KR20160102723A - Biodegradable polymer for administrating to a living body or for cosmetic surgery containing sodium 2-mercaptoethane sulfonate as an osmotic agent - Google Patents

Abstract

The present invention relates to a composition containing sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator. More specifically, the present invention relates to a composition containing sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator, which enables osmotic pressure regulation in an easy way, while maintaining stable material properties before and after sterilization. Particularly, the present invention relates to a biodegradable polymer composition for bioinjection, containing hyaluronic acid or a derivative thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to a biodegradable polymer for administration or a cosmetic surgery containing sodium 2-mercaptoethane sulfonate as an osmotic agent containing sodium 2-mercaptoethanesulfonate as an osmotic pressure-

The present invention relates to a composition containing sodium 2-mercaptoethanesulfonate as an osmotic pressure regulator, and more particularly, to a composition containing sodium 2-mercaptoethanesulfonate as an osmotic pressure regulator so that osmotic pressure can be easily controlled, To a biodegradable polymer composition for biomedical application comprising a composition in which the physical properties of the composition are maintained constant, particularly a derivative of hyaluronic acid or hyaluronic acid.

Hyaluronic acid is a complex polysaccharide composed of amino acid and uronic acid, and is a macromolecular compound having a molecular weight of 200,000 to 400,000 in which N-acetylglucosamine and glucuronic acid are alternately linked in a chain. It is involved in cell division, differentiation and migration, as well as being involved in storage and diffusion of water retention, intercellular space maintenance, cell growth factors and nutrients as main constituents of extracellular matrix. Hyaluronic acid is a component that exists in many vitamins (琉璃 體), joint fluid, cartilage, and skin of animal. It is combined with a large amount of water to become a gel state, and is involved in lubrication of joints and flexibility of skin. It also plays an important role in preventing penetration and penetration of toxins into the skin.

It has been reported that hyaluronic acid is a component existing naturally in all living organisms. It has been reported that more than 50% of hyaluronic acid present in the mammalian body is distributed in the intercellular spaces of the skin, especially the intercellular spaces of the epidermis and the connective tissues of the dermis. Are mainly synthesized by keratinocytes and fibroblasts. Hyaluronic acid makes skin elastic and reduces damage to the lower part of the skin when it is damaged. And important collagen smoothes the movement between cells, and acts as lubricant to smooth movements of bones and joints. Hyaluronic acid also prevents penetration of foreign substances such as bacteria and prevents skin diseases such as infection.

Recently, as interest in beauty has increased, various methods of giving a volume feeling to the face have appeared. Typically, there is a surgical method for implantation, a non-surgical method for injecting a material by injection such as a fat graft or a filler. Of these, the filler is of interest because it is simple to perform and does not require a separate recovery period.

Hyaluronic acid is especially popular as a filler material because hyaluronic acid is a substance present in the body. Therefore, it is safe because there are no adverse reactions even when it is injected into the body and there are few side effects. In addition, This is because it moisturizes the skin itself and is effective for moisturizing the skin.

Since the filler using hyaluronic acid is a substance that can be directly injected into the body, the osmotic pressure control is required to be suitable for administration to a living body. In addition, the composition for vivo administration must be sterilized in a manufacturing process. However, there is a problem that the rheology of the composition changes during the course of the sterilization process, resulting in denaturation of the composition. There has been no satisfactory method as an approach to solve all of these problems.

Korean Patent Laid-Open No. 10-2013-0132503 (published Dec. 14, 2013) Korean Patent Laid-Open No. 10-2004-0020789 (published on March 30, 2004)

Kim, Mi Sook et al., Biomaterials Application of Hyaluronic Acid Derivatives, Biomaterials Research (2008) 12 (3): 83-95

The present inventors intend to find a means for easily controlling osmotic pressure in a composition containing hyaluronic acid which can be directly administered into the body. Surprisingly, when sodium 2-mercaptoethanesulfonate is mixedly used, the osmotic pressure is effectively controlled , And that the physical properties of the composition after sterilization can be stably maintained. Thus, the present invention has been completed.

Accordingly, it is an object of the present invention to provide a composition for in vivo administration using sodium 2-mercaptoethanesulfonate as an osmotic pressure-controlling agent.

In order to accomplish the above object, the present invention provides a biodegradable polymer composition for biomedical administration, which contains sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator.

More preferably, the present invention provides a biodegradable polymer composition for biomedical administration comprising hyaluronic acid or a derivative thereof containing sodium 2-mercaptoethanesulfonate as an osmotic pressure controlling agent and having improved sterility stability.

The composition of the present invention contains sodium 2-mercaptoethanesulfonate as an osmotic pressure controlling agent, so that osmotic pressure can be easily adjusted to an appropriate range in a biodegradable polymer composition for in vivo administration, and in particular, a composition comprising hyaluronic acid or a derivative thereof It is possible to easily control the osmotic pressure and to prevent denaturation of the composition due to the sterilization treatment and thus to stably maintain the action and action of hyaluronic acid or its derivatives in the skin and in the case of using the hyaluronic acid product of the conventional formulation ≪ / RTI > can provide enhanced efficacy compared to < RTI ID =

Figure 1 shows rheological measurements of a composition comprising hyaluronic acid and MESNA, NaCl or mannitol before and after sterilization, taking into account the osmotic pressure range suitable for the administration of the body, MESNA, NaCl or mannitol so that the osmotic pressure of the final composition is 300 mOsm .
Figure 2 shows the rheological measurements before and after sterilization of a composition comprising hyaluronic acid and MESNA, NaCl or mannitol, wherein MESNA, NaCl and mannitol were all used in equal amounts in each composition.

The present invention relates to an osmotic pressure-controlling agent suitable for use in a composition comprising hyaluronic acid or a derivative thereof, and a biodegradable polymer composition, preferably a biodegradable polymer composition for cosmetic molding, which can be administered or injected into the body, More preferably, the present invention relates to a biodegradable polymer composition for biopsy.

The composition according to the present invention has an osmotic pressure suitable for the administration or injection of a living body, and is excellent in formulation stability before and after sterilization.

As used herein, the term " biodegradable polymer " refers to a substance capable of degradation in the body when it is inserted into a living body. Examples of the biodegradable polymer include natural polymers such as hyaluronic acid, collagen, albumin, and chitosan, polyglycolide, polylactide, And synthetic polymers such as polyvinyl alcohol and polyvinyl alcohol.

As the derivatives of hyaluronic acid, there are no particular limitations on the kind of hyaluronic acid. Examples of hyaluronic acid derivatives include hyaluronic acid-collagen complex, hyaluronic acid-polycarboxylic acid-containing natural polymer complex, hyaluronic acid-chitosan complex, hyaluronic acid-based blend (For example, a blend of polyvinyl alcohol or polyacrylic acid and hyaluronic acid), graft hyaluronic acid copolymer (refer to Biomaterials Research (2008) 12 (3): 83-95, application of biomaterials of hyaluronic acid derivatives, .

The composition of the present invention comprises 2-mercaptoethanesulfonate and salts thereof as an osmotic pressure regulator, preferably a metal salt of 2-mercaptoethanesulfonate, to provide osmotic pressure control suitable for in vivo administration and / Can be used. The type of the metal ion forming the metal salt is not particularly limited, but includes sodium, potassium, lithium, calcium, magnesium and the like, and sodium cation is particularly preferably used.

In particular, a composition comprising hyaluronic acid or a derivative thereof, wherein the 2-mercaptoethanesulfonate is used as an osmotic pressure regulator, maintains the physical properties of the composition before and after the sterilization so that the product can be sterilized The stability can be secured.

In the present invention, 2-mercaptoethanesulfonate and its salts, alone or in combination with other osmo-regulators, may be contained in the composition in an amount that maintains the osmotic pressure of the composition at a suitable osmotic pressure for bioavailability. As other osmotic pressure regulators, those known in the art as osmotic pressure regulators for cosmetics and pharmaceuticals can be used, but NaCl and mannitol can be preferably used.

In addition, 2-mercaptoethanesulfonate and its salts can serve as pH adjusting agents in the preparation process so that the composition has a pH suitable for in vivo administration. In the present invention, 2-mercaptoethanesulfonate and its salts, alone or in combination with other pH control agents, may be contained in the composition in an amount to maintain the pH of the composition at a pH suitable for biologic administration. Other pH adjusters may be those known in the art as pH adjusting agents for cosmetics and pharmaceuticals, including but not limited to HCl (to make the composition acidic), NaOH (to make the composition basic ). The pH of the final composition according to the present invention may preferably be maintained in a range suitable for vital administration, that is, in the range of pH 6.5 to 7.5, preferably in the range of pH 6.7 to 7.3, and most preferably at pH 7. [

The sodium 2-mercaptoethanesulfonate used in the present invention is a compound represented by the following formula (1) and is referred to as 2-mercaptoethane sulfonate Na or briefly MESNA (hereinafter referred to as "MESNA" Quot;).

[Chemical Formula 1]

The composition of the present invention may contain 0.0001 to 20 wt.%, Preferably 0.0005 to 15 wt.%, More preferably 0.001 to 10 wt.%, Still more preferably 0.005 to 2 wt.% MESNA, Preferably in an amount of 0.01 to 1.5% by weight. If it is less than 0.0001% by weight, the desired effect can not be obtained, and it is inappropriate to exceed 20% by weight in consideration of irritation to the skin and blending with other ingredients.

When the composition of the present invention is formulated into a liquid parenteral preparation such as an injectable solution or a filler, the osmotic pressure of the final product is in the range suitable for biological administration, that is, 250 to 350 mOsm, It is advisable to include MESNA in the range of 300 to 350 mOsm. Considering this osmotic pressure range, for liquid parenteral administration, MESNA may be included in an amount of 0.0001 to 100 mg, preferably 0.001 to 20 mg, more preferably 0.001 to 15 mg per 1 ml of the composition volume per 1 ml of the composition volume .

According to the present invention, MESNA can ensure the stability of the composition against sterilization by maintaining the physical properties of the composition, particularly the composition including hyaluronic acid, constant before and after sterilization while controlling the osmotic pressure for vital administration to an appropriate range, Accordingly, the action effect of hyaluronic acid in the skin can be stably maintained.

The sterilization method for the composition for vital administration is not limited thereto, but a high-pressure autoclave method is widely used. In order to destroy the endogenous spores of bacteria, it is effective to use a high-pressure sterilization method since sterilization is required at a high vapor pressure of 100 ° C or higher. At present, high-pressure sterilization is carried out for about 15 minutes under the conditions of 121 캜 and 15 lb psi, which can destroy the endogenous spores of bacteria in the composition and change the physical properties of the composition. However, in the case of a composition containing MESNA as an osmotic pressure controlling agent, the properties of the composition can be stably maintained after sterilization.

The composition for vital administration of the present invention contains hyaluronic acid or a derivative thereof in an amount of 0.001 to 90% by weight, preferably 0.005 to 70% by weight, more preferably 0.01 to 50% by weight, based on the total weight of the composition.

According to the present invention, when a composition containing both hyaluronic acid or a derivative thereof and MESNA is formulated into a product for body tissue collection such as injection or filler, or a liquid parenteral bioavailability product such as eye drops, It is possible to stably maintain the physical properties of the composition before and after the sterilization treatment that must be performed in the process.

The composition of the present invention may also be formulated as an external preparation for skin, in particular as a cosmetic composition, and may be formulated containing a cosmetically or dermatologically acceptable medium or base. These are all formulations suitable for topical application, for example as a solution, a gel, a solid, a paste anhydrous product, an emulsion obtained by dispersing an oil phase in water, a suspension, a microemulsion, a microcapsule, a microgranule or an ionic form (liposome) In the form of ionic fibrin dispersions, or in the form of creams, skins, lotions, powders, ointments, sprays or conical sticks. It can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

The composition of the present invention can be used on the face, especially around the eyes, around the mouth, on the cheeks, or on the forehead, neck, hands, feet, but is not limited thereto. Specifically, the composition may include softening longevity (skin lotion and milk lotion) A body lotion, a body cream, a body oil, and a body essence, selected from the group consisting of body lotion, essence, nutritional cream, massage cream, pack, gel, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, May be prepared in one or more formulations, but is not limited thereto. These compositions may be prepared according to conventional methods in the art.

In addition, the composition according to the present invention may further comprise at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickening agents, gelling agents, softening agents, antioxidants, suspending agents, stabilizing agents, Such as fillers, emulsifiers, emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blockers, moisturizers, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or any other ingredient commonly used in cosmetics May contain adjuvants commonly used in the field of cosmetics or dermatology. Such adjuvants are introduced in amounts commonly used in the cosmetics or dermatological fields.

In addition, the cosmetic composition of the present invention may contain a skin absorption promoting substance to increase the effect.

In addition, the composition of the present invention can be formulated as a pharmaceutical composition. When the composition according to the present invention is applied to medicines, it may be formulated into a parenteral administration form in the form of a semi-solid or a liquid by adding an inorganic or organic carrier compatible with the active ingredient used in the present invention. The pharmaceutical composition may be administered parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like.

Examples of the formulations for parenteral administration include injections, drops, ointments, lotions, sprays, suspensions, emulsions, suppositories, and the like. The composition according to the present invention can be easily formulated into an active ingredient by carrying out a conventional method well known in the art, wherein the surfactant, excipient, coloring agent, spice, preservative, stabilizer, buffer, Commercially available adjuvants can be used appropriately.

In particular, when the composition of the present invention is formulated in the form of injections, fillers, etc., it can be formulated into prefilled syringes, vials and the like.

The dosage of the active ingredient of the pharmaceutical composition of the present invention will vary depending on the age, sex, body weight, pathological condition and severity of the subject to be treated, route of administration, or judgment of the prescriber. Determination of the appropriate dose based on these factors is well within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / / Day, but is not limited thereto.

Hereinafter, the constitution and effects of the present invention will be described in more detail with reference to test examples and formulation examples. However, these test examples and formulation examples are provided for illustrative purposes only for the sake of understanding of the present invention, and the scope and scope of the present invention are not limited by the following examples.

[Test Example 1] Evaluation of sterility stability of hyaluronic acid-containing composition

1. Sample

For the sterilization stability test, the test samples of Example 1 and Comparative Examples 1 to 4 were prepared. In this case, Example 1 and Comparative Examples 1 to 4 consisted of a sol-state liquid containing a test substance and a gel-state liquid containing hyaluronic acid (HA) : 4 in volume ratio was used as a sample. In Example 1, Comparative Example 1 and Comparative Example 2, MESNA, NaCl and mannitol were respectively formulated so that the osmotic pressure of the final composition became 300 mOsm. In Comparative Example 3 and Comparative Example 4, the amount of NaCl and mannitol used was the same as in Example 1 Of MESNA use. Specific compositions are shown in Table 1 below, and hyaluronic acid materials used as gels are specifically described below.

(When the total volume is 3 mL) division ingredient Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Sol
(1.8 mL) ¹⁾ Phosphate buffer 10 mM 1.8 mL 1.8 mL 1.8 mL 1.8 mL 1.8 mL ²⁾ Lidocaine 9 mg 9 mg 9 mg 9 mg 9 mg ³⁾ MESNA 45 mg - - - - ³⁾ NaCl - 23.7 mg - 45 mg - ³⁾ Mannitol - - 144 mg - 45 mg HA gel ⁴⁾ Hyaluronic acid 1.2 mL 1.2 mL 1.2 mL 1.2 mL 1.2 mL

1) Phosphate buffer 10 mM

= Sodium phosphate monobasic dehydrate 0.49 g

+ Sodium phosphate dibasic dehydrate (2.45 g)

+ Distilled water 1L

2) Lidocaine: added to a concentration of 0.3%

3) - MESNA: Jiangsu Hengrui Medicin.Co., Batch number 642130904

- NaCl: Samchun chemical, lot 080207

- Mannitol: Sigma, lot 31K0003

4) Hyaluronic acid:

1 g of sodium hyaluronate fiber (NaHA, Mw = 0.5 to 3 MDa) was mixed with 10 g of 1% sodium hydroxide solution and the mixture was allowed to hydrate for 5 hours. 150 mg of 1,4-butanediol diglycidyl ether was added to the NaHA gel to homogeneously mix the mixture, and the resulting crosslinked hydrogel was neutralized with an equimolar amount of hydrochloric acid (HCl) (pH about 7). The hydrogel thus obtained was mechanically homogenized and used in the preparation of the examples and comparative examples.

2. Test protocol

Samples of Example 1 and Comparative Examples 1 to 4 prepared in the amounts shown in Table 1 were precisely weighed into vials. The rheology of the five samples was measured prior to sterilization (AR Rheometer, TA Instruments, USA). The sterilization was performed using a high-pressure sterilizer (Automatic Autoclave, Sterilizer; J-NAS 62 from JISICO). The rheology of the samples of the sterilized Example 1 and Comparative Examples 1 to 4 was then measured.

The measurement results are shown in Tables 2 and 3 and Figs. 1 and 2 below. In the following Tables 2 and 3, G 'means storage elasticity (elastic), G' means loss elasticity (viscosity), and tan delta (G '/ G') means viscosity to elasticity ratio , Indicating that the modulus of elasticity varies with temperature. The larger the value of tan delta, the more viscous. The smaller the value, the more elastic.

G ' G '' tan delta Before sterilization Example 1
(MESNA) 43.74 22.61 0.52 Comparative Example 1
(NaCl) 55.43 24.86 0.45 Comparative Example 2
(Mannitol) 27.78 28.75 1.03 After sterilization Example 1
(MESNA) 35.17 19.16 0.54 Comparative Example 1
(NaCl) 21.53 15.57 0.72 Comparative Example 2
(Mannitol) 20.63 17.11 0.83

In Table 2 and FIG. 1, NaCl> MESNA> mannitol was shown in order of rheology (G ') before sterilization, whereas MESNA> NaCl> mannitol was shown in order of rheology (G') after sterilization. For the tan delta values, the fluctuation width was in the order of NaCl> mannitol> MESNA. Based on these results, it can be confirmed that MESNA guarantees the best sterilization stability considering the post-sterilization rheology and the variation range of tan delta.

G ' G '' tan delta Before sterilization Example 1
(MESNA) 44.33 29.79 0.67 Comparative Example 3
(NaCl) 38.04 23.96 0.63 Comparative Example 4
(Mannitol) 46.98 37.00 0.79 After sterilization Example 1
(MESNA) 41.10 26.03 0.63 Comparative Example 3
(NaCl) 20.60 13.76 0.67 Comparative Example 4
(Mannitol) 33.94 20.94 0.62

In Table 3 and FIG. 2, when the same amount of osmotic pressure regulator was used, mannitol>MESNA> NaCl was shown in order of rheology (G ') before sterilization whereas MESNA>Mannitol> NaCl. For the tan delta value, the variation width was in the order of mannitol> NaCl = MESNA. Based on these results, it can be confirmed that MESNA guarantees the best sterilization stability considering the post-sterilization rheology and the variation range of tan delta.

The above results show that the use of an osmo-regulator can adjust the sterility stability of a composition containing hyaluronic acid. In the case of NaCl and mannitol, the rheology change amount of the composition before sterilization is large, , And in the case of MESNA, the rheology of the composition before and after sterilization was stably maintained, indicating that the stability against sterilization was greatly improved.

Claims (12)

A biodegradable polymer composition for in vivo administration or cosmetic molding, comprising sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator. 2. The composition of claim 1, wherein the sodium 2-mercaptoethanesulfonate is contained in an amount that maintains the osmotic pressure of the composition alone or in combination with another osmoticum control agent at an osmotic pressure suitable for bioavailability. The composition of claim 1, wherein the sodium 2-mercaptoethanesulfonate is contained, alone or in combination with another pH adjusting agent, in an amount to maintain the pH of the composition at a pH suitable for biologic administration. The composition of claim 1, wherein the biodegradable polymer is hyaluronic acid or a derivative thereof. The composition according to claim 1, wherein the osmolality-adjusting agent is contained in an amount of 0.0001 to 20% by weight based on the total weight of the composition. 6. The composition according to any one of claims 1 to 5, characterized in that the composition has increased stability to the sterilization treatment. 6. The composition according to any one of claims 1 to 5, wherein the composition is an external preparation for skin. A prefilled syringe comprising hyaluronic acid or derivatives thereof containing sodium 2-mercaptoethanesulfonate as an osmotic pressure regulator. 9. The pre-field syringe of claim 8, wherein the syringe has increased stability to sterilization treatment. An injection containing hyaluronic acid or a derivative thereof, containing sodium 2-mercaptoethanesulfonate as an osmotic pressure-controlling agent. 11. An injection according to claim 10, wherein said injection is formulated in the form of a vial. 12. An injection according to claim 10 or 11, wherein the injection has increased stability to the sterilization treatment.

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