KR20220080880A - Pharmaceutical composition comprising empagliflozin co-crystal - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing a co-crystal of empagliflozin and having a water content of 3% or less in the composition, and a pharmaceutical formulation comprising the same. The pharmaceutical composition of the present invention can maintain the empagliflozin co-crystal, and exhibits an effect of preventing the browning phenomenon that occurs when lactose is used in the formulation of the empagliflozin co-crystal. In addition, the pharmaceutical formulation of the present invention can maximize the conventional blocking effect by including a coating base that can block the conventionality of empagliflozin co-crystal.

Description

Pharmaceutical composition comprising empagliflozin co-crystal {Pharmaceutical composition comprising empagliflozin co-crystal}

The present invention relates to a pharmaceutical composition containing empagliflozin co-crystal and a pharmaceutical formulation comprising the same.

Empagliflozin is a SGLT2 (Sodium Glucose Co-Transporter 2) inhibitor-based drug represented by the following formula (I), and is marketed as a type 2 diabetes treatment, and a treatment for chronic heart failure It is also being developed as

[Formula I]

Empagliflozin may be used as a main component in a crystalline or amorphous form of a free base, and co-crystals may also be used.

It was found that empagliflozin co-crystal is difficult to maintain structure due to the structural characteristics of the co-crystal and external factors (moisture, temperature, etc.), and in particular, it is difficult to maintain the structure due to moisture. If the empagliflozin co-crystal is not maintained, the physicochemical properties may change, which may affect absorption in the body. Therefore, it is necessary to develop a pharmaceutical technology capable of maintaining the co-crystal.

In addition, the empagliflozin co-crystal was observed to brown when lactose, which is a diluent used in the reference drug and one of the most commonly used diluents in formulation, was used during the formulation process. Therefore, there is a need for pharmaceutical technology that can also improve these problems.

Republic of Korea Patent Publication No. 10-2008-0015424

It is an object of the present invention to provide a pharmaceutical composition capable of maintaining the empagliflozin co-crystal form.

Another object of the present invention is to provide a pharmaceutical composition that prevents the browning phenomenon that occurs when lactose, which is a diluent used in a reference drug and one of the most commonly used diluents in formulation, is used when empagliflozin co-crystal is formulated. will do

Another object of the present invention is to provide a pharmaceutical formulation comprising a coating base capable of blocking the conventionality of empagliflozin co-crystals.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

According to one embodiment of the present invention, the present invention provides a pharmaceutical composition containing empagliflozin co-crystal and having a water content of 3% or less in the composition.

In the pharmaceutical composition of the present invention, the empagliflozin co-crystal may be included in an amount of 0.1 to 30% by weight, preferably 0.3 to 20% by weight, based on the total composition. Also, the empagliflozin co-crystal may be empagliflozin L-proline.

In the pharmaceutical composition of the present invention, the water content in the composition is minimized to 3% or less, so that the empagliflozin co-crystal structure can be maintained. That is, it is more preferable that the moisture content is minimized, and accordingly, there is a technical characteristic in the upper limit of the numerical range. However, the moisture content may be 0.1 to 3%.

In the pharmaceutical composition of the present invention, in the association process with the empagliflozin co-crystal for the preparation of the pharmaceutical composition, an organic solvent having a moisture content of less than 5% may be used as the binding solvent. Specifically, the organic solvent may be absolute ethanol (eg, USP 99.5% or more) or isopropyl alcohol, but any organic solvent containing less than 5% moisture may be used without limitation.

In the pharmaceutical composition of the present invention, the pharmaceutical composition may further include one or more additives selected from the group consisting of a diluent, a binder, a disintegrant and a lubricant.

In the pharmaceutical composition of the present invention, the diluent may not contain lactose. In addition, the diluent may include a sugar alcohol. For example, the sugar alcohol may be one or more selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol and maltitol, and mannitol may be preferably used. When the sugar alcohol is used instead of lactose as a diluent, it is possible to prevent the browning phenomenon observed when the formulation includes lactose. On the other hand, the sugar alcohol may be included in an amount of 30 to 70% by weight based on the total weight of the composition, and specifically, it may be included in an amount of 40 to 60% by weight.

In addition, as the diluent, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, silicified microcrystalline cellulose, dextrate, dextrose, fructose and sucrose It may further include one or more selected from the group consisting of, but is not limited thereto. On the other hand, other diluents added in addition to the sugar alcohol may be included in an amount of 10 to 40% by weight, specifically, in an amount of 15 to 30% by weight, based on the total weight of the composition.

In addition, the binder is selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, starch, pregelatinized starch, carbomer, xanthan gum, polyvinyl alcohol, vinyl pyrrolidone and povidone. It may be 1 or more, but is not limited thereto. On the other hand, the binder may be included in an amount of 0.5 to 10% by weight, specifically, may be included in an amount of 1 to 4% by weight based on the total weight of the composition.

In addition, the disintegrant is crospovidone, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, croscarmellose sodium and a group consisting of low-substituted hydroxypropyl cellulose It may be one or more selected from, but is not limited thereto. On the other hand, the disintegrant may be included in an amount of 2 to 20% by weight relative to the total composition, specifically, may be included in an amount of 4 to 12% by weight.

In addition, the lubricant may be at least one selected from the group consisting of talc, colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate and glyceryl behenate, but is not limited thereto. Meanwhile, the lubricant may be included in an amount of 0.1 to 10% by weight, specifically, in an amount of 0.5 to 4% by weight, based on the total weight of the composition.

According to another embodiment of the present invention, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the present invention.

In the pharmaceutical formulation of the present invention, the formulation may be a tablet, capsule, pellet, granule or powder, preferably a tablet. In addition, the tablet may be a film-coated tablet.

In the pharmaceutical preparation of the present invention, particularly, in the film-coated tablet, the coating base may not contain hypromellose. Instead, polyvinyl alcohol (PVA) may be included in the coating base. Empagliflozin L-proline has a strong habitability problem, and a polyvinyl alcohol coating base can be used to maximally block habit formation by moisture.

On the other hand, the pharmaceutical formulation of the present invention can be used to treat diabetes, diabetic complications, or chronic heart failure. The diabetes may be type 1 diabetes or type 2 diabetes, preferably type 2 diabetes. In addition, the diabetic complications may be retinopathy, nephropathy or neuropathy, diabetic foot ulcer, tumor or macroangiopathy. In addition, the chronic heart failure may be heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).

In addition, according to one embodiment of the present invention, the pharmaceutical preparation of the present invention may further include one or more drugs used for the treatment of diabetes, diabetic complications, or chronic heart failure. Specifically, the drug is a biguanide drug, a thiazolidinedione (TZD) class drug, a DPP-IV inhibitor, a SGLT2 inhibitor, a SGLT1/SGLT2 dual inhibitor, a GLP-1 receptor agonist, a sulfonylurea (SU) class drug, It may be at least one drug selected from the group consisting of a meglitinide analog drug and an alpha-glucosidase inhibitor (AGI).

The biguanide drug, thiazolidinedione (TZD) class drug, DPP-IV inhibitor, SGLT2 inhibitor, SGLT1/SGLT2 dual inhibitor, GLP-1 receptor agonist, sulfonylurea (SU) class drug, meglitinide analog drug And examples of drugs belonging to alpha-glucosidase inhibitors (AGIs) are:

Biguanide drugs: metformin and the like;

Thiazolidinedione (TZD) class drugs: lobeglitazone, rosiglitazone, or pioglitazone, etc.;

DPP-IV inhibitors: sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, teneliglip liptin (teneligliptin), anagliptin (anagliptin) or evogliptin (evogliptin) and the like;

SGLT-2 inhibitors: dapagliflozin, canagliflozin or ipragliflozin, etc.;

SGLT1/SGLT2 dual inhibitors: sotagliflozin et al;

GLP-1 receptor agonists: semaglutide and the like;

Sulfonylurea (SU) class drugs: glimepiride, glibenclamide, gliclazide or glipizide, etc.

Meglitinide analogue drugs: nateglinide, repaglinide, etc.

Alpha-glucosidase inhibitors (AGIs): acarbose, voglibose or miglitol, etc.

The pharmaceutical composition of the present invention exhibits an effect capable of maintaining the empagliflozin co-crystal form.

In addition, the pharmaceutical composition of the present invention has an effect of preventing the browning phenomenon that occurs when lactose, which is a diluent used in the reference drug and one of the most commonly used diluents in formulation, is used in the formulation of empagliflozin co-crystal. indicates

In addition, the pharmaceutical formulation of the present invention can maximize the conventional blocking effect by including a coating base that can block the conventionality of empagliflozin co-crystal.

1 is an XRD result of observing whether a co-crystal is maintained or changed in Experimental Example 1.
2 and 3 are XRD results observing whether the co-crystal is maintained or changed in Experimental Example 2 (FIG. 2: ethanol, FIG. 3: isopropyl alcohol).
4 is a photograph observing whether or not browning occurs according to the type of diluent in Experimental Example 3.

Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.

Experimental Example 1. Co-crystal maintenance confirmation test according to moisture content

The coated tablet of Example 1 was prepared with the composition shown in Table 1 below. The moisture content of Example 1 is 1.6%.

[Table 1]

In addition, the coated tablets of Examples 2 and 3 were prepared in the same composition as in Example 1, except that the moisture content was adjusted to 2.6% and 2.9%. In addition, the coated tablets of Comparative Examples 1 to 3 were prepared in the same composition as in Example 1, except that the moisture content was adjusted to 3.2%, 3.6%, and 4.0%.

The results of maintaining or changing the co-crystal according to the moisture content of Examples 1 to 3 and Comparative Examples 1 to 3 are summarized in Table 2 below.

[Table 2]

As confirmed in Table 2 and Figure 1 above, the coated tablets of Examples 1 to 3 maintained empagliflozin co-crystal (L-proline), whereas the coated tablets of Comparative Examples 1 to 3 were empagliflozin. A change in co-crystal (L-proline) was observed.

Experimental Example 2. Co-crystal maintenance confirmation test according to moisture in organic solvent

The composition of Example 4 was prepared with the composition shown in Table 3 below. When preparing the composition of Example 4, absolute ethanol was used in the kneading process.

[Table 3]

In addition, compositions of Comparative Examples 4 and 5 were prepared in the same composition as in Example 4, except that the moisture content of the binding solution was adjusted to 5% and 10%. In addition, the compositions of Examples 5, 6 and 7 were prepared in the same composition as in Example 4, except that isopropyl alcohol was used instead of ethanol and the moisture content of the binding solution was adjusted to 0%, 5%, and 10%. .

The results of maintaining or changing the co-crystals of Examples 4 and 5 and Comparative Examples 4 to 7 are summarized in Table 4 below.

[Table 4]

As can be seen in Table 4 and FIGS. 2 and 3 above, the compositions of Examples 4 and 5 maintained empagliflozin co-crystal (L-proline), whereas the compositions of Comparative Examples 4 to 7 contained empagliflozin. A change in rosin co-crystal (L-proline) was observed.

Experimental Example 3. Browning phenomenon confirmation test according to the type of diluent

Compositions of Example 6 and Comparative Example 8 were prepared with the compositions shown in Table 5 below.

[Table 5]

As can be seen in FIG. 4 , in Comparative Example 8 using lactose as a diluent, discoloration was observed. This is presumed to be caused by the reaction between the amine group of L-florin and the reducing sugar of lactose, resulting in browning (Mailard reaction).

On the other hand, in Example 6 using mannitol instead of lactose, browning was not observed.

Experimental Example 4. Conventional confirmation test according to the type of coating base

A coated tablet of Example 7 having a moisture content of 2.3% was prepared in the same composition as in Example 1. In addition, a coated tablet of Comparative Example 9 having a moisture content of 2.3% was prepared with the composition shown in Table 6 below.

[Table 6]

The conventionality of Example 7 and Comparative Example 9 was compared under accelerated conditions (40±2° C./RH 75±5%, close 6M), and the results are shown in Table 7 below.

[Table 7]

As can be seen in Table 7 above, in Comparative Example 9 using HPMC as the coating base, the moisture change increased by about 2.2% from 2.3% to 4.5%, whereas Example 7 using PVA as the coating base showed a moisture change It was observed that only about 0.3% moisture increase from 2.3% to 2.6%. Therefore, in order to block the habitability of empagliflozin L-proline, it is preferable to use PVA as a coating base rather than HPMC.

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims to be described later and their equivalents.

Claims (16)

A pharmaceutical composition comprising empagliflozin co-crystal, wherein the water content in the composition is 3% or less. The pharmaceutical composition according to claim 1, wherein the empagliflozin co-crystal is empagliflozin L-proline. The pharmaceutical composition according to claim 1, wherein the moisture content in the composition is 0.1 to 3%. The pharmaceutical composition according to claim 1, wherein an organic solvent with less than 5% water content is used as the binding solvent in the association process with empagliflozin co-crystal. The pharmaceutical composition according to claim 1, further comprising at least one additive selected from the group consisting of a diluent, a binder, a disintegrant and a lubricant. The pharmaceutical composition according to claim 5, wherein the diluent does not contain lactose. The pharmaceutical composition according to claim 6, comprising a sugar alcohol as the diluent. The pharmaceutical composition according to claim 7, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol and maltitol. A pharmaceutical preparation comprising the pharmaceutical composition according to any one of claims 1 to 8. The pharmaceutical formulation according to claim 9, wherein the formulation is a tablet, capsule, pellet, granule or powder. The pharmaceutical formulation according to claim 10, wherein the tablet is a film-coated tablet. The pharmaceutical formulation of claim 11, wherein the coating base does not contain hydroxypropylmethylcellulose. The pharmaceutical formulation according to claim 12, comprising polyvinyl alcohol in the coating base. The pharmaceutical formulation according to claim 9, which is used for the treatment of diabetes, diabetic complications, or chronic heart failure. 15. The pharmaceutical formulation according to claim 14, further comprising one or more drugs used for the treatment of diabetes, diabetic complications, or chronic heart failure. 16. The method of claim 15, wherein the drug is a biguanide drug, a thiazolidinedione (TZD) class drug, a DPP-IV inhibitor, a SGLT2 inhibitor, a SGLT1/SGLT2 dual inhibitor, a GLP-1 receptor agonist, a sulfonylurea (SU) A pharmaceutical agent, which is at least one drug selected from the group consisting of class drugs, meglitinide analog drugs, and alpha-glucosidase inhibitors (AGIs).

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