KR100532837B1 - Injectable bulking agent using biodegradable polymers for urinary incontinence treatment - Google Patents

Abstract

The present invention relates to a biodegradable polymer injectable agent that shows excellent efficacy for treating urinary incontinence, and more particularly, to a biodegradable polymer that forms a dense layered structure upon injection into a biodegradable polymer which is in solution in vitro but solidifies in the body. The present invention relates to an injectable drug product that has the ease of injection injection, stability in the body, and long-term volume retention performance by mixing the polymer fine particles, and forms a densely laminated structure due to the biodegradable polymer that solidifies initially when injected into the body as a urinary incontinence drug. It is suppressed that the polymer particles are remotely moved to other organs or tissues, thereby maintaining the volume and form of the injected injectable drug, and as the biodegradable polymers are gradually decomposed over time, the surrounding tissue is filled into the space. Maintain initial injection volume for a long time The present invention relates to an injectable drug for urinary incontinence treatment, which has excellent stability and volume retention in the body, which can solve all problems of the conventional injectable incontinence drug.

Description

Injectable bulking agent using biodegradable polymers for urinary incontinence treatment}

The present invention relates to a biodegradable polymer injectable agent that shows excellent efficacy for treating urinary incontinence, and more particularly, to a biodegradable polymer that forms a dense layered structure upon injection into a biodegradable polymer which is in solution in vitro but solidifies in the body. The present invention relates to an injectable drug product that has the ease of injection injection, stability in the body, and long-term volume retention performance by mixing the polymer fine particles, and forms a densely laminated structure due to the biodegradable polymer that solidifies initially when injected into the body as an incontinence treatment Remote migration (migration) of the polymer particles to other organs or tissues is suppressed, thereby maintaining the volume and form of the injected injection, and gradually decomposing the biodegradable polymer over time into the surrounding tissues. To keep the initial volume injected for a long time The present invention relates to an injectable drug for treating urinary incontinence, which is excellent in stability and volume retention in the body, which can solve all problems of existing injectable incontinence drugs.

Urinary incontinence is defined by the International Urinary Incontinence Society as causing social or hygiene problems beyond urinary leakage, irrespective of one's will (P. Abrams, et al., "Standardization of terminology of lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society ", Neurourol. Urodyn. , 21, 167-178 (2002)). The incidence of urinary incontinence complains of urinary incontinence in about 30% of the middle-aged female population in Korea, and the incidence in the elderly is much higher, and it is reported that the incidence of urinary incontinence is more than 40% when it is housed in a protective facility. Urinary incontinence is not life-threatening like tumors or other wasting diseases, but it can gradually become isolated and cause mental disorders due to discomfort, shame, and the constraints of social activities caused by incontinence (TW Hu, "Impact of urinary incontinence on health -care costs ", J. Am. Geriatr. Soc. , 38, 292-295 (1990)). Urinary incontinence can be divided into three types, which are shown below.

-Stress incontinence

Stress urinary incontinence is urine discharged unknowingly when you laugh, sneeze, jump, etc. If severe, even when walking or sitting, the urine comes out of the bladder function is normal. In normal people, when abdominal pressure suddenly increases due to laughter, sneezing, or jumping, the increased abdominal pressure is simultaneously transmitted to the bladder and urethra at the same level, so even if the pressure in the bladder increases, the urethra's resistance increases so much that urine is not discharged. However, when the pelvic muscle layer is weakened, the urethra or bladder neck is struck down and the degree of abdominal pressure transmitted to the urethra is not high enough to release urine. The reason for the weakening of the pelvic muscles is due to the rupture of the pelvic muscles or fascia ligaments by the head of the fetus during childbirth, which causes the bladder neck and urethra to be squeezed backwards or weakens gradually as the body ages. Therefore, stress urinary incontinence is an important trigger of natural delivery and is the most frequent among female urinary incontinence and increases with age. As such, urinary incontinence caused by hypermobility of the urethra, which causes the bladder neck or urethra to swell more than normal, is called genuine stress incontinence and is the most common cause of female urinary incontinence. On the other hand, stress urinary incontinence due to a weakening of the urethra's lock function, commonly called intrinsic sphincter deficiency (ISD), is commonly caused by difficulty in damaging the genital nerves or pelvic muscles of the fetus in the birth canal. Gradually, atrophy and deterioration of the sphincter will appear. In addition, when the urethra is congenital or the urinary incontinence is unsuccessful, ISD may appear in the genital nerves after radical hysterectomy, radical rectal resection, or neurogenic bladder such as meninges. The urethra's hyperdifferentiation and ISD may appear independently, but as you get older, more than one can exist at the same time. 50-70% of incontinence patients fall into this category.

-Urgent Incontinence

Urgent urinary incontinence is an abnormal condition in which the bladder contracts abnormally and the urine is discharged. Urgency incontinence can be aggravated by hearing water, especially when you've held your urine for a long time or wash your hands. Urgent urinary incontinence is an unstable bladder secondary to detrusor hyperreflexia or bladder outlet obstruction caused by brain disorders such as stroke or Parkinson's disease or spinal cord injury, chronic inflammation of the bladder, and special causes. It also appears as a single episode, and complains of urge incontinence with an unstable bladder, especially in about 30% of women with stress urinary incontinence.

First-class incontinence

 Your bladder is full of urine and can't be stored anymore. Loss of bladder contractility or urethral obstruction is a major cause of diabetes, peripheral nerve disease, and hysterectomy.

The most commonly used methods for the treatment of urinary incontinence are surgical methods such as sling method and sub-urethral mucosal infusion therapy (using injection-type therapeutics), which is a simple injection injection into the urethra. Sling surgery is a technique in which the abdominal fascia, femoral fascia, or synthetic material (Goretex, etc.) is made into a long band and then the bladder neck is sled up to lift both ends of the sling up, and the tissue used for sling supports the urethral sphincter. Restores weakened sphincter function. Recently, vaginal wall sling surgery using sling directly using the vaginal wall devised by Raz et al. Has been widely used because of its simple operation and excellent therapeutic effect (S. Raz, et al., "Vaginal wall sling", J. Urol. , 141, 43-46 (1989)). However, it is still a surgical method requires general anesthesia, and has the disadvantage of being hospitalized for a certain period of time. On the contrary, the urethral mucosal infusion therapy does not require skin incision and can be operated under local anesthesia and is simple to operate. In the treatment mechanism of injection infusion therapy, the contents injected into the urethra mucosa thicken the bladder neck and proximal urethral sphincter and increase the length of urethral function to increase the exit resistance. Urinary submucosal infusion has been performed since Murless et al. In 1938 injected sodium morrhuate, a caustic, into the vaginal wall (BC Murless, "The injection treatment of stress incontinence", J. Obstet. Gynaecol. Br. Emp. , 45, 521-524 ( 1938), and in 1955, Quackel treated urinary incontinence by injecting paraffin around the perineum (R. Quackles, "Deux incontinences apres adenomectomie gueries par injection de paraffine dans le perinee", Acta. Urol. Belg. , 23, 259 -262 (1955)) and in 1973 Politano et al. Used Polytef to treat urinary incontinence (VA Politano, et al., "Periurethral Teflon injection in urinary incontinence", J. Urol. , 111, 180-183 (1974) ). Since then, bovine collagen (Contigel), autologous fat, and recently silicone (Macroplastique) and bioglass particles from cow dermis have been injected. Teflon particles have a strong local inflammatory reaction after injection and are not widely used as side effects such as remote transfer of substances.In addition, Teflon particles have advantages in that they can be easily obtained, inexpensive, and have low foreign body reactions. This is often absorbed and re-treatment is necessary. Collagen has the advantage of low foreign body reaction or inflammatory reaction and easy injection, while high absorption rate after initial injection requires repeated injection and relatively high price (1.3 million won / mL). Macroplastique has very low absorption rate after injection. Foreign body reactions are less common, but they do not decompose and remain in the body as foreign substances, and have a disadvantage of being expensive (RR Dmochowski, et al., "Injectable agents in the treatment of stress urinary incontinence in women: where are we now?", Urology , 56, 32-40 (2000)).

In addition, when using existing materials, the success rate of treatment of urinary incontinence is still 40 to 60%, and still does not perform as a perfect therapeutic agent.

As such, many researches for urinary incontinence are being conducted, but due to the above-mentioned problems, the use of conventional materials does not have a correspondingly expensive effect even though the treatment is expensive.

In order to solve the above problems, the present invention utilizes relatively inexpensive synthetic polymers having biocompatibility and biodegradability and a solvent that is harmless even after being injected into a human body in a certain amount, and thus, incontinence treatment having excellent body stability and long-term volume maintenance performance Injectable preparations were prepared to complete the present invention. Two types of biodegradable polymers with different properties were used in the preparation of injectables. One of them was biodegradable polymer microparticles, which were prepared by phase separation, and the other was prepared in the form of a biodegradable polymer solution that solidified in the body but in solution. The present invention was completed by uniformly mixing the two at a constant ratio. At this time, the biodegradable polymer constituting the polymer microparticles has a slower absorption and decomposition rate in the body than the biodegradable polymer used in the solution state, and has a property of being insoluble in the solvent used for preparing the polymer solution. The action mechanism formed when the injection of the present invention is injected into the body is shown in FIG. 1.

The biodegradable polymer microparticles / biodegradable polymer mixture solution injected into the sieve through the syringe needle maintains the shape and volume at the time of injection due to the solidified structure and the dense lamination structure of the polymer microparticles in the sieve. As time passes, the solidified polymer surrounding the polymer microparticles begins to be decomposed and absorbed. At the same time, the surrounding cells and tissues penetrate into the empty space where the polymer is decomposed and absorbed. At this time, the polymer microparticles are not decomposed and play a role as a support of the infiltrated cells and tissues. When cells and tissues infiltrate into a stable state without change in volume or form, the polymer particles with relatively slow decomposition rate start to degrade slowly and are filled with cells and tissues in this space to keep the initial injection volume and form stable. Can be.

Therefore, in the present invention, biodegradable polymers having different decomposition rates are prepared and mixed in the form of fine particles and solution, respectively, so that they can be easily injected into the body and solidified after the injection. The aim is to provide an injectable drug for treating urinary incontinence, which is inexpensive and has an effective therapeutic effect.

In the present invention, biodegradable polymers are prepared and mixed in the form of fine particles and solution, respectively, so that they can be easily injected into the body, and after injection, solidification and compact structure of the polymer microparticles ensure stability and volume retention in the body. This excellent, low-cost and effective treatment for urinary incontinence is characterized by its injectables.

Referring to the present invention in more detail as follows.

The present invention has a molecular weight of 1,000 ~ 1,000,000 g / mol, and produced and mixed two types of biodegradable polymers, each in the form of particles and in the form of a solution, which exhibits different characteristics of decomposition rate and solvent, and has excellent stability and volumetric performance in the body. It is characterized by an injectable preparation for treating urinary incontinence.

Biodegradable polymer that can be used in the form of particles having a molecular weight of 1,000 to 1,000,000 g / mol used in the present invention is polylactic acid (poly (lactic acid)) (PLA), polyglycolic acid (poly (glycolic acid)) (PGA ), Polylactic acid-co-glycolic acid (poly (lactic acid-co-glycolic acid)) (PLGA), polydioxanone, polycaprolactone (poly (ε-caprolactone)) (PCL), poly Poly (β-hydroxybutyrate) (PHB), polyhydroxybutyric acid-co-hydroxyvaleric acid, poly (γ-ethyl glutamate) (poly ( γ-ethyl glutamate)), polyanhydrides (polyanhydrides), polyethylene oxide-polylactic acid copolymers (PEO-PLA), polyethylene oxide-polylactic glycolic acid (polyethylene oxide-poly (lactic-co-glycolic acid) copolymer (PEO-PLGA), polyethylene oxide-polycaprolactone (poly ethylene oxide-polycaprolactone) copolymer (PEO-PCL) may be used alone or two or more kinds,

The biodegradable polymer that can be used in a solution state having a molecular weight of 1,000 to 1,000,000 g / mol may be used alone or two or more selected from PLGA, PEO-PLA, PEO-PLGA, and PEO-PCL.

In addition, the solvent that is harmless to the human body when the amount is used is tetraglycol, 1-methyl-2-pyrrolidinone (1-methyl-2-pyrrolidinone (NMP)), triacetin, benzyl alcohol Etc. can be used alone or as a mixture of two or more thereof.

In addition, the polymer particle size is preferably 50 ~ 300 ㎛ diameter, more preferably 100 ~ 200 ㎛. If the particle size is less than 50 ㎛ there is a problem that the migration (migration) is easily generated in the body, if more than 300 ㎛ there is a problem that injection injection is difficult. In the method for preparing a polymer solution by dissolving the biodegradable polymer in the solvent, the mixing ratio of the solvent and the biodegradable polymer is preferably 1: 0.01 to 0.5 by weight, and the mixing ratio of the solvent and the biodegradable polymer is 1: 0.1 to 0.3 by weight. More preferred. If the mixing ratio is less than 1: 0.01, there is a problem that it is difficult to maintain the injected form and volume due to the solidification, and when the mixing ratio is 1: 0.5 or more, the viscosity of the sample is high, making injection injection difficult. In addition, in the method of preparing the injection preparation by mixing the polymer solution and the polymer particles, the mixing ratio of the polymer solution and the polymer particles is preferably 1: 0.05 to 2 volume ratio, and the mixing ratio of the polymer particles and the polymer solution 1: 0.5 to 1 volume ratio. More preferred. If the mixing ratio is less than 1: 0.05, there is a problem that the solidified polymer that is rapidly decomposed has a long distance between the polymer particles, resulting in a volume reduction, and that the polymer particles are difficult to act as a support to the surrounding cells and tissues. If it is 1: 2 or more, there is a problem that smooth injection injection of the sample is difficult.

Injectable preparations prepared by mixing and dissolving two types of biodegradable polymers, which exhibit different characteristics with respect to a solvent that is harmless to the human body when using a predetermined amount in accordance with the present invention, in the form of particles and in solution, are easily injected and As it shows stability in the body and maintains volume, it can work very effectively as a treatment for incontinence.

Although this invention is demonstrated in detail based on an Example, this invention is not limited to an Example.

Example 1

In order to prepare urinary incontinence preparations with excellent stability and volume retention in the body, two biodegradable polymers each having different characteristics for solvents that are harmless to the human body when decomposed and in a certain amount are used, respectively, are prepared in the form of particles and solutions. And mixing was used. One method is as follows.

Polycaprolactone (PCL), a biodegradable polymer, Tween 80, a surfactant, and Pluronic F127, a PEO-PPO copolymer, were mixed at a predetermined ratio (PCL: Tween 80: Pluronic F127 1: 4: 8 weight ratio) and heated to 140 ° C. Stirring, cooling, washing [Similar to Korean Patent Application No. 2001-57587], separated by size using a micro sieve (micro sieve) by diameter 100 ~ 200 ㎛ (inhibition of remote movement of particles and injection injection Polymer microparticles having this diameter). In addition, when a certain amount is used, biodegradable polymer PLGA was mixed and dissolved in tetraglycol, which is harmless to human body, in a 1: 0.1 weight ratio. Thus prepared PCL particles and PLGA solution was mixed in a 1: 1 volume ratio to prepare an injectable drug for urinary incontinence treatment having stability in the body and excellent volume retention performance.

The injection preparation prepared by the above method was precipitated in an aqueous solution and dried to observe the form by scanning electron microscope (SEM), and the results are shown in FIG. 2.

As shown in FIG. 2, the injection preparation prepared in Example 1 of the present invention solidifies PLGA by the interchange of tetraglycol and water in an aqueous solution to stably surround the PCL particles, and the prepared injection preparation meets the aqueous solution. It was observed that the instantaneous formation (spherical) was maintained as it is.

Examples 2-4

Biodegradable polymers, polylactic acid (PLA), polyglycolic acid (PGA), and polydioxanone were prepared using the method of Example 1, and the fine particles were prepared in the same manner as in Example 1 Injectables for the treatment of urinary incontinence mixed with a PLGA solution were prepared.

The injection preparation prepared by the above method was precipitated in an aqueous solution and dried to observe a scanning electron microscope (SEM), which showed a form similar to that shown in FIG. 2.

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Example 5

In order to evaluate the stability and volume retention performance of the injectable incontinence drug prepared in Examples 1 to 4, the urinary incontinence drug was injected into the back of genetically engineered hairless mice to observe the volume change. First, ketamine hydrochloride (10 mg / kg) and 2% nitrazine hydrochloride (2 mg / kg) were mixed, followed by anesthesia by injection into the lower abdomen of rats. 0.2 mL of the therapeutic agent prepared in the present invention was injected into the anesthetized rat. The volume change over time of the injected therapeutic agent is shown in FIG. 3.

As shown in Figure 3, it can be observed that the initial injection volume is well maintained for a long time without changing the volume even after time.

As described above, the present invention is prepared by injecting two or more types of biodegradable polymers having different characteristics with respect to a solvent that is harmless to the human body when used in a certain amount, in the form of particles and in solution, and mixing them. Easily injectable, stability in the body and excellent volume retention performance can be very useful as a treatment for urinary incontinence, and in addition to the treatment of incontinence can be applied to a variety of injection molding fillers.

1 is a schematic diagram of the mechanism of action formed when the injection prepared in the present invention into the body.

2 is a scanning electron microscope (SEM) photograph observing the form after the preparation of the injection preparation prepared in Example 1 of the present invention in an aqueous solution.

Figure 3 is a photograph observing the volume change with time after injecting the injection preparation prepared in Example 1 of the present invention in the rat.

Claims (6)

Injectable preparation, characterized in that the two or more types of biodegradable polymers having a molecular weight of 1,000 to 1,000,000 g / mol are obtained by preparing and mixing them in the form of particles and solutions respectively. The method of claim 1, Injectable drug, characterized in that the biodegradable polymer constituting the particles is a slower absorption and decomposition rate in the body than the biodegradable polymer used in the solution state, the particles are not dissolved in the solvent used in the preparation of the polymer solution. The method of claim 1, Injectable drug, characterized in that the diameter of the polymer particles is 50 ~ 300 ㎛. The method of claim 1, Injectable preparation, characterized in that the mixing ratio of the solvent and the biodegradable polymer is 1: 0.01 to 0.5 by weight in the preparation of the solution-degradable polymer. The method of claim 1, Injectable preparation, characterized in that the mixing ratio of the biodegradable polymer solution and biodegradable polymer particles is 1: 0.05 ~ 2 volume ratio. The method of claim 1, The biodegradable polymer that can be used in the form of particles having a molecular weight of 1,000 to 1,000,000 g / mol is polylactic acid (poly (lactic acid)), polyglycolic acid (poly (glycolic acid)), polylactic acid-glycolic acid copolymer ( poly (lactic acid-co-glycolic acid), polydioxanone, poly (ε-caprolactone), polyhydroxybutyrate and polyhydroxybutyric acid Polyhydroxybutyric acid-co-hydroxyvaleric acid, poly (γ-ethyl glutamate), polyanhydrides, polyethylene oxide-polylactic acid (polyethylene oxide-polylactic acid) copolymer, polyethylene oxide-polylactic-co-glycolic acid copolymer, polyethylene oxide-polycaprolactone copolymer alone or selected from It is two or more kinds, The biodegradable polymer that can be used in a solution state having a molecular weight of 1,000 to 1,000,000 g / mol is polylactic acid-glycolic acid copolymer (poly (lactic acid-co-glycolic acid)), polyethylene oxide-polylactic acid- single or two selected from a polylactic acid copolymer, a polyethylene oxide-poly (lactic-co-glycolic acid) copolymer, and a polyethylene oxide-polycaprolactone copolymer In addition, the solvent that is harmless to the human body when the predetermined amount is used is tetraglycol, 1-methyl-2-pyrrolidinone (1-methyl-2-pyrrolidinone (NMP)), triacetin triacetin, benzyl alcohol Injectables, characterized in that one or a mixture of two or more.