KR20190113163A - Colonic-specific lipase releasing pharmaceutical composition, Oral dosage form comprising the same, and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a colonic-specific lipase releasing pharmaceutical composition, an oral formulation comprising the same, and a method for manufacturing the same. More specifically, the present invention relates to: a lipase releasing pharmaceutical composition comprising a time-specific, pH-specific or colonic-specific polymer, as a pharmaceutical composition for preventing or treating obesity or hyperlipidemia; the oral formulation comprising the same; and the method for manufacturing the same. According to the present invention, the pharmaceutical composition and the oral formulation comprising the same do not hydrolyze in the small intestine by lipase inhibitors, thereby specifically breaking down dietary fat that has migrated to the large intestine to alleviate side effects of lipase inhibitors such as farts comprising secretion, fecal urgency, oily spotting, fecal frequency, defacation incontinence and the like. Therefore, the pharmaceutical composition and the oral formulation comprising the same can improve medication compliance of a patient.

Description

Colon-specific lipase-releasing pharmaceutical composition, oral formulation comprising same and preparation method thereof {Colonic-specific lipase releasing pharmaceutical composition, Oral dosage form comprising the same, and manufacturing method

The present invention relates to a colon-specific lipase-releasing pharmaceutical composition, an oral preparation comprising the same, and a method for preparing the same, more specifically lipase and time-specific as a pharmaceutical composition for preventing or treating obesity or hyperlipidemia, Large intestine to improve the side effects caused by lipase inhibitors by allowing the lipase to be specifically released in the large intestine, including pH-specific, colon-microbial-specific released polymers, to break down dietary fats in the small intestine, Specific lipase release pharmaceutical compositions, oral formulations comprising the same, and methods of making the same.

As westernized eating habits and traffic developed, obesity increased rapidly to 30-35% of the Korean adult population. Obesity refers to an over-accumulated state of body fat and currently uses the Body Mass Index (BMI) to diagnose it. The World Health Organization defines BMI 30kg / m ² or more as obesity, and the Asia-Pacific region and the Korean Society of Obesity define BMI 25 kg / m ² or more as obesity.

Diet, exercise, behavior, and medication are given to treat obesity. Medication is administered to patients with cardiovascular disease, abdominal obesity, and obesity with BMI 25 kg / m ² or more.

Drugs for the treatment of obesity are largely divided into drugs that can be used for a short time and drugs that can be used for a long time. Lipase inhibitors, which are drugs that can be used for a long time, have proven to be safe and effective in the treatment of obesity even with long-term use. Lipase inhibitors are compounds that reversibly inhibit the action of lipase secreted in the mouth, stomach, and pancreas, and orlistat is the most representative. Lipase inhibitors inactivate the pancreatic lipase secreted by the small intestine, which is the fat absorption pathway. It results in a calorie reduction, resulting in weight loss and maintenance. However, when taking lipase inhibitors, these mechanisms of action shift triglyceride-like dietary fats to the large intestine, which are not degraded to the large intestine. Causing a decrease in patient compliance.

In particular, the anal outflow of oils, such as oily stools, is a common side effect in patients taking lipase inhibitors, where some 30% of unabsorbed fat is physically separated from the mass of solids downstream of the large intestine into the oil phase. It is being discharged, causing inconveniences in daily life, discontinuation of treatment, and the like.

Therefore, it is expected that the development of a formulation that can be used for a long time and improves such side effects of a lipase inhibitor having proven therapeutic effect and safety will show great marketability.

At present, in order to reduce side effects of the drug that can be used for a long time as described above, various attempts have been continuously made such as increasing the viscosity using a fat adsorbate and the like, but have not been clearly solved.

Accordingly, the present inventors have made intensive studies to improve the side effects of conventional lipase inhibitors. It was confirmed that the lipase including microbial specific polymers was released in the large intestine so that dietary fats that could not be degraded in the small intestine could be resolved in the large intestine, thereby improving side effects caused by lipase inhibitors.

US 6933152 B1

In order to solve the above problems, the colon-specific lipase-releasing pharmaceutical composition which can improve side effects caused by lipase inhibitors by releasing lipase in the large intestine and thus breaking down dietary fat in the small intestine The purpose is to provide.

In addition, an object of the present invention is to provide an oral preparation for the prevention or treatment of obesity or hyperlipidemia comprising the colon-specific lipase-releasing pharmaceutical composition.

In addition, an object of the present invention is to provide a method for producing an oral preparation for the prevention or treatment of obesity or hyperlipidemia.

According to one aspect of the invention, the invention provides a colon specific lipase releasing pharmaceutical composition comprising a lipase inhibitor, a lipase and a polymer.

Lipase inhibitors are drugs that are prescribed for the prevention or treatment of obesity or hyperlipidemia, which prevent the absorption of dietary fat in the body by preventing the inactivation of lipase to prevent hydrolysis of dietary fat in the small intestine. However, as the undigested dietary fat moves to the large intestine in undissolved form, side effects such as farts, urination, urinary punctate, and stool emptying and fecal incontinence, including secretions, are caused. Less compliance.

Accordingly, the inventors of the present invention have developed a pharmaceutical composition that is excellent in preventing or treating obesity or hyperlipidemia, as well as reducing side effects caused by lipase inhibitors, thereby increasing patient compliance.

In the colon specific lipase releasing pharmaceutical composition of the present invention, the polymer is characterized in that the time-specific polymer, pH-specific polymer or colon microorganism specific polymer.

In the colon-specific lipase-releasing pharmaceutical composition of the present invention, the time-specific polymer refers to a polymer that allows lipase to be released after 5 to 7 hours, which is a time passing through the stomach and the small intestine after ingestion. The time-specific polymer may be used any polymer that allows the lipase to be released in the large intestine 5 to 7 hours after ingestion, preferably hydroxypropyl methylcellulose (HPMC) or ethyl cellulose ) May be used, but is not limited thereto.

In the colon-specific lipase-releasing pharmaceutical composition of the present invention, the pH-specific polymer refers to a polymer that does not decompose at low pH, such as pH 1.2 of the stomach and pH 6.8 of the small intestine, but decomposes at pH 7.0 or higher. The pH-specific polymer may be used any polymer that can be degraded in the large intestine pH 7.0 or more to allow the lipase to be released, preferably Eudragit S100 may be used, but is not limited thereto.

In addition, in the colon-specific lipase-releasing pharmaceutical composition of the present invention, the microorganism-specific polymer refers to a polymer that is specifically degraded in the large intestine by an intestinal microorganism without being degraded by enzymes secreted in the body. The microorganism-specific polymer may be used any polymer that is specifically degraded by the intestinal microorganism, preferably amylose (amylose) or guar gum (guar gum) may be used, but is not limited thereto.

In addition, in the colon-specific lipase-releasing pharmaceutical composition of the present invention, the colonic microorganisms include Enterococcus faecalis, Bacteroides, Bifidobacteria, Peptococcus, Peptostreptococcus (Peptostreptococcus), and Luminococcus (Ruminococcus), Caprobacillus (Caprobacillus) is characterized in that at least one colon microorganism selected from the group.

In the colon specific lipase releasing pharmaceutical composition of the present invention, the lipase inhibitor is characterized in that orlistat (orlistat).

In the large intestine specific lipase-releasing pharmaceutical composition of the present invention, the pharmaceutical composition is characterized in that the large intestine specifically breaks down dietary fat that is not degraded in the small intestine.

According to one experimental example of the present invention, as a result of treating the composition according to the present invention, it was confirmed that the volume of the fat layer decreases as the concentration of lipase to orlistat increases for 30 hours during which the stool stays in the large intestine (Table 2 and FIG. 1). These results indicate that the pharmaceutical composition according to the present invention does not decompose in the small intestine but decomposes the dietary fat, which is transferred to the large intestine, which contains secretions, lipase inhibitors such as defecation, ecchymosis, oily stool, and stool bins, fecal incontinence, etc. Suggests that side effects may be improved.

The colon-specific lipase-releasing pharmaceutical composition of the present invention is characterized in that it is for the prevention or treatment of obesity or hyperlipidemia.

The present invention also provides an oral preparation for the prevention or treatment of obesity or hyperlipidemia comprising the colon-specific lipase-releasing pharmaceutical composition according to the present invention.

Oral preparations for the prevention or treatment of obesity or hyperlipidemia of the present invention are characterized by releasing lipase specifically in the large intestine.

Oral preparations for the prevention or treatment of obesity or hyperlipidemia of the present invention are characterized in that they release lipase within 10 to 30 hours after administration.

Oral preparations for the prevention or treatment of obesity or hyperlipidemia of the present invention are characterized by releasing lipase from pH 7.0 to pH 14.

Oral preparations for the prevention or treatment of obesity or hyperlipidemia of the present invention are characterized by being released by colon microorganisms to release lipases.

According to another aspect of the present invention, the present invention,

(A) mixing and granulating the lipase and the polymer; And

It provides a method for producing an oral preparation for the prevention or treatment of obesity or hyperlipidemia comprising (B) mixing orlistat into the granules prepared in step (A) and then tableting to prepare a tablet.

As described above, the present invention specifically breaks down dietary fat that has not been hydrolyzed from the small intestine to the large intestine by lipase inhibitors, thereby producing secretions, feces, fecal incontinence, and fecal insufficiency. The side effects of such lipase inhibitors can be improved, thereby improving patient compliance with the medication.

1 is a view showing the results according to Experimental Example 1. FIG.
2 is a graph showing the results according to Experimental Example 2. FIG.

Hereinafter, the present invention will be described in more detail with reference to Examples. Since these examples are only for illustrating the present invention, the scope of the present invention is not to be construed as being limited by these examples.

Preparation Example: Preparation of Artificial Rheology with Oristat and Lipase Ratio

Referring to US Patent No. 6933152, 11.1 g of gelatin, 400 g of corn starch, and 16.3 g of dry silica were mixed. Thereafter, 506.7 mL of X1 PBS buffer was added to prepare artificial stools for the experiment. Rheology to be used in the experiment was prepared by mixing artificial stools 30g, olive oil 2.75 mL.

Then, lipase and orlistat, a dietary fat absorption inhibitor, were combined at the same ratio as the composition of Table 1 to prepare lipase inhibitors (Examples 1 to 5).

Comparative example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Artificial stools (g) 30 g 30 g 30 g 30 g 30 g 30 g 30 g Olive oil (mL) 2.75 mL 2.75 mL 2.75 mL 2.75 mL 2.75 mL 2.75 mL 2.75 mL Orlistat (mg) 36 mg 36 mg 36 mg 36 mg 36 mg 36 mg 36 mg Bile acids (mg) 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg Lipase (mg) 0 mg 0.3 mg 1 mg 5 mg 10 mg 20 mg 80 mg

Experimental Example 1: Confirmation of lipolysis effect according to the lipase ratio in the presence of orlistat

The lipolytic effect of the compositions of Comparative Examples and Examples 1 to 6 prepared in the above Preparation Example was confirmed.

Specifically, the compositions of Comparative Examples and Examples 1 to 6 were placed in a 50 mL conical tube and mixed using a vortex, and then reacted at 37 ° C. and 50 rpm using a constant temperature water bath for 30 hours. Then, the fat layer was separated by centrifugation at 1500 rpm / min for 5 minutes using a centrifuge. After separation, the height of the fat layer was measured to calculate the volume of the fat layer, and the results are shown in Table 2 and FIG. 1.

Comparative example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Height of fat layer (mm) 5 mm 4.8 mm 4.8 mm 4.5 mm 4.5 mm 4.0 mm 3.0 mm Volume of fat layer (mL) 3.1 mL 3.0 mL 3.0 mL 2.8 mL 2.8 mL 2.5 mL 1.9 mL

As can be seen in Table 2 and Figure 1, it was confirmed that the volume of the fat layer decreases as the concentration of the lipase to the orlistat ratio increases.

Experimental Example 2: Confirmation of Viscosity Change of Solids According to Lipase Ratio in the Presence of Orlistat

The viscosity change according to the lipase ratio in the presence of orlistat of the compositions of Comparative Examples and Examples 1 to 6 prepared in the above Preparation Example was confirmed.

Specifically, the compositions of Comparative Examples and Examples 1 to 6 prepared in the above Preparation Example were placed in a 50 mL conical tube and mixed using a vortex, and then mixed at a constant temperature water bath at 37 ° C. and 50 rpm for 30 hours. Reacted.

After the reaction, the viscosity was measured using a viscometer after remixing using a vortex before measuring the viscosity, the results are shown in Table 3 and FIG.

Comparative example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Viscosity (cp) 5230 cp 1305 cp 1150 cp 1555 cp 1280 cp 1435 cp 630 cp

As can be seen in Table 3 and FIG. 2, it was observed that the viscosity was lowered in Examples 1 to 6 to which orlistat was added as compared to the comparative example without lipase.

In the case of the comparative example does not contain lipase, it was confirmed that this result due to the specific result on the viscosity of the solid mass when measuring the viscosity by the physical phenomenon that the olive oil is separated from the solid mass.

In addition, in Examples 1 to 6 to which orlistat was added, it was confirmed that the affinity between water was increased through decomposition of the monoglyceride and free fatty acid of olive oil by orlistat, thereby improving the solid mass mixing, and thus showing low viscosity. .

However, for Example 6, too much lipase ratio was found to show a too low viscosity through excessive decomposition of olive oil.

Claims (14)

A colon specific lipase releasing pharmaceutical composition comprising a lipase, a lipase inhibitor and a polymer.
The method of claim 1,
The polymer is a time specific, pH specific or colon specific polymer
Colon specific lipase releasing pharmaceutical composition.
The method of claim 2,
The time specific polymer is a polymer that degrades to release lipase 5 to 7 hours after administration.
Colon specific lipase releasing pharmaceutical composition.
The method of claim 2,
The pH specific polymer is a polymer that is decomposed at pH 7.0 or more
Colon specific lipase releasing pharmaceutical composition.
The method of claim 2,
The microorganism-specific polymer is a polymer that is specifically degraded in the large intestine by the intestinal microorganism
Colon specific lipase releasing pharmaceutical composition.
The method of claim 1,
The lipase inhibitor is orlistat
Colon specific lipase releasing pharmaceutical composition.
The method of claim 1,
The pharmaceutical composition is to specifically break down dietary fat that is not broken down in the small intestine
Colon specific lipase releasing pharmaceutical composition.
The method of claim 1,
The pharmaceutical composition is for the prevention or treatment of obesity or hyperlipidemia
Colon specific lipase releasing pharmaceutical composition.
An oral preparation for the prevention or treatment of obesity or hyperlipidemia comprising the pharmaceutical composition according to any one of claims 1 to 8.
The method of claim 9,
The oral formulation is to release lipase in the large intestine
Oral preparations for the prevention or treatment of obesity or hyperlipidemia.
The method of claim 9,
The oral formulation is to release the lipase within 10 to 30 hours after administration
Oral preparations for the prevention or treatment of obesity or hyperlipidemia.
The method of claim 9,
The oral formulation is to release the lipase from pH 7.0 to pH 14
Oral preparations for the prevention or treatment of obesity or hyperlipidemia.
The method of claim 9,
The oral preparation is to be degraded by colon microorganisms to release lipase
Oral preparations for the prevention or treatment of obesity or hyperlipidemia.
(A) mixing and granulating the lipase and the polymer; And
(B) mixing orlistat with the granules prepared in step (A) and then tableting to prepare tablets; comprising
A method for preparing an oral preparation for the prevention or treatment of obesity or hyperlipidemia according to claim 9.

Images