JP4877899B2 - Drug sustained release spherical fine particles and method for producing the same - Google Patents

Description

  The present invention relates to a fat-soluble drug sustained-release fine particle and a method for producing the same, using a fat-soluble vitamin and a biodegradable polymer as a drug solvent and a carrier, respectively. The present invention also relates to an injectable preparation comprising the drug sustained-release fine particles.

  As a technique for making a fat-soluble drug into a sustained-release preparation, a method is known in which the drug is encapsulated in liposomes (lipid membrane vesicles) or fine particles using a polymer as a carrier. The method using liposome encapsulates a fat-soluble drug with a coating such as lecithin or lecithin and cholesterol, and the method using polymer fine particles encapsulates the drug in biodegradable polymer fine particles such as polylactic acid.

  When encapsulating a fat-soluble drug in a liposome or polymer, lecithin, polymer, or the like is dissolved in an organic solvent, and further, the fat-soluble drug is added and dissolved, and then dispersed in water to evaporate the organic solvent. A method of encapsulating a lipophilic drug in liposomes or polymer particles by forming liposomes or polymer particles in water is common.

  Here, Non-Patent Document 1 discloses a technique in which a taxoid compound such as paclitaxel, which is an antineoplastic drug, is encapsulated in phospholipid phosphatidylglycerol and phosphatidylcholine (lecithin) liposomes. Further, Non-Patent Document 2 discloses a technique for making paclitaxel an oil-in-water (o / w) emulsion preparation having a diameter of 100 to 200 nm.

  On the other hand, Patent Document 1 discloses a microparticle in which paclitaxel is encapsulated in albumin microparticles as a sustained-release preparation using polymer microparticles. In the preparation disclosed in Patent Document 1, since the drug is encapsulated in albumin microparticles, which are biomolecules, there is no side effect due to the additive, and it is possible to administer a high dose of paclitaxel to the patient.

  In addition, a step of producing two or more primary milk phases or emulsions by dissolving or dispersing a drug in two or more types of milk phases in which biodegradable polymers are dissolved, and two or more types of produced ones. The step of dispersing the next milk phase or emulsion in one aqueous phase simultaneously or continuously, and encapsulating the drug in a carrier made of biodegradable polymer such as cellulose acetate in which the drug is dispersed, Patent Document 2 discloses a method for producing sustained-release microspheres by a multiple emulsion method capable of controlling the release of a drug. The production method disclosed in Patent Document 2 can produce a mixture of microparticles having various drug release characteristics by a single process, and theoretically, from the drug release characteristics of the microparticles manufactured by each process. The combination is supposed to provide a microparticle formulation that can induce sustained release over a period of time.

Further, Patent Document 3 discloses fine particles for intravenous injection in which a prostanoid or steroid is encapsulated in a polylactic acid / glycolic acid copolymer or polylactic acid fine particles, and a surfactant such as lecithin is adsorbed on the surface of the fine particles. Has been. By using the biodegradable polymer fine particles disclosed in Patent Document 3 as a carrier for a fat-soluble drug, a sufficient sustained release effect can be obtained as compared with the case of using fat fine particles, and the drug encapsulation rate is also excellent. It is said.
JP 2001-354559 A Japanese Patent Laid-Open No. 2002-20269 JP 2003-342196 A Amarnath Sharma et al., Journal of Pharmaceutical Sciences, Vol.84, No.12, December (1995) Panayiotis P. Constantinides et al., Pharmaceutical Research, Vol. 17, No. 2 (2000)

  However, even if a liposome comprising lecithin is a cholesterol-containing liposome that is recognized as a hard liposome due to the interaction with cholesterol, the encapsulated drug is rapidly released when the liposome is administered into the blood vessel (initial burst). ). This phenomenon is thought to be due to the strong interaction between lecithin and cholesterol, the osmotic pressure of water, and the poor food by the reticuloendothelial system such as macrophages.

  When the sustained-release liposomes administered into the blood vessels are initially burst, the drug that should be administered over a long period of time due to the slow release is in the same state as when it is rapidly administered. When an antineoplastic agent or the like that exhibits a pharmacological action in a very small amount is encapsulated in liposomes, the antineoplastic agent or the like may damage normal tissues due to the occurrence of an initial burst.

  In addition, even when a biodegradable polymer is used as a carrier for a fat-soluble drug, the organic solvent is rapidly removed from nanoparticles prepared by dispersing a drug dissolved in an organic solvent and the biodegradable polymer in water. Since it is difficult to remove, there is a high possibility that the organic solvent remains inside the nanoparticle. The inability to quickly remove the organic solvent from the water in this way is also a cause of a decrease in the encapsulation rate of the fat-soluble drug in the fine particles.

  In addition, an additive such as a surfactant may be used to dissolve the fat-soluble drug in an organic solvent and to increase the encapsulation rate of the fat-soluble drug in the fine particles. Many of such additives are harmful to the living body, and remaining in the preparation adversely affects the living body.

  In addition, fat-soluble drugs have the property of quickly and firmly adsorbing to biodegradable polymers, so the outer surface area may be larger than the inner area of the nanoparticulates, which is why the drug encapsulation rate is low It has become. The drug entrapment rate of the microparticles (microspheres) of commercially available anti-cancer drugs (prostate cancer, endometriosis and early puberty treatment) and leuprorelin acetate (manufactured by Takeda Pharmaceutical) is 14%, This is the formulation with the highest encapsulation rate. In addition, at the level of presentation at academic conferences, it is considered that the encapsulation rate of fat-soluble drugs in sustained-release fine particles should be 5%.

  An object of the present invention is to overcome the above-mentioned disadvantages of conventional drug sustained-release preparations by using fat-soluble vitamins as drug solvents and liposomes or biodegradable polymers as drug carriers. . That is, an object of the present invention is to provide a fat-soluble drug sustained-release fine particle having a high encapsulation rate of a fat-soluble drug, hardly causing an initial burst, and using no harmful additive, and a method for producing the same.

  As a result of diligent studies to solve the above problems, the present inventor dissolved a fat-soluble drug and a biodegradable polymer in a fat-soluble vitamin, dispersed in water or physiological saline, and contacted with a phospholipid thin film. Then, when ultrasonic irradiation or homogenization operation is carried out, it is found that a lipid-soluble vitamin in which a fat-soluble drug and a biodegradable polymer are dissolved is encapsulated inside a thin film of phospholipid, and spherical fine particles are formed. It came to complete.

Specifically, the present invention
A fine particle composed of a core and a shell,
The core is a fat-soluble vitamin in which a fat-soluble drug and a biodegradable polymer are dissolved,
The shell is composed of a thin film of phospholipid;
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
The fat-soluble vitamin is tocotrienols or tocopherols,
The phospholipid is hydrogenated lecithin;
Nuclear is sealed shell, about the drug sustained release spherical particles having a diameter and wherein the der Rukoto below 800 nm.

The present invention also provides:
A step (a1) of preparing a phospholipid thin film by evaporating and drying phospholipid dissolved in an organic solvent;
A step (b1) of preparing a drug-polymer-dissolved fat-soluble vitamin by dissolving a fat-soluble drug and a biodegradable polymer in the fat-soluble vitamin;
Contacting the drug / polymer-dissolved fat-soluble vitamin prepared in the step (b1) and water or physiological saline with the phospholipid thin film prepared in the step (a1);
By ultrasonic irradiation or homogenization operation, the drug-polymer dissolved fat-soluble vitamins, see contains the step (d1) to enclose the interior of the thin film of the phospholipid,
The phospholipid is hydrogenated lecithin;
The fat-soluble vitamin is tocotrienols or tocopherols,
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
About the method of manufacturing a drug-sustained release spherical fine particles, wherein the diameter of the spherical fine particles obtained by the step (d1) is 800nm or less.

Furthermore, the present invention provides
A step (a2) of preparing a thin film composed of phospholipid and cholesterol by evaporating and drying phospholipid and cholesterol dissolved in an organic solvent;
A step (b2) of preparing a drug-polymer-vegetable oil-soluble fat-soluble vitamin by dissolving a fat-soluble drug, a biodegradable polymer and a vegetable oil in the fat-soluble vitamin;
The drug / polymer / vegetable oil-soluble fat-soluble vitamin prepared in the step (b2) and water or physiological saline are contacted with the thin film composed of the phospholipid and cholesterol prepared in the step (a2). Step (c2)
By ultrasonic irradiation or homogenization operation, the drug-polymer vegetable oil dissolved fat soluble vitamins, see contains a step (d2) to enclose the interior of the thin film of the phospholipid,
The phospholipid is hydrogenated lecithin;
The fat-soluble vitamin is tocotrienols or tocopherols,
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
About the method of manufacturing a drug-sustained release spherical fine particles, wherein the diameter of the spherical fine particles obtained by the step (d2) is 800nm or less.

Phosphorus lipid used is a hydrogenated lecithin has high stability in air.

Biodegradable polymers, Ru high polylactic acid or lactic acid / glycolic acid copolymer der biocompatibility.

Fat-soluble vitamins can be prepared by dissolving the biodegradable polymer is a drug carrier, more robust coupling with the lecithin, Ru tocotrienols or tocopherols der which is also antioxidant power.

The nucleus also has preferably further contain a vegetable oil such as soybean oil.

Shell, it also has preferably a thin film composed of lecithin and cholesterol.

The lipid-soluble drugs, Ru can be exemplified antineoplastic agents. Antineoplastic drugs are usually intravenously administered as an intravenous drip. However, if encapsulated in the sustained-release microparticles of the present invention and injected around the affected area as an injectable preparation, the antineoplastic drug is placed around the affected area for a long time. that Do and can be administered.

The antineoplastic agents, the taxoid compound or irinotecan-based compound is not preferable.

  Since the sustained-release drug fine particles of the present invention dissolve fat-soluble drugs in fat-soluble vitamins, it is not necessary to dissolve fat-soluble drugs using harmful organic solvents or additives. In addition, unlike an organic solvent, fat-soluble vitamins remain inside fine particles composed of a thin film of phospholipid, so that compared with conventional liposomes and fine particles using biodegradable polymers, the fat-soluble drug encapsulation rate and The introduction rate is high. Furthermore, if fat-soluble vitamins having antioxidative power are used, oxidation of phospholipids can be prevented, so that the stability of fine particles during storage and in vivo is high.

  In addition, since the drug sustained-release fine particles of the present invention have a strong interaction (adsorption) between phospholipids, fat-soluble vitamins and biodegradable polymers, the fine particles of the fine particles are administered after being administered in vivo. The initial burst is unlikely to occur and the fat-soluble drug can be kept in the oily fat-soluble vitamin for a long time. Even if the fine particles are poorly eaten, the fat-soluble drug contained in the fat-soluble vitamin can be kept locally in the vicinity of the affected area in a form adsorbed on the biodegradable polymer.

  Embodiments of the present invention will be described below with reference to the drawings as appropriate. The present invention is not limited to these.

  First, the structure of the sustained-release drug fine particles of the present invention is shown in FIG. The drug sustained-release fine particles 3 of the present invention have a structure in which a phospholipid thin film 2 encloses a nucleus 1 made of a fat-soluble vitamin in which a fat-soluble drug and a biodegradable polymer are dissolved.

  As described above, in the present invention, since fat-soluble vitamins are used as a solvent for fat-soluble drugs, the core 1 does not contain organic solvents and additives in principle. For this reason, even if it administers in the living body, the trouble by the organic solvent and the additive does not occur. In addition, the fat-soluble vitamin does not volatilize unlike an organic solvent, and therefore remains in the core 1. For this reason, compared with the conventional drug slow-release fine particles using liposomes or biodegradable polymers, the amount of the fat-soluble drug that can be encapsulated inside the fine particles is large, and the drug encapsulation rate is high.

  Unlike strong conventional drug sustained-release microparticles, initial bursts are unlikely to occur because of strong interactions between the fat-soluble vitamin and phospholipid thin film 2 and between the phospholipid thin film 2 and the biodegradable polymer. .

  Since the biodegradable polymer dissolved in the fat-soluble vitamin strongly adsorbs the fat-soluble drug, it plays the role of gradually releasing the fat-soluble drug. For this reason, the drug sustained-release fine particles 3 of the present invention, combined with a high drug encapsulation rate, can release a fat-soluble drug in vivo for a long period of time by a single administration.

  Furthermore, if a fat-soluble vitamin having an antioxidant power such as tocotrienol or tocopherol is used as the fat-soluble vitamin, oxidation of the fat-soluble drug contained in the core 1 and the phospholipid thin film 2 can also be prevented.

  The biodegradable polymer used in the present invention is not particularly limited as long as it is poorly soluble in water, has an affinity for phospholipids, and can be dissolved in fat-soluble vitamins. There may be. Preferable specific examples include polylactic acid and lactic acid / glycolic acid copolymer.

  The fat-soluble drug encapsulated in the sustained-release drug fine particles of the present invention is not particularly limited, but is suitable for an antineoplastic drug (anticancer drug).

  Here, a taxoid compound which is an antineoplastic agent is a chemotherapeutic agent also called a mitotic inhibitor because of its influence on cell division. Representative taxoid compounds include paclitaxel (trade name “Taxol” (registered trademark)) and docetaxel (trade name “Taxotere” (registered trademark)), and treatment of breast cancer, non-small cell lung cancer, ovarian cancer, etc. Widely used. The time required for intravenous infusion is 3 hours or more for paclitaxel and 1 hour or more for docetaxel.

  Similarly, irinotecan compounds are chemotherapeutic agents known as topoisomerase inhibitors. A typical drug, irinotecan (trade names “Kampto” and “Topotecin”, both registered trademarks) is widely used for the treatment of colorectal cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, etc. . The time required for intravenous infusion is one and a half hours.

  For example, commercially available paclitaxel injectable preparations use polyoxyethylene castor oil and absolute ethanol as solvents because paclitaxel is very difficult to dissolve in water, but polyoxyethylene castor oil is used for the pharmacokinetics of paclitaxel. It has also been reported that the absorptivity is greatly changed and that severe hypersensitivity such as shock is caused.

  Furthermore, it is well known that in the medical field, polyoxyethylene castor oil may crystallize in the tube because it is mixed with 5% glucose or physiological saline, and is difficult to handle. .

  Therefore, if the drug sustained-release fine particles of the present invention are applied to a fat-soluble antineoplastic agent such as paclitaxel, the problems due to the above-mentioned commercial preparation can be solved.

  As described above, by enclosing the widely used antineoplastic agent in the sustained-release drug fine particles of the present invention and injecting it around the affected area as an injectable preparation, there is a concern about side effects on the whole body of the antineoplastic agent. No safe and effective cancer treatment is possible. In addition, it is not necessary to restrain the patient for infusion for a long time.

  In the examples described below, among the lipophilic drugs, paclitaxel and docetaxel were used as taxoid compounds, and irinotecan was used as an irinotecan compound.

  Next, the manufacturing method of Example 1 of this invention is demonstrated concretely. The components used in the production of Example 1 and the amounts thereof are shown in Table 1.

  First, hydrogenated lecithin was added as a phospholipid to an eggplant-shaped flask, and 1 mL of chloroform was added and completely dissolved. Thereafter, it was evaporated to dryness using a rotary evaporator. In order to completely remove chloroform, it was further dried for 3 hours in a desiccator under reduced pressure to prepare a lecithin thin film. In addition, although hydrogenated lecithin was used here, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine can also be used besides this.

  Next, paclitaxel as a fat-soluble drug was completely dissolved in oily tocotrienol under ultrasonic irradiation (Bransonic 12). Furthermore, a lactic acid / glycolic acid copolymer as a biodegradable polymer was added to tocotrienol and completely dissolved while being irradiated with ultrasonic waves. In addition to tocotrienol, it is also possible to use tocopherol.

  Next, an oily tocotrienol containing paclitaxel and a polylactic acid-glycolic acid copolymer was left in the dark for 1 hour, and then the oily tocotrienol (drug and biodegradable) was applied to the lecithin thin film attached to the inner wall of the eggplant-shaped flask. The polymer (dissolving) is brought into contact (attached or sprayed). Note that the inside of the eggplant-shaped flask is preferably previously substituted with nitrogen in order to prevent oxidation of hydrogenated lecithin and tocotrienol.

  Further, purified water (60 ° C.) was added to the eggplant-shaped flask and subjected to ultrasonic irradiation (Bransonic 12) for 30 minutes, whereby fine particles of oily tocotrienol and lecithin thin film containing paclitaxel and polylactic acid-glycolic acid copolymer were formed. The oily tocotrienol was encapsulated inside the fine particles made of lecithin thin film. As a result, a suspension containing sustained-release drug fine particles was obtained. However, this operation is preferably performed in a dark place.

  In addition, even when the tocotrienol was made into fine particles using a homogenizer (Branson Sonifier model 250; output 25 W) instead of ultrasonic irradiation, a suspension containing the same sustained-release drug fine particles was obtained. This operation is also preferably performed in a dark place.

  As a result of microscopic observation and membrane filter filtration operation, the obtained drug sustained-release fine particles had a diameter of 800 nm or less (about 100 nm to 800 nm). Note that the particle size can be further reduced by using a higher performance device than the ultrasonic irradiation device or homogenizer used this time.

  The sustained-release drug fine particles of the present invention preferably have a diameter of 100 nm or less. This is because, when the diameter exceeds 100 nm, for example, there is a disadvantage that it is taken into the reticuloendothelial system and easily eaten.

[Fine particle for blank test]
Fine particles were produced by performing the same operation as in Example except that paclitaxel was not used as the fine particles for blank test, and a suspension containing fine particles for blank test was obtained.

[Comparative Example 1]
As Comparative Example 1, a commercially available paclitaxel formulation (Taxol (registered trademark) Note manufactured by Bristol-Myers Co., Ltd.) was used as it was.

  Here, a test was conducted in which the sustained-release drug fine particles of the present invention were administered to an experimental animal, and the effect and the presence or absence of an initial burst were confirmed. Hereinafter, specific experimental methods and the like will be described.

(Experimental example 1: Life extension effect)
As Experimental Example 1, a suspension containing the sustained-release drug fine particles of Example 1 was administered to mice and evaluated as a therapeutic agent for ovarian cancer while being compared with the fine particles for blank test and Comparative Example 1.

  First, human ovarian cancer cells (SKOV3) were transplanted into the abdominal cavity of 6-week-old female Balb / c nude mice. SKOV3 is a paclitaxel sensitive strain.

  Next, the nude mice on the seventh day of transplantation were treated with the first group of suspension of Example 1, the suspension of fine particles for blank test, and the first group of Comparative Example 1 as paclitaxel, 10 mg / kg, Group 2 was administered intraperitoneally as it was at a dose of 20 mg / kg, and thereafter, once every 5 days, the intraperitoneal administration was repeated at the same dose once for a total of 4 times to determine the life-prolonging effect of each injection on nude mice. The experimental conditions are shown in Table 2, and the results of the life extension test are shown in FIG.

  Compared with the administration test of the suspension of fine particles for blank test which is a control test, the survival days of the transplanted mice administered with Comparative Example 1 were greatly shortened (0.3 to 0.5 times) in both the first group and the second group. . This was presumed to be due to the cytotoxicity of polyoxyethylene castor oil contained in Comparative Example 1 as a solvent. On the other hand, in the second group of transplanted mice administered with the suspension of Example 1, the survival days were extended (1.5 to 2.0 times) compared to the administration test of the suspension of fine particles for blank test. .

  Thus, if the suspension of Example 1 of the present invention is administered as an injection into the abdominal cavity as it is, a life prolonging effect superior to that of a commercially available paclitaxel preparation can be obtained for a model animal of ovarian cancer. It was confirmed.

(Experimental example 2: Blood transferability)
As Experimental Example 2, the suspension of Example 1 and Comparative Example 1 were directly administered into the abdominal cavity of a ddY female mouse, and the blood paclitaxel concentration after administration was compared. The dosage is 20 mg / kg as paclitaxel for both injections.
Prior to quantification of blood paclitaxel concentration, mouse blood was processed by the processing method shown in FIG. That is, blood was collected in a disposable centrifuge tube and centrifuged at 10,000 rpm for 2 minutes. Next, 75 μL of supernatant plasma was collected, 75 μL of internal standard solution and 3 mL of chloroform were added and shaken.

  Next, the mixture was centrifuged at 3000 rpm for 10 minutes, and the chloroform layer was separated into flasks. After evaporating chloroform, 100 μL of high-performance liquid chromatography (HPLC) mobile phase was added to the flask to dissolve the residue. This solution was analyzed by HPLC to quantify paclitaxel. The HPLC quantification conditions are as shown in Table 3, and the quantification results are shown in FIG.

  The ratio of the peak area of paclitaxel in blood after intraperitoneal administration to the peak area of the internal standard substance was measured up to 120 hours after administration. The paclitaxel migrated, and the ratio became zero 8 hours after administration. This result shows that paclitaxel of Comparative Example 1 was transferred to the blood immediately after administration and disappeared from the blood 8 hours after administration.

  On the other hand, in the mice administered with the suspension of Example 1, no paclitaxel was detected in the blood until 120 hours after the administration. This result shows that the sustained-release drug fine particles encapsulating paclitaxel of Example 1 remain unbroken (without initial burst) for 120 hours after administration, or if an initial burst occurs. Even so, it is suggested that due to the strong interaction with the lactic acid / glycolic acid copolymer and tocotrienol, paclitaxel does not migrate into the blood but remains in the abdominal cavity and does not migrate into the blood.

  As Example 2, a 2′-ethyl carbonate body (molecular weight 924), which is a prodrug of paclitaxel (molecular weight 854), was used in the same manner as in Example 1, and the prodrug of paclitaxel was applied to a hydrogenated lecithin thin film. A suspension containing the sustained-release drug fine particles was produced.

(Experimental example 3: Drug encapsulation rate and drug introduction rate)
Using the suspension of Example 2, the drug encapsulation rate and drug introduction rate were evaluated by in vitro experiments.

  (1) The drug encapsulation rate was determined by dividing the prodrug concentration of paclitaxel remaining 48 hours after in vitro rat serum by the drug concentration in the prepared microparticle suspension. It has been found from inventor's past experimental results that this prodrug is converted into paclitaxel in 15 minutes in rat serum in vitro. For this reason, the drug encapsulation rate was calculated 48 hours after mixing with rat serum. In this case, only the prodrug encapsulated in the fine particles remains as a 2'-ethyl carbonate body, and all the others are converted to paclitaxel.

  Here, the experimental method of the drug encapsulation rate is shown in FIG. The quantitative conditions are the same as in Table 3. As a result of quantifying the prodrug, it was found that 17% of the prodrug remained in the suspension of Example 2. Therefore, the drug encapsulation rate was considered to be at least 17%.

  (2) Next, FIG. 6 shows an experimental method for the drug introduction rate. The suspension of Example 2 was subjected to gel filtration to collect fine particles eluting from the column. The prodrug in the eluate was quantified, and the drug introduction rate (%) was calculated by the formula: (drug concentration in the eluate) / (drug concentration in the prepared microparticle suspension) × 100. The gel filtration conditions are as shown in Table 4, and the prodrug quantitative conditions are the same as in Table 3.

  As a result of quantifying the prodrug using HPLC, the drug encapsulation rate of Example 2 was about 98%. Thus, the suspension of Example 2 of the present invention showed a high drug encapsulation rate exceeding 14%, which is the maximum value of the drug encapsulation rate in microparticles encapsulating a conventional antineoplastic drug. The drug introduction rate was almost 100%. Since the drug introduction rate was very high, in the drug sustained-release preparation of Example 2, free tocotrienol in which the prodrug and lactic acid / glycolic acid copolymer were dissolved was encapsulated inside the lecithin microparticles. It was speculated that it was adsorbed not only on the outer surface of the lecithin microparticles.

  Next, the manufacturing method of Example 3 of the present invention will be specifically described. The constituent components used in the production of Example 3 and the amounts thereof are shown in Table 5.

  In this example, dipamiltoylphosphatidylcholine, which is a phospholipid, and cholesterol were completely dissolved in 1 mL of chloroform in an eggplant type flask, and then evaporated to dryness using a rotary evaporator. In order to completely remove chloroform, it was further dried for 3 hours in a desiccator under reduced pressure to prepare a lecithin / cholesterol thin film.

  Next, irinotecan as a fat-soluble drug was completely dissolved in oily α-tocopherol under ultrasonic irradiation (Bransonic 12). Furthermore, polylactic acid as a biodegradable polymer and soybean oil as a vegetable oil were added to α-tocopherol and completely dissolved while being irradiated with ultrasonic waves.

  Next, the oily α-tocopherol containing irinotecan, polylactic acid and soybean oil was left for 1 hour in the dark, and then the oily α-tocopherol (drug, drug, The biodegradable polymer and vegetable oil are dissolved (contacted (attached or sprayed)). The eggplant-shaped flask is preferably substituted with nitrogen in advance to prevent oxidation of dipamyltoylphosphatidylcholine and α-tocopherol.

  Furthermore, oily α-tocopherol and lecithin / containing irinotecan, polylactic acid and soybean oil were added to the eggplant-shaped flask by adding 15% glycerin heated to 60 ° C. and ultrasonic irradiation (Bransonic 12) for 30 minutes. The cholesterol thin film was made into fine particles, and the oily α-tocopherol was encapsulated inside the fine particles made of lecithin / cholesterol thin film. As a result, a suspension containing sustained-release drug fine particles was obtained.

  Also in Example 3, the sustained-release fine drug particles similar to Example 1 were obtained. As for Example 3, the diameter of the fine particles was measured in the same manner as in Example 1. As a result, it was 450 nm or less (about 100 nm to 450 nm), and in Example 3, the diameter of the fine particles was small.

  As Example 4, drug sustained-release fine particles were produced by the same production method as Example 3 except that docetaxel was used instead of irinotecan in Table 5. As a result of measuring the particle size distribution of Example 4 in the same manner as Example 1, it was almost the same as Example 3.

  As Example 5, drug sustained-release fine particles were produced by the same production method as Example 3 except that 2 mg of hydrogenated lecithin (derived from egg yolk) was used instead of 2 mg of dipamyltoylphosphatidylcholine in Table 5. As a result of measuring the particle size distribution of Example 5 in the same manner as Example 1, it was almost the same as Example 3.

  As described above, the drug sustained-release microparticles of the present invention are the problems of the prior art, such as low drug encapsulation rate, initial burst, toxicity due to additives such as organic solvents, and drug migration into the blood. It overcomes the side effects on the whole body. Cancer patients because they can encapsulate antineoplastic drugs as fat-soluble drugs and administer them as injections around the affected area, minimizing side effects and administering the antineoplastic drugs to the affected area for a long time Expected to have a life-prolonging effect for the treatment of

  The sustained-release drug fine particles and the method for producing the same according to the present invention are useful as a sustained-release drug-injectable preparation in the pharmaceutical field and a production method therefor.

It is a figure which shows the structure of the drug sustained release fine particle of this invention. It is a figure which shows the result of the life extension effect of Experimental example 1. FIG. It is a figure which shows the blood processing method of Experimental example 2. FIG. It is a figure which shows the fixed_quantity | quantitative_assay result of the paclitaxel of Experimental example 2. FIG. It is a figure which shows the experimental method of the drug encapsulation rate of Experimental example 3. FIG. It is a figure which shows the experimental method of the drug introduction rate of Experimental example 3. FIG.

Explanation of symbols

1: Nucleus 2: Phospholipid thin film 3: Drug sustained-release fine particles

Claims (10)

A fine particle composed of a core and a shell,
The core is a fat-soluble vitamin in which a fat-soluble drug and a biodegradable polymer are dissolved ,
The shell is composed of a thin film of phospholipid;
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
The fat-soluble vitamin is tocotrienols or tocopherols,
The phospholipid is hydrogenated lecithin;
Nuclear is sealed shell, a drug sustained release spherical particles having a diameter and wherein the der Rukoto below 800 nm. The drug sustained-release spherical fine particles according to claim 1 , wherein the core further contains vegetable oil. The drug sustained-release spherical fine particles according to claim 1 or 2 , wherein the shell further contains cholesterol. The sustained-release spherical fine particles according to any one of claims 1 to 3 , wherein the fat-soluble drug is an antineoplastic drug. The drug sustained-release spherical fine particles according to claim 4, wherein the antineoplastic agent is a taxoid compound or an irinotecan compound. An injectable preparation which is a suspension containing the sustained-release spherical fine particles of any one of claims 1 to 5 . A step (a1) of preparing a phospholipid thin film by evaporating and drying phospholipid dissolved in an organic solvent;
A step (b1) of preparing a drug-polymer-dissolved fat-soluble vitamin by dissolving a fat-soluble drug and a biodegradable polymer in the fat-soluble vitamin;
Contacting the drug / polymer-dissolved fat-soluble vitamin prepared in the step (b1) and water or physiological saline with the phospholipid thin film prepared in the step (a1);
By ultrasonic irradiation or homogenization operation, the drug-polymer dissolved fat-soluble vitamins, see contains the step (d1) to enclose the interior of the thin film of the phospholipid,
The phospholipid is hydrogenated lecithin;
The fat-soluble vitamin is tocotrienols or tocopherols,
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
A method for producing a drug sustained-release spherical fine particle, wherein the spherical fine particle obtained by the step (d1) has a diameter of 800 nm or less . A step (a2) of preparing a thin film composed of phospholipid and cholesterol by evaporating and drying phospholipid and cholesterol dissolved in an organic solvent;
A step (b2) of preparing a drug-polymer-vegetable oil-soluble fat-soluble vitamin by dissolving a fat-soluble drug, a biodegradable polymer and a vegetable oil in the fat-soluble vitamin;
The drug / polymer / vegetable oil-soluble fat-soluble vitamin prepared in the step (b2) and water or physiological saline are contacted with the thin film composed of the phospholipid and cholesterol prepared in the step (a2). Step (c2)
By ultrasonic irradiation or homogenization operation, the drug-polymer vegetable oil dissolved fat soluble vitamins, see contains a step (d2) to enclose the interior of the thin film of the phospholipid,
The phospholipid is hydrogenated lecithin;
The fat-soluble vitamin is tocotrienols or tocopherols,
The biodegradable polymer is polylactic acid or a lactic acid / glycolic acid copolymer;
A method for producing sustained-release drug-use spherical fine particles, wherein the spherical fine particles obtained by the step (d2) have a diameter of 800 nm or less . 9. The method for producing sustained-release spherical fine particles according to claim 7 or 8 , wherein the fat-soluble drug in the step (a1) or (a2) is an antineoplastic drug. 10. The method for producing sustained-release spherical fine particles according to claim 9 , wherein the antineoplastic agent is a taxoid compound or an irinotecan compound.

Images