JPS5874604A - Production of novel type of tablet containing ifenprodyl - Google Patents

Abstract

PURPOSE:Granules made from lactose and hydroxypropylcellulose, powdery ifenprodyl tartarate and a powdery diluting agent are mixed without a disintegrator and tabletted to produce the titled tablets with a small size that can be taken with ease in high quality and high stability. CONSTITUTION:Granules made from lactose and hydroxypropylcellulose, powdery ifenprodyl tartarate and a powdery diluting agent are mixed without a disintegrator to prepare a tabletting composition and the resultant composition is tabletted. As the diluting agent, is used 5-20wt% of crystalline cellulose based on the composition. As a lubricant, is used 0.5-2wt% of magnesium stearate based on the composition. Since a disintegrator is not used, there occurs no deterioration in hardness, weariness and moldability. Troubles can be avoided in deterioration of tablet characteristics and on tabletting operation, because the composition contains a small amount of a binder.

Description

Detailed Description of the Invention The present invention provides ifenprodil tartrate (ifenprodil tartrate) as a pharmaceutically active ingredient.
1-(4-Hydroxyphenyl)-2-(4-penzylbiyridino)'-1-propatur tartrate]. Ifenprodil tartrate is a useful substance used as a medicine because it has vasodilatory effects, etc. However, its physicochemical properties include that it is an amine derivative, that it is a crystalline powder, and its particles are extremely free-flowing. Under normal conditions, it always exists in a water-containing state, and even if it is forced to be anhydrous,
When placed indoors, etc., it has various properties that pose problems in terms of formulation, such as the fact that it absorbs moisture extremely quickly. However, due to these characteristics, it is technically difficult to produce tablets of excellent quality.

The present invention provides a method for producing tablets containing ifenprodil tartrate as a pharmaceutically active ingredient and exhibiting excellent properties as a product by a simple means.

The present inventors have studied the physicochemical properties of iaenprodil tartrate, and as a result of intensive research into a method for producing tablets with excellent quality characteristics, it was surprisingly found that iaenprodil tartrate itself It has been found that certain tableting compositions can be prepared without the use of disintegrants, resulting in tablets with excellent properties. The present invention has been made based on this knowledge.

That is, the present invention mixes granules produced from lactose and hydroxypropylcellulose, ifeciprodil tartrate in powder form, and excipients in powder form without adding a disintegrant. The present invention provides a method for producing fresh tablets containing iaenprodil tartrate, which comprises preparing a composition for tableting and tableting the composition.

The first feature of the method of the present invention is that it does not use a disintegrant, which is generally essential for this type of tablet. The present inventors have surprisingly found that iaenprodil tartrate itself has a tablet disintegrating effect. This fact was confirmed by tablet disintegration experiments. The advantage of not using a disintegrant in the tablet manufacturing method of the present invention is not only the economical advantage of not requiring a disintegrant, but also the ability to prevent deterioration of various tablet properties, especially hardness, friability, and moldability. This brings about many advantages, such as being able to avoid this problem and requiring only a small amount of binder. The fact that the amount of binder used is small is one of the advantages of avoiding the deterioration of tablet properties due to the use of a large amount and the occurrence of troubles during tableting operations.

The second feature of the method of the present invention is that the tablet composition is prepared by simply mixing the pharmaceutically active ingredient iaenzolodil tartrate and the excipient in their respective powder states without forming them into granules. be. Iaenprodil tartrate has the characteristic of extremely poor free-flowing properties, so it is not made into granules, but is made into a tableting composition in powder form, thereby producing tablets with excellent tablet properties. It's amazing that it's possible. Generally, when the active ingredient or substance of a drug to be made into a tablet form has poor free-flowing properties, a wet granulation method is used together with excipients to prepare these granules. However, in the case of iaenprodil tartrate, it is produced by wet granulation with excipients such as lactose and starches.
When tablets are manufactured, the products are inferior in hardness and friability, and the quality of the tablets is significantly reduced.

According to the method for producing tablets containing iaenprodil tartrate of the present invention, tablets with stable and excellent quality characteristics with little variation are always obtained. Moreover, according to the method of the present invention, no disintegrant is used in the formulation of the composition for tabletting, and therefore,
Since the amount of binder used is also small, the total amount of the formulation is small, making it possible to provide small tablets that are easy to take clinically.

Furthermore, in the present invention, both iaenzolodil tartrate and excipients are used as a tableting composition in a powdered state without being made into granules.2) They have excellent quality characteristics and are stable. This method not only provides the advantage of being able to obtain tablets with excellent properties, but also provides an excellent advantage in terms of work efficiency since the tablet manufacturing method itself requires complicated steps such as wet granulation. It will be done.

Granules produced from lactose and hydroxypropyl cellulose used in the method of the present invention may include those in which the ratio of pre-cooked and latter is 75 to 98 parts by weight to 2 to 25 parts by weight; The proportion of the whole composition for tableting is usually 60 to 90% by weight, preferably 70 to 80% by weight.
% parts by weight. For the production of this granule component, commonly used granulation methods can be applied. Specifically, lactose and hydroxypropyl cellulose are kneaded with water or an organic solvent such as ethanol or methanol, or a mixed solvent thereof, and extruded into granules by extrusion through a wire mesh or punching tar, or by scattering in a granulator. The granules can be granulated by a fluidized bed granulation method in which a hydroxypropyl cellulose solution prepared by dissolving the lactose powder in water, an organic solvent such as ethanol or methanol, or a mixed solvent thereof is sprayed onto the lactose powder. The granules thus obtained are
Use as is or after sieving and grading. Examples of the excipient include lactose, crystalline cellulose, and starches such as corn starch and potato starch, and the proportion used is preferably in the range of 5 to 20% by weight. Examples of lubricants include magnesium stearate, talc, etc., which can preferably be used in an amount of 0.5 to 2 parts by weight.

In the present invention, the method for tabletting the tablet composition is as follows:
A high-speed tableting method using a commonly used tableting machine, such as a rotary tablet machine or an eccentric tablet machine, is preferred.

High-speed tableting methods using rotary tablet machines are particularly preferred in terms of obtaining homogeneous tablets. (Then, a powder component consisting of inenprodil tartrate and an excipient and a granule component consisting of lactose and hydroxypropylcellulose are mixed, a commonly used lubricant is added thereto, and the mixture is run in a tablet machine. Tablets can be easily produced by the following method.The tablets obtained can be made into film-coated tablets or sugar-coated tablets by a commonly used method.

Examples of coating agents used for film coating include hydroxypropyl methyl cellulose, ethyl cellulose, titanium oxide, and macrogol 40.
Examples of polishing and polishing agents include carnauba wax and the like. In addition, examples of sugar coating bases used in sugar coating include sucrose, and examples of binders include:
Gum arabic, gelatin, polyvinylpyrrolidone, etc.
Examples of dispersing agents include talc, starch, calcium sulfate, white sugar, etc., and examples of suspending agents include precipitated calcium carbonate,
Examples of talc, starch, white sugar, and coloring agents include various food colors and lake colors, and examples of polishing agents include beeswax, rough-in, carnauba wax, and the like. Examples of the coating method include a pan coating method and a fluid coating method.

First, the method of the present invention has the advantage that it does not use a disintegrant, so it does not cause unfavorable effects that the use of a disintegrant usually has on tablet properties, especially deterioration in hardness, friability, moldability, etc. In addition, disintegrants usually have the effect of inhibiting the binding force of binders, so when a disintegrant is added to a tableting composition, a large amount of When a binder is added, it has the effect of avoiding the deterioration of tablet properties due to the use of a large amount of such a binder and the occurrence of troubles during tabletting operations, so its advantages are significant. big.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 Using a fluidized bed spray granulator (model WSG-5 manufactured by Okawara Seisakusho), lactose 44759 was charged, and while the lactose was being scattered, 25
6? A 1% aqueous solution of hydroxypropylcellulose 1[] was sprayed. The obtained granules were sieved and sized using a sieve (24 mesh).

This 4396PK ifenprodil tartrate 2802 crystalline cellulose (trade name, Avicel) 924r and magnesium stearate 569 were added and mixed uniformly to produce a tableting composition. This composition was compressed using a high-speed rotary tabletting machine (Model RT-822-H-1 manufactured by Kikusui Seisakusho) to obtain tablets weighing 202 mg.

Example 2 Fluidized bed spray granulation device (WS G-s type manufactured by Okawara Seisakusho)
Using lactose 4131F, under the scattering of lactose, K, 4
A 10% water-ethanol (70% Engineering II/L) solution of 59F hydroxypropylcellulose was sprayed. The obtained granules were sieved and sized using a sieve (24 mesh). Ifenprodil tartrate 240 is added to this 3672t.
t, crystalline cellulose (trade name Avicel) 7209, and magnesium stearate 489 were added and mixed uniformly to produce a tableting composition. This composition was compressed into tablets in the same manner as in Example 1 to obtain tablets weighing 19519 per tablet.

Examples 3 to 8 In the same manner as in Example 1, tablet compositions were prepared according to the following formulations, and tablets were manufactured.

Example 3 Prescription (per tablet) Ifenprodil tartrate 1011? Lactose 172 g Hydroxypropyl cellulose 7 layers g Crystalline cellulose (trade name Avicel) 11Q02Q Example 4 Prescription (per 1 tablet) Ifenprodil tartrate 1019 Lactose
1441I9 Hydroxypropyl cellulose. -su 81g crystalline cellulose (
Product name Avicel) 12Q corn starch
25 layers 9021g Example 5 Prescription (per tablet) Ifenprodil tartrate 1511! ? milk
Sugar 1501 Ig Hydroxypropyl cellulose 7 layers g Crystalline cellulose (trade name Avicel) 28119 Magnesium stearate 2 liters 9202 g Example 6 Prescription (per tablet) Ifenprodil tartrate 20 Ig Lactose Sugar 139 ■ Hydroxypropyl cellulose 7 '119 Crystalline cellulose (
Brand name: Avicel) 30Q Magnesium stearate 4ay00mg Example 7 Prescription (per 1 tablet) Ifenfutidyl tartrate 20g Lactose
133 servings 9 Hydroxypropyl cellulose 5119 Corn starch 40g 1g Magnesium stearate
41g202g Example 8 Prescription (per tablet) Ifenprodil tartrate 30mg Lactose
176g hydroxypropyl cellulose 9g potato starch
301g magnesium stearate
5m+? 250 g Example 9 'A tablet composition was prepared in the same manner as in Example 2 according to the following formulation, and tablets were manufactured.

Prescription (per tablet) Ifenprodil tartrate 10Q lactose
132% Hydroxypropyl cellulose 15mg Corn starch 40■ Talc
5Q 02my Example 10 25,000 tablets obtained by the method of Example 1 were mixed with hydroxymethyl cellulose 142. ! M, cellulose 42. !
M, titanium oxide 52, macrogol 400; 202,
Using a suspension of methylene chloride 920d-ethanol 1080ml containing magnesium aluminum metasilicate Z5V and silicone resin 6.5%, a coating machine [FM-2 model manufactured by Freund Sangyo ■]k was used for one coat. After coating until the weight becomes 210.961jJF, polish it with carnauba wax and make one tablet 21
1. Film-coated tablets weighing 0 g were obtained.

Example 11 A tableting composition was prepared in the same manner as in Example 1, and the composition was processed using a high-speed rotary tabletting machine (RT-822-H manufactured by Kikusui Manufacturing Co., Ltd.).
Type 1 voice was pressed into tablets. The 12,000 tablets obtained were coated with the following sugar-coating recipe using a coating machine [FM made by Freund Sangyo Co., Ltd.].
-2 type] to make sugar-coated tablets.

Prescription (per tablet) Refined white sugar 1174 g Gelatin! 1.5
mg tarri 62
Q Titanium oxide Gen. 156 9 Gum arabic powder 3.5 liters 9 Carnauba wax
The following table lists the results of tests conducted to examine the quality characteristics of the tablets obtained in these Examples. The hardness was measured using a Monsanto hardness tester according to a conventional method, and the disintegration property was measured by the Ninth Edition Nippon Yaku.

table

Claims (1)

[Claims] 1) Lactose! : Granules produced from hydroxyprobyl cellulose toca, ifenprodil tartrate in a powdered state, and excipients in a powdered state are mixed without adding a disintegrant to prepare a χ tablet composition, A novel method for producing ifenprodil tartrate-containing tablets, which comprises compressing the composition into tablets. 2) Claim 1, wherein the excipient is crystalline cellulose in a proportion of 5 to 20 parts by weight based on the tableting composition.
Method for manufacturing the tablets described in Section 1. 3) When compressing the composition into tablets, magnesium stearate is used as a lubricant in an amount of 0.5 to 2 parts by weight based on the tablet composition. Method for manufacturing the tablets described.