JPH0656659A - Pharmaceutical composition which can be directly made into tablet and preparation of said tablet - Google Patents

Abstract

PURPOSE: To provide an acetoaminophene tablet having characteristic including particularly high hardness and short elution time. CONSTITUTION: This table is produced from (a) acetoaminophene of 85 to 95% w/w of the dry weight of the entire compsn., (b) polyvinyl pyrrolidone(PVD) of 4 to 5% w/w of the dry weight of the entire compsn., (c) a disintegrator of 1 to 10% w/w of the dry weight of the entire compsn. and (d) a suitable amt. of a preferable lubricant. The acetoaminophene is put into a fluidized bend granule producing device and a soln. of 5 to 10% polyvinyl pyrrolidone(PVD) is sprayed to the fluidized bed. The fluidized bed is dried to its humidity of 0.5 to 2% w/w and finally, the disintegrator is added and the mixture is directly tableted.

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing tablets, particularly acetaminophen, which is characterized by high hardness and short elution time, and is originally named diacetyl-P.
-Aminophenol (acetyl-P-aminop
and a powdery excipient, a binder, a disintegrating agent or the like to make the mixture homogeneous, and the mixture is compressed with a tablet machine to be solidified into a disk shape. [0002] In general, the basic drawbacks associated with the formulation of tablets include poor flowability of granules, slow dissolution rate, and disintegration of tablets by capping. The only way to solve it is to select appropriate substances such as binders, disintegrants and lubricants, or improve the manufacturing method. Only tablets, mainly compressed tablets, and there are four types of tablet manufacturing processes: a dry method, a dry granule compression method, a wet method, and a wet granule compression method. In the dry method, the drug is mixed with an excipient or a disintegrant and mixed evenly. A method of forming a thin, large flat tablet by high-pressure molding with a low-speed compressor and crushing it to obtain granules having a sieve of a constant size. The dry granule compression method is a tableting method in which the granules obtained by the dry method are directly compressed with a compressor. These two methods do not use chemicals that change easily by mixing water or chemicals that cannot be heated and dried. That is, the chemicals have hygroscopicity and low fluidity. Or the powder is too bulky to press directly for compression, and the tablet manufacturing process of wet method or wet granule compression method is not performed. At that time, generally, a wet method or a wet granule method is used. In the wet granule compression method, an excipient and a disintegrant are mixed with water, or a liquid binder is added to a chemical to soften an appropriate size. A lump is made, and the granules are passed through a granulator or a sieve to produce granules and dried. After drying, the large granules are crushed, only a certain size is collected, a lubricant is added, and the mixture is tableted with a tableting machine. The wet method increases the size of drug granules,
There are advantages such as reducing electrostatic attraction or improving the fluidity of chemicals. That is, a high content of binder is added to increase the tablet hardness or the dissolution rate from an appropriate amount of disintegrant. However, there is a drawback in that the wet process formulation process takes time and the process is not easy to control. Remedies for the wet process can only improve the formulation. The dry method does not use water in the process of formulation process due to the wet method and may not be able to add heat. As a result, formulation time is shortened and energy can be saved. However, in order to obtain granules of a certain size by the dry method, fine powder is produced by crushing tablet presses, resulting in a low production rate or recovery of fine powder. There are some things that must be done. [0004] In the formulation process of the above dry method and dry granule compression method, when crushed into a compressed tablet, a fine powder is produced, and the chemical yield is low or difficult to mold. The problem of insufficient tablet hardness exists, and in order to solve the problem, it was generally a method of improving the equipment of the formulation process, but the effect was not obtained. Antipyretic analgesics acetaminophen (acetaminop), such as the conventional succinic acid
hen), that is, diacetyl-P-aminophenol (N-acetyl-P-aminophenol),
The physical properties of the drug are white crystals or crystalline powder, which has many drawbacks such as poor fluidity of powder, non-granulation, or capping in the formulation process. Solutions such as improved formulation to increase tablet hardness and shorten elution time are desired. Acetaminophen and carboxymethyl cellulose (carbboxy
pregerlatinized starch (pregelati) after mixing with methyl cellulose (CNC)
The sized solution) is added. 90% acetaminophen product is produced, US Pat. No. 4,439,453
90% acetaminophen product is described in US Pat. No. 4,600,579 by a special spray drying method described in US Pat. Pregelatinized starch as a binder by the floor method (preg
Electrified Starch), 90
A directly tabletable pharmaceutical composition containing% acetaminophen is described in US Pat. No. 4,757,090, wherein polyvinylpyrrolidone (PVP) is used as a binder and isoprolol alcohol.
There is also a pharmaceutical composition which can be made into a bulk tablet containing acetaminophen by using a solution prepared by dissolving it in (l): (DrugD
evelp & Ind. pharm. 15 (8) PP
1751 :), but that method cannot completely improve the properties of acetaminophen powder with an aqueous polyvinylpyrrolidone (PVP) solution. The inventors of the present invention obtained a pharmaceutical composition which can be directly tableted by adding an aqueous polyvinylpyrrolidone (PVP) solution as a binder to acetaminophen powder to obtain a pharmaceutical composition. It does not extend to the pharmaceutical composition of the present invention even if it contains a lubricant. A specific example is polyvinylpyrrolidone (P) on acetaminophen placed in a fluid bed granulator dryer.
VP) 5-10 w / v% is sprayed and the humidity is 0.5-2% w
/ W, and a disintegrating agent and a lubricant were added and uniformly kneaded, and then directly tableted. The tablets were high in hardness and short in elution time. Conventional tablet compositions prepared by direct compression containing acetaminophen may use a pharmaceutical composition in which large crystalline acetaminophen is directly mixed with a tableting excipient, or may have a high acetaminophen content. There are two types of direct compression pharmaceutical compositions.
When the above-mentioned large crystals are directly mixed with a tableting excipient, there is a drawback that the elution time of acetaminophen is long.
If small crystalline acetaminophen is used, there are drawbacks such that a considerably large amount of direct compression excipient must be mixed thereafter, the manufacturing process is troublesome, and the cost is increased economically. As a result, according to Vogel described in the prior art (carb boxy methy
Cellulose (CMC) and acetaminophen and then a starch solution is sprayed onto acetaminophen, or a direct compression pharmaceutical composition of 90% acetaminophen with steariic acid as an excipient, or Is polyvinylpyrrolidone (PVP) isopropyl as a binder by Patel.
It is difficult to manufacture an acetaminophen pharmaceutical composition which has high hardness and a short elution time even if the method for producing an acetaminophen pharmaceutical composition is dissolved in water. The inventors of the present invention have conducted intensive studies to solve the above-mentioned drawbacks of the pharmaceutical composition of acetaminophen. As a result, polyvinylpyrrolidone (PV
P) An aqueous solution was used and an appropriate disintegrant was added, and a pharmaceutical composition for direct compression of acetaminophen was invented. The use of polyvinylpyrrolidone (PVP) as a binder in the present invention means that the starch used in the prior art (carb b
oxy-methyl cellulose, CM
C), different from the isopropyl solution of polyvinylpyrrolidone (PVP). The manufacturing method of the granules in the manufacturing process of the present invention is different from the spray drying method of the above-mentioned technique, and the composition containing acetaminophen and polyvinylpyrrolidone (PVP) of the present invention includes only one disintegrant, and the prior art is acetaminophen. It is also different in that it contains excipients, binders, disintegrants, moisturizers, lubricants, etc. It has been revealed that the raw material of the pharmaceutical composition of the present invention for producing granules is different from the prior art, and its characteristic is to improve hardness and shorten elution time. The features of the present invention will be specifically described below, and the method for measuring the physical constants of the powder and tablet will be described first. "Direct compression" means that the drug composition is added with excipients,
Kg is used as a unit used when tableting can be directly performed using a conventional manufacturing method and apparatus, and hardness of the tablet and a measured value of a hardness meter are used. "Granule repose angle (°)": Granules of the same particle size flowed from the funnel, the surface area and height of the container were precisely measured, and the tangent value was calculated to obtain the repose angle of the granule. Repeat the measurement three times with to calculate the average angle of repose. "Granule particle size distribution%" About 50 g of this composition is precisely weighed, and it is 20 to 10 for 3 minutes.
Erwe passed through 0 mesh (tyler) sieve
Put it in a Ka Rotap shaker and determine the particle size distribution. [Tablet hardness (Kg)] Using an Erweka hardness meter; when the spring compression is applied, the force is applied in the diametrical direction of the tablet, and the pressure when the tablet is broken is read. Repeated measurement is repeated 10 times to calculate the average hardness. To do. [Tablet friability (%)] 1 for the Roche tablet friability meter
Insert 0 tablets, rotate for 4 minutes, take out the tablets, remove the powder and small particles that have been broken and separated by sieving, measure the weight, and display the weight loss as a percentage of the original weight. Yes, repeat the measurement three times to calculate the average friability. [Tablet elution time (minutes)] The tablet elution time is measured by the test method of the United States Pharmacopeia (USP) Version XXI using the elution meter of JASCO Corporation DT-610. The average value is obtained by repeating the measurement six times. calculate. [Table Tablet weight deviation (%)] Mettler AE240
Using a precision electronic analysis scale, USP (USP) X
Measure the weight with the test method of XI version, calculate the average weight,
The weight deviation rate is calculated. The components of the acetaminophen composition will be described. Since acetaminophen is colorless, has a low granular density, has a crystal that can be neglected, and has a property of being difficult to compress, a polyvinylpyrrolidone (PVP) solution is used in the present invention. However, 0.5 to 2% water content of acetaminophen can be stored by a fluidized drying method without addition, and when this acetaminophen composition is directly tableted, a tablet having high hardness and short elution time can be produced. Polyvinylpyrrolidone (PVP) is a colorless to yellow, light-colored powder, the molecular weight of which is controlled by adjusting the amount of catalyst, reaction temperature, reaction time, etc.
Polyvinylpyrrolidone (PVP), which has 0 to 1,200,000, is a nonionic, fairly stable resin that dissolves in water to form a slightly acidic solution. It should be noted that the solution increases the dispersion stability of acetaminophen granules when mixed with the cellulose derivative. The present invention uses a polyvinylpyrrolidone (PVP) solution and uses acetaminophen produced by a fluidized bed granulation method.
Compared with the use of well-known crystalline cellulose, the present invention, when using the dry granule manufacturing method, can suppress the granulation of the granules by the wet method to produce a fine powder, and increase the production amount. There is an advantage that you can increase. The present invention relates to an acetaminophen pharmaceutical composition having a high hardness, a short elution time, direct tableting and good fluidity. The composition comprises (a) N-diacetyl-P-aminophenol (b) polyvinylpyrrolidone (PVP). Since the present invention can be directly tableted, acetaminophen is 85% by dry weight of the entire composition.
~ 90% w / w, polyvinylpyrrolidone (PVP) is 4
.About.5%, disintegrant 1 to 10% w / w, and a lubricant may be added. Each component of the pharmaceutical composition will be specifically described. Acetaminophen is aerosil ® 200
0 (Degussa company's silicon dioxide, Silicon
It is mixed with edioxide) and passed through 80 mesh sieve and 100 mesh sieve. Polyvinylpyrrolidone (PVP) is a German BASF company product, crospovidone®, or US G
AF company products, of which those prescribed in US Pharmacopeia XXI version are preferred. The pharmaceutical composition of the present invention is (P
VP) is included to adjust the fluidity and bondability of the composition. Depending on the amount added, a hardness of 5 kg or more and a capping rate of 1% or less can be obtained. Generally 2% to 10% polyvinylpyrrolidone (PVP) may be added, based on the weight of the total composition, an addition amount of 3% to 6% being preferred for the present invention. Starch, polyvinylpyrrolidone (PVP), starch hydroxyethyl sodium, and gelatinized starch are used as disintegrants in order to give a short elution time to the acetaminophen composition in water or gastric juice. Generally crospovido based on weight of total composition
ne, 1 to 3% of sodium starch ethylene oxide may be added, and 3 to 10% may be added to the pregelatinized denbun. Regarding the addition of a lubricant, it prevents the chemicals from adhering to the shavings during tableting, and also enhances the pressure transmission during compression. Tableting becomes very easy by adding an appropriate amount of lubricant, and tablets with a beautiful surface can be produced.
However, if the added amount is too large, the hardness decreases. The lubricant added according to the present invention is stearic acid or a metal salt such as magnesium stearate or purified talc stearic acid, for example, sodium, calcium or zinc. Generally 0.10% to 1.0% by weight of the total composition
Amount of 0.5% to 1.0% for the present invention
Is desirable. A tablet obtained by directly compressing the composition is characterized by having a hardness of 5 Kg or being capable of eluting 80% acetaminophen in 20 minutes. [Table 1] [Table 2] The present invention produces an acetaminophen composition by a fluid bed granule manufacturing method. First, choose an appropriate fluidized bed. Place acetaminophen powder mixed with silicate in advance on the fluidized bed, fluidize it until its complete temperature rises, and then dissolve polyvinylpyrrolidone (PVP) in the oven. 5w / w%
Prepare the solution, spray on acetaminophen powder on the fluidized bed, add crospovidone, or disintegrant, or magnesium stearic acid or lubricant, fluidize the humidity to 0.5 to 2 weight percent, and add Glatt.
A Quick sieve or the like is used to produce a desired particle size distribution, and the disintegrant and lubricant PVP described in the above process are put into a conical cylinder mixer and mixed sufficiently. The method for preparing the acetaminophen pharmaceutical composition which can be directly tabletted according to the present invention includes the following steps. (A) Diacetyl-P-aminophenol was placed in a fluid bed granulator dryer, and (B) polyvinylpyrrolidone was dissolved in water to make a 5-10 w / v% solution, and this solution was 20
~ 35% fluidized bed sprayed onto diacetyl-P-aminophenol powder (C) Sprayed diacetyl-P-aminophenol powder is dried to a humidity of 0.5 to 2 weight percent (D) 1 to 5 % Disintegrant is added and (E) the humidity is 0.5 to 2% by weight. The above components are sufficiently mixed. (F) Tablet directly. In the present invention, the operating conditions for preparing granules in a fluidized bed are as follows: air heated to 25 to 45 ° C. rises from under the fluidized bed, the collar valve is opened and closed, the temperature is adjusted, and the spray rate of polyvinylpyrrolidone (PVP) solution is set. Adjust appropriately.
What is the particle size of the produced acetaminophen granules? It changes depending on the spray pressure of the polyvinylpyrrolidone (PVP) solution and the water content of the fluidized bed, and the adjusted parameter influences the particle size. If a Glatt Quick sieve or the like is used, the particle size becomes fixed. The objects, features and advantages of the present invention are given by way of example, without any limitation of the invention, although there may be some examples. The tablet hardness is an average value of 10 tablet hardness, and the tablet weight is an average value of 20 tablet weight. Examples 1-3 Acetaminophen composition granule fluidized bed granulation dryer (Gl
att Air Technologies, Inc. GP
CG-1). The number of machines and prescriptions are shown in Table 3,
Particle size distribution (particle size) and cumulative ratio (c
umulative permanent retaine
d) was tested under the conditions shown in Table 4. As a result, the concentration of the polyvinylpyrrolidone (PVP) aqueous solution is 5% and the flowability of 7.5% w / v can be directly tableted. [Table 3] [Table 4] Examples 4-6 Direct compression drug compositions were prepared using the samples shown in Table 5 below, the properties of which are shown in Table 6: [Table 6]

Claims (1)

Claims (1) (A) Diacetyl-P-aminophenol (ac
etyl-P-aminophenol) placed in a fluidized bed, (B) polyvinylpyrrolidone (polyvinyl)
Pyrolidone (PVP) is dissolved in water, 5-10
It becomes a w / v% solution, which is sprayed on diacetyl-P-aminophenol powder in a fluidized bed with a flow rate of 20-35%, (C) The sprayed diacetyl-P-aminophenol powder is a fluidized bed drip. Humidity of the atmosphere is dried to 0.5 to 2% by weight, (D) Fluidization is stopped and both are 1 to 5
% Disintegrant is added, and (E) the humidity is adjusted to 0.5 to 2 weight percent, the above components are sufficiently mixed in a fluidized bed, and (F) direct compression is performed. A method for producing a diacetyl-P-aminophenol tablet, which comprises the steps (A) to (F) above. (2) The composition according to claim 1, wherein the disintegrant in the tablet manufacturing method contains polyvinylpyrrolidone (PVP) crospovidone. (3) In the above tablet manufacturing method, the disintegrant is sodium starch ethylene oxide (Soldiumstarch).
A composition according to claim 1, which comprises a glycolate. (4) The tablet is a composition produced by the tablet production method, which is the method described in claim 1.