KR102329495B1 - 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 adjusting agent, and more particularly, by containing sodium 2-mercaptoethane sulfonate as an osmotic pressure adjusting agent, osmotic pressure control is facilitated while additionally sterilized. It relates to a composition in which physical properties are maintained constant before and after, in particular, to a biodegradable polymer composition for in vivo administration comprising hyaluronic acid or a derivative of hyaluronic acid.

Description

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

The present invention relates to a composition containing sodium 2-mercaptoethane sulfonate as an osmotic pressure adjusting agent, and more particularly, by containing sodium 2-mercaptoethane sulfonate as an osmotic pressure adjusting agent, osmotic pressure control is facilitated while additionally sterilized. It relates to a composition in which physical properties are kept constant before and after, in particular, to a biodegradable polymer composition for in vivo administration comprising hyaluronic acid or a derivative of hyaluronic acid.

Hyaluronic acid is one of the complex polysaccharides composed of amino acids and uronic acid, and is a high molecular weight compound with a molecular weight of 200,000 to 400,000 in which N-acetylglucosamine and glucuronic acid are alternately combined in a chain shape. As a major component of the extracellular matrix, it is involved in water retention, intercellular spacing, storage and diffusion of cell growth factors and nutrients, as well as cell division, differentiation, and migration. Hyaluronic acid is a component abundantly present in the vitreous body, joint fluid, cartilage, and skin of animals. It combines with a large amount of water to form a gel state, and is involved in joint lubrication and skin flexibility. It also plays an important role in preventing invasion or penetration of poison into the skin.

The hyaluronic acid is a component naturally present in all living organisms, and it has been reported that more than 50% of the hyaluronic acid present in the body of a mammal is distributed in the skin, particularly the intercellular space of the epidermis and the connective tissue of the dermis, such hyaluronic acid is known to be synthesized mainly by keratinocytes and fibroblasts. Hyaluronic acid plays a role in making the skin elastic and reducing damage to the lower layer of the skin when the skin is damaged. And important collagen facilitates the movement between cells and acts like a lubricant to smooth the movement of bones and joints. Hyaluronic acid also prevents the penetration of substances such as bacteria from the outside, thereby preventing diseases such as skin infections.

Recently, as interest in beauty has increased, various treatment methods that give volume to the face have emerged. Representative examples include a surgical method of inserting an implant, a non-surgical method of injecting substances by injection, such as fat grafting, and fillers. Among them, fillers are attracting attention because the procedure is simple and does not require a separate recovery period.

As a filler material, hyaluronic acid is particularly popular. Since hyaluronic acid is a substance present in the body, it is safe because there are no adverse reactions even when injected into the body and there are few side effects. Because it moisturizes the skin itself, it is also effective in moisturizing the skin.

As such, the filler using hyaluronic acid is a material that can be directly injected into the body, so it is necessary to control the osmotic pressure to be suitable for in vivo administration. In addition, the composition for in vivo administration must be sterilized for manufacturing, but there is a problem that the rheology of the composition is changed during this process, so that the composition may be denatured. As an approach for solving all these problems, there has not been a satisfactory method in the past.

Domestic Patent Publication No. 10-2013-0132503 (published on Dec. 4, 2013) Domestic Patent Publication No. 10-2004-0020789 (published on March 9, 2004)

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

The present inventors have tried to find a means to easily control the osmotic pressure in a composition containing hyaluronic acid that can be administered directly into the body, and surprisingly, when sodium 2-mercaptoethane sulfonate is mixed and used, the osmotic pressure is effectively controlled , also found that the physical properties of the composition can be stably maintained before and after sterilization, and completed the present invention.

Accordingly, an object of the present invention is to provide a composition for in vivo administration using sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator.

In order to achieve the above object, the present invention provides a biodegradable polymer composition for in vivo administration, containing sodium 2-mercaptoethane sulfonate (sodium 2-mercaptoethane sulfonate) as an osmotic pressure regulator.

More preferably, the present invention provides a biodegradable polymer composition for in vivo administration comprising sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator, and sterilization stability is improved, comprising hyaluronic acid or a derivative thereof.

The composition of the present invention contains sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator, so that the osmotic pressure can be easily adjusted to an appropriate range in a biodegradable polymer composition for in vivo administration, in particular, a composition comprising hyaluronic acid or a derivative thereof In the case of using a hyaluronic acid product of an existing formulation, it is possible to easily control the osmotic pressure and prevent denaturation of the composition due to sterilization, thus stably maintaining the action and effect of hyaluronic acid or a derivative thereof in the skin. It can provide enhanced efficacy compared to

1 shows the rheological measurement values before and after sterilization of a composition containing hyaluronic acid and MESNA, NaCl or mannitol. Considering the osmotic pressure range suitable for in vivo administration, MESNA, NaCl or mannitol is added so that the osmotic pressure of the final composition is 300 mOsm. added.
Figure 2 shows the rheological measurements before and after sterilization of a composition containing hyaluronic acid and MESNA, NaCl or mannitol, and MESNA, NaCl and mannitol were all used in the same amount in each composition.

The present invention relates to an osmotic pressure regulator suitable for use in a composition comprising hyaluronic acid or a derivative thereof, and a biodegradable polymer composition that can be administered or injected into a living body, preferably a biodegradable polymer composition for cosmetic surgery, More preferably, it relates to a biodegradable polymer composition for tissue repair.

The composition according to the present invention has an osmotic pressure suitable for in vivo administration or injection, and at the same time has excellent formulation stability before and after sterilization.

As used herein, "biodegradable polymer" refers to a substance that can be decomposed in the body when inserted into a living body, for example, natural polymers such as hyaluronic acid, collagen, albumin, chitosan, polyglycolide, polylactide, polyhydroxy There is a polyester-based synthetic polymer such as valate.

In the present application, the type of hyaluronic acid derivative is not particularly limited, but hyaluronic acid-collagen complex, hyaluronic acid-polycarboxylic acid-containing natural polymer complex, hyaluronic acid-chitosan complex, hyaluronic acid-based blend (eg For example, polyvinyl alcohol or a blend of polyacrylic acid and hyaluronic acid), graft hyaluronic acid copolymer (Kim Mi-sook et al., biomaterial application of hyaluronic acid derivatives, Biomaterials Research (2008) 12(3): see 83-95), etc. includes

The composition of the present invention includes 2-mercaptoethane sulfonate and a salt thereof as an osmotic pressure regulator in order to provide osmotic pressure control suitable for in vivo administration and/or in vivo injection, preferably a metal salt of 2-mercaptoethane sulfonate this can be used In addition, 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 a sodium cation is particularly preferably used.

In particular, in the composition containing hyaluronic acid or a derivative thereof, in which the 2-mercaptoethane sulfonate is used as an osmotic pressure regulator, the physical properties of the composition before and after sterilization are maintained constant, so that the sterilization of the product is performed without a separate additional process in the manufacturing process. stability can be ensured.

In the present invention, 2-mercaptoethane sulfonate and its salt may be contained in the composition in an amount that maintains the osmotic pressure of the composition at an osmotic pressure suitable for in vivo administration alone or together with other osmotic pressure adjusting agents. Other osmotic pressure regulators may be those widely known in the art as osmotic pressure regulators for cosmetics and pharmaceuticals, but preferably NaCl or mannitol.

In addition, 2-mercaptoethane sulfonate and its salt may serve as a pH adjuster in the manufacturing process so that the composition has a pH suitable for in vivo administration. In the present invention, 2-mercaptoethane sulfonate and salts thereof may be contained in the composition alone or in combination with other pH adjusting agents in an amount to maintain the pH of the composition at a pH suitable for in vivo administration. Other pH adjusters may be those well known in the art as pH adjusters for cosmetics and pharmaceuticals, examples of which include, but are not limited to, HCl (for making the composition acidic), NaOH (for making the composition basic) ), etc. The pH of the final composition according to the present invention is preferably maintained in a range suitable for in vivo 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 in pH 7.

Sodium 2-mercaptoethane sulfonate used in the present invention is a compound represented by the following Chemical Formula 1, and is referred to as 2-mercaptoethane sulfonate Na (2-mercaptoethane sulfonate Na) or MESNA for short (hereinafter, “MESNA”). referred to as ).

[Formula 1]

The composition of the present invention contains MESNA in an amount of 0.0001 to 20% by weight, preferably 0.0005 to 15% by weight, more preferably 0.001 to 10% by weight, even more preferably 0.005 to 2% by weight, even more with respect to the total weight of the composition. Preferably, it contains in an amount of 0.01 to 1.5% by weight. If it is less than 0.0001% by weight, the desired effect cannot be obtained, and when considering the combination with skin irritation and other ingredients, it is not appropriate to exceed 20% by weight.

In addition, when the composition of the present invention is formulated as a liquid parenteral administration agent such as an injection or filler, the osmotic pressure of the final product is in a range suitable for in vivo administration, that is, 250 to 350 mOsm, which is the same as the osmotic pressure inside the human body, preferably It is recommended to include MESNA in the range of 300-350 mOsm. Considering such an osmotic pressure range, MESNA may be included in an amount of 0.0001 to 100 mg per 1 ml of composition volume, preferably 0.001 to 20 mg, more preferably 0.001 to 15 mg per 1 ml of composition volume for parenteral administration in liquid form. .

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

The sterilization method made for the composition for in vivo administration is not limited thereto, but in general, an autoclave method is widely used. In order to destroy bacterial endospores, it is necessary to sterilize at 100°C or higher with high steam pressure, so it is effective to use the autoclaving method. Currently, autoclaving is carried out for about 15 minutes under conditions of 121° C. and 15 lb psi. These conditions destroy endospores of bacteria in the composition and also change the physical properties of the composition. However, in the case of a composition containing MESNA as an osmotic pressure regulator, the physical properties of the composition before and after sterilization may be stably maintained.

The composition for in vivo 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 the composition containing both hyaluronic acid or a derivative thereof and MESNA is formulated into a biotissue repair product such as an injection or a filler, or a liquid form for parenteral administration such as eye drops, the preparation of these products It becomes possible to stably maintain the physical properties of the composition before and after the sterilization treatment that must be passed in the process.

The composition of the present invention may also be formulated as a composition for external application to the skin, particularly 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, solutions, gels, solids, kneaded dry products, emulsions obtained by dispersing an oily phase in an aqueous phase, suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes) and non It may be provided in the form of an ionic vesicular dispersant, or in the form of a cream, skin, lotion, powder, ointment, spray or cone stick. 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 may be used on the face, especially around the eyes, around the mouth, on the cheeks, or on the forehead, on the neck, hands, feet, etc., but is not limited thereto, and specifically, a softening lotion (skin lotion and milk lotion), a nourishing lotion , essence, nourishing cream, massage cream, pack, gel, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil and body essence It may be prepared in one or more formulations, but is not limited thereto. These compositions can be prepared according to conventional methods in the art.

In addition, the composition according to the present invention comprises a fatty substance, an organic solvent, a solubilizer, a thickening agent, a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, ionic or nonionic such as emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other ingredient commonly used in cosmetics. It may contain adjuvants commonly used in the field of cosmetology or dermatology. The adjuvant is introduced in an amount generally used in the field of cosmetology or dermatology.

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

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

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 by carrying out according to a conventional method well known in the art, and at this time, surfactants, excipients, colorants, spices, preservatives, stabilizers, buffers, suspending agents, etc. A commercially available adjuvant may be appropriately used.

In particular, when the composition of the present invention is formulated in the form of an injection, a filler, etc., it may be formulated as a prefilled syringe, a vial, or the like.

The dosage of the active ingredient of the pharmaceutical composition of the present invention will vary depending on the age, sex, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Determination of an appropriate dose based on these factors is within the level of one skilled in the art, and its daily dose is for example 0.1 mg/kg/day to 100 mg/kg/day, more specifically 5 mg/kg/day to 50 mg/kg It can be, but is not limited to, /work.

Hereinafter, the composition and effect 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 only for the purpose of illustration to help the 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 sterilization stability of compositions containing hyaluronic acid

1. Sample

For the sterilization stability test, the test samples of Example 1 and Comparative Examples 1 to 4 were prepared. At this time, Examples 1 and Comparative Examples 1 to 4 consisted of a sol liquid containing the test substance and a gel liquid containing hyaluronic acid (HA), and the sol and the gel 6 A mixture of :4 in a volume ratio was used as a sample. In addition, in Example 1, Comparative Example 1 and Comparative Example 2, MESNA, NaCl, and mannitol were each prescribed so that the osmotic pressure of the final composition was 300 mOsm, and Comparative Examples 3 and 4 were the amounts of NaCl and mannitol used in Example 1 It was prescribed to be the same as the amount of MESNA used. The specific composition is shown in Table 1 below, and the hyaluronic acid material used as the gel was specifically described below.

(If the total volume is 3mL) division ingredient Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 pawn
(1.8mL) ¹⁾ Phosphate Buffer 10mM 1.8mL 1.8mL 1.8mL 1.8mL 1.8mL ²⁾ lidocaine 9mg 9mg 9mg 9mg 9mg ³⁾ MESNA 45mg - - - - ³⁾ NaCl - 23.7mg - 45mg - ³⁾ mannitol - - 144mg - 45mg HA gel ⁴⁾ hyaluronic acid 1.2mL 1.2mL 1.2mL 1.2mL 1.2mL

1) Phosphate Buffer 10mM

= Sodium phosphate monobasic dehydrate 0.49g

+ 2.45g Sodium phosphate dibasic dehydrate

+ 1L distilled water

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. Here, 150 mg of 1,4-butanediol diglycidyl ether was added to the NaHA gel to uniformly mix the mixture, and the resulting cross-linked hydrogel was neutralized with an equimolar amount of hydrochloric acid (HCl), which was (pH about 7). The hydrogel thus obtained was mechanically homogenized, and it was used in the preparation of Examples and Comparative Examples.

2. Test protocol

The samples of Example 1 and Comparative Examples 1 to 4 prepared in the amounts shown in Table 1 were precisely quantified and put into a vial. Prior to sterilization, the rheology of five samples was measured (AR Rheometer, TA Instruments, USA). Sterilization was performed using an autoclave (Autoclave, Sterilizer; JISICO J-NAS 62). Then, the rheology of the samples of Example 1 and Comparative Examples 1 to 4 subjected to sterilization was measured.

The measurement results are shown in Tables 2 and 3, and FIGS. 1 and 2 below. In Tables 2 and 3 below, G' means storage modulus (elasticity), G" means loss modulus (viscosity), and tan delta (G"/G') means the ratio of viscosity to elasticity. , indicates that the modulus of elasticity of the polymer varies with temperature. A larger value of tan delta indicates a viscous state, and a smaller value indicates an elastic state.

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

Referring to Table 2 and FIG. 1, for the rheology (G') before sterilization, NaCl > MESNA > mannitol was shown in the order, whereas for the rheology (G ') after sterilization, MESNA > NaCl > mannitol was shown in the order. In addition, for the tan delta value, the fluctuation range was shown in the order of NaCl > mannitol > MESNA. Based on these results, considering the rheology and tan delta fluctuation range before and after sterilization, it can be confirmed that MESNA guarantees the best sterilization stability among them.

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

Referring to Table 3 and Figure 2, when the osmotic pressure regulator is used in the same amount, mannitol > MESNA > NaCl for the rheology before sterilization (G ') is shown in the order, whereas the rheology (G ') after sterilization is MESNA > It appeared in the order of mannitol > NaCl. In addition, for the tan delta value, the fluctuation range was found in the order of mannitol > NaCl = MESNA. Based on these results, considering the rheology and tan delta fluctuation range before and after sterilization, it can be confirmed that MESNA guarantees the best sterilization stability among them.

As a result, the sterilization stability of the composition containing hyaluronic acid can be adjusted by the use of an osmotic pressure regulator. In the case of NaCl and mannitol, which were previously used, the rheological change of the composition before and after sterilization was large, so sterilization stability was not ensured. , in the case of MESNA, the rheology of the composition before and after sterilization was maintained stably, suggesting that the stability against sterilization was greatly improved.

Claims (12)

Sodium 2-mercaptoethane sulfonate (sodium 2-mercaptoethane sulfonate) containing as an osmotic pressure regulator, a biodegradable polymer composition for administration or cosmetic surgery,
wherein said composition has increased stability to sterilization treatment. The composition according to claim 1, wherein the sodium 2-mercaptoethane sulfonate is contained in an amount that maintains the osmotic pressure of the composition alone or in combination with other osmotic pressure adjusting agents at an osmotic pressure suitable for in vivo administration. The composition according to claim 1, wherein the sodium 2-mercaptoethane sulfonate is contained alone or in combination with other pH adjusting agents in an amount to maintain the pH of the composition at a pH suitable for in vivo administration. According to claim 1, wherein the biodegradable polymer is hyaluronic acid or a derivative thereof,
The hyaluronic acid derivative is hyaluronic acid-collagen complex, hyaluronic acid-polycarboxylic acid containing natural polymer complex, hyaluronic acid-chitosan complex, polyvinyl alcohol and hyaluronic acid blend, polyacrylic acid and hyaluronic acid blend and graft hyaluronic acid The composition is selected from ronic acid copolymers. The composition of claim 1, wherein the osmotic pressure regulator is contained in an amount of 0.0001 to 20% by weight based on the total weight of the composition. delete The composition according to any one of claims 1 to 5, wherein the composition is an external preparation for skin. With a prefilled syringe containing hyaluronic acid or a derivative thereof, containing sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator,
The syringe is characterized in that it has increased stability to sterilization treatment,
The hyaluronic acid derivative is hyaluronic acid-collagen complex, hyaluronic acid-polycarboxylic acid containing natural polymer complex, hyaluronic acid-chitosan complex, polyvinyl alcohol and hyaluronic acid blend, polyacrylic acid and hyaluronic acid blend and graft hyaluronic acid A prefilled syringe, which is selected from ronic acid copolymers. delete An injection containing hyaluronic acid or a derivative thereof, containing sodium 2-mercaptoethane sulfonate as an osmotic pressure regulator,
The injection is characterized by having increased stability against sterilization,
The hyaluronic acid derivative is hyaluronic acid-collagen complex, hyaluronic acid-polycarboxylic acid containing natural polymer complex, hyaluronic acid-chitosan complex, polyvinyl alcohol and hyaluronic acid blend, polyacrylic acid and hyaluronic acid blend and graft hyaluronic acid Which is selected from ronic acid copolymers, injections. The injection according to claim 10, wherein the injection is formulated in the form of a vial. delete

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