JP2007091716A - Drug-sustained releasing fine particle in water and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide sustained releasing fine particles in water, equipped with a sustained releasing performance of gradually releasing a drug into water and also having an excellent skin film strength. <P>SOLUTION: The drug-sustained releasing fine particles are characterized by covering the drug aiming at its sustained release, with a polyvinyl alcohol-based polymer. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an underwater drug sustained-release fine particle obtained by coating a drug intended for sustained release or a porous body containing the drug with a polyvinyl alcohol (hereinafter referred to as PVA) polymer, and a method for producing the same.

  Porous fine particles encapsulating various drugs have been conventionally studied as various types of microcapsules for various uses. However, simply encapsulating the microparticles diffuses rapidly in water and lacks sustainability. For this reason, development of a sustained release function in which a drug is gradually released from a base material into water has been actively developed in the fields of pharmaceuticals and agricultural chemicals. As the sustained release mechanism, for example, a drug is dispersed in a water-insoluble base such as wax, and a sustained release function is provided by coating with a salt or a water-insoluble polymer.

Among them, there are disclosed sustained-release fine particles having sustained release properties by coating a supported material in which porous fine particles carry pigments, fragrances, agricultural chemicals, medicines, etc., and a method for producing the same. (For example, refer to Patent Document 1). However, when the supported substance is coated with a substantially water-insoluble permeable substance as in Patent Document 1, it is difficult to control the sustained release into water.
In some cases, water-soluble natural polymers such as gelatin are used, but water-soluble natural polymers are generally very weak in film strength and are difficult to apply depending on the conditions of use. Therefore, it is easy to biodegrade, and when exposed to the natural world such as in the sea, the life that contributes to sustained release is remarkably shortened. Further, the coating method does not take into account the suppression of aggregation of the generated fine particles.

JP 2003-286196 A

  An object of the present invention is to provide sustained-release microparticles in water that have a sustained-release capability for gradually releasing a drug into water and that have excellent film strength.

As a result of diligent studies to achieve the above-mentioned problems, the present inventors have made into a fine particle coated with a PVA polymer a drug intended for sustained release or a porous body containing the drug. It was found that sustained-release drug-in-water fine particles having excellent sustained release control and excellent film strength can be obtained.
That is, the present invention is a drug-in-water sustained release fine particle characterized in that a drug intended for sustained release is coated with a PVA polymer, and preferably the drug intended for sustained release is encapsulated in a porous material. Further, the above-mentioned sustained-release drug-in-water fine particles are characterized in that the porous body is coated with a PVA polymer, more preferably 1 to 95% by mass of the PVA polymer is coated per fine particle. The above-mentioned sustained-release drug-in-water fine particles.

  Then, the present invention provides the above-mentioned drug in water in which the drug intended for sustained release is emulsified in a solution in which the PVA polymer is dissolved, and then the emulsified drug is coated with the PVA polymer by removing the solvent. It is a method for producing sustained-release fine particles, or after immersing a porous body containing a drug intended for sustained release in a solution in which a PVA polymer is dissolved, the solvent is removed to remove the porous body from polyvinyl alcohol. The above-mentioned method for producing sustained-release drug-in-water fine particles coated with a polymer, more preferably, the above-described method for producing sustained-release drug-in-water fine particles, characterized by heat-treating a PVA-based polymer, more preferably The method for producing the above-mentioned sustained-release drug-in-water fine particles, wherein the solvent is removed by a spray drying method.

  The fine particles of the present invention can be used for various purposes, and can be suitably used in the fields of agriculture and forestry, fisheries, medicine, and other sustained release purposes.

Hereinafter, the present invention will be specifically described.
In the underwater drug sustained-release fine particles of the present invention, the coating material for coating the drug intended for sustained release is preferably water-soluble from the viewpoint of ease of control. In order to release the drug gradually, the dissolution can be controlled by gradually dissolving the water-soluble coating material. Examples of the water-soluble polymer include PVA, polyethylene glycol, polypropylene glycol, polyacrylamide, polyacrylic acid, polyvinyl pyrrolidone, water-soluble alkyd, polyvinyl ether, polymaleic acid copolymer, and polyethyleneimine. It must be a polymer.
PVA-based polymers have the property of being superior in film strength compared to other water-soluble polymers, and are optimal among water-soluble polymers. PVA-based polymers not only form strong hydrogen bonds due to hydroxyl groups in the molecule, but also have excellent affinity with inorganic porous particles and polar organic porous particles, and have excellent properties as a film against these. . Further, not only the drug contained in the PVA-coated part dissolves in water, but also the sustained release of the drug can be controlled at the molecular sieve level because the coated PVA swells.
Also, in terms of biodegradability, PVA polymers tend to be decomposed only by microorganisms such as Pseudomonas, so that they are suitable as sustained release materials compared to water-soluble natural polymers, which will be described later.
In addition, anionic and cationic polymers such as polyacrylic acid and polyethyleneimine are not preferred because their water solubility tends to decrease in seawater. However, since PVA polymers are basically nonionic, their water solubility in seawater is also undesirable. Has the feature that sustained release is ensured without greatly changing.

On the other hand, in the case of a low molecule such as a salt, the dissolution control is very difficult and it is difficult to coat.
In addition, water-soluble natural polymer compounds generally have poor crystallinity, so the film strength is weak, and depending on the conditions of use, the film can easily disintegrate, which may shorten the sustained release life, and is a natural product. Therefore, it is easily biodegradable, and when it is exposed to the natural world such as in the sea, the life that contributes to sustained release is remarkably shortened. Furthermore, natural polymers are not preferable even if the cultivar and production area are the same, the molecular weight slightly changes depending on the temperature, weather, and sampling time, and the physical properties may change.
Furthermore, sustained release becomes very difficult with a water-insoluble coating material. As a permeable substance, introduction of continuous pores by phase separation as used in hollow filtration membranes such as dialysis can be considered, but there is a need for pore size control according to the drug carried, and it is extremely inferior in versatility. It becomes.

  The PVA used in the present invention is not particularly limited, but a polymer having 70 mol% or more of vinyl alcohol units is preferably used. Of course, if desired, it may have structural units such as ethylene, vinyl acetate, itaconic acid, vinylamine, acrylamide, vinyl pivalate, maleic anhydride, and sulfonic acid-containing vinyl compounds. However, the lower the crystallinity of the polymer constituting the film, the lower the water resistance, and a large amount of PVA is required for “sustained release”, so that the vinyl alcohol unit is 95 mol% or more in order to promote crystallization. Polymers are preferably used.

  Further, it is preferable that the sustained-release drug-in-water fine particles of the present invention are in a state of a porous body containing a drug intended for sustained release, and further the porous body is coated with a PVA polymer. It is generally difficult to emulsify and microparticulate a drug for sustained release, and it can be emulsified with a PVA polymer having a protective colloid effect, but depending on the drug, stable emulsification may be difficult and may not be microparticulated. . In such a case, a drug intended for sustained release may be supported in advance on porous fine particles, which will be described later, to form a porous body containing the drug, and then the surface of the porous body may be covered with a PVA polymer. .

  In the present invention, the PVA polymer is preferably coated with 1 to 95% by mass per fine particle. When the amount is less than 1% by mass, not only the coating amount is small, but also there are many coating spots, the drug release amount is almost the same as that of the uncoated, and cannot be “sustained release”, which is unsuitable. On the other hand, when the coverage is more than 95% by mass, the content of the drug intended for sustained release per particle is small, and therefore, the drug release amount is small, which is not suitable. The coverage may be controlled within the range according to the required sustained release performance, but it is more preferably 5 to 90% by mass, and further preferably 10 to 80% by mass in terms of sustained release life.

The drug for the purpose of sustained release in the present invention is not particularly limited, and any drug that can be carried on fine particles, such as agricultural chemicals, medicines, fragrances, pigments, oxygen, etc. may be used.
Further, the porous fine particles used for the porous material encapsulating the drug are not particularly limited, and may be inorganic porous fine particles such as silicon dioxide, calcium silicate, zeolite, polyurethane, cellulose, phenol resin, epoxy resin, etc. Organic porous fine particles may be used.
In order to obtain a drug-in-water sustained-release fine particle by coating a PVA polymer on a porous body encapsulating a drug, the average particle diameter of the porous body is preferably 50 μm or less.

Next, the method for producing sustained-release fine particles in water of the present invention will be described.
In order to obtain the sustained-release fine particles in water of the present invention, a drug intended for sustained release is dispersed in a solution in which a PVA polymer is dissolved, and then the solvent is removed by heating or the like to remove the drug from the PVA system. After the porous body containing the drug is dispersed in a solution in which the polymer is coated or the PVA polymer is dissolved, the solvent is removed by heating or the like, and the porous body containing the drug is removed from the PVA system. Obtained by coating with polymer.
The method for dissolving the PVA-based polymer and the method for removing the solvent are not particularly limited and can be selected according to the use. However, as a method for coating a drug intended for sustained release with a PVA-based polymer, 1) Fine particles obtained by coating a drug intended for sustained release with a PVA polymer, and 2) Fine particles obtained by coating a porous material containing the drug with a PVA polymer.
For the case of the former 1), it is sufficient that the drug intended for sustained release is dispersed in the fine particles composed of the PVA polymer, that is, the PVA polymer is substantially covered with the drug. When the drug is water-soluble, the drug is dissolved in the PVA polymer solution, and then water in the solution is dried to obtain fine particles coated with the PVA polymer.
When the drug is water-insoluble, after the drug is heated to the melting point or higher and melted in a PVA polymer solution, the solvent in the solution is dried and removed. It is only necessary to obtain fine particles coated with a PVA polymer, or simply disperse a drug itself in a PVA polymer solution at a temperature below the melting point and then perform the same treatment to obtain fine particles coated with the PVA polymer. May be obtained.
In the case of the latter 2), the above-mentioned porous body is encapsulated with a drug intended for sustained release, added to the solution in which the PVA polymer is dissolved, and then the solvent is removed. It is done. The method of encapsulating the drug in the porous body may be a method of immersing the porous body in a melt in which the drug is heated to a melting point or higher, or into a solution in which the drug can be dissolved. A method of immersing the porous body may be used.
The immersion dispersion concentration of the porous body may be appropriately adjusted depending on the dispersion stability of the porous body in the PVA polymer aqueous solution. However, if the dispersion concentration of the porous body is too low, the porous body is dried. Such energy is inefficient and inefficient, and if too much, dispersion becomes unstable, causing problems such as secondary aggregation, sedimentation, and thixotropic properties. Preferably it is 1-30 mass%, Furthermore, 5-20 mass% is suitable.

  It is also preferable to heat treat the PVA polymer for the purpose of controlling the sustained release rate. In general, crystallization is promoted by heat-treating a PVA polymer that is a crystalline water-soluble synthetic polymer, and the sustained release rate can be controlled by causing a change in the water rate and swelling degree of the film. The sustained release rate can be controlled by the heat treatment temperature and time.

Furthermore, in order to obtain the underwater drug sustained-release fine particles of the present invention, after dispersing a drug intended for sustained release in a solution in which a PVA polymer is dissolved, or after dispersing a porous body containing the drug, Although it can be obtained by removing the solvent by heating or the like, it is preferable to employ a spray drying method for removing the solvent. In the method of simply putting it into the dryer, the coating resin contributes as a binder between the fine particles, and as a result, only particles in which the fine particles are largely aggregated are often obtained.
In the spray drying method, fine particles sprayed in a mist form from the spray nozzle are completely dried while the cyclone air stays, and therefore, very good fine particles without aggregation can be obtained. Moreover, since it can dry with a dispersion liquid, pick-up fluctuation | variation is not seen. In carrying out the spray drying method, there are no particular restrictions on other conditions such as solution and immersion, but if it adheres to the wall surface of the device in the form of a spray mist, scale accumulates on the wall surface, which is undesirable in terms of yield. It is necessary to make the condition that does not adhere to the wall surface. The drying temperature needs to be equal to or higher than the boiling point of the solvent. In the case of water, drying can be performed at 100 ° C. or higher, preferably 120 ° C. or higher. Further, since the wall surface adhesion depends on the distance from the spray nozzle to the wall surface and the spray amount, it is necessary to adjust appropriately according to the apparatus.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited at all by these Examples. In the examples of the present invention, the PVA coverage and the sustained-release agent concentration are measured by the following methods.

[PVA coverage%]
It calculated by the following method using the iodine color reaction of PVA.
1) 1 g of fine particles coated with PVA are precisely weighed [A (g)], put into 100 ml of water, and stirred at 95 ° C. for 60 minutes to dissolve the coated PVA. After filtration, the filtrate is collected in a 10 ml stoppered test tube, 10 ml of PVA detection solution is added and mixed, and after 10 minutes, the absorbance at a wavelength of 670 nm is measured with an AKA photoelectric colorimeter.
2) Separately, the same absorbance is measured with a PVA aqueous solution having a known concentration, and a calibration curve is created at three or more points.
3) From the calibration curve, the amount of PVA [B (g)] in the coated PVA solution is calculated.
4) The PVA coverage on the fine particles is calculated by the following formula.
PVA coverage (%) = B (g) × [100 (ml) / 10 (ml)] / A (g) × 100
The PVA detection solution is an aqueous solution containing 107 g / l iodine and 21 g / l boric acid.

[Sustained release agent concentration%]
The sample solution was filtered through a 0.5 μm membrane filter, and 5 μL was injected into a high performance liquid chromatograph and measured. Separately, a calibration curve was prepared by measuring a solution having a known sustained release agent concentration, and the sustained release agent concentration in the sample solution was calculated from the calibration curve. Measurement conditions are as follows.
Measuring instrument: Tosoh Corporation high performance liquid chromatograph (HPLC)
Eluent: acetonitrile / distilled water = 8/2 (volume ratio)
Column oven temperature; 45 ° C
Flow rate: 0.8mL / min
Detection UV wavelength: 285 nm

[Example 1]
(1) PVA (dichloro-2-n-octyl-4-isothiazolin-3-one as a drug intended for sustained release with respect to 100 parts by mass of a 2% by weight aqueous solution of “PVA-117” manufactured by Kuraray Co., Ltd.) Add 50% by mass with respect to PVA and stir at 1000 rpm for 3 minutes or more with dichloro-2-n-octyl-4-isothiazolin-3-one melted at 50 ° C. A dispersed fine particle dispersion was prepared, and the dispersion was spray-dried at a drying temperature of 120 ° C. using a spray drying apparatus (manufactured by Tokyo Rika Co., Ltd., desktop spray dryer “SD-1 type”) to obtain a PVA coverage. 65.8% by mass of fine particles were prepared, which consisted only of the drug and PVA, and the content of the drug was 34.2% by mass of the fine particles.
(2) The obtained fine particles were suspended at a concentration of 0.01 g / l in seawater (collected from off Ushimado, Okayama Prefecture), and shaken at 25 ° C. and 20 rpm / min for a predetermined time using a shaker. Immersion seawater was sampled every predetermined time, and the sustained-release agent concentration in the seawater was measured by liquid chromatography to determine the sustained-release agent concentration present in the fine particles. The sustained release performance is shown in Table 1.

[Example 2]
A solution prepared by dissolving 50% by mass of dichloro-2-n-octyl-4-isothiazolin-3-one, a drug intended for sustained release, in methanol at 40 ° C. was prepared, and 100 parts by mass of this 40 ° C. solution. 10 parts by mass of porous silica fine particles (“Microid ML-384” manufactured by Tokai Chemical Industry Co., Ltd.) are added to the inside of the porous silica fine particles to dichloro-2-n-octyl- After injecting 4-isothiazolin-3-one, the mixture was filtered on filter paper, the particle surface was washed with methanol at 20 ° C., and allowed to stand at 30 ° C. overnight, whereby dichloro-2-n-octyl-4- A porous body containing 30.3% by mass of isothiazoline-3-one was produced. Except for mixing 20 parts by mass of this porous body and 100 parts by mass of a 10% by mass aqueous solution of PVA (manufactured by Kuraray Co., Ltd. “PVA-117”), a uniform fine particle dispersion was prepared, as in Example 1. Spray drying was performed to produce fine particles with a PVA coverage of 33.8%. The fine particles were composed of the drug, a porous body containing the drug, and PVA, and the content of the drug was 20.2 mass% per fine particle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Example 3]
Fine particles were produced in the same manner as in Example 2 except that the 10% by mass aqueous solution of PVA was changed to 20 parts by mass. As a result, the PVA coverage was 7.0% and the drug content was 28.2% by mass per fine particle. It was. The sustained release performance of the obtained fine particles is shown in Table 1.

[Example 4]
In Example 2, the coated PVA was heat treated at 200 ° C. for 5 minutes. The PVA coverage was 33.8% as in the example, and the drug content was 20.2% by mass per fine particle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Comparative Example 1]
Fine particles were prepared in the same manner as in Example 2 except that the 1% by mass aqueous solution of PVA was changed to 6 parts by mass. The PVA coverage was 0.3% and the drug content was 29.8% by mass per microparticle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Comparative Example 2]
The same as Example 1 except that 100 parts by mass of an ethylene vinyl acetate copolymer emulsion (Kuraray Co., Ltd. “Panflex OM-4000”) prepared in an aqueous solution having a solid content concentration of 10% by mass was selected as the coating polymer material. Ethylene vinyl acetate copolymer-coated fine particles were produced by the production method. The ethylene vinyl acetate copolymer coverage calculated from the weight increase due to coating was 38.3%, and the drug content was 18.7 mass% per fine particle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Comparative Example 3]
Gelatin-coated fine particles were produced by the same production method as in Example 1 except that the coating polymer material was 100 parts by weight of a 10% by weight aqueous solution of gelatin (manufactured by Wako Pure Chemical Industries, Ltd.). The gelatin coverage calculated from the weight increase due to coating was 35.5%, and the drug content was 19.5 mass% per fine particle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Comparative Example 4]
The manufacturing method is the same as in Example 2 except that 100 parts by mass of a 10% by mass aqueous solution of polyacrylic acid (“AC-10L” manufactured by Nippon Pure Chemical Co., Ltd., weight average molecular weight 25,000) is used as the covering polymer material. Thus, polyacrylic acid-coated fine particles were produced. The polyacrylic acid coverage calculated from the weight increase due to coating was 32.4%, and the drug content was 20.5% by mass per fine particle. The sustained release performance of the obtained fine particles is shown in Table 1.

[Reference Example 1]
Underwater sustained-release fine particles were prepared in the same manner as in Example 2 that was not subjected to PVA coating treatment, and the sustained-release performance was measured. The results are shown in Table 1.

As shown in Table 1, in Examples 1 to 4 using a PVA polymer, suppression of elution of the sustained release agent was confirmed. It was also confirmed that the elution rate can be changed by adjusting the coverage and heat treatment.
On the other hand, in Comparative Example 1 in which the coverage was less than 1% by mass, the same result as in Reference Example 1 in which PVA was not coated was obtained. Further, Comparative Example 2 coated with a non-water-soluble polymer did not elute at all, and it was difficult to control the sustained release.
Furthermore, in Comparative Example 3 in which gelatin, which is a natural water-soluble polymer, was coated, the drug content was significantly reduced after 240 hours of immersion. This is because the film strength of gelatin is weak and the destruction of fine particles has occurred over time due to shaking, but on the other hand, gelatin is biodegraded by microorganisms in seawater. It was short.
In Comparative Example 4 coated with polyacrylic acid, which is a water-soluble synthetic polymer, the dissolution rate in seawater was lower than in freshwater because the polymer was an anion. Since the strength itself was weak, the fine particles were destroyed over time by shaking, and after 240 hours, a large amount of the silica porous body falling off inside the fine particles was observed.

The fine particles of the present invention can be suitably used in all fields of application such as agriculture and forestry, fisheries, medicine, and other sustained release purposes. Also, the use form is not particularly limited, and it can be used in a form according to the purpose such as spraying as it is, sticking to the surface of a fiber or fabric, adding to a paint or the like.

Claims (7)

  An underwater drug sustained-release fine particle characterized in that a drug intended for sustained release is coated with a polyvinyl alcohol polymer.   The sustained-release drug-in-water fine particles according to claim 1, wherein a drug intended for sustained release is encapsulated in a porous material, and the porous material is further coated with a polyvinyl alcohol polymer.   The sustained-release drug-in-water fine particles according to claim 1 or 2, wherein the polyvinyl alcohol polymer is coated in an amount of 1 to 95% by mass per fine particle.   4. The method according to claim 1, wherein the drug intended for sustained release is emulsified in a solution in which the polyvinyl alcohol polymer is dissolved, and then the emulsified drug is coated with the polyvinyl alcohol polymer by removing the solvent. A process for producing sustained-release fine particles of an underwater drug according to claim 1.   The porous body is coated with the polyvinyl alcohol polymer by removing the solvent after immersing the porous body containing a drug intended for sustained release in a solution in which the polyvinyl alcohol polymer is dissolved. The manufacturing method of the underwater chemical | medical agent sustained release fine particle of any one of Claims 1.   The method for producing sustained-release fine particles of drug in water according to claim 4 or 5, wherein the polyvinyl alcohol polymer is heat-treated. 6. The method for producing fine drug sustained-release fine particles in water according to claim 4, wherein the solvent is removed by a spray drying method.