KR20200076642A - Pharmaceutical composition for oral administration comprising GLP-1 agonist - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration containing a GLP-1 analogue as an active component. Specifically, the present invention relates to: a pharmaceutical composition for oral administration which enables effective oral administration of a GLP-1 analogue to exhibit a sufficient blood sugar lowering effect while increasing the convenience of administration compared to an existing injection; and a manufacturing method thereof.

Description

Pharmaceutical composition for oral administration comprising GLP-1 agonist}

The present invention relates to a pharmaceutical composition for oral administration comprising a glucagon-like peptide 1 ("GLP-1") analog and a method for manufacturing the same. Specifically, the present invention relates to a pharmaceutical composition for oral administration comprising a GLP-1 analog, polyoxylglyceride, acylglycerol complex and polyethylene glycol, and a method for manufacturing the same.

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

The study of GLP-1's intracellular mechanism of action is mainly carried out in the beta cells of the islets where the GLP-1 receptor is present. “GLP-1” that reaches the beta cells of the pancreas is bound to the “GLP-1” receptor, and the “GLP-1” receptor activated by the binding of the GLP-1 activates intracellular proteins in several different pathways to exert the effect of “GLP-1”. Will appear.

GLP-1 promotes various biological activities, such as promoting insulin secretion in beta cells, inhibiting glucagon secretion in alpha cells, delaying gastric emptying, suppressing food intake, suppressing stomach emptying, suppressing gastric or intestinal movement, promoting glucose use, and inducing weight loss. Induce effect. In addition, 　GLP-1 prevents pancreatic beta-cell degeneration caused by the progression of type 2 diabetes, type-diabetes, non-insulin dependence diabetes mellitus (NIDDM), and promotes the production of new beta cells. It is known that it can act, such as recovery of insulin secretion ability.

In particular, GLP-1 is effective in reducing blood sugar after eating, and when blood sugar is normal or low, it has little effect on insulin or glucagon and thus does not carry a risk of hypoglycemia. In addition, it is known that it does not cause side effects such as death and necrosis of beta cells in the pancreas due to long-term use of a blood sugar lowering agent, sulfonlurea. 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 lacks its own activity, and the two truncated naturally occurring peptides, GLP-1(7-37)OH and GLP-1(7-36)NH _2, are rapidly removed in vivo, thereby Because the half-life is very short, the usefulness of the therapy involving the GLP-1 peptide has been limited. In particular, the endogenously produced dipeptidyl peptidase-₃ (DPP-₃) is GLP- by removing the N-terminal histidine (#7) residue and alanine (#8) residue of GLP-1. 1 Peptide inactivation, which is known to be a major cause for short in vivo half-life. In other words, the short half-life (t _1/2 <2 min) of GLP-1 resulting from degradation by DPP-₃ prevents 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 modification to the structure of the peptide GLP-1 (7-37), the duration in vivo is extended, but the non-insulin-dependent intrinsic property of the "GLP-1 analog" having an effect similar to that of natural GLP-1 is extended. 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 Baietafen and Rixumiafen, respectively.  And Victor Zafen  It is commercially available as and is administered by subcutaneous injection to the abdomen, thigh, and brachial region once or twice a day.

Subcutaneous injections of these commercially available GLP-1 analogues are not easy to store, and the process of disinfecting and injecting the injection site at a given time every day is complicated, thus reducing convenience in taking, and rash and swelling of the injection site may occur. .

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

However, despite the excellent effect of treating type 2 diabetes, GLP-1 analogs are currently manufactured and sold only in the form of subcutaneous injections in Korea due to the limitation of low bioavailability due to decomposition in the stomach when administered orally.

In order to solve this problem, the present inventors studied to develop a formulation for oral administration containing the GLP-1 analog as an active ingredient, and resulted in the GLP-1 analog, polyoxylglyceride, acylglycerol complex and polyethylene glycol. It was brought to the present invention by confirming that the composition was formulated to be orally administrable, yet exhibiting a sufficient hypoglycemic effect.

The present invention is to provide a pharmaceutical composition for oral administration comprising a GLP-1 analog as an active ingredient.

Specifically, the present invention includes a GLP-1 analog, polyoxylglyceride, acylglycerol complex, and polyethylene glycol, and the pharmaceutical composition for oral administration exhibiting sufficient hypoglycemic effect while having superior ease of taking than conventional injections and its preparation I want to provide a method.

The present invention provides a pharmaceutical composition for oral administration comprising a GLP-1 analog (GLP-1 agonist) as an active ingredient and a polyoxylglyceride, acylglycerol complex and polyethylene glycol as excipients. The GLP-1 analog may be liraglutide, exenatide, lixisenatide, albiglutide or dunaglutide, preferably liraglutide. It may be a tide or exenatide, but is not limited thereto.

In the pharmaceutical composition for oral administration of the present invention, polyoxylglyceride is caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride and stearo One or more polyoxylglycerides may be selected from the group consisting of polyoxylglycerides, preferably caprylocaproyl polyoxylglycerides. The polyoxylglyceride 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 It can be included as 50% (v/v).

In addition, in the pharmaceutical composition for oral administration of the present invention, the acylglycerol complex may be selected from one or more of the group consisting of glyceryl monooleate, glyceryl behenate, glyceryl stearate and glyceryl palmitostearate, preferably It may be glyceryl monooleate. The acylglycerol complex may be included in 10 to 60% (v/v) or 30 to 55% (v/v) based on the total volume of the excipient, preferably 35 to 45, more preferably Can 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 5 to 30% (v/v) based on the total volume of the excipient, and preferably 10% (v/v).

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

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). .

In addition, the present invention,

1) dissolving the GLP-1 analog with an organic solvent to prepare a solution,

2) adding polyoxylglyceride 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 decrease in bioavailability when taken orally of the GLP-1 analog, and has a superior blood glucose lowering effect while being superior in ease of administration compared to the conventional GLP-1 analog drug used as an injection. It can be used as a therapeutic agent for diabetes that can be achieved.

Figure 1 shows the properties of the solutions prepared in Examples 1-6.
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 the blood sugar drop test using a mouse.

The present invention relates to a pharmaceutical composition for oral administration comprising a GLP-1 analog as an active ingredient and a polyoxylglyceride, acylglycerol complex and polyethylene glycol.

The present invention also relates to a pharmaceutical composition for oral administration comprising a GLP-1 analog as an active ingredient, a polyoxylglyceride, an acylglycerol complex, polyethylene glycol and a surfactant.

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

The polyoxylglyceride may be caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride or stearoyl polyoxylglyceride. It is 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 a GLP-1 analog as an active ingredient, comprising the following steps:

1) dissolving the GLP-1 analog with an organic solvent to prepare a solution,

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

3) Adding acylglycerol complex and polyethylene glycol.

The present invention, when the GLP-1 analog is orally administered, is decomposed in the stomach to overcome the disadvantage of low bioavailability, by using polyoxylglyceride, acylglycerol complex and polyethylene glycol as excipients, bioavailability is improved and blood glucose It is characterized by a pharmaceutical composition for oral administration that can achieve the therapeutic effect of diabetes by descent.

The composition according to the present invention can be formulated into a clear solution without forming a precipitate, exhibits a sufficient blood sugar lowering effect, and can be used as a therapeutic agent for diabetes excellent in taking convenience.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are provided for purposes of illustration only to aid 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 analogs

A composition for oral administration including a GLP-1 analog 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 glyceride (Caprylocaproyl polyoxylglyceride) 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 dissolving it transparently with an organic solvent, polyoxylglyceride was added and dried under reduced pressure at 30° C. for about 2 hours to completely remove the organic solvent. 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 of Table 2, a composition for oral administration including a GLP-1 analog was prepared in a similar manner to the above example.

Comparative example Main drug
(Liraglutide)
density
(mg/ml) Excipient (v/v, %) Acylglycerol complex (glycerol monooleate) Polyoxyl glyceride (Caprylocaproyl polyoxylglyceride) 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

Comparative Example 1 did not add polyoxylglyceride, Comparative Example 2 did not add polyethylene glycol, and Comparative Example 3 added an acylglycerol complex at 70% (v/v).

[Test Example 1]

Constellation test

The formulations 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 is a property of the formulations of Examples 1 to 6, it was confirmed that the formulations of Examples 1 to 6 are all clear oily solutions. On the other hand, as shown in Figure 2 (Comparative Example 1), Figure 3 (Comparative Example 2) and Figure 4 (Comparative Example 3), it is confirmed that the formulations of Comparative Examples 1 to 3 are in the form of an opaque dispersion having a white precipitate. Could.

After all, 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 unsuitable for formulation for oral administration.

[Test Example 2]

Blood glucose lowering effect test (dose 1.25mg/kg)

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

group 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

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

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

[Test Example 3]

Blood glucose lowering effect test (dosage 2.5mg/kg)

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

5 and 6, it was confirmed that the formulation of Example 1 exhibits a level of blood sugar lowering similar to or better than that of the case where the liraglutide was administered subcutaneously.

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, thus exhibiting superior bioavailability and hypoglycemic effect, while being more convenient to use than subcutaneous injection.

Claims (16)

A pharmaceutical composition for oral administration comprising a GLP-1 analog as an active ingredient and a polyoxylglyceride, acylglycerol complex and polyethylene glycol as excipients.
The polyoxylglyceride of claim 1, wherein the caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, linoleoyl polyoxylglyceride, oleoyl polyoxylglyceride and stearoyl polyoxylglyceride. Pharmaceutical composition for oral administration, characterized in that one or more selected from the group consisting of ride.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyoxylglyceride is caprylocaproyl polyoxylglyceride.
According to claim 1, wherein the acyl glycerol complex is for oral administration, characterized in that one or more selected from the group consisting of glyceryl monooleate, glyceryl behenate, glyceryl stearate and glyceryl palmitostearate. Pharmaceutical composition.
The pharmaceutical composition for oral administration according to claim 1, wherein the acylglycerol complex is glyceryl monooleate.
The method of claim 1, wherein the polyethylene glycol (PEG) is PEG 300, PEG 400, PEG 600 and PEG 900 can be selected from the group consisting of one or more pharmaceutical compositions for oral administration.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyethylene glycol is PEG 300.
The pharmaceutical composition for oral administration according to claim 1, wherein the GLP-1 analog is liraglutide or exenatide.
The pharmaceutical composition for oral administration according to claim 1, wherein the polyoxylglyceride is contained in an amount of 30 to 80% (v/v) based on the total volume of the excipient.
According to claim 1, wherein the acyl glycerol complex, based on the total volume of the excipient, 10 to 60% (v / v) pharmaceutical composition for oral administration characterized in that it is included.
According to claim 1, The polyethylene glycol, based on the total volume of the excipient, oral pharmaceutical composition characterized in that it is included in 5 to 30% (v / v).
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 excipient.
GLP-1 analogs as active ingredients;
As an excipient, based on the total volume of the excipient,
Polyoxylglyceride 30 to 80% (v/v);
Acylglycerol complex 10 to 60% (v/v);
Polyethylene glycol 5 to 30% (v/v); And
Pharmaceutical composition for oral administration comprising 0 to 15% (v / v) of the surfactant, the sum of the total volume of the excipient does not exceed 100%.
Ligglutide, a GLP-1 analogue, as an active ingredient;
As an excipient, based on the total volume of the excipient,
Caprylocaproyl polyoxylglyceride 30 to 80% (v/v);
Glyceryl monooleate 10-60% (v/v);
PEG 300 5-30% (v/v); And
Pharmaceutical composition for oral administration comprising 0 to 15% (v / v) of the surfactant, the sum of the total volume of the excipient does not exceed 100%.
1) dissolving the GLP-1 analog with an organic solvent to prepare a solution,
2) adding polyoxylglyceride 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 adding an acylglycerol complex and polyethylene glycol.

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