KR100289471B1 - A controlled/sustained implant delivery containing fentanyls - Google Patents

Abstract

PURPOSE: A sustained release formulation obtained by subjecting narcotic drugs to inclusion into a biodegradable polymer is provided which is effective before and after operation and for the treatment of patients in chronic pain such as cancer or the like. CONSTITUTION: This sustained release formulation comprises 30 to 99.99% by weight of a biodegradable polymer and 0.01 to 70% by weight of a fentanyl-based narcotic drug, wherein the narcotic drug is included by the biodegradable polymer having a molecular weight of 5,000 to 1,000,000g/mol, selected from alginic acid, starch, dextrin, dextran, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymers, polyhydroxy butyric acid, polycaprolactone, polyanhydride and polyalkyl cyanoacrylate.

Description

Implantable sustained release preparation of catanyl anesthetics {A controlled / sustained implant delivery containing fentanyls}

The present invention relates to an implantable sustained release preparation of a butanyl-based anesthetic, and more specifically, anesthetics, which are widely used to relieve the pain of patients before or after surgery or chronic cancer patients, are encapsulated in a biodegradable polymer in a particulate form. It allows the continuous release of the drug and maintenance of a certain concentration by allowing the anesthetic to be released slowly. In particular, through this action, a local dosage method can be administered only where the anesthetic is affected and toxic by overdose. The present invention relates to implantable sustained release preparations of meptanyl-based anesthetics which can be eliminated and various side reactions.

Anesthesia is used to relieve pain in the lesions of patients with surgery or chronic cancer. Clinically, it is administered at regular intervals using needles or syringes for long-term administration locally or locally around wounds or lesions.

When the pain lasts more than one day, that is, chronic, it continues to be administered orally in a pill state or is administered for a long time using a childish catheter connected to an infusion pump. The disadvantage of this method is that there is a fatal problem that irreversible damage of nerve cells and body tissues is caused by local fluctuations of anesthetics and severe fluctuations of the concentrations around the human body. In addition, the most disadvantage of the method of injecting the anesthetics is that the anesthetics of the adjacent area to anesthetize the affected area and pain area, because the anesthetics are injected in the form of pulses, rather than zero-order release due to overdose There is a problem that the side effects are more serious, and therefore the optimal maximum time that can be anesthetized by this method is limited to 6 to 12 hours, it is common to not exceed 6 hours in the clinical practice. In addition, when the pump is used, the pump tube and the line are not only cumbersome, but the behavior of the patient is inconvenient. Moreover, the use of the pump is very limited in the case of a small child or a disabled person or a disabled person.

Representative methods of administration of such anesthetics are roughly divided into injections, ointments, oral preparations, and sustained release devices. In general anesthesia, the injection system is widely used, and the sustained-release device system has been widely applied locally and locally in a constant and controlled amount for a longer period of time than injection or ointment.

Such sustained-release preparations have been studied since the mid-1980s, and there are representative examples of sustained-release preparations consisting of polymer matrix liposomes and anesthetics whose drug release rate is controlled by diffusion and decomposition of the polymer matrix. At this time, the release pattern of the drug can be adjusted according to the final form such as the polymer matrix, the amount of inclusion of the drug, the preparation method and the microspheres, film and the like. The main advantage of the sustained-release preparation using such a biodegradable polymer is that even when the drug is released, the polymer matrix is slowly biodegraded in the patient's body, so that the re-treatment for removing the biodegradable polymer is not necessary.

Another specific example applied to anesthesia using such biodegradable polymers was prepared by inclusion of methoxyflurane in liposomes and lecithin microspheres [Haynes et al., Anesthesiology, 63, 490-499 (1985)]. However, they have a problem in that the lecithin and liposomes are rapidly decomposed in the human body in a few hours or are degraded by phagocytosis of leukocytes, so that the sustained release of anesthetics is difficult to obtain up to 3 days or more. And another example is the invention of topical sustained release odorant using a lipid similar to the above (Lipid), but these also have a problem that there are many limitations in use due to the above problems (US Patent No. 5,188,837).

In addition, there is an example of a topical-oriented anesthetic sustained-release preparation prepared by inclusion of bupivacaine in polylactic acid microspheres [Wakiyama et al., Chem. Pharm. Bull., 30, 3719-3727 (1982)], the polylactic acid microspheres were able to prolong biodegradability for almost one year or more than the lipid system described above, but there is a problem that inflammation occurs locally. In addition, an example of preparing a sustained release preparation by compression molding after mixing dibucaine as a polyanhydride polymer matrix [Berde et al., 1990 Annual Meeting, Am. Soc. Anesthesiologists, 73: A776 (Sept. 1990)], whose initial burst effects due to early bulk biodegradation were severely observed, more often causing infections, and encapsulation of enteric material or fibrin around these implants Serious problems such as touching nerve cells in the eye are caused, which is undesirable.

In another example, a polylactic acid-glycolic acid copolymer was used to prepare biodegradable microspheres containing bupivacaine and local anesthesia [WO 95/09613]. Because of the low initial drug content, there are many drug losses, and the sustained release has a problem of only 3 days. Similarly, ethidocaine, tetracaine, lidocaine, lidocaine, xylocaine and their chlorides [WO 94/05265] are also subjected to sustained-release preparations using biodegradable polymers. Though they had the same problem as above, the situation was in need of improvement.

In addition, there is an example in which sustained release of benzocaine and procaine using polymerized prodrug is induced [M. Kolli et al., Int. J. Pharm., 81, 103-110 (1992)], which is also undesirable because of problems such as falling short of actual potency.

In addition, morphine preparations for oral administration have been commercialized under the trademark MST ContinusTM, which contain a hydrophilic granule system in a hydrophobic matrix [J. Alvarez-Fueutes et al., Int. J. Pharm., 139, 237-241 (1996)], and sustained release by preparing microspheres by incorporating such morphine into a biodegradable polymer, which also can be sustained for only a short period of time within 48 hours. [E. Polard et al., Int. J. Pharm., 134, 37-46, (1996).

Meanwhile, the anesthetics used in the cited examples, methoxyflurane, bupivacaine, dibucaine, benzocaine, procaine, morphine, and morphine , Etiidocaine, tefracaine, lidocaine, lidocaine, xylocaine, xylocaine, xylazine, ketamine, etc. There have been problems associated with hypotension, nausea, vomiting, itching, erythema and headache. Therefore, in order to supplement the problems of these anesthetics, the drug efficacy is about 80 to 300 times stronger than morphine today, and in particular, side reactions among the currently used anesthetics are 7.8 × 10 ³ times stronger than those of carfentanil. The smallest is synthesized and used a fentanyl system known as RR Watson, Drugs of Abuse and Neurobiology, 69-83, 1992, CRC, Boca Raton, FL [US Pat. No. 3,141,823, 1964]. . However, their administration method is mainly made by injection only, the situation is that only the percutaneous administration (DuragesicTM, Alza Co., USA) has been developed as a sustained-release formulation as described above. Therefore, they cannot accurately adjust the dose of the drug through the skin, and the effect of anesthesia is greatly reduced, and most patients suffer from pain and the like.

Accordingly, the present inventors have described the method of preparing sustained-release pharmaceuticals using biodegradable polymers for Japanese encephalitis vaccine sustained-release preparations [Korean Application No. 96-29789 (1996. 7. 23)] and AZT anti-release preparations [Korean Application No. 97-31100]. (1997. 7. 4)] and the like, while developing a biodegradable sustained release formulation by specifying a biodegradable polymer more suitable for the anesthetic agent istanyl system. In particular, the inventors of the present invention, when the anesthetic is contained in the biodegradable polymer that is decomposed for a certain period of time in the human body, and the drug is injected into the human body, the concentration of the anesthetic agent in the plasma is constantly and continuously as the biodegradable polymer is biodegraded and the anesthetic drug is released slowly and continuously. The present invention has been completed by knowing that not only minimal control, but also the topical lesion can be continuously released to reduce the pain of the patient.

Therefore, the present invention is an implantable sustained release of the octanyl-based anesthetic to obtain a complete zero-order release rather than the first release effect, that is, the side effects of excessive or underdose in administration of the anesthetic and the initial burst effect according to the conventional manufacturing method The purpose is to provide a formulation.

1 is a graph showing the sustained release according to the initial inclusion rate of citrate cittanyl biodegradable polymer microspheres,

2 is a graph showing the sustained release according to the initial inclusion ratio of the citrate cittanyl biodegradable polymer pellets,

3 is a graph showing the sustained release according to the initial inclusion ratio of the citrate butanyl biodegradable polymer film.

The present invention is characterized by an implantable sustained release preparation of a butanyl-based anesthetic in which a fentanyl-based anesthetic is enclosed with a biodegradable polymer.

Referring to the present invention in more detail as follows.

According to the present invention, not only the fentanyl-based anesthetic drug is evenly enclosed by the biodegradable polymer, but also composed of fine particles of a certain size, the release of the anesthetic can be programmed according to the condition of the affected area without an initial burst effect. Since the administered polymer is biodegradable in the human body, it is characterized by a sustained-release preparation of a new concept of anesthetic, which requires no removal procedure.

First, the kind of anesthetics that can be applied to the present invention is a fentanyl-based, fentanyl, benzylpentanyl, α-methylfentanyl, ρ-fluoropentanyl (ρ-fluorofentanyl), 3-methylfentanyl, acetyl-α-methylfentanyl, α-methylacrylfentanyl, α-methylthiopentanyl (α-methylthiofentanyl), β-hydroxyfentanyl, β-hydroxy-3-methylpentanyl, β-hydroxy-3-methylfentanyl, 3-methylthiopentanyl, 3-methylthiofentanyl, Thiofentanyl, thenylfentanyl, suftannil, carfentanil, carfentanil, lofentanil and alfentanil and their chlorides, brominations, acetates, citrates And one or more selected from sulfated fentanyls. This is different from the anesthetics that have been used in the past, and it is difficult to encapsulate the biodegradable polymer by the conventional method, so that it is difficult to form a sustained-release preparation showing long-term efficacy, but in the present invention, by using a new biodegradable polymer having the characteristics described below This problem can be improved.

The present invention is characterized in that it selects a specific biodegradable polymer as a new clathrate of the anesthetic agent having the above-described characteristics, and defines the particle size and molecular weight of the roasted grain so as to obtain zero-delayed release for a long time. The selected biodegradable polymers are completely harmless to the human body and have properties that can be biodegraded within a desired period of time.

Biodegradable polymers used as anesthetic clathrates according to the invention include albumin, collagen, gelatin, fibrinogen, casein, fibrin, hemoglobin, transferrin, chitin, chitosan, hyaluronic acid, heparin, chondroitin, keratin sulfate , Alginic acid, starch, dextrin, dextran, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polyhydroxybutyric acid, polycarpolactone, polyanhydride and polyalkylcyanoacrylate It is possible to obtain more improved effects such as overcoming the problem of precisely controlling biodegradation period, which is a problem in biodegradable polymer inclusions. In particular, these biodegradable polymers preferably have a molecular weight of 5,000 to 1,000,000 g / mole. If the molecular weight is less than 5,000, the biodegradation period is too short to obtain the effect as a sustained release preparation required by the present invention, and the molecular weight exceeds 1,000,000. This is because the biodegradation period is too long, which is not preferable.

Implantable sustained release formulations of catanyl anesthetics according to the present invention may be used as slabs, beads, pellets, fine powders, microspheres, microcapsules, films and pastes.

The implantable sustained release preparation of the catanyl anesthetic according to the present invention is prepared in the form of fine particles using the biodegradable polymer described above by a conventional manufacturing method. (Solvent evaporation in O / W, W / O, O / O and W / O / W emulsification), non-solvent addition or phase separation by solvent separation, interfacial polymerization, and spray drying can be used. It is most preferred to use solvent evaporation in emulsion.

As an example of preparing the sustained-release microsphere preparation of the anesthetic agent according to the present invention, a manufacturing method using the emulsion solvent evaporation method will be described in detail.

First, the biodegradable polymer is dissolved in an organic solvent to prepare a solution of 0.5 to 30 W / V%. In this case, at least one selected from methylene chloride, acetonitrile, chloroform, dioxane, formamide and acetylamide may be used.

The biodegradable polymer prepared above is added so as to contain 0.01 to 70% by weight of anesthetics in 30 to 99.99% by weight, and prepared in solution or dispersed state using an ultrasonic mixer or homogenizer. Here, if the content of the anesthetic is less than 0.01% by weight, the concentration of the anesthetic is so low that the expression of the drug mechanism is difficult, and when more than 30% by weight, the initial release is too severe, causing side effects due to over-release problems and uneconomic problems Not desirable

The solution is added to another oil phase in which the emulsifier is dissolved at a concentration of 0.01 to 10 W / V%, followed by stirring at 300 to 20,000 rpm for 1 to 24 hours at a temperature of 10 to 50 ° C. to remove the organic solvent. . At this time, as the emulsifier, for example, one or more selected from polyvinyl alcohol, sodium dodecyl sulfate, and polystyrene oxide may be used, and commercially available products such as span, twee, breeze, and pluronic may be used. In addition, the stirring speed and the stirring time conditions are very important variables for controlling the size of the fine particles, so they should be appropriately adjusted as necessary.

Finally, the fine particles containing the anesthetic from the solution can be recovered using an ultracentrifuge and a filter, and these can be dried by normal temperature drying and freeze drying to obtain final fine particles.

In this case, it is preferable that the final fine particles are formulated to a diameter of 0.1 μm to 20 mm, because when the fine particle size is less than 0.1 μm, problems such as slow release control, that is, an initial burst effect, cannot be solved. If it exceeds, there is a problem of administration in the human body because it is not preferable.

The size control of these fine particles is controlled by the stirring speed in mixing the emulsion solution in which the anesthetic agent and the biodegradable polymer are mixed with the other oil phase in which the emulsifier is dispersed, the molecular weight of the biodegradable polymer used, and the solvent of the biodegradable polymer. Concentration, and the like, which are well known to those skilled in the art.

In addition, the implantable sustained release preparation of the catanyl anesthetic according to the present invention can be prepared in a pellet state by a conventional manufacturing method using the biodegradable polymer as described above. same.

30 to 99.99% by weight of the above-mentioned pulverized or powdered biodegradable polymer is added so as to contain 0.01 to 70% by weight of anesthetic, and these are mixed completely and uniformly with a general mixer. These polymer processing kneaders or screw-mounted injection machines are used to melt-jet between 150-250 ° C through a mold of diameter 1 mm. By cooling them in air and cutting 1 mm in length, a topical sustained release formulation of the anesthetic in final pellet form can be obtained. At this time, it is preferable to formulate the final pellets with a diameter of 50 μm to 10 mm and a length of 50 μm to 10 mm, because the same as in the case of the fine particles.

Another type of implantable sustained release preparation of the butanyl anesthetic according to the present invention may be prepared in a film state by a conventional manufacturing method using the biodegradable polymer described above. As follows.

The biodegradable polymer is dissolved in an organic solvent to prepare a solution of 0.5 to 30 W / V%. At this time, the solvent may be one or more selected from methylene chloride, acetonitrile, chloroform, dioxane, formamide and acetylamide. 30 to 99.99 wt% of the biodegradable polymer is added so as to contain 90 to 0.01 wt% of the anesthetic, and is prepared in solution or dispersed state using an ultrasonic mixer or homogenizer. After preparing these films in a film maker equipped with a doctor knife with a thickness of 0.5 μm to 10 mm, and then immersing these solutions in a non-solvent, drying them and cutting them to an appropriate size, the topical sustained release preparation of the final anesthetic Film state can be obtained.

The implantable sustained release preparation of the catanyl anesthetic according to the present invention can also be prepared in a paste state by a conventional manufacturing method using the biodegradable polymer as described above. .

The biodegradable polymer is dissolved in an organic solvent to prepare a paste state of 0.5 to 80 W / V%. In this case, as the solvent, microspheres and organic solvents used in the production of the film can be used in the same manner. To this biodegradable polymer, an anesthetic agent used in the present invention is added so as to contain 0.01 to 70% by weight, and an ultrasonic mixer or a homogenizer is used so as to spread uniformly in the paste state. This paste has the advantage of being directly administered to the affected area using a syringe syringe. Methods for preparing such anesthetics in the form of topical sustained release formulations can be prepared by known techniques well known to those skilled in the art. At this time, the biodegradable period and the sustained release pattern of the anesthetic are controlled by controlling the molecular weight of the biodegradable polymer used, the concentration of the biodegradable polymer in the solvent, and the concentration of the emulsifier in the preparation of the emulsion solution in which the anesthetic agent and the biodegradable polymer are mixed. It is possible.

The method of administration according to the form of the implantable sustained release preparation of the butanyl anesthetic prepared by the present invention is microspheres, fine powder, microcapsules, etc. are possible by injection of an appropriate gauge subcutaneously around the affected area, film, slab In the case of the bead state, the implant may be administered by performing an implant directly around the affected area, the pellet state may be administered through a trochar, and the paste state may be administered by injection subcutaneously.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.

Example 1

The copolymer was prepared by mixing lactic acid and glycolic acid at a ratio of 75: 25 wt% and thermally polymerizing the mixture at 170 ° C. and 100 rpm for 40 hours. The molecular weight of the copolymer thus dried (hereinafter referred to as "PLGA75") was 25,000 when analyzed by gel permeation chromatography (Gel Permeation Chromatography).

0.4 g of the prepared PLGA75 was evenly dissolved in 8 ml of methylene chloride, mixed with 0.05 g of cyantanyl citrate (initial drug inclusion rate; 5%, 10%, 20% and 50%), and then 40W. The solution was prepared for 30 seconds using an ultrasonic mixer. The solution was quickly poured onto a mineral oil in which Span 80 was dissolved by 0.05 W / V% and stirred at 250 rpm, followed by stirring at 250 rpm for 3 hours at 25 ° C. to remove methylene chloride contained in the solution. .

The centrifuge was then stirred at 3000 rpm for 15 minutes to collect the FC / PLGA75 particulates contained in the solution. The collected fine particles were washed with hexane and then dried and analyzed by a Coulteur counter, which resulted in FC / PLGA75 fine particles having a size of 45 ± 7 μm.

These biodegradable microparticles were tested for the amount of drug released in 37 ° C. PBS solution, and the results are shown in FIG. 1.

Example 2

0.8 g of polyhydroxybutyric acid (PHB) having a molecular weight of 15,000 was dissolved in 8 ml of chloroform and the solution was mixed with 0.2 g of benzyl fontanyl (BF), and then a solution was prepared using a 40 W ultrasonic mixer. It was carried out in the same manner as in Example 1 below.

The BF / PHB fine particles thus obtained were analyzed using the same particle size analyzer (Coulteur counter) as in Example 1, and as a result, BF / PHB fine particles having a size distribution of 270 ± 35 μm were obtained.

Example 3

1.2 g of polycaprolactone (PCL) having a molecular weight of 27,000 was dissolved in 8 ml of dioxane, which was mixed with 0.3 g of sucetanyl (SF) and a solution was prepared using a 40 W ultrasonic mixer.

Hereinafter, fine particles were obtained by the same method as Example 1, and the SF / PCL fine particles having a size distribution of 73 ± 20 μm were obtained as a result of analysis.

Example 4

A 1.0 W / V% solution of alginic acid containing 20% thiopentanil (TF) was sprayed into an aqueous calcium chloride solution at a concentration of 1.5 W / V% using an atomizer (air-atomizer, Turbotak), followed by crosslinking. It was coated with lysine (PL).

Hereinafter, fine particles were prepared in the same manner as in Example 1, and analyzed to obtain TF / PL fine particles having a size distribution of 47 ± 13 μm.

Example 5

The copolymer was prepared by mixing lactic acid and glycolic acid at a ratio of 50: 50% by weight and thermally polymerizing at 165 ° C. and 150 rpm for 24 hours. The molecular weight of the thus prepared copolymer (hereinafter referred to as "PLGA50") was measured using gel permeation chromatography and found to be 12,000. 0.5 g of PLGA50 was evenly dissolved in 6 ml dioxane, mixed with 0.1 g of β-hydroxypentanyl (HF), and HF-containing fine particles were prepared in the same manner as in Example 1. Analysis of these HF / PLGA50 particles showed a size distribution of 87 ± 16 μm.

Example 6

0.1 mg of butanyl was mixed with 10 ml of an aqueous solution containing 70% glucose 0.5% dextran and 0.05% citric acid, and then 2 ml of hexylisocyanoacrylate monomer was stirred at 900 rpm over 5 hours. Particles of size 2.3 ± 0.7 μm were prepared by addition into the reactor.

Example 7

200 g of PLGA 75 prepared in Example 1 was prepared as a powder, followed by 1 g of FC (initial drug inclusion rate; 1%, 2.5%, 5%, and 10%) and mixed thoroughly. This was injection molded at 170 ° C. using a Brabender (Prabender; Plasti-Corder REO6 type) equipped with a die having a diameter of 0.5 mm, and cut into a size of 0.5 mm in length to prepare pellets. These biodegradable pellets were tested for the release amount of FC drug in 37 ℃ PBS solution, the results are shown in Figure 2 below.

Example 8

6 g of PLGA75 prepared in Example 1 was evenly dissolved in 8 g of dimethylsulfoxide and mixed with 0.5 g of FC. At this time, in order to complete mixing, Span 80 was added 0.05 W / V%, and a paste having a viscosity of 230 cps was prepared using a homogenizer.

Example 9

50 g of PLGA 50 prepared in Example 5 was evenly dissolved in 100 ml of methylene chloride, and then 20 g of a butanyl (AF) was evenly dispersed by adding 0.05 W / V% of tween. This was evaporated for 24 hours at 75 ° C. in methylene chloride in an oven to obtain 50 pieces of PLGA containing AF. This was powdered using a grinder, and then a powder having a thickness of 50 μm or less was obtained using a 50 μm molecular sieve.

Example 10

0.8 g of polyanhydride having a molecular weight of 25,000 g / mole is dissolved in 80 ml of dioxane, and this solution is dissolved in 0.02 g of rosettetanyl (LF); initial drug inclusion rate; 5%, 10%, 20% and 50%. ) And Span 80 0.001 g and then a solution was prepared using a 40 W ultrasonic mixer for 30 seconds. Using a cutter equipped with a doctor knife to prepare a film having a final thickness of 0.7 mm. These biodegradable films were tested for the amount of LF drug released in 37 ℃ PBS solution, the results are shown in FIG.

As described above, according to FIG. 1, the implantable sustained release preparation of the butanyl-based anesthetic according to the embodiment of the present invention exhibits almost zero-order release for more than about 2 months in a day before and after surgery. Or it is very ideal for the treatment of patients with chronic pain, such as cancer.

Therefore, the implantable sustained-release sustained release formulation of the catanyl anesthetic according to the present invention is formulated by selecting a biodegradable polymer suitable for anesthetics unlike the conventional one, and thus, toxicity and other nausea, vomiting, headache, high blood pressure, Various side effects such as hypotension, itching and erythema can be avoided, and anesthesia / biodegradable polymer preparations can be programmed in advance according to the local anesthesia of the patient, and according to the desired dosage form of the patient according to the dosage requirements of the patient, It is possible to control the sustained release and to increase the initial drug inclusion rate compared to the conventional sustained-release drug, so that anesthesia effect can be obtained for a longer period of time, and the biodegradable polymer used as a drug carrier is naturally decomposed and absorbed in the body. In addition to oral administration of butanyl-based active ingredient having excellent efficacy There is an advantage that can be improved to enable other methods.

In addition, the sustained release of the anesthetic according to the present invention has a useful effect that can be used in a wide range of industries, such as application to other drugs.

Claims (11)

Fentanyl anesthetics include alginic acid, starch, dextrin, dextran, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymers, polyhydroxybutyric acid, polycaprolactone, polyanhydrides and polyalkylcyanos An implantable sustained release preparation of a catanyl anesthetic, characterized in that it is encapsulated with a biodegradable polymer having a molecular weight of 5,000 to 1,000,000 g / mol selected from acrylates, and has a particle diameter of 0.1 µm to 20 mm. According to claim 1, wherein the formulation is 30 to 99.99% by weight of biodegradable polymer and 0.01 to 70% by weight of fentanyl-based anesthetic agent implantable sustained-release formulation of the pentanyl-based anesthetic agent. The fentanyl-based anesthetic agent according to claim 1 or 2, wherein the fentanyl-based anesthetic agent is pentanyl, benzyl octanyl, α-methyl octane tanyl, α-methyl acryl octanyl, α-methylthio octane tanyl, β- Hydroxybutanyl, β-hydroxy-3-methylbutanyl, 3-methylchiobantanyl, thiotantanyl, netylbutanyl, serpentanyl, carbitanyl, rofitanyl and altantanyl and their chlorides, brominations, acetates Implantable sustained-release preparation of catanyl anesthetics, characterized in that at least one selected from hydrated, citric oxidized and sulfated. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in slab form. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in the form of a bead. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in pellet form. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in fine powder form. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in the form of microspheres. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in the form of microcapsules. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in the form of a film. 2. The implantable sustained release preparation of catanyl anesthetic according to claim 1, wherein the preparation is in paste form.