KR100501225B1 - Monomer extracted polyacrylamide and preparation method thereof - Google Patents

Abstract

The present invention relates to a polyacrylamide having a monomer acrylamide present in the polyacrylamide removed so as to be contained in an amount of 0.5 µg / g or less with respect to the polyacrylamide, a manufacturing method thereof, and a composition comprising the polyacrylamide. Polyacrylamide and the polyacrylamide which has not been reacted in the polyacrylamide gel obtained by chemically polymerizing the acrylamide in the monomer form with the bisacrylamide and the acrylamide which is harmful to the human body are removed by chemical reaction and / or centrifugation. It relates to a manufacturing method thereof. The present invention also relates to a composition for use as a prosthesis and ocular vitreous substitute used in human tissue augmentation procedures including facial wrinkle removal, contour correction, breast augmentation or genital augmentation comprising the polyacrylamide.

Description

Monomer removed polyacrylamide and preparation method thereof

The present invention relates to a polyacrylamide obtained by removing monomer acrylamide present in polyacrylamide so as to be contained in an amount of 0.5 µg / g or less with respect to polyacrylamide, a preparation method thereof, and a pharmaceutical composition comprising the gel. Polyacrylamide and the polyacrylamide which has not been reacted in the polyacrylamide gel obtained by chemically polymerizing the acrylamide in the monomer form with the bisacrylamide and the acrylamide which is harmful to the human body are removed by chemical reaction and / or centrifugation. It relates to a manufacturing method thereof. The present invention also relates to a composition for use as a prosthesis and ocular vitreous substitute used in human tissue augmentation procedures including facial wrinkle removal, contour correction, breast augmentation or genital augmentation comprising the polyacrylamide.

Polyacrylamide gel is a polymer obtained by chemically polymerizing acrylamide in monomer form with bisacrylamide and has a web like structure in three dimensions. Polyacrylamide gels are known to be harmless to biological tissues, but monomer acrylamides that remain unreacted after polymerization may cause neurological and muscular impairments, and are not only irritative to the skin, but also at high concentrations. Is a harmful substance known to cause cancer. The polyacrylamide gel is generally used for electrophoresis to analyze proteins and nucleic acids. Recently, research has been attempted to apply polyacrylamide gel, which has been used only for electrophoresis, for other purposes.

In Ukraine, research on using the polyacrylamide gel as a prosthesis for shaping the human body is underway, and it is directly injected and applied. However, in the application of polyacrylamide gels in Ukraine, cases have been reported that have been killed by direct injection without removing harmful monomers. In China, polyacrylamide gel is directly injected and applied to plastic surgery. However, the monomers harmful to the human body are not sufficiently removed to be safe for the human body.

Therefore, in order to apply the polyacrylamide gel as a molding prosthesis, it is important to remove the monomer present in the polyacrylamide gel to a concentration less than harmless to the human body.

Many countries already regulate the amount of acrylamide, which is 0.2 to 0.05% for factories and less than 0.05% for drinking water. In the case of drinking water, the daily intake per person is regulated to 0.05 μg / kg or less. There is no standard for monomer acrylamide concentrations in polyacrylamide gels used for implantation or insertion in humans. In 1993, Karajenco reported that more than 385 mg of monomer per kilogram of body weight was lethal. In many countries, up to 0.05μg / kg body weight has been defined as a daily intake.

Therefore, the present inventors can safely inject it directly into the human body if it is possible to manufacture a polyacrylamide in which the concentration of the monomer acrylamide present in the polyacrylamide is 0.5 μg / g or less with respect to the polyacrylamide, The present invention can be applied to a cosmetic product, such as a breast surgery bag, to develop a landmark implant in a plastic surgery.

The present invention has been made to solve the above problems of the prior art, an object of the present invention is to remove the polyacrylamide monomer contained in the polyacrylamide so as to include less than 0.5㎛ / g with respect to the polyacrylamide And to provide a method for producing the composition and the same.

The present invention is a polyacrylamide produced by polymerizing acrylamide and bisacrylamide, wherein the monomer acrylamide present in the polyacrylamide is 0.5 μg / g or less, preferably 0.25 μg / g or less with respect to the polyacrylamide. Polyacrylamide removed to be included in the furnace is provided.

The polyacrylamide of the present invention is preferably in the form of a gel or powder, and may be prepared in a gel of 1 to 30% by weight by adding a common solvent, such as water, to the polyacrylamide in a powder state.

Moreover, this invention provides the polyacrylamide which adjusted the intensity | strength superposed | polymerized by making the weight ratio of acrylamide and bisacrylamide into 1-20: 0.001-2.

The present invention also provides a method for preparing a polyacrylamide gel by polymerizing acrylamide and bisacrylamide, and removing monomer acrylamide present in the gel by organic solvent extraction, centrifugation or pressing.

In another aspect, the present invention is a method for extracting and removing monomer acrylamide comprising at least one step of putting the C _1-4 alcohol into the prepared polyacrylamide gel, crushing the gel, and removing the C _1-4 alcohol into a powder. To provide. In addition, the method of the present invention preferably further comprises the step of removing the unreacted acrylamide first by cutting the polyacrylamide gel and adding water and shaking before the process, further comprising the step of centrifuging after the process It is desirable to.

More preferably, the method of the present invention comprises a first step of cutting the polyacrylamide gel to add water and shaking to first remove unreacted acrylamide; A second step of putting C _1-4 alcohol into the polyacrylamide gel, crushing the gel, and removing C _1-4 alcohol into a powder; After re-gel converting the polyacrylamide powder, the collecting gel is precipitated by the addition to the C _1-4 alcohol in the converted gel and added to a C _1-4 alcohol in the gel is collected and re-crushed, and C ₁ A third step of removing the _-4 alcohol to a powder, and then distilled water to convert it into a gel; A fourth step of centrifuging the gel; And a fifth step of putting C _1-4 alcohol in the obtained gel, crushing the gel, and removing C _1-4 alcohol to make a powder.

As described above, the polyacrylamide gel of the present invention can control the viscosity, strength, and elasticity in various ways. The first method is to control the concentration of acrylamide. Increasing acrylamide at the same concentration of bisacrylamide increases elasticity and strength and lowers viscosity. The second method is to control the viscosity, strength and elasticity by adjusting the concentration of bisacrylamide at the same acrylamide concentration. In addition, the polyacrylamide gel of the present invention is different from the existing polyacrylamide gel, so that the polymer can be made into a powder rather than a gel state, and thus the viscosity, elasticity and strength can be controlled by varying the amount of water to be dissolved. Due to the nature of the polyacrylamide of the present invention, gels of various types can be made to suit the characteristics of the tissue to be implanted or inserted.

In another aspect, the present invention provides a composition for removing wrinkles, contour correction, genital enlargement or tissue enlargement of the human body comprising a polyacrylamide gel.

In another aspect, the present invention provides a plastic surgery breast bag comprising the monomer-removed polyacrylamide gel.

In another aspect, the present invention is a method of directly injecting the monomer-removed polyacrylamide gel to the human body and the empty breast bag is injected into the human body, a method of injecting a monomer-removed polyacrylamide and a breast gel injected with a thick gel is injected into the human body And it provides a method of adjusting the volume with saline.

Conventional breast bags have two types of products, one of which is an empty silicone bag, in which case the bag is inserted into the chest and saline is injected from the outside through the port. This product is easy to process but has a bad side and many side effects when it is broken. The other type is a prefilled bag that has 50% dextrose or liquid silicone pre-filled in a portless silicone bag, which is bulky and difficult to insert during surgery and is not easy to remove if burst. It has several side effects.

Polyacrylamide of the present invention is a product made by separating only a polymer into a fine powder form in a conventional polyacrylamide gel. This property allows the polyacrylamide of the present invention to have different characteristics from the existing polyacrylamide gel in the form of liquid gel, thereby enabling various types of breast bags as described above. In addition, since the polyacrylamide gel of the present invention is a gel obtained by absorbing water of a small particle polymer, it is easier to insert by injection than a liquid gel of the same concentration. That is, the conventional liquid polyacrylamide gel is too viscous to be almost impossible to be injected from the outside, but the polyacrylamide gel of the present invention can be injected from the outside even at a high concentration with excellent touch. This feature makes breast augmentation easier by inserting the bag into the chest and injecting it from the outside using a pot like a saline bag. In addition, the existing polyacrylamide gel absorbs a certain amount of water and no longer absorbs water, but the polyacrylamide in the form of particles of the polyacrylamide of the present invention has a strong hydrophilic property and thus absorbs a much larger amount of water. After the polyacrylamide inherent characteristics of the polyacrylamide gel (concentrated form of 10 times or more) of the present invention in a silicon bag, a collapsed silicone bag (collapsed sillicon bag) was made and treated on the patient's chest. In addition, by injecting an appropriate amount of saline from the outside, it is possible to form a new silicon bag that can be performed breast augmentation.

For example, the concentration of the monomer in the polyacrylamide gel (1%) of the present invention is 5 µg / kg of the gel solution, and when used in a breast bag, the concentration of the actual acrylamide monomer is 2.5 µg based on 500 ml per person. It is as follows. These concentrations mean that when the silicone bag bursts, in the worst case, all polyacrylamide is exposed to the human body less than the daily intake limit (0.05 µg per kg, 3 µg on a 60 kg basis), even if exposed to the human body per day. do. When used as a wrinkle remover, since several tens of ml of polyacrylamide is used, the amount of acrylamide monomer is actually only several tens of ng. Therefore, the polyacrylamide of the present invention is harmless to the human body.

Hereinafter, the present invention will be described in detail with an example of a manufacturing method.

An appropriate amount of acrylamide and bis-acrylamide are dissolved in tertiary distilled water to prepare a polyacrylamide solution, and then, an appropriate amount of ammonium persulfate and TEMED are added, followed by filtering to form a polyacrylamide gel. The polyacrylamide gel prepared above is cut out, distilled water is added, and shaking to roughly remove unreacted acrylamide monomer. It is preferable to repeat operation which adds distilled water and shakes several times. C _1-4 alcohols such as methanol, ethanol, propanol, and the like are added to the polyacrylamide gel, and the gel is pulverized with a conventional crusher (eg, a mixer), and C _1-4 alcohol is removed to obtain a powder. The operation of adding and crushing the C _1-4 alcohol can be repeated several times. Thereafter, for example, sodium sulfite (Na ₂ SO ₃ ) is poured into the polyacrylamide powder, and the mixture is mixed and converted back into a gel. The gel was added to C _1-4 alcohol, and the precipitated gel was collected by filtration with a gauze towel or the like, the precipitated gel was added to C _1-4 alcohol, crushed again, and the C _1-4 alcohol was removed to obtain a powder. Then, distilled water is poured again into a gel. This operation is preferably repeated several times. The gel is centrifuged, C _1-4 alcohol is added to the obtained gel, the gel is crushed by a conventional crusher, and C _1-4 alcohol is removed to prepare polyacrylamide of the present invention in powder form. This operation is preferably repeated several times.

In addition, the saline solution is put in the powdered polyacrylamide of the present invention to obtain a polyacrylamide gel of the present invention.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are intended to illustrate the present invention, but are not limited thereto.

Example 1

Preparation of Monomer Removed Polyacrylamide

17.5 g of acrylamide and 0.25 g of bis-acrylamide were dissolved in tertiary distilled water to form a 100 ml solution (17.5% concentrate). 400 ml of tertiary distilled water was added to the concentrate to form a 3.5% (final concentration) acrylamide solution, followed by 2 ml of ammonium persulfate (10%) and 0.4 ml of TEMED, followed by filter paper (pore size 0.22). Filtered at and left at room temperature for 2 hours to make a polyacrylamide gel. The prepared gel was cut to a suitable size (3 cm or more in diameter) and reacted with 10 L distilled water by shaking for 4 hours. Then, the distilled water was removed, and fresh distilled water was added and reacted by shaking for 4 hours. This was repeated three times to roughly remove unreacted acrylamide. The resulting gel was placed in a mixer, 1500 ml of methyl alcohol (95% or more) was poured and mixed well, and then finely ground at 40 ° C. for 30 minutes. The finely ground gel was filtered to remove alcohol. 1500 ml methyl alcohol was poured into the gel again, and finely pulverized at 40 ° C. for 1 hour using a mixer, followed by filtering to remove alcohol. After repeating the above procedure to confirm that the gel was completely powdered, 500 ml of 50 mM sodium sulfite (Na ₂ SO ₃ ) was poured and mixed well, and then converted into a gel form. The gel was reacted at room temperature for 2 hours. 1,000 mL of methyl alcohol was poured into the reacted gel, and the precipitated gel was collected by filtering with a gauze towel. Pour 1,500 ml of alcohol into the precipitated gel, chop it for 1 hour at 40 ° C with a mixer, then cool the gel and remove the alcohol by filtering, making the gel completely powdered, and then pouring 500 ml of tertiary distilled water Mix well until converted to gel form. The resulting gel is centrifuged at 10,000 rpm for 1 hour to remove the unsettled solution to collect only the gel. The gel thus obtained was further centrifuged at 40,000 rpm for 1 hour to remove the solution floating thereon, and only the gel was collected. 500 ml of ethyl alcohol was added to the gel thus obtained, pulverized with a mixer at 40 ° C. for 30 minutes, powdered, and filtered to remove alcohol. The obtained powder was dried in a hot oven (80 ° C.) for at least 2 hours to prepare polyacrylamide of the present invention. In addition, 500 mL of saline solution was poured into the polyacrylamide, and the mixture was well mixed to prepare a polyacrylamide gel of the present invention. The final polyacrylamide gel can be used at a final concentration of 1-30% depending on the application.

Example 2

Preparation of Monomer Removed Polyacrylamide 2

Polyacrylamide gel was prepared as in Example 1. The prepared gel was cut to a suitable size (3 cm or more in diameter) and reacted with 10 L distilled water by shaking for 4 hours. Then, the distilled water was removed, and fresh distilled water was added and reacted by shaking for 4 hours. This was repeated four times to roughly remove unreacted acrylamide. The gel was placed in a mixer and poured into 2,000 ml methyl alcohol (95% or more), mixed well, and finely chopped at 40 degrees for 1 hour. The finely ground gel was filtered to remove alcohol. Pour 1,500 ml of methyl alcohol back into the gel, finely chopped at 40 ° C. for 1 hour using a mixer, and then filter to remove alcohol. After confirming that the gel was completely powdered, 500 ml of 50 mM sodium sulfite (Na ₂ SO ₃ ) was poured, mixed well, and converted into a gel form. The gel was reacted at room temperature for 1 hour. 1000 mL of methyl alcohol was poured into the reacted gel, and the precipitated gel was collected by filtration with a gauze towel. 1500 ml of alcohol was poured into the precipitated gel, and the mixture was finely chopped at 40 ° C. for 1 hour, and the gel was allowed to settle and filtered to remove alcohol. After the gel was completely formed in powder form, 500 ml of tertiary distilled water was poured and mixed well until the powder was completely converted into gel form. Centrifuge the resulting gel at 15,000 rpm for 1 hour to remove the unsettled solution and collect only the gel. The gel thus obtained was further centrifuged at 50,000 rpm for 45 minutes to remove the supernatant solution and only the gel was collected. 500 ml of ethyl alcohol was added to the gel thus obtained, pulverized with a mixer at 40 ° C. for 30 minutes, powdered, and filtered to remove alcohol. The obtained powder was dried in a hot oven (100 ° C.) for at least 2 hours to prepare polyacrylamide of the present invention.

In addition, 500 mL of a saline solution was poured into the polyacrylamide, and then mixed well to prepare a polyacrylamide gel of the present invention.

Experimental Example 1

Measurement of Amount and Durability of Monomer in Polyacrylamide Gel of the Present Invention

40 ml of alcohol was added to 10 ml of polyacrylamide gel of Example 1, and extracted at 40 ° C. for 1 hour (1), 10 ml of polyacrylamide gel of Example 1 was boiled for 30 minutes to evaporate water (2), and also Example 10 ml of polyacrylamide gel of 1 was stored at 37 ° C. for 6 months (3) and the monomer concentration was measured by HPLC method, and the solidified gel was dried and weighed to investigate the durability of the gel. 1 is shown.

Amount of Monomer (µg / g) Amount of polymer (g ± S.D.) Experiment (1) 0.46 μg 0.35 g ± 0.016 Experiment (2) 0.36 μg 0.036g ± 0.02

Experiment (3) 0.23 µg 0.035 g

As described above, the amount of monomer present in the polyacrylamide gel of the present invention was found to be 0.5 µg / g or less relative to the polyacrylamide. In addition, the polyacrylamide gel of the present invention shows that the properties of the polymer are maintained as it is even at the boiling temperature of water, and also the amount of the polymer and the monomer in the polyacrylamide gel of the present invention which is stored and boiled at 37 ° C. for 6 months. This same result shows that the polyacrylamide of the present invention is a physically very stable polymer.

Example 3

Control of Viscosity, Elasticity, and Strength of the Polyacrylamide Gel of the Present Invention

(1) A polyacrylamide gel was prepared in the same manner as in Example 1 by adding 20 g (4%) and 30 g (6%) of acrylamide to 0.25 g of bis-acrylamide. The gel was measured using BOHLIN Vico88 BV to measure changes in viscosity and shear stress while increasing shear rate and analyzed using the Viscosoft Viscometry Software Version3.0 program. 4 is shown.

As shown in FIG. 4, when the concentration of bis-acryl is fixed and the concentration of acryl is increased, the yield value is very low when the gel is 6% than 4%, and the shear stress is increased. It is guessed by the result which the molecular weight increased. These results indicate that the elasticity and strength increase slightly with increasing acrylic concentration at low shear rate. On the other hand, viscosity decreases in inverse proportion to acryl concentration.

(2) 2.5 g (0.05%) and 10 g (2%) of bisacrylamide was added to 30 g (6%) of acrylamide to prepare a polyacrylamide gel as in Example 1. In the same manner as the test, the results are shown in FIG.

As shown in Figure 5, increasing the concentration of bis-acryl at a constant condition of acryl did not change in viscosity, but it was found that the shear stress was increased in a state of high shear rate. This result means that the elasticity and strength increase significantly with increasing bis-acryl concentration under high contact pressure (there is little difference at low shear speed). On the other hand, unlike the results of (1), the viscosity hardly changed.

According to the amount of acrylamide, bis-acrylamide and water added as described above it is possible to control the viscosity, elasticity, strength, it is possible to make a variety of gels to suit the characteristics of the tissue to be implanted or inserted.

Example 4

Preparation of Breast Bag Using Polyacrylamide of the Present Invention

The breast bag of the present invention was prepared by putting 100, 200, and 300 ml of the polyacrylamide gel (3% by weight) of Example 1 into a conventional silicone bag, and the polyacrylamide gel (30% by weight) of Example 2 was used. A breast bag of the present invention was prepared by putting 10, 20, and 30 ml in a silicon bag.

Experimental Example 2

Direct injection of the polyacrylamide gel prepared in Example 1 and the resulting inflammatory response were measured. Conventional liquid polyacrylamide gel is too viscous to be injected from the outside, but the polyacrylamide gel of the present invention is a gel made by absorbing water of small particles of the polymer, so it is injected from the outside even at a high concentration with excellent touch. It was easy to insert into.

In addition, to measure the inflammatory response, the conventional silicone and polyacrylamide gel of Example 1 were injected and compared. Inflammatory responses of conventional silicone injections and polyacrylamide gels of Example 1 were injected at various sites in a large amount of tissues and at one site of tissues, and are shown in FIGS. 1, 2 and 3. It was.

In case of injection of conventional silicone, the inflammatory reaction occurred severely as shown in FIG. 1 (yellow portion of the photo is silicon and black dots show inflammatory reaction), but the polyacrylamide gel of Example 1 When injected into the site, the inflammatory reaction hardly occurred (the polyacrylamide gel of Example 1 is black in various parts, and it is difficult to observe the inflammatory reaction around). There was no inflammatory reaction (the lower round black circle is the polyacrylamide gel of Example 1).

Therefore, the polyacrylamide gel of the present invention may be used as a implant used in a tissue augmentation procedure by directly injecting the human body for facial wrinkle removal, contour correction, breast enlargement or genital enlargement. It can also be used as a substitute for ocular vitreous by processing it.

Experimental Example 3

(1) Breast augmentation surgery was performed using the breast bag prepared in Example 4.

(2) In addition, as in the conventional saline bag operation, a bag without contents was inserted into the chest and breast augmentation surgery was performed by injecting the polyacrylamide gel of Example 1 from the outside using a port.

(3) In addition, the polyacrylamide gel (concentrated form of 10 times or more) of Example 3 prepared in a high concentration in a silicon bag was prepared, and a capped silicon bag was applied to the patient's chest, and then an appropriate amount of saline was added from the outside. A chest enlargement surgery was performed.

As described above, in the operation of (1) and (2), there was no side effect such as postoperative inflammatory reaction, and the touch of breast bag was much better than that of conventional saline bag or dextrose bag. In addition, the side effects of the conventional silicone bag and the side effects of the monomer acrylamide present in the conventional polyacrylamide gel are completely improved.

In addition, the collapsed silicone bag as shown in (3) is a new type of bag that does not exist in the past, and has various forms of gel that are commercialized as a pre-filled bag that is highly viscous and elastic and cannot be injected from the outside. It can also be applied in.

As can be seen from the above, the polyacrylamide gel of the present invention removes the monomer acrylamide present in the gel to 0.5 µg / g or less, and thus includes facial wrinkle removal, contour correction, breast enlargement or genital enlargement very safely. It can be used as a substitute for human tissue augmentation procedures and ocular vitreous substitutes, and by putting the gel in an existing breast bag, it is possible to produce a breast bag that is superior in touch and safer than a conventional breast bag and can be variously treated.

1 is a photograph showing the inflammatory response in the injection of conventional silicone tissue,

Figure 2 is a photograph showing the inflammatory response when injection of a large amount of polyacrylamide gel of one example according to the present invention in various parts of the tissue,

Figure 3 is a photograph showing the inflammatory response when injecting an example polyacrylamide gel according to the present invention to a site of tissue,

4 is a graph showing the viscosity and shear stress of an example polyacrylamide gel according to the present invention,

5 is a graph showing the viscosity and shear stress of another example polyacrylamide gel according to the present invention.

Claims (11)

delete delete delete delete delete delete delete delete In the polyacrylamide produced by polymerizing acrylamide and bisacrylamide, a human body including a polyacrylamide gel in which the monomer acrylamide present in the polyacrylamide is removed to be contained at 0.5 μg / g or less with respect to the polyacrylamide. Wrinkle removal, contour correction, genital enlargement or tissue enlargement composition. Plastic surgery breast bag comprising the composition of claim 9. The composition according to claim 9, wherein the polyacrylamide gel is polymerized with a weight ratio of acrylamide and bisacrylamide of 1 to 20: 0.001 to 2.