KR20080023417A - Solid preparation comprising diethylpropione hydrochloride improved stability for oral administration - Google Patents

Abstract

A solid preparation comprising diethylpropione hydrochloride for oral administration is provided to improve the content stability by inhibiting swelling and lowered hardness of the preparation caused by absorbing water and delaying hydrolysis, and suppress browning reaction and bad smell of the preparation by packing with packing materials. A solid preparation for oral administration comprises 10-30 wt.% of diethylpropione hydrochloride, 25-60 wt.% of microcrystalline cellulose, 1.0-5.0 wt.% of citric acid and 0.01-0.02 wt.% of butylhydroxyanisole, further comprises 15-35 wt.% of low substituted hydroxypropylcellulose, 0.1-5.0 wt.% of hydroxypropylcellulose, 1-10 wt.% of gelated starch, 1.0-8.0 wt.% of colloidal silicon dioxide and 1.0-8.0 wt.% of stearic acid magnesium, is packed with packing materials such as PVDC(polyvinylidende chloride) coating PVC(polyvinyl chloride), and is formulated as tablet, powder, granule or capsule.

Description

Solid preparation comprising diethylpropione hydrochloride improved stability for oral administration

The present invention relates to a solid preparation for oral administration comprising diethylpropion hydrochloride with improved stability.

Diethylpropione; 2- (diethylamino) -1-phenyl-1-propanone; Amphepramone] hydrochloride is a drug that acts on the autonomic nerves, arouses excitement by arousing the central nervous system. The drug was first synthesized by Firma Temmler-Werke of Germany in 1961, has a molecular weight of 241.76, a molecular formula of C ₁₃ H ₁₉ NO.HCl, and the structure is represented by the following Chemical Formula 1. .

The efficacy and effect of the drug is used as an adjuvant of dietary therapy that is sustained under medical obesity management for a short period of time (for example, several weeks) in patients who do not respond to diet or exercise therapy, which is an appropriate method of weight loss. Or obesity patients with an initial body mass index (BMI) of 30 kg / m 2 or greater, or other risk factors (eg, hypertension, diabetes, hyperlipidemia) and obesity patients with a body mass index of 27 kg / m 2 or greater.

Diethylpropion hydrochloride is an unstable substance, and has a property of being rapidly hydrolyzed when reacted with moisture, so it should be protected from moisture because of its strong hygroscopic properties. In particular, the correlation between the stability of diethylpropion hydrochloride and pH, as is generally known, the more active the hydrolysis proceeds at pH 3.5 or more to form an enamine structure, the hydrolysis product 1 Since it becomes a rapidly unstable compound by forming -phenyl-1,2-propanedione, solid preparations based on diethylpropion hydrochloride have no effect on the content reduction during the effective period. Has been reported to degrade product quality (J. Pharm. Sci. 1980. Oct 69. 1206-9.).

Therefore, since the main component having a problem in stability contained in the solid formulation changes sensitively to changes in water and pH, studies to prevent a phenomenon in which the stability of the main component is lowered are continuously conducted.

As an example of such a study, many studies have been conducted to improve stability of bupropion hydrochloride, as follows.

U.S. Pat.No. 5,358,970 describes a pharmaceutical composition containing bupropion hydrochloride and a stabilizer, wherein the stabilizer used herein is a weak acid-based stabilizer which increases the stability of the main component and is used. L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfide, citric acid, tartaric acid and L -Cysteine dihydrochloride (L-cystine dihydrochloride).

WO 99/33456 describes a pharmaceutical composition containing bupropion hydrochloride and an inorganic acid as a stabilizer, wherein hydrochloric acid, nitric acid, phosphoric acid or sulfuric acid are used.

WO 99/33457 relates to a pharmaceutical composition containing dicarboxylic acid as a bupropion hydrochloride and stabilizer, wherein the dicarboxylic acid includes oxalic acld, succinic acid, adipic acid. ), Fumaric acid, and phthalic acid were used, and the method of increasing the stability of the main components by adjusting the pH to 4.0-9.0 while controlling the amount of these acids was used.

U. S. Patent No. 6,153, 223 discloses a mixture of a stabilizing amount of (a) an unstable pharmaceutical formulation above pH 3.5, and (b) an acidic pharmaceutically acceptable carrier to stabilize the pharmaceutical formulation to enhance the stability of bupropion hydrochloride. A stabilized pharmaceutical composition is described that includes. The method mainly used here was a method of increasing the stability of the main component by adjusting bupropion hydrochloride to pH 3.5 or less by using hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and the like.

As such, these known techniques attempt to increase the stability of bupropion hydrochloride by using only weak and strong acids as a means to control the pH of pharmaceutical formulations.

In particular, the method used in US Pat. No. 6,153,223 uses hydrochloric acid, nitric acid, nitric acid, and nitric acid to lower the pH of the formulation to 3.5 or less using only the fact that bupropion hydrochloride is delayed in hydrolysis at pH 3.5 or lower, thereby increasing the stability of the main component content. By using strong acids such as sulfuric acid and phosphoric acid, there is a problem that it is difficult to apply to practical product production. That is, when strong acid is used to increase stability in the preparation of solid preparations, 1) the handling of strong acid is difficult and dangerous, and 2) the use of strong acid should be excluded from medicines administered to humans, and 3) moisture absorption. Problems such as the swelling phenomenon of tablets, or the hardness that occurs due to moisture condensation, which causes the tablets to break, occur, which makes it difficult to maintain the stability of the product for three years. A problem arises that is difficult to apply.

Therefore, there is an urgent need for a study of a pharmaceutical formulation with improved stability that improves the swelling phenomenon of tablets caused by moisture absorption, or the phenomena of tablets broken down due to moisture condensation.

Therefore, the present inventors have been studying the pharmaceutical formulations that improve the above problems and improve the stability of tablets, which are obtained by absorbing moisture in solid formulations containing diethylpropion hydrochloride, microcrystalline cellulose, citric acid and butylhydroxyanisole. It was confirmed that the swelling phenomenon or the hardness that appears due to the humidity of the water was lowered and the tablet breakage was suppressed, and the hydrolysis phenomenon was delayed to improve the content stability of the formulation. In addition, when the solid formulation was packaged using a packaging material of a specific material, it was confirmed that the content stability is excellent without the browning phenomenon and odor of color, and completed the present invention.

Accordingly, the present invention is to provide a solid preparation for oral administration comprising diethylpropion hydrochloride with excellent content stability during the shelf life of the product.

In addition, the present invention is to provide a solid formulation for oral administration to further increase the stability by packaging the solid formulation using a packaging material of PVDC material.

One aspect of the present invention provides a solid preparation for oral administration comprising diethylpropion hydrochloride, microcrystalline cellulose, citric acid and butylhydroxyanisole.

Hereinafter, the component contained in the solid preparation of this invention is demonstrated in detail.

In the manufacture of tablets, lactose is often used to reduce moldability and wear rate. However, diethylpropion hydrochloride, which is the main component of the solid preparation according to the present invention, has an amine group, and produces melanoidine, which is a brown substance, through an initial stage, an intermediate stage, and a final stage of condensation of an amino group with a carbonyl group of a lactose as a reducing sugar. It is difficult to use lactose because the browning of the tablet occurs due to the reaction, also known as amino-carbonyl (amino-carbonyl) reaction. Therefore, in the solid preparation of the present invention, microcrystalline cellulose, which is a cellulosic material, was used instead of lactose.

The microcrystalline cellulose contained in the solid preparation according to the present invention serves to remove voids between the powders during tableting and to improve the binding force between the powders. In general, in the manufacture of tablets, pores are generated between particles due to various particle distributions of the excipient mixture, and air is filled in the pores, thereby lowering the density of the powder. In the present invention, the above problems are solved by using microcrystalline cellulose.

The microcrystalline cellulose is 1) the average particle size is 150 ㎛ ~ 180 ㎛, 2) bulk density is 1.2 g / cm 3 ~ 1.4 g / cm 3, 3) angle of repose 30 ° ~ 40 °, 4) maximum It is preferable that the moisture content is within 5%.

The microcrystalline cellulose preferably contains 25 to 60% by weight based on the total weight of the solid formulation. If the content of the microcrystalline cellulose is out of the above range it is difficult to form the tablet and the wear rate is high.

Butylhydroxyanisole included in the solid preparation according to the present invention has an excellent antioxidant effect, so that diethylpropion hydrochloride is used as an antioxidant to prevent rapid browning phenomenon and oxidative property when contacted with air. In addition, the use of citric acid may further increase the antioxidant effect and eliminate the browning phenomenon that occurs when contacted with moisture. The concentration of butylhydroxyanisole is forbidden in the pharmaceutical product to use at least 0.02% by weight based on the total weight of the solid preparation, the purity is at least 98.5%, the heavy metal is at most 0.001%, and the residue is preferably at most 0.01%.

The butylhydroxyanisole and citric acid preferably contain 0.01 to 0.02 wt% and 1.0 to 5.0 wt%, respectively, based on the total weight of the solid formulation. If the content of butylhydroxyanisole and citric acid is out of the above range, the antioxidant effect is lowered, browning phenomenon appears.

In addition, the solid preparation according to the present invention may further include low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, gelling starch, colloidal silicon dioxide and magnesium stearate.

Low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose contained in the solid preparation according to the present invention serves to prevent swelling by reacting with moisture. The low-substituted hydroxypropyl cellulose has a ratio of 1) hydroxy to propoxy 11%, 2) density 0.32 g / cm 3, 3) tapped density 0.56 g / cm 3, and 4) It is preferred that the average particle size is 50 μm, and 5) the angle of repose is 49 °.

The low-substituted hydroxypropyl cellulose is preferably included 15 to 35% by weight based on the total weight of the solid formulation, the hydroxypropyl cellulose is preferably included 0.1 to 5.0% by weight relative to the total weight of the solid formulation. If the content of low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose is out of the above range, the tablet reacts with moisture under accelerated conditions, resulting in swelling and breaking of the tablet.

The gelled starch included in the solid preparation according to the present invention serves to prevent the swelling phenomenon that occurs when the solid preparation is in contact with water and to maintain a strong binding force of the tablet during molding. The gelling starch is 1) a structure (C ₆ H ₁₀ O ₅ ) _n (in the above, n = 300 ~ 1000) consisting of two polymers of amylose and amylopectin, 2) pH of the aqueous dispersion of 10% is 4.5 ~ 7.0 3) fluidity is 18-23%, 4) angle of repose is 40.7 °, and 5) particle distribution is preferably 30-150 μm. In the above, the angle of repose is a measure of fluidity in the powder, and means the angle between the horizontal plane and the inclined plane where the powder accumulates when the powder falls a certain amount at a certain height by natural drop, and the lower the angle of repose, The higher the angle, the lower the fluidity. The gelled starch is preferably included 1 to 10% by weight based on the total weight of the solid formulation. If the content of gelling starch is out of the above range, swelling phenomenon occurs when the tablet is in contact with water, and the binding strength of the tablet becomes weak during molding.

The solid preparations according to the invention comprise colloidal silicon dioxide and magnesium stearate in order to improve the fluidity of the granules during tableting. The colloidal silicon dioxide and magnesium stearate are preferably included 1.0 to 8.0% by weight relative to the total weight of the solid formulation. If the content of colloidal silicon dioxide and magnesium stearate is less than 1.0% by weight, respectively, the fluidity is lowered and the binding strength is also lowered. When the content of the colloidal silicon dioxide and magnesium stearate is less than 8.0% by weight, capping occurs during the manufacture of tablets, making tablets difficult to prepare.

The solid preparation according to the present invention comprises 10-30 wt% of diethylpropion hydrochloride, 25-60 wt% of microcrystalline cellulose, 1.0-5.0 wt% of citric acid, and 0.01-0.02 wt% of butylhydroxyanisole based on the total weight of the solid preparation. It is preferable to include.

In addition, the solid preparation according to the present invention is 15 to 35% by weight of low-substituted hydroxypropyl cellulose, 0.1 to 5.0% by weight of hydroxypropyl cellulose, 1 to 10% by weight gelling starch, colloidal silicon dioxide 1.0 based on the total weight of the solid preparation -8.0 wt% and magnesium stearate 1.0-8.0 wt% may be further included.

The solid preparation for oral administration containing diethylpropion hydrochloride according to the present invention has a disintegration time that is slower than conventional commercial tablets, a high hardness of tablets, and low wear and tear, resulting in breakage or brittleness during transportation and storage of tablets. Can be reduced.

In addition, the solid preparation for oral administration containing diethylpropion hydrochloride according to the present invention exhibits a dissolution rate equivalent to that of currently commercially available products, is uniform in content, and swells when stored in uncoated state at 40 ° C RH 75% under accelerated conditions. The delayed development resulted in delayed expansion of tablets 16 times, expansion of diameter of 8.5 times, expansion of thickness of 6 times, and expansion of swelling by water.

Another aspect of the present invention provides a solid formulation for oral administration which further increases the stability by packaging the solid formulation using a packaging material of PVDC material.

The packaging material of the PVDC material is to prevent the property of being rapidly hydrolyzed when reacting with moisture, and the packaging material of the PVDC (DUPLEX) material coated with polyvinylidene chloride (PVDC) on polyvinyl chloride (PVC). Means.

Polyvinyl chloride (PVC) is a film developed by Dow Chemical of the United States in 1939, also known as Saran, and used as a plastic pronoun so called PVC or vinyl. This material has excellent barrier property to moisture and air, and is inexpensive, and is widely used for packaging foods and medicines because of excellent barrier properties such as air permeability and moisture permeability, heat resistance and transparency.

The PVDC packaging material used in the present invention is a defect-free transparent film made of polyvinylidene chloride (PVDC) having a multi-layered coating of polyvinylidene chloride (PVDC) having an air permeability and water vapor permeability enhanced in a polyvinyl chloride (PVC) sheet. . The hard part of the packaging material is a polyvinyl chloride (PVC) film, the thickness of the polyvinyl chloride is 250 ~ 300 ㎛, the coating part is polyvinylidene chloride (PVDC) is coated with 40 ~ 90 g / ㎥ Blister-only film made of Duplex.

When the solid preparation according to the present invention is packaged using a packaging material made of PVDC material, the solid preparation is blocked from water and air, so that hydrolysis, such as a decrease in content, a cracking phenomenon, and a swelling phenomenon, which are present in commercially available formulations, is blocked. It does not occur browning or odor of the tablet properties appearing during the occurrence of excellent content stability.

In addition, when using the PVDC as a packaging material of the solid formulation, the content stability after 6 months in the accelerated conditions is superior to when using a PP bottle or PTP as the packaging material.

Therefore, the PVDC packaging material used in the present invention is an optimal packaging material that can maintain the stability of the content of diethylpropion hydrochloride, since the stability of the main component can be further increased to maintain the stability of the product for three years.

Solid preparations for oral administration according to the present invention can be prepared by tablets, powders, granules, capsules and the like by conventional methods, preferably tablets.

The solid preparation for oral administration according to the present invention preferably contains 20-30 mg of diethylpropion hydrochloride per solid preparation, and the dosage is weight, age, sex, health condition, diet, time of administration, method of administration, The range varies depending on the rate of excretion and the severity of the disease, and the daily dose of diethylpropion hydrochloride is about 0.3 to 1.5 mg / kg, preferably divided once to several times a day.

Hereinafter, preferred examples and experimental examples are presented to help understand the present invention. However, the following Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

Example  1-4 and Comparative example  1 ~ 4  : Preparation of Tablet

Citric acid, butyl hydroxyanisole and hydroxypropyl cellulose were precisely weighed and filtered through a No. 16 sieve, and the components were put into a mixing mixer and mixed homogeneously for 30 minutes to 1 hour. Ethanol and purified water were added to the mixture to prepare a binding solution.

Separately, diethylpropion hydrochloride and microcrystalline cellulose were precisely weighed and filtered through a No. 16 sieve, and the ingredients were added to a mixing mixer and mixed homogeneously for 30 minutes to 1 hour.

To the mixture was added a binder solution prepared with ethanol and purified water, and then a mixture was prepared in a mixing mixer. After the granulation was dry stipulated, low-substituted hydroxypropyl cellulose, gelled starch, colloidal silicon dioxide, magnesium stearate were precisely weighed and added and mixed homogeneously for 5 to 10 minutes. Thereafter, the mixture was compressed into tablets in a conventional manner.

The contents of the components included in the tablets of Examples 1 to 4 and Comparative Examples 1 to 4 are shown in Table 1.

                                                       (Unit: weight%) Raw material name Example Comparative example One 2 3 4 One 2 3 4 Diethylpropion hydrochloride 20.84 20.84 20.84 20.84 20.84 20.84 20.84 20.84 Lactose - - - - 44.13 48.66 - - Microcrystalline cellulose 35.64 39.13 42.10 40.14 0.83 - 52.95 56.26 Low Substituted Hydroxypropyl Cellulose 24.00 24.60 24.70 25.00 - - - - Corn starch - - - - - 9.00 - 4.87 Croscarmellose Sodium - - - - - - 13.33 - Gelling starch 4.50 4.60 5.00 5.00 1.70 13.00 - - Povidone - - - 3.90 Hydroxypropyl cellulose 2.00 1.50 1.00 2.00 - - - - Citric acid 3.00 1.31 2.34 3.00 - 5.00 6.22 6.83 Butylhydroxyanisole 0.02 0.02 0.02 0.02 - - - - Colloidal silicon dioxide 5.00 4.00 2.00 2.00 - - 4.44 4.87 Magnesium stearate 5.00 4.00 2.00 2.00 32.50 0.50 2.22 2.43 Talc - - - - - 3.00 - - Sum 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Experimental Example  One  Of tablets Disintegration Test

With respect to the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4, disintegration test was performed as described below according to the disintegration test method of the KP.

Take 6 tablets tableted and put one tablet into the glass tube of the tester in the disintegration test method of the Korean Pharmacopoeia General Test Method, and keep the tester at a temperature of 37 ± 2 ℃ in advance, Immersed in the test liquid of the beaker adjusted by adjusting the upper surface of the tester to coincide with the surface of the liquid. The state of the tablets in the glass tube was observed.

At this time, when water is used as a test solution and the auxiliary plate is put up and down for 30 minutes, and observed, it is determined that it is suitable when there is a substance on the sea surface or a little soft substance even if the residue of the tablet is not in the glass tube. Was measured.

The results are shown in Table 2.

division Example Comparative example One 2 3 4 One 2 3 4 Disintegration time Within 10 minutes Within 10 minutes Within 10 minutes Within 10 minutes Within 5 minutes Within 5 minutes Within 7 minutes 30 minutes or more

As shown in Table 2, in the case of the tablets prepared in Examples 1 to 4 it can be seen that the disintegration time is later than the tablets prepared in Comparative Examples 1 to 4. Both tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 satisfied the pharmacological disintegration test criteria of the drug. In other words, all of the disintegration conditions within 30 minutes, which is the standard for disintegration test of uncoated tablets, were satisfied, and a suitable standard for sale as a drug was shown.

Experimental Example  2  : Hardness test of tablet

Ten tablets of each of the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were taken and measured by using a hardness measuring device of the tablet for pharmacological test (PHARMA TEST PTB-411 serial No. 8736).

The results are shown in Table 3.

division Example Comparative example One 2 3 4 One 2 3 4 Hardness More than 8kp More than 8kp More than 8kp More than 8kp Less than 2kp Less than 2kp 7kp or more 7kp or more

As shown in Table 3, the tablets prepared in Examples 1 to 4 showed a hardness of 8 kp or more, whereas the tablets prepared in Comparative Examples 1 to 4 showed relatively low hardness values. In particular, the tablets prepared in Comparative Examples 1 and 2 were 2kp or less, which was relatively low in hardness compared to the tablets according to the present invention.

Experimental Example  3  Of tablets Wear and tear test

Twenty tablets of each of the tablets prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were taken and measured using a wear and tear measuring device for pharmacological test (PHARMA TEST PTB-411 serial No. 8736). At this time, the length of the drum (drum) in which tablets were put was measured, the amount of powder generated by the impact when rotating at 100 rotation for 4 minutes was measured.

The results are shown in Table 4.

division Example Comparative example One 2 3 4 One 2 3 4 Masson 0.1% or less 0.1% or less 0.1% or less 0.1% or less 0.5% or more 0.5% or more 0.3% or more 0.3% or more

As shown in Table 4, the wear degree of the tablets prepared in Examples 1 to 4 was 0.1% or less, whereas the tablets prepared in Comparative Examples 1 to 4 were prepared in Examples 1 to 4 by 0.3% or more. Compared with the tablet showed a relatively high degree of wear. In particular, the tablets prepared in Comparative Examples 1 and 2 exhibited at least 0.5% wear.

Experimental Example  4  : Comparative dissolution test of tablets In vitro in in vitro )

In order to confirm the drug efficacy of tablets containing diethylpropion hydrochloride according to the present invention (Example 3) and currently available tablets (Comparative Example 1), the following comparative dissolution test was carried out.

The test drug and the reference drug content used in the test were within 5% of the difference between the indicated amounts, and each control drug and the test drug were tested on 12 samples at four conditions of pH 1.2, pH 4.0, pH 6.8, and water. It was. The test time was measured for 2 hours at pH 1.2 and 6 hours at other test solutions. The test was terminated when the average dissolution rate of the reference drug exceeded 85%.

<< Dissolution test conditions >>

ㆍ Test Container: 2nd Law of the Korean Pharmacopoeia 8th Amendment

ㆍ Speed: 50 rpm

ㆍ Amount of test solution: Purified water (900 mL)

ㆍ Temperature of test solution: 37.5 ± 0.5 ℃

ㆍ Test solution: pH 1.2 is the first solution of the 8th Amendment Disintegration Test

            pH 6.8 is the second solution of the decomposition test method,

            pH 4.0 used the British Pharmacopoeia, phosphate buffer pH 4.0.

ㆍ Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes

27.7 mg of diethylpropion hydrochloride standard is precisely weighed and dissolved in 10 ml of each eluent (pH 1.2, pH 4.0, water, pH 6.8), where each 10 ml is taken and the mark is set to 100 ml using the respective eluent. It was made.

Separately, 12 containers of the dissolution tester were filled with a predetermined amount of dissolution medium, and the dissolution medium was warmed to 37.5 ± 0.5 ° C. Then, one tablet or test drug was added to each of the 12 containers, and the dissolution tester was operated at a predetermined speed. The inner bottom of the vessel and the distance of the paddles were maintained at 2.5 ± 0.2 cm, 10 ml was taken at the end of the predetermined time interval, Whatman filter pater no. 41 or equivalent was filtered to the sample solution. At this time, the dissolution medium surface and paddles were sampled at the center of the top and at least 1 cm from the wall of the vessel.

50 μl of the sample solution and the standard product were tested according to the liquid chromatograph method of the content uniformity test, and the peak areas At and As of the sample solution and the standard solution were obtained.

The results are shown in Table 5.

Test solution Test group Average dissolution rate (%) (mean ± standard deviation) 5 minutes 10 minutes 15 minutes 30 minutes 45 minutes 60 minutes 90 minutes pH 1.2 Example 3 77.2 ± 4.3 92.3 ± 1.8 92.7 ± 1.3 93.0 ± 0.8 - - - Comparative Example 1 34.6 ± 4.4 65.4 ± 2.5 86.5 ± 0.4 91.9 ± 3.8 - - - pH 4.0 Example 3 68.6 ± 2.5 87.7 ± 6.9 89.2 ± 4.0 91.3 ± 3.8 - - - Comparative Example 1 73.8 ± 2.9 83.2 ± 0.8 86.5 ± 1.6 97.0 ± 0.3 - - - pH 6.8 Example 3 57.7 ± 1.8 86.3 ± 1.3 90.9 ± 0.8 95.5 ± 2.9 - - - Comparative Example 1 28.4 ± 2.7 65.1 ± 2.3 87.0 ± 0.6 97.9 ± 1.1 - - - water Example 3 93.3 ± 4.0 94.2 ± 2.0 94.3 ± 2.0 94.3 ± 2.0 - - - Comparative Example 1 35.2 ± 2.8 70.7 ± 2.8 90.8 ± 3.4 96.3 ± 3.4 - - -

As shown in Table 5, the tablets containing diethylpropion hydrochloride according to the present invention (Example 3) and currently commercially available tablets (Comparative Example 1) were prepared after elution in pH 1.2, pH 4.0, pH 6.8 and water. Elution rates were equivalent at 15 minutes. Therefore, it can be seen that the preparation containing diethylpropion hydrochloride according to the present invention exhibits the same physical properties as those of commercially available products, and thus the in vitro test results are equivalent.

Experimental Example  5  : Content uniformity test of tablet

The tablets prepared in Example 3, which showed the most preferable results in hardness, friability, and disintegration test for the tablets containing diethylpropion hydrochloride prepared in Examples 1 to 4 and Comparative Examples 1 to 4, were selected as follows. Content homogeneity experiment was performed in the same manner.

40.0 mg of diethylpropion hydrochloride standard was added to a 250 ml volumetric flask, 250 ml of 0.1 N hydrochloric acid was added to a concentration of 160 µg / ml. It was set as the standard liquid according to the mark.

The mobile phase was separately dissolved in 136.1 g of monobasic potassium phosphate in 900 ml of water, 4.3 ml of phosphoric acid, and then adjusted to 1000 ml with water to form a phosphate buffer, followed by water, acetonitrile, phosphate buffer, 1.0 M Sodium nitrate was mixed by 730: 200: 50: 20 and then degassed.

Separately, by taking about 20 tablets or more tablets prepared in Example 3, weighed precisely and ground into powder, precisely weighed the amount corresponding to 40 mg of diethylpropion hydrochloride and placed in a 250 ml flask, 0.1 N 200 ml of hydrochloric acid was added thereto, stirred for 45 minutes, and then lined with 0.1 N hydrochloric acid. After filtration using a filter, the first 25 ml was discarded, the next 5 ml was taken and placed in a 100 ml volumetric flask, the mark was aligned with the mobile phase, and this solution was used as the sample solution.

The results are shown in Table 6.

<Analysis Condition>

-Device: Waters alliance

-Detector: Alliance waters 2487 Dual λ absorbance detector

-Column: Thermo Hypersil 250 X 4.6, 5 ㎛

Flow rate: 1 ml / min

1 time Episode 2 3rd time 4 times 5 times content(%) 99.33% 99.50% 99.48% 99.36% 99.42%

As shown in Table 6, it was confirmed that the content of the tablet containing diethylpropion hydrochloride according to the present invention (Example 3) appeared uniformly.

Experimental Example  6  : Stability and Swelling Stability Test of Tablet under Accelerated Condition

Tablets containing diethylpropion hydrochloride prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were stored in uncoated state under accelerated conditions at 40 ° C. RH, and stability experiments were conducted on the properties and swelling phenomenon of the tablets. It was.

The results are shown in Table 7.

division Early 30 minutes 60 minutes 120 minutes 240 minutes 360 minutes 480 minutes Example 1 Change of appearance Good Good Good Good Good Good Good Diameter change 0% 1% ↑ 1% ↑ 2% ↑ 3% ↑ 4% ↑ 5% ↑ Thickness change 0% 1% ↑ 3% ↑ 4% ↑ 5% ↑ 7% ↑ 9% ↑ Example 2 Change of appearance Good Good Good Good Good Good Good Diameter change 0% 1% ↑ 1% ↑ 2% ↑ 4% ↑ 5% ↑ 6% ↑ Thickness change 0% 1% ↑ 3% ↑ 3% ↑ 6% ↑ 7% ↑ 9% ↑ Example 3 Change of appearance Good Good Good Good Good Good Good Diameter change 0% 1% ↑ 1% ↑ 2% ↑ 3% ↑ 4% ↑ 5% ↑ Thickness change 0% 1% ↑ 3% ↑ 4% ↑ 5% ↑ 6% ↑ 7% ↑ Example 4 Change of appearance Good Good Good Good Good Good Good Diameter change 0% 1% ↑ 2% ↑ 3% ↑ 4% ↑ 5% ↑ 7% ↑ Thickness change 0% 1% ↑ 3% ↑ 5% ↑ 5% ↑ 8% ↑ 10% ↑ Comparative Example 1 Change of appearance Good fracture fracture Burst - - - Diameter change 0% 3% ↑ 8% ↑ 17% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Thickness change 0% 5% ↑ 18% ↑ 30% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Comparative Example 2 Change of appearance Good fracture fracture Burst - - - Diameter change 0% 3% ↑ 8% ↑ 17% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Thickness change 0% 5% ↑ 18% ↑ 30% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Comparative Example 3 Change of appearance Good fracture fracture Burst - - - Diameter change 0% 3% ↑ 8% ↑ 17% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Thickness change 0% 5% ↑ 18% ↑ 30% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Comparative Example 4 Change of appearance Good fracture fracture Burst - - - Diameter change 0% 3% ↑ 8% ↑ 17% ↑ Measurement difficulties Measurement difficulties Measurement difficulties Thickness change 0% 5% ↑ 18% ↑ 30% ↑ Measurement difficulties Measurement difficulties Measurement difficulties

As shown in Table 7, the tablet containing diethylpropion hydrochloride according to the present invention (Examples 1 to 4) is a phenomenon that the tablet is broken due to the delayed swelling phenomenon than the tablets prepared in Comparative Examples 1 to 4 16 times, the expansion rate of the expansion of the diameter is 8.5 times, the expansion rate of the expansion of the thickness is about 6 times, the delayed swelling phenomenon caused by the water.

Experimental Example  7  : Content Stability Test of Tablet under Accelerated Conditions

After filling the tablets prepared in Example 3 in each packaging container, stability experiments were conducted for 6 months under accelerated conditions of 35 ° C. RH 75% and 40 ° C. RH 75% to observe the properties and contents of the tablets. .

The results are shown in Table 8.

division Early 1 month 2 months 3 months 4 months 5 months 6 months 35 ℃ RH 75% PP bottle 99.13% 95.45% 91.40% 87.57% 85.24% 80.17% 75.21% PTP 99.13% 96.55% 94.38% 91.21% 88.54% 84.69% 82.55% PVDC 99.13% 99.11% 99.09% 99.07% 99.06% 99.05% 99.00% 40 ℃ RH 75% PP bottle 99.13% 95.18% 91.02% 85.38% 81.29% 77.25% 72.25% PTP 99.13% 96.35% 93.13% 91.23% 88.54% 84.15% 80.14% PVDC 99.13% 98.62% 98.34% 98.34% 98.20% 98.16% 98.11%

As shown in Table 8, when the tablet containing diethylpropion hydrochloride according to the present invention (Example 3) was packaged using PVDC as a packaging material, the acceleration conditions were higher than when packaging with a PP bottle or PTP packaging material. It was confirmed that the content stability after 6 months elapsed at.

In the solid preparation for oral administration containing diethylpropion hydrochloride according to the present invention, the swelling phenomenon of the tablet which appears by absorbing moisture, or the hardness that decreases due to the condensation of the water is lowered, the phenomenon that the tablet is broken, is suppressed, By delaying the decomposition phenomenon, the content stability of the preparation is excellent. In addition, when the solid formulation is packaged using a packaging material of the PVDC material, there is no effect of color change, odor, etc., and the content stability is more excellent.

Claims (7)

A solid preparation for oral administration comprising diethylpropion hydrochloride, microcrystalline cellulose, citric acid and butylhydroxyanisole. The solid preparation for oral administration according to claim 1, wherein the solid preparation further comprises low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, gelled starch, colloidal silicon dioxide, and magnesium stearate. The method according to claim 1, wherein the solid preparation is 10-30% by weight of diethylpropion hydrochloride, 25-60% by weight of microcrystalline cellulose, 1.0-5.0% by weight citric acid, and 0.01-0.02 of butylhydroxyanisole, based on the total weight of the solid preparation. A solid formulation for oral administration comprising a weight percent. The method according to claim 3, wherein the solid preparation is 15 to 35% by weight of low-substituted hydroxypropyl cellulose, 0.1 to 5.0% by weight of hydroxypropyl cellulose, 1 to 10% by weight gelling starch, colloidal silicon dioxide 1.0 based on the total weight of the solid preparation A solid preparation for oral administration, further comprising -8.0 wt% and 1.0-8.0 wt% magnesium stearate. The solid preparation for oral administration according to any one of claims 1 to 4, wherein the solid formulation is packaged using a packaging material made of PVDC material. The solid preparation for oral administration according to claim 5, wherein the PVDC material is coated with polyvinylidene chloride (PVDC) on polyvinyl chloride (PVC). The solid preparation for oral administration according to any one of claims 1 to 4, wherein the solid preparation is a tablet, powder, granule, or capsule.