JPS6097919A - Preparation of excipient for compression molding - Google Patents

Abstract

PURPOSE:To obtain the titled physiologically harmless excipient inexpensively and easily, by dispersing cellulose powder and hydroxypropyl starch powder in a specific ratio into water, subjecting the dispersion to spray drying. CONSTITUTION:Cellulose powder (powder pulp crushed in such a way that 90wt% of it paasses through 250 meshes sieve or crushed finer than it) and hydroxypropyl starch powder (hydroxypropoxyl group content in propylene glycol ether of starch is 1-8wt%) in a weight ratio of (9:1)-(4:6) are dispersed into water. In the operation, solid content of the dispersion is preferably 10-30wt%. The dispersion is subjected to spray drying by a machine of a type to use a dispersion plate rotating at high speed, to give an excipient for compression molding which is chemically inert, has improved flow properties as powder, high hardness, and improved collapse properties, without requiring special skill.

Description

[Detailed description of the invention] The present invention relates to a method for producing an excipient for compression molding.

Conventionally, when compression molding powders or granules, if the material to be molded is too small to mold, or if the material to be molded is difficult to compression mold, inert materials with excellent moldability are used. A method of compression molding after mixing with a substance is often used, and such inert substances with excellent moldability are called excipients.

Such measures are commonly used in the case of pharmaceuticals, veterinary drugs, agricultural chemicals, foods, cosmetics, or other chemical products.
Lactose, microcrystalline cellulose powder, calcium hydrogen phosphate, etc. are widely used as excipients.

However, each of these substances has the following drawbacks. In other words, lactose has the advantage of being inexpensive, chemically inert, and highly hard compression molded products, but on the other hand, especially in the case of pharmaceuticals, veterinary drugs, agricultural chemicals, etc., lactose is relatively stable in water or in the gastrointestinal tract. It is necessary that the molded product disintegrates within a short period of time, but the molded product using lactose as an excipient
It hardly collapses or it takes a very long time,
It is often not practical.

In order to overcome these difficulties, it is common practice to mix so-called disintegrants such as starch, calcium carboxymethylcellulose, and low-substituted hydroxyglobil methylcellulose in appropriate proportions. However, in this case, depending on the moldability of the material to be compression molded and the mixing ratio with the disintegrant, which disintegrant and in what proportion to use cannot be determined without the intuition and preliminary experiments of an experienced person. This is accompanied by significant industrial inconvenience. Furthermore, microcrystalline cellulose powder is excellent as an excipient because it is chemically inert and can produce molded products with relatively high hardness and good disintegration, but it has poor fluidity and is therefore not suitable for molding. It is not smooth when filling the mold, is extremely difficult to handle, and is expensive, which is an unavoidable industrial inconvenience. Calcium hydrogen phosphate also provides molded products with high hardness, but since it is an ionic substance, it cannot be said to be chemically inert, its range of use is limited, and its disintegrability is poor, resulting in great industrial inconvenience. I'm being forced to.

An object of the present invention is to provide a method for producing an excipient that overcomes all of the above-mentioned difficulties.

That is, an excipient that is chemically inert, highly fluid as a powder, allows moldings with high hardness and excellent disintegration to be obtained without requiring special skill, and is physiologically harmless. The objective is to provide a method for manufacturing at low cost.

The key point of the method of the present invention is to prepare a dispersion in which cellulose powder and hydroxypropyl starch powder are dispersed in water so that the weight ratio thereof is within the range of 9=1 to 4:6.
It is simply spray drying and can be carried out industrially very easily.

The hydroxypropyl starch used in the present invention is used as a filler for forming pharmaceutical tablets, and is known to have a relatively high disintegration property, but it has poor binding strength and is not suitable for the purpose of the present invention. It does not have satisfactory properties as a drug. In addition, it is known that when cellulose powder is mixed and used during molding, it has excellent binding properties, resulting in a product with relatively high strength. It is used as an excipient in some cases. However, cellulose powder completely lacks fluidity as a powder, and there are extremely serious difficulties in mixing it with other powders and filling it into molds, so it does not meet the purpose of the present invention. It is also well known that A simple mixture of the above-mentioned hydroxypropyl starch and cellulose powder exhibits the advantages of each, but at the same time, the disadvantages of each are exhibited as they are, and the fluidity of the powder is extremely poor, making it completely unpractical. All I got was something I couldn't stand.

However, by processing according to the method of the present invention, hydroxypropyl starch and cellulose powder become a composite material, the excellent properties of both are exhibited, and molded products with high strength and high disintegration can be obtained. Moreover, surprisingly, the spray-dried powder has extremely high fluidity and can be filled into molds very smoothly, making it an excipient that can withstand high-speed tableting machines. , was discovered through research by the present inventor.

The hydroxypropyl starch that can be used in the present invention is propylene glycol ether of starch, and any hydroxypropyl starch containing hydroxypropoxyl groups in the range of 1 to 8% by weight can be used. If it is more than 8 inches, it will gelatinize at around room temperature and will not meet the purpose of the present invention. The cellulose powder that can be used in the present invention is a commercially available cellulose powder of 2.
Powdered pulp that has been ground to pass 50 meshes or less may be freely used.

So-called microcrystalline cellulose powder can also be used, but it is disadvantageous in terms of cost.

To carry out the method of the invention, it is first necessary to disperse the aforementioned hydroxypropyl starch powder and cellulose powder in water. These powders may be added to water in any order and may be added at the same time. Alternatively, both dispersions may be mixed after being individually dispersed in water.

It is also possible to first prepare a concentrated dispersion of these powders and then dilute it by draining the water accordingly. The solid content concentration of the dispersion is not particularly limited as long as the dispersion can be smoothly sent to the spray dryer, but a range of 10 to 3 degrees is usually appropriate. Further, as the device used for dispersion, a commonly known device such as a paddle-type or turbine-type high-speed pulverizer is used.

There is no particular need for heating when preparing the dispersion.

Rather, it is necessary to maintain the temperature below the gelatinization temperature of the hydroxypropyl starch powder used. The gelatinization temperature of hydroxypropyl starch varies somewhat depending on the content of hydroxypropyl groups (for the hydroxypropyl starch used in the present invention, it is around 50°C, so it is at least 30°C).
It is necessary to ensure that the temperature does not exceed ℃.

It is desirable to constantly stir the dispersion obtained as described above so that the powdery solid content does not settle. 48
If left undisturbed for more than an hour, the settled powder layer exhibits strong dilatancy, and if you try to stir it suddenly, it will show very strong resistance and require a large amount of power.In fact, it is better to stir slowly for smooth re-use. Can be dispersed.

The dispersion is then spray-dried, and a spray dryer that uses a spray nozzle or a spray dryer that uses a rapidly rotating dispersion plate can be used, but the latter has a higher solids concentration. Dispersions with a high .

There is no particular restriction on the temperature of the drying air, and there is no problem at all even if the temperature at the inlet of the dryer is raised to about 300°C. It is a well-known method established in spray drying operations to adjust the amount and temperature of drying air to the amount of water in the dispersion so that the outlet temperature is necessarily low in order to save thermal energy and reduce manufacturing costs. The temperature of the outlet air is generally kept within a range of about 40° C.±5° C., and this is also adopted in the method VC of the present invention. Rather, what should be limited is the negative impact on quality caused by the outlet temperature being too high.Although it is usually very rare, if it exceeds 1001, problems such as coloring will occur, so it must be avoided. No.

As mentioned above, by the method of the present invention, an excipient that has extremely high fluidity as a powder and provides compression molded products with excellent hardness and disintegrability can be easily obtained industrially.

Another method of the present invention is to alleviate the dilatancy of the above-mentioned dispersion liquid, or to go further and impart thixotropy to facilitate stirring and stabilize the dispersion, without having a positive effect on the product. Another method uses an aqueous solution of starch or hydroxypropyl starch instead of water. In this method as well, the subsequent spray drying step may be completely the same as described above.

It is well known that protective colloids are generally added to systems having dilatancy to reduce dilatancy or impart thixotropy. In the case of the present invention, since water is used as a medium, it is generally effective for most water-bathable polymeric substances, but research by the present inventor has shown that good results can only be obtained with starch or hydroxystarch. The completely unexpected fact was discovered that polyvinyl alcohol and water-bathable cellulose rust conductors used in this invention improve the dilatancy of the dispersion system, but only result in compression-molded products with extremely low hardness. Polyvinyl alcohol and water bath cellulose derivatives are both substances used as binders for molding, and the reason why compression molded products with low hardness can be obtained when water bath liquids of these substances are used as dispersion media is unknown. I don't know for sure, but it's probably because the film strength of these polymeric substances is too strong, which imparts toughness to the particles obtained by spray drying, and a sweeping force acts on them during compression molding. It is imagined. On the other hand, starch and its derivatives, which are extremely weak remaining in the film, do not exert such repulsive force, so it is thought that this does not prevent molded products with high hardness from being obtained. The starch to be used may be any starch such as corn starch, potato starch, or Japanese starch, and hydroxypropyl starch may be used.
The same hydroxypropyl starch as mentioned above, ie, a hydroxypropyl starch having a content of hydroxypropoxyl groups in the range of 1% to 25% by weight, can be optionally used. The amount used is suitably in the range of 0.5% or more and 5% or less by weight based on the water used as a dispersion medium. This is because if the concentration is less than 0.5%, it lacks the ability to change dilatancy to thixotropic, and the purpose is not achieved.If the concentration is more than 5%, the dispersion changes sufficiently to be thixotropic, but the viscosity of the liquid decreases. This is because the liquid becomes extremely expensive, requires excessive power for stirring and pumping, makes it difficult to subdivide the liquid in the jet dryer, and increases the resistance to the type of machine, resulting in losses. Starch or hydroxypropyl starch can be easily converted into water by adding these substances to water and stirring and heating to a temperature higher than gelatinization temperature, as is known in the art.

In order to completely disperse the cellulose and hydroxypropyl starch powder in the starch or hydroxypropyl starch water bath solution obtained in this way, it can be carried out in the same manner as the above-mentioned dispersion in only water.

The resulting dispersion can be spray-dried in the same manner as the above-mentioned dispersion dispersed only in water. Of course, the precipitation of the starch or hydroxystarch powder in the dispersion is much slower than in the case of dispersion in water only, and there is no dilatancy, so it has the advantage that it can be prevented by very gentle stirring.

The mixture of cellulose and hydroxypropyl starch obtained in this way has the excellent properties of both, as mentioned above, and has completely improved the remarkable drawback of lacking fluidity as a powder. It has extremely high fluidity and is very useful as an excipient for compression molding.

Next, the present invention will be further explained by examples.

Example 1 Hydroxypropyl starch powder (commercially available from Freund Sangyo Co., Ltd., HPS-10) with a hydroxypropoxy group content of 2°98% by weight and a drying loss of 13.8%
15.5 powder and commercially available cellulose powder (manufactured by Sanyo Kokusaku Pulp Co., Ltd.).

KC70TSKUW-300 average particle size 45 microns)5.
5 Kf was added little by little into 28.5 q of water with vigorous stirring to obtain a dispersion with a solid content of 25.2%.

The resulting dispersion was then spray dried to obtain a white powder. The conditions for the rotating plate spray drying were as shown in Table 1.

Table 1 (Note: Loss on drying of the product was 4.0 inches) The powder obtained in this example had very good flowability. As a guideline, the raw materials hydroxypropyl starch and cellulose powder, the product of the present invention obtained in this example, and the hydroxypropyl starch and cellulose powder in the same ratio as in this example, but simply mechanically mixed. The angle of repose was measured using a three-wheeled angle of repose measuring machine. The results are in Table 2
He was a knowledgeable person.

15-Table 2 These were then compression molded using a rotary tablet press, and the results shown in Table 3 below were obtained.

Table 3 Note 1 Hardness: Measured using a Schleinger hardness meter.

The products of the present invention had extremely excellent performance in all respects.

Example 2 0.5 Kp of hydroxypropyl starch having a content of hydroxypropoxyl groups of 2.98 inches by weight and a loss on drying of 13.8 inches was dissolved in 24.5 Kt of water, and while stirring, 85 The temperature was raised to ~90°C and maintained for 516 minutes to dissolve. Add an additional 25Kf of drained water, cool to room temperature, and add 0.8 hydroxypropyl starch.
A 7% solution of 49.5 K was obtained. This liquid 11.52Kg
The content of hydroxypropoxyl groups in it was 2.98 Kf by weight, and after drying -Ji 13.8%, hydroxypropyl starch (manufactured by 8 Starch Chemical Co., Ltd.) was 2.24 Kf.
and an average particle size of 45 microns.

Powder pulp with a drying loss of 5.0 cm (KC manufactured by Sanyo Kokusaku Pulp)
) o9 W-300) 2.24Kf to 7Jl], t
Tekakenshi, solid content 26.0% dispersion 16.0~
I got it. This dispersion was then spray-dried under the conditions shown in Table 4.

Cloth 4 The powder obtained in this example had extremely good fluidity, and the angle of repose measured with a three-wheeled angle of repose measuring device was extremely small at 33°. Next, this was used alone or mixed with lactose powder and compression molded using a rotary type continuous automatic tabletting machine, resulting in the results shown in Table 5 below.

Clothing 5 This product showed extremely good performance both when used alone and when mixed with lactose. In particular, it disintegrates very quickly even in a mixture with disintegrating papillae, and can be used as a disintegrating agent satisfactorily.

Comparative Example 0.8 of hydroxypropyl starch used in Example 2
A 0.03% hydroxypropyl cellulose water bath solution was used instead of the 7% water bath solution, and all other conditions were the same as in Example 2 to obtain a powder product. The angle of repose t/i measured by the three-ringed angle of repose measuring device was 37°, and the fluidity was extremely good.When this was molded using a rotary tablet press as in the previous example, the hardness was 1.2 Kg. It was found that the strength was extremely poor.

Example 3 The same 0.80% water bath solution of hydroxypropyl starch used in Example 2 (12.52 Kf'fr) was used, and hydroxypropyl starch (content of hydroxypropoxyl groups 5.88%, loss on drying 11.5 Kf'fr) was used. 51) 1.3
41'v and cellulose powder (average particle size 60 microns,
KC-Flock W-250° Dry Area II 3.8%) 3
．． 14Kf was dispersed and spray-dried under the conditions shown in Table 6 below.

Table 6 When the obtained powder alone and the powder mixed with lactose at a ratio of 1=1 were compression molded using a rotary double tablet press, the molding was extremely smooth, and the results shown in Table 7 below were obtained. .

Table 7 Example 4 A 0.82% cornstarch water bath solution was prepared and 12.
Hydroxypropyl starch (hydroxypropoxy group content 4.63%, loss on drying 12°4%) 0
．． 71Kg and powder pulp (average particle size 45 microns, KC
-Flock W-300° dry area i 4.2ch) 2.82
Kf was dispersed and spray-dried under the conditions shown in Table 8.

Table 8 The obtained powder is extremely fluid and has a three-wheeled angle of repose F.
'i45°. When this powder was compression molded using a rotary tablet machine, it was molded very smoothly, and a measurement value of 10 was obtained as shown in the following table (Coating 9).

23- Table 9 Agent: Patent Attorney Masao Hori 24- Procedural amendment (voluntary) Showa 5g, July 21st /、Indication of incident Gu? -ノ0 bitterness/ Patent application filed on July/day, Showa rr. 2 Name of the invention Method for producing excipients for compression molding 3 Person making the amendment Relationship to the incident: Patent applicant Takadanobaba λ-/Hiro-2, Shinjuku-ku, Tokyo Freund Industry Co., Ltd. Hiro Agent〒ltg. j List of items to be corrected t Contents of correction (1) Amend the claims as per the attached sheet.

(2) ``High hardness and'' in line g of page 1 of the specification is amended to ``1 high hardness and''.

(3) “Hydroxypropoxyl group” on page 1 of the same page
Correct it to "hydroxypropoxyl group".

(4) "300℃" on page g/line I/- of the same page
℃”.

(5) [Hydroxy starch] on page 10, line j is
``Hydroxypropyl starch''.

(6) Correct the phrase "in dilatancy" on line 73 of page 2 to "1 dilatancy".

(7) If, /4' 1-hydroxypropoxy group in line aλ is corrected to ``hydroxypropoxyl group''.

(8) Correct the average particle diameter of "Vj microns" in the same No. ≠ page 7 to line g to "0% or more passes through 300 meshes".

(9) Correct the "dispersion liquid supply amount" in the λth line of page 1!5 (top row of the left column of Table 1) to 1 dispersion liquid supply rate.

Shout Correct “hydroxy” in the 3rd line of the same page/S page to “hydroxy” 01) Change the line after “was obtained.” in the 70th to // lines of the same page 16 Add text.

[Note that if the angle of repose measured by this method is less than pt', the powder has very good fluidity, and II! °−jt!
If it is less than °, the powder will be difficult to flow, and
If it is less than 75', there is almost no fluidity, and if it is 75' or more, it is judged that there is no fluidity at all. ” G2 “Schleuniger hardness tester” in the note/ below Table 3 on page 17 of the same page is corrected to “Schleuniger hardness tester”.

(11 Same page 1, page t to line 7, ``(8 Starch Chemical 1! RiJ)
/) Correct as J.

G4) Correct the "dispersion liquid supply amount" of the 199th weight item (top left column of the table) to "1 dispersion liquid supply rate".

G61 Change "micron passage" in the note below table j on page 20 of the same to "
It is corrected as ``passes through a micron sieve.''

t661 "Average particle size to
micron.

KO-flock w-2so, J to 1 KO-flock W-, 23090+ passed O mesh on 2 nights.
and correct it.

(1?) 1 of the same number, 222nd grade (top row of left column of Table 6)
The "dispersion liquid supply amount" is corrected to "1 dispersion liquid supply rate".

(To) "Hydroxypropoxy group" on page 23, line 1 is corrected to "hydroxypropoxyl group."

01 Same page, line 73, "KO-fook W-300, J" is "KC flock, W-300, made by Dezumi Kokusaku Pulp."
and correct it.

(a) Correct "Dispersion liquid supply amount" in the second line of the second page to "Dispersion liquid supply rate".

Claim 1: A compressed member characterized by dispersing cellulose powder and hydroxypropyl starch powder in water such that the weight ratio falls within the range of 1 to t:t, and then spray-drying this dispersion. Method for producing excipients for use.

2 0.0 of starch or hydroxypropyl starch.
/ to 5% by weight aqueous solution of cellulose powder and thydroxybrobyl starch powder at a weight ratio of / to 1'
1. A method for producing an excipient for compression molding, which comprises dispersing the excipient so as to fall within the range B, and then spray-drying the dispersion.

Procedural amendment 4! - (Method) Showa era - month, 7th Commissioner of the Patent Office t Incident display Showa SR special 'ff face No. 20337/No. 2 Name of invention Method for producing excipients for compression molding 3. Person who makes corrections Relationship to the incident: Patent applicant 2-IQ-2 Takadanobaba, Shinjuku-ku, Tokyo Freund Industry Co., Ltd. Hiro Agent〒16μ Date of amendment order Akio's cousin! January 3rd, 2019 (Shipping date) l Target of correction Specification attached to the application form (dated July 7, 1927).

7 Contents of amendment As shown in the attached sheet. Specification - M (no change in content).

Claims (1)

[Claims] i. Cellulose powder and hydroxypropyl starch powder are dispersed in water so that the weight ratio thereof is in the range of 9:1 to 4:6, and then the dispersion is mixed with I! A method for producing an excipient for compression molding, which comprises drying with JtS. 2 0.1 to 5% by weight of hydroxyglobil starch
A compression molding filler characterized by dispersing cellulose powder and hydroxypropyl starch powder in an aqueous solution so that the weight ratio thereof falls within a range of 9:1 to 4:6, and then spray-drying this dispersion. Method for manufacturing excipients.