JPH0511091B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a sustained release preparation containing a pharmacologically active substance in a highly water-containing, high-strength polyvinyl alcohol porous gel. [Prior Art] In recent years, interest in new drug delivery systems has increased significantly in the pharmaceutical field. The purpose of this is to maximize the efficacy of existing drugs while minimizing side effects. One of the means adopted for this purpose is sustained release of medicines using polymeric materials, and various polymeric materials are used. Hydrogel materials are one such material. Hydrogel is a gel that does not dissolve in water but contains water. Such hydrogels have been known for a long time, but in recent years, as interest in functional materials has increased, their properties have been attracting attention. For example, they are used as medical materials such as soft contact lenses and sustained-release carriers for medicines, as immobilized carriers for enzymes and microbial cells, as heat carriers for cold storage, and as sustained-release carriers for fragrances. Polymeric materials for hydrogels include gelatin, carrageenan, alginic acid, poly 2-hydroxyethyl methacrylate, cross-linked carboxylated methyl starch, acrylonitrile, grafted starch hydrolyzate, polyacrylonitrile derivatives, polyacrylates, and vinyl acetate. -Saponified methyl acrylate copolymer, polyoxyethylene,
Known examples include polyvinylpyrrolidone, polystyrene sulfonic acid, and polyvinyl alcohol. Polyvinyl alcohol (hereinafter abbreviated as PVA)
It is well known that when a concentrated aqueous solution of is left at room temperature or below, its viscosity gradually increases and eventually gels. However, the resulting gel is sticky and has poor mechanical strength. Therefore, in order to improve the mechanical strength of PVA hydrogel, there are methods to chemically cross-link PVA using cross-linking agents such as formaldehyde and glutaraldehyde, and methods to chemically cross-link PVA using cross-linking agents such as formaldehyde and glutaraldehyde. Proposed methods include gelling an aqueous solution, crosslinking PVA by irradiating it with gamma rays, electron beams, and ultraviolet rays, and adding metal compounds such as titanium, copper, and cobalt to create coordination bonds. . However, the PVA hydrogels obtained by these methods do not have a good balance between high water content and high strength. That is, if an attempt is made to increase the mechanical strength, the moisture content decreases, and if an attempt is made to increase the moisture content, the mechanical strength must be sacrificed. Maintains high moisture content without using additives
In an attempt to increase the mechanical strength of PVA hydrogel, a method has been proposed in which it is frozen in a concentrated aqueous solution of PVA at low temperature for a short period of time, and then thawed at room temperature for a short period of time (Japanese Patent Laid-Open No. 50-52296). . but,
The mechanical strength of the PVA hydrogel obtained by this method is not satisfactory, and it also has the disadvantage that it swells significantly when immersed in water. Additionally, a method has been proposed in which the frozen body is vacuum-dried without thawing after freezing (Japanese Patent Laid-Open No. 1983-
Publication No. 130543). This method involves casting an aqueous solution of PVA with a saponification degree of 95 mol% or more and a viscosity average polymerization degree of 1500 or less, and then freeze-molding it at a temperature lower than -6℃, and then vacuuming the frozen molded product without melting it. It is for drying. When using such a method,
A process called vacuum drying is required. The present inventors have conducted intensive research to resolve the drawbacks of conventional PVA hydrogel, and as a result, PVA hydrogel
By freezing an aqueous solution at a temperature below the freezing point to separate it into an ice layer and a polymer phase, and then crystallizing the polymer phase at a low temperature of 0 to 10℃, a porous PVA with a high water content and high strength is created. Hydrogel is obtained and PVA
The present inventors have discovered that adding a pharmacologically active substance to an aqueous solution provides an excellent sustained-release preparation, and have completed the present invention. [Problems to be solved by the invention] The present invention provides a porous material with a high moisture content and high strength.
The objective is to provide a gradual release formulation consisting of a complex of PVA hydrogel and a pharmacologically active substance. [Means for Solving the Problems] The present invention involves freezing a PVA aqueous solution containing a pharmacologically active substance at a temperature below the freezing point and separating it into an ice phase and a polymer phase to form a phase-separated microstructure. , 0~
This invention relates to a sustained-release preparation containing a pharmacologically active substance in a porous PVA hydrogel, which is obtained by crystallizing the polymer phase by leaving it at a low temperature of 10°C for 10 hours or more. [Function] The porous PVA hydrogel in the sustained release preparation of the present invention has excellent water retentivity and mechanical strength. The reason why such an excellent porous gel can be obtained is that it contains pharmacologically active substances.
When the PVA aqueous solution freezes below the freezing point,
PVA separates into a polymer phase and an ice phase to form a phase-separated microstructure, and as a result, the local concentration of PVA molecular chains increases and secondary bonds occur between PVA molecular chains to form crystal nuclei. It is thought that this is because of this. Then, when this frozen body is left at 0 to 10°C for 10 hours or more, the PVA crystallization progresses as the ice phase thaws.
The microcrystals formed at this time become crosslinking points and PVA
It is thought that a strong three-dimensional network structure (porous structure) is formed, and the gaps between them are filled with an aqueous phase containing the pharmacologically active substance. [Example] The sustained release preparation of the present invention contains a pharmacologically active substance and water in porous PVA having a strong three-dimensional network structure as described above. The PVA used in the present invention preferably has a saponification degree of 95 mol% or more, preferably 97 mol% or more, particularly 99 mol% or more. If the degree of saponification is lower than this, for example 85 mol% or less, only a weak gel is obtained. Average degree of polymerization is viscosity average of 1000 or more,
In particular, those with a value of 1700 or more are preferable. As the degree of polymerization of PVA decreases, so does the strength of the resulting gel.
It is best to use a product with a high polymerization degree of about 2000. In the present invention, first, a drug containing a pharmacologically active substance is used.
A concentrated aqueous solution of PVA is prepared, and the concentration is preferably in the range of 10 to 30% by weight.
Such a concentrated aqueous solution is prepared by heating and dissolving PVA. After cooling the PVA aqueous solution to room temperature, it is immediately frozen below the freezing point. The freezing temperature should be as long as the PVA aqueous solution is sufficiently frozen, and is preferably -5°C or lower, but from the viewpoint of the time required for sufficient freezing, it is particularly preferable to carry out the freezing at -20°C. Further, the freezing time is 5 hours or more, usually 10 to 24 hours.
This freezing operation freezes the water, separates the PVA polymer phase, and yields a phase-separated microstructure. In this case, the pharmacologically active substance is considered to be present on the surface of the polymer phase, ice phase, or polymer phase. The frozen phase-separated microstructure is then left to stand at 0 to 10°C to further crystallize the PVA to form a final gel, but the standing time is preferably 10 hours or more.
If the standing time is shorter than 10 hours, crystallization will be insufficient and a gel with high strength will not be obtained. The pharmacologically active substance is not particularly limited as long as it is a compound used for treatment or disease prevention in humans or animals. Further, it may be water-soluble or water-insoluble, and may be liquid, powder, or granule. The amount of the pharmacologically active substance to be mixed can be arbitrarily selected depending on the purpose of administration, dosage form, sustained release properties, etc., but is usually 0.01 to 500 parts per 100 parts (parts by weight, hereinafter the same) of PVA, preferably 0.01 to 500 parts. 10 to 50 copies. The sustained release properties of the formulation of the present invention can be achieved by adjusting the concentration of PVA, the amount of pharmacologically active substance, etc.
Can be controlled arbitrarily. The sustained release preparation of the present invention can be made into various dosage forms that require sustained release properties, such as suppositories, transdermal preparations, sublingual preparations, and oral preparations. Next, the sustained release preparation of the present invention will be explained with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. Reference example (Production and analysis of PVA porous hydrogel) Add water to PVA (manufactured by Unitika Co., Ltd., saponification degree 99.5 mol%, average polymerization degree 1700) to the concentration shown in Table 1, and add it in an autoclave. After heating at 110℃ for 2 hours to completely dissolve, cool to room temperature.
A PVA aqueous solution was prepared. Each PVA aqueous solution was then placed in a -20°C freezer and frozen for 24 hours. The obtained frozen product was thawed under the conditions shown in Table 1 to obtain PVA hydrogels 1 to 5.

【table】

[Table] Approximately 6 g of samples of Gels 1 and 3 and Comparative Gels 1 to 3 were immersed in 50 ml of distilled water, and the swelling degree and shrinkage were determined by weighing the gel samples every day in a constant temperature bath at 37°C. The degree was measured. Here, the degree of swelling and degree of shrinkage were determined from the weight change in water at 37°C using the following formula. Swelling degree (%) or shrinkage degree (%) = W - W ₀ /W ₀ ×100 W ₀ = Gel weight before swelling W = Gel weight after swelling Inventive samples of gels 1 and 3, comparative gels 1 and FIG. 1 shows the results of measuring changes over time in the degree of swelling and shrinkage in water at 37° C. of the rapidly thawed sample of No. 2 and the high-temperature slowly thawed sample of Comparative Gel 3. As is clear from FIG. 1, in the rapidly thawed samples of Comparative Gels 1 and 2, the degree of swelling increases with time for each PVA concentration and reaches a constant value after about 4 days. In addition, the swelling degree depends on the PVA concentration,
The higher the concentration, the greater the degree of swelling. On the other hand, comparative gel 3
The sample thawed at high temperature slowly swelled slightly at the beginning, and showed a decrease in shrinkage after 4 days. On the contrary, in the samples of the present invention, Gels 1 and 3, no swelling development was observed, but on the contrary, shrinkage development was observed. In this case, it also gradually shrinks until about 4 days, and then reaches a certain value. In addition, as well as the degree of swelling, changes in shrinkage also
PVA concentration dependence was observed, and the degree of shrinkage was greater in Gel 1 than in Gel 3. The swelling development observed in the rapidly thawed samples of gels 1 and 2 is due to the gel instability and partial dissolution of the microcrystals at 37°C, whereas the shrinkage development observed in the inventive samples of gels 1 and 3. This is considered to be because a part of the amorphous portion is further crystallized due to the annealing effect. These experimental results indicate that the thawing temperature after freezing, in other words, the crystallization conditions of the gel, greatly influences the formation of a strong gel. (Mechanical properties) Manufactured by Toyo Baldwin Co., Ltd., Tensilon/UTM−
Using 4-100, tensile speed 100mm/min, temperature 20
Gels 1-5 and Comparative Gel 3 at 65% relative humidity
-6 mechanical properties were measured. In addition, the gel sample is 2
A dumbbell-shaped tensile test piece with a thickness of mm was punched out and subjected to measurement, and the tensile strength and elongation at break were determined. The stress-strain curves of the inventive samples of Gels 1, 3 and 5 were as shown in FIG. This stress-strain curve is different from the curves of common plastics, fibers, elastomers, etc., and is rather similar to the mechanical properties of living tissue. Samples of the invention for Gels 1-5 and Comparative Gels 3-
The results of measuring the tensile strength and elongation of the high temperature slowly thawed sample of No. 6 are shown in FIGS. 3 and 4. The rapidly thawed samples of comparative gels 1 and 2 were too soft to measure. Figures 3 and 4 clearly show that
It has been shown that the crystallization conditions after freezing greatly affect the mechanical strength of the gel. Generally, when crosslinking is performed using a crosslinking agent or radiation, the strength increases as the crosslink density increases, but the elongation decreases. However, the gel used in the present invention
As is clear from Figure 4, as the strength increases, the elongation also increases. This suggests that the structure of gels obtained by low-temperature crystallization is essentially different from gels obtained by general chemical crosslinking. (Electron Microscope Observation) The morphology of the critical point dried gel sample was observed using a scanning electron microscope model MSM-9 manufactured by Akashi Corporation. If a gel sample is freeze-dried as it is, a large volumetric contraction will occur and the gel structure will be destroyed.
Samples were prepared using the critical point drying method. Gel 1, 3
As a result of observation using an operating electron microscope of the samples of the present invention No. 5 and 5, a porous structure was observed in each sample, and it was found that the pore size was largely dependent on the PVA concentration of the gel sample. Gel 1 had an average pore size of about 5 μm, Gel 3 had an average pore size of about 2-3 μm, and Gel 5 had an average pore size of about 1 μm. Examples 1 to 7 Water was added to PVA (manufactured by Unitika Co., Ltd., degree of saponification 99.5 mol%, average degree of polymerization 1700) to the concentration shown in Table 2, and heated in an autoclave at 110°C for 2 hours. After completely dissolving the mixture, the mixture was cooled to room temperature to prepare a PVA aqueous solution. Next, a second dose of water-soluble adriamycin (manufactured by Kyowa Hakko Kogyo Co., Ltd., hereinafter referred to as ADM), which is an anti-malignant tumor agent, was added to each PVA aqueous solution as a pharmacologically active substance.
After adding and dissolving the amount shown in the table, the mixture was placed in a 5 mm diameter test tube. Each test tube was placed in a -20°C freezer, and the aqueous solution was frozen for about 10 hours. The resulting frozen body was then thawed in a constant temperature bath at 5°C for about 10 hours.
A rod-shaped sustained release preparation of the present invention with a length of 1 cm and a diameter of 5 mm was obtained.

[Table] Using a dissolution tester (NTR-VS3, manufactured by Toyama Sangyo Co., Ltd.) that complies with the standards of the Japanese Pharmacopoeia, samples were taken at predetermined intervals. Measurements were performed by UV absorption at 482 nm. The results are shown in Figures 5-7. Figure 5 is a graph showing the change in release rate (wt%) over time when the PVA concentration is changed in the case of a PVA aqueous solution with an ADM concentration of 1.25 mg/ml.
In the case of a PVA aqueous solution with a concentration of 2.5 mg/ml, a graph showing the change in release rate (wt%) over time when the PVA concentration is changed, Figure 7 shows the PVA concentration of the PVA aqueous solution constant (10%). It is a graph showing the change in release rate (wt%) over time when the ADM concentration is changed. As shown in FIG. 5, each sample has a high elution rate at the initial stage of elution, but the higher the PVA concentration, the more difficult it is to elute. 10% concentration gel sample Example 1
already releases about 50% of ADM in 30 minutes, and the release is completed in about 4 hours. Gel sample Example 4 at 20% concentration shows approximately 40% release in 30 minutes and complete release in approximately 8 hours. On the other hand, for gel sample Example 6 with a concentration of 30%, the initial release is low at about 20% and shows about 70% release in 6 hours, but the subsequent release is extremely slow and shows about 75% release even after 13 hours. only released. By changing the PVA concentration in this way, the release time of ADM can be adjusted.
When the concentration of ADM is 2.5 mg/ml in PVA aqueous solution, the same tendency as shown in FIG. 5 is observed as shown in FIG. 6, and the release time can be significantly extended. As shown in FIG. 7, the relationship between ADM concentration and release rate is such that the release rate tends to decrease as the ADM concentration increases. Examples 8 to 11 Water was added to PVA (manufactured by Unitika Co., Ltd., degree of saponification 99.5 mol%, average degree of polymerization 1700) to the concentration shown in Table 3, and heated in an autoclave at 110°C for 2 hours. After dissolving PVA, the solution was cooled to room temperature to prepare a PVA aqueous solution. Next, a water-insoluble prostaglandin I ₂ analog (manufactured by Ono Pharmaceutical Co., Ltd., hereinafter referred to as PGI ₂ -A), which is a platelet aggregation inhibitor, was added to each PVA aqueous solution in the amount shown in Table 3 and dispersed. Afterwards, it was placed in a 5 mmφ test tube. Each test tube was placed in a -20°C freezer, and the aqueous solution was frozen for about 10 hours. The resulting frozen body was then thawed in a constant temperature bath at 5°C for about 10 hours.
A robot-shaped sustained release preparation of the present invention with a length of 1 cm and a diameter of 5 mm was obtained.

[Table] Using the dissolution tester used in Example 1, samples were taken at predetermined time intervals. Measurement was performed using high performance liquid chromatography (column: stainless steel 1.4 x 200
mm, wavelength: 210 nm). The results are shown in Figures 8-9. FIGS. 8 and 9 are graphs showing changes over time in the release rate (wt%) when the PVA concentration of the PVA aqueous solution was kept constant at 10% and 15%, respectively, and the PGI ₂ -A concentration was changed. As shown in Figure 8, the PGI ₂ -A concentration was 0.5mg/
In the case of mlPVA aqueous solution Example 8, about 40 minutes after 30 minutes
%, and the release stops after about 4 hours (about 65%).
%). However, when the PGI ₂ -A concentration is 2.0 mg/ml PVA aqueous solution, 100% of Example 9 is released after about 6 hours. In addition, if the PVA concentration is 15% (No. 9
There is a similar trend in Figure), but the release of PGI ₂ -A is delayed. From the results of the above examples, the sustained release preparation of the present invention exhibits effective sustained release properties, and the sustained release time and tendency can be controlled by appropriately combining the PVA concentration and/or the concentration of the pharmacologically active substance. It is clear that it can be controlled. [Effects of the Invention] The sustained-release preparation of the present invention does not use any chemical crosslinking agents or catalysts when gelling PVA, and also does not heat, so there is no reduction in the activity or denaturation of the pharmacologically active substance. There's nothing to do. Therefore,
It is possible to incorporate pharmacologically active substances into the gel in an extremely stable manner, and at the same time, it does not cause any irritation to living organisms. Furthermore, it is not only possible to uniformly incorporate the pharmacologically active substance into the PVA gel regardless of the properties and shape of the pharmacologically active substance, but also to control sustained release by changing the PVA concentration and the content of the pharmacologically active substance. You can also.

[Brief explanation of the drawing]

Figure 1 is a graph showing changes over time in the degree of swelling and shrinkage in water of the PVA hydrogel used in the present invention and the comparative gel, and Figure 2 is a graph showing changes over time in the degree of swelling and shrinkage in water of the PVA hydrogel used in the present invention and the comparative gel.
A graph showing the stress-strain curve of PVA hydrogel. Figure 3 is a graph showing the relationship between the tensile strength and PVA concentration of the PVA hydrogel used in the present invention and the comparative gel. Figure 4 is a graph showing the relationship between the PVA concentration and the PVA hydrogel used in the present invention.
Graph showing the relationship between elongation and PVA concentration of hydrogel and comparison gel, Figure 5 shows ADM concentration of 1.25
PVA of the sustained release formulation of the present invention in mg/ml PVA aqueous solution
Graph showing the change in release rate over time when the concentration is changed. Figure 6 is a graph showing the change over time in the release rate when the PVA concentration is changed for the sustained release preparation of the present invention having an ADM concentration of 2.5 mg/ml PVA aqueous solution. , FIG. 7 is a graph showing the change in release rate over time when the PVA concentration is constant (10%) and the ADM concentration is changed for the sustained-release preparation of the present invention, and FIG. 8 and FIG. 2 is a graph showing changes over time in the release rate when the PGI ₂ -A concentration of a sustained release preparation containing PGI ₂ -A is changed by setting the PVA concentration to 10% and 15%.

Claims (1)

[Claims] 1 A polyvinyl alcohol aqueous solution containing a pharmacologically active substance is frozen at a temperature below the freezing point, separated into an ice phase and a polymer phase to form a phase-separated microstructure, and then frozen at a low temperature of 0 to 10°C for 10 hours or more. A porous sustained-release preparation obtained by allowing the polymer phase to crystallize on standing.