JP7741552B2 - Intravaginal administration device, method for controlling ovarian function, and kit for administering a preparation into the vagina of livestock - Google Patents

Description

The present invention relates to an intravaginal administration device, a method for regulating ovarian function, and a kit for administering a formulation into the vagina of livestock.

In recent years, a decline in productivity due to the lengthening of the reproductive cycle associated with the extended open period after parturition in livestock has become a problem. Known methods for shortening the open period in livestock after parturition include administering GnRH preparations, progesterone preparations, etc. to livestock to forcibly induce ovulation. Another method, as described in Patent Document 1, involves administering neurokinin receptor agonists into the bloodstream, which act on the reproductive center to promote normal ovulation, thereby controlling follicle development.

In addition to the above-mentioned intravenous administration, methods of administering formulations to livestock include intravaginal administration. Intravaginal administration can be performed by manually inserting the formulation directly into the vagina, or by inserting an intravaginal administration device coated or adhered with the formulation into the vagina of the livestock. Non-Patent Document 1 describes an example of an intravaginal administration device for administering a progesterone formulation into the vagina of a goat.

Patent Publication No. 2017-81917

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

It is preferable that the intravaginal administration device remain in the vagina and do not fall out, so that the formulation is reliably taken up by the livestock. The intravaginal administration device described in Non-Patent Document 1 is for administering the formulation into the vagina of goats, and administration to other livestock is not considered. Furthermore, Patent Document 1 relates to administration of the formulation into the bloodstream, and does not mention intravaginal administration at all.

One aspect of the present invention has been made to solve the above-mentioned problems, and its purpose is to provide an intravaginal administration device that is less likely to fall out of the vagina of livestock.

In order to solve the above problems, one aspect of the present invention provides an intravaginal administration device that has an attachment part for attaching a formulation to be administered into the vagina of a livestock animal, and is equipped with an insertion part that is inserted into the vagina of the livestock animal, and a wing part that is connected to one end of the insertion part and has multiple wings that extend in a direction away from that end, and the ends of the wing part that face the end of the wing that is connected to the insertion part are in an open state where they are separated from each other, and when a force is applied in a direction that brings the ends closer together, the ends move into a closed state where they are close to each other.

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

A kit for administering a formulation according to one embodiment of the present invention into the vagina of a livestock animal includes an intravaginal administration device according to one embodiment of the present invention and the formulation.

One aspect of the present invention provides an intravaginal administration device that is less likely to fall out of the vagina.

1 is a diagram showing an intravaginal administration device according to a first embodiment of the present invention. FIG. FIG. 1 is a diagram showing a state in which a formulation is attached to the intravaginal administration device according to embodiment 1 of the present invention. FIG. 10 is a diagram showing an intravaginal administration device according to a second embodiment of the present invention. FIG. 10 is a diagram showing the state in which a formulation is attached to the intravaginal administration device according to embodiment 2 of the present invention. 1 is a diagram showing an intravaginal administration device according to one embodiment of the present invention. FIG. 1 shows changes in MUA volley intervals due to administration of a neurokinin receptor agonist into the blood. FIG. 1 shows changes in MUA volley interval and blood LH concentration due to intravaginal administration of a neurokinin receptor agonist. FIG. 1 shows the change in MUA volley interval due to intravaginal administration of a sustained-release preparation containing a neurokinin receptor agonist.

[Intravaginal administration device]
One aspect of the present invention relates to an intravaginal administration device for administering a formulation into the vagina of a livestock. The scope of the present invention also includes an intravaginal administration method that includes a step of administering a formulation into the vagina of a livestock using an intravaginal administration device according to one aspect of the present invention. The intravaginal administration method according to one aspect of the present invention may also be a method for regulating ovarian function, in which a formulation capable of regulating ovarian function in a livestock is administered into the vagina of the livestock using an intravaginal administration device according to one aspect of the present invention.

[Embodiment 1]
An intravaginal administration device according to a first embodiment of the present invention will be described below with reference to FIGS. 1-2 and 5. FIG. 1 is a diagram showing an intravaginal administration device 100 according to a first embodiment of the present invention. FIG. 2 is a diagram showing the intravaginal administration device 100 according to the first embodiment of the present invention with a formulation 12 attached thereto. 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. In FIG. 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. In FIGS. 1 and 2, the back view of the intravaginal administration device 100 is omitted because it is the same as the front view 1001 or 1011. FIG. 5 is a diagram showing an intravaginal administration device according to one aspect of the present invention.

As shown in Figures 1 and 2, the intravaginal administration device 100 comprises an insertion section 10 and wing sections 20. The entire or partial insertion section 10 and wing sections 20 of the intravaginal administration device 100 are inserted into the vagina of a livestock animal through its vaginal opening. The intravaginal administration device 100 is safe for insertion into the vagina of a livestock animal, and may be manufactured from a flexible material that does not damage the inside of the vagina when inserted into, retained in, or removed from the vagina. Preferably, at least the insertion section 10 and wing sections 20 of the intravaginal administration device 100 are made from medical-grade silicone. Furthermore, the wing sections 20 are preferably manufactured to have flexibility that allows the wing sections 20, described below, to be opened and closed to the desired extent.

(Insertion section 10)
The insertion part 10 has an attachment part 11 to which the formulation 12 to be administered into the vagina of the livestock is attached, and is inserted into the vagina of the livestock. When the intravaginal administration device 100 is inserted into the vagina of the livestock, the insertion part 10 is the part that is first inserted into the livestock's body. The insertion part 10 may have a size and shape that allows it to be inserted through the vaginal opening of the livestock and reach the vagina. From the viewpoint of facilitating insertion into the vagina of the livestock, the shape of the insertion part 10 may be, for example, a diamond shape, but is not limited to this.

In the intravaginal administration device 100, the attachment section 11 of the insertion section 10 is made up of grooves 11a and 11b provided on the outer edge of the insertion section 10. For example, by inserting the formulation 12 into the grooves 11a and 11b, the side walls of the grooves 11a and 11b hold the formulation 12 by sandwiching its sides. For example, the formulation 12 is a capsule of a shape and size specified in the Japanese Pharmacopoeia, so the grooves 11a and 11b need only be shaped to hold such a capsule. For example, the length of the grooves 11a and 11b is 3-5 cm, and the depth is 0.5-1 cm.

The attachment section 11 may be configured to be able to attach one or more formulations 12. As an example, as shown in Figures 1 and 2, grooves 11a and 11b may be provided on each of the two sides at the tip of the diamond-shaped insertion section 10, and a formulation 12 may be attached to each of them. Grooves may also be provided on the two sides of the diamond-shaped insertion section 10 facing the wing section 20, or on all four sides.

With the attachment unit 11 configured in this manner, the type and size (dosage) of the formulation 12 to be administered can be changed as needed, making it suitable for general use. The 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 ovarian function control method described below.

(Wing portion 20)
Wing portion 20 is connected to one end of insertion portion 10 and comprises a plurality of wings extending in a direction away from that end. Wing portion 20 is connected to the end of insertion portion 10 that faces the tip that is inserted into the vaginal opening. The wings extend from the end connected to insertion portion 10 in a direction away from insertion portion 10. Wing portion 20 needs to comprise at least two wings 21 a and 21 b, and may comprise three or more wings.

The ends of wings 21a and 21b of wing portion 20 that face the ends connected to insertion portion 10 are in an open state, separated from each other. When a force is applied in a direction that brings the separated ends of wings 21a and 21b closer to each other (the Y direction in Figure 1), wing portion 20 enters a closed state in which the ends approach each other. When a force is applied in a direction that brings the separated ends of wings 21a and 21b closer to each other, wing portion 20 can easily deform, bringing the ends closer together.

In this way, wing portion 20 is configured to transform from an open state in which wings 21a and 21b are open to a closed state in which they are closed. Therefore, by inserting wing portion 20 into the vagina with wing portion 20 in the closed state, intravaginal administration device 100 can be easily inserted into the vagina. Furthermore, if wing portion 20 is opened after intravaginal administration device 100 has been inserted into the vagina, open wings 21a and 21b will cause intravaginal administration device 100 to catch on the vaginal wall, making it less likely to fall off.

After inserting the intravaginal administration device 100 into the vagina with force applied to the separated ends of wings 21a and 21b in a direction that brings them closer together, the intravaginal administration device 100 can be inserted and secured in place simply by releasing that force. Furthermore, if the wings 20 are made of a highly flexible material that allows them to open and close easily with little force, the wings 20 can also be opened and closed by vaginal pulsation. This allows the intravaginal administration device 100 to be inserted deeper into the vagina, making it less likely for the intravaginal administration device 100 to fall out of the vagina.

A string 30 may be connected to at least a portion of the wing portion 20. As shown in FIG. 5, one end of the string 30 is fixed to a hole 23a provided in wing 21a, and the other end passes through a hole 23b provided in wing 21b, allowing the string 30 to be inserted and removed through hole 23b. As a result, when the string 30 is pulled in a direction away from wing portion 20 (particularly wing 21b), wing 21a is pulled toward wing 21b by the string 30, and wing portion 20 is deformed so that wing 21a approaches wing 21b, thereby entering a closed state.

The string 30 is designed so that when the insertion section 10 and the wing sections 20 are inside the vagina of the livestock, at least a portion of it is outside the livestock's body. Therefore, when the intravaginal administration device 100 remains inside the vagina, pulling the string 30 closes the wing sections 20, allowing the intravaginal administration device 100 to be removed from the vagina.

As such, when the intravaginal administration device 100 is inserted into the vagina or removed from the vagina, the wing portions 20 are in a closed state, making it easy to remove and preventing damage to the vaginal wall, etc. Furthermore, when the intravaginal administration device 100 remains in the vagina, the wing portions 20 are in an open state, so that the wings 21a and 21b catch on the vaginal wall, etc., and it is less likely to fall out of the vagina.

The string 30 may be connected by having one end fixed to the hole 23b and passing through the hole 23a. A ring 40 may also be attached to the end of the string 30 opposite the end fixed to the hole 23a or 23b (the end that is not fixed). Pulling the ring 40 thereby pulls the string 30, making it easier to pull the string 30.

The wing portion 20 may have a notch 22 at the connection between at least one of the wings 21a and 21b and the insertion portion 10. The shape of the notch 22 is not particularly limited, but is preferably a shape with at least a partial arc, such as a circle, semicircle, or fan shape. By providing the notch 22, the force required to open and close the wing portion 20 is reduced, making it easier to open and close. The ease with which the notch 22 can be opened and closed varies depending on its shape and size. For example, if the notch 22 is semicircular, the larger its diameter, the easier it is to open and close the wing portion 20.

The intravaginal administration device 100 is used to administer a formulation into the vagina of livestock. Examples of livestock that can use the intravaginal administration device include, but are not limited to, cattle, goats, and sheep. The size and shape of each part of the intravaginal administration device 100 can be appropriately set depending on the type of livestock used, the size of the livestock, and the shape and size of the livestock's vagina, etc.

For example, if the intravaginal administration device 100 is intended for use with cattle, the vaginal opening of a cattle is typically 6 to 9 cm, so the size should be determined accordingly. As an example, the major axis of the insertion section 10 (the longest diameter in the left-right direction in the front view 1001 of FIG. 1) is 3 to 7 cm, and the minor axis (the longest diameter in the up-down direction in the front view 1001 of FIG. 1) is 2 to 5 cm. Furthermore, the length of the wings 21a and 21b is 10 to 15 cm, the width is 10 to 15 cm, and the angle between the wings 21a and 21b is 40 to 100 degrees. Furthermore, if the notch 22 is semicircular, its diameter is 0.5 to 1.5 cm. An intravaginal administration device 100 of this size is preferable because it is less likely to place excessive strain on the vaginal wall, causing discomfort, pain, or inflammation in the cattle.

The intravaginal administration device 100 is unlikely to fall out of the vagina, allowing the formulation 12 to be administered appropriately into the vagina. This allows the formulation to be supplied to livestock in a stable manner, thereby more stably controlling the ovarian function of livestock.

[Embodiment 2]
Another embodiment of the present invention will be described below. For ease of explanation, the same reference numerals will be used to designate components having the same functions as those described in the above embodiment, and the description thereof will not be repeated. This embodiment is similar to the first embodiment described above, except for the configuration of the insertion section 210.

The intravaginal administration device according to embodiment 2 of the present invention will be described below with reference to Figures 3 to 5. Figure 3 is a diagram showing an intravaginal administration device 200 according to embodiment 2 of the present invention. Figure 4 is a diagram showing an intravaginal administration device 200 according to embodiment 2 of the present invention with formulation 12 attached. In Figure 3, 2001 indicates a front view, 2002 indicates a left side view, 2003 indicates a right side view, 2004 indicates a plan view, and 2005 indicates a bottom view. In Figure 4, 2011 indicates a front view, 2012 indicates a left side view, 2013 indicates a right side view, 2014 indicates a plan view, and 2015 indicates a bottom view. Note that in Figures 3 and 4, the back view of the intravaginal administration device 200 is omitted because it is the same as the front view 2001 or 2011. As shown in Figures 3 and 4, the intravaginal administration device 200 comprises an insertion section 210 and wing sections 20.

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

In the intravaginal administration device 200, the attachment part 211 of the insertion part 210 is a hole provided within the insertion part 210. As an example, the attachment part 211 is configured to hold the formulation 212 by inserting the formulation 212 into the hole. As an example, the formulation 212 is a capsule of a shape and size specified in the Japanese Pharmacopoeia, so the hole in the attachment part 211 need only be a shape that can hold such a capsule. As an example, the hole in the attachment part 211 is circular and has a diameter of 0.6 to 1 cm.

The attachment section may be configured to accommodate one or more formulations 212. As an example, as shown in Figures 3 and 4, four holes may be provided as attachment section 211 within the surface of diamond-shaped insertion section 210, and a formulation 212 may be attached to each of them. The diameters of the four holes in attachment section 211 may be the same or different. By providing multiple holes with different diameters in attachment section 211, it is possible to hold formulations 212 of various sizes. This allows the type and size (dosage) of formulation 212 to be administered to be changed as appropriate, allowing for general use. There are no particular limitations on the formulation 212 as long as it can be absorbed through the vagina, but one example is a formulation used in the ovarian function control method described below.

The intravaginal administration device 200 functions in the same way as the intravaginal administration device 100 and achieves the same effects. In other words, the intravaginal administration device 200 is less likely to fall out of the vagina, allowing the formulation 212 to be administered appropriately into the vagina. This allows the formulation to be supplied to livestock in a stable manner, thereby more stably controlling the ovarian function of livestock.

[Method for controlling ovarian function]
A method for regulating ovarian function according to one aspect of the present invention includes administering a formulation containing a neurokinin receptor agonist into the vagina of a livestock animal. The method for regulating ovarian function according to one aspect of the present invention may include administering a formulation containing a neurokinin receptor agonist into the vagina of a livestock animal using an intravaginal administration device according to one aspect of the present invention.

〔formulation〕
The formulation used in the method for controlling ovarian function contains a neurokinin receptor agonist that controls follicle development. By administering the formulation containing the neurokinin receptor agonist intravaginally to livestock, the formulation can be stably supplied to the livestock, thereby more stably controlling the ovarian function of the livestock.

(Neurokinin receptor agonist)
Neurokinin receptor agonists have a stimulating effect on the reproductive center that controls follicle development, and act on the central nervous system to continuously enhance the pulsatile neural firing activity of kisspeptin and neurokinin neurons, thereby promoting the frequency of LH secretion into the blood. Therefore, by administering neurokinin receptor agonists to livestock, immature follicles can be developed and matured normally, and normal ovulation can be promoted based on a mechanism similar to the ovulation mechanism in vivo. Neurokinin receptor agonists control follicle development by regulating mechanisms upstream of the secretion mechanism of sex hormones such as progesterone.

Examples of neurokinin receptor agonists include senktide, GR73632, GR64349, etc., or derivatives thereof. Neurokinin receptor agonists are commercially available and readily available to those skilled in the art. From the perspective of facilitating vaginal absorption, the molecular weight of the neurokinin receptor agonist is preferably 5,000 Da or less, and more preferably 1,000 Da or less.

The dose of the neurokinin receptor agonist can be adjusted appropriately depending on the type of livestock, etc. To facilitate delivery of the neurokinin receptor agonist to the brain of livestock, it is preferable to administer the same amount to 1.5 times the amount of neurokinin receptor agonist as when administered into the blood. From the perspective of continuously stimulating the ovarian function of livestock over a long period of time, for example, when administering a neurokinin receptor agonist to cattle, the dose is preferably 10 nmol or more and 1000 nmol or less per minute, and more preferably 30 nmol or more and 200 nmol or less.

In the ovarian function control method, the interval between pulsatile secretions of luteinizing hormone (LH) into the blood of livestock can be maintained at 20 minutes or more and 120 minutes or less for 1 to 72 hours after intravaginal administration of a neurokinin receptor agonist. In the ovarian function control method, the shortened interval between LH pulsatile secretions after administration of a neurokinin receptor agonist is maintained for a long period of time, and the effects of the neurokinin receptor agonist are sustained for a long period of time. Therefore, the ovarian function control method does not require continuous administration of a formulation with a catheter inserted into the livestock's blood vessels or frequent administration by injection, reducing the burden on the livestock and the burden on the worker. Furthermore, the ovarian function control method maintains a shortened interval between LH pulsatile secretions for a long period of time, allowing for more stable control of ovarian function.

(Other ingredients)
The formulation may contain other ingredients in addition to the neurokinin receptor agonist. The other ingredients may be any ingredients that do not affect the effects of the neurokinin receptor agonist and do not adversely affect the living body. Examples include excipients, lubricants, binders, disintegrants, etc. Furthermore, the formulation may contain additives such as preservatives, antioxidants, colorants, adsorbents, and humectants, as needed. Furthermore, the formulation may further contain an absorption enhancer to improve the absorption efficiency of the neurokinin receptor agonist from the mucosa and reduce loss.

(Form of formulation)
The form of the formulation is not particularly limited as long as it does not leak the neurokinin receptor agonist from the vagina of the livestock and can be formulated. Examples of formulations include solid formulations, solid or liquid formulations coated with a solid, and liquid formulations impregnated into a permeable and oozing carrier. Examples of formulations coated with a solid include capsules. Examples of formulations impregnated into a permeable and oozing carrier include sponges impregnated with the formulation. The formulation may be a formulation of a neurokinin receptor agonist prepared by a known method.

The formulation is preferably a sustained-release formulation. A sustained-release formulation allows for sustained stimulation of neurokinin receptors, resulting in more stable control of ovarian function. Sustained-release formulations containing neurokinin receptor agonists can be obtained by known methods.

The formulation preferably contains a mucosal adhesive silicone along with a neurokinin receptor agonist. The use of a mucosal adhesive silicone makes it less likely for the formulation to fall out of the vagina.

From the perspective of ensuring stability and safety, the formulation preferably contains silica, a water-soluble polymer, a formulation stabilizer, and a release promoter in addition to the neurokinin receptor agonist and mucoadhesive silicone. This composition also allows for greater flexibility in the formulation.

[Administration step]
In the administration step of administering a formulation containing a neurokinin receptor agonist into the vagina of a livestock, the method of administering the formulation into the vagina of the livestock is not particularly limited, and the formulation may be inserted directly into the vagina by hand, or the formulation may be inserted into the vagina using an intravaginal administration device. Alternatively, a tube with a sponge fixed to the tip may be inserted into the vagina of the livestock, and the tube may be connected to a syringe filled with the formulation, and the formulation in the syringe may be administered into the vagina using a pump.

In the administration step, it is preferable to insert the intravaginal administration device according to one aspect of the present invention, to which the formulation is attached, into the vagina of the livestock. By using the intravaginal administration device according to one aspect of the present invention, the formulation is less likely to fall out of the vagina, allowing the formulation to be administered appropriately into the vagina over an extended period of time. By using the intravaginal administration device according to one aspect of the present invention, the formulation can be supplied to livestock stably, thereby more stably controlling the ovarian function of livestock.

The livestock to which the formulation is administered intravaginally in the administration step is not particularly limited as long as it is a mammal, and examples include cows, goats, sheep, etc.

In the administration process, it is preferable that the livestock be livestock that has just given birth. This makes it possible to improve ovarian function, which is often sluggish after parturition, and by inducing estrus and ovulation early after parturition, it is possible to accelerate the chances of conception and shorten the open period.

In the method for controlling ovarian function, since the effects of the neurokinin receptor agonist are sustained for a long period of time, it is not necessary to perform the administration process multiple times, but it may be performed multiple times as appropriate. If the administration process is performed multiple times, the presence or absence of estrus or ovulation up to 21 days after the end of administration can be used as an indicator, and if these are not induced by the administration of the neurokinin receptor agonist, the process can be performed again.

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

The method for controlling ovarian function may also include a step of confirming the state of the livestock's ovaries, the state of follicle development, or the presence or absence of ovulation by ultrasound examination or palpation through the rectal wall of the ovaries, at least either before or after the administration step, and determining the necessity or effectiveness of administration.

When administering to livestock after parturition, the method for regulating ovarian function may also include a step of visually inspecting the condition of the livestock's vagina prior to the administration step to check for the presence or absence of damage caused by parturition, the state of recovery from such damage, and any lochia remaining in the vagina, and determining when to start administering the neurokinin receptor agonist.

The ovarian function control method may also include a step of determining the necessity or effectiveness of administering a neurokinin receptor agonist by confirming the presence or absence of estrus using commercially available technology for detecting estrus behavior or estrus detection technology that analyzes livestock activity records, at least either before or after the administration step.

[Ovarian function control kit]
A kit according to one embodiment of the present invention is a kit for administering a formulation into the vagina of a livestock animal. The kit for administering a formulation into the vagina of a livestock animal includes a formulation and an intravaginal administration device to which the formulation is attached. The kit for administering a formulation into the vagina of a livestock animal may be a kit for regulating ovarian function, including a formulation containing a neurokinin receptor agonist and an intravaginal administration device to which the formulation is attached. Furthermore, in the kit for administering a formulation into the vagina of a livestock animal, the intravaginal administration device may be the intravaginal administration device according to one embodiment of the present invention. By using a kit for administering a formulation into the vagina of a livestock animal, the formulation is less likely to fall out of the vagina, allowing the formulation to be administered appropriately into the vagina. This allows the formulation to be supplied stably to livestock, and therefore the ovarian function of livestock can be more stably controlled by using a formulation containing a neurokinin receptor agonist.

One aspect of the intravaginal administration device included in the kit for administration into the vagina of livestock is the intravaginal administration device according to one aspect of the present invention. One aspect of the formulation included in the kit for administration into the vagina of livestock is the formulation used in the method for regulating ovarian function according to one aspect of the present invention. Therefore, details of the kit for regulating ovarian function according to the present invention are the same as those described above for the intravaginal administration device according to one aspect of the present invention and the method for regulating ovarian function according to one aspect of the present invention.

The kit for ovarian function control according to one embodiment of the present invention may include other components as needed. One example of such other components is instructions for use of the kit for ovarian function control. The instructions for use of the kit for ovarian function control may include, for example, an example of a specific procedure for carrying out the method for ovarian function control according to one embodiment of the present invention.

The present invention described above can improve livestock productivity, thereby contributing to Goal 2 of the United Nations-led Sustainable Development Goals (SDGs), "Zero Hunger."

The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

Example 1: Administration of senktide into the blood
Ovariectomized goats (5 years old, multiparous) underwent surgical placement of recording electrodes near kisspeptin/neurokinin (NKB) neurons (KNDy neurons) in the hypothalamic arcuate nucleus. After a recovery period of approximately one month, neural activity in awake goats was measured in real time as multiple unit activity (MUA). Transient increases in MUA (MUA volleys) lasting approximately two minutes were observed at regular intervals.

MUA volleys reflect the neural activity of KNDy neurons, which secrete gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) in a pulsatile manner. In ovariectomized goats, the interval between endogenous, regular MUA volleys is typically approximately 25 minutes (±5 minutes), and although this varies slightly between individuals, the interval is fairly constant within the same individual (within ±2 minutes).

On the day of the test, a catheter was inserted into the goat's jugular vein. Next, an MUA measuring device was set up, and MUA was continuously recorded. Several endogenous MUA volleys were confirmed during the two-hour control period before the start of the test, and the volley intervals were determined. The catheter inserted into the jugular vein was connected with tubing to a 50 ml syringe filled with a solution containing senktide ([Succinyl-Asp6, NMePhe8]-Substance P(6-11), Senktide, ANASPEC, AS-22887, CA, USA). Senktide was continuously administered at 300 nmol/min for two hours using a microsyringe pump, and the MUA volley intervals were monitored during and after administration.

The results are shown in Figure 6. As shown in Figure 6, it was found that continuous administration of senktide into the blood shortened the MUA volley interval. Therefore, it was demonstrated that continuous administration of senktide into the blood can control follicle development.

Example 2: Intravaginal administration of senktide
Using the same method as in Example 1, it was confirmed that MUA volleys occurred at regular intervals in the same ovariectomized goats as in Example 1.

On the day of the test, a catheter was inserted into the jugular vein of the goat. Next, an MUA measuring device was set up, and MUA was continuously recorded. Several endogenous MUA volleys were confirmed during the control period of two hours before the start of the test, and the volley intervals were determined. A tube with a sponge attached to the tip was inserted into the goat's vagina and connected to a 50 ml syringe filled with a solution containing senktide. Senktide was administered continuously for two hours using a microsyringe pump at a rate of 60 nmol/30 μl/min, and the MUA volley intervals were confirmed during and after administration.

From two hours before the start of the test until two hours after its completion, blood samples of approximately 1 ml were taken every six minutes from a catheter attached to the jugular vein, and blood LH concentrations were measured using radioimmunoassay.

The results are shown in Figure 7. As shown in Figure 7, it was found that continuous vaginal administration of senktide shortened the MUA volley interval. It was also found that blood LH concentrations increased in conjunction with the MUA volley. Therefore, it was demonstrated that continuous vaginal administration of senktide can control follicle development.

Example 3: Intravaginal administration of sustained-release formulation containing senktide
Using the same method as in Example 1, it was confirmed that MUA volleys occurred at regular intervals in the same ovariectomized goats as in Example 1.

On the day of the test, an MUA measuring device was set up on the goat, and MUA was continuously recorded throughout the day. Several endogenous MUA volleys that occurred during the two-hour control period before the start of the test were confirmed, and the average volley interval (T) was determined. A sustained-release preparation (0.43 g) containing senktide (0.12 g) was prepared as the test sample and enclosed 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 deemed effective if the MUA volley interval was 80% or less of T.

The content of each component when the total mass of the sustained-release preparation is taken as 100% by mass is shown below. The sustained-release preparation was prepared according to the following recipe:
(Prescription of sustained-release preparations)
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 Figure 8. As shown in Figure 8, intravaginal administration of senktide resulted in the MUA volley interval being 80% or less of T between 1 and 40 hours after administration. Therefore, it was demonstrated that intravaginal administration of senktide can sustainably control follicle development.

Example 4: Intravaginal administration of a sustained-release formulation containing senktide to postpartum cows
Two Japanese Black cows (both 26 months old at birth, nulliparous) were used in the study. The day of birth was designated as day 0, and the study was conducted 6-7 days after birth. A sustained-release preparation (3.15 g) containing senktide (0.88 g) was prepared as the test sample according to the formula described above, and enclosed in two No. 000 gelatin capsules. The sustained-release preparation was loaded into an intravaginal administration device and inserted into the vagina. 72 hours after administration, the intravaginal administration device loaded with the sustained-release preparation was removed. The presence or absence of corpus luteum formation in the ovaries was confirmed by ultrasound examination as an indicator of the first ovulation after birth.

In the untreated group (11 cows) that gave birth at the same time, the average first ovulation date was 33.4 days after calving, while in the two treated cows, the first ovulation was confirmed on the 20th and 26th days after calving, respectively.

The present invention can be used for intravaginal administration to livestock at dairy farms, beef breeding farms, etc.

10, 210 Insertion part 11, 211 Wearing part 12 Preparation 20 Wing part 21a, 21b Wing 22 Slit part 30 String 100, 200 Intravaginal administration device

Claims (7)

an insertion part that has an attachment part for attaching a formulation to be administered into the vagina of the livestock and is inserted into the vagina of the livestock;
a wing portion connected to one end of the insertion portion opposite to the tip that is inserted into the vaginal opening , the wing portion having a plurality of wings that extend in a direction away from the one end,
The wing portions are in an open state in which the ends opposite the ends connected to the insertion portion of the wing are spaced apart, and when a force is applied in a direction that brings the ends closer together, the ends move into a closed state in which they are close to each other. an insertion part that has an attachment part for attaching a formulation to be administered into the vagina of the livestock and is inserted into the vagina of the livestock;
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 wing portions are in an open state in which the ends of the wing opposite the ends connected to the insertion portions are spaced apart from each other, and when a force is applied in a direction that brings the ends closer to each other, the ends are brought into a closed state in which they approach each other;
Further provided is a string connected to at least a portion of the wing portion, at least a portion of which is present outside the body of the livestock when the insertion portion and the wing portion are present in the vagina of the livestock,
The wing portion is in the closed state when the string is pulled in a direction away from the wing portion. an insertion part that has an attachment part for attaching a formulation to be administered into the vagina of the livestock and is inserted into the vagina of the livestock;
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 wing portions are in an open state in which the ends of the wing opposite the ends connected to the insertion portions are spaced apart from each other, and when a force is applied in a direction that brings the ends closer to each other, the ends are brought into a closed state in which they approach each other;
An intravaginal administration device, wherein the attachment portion is a groove provided on the outer edge of the insertion portion. an insertion part that has an attachment part for attaching a formulation to be administered into the vagina of the livestock and is inserted into the vagina of the livestock;
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 wing portions are in an open state in which the ends of the wing opposite the ends connected to the insertion portions are spaced apart from each other, and when a force is applied in a direction that brings the ends closer to each other, the ends are brought into a closed state in which they approach each other;
An intravaginal administration device, wherein the attachment portion is a hole provided in the insertion portion. The intravaginal administration device according to any one of claims 1 to 4, wherein the wing portions have a notch at a connection portion between at least one of the wings and the insertion portion. A method for regulating ovarian function, comprising administering a formulation containing a neurokinin receptor agonist into the vagina of a livestock animal using the intravaginal administration device described in any one of claims 1 to 5. The intravaginal administration device according to any one of claims 1 to 5,
A kit for administering a formulation into the vagina of a livestock, comprising: