, the preparation 12 can be appropriately administered into the vagina. As a result, the formulation can be stably supplied to livestock, and the ovarian function of livestock can be controlled more stably.

[Embodiment 2]
Other embodiments of the invention are described below. For convenience of description, members having the same functions as those of the members described in the above embodiments are denoted by the same reference numerals, and description thereof will not be repeated. This embodiment is the same as the first embodiment described above, except for the configuration of the insertion portion 210 .

A vaginal administration device according to Embodiment 2 of the present invention will be described below with reference to FIGS. FIG. 3 shows a vaginal administration device 200 according to Embodiment 2 of the present invention. FIG. 4 is a diagram showing a state in which the preparation 12 is attached to the vaginal administration device 200 according to Embodiment 2 of the present invention. In FIG. 3, 2001 shows a front view, 2002 shows a left side view, 2003 shows a right side view, 2004 shows a plan view, and 2005 shows a bottom view. 4, 2011 shows a front view, 2012 shows a left side view, 2013 shows a right side view, 2014 shows a plan view, and 2015 shows a bottom view. 3 and 4, the rear view of the intravaginal administration device 200 is omitted because it is the same as the front view 2001 or 2011. FIG. As shown in FIGS. 3 and 4, the vaginal administration device 200 includes an insertion section 210 and wings 20 .

(insertion portion 210)
The insertion part 210 has a mounting part 211 for mounting the preparation 12 to be administered into the vagina of the domestic animal, and is inserted into the vagina of the domestic animal. The insertion portion 210 is a portion that is first inserted into the livestock's body when the vaginal administration device 200 is inserted into the vagina of the livestock. The insertion portion 210 may have a size and shape that allows it to be inserted through the vaginal opening of a domestic animal and reach the vagina. From the viewpoint of facilitating insertion into the vagina of livestock, the shape of the insertion portion 210 may be, for example, a diamond shape, but is not limited to this.

In the vaginal administration device 200 , the mounting portion 211 of the insertion portion 210 is a hole provided inside the insertion portion 210 . As an example, the preparation 212 is held by inserting the preparation 212 into the hole of the mounting portion 211 . Since the preparation 212 is, for example, a capsule having a shape and size defined by the Japanese Pharmacopoeia, the hole of the mounting portion 211 may have a shape capable of holding such a capsule. As an example, the hole of the mounting portion 211 is circular and has a diameter of 0.6-1 cm.

It is sufficient that one or a plurality of preparations 212 can be attached to the attachment portion. As an example, as shown in FIGS. 3 and 4, four holes may be provided as mounting portions 211 in the plane of the diamond-shaped insertion portion 210, and formulations 212 may be mounted in each of them. The diameters of the four holes of the mounting portion 211 may be the same or different. Formulations 212 of various sizes can be held by providing a plurality of holes having different diameters as the mounting portion 211 . As a result, the type and size (dosage) of the drug product 212 to be administered can be changed as appropriate, so that it can be used universally. The formulation 212 is not particularly limited as long as it is a formulation that can be absorbed through the vagina, but one example is a formulation used in the ovarian function control method described below.

Vaginal administration device 200 functions in the same manner as vaginal administration device 100 and provides similar effects. That is, since the intravaginal administration device 200 does not easily fall out of the vagina, the preparation 212 can be appropriately administered into the vagina. As a result, the formulation can be stably supplied to livestock, and the ovarian function of livestock can be controlled more stably.

[Method for controlling ovarian function]
A method for regulating ovarian function according to one aspect of the present invention includes the step of intravaginally administering a preparation containing a neurokinin receptor agonist to livestock. A method for controlling ovarian function according to one aspect of the present invention can include a step of administering a formulation containing a neurokinin receptor agonist into the vagina of livestock using a vaginal administration device according to one aspect of the present invention.

〔formulation〕
Formulations used in methods of controlling ovarian function include neurokinin receptor agonists that control follicular development. By administering a formulation containing a neurokinin receptor agonist intravaginally to livestock, the formulation can be stably supplied to livestock, and thus the ovarian function of livestock can be controlled more stably.

(Neurokinin receptor agonist)
Neurokinin receptor agonists have a stimulating effect on the reproductive center that controls follicular development, and act on the central system to continuously enhance kisspeptin and neurokinin neuronal pulsatile neurofibrillation activity, thereby reducing blood flow. promotes the frequency of LH secretion into the Therefore, by administering a neurokinin receptor agonist to livestock, immature follicles can grow and mature normally, and normal ovulation can be promoted based on the same mechanism as the ovulation mechanism in vivo. Neurokinin receptor agonists control follicular development by regulating mechanisms upstream of the secretory mechanism of sex hormones such as progesterone.

Neurokinin receptor agonists are, for example, senktide, GR73632, GR64349, etc., or derivatives thereof. Neurokinin receptor agonists are commercially available and readily available to those skilled in the art. From the viewpoint of facilitating vaginal absorption, the neurokinin receptor agonist preferably has a molecular weight of 5000 Da or less, more preferably 1000 Da or less.

The dose of the neurokinin receptor agonist can be appropriately adjusted according to the type of livestock and the like. In order to make it easier for the neurokinin receptor agonist to reach the brains of domestic animals, it is preferable to administer the same to 1.5 times the amount of the neurokinin receptor agonist as compared to the case of blood administration. From the viewpoint of continuously stimulating the ovarian function of livestock over a long period of time, for example, when a neurokinin receptor agonist is administered to cattle, the dosage is preferably 10 nmol or more and 1000 nmol or less per minute, It is more preferably 30 nmol or more and 200 nmol or less.

In the method for controlling ovarian function, the interval of pulsatile secretion of luteinizing hormone (LH) into blood in livestock from 1 hour to 72 hours after intravaginal administration of a neurokinin receptor agonist is 20 minutes or more and 120 minutes or less. can be maintained. In the method for controlling ovarian function, the shortening of the pulsatile LH secretion interval after administration of the neurokinin receptor agonist is maintained for a long period of time, and the effect of the neurokinin receptor agonist is maintained for a long period of time. Therefore, according to the ovarian function control method, there is no need for continuous administration of the formulation with a catheter inserted into the blood vessel of livestock or frequent administration by injection, which reduces the burden on livestock and workers. . According to the method for controlling ovarian function, shortening of the LH pulsatile secretion interval continues for a long period of time, so that ovarian function can be controlled more stably.

(other ingredients)
The formulation may contain other ingredients in addition to the neurokinin receptor agonist. Other ingredients may be those that do not affect the effect of the neurokinin receptor agonist and do not adversely affect the living body. Examples include excipients, lubricants, binders, disintegrants, and the like. In addition, if desired, additives such as preservatives, antioxidants, coloring agents, adsorbents, and wetting agents may be included. In addition, the formulation may further contain an absorption enhancer in order to improve the absorption efficiency of the neurokinin receptor agonist through mucous membranes and reduce loss.

(form of formulation)
The form of the formulation is not particularly limited as long as the neurokinin receptor agonist does not leak out of the vagina of livestock and can be formulated. Formulations include, for example, solid formulations, forms in which the outside of solid or liquid formulations are coated with solids, and forms in which liquid formulations are impregnated with a carrier capable of impregnating and exuding. Forms in which the outside of the formulation is coated with a solid matter include capsules and the like. Examples of the form in which a liquid preparation is impregnated with a carrier capable of being impregnated and exuded include a sponge impregnated with the preparation. The formulation may be a neurokinin receptor agonist formulated by a known method.

Preferably the formulation is a sustained release formulation. Being a sustained-release formulation, it is possible to continuously stimulate neurokinin receptors, so that ovarian function can be controlled more stably. Sustained-release formulations containing neurokinin receptor agonists can be obtained by known methods.

The formulation preferably contains a mucoadhesive silicone together with a neurokinin receptor agonist. The use of mucoadhesive silicone can make the formulation less likely to fall out of the vagina.

From the viewpoint of ensuring stability and safety, the formulation preferably contains silica, a water-soluble polymer, a formulation stabilizer, and a release enhancer in addition to the neurokinin receptor agonist and mucoadhesive silicone. In addition, such a configuration increases the flexibility of the dosage form.

[Administration step]
In the administration step of administering a formulation containing a neurokinin receptor agonist into the vagina of livestock, the method of administering the formulation into the vagina of livestock is not particularly limited, and the formulation is directly inserted into the vagina by human hands. Alternatively, a vaginal administration device may be used to insert the formulation into the vagina. Alternatively, a tube with a sponge fixed to the tip thereof may be inserted into the vagina of livestock, a syringe filled with the formulation may be connected to the tube, and a pump may be used to administer the formulation in the syringe into the vagina.

In the administration step, it is preferable to insert the vaginal administration device according to one aspect of the present invention, to which the preparation is attached, into the vagina of the livestock. By using the intravaginal administration device according to one aspect of the present invention, it is difficult for the device to fall out of the vagina, so that the formulation can be appropriately administered into the vagina over a long period of time. By using the vaginal administration device according to one aspect of the present invention, it is possible to stably supply the formulation to domestic animals, and thus to more stably control the ovarian function of domestic animals.

Domestic animals to which the formulation is administered intravaginally in the administration step are not particularly limited as long as they are mammals, and examples thereof include cattle, goats, and sheep.

In the administering step, the livestock is preferably postpartum livestock. As a result, it is possible to improve the ovarian function, which is weak after parturition, and to induce estrus and ovulation early after parturition, thereby shortening the chance of conception and shortening the open period.

In the ovarian function control method, the effect of the neurokinin receptor agonist lasts for a long time, so the administration step need not be performed multiple times, but may be performed multiple times as appropriate. When the administration step is performed multiple times, the presence or absence of estrus or ovulation for 21 days after the end of administration is used as an index, and if these are not induced by the administration of the neurokinin receptor agonist, it may be performed again.

[Other processes]
The method for controlling ovarian function may include the step of measuring, monitoring and/or recording the blood LH concentration of the livestock at least one of before and after the administration step. The method of controlling ovarian function may also include the step of measuring, monitoring and/or recording multineuronal firing activity (MUA volley) in the livestock before and/or after the administering step.

In the ovarian function control method, at least one of before and after the administration step, the state of the ovaries, the state of follicle development, or the presence or absence of ovulation in domestic animals is confirmed by ultrasonic examination or palpation through the rectal wall of the ovaries. and determining the need for administration or the efficacy of administration.

In the method for controlling ovarian function, when administering to livestock after delivery, the state of the vagina of the livestock is visually observed before the administration step to determine the presence or absence of damage due to delivery or the recovery from the damage, and the vaginal It may also include a step of confirming lochia remaining in the body and determining the time to start administering the neurokinin receptor agonist.

In the method for controlling ovarian function, at least one of before and after the administration step, the presence or absence of estrus is determined using a commercially available technology for detecting estrus behavior or a technology for detecting estrus by analyzing livestock activity records. A step of determining the need for administration of a neurokinin receptor agonist or the efficacy of administration of a neurokinin receptor agonist may be included by confirming.

[Kit for controlling ovarian function]
A kit according to one aspect of the present invention is a kit for intravaginal administration to domestic animals. A kit for intravaginally administering to domestic animals comprises a preparation and a vaginal administration tool to which the preparation is attached. The kit for intravaginal administration to domestic animals may be a kit for controlling ovarian function, comprising a preparation containing a neurokinin receptor agonist and a vaginal administration device fitted with the preparation. In addition, in the kit for vaginal administration to livestock, the vaginal administration device may be the vaginal administration device according to one aspect of the present invention. By using a kit for intravaginally administering to livestock, the formulation is less likely to fall out of the vagina, and the formulation can be appropriately administered intravaginally. As a result, the formulation can be stably supplied to livestock, and therefore, the ovarian function of livestock can be controlled more stably by using the formulation containing the neurokinin receptor agonist.

One aspect of the vaginal administration device included in the kit for vaginal administration to livestock is the vaginal administration device according to one aspect of the present invention. One aspect of the formulation provided in the kit for intravaginal administration to livestock is the formulation used in the method for controlling ovarian function according to one aspect of the present invention. Therefore, the details of the ovarian function control kit of the present invention conform to the descriptions of the vaginal administration device according to one aspect of the present invention and the ovarian function control method according to one aspect of the present invention.

The ovarian function control kit according to one aspect of the present invention may contain other components as necessary. An example of another configuration includes instructions for use of the ovarian function control kit. The instruction manual of the ovarian function control kit may describe, for example, an example of specific procedures for performing the ovarian function control method according to one aspect of the present invention.

According to the present invention described above, since the productivity of livestock can be improved, it is possible to contribute to goal 2 "zero hunger" of the Sustainable Development Goals (SDGs) led by the United Nations.

The present invention is not limited to the above-described embodiments, but can be modified in various ways within the scope of the claims, and can be obtained by appropriately combining technical means disclosed in different embodiments. is also included in the technical scope of the present invention.

[Example 1: Blood administration of Senktide]
In ovariectomized goats (5 years old, parous), recording electrodes were surgically placed in the vicinity of kisspeptin/neurokinin (NKB) neurons (KNDy neurons) in the hypothalamic arcuate nucleus. After a recovery period of about one month, neural activity of the awakened goat was measured in real time as multiple unit activity (MUA). It was confirmed that a transient increase in MUA (MUA volley) lasting about 2 minutes occurred at regular intervals.

MUA volleys reflect the neural activity of KNDy neurons that pulsatilely secrete gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). In ovariectomized goats, the interval between MUA volleys that occurs endogenously and regularly is usually about 25 minutes (±5 minutes), and although it varies slightly from individual to individual, the interval is almost constant within the same individual ( within ±2 minutes).

On the day of the test, the goats were catheterized in the jugular vein. The MUA instrument was then set up and MUA was recorded continuously. Several endogenous MUA volleys occurring during the control period of 2 hours prior to the start of the study were identified and volley intervals were identified. A catheter attached to the jugular vein and a 50 ml syringe filled with a solution containing Senktide ([Succinyl-Asp6, NMePhe8]-Substance P (6-11), Senktide, ANASPEC, AS-22887, CA, USA) are connected with a tube. Then, senktide was administered continuously for 2 hours at 300 nmol/min using a microsyringe pump, and the MUA volley interval during and after administration was confirmed.

The results are shown in FIG. As shown in FIG. 6, continuous blood administration of senktide was found to shorten the MUA volley interval. Therefore, it was clarified that follicle development can be controlled by continuous blood administration of senktide.

[Example 2: Vaginal administration of Senktide]
By the same method as in Example 1, it was confirmed that MUA volleys occurred at regular intervals in the same ovariectomized goat as in Example 1.

On the day of the test, the goats were catheterized in the jugular vein. The MUA instrument was then set up and MUA was recorded continuously. Several endogenous MUA volleys that occurred during the control period of 2 hours prior to the start of the study were identified and volley intervals were confirmed. A tube with a sponge fixed to the tip was inserted into the vagina of the goat and connected to a 50 ml syringe filled with a solution containing senktide. Using a microsyringe pump, senktide was continuously administered at 60 nmol/30 μl/min for 2 hours, and the MUA volley interval during and after administration was confirmed.

About 1 ml of blood was frequently collected every 6 minutes from a catheter attached to the jugular vein from 2 hours before the start of the test to 2 hours after the end of the test, and the blood LH concentration was measured by radioimmunoassay.

The results are shown in FIG. As shown in FIG. 7, continuous vaginal administration of senktide was found to shorten the MUA volley interval. It was also found that the blood LH concentration increased associated with the MUA volley. Therefore, it was clarified that follicle development can be controlled by continuous transvaginal administration of senktide.

[Example 3: Vaginal administration of a sustained-release preparation containing senktide]
By the same method as in Example 1, it was confirmed that MUA volleys occurred at regular intervals in the same ovariectomized goat as in Example 1.

On the day of the test, the goat was set up with an MUA instrument, and MUA was recorded continuously throughout the day. Several endogenous MUA volleys that occurred during the 2-hour control period prior to the start of the study were identified, and the mean volley interval (T) was determined. As a test sample, a sustained-release preparation (0.43 g) containing senktide (0.12 g) was prepared and encapsulated in a No. 1 gelatin capsule. The test sample was inserted into the vagina, and the vaginal opening was plugged with a sponge to prevent leakage of the test sample. After administration, the test sample was judged to be effective when the MUA volley interval became 80% or less of T.

The content of each component when the total mass of the sustained-release preparation is 100% by mass is shown below. A sustained release formulation was prepared according to the following recipe:
(Prescription of sustained-release preparation)
Silicone oil: 48.8% by mass
Silica: 6.16% by mass
Stearyl alcohol: 1.71% by mass
Water-soluble polymer: 12.78% by mass
Polyethylene glycol: 2.78% by mass
Neurokinin receptor agonist: 27.77% by mass

The results are shown in FIG. As shown in FIG. 8, intravaginal administration of senktide reduced the MUA volley interval to less than 80% of T from 1 hour to 40 hours after administration. Therefore, it was clarified that intravaginal administration of senktide can continuously control follicle development.

[Example 4: Vaginal administration of a sustained release formulation containing senktide to postpartum cattle]
Two Japanese Black cows (both 26 months old at parturition, nulliparous) were tested. The day of delivery was designated as day 0, and the test was conducted on days 6-7 after delivery. As a test sample, a sustained-release preparation (3.15 g) containing senktide (0.88 g) was prepared according to the formulation described above and sealed in a No. 000 gelatin capsule. The sustained-release formulation was loaded into the vaginal administration device and inserted into the vagina. After 72 hours of administration, the vaginal administration device loaded with the sustained-release formulation was removed. As an index of the first ovulation after parturition, the presence or absence of luteinization of the ovary was confirmed by ultrasonography.

The average first ovulation day in the untreated herd (11 cows) that delivered at the same time was 33.4 days postpartum, whereas in the two treated cows, 20 days postpartum or 26 days postpartum, respectively. Confirmed first ovulation.

INDUSTRIAL APPLICABILITY The present invention can be used for intravaginal administration to livestock, such as in dairy farms and meat breeders.

10, 210 insertion section 11, 211 application section 12 formulation 20 wing section 21a, 21b wing section 22 incision section 30 string 100, 200 vaginal administration device

Claims (7)

an insertion part having an attachment part for attaching a formulation to be administered intravaginally to a domestic animal and inserted into the vagina of the domestic animal;
a wing portion connected to one end of the insertion portion and having a plurality of wings extending in a direction away from the one end;
The ends of the wings facing the ends connected to the insertion portions of the wings are in an open state separated from each other. in a closed position in close proximity to each other. A cord connected to at least part of the wing portion, wherein at least a portion of the cord is outside the livestock body when the insertion portion and the wing portion are present in the vagina of the livestock. ,
2. The intravaginal administration device according to claim 1, wherein said wings are in said closed state when said string is pulled in a direction away from said wings. The intravaginal administration device according to claim 1 or 2, wherein said wing portions are provided with a notch portion at a connection portion between at least one of said wing portions and said insertion portion. The intravaginal administration device according to any one of claims 1 to 3, wherein the mounting portion is a groove provided on the outer edge of the insertion portion. The intravaginal administration device according to any one of claims 1 to 3, wherein the mounting section is a hole provided in the insertion section. A method for controlling ovarian function, comprising the step of intravaginally administering a preparation containing a neurokinin receptor agonist to livestock using the vaginal administration device according to any one of claims 1 to 5. The vaginal administration device according to any one of claims 1 to 5,
A kit for intravaginally administering a formulation to a domestic animal, comprising the formulation.

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