JPH0525860B2 - - Google Patents

Description

[Detailed Description of the Invention] <Industrial Application Field> The present invention provides a practical aspirin that dissolves quickly during use and is stable even after long-term storage.
The present invention relates to a method for producing DL-lysine injection. <Prior art> Aspirin DL-lysine is a compound represented by the following formula [Formula] [Formula], and is widely used as an injection as a nonsteroidal anti-inflammatory drug to treat rheumatism, arthritis, neuralgia, myalgia, etc. (Refer to Japanese Patent Application Laid-Open No. 48-56815). Since this aspirin DL-lysine is unstable in aqueous solution, it is necessary to store it as a powder formulation until use. However, aspirin DL-lysine usually has a water content of about 0.3% (about 5 mol%).
Corresponding) The moisture causes the hydrolysis of aspirin DL-lysine, and the acetic acid produced further accelerates the decomposition reaction (Monthly Yakuji, 27 , 1969-1979)
(1985)), and even when stored sealed at 25°C under atmospheric pressure,
Approximately 3.1% decomposes (Monthly Pharmaceutical Affairs, 27 , 2187~
2195 (1985)), and it has been difficult to store it stably for a long period of time if it is simply made into a powder formulation because it lacks stability such as a decrease in the aspirin DL-lysine content and coloring. Therefore, conventionally, as a desiccant in this drug system,
Containing calcium chloride substantially excluding crystal water (see Japanese Patent Publication No. 61-21528), containing aminoacetic acid (glycine) as a coloring inhibitor (see Japanese Patent Publication No. 61-21529), etc. Efforts have been made. However, for example, a vial filled with a commercial preparation containing 100 mg of Japanese Pharmacopoeia aminoacetic acid as an anti-coloring agent and 50 mg of anhydrous calcium chloride as a desiccant per 900 mg of this aspirin DL-lysine was stored at 35 to 39°C under sealed conditions. In experiments, aspirin content after 5 months was 75.9 to 81.8.
% (Monthly Pharmaceutical Affairs,
27, 1969-1979 (1985)). Furthermore, although glycine is known to have a discoloration prevention effect, according to the experimental results of the present inventors, it is still difficult to say that this is sufficient, and the content stabilizing effect has not been substantially recognized. Therefore, there has been a desire for an injectable powder formulation of aspirin DL-lysine that is stable and does not cause a decrease in content or coloration even after long-term storage. Therefore, the present inventors have already conducted intensive studies in order to obtain a desiccant other than calcium chloride, which has been conventionally used, in order to obtain an injectable preparation in which this desiccant is present in the drug system, in view of drug stability, etc. As a result, it was discovered that the use of magnesium chloride exerts a remarkable stabilizing effect on the content of aspirin DL-lysine, and this was proposed in Japanese Patent Application No. 39226/1983. In addition, the present inventors have found that even when an injection of aspirin DL-lysine is a preparation containing calcium chloride as a desiccant, by coexisting an amide compound, the long-term storage stability is even better than that of calcium chloride alone. We have already proposed this on June 9, 1988. <Problems to be solved by the invention> As mentioned above, in order to produce an aspirin DL-lysine injection with excellent stability after long-term storage,
It is essential to include magnesium chloride or calcium chloride as a desiccant. Magnesium chloride or calcium chloride used as such a desiccant, that is, substantially water-free, can be obtained by heating and drying each aqueous solution to distill off water. However, according to the present inventors, when magnesium chloride or calcium chloride obtained by heating and drying such an aqueous solution is included in an aspirin DL-lysine injection, the However, there was a problem in that it took a considerable amount of time to dissolve. Furthermore, normally available magnesium chloride includes anhydrous and hexahydrate salts, but anhydrous magnesium chloride often contains impurities such as heavy metals. It is unsuitable for use in injections such as Therefore, it is necessary to purchase a water-containing substance such as magnesium chloride hexahydrate and reduce its moisture content in a practical way so that it does not contain impurities and can act as a desiccant. . In the literature, methods for reducing the moisture content of magnesium chloride include: 1. Carbon is added to magnesium oxide and the mixture is reacted with chlorine gas in a chlorination furnace. Alternatively, heat and dehydrate while passing chlorine gas. Alternatively, ammonium chloride or potassium chloride is added and the mixture is heated and dehydrated. 2. In the laboratory, methods such as obtaining it by thermal decomposition of magnesium ammonium chloride (Chemistry Dictionary, Edited by the Editorial Committee, No. 1, 1074 (1978) Kyoritsu Shuppan) are known, but these methods are It is not practical due to the contamination of raw materials such as chlorine gas, and it is extremely difficult to obtain high quality anhydrous magnesium chloride. Furthermore, magnesium chloride inherently has poor thermal stability, and when heated in the air it begins to decompose, releasing hydrogen chloride, becoming hydroxychloride, and when heated further, produces magnesium oxide. Injectables, especially ready-to-use injectables such as aspirin DL-lysine, there has been a problem in that the presence of such oxides results in partial insolubilization during preparation. <Means for solving the problem> As a result of various studies to overcome the problem, the present inventors have developed a method for producing magnesium chloride with low moisture content, utilizing the property that magnesium chloride is soluble in alcohol as well as water. He discovered a method that could be put to practical use and proposed it in Japanese Patent Application No. 307891/1983. Therefore, the present inventors have further discovered that the present invention has excellent stability after long-term storage, and also has excellent rapid dissolution when preparing injections.
The present invention was arrived at as a result of extensive research into a method for producing an aspirin DL-lysine injection that does not become partially insolubilized. That is, the present invention heat-dries a solution of magnesium chloride and/or calcium chloride containing lower alcohol as a main component to obtain magnesium chloride and/or calcium chloride containing substantially no water or a very small amount of water, Next, this and aspirin DL
- A method for producing a rapidly dissolving aspirin DL-lysine injection comprising combining lysine powder. In the present invention, first, normally available magnesium chloride hexahydrate and/or calcium chloride
A magnesium chloride and/or calcium chloride solution having a predetermined concentration is obtained by dissolving the dihydrate in a solvent containing a lower alcohol as a main component. The lower alcohol of the present invention is an alcohol having 1 to 5 carbon atoms, and includes, for example, methanol, ethanol, propyl alcohol, iso-propyl alcohol, butyl alcohol, n-amyl alcohol, and the like. Among these, ethanol is particularly preferred. In this case, the concentration of the magnesium chloride and/or calcium chloride solution depends on the required amount of desiccant, the accuracy of dispensing, the amount of processing, etc., but it is preferable to have a high concentration based on the drying time, equipment capacity, etc.
It is set at 10% by weight or more. The solution before heating
For example, filter with a 0.22μm membrane filter,
It is preferable to remove insoluble foreign substances and microorganisms. Next, the solution is heated to dryness to obtain magnesium chloride and/or calcium chloride containing substantially no or only a small amount of water. In the case of a calcium chloride solution, the heating conditions are preferably around 160°C under normal pressure, and drying can be done in a shorter time if it is carried out under reduced pressure. On the other hand, in the case of a magnesium chloride solution, since magnesium chloride is unstable to heat as described above, it is more preferable to heat and dry it under reduced pressure. Regarding such reduced pressure and heating conditions, in order to dry up in a short time while paying attention to bumping, the degree of vacuum should be set appropriately according to the heating temperature, first dry in a low vacuum, and then dry thoroughly and solidify. Wait for the mold to stabilize,
It is desirable to gradually move to high vacuum. In order to dry to the desired moisture content in a short period of time, the degree of vacuum is preferably higher, usually 5 mmHg or less,
Preferably it is set to 1 mmHg or less. Regarding the temperature of the solution (material temperature), if it is too low, it will take a long time to dry, which is undesirable, and if it exceeds 120°C, decomposition of magnesium chloride will occur in a very short time, which is not preferred. Therefore, the temperature range is preferably from 70 to 120°C. The product temperature may be the temperature set during low vacuum, or may be changed as appropriate to dry the product in a short time. In the case of magnesium chloride, the magnesium chloride and/or calcium chloride of the present invention obtained in this manner does not contain any water or contains only a very small amount of water, and in the case of magnesium chloride, the magnesium chloride is within its tetrahydrate salt, preferably within its trihydrate salt, More preferably, it contains less than a dihydrate amount of water, and in the case of calcium chloride, it is almost completely anhydrous. Even when a certain amount of moisture remains, magnesium chloride has a stronger hygroscopicity than similarly deliquescent calcium chloride, for example, anhydrous calcium chloride, and is therefore sufficient as a desiccant agent for the aspirin DL-lysine injection of the present invention. This goal is to be achieved. The amount of magnesium chloride and/or calcium chloride used in the present invention, which contains substantially no water or contains only a small amount of water, depends on the type and amount of drugs and other additives, the size of the container, and even the necessary amount. Although it depends on the storage period and storage conditions, it is generally 0.5 to 50% by weight, preferably 1 to 50% by weight based on the total content.
It is usually set to about 20% by weight, more preferably about 2 to 10% by weight. If the amount is extremely small, a sufficient drying effect cannot be obtained, and even if the amount is extremely large, the effect obtained is hardly noticeable. Magnesium chloride and/or calcium chloride dried to a desired moisture content may be sealed under vacuum to avoid moisture absorption, or replaced with dry air, dry nitrogen, etc. before being taken out. In general, when drying, consideration is given to the equipment, container shape, etc. to make the layer of the material to be dried as thin as possible, uniform heating, wide heat transfer area, and widen the evaporation area. However, from the above point of view, it is recommended to use a method in which, for example, a solution of magnesium chloride is supplied to a device similar to a kneader, heated through a screw or machine wall, and dried under reduced pressure. Further, depending on the purpose of use, suitable additives may be added to the magnesium chloride and/or calcium chloride, and the additives may be added to these solutions or mixed after drying. In the present invention, magnesium chloride and/or calcium chloride containing substantially no water or a very small amount of water is obtained by the method described above, and then this is combined with aspirin DL-lysine powder. A rapidly dissolving aspirin DL-lysine injection can be produced by the following method. In this case, by using aspirin DL-lysine obtained by lyophilizing an aqueous aspirin DL-lysine solution after filtration, for example, it can be mixed uniformly with additives, etc., and has excellent rapid solubility. This method is more desirable because it allows to obtain aspirin DL-lysine injection. The freeze-drying method is a commonly used method. Other additives may be filled into the system. Examples of such additives include color inhibitors, antioxidants, light stabilizers, soothing agents, solubilizing agents, excipients,
Examples include PH regulators, tonicity agents, dispersants, suspending agents, buffering agents, etc., but the amount used should be kept to the minimum necessary. The present inventors have found that among the above additives, when an amide compound, especially (iso)nicotinic acid amide, is used as a stabilizer, an excellent content stabilization effect can be obtained even after long-term storage of aspirin DL-lysine. Although we have already filed a patent application on June 9, 1988, the present invention also has (iso)
Favorable effects can be obtained by coexisting nicotinic acid amide. In this case, for example, an aqueous solution containing aspirin DL-lysine and (iso)nicotinamide may be freeze-dried as described above. As a specific manufacturing method according to the present invention, for example, a solution of magnesium chloride and/or calcium chloride is dispensed into vials, dried to a desired moisture content, and then separately freeze-dried aspirin.
DL-lysine may be filled as a powder, or aspirin DL-lysine aqueous solution may be dispensed into vials and freeze-dried, followed by separately dried magnesium chloride and/or
Alternatively, calcium chloride may be powder-filled. Furthermore, both may be processed separately and each may be filled with powder. Aspirin obtained by the above production method
DL-lysine injection is a practical preparation that has excellent rapid dissolution during use and can be stored stably for a long period of time. In particular, in the case of magnesium chloride, it does not produce oxides etc. when heated under the above-mentioned conditions and does not substantially contain precipitates detected as insoluble foreign substances, making it possible to obtain a more preferable preparation. The present invention will be further explained below with reference to Examples. Example 1 (For magnesium chloride (MgCl ₂ ) ethanol solution) (1) 13.2 g of MgCl ₂ .6 hydrate was dissolved in absolute ethanol to make 100 ml. The MgCl ₂ concentration in the ethanol solution at this time was 6.2% (wt/vol).
This liquid was filtered through a 0.22 μm membrane filter and dispensed into vials in 730 μm portions to give approximately 45 mg of MgCl ₂ (vials ~). (2) Take each vial bottle after dispensing the solution obtained above into a tray, set it in a vacuum dryer equipped with shelves that can uniformly control the temperature by circulating a heating medium, and remove the bottom plate of the tray. Ivy. Immediately apply the prescribed pressure,
After setting the internal pressure of the first stage system (low degree of vacuum), the temperature of the tray was raised to the temperature shown in Table 1, and the degree of vacuum was maintained until the MgCl ₂ solution was dried. After drying, the pressure in the system was gradually shifted to the second stage (high vacuum degree), and the time from the time when the vacuum degree of 1 mmHg was passed was changed as shown in Table 1 to further dry each sample. (3) Measurement of residual moisture content and dissolution time For the vials treated as above, (a)
The amount of moisture remaining in MgCl ₂ in the vial and
(b) Dissolve 900 mg of aspirin DL-lysine and 2.5 mg of nicotinic acid amide in water and filter it.
Table 1 shows the results of adding the desiccant to a vial at a ratio of ml/vial and measuring the time required for the desiccant to completely dissolve while shaking gently at room temperature. Example 2 (Calcium chloride (CaCl ₂ ) ethanol solution) (1) 8.1 g of CaCl ₂ dihydrate was dissolved in absolute ethanol to make 100 ml. The CaCl ₂ concentration in the ethanol solution at this time was 6.0% (wt/vol). This solution was treated in the same manner as in Example 1, and each 830μ
Approximately 50 mg of CaCl ₂ was dispensed into vials (vials). (2) In the same manner as in (2) of Example 1, the vial obtained above instead of Example 1 was treated and dried under the conditions shown in Table 1. Furthermore, in the same manner as in Example 1 (3), (a) residual water content and (b) dissolution time were measured, and the results are shown in Table 1. Comparative Example 1 (CaCl ₂ aqueous solution) (1) 20.2 g of CaCl ₂ dihydrate was dissolved in water to make 100 ml. The concentration of _CaCl2 in the aqueous solution at this time is 14.9
(wt/vol)%. This solution was treated in the same manner and dispensed into vials in 330μ portions to give approximately 50mg of CaCl ₂ . This vial was dried in a constant temperature bath at 160°C for 4 hours (vial (i)). (2) Using the vial obtained as above, measure (a) residual moisture content and (b) dissolution time in the same manner as in (3) of Example 1, and the results are shown in Table 1. Indicated. Comparative Example 2 (MgCl ₂ aqueous solution) (1) 17.1 g of MgCl _2.6 hydrate was dissolved in water to make 50 ml. The concentration of magnesium chloride in the aqueous solution at this time was 15.4% (wt/vol). This liquid
Filtered with 0.22μm membrane filter, 290μm
Each sample was dispensed into vials to give approximately 45 mg of MgCl ₂ . (2) The vials obtained above were treated in the same manner as in Example 1 (2) under the conditions shown in Table 1 and dried (vials (ii) to (iii)). Regarding these, (a) residual moisture content and (b) dissolution time were measured in the same manner as in Example 1 (3), and the results are shown in Table 1. [Table] As is clear from Table 1, those dried from the ethanol solution (Examples 1 and 2)
Both MgCl ₂ and CaCl ₂ have a porous structure when dried, so that their dissolution time is short and their use is extremely convenient. On the other hand, those dried from aqueous solutions require considerable dissolution time (Comparative Examples 1 and 2; vials (i) to (vi)). Also, at temperatures above 140°C, decomposition of magnesium chloride was observed, resulting in insolubilization. (Vials (vii) to (viii)). Example 3 (1) Aspirin DL-lysine 100g and aspirin
A mixture of 100 g of DL-lysine and 280 mg of nicotinic acid amide was each dissolved in distilled water cooled to 5° C. or lower to obtain an approximately 10% aqueous solution. After filtration, the mixture was placed in a clean tray and lyophilized using a conventional method. During drying, the product temperature is finally heated to 50℃,
The residual moisture was about 0.1%. (2) The desiccant-containing vials obtained in Examples 1 and 2 were each filled with aspirin DL-lysine powder at a concentration of 900 mg/vial as shown in Table 2. Subsequently, a butyl rubber plug was attached and fixed with an aluminum cap. (3) The powder preparation obtained as above was left in a constant temperature bath at 45℃ and 75% equivalent humidity (RH), and the content of aspirin DL-lysine was measured after 2 months. The results are shown in Table 2. It was shown to. Comparative Example 3 Instead of the vials ~ used in Example 3, the vials (i) ~ (viii) obtained in Comparative Examples 1 and 2 were used.
Using a vial (ix) in which no desiccant was present, each vial was filled with aspirin DL-lysine at 900 mg/vial in the same manner as in Example 3, and treated in the same manner. As in Example 3, the content of aspirin DL-lysine was measured after 2 months at 45°C, and the results are shown in Table 2. [Table] From Table 2, it can be seen that even in the case of the rapidly dissolving injection preparation dried from the ethanol solution of the present invention (Example 3), it has a long-term storage stabilization effect equal to or greater than that of the injection preparation dried from the aqueous solution. You can see that

Claims (1)

[Scope of Claims] 1. Magnesium chloride and/or calcium chloride containing substantially no water or a very small amount of water is obtained by heating and drying a solution of magnesium chloride and/or calcium chloride whose main component is a lower alcohol. A method for producing a fast-dissolving aspirin DL-lysine injection, which comprises obtaining the following: and then combining this with aspirin DL-lysine powder. 2. The method for producing a fast-dissolving aspirin DL-lysine injection according to claim 1, which comprises heating a solution of magnesium chloride whose main component is a lower alcohol at 70 to 120°C under 5 mmHg. 3 Aspirin DL-lysine is aspirin DL-
Aspirin lyophilized after filtering lysine aqueous solution
The fast-dissolving aspirin according to claim 1 or 2, which is DL-lysine.
Method for producing DL-lysine injection. 4. Production of a fast-dissolving aspirin DL-lysine injection according to any one of claims 1 to 3, characterized in that (iso)nicotinamide is further added as a stabilizer. Method.