KR101713219B1

KR101713219B1 - Injectable composition comprising phosphatidycholine and lysophosphatidylcholine, and manufacturing method thereof

Info

Publication number: KR101713219B1
Application number: KR1020150045919A
Authority: KR
Inventors: 문정선
Original assignee: 문정선
Priority date: 2015-04-01
Filing date: 2015-04-01
Publication date: 2017-03-07
Also published as: KR20160117902A

Abstract

The present invention relates to a composition for injections containing phosphatidylcholine and lysophosphatidylcholine, and a method for preparing the same, wherein the composition comprises phosphatidylcholine which is effective for decomposing fat and lysophosphatidylcholine, L-carnitine, benzyl alcohol, preservative, The present invention relates to a composition for injections containing purified water. The injectable composition of the present invention does not cause problems such as sedimentation or phase separation upon dilution of a conventional preparation, and is excellent in storage stability.

Description

TECHNICAL FIELD The present invention relates to an injectable composition comprising phosphatidylcholine and lysophosphatidylcholine and an injectable composition comprising the phosphatidylcholine and lysophosphatidylcholine,

The present invention relates to a composition for injection comprising phosphatidylcholine and lysophosphatidylcholine, and a method for preparing the same. More specifically, the present invention relates to a composition comprising 1% of a mixture of phosphatidylcholine and lysophosphatidylcholine, -Carnitine, benzyl alcohol, preservative, and purified water. The present invention relates to a composition having improved storage stability without causing precipitation or phase separation during dilution of a conventional preparation, and a method for producing the same.

Phosphatidylcholines are phospholipids in the cell membrane and are composed of fatty acids, which are the minimum units of lipids in chemical structure, and choline, which is one of the phosphorus and vitamin B complexes. Phosphatidylcholine, also known as lecithin, has a unique emulsifying action that causes water and oil to mix with each other due to the chemical structure described above. Because of this nature, lecithin constitutes a cell membrane that forms the boundary between cells and cells, To control the entry and exit of substances entering and exiting. Phosphatidylcholine, which is mainly extracted from soybean, is widely known as a lipolytic enzyme and has an effect of decomposing triglyceride in fat cells. In addition, collagen production induces skin elasticity, and in recent research it has been found to be effective in preventing skin aging. In other words, there is a close relationship between skin aging and cell phospholipid. When the cell ages, the fatty acid composition of phosphatidylcholine molecule changes in glycerol phospholipid, which is a type of phospholipid.

On the other hand, lysophosphatidylcholine is also a type of phospholipid, which is bonded in two positions with an acyl group bonded to an acyl group in a 1-position hydride group having a glycerol skeleton. As one of the products of hydrolysis by phospholipase A of phosphatidylcholine, lysophosphatidylcholine It is known to have a strengthening effect on the dermal-epidermal junction. Such lysophosphatidylcholine (LPC) is a major component of oxidized LDL, and is known to have a relatively useful effect on sepsis by activating various immune responsive cells including monocytes, phagocytic cells and neutrophilic leukocytes. In addition, peritonitis caused by peritonitis is significantly inhibited by the peritonitis animal model and LPC administration in cecal ligation and puncture (CLP) animal models, and peritonitis, pneumonia, osteomyelitis, It is known to be effective for the treatment of various bacterial infectious diseases including osteomyelitis. In addition, lysophosphatidylcholine is used as an emulsifier and has the effect of improving the stability of the emulsion.

The above-mentioned components have a very low solubility in the aqueous phase and are dissolved in water for preparing pharmaceutical products such as sterilized water, water for injection, deionized water and buffer solvent, There is a limit to the development of stable pharmaceutical preparations such as precipitation in body fluids and tissues immediately after administration into the body. Therefore, various attempts have been made to add or nanoize various additives such as sodium deoxycholate in various attempts to solubilize it.

However, there is a safety problem to the body during subcutaneous injection, and there is a problem about stability as a composition for injection, and it is urgent to develop a composition for injections that satisfies this.

KR 10-2013-0091093 A KR 10-2013-0112615 A KR 10-2014-0133721 A

It is an object of the present invention to provide a composition for injections containing phosphatidylcholine and lysophosphatidylcholine and a method for producing the same, and it has been found that the phosphatidylcholine contained in an injection solution is completely dissolved and the storage stability is improved.

In order to solve the above problems, the present invention provides a composition for injections, which comprises phosphatidylcholine, lysophosphatidylcholine, L-carnitine, an antiseptic, purified water, and benzyl alcohol.

According to a specific embodiment of the present invention, the phosphatidylcholine provides a composition of 1 to 3 wt%, more preferably 1 to 2 wt%, in the total composition.

The present invention also provides a composition comprising the lysophosphatidylcholine in an amount of 0.001 to 0.002% by weight.

In the present invention, the preservative may be a mixture of at least one selected from phenoxyethanol, methylparaben, ethylparaben, butylparaben and propylparaben. Preferably, all of the preservatives are mixed in the same amount. The preservative preferably comprises 0.3 to 0.4% by weight.

Also, it is preferable that the composition of the present invention contains 0.8 to 1% by weight of benzyl alcohol. And more preferably 0.8% by weight, is excellent in the solubility of phosphatidylcholine.

The present invention also provides a composition, wherein the composition comprises 0.0005% by weight of carnitine.

(2) adding a preservative and L-carnitine to the mixture and stirring the mixture, (3) adding benzyl alcohol and stirring the mixture, and (4) (4) A method for preparing an injectable composition, comprising the steps of (1) to (3), filling the mixture in a filling container while stirring the mixture.

In the above production method, phosphatidylcholine is contained in an amount of 1 to 2% by weight of the total composition, the lysophosphatidylcholine preferably contains 0.001 to 0.002% by weight, and the preservative may include 0.3 to 0.4% by weight.

Also, in the production method of the present invention, it is preferable that the benzyl alcohol contains 0.8 to 1% by weight.

The present invention relates to a composition for injections containing a phosphatidylcholine, a lysophosphatidylcholine, L-carnitine, an antiseptic, a purified water and a benzyl alcohol, and a method for preparing the same, Phosphatidylcholine is stably dissolved only in the mixing process without adding oil or surfactant, and is effective for safe injection preparation.

Hereinafter, preferred embodiments of the present invention will be described in detail. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

The phosphatidylcholine contained in the composition of the present invention is a lipolytic enzyme that shows an effect of decomposing triglycerides in adipocytes and induces collagen production to give skin elasticity. It also acts as an effective ingredient in preventing skin aging. Lysophosphatidylcholine has the effect of enhancing the dermal-epidermal junction and also enhances the stability of the emulsion as an emulsifier.

It is well known that carnitine contained in the composition of the present invention plays an important role in the lipid metabolism of human body. Carnitine binds enzymatically to fatty acids liberated from fat and has the action of a carrier that transports fatty acids into the mitochondria of intracellular organs, the site of burning lipids. The presence of excess lipid is caused not only by obesity by subcutaneous fat accumulation but also by cellulite formation, shine or stickiness of skin surface due to sebum excess, hair loss accompanying seborrheic dermatitis, acne, body odor, And the quality of life (QOL), in particular, the aging of the skin accompanied by the aging of the skin. In order for lipid metabolism to take place, fatty acids need to be introduced into the mitochondria, and carnitine is essential for its introduction. Therefore, the rate of lipid metabolism depends on the amount of carnitine present in the cells. Increasing the concentration of carnitine in tissues to promote lipid metabolism leads to the promotion of lipid metabolism, thereby preventing the lipid excess, and thereby eliminating the trouble due to lipid excess . The L-carnitine of the present invention can be used as a salt in a molecule, an inorganic salt such as a hydrochloride salt or a sodium salt, or an organic acid salt such as a oxalate salt, a tartarate salt or a fumarate.

The benzyl alcohol used in the present invention is a colorless transparent liquid having unique odor and bitter taste and is used as a solubilizer, an extractant, a volatile retention agent, a food flavoring agent and the like.

The present invention can be provided as a composition for injectable application by adding a buffering agent, an isotonic agent, and the like to the composition containing the above-mentioned components.

The method of administering the injectable composition of the present invention is not limited, but may be administered to the patient in a manner suitable for the patient depending on the degree of the disease and other conditions such as age, sex, and weight of the patient. It can also be administered by subcutaneous injection, intradermal injection, intravenous injection, intramuscular injection, intraperitoneal injection and the like, among which subcutaneous injection is most preferable.

The preferred dosage of the phosphatidylcholine in the injectable composition of the present invention varies depending on the condition and the weight of the patient, the degree of the disease, the drug form, the administration route and the period, but can be appropriately selected by those skilled in the art. However, for the desired effect, the present invention is preferably administered at a dose of 0.10 to 1 mg / kg, preferably 0.20 to 1 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.

Formulation example 1: Preparation of injection

Phosphatidylcholine 94.5 mg

Lysophosphatidylcholine 1.6 mg

Benzyl alcohol 80 mg

0.05 mg of L-carnitine

40 mg of preservative

Sterile sterilized residual water

(10 ml) according to the conventional injection preparation method.

94.5 mg of phosphatidylcholine and 1.6 mg of lysophosphatidylcholine are dissolved in sterilized distilled water and ethanol (10 ml), and the solvent is evaporated under reduced pressure. The prepared mixture was added to purified water, and the mixture was stirred for 1 hour while being heated to 65 캜. After the mixture was completely dissolved by stirring, benzyl alcohol and a preservative consisting of phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben and carnitine were added to the mixture at 40 DEG C while maintaining the temperature of the mixture at 40 DEG C, Is adjusted to rpm 20 to 25 and stirred for 2 hours. This is filtered and then introduced into a second stirrer and injected into the ampoule at the same time as stirring.

Formulation example 2: Preparation of injection

Phosphatidylcholine 189 mg

3.2 mg of lysophosphatidylcholine

Benzyl alcohol 80 mg

0.05 mg of L-carnitine

40 mg of preservative

Sterile sterilized residual water

189 mg of phosphatidylcholine and 3.2 mg of lysophosphatidylcholine are dissolved in sterilized distilled water and ethanol (10 ml), and the solvent is evaporated under reduced pressure. The prepared mixture was added to purified water, and the mixture was stirred for 1 hour while being heated to 65 캜. After the mixture was completely dissolved by stirring, the mixture was heated to 40 캜 while maintaining the temperature of the mixer, and carnitine was added thereto with a preservative consisting of benzyl alcohol and phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben, Is adjusted to 10 ml and stirred at a stirrer speed of 20 to 25 rpm for 2 hours. This is put into a second stirrer and injected into the ampoule at the same time as stirring.

Formulation example 3: Preparation of injection

Phosphatidylcholine 120 mg

2.6 mg of lysophosphatidylcholine

Benzyl alcohol 100 mg

0.05 mg of L-carnitine

40 mg of preservative

Sterile sterilized residual water

120 mg of phosphatidylcholine and 2.6 mg of lysophosphatidylcholine are dissolved in sterilized distilled water and 10 ml of ethanol, and the solvent is evaporated under reduced pressure. The prepared mixture was added to purified water, and the mixture was stirred for 1 hour while being heated to 65 캜. After the mixture was completely dissolved by stirring, the mixture was heated to 40 캜 while maintaining the temperature of the mixer, and carnitine was added thereto with a preservative consisting of benzyl alcohol and phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben, Is adjusted to 10 ml and stirred at a stirrer speed of 20 to 25 rpm for 2 hours. This is put into a second stirrer and injected into the ampoule at the same time as stirring.

Formulation example 4: Preparation of injection

Phosphatidylcholine 252 mg

3.2 mg of lysophosphatidylcholine

Benzyl alcohol 80 mg

0.05 mg of L-carnitine

40 mg of preservative

Sterile sterilized residual water

252 mg of phosphatidylcholine and 3.2 mg of lysophosphatidylcholine are dissolved in sterilized distilled water and 10 ml of ethanol, and the solvent is evaporated under reduced pressure. Using the prepared mixture, the injectable composition was prepared in the same manner as in Preparation Example 1,

Comparative Example 1: Preparation of injection

Phosphatidylcholine 100 mg

50 mg of sodium deoxycholate

Benzyl alcohol 50 mg

0.05 mg of L-carnitine

40 mg of preservative

Sterile sterilized residual water

100 mg of phosphatidylcholine, 50 mg of sodium deoxycholate, benzyl alcohol, carnitine and preservative were added to purified water and stirred.

Experimental Example 1

The compositions prepared as in Formulation Examples 1 to 4 and Comparative Example 1 were allowed to stand for one week, and then the presence or absence of sedimentation or phase separation was visually observed.

Table 1 shows the results of visual observation of the compositions of Examples 1 to 4 and Comparative Example 1. Samples containing lysophosphatidylcholine in the range of 1 to 2% by weight of phosphatidylcholine, as in Formulation Examples 1 to 3, exhibited precipitate formation or phase separation without phase separation, and were not included in Formulation Example 4 and lysophosphatidylcholine In the comparative example containing oxycholate, phase separation was observed.

Visual observation Exterior Sedimentation Phase separation Formulation Example 1 Off-white none none Formulation Example 2 Off-white none none Formulation Example 3 Off-white none none Formulation Example 4 Off-white has exist none Comparative Example 1 Light yellow has exist Phase separation

Table 2 shows the stability of the compositions of Formulation Examples 1 to 4 and Comparative Example 1, and it was confirmed that the stability of the composition at high temperature was superior to that of Comparative Example 1, which is generally used.

Test Items Formulation Example 1 Formulation Example 2 Formulation Example 3 Formulation Example 4 Comparative Example 1 Stability test Color change of composition after storage at 80 degrees for 3 days No change No change No change No change discoloration After 80 days of storage for 3 days, the residual rate of phosphatidylcholine 97.7% 97.1% 97. 3% 96% 92.2%

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. There will be. The invention is not limited by these variations and modifications, but is limited only by the claims appended hereto.

Claims

1 to 2% by weight of phosphatidylcholine,
0.001 to 0.002% by weight of lysophosphatidylcholine,
0.0005% by weight of L-carnitine,
0.3 to 0.4% by weight of preservative,
Purified water and
0.8 to 1% by weight of benzyl alcohol.

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The composition according to claim 1, wherein the preservative is a mixture of phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben

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(1) 1 to 2% by weight of phosphatidylcholine, 0.001 to 0.002% by weight of lysophosphatidylcholine purified water, and stirring
(2) adding 0.3 to 0.4% by weight of preservative and 0.0005% by weight of L-carnitine to the mixture and stirring,
(3) adding 0.8 to 1% by weight of benzyl alcohol and stirring,
(4) charging the mixture through the steps (1) to (3) into a filling container while stirring the mixture;
A method for producing an injectable composition

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