JP2024006889A - pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that can improve pharmacokinetics while reducing and alleviating pain.

SOLUTION: A pharmaceutical composition comprises an agent with a logP value of 3.0 or more. The pharmaceutical composition is used for shortening the time (t_max) required for the agent to reach the maximum blood concentration. The agent is intradermally administered.

SELECTED DRAWING: None

COPYRIGHT: (C)2024,JPO&INPIT

Description

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions.

According to an announcement by the Ministry of Health, Labor and Welfare, cancer has been the number one cause of death for Japanese people in Japan since 1981, and in recent years, more than 300,000 people die from cancer each year. Furthermore, it is estimated that one in two men and one in three women will develop cancer during their lifetime. However, on the other hand, cancer treatment in Japan is progressing, and the five-year survival rate is on the rise in many areas. Cancer treatment includes surgery and drug therapy (anticancer drug treatment). Among these drug treatments, there are anticancer treatments that have a high risk of emetic effects. Nausea and vomiting, such as breakthrough nausea, are frequently observed in such treatments. For this reason, antiemetics are administered for prophylactic purposes to reduce or alleviate breakthrough nausea or vomiting (prophylactic administration). However, even such treatment may not alleviate symptoms. At that time, an antiemetic agent with a different mechanism of action than that used during prophylactic administration is additionally administered. Antiemetics are usually oral drugs or injection drugs (intravenous injection, intramuscular injection) (Non-Patent Document 1).

Japanese Society of Cancer Therapy Cancer Treatment Guidelines <URL: http://www.jsco-cpg.jp/guideline/29.html>

It is presumed that this additional administration is effective when the blood concentration rises quickly (=t _max is fast), as in the case of breakthrough pain caused by cancer. However, oral drugs have the problem that it takes time for them to take effect after they are taken. Another problem with oral medications is that they are difficult to take when you experience nausea or vomiting, and even if you take antiemetics when you are already feeling unwell, you may end up vomiting. Injectable drugs are effective in a short period of time when administered intravenously. However, in the case of outpatient treatment, patients need to be treated at home, and intravenous injections need to be administered by medical professionals such as doctors and nurses, so they cannot be treated at home. In addition, although intramuscular injections take effect quickly, they carry the risk of damaging blood vessels and nerves, and are accompanied by pain and fear. For this reason, there is a need for a drug that suppresses pain and exhibits its medicinal effect quickly after administration.

Incidentally, as an administration method that can be performed at home, medical devices for intradermal administration, which are easy to administer, have been developed in recent years. However, the present inventors have confirmed that when administering a drug intradermally, there are cases in which the t _max is not sufficiently shortened compared to other administration methods. cannot necessarily be said.

Therefore, the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a pharmaceutical composition that can improve pharmacokinetics while reducing and alleviating pain.

In order to solve the above problems, the present inventors conducted extensive research and found that the above problems could be solved by intradermally administering a drug having a specific degree of hydrophobicity, and thus completed the present invention. .

That is, the above object is (1) a pharmaceutical composition containing a drug having a logP value of 3.0 or more, for shortening the time (t _max ) until the maximum blood concentration of the drug is reached, Said agent can be achieved by a pharmaceutical composition administered intradermally.

Here, in an embodiment of the present invention,
(2) Preferably, the drug is the pharmaceutical composition according to (1) above, which is administered intradermally through an injection needle having a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less.

(3) The drug is preferably the pharmaceutical composition according to (1) or (2) above, which has a logP value of 3.1 or more.

(4) The drug is preferably the pharmaceutical composition according to any one of (1) to (3) above, which is an antiemetic or an antipsychotic.

(5) The drug is preferably the pharmaceutical composition according to any one of (1) to (4) above, which is domperidone or chlorpromazine hydrochloride.

According to the present invention, it is possible to provide a pharmaceutical composition that can improve pharmacokinetics (the blood concentration rises quickly) while alleviating and alleviating pain.

FIG. 1 is a perspective view of an administration device according to an embodiment. FIG. 2 is an exploded view of a needle hub according to an embodiment. 1 is a partial cross-sectional view of an embodiment of a needle hub and syringe; FIG. FIG. 2 is a perspective view of a needle hub according to an embodiment. FIG. 2 is an enlarged cross-sectional view of a needle hub according to an embodiment. FIG. 3 is an enlarged plan view of the blade surface of the injection needle according to the embodiment. FIG. 3 is an enlarged perspective view of the blade surface of the injection needle according to the embodiment. 8(A) is a side view of the blade surface of the injection needle seen from the direction of arrow 8A shown in FIG. 6, and FIG. 8(B) is a perspective view of the blade surface of the injection needle seen from the direction of arrow 8B shown in FIG. FIG. 9(A) is a side view of the blade surface of the injection needle seen from the direction of arrow 9A shown in FIG. 6, and FIG. 9(B) is a perspective view of the blade surface of the injection needle seen from the direction of arrow 9B shown in FIG. FIG. FIG. 2 is a cross-sectional view schematically showing an example of use of the administration device. 11 is an enlarged cross-sectional view showing a broken line portion 11A shown in FIG. 10. FIG.

The present invention provides a pharmaceutical composition for shortening the time (t _max ) to reach the maximum blood concentration of the drug, which contains a drug having a logP value of 3.0 or more, wherein the drug is administered intradermally. A pharmaceutical composition for administration is provided. According to this configuration, the time (t _max ) for reaching the maximum blood concentration of the drug can be shortened (particularly compared to subcutaneous administration). In this way, the blood concentration rises quickly after administration, and pharmacokinetics can be improved, so the quality of life (QOL) of the subject (patient) can be improved. Additionally, since there are fewer nerves in the intradermal tissue than in the subcutaneous tissue, pain during administration can be reduced and alleviated. Therefore, according to the pharmaceutical composition of the present invention, pharmacokinetics can be improved (the blood concentration rises quickly) while reducing and alleviating pain. Furthermore, the pharmaceutical composition of the present invention can be administered at home.

In this specification, the time until the maximum blood concentration of a drug is reached (t _max ) is also simply referred to as "t _max ". Further, a drug having a logP value of 3.0 or more is also simply referred to as a "hydrophobic drug" or "hydrophobic drug according to the present invention."

Embodiments of the present invention will be described below. Note that the present invention is not limited only to the following embodiments. Each drawing is exaggerated for convenience of explanation, and the dimensional ratio of each component in each drawing may differ from the actual size. Furthermore, when the embodiments of the present invention are described with reference to the drawings, the same elements are denoted by the same reference numerals in the description of the drawings, and redundant explanation will be omitted.

The embodiments described in this specification can be combined arbitrarily to form other embodiments.

Furthermore, in this specification, the range "X to Y" includes X and Y, and means "more than or equal to X and less than or equal to Y." Further, unless otherwise specified, operations and measurements of physical properties, etc. are performed at room temperature (20 to 25°C)/relative humidity of 40 to 50%.

[Drug (hydrophobic drug)]
As mentioned above, prophylactic antiemetics are prescribed to reduce or alleviate nausea and vomiting that appear as side effects of anticancer drug treatment, and if breakthrough nausea and vomiting occur, additional antiemetics are administered. is prescribed. Currently prescribed antiemetics for additional administration are often oral medications to be taken at home, and usually multiple types of antiemetics in tablet or capsule form with different mechanisms of action are prescribed. However, oral medications are difficult to take when you feel nausea and vomiting, and even if you take antiemetics when you are already feeling unwell, you may end up vomiting, and it takes a considerable amount of time for the drug to take effect after taking it (blood There is a problem that the rise in concentration is slow (that is, the t _max is long). Furthermore, in the use of migraine therapeutic drugs (for example, sumatriptan), injections are most desirable in order to be effective quickly, but many patients show resistance to injections. For this reason, some patients choose oral medications or nasal sprays as an administration method other than injection. However, as mentioned above, it takes a considerable amount of time for oral medications to take effect after they are taken. Although nasal sprays are more effective than oral medications, there is a problem in that their effectiveness varies depending on how they are used. For this reason, there is a strong demand for an administration method other than oral administration that does not cause resistance in patients and has rapid effects (rapid rise in blood concentration, i.e., short t _max ). .

As a result of intensive investigation of the above-mentioned issues, the present inventors found that the drug for which no prolongation of t _max was observed upon intradermal administration had a specific logP value or higher, and determined that the specific logP value (degree of hydrophobicity) It has been found that the above problem (t _max can be shortened by administration forms other than oral administration) can be solved by intradermally administering a drug having the following properties.

In the present disclosure, the drug (hydrophobic drug) has a logP value of 3.0 or more. For drugs with a logP value of less than 3.0, the blood concentration rises slowly after administration, and the time (t _max ) required to reach the maximum blood concentration of the drug during intradermal administration may be delayed by using other administration routes (e.g., oral administration). administration, subcutaneous administration, especially subcutaneous administration). From the viewpoint of the effects of the present invention (particularly further reduction of t _max ), the logP value of the drug is preferably 3.1 or more, more preferably more than 3.5, and even more preferably 3.9 or more. Note that the upper limit of the logP value of the drug is, for example, 7.5 or less, preferably less than 6.0, and more preferably less than 5.5. That is, in one embodiment of the present invention, the logP value of the drug is 3.1 or more and 7.5 or less. In one embodiment of the invention, the drug has a logP value greater than 3.5 and less than 6.0. In one embodiment of the invention, the drug has a logP value of greater than or equal to 3.9 and less than 5.5.

The logP value is a numerical value that is an index of the hydrophobicity of a drug, and is a coefficient (1-octanol/water partition coefficient) that indicates the affinity of an organic compound for water and 1-octanol. The logP value (1-octanol/water partition coefficient) is the common logarithm value (=log ₁₀ C _O /C _W ; in the above formula, C _O is the equilibrium concentration of the compound in the 1-octanol phase, and C _W is the equilibrium concentration of the compound in the aqueous phase. The logP value is determined by the "fragment constant" method, which divides the structure into fragments (atoms/functional groups) and sums the values for each group (possibly using a structure correction factor) to calculate an estimate. In this specification, the log ^Kow value (actually measured value). If calculation is not possible using the software, use the OECD Test Guideline for the testing of chemicals 107, Partition coefficient (n-octanol/water ) or the value measured according to Japanese Industrial Standard Z7260-107 (2000) "Measurement of partition coefficient (1-octanol/water) - Shake flask method" is adopted. The disclosures of the above-mentioned OECD Test Guideline and Japanese Industrial Standard (JIS) Z7260-107 are incorporated by reference herein in their entirety. In this specification, when the logKow value (actual value) calculated using EPI Suite ^TM version 4.11 or the value measured according to the above OECD Test Guideline or Japanese Industrial Standard Z7260-107 is below the second decimal place In this case, the value obtained by rounding off the second decimal place to the first decimal place is adopted as the logP value.

The drug that can be used in the present disclosure is not particularly limited as long as it has a logP value of 3.0 or more, and is appropriately selected depending on the desired use. Examples include migraine therapeutics, antiemetics, antipsychotics, bipolar disorder therapeutics, antihistamines, gastrointestinal motility improving agents, and the like. Here, in cases such as anti-cancer drug treatment where the risk of emetics is high, a rapid antiemetic effect is desired. Furthermore, when the subject is in pain, such as a migraine, a quick analgesic effect is desired. Therefore, from the viewpoint of improving the subject's quality of life (QOL), the drug is preferably a migraine treatment agent, an antiemetic, or an antipsychotic, and more preferably an antiemetic or an antipsychotic. , domperidone or chlorpromazine hydrochloride. Specifically, olanzapine (logP value: 3.0), chlorpheniramine maleate (logP value: 3.4 (chlorpheniramine)), domperidone (logP value: 3.9), haloperidol (logP value :4.3), prochlorperazine maleate (logP value: 4.9 (prochlorperazine)), chlorpromazine hydrochloride (logP value: 5.4 (chlorpromazine)), and the like.

The dosage of the drug is determined by considering the therapeutically effective amount, but the nature of the disease or side effects of the subject (e.g., degree of nausea, vomiting, degree of migraine); Varies depending on size, weight, surface area, age, and sex; other medications administered; and the judgment of the attending physician. In view of the differing efficacies of the various available agents, it is expected that the required dosage may vary widely. Variations in these dosage levels can be adjusted using standard empirical procedures for optimum known in the art. Moreover, the above-mentioned dosage may be divided into once a day or multiple times a day. Or, in some cases, may be administered less frequently (eg, weekly or monthly). Additionally, the dosage may vary even for the same subject depending on the subject's symptoms, severity, nature of treatment, etc.

As used herein, "therapeutically effective amount" means an amount of an active ingredient or pharmaceutical composition effective to produce any desired suppressive effect, with a reasonable benefit/risk ratio applicable to any medical practice. means. For example, the dosage of the pharmaceutical composition according to the present invention varies depending on the target disease, recipient, and the like. The dose can be appropriately selected by those skilled in the art since it can easily vary depending on conditions such as the body weight of the subject. In addition, the attending physician ultimately makes an appropriate selection, taking into consideration the subject's symptoms and severity.

The pharmaceutical composition according to the present invention is an intradermally administered drug. For this reason, pharmaceutical compositions generally include a solvent (eg, sterile water, saline, PBS, acetic acid, medium chain fatty acid triglycerides) in addition to the drug. The content of the solvent is not particularly limited and is appropriately selected depending on the dosage and the like.

In addition to the drug and the solvent, the pharmaceutical composition also includes stabilizers, buffers (e.g., phosphate buffer, citrate buffer, citrate phosphate buffer, histidine buffer, Tris-HCl buffer, acetic acid buffer). buffers, carbonate buffers, glycine-NaOH buffers), solubilizing agents (e.g. acetic acid), tonicity agents (e.g. sodium chloride), pH adjusters (e.g. sodium hydroxide, potassium hydroxide, sodium carbonate) , bases such as potassium carbonate, acids such as sulfuric acid, hydrochloric acid, phosphoric acid), soothing agents, reducing agents, antioxidants, and solubilizing agents (eg, polysorbate 80). The other additive components mentioned above may be used alone or in combination of two or more. Further, when the pharmaceutical composition contains other additive components, the content is not particularly limited, and the same known amounts are applied.

[Subject (patient)]
The subject (patient) to whom the pharmaceutical composition according to the invention is administered can be a human or a non-human animal. Examples of non-human animals include, but are limited to, laboratory animals such as mice, rats, and hamsters; pets such as dogs, cats, and rabbits; livestock and poultry such as pigs, cows, goats, sheep, horses, and chickens. Not done. Preferably the subject is a human.

[Intradermal administration]
In the present disclosure, the pharmaceutical composition is administered intradermally via a needle. Here, the injection needle is appropriately selected depending on the subject. For example, when the administration target (subject) is a human, the skin includes an "epidermal layer" with a thickness of 50 μm to 200 μm from the skin surface, a "dermal layer" with a thickness of 0.5 to 3.5 mm continuing from the epidermal layer, It is composed of the subcutaneous tissue layer, which is deeper than the dermal layer. Further, for example, the thickness of the upper skin layer of human deltoid muscle, which consists of the epidermis layer and the dermis layer, is generally about 2 mm. For this reason, when the administration target (subject) is a human, the injection needle preferably includes a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less. That is, in a preferred form of the present invention, there is provided a pharmaceutical composition for shortening the time to reach the maximum blood concentration (t _max ) of a drug, which contains a drug having a logP value of 3.0 or more, A pharmaceutical composition is provided in which the drug is intradermally administered via an injection needle having a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less. In a more preferred form of the present invention, there is provided a pharmaceutical composition for shortening the time to reach the maximum blood concentration (t _max ) of the drug, which comprises a drug having a logP value of 3.0 or more, A pharmaceutical composition is provided in which the drug is intradermally administered to humans through an injection needle having a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less. Here, if the protrusion length is less than 0.9 mm or exceeds 1.4 mm, it may become difficult to reliably administer intradermally (the success rate of intradermal administration may decrease). From the viewpoint of the effects of the present invention (in particular, further improvement in the success rate of intradermal administration), the protruding length of the injection needle in this embodiment is preferably 1.0 mm or more and 1.3 mm or less. Alternatively, if the subject of administration (subject) is a small non-human animal such as a rodent (rat, mouse, rabbit, guinea pig, hamster, etc.), the injection needle should have a protrusion length of 0.1 mm or more and 0.6 mm. It is preferable to provide a needle tube whose protrusion length is as follows, and it is more preferable to provide a needle tube whose protrusion length is 0.45 mm or more and 0.50 mm or less.

The human epidermal layer is thin, and the thickness of the human epidermal layer depends on the age difference, gender difference, individual difference, medical history/treatment history, etc. of the subject (administration target). Therefore, when attempting intradermal administration using a drug administration device equipped with a needle used for conventional subcutaneous administration, it is not possible to unambiguously determine the depth of the administration site within the dermal layer, which is closer to the epidermis. It is not easy to properly position the tip of the injection needle within the dermal layer. Therefore, from the viewpoint of further improving the success rate of intradermal administration (when the administration target is a human, the protrusion length is set to 0.9 mm or more and 1.4 mm or less), published in Japanese Patent Publication No. 2012-503995 (WO 2010/038879) and Japanese Patent Application Publication No. 2010-172603 are preferably used.

In the following, preferred forms of the administration device 10 and needle assembly 100 having an injection needle with a needle tube will be described. Note that the present invention is not limited to the following form. Common members in each figure are given the same reference numerals.

[Administration device]
FIG. 1 is a perspective view schematically showing the overall configuration of the administration device 10. As shown in FIG.

The administration device 10 is used to administer a drug to the dermal layer s2 of a subject (intradermal administration), as shown in FIGS. 10 and 11.

FIGS. 10 and 11 are schematic cross-sectional views of the epidermal layer s1, dermal layer s2, and subcutaneous tissue layer s3 of a subject to whom drugs are administered. In this specification, the epidermis layer s1 and the dermis layer s2 are collectively referred to as the upper skin layer s4.

As shown in FIG. 1, the administration device 10 includes a needle assembly 100 including a needle hub 120 holding an injection needle 110, and a syringe 200 connectable to the needle assembly 100.

As shown in FIG. 3, inside the syringe 200, a liquid chamber 240 that can accommodate a drug (medicinal solution) is provided. A pusher 300 is inserted into the liquid chamber 240 of the syringe 200 to feed a drug from the liquid chamber 240 to the inner cavity 111a of the needle tube 111 of the injection needle 110.

In this embodiment, the extending direction of the injection needle 110 and the extending direction of the syringe 200 are also referred to as the "axial direction." The needle tip 112 side of the injection needle 110 is referred to as the "distal end side", and the end side opposite to the distal end side is referred to as the "proximal end side".

The subject, the operator, etc. (hereinafter also referred to as the "user") move the pusher 300 toward the distal end of the syringe 200 with the needle tip 112 of the injection needle 110 placed within the dermal layer s2. Accordingly, the drug can be intradermally administered to the subject through the tip opening 112a formed in the needle tip 112 (see FIG. 11). In this way, intradermal administration can be reliably performed by a simple operation of placing the needle tip 112 of the injection needle 110 at the intended administration site and injecting the drug. Further, the needle tip 112 is located within the guide portion 123 and is constructed so that it is not visible to the user during operation. Therefore, even subjects who are afraid of injections can administer the drug at home with little or no resistance.

The administration device 10 can be configured, for example, as a disposable device that fills the liquid chamber 240 with a drug (medicine solution) during intradermal administration and discards the filled drug each time it is administered. Note that the administration device 10 can also be configured as a prefilled device in which the liquid chamber 240 is filled with a drug in advance prior to intradermal administration. Further, there is no particular restriction on the drug (medicine to be administered intradermally) stored in the liquid chamber 240 as long as the logP value is 3.0 or more, but specifically, it is as explained in [Drug] above. be.

As shown in FIG. 1, the syringe 200 includes a first cylindrical portion 210 having a locking mechanism 205 (see FIG. 3) to which the needle hub 120 can be connected, and a proximal end of the first cylindrical portion 210. and a second cylindrical portion 220 disposed at.

The first cylindrical portion 210 and the second cylindrical portion 220 have a substantially cylindrical outer shape. The second cylindrical portion 220 disposed on the base end side of the first cylindrical portion 210 has a larger outer diameter than the first cylindrical portion 210 .

When performing intradermal administration using the administration device 10, the user can grasp the second cylindrical portion 220 located on the proximal end side of the syringe 200. Since the second cylindrical portion 220 has a larger diameter than the first cylindrical portion 210, it is easier for the user to grip the second cylindrical portion 220, and the grip strength when gripping the second cylindrical portion 220 is also increased. Therefore, when a user performs intradermal administration using the administration device 10, it is difficult for the user to firmly pierce the needle tip 112 of the injection needle 110 protruding toward the distal side of the administration device 10 into the epidermal layer s1. It becomes possible.

The locking mechanism 205 shown in FIG. 3 can be composed of, for example, a member having a threaded groove on its inner surface. In this embodiment, the second member 127 of the needle hub 120 is provided with a connecting portion 128 that can be screwed into the thread groove of the locking mechanism 205 at the base end. The user inserts the proximal end of the needle hub 120 inside the locking mechanism 205, and then rotates and screws the needle hub 120 to removably connect the needle hub 120 to the syringe 200. be able to.

For example, the threads provided on the locking mechanism 205 may be configured with female threads, and the connecting portion 128 provided on the needle hub 120 may be configured with male threads. However, the thread groove on the locking mechanism 205 side may be configured with a male thread, and the thread groove on the connecting portion 128 side may be configured with a female thread. Further, there is no particular restriction on the specific mechanism for connecting the needle hub 120 and the syringe 200. For example, the distal end of the syringe 200 may be inserted inside the proximal end of the needle hub 120 and the two may be fitted together. It is also possible to adopt a similar mechanism. Further, the needle hub 120 may be fixed to the syringe 200 using an adhesive or the like so that it cannot be separated.

As shown in FIG. 3, the liquid chamber 240 of the syringe 200 is communicated with the lumen 111a of the injection needle 110 (see FIG. 6) when the needle hub 120 and the syringe 200 are connected. As will be discussed below, needle 110 is secured within needle hub 120 by adhesive 126.

[Needle assembly]
As shown in FIGS. 1, 2, and 3, the needle assembly 100 includes an injection needle 110 and a needle hub 120 in which the injection needle 110 is held.

An exploded view of needle assembly 100 is shown in FIG.

As shown in FIG. 3, the needle hub 120 includes a first member 121 disposed on the distal end side of the needle hub 120 and a second member 127 disposed on the proximal end side of the first member 121.

The injection needle 110 is fixed to the first member 121 by an adhesive 126 filled inside the first member 121. An elastic member 125 is arranged between the base end of the first member 121 and the distal end of the second member 127. The injection needle 110 is disposed inside the needle hub 120 with the proximal end 115 of the injection needle 110 aligned with the distal end of the liquid chamber 240.

As shown in FIGS. 3, 4, and 5, the first member 121 of the needle hub 120 is formed by exposing a certain range from the needle tip 112 of the needle tube 111 of the injection needle 110 toward the proximal end. An adjustment section 122 for adjusting the protrusion length L1 of the adjustment section 122 and the needle tube 111 are arranged so as to surround the portions of the adjustment section 122 and the needle tube 111 that are exposed from the adjustment section 122, and to leave a space 122a between the adjustment section 122 and the needle tube 111. It has a guide part 123.

The adjustment portion 122 is provided at approximately the center position of the needle hub 120 in the plane direction. The adjustment portion 122 is configured with a hollow portion that exposes a portion of the needle tip 112 side of the injection needle 110. As shown in FIG. 5, the injection needle 110 is attached to the needle hub 120 with the adhesive 126 described above with a part of the needle tip 112 side exposed from the adjustment part 122 toward the tip side for a predetermined length L1. Fixed. Therefore, the needle hub 120 allows the injection needle 110 to move toward the proximal end side as the needle tip 112 of the injection needle 110 is pressed against the epidermal layer s1 of the subject when performing intradermal administration using the administration device 10. It is possible to prevent the protrusion length L1 from changing due to movement.

The guide section 123 is arranged concentrically with the adjustment section 122. Therefore, as shown in FIG. 4, a circular space 122a centered around the adjustment section 122 is formed around the adjustment section 122.

As shown in FIGS. 3 and 4, a flange portion 124 extending in a planar manner is disposed at a position further toward the outer circumference of the guide portion 123. As shown in FIGS. The flange portion 124, like the guide portion 123, is arranged concentrically with the adjustment portion 122. The flange portion 124 extends from near the base end of the guide portion 123 toward the outer circumference.

The elastic member 125 disposed near the proximal end 115 of the injection needle 110 increases liquid tightness at the connection between the liquid chamber 240 of the syringe 200 and the needle hub 120. Thereby, when the drug is delivered from the liquid chamber 240 to the inner cavity 111a of the injection needle 110, it is possible to prevent the drug from leaking near the proximal end of the injection needle 110.

The dispensing device 10 may include a cap member 130 as shown in FIG. Cap member 130 is configured to be connectable to first member 121 of needle hub 120 . The cap member 130 is disposed so as to cover the needle tip 112 of the injection needle 110 from the distal end side of the needle hub 120 while being connected to the needle hub 120 . By attaching the cap member 130 to the needle hub 120, the user can prevent the needle tip 112 of the injection needle 110 from being accidentally punctured.

Each part of the needle hub 120 shown in FIG. 5 can be formed, for example, with the following dimensions. However, the dimensions are not limited to the example dimensions shown below.

The distance T1 (corresponding to the horizontal width of the space 122a) from the outer circumferential edge of the adjustment part 122 to the inner circumferential edge of the guide part 123 can be set to, for example, 4.9 mm or more and 5.3 mm or less.

The distance T2 from the outer circumferential edge of the guide portion 123 to the outer circumferential edge of the flange portion 124 can be set to, for example, 2.9 mm or more and 3.1 mm or less.

The dimensional difference Hg between the adjustment part 122 and the guide part 123 in the protruding direction of the injection needle 110 can be set to, for example, 0.2 mm or more and 0.4 mm or less.

Each part of the needle hub 120 and the syringe 200 can be made of, for example, a known resin material or a known metal material. As an example, synthetic resins such as polycarbonate, polypropylene, and polyethylene, and metals such as stainless steel and aluminum can be used.

FIGS. 10 and 11 are schematic cross-sectional views when performing intradermal administration to a user using the injection needle 110.

As shown in FIG. 10, when the injection needle 110 perpendicularly punctures the epidermal layer s1, the adjustment part 122 comes into contact with the epidermal layer s1 and spreads the epidermal layer s1 around the injection needle 110. At this time, the skin layer s1 is spread flat within the space 122a provided between the adjustment section 122 and the guide section 123. By pressing the adjustment part 122 until the flange part 124 contacts the skin layer s1, the user can ensure that the force with which the adjustment part 122 and the needle tube 111 press against the skin layer s1 is equal to or higher than a predetermined value. The user inserts the injection needle 110, which is arranged so as to maintain a predetermined protrusion length L1, into the subject from the epidermal layer s1 side while pressing the adjustment part 122 and the flange part 124 against the epidermal layer s1. The needle tip 112 of the injection needle 110 can be appropriately guided into the dermal layer s2 without depending on variations in the state of the epidermal layer s1.

Note that the specific procedure of the intradermal administration method using the administration device 10 and the injection needle 110 according to the present embodiment will be explained in more detail through Examples described later.

6 to 9 show a portion of the distal end side (blade surface 113 side) of the injection needle 110 according to the present embodiment in an enlarged manner.

6 is a plan view of the front end opening 112a of the injection needle 110, and FIG. 7 is a perspective view of the injection needle 110. 8(A) is a side view (left side view) of the injection needle seen from the direction of arrow 8A shown in FIG. 6, and FIG. 8(B) is a perspective side view of the injection needle 110 seen from the direction of arrow 8B shown in FIG. It is. 9(A) is a side view (right side view) of the injection needle seen from the direction of arrow 9A shown in FIG. 6, and FIG. 9(B) is a perspective side view of the injection needle 110 seen from the direction of arrow 9B shown in FIG. It is.

As shown in FIG. 6, the injection needle 110 according to this embodiment includes a needle tube 111 in which a blade surface 113 is formed at the needle tip 112.

A straight line O1 shown in FIGS. 6 to 9 indicates a central axis along the extending direction of the injection needle 110 (needle tube 111).

A lumen 111a is formed inside the needle tube 111, through which a drug to be intradermally administered can flow. A tip opening 112a is formed at the tip of the needle tip 112 and communicates with the inner cavity 111a.

In the administration device 10 described above, the injection needle 110 is arranged such that a certain range on the proximal end side of the injection needle 110 is housed inside the needle hub 120 (inside the first member 121 and the second member 127). Ru. A portion of the distal end of the injection needle 110 is arranged so as to protrude further toward the distal end than the adjustment portion 122 of the needle hub 120 .

A portion of the injection needle 110 that is closer to the proximal end of the needle tube 111 than the portion where the blade surface 113 is formed and is exposed from the adjustment portion 122 constitutes a needle body portion 114 .

The injection needle 110 can be configured with a "lancet needle" or a "semi-lancet needle", for example. However, there are no particular restrictions on the specific shape or structure of the injection needle 110. For example, the injection needle 110 may be configured not only as a straight needle but also as a tapered needle in which at least a portion thereof is tapered, or that the radial cross-sectional shape of the needle tube 111 is a polygon such as a triangle. may have been done.

The injection needle 110 can be configured with a metal needle made of metal, for example. As the metal constituting the injection needle 110, for example, stainless steel, aluminum, aluminum alloy, titanium, titanium alloy, and other metals can be used.

As shown in FIGS. 6 and 7, the blade surface 113 has a first blade surface 113a located on the proximal end side of the needle tube 111, and a boundary located on the needle tip 112 side (distal end side) from the first blade surface 113a. It has a second blade surface 113b and a third blade surface 113c forming a ridgeline at 116.

The second blade surface 113b and the third blade surface 113c are formed symmetrically with respect to the boundary line 116 in the plan view shown in FIG. Therefore, the second blade surface angle θ2 and the third blade surface angle θ3, which will be described later, are substantially the same, and the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c are also substantially the same. The second blade surface 113b and the third blade surface 113c have different shapes (for example, the second blade surface angle θ2 and the third blade surface angle θ3 and/or the blade surface length L22 of the second blade surface 113b and the third blade surface angle θ3). The blade surface length L23 of the surface 113c may be formed in a different shape.

The first blade surface angle θ1 shown in FIGS. 8(A) and 9(A) is the angle formed by the central axis O1 of the needle tube 111 and the first blade surface 113a. The straight line H1 shown in FIGS. 8(A) and 8(B) is a virtual straight line along the first blade surface 113a. That is, the first blade angle θ1 is an angle formed by the central axis O1 and the straight line H1.

The second blade surface angle θ2 shown in FIG. 9(B) is the angle formed between the central axis O1 of the needle tube 111 and the second blade surface 113b. A straight line H2 shown in FIG. 9(B) is a virtual straight line along the second blade surface 113b. That is, the second blade surface angle θ2 is an angle formed by the central axis O1 and the straight line H2.

The third blade surface angle θ3 shown in FIG. 8(B) is the angle formed between the central axis O1 of the needle tube 111 and the third blade surface 113c. A straight line H3 shown in FIG. 8(B) is a virtual straight line along the third blade surface 113c. That is, the third blade surface angle θ3 is an angle formed by the central axis O1 and the straight line H3.

The ridgeline angle α1 shown in FIGS. 8(A) and 9(A) is the angle formed by the central axis O1 and the ridgeline formed at the boundary 116. The straight line B1 shown in FIGS. 8(A) and 8(B) is a virtual straight line along the ridgeline. That is, the ridgeline angle α1 is the angle formed by the central axis O1 and the straight line B1.

The first blade angle θ1 and the ridgeline angle α1 can be formed to be acute angles, for example. Further, the first blade angle θ1 can be formed to be more acute than the ridgeline angle α1. Note that "the degree of the acute angle is large" means that the angle is smaller within the acute angle range.

The second blade angle θ2 and the third blade angle θ3 can be formed into acute angles, for example. Further, the first blade angle θ1 can be formed to be more acute than each of the second blade angle θ2 and the third blade angle θ3.

Since the relationship between the blade angles θ1, θ2, θ3 and the ridge angle α1 is defined as described above, the injection needle 110 has a relatively short blade length L2, so that the needle tip 112 can be Penetration into the epidermal layer s1 is improved.

Next, examples of preferred dimensions of each part of the injection needle 110 according to this embodiment will be described with reference to FIGS. 6 to 9.

The outer diameter D1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.1 mm or more and 0.2 mm or less. Further, the outer diameter D1 of the needle tube 111 is more preferably 0.130 mm or more and 0.1845 mm or less from the viewpoint of enabling intradermal administration to a subject more reliably and easily.

The inner diameter Φ1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.07 mm or more and 0.1 mm or less.

The protrusion length L1 of the needle tube 111 shown in FIG. 6 is 0.9 mm or more and 1.4 mm or less.

The protruding length L1 of the needle tube 111 shown in FIG. 6 is a length suitable for intradermal administration of the pharmaceutical composition, and the needle tube 111 can be appropriately back-tanked depending on the subject to be administered. For example, when the administration target (subject) is a human, the protrusion length L1 of the needle tube 111 is preferably 0.9 mm or more and 1.4 mm or less. From the viewpoint of enabling intradermal administration to a subject more reliably and easily, the protrusion length L1 of the needle tube 111 is more preferably 1.0 mm or more and 1.3 mm or less. Further, for example, when the administration target (subject) is a small non-human animal such as a rodent (rat, mouse, rabbit, guinea pig, hamster, etc.), the protrusion length L1 of the needle tube 111 is 0.1 mm or more. The protrusion length L1 of the needle tube 111 is preferably 0.45 mm or more and 0.5 mm or less, from the viewpoint of enabling intradermal administration to the subject more reliably and easily. is more preferable.

The length (blade surface length) L2 of the blade surface 113 along the extending direction of the needle tube 111 (direction parallel to the central axis O1) shown in FIG. 6 can be formed to be less than 0.3 mm. Further, the length L2 of the blade surface 113 is more preferably 0.15 mm or more and 0.2 mm or less from the viewpoint of increasing the penetrating property of the subject's epidermal layer s1.

Note that the blade surface length L2 is the sum of the blade surface length L21 of the first blade surface 113a and the blade surface length L22 of the second blade surface 113b, or the blade surface length L21 of the first blade surface 113a and the third blade surface 113c. Blade length L
This is the total value of 23.

The needle barrel length L3 shown in FIG. 6 can be formed to be 0.05 mm or more and 0.5 mm or less. The needle barrel length L3 is more preferably 0.3 mm or more and 0.35 mm or less from the viewpoint of enabling intradermal administration to a subject more reliably and easily.

The wall thickness t1 of the needle tube 111 shown in FIG. 6 can be formed to be 0.01 mm or more and 0.06 mm or less. The wall thickness t1 of the needle tube 111 is 0.0215 mm or more and 0.0505 mm or less, from the viewpoint of setting the injection pressure of the drug by the injection needle 110 to an appropriate value in consideration of the outer diameter D1 of the needle tube 111 and the inner diameter Φ1 of the needle tube 111. It is more preferable that there be.

The ratio (L2/L22 and L2/L23) of the blade surface length L22 of the second blade surface 113b and the blade surface length L23 of the third blade surface 113c to the total length L2 of the blade surface 113 shown in FIG. 6 is 40% or more. 60% or less. The above-mentioned ratio is more preferably 47% or more and 56% or less from the viewpoint of improving the penetration property of the epidermal layer s1 of the subject.

In addition, in the case where the blade surface length L2 is 0.15 mm or more and 0.2 mm or less, and the above ratio is 47% or more and 56% or less, the blade surface length L22 of the second blade surface 113b and the third blade surface 113c The blade surface length L23 can be, for example, 0.05 mm or more and 0.09 mm or less. In this case, the blade surface length L21 of the first blade surface 113a can be formed to be, for example, 0.09 mm or more and 0.17 mm or less.

The first blade angle θ1 shown in FIGS. 8(A) and 9(A) can be formed to be greater than or equal to 10° and less than or equal to 65°. The first blade angle θ1 is more preferably 23° or more and 40° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

The second blade angle θ2 and the third blade angle θ3 shown in FIGS. 8(B) and 9(B) can be formed to be greater than or equal to 20° and less than or equal to 85°. The second blade angle θ2 and the third blade angle θ3 are more preferably 21° or more and 45° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

The ridgeline angle α1 shown in FIGS. 8(A) and 9(A) can be formed to be greater than or equal to 15° and less than or equal to 70°. The ridge angle α1 is more preferably 28° or more and 44° or less from the viewpoint of improving the penetration ability of the needle tip 112 into the epidermal layer s1.

[Intradermal administration method]
Next, the intradermal administration method according to this embodiment will be explained. That is, the present invention provides a method for intradermally administering a drug having a logP value of 3.0 or more through an injection needle. Further, in one embodiment of the present invention, a method for intradermally administering a drug having a logP value of 3.0 or more to a human via an injection needle equipped with a needle tube having a protrusion length of 0.9 mm or more and 1.4 mm or less I will provide a. Alternatively, the present invention provides a method for shortening the time to reach the maximum blood concentration (t _max ), which comprises intradermally administering a drug with a logP value of 3.0 or more via an injection needle. . Further, in an embodiment of the present invention, a drug having a logP value of 3.0 or more is intradermally administered to a human via an injection needle equipped with a needle tube having a protrusion length of 0.9 mm or more and 1.4 mm or less. Provided is a method for shortening the time to reach the maximum blood concentration (t _max ), having the following properties: Note that the present invention is not limited only to the following embodiments.

As described above, the injection needle 110 and administration device 10 according to this embodiment have a configuration suitable for intradermal administration to a subject.

Therefore, in this embodiment, the needle assembly includes an injection needle including a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less, and a needle hub that holds the injection needle, wherein the needle hub is , an adjustment part that adjusts the protrusion length of the needle tube by exposing a certain range from the needle tip of the needle tube toward the proximal end side; and a periphery of the adjustment part and the portion of the needle tube exposed from the adjustment part. a guide portion surrounding the adjustment portion and spaced between the adjustment portion and the needle tube; or a syringe connected to the needle hub. The syringe includes a first cylindrical portion disposed on the proximal side of the needle hub, and a first cylindrical portion disposed on the proximal side of the first cylindrical portion, the syringe having a larger outer diameter than the first cylindrical portion. A method for intradermally administering a drug to a subject using an administration device comprising a second cylindrical portion, the drug having a logP value of 3.0 or more, The subject (in particular A method for intradermal administration to humans is provided.

Further, in the present embodiment, a needle assembly includes an injection needle including a needle tube with a protrusion length of 0.9 mm or more and 1.4 mm or less, and a needle hub that holds the injection needle, wherein the needle hub is , an adjustment part that adjusts the protrusion length of the needle tube by exposing a certain range from the needle tip of the needle tube toward the proximal end side; and a periphery of the adjustment part and the portion of the needle tube exposed from the adjustment part. a guide portion surrounding the adjustment portion and spaced between the adjustment portion and the needle tube; or a syringe connected to the needle hub. The syringe includes a first cylindrical portion disposed on the proximal side of the needle hub, and a first cylindrical portion disposed on the proximal side of the first cylindrical portion, the syringe having a larger outer diameter than the first cylindrical portion. and a second cylindrical portion, the drug is intradermally administered to a subject (particularly a human) using the administration device, wherein the drug has a logP value of 3.0 or more, and the drug has a logP value of 3.0 or more, and pressing a guide portion of a needle hub holding an injection needle against the site where the drug is to be administered, and then intradermally administering the drug to the administration site through vertical puncture through the injection needle. , a method is provided for shortening the time to reach maximum blood concentration (t _max ) of said drug.

In one embodiment of the invention, the site of administration is the upper skin layer s4 having a dermal layer s2 with a thickness of less than 3.0 mm (preferably less than 2.0 mm). Moreover, in this embodiment, the thickness of the administration site is measured by an ultrasound imaging apparatus.

Further, the protrusion length L1 of the injection needle 110 used for intradermal administration is preferably such that the ratio of the protrusion length L1 of the injection needle 110 to the thickness of the upper skin layer s4 of the subject is less than 0.9. , is more preferably less than 0.8, and particularly preferably 0.7 or less. Thereby, the needle tube 111 can be more reliably placed in the upper skin layer s4, and the success rate of intradermal administration can be further improved.

In place of or in addition to the above, when performing intradermal injection, it is preferable that the entire blade surface 113 of the injection needle 110 be buried in the upper skin layer s4 of the subject. Thereby, leakage of medicine from the needle tube 111 can be suppressed.

Specifically, the blade length L2 is smaller than the thickness of the upper skin layer s4 of the subject, and the ratio of the blade length L2 of the injection needle 110 to the thickness of the upper skin layer s4 of the subject is 0. It is preferably less than .60, more preferably less than 0.56, even more preferably less than 0.50, and particularly preferably less than 0.35. Thereby, the entire amount of the drug can be more reliably injected into the upper skin layer s4, and the success rate of intradermal administration can be further improved.

In the intradermal administration method, first confirm the administration site on the subject. Note that a support member (hereinafter also simply referred to as "support member") for stabilizing vertical puncture is placed below the administration site of the subject (on the epidermal layer side located on the opposite side to the insertion direction of the injection needle 110). ) may be placed. At this time, the support member is preferably formed from silicone resin or the like. Since such a support member has appropriate hardness, it is possible to stably fix the administration site.

Alternatively, any part of the subject's upper skin layer s4 may be stretched flat to serve as the administration site. At this time, after pressing the guide part 123 of the needle hub 120 against the administration site, the guide part 123 may be separated from the administration site by a predetermined distance (moved in the direction of lifting it from the epidermal layer s1). This lowers the injection pressure of the drug (medicinal solution), allowing for good intradermal administration. In this case, it is preferable that the distance between the guide parts 123 is such that the injection pressure of the medicine can be sufficiently lowered. Specifically, the distance is preferably such that the injection pressure during administration is 5 to 20N, and more preferably the distance is such that the injection pressure during administration is 10 to 15N. The above "injection pressure" is based on the feeling of the hand when administering to the subject, and measures the pressure when pressing the digital force gauge with the same force, and this pressure is taken as the injection pressure. It is measured by.

By using the above intradermal administration method and the puncture resistance of the injection needle, it is possible to reliably and accurately deliver the drug into the subject's skin (upper skin layer s4).

Conventionally, the Mantoux method is well known as a method for administering a drug into the dermal layer s2 of a subject. The Mantoux method is a method in which the injection needle 110 is inserted obliquely into the upper skin layer s4 having the dermis layer s2. Here, as described above, the skin is composed of an upper skin layer s4 consisting of an epidermal layer s1 and a dermal layer s2, and a subcutaneous tissue layer s3. The thickness of the upper skin layer of the human deltoid muscle is generally as thin as about 2 mm. For this reason, intradermal administration to the upper skin layer s4 is difficult, and depending on the procedure and the diameter of the injection needle used, there is a possibility that the drug may leak into the subcutaneous tissue layer s3 or onto the skin surface. Furthermore, whether or not intradermal administration is successful may vary depending on the skill of the operator performing the injection. In contrast, according to the intradermal administration method according to the present embodiment (particularly the intradermal administration method using the administration device of the present disclosure), a predetermined amount of the drug can be reliably administered intradermally. In addition, since vertical puncture is used, the procedure is easy and variations among surgeons can be suppressed. Furthermore, leakage of medicine can be suppressed. Therefore, according to the intradermal administration method of this embodiment, a predetermined amount of the drug can be reliably and accurately delivered intradermally to the subject. Furthermore, since drugs with a specific degree of hydrophobicity (logP value) are administered intradermally, the drug's efficacy can be exerted in a shorter period of time compared to other administration routes (especially subcutaneous administration) (improving pharmacokinetics). ). Therefore, it can be expected that the administered drug will be effective even if the amount of the drug is smaller than before. Additionally, since there are fewer nerves in the intradermal tissue than in the subcutaneous tissue, pain during administration can be reduced and alleviated.

The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In addition, in the following examples, unless otherwise specified, operations were performed at room temperature (25° C.). Furthermore, unless otherwise specified, "%" and "parts" mean "% by mass" and "parts by mass", respectively.

Example 1
(Preparation of injection solution)
Olanzapine injection solution (20 mg/mL, LogP value of olanzapine = 3.0) was prepared by opening 10 mg of Zyprexa for intramuscular injection (Eli Lilly Japan Co., Ltd.) and adding and dissolving 0.525 mL of water for injection. Zyprexa 10mg for intramuscular injection contains 11.0mg of olanzapine as an active ingredient in one vial, but considering the loss of dissolved drug solution during suction and administration, 10mg can be injected from one vial. The amount is overfilled to ensure as much as possible.

(Preparation of administration device)
The needle assembly 100 (guide) shown in FIG. 3 is equipped with an injection needle (needle tube outer diameter: 0.1845 mm (34G), protrusion length: 0.5 mm, blade surface length: 0.2 mm, needle tip shape: semi-lancet). The administration device 10 shown in FIG. 1 was produced. The administration device 10 has a structure in which a syringe 200 is connected to a needle assembly 100. The thickness of the upper skin layer of the rat used, which consists of the epidermis layer and the dermis layer, is generally about 0.4 to 0.8 mm. Therefore, in the rat intradermal administration device, the protrusion length of the needle tube was set to 0.5 mm.

(Animals used)
Three male rats (Crl: CD (SD), 7 weeks old, purchased from Jackson Laboratory Japan Co., Ltd. (formerly Charles River Japan Co., Ltd.)) were given a 7-day quarantine and acclimatization period, and all rats were tested. After confirming that there were no abnormalities in health and no weight loss, the animals were submitted to the test. The rats were kept in a breeding environment with 12 hours of light, a temperature of 20 to 26°C, and a humidity of 30 to 70%, and were allowed free access to food and water. The experiment was conducted in accordance with Terumo Corporation's guidelines for animal experiments.

(administration)
The olanzapine injection solution prepared above was injected into the syringe 200 through the needle tube 111 in an amount such that the dose of olanzapine administered to rats was 2.5 mg/kg body weight. The dose (μL) per individual is determined by rounding off to the second decimal place based on the body weight on the day of administration using the formula (A) shown below to the first decimal place.

Each rat was anesthetized with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) (concentration setting: 2%). Next, under anesthesia, the rat's back was cut with hair clippers to create an administration site, and then the rat was made to lie down. After pressing the guide part 123 against this administration site, the olanzapine injection solution was intradermally administered to the back via the injection needle 110 (dosage administered to rats: 2.5 mg/kg body weight).

The intradermal administration site of each rat was visually confirmed. As a result, in all rats, no leakage of the injection solution was observed, the diameter of the wheal was 3 mm or more, and the color of the wheal was whiter than the surrounding skin, so it was judged that the intradermal administration was successful. Regarding wheal size (diameter), according to the US CDC (Centers for Disease Control and Prevention) guidelines, in humans, wheals with a diameter of 6 mm or more are formed when 100 μL of drug solution is administered. Intradermal administration was determined to be successful if the wheal diameter was 3 mm or more, as in the case of rats in this example, the volume of the administered solution was less than half the volume, 50 μL. . In addition, regarding the color of wheals, rat skin is softer than that of humans, so wheal-like things may be seen even when administered subcutaneously, so this was added to the criteria to distinguish it from subcutaneous administration.

(Measurement of t _max )
According to the method below, the plasma drug concentration was measured at a total of 8 time points before administration of olanzapine injection and 5, 10, 15, 30, 45, 60 and 120 minutes after administration of olanzapine injection, and the concentration was determined to reach the maximum blood concentration. The time (t _max ) (minutes) required to reach this point was determined.

1 mL syringe containing anticoagulant (SS-01P, Terumo Corporation) equipped with a 23G needle (NN02325R, Terumo Corporation) (heparin sodium (heparin Na injection 10,000 units/10 mL "Mochida", Mochida Pharmaceutical Co., Ltd.) 3 μL (filled with anticoagulant) was prepared.

At each time point, the neck (blood collection site) of each rat was shaved with clippers and then restrained, and 0.3 mL of blood was collected from the jugular vein using an anticoagulant-containing syringe. The collected blood was immediately transferred to a 1.5 mL polypropylene tube (1-1600-01, As One Corporation), the blood and anticoagulant were thoroughly mixed by tapping, and then centrifuged to separate plasma. .

To 10 μL of each plasma, 10 μL of internal standard substance (I.S.) (0.4 μg/mL, Olanzapine-d8 (CAYMAN CHEMICAL)) and 10 μL of ethanol were added and stirred. Next, 100 μL of 10 mM ammonium formate was added and stirred, and then 600 μL of t-butyl methyl ether was added and stirred. After centrifugation at 10,000×g for 5 minutes, the upper organic layer was removed and dried under a stream of nitrogen. After adding 200 μL of methanol to the residue and stirring, 200 μL of water was added and stirred (pretreatment) to prepare a measurement sample. Regarding the measurement sample obtained above, the plasma drug concentration was measured according to liquid chromatography tandem mass spectrometry (LC-MS/MS) under the following conditions. Plasma drug concentrations at each time point were compared and the time to reach the maximum blood concentration (t _max ) was determined; t _max during intradermal administration of olanzapine injection was 25.7 minutes (average value of 3 animals). )Met.

(LC setting conditions)
・HPLC system: Nexera system (Shimadzu Corporation)
・Analytical column: SUMIPAX (registered trademark) ODS Z-CLUE,
2.0mm ID×50mm L., 3μm (Sumika Analysis Center Co., Ltd.)
・Column temperature: 40℃
・Eluent: A 10mmoL/L ammonium formate,
B Methanol flow rate: 0.35mL/min
・Gradient conditions: As shown in Table 1 below

(MS/MS setting conditions)
・Tandem mass spectrometer: API5000 (AB Sciex Pte. Ltd.)
・Interface: Turbo-V spray
・Ionization method: Electrospray ionization (ESI), positive ion mode
・Scan mode: Multiple reaction monitoring (MRM) mode
・Heater gas temperature: 600℃
・Ion spray voltage (IS): 5500V
・Nebulizer gas (GS1): 60psi, air (1psi = 6.895kPa)
・Heater gas (GS2): 60psi, air
・Curtain gas: Setting value 15, nitrogen
・Collision gas: Setting value 10, nitrogen
・Monitor ion and collision energy olanzapine: m/z 313→m/z 256, 30 eV, I. S. : m/z 358 → m/z 198, 53 eV
Example 2
(Preparation of injection solution)
4.5 mL of water for injection was added to 0.5 mL of 0.1 mol/L acetate buffer (pH 5.0, 20°C) to prepare 0.01 mol/L acetate buffer. Separately, weigh 7.53 mg of domperidone (log P value = 3.9), add 9 μL of acetic acid to dissolve it, and then add 738 μL of the 0.01 mol/L acetate buffer prepared above and the 10 mol/L sodium hydroxide solution. Domperidone injection (10 mg/mL) was prepared by adding 5 μL. In addition, taking into consideration the loss of the dissolved drug solution during suction and administration, an excessive amount of domperidone was weighed to ensure an injectable amount of 7.52 mg.

(Preparation of administration device)
An administration device 10 was produced in the same manner as in Example 1.

(Animals used)
Three rats were subjected to the test in the same manner as in Example 1.

(administration)
The domperidone injection solution prepared above was injected into the syringe 200 through the needle tube 111 in such an amount that the dose of domperidone to the rat was 1.4 mg/kg body weight. The dose (μL) per individual was determined in the same manner as in Example 1.

Each rat was anesthetized with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) (concentration setting: 2%). Next, under anesthesia, the rat's back was cut with hair clippers to create an administration site, and then the rat was made to lie down. After pressing the guide part 123 against this administration site, the domperidone injection solution was intradermally administered to the back via the injection needle 110 (dosage administered to rats: 1.4 mg/kg body weight).

In the same manner as in Example 1, the intradermal administration site of each rat was visually confirmed. As a result, in all rats, no leakage of the injection solution was observed, the diameter of the wheal was 3 mm or more, and the color of the wheal was whiter than the surrounding skin, so it was judged that the intradermal administration was successful.

(Measurement of t _max )
In Example 1, the solvent added to each plasma in the pretreatment was methanol and I. S. were changed to Domperidone-d6 (Toronto Research Chemicals), the flow rate and gradient conditions of (LC setting conditions) were changed to 0.3 mL/min and the conditions listed in Table 2 below, and (MS/MS setting conditions) Example 1 except that the monitor ion and collision energy were changed from m/z 426 to m/z 147,56 eV (domperidone) and from m/z 432 to m/z 181,40 eV (I.S.). According to the same method, the plasma drug concentration was measured at a total of 8 time points before administration of domperidone injection and 5, 10, 15, 30, 45, 60 and 120 minutes after administration of domperidone injection. When the plasma drug concentration at each time point was compared and the time to reach the maximum blood concentration (t _max ) was determined, t _max during intradermal administration of domperidone injection was 10.0 minutes (average of 3 animals). value).

Example 3
(Preparation of injection solution)
Contomin 50 mg for intramuscular injection (containing 50.0 mg/5 mL of chlorpromazine hydrochloride) was prepared as a chlorpromazine injection solution (9 mg/mL, log P value of chlorpromazine = 5.4).

(Preparation of administration device)
An administration device 10 was produced in the same manner as in Example 1.

(Animals used)
Three rats were subjected to the test in the same manner as in Example 1.

(administration)
The chlorpromazine injection solution prepared above was injected into the syringe 200 through the needle tube 111 in an amount such that the dose of chlorpromazine administered to the rat was 1.2 mg/kg body weight. The dose (μL) per individual was determined in the same manner as in Example 1.

Each rat was anesthetized with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) (concentration setting: 2%). Next, under anesthesia, the rat's back was cut with hair clippers to create an administration site, and then the rat was made to lie down. After pressing the guide part 123 against this administration site, the chlorpromazine injection solution was intradermally administered to the back via the injection needle 110 (dosage administered to rats: 1.2 mg/kg body weight).

In the same manner as in Example 1, the intradermal administration site of each rat was visually confirmed. As a result, in all rats, no leakage of the injection solution was observed, the diameter of the wheal was 3 mm or more, and the color of the wheal was whiter than the surrounding skin, so it was judged that the intradermal administration was successful.

(Measurement of t _max )
In Example 1, the solvent added to each plasma in the pretreatment was methanol and I. S. and 0.05 μg/mL, Chlorpromazine-d6 Hydrochloride (Toronto Research Chemicals) respectively, then change the solvents to be added to 100 μL of borate pH standard solution (pH 9.18) and 700 μL of diethyl ether, and add to the residue. solvent was changed to 100 μL of methanol and 250 μL of 10 mmoL/L ammonium formate/formic acid (1000:1, v/v), and in (LC setting conditions), the HPLC system was changed to the LC-20A system (Shimadzu Corporation). , the eluent was changed to A 10 mmoL/L ammonium formate/formic acid (1000:1, v/v), B acetonitrile, the flow rate was changed to 0.4 mL/min, and the gradient conditions were as shown in Table 3 below. Furthermore, in (MS/MS setting conditions), change the nebulizer gas (GS1) to 50 psi, air, change the curtain gas to set value 20, nitrogen, and change the monitor ion and collision energy to m/z 319. → m/z 86,30 eV (chlorpromazine), m/z 325 → m/z 92,30 eV (IS), according to the same method as in Example 1, before administration of chlorpromazine injection, and plasma drug concentrations were measured by LC-MS/MS at a total of 14 time points, 5, 10, 15, 30, 45, 60, 120, 180, 240, 300, 360, 1440, and 2880 minutes after administration of chlorpromazine injection. did. The plasma drug concentrations at each time point were compared and the time to reach the maximum blood concentration (t _{max )} was determined; ), which was shorter than the t _max during intradermal administration of olanzapine injection.

Comparative examples 1 to 3
(Preparation of injection solution)
Olanzapine injection solution (20 mg/mL) was prepared in the same manner as in Example 1.

Domperidone injection solution (10 mg/mL) was prepared in the same manner as in Example 2.

Chlorpromazine injection (9 mg/mL) was prepared in the same manner as in Example 3.

(Preparation of administration device)
Microsyringe with 25G fixed needle (standard type microsyringe, 004000, Trajan Scientific Japan Co., Ltd.) (fixed needle type, capacity: 50μL, code: 50F, outer diameter of needle tube: 0.5mm (25G), needle length (length: 50 mm, needle tip shape: bevel, blade angle: 20°) was prepared.

(Animals used)
In the same manner as in Example 1, 3 rats/group (9 rats in total) were subjected to the test.

(administration)
Olanzapine injection, domperidone injection, and chlorpromazine injection prepared above were administered to rats in amounts such that the doses were 2.5 mg/kg body weight, 1.4 mg/kg body weight, and 1.2 mg/kg body weight. , respectively, were injected into a syringe. The dose (μL) per individual was determined in the same manner as in Example 1.

Each rat was anesthetized with isoflurane (isoflurane inhalation anesthetic solution "Pfizer", manufactured by Mylan Pharmaceutical Co., Ltd., sold by Pfizer Inc.) (concentration setting: 2%). Next, under anesthesia, the rat's back was cut with hair clippers to create an administration site, and then the rat was made to lie down. While pinching this administration site, insert the injection needle approximately 30 mm along the body axis. After confirming that the needle tip moves easily and is inserted subcutaneously, insert each injection solution through the injection needle. was administered subcutaneously to the back. After administration, the needle was gently removed and the injection site was pressed for a while to confirm that the administered solution did not leak. In addition, the doses of olanzapine injection, domperidone injection, and chlorpromazine injection to rats in the above procedure were 2.5 mg/kg body weight, 1.4 mg/kg body weight, and 1.2 mg/kg body weight, respectively. Ta.

(Measurement of t _max )
Following the same method as Example 1 (olanzapine), Example 2 (domperidone) and Example 3 (chlorpromazine), before administration of each injection and 5, 10, 15, 30, 45 after administration of each injection. , 60 and 120 minutes (however, for chlorpromazine, a total of 14 time points 5, 10, 15, 30, 45, 60, 120, 180, 240, 300, 360, 1440 and 2880 minutes after administration). Drug concentrations were each measured by LC-MS/MS. The plasma drug concentration at each time point was compared, and the time to reach the maximum blood concentration (t _max ) was determined. As a result, t _max for subcutaneous administration of olanzapine injection solution was 28.3 minutes (average value of 3 animals), which was slightly lower than that for intradermal administration of olanzapine injection solution (t _max = 25.7 minutes). It was long. The t _max for subcutaneous administration of domperidone injection solution was 45.7 minutes (average value of 3 animals), which was considerably longer than that for intradermal administration of domperidone injection solution (t _max = 10.0 minutes). Ta. The t _max for subcutaneous administration of chlorpromazine injection solution was 31.6 minutes (average value of 3 animals), which was longer than that for intradermal administration of chlorpromazine injection solution (t _max =5.0 minutes).

From the above results, among hydrophobic drugs, for drugs with a degree of hydrophobicity (logP value) of 3.0 or higher, intradermal administration has a shorter t _max than subcutaneous administration, and is useful for rescue drugs such as antiemetics. It is expected that it will be possible. Note that although the above effects were observed in rats, it is thought that similar effects are observed when intradermally administered to humans. Further, the above effect was confirmed using an antiemetic agent, but it is thought that a similar effect would be observed if the antiemetic agent has a similar degree of hydrophobicity (logP value).

Although the present invention has been described above based on the embodiments and examples, the present invention is not limited to the content described in this specification, and may be modified as appropriate based on the description of the claims. It is possible.

10 Administration device 100 Needle assembly 110 Injection needle 111 Needle tube 111a Inner lumen of needle tube 112 Needle tip 112a Tip opening 113 Blade surface 113a First blade surface 113b Second blade surface 113c Third blade surface 114 Needle body 115 Proximal end 116 Boundary 120 Needle hub 121 First member 122 Adjustment part 122a Space 123 Guide part 124 Flange part 127 Second member 130 Cap member 200 Syringe 210 First cylinder part 220 Second cylinder part 240 Liquid chamber D1 Outer diameter Hg of needle tube Adjustment part Dimension difference L1 in the protruding direction of the guide portion and the protruding length of the needle tube L2 Total length of the blade surface L21 Length of the first blade surface L22 Length of the second blade surface L23 Length of the third blade surface L3 Needle barrel length O1 Central axis of the needle T1 Distance between the adjustment part and the guide part T2 Distance between the guide part and the flange part s1 Epidermal layer s2 Dermal layer s3 Subcutaneous tissue layer s4 Upper skin layer t1 Thickness of the needle Φ1 Inner diameter of the needle α1 Ridge angle θ1 1st blade angle θ2 2nd blade angle θ3 3rd blade angle

Claims (5)

A pharmaceutical composition for shortening the time to reach the maximum blood concentration (t _max ) of a drug, the composition comprising a drug having a logP value of 3.0 or more,
The drug is a pharmaceutical composition administered intradermally. The pharmaceutical composition according to claim 1, wherein the drug is administered intradermally via an injection needle equipped with a needle tube having a protrusion length of 0.9 mm or more and 1.4 mm or less. The pharmaceutical composition according to claim 1, wherein the drug has a logP value of 3.1 or more. 2. A pharmaceutical composition according to claim 1, wherein the drug is an antiemetic or an antipsychotic. 2. A pharmaceutical composition according to claim 1, wherein the drug is domperidone or chlorpromazine hydrochloride.