JPS6185331A - Production of excipient for direct tableting - Google Patents

Abstract

PURPOSE:To obtain an excipient for direct tableting, having improved moldability, by spray-drying an aqueous solution or slurry of D-mannitol and starch hydrolyzate in a specific temperature range. CONSTITUTION:99.8-75pts.wt. D-mannitol and 0.2-25pts.wt. starch hydrolyzate are spray-dried at 110-150 deg.C exhaust heat temperature to give an excipient for direct tableting. If the aqueous solution or slurry of D-mannitol and the starch hydrolyzate has <=5 DE value [quality indication of starch sugar shows direct reducing sugar (as glucose)/total solid contentX100] are used, and the spray drying are carried out under the condition, the excipient for direct tableting having improved fluidity, disintegration properties, and moldability can be prepared without losing improved characteristics of D-mannitol. The excipient has d value at 5.33Angstrom and 5.15Angstrom in X-ray diffractionmetry as well, so correlation between moldability and the d value at 5.33A and 5.15A is ob served.

Description

DETAILED DESCRIPTION OF THE INVENTION A) Object of the Invention A] Industrial Field of Application The present invention relates to a method for producing excipients 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 starch hydrolyzate, and is useful for commercializing crude drugs for industrial pharmaceuticals and main ingredients for foods. , an excipient for direct injection consisting of a water-soluble D-mannitol firefly starch hydrolyzate composite powder that has good flowability, moldability, and disintegration without having any undesirable effect on the main drug or main material. It concerns the manufacturing method.

B] Conventional technology Commercially available D-mannitol has been widely used as a substitute sweetener in the pharmaceutical and food industries. Of course,
When used as an excipient, D-mannitol is rarely used alone; for example, to obtain compressed tablets such as troches and chewable tablets, it may be used in combination with other excipients with good compressibility. many. When trying to obtain a water-soluble preparation based on sugars, lactose etc. are mainly used [Pharmacia, 19(+2), 1268 (1983)]
In addition, in order to obtain stable preparations of herbal medicines, other additives such as binders and fillers are actually used. However, in the former case, the drug may lack stability against crude drugs due to the lactose content, and in the latter case, many of the binders and fillers are water-insoluble or poorly soluble. Therefore, there is a drawback that water-soluble preparations cannot be obtained.

C] Problems to be solved by the invention D- Mannitol's properties, such as a pleasant cool sweetness, non-hygroscopicity, high melting point, good stability, and no contraindications for combination with herbal medicines, etc. If we could obtain a water-soluble excipient for direct injection consisting of composite powder of mannitol and starch hydrolyzate, which has good fluidity, disintegration, and moldability, without causing any 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 drawback is due to the weak bonding force of commercially available D-mannitol itself, and have attempted to increase the bonding force using spray drying technology. - Mannitol powder granules were obtained [pending application].

However, in order to obtain moldable powders, it was thought to combine the combination with a selected binder and, in addition, the 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. That is, 0.2 to 10% of the binder hydroxypropylcellulose, methylcellulose, gelatin, or gum arabic was blended with D-mannitol, but the moldability of the resulting preparation was unexpectedly low. Therefore, we conducted further research to improve these improvements, and found that the desired excipient for direct injection could only be obtained by the production method described below, leading to the completion of the present invention.

(1) Structure of the invention A] Means for solving the problems In embodiments, (1) Production of a direct injection excipient characterized by spray-drying D-mannitol and a starch hydrolyzate. Law. (2) A method for producing an excipient for direct injection according to claim 1, which uses an aqueous solution or slurry of D-mannitol.

(3) A method for producing an excipient for direct compression according to claim 1, which uses an aqueous solution of starch hydrolyzate.

(4) A 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 starch hydrolyzate, (5) Spraying Claim 1 in which drying is carried out at a waste heat temperature of 110 to 150°C
Method for producing excipients for direct injection as described in Section 1.

(8) Starch hydrolyzate with a DE value of 5 or less (DE value is an indication of the quality of starch sugar and is expressed as direct reducing sugar (as glucose)/total solids x 100). The method for producing an excipient for direct injection according to claim 1 is used.

D-manni used in the present invention) -71/ Liquid extraction method from seaweed, ammonia electrolytic reduction method of glucose solution,
Japanese Pharmacopoeia, Food Additives Official Standards, USP Standards, obtained by any of the contact amount-based methods of sucrose solution;
Any D-mannitol suitable for BP standards may be used.

Starch hydrolyzate is a sugar composition consisting of oligosaccharides ranging from monosaccharides to heptasaccharides obtained by hydrolyzing raw material starch by a roasting method, an oxygenated roasting method, an acid decomposition method, or a fermentative decomposition method. , DE value of these sugar compositions (Dextrose E
Low D E (iCi starch hydrolyzate) with a quivalent) of 5 or less means that the sugar composition has few reducing end groups, so it will not have any effect on herbal medicines such as pharmaceuticals. Since there is no hygroscopicity, the hygroscopicity is low, and the protective colloidal properties are large, resulting in 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 the aqueous solution of starch hydrolyzate to obtain a final concentration of 20 to 500 to 50 parts by weight. Although prepared, 60
It may also be prepared by adding a condition of heating to ~80°C.

When obtaining D-mannitol/starch hydrolyzate composite powder, 99.8 to 75 parts by weight of D-mandole and 0.2 to 25 parts by weight of starch hydrolyzate are used, but 25 il
(;'If more than 1 part of starch hydrolyzate is used, the viscosity of the aqueous solution or slurry obtained by adjusting the temperature will start to rise suddenly, which will reduce the efficiency of the drying process and cause the wall of the dryer to Not only does this increase the number of powder grains per coat, which causes disadvantages in the process such as reducing the drying yield, but also the product obtained after drying has high hygroscopicity, and the disintegration of direct compression tablets is slow. A drawback arises.

Therefore, considering the possibility of improving drying ability, manufacturing conditions for preparation, drug quality such as disintegration and moldability, and the uniformity of the content of crude drugs and main ingredients by freely adjusting the particle size, it is possible to improve D-mannitol. Most favorable results are obtained using 99.8 to 75 parts by weight and 0.2 to 25 parts by weight of starch hydrolyzate.

When obtaining D-mannitol/starch hydrolyzate composite powder, the spray drying conditions in the drying process of the aqueous solution or slurry obtained by mixing and preparing D-mannitol and starch hydrolyzate are exhaust heat temperature 110~ 150
Can be selected from a relatively wide range of degrees Celsius. This means that there is a greater degree of freedom in the drying process, so
Coupled with the condition of the concentration of the aqueous solution or slurry liquid, it is very preferable that the particle shape obtained is from fine to fine granular powder, and even the width of the particle size distribution can be freely selected. If drying is carried out at a temperature below lIO'o 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 decline of crystals in X-ray crystallography, which will be described later. .

B1 action D-For an aqueous solution or slurry of mannitol, D
If an aqueous solution of starch hydrolyzate with an E value of 5 or less is added and spray-dried, fine particles or fine granular powder can be obtained. We made a surprising discovery by comparing the diffraction crystal plane spacing d [A] measured by X-ray diffraction between these products and the test product obtained in Reference Example [Table 2]. That is, the products obtained from the present invention have a d value, whereas D-mannitol powder, D-mannitol.
Test products with poor moldability obtained from reference examples such as starch hydrolyzate mixed powder or wet granulated powder of D-mannitol and starch hydrolyzate had a d value of only 5.33 [A]. , and D-mannitol powder 113
The test product of the reference example, which was melted to 0°C and had poor compression r&mold properties, had a d value of only 5.15 [A].

As described above, the products obtained in the examples of the present invention have good moldability, and the d values are 5.33 [A] and 5.15 [A] in the X-ray diffraction method. Despite finding a strong correlation between the presence of these drugs, we were unable to elucidate their mechanism of action here.

However, in any case, when blending the product obtained as in the example of the present invention, that is, the starch hydrolyzate, the dissolution state of D-mannitol and the starch hydrolyzate,
The spray-drying conditions act in concert, and the resulting fine-grained powder or fine particles shown in Figure 1 of the Drawings provide close packing properties and smooth propagation of compression, making the formulation undesirable. It is considered that it does not exhibit any characteristics such as capping or cracking.

C1 Example Below, examples and reference examples will be described to facilitate understanding of the present invention.

Example I D E (0.2 of starch hydrolyzate with i/i 3.2
1 portion of 25 kg of w/w% aqueous solution - Mannitol 9.
Add 95 kg, and while stirring, heat the solution to 75°C to form an aqueous solution. While maintaining this solution at a liquid temperature of 70-75°C, the heat input temperature is 221-225°C, and the exhaust heat temperature is 124-225°C.
Spray drying was performed at 130° C. using a rotating disk method to obtain 9.82 kg of fine granular powder.

Example 2 9.5 kg of 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 liquid (liquid temperature 70-75℃) is heated at a heat input temperature of 216-219℃, tJl, li8 temperature of 124-
Spray drying at 129℃ with rotating disk υ: 9.58k
g of fine granular powder was obtained.

Example 3 8.5 kg of D-mannitol was added to a 15.0% IO, Ow/w aqueous solution of starch hydrolyzate having a DE value of 1.9 and mixed uniformly. This mixed liquid (liquid temperature 20.6℃) is heated at a heat input temperature of 201 to 206℃ and an exhaust heat temperature of 120 to 126℃.
Spray drying was performed using a pressure nozzle method to obtain 9.48 kg of fine particles.

Example 4 7.5 kg of oral D-mannitol was added to 25.0 kg of an IO, Ow/w% aqueous solution of starch hydrolyzate having a DE value of 4.6 and mixed uniformly. Heat input temperature of this mixed liquid (liquid temperature 21.2℃) is 199 to 212℃, exhaust heat temperature is 12+-+23
Spray drying was performed at ℃ using a pressure nozzle method to obtain 9.81 kg of fine particles.

Reference example 1 Hidaka D-mannitol powder that passes through 100 meshes.

Reference example 2 Hidaka D-mannitol 4.25kg and DEi1ili1
．． Powder obtained by uniformly mixing 0.75 kg of starch hydrolyzate No. 9 into powder.

Reference Example 3 0.75 kg of starch hydrolyzate with a DE value of 1.9 and 0.75 kg of water.
6 kg was added to make a pasty liquid, and this was added to 4.25 kg of day-care D-mannitol and kneaded evenly. 30 minutes of this mixture
Crushed and granulated using a mesh screen, dry-smoked on a shelf, and further sieved through a 30-mesh sieve to produce 4.66 kg.
fine grains were obtained.

Reference Example 4 - Mannitol was placed in a porcelain dish, heated to about 168°C, melted, cooled, crushed, and sieved through a 30-mesh sieve.

The products obtained in Examples and Reference Examples of the present invention were subjected to physical property tests and formulation characteristic tests, and the results are shown in Tables 1 to 2.

Furthermore, Table 3 shows the results obtained by the X-ray diffraction method.

1) Accurately measure 1.000g in a Jf bottle,
Dry at 105°C for 3 hours and determine the weight loss.

2) Accurately weigh about 1.000g of the sample dried at 105°C for 3 hours and made into an anhydride.
After allowing the sample to stand still for 120 hours, the weight of the sample is measured, and the increase in weight is taken as the amount of moisture absorbed. Also, any change in appearance at this time is also observed on the same surface.

Tableting conditions: Add 1% magnesium stearin to each sample,
Static compression tableting is performed using a Brinell hardness tester (manufactured by Yonekura Seisakusho) using a mmφ parallel punch and a setting of 300 mg per tablet.

Tablet characteristics test method: 1. Tablet hardness: Measured for 20 tablets using a Monsanto hardness tester.
Find the average value.

2. Measure the thickness of 20 tablets using a micrometer,
Find 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. Heavy banding of the preparation Measurements are made for 20 tablets, and the average value is determined.

In the abuse test, the tablets of each sample were packed in 1 to 7 bags of Fulvic, and 4
0° and 40°-75XR) I conditions + and 3011 brutality ν.

Table ■ Usage Examples Prescription Table V Usage Examples Preparation Properties Test Usage Examples Sample 1 obtained in Example was mixed with crude drugs such as ascorbic acid, bicarbonate or acetylsalicylic acid, and directly compressed into tablets.

<Formulation> The powder or fine granular sample obtained in Example 2.3 or 4 was mixed with a crude drug according to the recipe in Table 1 and homogenized.

(Tableting conditions) The weight of one tablet was set to be 300n+H.HT/P
Using a 18-inch tablet press (manufactured by Hata Tekkosho), the diameter of the tablet was 9 m.
A mφR type mortar was assembled, a pressure of 2500 kg/cm 2 was applied, and tableting was performed 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 V).

<Usage example: Abuse test of active ingredient combination preparation> Use example: Tablets of formulation 2 packaged in 7μ thick polycello were subjected to abuse at 40°C for 3 months.

<result> It is shown in Table ■. There seems to be little change in the crude drug content.

Table■ Table of changes in crude drug content of usage example preparations based on abuse tests■ X-ray diffraction method X-ray diffraction method: X-ray diffraction device (RAD-201 manufactured by Rigaku Denki
A type), Target: Cu, 30KV-
Measured at 20mA.

■Ratio: 11/Ia However, IQ has a d value of 5.33, and ■1 has a d value of 5.15.
strength of. Also, the - mark indicates that the ratio ■ does not exist.

As is clear from the pyrotechnics, the bulk volume ratio of the products obtained in the examples of the present invention is as low as 1.99 to 2.3 Eiml/g;
In addition to showing a good angle of repose of 32 to 38 degrees, the hygroscopicity was also low.

1,000 to 3 of the products obtained in each example of the present invention,
When molding was performed at a tableting pressure of 000 kg/ca + 2, the hardness increased as the tableting pressure increased, but there was no carriage or cracking phenomenon that occurs when the tablet molding ability is poor (Table II). The initial rapid disintegration time and hardness of the prototype product, which was formulated with a hardness adjusted to 5 to 8 kg, remained unchanged even under heating or heating/humidification conditions, and the Monsando hardness was 13.
Even when the formulation was adjusted to ~17 kg, this tendency remained unchanged (Table 111-1 and Table 1-2).

In addition, when the products obtained in each example of the present invention are formulated with active ingredients such as antacids, vitamins, or analgesics (Table 2) and directly compressed into tablets, they meet the tablet disintegration test of the Japanese Pharmacopoeia. A preparation with fast disintegration properties can be obtained, and there is no unfavorable reduction in the preparation process such as capping, and the product has good fluidity.
Moreover, it was possible to obtain a formulation (Table V) with small variation in formulation weight.

c) Effects of the invention Data on fluidity, disintegration, and moldability of the products obtained by the present invention, and data on the products obtained by the present invention and herbal medicines.
The disintegration and moldability data for direct injection formulations of powders formulated with antacids were used as a starting point. In short, commercially available D-mannitol powder has poor moldability, but when adding the requirements of the amount of starch hydrolyzate added, the state of dissolution of D-mannitol and starch hydrolyzate, and the spray drying conditions, it is possible to form the powder for direct compression. We obtained D-mannitol/starch hydrolyzate composite powder that has moldability as a medicine, and the shape of the resulting particles not only ranges from fine granules to fine particles, but also moldability can be freely adjusted. The properties of fluidity, disintegration, and moldability of the formulation obtained from the present invention are favorable for formulation preparation, and even when the product of the present invention is actually used, for example, ascorbic acid, the above characteristics do not change in any way. Furthermore, the results of the abuse test also gave favorable results (Table V1).The excipient consisting of D-mannitol/starch hydrolyzate composite powder had the same effect on the properties of D-mannitol. It is useful as a direct injection excipient with good flowability, disintegration, and moldability, and has many effects on the formulation process.

[Brief explanation of drawings]

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. It was also used in ancient times to indicate the size of particles.

Claims (6)

[Claims] (1) A method for producing an excipient for direct injection, characterized by spray-drying D-mannitol and a starch hydrolyzate. (2) Aqueous solution or slurry of D-mannitol Claim 1 describes the use of A method for producing excipients for direct injection. (3) A method for producing an excipient for direct compression according to claim 1, which uses an aqueous solution of starch hydrolyzate. (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 starch hydrolyzate. (5) The method for producing an excipient for direct compression according to claim 1, in which spray drying is carried out at an exhaust heat temperature of 110 to 150°C. (6) DE value of starch hydrolyzate (however, The DE value is an indication of the quality of starch sugar. Direct reducing sugar (as glucose)/total (expressed as solid content x 100) is 5 or less Claim 1 that uses something Method for manufacturing the described excipient for direct injection.