WO2019083297A1 - Medicinal composition for preventing or treating liver diseases - Google Patents

Abstract

The present invention relates to a medicinal composition for preventing or treating liver diseases, the composition comprising, as active ingredients, carnitine orotate, anti-toxic liver extract, biphenyl dimethyl dicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin, and cyanocobalamin, and as an excipient, a cellulose component. The present invention can be provided in a tablet dosage form.

Description

A pharmaceutical composition for preventing or treating liver disease

The present invention relates to a pharmaceutical composition for treating liver diseases. Specifically, as active ingredients, carnitine orotate, liver extract antitoxic fraction, biphenyldimethyldicarboxylate (DDB), adenine hydrochloride, pyridoxine hydrochloride, The present invention relates to a pharmaceutical composition for preventing or treating liver diseases, which comprises a cellulose-based component as an excipient (filler), which comprises riboflavin and cyanocobalamin. Such a pharmaceutical composition can be provided as a tablet formulation by solving the problems of high moisture content, poor compressibility and the like of some effective ingredients. More particularly, the tablet formulation according to the present invention is characterized by its excellent hardness, which is easily disintegrated in an aqueous solvent, so that its initial dissolution rate is high, and the therapeutic effect is rapidly exhibited.

The liver is the largest organ in the body, and it purifies the blood and produces blood coagulation factors. It stores the nutrients and functions, supplies them when needed, harmlessly changes the drugs, foreign substances, It acts to detoxify. In addition, digestive enzymes produce bile, so the liver is not good digestion is bad. The liver may be the first to be attacked by alcohol or drugs, but it is difficult to detect because no pathological signs appear until it progresses considerably. If symptoms persist, such as fatigue, dyspepsia, nausea, vomiting, anorexia, drowsiness and boredom, jaundice may appear.

Therefore, prevention of liver disease is the best. Therefore, in addition to direct hepatitis B and C drugs such as interferon, lamivudine, and adefovir, a variety of medicines that can prevent or treat liver disease by restoring or promoting liver function are being used.

In particular, hepatic diseases such as hepatitis, hepatitis, and liver cancer are caused by various causes. Therefore, a therapeutic agent comprising a plurality of components is used. Typical products include orotic carnitine, anti-toxic liver extract, biphenyldimethyl dicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin, and cyano kobalraminreul may capsule agent godekseu ^® capsule (Celltrion Pharmaceuticals, South Korea) is known which contains as an active ingredient. Generally, there is a need for a tablet formulation because of the complexity of manufacturing the capsule formulation and the possibility of deterioration in circulation. However, when a tablet formulation is prepared on the basis of a conventional capsule dosage form, compressibility (hardness) and disintegration rate The problem occurred, and this part was not solved, and it was manufactured and sold only as a capsule formulation. Especially, when the commercial product is in the form of a capsule, the elution of the active ingredient tends to be significantly slower, and when the tablet is developed with a tablet, the disintegration and dissolution may be further delayed due to a high pressure, It can be a reason.

The inventors of the present invention have conducted studies to solve the above problems. As a result, the inventors of the present invention have found that such problems are caused by physical properties of the orotous carotene and anti-toxic soy sauce extracts, specifically high specificity and poor compressibility, , The present inventors have confirmed that the problem can be solved when the tablet is prepared using the excipient of the present invention.

The present invention provides a pharmaceutical composition for the prevention or treatment of liver disease. The present invention provides a pharmaceutical composition for the prevention or treatment of liver disease, comprising as an active ingredient orotic carotene, an anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin, The present invention provides a pharmaceutical composition for the prevention or treatment of liver diseases, which comprises cobalamin as an excipient and a cellulose-based component as an excipient.

It is a further object of the present invention to provide a pharmaceutical composition for preventing or treating liver disease as a tablet formulation.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, orotous carnitine, an anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin, Lt; RTI ID = 0.0 > pharmaceutically < / RTI >

In the above pharmaceutical composition, the cellulose-based excipient may be added to the total weight of the active ingredient comprising the orotic carotene, the anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin Wherein the pharmaceutical composition is contained in an amount of 0.6 to 2.5 times.

The cellulose-based excipient may be selected from the group consisting of crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropyl cellulose.

The orotous carnitine may be L-form.

In the above pharmaceutical composition, it may further comprise orotic acid or orotic acid hydrate.

In one aspect, the present invention provides a pharmaceutical composition comprising as an active ingredient: orotous carnitine, an anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin, A method of preventing or treating liver disease comprising administering to a subject in a pharmaceutically effective amount a tablet formulation pharmaceutical composition.

In another aspect, the invention discloses the use of said pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of liver disease.

In the case of the excipient (filler) commonly used in the production of tablets, for example, lactose, starch, pregelatinized starch, dibasic calcium phosphate, etc., The size of the tablets is increased, resulting in inconvenience. However, it is not only possible to prepare tablets of a size that can be taken without inconvenience when the cellulose-based ingredients are used, It is possible to solve the disintegration problem.

According to the present invention, there is provided a pharmaceutical composition for preventing or treating liver disease comprising, as an active ingredient, orotic carotene, an anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin, As well as cellulose-based components.

The carotenoid orotate of the present invention is an orotic acid salt of carnitine, in the form of an ionic complex salt, and has a structural formula shown below. Orotic carnitine has a higher uptake rate than the individual components, showing excellent permeability into the hepatocyte mitochondria, preventing deterioration of damaged hepatocytes, and useful for normal liver function recovery:

[Chemical Formula 1]

Carnitine promotes the oxidation of fatty acids by increasing the? -Oxidation process of fatty acids in hepatocyte mitochondria. The structural formula of carnitine is shown below:

(2)

The carnitine has D-type and L-type isomers. Among them, only L-type shows in vivo activity, and D-type shows rather side effects. Therefore, in the present invention, L-carnitine orotroic acid is used as an active ingredient and has an advantage of being able to reduce the dose by a single dose since the same effect can be obtained in a smaller amount than in the case of containing a racemate.

Orotic acid acts as an important intermediate in the pyrimidine biosynthetic pathway, promotes hepatocyte regeneration, and normalizes the liver enzyme system. The structural formula of orotic acid is represented by the following formula 3:

(3)

The liver extract antitoxic fraction of the present invention is an extract of the total amino acid mixture obtained by hydrolyzing the liver of cattle, supplying essential amino acids necessary for liver cell proliferation, normalizing blood nitrogen balance and having a dangling effect. The anti-toxic soy sauce extract is prepared by removing the proteins, albumin, peptides and other insoluble substances by heating the liver by extracting water from the liver of the cattle, vacuum-concentrating it, drying it appropriately and spraying it into fine powder, Brown fine powder.

The biphenyldimethyldicarboxylate (DDB) of the present invention is a lipid soluble component extracted from the internal lipids of Omija seed, promoting the cytochrome P450 activity of liver cell mitochondria, and coordinating the immune response to prevent hepatocyte inflammatory necrosis , Which quickly normalizes liver enzyme levels. The structural formula of biphenyldimethyldicarboxylate is shown below:

[Chemical Formula 4]

The adenine hydrochloride of the present invention is a purine-based base which forms a coenzyme and a nucleic acid, and is a precursor of energy-causing ATP and coenzyme (NAD, FAD), which are components of the mitochondrial respiratory chain.

The pyridoxine hydrochloride of the present invention is vitamin B ₆ , which regulates the activity of amino acid transporter (transaminase) involved in protein metabolism in liver cells and promotes biosynthesis of carnitine.

The riboflavin of the present invention acts as a vitamin B ₂ as a mitochondrial respiratory chain and as a coenzyme (FAD) which is important for the? -Oxidation of fatty acids.

The cyanocobalamin of the present invention is a vitamin B ₁₂ and is useful as a metabolic process in liver cells such as a urea cycle, nucleoside biosynthesis, cytochrome metabolism, etc. It functions as a methyl radical donor and promotes the biosynthesis of endogenous carnitine and various amino acids.

The pharmaceutical composition according to the present invention can be prepared into a tablet formulation by adding the aforementioned seven active ingredients, and adding a cellulose-based excipient thereto.

In the pharmaceutical composition according to the present invention, the excipients of the cellulose series are contained at a weight of 0.6 to 2.5 times the total weight of the above seven active ingredients. When the cellulose-based excipient is used at a ratio of less than 0.6 times, it can not have a hardness suitable for producing tablets, and thus it is not possible to produce a tablet that can be circulated. When the amount exceeds 2.5 times, the size of the tablet becomes too large A problem arises.

The cellulose-based excipient according to the present invention includes crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropyl cellulose. May be used.

The tablet according to the present invention can be produced through a conventional tablet manufacturing process, and can be further coated with a film to form a film-coated tablet.

In addition, the tablet composition of the present invention can be used as an ingredient known to be used in the treatment of liver disease, for example, urushodesexoxycholic acid, silymarin, glutathione, orotic acid, glycyrrhizin, liver extract, hepatocyte regeneration promoter, An adjuvant, an antiviral agent, an immunosuppressant, a fibrosis inhibitor, and the like, and may further include orotic acid or hydrate thereof.

The composition of the present invention may further include diluents, disintegrants, lubricants and the like which are conventionally used in the production of pharmaceutical compositions, in addition to cellulose-based excipients. For example, diluents such as lactose, lactose, lactose, corn starch, dextrose, sucrose, mannitol, calcium phosphate, disintegrants such as sodium starch glycolate and crospovidone, magnesium stearate, Silicon dioxide, and the like.

The preferred dosage of the pharmaceutical composition of the present invention may be appropriately selected by those skilled in the art depending on the body weight, age, sex, health condition, diet, degree of disease, administration route, number of administration, However, for the desired effect, the pharmaceutical composition of the present invention may be administered at a dose of 500 to 3000 mg per day, and may be administered once or divided into several times a day, most preferably 2 to 3 times per day.

The pharmaceutical composition according to the present invention exhibits an effect of preventing or treating liver disease. More specifically, it can be provided as a tablet formulation by using a specific excipient, and at the same time, it solves the problem of the dissolution rate of the conventional capsule, so that it can be conveniently administered and rapidly treated. In addition, as oral doses of L-carnitine alone were lowered, the conventional capsules had the same therapeutic effect even after taking 1 capsule twice per capsule, and thus the patient's compliance with the medication was improved .

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph comparing the dissolution rates of the tablet pharmaceutical composition of the present invention and the conventional capsule composition. Fig.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope and spirit of the present invention.

Example  1 to 5

The active ingredients, cellulose-based excipients and starch glycolic acid sodium were mixed according to the compositions of Examples 1 to 5 shown in Table 1 below, and silicon dioxide and magnesium stearate, which are lubricants, were added to the mixture in a 40 mesh standard mesh, Respectively. The mixture was compressed and dried in a dry granulation machine (Seoul Hi-Tech, RC-60 model) to produce dry granules, which were compressed and compressed into 1 tablet by a rotary tablet machine (STP Machinery Co., Ltd., SP198 model) .

Example  6

According to the composition of Example 6 shown in Table 1 below, 7 active ingredients and a mixture of orotic acid hydrate, cellulosic excipient, lactose hydrate and starch glycolic acid sodium were mixed with silicon dioxide and magnesium stearate, Followed by further addition and mixing. The mixture was compressed and dried in a dry granulation machine (Seoul Hi-Tech, RC-60 model) to produce dry granules, which were compressed and compressed into 1 tablet by a rotary tablet machine (STP Machinery Co., Ltd., SP198 model) .

ingredient	Example 1		Example 2		Example 3		Example 4		Example 5		Example 6
	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%
7 active ingredients *)	281.25	56.3	281.25	51.1	281.25	27.3	281.25	51.1	281.25	51.1	281.25	40.2
Orotic acid hydrate											82.3	11.8
Microcrystalline cellulose	168.75	33.8	208.75	38.0	698.75	67.8					206.45	29.5
Silicidated Crystalline Cellulose							208.45	38.0
Low-substituted hydroxypropylcellulose									208.75	38.0
Lactose baggage											30.00	4.3
Starch glycolate sodium (disintegrant)	30.0	6.0	40.0	7.3	30.0	2.9	40.0	7.3	40.0	7.3	70.0	10.0
Silicon dioxide (lubricant)	2.0	0.4	2.0	0.4	2.0	0.2	2.0	0.4	2.0	0.4	3.0	0.4
Magnesium stearate (lubricant)	18.0	3.6	18.0	3.3	18.0	1.7	18.0	3.3	18.0	3.3	27.0	3.9
Sum	500	100	550	100	1030	100	550	100	550	100	700	100

*) The composition of the seven active ingredients in the above table is shown in Table 2 below:

ingredient	Amount (mg)	Remarks
L-carnitine orotic acid	150	76.2 mg as L-carnitine 73.8 mg
Antioxidant soy extract	25
Biphenyldimethyldicarboxylate	50
Adenine hydrochloride	5
Pyridoxine hydrochloride	50
Riboflavin	One
Cyanocobalamin	0.25
total	281.25 mg

Comparative Example  1 to 4

The components except for silicon dioxide and magnesium stearate were mixed in the respective comparative examples according to the compositions of Comparative Examples 1 to 4 in Table 3 below. Then, silicon dioxide and magnesium stearate, which were lubricants, were added in a 40 mesh standard network and then added Mix. The mixture was compressed and dried in a dry granulation machine (Seoul Hi-Tech, RC-60 model) to produce dry granules. The mixture was compressed in a rotary tablet machine (STP Machinery Co., Ltd., SP198 model) by compression to one tablet.

ingredient	Comparative Example 1		Comparative Example 2		Comparative Example 3		Comparative Example 4
	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%	mg / tablet	weight%
7 active ingredients *)	281.25	58.6	281.25	56.3	281.25	56.3	281.25	56.3
Microcrystalline cellulose	140.75	29.3
Lactose baggage			168.75	33.8
Pregelatinized starch					168.75	33.8
Dibasic calcium phosphate							168.75	33.8
Starch glycolate sodium (disintegrant)	30.0	6.3	30.0	6.0	30.0	6.0	30.0	6.0
Silicon dioxide (lubricant)	2.0	0.4	2.0	0.4	2.0	0.4	2.0	0.4
Magnesium stearate (lubricant)	26.0	5.4	18.0	3.6	18.0	3.6	18.0	3.6
Sum	480	100	500	100	500	100	500	100

*) The composition of the seven active ingredients in the above table is the same as in Table 2 above.

Experimental Example  1. Hardness test

The tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were measured for hardness using a TBH-125 hardness meter manufactured by Erweka Inc. The results are shown in Table 4 below.

	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4
Hardness	10.3 kP	11.5 kP	16.7 kp	12.3 kP	12.2 kp	12.7 kp	10.2 kp	6.2 kP	7.2 kP	6.8 kp

In general, it is preferable that the tablet has a hardness of 10 kp or more in order to prevent problems such as the progress of the film coating process after tableting and tablet breakage during distribution. From the above experimental results, it was confirmed that the tablets of Examples 1 to 6 corresponding to the pharmaceutical composition of the present invention including the cellulose-based excipient exhibited a hardness of not less than 10 kp and could be manufactured and circulated in tablets, The tablets of Comparative Examples 2 to 4 using an excipient such as starch and dibasic calcium phosphate were hard to manufacture with tablets having a hardness of less than 10 kp, and it was confirmed that problems in distribution could occur.

Experimental Example 2. Disintegration  exam

For the tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 4, water was used as the test liquid as specified in General Test Methods of the Korean Pharmacopoeia,

The tablets were put into a tester and operated to perform a disintegration test (DIT-200 model of Labfine) to measure the time required for disintegration. The results are shown in Table 5 below.

refine	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Comparative Example 1	Comparative Example 2	Comparative Example 3	Comparative Example 4
Disintegration time	23 minutes	20 minutes	8 minutes	22 minutes	18 minutes	17 minutes	36 minutes	NT	NT	NT

The disintegration test confirms whether the tablets, capsules, granules, pills, and suppositories disintegrate within the specified time under the conditions specified in the test solution. According to the standard of the Korean Pharmacopoeia, the uncoated tablets shall be used for 30 minutes. From the above experimental results, it was confirmed that the disintegration of the tablets of Examples 1 to 6 corresponding to the medicinal composition of the present invention including the cellulose-based excipient was properly performed within 30 minutes, , Pregelatinized starch and dibasic calcium phosphate were disintegrated immediately after the initiation of the disintegration test. However, because of the low hardness, it is difficult to prepare tablets which can be circulated. It was confirmed that it does not have.

In addition, it was confirmed that the tablets of Comparative Example 1 containing cellulose excipients but only 0.5 times as much as the total weight of the seven effective ingredients exceeded 30 minutes, indicating that 7 kinds of active ingredients and cellulose Means that the weight ratio of the excipient of the series corresponds to 0.6 to 2.5 times as in the present invention, so that the disintegration criterion can be satisfied.

Experimental Example  3. Comparative dissolution test

Example 6 Purification and Pharmacopoeia 11th revision dissolution test Method 1, as defined in the general test method for against godekseu ^® capsules on the market manufactured in an effective and a dissolution test according to (the number of the eluate pH 1.2, rotation 50rpm) The dissolution rates of adenine hydrochloride in the components were compared and the results are shown in Fig.

The composition of the active ingredient contained per one godekseu ^® capsules on the market are administered orally to the same as those of Table 6, once every two capsules, one day or three times.

ingredient	Amount (mg)	Remarks
Carnitine orotic acid	150	76.2 mg as carnitine 73.8 mg
Antioxidant soy extract	12.5
Biphenyldimethyldicarboxylate	25
Adenine hydrochloride	2.5
Pyridoxine hydrochloride	25
Riboflavin	0.5
Cyanocobalamin	0.125
Gross weight	215.625 mg

As shown in the graph of FIG. 1, although the adenine hydrochloride is soluble in water, it takes about 120 minutes for the commercial product to show a dissolution rate of 80% or more due to the delay of disintegration, whereas the tablet of Example 6 according to the present invention, It was confirmed that the drug composition of the present invention shows a dissolution rate of 85% or more, which means that the pharmaceutical composition of the present invention has a large initial dissolution rate and thus can exhibit its rapid effect in vivo.

Claims (5)

1. The pharmaceutical composition of the present invention contains, as an active ingredient, orotic carotene, an anti-toxic soy sauce extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin,

   A pharmaceutical composition in tablet form containing a cellulose-based component as an excipient.
2. [Claim 3] The composition according to claim 1, wherein the component of the cellulose system is selected from the group consisting of the orotate carnitine, the anti-toxic soy extract, biphenyldimethyldicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin and cyanocobalamin Wherein the pharmaceutical composition is contained in an amount of 0.6 to 2.5 times.
3. The tablet formulation according to claim 1 or 2, wherein the cellulose-based component is at least one selected from the group consisting of crystalline cellulose, powdered cellulose, silicified crystalline cellulose and low-substituted hydroxypropylcellulose ≪ / RTI >
4. The pharmaceutical composition of claim 1, wherein the orotic carotin is L-form.
5. The pharmaceutical composition of claim 1, further comprising orotic acid or orotic acid hydrate.

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