KR20040044018A - Polyacrylamide hydrogel and its use as an endoprosthesis - Google Patents

Abstract

PURPOSE: Provided is a polyamide hydrogel useful in manufacturing prosthesis for plastic operations, regeneration operations using a soft tissue-filling endo-prosthesis, and treatments of incontinence, arthritis and reflux esophagitis. CONSTITUTION: The polyacrylamide hydrogel comprises a polyacrylamide in the amount less than 3.5 wt% based on the total weight of the hydrogel. The hydrogel is bioavailable, and is obtained by coupling acrylamide with methylene bis-acrylamide, performing radical initiated polymerization and washing the resultant product with water or saline with no heating source, wherein the mole ratio of the acrylamide to the methylene bis-acrylamide is 150:1-1000:1.

Description

POLYACRYLAMIDE HYDROGEL AND ITS USE AS AN ENDOPROSTHESIS}

Technical Field

The present invention relates to a novel polyacrylamide hydrogel crosslinked polyacrylamide. Hydrogels can be obtained by combining acrylamide and methylene bis-acrylamide in certain proportions that can impart certain physical properties to the hydrogel. The present invention also provides hydrogels for the manufacture of prosthetics for cosmetic surgery, regeneration surgery as endoprosthesis, internal prosthetics for incontinence treatment, internal prosthetics for arthritis, breast plastic surgery and ruminant esophagitis. It also concerns the use of.

Background of the Invention

As internal prosthetics, synthetic and natural polymers such as collagen, soya, glycerol, silicone, polyvinylpyrrolidone and hyaluronic acid have been used. Materials commonly used as internal prostheses usually mimic natural soft tissue and do not harm the health of patients.

Polyacrylamide gels have also been described. US 5,798,096 relates to biocompatible hydrogels containing 3.5 to 6.0% of crosslinked polyacrylamides. However, US 5,798,096 describes hydrogels becoming unstable when the concentration is below 3.5%.

GB 2114578 relates to polyacrylamide gels for medical and biological purposes, consisting of 3 to 28% polyacrylamide and the remainder in physiological solution.

US 5,658,329 relates to implantable prostheses comprising a shell filled with polyacrylamide gel containing 2 to 20% by weight of polyacrylamide and having a viscosity in the range of 15 to 75 Pas.

Formacryl Polyacrylamide is a commercially available injectable device for medical or dental use to correct congenital or acquired defects such as wrinkles, thin lines and scars, which is a 5% reticulated polyacrylamide polymer. Consists of% apyrogenic water.

US 5,306,404 describes a process for preparing polyacrylamide gel pastes for electrophoresis.

WO 99/10021 relates to injectable and biocompatible hydrogels comprising 0.5 to 10% of polyacrylamide and antibiotics or preservatives. WO 99/10021 relates to sappuration problems and internal prostheses. To solve the problem of gel rejection in use.

Summary of the Invention

The present invention generally combines acrylamide and methylene bis-acrylamide such that the polyacrylamide content is about 0.5 to 25% by weight of the total weight of the desired hydrogel; Radical initiation; And biostable hydrogels obtained by washing with pyrogen-free water or saline solution. The molecular weight of this bio-stable hydrogel is usually in the range of 0.01 x 10 ⁶ to 20 x 10 ⁶ . The polymer is resistant to biodegradation and does not cross biofilms. The polyacrylamide hydrogels of the present invention are wholly biocompatible (based on ISO standard test ISO-10993). Polyacrylamide hydrogels have no cytotoxic effect on human fibroblasts, and are not only nontoxic, noncarcinogenic, nonallergenic, nonmutagenic, but also resistant to degradation by enzymes and microorganisms. In addition, this polymer is water-insoluble. Hydrogels are useful in the amount of internal prosthetics and can be tailored to the defect site to be corrected.

The invention relates in one aspect to a biocompatible hydrogel comprising i) less than 3.5% (wt / wt) polyacrylamide crosslinked with methylene bis-acrylamide and ii) pyrogen-free water. More specifically, the present invention relates to a hydrogel containing less than 3.5% by weight of polyacrylamide, obtained by combining acrylamide and methylene bis-acrylamide, starting radicals, and washing with pyrogen-free water, wherein The bonding is carried out in a molar ratio of 150: 1 to 1000: 1.

One object of the present invention is injectable or implantable containing i) less than 3.5% (wt / wt) polyacrylamide crosslinked with methylene bis-acrylamide and ii) pyrogen-free water or saline solution. (Implantable) to provide a hydrogel usable as an internal prosthesis. The present invention also provides a method for preparing a hydrogel, comprising combining acrylamide and methylene bis-acrylamide, starting radicals and washing with pyrogen-free water such that the polyacrylamide content is less than 3.5% by weight. It is about.

Another object of the present invention is to provide an injectable or implantable internal prosthesis which comprises i) less than 3.5% by weight of polyacrylamide crosslinked with methylene bis-acrylamide and ii) a pyrogen-free water or saline solution. . The invention also provides for the preparation of internal prostheses for cosmetic shaping, regenerative molding and the treatment of i) containing less than 3.5% by weight of polyacrylamide crosslinked with methylene bis-acrylamide and ii) pyrogen-free water or saline solutions. It also concerns the use of hydrogels. Injectable, comprising mixing acrylamide and methylene bis-acrylamide so that the polyacrylamide content is less than 3.5% by weight, starting the radicals, and then washing the pyrogen-free water or saline solution. A method of making an implantable home prosthesis will be described.

In addition, the present invention:

a) preparing a polyacrylamide hydrogel having a polyacrylamide content of less than 3.5% by weight, crosslinked using methylene bis-acrylamide,

b) a method of treating a cosmetic or functional defect site with an injectable or implantable biocompatible internal prosthesis, which comprises injecting or implanting a sufficient amount of said hydrogel into the cosmetic or functionally defective body part to be treated; Do too.

Hydrogels with higher polyacrylamide contents than the above concentrations are also embodied in the present invention in connection with certain medical purposes. Another object of the invention is i) implantation for breastplastic reconstruction, comprising i) polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel and ii) water or saline solution without pyrogen. It is to provide a method of producing an internal prosthesis possible.

Another object of the present invention relates to the use of a hydrogel in the preparation of implantable internal prostheses for body contouring, comprising polyacrylamide in an amount exceeding 9.5% by weight relative to the total weight of the hydrogel. .

The present invention also provides a method for treating ruminant esophagitis. Another object of the present invention is the use of a hydrogel containing greater than 6% by weight of polyacrylamide relative to the total weight of the hydrogel in the manufacture of implantable internal prostheses for the treatment of (reflux) esophagitis, and hydrogel guns. It is to provide a method of treating (reflux) esophagitis by implanting or injecting a polyacrylamide hydrogel internal prosthesis containing more than 6% by weight of polyacrylamide by weight.

Mammoplasty is also included in the present invention. The present invention also relates to a method of cosmetically modifying a breast of a mammal or a part or all of breast reconstructive surgery in a female, comprising transplanting a polyacrylamide hydrogel; Wherein the hydrogel comprises polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) a pyrogen-free water or saline solution.

In addition, cosmetic surgery (hereinafter referred to as body contouring) performed on the body (except the face) also belongs to the scope of the present invention. The present invention also relates to a method of beautifully changing the body of a mammal (body contouring surgery) by implanting a polyacrylamide hydrogel internal prosthesis, wherein the hydrogel exceeds 9.5% by weight relative to the total weight of the hydrogel. Amounts of polyacrylamide and ii) pyrogen-free water or saline solutions.

In another aspect, the invention relates to a hydrogel used as a soft tissue filler internal prosthesis, wherein the hydrogel has an acrylamide and methylene bis- such that the polyacrylamide content is less than 3.5% by weight relative to the total weight of the hydrogel. Combining radicals to initiate radicals; This can be obtained by washing with a pyrogen-free water or saline solution.

In another aspect, the present invention also relates to the use of a hydrogel containing less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel in the preparation of soft tissue filling internal prostheses. Likewise, the present invention relates to a method for filling soft tissues in a mammal, comprising administering a hydrogel internal prosthesis containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel.

Another object of the present invention is to provide a prosthetic device for soft tissue augmentation, wherein the device is injectable and comprises a polyacrylamide hydrogel; Here, the hydrogel is combined with acrylamide and methylene bis-acrylamide so that the polyacrylamide content is less than 3.5% by weight relative to the total weight of the hydrogel, and the radical is initiated by washing with a water or saline solution without a pyrogen source. You can get it.

One important aspect of the invention relates to the use of bio-stable hydrogels in the treatment and prevention of incontinence and bladder urinary regurgitation, wherein the hydrogels have a polyacrylamide content of about 0.5 to about the total weight of the hydrogel. Acrylamide and methylene bis-acrylamide are combined to be 25% by weight, and can be obtained by radical initiation and washing with water or saline solution without a pyrogen source.

Another aspect of the present invention is a bio-stable hydro containing about 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel in the manufacture of internal prostheses for the treatment and prevention of incontinence and bladder urinary regurgitation. A method of treating or preventing incontinence or bladder tract reflux by administering to a mammal the use of a gel and a hydrogel containing polyacrylamide in an amount of about 0.5 to 25% by weight relative to the total weight of the hydrogel. .

One important aspect of the invention is the urethra for treating urinary incontinence, anal incontinence and bladder urinary regurgitation, respectively; Rectal or colon; And a prosthetic device for increasing resistance of an intraconduit selected from pyelone; Wherein the device is injectable and comprises the bio-stable hydrogel of the invention.

One object of the present invention is to provide a polyacrylamide hydrogel used as a prosthetic device for replenishing, enlarging or replacing the cartilage of the intra-articular cavity of a joint. Soft materials are advantageous in at least two aspects: that is, they are not only biocompatible but also biostable first; Second, the mechanical resilience does not easily shift, tear, shred, or collapse under mechanical stress. This material may be injected or implanted and manipulated to distribute the support provided by the material uniformly or as needed by the patient. This hydrogel also lubricates joints and pre-existing cartilage.

A central object of the present invention is to provide a hydrogel for use in the treatment or prevention of arthritis, wherein the hydrogel has acrylamide and methylene so that the polyacrylamide content is about 0.5 to 25% by weight relative to the total weight of the hydrogel. By binding bis-acrylamides; Radical initiation; Obtained by washing with a pyrogen-free water or saline solution.

Another object of the present invention is the use of a hydrogel in the manufacture of internal prostheses for the relief or prevention of symptoms associated with arthritis, wherein the hydrogel contains about 0.5 to 25 weight percent polyacrylamide relative to its total weight. It is contained in the amount of%.

Still another object of the present invention is to provide a method for treating or preventing arthritis, which comprises administering to a mammal a hydrogel containing 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel. will be.

Another aspect of the invention relates to a prosthetic device for the treatment of arthritis, wherein the device contains a polyacrylamide hydrogel comprising 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel, The device is administered to the internal joint lumen of the joint. In other words, the prosthetic device of the present invention is intended to enlarge or replace the cartilage inside the internal joint cavity of the joint, polyacrylamide hydrogel containing polyacrylamide in an amount of 0.5 to 25% by weight based on the total weight of the hydrogel. It contains.

1 is a view showing the structural formula of the hydrogel.

2 shows the swelling profile of a high viscosity hydrogel.

Figure 3 shows the swelling profile of low viscosity hydrogels.

Hydrogel and preparation method thereof

The success of plastic surgery or regeneration is usually dependent on the physical properties of the materials used. These materials must be clearly biocompatible, stable and non-toxic, and must also have physical properties that mimic the body tissues they replace, such as in regenerative surgery, or near body prostheses, such as in cosmetic surgery. Should be.

Materials such as collagen are reabsorbed into the body within a short time. Silicon and Soya face serious safety concerns. Therefore, there is a need for a safe, stable and biocompatible material having physical properties that mimic soft tissue.

The inventors have surprisingly found that polyacrylamide hydrogels containing less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel can be effective internal prostheses with advantageous physical properties. In contrast to the content of US 5,798,096, this polyacrylamide gel is stable. The hydrogels produced by the process of the invention are crosslinked with methylene bis-acrylamide to such an extent that the internal prosthetics made from the hydrogels may have desirable physical properties. The hydrogels according to the invention are new chemical entities, as their new and advantageous physical properties indicate. These secondary properties indicate that the degree of crosslinking of the hydrogels of the invention differs greatly from the polyacrylamide hydrogels produced by known methods. This degree of crosslinking is an important factor in determining its physical properties.

The inventors have combined acrylamide and methylene bis-acrylamide such that the polyacrylamide content is about 0.5 to 25% by weight relative to the total weight of the hydrogel; Radical initiation; And bio-stable hydrogels that can be obtained by washing with pyrogen-free water or saline solutions. These bio-stable hydrogels typically have molecular weights ranging from 0.01 x 10 ⁶ and 20 x 10 ⁶ . This polymer is resistant to biological degradation and impermeable to biological membranes. The polyacrylamide hydrogels of the present invention are wholly biocompatible (based on ISO standard test ISO-10993). This polyacrylamide hydrogel does not have any cytotoxic effect on human fibroblasts, and is nontoxic, noncarcinogenic, nonallergenic, nonmutagenic, and resistant to enzymatic degradation or degradation by microorganisms. In addition, the polymer is water-insoluble. It is a primary object of the present invention to provide a hydrogel containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel, wherein the hydrogel combines acrylamide and methylene bis-acrylamide And then by washing with pyrogen-free water or saline solution; The hydrogel is biocompatible, wherein the binding ratio is from 150: 1 to 1000: 1 in molar ratio.

It is a primary object of the present invention to provide a hydrogel containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel, wherein the hydrogel combines acrylamide and methylene bis-acrylamide And then by washing with pyrogen-free water or saline solution; The hydrogel is biocompatible, wherein the binding ratio is from 150: 1 to 1000: 1 in molar ratio.

Defined another way, one aspect of the present invention comprises i) less than 3.5% by weight of polyacrylamide and ii) pyrogen-free water or saline solution crosslinked with methylene bis-acrylamide and ii) at least 95% pyrogen-free. It is related with the hydrogel which consists of.

Another aspect of the invention consists of i) containing less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel, crosslinked with methylene bis-acrylamide and ii) at least 95% pyrogen-free water or saline solution. It relates to the use of hydrogels as injectable or implantable internal prostheses.

In all embodiments in which the hydrogel contains less than 3.5% by weight polyacrylamide relative to the total weight of the hydrogel, the hydrogel further contains at least 95% pyrogen-free water or saline solution.

The hydrogels of the present invention comprise less than 3.5% by weight, preferably at least 0.5% by weight, such as at least 1% by weight, preferably at least 1.5% by weight of polyacrylamide, such as at least 1.6, based on the total weight of the hydrogel. It is preferable to contain the polyacrylamide in weight%.

Hydrogels of the invention containing less than 3.5% by weight of polyacrylamide are chemically stable and bio-stable, but can be very fluid, such that their complex viscosity is at least 2 Pas, such as 3 Pas , 4 Pas or 5 Pas or more. In suitable embodiments, hydrogels containing less than 3.5% polyacrylamide have a composite viscosity of about 2 to 90 Pas, such as about 5 to 80 Pas, preferably about 6 to 76 Pas, such as about 6 to 60 Pas. , 6 to 40 Pas, 6 to 20 Pas, such as 6 to 15 Pas.

Hydrogels of the invention containing less than 3.5% polyacrylamide have elastic properties, the elastic modules of which are at least 10 Pa, such as at least 20, 25, 30, 31, 32, 33, 34 or 35 Pa, such as , 38 Pa or more. Generally the elastic module of this hydrogel is about 10 to 700 Pa, such as about 35 to 480 Pa.

These rheological properties are due in part to the degree of crosslinking and swelling of the hydrogel. Hydrogels containing polyacrylamide in an amount of less than 3.5% may be characterized by the crosslinked polyacrylamide having an effective crosslinking density of about 0.2 to 0.5%, preferably about 0.25 to 0.4%.

This crosslink density is due in part to the molar ratio between acrylamide and methylene-bis-acrylamide. Generally the ratio is in the range of 175: 1 to 800: 1, such as 225: 1 to 600: 1, preferably 250: 1 to 550: 1, most preferably 250: 1 to 500: 1. The absolute and relative amounts of redox agent (TEMED) and initiator also affect the degree of crosslinking. As can be seen in Tables 1, 2, 3 and 4, we adjusted these variables to influence the rheological properties of the hydrogels of the invention.

Biocompatible hydrogels of the invention containing less than 3.5% polyacrylamide may be suitably characterized, at least in part, by one or more of the following properties: i) 0.2% to 0.5% crosslinking degree; ii) elastic module (G ′) 10 to 700 Pa; iii) a composite viscosity of 2 to 90 Pas; iv) dry matter content less than 3.5%, such as less than 3.4%, such as less than 3.3%, such as less than 3.2%, such as less than 3.1%, such as less than 3.0%, such as less than 2.9%, such as less than 2.8%, such as less than 2.7% Less than 2.6%; v) refractive index from 1.33 to 1.34.

As noted above, in all aspects of the invention where the hydrogel contains less than 3.5 weight percent polyacrylamide relative to the total weight of the hydrogel, the hydrogel further contains at least 95% pyrogen-free water or saline solution. do. In all embodiments wherein the hydrogel further contains a saline solution, the hydrogel preferably contains less than 3% by weight of polyacrylamide relative to the total weight of the hydrogel.

The hydrogels of the present invention are substantially free of materials capable of occupying high content (solid weight content), with the exception of acrylamide, methylene-bis-acrylamide and residual (if any) initiators. Hydrogels are actually free of any other polymer content. The hydrogels of the present invention further comprise at least 75% by weight of pyrogen-free water or saline solution, preferably pyrogen-free water. In a suitable embodiment of the invention, the hydrogel contains at least 80% by weight of pyrogen-free water or saline essences, preferably at least 85% by weight, more preferably at least 90% by weight, even more preferably at least 95% by weight. It is recommended to contain water or saline solution without pyrogen.

The hydrogels of the present invention contain a pyrogen-free water or saline solution. Thus, binding of reagents and shaping of the gel can be done in water or saline solution without pyrogen. By using the saline solution, the total high content of the hydrogel will obviously increase, but does not have a significant effect on the polyacrylamide content during the polymerization reaction.

Suitable saline solutions have an osmotic pressure similar to liquids in organs. Suitable saline solutions include, but are not limited to, 0.25-1% sodium chloride solution, Ringer-Lockart solution, Earle solution, Hanks solution, Eagle medium, 0.25-1% glucose solution, potassium chloride solution, calcium chloride solution. In a preferred embodiment, the saline solution is about 0.8-1% aqueous sodium chloride solution, such as 0.8%, 0.9% or 1% aqueous sodium chloride solution.

As mentioned above, pyrogen-free water or saline solutions are used in the washing process. The washing process serves in part to remove all but trace amounts of monomer acrylamide and N, N'-methylene-bis-acrylamide. These monomers are not only toxic to patients but also adversely affect the stability of the hydrogel. The washing step has a concentration of monomer acrylamide and N, N'-methylene-bis-acrylamide of less than 50 ppm, more preferably less than 40 ppm, such as less than 30 ppm, most preferably less than 20 ppm, generally 10 ppm. It is preferred to carry out to less than, usually less than 5 ppm. In the process of the invention, the washing step comprises swelling the product for 50 to 250 hours, more generally 70 to 200 hours.

Hydrogels containing less than 3.5% polyacrylamide have been found to be surprisingly stable even at very low high contents, contrary to the description of US 5,798,096. We have made a polyacrylamide hydrogel with a high content of 0.5%. Preferred embodiments of the present hydrogel contain at least 0.5% by weight, such as at least 1% by weight, preferably at least 1.5% by weight, such as at least 1.6% by weight, based on the total weight of the hydrogel.

Such hydrogels are suitably a composite of crosslinked polyacrylamide chains and pyrogen-free water. Water contained as part of the complex in the hydrogel is loosely linked to the polymer chain. When present in the body, some of the water molecules migrate into the tissue by osmosis, resulting in a smoothing out of the missing skin surface. In embodiments in which the hydrogel contains a saline solution, iso-osmolarity between the saline solution and the interstitial fluid minimizes the immune response.

As mentioned above, the physical properties of hydrogels are partially affected by the degree of crosslinking. The degree of crosslinking can be controlled in part by the molar ratio of the crosslinking agent, methylene bis-acrylamide to acrylamide.

Accordingly, another object of the present invention is to initiate radicals by combining acrylamide and methylene bis-acrylamide to contain less than 3.5% by weight of polyacrylamide relative to the total weight of polyacrylamide, followed by It comprises a step of washing with a saline solution, the method of producing a hydrogel. This method preferably comprises the hydrogel containing at least 0.5% by weight, such as at least 1% by weight, preferably at least 1.5% by weight, such as 1.6% by weight, of polyacrylamide relative to the total weight of the hydrogel.

In a particularly preferred embodiment of the invention, acrylamide and methylene bis-acrylamide are combined in an amount of 150: 1 to 1000: 1 in an amount of 1.6 to 3.5% by weight of polyacrylamide, and then radicals are initiated. Hydrogel can be obtained by washing with water or saline solution without pyrogen.

The combination of acrylamide and methylene bis-acrylamide preferably has a molar ratio between acrylamide and methylene bis-acrylamide 175: 1 to 800: 1, such as 225: 1 to 600: 1, preferably 250: 1. To 550: 1, most preferably 250: 1 to 500: 1.

An exemplary method for preparing a hydrogel according to the present invention has been described in Example 1. Hydrogels with desired physical properties can be combined with acrylamide and methylene bis-acrylamide in a ratio of about 500: 1, such as 498: 1, 496: 1, 494: 1, 492: 1 or 490: 1. Acrylamide and methylene bis-acrylamide were obtained by combining in a ratio of about 250: 1, such as 252: 1, 254: 1, 256: 1, 258: 1 and 260: 1. Hydrogels according to the invention preferably have a complex viscosity of about 2 to 90, such as 5 to 80 Pas, typically about 6 to 76 Pas, such as about 6 to 60, 6 to 40, 6 to 20, such as 6 to It is good to be 15 Pas. In a suitable embodiment, the washing step comprises swelling the product of the radical initiation step until the composite viscosity is in the range of about 6 to 100 Pas.

In a suitable embodiment of the invention, the hydrogel has a degree of crosslinking such that the composite viscosity is at least 2 Pas, such as at least 3, 4, 5 Pas, such as at least 5.5 Pas, such as at least Pas, preferably at least 6.2 Pas.

An elastic module is another physical property of the hydrogel, which partially indicates the degree of crosslinking of the hydrogel according to the invention. In general, the degree of crosslinking is such that the elastic module of the hydrogel is 10 Pa or more, for example, 25, 30, 31, 32, 33, 34 or 35 Pa or more, for example, 38 Pa or more. The gel may be characterized as having an elastic module of 10 to 700 Pa, such as about 35 to 480 Pa.

As described above, in the most preferred embodiment, the hydrogel is acrylamide and methylene bis-acrylamide in an amount that provides a polyacrylamide content of 1.6 to 3.5% by weight, in a molar ratio of 150: 1 to 1000: 1. It can be combined and obtained via radical initiation and washing with a pyrogen-free water or saline solution. The hydrogels obtained in the radical initiation stage still contain toxic reagents and do not yet possess the desirable properties of the hydrogels of the invention. The washing step includes swelling the hydrogel resulting from the radical initiation step until the composite viscosity is about 2 to 90 Pas.

Alternatively measured, the washing step may comprise swelling the product of the radical initiation step until the elastic module is about 10 to 700 Pa, such as about 35 to 480 Pa.

Inherently, a low degree of crosslinking generally results in a high swelling rate, which results in a lowering of the elastic modulus and viscosity as well as the dry matter content (acrylamide percentage). Thus, in addition to the degree of crosslinking, the duration of exposure of the hydrogel to the washing step affects the degree of physical properties of the gel.

In general, the washing step comprises swelling the product for about 80 to 100 hours, such as 90 to 95 hours. This usually results in an increase in the weight of the hydrogel of about 70 to 150%, more generally about 100%.

In addition, the amount of free-radical initiator and the amount of co-initiator in the radical initiation step also affects the physical properties of the hydrogel since it affects the chain length. In a general method of preparing hydrogels, N-, N-, N-, N-tetramethyl ethylene diamine (TMED) is used as co-initiator and ammonium persulfate (APS) is a free-radical initiator (redox system) It is used as). Appropriate amounts of initiator and co-initiator are required to obtain the hydrogel according to the present invention. As an example, an insufficient amount of such reagents will result in shorter chain lengths that will eventually affect the degree of crosslinking and also affect the physical properties of the hydrogel. Other reaction conditions, such as temperature, also affect the chain length.

As mentioned above, the degree of crosslinking affects the physical properties of the hydrogel. The degree of crosslinking of the hydrogel of the present invention can be indirectly measured by the elastic module and / or composite viscosity as described above. Another method of measuring the degree of crosslinking of a hydrogel is its effective cross-linking density. The hydrogels of the present invention are preferably 1.6-crosslinked with methylene bis-acrylamide so as to have a crosslinking density of about 0.2 to 0.5%, more preferably about 0.25 to 0.4%, as measured by their effective crosslinking density. 3.5 (wt / wt)% polyacrylamide and ii) pyrogen-free water or saline solution.

In a suitable embodiment of the invention, the hydrogel is 1.6 to 3.25% (wt / wt) polyacrylamide, such as 1.8 to 3.1, 2.0 to 3.0, 2.0 to 2.9, preferably 2.0 to 2.8 (wt / wt) polyacrylic It may contain an amide.

Medical Uses of Polyacrylamide Hydrogels

The hydrogel of the present invention is intended to be used as an internal prosthetic device. The internal prosthetic device of the present invention and the treatment methods described herein can utilize the hydrogels of any of the embodiments described above.

The internal prosthetic device may be administered to the subject's body by injection via a syringe or catheter, or by surgical implantation. In embodiments in which the hydrogel is used as an implantable internal prosthesis, the hydrogel may optionally act as a filler in the envelope, which is implanted in its entirety into the body. Thus, the hydrogel or internal prosthesis may be made of a silicone-based envelope that incorporates a hydrogel.

As mentioned above, one object of the present invention is to

a) preparing 1.6 to 3.5% by weight of polyacrylamide hydrogel crosslinked using methylene bis-acrylamide,

b) a method of treating a cosmetic or functional defect site with an injectable biocompatible internal prosthesis, which comprises injecting a sufficient amount of said hydrogel into a cosmetic or functionally defective body part. The hydrogel injected at the defect site combines acrylamide and methylene bis-acrylamide in a molar ratio of 150: 1 to 1000: 1, in an amount of 1.6 to 3.5% by weight of polyacrylamide, and then starts radical. Obtained by washing with a pyrogen-free water or saline solution. The ratio of acrylamide to methylene bis-acrylamide has a complex viscosity of 2 to 90 Pas, such as 5 to 80 Pas, preferably 6 to 76 Pas, or its elastic module is 10 to 700 Pa, such as 35 to 480 Pa. It is good to be. The washing step can be carried out to the extent that the composite viscosity is about 6 to 80 Pas or the elastic module is 10 to 700 Pa, such as 35 to 480 Pa.

The endoprosthetic device may include any embodiment of the hydrogels discussed herein and may be implantable or injectable. Therefore, an important aspect of the present invention is cosmetic molding, regeneration molding and its containing i) containing less than 3.5% by weight of polyacrylamide crosslinked with methylene bis-acrylamide and ii) at least 95% pyrogen-free water or saline solution. In the use of hydrogels for the manufacture of internal prostheses for treatment. In a particularly interesting embodiment of the invention the internal prosthesis is injectable.

Another object of the present invention is a hydrogel as described above used in the production of internal prostheses. Specifically, an object of the present invention is cosmetic shaping, regeneration molding and i) containing i) 1.6 to 3.5% by weight of polyacrylamide crosslinked using methylene bis-acrylamide and ii) a pyrogen-free water or saline solution. Use of hydrogels for the manufacture of internal prostheses for treatment. Internal prostheses according to the invention may be implantable or injectable. Cosmetic and regenerative shaping may be for various facial corrections known to those skilled in the art, as well as for facial correction such as changing the shape of the nose or changing the shape or size of the lips for the treatment of wrinkles or facial imbalances.

In addition, cosmetic and regenerative shaping can correct deficits due to diseases or trauma such as hemiphlegia and the like.

Hydrogel as described above may be used for the production of internal prosthetics. Accordingly, another object of the present invention is to provide an injectable prosthesis containing i) 1.6 to 3.5% by weight of polyacrylamide crosslinked with methylene bis-acrylamide and ii) pyrogen-free water or saline solution. . Injectable prostheses according to the present invention have a complex viscosity of about 2 to 90, such as 5 to 80 Pas, preferably 6 to 76, such as 6 to 60, 6 to 40, 6 to 20, such as 6 to 15 Pas. It is preferable.

In the injection of internal prostheses, the hydrogel is generally somewhat fluid in nature.

Numerous disorders are associated with the loss of effective activity of tissue at the functional interface of both organs. Urinary incontinence, for example, is associated with insufficient sphincter between the bladder and urethra. Disorders can be remarkably controlled by narrowing the urethra by injecting or implanting the internal prosthesis made of the hydrogel according to the present invention into the proximal submucosa of the urethra. Likewise, reflux esophagitis is associated with insufficient resistance between the esophagus and the stomach. Injecting or implanting an internal prosthesis made of a hydrogel according to the present invention along the sphincter between the esophagus and the stomach can reduce contact between the contents of the stomach and the esophagus. Thus, in a suitable embodiment, hydrogels are used to make internal prostheses for treating urinary incontinence or reflux esophagitis. In general, internal prosthetics can be used to treat disorders related to insufficient resistance of functional interfaces between two organs or between segments of one organ.

In addition to the degree of crosslinking, the high content of weight percent acrylamide, as measured after the washing step, is adjusted according to the use of the internal prosthesis made of the hydrogel. In a preferred embodiment, the internal prosthesis comprises 1.6 to 3.25% (wt / wt) of polyacrylamide, such as 1.8 to 3.1, 2.0 to 3.0, 2.0 to 2.9, preferably 2.0 to 2.8% (wt / wt) of polyacrylamide. It is preferably made of a hydrogel containing. In other words, the crosslinking degree of the hydrogel for internal prosthesis may be that the complex viscosity of the hydrogel is 2.0 to 15 Pas, such as 5.5 to 15 Pas, such as 6 to 12 Pas. If measured differently, the degree of crosslinking of the hydrogel for facial correction is preferably 10 to 100 Pa, such as 35 to 75, in particular 35 to 60 Pa, such as 35 to 50 Pa.

Internal prostheses can correct congenital defects as well as defect sites that are the result of trauma such as tumors or body damage.

In a suitable embodiment of the present invention, the hydrogel described above is used as a filling material to fill or partially fill a silicone-based reservoir or shell for making implantable internal prostheses. Accordingly, another object of the present invention is i) a hydrogel containing 1.6 to 3.5% (wt / wt) of polyacrylamide crosslinked with methylene bis-acrylamide and a pyrogen-free water or saline solution, ii) the hydrogel It is to provide an implantable prosthesis comprising a silicone-based shell adapted to hold a gel. The hydrogel for filling or partially filling the silicone-based shell comprises an acrylamide and methylene bis-acrylamide in a molar ratio of 150: 1 to 1000: 1, in an amount of 1.6 to 3.5% by weight of polyacrylamide. It can be a hydrogel obtained by binding, starting radicals, and then washing with a pyrogen-free water or saline solution. In embodiments in which an internal prosthesis is implantable, the method of making the internal prosthesis from a hydrogel optionally further comprises inserting the hydrogel into a silicone-based shell.

After placing the hydrogel into a silicon-based shell, it may be desirable to seal it by chemical, mechanical or thermal means or by laser or light. Typically, the outer surface of the shell is chemically or physically modified to have a coefficient of friction that is biocompatible and minimizes movement or slippage.

In another embodiment of the present invention, the internal prosthesis may contain a medicament for use in treatment.

Polyacrylamide Hydrogel as Soft Tissue Filler Internal Prosthesis

In this aspect of the invention the term "face" does not mean only the cheek, chin, neck, forehead, under eyes, head, nose, etc., but the entire face.

The term "body contouring" means cosmetic or regenerative shaping which enlarges soft tissue to correct cosmetic or non-beauty defects of body soft tissues except face, lips, breast and penis. In the aspects of the present invention, the internal prosthesis relates to facial correction, lip enlargement, and body contouring.

In this aspect of the invention, the term "hydrogel" relates to a polyacrylamide polymer of the invention containing less than 3.5% polyacrylamide and at least 95% pyrogen-free water or saline solution, whereas the term "internal" Prosthesis "relates to hydrogels present in the body.

Polyacrylamide hydrogels can be obtained by polymerizing monomeric acrylamide and N, N'-methylene-bis-acrylamide under the onset of radicals and then washing the polymer with a pyrogen-free water or saline solution. Because the polymer absorbs water or saline solutions without pyrogen, washing the polymer results in swelling of the gel. Swelling of the hydrogel affects the high content of the gel, ie the amount of polyacrylamide, a polymeric material. The high content of hydrogels affects at least in part the physical (rheological) properties of the hydrogels and thus their ability to mimic human tissue when used as an internal prosthesis.

The inventors have prepared hydrogels with desirable rheological properties that act as totally nonpoisonous, stable and non-absorbable soft tissue filler internal prostheses. The inventors have developed hydrogels that can be used particularly for facial cosmetic or regenerative shaping, body contouring and lip enlargement or regenerative internal prostheses. Hydrogels according to this aspect of the invention do not relate to the use of internal prostheses for breast or penis enlargement.

The first of these aspects of the invention relates to a hydrogel used as a soft tissue filler internal prosthesis, wherein the hydrogel has an acrylamide and methylene so that the polyacrylamide content is less than 3.5% by weight relative to the total weight of the hydrogel. Combining radicals to initiate bis-acrylamide; It can be obtained by washing with a pyrogen-free water or saline solution. Typically, hydrogels are obtained by combining acrylamide and methylene bis-acrylamide in a molar ratio of 150: 1 to 1000: 1. The hydrogel obtained in this way has a structural formula as shown in FIG. 1, and has a sterile, transparent or colorless appearance, and has a pH in the range of 6.5 to 9.0, typically 7.0 to 9.0. In addition, the hydrogel of the present invention is stable to oxygen, high pressure, high temperature and low temperature, enzymes and bacteria.

This aspect of the present invention therefore relates to the use of a hydrogel for the preparation of soft tissue filling internal prostheses which contains less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel. Assuming the use of a hydrogel according to this aspect of the invention for internal prosthetics, the hydrogel must be stable. Furthermore, assuming that the use of the hydrogel according to the invention is for internal prostheses for use in selected fields of human anatomy, the hydrogel is typically at least 0.5% by weight of polyacrylamide, preferably at least relative to the total weight of the hydrogel 1.0 weight percent polyacrylamide, more preferably at least 1.5 weight percent polyacrylamide, such as at least 1.6 weight percent polyacrylamide relative to the total weight of the hydrogel. Typically, the hydrogels of the present invention have 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 relative to the total weight of the hydrogel. , 3,2, 3.3, 3.4, or 3.5% polyacrylamide.

In a preferred embodiment of this aspect of the invention, the hydrogel contains about 1.9 to 2.9 weight percent polyacrylamide relative to the total weight of the hydrogel. Typically the hydrogel further contains at least 95% by weight pyrogen-free water or saline solution, preferably pyrogen-free water. In a preferred embodiment, the hydrogel has at least 96% by weight of pyrogen-free water or saline solution, preferably no pyrogenous water, more preferably at least 97% by weight pyrogen-free water or saline solution, preferably pyrogen Free water, such as 95%, 95.5%, 96%, 96.5%, 97%, or 97.5% by weight pyrogen-free water or saline solution, preferably pyrogen-free water.

Suitable saline solutions have an osmolarity similar to the interstitial fluid. Suitable saline solutions include, but are not limited to, 0.25-1% sodium chloride solution, Ringer-Lockart solution, Earle solution, Hanks solution, Eagle medium, 0.25-1% glucose solution, potassium chloride solution, calcium chloride solution. In a preferred embodiment, the saline solution is about 0.8-1% aqueous sodium chloride solution, such as 0.8%, 0.9% or 1% aqueous sodium chloride solution.

A pyrogen-free water or saline solution is used for the cleaning process. The washing process serves in part to remove all but trace amounts of monomer acrylamide and N, N'-methylene-bis-acrylamide. These monomers are not only toxic to patients but also adversely affect the stability of the hydrogel. The washing step has a concentration of monomer acrylamide and N, N'-methylene-bis-acrylamide of less than 50 ppm, more preferably less than 40 ppm, such as less than 30 ppm, particularly preferably less than 20 ppm, generally 10 ppm. It is preferred to carry out to less than, most preferably less than 5 ppm.

The high content of the hydrogel of the present invention essentially consists of polyacrylamide, N, N'-methylene-bis-acrylamide and residual amount of initiator. Hydrogels are actually free of any other polymer content.

As stated, the hydrogels of the present invention are biocompatible, non-toxic, non-allergenic, non-resorbable, chemically inert and stable to oxygen, high pressure, high temperature and low temperature, enzymes and bacteria. When a hydrogel is exposed to excess UV light, the physical properties of the hydrogel change and are converted to glue-like materials. This material is also advantageously non-toxic.

Administration of the hydrogel causes a thin layer of connective tissue to surround the internal prosthesis, thereby making the internal prosthesis stable as part of the connective tissue. Due to the bio-stability and thin layer of connective tissue of the hydrogel, it can be easily removed from the patient if the internal prosthesis is in the subcutaneous tissue. This benefit comes at least in part from the stability of the hydrogel and therefore at least partly from the washing process.

Several factors influence the washing process as well as the rheological properties of the hydrogel, such as the relative amount of monomers used, the relative amount of initiator, temperature, polymerization time, and other variables of the polymerization process. The polymerization process can thus give the hydrogel a matrix of rows of viscosities with a high content of less than 3.5%. The present invention relates to a hydrogel as a soft tissue filler internal prosthesis, and therefore the hydrogel preferably has a viscosity that can be tailored to soft tissue to mimic. The hydrogels of the present invention are typically used as injectable prostheses for cosmetic or regenerative shaping of the face, for cosmetic or regenerative shaping of the body (body contouring) and for enlargement or regenerative shaping of the lips.

The hydrogels of this aspect of the invention may be injectable or implantable in the subcutaneous layer of the epidermis, preferably the hydrogels are injectable.

In one embodiment of this aspect of the invention, the prosthesis is used for facial cosmetic or regenerative molding and the hydrogel is about 2 to 1200 Pas, preferably about 5 to 90 Pas, such as 5 to 60 Pas, such as about 10 To a complex viscosity of from 60 Pas. Most preferably, the internal prosthetics for facial cosmetic or regenerative shaping is achieved by injecting hydrogels.

Depending on the health and area of the facial epidermis (eg, jaw as opposed to the cheeks), which requires a soft tissue filler, the viscosity of the hydrogel may vary. Thus, hydrogels can be used for facial cosmetic or regenerative molding and their complex viscosity is about 2 to 20 Pas, preferably about 2 to 18 Pas, such as about 2 to 15 Pas or 2 to 10 Pas, more preferably 2 to 7 Pas, most preferably 3 to 5 Pas.

In a typical embodiment, internal prostheses may be used to correct facial contour deformities due to aging, acne, trauma, surgery, infection or congenital malformations. Common facial features that require correction include, for example, cheekbones, nasolabial folds, glabellar frowns, depressed contours of the size or shape of the mouth, jaw, and lips. ) And of course other soft tissue defects on the face. Hydrogels can be used in the preparation of injectable hydrogels for lip amelioration and can correct aesthetic defects due to congenital, traumatic or aging modifications.

As stated, this aspect of the present invention relates to the use of hydrogels in the manufacture of soft tissue filling internal prostheses selected from soft tissues of the face and lips and soft tissues of the body. The hydrogels of the present invention are directed to the use in the cosmetic or regenerative shaping of the body (body contouring), which is about 5 to 50 Pas, preferably about 7 to 40 Pas, most preferably about 7 to 30 Pas It is good to have complex viscosity.

In embodiments in which the hydrogel is used for the preparation of internal prostheses for lip augmentation or lip regeneration, the complex viscosity of the hydrogel is preferably about 2 to 10 Pas, more preferably 2 to 7 Pas, most preferably 3 To 5 Pas is preferred.

Another object of this aspect of the present invention is to provide a prosthetic device for soft tissue enlargement, wherein the device is injectable and contains polyacrylamide hydrogel, wherein the hydrogel is poly Acrylamide and methylene bis-acrylamide can be combined so that the acrylamide content is less than 3.5% by weight, and can be obtained by radical initiation and washing with a pyrogen-free water or saline solution.

The prosthesis of this aspect of the invention comprises at least 0.5% by weight of polyacrylamide, preferably at least 1% by weight of polyacrylamide, more preferably at least 1.5% by weight of polyacrylamide, relative to the total weight of the hydrogel, It is preferred to include hydrogels containing, for example, at least 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel. Typically, the hydrogel contains from about 1.9 to 2.9 weight percent polyacrylamide relative to the total weight of the hydrogel. Prosthetics typically comprise a hydrogel containing at least 95% by weight of pyrogen-free water or saline, preferably pyrogen-free water.

Another aspect of the invention relates to a method for filling soft tissue, comprising administering a hydrogel internal prosthesis containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel. The hydrogel is as described above.

In another embodiment of the present invention, the prosthetic device comprises a cell, such as a stem cell. Polyacrylamide provides an excellent template and matrix for cell growth. Although the hydrogel of the present invention, by its nature, may allow a thin layer of connective tissue of the patient's body to surround the device, the use of the cells in combination with the hydrogel of the present invention in the manufacture of the device is a periphery tissue. It is for cellular engraftment of cells in a surrounding tissue.

The method of this aspect of the present invention involves administering the hydrogel of the present invention by injecting the hydrogel into the subcutaneous layer of the skin generally in embodiments where the internal prosthesis is used for facial cosmetic or regenerative forms or body contouring. In embodiments where internal prosthetics are used for lip augmentation or lip regeneration, hydrogels are injected over the muscle tissue of the lips.

It is a further object of the present invention to prepare an implantable internal prosthesis for body contouring, i) polyacrylamide in an amount of greater than 9.5% by weight relative to the total weight of the hydrogel and ii) pyrogen-free water or saline In the use of hydrogels containing solutions. Of a mammal comprising a transplant of polyacrylamide hydrogel prosthetics, wherein the hydrogel contains polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel and ii) pyrogen-free water or saline solution. The method of changing the body beautifully (body contour surgery) can be done by injecting or implanting hydrogel into the soft tissue of the patient.

As stated, another embodiment of this aspect of the present invention involves combining and administering the hydrogel of the present invention with cells, such as rodent cells, to allow cell engraftment of the prosthetic device.

The method of this aspect of the invention may comprise injection one or more times to cover a predetermined area or to achieve the desired effect. In general, the gel to be injected is stored in a syringe suitable for injection in the amount required for single session treatment. Depending on the pain zone, the amount of gel will vary and thus the volume of the syringe, such as a syringe with a volume of 0.25 to 25 mL, such as 0.5 mL, 0.7 mL, 1.0 mL, 1.5 mL, 2.0 mL, 2.5 mL, 5.0 mL, 7.5 syringe, selected from mL, 10 mL, 12.5 mL, 15 mL, 20 mL and 25 mL and the like. Clearly, the facelift or lip enlargement prosthesis to be fed into various volumes of syringes is typically smaller in volume than the volume of the prosthesis for body contouring. For example, the device for lip augmentation may be supplied in a volume of 0.5 ml or 0.7 ml or 1.0 ml, while the body contouring device may be supplied in a volume of 2 mL, 5 mL, or 10 mL. It is merely an example embodiment and is not intended to limit the scope of the invention in any way. The apparatus of the invention can be supplied in any volume necessary to carry out the method.

As stated, hydrogels are very biocompatible. The method of the present invention does not add antibiotics, analgesics or anti-inflammatory agents to the hydrogel.

In a preferred embodiment of the method comprising the injection of an internal prosthesis, the injection comprises the use of a syringe having a thin gauge needle, such as a 21-29 G needle. The required amount of gel is subcutaneously injected by backing the needle by injecting the gel. After injection, light manipulation may be necessary to ensure a flat distribution of the gel. Postoperative edema can be treated topically with ice packs and may experience mild pain and redness for the first two to three days after injection.

In embodiments of the method comprising injection of a lip enlargement or facial correction prosthesis, the needle of the syringe is usually particularly fine, such as a 25-29 G needle. In the case of body contouring, the needle of the syringe may range from 21 to 23 G.

Polyacrylamide Hydrogel for Breast Plastic Surgery

Preferred embodiments of this aspect of the invention are hydrogels containing less than 3.5% by weight polyacrylamide and at least 95% pyrogen-free water or saline solution in the manufacture of internal prostheses for breast regeneration. The use of the is mentioned. The hydrogel is most preferably implantable and may further comprise a silicone-based envelope containing the hydrogel.

In embodiments wherein the hydrogel contains less than 3.5% by weight polyacrylamide, the hydrogel contains at least 1% by weight of polyacrylamide, preferably at least 1.5%, such as the total weight of the hydrogel, relative to the total weight of the hydrogel. Preferably at least 1.6% by weight of polyacrylamide.

Mastectomy hydrogels containing less than 3.5% by weight of polyacrylamide are preferably injectable. Said injectable prosthesis according to the invention is a combination of about 2 to 90, such as 5 to 80 Pas, preferably about 6 to 76, such as about 6 to 60, 6 to 40, 6 to 20, such as 6 to 15 Pas. It is preferable to have a viscosity.

Another object of the present invention is based on the high high content hydrogel produced by the inventors. Still another object of the present invention is to provide i) polyacrylamide and ii) pyrogen-free water in the manufacture of internal prostheses for breast augmentation or regeneration. It is in the use of a hydrogel containing a saline solution. In other words, another object of the present invention relates to a method of performing partial or total breast remodeling in a female or to beautifully modifying a mammal's breast, which consists in implanting a polyacrylamide hydrogel internal prosthesis. Wherein the hydrogel contains polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel and ii) a pyrogen-free water or saline solution.

In embodiments in which the mastoplasty hydrogel contains polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, the hydrogel is typically less than 25% by weight, such as 20, based on the total weight of the hydrogel. It contains less than weight percent polyacrylamide.

Mammoplasty prosthetic devices in which the hydrogel contains polyacrylamide in an amount greater than 9.5% by weight are usually implantable. In such embodiments, the internal prosthesis may further comprise a silicon-based envelope.

In the correction of some or all mastectomy, the internal prosthesis may be injectable or implantable. When an internal prosthesis is implanted, the internal prosthesis may contain the hydrogel itself according to the invention. The size and shape of the gel can be determined by preparing the gel in a mold or cast or sculpting the gel into a predetermined shape and size. Alternatively, the gel may be inserted into a silicone-based shell that acts to partially contain the hydrogel before or during implantation of the gel.

In embodiments in which implantable prosthetics comprising a silicon-based shell are preferred, the hydrogel may be somewhat fluid or fixed resting shape. In embodiments wherein the prosthesis further comprises a silicone-based shell and the hydrogel is stationary in shape, the size and shape of the gel is adjusted to the requirements of the patient, making the gel in a mold or cast, or It can be determined by engraving to a predetermined shape and size. The shell can also be adjusted according to the size or shape of the hydrogel to contain. In embodiments where the implantable internal prosthesis does not contain a silicone-based shell, but the hydrogel itself is implanted, the hydrogel is generally in a fixed stop shape. As stated, the shape and size of the gel can be adjusted according to the requirements of the patient, and can be determined by preparing the gel in a mold or cast or sculpting the gel into a predetermined shape and size.

When the internal prosthesis is injected for the correction of some or all mastectomy, the internal prosthesis contains 2.0 to 3.0% polyacrylamide, such as 2.2 to 3.0% polyacrylamide, the complex viscosity of about 10 to 90 From hydrogels having a Pas, such as 20 to 90, 30 to 90, or 40 to 80 Pas, the elastic module of which is about 50 to 700 Pa, such as 75 to 600, such as 100 to 500, preferably about 200 to 500 Pa. It is good to be manufactured. Typically, the hydrogel has a complex viscosity of at least 10 Pas, such as at least 15 Pas, preferably at least 20 Pas, more preferably at least 30 Pas, most preferably at least 40 Pas.

Polyacrylamide Hydrogels for Incontinence and Bladder Urinary Reflux Treatment

Loss of voluntary control of the sphincter is the primary cause of urinary incontinence and anal incontinence. Urinary incontinence, which cannot voluntarily retain urine in the bladder, is common among older people. Contraction of the bladder detrusor is voluntary and can cause stress, reflex or urge. If the bladder sphincter does not contract in number, stress-induced deflation of the detrusor muscle leads to involuntary urination. In the case of loss of control of the bladder sphincter, urination may be accompanied by some stress, such as slight stress, during daily activities, sneezing, coughing, laughter, gas retention, surprises, and other myriad stimuli that may constrict the detrusor muscle. It may be caused by abdominal contractions. Similar principles underlie anal incontinence, which undermines control of the anal sphincter. Urinary incontinence and anal incontinence can be caused by aging, trauma (such as in the case of a disabled person), or innate associations.

Bladder urinary regurgitation results from decreased ureter resistance resulting in urine in the bladder to the kidneys. This is caused by the migration of bacteria through the ureter, calyceal dilation, renal pyramids and kidneys, from the bladder to reverse physiological damage to the renal parenchyma, as well as infection and recurrent pyelonephritis. May cause This can cause kidney failure.

Urinary incontinence, anal incontinence, and bladder urinary regurgitation can be treated by increasing passage resistance through the urethra, colon or rectal or canalis analis, or ureters, also known as the bulking process.

Attempts have been made to treat urinary incontinence, for example in connection with hydraulic devices such as WO 01/50833 and US 4,969,474 and other controllable devices such as prosthetic sphincter with inflatable cuffs in US 4,571,749 and WO 01/47433. come. Weight loss, exercise, medication and surgical procedures usually involve bladder neck elevation or contraction of increased resistance through the urethra with surrounding tissue or prosthetic material. Materials such as collagen, PTEE, silicone and Teflon are used for this reason (of references to be added).

It has also focused on anal incontinence through controllable devices such as in WO 01/47431. Bladder urinary regurgitation has been treated with surgery (usually in the case of infants, dilating the ureters) and antibiotics have been used.

The primary object of this aspect of the present invention is to provide a polyacrylamide hydrogel that increases resistance in the appropriate conduit in the treatment of incontinence and bladder urinary regurgitation.

US 6,129,761 discloses the use of injectable hydrogels and cell compositions for this reason. The composition is a cell suspension which is a mixture of biocompatible and biodegradable polymers and cells. The polymer provides a medium and template to allow cells to grow and engraft cells in surrounding tissue. Cell growth occurs simultaneously with polymer degradation to grow the desired tissue. US 6,129,761 describes alginates such as modified alginates, bacterial polysaccharides such as gellan gum, vegetable polysaccharides such as carrageenan, hyaluronic acid, polyethylene oxide-polypropylene glycol block copolymers, fibrin, proteins such as collagen and gelatin, polyethylene Macromers such as mixtures of oxides and polyacrylic acids, crosslinked chitosans, photochemically crosslinked ethylenically unsaturated groups, PEG-oligolactyl-acrylates, polyethyleneamines, poly-lysine, poly (vinylamine) and poly (allylamine) A constructed polymeric material is disclosed. US 6,129,761 discloses degradable poly (vinylamine) without discloses the use of stable polyacrylamide hydrogels. Assuming that the polymers required in the invention according to US Pat. No. 6,129,761 are altered according to the process of the invention, biostable polymers, such as the biostable polyacrylamides of the invention, are not suitable for the process of US 6,129,761.

RU 2148957 relates to a method of treating bladder tract reflux using polyacrylamide hydrogel.

Thus, the injectable materials used so far are synthetic materials (teflon, silicon, coal particles) and natural materials (connective tissue extract, fat). One year after the observation, about half of the treated patients have recurrent incontinence and are not effective for a relatively long time. Therefore, there is a need for a material that is biocompatible with tissue and at the same time is not absorbed or released by the body (biostable). In addition, the material must have suitable rheological properties in order to function effectively.

It is an object of this aspect of the present invention to provide a biocompatible and bio-stable polyacrylamide hydrogel in increasing the resistance of the catheter in the treatment of incontinence and bladder urinary regurgitation.

The term "bio-stable" means that the substance does not degrade to a substantial extent in the interstitial fluid or body tissue.

The first object of this aspect of the present invention is to provide acrylamide such that the amount of polyacrylamide is about 0.5 to 25% by weight relative to the total weight of the hydrogel in use for the treatment and prevention of incontinence and bladder tract reflux. Combining methylene bis-acrylamide with; Radical initiation; And it relates to a biostable hydrogel obtained by washing with a pyrogen-free water or saline solution. The molecular weight of this bio-stable hydrogel is usually in the range of 0.01 x 10 ⁶ to 20 x 10 ⁶ . The polymer is resistant to biodegradation and does not cross biofilms. The polyacrylamide hydrogels of the present invention are wholly biocompatible (based on ISO standard test ISO-10993). Polyacrylamide hydrogels have no cytotoxic effect on human fibroblasts, and are not only nontoxic, noncarcinogenic, nonallergenic, nonmutagenic, but also resistant to degradation by enzymes and microorganisms. In addition, this polymer is water-insoluble.

The inventors have found that biostable gels are effective as bulking agents and suitable for the treatment of incontinence and bladder urinary regurgitation, assuming that the gel is biocompatible, not biodegradable and does not fall off from the site of application in the catheter.

Biostable hydrogels of this aspect of the invention are usually obtained by combining acrylamide and methylene bis-acrylamide in a molar ratio of 150: 1 to 1000: 1. In a preferred embodiment, the hydrogel is less than 15% by weight of polyacrylamide, preferably less than 10%, more preferably less than 7.5%, even more preferably less than 5%, most preferred to the total weight of the hydrogel Preferably less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel.

Assuming that the hydrogel of this aspect of the invention is used as a permanent internal prosthesis, the hydrogel must be stable. Furthermore, assuming that the use of the hydrogel according to the invention is for internal prostheses for use in selected fields of human anatomy, the hydrogel is typically at least 0.5% by weight of polyacrylamide, preferably at least relative to the total weight of the hydrogel 1.0 weight percent polyacrylamide, more preferably at least 1.5 weight percent polyacrylamide, such as at least 1.6 weight percent polyacrylamide relative to the total weight of the hydrogel. Typically, the hydrogels of the present invention have 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 relative to the total weight of the hydrogel. , 3,2, 3.3, 3.4, or 3.5% polyacrylamide.

In the treatment of bladder tract reflux, the hydrogel contains less than 3.5% by weight of polyacrylamide and about 96.5% pyrogen-free water or saline solution, such as 97.5% pyrogen-free water or saline solution, relative to the total weight of the hydrogel. It is desirable to.

The viscosity of a biostable hydrogel is usually sufficient to be infused. In suitable embodiments, the hydrogel has a complex viscosity of about 2 to 50 Pas, such as about 2 to 40 Pas, preferably about 2 to 30 Pas, more preferably about 2 to 20 Pas.

The device may have a viscosity enough to be injected. In embodiments in which the hydrogel is injected, the hydrogel is about 2 to 30 Pas, such as about 2 to 20 Pas, preferably about 3 to 18 Pas, most preferably about 3 to 15 Pas, such as 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15 Pas.

The device also has elastic properties at least in part due to the high water binding capacity of the hydrogel in water. This is quite appropriate, at least in terms of durability and the ability to provide resistance through conduits. In a preferred embodiment, the hydrogel of the present invention has an elastic module of about 1 to 200 Pa, such as about 2 to 175 Pa, usually about 5 to 150 Pa, such as 10 to 100 Pa.

The elastic module and composite viscosity of the prosthetic device generally relates to a factor of 5.8 to 6.4. The present invention thus provides a hydrogel having the advantageous bonding property of elasticity which provides a suitable viscosity and increased resistance to injection. In a combination of preferred embodiments, the hydrogel has a composite viscosity of less than 25 Pas and an elastic module of less than 200 Pa, preferably a composite viscosity of less than 15 Pas and an elastic module of less than 100.

Examples 1, Tables 1, 2, 3 and 4 illustrate suitable conditions for preparing exemplary hydrogels. As can be seen, the hydrogel can have several values of dry-weight content percentages within the preferred bonding embodiments having a viscosity of less than 25 Pas and an elastic module of less than 200 Pa.

In addition, within preferred embodiments having a viscosity of less than 25 Pas and an elasticity of less than 200 Pa, such as a composite viscosity of less than 15 Pas and an elasticity of less than 100, the hydrogel is about 275 to 1000, usually 300 to 800, preferably It can be obtained by combining acrylamide and methylene-bis-acrylamide in a molar ratio of about 300 to 500.

The hydrogels of the present invention are substantially free of materials capable of occupying high content, with the exception of acrylamide, methylene-bis-acrylamide and residual (if any) initiators. Hydrogels are actually free of any other polymer content. The hydrogels of the present invention further comprise at least 75% by weight of pyrogen-free water or saline solution, preferably pyrogen-free water. In a suitable embodiment of the invention, the hydrogel contains at least 80% by weight of pyrogen-free water or saline essences, preferably at least 85% by weight, more preferably at least 90% by weight, even more preferably at least 95% by weight. It is recommended to contain water or saline solution without pyrogen.

Suitable saline solutions have an osmolality similar to interstitial fluid. Suitable saline solutions include, but are not limited to, 0.25-1% sodium chloride solution, Ringer-Lockart solution, Earle solution, Hanks solution, Eagle's medium, 0.25-1% glucose solution, potassium chloride solution, calcium chloride solution. In a preferred embodiment, the saline solution is about 0.8-1% aqueous sodium chloride solution, such as 0.8%, 0.9% or 1% aqueous sodium chloride solution.

In a particularly suitable embodiment of this aspect of the invention, the hydrogel contains about 2.5 weight 5 polyacrylamide and about 97.5% pyrogen-free water relative to the total weight of the hydrogel.

A pyrogen-free water or saline solution is used for the cleaning process. The washing process serves in part to remove all but trace amounts of monomer acrylamide and N, N'-methylene-bis-acrylamide. These monomers are not only toxic to patients but also adversely affect the stability of the hydrogel. The washing step has a concentration of monomer acrylamide and N, N'-methylene-bis-acrylamide of less than 50 ppm, more preferably less than 40 ppm, such as less than 30 ppm, most preferably less than 20 ppm, generally 10 ppm. It is preferred to carry out to less than, usually less than 5 ppm.

The washing step can suitably be carried out for 15 to 250 hours, such as 20 to 225 hours. Tables 2 and 3 show that the washing step is usually carried out for 50 to 100 hours, more generally 70 to 100 hours.

In another embodiment of this aspect of the invention, the prosthetic device contains a cell, such as a rod. Polyacrylamide provides an excellent template and matrix for cell growth. The use of the hydrogels and cells of the present invention in the manufacture of devices is to allow cells to engraft in surrounding tissues in the ureters, urethra or analis canalis. Due to the hydrogel and the appropriate cell device of the present invention, it is possible to increase resistance and efficacy in providing resistance.

In a preferred embodiment of this aspect of the invention, the hydrogels of the invention are used to treat urinary incontinence and anal incontinence, more preferably urinary incontinence.

Urinary incontinence may be stress or reflex urinary incontinence or urge urinary incontinence. In general, the hydrogels of the present invention are suitable for the treatment of stress or reflex urinary incontinence.

In another object of this aspect of the invention, the hydrogel of the invention is used for the production of internal prostheses. Accordingly, another object of the present invention is the use of an internal prosthesis for the treatment and prevention of incontinence and urinary tract regurgitation of hydrogels containing 0.5 to 25% by weight of polyacrylamide, as described above. Used as

The internal prosthesis is suitably formulated as an injectable suspension. This suspension comprises a homogenized composition of a hydrogel. Generally, this suspension is filled into a syringe.

Another object of this aspect of the invention is to treat incontinence or bladder tract reflux, comprising administering to a mammal a hydrogel containing 0.5 to 25 weight percent polyacrylamide relative to the total weight of the hydrogel; It is about how to prevent. Hydrogels according to any of the foregoing embodiments are suitable for carrying out this method of the invention.

When administered hydrogel, a thin layer of connective tissue surrounds the internal prosthesis, making the internal prosthesis a stable part of the connective tissue. Due to the stability of the thin layer of connective tissue and the hydrogel, the internal prosthesis can be removed from the patient. This advantage is at least in part attributable to the stability of the hydrogel which is again at least partly the reason for the washing step.

Several factors affect the rheological properties of the hydrogel, such as the relative amount of monomer used, the relative amount of initiator, the temperature and other variables of the polymerization process, and the washing step. Thus, the polymerization process can provide hydrogel arrays with different viscosities. The present invention generally relates to internal prostheses for use in the urethra, rectal or colon (or anal canal) or ureters and can therefore be tailored to the requirements of the conduit.

One important object of the present invention is the urethra for the treatment of urinary incontinence, anal incontinence and bladder urinary regurgitation; Rectal or colon (analyst); And a prosthetic device for increasing the resistance of the conduit selected from the ureters; Wherein the device is injectable and is made comprising the hydrogel described above.

The method of this aspect of the invention preferably administers the hydrogel by injecting the hydrogel into an appropriate conduit. In the treatment of urinary incontinence, hydrogels are generally injected into the submucosal membrane of the urethra, particularly the submucosal tissue of the urethra. Injection is done into the submucosa membrane via the outer surface of the urethra.

We have found that 2-5 mL of hydrogels are generally suitable for imparting adequate resistance to urethra by bulking the urethra. It is generally desirable to distribute 3 mL, preferably 2-5 mL, of the hydrogel by depositing the gel on at least two cross sections along a single straight position of the urethra. In a particularly suitable embodiment, at least three depots were made along one longitudinal position of the urethra. The inventors have found that depots 0.5 cm away from the cystoscope are particularly suitable.

The inventors have found that injection into the submucosal tissue at 10, 2 and 6 o'clock of the cross section of the urethra is particularly suitable for treating urinary incontinence.

Depots are generally made with a syringe or with a cytoscope or catheter. It is suitable to inject using a needle of 21 to 27G.

To treat anal incontinence, hydrogels are generally injected beneath the membranes of the submucosal tissue of the rectum or colon, particularly the rectum or colon. Injection is suitably in an amount of 2 to 6 mL. It is desirable to distribute the hydrogel in at least two cross-sectional locations along a single longitudinal direction of the colon or rectum. In a particularly suitable embodiment, at least three depots are made along a single longitudinal direction of the rectum or colon, preferably at positions 10, 2 and 6 o'clock of the cross-sectional axis of the rectum or colon.

For the treatment of bladder urinary regurgitation, submucosal injection into the ureter of a patient is required. Injection is appropriate from 2 to 5 mL. The hydrogel is preferably distributed in at least two locations along a single longitudinal direction of the ureter. In a particularly preferred embodiment, three or more depots are made along the single longitudinal direction of the ureter, preferably at the 10, 2 and 6 o'clock positions of the cross-sectional axis of the ureter.

In embodiments of this aspect of the invention, the method may use prosthetic devices containing cells such as stem cells. Polyacrylamide provides an excellent template and matrix for cell growth. The use of cells in conjunction with the hydrogels of the present invention in the manufacture of prosthetic devices will allow intracellular transplantation into peripheral tissues in the ureters, urethra or anal canal. By using the hydrogels of the present invention and the appropriate cells, greater resistance may be provided with greater efficiency.

Polyacrylamide Hydrogel for the Treatment of Arthritis

Arthritis is a degenerative condition that causes pain and limited mobility when it affects weight-bearing joints such as the hip and knee joints. Any joint can be a target of arthritis. Degeneration of joints and meniscal cartilage can cause pain by causing damage to surfaces separated by cartilage. Aging is a major cause of cartilage degeneration. Such degeneration may also occur, for example, by congenital etiology or trauma, such as repetitive joint splicing.

Arthritis has traditionally been treated by physiotherapy and more aggressive therapies such as orthopedic surgery and insertion of artificial joint components. Although the use of non-steroidal anti-inflammatory drugs has been somewhat successful, these drugs can have adverse side effects that restrict proteoglycan synthesis in collagen and cartilage, as well as undesirable side effects. Injecting cortisone also weakens joint cartilage over time.

Soft, soft materials have been developed that are used to replace cartilage to absorb the load on the joints and distribute the load evenly. US 4,344,193 discloses silicone rubber as a prosthetic device. One difficulty with this device is to keep the prosthesis in place, for which various anchoring systems have been developed (US 5,171,322; US 4,502,161; US 4,919,667).

Other prosthetic devices such as those disclosed in US 5,344,459 are expandable. MacIntosh knee is a hard prosthesis that causes pain when used.

WO 00/78356 discloses injectable compositions for promoting bone and / or cartilage growth comprising hyaluronic acid crosslinked in sulfated polysaccharides.

WO 96/24129 discloses prostheses for hands and feet, made of biocompatible materials such as mixtures of biocompatible resins and plastics. Particular materials mentioned include polymethyl methacrylate polymers. This prosthesis is implanted into the joint. WO 00/59411 discloses a surgically implanted knee prosthesis, in which a device for distributing a load is made of a material made of a thermoset polymer or a thermoplastic polymer. Hyaluronate and hyaluronic acid were used for prosthetics, and prosthetics were administered by injection into the internal joint cavity of the knee, for long-term pain relief and improved knee joint function. It has the proper viscosity and elasticity, but tends to shear due to mechanical stress and is biodegradable and faces resorption problems.

Therefore, the current state of the art requires a new material to be used as artificial cartilage, such as a load-bearing joint. The present invention relates to materials and prosthetic devices that can be used to treat arthritis and to augment and replace cartilage.

Polyacrylamide hydrogels are resistant to biological degradation and impermeable to biological membranes. The polyacrylamide hydrogel of the present invention is wholly biocompatible (according to ISO standard test ISO-10993). The polyacrylamide hydrogel of the present invention does not cause cytopathic effect on human fibroblasts, is nontoxic, non-carcinogenic, non-allergenic, non-mutagenic, and resistant to degradation by enzymes and microorganisms. Indicates. In addition, the polymer of the present invention is insoluble in water. What is unique about the present invention is that the polymers of the present invention are resilient to mechanical stress.

The hydrogels of this aspect of the invention combine acrylamide and methylene bis-acrylamide followed by radical initiation; A hydrogel obtained by washing with a pyrogen-free water or saline solution is used for the treatment or prevention of arthritis, wherein the binding amount and the washing step are about 0.5 to 25% by weight of polyacrylamide based on the total weight of the hydrogel. Do it if possible. The obtained hydrogel was shown to be biostable and biocompatible by the present inventors and was not reabsorbed by the human body. In addition, the inventors have demonstrated that hydrogels are resilient to mechanical stress.

Generally, the hydrogels of this aspect of the invention are obtained by combining acrylamide and methylene bis-acrylamide in a molar ratio of 150: 1 to 1000: 1. Conditions for obtaining the hydrogel can be adjusted according to, for example, the nature of the joint in which the hydrogel is to be injected. Desired rheological properties such as elasticity and viscosity are at least partially adjustable by the high content of the hydrogel. The hydrogel of the present invention contains about 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel. In a suitable embodiment of the invention, the hydrogel has less than 15% by weight of polyacrylamide, preferably less than 10% by weight, more preferably less than 7.5% by weight, more preferably 5% by weight relative to the total weight of the hydrogel. Less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel.

If the hydrogels of this aspect of the invention are used in internal prostheses, they will be stable. In general, the hydrogel contains at least 1% by weight of polyacrylamide, preferably at least 1.5% by weight, such as at least 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel. In suitable embodiments, the high content of the hydrogels of the present invention is polyacrylamide in an amount of at least 1.5% by weight and less than 3.5% by weight relative to the total weight of the hydrogel, such as 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 , 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3 and 3.4% by weight of polyacrylamide.

The bonding is carried out in such a way that the reagent components acrylamide and methylene bis-acrylamide are generally degassed to minimize contact of the operator. The reagent components may optionally be combined first to form an inert mixture. Inert mixtures refer to no chemical reaction between reagent components. Bonding includes combining acrylamide, methylene-bis-acrylamide and radical initiator components. In a suitable embodiment, an inert premix of acrylamide, methylene-bis-acrylamide (crosslinker) alc quencher is combined with AMPS initiator solution. However, these components may be combined individually or alternatively may be combined as a plurality of premixes.

Acrylamide and methylene-bis-acrylamide are about 100: 1 to 1000: 1, generally about 150: 1 to 900: 1, preferably about 175: 1 to 800: 1, more preferably about 200: Suitably combined in a molar ratio of 1 to 600: 1, most preferably about 250: 1 to 500: 1. As shown in Tables 2 and 3, hydrogels having different high content and rheological properties can be prepared in a controlled manner. Acrylamide and methylene-bis-acrylamide are about 250; 1, about 260: 1, about 270: 1, about 280: 1, about 290: 1, about 300: 1, about 310: 1, about 320: 1, About 330: 1, about 340: 1, about 350: 1, about 360: 1, about 370: 1, about 380: 1, about 390: 1, about 400: 1, about 410: 1, about 420: 1, Rheological properties desired by combining at a ratio of about 430: 1, about 440: 1, about 450: 1, about 460: 1, about 470: 1, about 480: 1, about 490: 1, and about 500: 1. A hydrogel having was obtained.

As can also be seen from Tables 2 and 3, the relative amounts of monomers (acrylamide and methylene-bis-acrylamide) are fairly constant from composition to composition for TEMED. Thus, in a preferred embodiment of the process of the invention, the ratio of monomer to TEMED is relatively constant from batch to batch and is not used to control the rheological properties of the polymer. In embodiments wherein the polymer is polyacrylamide, the ratio of monomer acrylamide and methylene-bis-acrylamide to TEMED is about 100: 1 to 700: 1, such as 200: 1 to 600: 1, generally 200: 1 to 500: 1, preferably 200: 1 to 400: 1, most preferably 200: 1 to 350: 1.

Likewise, the relative amounts of monomers (acrylamide and methylene-bis-acrylamide) are substantially constant from composition to composition relative to the amount of initiator. Thus, in a preferred embodiment of the process of the invention, the ratio of monomer to initiator is relatively constant from batch to batch and is not used to control the rheological properties of the polymer. In embodiments where the polymer is polyacrylamide, the ratio of monomer acrylamide and methylene-bis-acrylamide to initiator is about 100; 1 to 700: 1, such as 200; 1 to 600: 1, generally 200: 1 To 500: 1, preferably 200: 1 to 400: 1, most preferably 200: 1 to 350: 1.

The viscosity of the hydrogel is suitably injectable. In a typical embodiment, the complex viscosity of the hydrogel is about 2 to 20 Pa s, such as about 3 to 18 Pa s, preferably about 3 to 15 Pa s, most preferably about 2 to 13 Pa s.

The hydrogels of the present invention are virtually free of substances that occupy high content other than acrylamide, methylene-bis-acrylamide and residual (if any) initiators. Hydrogels actually do not have any other polymer components. The hydrogel also further contains at least 75% by weight pyrogen-free water or saline solution, preferably pyrogen-free water. In a suitable embodiment of the invention, the hydrogel contains at least 80% by weight of pyrogen-free water or saline solution, preferably at least 85% by weight, more preferably at least 90% by weight, more preferably at least 95% by weight. Contains pyrogen-free water or saline solution.

Osmomol concentration of the appropriate saline solution is similar to that of the intestinal fluid. Suitable saline solutions include, but are not limited to, 0.25-1% sodium chloride solution, Ringer-Lockart solution, Earle solution, Hanks solution, Eagle medium, 0.25-1% glucose solution, potassium chloride solution, and calcium chloride solution. In a preferred embodiment, the saline solution is an aqueous 0.8-1% sodium chloride solution, such as an aqueous 0.8, 0.9, or 1% sodium chloride solution, most preferably about 0.9% aqueous sodium chloride solution.

As will be appreciated by those skilled in the art, the high content of gels in embodiments in which saline solutions are used for the preparation and / or cleaning of the gels will be higher than that occupied by polyacrylamide, but usually at an additional 1%. It will not exceed.

In a particularly suitable embodiment of the invention, the hydrogel contains about 2.5% by weight of polyacrylamide and about 97.5% by weight of pyrogen-free water relative to the total weight of the hydrogel.

A pyrogen-free water or saline solution is used for the cleaning process. The washing process partially serves to remove trace amounts of monomer acrylamide and N, N'-methylene-bis-acrylamide. These monomers not only adversely affect the stability of the hydrogel, but are also toxic to patients. The washing process has a concentration of monomer acrylamide and N, N'-methylene-bis-acryrangamide of less than 50 ppm, more preferably less than 40 ppm, such as less than 30 ppm, most preferably less than 20 ppm, typically Is preferably carried out to less than 10 ppm, particularly preferably less than 5 ppm.

In another embodiment of the present invention, the hydrogel is implantable intraarticular because of its higher solidconsistency. In this embodiment where the hydrogel is tacky, the hydrogel can be surface-modified to minimize slip from the site where it is implanted. Surface modification can be inherently chemical or physical. Hydrogels having a high solids content, such as those suitable for implantation and very easy to modify the surface, have been prepared rather than suitable for injection.

In embodiments where the hydrogel is implantable, the viscosity of the solid sample is clearly very high. In embodiments in which the hydrogel is implantable, the complex viscosity of the hydrogel is about 20-1500 Pa s, generally 20-1000 Pa s.

In embodiments of this aspect of the invention wherein the hydrogel is implantable and further surface-modified, when the hydrogel is surface modified by chemical treatment, such chemical treatment results in 1% of the hydrogel weight relative to the total hydrogel weight. It is expected to occupy less. The chemical treatment may be using a topical acting agent to chemically modify the polyacrylamide at the surface coating or hydrogel surface.

The hydrogels of this aspect of the invention are used for the production of internal prostheses to be inserted into the intra-articular cavity of the joint. The gel is intended to be used as an internal prosthetic device in treating arthritis. The internal prosthetic device of the present invention consists of a polyacrylamide hydrogel containing 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel and is administered to the internal joint lumen of the joint.

The prosthetic device can be any embodiment of the hydrogel described above. Thus, such a prosthetic device enlarges or replaces the cartilage of the internal joint cavity of the joint, wherein the device comprises a polyacrylamide hydrogel containing 0.5 to 25 weight percent polyacrylamide based on the total weight of the hydrogel. . Hydrogels in the prosthetic device of the invention generally further comprise at least 75% by weight of pyrogen-free water or saline solution, preferably pyrogen-free water. It may be administered by injection or implantation into the internal joint cavity of the joint. Preferably, the device is injected.

The prosthetic device of the present invention may have a viscosity that can be injected. In embodiments in which the hydrogel is injected, the complex viscosity of the hydrogel is about 2 to 25 Pa s, such as about 3 to 20 Pa s, preferably about 3 to 18 Pa s, most preferably about 3 to 15 Pa s For example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 Pa s.

In embodiments where hydrogel is injected into a weight bearing joint, the elasticity of the hydrogel and the prosthesis is an important issue. In a preferred embodiment, the elastic module of the hydrogel of the present invention is about 1 to 200 Pa, such as about 2 to 175 Pa, generally about 5 to 150 Pa, such as about 10 to 100 Pa.

The elastic module and composite viscosity of the prosthetic device are generally related by a factor of 5.8 to 6.4. The present invention therefore provides a preferred hydrogel incorporating elastic properties that provide the ability to withstand viscosity and weight suitable for injection. In a preferred binding embodiment, the hydrogel has a composite viscosity of less than 25 Pa s and the elastic module is less than 200 Pa, preferably the composite viscosity is less than 15 Pa s and the elastic module is less than 100 Pa.

Examples 1, Tables 1, 2, and 3 describe suitable conditions for preparing exemplary examples of hydrogels. In a preferred bonding embodiment having a viscosity of less than 25 Pa s and an elastic module of less than 200 Pa, such as a composite viscosity of less than 15 Pa, less than 100 Pa of elastic module, the hydrogel may have a dry-weight content percentage array.

Further, in preferred binding embodiments with a viscosity of less than 25 pa s and an elasticity of less than 200 Pa, such as a composite viscosity of less than 15 Pa s and an elasticity of less than 100, the acrylamide and methylene-bis-acrylamide molar ratio of about 275 to Hydrogels can be obtained by binding at a ratio of 1000, generally 300 to 800, preferably about 300 to 500.

The hydrogels of the present invention not only provide lubricity in the joint but also exhibit resiliency against mechanical stress. This mimics the binding of naturally occurring cartilage to synovial fluid in the joints. Articular cysts are produced by the synovial membrane and form at the interface of both the cartilage of the joint and the synovial membrane. It functions to nourish cartilage, absorb lubrication, load bearing and absorb shock (see Gomez and Thurston, BIotheology 30, 409-427 (1993)). Joint salivary fluid is a solution of a highly sophisticated polymer composite made of linear hyaluronic acid backbone with protein branches, with an elastic modulus G 'of 60 Pa and a composite viscosity of about 1-10 Pa s. Certain embodiments of the hydrogels of the present invention generally have viscosities and elastic modules very similar thereto.

Joint sac fluid is a very long tooth and has a time (about 100 seconds). Relaxation time is defined as the time taken for stress to collapse to 37% of its initial value in a stress relaxation experiment. The long relaxation time in this way means a rapid movement (response as a very elastic material at zero when stress is suddenly applied, while acting like a lubricant at low stress. The low viscosity composition of the hydrogel of the present invention) Is like a fluid, so when homogenized, it has a very long relaxation time, like a liquid, and exhibits a liquid-like property of the articular cyst.The present invention thus injects isotonic (NaCl) water, eg lasting only 1-3 days. Or an injection of hyaluronic acid solution, which is faced with resorption problems, provides an excellent alternative to prior art arthritis.

As noted above, in embodiments in which the hydrogel has a low viscosity composition, at least in part, the hydrogel attempts to mimic the properties of articular sac. Joint fluid in that the hydrogel is a highly elastic material having an infinite relaxation time, in embodiments having a higher viscosity of the hydrogel, such as a viscosity above 10 Pa s, eg above 15 Pa s. It further mimics the combined properties of and cartilage.

In view of the resilience to mechanical stress, the hydrogels of the present invention have demonstrated a complete reconstruction behavior. In addition, the elastic properties of the hydrogel of the present invention allows the hydrogel to return to its starting position when releasing stress in a creep experiment.

Cartilage present in the joint or joints may have increased lubricity, increased load bearing capacity, or joints such as knee joints; Hip joint; Prostheses may be administered into the internal joint cavity array if it requires increased protection of the bone opposite the joint, such as but not limited to metacarpal-phalangeal joints and interpharlangeal joints of the elbow, hands and feet Can be.

Proper positioning and placement of hydrogels are critical to the delivery of the device to the patient. To aid in the positioning of the gel, it is useful to the operator to visualize the location of the prosthetic device. For embodiments in which the device is administered by injection, it is advantageous to visualize the device to establish the location and required amount of the device. Visualization of the hydrogel at the time of administration can be facilitated by radio-labeling the hydrogel. Thus, in one preferred embodiment, the hydrogels are preferably radiolabeled.

As mentioned above, the surface treatment of the hydrogel can help to secure autonomy in the joint cavity. However, in embodiments of injectable hydrogels, the prosthetic device may be secured by bone tissue that delimits the joint cavity into which the gel is injected.

In addition, as described above, one aspect of the present invention is to prepare an internal prosthesis for the relief or prevention of symptoms associated with arthritis, containing polyacrylamide in an amount of about 0.5 to 25% by weight relative to the total amount of hydrogel It relates to the use of a hydrogel. Accordingly, the method of the present invention may be defined as a method of treating or preventing arthritis, comprising administering to a mammal a hydrogel containing polyacrylamide in an amount of 0.5 to 25% by weight relative to the total weight of the hydrogel. There will be. The method comprises using the hydrogel as defined above and the internal prosthesis as defined above.

The method may comprise a first series or treatment session injecting or implanting the device, followed by analyzing, evaluating or attempting to assist with the degree of assistance provided by the device and further treatment series if necessary. In embodiments where the joints need to primarily increase the load bearing capacity, the support or elasticity provided by the prosthesis may weaken over time. However, one advantage of the method of the present invention is that the injectable composition of the prosthetic device can be administered to augment an existing device. This treatment can be repeated as needed by the patient to alleviate the pain associated with the symptoms. Similarly, when the prosthesis is administered primarily to increase the lubricity of the joints, and when the resilience of the prosthetic device decreases over time, the method of the present invention can be repeated as needed with only a simple injection.

Polyacrylamide Hydrogel for Penis Plastic Surgery

Still another object of the present invention is to provide i) a use for the preparation of an internal prosthesis for penile enlargement of a hydrogel comprising less than 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel. This method of enlarging the penis size, which comprises administering a polyacrylamide hydrogel containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel, is generally carried out by means of injection. Administration by means of injection is carried out into the cavernous tissue.

Hydrogels generally comprise further water or saline solutions that are at least 95% pyrogen free. Thus, a particularly interesting embodiment is an internal prosthesis for penile enlargement of a hydrogel comprising i) 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel and ii) at least 95% pyrogen-free water or saline solution, Preferably for use in the manufacture of injectable internal prostheses. The complex viscosity of the injectable prosthesis for penis enlargement is generally less than 20 Pa s, such as less than 18 Pa s, preferably less than 15 Pa s. In addition, the elastic module of the internal prosthesis is generally less than 150 Pa, generally less than 100 Pa.

Another object of this aspect of the present invention is penile enlargement of a hydrogel comprising i) polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) a pyrogen-free water or saline solution. To provide an implantable internal prosthetic manufacturing use for. This method of enlarging penis size consists of implanting polyacrylamide hydrogel internal prostheses comprising i) polyacrylamide in an amount greater than 9.5% by weight, and ii) pyrogen-free water or saline solution. By implanting or injecting the device.

The hydrogel for penis enlargement prosthetic device comprising at least 9.5% by weight of polyacrylamide is at least 10 9.5 Pa s, such as at least 15 Pa s, preferably at least 20 Pa s, more preferably at least 30 Pa s Most preferably have a complex viscosity of at least 40 Pa s. High viscosity gels are suitable for implantation and have semi-flacid to semi-rigid viscosity suitable for this purpose.

Polyacrylamide Hydrogel for the Treatment of Esophagitis

Another object of the present invention is to treat (reflux) esophagitis of a hydrogel comprising i) polyacrylamide in an amount greater than 6% by weight relative to the total weight of the hydrogel and ii) a pyrogen-free water or saline solution. To provide a use for the production of internal prostheses. In a suitable embodiment, the hydrogel contains polyacrylamide in an amount greater than 7, 8, or 9%. Treatment of this (reflux) esophagitis, comprising implanting or injecting a polyacrylamide hydrogel internal prosthesis containing polyacrylamide in an amount greater than 6% by weight relative to the total weight of the hydrogel, involves implanting an internal prosthetic device or By injection, this can typically be done by injection or implantation into the submucosal layer of tissue.

Another object of the present invention is to provide an internal treatment for (reflux) esophagitis of a hydrogel comprising i) less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel and ii) a pyrogen-free water or saline solution. It is to provide a use for the production of prostheses. This method for treating (reflux) esophagitis may be by implanting or injecting a hydrogel containing polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel. i) In the treatment of (reflux) esophagitis with hydrogels containing less than 3.5% by weight of polyacrylamide, the hydrogels generally further contain at least 95% by weight of water or saline solution and are usually treated by injection. Is done. In these embodiments, the degree of crosslinking preferably has a viscosity of at least 6.0 Pa s, such as 6.0 to 90 Pas, such as 10 to 80 Pas, preferably 20 to 80 Pas. The degree of crosslinking of the hydrogels used in the manufacture of internal prostheses for the treatment of reflux esophagitis may be such that the elastic module is about 50 to 700 Pa, such as 75 to 600, such as 100 to 500, preferably about 200 to 500 Pa. . In general, the complex viscosity of the hydrogel is preferably at least 20 Pa s, more preferably at least 30 Pa s, most preferably at least 40 Pa s.

The present invention will be described in more detail with reference to the following Examples, but the present invention is not limited to these Examples in any way.

Example

Example 1

Preparation of Hydrogel

The gel is a polyacrylamide gel prepared by polymerizing N, N'-methylene-bis-acrylamide and acrylamide monomers. The viscosity of the finished product can be different.

The experimental formula of the hydrogel is [C ₃ H ₅ NO] _x [C ₇ H ₁₀ N ₂ O ₂ ] _y , the structural formula is as shown in FIG.

Hydrogels generally contain about 95% water. The concentrations of the monomers acrylamide and N, N'-methylene-bis-acrylamide were found to be less than 10 ppm and are suitable concentrations for the desired stability of the final product, usually less than 5 ppm.

The finished product should be pH-appropriate, free of heavy metals, have adequate refractive index and stability, free of pyrogen, sterilized, inert and indeed free of monomers.

Preparation Example 1.1

The synthesis method is suited to the following operating sequence:

1. Prepare two mixtures A1 and A2. A1 contains water, acrylamide, N, N'-methylene-bis-acrylamide, N, N, N ', N'-tetramethylene-ethylene-diamine (TEMED). A2 contains water and ammonium persulfate;

2. Combine the two mixtures with 1990 mL of Al at a rate of 10 mL and then keep at 45 ° C. to degas nitrogen for 20 seconds;

3. Cast (cast) the reaction mixture into several 100 mL beakers;

4. Polymerize for 0.5 to 1.5 hours.

5. Remove the gel from the mold.

6. The remaining monomers are extracted and equilibrated in WFI water for 92 hours, then the water is changed several times, usually eight times, for 92 hours.

7. Grind the purified gel using a vertically oscillating grid;

8. Fill the syringe with homogenized gel material;

9. Autoclave the syringe.

Typical methods of making hydrogels can be summarized as follows:

Preparation Example 1.2

Summary of Manufacturing Process: Aqueous monomer solution of acrylamide (AM) and N, N'-methylene-bis-acrylamide (BISAM) as crosslinking agent is used as co-initiator N, N, N ', N'-tetra Gels are prepared by mixing with methylene ethylene diamine (TMED) and ammonium persulfate (APS) as free-radical initiator (redox system). After the last polymerization, the gel is transferred to a wash tank equipped with a net tray where the gel is to be placed. The gel swells while washing with water and the monomer residue is extracted. The swollen gel is filled and introduced into a filling unit with the gel transferred to a syringe and then autoclaved.

Two alternating compositions, ie lower- and upper-viscosity compositions, were prepared. Both compositions have a high content of less than 3.5% and complex viscosities ranging from 2 to 50 Pa s, generally 3 to 20 Pas.

The above is a typical preparation of the hydrogel and can be adjusted within a specific range.

Preparation Example 1.3

Polyacrylamide Compositions from Inline Crosslinking Process

Particularly interesting methods of preparing the hydrogels of the present invention relate to the inline cross-linking process. Two separate, actually degassed flows, one of which is a pre-mix of acrylamide, bis-methylene acrylamide (crosslinker) and TEMED, and the other is an AMPS initiator solution, are pumped and mixed into an electrostatic mixer for chemical initiation and subsequently Teflon. Or injected downstream into a pipe reactor made of steel, in which polymerization takes place. Washing of the gel is simple because the surface area of the gel from the reactor is large.

By selecting monomer, crosslinker and initiator concentrations and their relative molar ratios, and by controlling the two flow rates and polymerization temperatures, it is possible to make gels that differ in crosslinking degree and high degree of content.

Preparation Example 1.4

The reagents were combined in the proportions described in Tables 2, 3, and 4 and then washed as described in these tables to produce low, medium and high viscosity compositions (with water without pyrogen unless otherwise stated). Hydrogels having a high content of 0.5 to 25 polyacrylamide weight percent were prepared.

Table 2 (continued)

a) The cleaning was a dilution because the material was a liquid.

b) infinite

c) Since washing was dilution rather than extraction, residual monomers only decreased by dilution parameters (from 508 ppm to 254 ppm).

d) casting (casting) and washing with 0.9% aqueous NaCl solution

e) casting with water; Washing was performed using 0.9% NaCl aqueous solution

f) pre-wash value—washing generally reduces the value by 30-50%

g) pre-wash value—washing generally reduces the value by 20-40%

h) very sensitive to notches

i) The non-uniformity of the measurement may be due to the technique of performing the measurement or the location of the batch from which the sample was taken.

Example 2

Hydrogel Analysis

Characterization of the gel

The washed hydrogel will have the general characteristics outlined next.

Example 3

Swelling will occur during the washing step and will generally exhibit a swelling profile as shown in FIGS. 2 and 3.

Example 4

Administration method in reflux esophagitis

Treatment by injection

Polyacrylamide hydrogels (2.5% high and about 97.5% pyrogen-free water) are injected under the mucosa of the connective duct from the stomach to increase the density of the bronchus or duct. This is done for a short course with very little complication.

Example 5

Administration method for body contouring

Treatment by injection

a) Injection of the gel can be performed under local anesthesia.

b) This process must be carried out under sterile conditions. The drug should not be injected into the gel.

c) The gel is prefilled with 1 mL of luer-lock sterile syringe and subcutaneously injected using a thin gauge needle, such as a 27 G needle. The needle must be CE-labeled.

d) Subcutaneously inject the required amount of gel in a retrograde manner by injecting the gel with the needle removed. The patient's record label is removable from the patient record so that the product can be tracked as part of the package.

e) After scanning is complete, light treatment may be performed to distribute the gel to a uniform and desired location. The injected gel will form a stable, soft part of the connective tissue and will provide a long lasting cosmetically pleasing appearance.

f) Additional injection sessions may be performed to achieve the desired effect.

Transplant treatment

Gels optionally sealed in the silicone-based envelope are placed subcutaneously into the soft tissue of the patient.

Example 6

Administration method in reflux esophagitis

Treatment by injection

Polyacrylamide hydrogels (2.5% high and about 97.5% pyrogen-free water) are injected under the mucosa of the duct between the esophagus and the stomach, such as, for example, to strengthen the sphincter to increase the density of the duct. This is done with a short course with almost no complications.

Example 7

Dosing method for body contour surgery

Treatment by injection

a) Injection of the gel can be performed under local anesthesia.

b) This process must be carried out under sterile conditions. The drug should not be injected into the gel.

c) The gel is prefilled with 1 mL of luer-lock sterile syringe and subcutaneously injected using a thin gauge needle, such as a 27 G needle. The needle must be CE-labeled.

d) Subcutaneously inject the required amount of gel in a retrograde manner by injecting the gel with the needle removed. The patient's record label is removable from the patient record so that the product can be tracked as part of the package.

e) After scanning is complete, light treatment may be performed to distribute the gel to a uniform and desired location. The injected gel will form a stable, soft part of the connective tissue and will provide a long lasting cosmetically pleasing appearance.

f) Additional injection sessions may be performed to achieve the desired effect.

Transplant treatment

Gels optionally sealed in the silicone-based envelope are placed subcutaneously into the soft tissue of the patient.

Example 8

Dosing method for soft tissue filling

a) Injection of the gel may be performed under local anesthesia, but for the correction of wrinkles and folds, local anesthesia is not necessary. For lip expansion, anesthesia via nerve block is recommended.

b) This process must be carried out under sterile conditions. The drug should not be injected into the gel.

c) The gel is prefilled with 1 mL of luer-lock sterile syringe and subcutaneously injected using a thin gauge needle, such as a 27 G needle. The needle must be CE-labeled.

d) Subcutaneously inject the required amount of gel in a retrograde manner by injecting the gel with the needle removed. The patient's record label is removable from the patient record so that the product can be tracked as part of the package.

e) After scanning is complete, light treatment may be performed to distribute the gel to a uniform and desired location. The injected gel will form a stable, soft part of the connective tissue and will provide a long lasting cosmetically pleasing appearance.

f) Additional injection sessions may be performed to achieve the desired effect.

Postoperative Course

If you have edema, you can ice it locally. Initial exposure to sunlight or extreme cold or heat is recommended until swelling and redness are alleviated.

Bad situation / side effects

It is not uncommon for a patient to feel pain within the first 2-3 days after surgery. In the first 2-3 days after the injection, some patients will develop mild edema.

Orthodontic injection techniques are critical to the final outcome of the treatment and must be performed by an authorized practitioner.

The gel is sterilized (eg by wet heating or autoclaving). If the package is damaged or opened unused, the sterilization cannot be assured and the contents should be discarded. Resterilization is not advisable.

Example 9

Clinical Trials for Soft Tissue Filling

1) About 900 patients underwent facial correction using gel. Overall cosmetic results were very good and the frequency of adverse events was only 0.02% (Kovanskaya V.A .: Scientific conference, 13-16 October 2000).

2) A total of 150 adult subjects were treated with injectable gel to correct facial defects. The injection amount of gel was 0.2-11 mL.

Schedule visits to patients on screening dates (day 3 to day 3), day 0 (first day of injection), days 7, 28, 3 months, 6 months and finally 12 months Conduct vital sign tests, pregnancy tests, blood and serum assays, hematology tests, immunology tests, urinalysis, collateral therapy, analysis of side effects and various conditions, and analysis of cosmetic results by patients and practitioners. And completed various surveys according to the other schedules in Table 6.

result

The overall score of the surgical results was very good in both the patient and the surgeon. In some cases, patients hoped to continue injecting further treatment. Some surgeons responded voluntarily to the questionnaire that patients were satisfied with the results and that the gel was easy to handle and easy to administer.

The gel was very well tolerated. Only a few adverse events were recorded, and adverse edema and inflammation were reported by the patient. The bad situation naturally resolved a few days later.

Example 10

Dosing Methods and Clinical Results for Incontinence Treatment

Treatment by injection

Polyacrylamide hydrogels (2.5% high and about 97.5% pyrogen-free water) were injected under the urethral mucosa to increase urethral density, with little short-term complications.

This medical procedure involves injecting a polyacrylamide gel under the urethral mucosa of a woman with incontinence. Injection is performed through the outer surface of the urethra into the membrane of the submucosal tissue. Three depots were injected into three depots along one longitudinal direction of the urethra. These depots were 0.5 cm away from the cystoscope.

Injections were performed under local anesthesia to allow the bladder to be subsequently filled and to sneeze the patient to see immediately whether sufficient density was achieved for urinary incontinence treatment. If not effective, the injection can be repeated, which is common in treatment by injection.

According to the criteria and regime of the Gynecological-Obesity Department of Copenhagen's Amstsygehus (Local Hospital) in Glostrup, the results of the injections of these female patients were found to be adequate. Treatment results and any complications were monitored at the screening every three months for one year after the procedure.

The polyacrylamide hydrogel provided in the present invention can be used to prepare biostable and biocompatible prosthetic devices for treating incontinence, arthritis, breast plastic surgery and reflux esophagitis as a cosmetic surgery, soft tissue filling internal prosthesis. Can be.

Claims (61)

A hydrogel containing less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel, Wherein the hydrogel can be obtained by combining acrylamide and methylene bis-acrylamide followed by radical initiation and washing with a pyrogen-free water or saline solution; The hydrogel is biocompatible; The bonding ratio is a hydrogel in a molar ratio of 150: 1 to 1000: 1. a hydrogel comprising i) less than 3.5% by weight of polyacrylamide, crosslinked with methylene-bis-acrylamide relative to the total weight of the hydrogel, and ii) water or saline solution free of at least 95% pyrogen. injectable hydrogel comprising i) less than 3.5% by weight of polyacrylamide, crosslinked with methylene-bis-acrylamide relative to the total weight of the hydrogel, and ii) at least 95% pyrogen-free water or saline solution As internal or implantable internal prosthesis. The hydrogel of claim 1 further comprising at least 95% pyrogen-free water or saline solution. The polyacrylamide according to any one of claims 1 to 3, containing at least 0.5% by weight, such as at least 1% by weight, preferably at least 1.5% by weight, such as at least 1.6% by weight, based on the total weight of the hydrogel. Hydrogel. The hydrogel according to any one of claims 1 to 3, wherein the complex viscosity is at least 2 Pas, such as at least 3, 4, or 5 Pas. The compound viscosity of claim 1, wherein the complex viscosity is about 2 to 90, such as about 5 to 80 Pas, preferably about 6 to 76, such as about 6 to 60, 6 to 40, 6 to 20, Hydrogels such as 6 to 15 Pas. The elastic module according to claim 1, wherein the elastic module is at least 10 Pa, such as at least 20 Pa, at least 25 Pa, at least 30 Pa, at least 31 Pa, at least 32 Pa, at least 33 Pa, at least 34 Pa, or 35. Hydrogels of at least Pa, such as at least 38 Pa. A hydrogel according to any one of claims 1 to 3, having an elastic module of about 10 to 700 Pa, such as about 35 to 480 Pa. 4. The hydrogel according to claim 1, wherein the degree of crosslinking of the polyacrylamide is such that the effective crosslinking density is from about 0.2 to 0.5%, preferably from about 0.25 to 0.4%. 2. Hydro according to claim 1, wherein the molar ratio is 175: 1 to 800: 1, such as 225: 1 to 600: 1, preferably 250: 1 to 550: 1, most preferably 250: 1 to 500: 1. Gel. 4. The hydrogel of claim 3, wherein the implantable internal prosthesis optionally comprises a silicone-based envelope containing the hydrogel. Implantable or injectable internal prosthesis comprising a hydrogel as defined in any one of claims 1 to 2. 14. The internal prosthesis of claim 13 further comprising a silicon-based envelope containing a hydrogel. Internal prostheses for cosmetic surgery, regenerative surgery and treatment of hydrogels comprising i) less than 3.5% by weight of polyacrylamide crosslinked with methylene bis-acrylamide and ii) at least 95% pyrogen-free water or saline solution Use for the manufacture of. 16. The use according to claim 15, wherein the internal prosthesis is used for the purpose of breast augmentation or regeneration, treatment of reflux esophagitis, body contouring and penis enlargement. Use according to claim 15, wherein the internal prosthesis is injectable. 17. The use according to claim 16, wherein the internal prosthesis for breast regeneration is implantable and further comprises a silicone-based envelope containing the hydrogel. Use of the preparation of an internal prosthesis for breast augmentation or regeneration of a hydrogel comprising i) polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) a pyrogen-free water or saline solution. 20. The use of claim 19, wherein the internal prosthesis further comprises a silicone-based envelope that is implantable and contains a hydrogel. Use of the preparation of an internal prosthesis for penis enlargement of a hydrogel, comprising i) less than 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel, and ii) at least 95% pyrogen-free water or saline solution. Use of the preparation of implantable internal prostheses for penile enlargement of a hydrogel comprising i) polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) pyrogen-free water or saline solution. 23. Use according to claim 22, wherein the complex viscosity of the hydrogel is at least 10 Pa s, such as at least 15 Pa s, preferably at least 20 Pa s, more preferably at least 30 Pa s, most preferably at least 40 Pa s. . The use of claim 21, wherein the internal prosthesis is injectable. Use of the preparation of implantable internal prostheses for body contouring of hydrogels comprising i) polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) pyrogen-free water or saline solutions. . Use of the preparation of internal prostheses for the treatment of (reflux) esophagitis of hydrogels comprising i) polyacrylamide in an amount greater than 6% by weight relative to the total weight of the hydrogel, and ii) pyrogen-free water or saline solutions. . Use of the preparation of an internal prosthesis for the treatment of (reflux) esophagitis of a hydrogel comprising i) less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel, and ii) a pyrogen-free water or saline solution. Use according to any of claims 16 to 17, wherein the internal prosthesis further comprises a silicone-based envelope containing the hydrogel. Hydrogel comprising combining acrylamide and methylene bis-acrylamide followed by radical initiation and washing with pyrogen-free water such that the polyacrylamide content is less than 3.5% by weight relative to the total weight of polyacrylamide Manufacturing method. 30. The method of claim 29, wherein the hydrogel contains at least 1.5 weight percent polyacrylamide, such as at least 1.6 weight percent polyacrylamide, relative to the total weight of the hydrogel. The method of claim 29, wherein the washing step comprises swelling the product of the radical initiation step until the composite viscosity is about 6 to 100 Pas. 30. The method of claim 29, wherein the washing step comprises swelling the product of the radical initiation step until the elastic module is between about 10 and 700 Pa, such as between about 35 and 480 Pa. 30. The method of claim 29, wherein the washing step comprises swelling the product for 50 to 250 hours, more generally 70 to 200 hours. The method of claim 29, wherein the bonding ratio of acrylamide and methylene bis-acrylamide is about 150: 1 to 1000: 1. The method of claim 34 wherein the ratio of acrylamide to methylene bis-acrylamide is from about 175: 1 to 800: 1, such as from about 225: 1 to 600: 1, preferably from about 250: 1 to 550: 1, most preferred. Preferably about 250: 1 to 500: 1. a) preparing a polyacrylamide hydrogel containing less than 3.5% by weight of polyacrylamide crosslinked using methylene bis-acrylamide, b) A method of treating cosmetic or functional defects using injectable or implantable biocompatible internal prostheses, comprising injecting or implanting a sufficient amount of said hydrogel into a cosmetically or functionally defective body part. 37. The polyacrylamide hydrogel of claim 36, wherein the polyacrylamide hydrogel comprises at least 0.5% by weight of polyacrylamide, such as at least 1% by weight, such as at least 1.5% by weight, i.e. at least 1.6% by weight, based on the total weight of the hydrogel. By the way. 37. The method of claim 36, wherein the preparation of the hydrogel is according to the method as defined in any one of claims 29 to 35. The method of claim 36, wherein the internal prosthesis is for breast augmentation or regeneration, treatment of reflux esophagitis, contouring, and penis enlargement. The method of claim 39, wherein the internal prosthesis for mammary augmentation or regeneration is injectable or implantable. 40. The hydrogel of claim 39 wherein the hydrogel contains less than 1.6 weight percent polyacrylamide relative to the total weight of the hydrogel and the internal prosthesis for breast regeneration is implantable and the internal prosthesis is a silicone-based envelope. Optionally further comprising. 43. The method of claim 42, wherein the hydrogel comprises at least 1 weight percent polyacrylamide relative to the total weight of the hydrogel. Implanting an internal prosthesis made of polyacrylamide hydrogel, comprising polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) at least 75% pyrogen-free water or saline solution. A method for cosmetically modifying a breast of a mammal, or for performing partial or complete breast augmentation, comprising. A method of enlarging a penis size comprising administering a polyacrylamide hydrogel containing less than 3.5 weight percent polyacrylamide relative to the total weight of the hydrogel. enlargement of the penis, comprising implanting an internal prosthesis made of polyacrylamide hydrogel comprising i) polyacrylamide in an amount greater than 9.5% by weight, and ii) pyrogen-free water or saline solution. Way. A polyacrylamide hydrogel internal prosthesis comprising a polyacrylamide in an amount greater than 9.5% by weight relative to the total weight of the hydrogel, and ii) a pyrogen-free water or saline solution Cosmetic transformation of the body of the body (body contouring) method. A method of treating (reflux) esophagitis comprising implanting or injecting a polyacrylamide hydrogel prosthesis containing polyacrylamide in an amount greater than 6% by weight relative to the total weight of the hydrogel. Combining acrylamide and methylene bis-acrylamide to contain polyacrylamide in an amount of about 0.5 to 25% by weight relative to the total weight of the hydrogel; Radical initiation; Hydrogel for use in the treatment or prevention of arthritis, which can be obtained by washing with a pyrogen-free water or saline solution. Combining acrylamide and methylene bis-acrylamide to contain polyacrylamide in an amount of less than 3.5% by weight relative to the total weight of the hydrogel; Radical initiation; A hydrogel for use as a soft tissue filled internal prosthesis, obtainable by washing with a pyrogen-free water or saline solution. Combining acrylamide and methylene bis-acrylamide to contain polyacrylamide in an amount of about 0.5 to 25% by weight relative to the total weight of the hydrogel; Radical initiation; A bio-stable hydrogel for use in the treatment or prevention of incontinence and bladder tract reflux, which can be obtained by washing with a pyrogen-free water or saline solution. Use of a hydrogel containing about 0.5 to 25 weight percent polyacrylamide relative to the total weight of the hydrogel for the relief or prevention of symptoms associated with arthritis. Use of the preparation of hydrogels containing soft tissue filling internal prostheses, wherein the hydrogel contains less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel. The hydrogel in the preparation of an internal prosthesis for use in the treatment or prevention of incontinence and bladder urinary regurgitation comprising administering to a mammal a hydrogel containing 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel. Use of the gel. A method of treating or preventing arthritis, comprising administering to a mammal a hydrogel containing 0.5 to 25 weight percent polyacrylamide relative to the total weight of the hydrogel. Urethra to treat urinary incontinence, anal incontinence and bladder urinary regurgitation, respectively; Rectal or colon; And a prosthetic device for increasing the resistance of the intracavitary selected from the ureters; Wherein the device is injectable and comprises a hydrogel containing i) 0.5 to 25% by weight of polyacrylamide and ii) pyrogen-free water or saline solution relative to the total weight of the hydrogel. A prosthetic device for the treatment of arthritis comprising a polyacrylamide hydrogel containing 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel, wherein the device is administered into the internal joint cavity of the joint . A prosthetic device for augmenting or replacing cartilage in the internal joint cavity of a joint, comprising polyacrylamide hydrogel containing 0.5 to 25% by weight of polyacrylamide relative to the total weight of the hydrogel. A method of filling soft tissues comprising administering an internal prosthesis comprising a hydrogel containing less than 3.5% by weight of polyacrylamide relative to the total weight of the hydrogel. Combining acrylamide and methylene bis-acrylamide such that the polyacrylamide content is less than 3.5% by weight relative to the total weight of the hydrogel; Radical initiation; An injectable prosthetic device for soft tissue enlargement comprising a polyacrylamide hydrogel obtained by washing with a pyrogen-free water or saline solution. 60. The hydrogel of claim 59, wherein the hydrogel is at least 0.5% by weight of polyacrylamide, preferably at least 1% by weight of polyacrylamide, more preferably at least 1.5% by weight of polyacrylamide, such as Prosthetic device containing at least 1.6% by weight of polyacrylamide relative to the total weight of the hydrogel. 61. The prosthetic device of any of claims 55, 59, and 60, further comprising cells, such as stem cells, for cell engraftment into surrounding tissue.