JP2008201778A - Vancomycin liquid formulation - Google Patents

Abstract

An object of the present invention is to provide a vancomycin aqueous solution preparation having improved stability of vancomycin in an aqueous solution and capable of long-term storage, and an oral solution of vancomycin with improved dosing property.
SOLUTION: The composition contains vancomycin, 65% by mass or more of glycerin with respect to the amount of water contained in the preparation, D-form or DL-form alanine and / or D-form or DL-form lactic acid, and a pH of 3. Vancomycin aqueous solution preparation adjusted to 6-4.6.
[Selection figure] None

Description

  The present invention relates to a vancomycin aqueous solution formulation having improved stability of vancomycin in an aqueous solution. Furthermore, the present invention relates to an oral vancomycin liquid preparation which is stable and taste-improved in an oral vancomycin preparation.

  Vancomycin is a glycopeptide antibiotic derived from Streptmyces orientalis and is mainly effective against gram-positive bacteria. Vancomycin is mainly used for MRSA infection as an injection, and is used as an oral preparation for pseudomembranous colitis caused by Clostridium difficile and for gastrointestinal sterilization during bone marrow transplantation. . The usual amount used per dose is 0.5 g as vancomycin, 5-10 mL for oral preparations, 100 mL or more in water or infusion for injections, and usually 4 times a day for oral preparations. In the case of injection, it is usually administered 4 times per day. Vancomycin is easily degraded by deamidation in aqueous solution due to its structure, and lyophilization is considered necessary to ensure long-term stability. Only freeze-dried preparations. In general, the storage stability of pharmaceuticals is known to be better when the water content is as low as 2% or less, and the stability is improved by using a freeze-dried preparation (Non-patent Document 1). And 2).

  In addition, in the study on the stability of the model peptide that decomposes by deamidation reaction similar to vancomycin, the lyophilized model peptide containing sucrose shows high storage stability, whereas sucrose is stabilized in aqueous solution. There is a report that the effect is hardly exhibited, and it is shown that the stabilizing method effective in the lyophilized product does not necessarily show the stabilizing effect in the solution (Non-patent Document 3).

  Conventional vancomycin preparations are supplied as lyophilized preparations to ensure stability. However, the cost of production is large, and the dissolution operation is required even during use, which is troublesome and takes time until administration. Have In order to solve these problems, an aqueous solution preparation is desired. However, as described above, since it is chemically unstable, an aqueous solution preparation that can withstand practically long-term storage has not been developed.

The vancomycin oral preparation currently used in the medical field is a sterile freeze-dried preparation in a vial, and since it is difficult to distinguish it from an injection in appearance, there is a fear of a medical error that it is erroneously injected. However, as long as the vancomycin oral preparation is a sterile lyophilized preparation, the containers that can be used in production are limited to glass vials or ampoules, and it is difficult to use a plastic container that can be easily distinguished from an injection. From this point of view, a stable aqueous solution preparation capable of aseptic filtration is desired. Furthermore, it is known that conventional vancomycin oral preparations have a problem of poor dosing because they exhibit an unpleasant taste resulting from a bitter taste and a unique acidity. For this reason, when taking a patient at a medical site, it is often taken after dissolving with a simple syrup (component: sucrose), etc., but taking only the simple syrup suppresses the bitter taste of vancomycin hydrochloride. It is difficult to improve sex, and it has been reported that patient compliance is often reduced (Non-patent Document 4). In addition, vancomycin hydrochloride, which is a freeze-dried preparation, is known to have poor stability in a chemical solution obtained by dissolving only in water (Non-Patent Document 5). In a medical institution, it is necessary to dissolve immediately before taking, or to dissolve only the portion taken by a patient in a short period and store it in a refrigerator, which is complicated. From the above, it can be said that there is a long-awaited long-term stable aqueous solution preparation that can be sterile filtered in a vancomycin preparation. In particular, in the case of oral preparations, in addition to these requirements, an aqueous solution preparation with good dosing is required.

Regarding the injection of vancomycin, there is a disclosure that coloring can be suppressed by containing an organic acid, and a disclosure that an optimum pH is 3.00 to 3.40. As an example, about 0 to vancomycin. A lyophilized preparation to which citric acid, lactic acid, or malonic acid is added in the range of 4 to 2% by weight is tested for coloration under severe conditions (Patent Document 1).
In addition, there is a disclosure that coloring can be suppressed by adding an amino acid to an injection of vancomycin. As an example, a lyophilized preparation containing about 4% by weight of glycine with respect to vancomycin is colored under severe conditions. The degree is tested (Patent Document 2).

  However, conventionally known documents do not disclose stabilization of vancomycin in an aqueous solution in an aqueous vancomycin preparation, and in particular, no aqueous solution that can be stored for a long period of time is known. In addition, there is no known vancomycin preparation that has improved taste ingestion.

Cameron P., Good Pharmaceutical Freeze-Drying Practice, pp.2-4,1997 Bhalla H. L., STATUS OF FREEZE-DRYING IN PHARMACEUTICAL PRODUCTS, Proceeding of Workshop on Freeze Drying, pp.91, 1980 Li B et al., Effect of sucrose and mannitol on asparagines deamidation rates of model peptides in solution and in the solid state., J Pharm Sci, 94 (8), 1723-1735, 2005 Hashimoto, et al., Pharmaceutical considerations for bone marrow transplantation, JJSHP, 23 (12), 17-20, 1987 Miki Ito et al., Pharmacological examination of vancomycin hydrochloride ophthalmic solution and its application to MRSA eye infection, YAKUGAKU ZASSHI, 121 (6), 433-439, 2001 Japanese Patent Laid-Open No. 11-5743 Japanese Patent Laid-Open No. 11-80021

  The present invention relates to a stable vancomycin aqueous solution preparation capable of aseptic filtration, in particular, physical stability that prevents precipitation and gelation of vancomycin in the aqueous solution and enables long-term storage of the sterile filtration and preparation, and vancomycin in the aqueous solution. It is an object of the present invention to provide a pharmaceutical preparation that is compatible with chemical stability that suppresses a decrease in activity due to chemical decomposition of the drug and enables long-term storage of the preparation. Furthermore, an object of the present invention is to provide a vancomycin oral solution that can be aseptically filtered, is stable, and has improved dosage.

As a result of intensive investigations to make vancomycin, which is an active ingredient, into a substantially stable and practicable aqueous solution preparation during long-term storage required as a pharmaceutical product, the present inventors have set the pH of the aqueous solution to 3. 6 to 4.6, and by combining a specific amount of glycerin with D-form or DL-form alanine and / or D-form or DL-form lactic acid, vancomycin does not precipitate over a long period of time. And, it was found that it can be chemically stabilized over the effective period until it is considered to be substantially stable as a pharmaceutical product. It has also been found that glycerin contributing to stabilization has the effect of being able to bring out the taste of the corrigent even in the presence of vancomycin, and further adding l-menthol or vanillin to improve the taste of this aqueous solution. The present invention has been completed by confirming that there is an effect of improving and making it easy to take the vancomycin aqueous solution preparation. That is, the present invention
(1) It contains vancomycin, 65% by mass or more of glycerin with respect to the amount of water contained in the preparation, D-form or DL-form alanine and / or D-form or DL-form lactic acid, and has a pH of 3.6. It is a vancomycin aqueous solution preparation adjusted to ˜4.6.

In particular,
(2) The vancomycin aqueous solution preparation according to the above (1), wherein the content of alanine in D-form or DL-form is 1% by mass or more with respect to vancomycin as D-alanine,
(3) The vancomycin aqueous solution preparation according to any one of the above (1) or (2), wherein the lactic acid content of D-form or DL-form is 1% by mass or more with respect to vancomycin as D-lactic acid,
(4) The vancomycin aqueous solution formulation according to any one of (1) to (3) above, comprising 1 to 15% by mass of vancomycin with respect to the total amount of the formulation,
(5) 1 to 15% by mass of vancomycin with respect to the total amount of the formulation, 65% by mass or more of glycerin with respect to the amount of water contained in the formulation, and 1% by mass or more of D-form with respect to vancomycin as D-alanine Alternatively, a vancomycin aqueous solution preparation containing DL alanine and D-lactic acid in an amount of 1% by mass or more with respect to vancomycin as D-lactic acid and having a pH adjusted to 3.6 to 4.6,
(6) 2 to 10% by mass of vancomycin with respect to the total amount of the formulation, 70 to 100% by mass of glycerin with respect to the amount of water contained in the formulation, and 6 to 25% by mass with respect to vancomycin as D-alanine Vancomycin aqueous solution preparation containing D-form or DL-form alanine and D-lactic acid of 6 to 20% by mass of D-form or DL-form lactic acid with respect to vancomycin and having a pH adjusted to 3.6 to 4.6 ,
(7) A vancomycin aqueous solution preparation as an oral preparation according to any one of (1) to (6) above, which contains 1-menthol or vanillin,
(8) Vancomycin aqueous solution as an oral preparation according to (7) above, containing 0.005 to 0.1% by mass of l-menthol or 0.05 to 1% by mass of vanillin with respect to the total amount of the preparation Formulation,
(9) The vancomycin aqueous solution preparation according to any one of the above (1) to (8), wherein the D-alanine or DL-alanine content is 5% by mass or more with respect to vancomycin as D-alanine,
(10) The vancomycin aqueous solution preparation according to any one of the above (1) to (9), wherein the D-lactic acid content or DL-lactic acid content is 4% by mass or more with respect to vancomycin as D-lactic acid,
(11) 1 to 15% by mass of vancomycin with respect to the total amount of the formulation, 65% by mass or more of glycerin with respect to the amount of water contained in the formulation, and 5% by mass or more of D-form with respect to vancomycin as D-alanine Or DL-containing alanine and 4 mass% or more of D-form or DL-form lactic acid as D-lactic acid with respect to vancomycin, and the pH is adjusted to 3.6 to 4.6. (10) The vancomycin aqueous solution formulation according to any one of
(12) 2 to 10% by mass of vancomycin with respect to the total amount of the formulation, 65 to 125% by mass of glycerin with respect to the amount of water contained in the formulation, and 6 to 25% by mass with respect to vancomycin as D-alanine The D-form or DL-form alanine and D-lactic acid containing 4 to 24% by mass of the D-form or DL-form lactic acid with respect to vancomycin, and the pH is adjusted to 3.6 to 4.6 (the above) 1) A vancomycin aqueous solution preparation according to any one of (11),
(13) The vancomycin aqueous solution preparation according to any one of (1) to (12) above, wherein the pH is adjusted to 3.9 to 4.2,
(14) In any one of the above (1) to (13), the active ingredient has a residual ratio of 90% or more after storage / at the start of storage when stored at 10 ° C. for 2 years The vancomycin aqueous solution formulation,
(15) In any one of the above (1) to (14), the active ingredient has a residual ratio of 60% or more after storage at the start of storage at 50 ° C. for 2 weeks. The vancomycin aqueous solution formulation,
(16) In any one of the above (1) to (15), the active ingredient has a residual ratio of 70% or more after storage at the start of storage when stored at 50 ° C. for 2 weeks. The vancomycin aqueous solution formulation,
(17) The vancomycin aqueous solution formulation according to any one of (1) to (16) above, wherein the total amount of the formulation is 3 to 20 g,
(18) The vancomycin aqueous solution preparation according to any one of (1) to (17) above, which is filled in a plastic container,
(19) The vancomycin aqueous solution preparation according to any one of (1) to (18) above, which is sterile filtered.

  According to the present invention, physical stability that prevents precipitation and gelation of vancomycin in an aqueous solution and enables long-term storage of sterile filtration and preparation, and suppresses a decrease in activity due to chemical degradation of vancomycin in an aqueous solution. It is possible to obtain a preparation compatible with chemical stability that enables long-term storage of the preparation. By maintaining physical stability and chemical stability, it has become possible to provide a vancomycin aqueous solution formulation that maintains the biological stability required for use as a pharmaceutical product over a long period of time. Since vancomycin can be made into a stabilized aqueous solution preparation, no preparation operation is required at the time of use, and rapid and simple administration is possible. Further, since lyophilization is not required, it can be filled and supplied in a plastic container, and there are advantages that misuse with a conventional lyophilized injection preparation is prevented and the disposal of the container is facilitated. Furthermore, by using an aqueous solution formulation, l-menthol or vanillin, which was difficult to add in conventional lyophilized formulations, can be added, and the bitter and unpleasant taste of vancomycin has been reduced, improving the feeling of administration. Oral formulations can be provided.

  As the vancomycin used in the present invention, a commercially available pharmaceutical grade drug substance can be used. Since the free base of vancomycin is hardly soluble in water, the free base is converted into a water-soluble salt and then supplied as an active pharmaceutical ingredient. Accordingly, pharmaceutically acceptable salts of vancomycin used in the present invention include water-soluble salts such as hydrochlorides and sulfates, but it is preferable to use hydrochlorides that are excellent in production cost and stability. The solubility of vancomycin hydrochloride in water is about 200 mg / mL, but if it exceeds 100 mg / mL, it tends to form a gel due to association. In addition, when vancomycin is administered intravenously, it is administered after being diluted with an infusion solution so that it is 5 mg / mL or less. However, vancomycin degrades in a short period of time and is not suitable for long-term storage. . The aqueous solution preparation of the present invention needs to have a vancomycin concentration suitable for long-term storage. The preferable vancomycin content in the preparation of the present invention is 1 to 15% by mass, more preferably 2 to 10% by mass, and particularly preferably 3 to 8% by mass with respect to the total amount of the formulation.

Glycerin used in the present invention has an effect of increasing the chemical stability of vancomycin and an effect of increasing physical stability such as precipitation suppression. In particular, the inventors have found that when glycerin and alanine and / or lactic acid are used in combination, the aqueous solution preparation exhibits a stabilizing effect that enables long-term storage. Furthermore, it discovered that glycerin had the effect that the taste of a corrigent can be pulled out also in vancomycin presence. In order to improve the stability of vancomycin in aqueous solution and to suppress decomposition, precipitation, and precipitation during long-term storage, it is necessary to contain a certain amount or more of glycerin, which is the amount of water contained in the formulation It is 65 mass% or more with respect to. The upper limit of the content is preferably within the range of the viscosity that is stable as an aqueous solution preparation and does not become difficult to perform operations such as sterile filtration, and that the daily dosage does not exceed the actual use of pharmaceutical products. The range that does not exceed the drug use record as the daily dose can be determined with reference to the maximum use amount described in, for example, the Pharmaceutical Additives Dictionary 2005 (edited by Japan Pharmaceutical Additives Association; Yakuji Nipposha, 2005). . On the other hand, when the glycerin content is too high, precipitation of water-soluble components and irritation to the oral mucosa of glycerin when used as an oral agent become problematic. In consideration of these, the content of glycerin in the preparation is preferably 65 to 150% by mass, more preferably 65 to 125% by mass, and further preferably 70 to 125% by mass with respect to the amount of water contained in the formulation. 100% by mass.

  The alanine used in the present invention is D-form or DL-form alanine. A stabilizing effect cannot be obtained only with L-alanine. What is necessary is just to prescribe | regulate content to a formulation as the quantity of D-alanine (D-form alanine), and the preferable content as D-alanine is 1 mass% or more with respect to vancomycin, More preferably, it is 5 mass% or more. is there. The upper limit of the content is preferably a range that is stable as an aqueous preparation and does not cause precipitation, and that the daily dosage does not exceed the actual use of pharmaceutical products. Preferably it is 1-39 mass%, More preferably, it is 5-30 mass%, More preferably, it is 6-25 mass%, Most preferably, it is 8-20 mass%. Moreover, what is necessary is just to consider the half amount as content of D-alanine, when using a DL body (racemic body). That is, the preferable content as DL-alanine is 2 mass% or more with respect to vancomycin, More preferably, it is 10 mass% or more.

  The lactic acid used in the present invention is D-form or DL-form lactic acid. A stabilizing effect cannot be obtained only with L-form lactic acid. The content in the preparation may be defined as the amount of D-lactic acid (D-lactic acid), and the preferable content as D-lactic acid is 1% by mass or more, more preferably 4% by mass or more with respect to vancomycin. is there. The upper limit of the content is preferably a range that is stable as an aqueous preparation and does not cause precipitation, and that the daily dosage does not exceed the actual use of pharmaceutical products. Preferably it is 1-39 mass%, More preferably, it is 4-24 mass%, More preferably, it is 6-20 mass%, Most preferably, it is 7-16 mass%. Moreover, what is necessary is just to consider the half amount as content of D-lactic acid, when using a DL body (racemic body). That is, the preferable content as DL-lactic acid is 2 mass% or more with respect to vancomycin, More preferably, it is 7 mass% or more.

  In the preparation of the present invention, alanine and / or lactic acid exhibit a stabilizing effect that enables long-term storage of an aqueous preparation by coexisting with glycerin. When coexisting with glycerin, alanine and lactic acid may be used alone, but a synergistic stabilizing effect is shown by using alanine and lactic acid together. Therefore, a preferred form of the present invention includes vancomycin, 65% by mass or more of glycerin with respect to the amount of water contained in the preparation, D-form or DL-form alanine, and D-form or DL-form lactic acid, It is a vancomycin aqueous solution formulation having a pH adjusted to 3.6 to 4.6. Each content in the case of using alanine and lactic acid together may be determined according to the preferable content range of each component described above, and the content ratio of both components can be determined appropriately by a technique that can be commonly used by those skilled in the art.

  In order to stably store the vancomycin aqueous solution preparation for a long period of time, the preferred pH is 3.6 to 4.6, more preferably 3.9 to 4.2. While this pH range is suitable for the chemical stability of vancomycin, on the other hand, vancomycin is difficult to dissolve with purified water or buffer alone, or is likely to precipitate once dissolved. . In order to realize a vancomycin aqueous solution formulation that maintains solubility in the above pH range and can be stably stored for a long period of time, the presence of a certain amount of glycerin and alanine and / or lactic acid is necessary. Since alanine and / or lactic acid have a pH adjusting action, it is possible to adjust to an appropriate pH by adding them, but a pharmaceutically acceptable pH adjusting agent may be contained in addition. Examples of such pH adjusters include sodium lactate, citric acid, sodium citrate, sodium hydrogen phosphate, acetic acid, sodium acetate, phosphoric acid, propionic acid, butyric acid, valeric acid, glycolic acid, oxalic acid, malonic acid, and succinic acid. , Glutaric acid, adipic acid, malic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phthalic acid, tartaric acid, hydrochloric acid, sodium hydroxide, etc.

  The aqueous solution preparation of the present invention can be used as an oral preparation as a liquid preparation. A preferred embodiment is an oral preparation, and in the case of an oral preparation, the preparation of the present invention can be administered as it is. The total amount (capacity or mass) of the aqueous solution preparation of the present invention per container can be appropriately selected in consideration of storage, distribution and subsequent use when used as a pharmaceutical product. Considering the storage space in medical facilities, the convenience during use and the maintenance of sterility during administration, it is preferable to contain a single use amount of the preparation per container, and the total preparation amount suitable as a single use amount (Mass) is 3 g to 20 g / 1 container, particularly preferably 5 g to 15 g / 1 container.

  When the aqueous solution of the present invention is used as an oral preparation, in order to improve the unpleasant taste derived from vancomycin, a flavourant, a fragrance and the like used for pharmaceuticals are added within a range not inhibiting the stability of the preparation of the present invention. can do. Specifically, a particularly suitable flavoring agent for improving the unpleasant taste of vancomycin is l-menthol or vanillin. In the case of 1-menthol, the preferable content is 0.005-0.1 mass% with respect to the formulation whole quantity, More preferably, it is 0.01-0.05 mass%. On the other hand, in the case of vanillin, the preferable content is 0.05 to 1% by mass, and more preferably 0.1 to 0.5% by mass with respect to the total amount of the preparation. Moreover, it is possible to adjust a taste and flavor by using combining these components and another fragrance | flavor. In particular, a combination of l-menthol and a citrus flavor such as lemon or orange, or a combination of vanillin and a flavor such as milk or strawberry is preferred. In order to add sweetness, sugars, sugar alcohols, thaumatin, saccharin, and the like can be added. These taste-masking agents are mixed with the bitter taste of vancomycin in the absence of glycerin and cannot exhibit a sufficient effect, but the presence of glycerin allows the taste of the taste-masking agent to be felt even in the presence of vancomycin. Become. That is, in order to obtain a vancomycin oral preparation with improved taste ingestion, it is necessary to use glycerin in combination with a corrigent.

  In the aqueous solution of the present invention, in addition to these essential components, pharmaceutically acceptable optional components can be contained within a range that does not impair the effects of the invention. Examples of such optional components include antioxidants such as sodium bisulfite, sodium sulfite, propyl gallate, sodium ascorbate, and sodium erythorbate, and preservatives such as methyl parahydroxybenzoate and propyl paraoxybenzoate.

  The method for producing the aqueous solution of the present invention may be carried out in accordance with a conventional method, for example, a method in which all preparation components are dissolved, sterilized by filtration, filled into a suitable container and sealed. In addition, it is preferable to pass nitrogen through the water to be used or to replace the void portion of the container with nitrogen in order to prevent coloring due to oxidation and improve stability.

The material of the container filled with the aqueous solution preparation of the present invention can be any pharmaceutically acceptable material. Such materials are roughly classified into glass and plastic, and examples of the plastic include polyethylene, polypropylene, and polyethylene terephthalate (PET). As described above, the plastic container is preferably used as an oral preparation container having improved discrimination from an injection, and is preferably made of polyethylene from the viewpoint of cost. On the other hand, plastic containers generally have higher moisture permeability and gas permeability than glass, so from the viewpoint of formulation stability, materials with low oxygen permeability such as PET can be used as the material, or the container can be made of an aluminum laminate film. It is preferable to carry out secondary packaging by such as. Since the aqueous preparation of the present invention has improved long-term storage stability, it can be supplied as a pharmaceutical even in a plastic container that is more likely to affect the stability than a glass container. As a shape of the container filled with the aqueous solution preparation of the present invention, any shape acceptable as a pharmaceutical product can be used. Such container shapes are roughly classified into containers that can be recapted and integrally molded containers that cannot be recaptured by cutting the tip during use. Recapable containers are highly distinguishable from injections,
Moreover, in order to improve the meterability at the time of medication, a container having a measuring cup type or a dropper type cap is preferable. Measuring cups and syringes can be attached separately from the normal cap. In order to enable divided administration, it is more preferable that the container main body and / or the cap has a scale for measurement.

  The vancomycin aqueous solution preparation of the present invention has the physical stability that prevents the precipitation and gelation of vancomycin in the aqueous solution and enables aseptic filtration and long-term storage of the preparation, and the decrease in activity due to the chemical degradation of vancomycin in the aqueous solution. It is a preparation that is compatible with chemical stability that enables long-term storage of the preparation. The presence or absence of vancomycin precipitation or gelation can be confirmed by visual observation, centrifugation, or absorbance measurement. The degree of vancomycin degradation can be confirmed by measuring vancomycin content by liquid chromatography after storage / at the start of storage.

  Long-term storage refers to a storage period in consideration of storage, distribution and subsequent use when used as a pharmaceutical product. For example, under storage conditions after marketing (room temperature, storage in a cold place (15 ° C or lower), etc.) Storage for 12 months is expected. The stability in long-term storage can be estimated from the stability in the accelerated test. In general, in a preparation stored at room temperature, long-term storage stability at 25 ° C. (room temperature) for 3 years can be predicted by an accelerated test at 40 ° C. for 6 months. Usually, the accelerated test may be set under the storage condition of + 15 ° C. In the case of storage at 10-15 ° C, the accelerated test is set at 25-30 ° C. One of the preferred embodiments of the preparation of the present invention is a vancomycin aqueous solution preparation having a stability in which the content (residual ratio) of the active ingredient after storage at the start of storage at 10 ° C. for 2 years is 90% or more. . In the case where the stability is evaluated in a shorter period than the 6-month accelerated test, an appropriate period and remaining rate may be set under a higher temperature condition. Specifically, the residual rate is 60% or more in the test at 50 ° C. for 2 weeks, more preferably the residual rate is 70% or more, most preferably the residual rate is 90% or more, and the residual rate is 80% or more in the test at 40 ° C. for one month. Illustrated.

  EXAMPLES Examples and experimental examples for explaining the present invention in more detail are given below, but the present invention is not limited by these.

Preparation of Examples 1 to 16 and Comparative Examples 1 to 11 Vancomycin hydrochloride and additives were weighed and dissolved using a handy homogenizer (Microtalx, manufactured by IKA), and then a membrane filter (Mirex GV, pore size 0.22 μm, Millipore). And a glass container was filled to obtain vancomycin aqueous solution formulations having the compositions shown in Tables 2 and 3 (Examples 1 to 16 and Comparative Examples 1 to 11).

Test example 1
The aqueous solution preparations of the present invention of Examples 1 to 16 and the aqueous solution preparations of Comparative Examples 1 to 11 were stored under accelerated conditions of 30 to 50 ° C. The peak area of the substance (decomposed product) was determined. The vancomycin content was quantified using a vancomycin standard, and the residual rate relative to the start was calculated. Furthermore, the percentage (%) of the total related substance peak area to the total peak area of vancomycin and all related substances was calculated.

HPLC system: alliance UV system (Nippon Waters Corporation)
Detection wavelength: UV254nm
Column used: Develosil C30-UG-5 (4.6mm x 250mm)
Mobile phase composition Mobile phase A Acetonitrile: tetrahydrofuran: triethylamine buffer = 7: 1:
92
Mobile phase B acetonitrile: tetrahydrofuran: triethylamine buffer = 29: 1: 70
The liquids A and B were fed according to the program shown in Table 1 below using a gradient method.

Test results As shown in Table 2, DL-alanine showed a higher stabilizing effect than other amino acids, and the stability was further improved by the combined use with DL-lactic acid. In addition, it was confirmed that a suitable pH was in the range of 3.6 to 4.6, and precipitation was observed during storage in Comparative Example 1 in which the glycerin content was 59% by mass with respect to the amount of water in the preparation. . On the other hand, the aqueous solution preparation of Comparative Example 4 containing citric acid and glycine, which are considered to have a coloring suppression effect in Patent Documents 1 and 2, respectively, has not been confirmed to have a stabilizing effect during storage. The stabilization effect in aqueous solution may be a different mechanism. As shown in Table 3, Example 11 shows a higher residual rate of the main agent and a lower decomposition product generation rate than Comparative Example 7 containing only glycerin and Comparative Example 8 containing only DL-alanine and DL-lactic acid. It was revealed that a high stabilizing effect can be obtained only by combining DL-alanine and / or DL-lactic acid. Moreover, vancomycin did not melt | dissolve in the comparative example 6 which does not contain DL-alanine, DL-lactic acid, and glycerol. It was suggested that the solubility of vancomycin cannot be maintained unless a certain amount of glycerin is present in the range of 3.6 to 4.6, which is a pH suitable for long-term storage. Table 4 shows the stabilizing effect of the optical isomers of alanine and lactic acid. Compared to Comparative Example 9 containing only glycerin and Comparative Examples 10 and 11 containing glycerin and L-form alanine or lactic acid, the Examples containing glycerin and D-form alanine and / or lactic acid showed a remarkable stabilizing effect. It was. In the case where both alanine and lactic acid are added in the same amount, the D-form has a higher stabilizing effect than the DL-form. Therefore, it was confirmed that the stabilizing effect increases as the D-form content increases. Since only L-alanine or L-lactic acid did not provide a stabilizing effect, the D-isomer shows an effect on the chemical stability of vancomycin in an aqueous solution. Was suggested to increase. Further, when alanine or lactic acid is used alone, it becomes a blending amount-dependent stabilization effect, but by using both in combination, a stabilization effect exceeding the amount-dependent effect was obtained.

Preparation of Examples 17 to 24 and Comparative Examples 12 to 14 After weighing vancomycin hydrochloride and additives, water-soluble components including vancomycin hydrochloride were added as they were to water, and a handy homogenizer (Microtalx, manufactured by IKA) was used. Dissolved. Next, methyl paraoxybenzoate, propyl paraoxybenzoate and menthol dissolved in ethanol are added, mixed using a handy homogenizer, filtered using a membrane filter (Mirex GV, manufactured by Millipore), and filled into a polyethylene plastic container. And the vancomycin aqueous solution formulation of the composition (Examples 17-24 and Comparative Examples 12-14) shown in Table 5 was obtained.

Test example 2
The bitterness which is one of the unpleasant tastes of vancomycin was evaluated using a taste recognition device (SA402B, manufactured by Insent). Using two types of sensors (ACO, ANO) that can detect the bitter taste of basic drugs such as quinine, the aqueous solution formulations of Examples 17 to 24 and the aqueous solution formulations of Comparative Examples 12 to 14 are sustained. The intensity of bitterness (aftertaste) was measured, and the decrease in the degree of relative bitterness from Comparative Example 12 (an aqueous solution of vancomycin hydrochloride alone) was quantified. It means that the bitterness decreases as the numerical value decreases, that is, as the numerical value increases toward the minus side. The results are shown in FIG.

Test Results FIG. 1 is a two-dimensional plot of the bitterness scale obtained by measuring with two types of bitterness sensors for each sample. Currently, vancomycin lyophilized preparations are dissolved and taken in water or simple syrup at clinical sites, but almost no bitterness reduction effect was observed in Comparative Examples 13 to 14 prepared in accordance with these uses. Moreover, although the bitterness reduction was not recognized by the prescription (Example 18) which contains glycerin and does not contain white sugar, the bitterness reduction effect was recognized by the prescription (Example 17) which added white sugar to the prescription containing glycerin. . Furthermore, it was suggested that the vancomycin aqueous solution formulation which added 1-menthol or vanillin in combination with other fragrances has reduced bitterness and improved ingestion. Moreover, the bitterness reduction effect was maintained also in the prescription (Examples 21 and 22) in which sucrose was replaced with trehalose with less sweetness. From these facts, it is possible to bring out the taste of the corrigent even in the presence of vancomycin by using glycerin and the corrigent together, where the taste disappears with the bitter taste of vancomycin alone. It can improve the dosage.

Preparation of Examples 25 to 31 and Comparative Example 15 After weighing vancomycin hydrochloride and the additive, water less than the prescribed amount was added and dissolved using a handy homogenizer (Microtalx, manufactured by IKA). After adjusting the pH to about 4.1 using a hydrochloric acid solution or a sodium hydroxide solution, water was added to a specified amount. The solution was filtered using a membrane filter (Mirex GV, pore size 0.22 μm, manufactured by Millipore) and filled in a glass container to obtain a vancomycin aqueous solution formulation having the composition shown in Table 6 (Examples 25 to 31 and Comparative Example 15).

Test example 3
These aqueous preparations were stored under accelerated conditions of 50 ° C. for 2 weeks, the vancomycin content was quantified under the conditions of Test Example 1, and the residual ratio relative to the start of the stored preparation was calculated. Further, the percentage (%) of the peak area of all related substances relative to the total peak area of vancomycin and all related substances was calculated. The results are shown in Table 6.

Test result As shown in Table 6, in Examples 25-31, the outstanding stabilization effect was shown. On the other hand, Comparative Example 15 containing neither D-alanine nor D-lactic acid resulted in a low residual rate and a high related substance peak area compared to the other Example compositions.

Formulation Example 1
An oral solution having the following composition was prepared by a conventional method. This drug did not feel the bitter taste of vancomycin, and excellent dosage was confirmed.
Vancomycin hydrochloride 510mg Potency concentrated glycerin 2500mg
DL-alanine 100mg
D-lactic acid 120mg
Purified white sugar 550mg
Sodium citrate 120mg
Methyl paraoxybenzoate 5mg
Propyl paraoxybenzoate 1mg
Sodium bisulfite 7mg
L-menthol 1mg
Lemon Essence 6mg
Purified water appropriate amount total 6500mg

It is a graph which shows the measurement result by the bitterness sensor about each sample.

Claims (10)

  It contains vancomycin, 65% by mass or more of glycerol with respect to the amount of water contained in the preparation, D-form or DL-form alanine and / or D-form or DL-form lactic acid, and has a pH of 3.6 to 4. Vancomycin aqueous solution preparation adjusted to 6.   The vancomycin aqueous solution preparation according to claim 1, wherein the content of alanine in the D form or DL form is 1% by mass or more with respect to vancomycin as D-alanine.   The vancomycin aqueous solution preparation according to claim 1 or 2, wherein the D-form or DL-form has a lactic acid content of 1% by mass or more based on vancomycin as D-lactic acid.   The vancomycin aqueous solution preparation according to any one of claims 1 to 3, comprising 1 to 15% by mass of vancomycin with respect to the total amount of the preparation.   1 to 15% by mass of vancomycin with respect to the total amount of the formulation, 65% by mass or more of glycerin with respect to the amount of water contained in the formulation, and 1% by mass or more of D-form or DL-form with respect to vancomycin as D-alanine A vancomycin aqueous solution preparation containing 1% by mass or more of D-lactic acid and 1% by mass or more of D-form or DL-form lactic acid as D-lactic acid, and having a pH adjusted to 3.6 to 4.6.   The vancomycin aqueous solution preparation as an oral preparation according to any one of claims 1 to 5, comprising 1-menthol or vanillin.   The vancomycin aqueous solution preparation as an oral preparation according to claim 6, comprising 0.005 to 0.1% by mass of l-menthol or 0.05 to 1% by mass of vanillin based on the total amount of the formulation.   The vancomycin aqueous solution preparation according to any one of claims 1 to 7, wherein a D-alanine or DL-alanine content is 5% by mass or more based on vancomycin as D-alanine.   The vancomycin aqueous solution preparation according to any one of claims 1 to 8, wherein a D-form or DL-form lactic acid content is 4% by mass or more based on vancomycin as D-lactic acid.   1 to 15% by mass of vancomycin with respect to the total amount of the formulation, 65% by mass or more of glycerin with respect to the amount of water contained in the formulation, and 5% by mass or more of D-form or DL-form with respect to vancomycin as D-alanine Any one of Alanine and 4 mass% or more D-form or DL-form lactic acid with respect to vancomycin as D-lactic acid, and pH was adjusted to 3.6-4.6. The vancomycin aqueous solution formulation described in 1.

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