KR20200121480A - Packing material for improving the stability of a vidagliptin hydrochloride-containing composite formulation - Google Patents

Abstract

According to a technology disclosed in the present invention, provided is a packing material for pharmaceutical formulations containing vildagliptin, wherein the packing material has a water vapor transmission rate (WVTR) of 0.2 g/m^2/day or less at about 38°C and about 90% relative humidity. The packing material according to the present invention significantly improves the stability against moisture even during long-term storage of a complex formulation containing vildagliptin.

Description

Packing material for improving the stability of a vidagliptin hydrochloride-containing composite formulation

The technology disclosed in the present specification relates to a packaging material for improving the stability of a composite composition containing vildagliptin hydrochloride, and more particularly, to a packaging material having improved storage stability of a composite formulation containing vildagliptin and metformin.

The content described in this section merely provides background information on the present embodiment and does not constitute the prior art.

A hormone called incretin, which is secreted from the gastrointestinal tract when food is consumed, regulates blood sugar by controlling the secretion of insulin and glucagon dependent on blood sugar. DPP-4 (dipeptidyl peptidase-4) inhibitors regulate blood sugar by increasing insulin secretion by inhibiting an enzyme called DPP-4 that degrades these incretins.

Examples of such DPP-4 inhibitors include sitagliptin (trade name: Janubia), vildagliptin (trade name: Gabbs), which inhibit enzymes, and saxagliptin (trade name: Onglyza) was in 2009, Linagliptin Liptin (tradename: Tragenta) are drugs approved by the US FDA in April 2011. These drugs can enhance the role of incretin by maintaining the activity of incretin for a long time by interfering with the enzyme DPP-4, which normally inactivates incretin.

In addition, Garber et al. reported that when vildagliptin 50mg or 100mg was added to 322 patients with type 2 diabetes whose blood sugar was not sufficiently controlled with SU, blood glucose decreased by 0.58% and 0.63%, respectively, in both groups. It was announced that hyperglycemia was improved.

In addition, in the treatment of type 2 diabetic patients, the results that adding vildagliptin to metformin improves the therapeutic effect rather than increasing the dose of metformin have been published in the American Diabetes Association (ADA) 2012. Specifically, the vildagliptin group was less in terms of reducing fasting blood sugar and reducing adverse drug-related reactions, and it was reported that there was no difference between the two groups in terms of insulin resistance change, insulin secretion, and lipid change.

Korean Patent Registration No. 1259645 (invention title: direct compression formulation and method) and Korean Patent Publication No. 2013-7035015 (invention title: formulation containing metformin and vildagliptin) include dry granules or direct compression methods, or A technology for producing a combination agent is disclosed by adding vildagliptin to a post-mixing unit after metformin hydrochloride wet granulation (high shear mixer, HSM).

According to the disclosures of the above patent documents, in order to eliminate the instability against moisture, a combination formulation using dry granules or direct compression method or metformin hydrochloride wet granulation (high shear mixer, HSM) and then vildagliptin in the post mixing unit. To produce. However, such a method has inconveniences that take many steps and time, such as a process of drying the granule moisture to a level of 2% after granulation production, a process of establishing a hard wet granule powder, and a process of removing moisture from the tablet after tableting. .

Accordingly, the present inventors have completed the present invention by studying a technique capable of supplementing the problems of the prior art and securing the simplicity of the process and water stability.

Patent Document 1: Korean Patent Registration No. 1259645 Patent Document 2: Korean Patent Publication No. 2013-7035015

In the complex formulation containing vildagliptin, related substances may be produced over time by the moisture contained in the formulation, which may affect the stability of the drug. Accordingly, the present invention was completed by focusing on the fact that stability against moisture of the formulation can be secured by appropriately controlling the moisture in the complex formulation containing vildagliptin and the head space.

Accordingly, an object of the present invention is to provide a packaging material capable of improving the stability against moisture of a composite formulation containing vildagliptin hydrochloride.

In addition, an object of the present invention is to provide a pharmaceutical article comprising a packaging container composed of the above packaging material and a complex formulation containing vildagliptin and a method for manufacturing the same.

Other objects not specified in the present invention may be additionally considered within a range that can be easily deduced from the following detailed description and effects thereof.

In order to achieve the above object, the present invention is a packaging material for complex formulations containing vildagliptin, wherein the packaging material has a moisture permeability (WVTR) of 0.2 g/m ² /day or less at 38°C and 90% relative humidity. It provides a packaging material characterized by.

In addition, in order to achieve the above object, the present invention further comprises a dehumidifying agent, and the dehumidifying agent contains vildagliptin hydrochloride containing at least 1.5 g per 100 g of the complex formulation containing vildagliptin hydrochloride. Provides.

In addition, in order to achieve the above object, the present invention has a moisture permeability (WVTR) of 0.005 g/m ² /day or less at 38° C. and 90% relative humidity, and 100 g of a composite formulation containing vildagliptin hydrochloride Provide a packaging material containing 0.3g or more of dehumidifying agent per sugar.

In order to achieve the above other object, the present invention is a packaging container consisting of a packaging material having a moisture permeability of 0.2g / m ² / day or less at 38 ℃ and 90% relative humidity; And it provides a pharmaceutical article comprising a complex formulation containing vildagliptin contained in the packaging container.

In addition, the present invention is a method for manufacturing a pharmaceutical article containing vildagliptin hydrochloride-containing pharmaceutical formulations, in order to achieve the above other object, by preparing a pharmaceutical composition containing vildagliptin hydrochloride by wet granulation by a fluid bed granulation process Step to do; And it provides a method comprising the step of packaging the pharmaceutical formulation containing the wet granules containing vildagliptin hydrochloride, a dehumidifying agent.

The packaging material according to the present invention significantly improves the stability against moisture even during long-term storage of the complex formulation containing vildagliptin, and is very suitable as a packaging material for formulations containing vildagliptin.

It is possible to improve the stability against moisture during storage, especially the stability by moisture of the formulation itself, so that the formation and increase of related substances can be suppressed. In particular, even in the case of an aluminum blister packaging material having a very low moisture permeability, according to the present invention, there is an effect that the stability of related materials is improved by more than two times compared to a conventional packaging material.

Even if it is an effect not explicitly mentioned here, the effect described in the following specification expected by the technical feature of the present invention and its provisional effect are treated as described in the specification of the present invention.

1 is a graph showing the results of a stability test of the formulations of Example 1 and Comparative Example 1 under accelerated moisture supersaturation storage conditions.
2 is a graph showing the results of a stability test of the formulations of Examples 3 and 4 and Comparative Examples 3, 4 and 5 under accelerated moisture and saturation storage conditions.

Hereinafter, a packaging material for a complex formulation containing vildagliptin according to the present invention, a pharmaceutical article including the complex formulation containing vildagliptin, and a manufacturing method thereof will be described in more detail. However, the present invention may be implemented in various different forms, and is not limited to the described embodiments.

Hereinafter, terms used in the present invention are defined.

The term “packaging material” as used herein refers to a material used to package pharmaceutical formulations, such as tablets, capsules, etc., for distribution, and “packaging material for complex formulations containing vildagliptin” or “Villada The term "packaging for a gliptin-containing complex formulation" includes a substance, a material used to package a pharmaceutical formulation containing vildagliptin, or a product made therefrom.

The term "packaging container" as used herein refers to a container for packaging a pharmaceutical preparation, manufactured using part or all of the packaging material.

The term “moisture moisture permeability (WVTR)” as used herein refers to the amount of moisture permeated per time per unit area, and the WVTR value in this specification is about 38° C., about 90% relative humidity ( RH) refers to the amount of moisture permeated/unit area/unit time.

The present invention relates to a packaging material for complex formulations comprising vildagliptin, wherein the packaging material has a moisture permeability (WVTR) of about 0.2 g/m ² /day or less at about 38°C and about 90% relative humidity. do.

In addition, it is preferable that the packaging material for a complex formulation containing vildagliptin according to the present invention further includes a dehumidifying agent to control moisture released from the formulation itself. According to an embodiment, when the packaging material has a moisture permeability (WVTR) of 0.2 g/m ² /day or less at 38° C. and 90% relative humidity, the dehumidifying agent is 1.5 per 100 g of the complex formulation containing vildagliptin hydrochloride. It is preferable to contain more than g.

In addition, according to an embodiment, when the packaging material has a moisture permeability (WVTR) of 0.005 g/m ² /day or less at 38° C. and 90% relative humidity, the dehumidifying agent is a composite formulation containing vildagliptin hydrochloride It is preferable to contain 0.3g or more per 100g.

In order to satisfy such moisture permeability, the packaging material according to the present invention is specifically made of glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), and polychlorotrifluoro. A packaging material may be manufactured using a material selected from the group consisting of ethylene (PCTFE), cycloolefin polymer (COP), cycloolefin copolymer (COC), polyolefin (PO), aluminum (Al), and combinations thereof. More specifically, a packaging material may be manufactured using a material composed of various combinations of PVDC-Al, PCTFE-Al, PVC-Al+Al, and PO-Al-Al. In the case of a material made of a PO or PVC-Al-Al combination, there is an advantage in that it is easy to mold and produce to contain a dehumidifying agent.

Glass, HDPE, PP, PVC, PVDC, PCTFE, COP, COC, PO and Al used in the present invention may be those commonly used in the packaging of pharmaceutical products in the pharmaceutical field. For example, the HDPE may have a weight average molecular weight of about 50,000 to 150,000, and a density of about 0.941 g/cm 3 to 0.965 g/cm 3. The PP may have a weight average molecular weight of about 200,000 to 600,000, and the PVC may have a molecular weight distribution (Mw/Mn) of about 1.7 to 2.0 and a density of about 1.16 g/cm 3 to 1.35 g/cm 3. The PVDC may have a density of about 65 g/cm 3 to 1.72 g/cm 3, the PCTFE may have a specific gravity of about 2.12, and the PO, COP and COC may have a density of about 1.02 g/cm 3 or less.

Complex preparations containing the vildagliptin are described above about 38 ℃ and about 90% at a relative humidity of about 0.2g / m ² / day or less, and further 0.005g / m flexible when stored in packaging material having a moisture permeability of not more than ² water / day The production of substances is significantly suppressed. Considering that the production of related substances in pharmaceuticals affects the efficacy of drugs, the fact that the pharmacological properties of the vildagliptin-containing preparation can be maintained for a long period of time by using the packaging material of the present invention is a very great advantage.

The packaging material according to the present invention can be used as a material constituting a packaging container. Containers that can be manufactured using the packaging material according to the present invention include bottles, blisters, or pouches.

For example, the bottle may be made of a HDPE bottle, and the cap included in the bottle may be made of a PP material.

The blister is made of a top plate containing one or two or more materials selected from the group consisting of PVC, PVDC, PCTFE, PP, PE, COP, COC, PO, Al, and combinations thereof, and a lower plate containing Al material. I can. The upper plate and/or lower plate may have a single structure or two or more structures. When the blister is made of PVC, PVC is not used alone, but one or two or more materials selected from the group consisting of PVDC, PCTFE, Al, and combinations thereof are bonded together, or the blister is used. It is preferable to use it in the form of sealing the pouch or wrapping the PVC upper plate with an Al material film.

Specifically, in the blister, the upper plate contains an Al material, the lower plate contains an Al material, the upper plate contains a PO material, and the lower plate contains an Al material, the upper plate contains a PVDC material, and the lower plate contains Al. The material may be included, or the upper panel may include a PCTFE material and the lower panel may include an Al material. In this case, the PO is a polymer that may be included to maintain the shape of the upper plate, and a PVC material may be used instead of PO. Further, Al, PVDC or PCTFE used as the top plate of the blister is Al-PVC, PVDC-PVC, PCTFE-PVC or Al in which Al, PVDC or PCTFE is coated or bonded on a film made of PVC or PO. It may be a duplex structure such as -PO, PVDC-PO, or PCTFE-PO. Or PVDC-PE-PVC, PVDC-PP-PVC, PCTFE- in which PVDC-PE, PVDC-PP, or PCTFE-PE is coated or bonded on a PVC film to increase the adhesion between the films and the blister easily. It may be a triplex structure such as PE-PVC, or a higher structure. On the other hand, the upper plate of the blister may be in a form in which a PVC material film is wrapped with an Al material film. Furthermore, the PVC may be made of a material such as PP, PE, COP, COC, or PO.

In one embodiment of the present invention, the thickness of the blister top plate may be 50 μm to 600 μm, specifically 75 μm to 600 μm, 100 μm to 500 μm, or 150 μm to 400 μm. In one embodiment of the present invention, the thickness of the PVC film may be 15 μm to 500 μm, in detail, 15 μm to 300 μm, 30 μm to 300 μm, or 30 μm to 250 μm. At this time, the thickness of the entire double structure or triple structure including the PVC film corresponding to the thickness range may be 100 μm to 600 μm, and in detail, 150 μm to 600 μm, 150 μm to 500 μm, or 150 μm to 400 μm. In addition, the thickness of the Al may be 10 μm to 100 μm, 15 μm to 85 μm, or 15 μm to 70 μm, in detail 15 μm to 50 μm, or 10 μm to 40 μm, more specifically 15 μm to 30 μm.

Furthermore, the pouch is a container for additional sealing after blister packaging, and may be to additionally seal the blister packaging material using, for example, an aluminum film.

Meanwhile, the dehumidifying agent may be included in a form integrated into a packaging material or a packaging container or separately included. In the case of a bottle, it may be combined with the bottle cap and integrated, or may be contained in a paper bag or plastic bag and separately included. In the case of a blister, a dehumidifying agent may be included in the top plate, and for example, a layer containing a dehumidifying agent may be included in the top plate. For example, a layer containing a dehumidifying agent may be included in a layer containing a dehumidifying agent in a film size of 1 m ² (mass about 200 g) made of a PO or PVC material, of which about 10 to 30% by weight of a dehumidifying agent may be included.

The present invention also includes a packaging container composed of a packaging material having a moisture permeability of 0.2g/m ² /day or less, or 0.005g/m ² /day or less at 38°C and 90% relative humidity; And it provides a pharmaceutical article comprising a complex formulation containing vildagliptin contained in the packaging container. The packaging material and packaging are as described above.

The complex formulation containing vildagliptin may be made of a pharmaceutical composition containing vildagliptin hydrochloride as an active ingredient.

The complex formulation containing vildagliptin may be a tablet formulation, and the tablet may be a simple form, a film or sugar coated form, embossed or layered, or a sustained release formulation. They can be manufactured in a variety of sizes, shapes and colors.

Tablets can be prepared by compressing wet granules. The wet granulation is preferably formed by a fluid bed granulation process.

According to this fluidized bed granulation process, the drying process is simpler than the high shear granulation process by controlling the injection speed and temperature of the binder solution, the fact that the sizing process is simple due to the formation of generally uniform granules, and the moisture of vildagliptin hydrochloride It can provide various advantages, such as minimizing contact, and, above all, securing the stability of related substances of a product even if the main components are manufactured as wet granules with wet granulation through a fluid bed granulator.

In addition, the pharmaceutical composition may further include metformin hydrochloride as an active ingredient. Vildagliptin hydrochloride is preferred because it can provide insulin secretion stability while lowering fasting blood sugar than when used alone. When vildagliptin hydrochloride and metformin hydrochloride are mixed and formulated as wet granules, it is preferable in that stability from moisture and persistence of medicinal effects can be secured.

Since metformin has the property of hardening during storage, it is desirable to prepare it by decompaction using Erweka all-purpose (AR-402) equipped with a 0.85mm screen as an example, and other raw materials also use a 0.6mm screen. It is preferable to prepare by sifting.

The pharmaceutical composition may further include an excipient used as a binder. In addition, pharmaceutically acceptable additives, for example, a lubricant, a disintegrant, a lubricant, a filler, a colorant, a flavoring agent, etc. may be further included as necessary.

As a binder, various products of hydroxypropyl cellulose such as HPC-L (hydroxypropyl cellulose-L type) and HPC-EXF (hydroxypropyl cellulose-EXF type) can be used, depending on the desired viscosity. , E, L, J, G, M or H can be selected and used. In addition, XF refers to a product having a more finely divided particle size, and similarly, it can be selected and used according to the required viscosity.

In order to secure the ease of viscosity control when an excipient used as a binder such as HPC-L, HPC-EXF, etc. is dissolved in water to make a binder, the amount to be added to the granule (X/-) and the amount to be added ( -/Y) is divided and weighed, and purified water is used to prepare a binding solution, and the binding agent can be prepared in a ratio of 5 to 10% (w/w), for example.

For example, the packaging material may be a material having a WVTR of 0.2g/m ² /day or less. In this case, the packaging material preferably contains 1.5 g or more and 10.5 g or less per 100 g of the composite formulation, preferably 2.0 g or more and 10.5 g or less, and more preferably 3.0 g or more and 10.5 g or less. By using a packaging material containing a dehumidifying agent within the above range, in addition to controlling moisture by the moisture permeability of the packaging material, moisture released from the formulation itself can be effectively removed, and the moisture stability of the formulation can be improved by 1.5 times or more. According to an embodiment, 1.5 g or more per 100 tablet formulations containing vildagliptin hydrochloride and metformin hydrochloride wet granules may be included. On the other hand, when the dehumidifying agent is contained in an amount of 10.5 g or less per 100 g of the formulation, it is possible to prevent deformation of the formulation due to the removal of excess moisture, and also, it is possible to integrate the cap of the bottle and the dehumidifying agent, so that it is convenient in management and use of the dehumidifying agent. I can give it, and it is desirable.

As another example, the packaging material may be a material having a WVTR of 0.005 g/m ² /day or less, and it is more preferable to include a dehumidifying agent. In this case, the dehumidifying agent is preferably contained 0.2 g or more and 1.6 g or less per 100 g of the composite formulation, more preferably 0.3 g or more and 1.0 g or less, and more preferably 0.5 g or more and 1.0 g or less per 100 g of the composite formulation. It is included. It is preferable to contain 1.6 g or less per 100 g of the formulation as it can improve the processability and storage stability of the packaging material.

Silica gel may be used as the dehumidifying agent, and other pharmaceutically acceptable dehumidifying agents may be used.

In addition, the present invention is a method for producing a pharmaceutical article comprising a preparation containing vildagliptin hydrochloride, comprising: preparing a pharmaceutical composition containing vildagliptin hydrochloride into wet granules by a fluid bed granulation process; And packaging the pharmaceutical formulation containing the vildagliptin hydrochloride-containing wet granules with a packaging material containing a dehumidifying agent.

The formulation containing vildagliptin hydrochloride is preferably a complex formulation containing metformin hydrochloride, and by mixing vildagliptin hydrochloride and metformin hydrochloride and providing them as mixed wet granules, stability from moisture and persistence of medicinal effects can be secured. More preferable.

Among the raw materials used, metformin has the property of curing during storage, so it is desirable to prepare it by decompaction using Erweka all-purpose (AR-402) equipped with a 0.85mm screen as an example, and other raw materials are also 0.6 It is preferable to prepare by sieving using a mm screen.

If necessary, an excipient used as a binder such as HPC-L and HPC-EXF may be included, and pharmaceutically acceptable additives may be further included.

Next, the excipients used as binders such as HPC-L, HPC-EXF, etc., are measured by dividing the amount into the granular part (X/-) and the amount into the binder solution (-/Y), and the binder solution is prepared using purified water. , The binder may be prepared in a 5-10% (w/w) ratio as an example.

At this time, the fluidized bed granulation process is, for example, the metformin hydrochloride, vildagliptin, or a pharmaceutically acceptable salt thereof, and a binder are added to a fluidized bed granulator (GR, XP-70) and mixed so that they are homogeneously mixed for 1 to 10 minutes, and then the tower It is preferable to form granules by injecting the binder solution in a spray (Top spray) method.

When the addition of the binder is completed, the granules are dried until the drying temperature of the FBG process conditions is reached, and then sieved using a cored mill combined with a 0.6 mm sieve.

Then, after adding the disintegrant using a V-mixer, the mixture is mixed at 10 to 100 rpm for 1 to 20 minutes, and then the lubricant is added and further mixing is performed for 1 to 10 minutes.

The mixed granules are tableted with a tablet press of 7 to 9 kgf using a rotary tablet press (GRC-18, Sejong), and the compressed core tablet is coated with a coating machine (SFC-30) of 3 mg/cm ² or less. Can be applied and tableted.

As described above, the packaging material may be a material having a moisture permeability of 0.2 g/m ² /day or less. At this time, the packaging material preferably contains at least 1.5 g of a dehumidifying agent per 100 g of the filling contents, and within this range, stability may be improved by 1.5 times or more. Such a packaging material may be in the form of a bottle, for example. The filling content is a pharmaceutical preparation containing vildagliptin hydrochloride, or a complex preparation further containing metformin hydrochloride, and for example, the preparation may be in the form of a tablet.

In addition, it is preferable that the packaging material has a moisture permeability of 0.005 g/m ² /day or less, and a dehumidifying agent contains 0.3 g or more per 100 g of the filling contents. Such a packaging material may be in the form of a blister, for example.

At this time, as the dehumidifying agent, a conventional component used to dehumidify drugs or food, such as silica gel, may be used.

A preferred example of the packaging material according to the present invention is that the WVTR is 0.005 g/m ² /day or less, and the silica gel as a dehumidifying agent includes 0.3 g or more per 100 g of the composite tablet containing vildagliptin hydrochloride and metformin hydrochloride.

Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention, but the following examples are only illustrative of the present invention, and various changes and modifications are possible within the scope of the present invention and the scope of the technical idea, which is obvious to those skilled in the art. It is natural that such modifications and modifications fall within the appended claims.

Example

Preparation Examples 1 and 2

In the contents shown in Table 1 below, vildagliptin hydrochloride, metformin hydrochloride, HPC-L and HPC-EXF were prepared as binders, and croscarmellose sodium (Cros CMC Na), crospovidone, lubricant as a disintegrant As a magnesium stearate was prepared.

Among the above raw materials, metformin is hardened during storage, so it was prepared by decompaction using Erweka all-purpose (AR-402) equipped with a 0.85mm screen, and other raw materials were also sieved using a 0.6mm screen. Ready.

Subsequently, HPC-L and HPC-EXF were weighed by dividing the amount into the granular part (X/-) and the amount into the binding liquid (-/Y), and a binding liquid was prepared using purified water. At this time, the binder was prepared in a ratio of 5 to 10% (w/w).

In a fluid bed granulator (GR, XP-70), metformin hydrochloride, vildagliptin, or a pharmaceutically possible salt thereof, and a binder disclosed in Table 1 are added, mixed to be homogeneously mixed for 3 minutes, and then combined by a top spray method. The liquid was added to form granules.

When the addition of the binder was completed, the granules were dried until the drying temperature of the FBG process conditions was reached, and then sieved using a cored mill combined with a 0.6 mm sieve. At this time, the FBG process conditions used the conditions in Table 2 below.

Subsequently, after the disintegrant was added using a V-mixer, the mixture was mixed at 50 rpm for 5 minutes, and then the lubricant was added and further mixing was performed for 3 minutes.

Compressed granules are tableted with a tablet press of 7 to 9 kgf using a rotary tablet press (GRC-18, Sejong), and a coating weight of about 3 mg/cm ² is applied to the compressed core tablets using a coating machine (SFC-30). I did. The prepared tablet was about 1.2g/pill.

The types of packaging materials, packaging forms, and amounts of silica gel for the tablets of Examples 1 to 10 are shown in Table 3 below, and the types of packaging materials, packaging forms, and amounts of silica gel for the tablets of Comparative Examples 1 to 5 are shown in Table 4 below. Shown in. For 100T tablets, 250mL/1 bottle, for 30T tablets, 125mL/bottle was used as a packaging material, and the blister was used as a packaging material with a size of about 8cm ² per pack.

Experimental example : Packaging and moisture in various packaging materials for oral solid preparations Breathable Measure

According to Examples 1 to 10 and Comparative Examples 1 to 5 (see Table 3 and Table 4), the composite composition containing vildagliptin hydrochloride prepared in Preparation Examples 1 to 2 (see Table 1), Al-Al, It was packaged in the form of blisters, bottles, etc. using packaging materials made of HDPE and PVDC-Al.

At this time, the Al-PO (with silica)-Al is a brand name: Formpack ^® with desiccant, a source: amcor, Al is a brand name TEKNILID ^® 1207, a source: Tekniplex, HDPE is a brand name: BTH-250, source: Ewha Engineering, and PP-Cap (including silicagel) brand names: MH-Cap (0.5g), MH-Cap (1.5g), MH-Cap (2.5g), MH-Cap (3.8g), source: Ewha and engineering, PVDC is a trade name: was obtained from Tekniplex: TEKNIFLEXVDC ^® 250-40, available destinations.

Experimental example One

The moisture content of the tablets according to Preparation Examples 1 to 2 was measured, and the results are shown in Table 5 below. Specifically, for the tablets according to Examples and Comparative Examples, the moisture content was measured using Karl fischer (metrohm, 870 KF titrino plus).

Experimental example 2

Tablets prepared according to Preparation Examples 1 to 2 were packaged with the packaging materials of Examples 1 to 10 or Comparative Examples 1 to 5, respectively, in a 60°C chamber (Labfine, FLT-600S) for 4 weeks, 40°C/90% After storage in the RH chamber (Labfine, FLT-600S) for 2 weeks, 4 weeks and 8 weeks, a test was conducted to measure related substances.

Liquid chromatography using an appropriate diluted solution capable of extracting the main component, for example, a solution of 0.01 M aqueous hydrochloric acid and acetonitrile in an appropriate ratio, and adjusted so that the final concentration as vildagliptin is 2000 μg/mL as the sample solution Was performed, and the degree of generation of related substances was analyzed. At this time, the analysis conditions were as follows:

<Analysis conditions>

Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm)

Column: 250 mm C18 column

Mobile phase: pH 8.2 buffer, pH 4.2 buffer, gradient solvent transfer method of methanol

Flow rate: 1.0 ml/min

Column temperature: 30°C

The oral solids of Examples 1 to 10 and Comparative Examples 1 to 5 prepared in this way were stored for 4 weeks under a severe storage condition of 60°C, and then the amount of related substances produced was measured, and is shown in Table 6 below.

Vildagliptin amide related substances (Imp.7) and dimer related substances (Imp.5) are related substances that increase under moisture conditions, and amide related substances are produced at 2% or less and dimer related substances at 0.5% or less. It is desirable to be. As can be seen from Table 6, as a result of the stability test under severe conditions, in the case of the comparative example, particularly, the dimer-related material increased by 0.5% or more.

In particular, in the case of Comparative Example 4 (Al-Al blister) packaging, it was confirmed that the amount of related substances increased significantly compared to other packaging materials.This was not provided with a dehumidifying agent in addition to the low moisture permeability of the packaging material, so that the moisture contained in the tablet was not This is because they were trapped and could not get out of the packaging. As such, it can be seen that the composition of the composite formulation containing vildagliptin hydrochloride is very important to remove moisture generated from the inside of the packaging material, and that the use of a packaging material containing a dehumidifying agent can significantly suppress the formation of related substances. have.

Experimental example 3

The oral solids of Examples 1 to 10 and Comparative Examples 1 to 5 prepared in this way were stored for 1 month under 40°C/90%RH, which is an accelerated moisture supersaturation storage condition, and then the related substances were measured, and are shown in Table 7 below. Done.

Experimental example 4

The oral solids of Examples 1 to 10 and Comparative Examples 1 to 5 prepared in this way were stored for 3 months under 40°C/90%RH, which is an accelerated moisture supersaturation storage condition, and then the related substances were measured, and are shown in Table 8 below. Done.

1) It is a compound having the following exemplary structure.

(C ₁₇ H ₂₇ N ₃ O ₃ / MW: 321.42)

2) It is a compound having the following exemplary structure.

(C ₂₄ H ₃₃ N ₅ O ₃ / MW: 439.56)

As shown in Tables 7 and 8 and FIGS. 1 and 2, the moisture contained in the tablet through the results of the stability test under accelerated moisture supersaturation storage conditions, Examples 1 and 6, and Examples 3 and 8 Even if there is a difference in the content of, it was confirmed that the increase in related substances can be suppressed by using 1.5 g or more per 100 g of the dehumidifying agent. When using 2.0g or more per 100g of tablets, it was confirmed that the increase in related substances can be further suppressed and thus more preferable.

In addition, as a result of the 1-month and 3-month related substance test results of Example 1 and Comparative Example 1, it was confirmed that the tendency of increasing the related substance was maintained until 3 months when the dehumidifying agent was used at least 2.0 g per 100 g of the tablet, as in Example 1. , When using less than 1.5g (1.2g) per 100g of the dehumidifying agent as in Comparative Example 1, it was confirmed that a similar increase in related substances was shown until 1 month, but the related substances increased by about 1.7 times at 3 months. This trend was the same in all Examples 3 and 4 and Comparative Examples 3 and 4. In addition, as can be seen from Comparative Examples 3 and 4, it can be seen that there is a difference in the tendency to increase related substances according to the moisture permeability of the packaging material.

The above description is only an embodiment of the present invention, and those of ordinary skill in the technical field to which the present invention pertains may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the scope of the present invention is not limited to the above-described embodiments, and should be construed to include various embodiments within the scope equivalent to those described in the claims.

Claims (16)

As a packaging material for complex formulations containing vildagliptin hydrochloride,
The packaging material for complex formulations containing vildagliptin hydrochloride, characterized in that the packaging material has a moisture permeability (WVTR) of 0.2 g/m ² /day or less at 38° C. and 90% relative humidity. The method of claim 1,
The packaging material further comprises a dehumidifying agent,
The dehumidifying agent contains 1.5 g or more per 100 g of the complex formulation containing vildagliptin hydrochloride, a packaging material for a complex formulation containing vildagliptin hydrochloride. The method of claim 1,
The packaging material has a moisture permeability (WVTR) of 0.005 g/m ² /day or less at 38° C. and 90% relative humidity, and further comprises 0.3 g or more of a dehumidifying agent per 100 g of the composite formulation containing the vildagliptin hydrochloride. That is, packaging material for complex formulations containing vildagliptin hydrochloride. The method according to any one of claims 1 to 3,
The packaging material is glass, high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), cycloolefin polymer (COP), cyclo An olefin copolymer (COC), polyolefin (PO), aluminum (Al), and a combination thereof, which is selected from the group consisting of, a composite formulation containing vildagliptin hydrochloride. The method according to any one of claims 1 to 3,
The packaging material for complex formulations containing vildagliptin hydrochloride, wherein the packaging material has a packaging form selected from the group consisting of bottles, blisters and pouches. The method of claim 5,
Vildagliptin hydrochloride wherein the blister is composed of a top plate containing a material selected from the group consisting of PVC, PVDC, PCTFE, PP, PE, COP, COC, PO, Al, and a combination thereof, and a lower plate containing an Al material. Packaging material for complex formulations containing. The method of claim 5,
The packaging material for complex formulations containing vildagliptin hydrochloride, wherein the pouch is made of an Al material. The method according to any one of claims 1 to 3,
The packaging material for complex formulations containing vildagliptin hydrochloride, wherein the dehumidifying agent is silica gel. The method according to any one of claims 1 to 3,
The composite formulation containing vildagliptin hydrochloride is a packaging material for a composite formulation containing vildagliptin hydrochloride, which comprises wet granules formed by a fluid bed granulation process. The method according to any one of claims 1 to 3,
The wet granules further comprise metformin hydrochloride, vildagliptin hydrochloride-containing composite formulation packaging. The method according to any one of claims 1 to 3,
The composite formulation is a tablet formulation, packaging material for a composite formulation containing vildagliptin hydrochloride. Preparing a pharmaceutical composition containing vildagliptin hydrochloride into wet granules by a fluid bed granulation process; And
A method for producing a pharmaceutical article containing vildagliptin hydrochloride comprising the step of packaging the pharmaceutical formulation containing the vildagliptin hydrochloride-containing wet granules with a packaging material containing a dehumidifying agent. The method of claim 12,
The wet granulation method of manufacturing a pharmaceutical article further comprising metformin hydrochloride. The method of claim 12,
The packaging material has a moisture permeability (WVTR) of 0.2 g/m ² /day or less, and a method of manufacturing a pharmaceutical article using a material containing 1.5 g or more per 100 g of the formulation. The method of claim 12,
The packaging material has a moisture permeability (WVTR) of 0.005 g/m ² /day or less, and uses a material containing 0.5 g or more per 100 g of the formulation as the dehumidifying agent. A pharmaceutical article prepared according to any one of claims 12 to 15.

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