JPH0415207B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a sustained-release base, and particularly relates to a method for producing a sustained-release base that imparts excellent sustained-release properties to a drug when mixed with the base. . Polycondensates of lactic acid, glycolic acid, etc., ie, polylactide and polyglycolide, are biodegradable polymers that have recently been applied to medical implant materials such as sutures, artificial tracheas, and artificial blood vessels. On the other hand, it is also being applied as a sustained release base for drugs such as physiologically active substances and agricultural chemicals. Desired properties for these materials include not only biocompatibility and biodegradability, but also
For materials impregnated with drugs, etc., sustained release control, which involves releasing the drug from the base within a certain period of time, is an issue. (Prior art) Conventionally, as a method for sustained release of drugs using polymers such as polylactide and polyglycolide, a fertilizer salt such as urea and polylactide having a weight average molecular weight of 130,000 are melt-mixed and pelletized. It is known that sustained release can be achieved by (Environ.Sci.
Technol., 7 (10), 955 (1973)) However, simply melt-mixing a polymer such as polylactide and a drug such as fertilizer salt in this way will cause the hydrolysis of the polymer to be rapid due to the effects of decomposition products. Drugs are rapidly released after a certain period of time, and there have been problems with controlling drug release over a long period of time. As a method to improve this, attempts have been made to improve control of the sustained release period by using polylactide with an initial molecular weight as high as possible, but the effect is not sufficient, and the use of high molecular weight polylactide and polyglycolide has been attempted. Obtaining it itself requires a great deal of effort, and at present no excellent sustained-release base has yet been obtained. (Problems to be Solved by the Invention) Under the current circumstances, the present inventors have solved the above-mentioned problems and developed a method for slowing release amount, release time, etc. as a base for sustained release of drugs, etc. We conducted intensive research to develop an excellent sustained-release base that can easily control release. (Means for Solving the Problems) As a result, the present inventors used an aluminum salt selected from polylactide, polyglycolide, or a copolycondensate thereof together with a higher alcohol, an ester of a higher fatty acid, or a paraffin. As a result, the inventors discovered that the above-mentioned sustained release properties are excellent, leading to the completion of the present invention. That is, the present invention relates to a sustained release base comprising an aluminum salt selected from polylactide, polyglycolide, or a copolycondensate thereof, and a higher alcohol, an ester of higher fatty acid, or paraffin. (Function) To explain the sustained release base of the present invention in more detail,
First, the sustained release base of the invention uses an aluminum salt selected from polylactide, polyglycolide, or a copolycondensate thereof; , obtained by reacting higher fatty acids with aluminum salts, aluminum alcoholates, or anhydrous aluminum chloride. First, polylactide, polyglycolide, or a copolycondensate thereof as a raw material used in the present invention may be any one produced by a common method. For example, polylactide and polyglycolide can be obtained by directly dehydrating and polycondensing lactic acid and glycolic acid under reduced pressure. (Yubara et al., Koka. 67 (2), 362
(1964)) In addition, lactic acid and glycolic acid are distilled in the presence of a catalyst such as zinc oxide to obtain lactide and glycolide, which are then polymerized in the presence of a catalyst such as tetraphenyltin or stannous chloride. It can also be produced by (Kulkarni, J. Biomed. Mater.
Res., 5 , 169 (1971)) Furthermore, the lactic acid monomer used in these cases may be of the D-form, L-form, or DL-form. In the present invention, the number average molecular weight of polylactide or polyglycolide obtained in this way is usually
Use something between 500 and 15,000. Next, regarding aluminum salts of higher fatty acids, aluminum stearate, aluminum palmitate, aluminum laurate, aluminum myristate, aluminum octylate, aluminum oleate, sorbitan aluminum monooleate, sorbitan aluminum monostearate, aluminum cinnamate. , aluminum 3-phenylpropionate, and the like. In addition, aluminum alcoholates include aluminum isopropoxide, aluminum methoxide, aluminum ethoxide, aluminum
Examples include n-butoxide, aluminum phenyl methoxide, and aluminum phenyl ethoxide. The sustained release base of the present invention cannot be obtained by using aluminum salts of higher fatty acids, aluminum alcoholates, or aluminum salts other than anhydrous aluminum chloride. Next, polylactide, polyglycolide, or a copolycondensate thereof is reacted with an aluminum salt of a higher fatty acid, aluminum alcoholate, or anhydrous aluminum chloride to obtain an aluminum salt of polylactide, polyglycolide, or a copolycondensate thereof. However, the method recommended by the present inventors first involves
A method of heating and melting mixing polylactide, polyglycolide, or their copolycondensates with drugs for sustained release such as various inorganic salts, and adding and reacting aluminum salts of higher fatty acids, aluminum alcoholates, or anhydrous aluminum chloride. This is done by Although there is no particular limitation on the order of addition, the above order of addition is preferable in that the sustained-release drug can be most uniformly dispersed in the base. In this case, polylactide, polyglycolide, or a copolycondensate thereof needs to react with the aluminum salt to become an aluminum salt of polylactide, polyglycolide, or a copolycondensate thereof; The effects of the present invention cannot be obtained with a mixture of the following. Therefore, according to the above-mentioned heating melt mixing method, the reaction conditions must be at a temperature of 150° C. or higher. Regarding reaction time, the type of drug used,
It varies depending on the raw materials, type of mixer, etc., but approximately 1
It takes about an hour. Yet another method is to use chloroform,
By using organic solvents such as dioxane,
It is possible to carry out the abovementioned reactions without heating. Regarding the proportions of polylactide, polyglycolide, or copolycondensates thereof and aluminum salts, aluminum alcoholates, or anhydrous aluminum chloride of higher fatty acids, the aluminum salts, aluminum alcoholates, or anhydrous aluminum chloride of higher fatty acids are: Approximately 1 for polylactide, polyglycolide, or their copolycondensates
Use in the range of ~100% by weight. In this case, generally speaking, the higher the proportion of higher fatty acid aluminum salt, aluminum alcoholate, or anhydrous aluminum chloride used relative to the amount of polymer, the longer the slowing time of the base of the present invention, and The amount of sustained release becomes constant. Therefore, by selecting these usage ratios, it is possible to control the sustained release time and sustained release amount. Furthermore, if the proportion of aluminum salts, aluminum alcoholates, or anhydrous aluminum chloride of these higher fatty acids used exceeds the above range and is below the lower limit, not only will the control of the sustained release time not be improved, but the drug will not last for a certain period of time. In this case, a large amount is released and the substance loses its ability as a sustained release base, making it impossible to obtain the excellent sustained release base of the present invention. Moreover, even if it is used in excess of the upper limit, no great effect can be expected and it is not economical. The present invention provides the polylactide thus obtained,
A sustained release base consisting of an aluminum salt selected from polyglycolide or a copolycondensate thereof, and a higher alcohol, an ester of a higher fatty acid, or paraffin. , which improves sustained release properties. That is, by using these higher alcohols in combination,
The sustained release time of the base is further extended, and the sustained release amount of the drug is maintained uniformly over a long period of time. The higher alcohol, higher fatty acid ester or paraffin used in the present invention includes natural candelilla wax, rice wax, carnauba wax, Japanese wax wax, beeswax, etc., or synthetic paraffin wax, low molecular weight polyethylene wax, micro Examples include crystalline wax, sorbitan monolaurate, sorbitan monostearate, and the like. The proportion used is approximately 3 to 40% by weight based on polylactide, polyglycolide, or a copolycondensate thereof. In this case, the higher the proportion used, the longer the sustained release time of the base of the present invention becomes, and the more constant the sustained release amount for each predetermined period of time becomes. Therefore, by selecting these usage ratios, the sustained release time and sustained release amount can be easily controlled. There is no particular limitation on the timing of adding these higher alcohols, esters of higher fatty acids, or paraffin, and polylactide, polyglycolide or their copolycondensates, aluminum salts of higher fatty acids,
There is no problem in adding it before the reaction with aluminum alcoholate or anhydrous aluminum chloride. Regarding the addition method, appropriate mixing and stirring may be performed so that these substances are uniformly contained in the base. The sustained release base of the present invention obtained in this way is
Due to its excellent sustained release properties as mentioned above, it can be used not only as a matrix for drugs and implant materials, but also as a holding agent for bacterial cells and microorganisms, a carrier as a microcapsule, a soil conditioner, a disintegrating agricultural film, It can be used in a wide range of applications, including fruit quality improvers, gas separation permeable membranes, and aromatics. (Example) The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.
It should be noted that all percentages are by weight unless otherwise specified. Example 1 500ml with thermometer, stirrer and condenser
50 g of a poly-L-lactide-glycolide copolycondensate having a number average molecular weight of 3100 (lactide:glycolide molar ratio 78:22) and 185 g of chloroform were placed in a separable flask and dissolved with stirring. Next, 6.2 g of butamben (p-aminobenzoic acid n-butyl ester) was added to this, and the mixture was stirred and dissolved. A solution prepared by dispersing 3.3 g of aluminum isopropoxide in 60 g of chloroform was added to this, and the mixture was heated at 45°C.
After heating for 30 minutes, the reaction solidified product was dried under reduced pressure and pulverized to obtain a base. In this method, after adding butamben, 5 g of beeswax was added, uniformly dispersed, and treated to obtain the sustained release base of the present invention. Furthermore, for comparison, each of the above copolycondensates, beeswax, and aluminum isopropoxide alone,
Alternatively, a base was obtained in the same manner by combining the two. The sustained release base containing butamben obtained in this way was sieved to a particle size of 149 to 250 μm 3
Take g
Dispersed in 90g. Next, the solution was sampled at predetermined time intervals while the solution was left standing, and the amount of butamben dissolved into the phosphate buffer solution was measured. In addition, the elution amount of butaneben was determined using an absorption photometer at 284 nm.
Measurements were carried out at These results are shown in Table 1.

[Table] *2 Abbreviation for aluminum isopropoxide
The number in parentheses indicates the amount used (g).
Example 2 12.8 g of poly-L-lactide having a number average molecular weight of 3030 was placed in an evaporating dish and heated at 250°C to melt it. Add 16 g of potassium chloride to this, further add aluminum salts of higher fatty acids, aluminum alcoholates, or anhydrous aluminum chloride shown in Table 2, further add higher alcohols, esters of higher fatty acids, or paraffin, melt-mix, The reaction was carried out. When the reactant becomes rubbery, cool it down.
The mixture was pulverized to obtain the sustained release base of the present invention. The potassium chloride-containing base obtained in this manner was sieved, and 5 g of the powder having a particle size of 4.8 to 6.7 mm was taken and dispersed in 150 g of distilled water. This temperature is 37℃
The solution was sampled at predetermined time intervals, and the amount of potassium ions eluted into water was measured. The results are shown in Table 2. The amount of potassium ions eluted was measured by the following method. First, 5 g of the base material was sieved to have a particle size of 4.8 to 6.7 mm and dispersed in 150 g of distilled water. This was left standing at a temperature of 37°C, and the liquid was sampled at predetermined time intervals to measure the amount of potassium ions eluted into water. Note that potassium ions were determined by atomic absorption spectrophotometry.

[Table] Example 3 Similar to Example 2, polyamide with a number average molecular weight of 5400
A predetermined amount of DL-lactide was heated and melted at the ratio shown in Table 3. To this was added 20 g of potassium chloride, and further added predetermined amounts of aluminum stearate and polyethylene wax (110P manufactured by Mitsui Petrochemicals) in the proportions shown in Table 3, followed by melt mixing and reaction. This was cooled and formed into a spherical shape to have a spherical diameter of 1.4 cm (approximately 1.6 g) to obtain a sustained release base of the present invention. The potassium chloride-containing base thus obtained was dispersed in 50 g of water, allowed to stand at a temperature of 37°C, and the amount of potassium ions eluted at predetermined intervals was measured. These results are shown in Table 3.

【table】

Claims (1)

[Scope of Claims] 1. A sustained release base comprising an aluminum salt selected from polylactide, polyglycolide, or copolycondensates thereof, and a higher alcohol, an ester of higher fatty acid, or paraffin. 2 An aluminum salt selected from polylactide, polyglycolide, or a copolycondensate thereof is reacted with polylactide, polyglycolide, or a copolycondensate thereof, and an aluminum salt of a higher fatty acid, aluminum alcoholate, or anhydrous aluminum chloride. The sustained release base according to claim 1, which is obtained by