KR102363007B1 - HA filler having the properties of mono-phasic HA filler and bi-phasic HA filler, syringe used for the HA filler and, manufacturing methods for the HA filler - Google Patents

Abstract

The HA filler according to the present invention has the advantages of both a monophasic HA filler and a biphasic HA filler, so it has a low mobility when injected into the skin and maintains its shape for a long time, is suitable for Superficial Dermis or Middle Dermis, and is crosslinked Since the particles of hyaluronic acid have a spherical shape, even if a small amount of linear hyaluronic acid is included, it can be injected into the human body with a small extrusion force. small.
In addition, since the syringe for filler according to the present invention can reverse the pusher using the thumb of the hand holding the syringe, no pain is caused to the patient when the pusher is retracted, and it is possible to prevent the pusher from coming out of the syringe, and the pusher Since the pressing part has an ergonomic structure, it is possible to prevent injuries to the palms.

Description

HA filler having the characteristics of mono-phasic HA filler and bi-phasic HA filler together, a syringe used for filler injection, and a method for manufacturing the filler phasic HA filler, syringe used for the HA filler and, manufacturing methods for the HA filler}

The present invention relates to a hyaluronic acid filler, and more particularly, to a hyaluronic acid filler having high viscosity of a monophasic HA filler and high elasticity of a biphasic HA filler. In addition, the present invention also relates to a syringe for injecting the HA filler into the skin, and a method for manufacturing the filler.

In general, tissue augmentation, such as soft tissue augmentation, has been used for medical and cosmetic purposes. Such augmentation may be made surgically through plastic surgery or by a non-surgical method of increasing the volume of soft tissue by injecting a biocompatible material (filler). For example, fillers have been used cosmetically to enlarge the volume of the cheeks, lips, breasts, and buttocks, and to reduce fine lines and deep wrinkles of the skin.

Hyaluronic acid (hereinafter referred to as 'HA') is a biopolymer material in which repeating units composed of N-acetyl-D-glucosamine and D-glucuronic acid are linearly connected. It is widely used in medical and medical tools and cosmetics, such as ophthalmic surgical aids, joint function improving agents, drug delivery materials, eye drops, and wrinkle improving agents, because it is present in many places in the power plant and has excellent biocompatibility.

However, hyaluronic acid itself has a short half-life of only a few hours in the human body, so there is a limit to its application. For example, examples of synthesizing a crosslinked hyaluron derivative using a compound having two functional groups, such as divinylsulfone, bisepoxide, bishalide, formaldehyde, etc., as a crosslinking agent have been reported in several literatures, Various products are marketed as dermal fillers for enhancing skin soft tissue. U.S. Patent No. 4,582,865 discloses a hyaluron derivative crosslinked using divinylsulfone (DVS) as a crosslinking agent, and its hydrogel form is marketed under the trade name Hylaform ^® , and U.S. Patent No. 5,827,937 is a multifunctional epoxy compound Disclosed is a method for preparing a cross-linked product of hyaluronic acid by using as a cross-linking agent, and among them, a hydrogel of a cross-linked hyaluronic acid prepared using 1,4-butanediol diglycidyl ether (BDDE) as a cross-linking agent as a multifunctional epoxy compound Restylane ^® in its form has been approved by the US FDA and is marketed worldwide as a filler for tissue enhancement. All of these products are produced by combining the hydroxyl group of hyaluronic acid with a cross-linking agent, and the durability of the product in vivo is increased compared to that of uncross-linked hyaluronic acid.

Such crosslinked HA fillers include a single-phase filler (mono-phasic HA filler) and a biphasic HA filler (bi-phasic HA filler).

Since monophasic HA fillers are prepared using a homogenate containing cross-linked HA, they generally have low elasticity and high viscosity. Accordingly, when the monophasic HA filler is injected into the skin, there is a low possibility of it departing from the injected site, but there is a problem that the injected shape cannot be maintained for a long time and the shape (shape) maintenance period is only about 2 months after the procedure. .

Biphasic HA fillers are prepared by mixing crosslinked HA particles with liquid non-crosslinked HA (untreated uncrosslinked hyaluronic acid, linear HA), so generally the elasticity is high and the viscosity is low. Accordingly, when the biphasic HA filler is injected into the skin, the shape can be maintained for a long time, but there is a problem in that there is a high possibility that the biphasic HA filler is separated from the injected site.

As such, the monophasic HA filler and the biphasic HA filler each have advantages and disadvantages, but there is a need for a filler that can maintain its shape for a long time while having a low possibility of leaving the injected site.

On the other hand, when the biphasic HA filler is injected into the human body using a syringe, linear hyaluronic acid (untreated uncrosslinked hyaluronic acid, linear HA) contained in the filler acts as a lubricant. However, the higher the content of the linear hyaluronic acid, the easier it is to inject into the human body, but the linear hyaluronic acid is easily decomposed in the human body, so it is not preferable for maintaining its shape. Therefore, there is a need for a filler that contains a small amount of linear hyaluronic acid and has a small syringe extrusion force.

In addition, the syringe used when injecting the filler into the skin has a circular plate that is pressed with the palm of the hand.

And, after the needle is pierced into the skin, the pusher (piston) should be moved back slightly to check whether the needle punctured the blood vessel.

Furthermore, when the pusher moves backward, the pusher is moved backward with the left hand while holding the syringe with the right hand. At this time, the syringe shakes, causing great pain to the patient.

The present invention has been proposed to solve the above problems, and it is a filler having both the advantages of a mono-phasic HA filler and a bi-phasic HA filler, that is, it is less likely to depart from the injected site and can maintain its shape for a long time. It is injected into the Superficial Dermis or Middle Dermis of the skin to provide a filler that can be used for wrinkle improvement and shape formation.

Another object of the present invention is to provide a filler that can be injected into the human body with a small extrusion force even if it contains a small amount of linear hyaluronic acid.

Another object of the present invention is to provide a method for manufacturing such a filler.

Another object of the present invention is to provide a syringe capable of preventing a palm injury by uniformly distributing the load applied to the palm when injecting the filler into the skin.

Another object of the present invention is to provide a syringe that can prevent the pusher from separating from the syringe when the pusher is retracted after pricking the needle into the skin, and can prevent shaking of the syringe by reversing the pusher with the hand holding the syringe is to provide.

As a result of many studies and clinical tests to solve the above problems, the present applicant has a high viscosity of a monophasic filler and a high elasticity of a biphasic filler when the cross-linked HA has a size (diameter) in a specific range, Accordingly, we found an unexpected surprise that it is easy to make a shape (shape) when injected into the Superficial Dermis or Middle Dermis, the shape lasts for about 6 months, and the filler does not move to other places.

And, if the particles of cross-linked HA are made into a spherical shape, and the cross-linked HA of spherical shape is mixed with linear HA (untreated and non-cross-linked HA) in a certain ratio, excessive force when injected with a syringe is reduced. It has also been found that the injection can be performed without application, and at the same time, the shape (form) can be maintained for a long time.

Furthermore, Applicants have found that when cross-linked HA is made into an entangled molecular structure through a condensation process, its shape (shape) lasts longer, whereby the filler effect lasts longer while using less cross-linking agent. can make it

The HA filler according to a preferred embodiment of the present invention is a water-containing bi-phasic filler, which is injected into the Superficial Dermis or Middle Dermis of human skin to contribute to wrinkle improvement and shape formation.

Specifically, the HA filler contains 0.9 to 2.5 parts by weight of hyaluronic acid, based on 100 parts by weight of water included in the filler; 0.2 to 0.5 parts by weight of anesthetic; And, 5 to 15 parts by weight of P.B.S.; It is a composition in a gel state, including.

Among the hyaluronic acid, 50 wt% to 90 wt% of hyaluronic acid that has undergone a crosslinking process using a crosslinking agent is 10 wt% to 50 wt% of untreated and non-crosslinked linear hyaluronic acid. And, the cross-linked particles of hyaluronic acid have a spherical shape and a diameter of 30 μm to 150 μm.

Preferably, the hyaluronic acid is 1.1 to 2.3 parts by weight based on 100 parts by weight of water, and the particle diameter is 50 μm to 100 μm. In addition, the filler preferably has a viscosity of 5000 cP to 7000 cP at 1 Hz when measured with a rheometer, a G' (dynamic modulus of elasticity) of 15 Pa to 30 Pa, and a G'' (loss modulus) of 20 Pa to 40 Pa.

The cross-linked hyaluronic acid may have an entangled molecular structure.

Preferably, the anesthetic agent is lidocaine, and the crosslinking agent is BDDE.

The method for producing a HA filler according to the present invention comprises the steps of: (a) preparing a cross-linked hyaluronic acid (cHA) composition by adding a cross-linking agent after adding a high molecular weight hyaluronic acid to an aqueous alkali solution and stirring; (b) after cutting the hyaluronic acid composition to be refined, neutralizing it by putting it in an acidic aqueous solution; (c) placing the neutralized composition on a plate in which the circular through-holes are formed and then applying pressure to the composition to make the composition move downward through the circular through-holes to form spherical particles having a constant diameter; And, (d) mixing the unmodified and non-crosslinked linear hyaluronic acid with the composition that has undergone step (c) so that the hyaluronic acid is 0.7wt% to 2.2wt% of the total composition.

Between steps (c) and (d), or between steps (b) and (c), (a) the spherical particle hyaluronic acid composition or the neutralized hyaluronic acid composition is heated to 30 ° C. to The step of removing a part of the liquid component by stirring at 70 ° C. so that the hyaluronic acid in the composition becomes 0.7 wt% or more and 2.2 wt% or less, and the cross-linked hyaluronic acid molecule has an entangled structure; may further include have.

The mixing ratio of step (d) is 50 wt% to 90 wt% of the composition that has undergone step (c), and 10 wt% to 50 wt% of unmodified and uncrosslinked linear hyaluronic acid. And, the diameter of the particles in the final product is 30 μm to 150 μm.

The most preferred diameter of the particles in the final product is 50 μm to 100 μm. And, when measured with a rheometer, it is preferable that the viscosity at 1 Hz is 5000 cP ~ 7000 cP, G' (dynamic modulus) is 15 Pa ~ 30 Pa, and G'' (loss modulus) is 20 Pa ~ 40 Pa.

In step (a), the spherical particle hyaluronic acid composition or the neutralized hyaluronic acid composition is placed in a container of a stirrer and 100R.P.M. It can be achieved by stirring under a gauge pressure of -0.85 bar to -0.9 bar for 48 to 72 hours at ~ 200 R.P.M.

And, in step (a), it is preferable to mix 1.45 to 4.3 wt% of the polymeric hyaluronic acid and 1.45 to 4.3 wt% of the crosslinking agent as BDDE with respect to the crosslinked hyaluronic acid (cHA) composition.

Before step (d), unmodified and non-crosslinked hyaluronic acid powder and P.B.S. and mixing lidocaine to make a linear hyaluronic acid mixture. Therefore, in step (d), the linear hyaluronic acid mixture is mixed with a hyaluronic acid composition having a twisted molecular structure and spherical particles.

The micronization is preferably cut into a cube of 3mm ³ to 10mm ³ of the hyaluronic acid composition. In addition, the diameter of the circular through-hole is preferably 60% to 80% of the particle diameter of the final product.

In addition, the step of gelling the cross-linked hyaluronic acid composition in an oven at 20° C. to 50° C. for 24 hours to 72 hours between steps (a) and (b) may be further included.

Another aspect of the present invention, a syringe for a filler, accommodates the filler therein and has an open top and a cylinder 110 on which a needle is mounted at the bottom; Handle 130 installed on the top of the cylinder 110; and a pusher 150 inserted and installed in the cylinder 130 .

The pusher 150 includes a rod 152 inserted into the cylinder 110; and a pressing unit 156 having an elliptical shape and horizontally coupled to the upper end of the rod 152 .

The pressing part 156 is curved upward toward both sides from the middle part so as to conform to the shape of the lower part of the thumb of the palm, and both ends 157 of the pressing part 156 are curved downward.

A circular protrusion 112 protruding laterally is formed on the upper end of the cylinder 110 , a groove 132 is formed by concave in the lateral direction in the central portion of the handle 130 , and a circular protrusion is formed on the inner circumferential surface of the groove 132 . A fastening groove 134 into which the protrusion 112 can be inserted is formed.

The diameter of the fastening recess 134 at the entrance of the groove 132 is smaller than the outer diameter of the circular protrusion 112, and the diameter of the fastening recess 134 on the inside of the groove 132 is such that the circular protrusion 112 can be seated. It is preferable to have the same size as the outer diameter of the circular protrusion 112 . Accordingly, when the circular projection 112 is inserted and fitted, the entrance of the fastening recess 134 is slightly opened in the lateral direction, and the circular projection 112 is inserted. In addition, the handle 130 may be rotated in a state in which the circular protrusion 112 is seated in the fastening groove 134 .

A chin 154 is formed at the lower end of the rod 152 , and a step 136 may be formed on the fastening recess 134 on the inner circumferential surface of the groove 132 . The jaw 154 is formed so that the lower end of the rod 152 protrudes in the lateral direction, and the step 136 is formed so that the upper surface of the pressing part 156 protrudes toward the center of the groove 132 . Accordingly, when the pusher 150 is retracted, the jaw 154 is caught on the step 136 , thereby restricting the reversing, and thus the pusher 150 is prevented from being separated from the cylinder 110 .

The filler according to the present invention has the following effects.

First, a filler that has both the advantages of a monophasic HA filler and a biphasic HA filler, that is, it is less likely to depart from the injected site, but it can maintain its shape for a long time and is injected into the Superficial Dermis or Middle Dermis of human skin to improve wrinkles and shape forming.

Second, even if a small amount of linear hyaluronic acid is included, it can be injected into the human body with a small extrusion force.

On the other hand, the syringe according to the present invention has the following effects.

First, since the pressing part of the pusher has an ergonomic structure that conforms to the palm, it is possible to prevent a palm injury by uniformly distributing the load applied to the palm when injecting the filler into the skin.

Second, when the pusher is retracted after the needle is pierced into the skin, it is possible to prevent the pusher from being separated from the syringe, and by reversing the pusher with the hand holding the syringe, it is possible to prevent the syringe from shaking, and thus the patient's pain can prevent

1 is a flow chart showing the process of manufacturing an HA filler according to a preferred embodiment of the present invention.
2 is a diagram showing the linear molecular structure of hyaluronic acid (cHA) cross-linked by a cross-linking agent.
3 is a view showing that cross-linked hyaluronic acid (cHA) having a linear molecular structure is converted into an entangled structure by a condensation process.
Figure 4 is a photograph showing a syringe for injecting the filler into the skin.
Figure 5 is an exploded perspective view showing the syringe of Figure 4;
Figure 6 is a perspective view showing a handle provided in the syringe of Figure 4;
Figure 7 is a front view showing a pusher provided in the syringe of Figure 4;
Figure 8 is a photograph of a state in which the syringe is gripped by hand for filler injection.
9 is a photograph of a hand grip for reversing the pusher.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings. Prior to this, the terms or words used in the present specification and claims should not be construed as being limited to conventional or dictionary meanings, and the inventor should properly understand the concept of the term in order to best describe his invention. Based on the principle that it can be defined, it should be interpreted as meaning and concept consistent with the technical idea of the present invention. Accordingly, the embodiments described in this specification and the configurations shown in the drawings are merely embodiments of the present invention and do not represent all the technical spirit of the present invention, so various equivalents that can be substituted for them at the time of the present application It should be understood that there may be variations and examples.

1 is a flow chart showing a process for manufacturing a filler according to a preferred embodiment of the present invention.

As shown in the figure, the filler manufacturing method according to the present invention includes the steps of preparing a cross-linked hyaluronic acid composition solution (S1), gelling the cross-linked hyaluronic acid composition solution (S2), and gelling the hyaluronic acid composition cutting into small sizes (S3), neutralizing the hyaluronic acid composition cut into small sizes (S4), removing impurities such as unreacted crosslinking agents from the neutralized hyaluronic acid composition (S5), Step (S6) of making the removed hyaluronic acid composition into spherical particles with a constant diameter (S6), condensing the particle size-controlled hyaluronic acid composition into an entangled structure (S7), linear hyaluronic acid (untreated and Preparing a linear hyaluronic acid mixture by mixing PBS (phosphate buffer saline) and anesthetic with non-cross-linked HA) (S8), sterilizing the cross-linked hyaluronic acid composition and linear hyaluronic acid mixture, respectively (S9), Mixing the linear hyaluronic acid mixture to the cross-linked hyaluronic acid composition (S10), and a step of defoaming (S11). Among the above steps, step S6 may be performed before step S7, but may also be performed after step S7.

Hereinafter, each step will be described in order.

(1) cross-linking (S1) and gelation (S2)

Polymer hyaluronic acid is placed in an aqueous alkali solution, and the hyaluronic acid is dispersed and linearized by first stirring, and then a cross-linking agent is added thereto, followed by second stirring to prepare a cross-linked hyaluronic acid solution. In the crosslinked hyaluronic acid (cHA) solution, it is preferable to mix 1.45 wt% to 4.3 wt% of polymer hyaluronic acid, and 1.45 wt% to 4.3 wt% of crosslinking agent as BDDE. More preferably, the polymeric hyaluronic acid is 2.5wt% to 3.5wt% and the crosslinking agent is 2.5wt% to 3.5wt% as BDDE.

It is preferable that the temperature of the reaction (the temperature of the aqueous alkali solution) is made at 30°C to 50°C.

In the present invention, the form of hyaluronic acid may be a physiologically acceptable salt of hyaluronic acid. For example, a hyaluronic acid metal salt, such as sodium salt or potassium salt, or a mixture thereof may be used, but is not necessarily limited thereto. Preferably, sodium salt (Sodium Hyaluronate) may be used.

And, depending on the pH of the aqueous alkali solution, the crosslinking rate of the composition may change and physical properties may change. Preferably, 0.1 to 0.2N NaOH is used. In addition, it is preferable that the average molecular weight of the hyaluronic acid (HA) used is approximately 1 million to 1.5 million Daltons.

Specifically, 6 g of hyaluronic acid (HA) having an average molecular weight of 1.1 million Daltons is added to 171.5 ml (172 g) of 0.1N NaOH, and the hyaluronic acid (HA) has a linear structure by first stirring. The first stirring is performed at 30° C. to 50° C. for 3 hours to 7 hours, preferably at 35° C. for 5 hours.

Then, the linear hyaluronic acid is crosslinked by adding a crosslinking agent to the mixture of hyaluronic acid and aqueous alkali solution to proceed with a crosslinking reaction. Specifically, 6 g of BDDE and 19.06 ml (15 g) of ethanol were mixed in a NaOH solution in which HA was dispersed, followed by secondary stirring to cross-link the hyaluronic acid (HA). The secondary stirring is performed at 30° C. to 50° C. for 38 hours to 58 hours, preferably at 35° C. for 45 hours to 50 hours.

The crosslinking agent is not limited as long as it can crosslink the polymer chain of hyaluronic acid by chemical bonding, for example, 1,3-butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadiene diepoxy alkyl diepoxy such as de; diglycidyl ethers such as ethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, and bisphenol A diglycidyl ether; divinyl sulfone; Epichlorhydrin and the like may be used. In the present invention, BDDE was used as a crosslinking agent.

Then, the cross-linked hyaluronic acid composition solution is placed in a dish, covered with a wrap, and then placed in an oven to gel. Specifically, the inside of the oven is maintained at 20° C. to 50° C., preferably at 30° C. for 24 hours to 72 hours, preferably 45 hours to gel.

(2) cleavage (S3) and neutralization reaction (S4)

After cutting the gelled hyaluronic acid composition into small sizes for refinement, it is neutralized by putting it in an acidic aqueous solution. Since the composition was cut into small sizes, the neutralization reaction in the acidic aqueous solution can be smoothly performed.

Specifically, using a cutter or the like, the gelled hyaluronic acid composition is cut into a cube of 3mm ³ to 10mm ³ (cube), preferably a cube of 5mm ³ . Then, the cut composition is neutralized by putting it in 171.5 ml (172 g) of 0.1N HCl aqueous solution.

(3) Wash (S5)

After the neutralization step, impurities included in the neutralized composition (unpurified cHA hydrogel), such as unreacted crosslinking agent (reacted BDDE), are removed.

Specifically, the neutralized composition is placed in a mesh container (made of stainless steel) and first purified and purified with 50% ethanol, followed by secondary purification and purification with deionized water (D.I. water).

The purified and purified hyaluronic acid composition is a bulk hydrogel, in which most of the unreacted crosslinking agent (BDDE) has been removed.

(4) Particle size adjustment (S6)

The purified and purified hyaluronic acid composition is made into spherical particles having a constant diameter.

Specifically, after placing the composition on a plate in which a circular through-hole of a certain diameter is formed, a pressure (approximately 7 to 20 bar) is applied to the composition to cause the composition to move downward through the circular through-hole, thereby spherical particles having a constant diameter. make it become A sieving machine for nitrogen may be used in this process.

The diameter of the circular through-hole may be determined in consideration of the final particle diameter (about 30 μm to 150 μm, preferably 50 μm to 100 μm) of the product (filler) to be manufactured. Specifically, the circular through-hole preferably has a diameter of 60% to 80% of the final particle diameter, and most preferably has a diameter of 70%. Since the purified/purified hyaluronic acid composition expands after passing through the circular through-holes, the circular through-holes are formed smaller than the particle diameter of the final product.

As described above, step S6 may be performed before step S7, but may also be performed after step S7.

On the other hand, in the past, filler particles were made by putting the purified and purified hyaluronic acid composition into an extrusion device and then extruding it through a narrow hole. couldn't

(5) Condensation (S7)

The content of cHA is 0.7 by condensing the particle size-controlled composition (cHA hydrogel, when step S6 is performed before step S7) or purified/purified hyaluronic acid composition (when step S6 is performed after step S7) wt% to 2.2 wt%, preferably 0.9 wt% to 2.0 wt%, so that the crosslinked hyaluronic acid molecules have an entangled structure with each other.

The spherical particles of the composition whose particle size is controlled have a linear molecular structure as shown in FIG. 2, and the linear molecular structure becomes an entangled structure due to a condensation process. As shown in FIG. 3, the twisted structure is a structure in which the linear molecular structure is twisted and mixed with each other. increase and increase resistance to deformation. Accordingly, the filler containing hyaluronic acid that has undergone the condensation process is advantageous because it can last longer in the human body. Therefore, when the same amount of crosslinking agent (BDDE) is used, the filler containing cHA (cross-linked hyaluronic acid) that has undergone the condensation process retains its shape for a longer time in the human body than the filler containing cHA that has not undergone the condensation process. can For reference, in FIGS. 2 and 3 , a yellow bar indicates cross-linking by a cross-linking agent, and a red circle indicates a portion having a twisted structure.

Specifically, the particle size-controlled composition (cHA) or the purified/purified hyaluronic acid composition is placed in a container of a stirrer and held at 30° C. to 70° C., preferably at 50° C., at 100 to 200 RPM for 48 to 72 hours. A part of the liquid component (eg, water, ethanol, etc.) in the composition is removed by stirring under a gauge pressure of -0.85 bar to -0.9 bar. For example, by removing 1600 g of the liquid component from 2000 g of the particle size-controlled composition (cHA hydrogel) or the purified/purified HA hydrogel to become 400 g, the molecular structure is twisted and the concentration of HA is increased.

In addition, P.B.S. may be added to the condensed cHA.

As described above, in the present invention, after making cHA using a crosslinking agent, the cHA is made into an entangled structure so that the duration in the human body is longer.

(6) Preparation of a mixture of linear hyaluronic acid (uncrosslinked unmodified hyaluronic acid) (S8)

A linear hyaluronic acid mixture to be mixed with the condensed cHA is prepared. Specifically, hyaluronic acid powder (HA powder) and P.B.S. And an anesthetic (preferably lidocaine) is mixed in a hot water container to prepare a mixture containing 0.7 wt% to 2.2 wt% of linear hyaluronic acid. As the hyaluronic acid powder (HA powder), the same hyaluronic acid used to prepare cHA may be used.

As described above, linear hyaluronic acid is an unmodified hyaluronic acid that is not cross-linked, and acts as a lubricant when injecting a filler into the human body using a syringe.

(7) sterilization (S9), mixing the linear hyaluronic acid mixture with the cross-linked hyaluronic acid composition (S10), and defoaming (S11)

The linear hyaluronic acid (linear HA) mixture made in the S8 process and the cross-linked hyaluronic acid (cHA) composition made in the S7 process are sterilized, respectively. Specifically, the linear hyaluronic acid mixture and the cross-linked hyaluronic acid composition are put in an autoclave, respectively, and sterilized by maintaining at 110 to 130° C. for about 20 to 40 minutes.

Then, the sterilized linear hyaluronic acid (linear HA) mixture and the cross-linked hyaluronic acid (cHA) composition are mixed, but in the total composition, hyaluronic acid (HA) is 0.7wt% to 2.2wt%, preferably 0.9wt% ~ 2.0 wt%.

At this time, the mixing ratio is 50 wt% to 90 wt% of the cross-linked hyaluronic acid (cHA) composition (composition sterilized after S6 or S7 process) and linear hyaluronic acid (composition sterilized after being made in S8 process) It is made to be 10wt% to 50wt%, preferably the cross-linked hyaluronic acid (cHA) composition is 50wt% to 70wt%, and the linear hyaluronic acid is 30wt% to 50wt%.

Then, after the mixing, after removing the air bubbles contained in the mixture, the syringe is filled (S11).

As such, the filler according to the present invention has an advantage in that the content of linear hyaluronic acid is smaller than that of other fillers and the content of cross-linked hyaluronic acid is high, so the duration in the human body is longer. In addition, since the cross-linked HA has a twisted structure through the condensation process, there is an advantage that the duration in the human body is longer even if the content of the cross-linking agent is low.

In addition, since the cross-linked hyaluronic acid is spherical particles in the filler according to the present invention, compared to other products made of cubic particles, even if the content of linear hyaluronic acid is small, the same or lower extrusion force It can be injected into the body. Since the content of linear hyaluronic acid can be lowered and the ratio of cross-linked hyaluronic acid can be increased, the shape can be maintained in the human body longer than other products.

The composition ratio of the filler made in this way is based on 100 parts by weight of water for injection (WFI) contained in the filler, hyaluronic acid (sum of cross-linked HA and linear HA) 0.9 to 2.5 parts by weight (preferably 1.1 to 2.3 parts by weight), 0.2 to 0.5 parts by weight of an anesthetic such as lidocaine hydrochloride, and PBS 5 to 15 parts by weight. Among the hyaluronic acids, the cross-linked hyaluronic acid (composition sterilized after cHA, S6 or S7 process) is 50 wt% to 90 wt%, and linear hyaluronic acid (linear HA, sterilized composition made by S8 process) This is 10wt% to 50wt%, preferably the cross-linked hyaluronic acid (cHA) is 50wt% to 70wt% and the linear hyaluronic acid (linear HA) is 30wt% to 50wt%. And, the non-crosslinked BDDE relative to the filler weight is less than 1 ppm. In addition, when measured with a rheometer, G' (dynamic modulus) of the filler at 1 Hz is 15-30 Pa (preferably 22 Pa), G'' (loss modulus) is 20-40 Pa (preferably 30.4 Pa), and the viscosity ( Viscosity is 5000-7000 cP (preferably 5999 cP).

If the content of the linear HA is less than 10 wt%, there is a problem in that an excessively large extrusion force is required when injecting the filler with a syringe. And, when the content of the linear HA exceeds 50 wt%, the extrusion force is too low, the filler is continuously pushed out little by little from the syringe even under one pressure load, and it is not preferable because the elastic modulus after sterilization is too low.

On the other hand, in the filler, the crosslinked particles of hyaluronic acid are spherical in shape and have a diameter of 30 μm to 150 μm, preferably, the sphere diameter is 50 μm to 100 μm.

If the diameter is less than 30 μm, it is not preferable because fat cells surround the filler and engulf it when injected into the skin. And, when the diameter exceeds 150 μm, it is not preferable because a lump is generated on the skin surface when injected into the Superficial Dermis or Middle Dermis of the skin.

Hereinafter, examples and experimental examples will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

[Example 1]

6 g of hyaluronic acid (HA) having an average molecular weight of 1.1 million daltons was added to 171.5 ml (172 g) of 0.1N NaOH aqueous solution, followed by primary stirring to obtain an aqueous solution of linear hyaluronic acid (HA). Then, 6 g of BDDE and 19.06 ml (15 g) of ethanol were mixed with the hyaluronic acid and NaOH solution, and the hyaluronic acid (HA) was cross-linked by second stirring. The above procedures were carried out at 35° C., the first stirring was performed for 5 hours, and the second stirring was performed for 48 hours.

Then, the cross-linked HA composition solution was placed in an oven at 30° C. for 45 hours to gel, and then cut into a cube (cube) of 5 mm ³ . Next, the cut gel was neutralized by putting it in 171.5 ml (172 g) of 0.1N HCl, and after primary purification and purification of the neutralized gel with 50% ethanol, secondary purification and purification with deionized water (DI water) Almost all unreacted BDDE is removed.

The purified/purified gel is placed on a plate having a circular through-hole having a diameter of 35 μm and a pressure (12 bar) is applied to allow the gel to pass through the circular through-hole. The gel passing through the circular through-hole becomes spherical particles having a constant diameter.

Then, a gel consisting of spherical particles of a certain diameter is put in a container and stirred under a pressure of -0.85 bar to -0.9 bar for 48 to 72 hours at 150 R.PM at 50° C. to remove a part of the liquid component contained in the gel. condensed. Specifically, 1,600 g of the liquid component in 2,000 g of the particle size-controlled gel is removed and condensed. By this condensation process, HA becomes an entangled structure from a linear structure.

On the other hand, linear HA powder (untreated and uncrosslinked HA) and P.B.S. and lidocaine to make a mixture containing 1.5 wt% of linear HA, sterilize the linear HA mixture and the condensed mixture, respectively, and mix in a weight ratio of 70 (condensed mixture):30 (linear HA mixture) . Then, the air bubbles contained in the mixture are removed and the syringe is filled.

The composition ratio of the filler made by this process, based on 100 parts by weight of water for injection (WFI) contained in the filler, 1.7 parts by weight of hyaluronic acid (the sum of cross-linked HA and linear HA), 0.3 parts by weight of lidocaine and, PBS 11 parts by weight. And, the weight ratio of the condensed mixture and the linear HA mixture is 70:30, and the diameter of the spherical particles is 70 μm.

[Example 2]

It is the same as in Example 1 except that the condensation step (S7) is not performed.

[Example 3]

The same as in Example 1, except that the diameter of the spherical particles in the final product was 30 μm.

[Example 4]

The same as in Example 1 except that the diameter of the spherical particles in the final product was 150 μm.

[Example 5]

The same as in Example 1, except that the weight ratio of the condensed mixture to the linear HA mixture in the final product was 90 (condensed mixture):10 (linear HA mixture).

[Example 6]

The same as in Example 1, except that the weight ratio of the condensed mixture to the linear HA mixture in the final product was 50 (condensed mixture):50 (linear HA mixture).

[Comparative Example 1]

The same as in Example 1 except that the diameter of the spherical particles in the final product was 20 μm.

[Comparative Example 2]

The same as in Example 1, except that the diameter of the spherical particles in the final product was 160 μm.

[Comparative Example 3]

The same as in Example 1, except that the weight ratio of the condensed mixture to the linear HA mixture in the final product was 95 (condensed mixture):5 (linear HA mixture).

[Comparative Example 4]

The same as in Example 1, except that the weight ratio of the condensed mixture to the linear HA mixture in the final product was 40 (condensed mixture):60 (linear HA mixture).

[Comparative Example 5]

The cross-linked hyaluronic acid (cHA) gel made in the condensation process was passed by applying pressure to a plate with a 'square' through hole, so that the final product became cubic particles with a side length of 40.3 μm. Except for this point, Comparative Example 5 is the same as Example 1.

On the other hand, the volume of the cube particle having a side length of 40.3 μm is the same as the volume of the spherical particle (diameter 50 μm) of Example 1.

[Experimental Example 1]

In order to improve nasolabial folds, after injecting the fillers of Examples 1 to 4 and Comparative Examples 1 and 2 into Superficial Dermis, the severity of wrinkles (WSRS average value, Wrinkle Severity Rating Scale) was measured and the The results are shown in [Table 1].

[Table 1]

As shown in [Table 1], it can be seen that the effects of Examples 1 to 4 are maintained until 6 months after the procedure.

Specifically, it can be seen that Example 2, which was not subjected to the condensation process, had a slightly lower wrinkle improvement effect than Example 1 at 4 to 6 months after the procedure, but was superior to that of Comparative Example 1.

In addition, it can be seen that the wrinkle improvement effect of Example 3 (diameter of spherical particles: 30 μm) and Example 4 (diameter of spherical particles of 150 μm) is almost similar to that of Example 1.

In comparison, Comparative Example 1 (diameter of spherical particles 20 μm) showed that the wrinkle improvement effect was similar to Examples 1 to 4 and Comparative Example 1 at 2 months after the procedure, but the wrinkle improvement effect was significantly reduced from 4 months after the procedure Able to know. This is thought to be because the filler particles are surrounded by fat cells and are engulfed.

And, Comparative Example 2 (diameter of spherical particles 160 μm) had a wrinkle improvement effect similar to Examples 1 to 4, but when injected into Superficial Dermis, a lump was generated on the skin surface, and thus the appearance was not good. In addition, in Comparative Example 2, it was observed that the filler was moved from the injected place, which is considered to be due to the lack of viscosity.

[Experimental Example 2]

Extrusion force (extrusion pressure, extrusion force) was measured for the fillers of Examples 1, 5, 6, and Comparative Examples 3-5, and the results are summarized in [Table 2]. The extrusion force was measured up to 6 mm at a constant speed of 2 mm/min using EZ-S SHIMADZU equipment with a 28-gauge needle mounted on a syringe.

[Table 2]

As shown in [Table 2], it can be seen that in Examples 1, 5, and 6, the protrusion pressure is within an appropriate range.

On the other hand, in Comparative Example 3, the content (5 wt%) of the linear HA is too small, so it can be seen that the pressure required for injection using a syringe is too large. In this case, there is a risk that a wound may occur on the palm that presses the syringe.

And, in Comparative Example 4, since the content (60wt%) of the linear HA serving as a lubricant when injected into a syringe was too large, there was a problem in that the filler continued to flow even after the pressure on the syringe was removed.

In Comparative Example 5, the filler particles have a cube shape, but it can be seen that the protruding pressure is too large. In this case, similarly to Comparative Example 3, there is a fear that a wound may occur on the palm that presses the syringe.

syringe for filler

The filler described above is injected into the skin using a syringe. Unlike a typical syringe, this filler syringe holds the syringe with the right hand and pricks the skin with a needle, then presses the top of the syringe with the palm of the hand.

4 is a photograph showing a syringe for filler, and FIG. 5 is an exploded perspective view of the syringe.

As shown in the drawing, the syringe 100 includes a cylinder 110 , a handle 130 installed on the upper end of the cylinder 110 , and a pusher 150 inserted and installed in the cylinder 110 . The syringe 100 may be made of a synthetic resin made of a transparent material except for the packing material 153 and the stopper 120 .

The cylinder 110 accommodates a filler (not shown in the drawing) therein. An injection needle (not shown) is mounted on the lower end of the cylinder 110, and the upper end of the cylinder 110 is opened so that the pusher 150 can be inserted. Although the drawing shows that the stopper 120 is installed at the bottom of the cylinder, this is to prevent leakage and contamination of the filler during product manufacturing and distribution, and during the procedure, the stopper 120 is removed and then the injection needle is mounted. The stopper 120 may be coupled to the lower end of the cylinder 110 by screwing.

A circular protrusion 112 is formed around the upper end of the cylinder 110 . The circular protrusion 112 is formed to protrude laterally around the upper end. The circular protrusion 112 is inserted and fitted into the fastening groove 134 of the handle 130 .

6, the handle 130 is formed in an elliptical shape. The handle 130 is a part on which the index and middle fingers are mounted during filler injection. Specifically, as shown in FIG. 8 , when injecting the filler, the pusher 150 is pushed down by pressing the pressing part 156 with the palm of the hand in a state where the index finger is caught on one side of the handle 130 and the middle finger is caught on the other side. move it

The handle 130 preferably has a structure that is slightly curved downward toward both ends thereof. This structure prevents the index and middle fingers from being separated from the handle 130 when the pressing part 156 is pressed with the palm for filler injection. can do.

In the central portion of the handle 130, a groove 132 is formed by concave in the lateral direction. In addition, a fastening groove 134 and a step 136 are formed on the inner circumferential surface of the groove 132 .

At the entrance of the groove 132, the diameter of the fastening recess 134 is slightly smaller than the outer diameter of the circular protrusion 112, and the diameter of the fastening recess 134 on the inside of the groove 132 is such that the circular protrusion 112 can be seated. It has the same size as the outer diameter of the circular protrusion 112 . Accordingly, when the circular protrusion 112 is inserted and fitted, the entrance of the fastening groove 134 is slightly opened in the lateral direction, and the circular protrusion 112 is inserted, and once the circular protrusion 112 is seated in the fastening recess 134 . After this, the circular protrusion 112 does not deviate from the fastening recess 134 unless an external force is artificially applied laterally. In addition, the handle 130 is rotatable in a state in which the circular protrusion 112 is seated in the fastening groove 134 .

Step 136 is formed on the fastening groove 134 on the inner peripheral surface of the groove (132). Specifically, the step 136 is formed so that the upper surface of the handle 130 slightly protrudes toward the center of the groove 132 .

The step 136 is a portion to which the jaw 154 is caught when the pusher 150 moves backward, and the pusher 150 is restricted from moving backward by the step 136 and the jaw 154 , and accordingly, the pusher 150 ) is prevented from being separated from the cylinder 110 .

The pusher 150 includes a rod 152 and a pressing part 156 coupled to the upper end of the rod 152 .

The rod 152 is inserted into the inner space of the cylinder 110 . The rod 152 moves in the longitudinal direction of the cylinder 110 while being inserted into the inner space so that the filler is discharged to the outside through an injection needle (not shown in the drawing).

A jaw 154 is formed at the lower end of the rod 152 , and a packing material 153 is installed below the jaw 154 . The packing material 153 serves to seal between the inner peripheral surface of the cylinder 110 and the rod 153 . And, the chin 154 is formed by protruding the lower end of the rod 152 in the lateral direction, and the step 136 is formed so that the upper surface of the pressing part 156 protrudes toward the center of the groove 132 . Accordingly, when the pusher 150 is retracted, the jaw 154 is caught on the step 136 , and the pusher 150 is prevented from being separated from the cylinder 110 .

The pressing part 156 is a part that is pressed with the palm of the hand when the filler is injected into the skin. The pressing part 156 is formed in an elliptical shape, and has a structure that matches the shape of the palm. Specifically, as shown in FIG. 7 , the pressing part 156 is curved upward toward both sides from the center part, and both ends 157 of the pressing part 156 are curved downward.

The structure curved upward toward both sides from the center of the pressing part 156 matches the lower part of the thumb among the palms. Accordingly, when the pressing part 156 is pressed with the palm part, the entire upper surface of the pressing part 156 is in close contact with the palm, so that the load can be evenly distributed, thereby preventing palm injury. On the other hand, the conventional filler syringe has a circular pressing part, which has a problem that the circular pressing part often causes a palm injury.

Meanwhile, both ends 157 of the pressing part 156 have a downwardly curved structure. With this structure, the pusher 150 can be moved backward with the thumb.

After the injection needle is pierced into the skin for filler injection, the pusher 150 is slightly moved backward to determine whether the injection needle has pierced the blood vessel to test whether blood is discharged into the syringe. In the past, the user (doctor) pulled back the pusher 150 with his left hand while holding the syringe with his right hand, and in this case, there was a problem that the syringe vibrated a lot and the patient felt great pain.

In order to solve this problem, the present applicant bends both ends 157 of the pressing part 150 downward, and as shown in FIG. 9, the thumb of the right hand (hand holding the syringe) is caught on the curved part Thus, the pusher 150 could be moved backward. At this time, the structure in which both ends 157 of the pressing part 150 are bent downward prevents the thumb from sliding.

Claims (5)

A water-containing biphasic filler comprising:
Based on 100 parts by weight of water contained in the filler,
1.1 to 2.3 parts by weight of hyaluronic acid; and,
0.2 to 0.5 parts by weight of an anesthetic agent; it is a composition in a gel state,
Among the hyaluronic acid, 50 wt% to 90 wt% of hyaluronic acid that has undergone a crosslinking process using a crosslinking agent is 10 wt% to 50 wt% of untreated and non-crosslinked linear hyaluronic acid,
The cross-linked particles of hyaluronic acid are spherical in shape and have a diameter of 50 μm to 100 μm,
HA filler, characterized in that at 1 Hz when measured with a rheometer, the viscosity (viscosity) is 5000 cP ~ 7000 cP, G' (dynamic modulus) is 15 Pa ~ 30 Pa, and G'' (loss modulus) is 20 Pa ~ 40 Pa. delete The method of claim 1,
Further comprising 5 to 15 parts by weight of PBS,
The cross-linked hyaluronic acid has an entangled molecular structure,
the anesthetic agent is lidocaine, the crosslinking agent is BDDE,
HA filler, characterized in that it contributes to wrinkle improvement and shape formation by being injected into the Superficial Dermis or Middle Dermis of human skin. A method for producing a biphasic HA filler containing water,
(a) preparing a cross-linked hyaluronic acid (cHA) composition by adding a crosslinking agent to the polymer hyaluronic acid in an aqueous alkali solution and stirring;
(b) after cutting the hyaluronic acid composition to be refined, neutralizing it by putting it in an acidic aqueous solution;
(c) placing the neutralized composition on a plate in which the circular through-holes are formed and then applying pressure to the composition to make the composition move downward through the circular through-holes to form spherical particles having a constant diameter;
(d) mixing the unmodified and non-crosslinked linear hyaluronic acid with the composition that has undergone step (c) so that the hyaluronic acid is 0.7wt% to 2.2wt% of the total composition;
The mixing ratio of step (d) is 50 wt% to 90 wt% of the composition that has undergone step (c), and 10 wt% to 50 wt% of unmodified and uncrosslinked linear hyaluronic acid,
The diameter of the particles in the final product is 50 μm to 100 μm,
Based on 100 parts by weight of water included in the filler, which is the final product, the gel composition,
1.1 to 2.3 parts by weight of hyaluronic acid; and,
0.2 to 0.5 parts by weight of an anesthetic agent;
When the final product, the filler, is measured with a rheometer, the viscosity at 1 Hz is 5000 cP to 7000 cP, G' (dynamic modulus) is 15 Pa to 30 Pa, and G' (loss modulus) is 20 Pa to 40 Pa. Way.

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