JP2024023047A - Pharmaceutical containing vildagliptin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical stably containing vildagliptin.

SOLUTION: A pharmaceutical comprises a vildagliptin-containing solid preparation that is stored in a hermetically sealed package containing a desiccant and/or an oxygen absorber selected from zeolite, calcium chloride, and silica alumina.

SELECTED DRAWING: None

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention relates to vildagliptin-containing pharmaceuticals.

Vildagliptin has a selective DPP-IV inhibitory effect and is used as a therapeutic drug for type 2 diabetes. It is known that vildagliptin is an unstable compound and is preferably formed into tablets by direct compression (Patent Document 1).
Attempts have also been made to solve the instability of vildagliptin by selecting additives, such as techniques to incorporate specific amounts of D-mannitol, lactose, trehalose, corn starch, crystalline cellulose, etc. (Patent Document 2), excipients, etc. A technique of blending trehalose, cyclodextrin, hydroxypropyl starch, phosphate, etc. as an agent (Patent Document 3), a technique of blending crystalline cellulose, which affects the stability of vildagliptin, outside vildagliptin-containing granules to form tablets (Patent Document 3). Patent Document 4) has been reported.

Patent No. 5122144 JP2021-88541A JP2019-182756A Japanese Patent Application Publication No. 2021-165266

An object of the present invention is to provide a pharmaceutical product stably containing vildagliptin.

Therefore, as a result of various studies taking into account not only the known analogues of vildagliptin but also the production of other analogues, the present inventor developed a vildagliptin-containing solid preparation made of a dry material selected from zeolite, calcium chloride, and silica alumina. It has been found that if the vildagliptin is housed in an airtight package containing an agent and/or an oxygen scavenger, the production of not only known analogs of vildagliptin but also other analogs can be suppressed. Furthermore, we have discovered a good combination of pharmaceutical additives to be incorporated into solid formulations to maintain vildagliptin stability.

That is, the present invention provides the following inventions [1] to [11].
[1] A pharmaceutical product comprising a solid preparation containing vildagliptin housed in an airtight package containing a desiccant and/or an oxygen scavenger selected from zeolite, calcium chloride, and silica alumina.
[2] The vildagliptin-containing solid preparation is packaged in PTP, the airtight package is a pillow package, and a desiccant selected from zeolite, calcium chloride, and silica alumina is provided between the PTP package and the pillow package. Or the pharmaceutical according to [1], which is encapsulated with an oxygen absorber.
[3] The pharmaceutical according to [1] or [2], wherein an oxygen absorber is enclosed in an airtight package.
[4] The pharmaceutical according to any one of [1] to [3], wherein the vildagliptin-containing solid preparation is a solid preparation containing vildagliptin, an excipient, a binder, a disintegrant, and a lubricant.
[5] The pharmaceutical according to [4], wherein the excipient is one or more selected from D-mannitol, lactose hydrate, and anhydrous lactose.
[6] The pharmaceutical according to [4] or [5], wherein the binder is one or more selected from hydroxypropyl cellulose, hypromellose, and partially saponified polyvinyl alcohol.
[7] The pharmaceutical according to any one of [4] to [6], wherein the disintegrant is one or more selected from crospovidone, low-substituted hydroxypropylcellulose, and sodium starch glycolate.
[8] The pharmaceutical according to any one of [4] to [7], wherein the lubricant is one or more selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, and talc.
[9] A vildagliptin-containing solid preparation containing vildagliptin, D-mannitol, hydroxypropylcellulose, sodium starch glycolate, and sodium stearyl fumarate.
[10] A vildagliptin-containing tablet containing vildagliptin, D-mannitol, hydroxypropylcellulose, sodium starch glycolate, and sodium stearyl fumarate.
[11] The vildagliptin-containing solid preparation according to [9] or the vildagliptin-containing tablet according to [10] is housed in an airtight package containing a desiccant and/or an oxygen absorber selected from zeolite, calcium chloride, and silica alumina. Pharmaceutical products made by

The pharmaceutical of the present invention can suppress the production of not only known analogs of vildagliptin but also unknown analogs of vildagliptin. Furthermore, elution delay can also be suppressed.

One embodiment of the pharmaceutical product of the present invention is characterized in that a solid preparation containing vildagliptin is housed in an airtight package in which a desiccant and/or an oxygen scavenger selected from zeolite, calcium chloride, and silica alumina are enclosed.
The active ingredient of the pharmaceutical of the present invention is vildagliptin. Vildagliptin, whose chemical name is (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidine, has a selective DPP-IV inhibitory effect as described above, and is effective against type 2 diabetes. Known as an active ingredient in therapeutic drugs. Therefore, the medicament of the present invention is used as a therapeutic agent for type 2 diabetes.
A solid preparation containing vildagliptin is usually orally administered to adults at 50 mg as vildagliptin twice a day in the morning and evening, and 50 mg can be administered once a day in the morning depending on the patient's condition. Therefore, it is preferable that the vildagliptin-containing solid preparation contains 25 mg to 50 mg of vildagliptin. Further, the vildagliptin content in the vildagliptin-containing solid preparation is preferably 10 to 50% by mass, more preferably 10 to 40% by mass.

As mentioned above, vildagliptin is an unstable compound and is known to give rise to known related substances. On the other hand, according to the inventor's study, as shown in the Examples below, when vildagliptin is stored under accelerated conditions or severe conditions, unknown analogues of vildagliptin may be generated in addition to known analogues. found. Therefore, as a result of studies to suppress the production of both known and unknown related substances of vildagliptin, the present inventor has found that a desiccant and/or oxygen scavenger selected from zeolite, calcium chloride, and silica alumina is encapsulated. It has been found that by housing the vildagliptin-containing solid preparation in an airtight package, the production of both of these can be effectively suppressed.

The desiccant used in the present invention is selected from zeolite, calcium chloride, and silica alumina. Zeolites, calcium chloride, and silica alumina inhibit the formation of known analogs of vildagliptin to a greater extent than other known desiccant agents such as silica gel. Among these, zeolite is particularly preferred.
Zeolite is a microporous crystalline aluminosilicate, and its pore diameter is said to be 0.3 to 1 nm. Moreover, both natural zeolite and synthetic zeolite can be used in the present invention. Silica alumina is also called silica alumina gel, and commercially available products can be used.
The amount of desiccant selected from zeolite, calcium chloride, and silica alumina to be used depends on the volume and material of the airtight package containing the vildagliptin-containing solid preparation, but it is usually 0.5 g to 10 g in one airtight package. Just enclose it.

In addition to the effect of suppressing the production of known analogues of vildagliptin, oxygen scavengers also particularly significantly inhibit the production of unknown analogues.
Oxygen scavengers include metal powders such as iron powder, ferrous salts, dithionites, sulfites, metal halides, and other inorganic substances; ascorbic acid, erythorbic acid, and their salts. Oxygen scavengers based on organic compounds such as polyphenols such as hydroquinone and catechol are known. Further, there are two types of oxygen scavengers: self-reacting type and moisture-dependent type, and both can be used in the present invention, but self-reacting type which does not depend on moisture is more preferable.
Commercially available oxygen scavengers include "Ageless" (product name) S type, SS type, Z type, FX type, ZM type, SA type, GL type, and "Pharma Keep" (product name) manufactured by Mitsubishi Gas Chemical Co., Ltd. ``Pharmakeep'', which is an oxygen scavenger with a drying function, is more preferable. Further, as commercially available oxygen scavengers, "Tamotsu" (trade name) VX type, D type, "Oxygen Cut" (trade name) GD type, etc. manufactured by Oe Chemical Industry Co., Ltd. can be used.
The amount of oxygen scavenger used depends on the volume, material, etc. of the airtight package that houses the vildagliptin-containing solid preparation, but it is usually one that has an oxygen absorption capacity of 3 ml to 400 ml, and preferably one that has a water adsorption capacity of 0.0 ml. One having a capacity of 0.7 g to 3.0 g may be enclosed in an airtight package.

In the present invention, one or both of a desiccant and an oxygen scavenger selected from zeolite, calcium chloride, and silica alumina can be used, but it is more preferable to use an oxygen scavenger, and an oxygen scavenger with a drying function is preferably used. It is even more preferable to use

Examples of the form of the vildagliptin-containing solid preparation used in the present invention include tablets, granules, and capsules, but tablets are preferred from the viewpoint of suppressing the production of known and unknown analogs of vildagliptin.

The solid preparation containing vildagliptin is preferably a solid preparation containing vildagliptin, an excipient, a binder, a disintegrant, and a lubricant, from the viewpoint of suppressing the production of known analogues and unknown analogues of vildagliptin. , vildagliptin, an excipient, a binder, a disintegrant and a lubricant.

The excipient is preferably one or more selected from D-mannitol, lactose hydrate, anhydrous lactose, and cornstarch, from the viewpoint of suppressing the production of known and unknown related substances of vildagliptin. , lactose hydrate, and anhydrous lactose are more preferred, and D-mannitol is even more preferred.
The content of excipients in the vildagliptin-containing solid preparation is preferably 20 to 80% by mass, more preferably 30 to 75% by mass, from the viewpoint of suppressing the production of known analogues and isomers of vildagliptin.

The binder is preferably one or more selected from hydroxypropyl cellulose, hypromellose, and partially saponified polyvinyl alcohol, from the viewpoint of suppressing the production of known analogs and unknown analogs of vildagliptin. One or more selected types are more preferred, and hydroxypropylcellulose is even more preferred.
The content of the binder in the vildagliptin-containing solid preparation is preferably 0.5 to 5% by mass, from the viewpoint of functioning as a binder and suppressing the production of known analogues and unknown analogues of vildagliptin. ~5% by mass is more preferred.

The disintegrant is preferably one or more selected from crospovidone, low-substituted hydroxypropylcellulose, and sodium starch glycolate, from the viewpoint of suppressing the production of known analogs and unknown analogs of vildagliptin. One or more selected from sodium starch glycolate is more preferred, and sodium starch glycolate is even more preferred from the viewpoint of suppressing the production of known analogs and unknown analogs of vildagliptin, and from the viewpoint of maintaining dissolution properties after storage. .
The content of the disintegrant in the vildagliptin-containing solid preparation is preferably 1 to 15% by mass, and 2 to 10% by mass, from the viewpoint of disintegrating the preparation and suppressing the production of known analogues and unknown analogues of vildagliptin. Mass% is more preferred.

The lubricant is preferably one or more selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, and talc, from the viewpoint of suppressing the production of known analogues and unknown analogues of vildagliptin. One or more selected from sodium and magnesium stearate are more preferred, and sodium stearyl fumarate is even more preferred.
The content of the lubricant in the vildagliptin-containing solid preparation is preferably 0.5 to 10% by mass from the viewpoint of preparation productivity and suppressing the production of known analogues and unknown analogues of vildagliptin. More preferably 1 to 8% by mass.

In addition to the above ingredients, vildagliptin-containing solid preparations contain fragrances, sweeteners, flavoring agents, pigments, stabilizers, antioxidants, solubilizing agents, surfactants, flow agents, plasticizers, etc. Good too. Additionally, a film coating layer may be provided.

The vildagliptin-containing solid preparation can be manufactured according to a conventional method for solid preparations. For example, vildagliptin-containing tablets can be manufactured by producing vildagliptin-containing granules by wet granulation or dry granulation, and then compression-molding a mixture of the granules with a lubricant, etc. can.

The pharmaceutical product of the present invention can be produced, for example, by housing a desiccant and/or oxygen scavenger selected from zeolite, calcium chloride, and silica alumina, and a solid preparation containing vildagliptin in an airtight package.
Airtight packaging is a packaging that can substantially prevent solids and liquids from entering from outside the packaging during normal handling, and is defined as an "airtight container" and Includes “sealed containers”. Specific examples include bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.
In the present invention, since a desiccant and/or an oxygen scavenger selected from zeolite, calcium chloride, and silica alumina and a vildagliptin-containing solid preparation are housed in an airtight package, the vildagliptin-containing solid preparation is packaged in PTP packaging. It is preferable to package the PTP package and house the desiccant and/or oxygen absorber selected from zeolite, calcium chloride, and silica alumina in a pillow package.

Packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), biaxially oriented nylon (ONy, PA), and low density polyethylene. (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), biaxially oriented polyvinylidene chloride (PVDC), polychlorotrifluoro Examples include resins such as ethylene (PCTFE), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), and cyclic polyolefin (COC), and metal foils such as aluminum foil (AL). A multilayer structure may be formed by appropriately combining two or more types. Preferred packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are polyvinyl chloride, polyvinylidene chloride, aluminum foil, and aluminum laminate film.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Test example 1
We have investigated various methods for testing the purity of vildagliptin in bulk drug substances or vildagliptin-containing solid preparations. Purity test method A below mainly detects known related substances, while purity test method B detects mainly known related substances. It was found that isomers and unknown related substances were detected. The relationship between the resulting vildagliptin analogs and test methods is shown in Table 1.
・Purity test method A
Related substances are measured using reverse phase liquid chromatography at a measurement wavelength of 210 nm.
・Purity test method B
Related substances are measured by normal phase liquid chromatography at a measurement wavelength of 210 nm.

Test example 2
<Contact stability test method (contact stability test by test method A)>
After weighing the drug substance and additives in the proportions shown in Table 2, they were mixed in a pestle and mortar. The resulting mixture was placed in a glass bottle, placed in a stability tester under accelerated conditions (40° C., 75% RH), and stored for one month.
The amount of related substances was measured using purity test method A before and after storage. The results are shown in Table 2.

From Table 2, as excipients, one or more types selected from D-mannitol, lactose hydrate, and anhydrous lactose are preferable as components that contribute to suppressing the production of known analogues of vildagliptin, and D-mannitol is particularly preferable. It has been found. It has been found that the binder is preferably one or more selected from hydroxypropylcellulose, hypromellose, and partially saponified polyvinyl alcohol, and hydroxypropylcellulose is particularly preferred. It has been found that the disintegrant is preferably one or more selected from crospovidone, low-substituted hydroxypropylcellulose, and sodium starch glycolate, and crospovidone is particularly preferred. It has been found that the lubricant is preferably one or more selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, and talc, and sodium stearyl fumarate is particularly preferred.

Test example 3
<Contact stability test method (contact stability test according to purity test method B)>
In purity test method A, for the additive that showed the best contact stability among the respective excipients (excipients, binders, disintegrants, lubricants), the drug substance and excipient were mixed in a ratio of 1:1. After weighing, the mixture was mixed using a pestle and mortar. The resulting mixture was placed in a glass bottle, placed in a severe condition stability tester (60°C), and stored for one month.
The amount of related substances was measured using purity test method B before and after storage. The results are shown in Table 3.

From Table 3, the additives that suppressed the production of known analogs of vildagliptin in Purity Test Method A also suppressed the production of related substances in Purity Test Method B (N/A: less than 0.05%).

Test example 4
<Tablet stability test>
Tablets were manufactured according to the formulation shown in Table 4, and the tablets were packaged in PTP and then in pillow packaging, stored under accelerated conditions (40°C, 75% RH), and tested for stability using purity test method A and purity test method B. Tested. As for the storage method, a case where zeolite was sealed between PTP packaging and pillow packaging was compared with a case where zeolite was not sealed (Table 5). The results are shown in Tables 6 and 7.

<Production method of formulation 1>
Vildagliptin, D-mannitol, and crospovidone were charged into a fluidized bed granulator. Hydroxypropyl cellulose aqueous solution (5% aqueous solution) was sprayed and fluidized bed granulation was performed. Ethyl maltol and sodium stearyl fumarate were added to the granulated powder and mixed. The mixed powder was compressed into tablets.

From Tables 6 and 7, it can be seen that the formulation in Table 4 can significantly suppress the increase in known analogues of vildagliptin compared to the tablet of Reference Example. It is also seen that by adding zeolite to the airtight package, the increase in known analogues of vildagliptin can be significantly suppressed. On the other hand, in purity test method B, although the increase in the total amount of related substances was suppressed by adding zeolite, it was found that the increasing tendency of the unknown related substance, which is one of the individual related substances, became larger. . Although the target of the present invention of 0.2% or less was achieved, it was found that when adding zeolite, care and management of unknown related substances is required, or that further improvement is desirable.
In addition, when calcium chloride was used instead of zeolite as the desiccant added to the airtight package, the production of known analogues of vildagliptin was 0.11% after 3 months of acceleration in purity test method A, which was very strong. It turns out that it can be suppressed.
Furthermore, when silica gel was used instead of zeolite as the desiccant added to the airtight package, the formation of known analogues of vildagliptin could not be suppressed.

Test example 5
Compared to Example 1, a formulation capable of suppressing the production of unknown analogues of vildagliptin was investigated. Tablets having the formulation shown in Table 8 were manufactured, packaged in PTP as shown in Table 9, and then sealed in a pillow package and stored under severe conditions (60°C). The results are shown in Tables 10 and 11.

It was found that by changing the disintegrant from crospovidone to sodium starch glycolate, it was possible to suppress the increase in known related substances and total related substances in purity test method A (Table 10). In addition, by changing the disintegrant from crospovidone to sodium starch glycolate, it is possible to suppress the increase in unknown related substances and total related substances of vildagliptin in purity test method B even if a desiccant (zeolite) is attached. was found (Table 11).

Test example 6
<Consideration of additives for airtight packaging>
We investigated additives other than zeolite for airtight packaging.
The tablets of Formulation 2 and Formulation 3 (Table 8) were packaged in PTP, which was further enclosed in a pillow package (Table 12) and stored under severe conditions (60°C). The results are shown in Tables 13 and 14.

By adding an oxygen scavenger, the increase in known related substances and total related substances can be suppressed to the same extent as zeolite in purity test method A (Table 13).
By adding an oxygen scavenger, it is possible to suppress the increase in unknown related substances of vildagliptin compared to zeolite in purity test method B (Table 14) (Example 2 vs Example 4, Example 3 vs Example 5) )

Test example 7
After storing the pharmaceutical of the present invention of Example 3 under severe conditions (60° C.) for 4 weeks, the dissolution rate of vildagliptin was measured. The results are shown in Table 15.
<Elution test conditions>
Test solution: pH 1.2 (Japanese Pharmacopoeia No. 1 solution), 900 mL
Test method: 18th edition Japanese Pharmacopoeia dissolution test method (paddle method)
Paddle rotation speed: 50rpm
Bessel number (n number): 3

From Table 15, reference example 1 (originator formulation Equa ^TM tablets 50 mg) had delayed dissolution to around 85% at 15 minutes after storage for 4 weeks, whereas Example 3 (formulation 3: starch glycolic acid Sodium) showed no elution delay and an elution rate of about 100%.

Claims (11)

A pharmaceutical product comprising a solid preparation containing vildagliptin housed in an airtight package containing a desiccant and/or an oxygen scavenger selected from zeolite, calcium chloride, and silica alumina. The vildagliptin-containing solid preparation is packaged in PTP, the airtight package is a pillow package, and a desiccant selected from zeolite, calcium chloride, and silica alumina and/or a deoxidizer is placed between the PTP package and the pillow package. The pharmaceutical according to claim 1, wherein the pharmaceutical agent is encapsulated. 3. The pharmaceutical product according to claim 1 or 2, wherein an oxygen absorber is enclosed in the airtight package. The pharmaceutical according to any one of claims 1 to 3, wherein the vildagliptin-containing solid preparation is a solid preparation containing vildagliptin, an excipient, a binder, a disintegrant, and a lubricant. 5. The pharmaceutical according to claim 4, wherein the excipient is one or more selected from D-mannitol, lactose hydrate, and anhydrous lactose. 6. The pharmaceutical product according to claim 4, wherein the binder is one or more selected from hydroxypropylcellulose, hypromellose, and partially saponified polyvinyl alcohol. The pharmaceutical according to any one of claims 4 to 6, wherein the disintegrant is one or more selected from crospovidone, low-substituted hydroxypropylcellulose, and sodium starch glycolate. The pharmaceutical according to any one of claims 4 to 7, wherein the lubricant is one or more selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, and talc. A solid preparation containing vildagliptin, which contains vildagliptin, D-mannitol, hydroxypropylcellulose, sodium starch glycolate, and sodium stearyl fumarate. A vildagliptin-containing tablet containing vildagliptin, D-mannitol, hydroxypropylcellulose, sodium starch glycolate, and sodium stearyl fumarate. The vildagliptin-containing solid preparation according to claim 9 or the vildagliptin-containing tablet according to claim 10 is housed in an airtight package encapsulating a desiccant and/or oxygen absorber selected from zeolite, calcium chloride, and silica alumina. Pharmaceutical products.