JPH0136806B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides ifenprodil tartrate [1-(4-hydroxyphenyl)-2-
(4-benzylpiperidino)-1-propanol 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. However, under normal conditions, it always contains water, and even if the board is forced to be anhydrous, it will absorb moisture extremely quickly when placed indoors, etc. It has various characteristics that are of concern. However, it is technically difficult to produce tablets with excellent quality due to these characteristics. 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 ifenprodil tartrate, and have conducted intensive research on a method for producing tablets with excellent quality characteristics.
Surprisingly, ifenprodil tartrate itself has a disintegrating effect, and accordingly certain tableting compositions can be prepared without the use of disintegrants;
As a result, it has been found that tablets with excellent properties can be obtained. The present invention has been made based on this knowledge. That is, in the present invention, granules made from lactose and hydroxypropyl cellulose, ifenprodil tartrate in powder form, and excipients in powder form are mixed without adding a disintegrant. The present invention provides a novel method for producing ifenprodil tartrate-containing tablets, which comprises preparing a composition for tabletting and then tableting the composition. The first feature of the method of the present invention is that it does not use a disintegrant, which is generally necessary for this type of tablet. The present inventors have surprisingly found that ifenprodil 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 economical because no disintegrant is required, but also avoids deterioration of various tablet properties, especially hardness, friability, and moldability. This provides many advantages, such as the ability to use only a small amount of binder and the use of a small amount of binder. The fact that the amount of binder used is small makes it possible to avoid the deterioration of tablet properties due to the use of a large amount and the occurrence of troubles during tabletting operations, which is also one of the major advantages when manufacturing tablets. The second feature of the method of the present invention is that the tableting composition is prepared by simply mixing ifenprodil tartrate, which is a pharmaceutically active ingredient, and an excipient in their respective powder states without forming them into granules. That's true. Ifenprodil tartrate has the property of being extremely free-flowing, so we made it into a tableting composition in powder form without granulating it, 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 tablet form has poor free-flowing properties, a method is adopted in which granules are prepared by wet granulation together with excipients. In the case of ifenprodil tartrate, when tablets are manufactured by wet granulation with excipients such as lactose and starches, the product has poor hardness and friability, and the quality of the tablets is significantly reduced. According to the method for producing ifenprodil tartrate-containing tablets of the present invention, tablets with stable and excellent quality characteristics with little variation can always be obtained. Furthermore, according to the method of the present invention, a disintegrant is not used in the formulation of the composition for tabletting, and therefore the amount of binder used is small, so the total amount of the formulation is small. This makes it possible to provide small tablets that are clinically easy to take. Furthermore, in the present invention, both ifenprodil tartrate and the excipient are used as a tableting composition in a powdered state without being made into granules. Not only does this have the advantage of producing tablets with excellent quality, but it also provides an excellent advantage in terms of work efficiency since there is no need to perform complicated processes such as wet granulation in the tablet manufacturing method itself. It will be done. The granules produced from lactose and hydroxypropyl cellulose used in the method of the present invention have a ratio of 75 to 98% by weight of the former to 2 to 25 parts by weight.
% parts by weight, and the proportion of these granules in the entire composition for tableting is usually 60 to 90 parts by weight.
% parts by weight, preferably 70-80% parts by weight. Regarding the structure of this granule component, a commonly used granulation method 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 the mixture is extruded through a wire mesh or punched metal to form granules. 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 used as they are or after being sized by sieving. Types of excipients include lactose, crystalline cellulose, etc., and the proportion used is preferably in the range of 5 to 20% by weight. Examples of lubricants include magnesium stearate, talc, etc.
It can preferably be used in amounts of 0.5 to 2% by weight. In the present invention, the method for compressing the tableting composition into tablets is preferably a high-speed tableting method using a commonly used tabletting machine, such as a rotary tablet machine or an eccentric tablet machine. High-speed tableting methods using rotary tablet machines are particularly preferred in terms of obtaining homogeneous tablets. Thus, by mixing a powder component consisting of ifenprodil tartrate and an excipient with a granule component consisting of lactose and hydroxypropyl cellulose, adding a commonly used lubricant, and applying it to a tablet machine. Tablets can be easily manufactured.
The obtained tablets can be made into film-coated tablets or sugar-coated tablets by a commonly used method. Examples of coating agents used in film coating include hydroxypropyl cellulose, ethyl cellulose, titanium oxide, macrogol 400, magnesium aluminate metasilicate, and silicone resin, and examples of polishing agents include carnauba wax. can. In addition, the sugar coating base used in sugar coating is sucrose, examples of binders include gum arabic, gelatin, polyvinylpyrrolidone, etc., and examples of dispersing agents include talc, starch, calcium sulfate, sucrose, etc. Examples of suspending agents include precipitated calcium carbonate, talc, starch, and sucrose; examples of coloring agents include various food colors and lake colors; examples of polishing agents include beeswax, paraffin,
Carnauba wax and the like can be mentioned. 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, because it does not use a disintegrant, there is no unfavorable influence 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 The use of a binder as an additive has the effect of avoiding 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. . Next, the present invention will be specifically explained with reference to Examples. Example 1 Fluidized bed spray granulation device (WSG- manufactured by Okawara Seisakusho)
5 type), 4,475 g of lactose was added, and 236 g of hydroxypropyl cellulose 10 was added under the lactose scattering.
% aqueous solution was sprayed. Sift the resulting granules (24
The particles were sieved and sized using a mesh filter. To this 4396 g, 280 g of ifenprodil tartrate, 924 g of crystalline cellulose (trade name, Avicel), and 56 g of magnesium stearate were added and mixed uniformly to produce a tablet composition. This composition was compressed into tablets using a high-speed rotary tablet machine (Model RT-S22-H-1 manufactured by Kikusui Seisakusho) to obtain tablets each weighing 202 mg. Example 2 Fluidized bed spray granulation device (WSG- manufactured by Okawara Seisakusho)
5 type), 4131 g of lactose was added, and 459 g of hydroxypropyl cellulose 10 was added under the lactose scattering.
% water-ethanol (70% ethanol) solution. The obtained granules were sieved and sized using a sieve (24 mesh). To this 3672g, ifenprodil tartrate 240g, crystalline cellulose (trade name Avicel) 720g and magnesium stearate 48g.
g and mixed uniformly to produce a tableting composition. This composition was compressed into tablets in the same manner as in Example 1,
Tablets weighing 195 mg per tablet were obtained. Examples 3 to 5 In the same manner as in Example 1, tablet compositions were prepared according to the following formulations, and tablets were manufactured. Example 3 Formula (per tablet) Ifenprodil tartrate 10mg Lactose 172mg Hydroxypropyl cellulose 7mg Crystalline cellulose (trade name Avicel) 11mg Magnesium stearate 2mg 202mg Example 4 Formula (per tablet) Ifenprodil tartrate 15mg Lactose 150mg Hydroxy Propyl cellulose 7mg Crystalline cellulose (product name Avicel) 28mg Magnesium stearate 2mg 202mg Example 5 Prescription (per tablet) Ifenprodil tartrate 20mg Lactose 139mg Hydroxypropylcellulose 7mg Crystalline cellulose (product name Avicel) 30mg Magnesium stearate 4mg 200mg Reference example 1 25,000 tablets obtained by the method of Example 1 were mixed with 142.5 g of hydroxypropyl cellulose, 42.5 g of ethyl cellulose, 5 g of titanium oxide, and 400 macrogol;
20g, magnesium aluminate metasilicate 7.5g
Using a suspension of 920 ml of methylene chloride and 1080 ml of ethanol containing 6.5 g of silicone resin,
Coating machine [FM-2 manufactured by Freund Sangyo Co., Ltd.
The tablets were coated until the weight per tablet was 210.96 mg, and then polished with carnauba wax to obtain film-coated tablets weighing 211.04 mg per tablet. Reference Example 2 A tableting composition was prepared in the same manner as in Example 1,
This is then processed using a high-speed rotary tablet press (manufactured by Kikusui Seisakusho).
RT-S22-H-1 type). The 12,000 tablets obtained were made into sugar-coated tablets using a coating machine (Model FM-2, manufactured by Freund Sangyo Co., Ltd.) according to the following sugar-coating recipe. Formula (per tablet) Refined white sugar 117.4mg Gelatin 3.5mg Talc 62mg Titanium oxide 13.6mg Gum arabic powder 3.5mg Carnauba wax Trace amount of refined shellac 200mg Test results conducted to examine the quality characteristics of the tablets obtained in these examples are listed in the table below. The hardness was measured using a Monsanto hardness tester according to a conventional method, and the disintegration property was measured according to the method described in the Ninth Edition Japanese Pharmacopoeia (691-695). 【table】

Claims (1)

[Claims] 1. Granules produced from lactose and hydroxypropylcellulose, ifenprodil tartrate in powder form, and excipients in powder form are mixed without adding a disintegrant. A novel method for producing ifenprodil tartrate-containing tablets, which comprises preparing a composition for tabletting and tableting the composition. 2 The excipients may be added to the tableting composition in an amount of 5 to
The method for producing a tablet according to claim 1, wherein the tablet is made of crystalline cellulose in a proportion of 20% by weight. 3. The tablet according to claim 1, wherein magnesium stearate is used as a lubricant in the tabletting composition in an amount of 0.5 to 2% by weight based on the tableting composition. manufacturing method.