JP7385881B2 - Injections containing oxicam drugs - Google Patents

Description

The present invention relates to an oxicam drug-containing injection that is transparent and has excellent stability and safety.

Oxicams, represented by meloxicam, piroxicam, lornoxicam, etc., are a type of non-steroidal anti-inflammatory drugs (NSAIDs) and have excellent anti-inflammatory effects, but are poorly water-soluble. Due to the fact that the solubility in water specified in the Japanese Pharmacopoeia and General Rules is "almost insoluble" (the amount of solvent required to dissolve 1 g or 1 mL of solute is 10,000 mL or more: the solute corresponds to the drug and the solvent corresponds to water). )) Currently, the forms of its preparation are limited to oral preparations, external preparations, suppositories, and the like. Against this background, in recent years there has been a strong desire for a method of administering oxicam drugs as injections. A well-known method for administering poorly water-soluble drugs such as oxicam drugs as injections is to make them into fat emulsions. It is a milky-white preparation that uses fats and oils (the content of which is estimated at least 100 mg/mL or more), and it is difficult to visually confirm the presence or absence of deterioration or the presence of foreign substances, or changes in the formulation. It has the limitation that it is difficult to Therefore, the present inventor has proposed in Patent Document 1 a drug-containing fat emulsion that is transparent and has excellent stability, in which such restrictions are relaxed.

The drug-containing fat emulsion proposed by the present inventor in Patent Document 1 can be produced by increasing the oil content to a maximum of 2 mg/mL, and is a drug-containing fat emulsion that has transparency and excellent stability. It is evaluated as an emulsion. However, this drug-containing fat emulsion has a low oil content of 2 mg/mL at most, which limits the amount of drug that the fat emulsion can support. There is a need for a drug-containing fat emulsion that uses a larger amount of fat to support the drug, yet has transparency and excellent stability. In addition, among the known emulsifiers for producing fat emulsions, lecithin has a weak emulsifying power and is not necessarily easy to handle due to its high viscosity at high concentrations. However, it is expected to be highly safe, and in order to meet these demands, the present inventor has attempted to develop it, but so far has not been able to find an effective solution.

Patent No. 5340954

Therefore, an object of the present invention is to provide an injection containing an oxicam drug that is transparent and has excellent stability and safety.

As a result of intensive research in view of the above points, the present inventors have found that by using at least oxicam drugs, lecithin, metal salts of fatty acids, macrogol, N,N-dimethylacetamide, and an aqueous medium as constituent components, transparent The present inventors have discovered that it is possible to produce an injection containing an oxicam drug that has excellent stability and safety as well as properties.

The oxicam drug-containing injection preparation of the present invention, which has been developed based on the above findings, has the following features:
(1) Oxicams (2) Lecithin and polysorbate (however, polysorbate is 50% by weight or less)
(3) Pharmaceutically acceptable salts of fatty acids (4) Macrogol and/or N,N-dimethylacetamide (5) Aqueous medium (6) Oil and/or tocopherol compounds as at least a constituent component; The content of tocopherol compounds is 5 to 100 mg/mL, and the weight ratio of oxicam drugs to fats and oils and/or tocopherol compounds (oxicam drugs/fats and/or tocopherol compounds) is 0.01 to 2 (however, the weight ratio of oxicam drugs to fats and oils and/or tocopherol compounds) is 0.01 to 2. / or the total content of tocopherol compounds is at most 125 mg/mL), the turbidity is 0.5 or less, and the residual content of oxicam drugs is 90% or more of the original content even after storage at room temperature for one month It is characterized by having storage stability of
Furthermore, the oxicam drug-containing injection preparation according to claim 2 is the oxicam drug-containing injection preparation according to claim 1, in which the content of the oxicam drug is 0.1 to 50 mg/mL, and the content of lecithin and polysorbate (however, polysorbate is 50 mg/mL). % by weight or less) is 50 to 200 mg/mL .
Furthermore , the oxicam drug-containing injection preparation according to claim 3 is the oxicam drug-containing injection preparation according to claim 1, further comprising a saccharide as a constituent component.

According to the present invention, it is possible to provide an injection containing an oxicam drug that is transparent and has excellent stability and safety.

The oxicam drug-containing injection of the present invention includes:
(1) Oxicams (2) Lecithin (up to 50% by weight of the lecithin used may be replaced with polysorbate)
(3) A pharmaceutically acceptable salt of a fatty acid (4) Macrogol and/or N,N-dimethylacetamide (5) It is characterized by having at least an aqueous medium as a constituent component and having a turbidity of 0.5 or less. It is something to do.

In the present invention, examples of oxicam drugs include meloxicam represented by the chemical structural formula below, as well as piroxicam, lornoxicam, ampiroxicam, droxicam, tenoxicam, isoxicam, sudoxicam, tesicam, and the like. All of these are sparingly soluble in water.

In the present invention, lecithins that serve as solubilizers and emulsifiers include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin. In addition, in order to maintain the safety of lecithin while supplementing the solubilizing power and emulsifying power of lecithin and suppressing the increase in viscosity when lecithin is used at high concentrations, the amount of lecithin used should be 50% by weight or less. may be replaced with a polysorbate (polyoxyethylene sorbitan fatty acid ester) such as polysorbate 20, 40, 60, 65, or 80 (in order for the replaced polysorbate to fully exhibit its effect, 10% by weight or more of the lecithin used may be used). (preferably replaced).

In the present invention, pharmaceutically acceptable salts of fatty acids include medium chain fatty acids with 8 to 12 carbon atoms (caprylic acid, capric acid, lauric acid, etc.) and long chain fatty acids with 14 to 18 carbon atoms ( Pharmaceutically acceptable salts of myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, etc.), such as alkali metal salts such as sodium salts and potassium salts, calcium salts and magnesium salts. Examples include alkaline earth metal salts such as salts. Fatty acids may be saturated or unsaturated.

In the present invention, examples of macrogol (polyethylene glycol) include macrogol 200, 300, 400, and 600.

In the present invention, the aqueous medium includes water (pure water, purified water, water for injection, etc.), acetic acid-sodium acetate, boric acid-sodium carbonate, boric acid-sodium tetraborate, hydrochloric acid-sodium tetraborate, Phosphoric acid - sodium phosphate, sodium dihydrogen phosphate - disodium hydrogen phosphate, citric acid - sodium hydroxide, hydrochloric acid - potassium hydrogen phthalate, sodium hydroxide - potassium hydrogen phthalate, citric acid - disodium hydrogen phosphate , succinic acid - sodium tetraborate, ammonia - ammonium chloride, potassium dihydrogen phosphate - disodium hydrogen phosphate - phosphoric acid, potassium dihydrogen phosphate - disodium hydrogen phosphate - sodium hydroxide, potassium dihydrogen phosphate - Disodium hydrogen phosphate, potassium dihydrogen phosphate - Sodium hydroxide, disodium hydrogen phosphate - Sodium hydroxide, Tris (abbreviation for trishydroxymethylaminomethane, the same hereinafter) - Hydrochloric acid, Tris-EDTA, Tris-acetic acid - EDTA, trisodium citrate - sodium hydroxide - sodium chloride, sodium dihydrogen phosphate - EDTA - sodium chloride, etc. are added to water to adjust the pH to a predetermined value, for example 3.5 to 9.0, preferably 5. Examples include buffers adjusted to a pH in the range of 0 to 8.5, more preferably 6.5 to 8.0.

The content of oxicam drug may be, for example, 0.1 to 50 mg/mL. The content of lecithin is preferably 50 to 200 mg/mL, more preferably 60 to 180 mg/mL, even more preferably 70 to 160 mg/mL. If it is less than 50 mg/mL, it may be difficult to exhibit the solubilizing effect on oxicam drugs, while if it is more than 200 mg/mL, the viscosity may increase, making it difficult to solubilize oxicam drugs. . As mentioned above, 50% by weight or less of the lecithin used may be replaced with polysorbate. In this case, the total content of lecithin and polysorbate is 50 to 200 mg/mL, consisting of 50% by weight or more of lecithin and 50% by weight or less of polysorbate. The content of pharmaceutically acceptable salts of fatty acids is preferably 0.1 to 50 mg/mL, more preferably 1 to 30 mg/mL, and even more preferably 5 to 25 mg/mL. If the amount is less than 0.1 mg/mL, the oxicam drug may easily aggregate or precipitate, while if it is more than 50 mg/mL, the oxicam drug may deteriorate. The content of macrogol and/or N,N-dimethylacetamide is preferably 0.2 to 300 mg/mL, more preferably 1 to 250 mg/mL, and even more preferably 2 to 200 mg/mL. If it is less than 0.2 mg/mL, it may be difficult to improve the solubility and stability of oxicam drugs, while if it is more than 300 mg/mL, the viscosity and osmotic pressure will increase, causing oxicam drugs to It may be difficult to solubilize or formulate an injection.

The oxicam drug-containing injection of the present invention may be a fat emulsion by further comprising oil and/or a tocopherol compound. Oils include vegetable oils such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, and cottonseed oil, as well as animal oils such as lanolin, mineral oils such as egg yolk oil, fish oil, liquid paraffin, etc. Known fats and oils that can be used as fats and oils include chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons. Examples of tocopherol compounds include tocopherol (vitamin E) and tocopherol acetate.

When the oxicam drug-containing injection of the present invention is a fat emulsion by further comprising oil and fat and/or tocopherol compound, the content of oil and fat and/or tocopherol compound is preferably 5 to 100 mg/mL, More preferably 10 to 75 mg/mL, even more preferably 15 to 50 mg/mL. If it is less than 5 mg/mL, the amount of oxicam drug that can be supported by the fat emulsion will be reduced, while if it is more than 100 mg/mL, the amount of fat and/or tocopherol compound may be too large, making emulsification difficult. There is. The weight ratio of oxicam drug to fat and oil and/or tocopherol compound (oxicam drug/fat and/or tocopherol compound) is preferably 0.01 to 2, more preferably 0.05 to 1, and 0.1 to 0. 5 is more desirable. If it is smaller than 0.01, the fat and/or tocopherol compound will be too much for the oxicam drug, resulting in unnecessary administration of fat and/or tocopherol compound to the patient, while if it is larger than 2 There is a possibility that the oxicam drug becomes excessive in proportion to the fat and oil and/or the tocopherol compound, and the stability of the oxicam drug is impaired, making it easier for the oxicam drug to aggregate or precipitate. The total content of the oxicam drug, oil, and/or tocopherol compound is preferably at most 125 mg/mL, more preferably 3 to 100 mg/mL, and even more preferably 5 to 75 mg/mL. If the amount exceeds 125 mg/mL, emulsification to obtain a transparent fat emulsion may become difficult. By setting the weight ratio of lecithin to fat and oil and/or tocopherol compound (lecithin/fat and/or tocopherol compound) to 1 to 100, preferably 1.5 to 50, more preferably 2 to 25, it has transparency and It becomes easier to obtain a fat emulsion with excellent stability (if the weight ratio of lecithin to fats and oils and/or tocopherol compounds exceeds 100, there is a strong possibility that lecithin will aggregate or precipitate). As mentioned above, 50% by weight or less of the lecithin used may be replaced with polysorbate. As mentioned above, the content of the oxicam drug may be, for example, 0.1 to 50 mg/mL, but by using an amount of oil and/or tocopherol compound exceeding 2 mg/mL, it is possible to An oxicam drug that has the following properties is dissolved in fat and/or a tocopherol compound, and an oxicam drug that cannot be completely dissolved in the fat and/or tocopherol compound is dissolved with lecithin at the interface between water and the fat and/or tocopherol compound. By coexisting, a larger amount is supported in the fat emulsion.

The oxicam drug-containing injection of the present invention has, for example, the content of an oxicam drug, lecithin, a pharmaceutically acceptable salt of a fatty acid, macrogol, and/or N,N-dimethylacetamide set within the above numerical range. After dissolving the oxicam drug in macrogol and/or N,N-dimethylacetamide, lecithin was added, and then a solution of a pharmaceutically acceptable salt of a fatty acid dissolved in an aqueous medium was added, and an ultrasonic emulsifying machine was used. It can be produced by solubilizing using. In addition, when the oxicam drug-containing injection of the present invention is a fat emulsion by further containing oil and/or a tocopherol compound, for example, the content of the oil and/or tocopherol compound, the content of the oil and/or tocopherol compound, Alternatively, the weight ratio of oxicam drugs to tocopherol compounds, the total content of oxicam drugs, fats and oils, and/or tocopherol compounds are set within the above numerical range, and the oxicam drugs are dissolved in macrogol and/or N,N-dimethylacetamide. After that, lecithin, oil and fat and/or a tocopherol compound are added to form an oil phase, and a solution of a pharmaceutically acceptable salt of a fatty acid dissolved in an aqueous medium is added and emulsified using an ultrasonic emulsifier. Alternatively, a rough emulsion may be prepared by stirring strongly (for example, by stirring at a rotational speed of 10,000 to 15,000 rpm for 5 to 30 minutes), and then the rough emulsion may be emulsified using a high-pressure emulsifier such as a Manton-Gorlin homogenizer. It can be manufactured by By adjusting the operating conditions and emulsification time of the emulsifier, the particle size distribution of fat particles can be narrowed. Further, in order to narrow the particle size distribution of the fat particles, emulsification may be performed multiple times (for example, 3 to 50 times). Of particular note are the content of oxicams, lecithin, pharmaceutically acceptable salts of fatty acids, macrogol and/or N,N-dimethylacetamide, fats and oils and/or tocopherol compounds; By setting the weight ratio of oxicam drugs and the total content of oxicam drugs and fats and/or tocopherol compounds within the above numerical range, solubilization and emulsification can be performed using an ultrasonic emulsifier. by emulsifying at a pressure of, for example, 1500 bar or less, preferably 350 to 1400 bar, so that the average particle diameter of the oxicam drug-supported particles is 200 nm or less, preferably 180 nm or less, more preferably 120 nm or less, and even more preferably 100 nm or less (the lower limit is, for example, 1 nm), and the turbidity is 0.5 or less, preferably 0.4 or less, more preferably 0.3 or less, even more preferably 0.2 or less, and transparency. This makes it easier to obtain oxicam drug-containing injections that have the following properties and have excellent stability.

In addition, the constituent components of the oxicam drug-containing injection of the present invention include propylene glycol, glycerin, lactic acid, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or its salts (sodium salt, etc.), hyaluronic acid or its salts (sodium salt, etc.). ), glycyrrhizic acid or its salts (sodium salt, ammonium salt, etc.) can improve the solubility of oxicam drugs, improve the stability of fat emulsions and oxicam drugs, and make fat emulsions isotonic. You may also try something like this. These contents are similar to those of macrogol and/or N,N-dimethylacetamide.

Further, by further using saccharides as a constituent of the drug-containing injection of the present invention, it is possible to effectively suppress the occurrence of floating precipitates that may sometimes occur. Suitable saccharides include monosaccharides such as inositol, glucose, sorbitol, fructose, and mannitol, disaccharides such as trehalose, lactose, sucrose, and maltose, as well as dextrin, cyclodextrin, dextran, and xylitol. The sugar content is preferably 10 to 600 mg/mL.

In addition, as a component of the oxicam drug-containing injection of the present invention, a well-known pH adjuster or osmotic pressure adjuster may be further used to adjust the pH (for example, 3.5 to 9.0) or increase the osmotic pressure. The formulation may be stabilized by adjustment. It goes without saying that a substance that functions as a preservative, an antioxidant, a stabilizer, etc. (for example, a metal salt of ethylenediaminetetraacetic acid) may be used as a constituent component, if necessary. Furthermore, the oxicam drug-containing injection preparation of the present invention may contain other drugs in addition to the oxicam drug.

The oxicam drug-containing injection preparation of the present invention can be easily sterilized by filtration, for example by setting the average particle diameter to 200 nm or less, and can also be sterilized by high-pressure steam. High-pressure steam sterilization may be carried out under general conditions (for example, 120 to 122°C for 10 to 15 minutes) after filling the oxicam drug-containing injection of the present invention into a glass ampoule or synthetic resin container.

The oxicam drug-containing injection preparation of the present invention has excellent stability and can be stored at room temperature (eg, 5 to 30°C). In addition, transparency makes it easy to visually confirm the presence or absence of deterioration or foreign matter contamination, as well as changes in the composition, and also provides a sense of security to patients receiving the drug.

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to examples, but the present invention should not be interpreted as being limited to the following description.

Example 1: Meloxicam-containing injection (Part 1)
Weigh out 20 mg of meloxicam and 160 mg of N,N-dimethylacetamide, and dissolve them uniformly at 50°C for 15 minutes using a small ultrasonic cleaner (manufactured by As One, the same applies hereinafter), and then add commercially available dl-α-tocopherol. 80 mg and 400 mg of purified egg yolk lecithin (PC-98: manufactured by Kewpie, same hereinafter) were added and mixed uniformly at 50° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 3 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. While adding the aqueous phase to the oil phase, it was emulsified for 20 minutes using an ultrasonic emulsifier (manufactured by SMT, same hereinafter). After adjusting the pH to 7.2 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and then a 0.22 μmφ cellulose acetate membrane (CA membrane, the same hereinafter) was added. Filtration sterilization was performed to obtain the desired yellow transparent injection (emulsion) containing meloxicam. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 2: Meloxicam-containing injection (Part 2)
Weigh out 20 mg of meloxicam and 160 mg of N,N-dimethylacetamide and dissolve them uniformly at 50°C for 15 minutes using a small ultrasonic cleaner, then add 80 mg of commercially available dl-α-tocopherol, 400 mg of purified egg yolk lecithin, and polysorbate 80 (GS: manufactured by NOF Corporation, hereinafter the same) was added and mixed uniformly at 50° C. for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium oleate and 2.7 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 10 minutes using an ultrasonic emulsifier. After adjusting the pH to 7.1 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and sterilization was performed by filtration using a 0.22 μmφ CA membrane to obtain the desired amount. A yellow slightly cloudy injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 3: Meloxicam-containing injection (part 3)
275 mg of meloxicam and 2.2 g of N,N-dimethylacetamide were weighed out and dissolved uniformly at 50°C using a hot stirrer, and then 5.5 g of purified egg yolk lecithin was added and mixed uniformly by stirring slowly. . On the other hand, 550 mg of sodium oleate and 40 mL of pure water were weighed out and uniformly dissolved at 60° C. using a hot stirrer. The obtained solution was solubilized for 60 minutes using an ultrasonic emulsifier while being added to the meloxicam solution, and then 5.5 g of glucose was added and stirred and dissolved using a stirrer. After adjusting the pH to 7.3 by adding 1N hydrochloric acid aqueous solution to the solubilized solution obtained in this way, pure water was added to bring the total volume to 55 mL, and sterilization was performed by filtration with a 0.22 μmφ CA membrane. A yellow, slightly cloudy injection containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 4: Meloxicam-containing injection (part 4)
Weigh out 275 mg of meloxicam and 2.2 g of N,N-dimethylacetamide and dissolve them uniformly at 50°C using a hot stirrer, then add 1.1 g of commercially available dl-α-tocopherol, 2.75 g of purified egg yolk lecithin, 2.75 g of polysorbate 80 was added and mixed uniformly by slow stirring to form an oil phase. On the other hand, 550 mg of sodium oleate and 39 mL of pure water were weighed and dissolved uniformly at 60° C. using a hot stirrer to form an aqueous phase. While adding the aqueous phase to the oil phase, the mixture was emulsified for 60 minutes using an ultrasonic emulsifier, and then 5.5 g of glucose was added and stirred and dissolved using a stirrer. After adjusting the pH to 7.2 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 55 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane to obtain the desired amount. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 5: Meloxicam-containing injection (part 5)
20 mg of meloxicam and 160 mg of N,N-dimethylacetamide were weighed out and dissolved uniformly at 50°C for 15 minutes using a small ultrasonic cleaner, and then 80 mg of commercially available medium chain fatty acid triglyceride and 400 mg of purified egg yolk lecithin were added. The mixture was uniformly mixed at 50° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 2.8 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. While adding the aqueous phase to the oil phase, the mixture was emulsified for 20 minutes using an ultrasonic emulsifier, and then 400 mg of fructose was added and dissolved by stirring using a stirrer. After adjusting the pH to 6.9 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and sterilization was performed by filtration with a 0.22 μmφ CA membrane. A yellow slightly cloudy injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 6: Meloxicam-containing injection (part 6)
Weigh out 20 mg of meloxicam and 160 mg of N,N-dimethylacetamide and dissolve them uniformly at 50°C for 15 minutes using a small ultrasonic cleaner, then add 200 mg of commercially available purified soybean oil, 200 mg of purified egg yolk lecithin, and 200 mg of polysorbate 80. was added and mixed uniformly at 50°C for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium oleate and 2.6 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. While adding the aqueous phase to the oil phase, the mixture was emulsified for 20 minutes using an ultrasonic emulsifier, and then 400 mg of trehalose was added and stirred and dissolved using a stirrer. After adjusting the pH to 7.0 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and sterilization was performed by filtration using a 0.22 μmφ CA membrane. A yellow slightly cloudy injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 7: Meloxicam-containing injection (part 7)
Weigh out 1 g of meloxicam and 8 g of N,N-dimethylacetamide, and dissolve them uniformly at 50°C using a hot stirrer. Then, add 4 g of commercially available medium chain fatty acid triglyceride and 20 g of purified egg yolk lecithin, and use a general-purpose mixer to dissolve them. The mixture was mixed uniformly at 50°C to form an oil phase. On the other hand, 2 g of sodium oleate and 160 mL of pure water were weighed and dissolved uniformly at 50° C. using a general-purpose mixer to obtain an aqueous phase. The aqueous phase was added to the oil phase while stirring using a Hyflex Disperser (manufactured by SMT), and after the addition was completed, the mixture was coarsely emulsified at 10,000 rpm for 10 minutes. After further adding pure water to make the total volume 200 mL, precision emulsification was performed using a high-pressure homogenizer (manufactured by APV). The emulsification pressure was 1000 bar, and the number of emulsifications was 15 (cyclic emulsification). After adjusting the pH to 7.3 by adding 1N hydrochloric acid aqueous solution to the emulsion obtained in this way, filtration sterilization was performed through a 0.22 μmφ CA membrane to obtain the desired yellow, cloudy meloxicam-containing injection (emulsion). I got it. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 8: Meloxicam-containing injection (Part 8)
Weigh out 275 mg of meloxicam and 3.3 g of N,N-dimethylacetamide, and dissolve them uniformly at 50°C using a hot stirrer, then add 2.75 g of commercially available medium chain fatty acid triglyceride, 2.75 g of purified egg yolk lecithin, and polysorbate. 80 was added and mixed uniformly by slow stirring to form an oil phase. On the other hand, 550 mg of sodium oleate and 38 mL of pure water were weighed and dissolved uniformly at 60° C. using a hot stirrer to form an aqueous phase. While adding the aqueous phase to the oil phase, the mixture was emulsified for 90 minutes using an ultrasonic emulsifier, and then 5.5 g of glucose was added and dissolved by stirring using a stirrer. After adjusting the pH to 7.3 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 55 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane to obtain the desired amount. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 9: Meloxicam-containing injection (Part 9)
Weigh out 80 mg of meloxicam and 240 mg of N,N-dimethylacetamide, dissolve as much as possible at 50°C for 15 minutes using a small ultrasonic cleaner, and then add 200 mg of commercially available medium chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added and mixed uniformly for 10 minutes using an ultrasonic emulsifier to form an oil phase. On the other hand, 80 mg of sodium oleate, 160 mg of fructose, and 2.8 mL of pure water were weighed out and uniformly dissolved at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 15 minutes using an ultrasonic emulsifier. After adding 1N sodium hydroxide aqueous solution to the emulsion thus obtained and adjusting the pH to 7.5, pure water was added to bring the total volume to 4 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 10: Meloxicam-containing injection (Part 10)
Weigh out 40 mg of meloxicam and 120 mg of N,N-dimethylacetamide, dissolve as much as possible at 50°C for 15 minutes using a small ultrasonic cleaner, and then add 100 mg of commercially available medium chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added and mixed uniformly for 10 minutes using an ultrasonic emulsifier to form an oil phase. On the other hand, 60 mg of sodium caprylate, 120 mg of fructose, and 3 mL of pure water were weighed out and uniformly dissolved at 50° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 5 minutes using an ultrasonic emulsifier. After adding 1N sodium hydroxide aqueous solution to the emulsion thus obtained and adjusting the pH to 7.5, pure water was added to bring the total volume to 4 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 11: Meloxicam-containing injection (Part 11)
Weigh out 20 mg of meloxicam and 40 mg of N,N-dimethylacetamide, dissolve as much as possible at 50°C for 15 minutes using a small ultrasonic cleaner, and then add 60 mg of commercially available medium chain fatty acid triglyceride, 160 mg of purified egg yolk lecithin, 160 mg of polysorbate 80 was added and mixed uniformly at 50° C. for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium caprylate and 3.2 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner, and then 80 mg of fructose was dissolved to form an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 10 minutes using an ultrasonic emulsifier. After adding 1N sodium hydroxide aqueous solution to the emulsion thus obtained and adjusting the pH to 7.5, pure water was added to bring the total volume to 4 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 12: Meloxicam-containing injection (Part 12)
Weigh out 20 mg of meloxicam and 200 mg of macrogol 400, dissolve as much as possible at 50°C for 15 minutes using a small ultrasonic cleaner, and then add 120 mg of commercially available medium chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, and 200 mg of polysorbate 80. was added and mixed uniformly at 50°C for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium caprylate and 3 mL of pure water were weighed out and uniformly dissolved at 50° C. for 15 minutes using a small ultrasonic cleaner, and then 100 mg of fructose was dissolved to form an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 10 minutes using an ultrasonic emulsifier. After adding 1N sodium hydroxide aqueous solution to the emulsion thus obtained and adjusting the pH to 7.5, pure water was added to bring the total volume to 4 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane. A transparent yellow injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 13: Meloxicam-containing injection (Part 13)
Weigh out 100 mg of meloxicam and 1 g of Macrogol 400, dissolve them as much as possible at 50°C for 10 minutes using a hot stirrer, and then add 600 mg of commercially available medium chain fatty acid triglyceride, 1 g of purified egg yolk lecithin, and 1 g of polysorbate 80. The mixture was uniformly mixed at 50° C. for 30 minutes to obtain an oil phase. On the other hand, 200 mg of sodium caprylate and 15 mL of phosphoric acid-sodium phosphate buffer (0.18 mol/L, pH 6.9) were weighed and dissolved uniformly using a stirrer, and then 500 mg of trehalose was dissolved and added to the aqueous phase. did. While adding the aqueous phase to the oil phase, emulsify for 30 minutes using an ultrasonic emulsifier, then add the above buffer to make a total volume of 20 mL, and then filter sterilize with a 0.22 μmφ CA membrane. The desired pale yellow and transparent injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 14: Piroxicam-containing injection (Part 1)
Weigh out 20 mg of piroxicam and 160 mg of N,N-dimethylacetamide, and dissolve them uniformly at 50°C for 15 minutes using a small ultrasonic cleaner. 200 mg was added and mixed uniformly at 50° C. for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium oleate and 2.8 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner, and then 400 mg of fructose was dissolved to form an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 20 minutes using an ultrasonic emulsifier. After adjusting the pH to 7.2 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and sterilization was performed by filtration using a 0.22 μmφ CA membrane. A pale yellow transparent injection (emulsion) containing piroxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 15: Lornoxicam-containing injection (Part 1)
Weighed out 20 mg of lornoxicam and 480 mg of N,N-dimethylacetamide, dissolved them as much as possible at 50°C for 15 minutes using a small ultrasonic cleaner, and then added 80 mg of commercially available medium chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added and mixed uniformly at 50° C. for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium oleate and 2.5 mL of pure water were weighed and dissolved uniformly at 50° C. for 15 minutes using a small ultrasonic cleaner, and then 400 mg of fructose was dissolved to form an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 20 minutes using an ultrasonic emulsifier. After adjusting the pH to 7.3 by adding 1N hydrochloric acid aqueous solution to the emulsion thus obtained, pure water was added to bring the total volume to 4 mL, and sterilization was performed by filtration with a 0.22 μmφ CA membrane to obtain the desired amount. A transparent yellow injection (emulsion) containing lornoxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 16: Meloxicam-containing injection (Part 14)
100 mg of meloxicam, 1 g of macrogol 400, 600 mg of commercially available medium chain fatty acid triglyceride, and 1 g of polysorbate 80 were weighed out and dissolved as much as possible at 40° C. for 40 minutes using a hot stirrer. Furthermore, 1 g of purified egg yolk lecithin was added and mixed uniformly at 60° C. for 20 minutes to form an oil phase. On the other hand, weigh out 200 mg of sodium caprylate and 15 mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer (0.05 mol/L, pH 6.9, same hereinafter) and dissolve them uniformly at 40°C using a hot stirrer. After that, 500 mg of trehalose was dissolved to form an aqueous phase. While adding the aqueous phase to the oil phase, emulsify for 30 minutes using an ultrasonic emulsifier, then add the above buffer to make a total volume of 20 mL, and then filter sterilize with a 0.22 μmφ CA membrane. A desired yellow transparent injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 17: Meloxicam-containing injection (Part 15)
100 mg of meloxicam and 1 g of macrogol 400 were weighed out and dissolved as much as possible at 50° C. for 40 minutes using a hot stirrer. Further, 600 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin, and 1 g of polysorbate 80 were added and mixed uniformly at 50° C. for 20 minutes to obtain an oil phase. On the other hand, 200 mg of sodium oleate, 500 mg of trehalose, and 13 mL of pure water were weighed out and uniformly dissolved at 50° C. using a hot stirrer to form an aqueous phase. The aqueous phase was added to the oil phase and emulsified for 30 minutes using an ultrasonic emulsifier. After adjusting the pH to 7.4 by adding 1N hydrochloric acid aqueous solution to the emulsion obtained in this way, pure water was added to bring the total volume to 20 mL, and filter sterilization was performed using a 0.22 μmφ CA membrane to obtain the desired amount. A pale yellow transparent injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 18: Meloxicam-containing injection (Part 16)
The desired pale yellow and transparent meloxicam-containing injection (emulsion) was obtained in the same manner as in Example 17 except that the pure water was changed to potassium dihydrogen phosphate-disodium hydrogen phosphate buffer. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 19: Meloxicam-containing injection (Part 17)
100 mg of meloxicam and 1 g of macrogol 400 were weighed out and dissolved as much as possible at 50° C. for 40 minutes using a hot stirrer. Furthermore, 600 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin, and 1 g of polysorbate 80 were added and mixed uniformly at 60° C. for 20 minutes to obtain an oil phase. On the other hand, 100 mg of sodium oleate, 100 mg of sodium caprylate, and 15 mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer were weighed out and uniformly dissolved at 50°C using a hot stirrer, and then 1 g of trehalose was dissolved. It was made into an aqueous phase. While adding the aqueous phase to the oil phase, emulsify for 30 minutes using an ultrasonic emulsifier, then add the above buffer to make a total volume of 20 mL, and then filter sterilize with a 0.22 μmφ CA membrane. The desired pale yellow and transparent injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Example 20: Meloxicam-containing injection (Part 18)
100 mg of meloxicam and 1 g of macrogol 400 were weighed out and dissolved as much as possible at 50° C. for 40 minutes using a hot stirrer. Further, 400 mg of commercially available medium-chain fatty acid triglyceride, 800 mg of purified egg yolk lecithin, and 700 mg of polysorbate 80 were added and mixed uniformly at 60° C. for 40 minutes to obtain an oil phase. On the other hand, 200 mg of sodium oleate and 15 mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer were weighed out and uniformly dissolved at 50° C. using a hot stirrer, and then 1 g of trehalose was dissolved to obtain an aqueous phase. While adding the aqueous phase to the oil phase, emulsify for 30 minutes using an ultrasonic emulsifier, then add the above buffer to make a total volume of 20 mL, and then filter sterilize with a 0.22 μmφ CA membrane. The desired pale yellow and transparent injection (emulsion) containing meloxicam was obtained. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Comparative example 1:
After weighing out 20 mg of meloxicam and 200 mg of N,N-dimethylacetamide and uniformly dissolving them at 50°C using a hot stirrer, 40 mg of commercially available refined soybean oil and 320 mg of polysorbate 80 were added and mixed uniformly to form an oil phase. And so. While adding 3.4 mL of pure water to the oil phase, it was emulsified for 10 minutes using an ultrasonic emulsifier. When pure water was added to the emulsion thus obtained to bring the total volume to 4 mL, it turned out to be a cloudy yellow liquid with precipitates present from the beginning of the addition of the pure water. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Comparative example 2:
Weigh out 20 mg of meloxicam and 160 mg of N,N-dimethylacetamide, use a hot stirrer to uniformly dissolve them at 50°C, then add 400 mg of purified egg yolk lecithin, mix uniformly, and then add 3.4 mL of pure water. At the same time, solubilization was carried out for 10 minutes using an ultrasonic emulsifier. When pure water was added to the solubilized solution thus obtained to make the total volume 4 mL, at the beginning of the addition of the pure water, it was a yellow cloudy liquid, and as time passed, precipitates were generated and precipitated. Its composition and physical property values are shown in Tables 1 and 2, respectively.

Comparative example 3:
Weigh out 20 mg of meloxicam and 160 mg of N,N-dimethylacetamide and dissolve them uniformly at 50°C using a hot stirrer, then add 80 mg of dl-α-tocopherol, 400 mg of purified egg yolk lecithin, and 400 mg of polysorbate 80, and dissolve them uniformly. The mixture was mixed to form an oil phase. While adding 2.8 mL of pure water to the oil phase, it was emulsified for 10 minutes using an ultrasonic emulsifier. When pure water was added to the emulsion obtained in this way to bring the total volume to 4 mL, at the beginning of the addition of pure water, it was a yellowish liquid, and over time, a precipitate was generated and precipitated (a smaller amount than in Comparative Example 2). Its composition and physical property values are shown in Tables 1 and 2, respectively.

The turbidity was measured using an ultraviolet spectrophotometer (UV1800, manufactured by Shimadzu Corporation) at a wavelength of λ=620 nm by placing the sample in a measurement cell with a cell width of 1 cm (the blank was water). The transparent to semi-transparent region where the sample can be seen through and it is easy to visually check for changes in quality, such as agglomeration or precipitation, the presence of foreign matter, and changes in the composition, has Abs (absorbance) of 0.5 or less, so this turbidity can be easily checked. The boundary was set as pass/fail. The average particle diameter was measured using a particle diameter measuring device (Zetasizer Nano ZS: manufactured by Malvern) using a photon correlation method.

As is clear from Table 2, all of the oxicam drug-containing injections of Examples 1 to 20 had an average particle diameter of approximately 100 nm or less and had extremely high transparency (turbidity of 0.5 nm). 5 or less), and had excellent storage stability with no changes that would be a hindrance in practical use even after being stored at room temperature for one month (presence of phase separation, precipitation, precipitation, phase change, etc.). (By visual observation and confirmation that the residual content of oxicam drugs is 90% or more of the original content). On the other hand, the reason why the desired transparent oxicam drug-containing fat emulsion could not be obtained in Comparative Example 1 was thought to be due to the fact that lecithin and pharmaceutically acceptable salts of fatty acids were not included as constituent components. The reason why the desired transparent oxicam drug-containing fat emulsions could not be obtained in Comparative Examples 2 and 3 was thought to be due to the fact that a pharmaceutically acceptable salt of a fatty acid was not included as a constituent.

Example 21: Meloxicam-containing injection (Part 19)
A meloxicam-containing injection having the same physical properties as the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16, except that the amount of macrogol 400 used was changed to 500 mg.

Example 22: Meloxicam-containing injection (Part 20)
A meloxicam-containing injection having the same physical properties as the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16, except that the amount of macrogol 400 used was changed to 2 g.

Example 23: Ampiroxicam-containing injection (Part 1)
An ampiroxicam-containing injection having the same physical properties as the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16, except that meloxicam was changed to ampiroxicam.

INDUSTRIAL APPLICABILITY The present invention has industrial applicability in that it can provide an injection containing an oxicam drug that is transparent and has excellent stability and safety.

Claims (3)

(1) Oxicams (2) Lecithin and polysorbate (however, polysorbate is 50% by weight or less)
(3) Pharmaceutically acceptable salts of fatty acids (4) Macrogol and/or N,N-dimethylacetamide (5) Aqueous medium (6) Oil and/or tocopherol compounds as at least a constituent component; The content of tocopherol compounds is 5 to 100 mg/mL, and the weight ratio of oxicam drugs to fats and oils and/or tocopherol compounds (oxicam drugs/fats and/or tocopherol compounds) is 0.01 to 2 (however, the weight ratio of oxicam drugs to fats and oils and/or tocopherol compounds) is 0.01 to 2. / or the total content of tocopherol compounds is at most 125 mg/mL), the turbidity is 0.5 or less, and the residual content of oxicam drugs is 90% or more of the original content even after storage at room temperature for one month An injection containing an oxicam drug, characterized by having storage stability of . The oxicam drug-containing composition according to claim 1, wherein the content of the oxicam drug is 0.1 to 50 mg/mL, and the content of lecithin and polysorbate (however, polysorbate is 50% by weight or less) is 50 to 200 mg/mL. Injection. The oxicam drug-containing injection according to claim 1, further comprising a saccharide.