JPH0586373B2 - - Google Patents

Description

[Detailed description of the invention]

B. Objective of the invention A: Industrial application field The present invention relates to a method for producing an excipient for direct injection. More specifically, it relates to a method for producing an excipient for direct injection, which is characterized by spray-drying D-mannitol and a starch hydrolyzate with a specified DE value. When commercializing the main ingredients, we use water-soluble D-mannitol, which has good fluidity, moldability, and disintegration, without having any undesirable effects on the main ingredients.
The present invention relates to a method for producing a direct injection excipient made of starch hydrolyzate composite powder. B. Prior Art Commercially available D-mannitol is used alone as an alternative sweetener in the pharmaceutical and food industries. However, when used as an excipient, D-
Mannitol is rarely used alone;
For example, to obtain compressed tablets such as troches and chewable tablets, they are often used in combination with other excipients with good compressibility. When trying to obtain a water-soluble preparation based on saccharides, lactose etc. are mainly used [Pharmacia, 19(12), 1268 (1983)], and in order to obtain a drug-stabilized preparation, In reality, they are used in combination with other additives such as binders, fillers, etc. However, in the former case, there may be a lack of stability with respect to the main drug of the drug due to the combination of lactose, and in the latter case, most of the binders and fillers are water-insoluble or poorly soluble. However, it has the disadvantage that water-soluble formulations cannot be obtained. C. Problems to be solved by the invention D-Mannitol has no adverse effect on its properties, such as pleasant, cool sweetness, non-hygroscopicity, high melting point, good stability, and no contraindications for combination with the main drug. If water-soluble direct injection excipients made of D-mannitol/starch hydrolyzate composite powders with good flowability, disintegration, and moldability can be obtained, the amount of active ingredient caused by formulation additives can be reduced. It is considered preferable because there is less variation in bioavailability and formulation analysis can be easily performed. The present inventors believe that the root of the above-mentioned drawbacks is due to the weak bonding force of commercially available D-mannitol itself, and by using spray drying technology to increase the bonding force, it has been found that the moldability is somewhat satisfactory. D-mannitol powder was obtained [pending application]. However, in order to obtain moldable granules, it was thought to combine with a selected binder and in addition to this a spray drying technique. Synthetic cellulose, natural proteins, and resins are selected from water-soluble binders frequently used as binders, and a mixture of each of them and D-mannitol is spray-dried to obtain powder particles. The moldability of the material was investigated. i.e. 0.2 to 10 of the binder hydroxypropylcellulose, methylcellulose, gelatin, or gum arabic.
% of D-mannitol, but contrary to expectations, the moldability of the resulting formulation was poor. Incidentally, this preparation had a Monsart hardness of 5.0 to 10.1 Kg at a tableting pressure of 1000 to 2000 Kg/cm ² , but capping occurred and molding was impossible at a tableting pressure of 2000 Kg/cm ² or higher. Therefore, we conducted further research into improving these improvements, and found that it was possible to obtain the desired excipient for direct injection only by the manufacturing method described below, which led us to complete the present invention. . B. Structure of the invention A Means for solving the problem In embodiments, (1) D-mannitol and DE
A method for producing an excipient for direct injection, characterized by spray-drying a starch hydrolyzate having a value of 5 or less. (2)D-
A method for producing a direct injection excipient according to claim 1, which uses an aqueous solution or slurry of mannitol.
(3) A method for producing an excipient for direct injection according to claim 1, which uses an aqueous solution of starch hydrolyzate having a DE value of 5 or less. (4) A method for producing an excipient for direct compression according to claim 1, using 99.8 to 75% by weight of D-mannitol and 0.2 to 25 parts by weight of starch hydrolyzate.
(5) The method for producing an excipient for direct injection according to claim 1, in which spray drying is carried out at an exhaust heat temperature of 110 to 150°C. D-mannitol used in the present invention is obtained by any of the following methods: liquid extraction from seaweed, ammonia electrolytic reduction of a glucose solution, or catalytic reduction of a sucrose solution. Any D-mannitol suitable for official standards, USP standards, and BP standards may be used. Starch hydrolyzate is a sugar composition consisting of oligosaccharides ranging from monosaccharides to heptasaccharides obtained by hydrolyzing raw starch by a culture method, an oxygenated culture method, an acid decomposition method, or an enzymatic decomposition method. Of those sugar compositions
Low DE value (Dextrose Equivalent) of 5 or less
If it is selected from starch hydrolyzates, it means that the sugar composition has fewer reducing end groups, so it will not have any effect on the main ingredients of pharmaceuticals, etc., and will have less hygroscopicity and will be more protective. The high colloidal nature gives favorable results. When spray drying a blend of D-mannitol and starch hydrolyzate, add either an aqueous solution or a slurry of D-mannitol to an aqueous solution of starch hydrolyzate with a DE value of 5 or less to obtain a final concentration.
It is adjusted to a concentration of 20 to 50 wt/wt%, but may be prepared by adding a condition of heating to 60 to 80°C. When obtaining D-mannitol/starch hydrolyzate composite powder, 99.8 to 75 parts by weight of D-mannitol and 0.2 to 25 parts by weight of starch hydrolyzate with a DE value of 5 or less are used, but 25 parts by weight or more is used. If starch hydrolyzate is used, the viscosity of the aqueous solution or slurry obtained by mixing and preparation will begin to rise suddenly, which will reduce the efficiency of the drying process and increase the adhesion of powder particles to the dryer wall. Not only does this result in process disadvantages such as reduced drying yield, but also the product obtained after drying is highly hygroscopic and has the disadvantage of slow disintegration of direct compression tablets. Therefore, if we take into account the drying capacity, manufacturing conditions for preparation, drug quality such as disintegration and moldability, and the possibility of improving the uniformity of the content of the main drug and main ingredient by freely adjusting the particle size, D- Most favorable results are obtained using 99.8 to 75 parts by weight of mannitol and 0.2 to 25 parts by weight of starch hydrolyzate with a DE value of 5 or less. When obtaining D-mannitol/starch hydrolyzate composite powder, the spray-drying conditions in the drying process of an aqueous solution or slurry obtained by mixing and preparing D-mannitol and a starch hydrolyzate with a DE value of 5 or less are as follows: , exhaust heat temperature can be selected from a relatively wide range of 110 to 150℃. This means that there is a greater degree of freedom in the drying process, so depending on the concentration conditions of the aqueous solution or slurry liquid, the resulting particle shape may vary from fine to fine granular powder, and the particle size distribution may vary. Even the width can be freely selected, which is very desirable. If dried at temperatures below 110°C or above 160°C, it is difficult to obtain a good product because the formability of the resulting product is related to the growth and development of crystals in X-ray crystallography, which will be described later. . B Effect If an aqueous solution of a starch hydrolyzate having a DE value of 5 or less is added to an aqueous solution or slurry of D-mannitol and spray-dried, fine granules or fine granular powder can be obtained. We made a surprising discovery by comparing the diffraction crystal plane spacing d [Å] measured by X-ray diffraction between these products and the test product obtained in Reference Example [Table]. That is, the products obtained from the present invention have d values of 5.33 [Å] and 5.15.
While admitting that it exists with [Å],
Test products with poor moldability obtained from reference examples such as D-mannitol powder, D-mannitol/starch hydrolyzate mixed powder, or D-mannitol/starch hydrolyzate wet granulation powder had a d value.
The d value of the reference example, in which D-mannitol powder was melted to 160°C and had poor compression moldability, was only recognized to have a d value of 5.15 [Å]. . As described above, the products obtained in the examples of the present invention have good moldability characteristics, and the d values are 5.33 [Å] and 5.15 [Å] in the X-ray diffraction method. Although we found a strong correlation between the recognition of However, in any case, when blending the product obtained as in the example of the present invention, that is, a starch hydrolyzate with a DE value of 5 or less, D-mannitol, the state of dissolution of the starch hydrolyzate, and the spray drying The resulting fine-grained powder or the fine particles shown in Figure 1 of the "Drawings" provide close packing properties and smooth propagation of compression, and therefore have unfavorable properties in terms of formulations, i.e. It is thought that phenomena such as capping and cracking will not be exhibited. C. Examples Examples and reference examples are described below to facilitate understanding of the present invention. Example 1 9.95 kg of Japanese Pharmacopoeia D-mannitol was added to 25 kg of a 0.2 w/w % aqueous solution of starch hydrolyzate having a DE value of 3.2, and the solution was heated to 75° C. with stirring to form an aqueous solution. While maintaining this solution at a temperature of 70 to 75℃, the heat input temperature
Spray drying was performed by a rotating disk method at 221-225°C and exhaust heat temperature 124-130°C to obtain 9.62 kg of fine granular powder. Example 2 9.5 kg of JP D-mannitol was added to 20.0 kg of a 2.5 w/w% aqueous solution of starch hydrolyzate having a DE value of 1.9 and mixed uniformly. This mixed solution (liquid temperature 70-75°C) was spray-dried using a rotating disk method at a heat input temperature of 216-219°C and an exhaust heat temperature of 124-129°C to obtain a fine granular powder weighing 9.58 kg. Example 3 8.5 kg of JP D-mannitol was added to 15.0 kg of a 10.0 w/w% aqueous solution of starch hydrolyzate having a DE value of 1.9 and mixed uniformly. This mixed solution (liquid temperature 20.6°C) was spray-dried using a pressure nozzle method at a heat input temperature of 201 to 206°C and an exhaust heat temperature of 120 to 126°C to obtain fine particles of 9.48 kg. Example 4 7.5 kg of JP D-mannitol was added to 25.0 kg of a 10.0 w/w% aqueous solution of starch hydrolyzate having a DE value of 4.6 and mixed uniformly. This mixed solution (liquid temperature 21.2°C) was spray-dried using a pressure nozzle method at a heat input temperature of 199 to 212°C and an exhaust heat temperature of 121 to 123°C to obtain fine particles of 9.61 kg. The DE value of the starch hydrolyzate was measured as follows. Accurately weigh 6.0g of starch hydrolyzate, dissolve it in pure water, add up to 200ml, and transfer 10ml of it to a 200ml stoppered Erlenmeyer flask.
Add 10 ml of N/25 iodine solution, and quickly add 15 ml of N/25 NaOH solution within about 15 seconds while shaking the flask at 15-20°C to mix. Then, cap the flask and leave in the dark for 20 minutes. Next, diluted hydrochloric acid (1:
5) Rapidly add 5 ml with a sesame pipette and mix, then titrate with N/25 sodium thiosulfate solution. When the color of the liquid becomes slightly yellow at the end of the titration, 2 drops of the soluble starch solution are added, and the titration is continued until the color of the liquid disappears after exactly half a drop, which is the end point. At the same time, the same treatment was performed using pure water instead of the starch hydrolyzate, and the titration value was used as a blank to calculate the DE of the starch hydrolyzate using the following formula.
Calculate the value. DE=(ba-a)f×7.204/(100-M)S×100 In the above formula, a is the titration value of starch hydrolyzate with N/25 sodium thiosulfate, and b is N/25
Titration value of blank of starch hydrolyzate with sodium thiosulfate (ml), f is factor of starch hydrolyzate, M is water content (%) of starch hydrolyzate (70℃, 5 hours drying), S is starch hydrate This is the amount (g) of the decomposition product collected. Reference example 1 100 mesh powder of JP D-mannitol. Reference Example 2 Powder obtained by uniformly mixing 4.25 kg of JP D-mannitol and 0.75 kg of starch hydrolyzate with a DE value of 1.9. Reference example 3 Add 0.6 kg of water to 0.75 kg of starch hydrolyzate with a DE value of 1.9 to make a pasty liquid, and add this to JP D-mannitol.
Add to 4.25Kg and mix uniformly. This mixture was crushed and granulated using a 30-mesh screen, dried on a shelf, and further sieved through a 30-mesh sieve for granulation.
Kg of granules were obtained. Reference example 4 Take Japanese Bureau D-Mannitol in a porcelain plate and add approximately 168
The mixture was heated and melted at ℃, and after cooling, it was crushed and sieved through a 30-mesh sieve. The products obtained in the Examples and Reference Examples of the present invention were subjected to physical property tests and formulation property tests, and the results are shown in the table below.
Shown in the table. The table also shows the results obtained by X-ray diffraction.

[Table] 1. Accurately weigh 1000g of sample into a weighing bottle and heat it to 105℃.
Dry for 3 hours and determine the weight loss. 2 Accurately weigh about 1000g of anhydrous sample after drying it at 105℃ for 3 hours, leave it for 120 hours at 40℃ and 75%RH, measure the weight of the sample, and absorb the increased weight. Quantity. Also, any change in appearance at this time will be observed at the same time.

【table】

[Table] Tableting conditions: Add 1% magnesium stearate to each sample, use a 10mmφ parallel punch, and set each tablet to 300mg.
Static compression tableting is performed using a Brinell hardness tester (manufactured by Yonekura Seisakusho). Tablet characteristics test method: 1. Tablet hardness Measure each of 20 tablets using a Monsanto hardness tester and calculate the average value. 2. Tablet thickness Measure each of 20 tablets using a micrometer and calculate the average value. 3 Disintegration test Average time measured according to the disintegration test method of the Japanese Pharmacopoeia. However, no auxiliary board will be used. 4 Weight of the preparation Measure 20 tablets each and calculate the average value.

【table】

[Table] In the abuse test, the tablets of each sample are packaged in 7μ thick polycello and subjected to abuse under conditions of 40° and 40°-75% RH for 30 days.

【table】

[Table] Usage Examples The samples obtained in the examples were mixed with main drugs such as ascorbic acid, sodium bicarbonate, or acetylsalicylic acid, and directly compressed into tablets. <Formulation> The powdered or fine granular samples obtained in Examples 2, 3, or 4 were mixed with the active ingredient according to the table recipe and homogenized. <Tableting conditions> The weight of each tablet was set to be 300 mg. HT・
Using a P18 type tablet press (manufactured by Hata Tekkosho), assemble a tablet diameter 9mmφR type mortar, apply a pressure of 2500Kg/ ^cm2 ,
Tablets were compressed at 30 rpm. <Results> The characteristic values of the tablets obtained in the usage example tests are as follows, and they conformed to the Japanese Pharmacopoeia tablet standards (Table). <Usage example: Abuse test for formulations containing active ingredients> Use example: Tablets of formulation 2 packaged in 7μ thick polycello are subjected to abuse at 40°C for 3 months. <Results> Shown in the table. There seems to be little change in the active ingredient content.

【table】

[Table] X-ray diffraction method: X-ray diffraction device (RAD manufactured by Rigaku Denki)
-20A type), Target: Cu, 30KV-
Measured at 20mA. I ratio: I ₁ /I ₀ However, I ₀ is the intensity with a d value of 5.33, and I ₁ is the intensity with a d value of 5.15.
Also, the - mark indicates that the I ratio does not exist. As is clear from the table, the bulk specific volume of the products obtained in the examples of the present invention was low at 1.89 to 2.36 ml/g, and the angle of repose was good at 32 to 38 degrees, and the hygroscopicity was also low. Ta. 1000 to 3000 products obtained in each example of the present invention.
When molding was performed at a tableting pressure of Kg/ ^cm2 , the hardness increased as the tableting pressure increased, but the capping and cracking phenomena that occur when tablet molding performance was poor were not observed (Table), and the Monsanto hardness was increased to 5. The initial fast disintegration time and hardness of the prototype product adjusted to ~8Kg remained unchanged even under heating or abuse conditions under heating and humidification, and the Monsanto hardness was adjusted to 13 to 17Kg. This tendency remains the same even when the product is formulated into a formulation (Tables 1 and 2). Furthermore, when the products obtained in each example of the present invention are formulated with active agents such as antacids, vitamins, or analgesics (see table) and directly compressed into tablets, they meet the tablet disintegration test of the Japanese Pharmacopoeia. A preparation with rapid disintegration properties was obtained, and a preparation (table) with good flowability and small variation in preparation weight was obtained without unfavorable decreases in preparation such as capping. C. Effects of the Invention Data on fluidity, disintegration, and moldability of the product obtained by the present invention, as well as direct data on the powder obtained by blending the product obtained by the present invention with the active ingredient/antacid. The disintegration and moldability data regarding the percussion product have been described above. In short, commercially available D-mannitol powder has poor moldability, but when adding the requirements of the amount of starch hydrolyzate with a DE value of 5 or less, the state of dissolution of D-mannitol and starch hydrolyzate, and the spray drying conditions. , D-mannitol/starch hydrolyzate composite powder particles with moldability as excipients for direct injection were obtained, and the resulting granule shapes ranged from fine granules to fine granules, and also had moldability. The fluidity, disintegration, and moldability properties of the formulation obtained from the present invention are favorable for formulation preparation, even when the product of the present invention, for example, ascorbic acid, is used in actual use. , the above characteristics did not change at all, and the results of the abuse test also gave favorable results (Table). Therefore,
The excipient made of D-mannitol/starch hydrolyzate composite powder does not affect the properties of D-mannitol in any way, and can be used as a direct injection excipient with good flowability, disintegration, and moldability. It is useful and has a great effect on the formulation process.

[Brief explanation of the drawing]

FIG. 1 is a scanning electron micrograph of Example 2 of the present invention. They are fine grains with some hollow spheres. FIG. 2 is a scanning electron micrograph of Reference Example 1. Forms columnar crystals. or,
A note was added to indicate the particle size.

Claims (1)

[Scope of Claims] 1. A method for producing an excipient for direct injection, which comprises spray-drying D-mannitol and a starch hydrolyzate having a DE value of 5 or less. 2. The method for producing an excipient for direct injection according to claim 1, which uses an aqueous solution or slurry of D-mannitol. 3. The method for producing an excipient for direct injection according to claim 1, which uses an aqueous solution of starch hydrolyzate having a DE value of 5 or less. 4. The method for producing an excipient for direct injection according to claim 1, using 99.8 to 75 parts by weight of D-mannitol and 0.2 to 25 parts by weight of a starch hydrolyzate having a DE value of 5 or less. 5. The method for producing an excipient for direct compression according to claim 1, wherein the spray drying is carried out at an exhaust heat temperature of 110 to 150°C.