JPS6133007B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to sustained release formulations of isosorbitol nitrate (hereinafter referred to as ISDN). Many methods are known for producing sustained release formulations. However, the main drug contained in the drug has different solubility in the gastrointestinal tract, absorption site, etc. depending on its properties, so in order to obtain the blood concentration curve required for each drug, it is necessary to design the most suitable drug for that drug. There is a need to do. ISDN is widely used as a treatment for exertional angina and angina associated with myocardial infarction.
Because of the large first-pass effect in the liver of ISDN,
Conventional preparations reach their maximum blood concentration 15 minutes after oral administration, and disappear from the blood in about 4 hours.
Therefore, frequent administration is required, and temporary
The blood concentration of ISDN increases dramatically, resulting in severe headaches and
Side effects such as a sudden drop in blood pressure occur. Therefore, it has been desired to develop a sustained-release preparation that has fewer side effects and maintains an effective blood concentration for a long period of time. ISDN has a low melting point (70°C), easily vaporizes and decomposes at high temperatures, and may explode if rapidly heated or subjected to impact, so special care must be taken when formulating it. In addition, when producing sustained-release preparations, halogenated hydrocarbons such as carbon tetrachloride and chloroform, hydrocarbons such as hexane and benzene, lower alcohols, and acetone are commonly used as solvents, but they pose problems of environmental pollution. Must be considered. Recently, there has been a demand for ISDN preparations that reach an effective blood concentration immediately after administration and maintain a constant effective blood concentration for a long period of time. ISDN long-acting preparations manufactured by various conventional methods may not disintegrate and be excreted in their original form when administered to humans, or the release of ISDN may be transient, resulting in a lack of long-lasting effects. It was enough.
In addition, even if the elution of ISDN is simply suppressed and the blood concentration is sustained as a result, it will take time for absorption to start after administration, and the increase in blood concentration will be delayed, or the same dose may not be sustained. The drawback is that the absorption rate is significantly lower than that of pharmaceutical preparations. The present inventors conducted various studies in order to obtain a long-acting ISDN preparation that can eliminate the drawbacks of conventional methods, can reliably control the release of ISDN, and is easy to manufacture. As a result, a slow-soluble composition containing ISDN, a specific synthetic polymer substance, and hydrogenated oil and/or waxes (hereinafter referred to as lipids) as essential components.
We have discovered that by combining ISDN-containing fast-dissolving compositions in a fixed ratio, the release rate of ISDN can be freely adjusted and that the blood concentration can be maintained when administered to humans, making it possible to create a formulation suitable for treatment. The invention has been completed. The present invention provides a fast-dissolving isosorbitol nitrate composition and a slow-dissolving isosorbitol nitrate composition containing ethyl cellulose and/or an acrylic acid/methacrylic acid ester copolymer and a hydrogenated oil and/or a wax as a slow-dissolving component. , contained in combination within the range of content equivalent weight ratio of 30:70 to 60:40, and the amount of ethyl cellulose and/or acrylic acid/methacrylic acid ester copolymer is 1 to 1 to the weight of the slow-soluble composition. 20% by weight, and the amount of hydrogenated oil and/or wax is 10 to 50% by weight, and the blending ratio of both is 1:1 to 40. The preparation of the present invention is a preparation in which a slow-dissolving composition using a specific synthetic polymer substance and lipid as a hydrophobic substance and a composition consisting of fast-dissolving granules that do not disintegrate rapidly are mixed in a fixed ratio, After oral administration, it gradually disintegrates in the intestine and remains in the form of granules, releasing the drug slowly. In addition, a film-forming synthetic polymer substance that is water-insoluble and water-permeable and a water-repellent lipid act appropriately on ISDN,
A novel pharmaceutical preparation with a controlled release form of ISDN. The formulation of the invention consists of two compositions:
A fast-dissolving composition containing ISDN (granules A),
A slow-dissolving composition (granules B) containing ISDN, a synthetic polymeric substance, and a lipid is mixed by a conventional method and compressed to form a tablet, or each layer is compressed into separate layers to form a multilayer tablet or a cored tablet. It can be made into tablets by making it into tablets. When producing the formulation of the present invention, first, granules A and B are produced. Granule A is obtained by mixing ISDN and additives commonly used in oral preparations and granulating the resulting mixture. As the granulation method, extrusion granulation method, crush granulation method, rolling granulation method, spray granulation method, fluidized bed granulation method, dry granulation method, etc. are used. Granular material B is a granular material (B-1) obtained by adding and mixing a synthetic polymeric substance and a lipid to ISDN, and then kneading and granulating it, or a mixed solution of a synthetic polymeric substance and a lipid containing small particles containing ISDN. Granules coated with (B
-2) or a mixture of both. The granules (B-1) are obtained by adding a liquid mixture in which a synthetic polymer substance and a lipid are dissolved in a solvent in advance to ISDN or a powder mixture of ISDN and additives, stirring and kneading the mixture, and then granulating the mixture. For granulation, a spray granulation device or a centrifugal flow granulation device can also be used. However, after adjusting the amount of solvent in the kneaded product, it is preferable to granulate it by a wet granulation method that is easy to operate and does not require expensive equipment, and then to dry and size the granules. The granular material (B-2) is a mixed solution in which the granular material (B-1) is placed in a coating pan, the synthetic polymer substance and lipid are dissolved in an organic solvent, and talc or the like is suspended as an anti-adhesive agent if necessary. It can be obtained by coating with The amount of synthetic polymeric material is between 1 and 20% by weight of the granules B, preferably between 2 and 10%. The amount of lipid is 10-50% by weight of granules B. The amount of solvent may be an amount that can dissolve the synthetic polymer substance and lipid. The ratio of synthetic polymeric substance to lipid is 1:1-40, preferably 1:3-20. The amount of coating is less than 10% by weight of granules B. The ethyl cellulose and acrylic acid/methacrylic ester copolymer used in the present invention are soluble in ethyl alcohol, and the solubility does not depend on pH. Both can also be used as a mixture. Ethyl cellulose has a viscosity of 5 to 100 cps at 20°C (ethoxy group content 44 to 51% by weight), especially
Those having a viscosity of 50 cps at 25°C (ethoxy group content 48-49% by weight) are preferred. Moreover, as the acrylic acid/methacrylic acid ester copolymer, Eudragit Retard (Eudragit RL, Eudragit RS) is preferable. The hydrogenated oil or wax used as the lipid preferably has a melting point of 50 to 90°C and is highly soluble in ethanol. Hydrogenated oils are hydrogenated vegetable oils or hydrogenated animal oils. Waxes include paraffin wax, petroleum wax,
Mineral waxes such as Utah wax and Montan wax, insect waxes such as beeswax and white beeswax, and vegetable waxes such as carnauba wax and tree wax are preferred. These can also be used in combination. As additives, those commonly used in oral preparations, such as excipients, plasticizers, binders, lubricants, coloring agents, and flavoring agents, are used. Examples of excipients include lactose, starch, sucrose, crystalline cellulose, talc, etc., and binders include starch, hydroxypropylcellulose, methylcellulose,
Examples of lubricants such as gelatin include talc, magnesium stearate, and silicic anhydride. The organic solvent may be any solvent as long as it is volatile, non-reactive with the nitrite ester derivative, and capable of dissolving the synthetic polymer substance and lipid. Examples of solvents that meet these conditions include methylene chloride, chloroform, methyl ethyl ketone, acetone, methyl alcohol, and ethyl alcohol. Ethyl alcohol, which is less toxic, is most preferred. Next, the weight ratio of granules A and granules B in terms of content
The formulation of the present invention is obtained by mixing at a ratio of 30:70 to 60:40 and compression molding by a conventional method. The dissolution rate and duration of the formulation of the present invention can be adjusted by changing the ratio of granules A and granules B. Furthermore, by setting the weight ratio of granules A and B to 30:70 to 60:40, the blood concentration can rise quickly after administration, and the effective blood concentration can be maintained for a long time. . Furthermore, the formulation of the present invention has little change in release rate due to variations in granule size, preparation method, tablet hardness, etc., and therefore has extremely good reproducibility of release rate, making it suitable for mass production. Further, operations from preparation of granules to compression molding can be performed using conventional manufacturing equipment. Example 1 (a) Manufacturing method of fast-dissolving ISDN composition: 200 g of ISDN, 570 g of lactose, and 150 g of cornstarch
g and 80 g of crystalline cellulose and mix well with a mixer. Next, a solution obtained by dissolving 10 g of methylcellulose in distilled water is used as a kneading solution. This is granulated, dried, and sized to produce granules (particle size distribution: 32
~16 meters). (b) Manufacturing method of slow-soluble ISDN composition: 200 g of ISDN, 440 g of lactose and crystalline cellulose
Add 70g and mix well with a mixer. Next, add 40 g of ethyl cellulose and hydrogenated oil to warm ethanol.
Add the solution containing 250g and mix with stirring. This kneaded product is granulated using a pelletizer, then dried and sized to form granules (particle size distribution: 32 to 16 mesh). (c) Manufacturing method of coating composition: 900 g of the granules obtained in (b) are placed in a coating pan and spray coated with a coating liquid consisting of 5 g of ethyl cellulose, 25 g of hydrogenated oil, and ethanol. (d) Manufacturing method for long-acting preparations consisting of fast-dissolving compositions and slow-dissolving compositions: Mix each granule in the content-based weight ratio shown in Table 1, add appropriate amounts of talc and silicic anhydride as lubricants, and form tablets. shall be.

[Table] Example 2 (a) Manufacturing method of slow-soluble ISDN composition: The following ingredients are granulated in the same manner as in Example 1-(b) ISDN 200g Lactose 350g Crystalline cellulose 70g Elchicellulose 30g Hydrogenated oil 150g Talc 100g Carnauba wax 100g (b) Method for producing a long-acting preparation consisting of a fast-dissolving composition and a slow-dissolving composition: Mix equal amounts of the fast-dissolving composition of Example 1-(a) and the slow-dissolving composition described above, and prepare a lubricant. 1 by adding appropriate amounts of talc and magnesium stearate as agents.
Each tablet contains 20 mg of ISDN (V). Example 3 (a) Manufacturing method of fast-dissolving ISDN composition: 200 g of ISDN, 565 g of lactose, and 150 g of cornstarch
g and 70 g of crystalline cellulose and mix well with a mixer. Next, a solution prepared by dissolving 15 g of hydroxypropyl cellulose in water and ethanol is added and kneaded. This is granulated, dried, and sized to form granules. (b) Manufacturing method of slow-soluble ISDN composition: Add 450 g of lactose and 100 g of talc to 200 g of ISDN and mix well with a mixer. Next, add 100g of Eudragit RL-100 and hydrogenated oil to warm ethanol.
Add 150g of the mixed and dissolved liquid and stir and knead. This kneaded mixture is granulated using a pelletizer. (c) Manufacturing method of coating composition: Put 800g of the granules obtained in (b) into a coating device, add 10g of ethyl cellulose, 30g of hydrogenated oil,
Coating is performed with a coating solution in which 10 g of carnauba wax and 2.0 g of talc are dissolved in ethanol. (d) Method for producing a long-acting preparation consisting of a fast-dissolving composition and a slow-dissolving composition: 40 parts of the fast-dissolving composition of (a), 20 parts of the slow-dissolving composition of (b)
Mix 40 parts of the coating composition of parts (c) and (c), and add appropriate amounts of talc and magnesium stearate as lubricants to make tablets () containing 20 mg of ISDN per tablet. Test Example 1 A dissolution test was conducted using a disintegration tester described in the Japanese Pharmacopoeia. After placing a sample containing 120 mg of ISDN evenly into the auxiliary tube, the test device was immersed in 900 ml of eluate (first solution) at 37°C, and the test device was moved up and down 30 times per minute. was collected and the elution rate of ISDN was measured. ISDN was quantified according to the ISDN tablet quantification method described in the Japanese Pharmacopoeia. The results are shown in FIG. In the figure, and represent each formulation of Example 1, Example 2, and Example 3,
1-(a), 1-(b), and 1-(c) respectively represent the fast-dissolving composition, slow-dissolving composition, and coating composition of Example 1 for comparison. As the proportion of slowly soluble composition increases, the duration increases. However, from the relationship between the dissolution test and the blood concentration measurement results, in order to create an ISDN formulation that increases the blood concentration quickly after administration and maintains it for a long time, the T ₅₀ (dissolution rate is 50
%) is desirably 1 hour or more and 4 hours or less, so it is usually preferable to combine the fast-dissolving composition and slow-dissolving composition in a content-based weight ratio of 30:70 to 60:40. Good things are known. Test Example 2 ISDN formulation was orally administered to 3 healthy subjects.
The plasma concentration of ISDN was investigated. After oral administration of the same sample as in Test Example 1 at a rate of 20.0 mg/human (5.0 mg/human for 1-(a)), blood was collected over time, and ISDN in plasma separated from this blood was analyzed by gas chromatography. Quantitated by method. The result is the third ~
As shown in Figure 5 (symbols in the figure are the same as in Figure 1). Each composition alone is as shown in FIG. In the case of particulate material A (Example 1-(a)), the blood concentration rose quickly, reaching a peak 15 minutes after administration, and 2
It disappears from the blood in ~4 hours. Granular material B-1
In (Example 1-(b)), it showed a peak at 3 to 4 hours and disappeared from the blood in 12 hours. Granules B-
In Example 2 (Example 1-(c)), the blood concentration gradually increased, peaked at 4 to 6 hours, and disappeared from the blood in 12 hours. FIG. 4 shows the ratio of the fast-dissolving composition (granules A) and the slow-dissolving composition (granules B) to 30:70 and 45:3, respectively.
FIG. 5 shows the time course of the blood concentration obtained by a single administration of the preparations (containing 20 mg of ISDN) in combination at a content ratio of 55 and 60:40 and the preparations of Examples 1, 2, and 3. The effective blood concentration of ISDN is approximately 1 ng/ml, and the weight ratio of particulate matter A and particulate B is 30:70 to 60:
It is known that the preparation of the present invention containing a compound having a concentration in the range of 40% reaches an effective blood concentration immediately after administration, and maintains the effective blood concentration for a long period of time. In addition, the maximum plasma concentration (C _nax ), the time required to reach the maximum plasma concentration (T _nax ), and the area under the plasma concentration-time curve (AUC) between sample 1-(a) and the sample are calculated. It is shown in Table 2. Based on these results, despite the long duration of effective blood concentration of the sample of the present invention, there was no significant difference in total absorption amount from the rapidly soluble sample 1-(a), and absorption through processing was not observed. It is known that the rate is intact.

[Table] Comparative example 1 ISDN 200g, lactose 730g and crystalline cellulose 50
A solution prepared by dissolving 20 g of hydroxypropylcellulose in distilled water was added to the mixture consisting of g, and the mixture was stirred and kneaded. This is granulated, dried, and sized to form granules (particle size distribution: 32 to 16 mesh). The granules are coated with a coating solution containing 70 g of hydroxypropyl methylcellulose phthalate dissolved in a methylene chloride/acetone mixture. The resulting granules do not contain hydrogenated oil. Comparative example 2 ISDN 100g, lactose 450g, crystalline cellulose 70
A solution prepared by dissolving 30 g of ethyl cellulose in ethanol was added to a mixture consisting of 300 g of talc, 300 g of talc, and 50 g of magnesium aluminate metasilicate, and the mixture was stirred and kneaded. This is granulated, dried, and sized to form granules (particle size distribution: 32-16 mesh, no hydrogenated oil). Comparative example 3 ISDN 100g, lactose 80g, crystalline cellulose 70g,
A solution obtained by dissolving 400 g of hydrogenated oil in ethanol is added to a mixture consisting of 300 g of talc and 50 g of magnesium aluminate metasilicate, and the mixture is stirred and kneaded. This is made into granules (containing no synthetic polymer material) in the same manner as in Comparative Example 2. Comparative example 4 ISDN 200g, lactose 530g, crystalline cellulose 70g
A solution prepared by dissolving 50 g of ethyl cellulose and 50 g (less than 10%) of hydrogenated oil in ethanol is added to a mixture consisting of 100 g of talc and 100 g of talc, and the mixture is stirred and kneaded.
This is made into granules in the same manner as in Comparative Example 2. Comparative example 5 ISDN 200g, lactose 322g and crystalline cellulose 70
A solution prepared by dissolving 8 g of ethyl cellulose and 400 g of hydrogenated oil (ratio of the two in a ratio of 1:50) in ethanol is added to the mixture consisting of g, and the mixture is stirred and kneaded. This is made into granules in the same manner as in Comparative Example 2. Test Example 3 The granules of Comparative Examples 1 to 5 were orally administered to healthy human subjects, and the plasma concentration of ISDN was investigated. ISDN the sample
After oral administration at a rate of 20.0 mg/person (7.0 mg/person only in Comparative Example 1), blood was collected over time, and ISDN in the plasma separated from the blood was quantified by gas chromatography. The results are shown in Table 3. In the case of the formulations of Comparative Examples 1 to 5, the plasma concentration of ISDN after 6 hours after administration was 1 ng/ml.
It is known that the practical value is significantly inferior.

【table】

【table】 [Brief explanation of the drawing]

Figure 1 is a graph showing the results of dissolution tests for samples obtained in Examples 1 to 3, Figure 2 is a graph showing the relationship between the blending ratio of granules A and B and T ₅₀ , and Figure 3 is a graph showing the results of dissolution tests for samples obtained in Examples 1 to 3. Samples 1-(a), 1-(b) and 1 obtained in Example 1
- (C) A graph showing the plasma ISDN concentration in the human test, Figure 4 shows the human test of samples 1 to 1 obtained in Example 1, and Figure 5 shows the human test of samples 1 to 3 obtained in Examples 1 to 3. It is a graph showing ISDN concentration in plasma.

Claims (1)

[Scope of Claims] 1. Fast-dissolving isosorbitol nitrate composition and slow-dissolving isosorbitol nitrate containing ethyl cellulose and/or acrylic acid/methacrylate copolymer and hydrogenated oil and/or waxes as slow-dissolving components. Composition, content equivalent weight ratio
Ethyl cellulose and/or
Or, the amount of acrylic acid/methacrylic acid ester copolymer is 1 to 20% by weight, the amount of hydrogenated oil and/or wax is 10 to 50% by weight, and the blending ratio of both is 1:1 to 40. An isosorbitol nitrate preparation, characterized in that: 2. The formulation according to claim 1, whose dosage form is a tablet.