KR102327750B1 - Pharmaceutical composition for oral administration comprising GLP-1 agonist - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising a GLP-1 analogue as an active ingredient. Specifically, the present invention relates to a pharmaceutical composition for oral administration that enables effective oral administration of a GLP-1 analogue, and exhibits a sufficient hypoglycemic effect while increasing the convenience of administration compared to conventional injections, and a method for preparing the same.

Description

Pharmaceutical composition for oral administration comprising a GLP-1 analogue

The present invention relates to a pharmaceutical composition for oral administration comprising an analog of glucagon-like peptide 1 ("GLP-1") and a method for preparing the same. Specifically, the present invention relates to a pharmaceutical composition for oral administration comprising a GLP-1 analogue, polyoxyl glyceride, an acyl glycerol complex, and polyethylene glycol, and a method for preparing the same.

Glucagon-like peptide-1 (glucagon-like peptide-1; GLP-1) is a hormone composed of 30 amino acids and is produced from a pro-hormone called proglucagon in intestinal L-cells. This proglucagon is converted into glucagon by prohormone convertase 2 in the pancreas, and into GLP-1, GLP-2, etc. by prohormone convertases 1 and 3 in the intestine and brain (Kieffer et al. ., Endocr Rev 1999, 20 , 876-913).

Studies on the intracellular mechanism of action of GLP-1 are mainly conducted in beta cells of islet where GLP-1 receptors exist.　GLP-1 reaching the beta cells of the islet binds to the GLP-1 receptor, and the GLP-1 receptor activated by GLP-1 binding activates intracellular proteins of several different pathways, thereby reducing the effect of GLP-1. will show

GLP-1 promotes insulin secretion in beta cells, suppresses glucagon secretion in alpha cells, delays gastric emptying, suppresses food intake, suppresses gastric emptying, suppresses gastric or intestinal motility, promotes glucose use and induces weight loss. induce effect. In addition, 　GLP-1 is effective in preventing pancreatic beta cell degeneration caused by the progression of type 2 diabetes, non-insulin dependence diabetes mellitus (NIDDM), and promoting the generation of new beta cells. It is known that it can have an effect such as restoration of insulin secretion by

In particular, GLP-1 is effective in lowering postprandial blood sugar, and when blood sugar is normal or low, it has little effect on insulin or glucagon, so there is no risk of hypoglycemia. In addition, it is known that long-term administration of sulfonylurea, which is a blood sugar lowering agent, does not cause side effects such as death and necrosis of beta cells in the pancreas. Therefore, GLP-1 is considered to be a very effective substance in the treatment of type 2 diabetes (Todd et al., Eur J Clin Invest 1997, 27 , 533-536; Drucker et al., J Clin Invest 2007, 117 , 24-32).

However, GLP-1 itself has insufficient activity, and two cleaved naturally occurring peptides, GLP-1(7-37)OH and GLP-1(7-36)NH _{2 ,} are rapidly removed in vivo. The very short half-life has limited the usefulness of therapies involving GLP-1 peptides. In particular, the endogenously produced dipeptidyl peptidase-₃ (dipeptidyl peptidase-₃; DPP-₃) is a GLP- Inactivates 1 peptide, which is known to be the main reason for its short half-life in vivo. That is, the short half-life (t _1/2 < 2 min) of GLP-1 resulting from degradation by DPP-₃ hinders the application of GLP-1 for the treatment of insulin-resistant type 2 diabetes (Deacon et al. , J. Clin. Endocrinol. Metab. 1995, 80, 952-957).

Therefore, by adding some modifications to the structure of the peptide GLP-1 (7-37), the duration in vivo was extended, but a "GLP-1 analogue" having an effect similar to that of natural GLP-1 was developed as a non-insulin-dependent intrinsic substance. It has been used to treat diabetes, insulin-dependent diabetes mellitus or obesity.

Exenatide, Lixisenatide, and Liraglutide, which are currently representative GLP-1 analogues, are trade names Bayetafen and Lixumiapen, respectively.and Victoria PennsylvaniaIt is marketed as, and is administered by subcutaneous injection into the abdomen, thigh, and upper arm once or twice a day.

These commercially available subcutaneous injections of GLP-1 analogues are not easy to store, and the process of disinfecting and injecting the injection site at a set time every day is complicated, making it less convenient to take, and there are disadvantages that rash and swelling at the injection site may occur. .

On the other hand, oral administration formulations can improve the quality of life of patients and reduce health care costs by relieving the inconvenience of storing and taking subcutaneous injections for diabetic patients who need continuous administration of the therapeutic agent.

However, despite the excellent effect of treating type 2 diabetes, the GLP-1 analogue is currently manufactured and sold only in the form of a subcutaneous injection in Korea due to the limitation that it is degraded in the stomach and low in bioavailability when administered orally.

In order to solve this problem, the present inventors studied to develop a formulation for oral administration containing a GLP-1 analogue as an active ingredient, and as a result, a GLP-1 analogue, polyoxylglyceride, acylglycerol complex and The present invention was reached by confirming that the composition exhibits a sufficient blood sugar lowering effect while being formulated for oral administration.

An object of the present invention is to provide a pharmaceutical composition for oral administration comprising a GLP-1 analogue as an active ingredient.

Specifically, the present invention provides a pharmaceutical composition for oral administration that is superior to conventional injections and exhibits sufficient blood sugar lowering effect, including GLP-1 analogues, polyoxyl glycerides, acyl glycerol complexes, and polyethylene glycol, and preparation thereof We want to provide a way

The present invention provides a pharmaceutical composition for oral administration comprising a GLP-1 analog (GLP-1 agonist) as an active ingredient and polyoxyl glyceride, an acyl glycerol complex and polyethylene glycol as excipients. The GLP-1 analog may be Liraglutide, Exenatide, Lixisenatide, Albiglutide or Dulaglutide, preferably Liraglutide. tide or exenatide, but is not limited thereto.

In the pharmaceutical composition for oral administration of the present invention, polyoxyl glyceride is caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, linoleoyl polyoxyl glyceride, oleoyl polyoxyl glyceride and stearo One or more may be selected from the group consisting of polyoxyl glycerides, and may preferably be caprylocaproyl polyoxyl glycerides. The polyoxyl glyceride may be included in 30 to 80% (v/v) or 40 to 60% (v/v) based on the total volume of the excipient, preferably 45 to 55, more preferably For example, it may be included as 50% (v/v).

In addition, in the pharmaceutical composition for oral administration of the present invention, the acylglycerol complex may be one or more selected from the group consisting of glyceryl monooleate, glyceryl behenate, glyceryl stearate and glyceryl palmitostearate, preferably Preferably, it may be glyceryl monooleate. The acylglycerol complex may be included in an amount of 10 to 60% (v/v) or 30 to 55% (v/v), preferably 35 to 45, more preferably based on the total volume of the excipient. may be included as 40% (v/v).

In the pharmaceutical composition for oral administration of the present invention, polyethylene glycol (PEG) may be one or more selected from the group consisting of PEG 300, PEG 400, PEG 600 and PEG 900, preferably PEG 300. The polyethylene glycol may be included in an amount of 5 to 30% (v/v), preferably 10% (v/v), based on the total volume of the excipient.

In addition, the pharmaceutical composition for oral administration of the present invention may further include a surfactant, wherein the surfactant is preferably included in an amount of 0.1 to 15% (v/v) based on the total volume of the excipients.

The surfactant of the present invention may be, but is not limited to, polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween) or polyoxyethylene ether (Brij) .

Also, the present invention

1) preparing a solution by dissolving the GLP-1 analogue in an organic solvent;

2) adding polyoxyl glyceride to the solution and drying under reduced pressure to remove the organic solvent, and

3) It provides a method for preparing a pharmaceutical composition for oral administration, comprising the step of adding glyceryl monooleate and polyethylene glycol.

The pharmaceutical composition for oral administration of the present invention solves the problem of lowering bioavailability during oral administration of GLP-1 analogues, so that it is more convenient to take than the existing GLP-1 analogues used as injections and has a sufficient blood sugar lowering effect. It can be used as an achievable diabetes treatment.

1 shows the properties of the solutions prepared in Examples 1 to 6.
Figure 2 shows the properties of the solution prepared in Comparative Example 1.
3 shows the properties of the solution prepared in Comparative Example 2.
4 shows the properties of the solution prepared in Comparative Example 3.
5 and 6 show the results of a blood glucose lowering confirmation test using a mouse.

The present invention relates to a pharmaceutical composition for oral administration comprising a GLP-1 analogue as an active ingredient, and comprising polyoxyl glyceride, an acyl glycerol complex and polyethylene glycol.

The present invention also relates to a pharmaceutical composition for oral administration comprising a GLP-1 analogue as an active ingredient, and comprising polyoxyl glyceride, an acyl glycerol complex, polyethylene glycol and a surfactant.

The GLP-1 analogue of the present invention may be liraglutide or exenatide, but is not limited thereto.

The polyoxyl glyceride may be caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, linoleoyl polyoxyl glyceride, oleoyl polyoxyl glyceride or stearoyl polyoxyl glyceride, but not limited

The acylglycerol complex may be glyceryl monooleate, glyceryl behenate, glyceryl stearate or glyceryl palmitostearate, but is not limited thereto.

The polyethylene glycol may be PEG (polyethylene glycol) 300, PEG 400, PEG 600 or PEG 900, but is not limited thereto.

The present invention also relates to a method for preparing a formulation for oral administration comprising the steps of:

1) preparing a solution by dissolving the GLP-1 analogue in an organic solvent;

2) adding polyoxyl glyceride to the solution and drying under reduced pressure to remove the organic solvent, and

3) adding the acylglycerol complex and polyethylene glycol.

The present invention uses polyoxyl glyceride, acyl glycerol complex and polyethylene glycol as excipients to overcome the disadvantage of low bioavailability due to degradation in the stomach when GLP-1 analogue is administered orally, thereby improving bioavailability and improving blood glucose A pharmaceutical composition for oral administration capable of achieving a diabetic therapeutic effect by lowering is technically characterized.

The composition according to the present invention can be formulated in the form of a clear solution without the formation of a precipitate, exhibits a sufficient blood sugar lowering effect, and can be used as a therapeutic agent for diabetes with excellent ease of administration.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are provided only for the purpose of illustration to help the understanding of the present invention, and the scope of the present invention is not limited by the following examples.

[Examples 1 to 6]

Formulations for oral administration containing GLP-1 analogues

A composition for oral administration containing a GLP-1 analogue was prepared according to the components and contents of Table 1 below.

Example main drug
(Liraglutide)
density
(mg/ml) excipient (v/v, %) Acylglycerol Complex (Glycerol Monooleate) Polyoxyl Glycerides (Caprylocaproyl Polyoxyl Glycerides) Polyethylene glycol (PEG 300) Surfactant (Tween) One 0.5 40 50 10 0 2 One 50 40 5 5 3 0.5 60 30 5 5 4 One 40 40 15 5 5 One 20 35 30 15 6 One 10 50 30 10

After weighing the main drug and transparently dissolving it in an organic solvent, polyoxyl glyceride was added and the organic solvent was completely removed by drying under reduced pressure at 30° C. for about 2 hours. Acylglycerol complex, polyethylene glycol and surfactant (Examples 2 to 6) were further added and stirred for about 1 hour.

[Comparative Examples 1 to 3]

According to the components and contents shown in Table 2 below, a composition for oral administration containing a GLP-1 analogue was prepared in a similar manner to that of Example.

comparative example main drug
(Liraglutide)
density
(mg/ml) excipient (v/v, %) Acylglycerol Complex (Glycerol Monooleate) Polyoxyl Glycerides (Caprylocaproyl Polyoxyl Glycerides) Polyethylene glycol (PEG 300) Surfactant (Tween) One 0.5 60 - 30 10 2 0.5 70 20 - 10 3 0.5 70 10 10 10

In Comparative Example 1, polyoxyl glyceride was not added, in Comparative Example 2, polyethylene glycol was not added, and in Comparative Example 3, an acyl glycerol complex was added at 70% (v/v).

[Test Example 1]

property test

Preparations of Examples 1 to 6 and Comparative Examples 1 to 3 were prepared, and the results of confirming the properties are shown in FIGS. 1 to 4 .

1 shows the properties of the formulations of Examples 1 to 6, and it was confirmed that the formulations of Examples 1 to 6 were all clear oily solutions. On the other hand, as shown in FIGS. 2 (Comparative Example 1), 3 (Comparative Example 2) and 4 (Comparative Example 3), the formulations of Comparative Examples 1 to 3 were in the form of an opaque dispersion having a white precipitate. could

As a result, it was found that the formulations having the components and contents of Examples 1 to 6 can be formulated for oral administration, but the formulations having the components and contents of Comparative Examples 1 to 3 are not suitable for oral administration.

[Test Example 2]

Blood sugar lowering effect test (administration dose 1.25mg/kg)

In order to confirm the hypoglycemic effect of the preparation containing the GLP-1 analogue prepared in Example 1, a test was performed using C57BL/6 mice under the conditions shown in Table 3 below.

army type test substance route of administration Dosage
(mg/Kg) G1 C57BL/6 (Wild) placebo oral administration - G2 C57BL/6 (Db/db) placebo oral administration - G3 C57BL/6 (Db/db) Liraglutide subcutaneous injection 0.2 G4 C57BL/6 (Db/db) Formulation of Example 1 oral administration 1.25

In the G1 group, a placebo was orally administered to C57BL/6 wild-type mice. Groups G2 to G4 were tested in a diabetic mouse model (C57BL/6 (db/db)). A placebo was orally administered to the G2 group, 0.2 mg/kg of liraglutide was administered subcutaneously to the G3 group, and 1.25 mg/kg of the formulation of Example 1 was orally administered to the G4 group.

In each group, glucose (1 g/kg) was intraperitoneally injected at the time of administration of the test substance, and each test substance was administered 0.5 hours before, at the time of administration, after 0.5 hours, after 1 hour, after 2 hours and 3 hours after administration of the mouse blood. was sampled to measure blood glucose concentration (mg/dL). The measured blood glucose values are shown in FIG. 5 .

[Test Example 3]

Blood sugar lowering effect test (dose 2.5mg/kg)

The test was performed in the same manner as in Test Example 1, except that the dosage of the formulation of Example 1 administered to the G4 group was changed to 2.5 mg/kg, and the blood glucose concentration of each group is shown in FIG. 6 .

As can be seen in FIGS. 5 and 6 , it was confirmed that the formulation of Example 1 exhibited a hypoglycemic effect at a level similar to or superior to that of subcutaneous administration of liraglutide.

That is, it can be seen that the composition containing the GLP-1 analogue according to the present invention can be formulated for oral use, and thus has superior dosing convenience compared to subcutaneous injections, and exhibits excellent bioavailability and hypoglycemic effect.

Claims (16)

A pharmaceutical composition for oral administration comprising liraglutide as an active ingredient and polyoxyl glyceride, an acyl glycerol complex and polyethylene glycol as excipients.
According to claim 1, wherein the polyoxyl glyceride is caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, linoleoyl polyoxyl glyceride, oleoyl polyoxyl glyceride and stearoyl polyoxyl glyceride A pharmaceutical composition for oral administration, characterized in that one or more may be selected from the group consisting of ride.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyoxyl glyceride is caprylocaproyl polyoxyl glyceride.
According to claim 1, wherein the acyl glycerol complex is glyceryl monooleate, glyceryl behenate, glyceryl stearate and glyceryl palmitostearate for oral administration, characterized in that at least one selected from the group consisting of pharmaceutical composition.
The pharmaceutical composition for oral administration according to claim 1, wherein the acyl glycerol complex is glyceryl monooleate.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyethylene glycol (PEG) is at least one selected from the group consisting of PEG 300, PEG 400, PEG 600 and PEG 900.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyethylene glycol is PEG 300.
delete The pharmaceutical composition for oral administration according to claim 1, wherein the polyoxyl glyceride is included in an amount of 30 to 80% (v/v) based on the total volume of the excipients.
The pharmaceutical composition for oral administration according to claim 1, wherein the acylglycerol complex is comprised in an amount of 10 to 60% (v/v) based on the total volume of the excipients.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyethylene glycol is contained in an amount of 5 to 30% (v/v) based on the total volume of the excipient.
The pharmaceutical composition for oral administration according to claim 1, further comprising a surfactant.
The pharmaceutical composition for oral administration according to claim 12, wherein the surfactant is included in an amount of 0.1 to 15% (v/v) based on the total volume of the excipients.
containing liraglutide as an active ingredient;
As an excipient, based on the total volume of the excipient,
30 to 80% (v/v) polyoxylglycerides;
10 to 60% (v/v) of acylglycerol complex;
Polyethylene glycol 5 to 30% (v/v); and
A pharmaceutical composition for oral administration comprising 0 to 15% (v/v) of a surfactant, wherein the sum of the total volumes of the excipients does not exceed 100%.
containing liraglutide as an active ingredient;
As an excipient, based on the total volume of the excipient,
caprylocaproyl polyoxylglyceride 30 to 80% (v/v);
glyceryl monooleate 10 to 60% (v/v);
PEG 300 5-30% (v/v); and
A pharmaceutical composition for oral administration comprising 0 to 15% (v/v) of a surfactant, wherein the sum of the total volumes of the excipients does not exceed 100%.
1) preparing a solution by dissolving liraglutide in an organic solvent;
2) adding polyoxyl glyceride to the solution and drying under reduced pressure to remove the organic solvent, and
3) A method for preparing a pharmaceutical composition for oral administration, comprising the step of adding an acylglycerol complex and polyethylene glycol.

Images