KR20150042408A - Sustained release pharmaceutical composition comprising tramadol and acetaminophen - Google Patents

Abstract

The present invention relates to a novel pharmaceutical composition whose drug release is regulated to be constant and stable in relation to sustained release pharmaceutical composition including acetaminophen and tramadol. Provided is a sustained release pharmaceutical composition, which includes first sustained release granules including acetaminophen and tramadol; and an immediate tramadol release part, wherein acetaminophen controls the release of tramadol. When the composition is injected one time in an empty stomach and after high fat diet, 4,400-7,000 ng/mL of maximum blood acetaminophen concentration on average is provided during average 0.5-3 hours after injection, and 150-250 ng/mL of maximum blood tramadol concentration on average is provided during average 1.5-5 hours after injection.

Description

[0001] SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING TRAMADOL AND ACETAMINOPHEN [0002]

The present invention relates to a pharmaceutical composition comprising tramadol and acetaminophen and having a specific drug release pattern. More particularly, the present invention relates to a sustained release pharmaceutical composition comprising tramadol and acetaminophen, which can be administered to a patient in a variety of body-affecting factors such as pH changes in the gastrointestinal tract, change in locomotor activity, increase in digestive enzymes, Characterized in that the drug release pattern exhibits no significant effects and variability and exhibits stable release. The present invention also relates to a pharmaceutical composition comprising a tramadol and acetaminophen as a sustained-release pharmaceutical composition, wherein the pharmaceutical composition exhibits a specific drug release pattern to thereby reduce side effects. Further, the present invention relates to a sustained-release pharmaceutical composition comprising tramadol and acetaminophen, wherein the release of tramadol is controlled using acetaminophen to prevent the size of the unit dosage form from increasing as the content of the active ingredient increases The present invention relates to a novel control emission means which is based on a novel idea and which did not exist in the past.

The present invention relates to tramadol or a derivative thereof and an acetaminophen-containing sustained-release tablet, which comprises tramadol or a derivative thereof, 1N-oxide, o-desmethyl derivative, or a stereoisomer thereof and a mixture thereof (e.g. racemate) Pharmaceutically acceptable salts (including, for example, hydrochloride or solvate) are all known compounds used as analgesics and disclosed in U.S. Patent No. 3652589.

Acetaminophen also has analgesic action, for example the known compounds described in U.S. Pat. No. 2,998,450.

Korean Patent No. 243956 discloses a composition for treating pain wherein tramadol: acetaminophen is present at a weight ratio of about 1: 5 to 1: 50 and is expected to be synergistic. Ultraset® tablets are non-narcotic analgesics that exhibit rapid and potent pain relief and have the advantage of significantly less side effects from long-term use than NSAIDs, Was short and had to take 4 times a day.

For this reason, research and development of sustained-release medicines including tramadol and acetaminophen have been actively conducted in the art. For example, in Patent Publication 10-2010-0069685, tramadol and acetaminophen are used. Lt; RTI ID = 0.0 > a < / RTI > double-layer composition,

a. A first layer defining the rapid releases portion of the composition and comprising acetaminophen; And

b. Characterized in that it comprises a second layer which defines a sustained release portion of said composition and comprises acetaminophen, tramadol and cross-linked high-amylose starch, wherein acetaminophen and tramadol are released in a specific kinetics. Compositions are disclosed.

In addition, Japanese Patent Application Laid-Open No. 10-2011-0036858 discloses a pharmaceutical composition comprising acetaminophen and a tramadol complex (such as a carrageenan complex) and having a sustained release of 4 to achieve a cumulative tramadol release and acetaminophen cumulative release over time -12 hours, the cumulative% cumulative release of acetaminophen from the cumulative release of tramadol is less than 10-25% by weight when the cumulative weighted release of tramadol is 40% by weight, and the sustained release composition comprises a disintegrant, An extended release pharmaceutical composition has been disclosed which comprises aminophen and tramadol non-complex cargo.

However, when a pharmaceutical composition containing acetaminophen and tramadol is prepared in a sustained-release form, the active ingredient must be contained in a higher content than that of the conventional formulation (rapid-release formulation), so that it is difficult to control the release thereof. Particularly, according to the studies of the present inventors, the sustained-release pharmaceutical composition comprising acetaminophen and tramadol has various effects on the body, such as changes in the pH of the gastrointestinal tract, changes in locomotor activity, increase in digestive enzymes, The gastric emptying rate and the rate of gastric emptying, the release is not constantly and stably controlled. Therefore, it has been found that the adverse reaction (adverse effect) is manifested to a great extent and it is necessary to find a means to solve this problem Has reached the invention. Further, in the case of releasing acetaminophen and tramadol, it is necessary to use a controlled release polymer. In this case, the size of the unit dosage form must be increased. This means that the compliance of the drug is lowered. The inventors of the present invention have reached the present invention by realizing that a means for reducing the size of the unit dosage form is required by drastically reducing the amount of the polymer used.

Accordingly, it is an object of the present invention to provide a novel pharmaceutical composition which is constantly and stably controlled in drug release, in association with a sustained-release pharmaceutical composition comprising acetaminophen and tramadol.

More specifically, the present invention relates to a pharmaceutical composition which does not show significant influences and variability in various body influencing factors affecting drug release, for example, pH change in gastrointestinal tract, change in locomotor activity, increase digestive enzymes, gastric emptying, gastrointestinal transit rate, The present invention provides a pharmaceutical composition which can be used as a pharmaceutical composition.

Furthermore, it is an object of the present invention to provide a pharmaceutical composition which is characterized in that the drug release is stabilized and side effects are reduced as compared with the conventional sustained-release preparations containing acetaminophen and tramadol.

It is another object of the present invention to provide a pharmaceutical composition capable of reducing the size of the final unit dosage form by controlling the release of tramadol using another active ingredient acetaminophen, thereby reducing the amount of the controlled release polymer used .

As means for solving the above problems, the present invention provides a pharmaceutical composition as described below.

A sustained release pharmaceutical composition comprising acetaminophen and tramadol,

A first sustained release granule comprising acetaminophen and tramadol;

A second western granule comprising acetaminophen;

An inner granule containing acetaminophen; And

Wherein the composition provides an average maximum blood concentration of 4,400 to 7,000 ng / mL of acetaminophen at a single administration after the fasting state and the high fat diet, and an average of 0.5 to 3 hours after administration, , And an average maximum blood concentration of tramadol of 150 to 250 ng / mL at an average of 1.5 to 5 hours after administration, and 35 to 55 ng / mL of "O-desmethyltramarol" (Hereinafter referred to as " tramadol metabolite (M1) ").

In the composition, when the composition is repeatedly administered every 12 hours, an average maximum blood concentration of acetaminophen of 5,000 to 7,800 ng / mL is provided at an average of 0.17 to 4 hours, and an average of 0.5 to 5 hours Provides an average maximum blood concentration of tramadol of 240 to 380 ng / mL, and provides an average maximum blood concentration of tramadol (M1) of 45 to 72 ng / mL at an average of 1 to 6 hours after administration. A sex pharmacological composition is provided.

Wherein said composition has a mean AUC _inf for acetaminophen, tramadol and tramadol metabolites (M1) of from 28,000 to 44,000 hr * ng / mL and from 1,600 to 2,500 hr * ng / mL, and 470-740 hr * ng / mL.

When the composition is repeatedly administered every 12 hours, the average AUC _{0-12 hrs, ss} for acetaminophen, tramadol and tramadol metabolites (M1) are 26,000 to 40,000 hr * ng / mL, 3,000 hr * ng / mL, and 400 to 640 hr * ng / mL.

In the composition, the sustained release pharmaceutical composition is characterized by comprising 75 mg of tramadol and 650 mg of acetaminophen per unit dosage form.

In the composition, the sustained release pharmaceutical composition is characterized in that the first sustained release granule or the second sustained release granule is coated with a release modifying polymer.

A method for preparing a sustained release pharmaceutical composition comprising acetaminophen and tramadol,

(a) preparing a first sustained release granule comprising acetaminophen, tramadol and a pharmaceutically acceptable excipient;

(b) preparing a second western granule comprising acetaminophen and a pharmaceutically acceptable excipient;

(c) preparing a morning granule comprising acetaminophen and a pharmaceutically acceptable excipient;

(d) post-mixing the first sustained release granule, the second sustained release granule and the inner granule with tramadol and a pharmaceutically acceptable excipient; And

(e) A method for producing a sustained release pharmaceutical composition comprising acetaminophen and tramadol by tableting or filling the resultant of step (d) in capsules.

Further, in the above production method, the first sustained-release granule and the second sustained-release granule of the step (a) and the step (b) are coated with the release-controlling polymer.

 The sustained release pharmaceutical compositions comprising acetaminophen and tramadol according to the present invention may be used in a variety of body-affecting factors that affect drug release, such as pH changes in the gastrointestinal tract, locomotor changes, increase in digestive enzymes, gastric emptying, And exhibits stable release without exhibiting a significant effect and variability in the amount of water.

In particular, the sustained release pharmaceutical composition according to the present invention has a remarkable effect that the side effects are reduced as a result of stabilization of the drug release, as compared with the conventional sustained release preparation containing acetaminophen and tramadol.

Figures 1 and 2 show the protocol of a clinical trial for comparing the pharmacokinetic and pharmacological properties of Example 1 of the present invention and ultraset immediate-release definition.
3 and 4 are graphs showing the results of evaluating the dissolution rate according to pH change of the eluate.
5 and 6 are graphs showing the results of evaluating the dissolution rate according to the rotation speed change of the paddles in the dissolution test.
7 and 8 are graphs showing the results of evaluating the dissolution rate depending on the presence / absence of surfactant in the dissolution test.
Figures 9 and 10 are estimates of dissolution rates according to the body disintegration and erroneous dosing methods of the formulations.
Figs. 11 and 12 are diagrams for evaluating dissolution rates of Example 1 and Comparative Example 1. Fig.
13 and 14 are diagrams for evaluating the dissolution rate obtained by formulating the formulation of Example 1 in half volume.
15 and 16 are diagrams for evaluating the dissolution rates of Example 1 and Comparative Example 2. Fig.

The present invention relates to a composition comprising tramadol and acetaminophen. Tramadol is used herein to refer to (1R, 2R or 1S, 2S) - (dimethylaminomethyl) -1- (3-methoxyphenyl) -cyclohexanol (tramadol), its N-oxide derivative -Oxide "), and its metabolite (M1) or a mixture thereof. Tramadol also includes a mixture of each stereoisomer, stereoisomer (e.g., racemate), a pharmaceutically acceptable amine salt such as a hydrochloride salt, a solvate, and a polymorphic tramadol material. The pharmacology of acetaminophen is described in [B. Ameer et al., Ann.

Int. Med., 87, 202 (1977)] and the preparation of acetaminophen is described in U.S. Patent No. 2,998,450.

Composite preparations containing acetaminophen and tramadol are known, and Ultraset® is known as an immediate release preparation, and Ultraset® immediate release tablet as a sustained release preparation is commercially available.

On the other hand, in the case of a sustained-release preparation containing acetaminophen and tramadol, it should contain twice the effective ingredient contained in the immediate release preparation, and sufficient analgesic action should be secured by administration twice a day. The present inventors have found that the combined release preparation of acetaminophen and tramadol in the sustained-release preparation has the following problems.

First, it was found that the dissolution pattern of the preparation varies depending on the pH of the dissolution test liquid in the in vitro dissolution test. That is, in the case of the conventional sustained-release preparation containing acetaminophen and tramadol, it was found that the difference in the dissolution rate of acetaminophen varied up to 20% in the case of acetaminophen and 25% in the case of tramadol depending on the pH of the dissolution test liquid. Given the fasting or taking before or after meals, the pH environment in the body (gastrointestinal tract) may be different depending on the time of taking. Therefore, we found that if the dissolution rate of the sustained-release preparation is greatly changed according to the pH, the release pattern of the drug in the body may be greatly changed. This is because, with respect to the time point of taking the drug and the position of drug release in the body, the pH, Gastric empting time, and GI transit time change This indicates that the release pattern of the drug according to the present invention is greatly changed, and thus it can not exhibit a certain pharmacological effect.

Second, it was found that the elution pattern of the preparation varies depending on the elution rate of the eluent in the in vitro dissolution test. That is, in the case of the conventional sustained-release preparation containing acetaminophen and tramadol, it was found that the difference in the dissolution rate varied up to 5% in the case of tramadol and up to 8% in the case of tramadol. Regarding the time point of administration of the drug, this also means that the release pattern of the drug is greatly changed in consideration of the change in the locomotive force of the gastrointestinal tract when administered at the time of fasting and post-prandial administration, It indicates that it is not possible.

Third, we found that the dissolution pattern of the preparation changes depending on the presence or absence of surfactant in the in vitro dissolution test. That is, in the case of the conventional sustained-release preparation containing acetaminophen and tramadol, it was found that the difference in the dissolution rate varied by up to 3% for acetaminophen and up to 5% for tramadol. This means that the release pattern of the drug differs in consideration of the physical characteristics inherent to the person taking the drug, the difference in the digestive enzymes when administered at the time of fasting and after the meal, and therefore the drug can not exhibit a certain pharmacological effect .

Fourth, when the tablet was divided, it was found that the dissolution pattern of the preparation changed. That is, in the case of the conventional sustained-release preparation containing acetaminophen and tramadol, it was found that when the test was divided, the dissolution rate varied by up to 6% for acetaminophen and up to 9% for tramadol. This indicates that in the case of a sustained-release layer of the matrix in the form of a collapse or a false medication, the drug is released in a different pattern from the drug release pattern desired by the original preparation, and thus can not exhibit a certain pharmacological effect.

Fifth, in the case of a two-layer sustained release preparation in the form of a matrix in general, there is a problem in that drug release rate is lowered due to the influence of drug release in the immediate layer due to the viscosity of the sustained-release polymer at the interface between the slow layer and the immediate layer. However, the composition of the present invention was confirmed to be completely disintegrated in about 5 minutes in the in vitro evaluation of the composition, and it was confirmed that the western part and the inner part had no effect on mutual drug release.

Sixth, with respect to the size of the final unit dosage form, a controlled release polymer capable of controlling the release of tramadol and acetaminophen should be used. Considering the amount of active ingredient, conventional sustained release materials may be used or conventional sustained release The amount of the active ingredient contained in one unit dosage form, the amount of the sustained release substance and the amount of the other excipient are taken into consideration, and the size of the dosage form becomes too large and the adherence compliance of the dosage drops sharply. This indicates that an unusual means is needed to reduce the size of the unit dosage form.

In the above description, the evaluation of the effect of drug release according to the environmental change was evaluated by the in vitro evaluation of the environmental change factor in the in vivo, but the change of the gastrointestinal pH, Drug release rates may change drastically if changes in the body's drug release environment, such as digestive enzymes, matrix-like slow-release viscous gelation-time differences, gel-tension, rigidity differences, , Which may cause side-effect (adverse effect, AE) increase by dose-dumping and can not exhibit a certain pharmacological effect.

The inventors of the present invention recognized that the conventional sustained-release preparation containing acetaminophen and tramadol had the above-mentioned problems. As a result of intensive studies on a novel means for solving the problem, the present inventors have found that a sustained-release preparation And thus it is possible to solve all of the problems listed above.

That is, in the present invention, in the sustained-release pharmaceutical composition comprising acetaminophen and tramadol,

A first sustained release granule comprising acetaminophen and tramadol; And

Tramadol's internal preservation

Wherein the acetaminophen controls the release of tramadol and provides an average maximum blood concentration of acetaminophen of 4,000 to 7,000 ng / mL at a single administration time of 0.5 to 3 hours after administration of the composition, The mean maximum blood concentration of tramadol was 150 to 240 ng / mL at an average of 1.5 to 5 hours after administration, and the mean maximum blood concentration of tramadol (M1) of 35 to 55 ng / mL at an average of 1.5 to 6 hours after administration Or a pharmaceutically acceptable salt thereof.

The inventors of the present invention have conducted studies for solubilizing acetaminophen and tramadol in developing sustained-release unit formulations containing acetaminophen and tramadol. However, the present inventors have found that conventional known sustained release means, that is, Is not suitable for commercial formulation because it is difficult to achieve the desired release pattern and the size of the final unit dosage form is excessively increased.

Thus, as a result of continuing the study, it was surprisingly found that, when acetaminophen and tramadol are composed of one granule, acetaminophen solubilizes the release of tramadol. As is well known in the art, when the release of the drug is constituted by the sustained release, a means for delaying the diffusion of the drug by mixing or coating the sustained release polymeric material (controlled release polymer) or the like in a matrix form or coating is common , The present inventors have discovered that one active ingredient (acetaminophen), which is not known at all in the prior art, delays the release of another active ingredient (tramadol).

Thus, a first technical feature of the present invention is to provide a formulation wherein acetaminophen is delayed release of tramadol to achieve the pharmacokinetic profile described below.

The reason why acetaminophen releases the release pattern of tramadol is that the solubility (1: 300) of acetaminophen (about 10 mg / mL, tramadol about 3,000 mg / mL in water ), Differences in the local environment surrounding the drug, such as the difference in physical drug concentration, the difference in drug molecular weight, and the surrounding pH, due to the difference in competitive drug release by the drug (8.7: 1) (acetaminophen 650 mg, tramadol 75 mg) .

The first sustained-release granules containing acetaminophen and tramadol as referred to in the present invention are prepared by mixing an active ingredient acetaminophen and tramadol together with pharmaceutically acceptable excipients such as a lubricant and a disintegrant, For example, purified water, ethanol or the like, using a binding solution prepared by dissolving a binder and a solubilizer in a conventional manner, drying and sizing.

The pharmaceutically acceptable excipient to be used at this time is not limited, but preferably it may be one or more selected from excipients, disintegrants and excipients, and the excipients, disintegrants and lubricants may be easily selected by those skilled in the art. For example, as the excipient, at least one selected from hydroxypropylcellulose, cellactose, kollidon, and silicified microcrystalline cellulose may be used, and disintegrant may be sodium croscarmellose Magnesium stearate may be used as the lubricant.

Also, the first sustained release granules so obtained may be release modifying coated, for example, the release modifying coating may be coated with a release modifying polymer. Although the type of the release-controlling polymer is not limited, it is preferably made of a water-insoluble cellulose, a derivative of water-insoluble cellulose, a polymethacrylate polyalkylacrylate and a methacrylic acid-ethyl acrylate copolymer Lt; / RTI > The water-insoluble cellulose may preferably be alkylcellulose, more preferably ethylcellulose. The derivative of the water-insoluble cellulose may preferably be at least one selected from the group consisting of cellulose acetate, cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate.

In addition, it may contain sodium hydroxide as a release-controlling substance, and a plasticizer such as polyethylene glycol or triacerine may be included in the coating liquid, for example.

Such a coating process can be carried out once or several times, and it is also possible to perform the coating process in the same coating liquid or in a coating liquid prepared using different materials. However, as mentioned above, since the acetaminophen itself functions to delay the release of tramadol, it is a matter of course that the use amount of the release-controlling substance is greatly reduced.

Further, in the present invention, in addition to the first sustained-release granule containing acetaminophen and tramadol, if necessary, a second sustained release granule containing acetaminophen; Or acetaminophen; Or tramadol emulsion. Also in this case, the average maximum blood concentration of acetaminophen of 4,000 to 7,000 ng / mL is provided at an average of 0.5 to 3 hours after the single administration of the composition, and 150 to 240 ng / mL of tramadol and provides an average maximum blood concentration of tramadol (M1) of 35 to 55 ng / mL at an average of 1.5 to 6 hours after administration. According to the present invention, acetaminophen and tramadol can be sustained release over a period of 12 hours, and a sustained release pattern that is not affected by the pH or motility of the gastrointestinal tract can be maintained. Furthermore, the presence of digestive enzymes and the administration of the agent in divided doses can maintain the release as designed for the formulation.

That is, acetaminophen and tramadol, which are effective components of the pharmaceutical composition of the present invention, may exist in, for example, three different granules. A first western granule comprising acetaminophen and tramadol; A second sustained-release granule containing acetaminophen and a second sustained-release granule containing acetaminophen.

As described above, the first sustained-release granule may be a sustained-release granule containing acetaminophen and tramadol as active ingredients, and acetaminophen is a granule capable of releasing the release of tramadol.

The second sustained-release granules containing acetaminophen may be prepared by mixing the active ingredient acetaminophen together with pharmaceutically acceptable excipients such as lubricants, disintegrants and the like, and then adding a suitable pharmaceutically acceptable solvent, for example, For example, it can be obtained by assembling by a conventional method using a binding solution obtained by dissolving a binder and a solubilizing agent in purified water or ethanol, drying and sizing.

The pharmaceutically acceptable excipient to be used at this time is not limited, but preferably it may be one or more selected from excipients, disintegrants and excipients, and the excipients, disintegrants and lubricants may be easily selected by those skilled in the art. For example, as the excipient, at least one selected from hydroxypropyl cellulose, cellactose, kollidon, and silicified microcrystalline cellulose may be used, sodium croscarmellose as a disintegrant, Magnesium stearate may be used as the lubricant.

Also, the second sustained release granules so obtained may be release modifying coated, for example, the release modifying coating may be coated with a release modifying polymer. The type of the release-controlling polymer is not limited, but it is preferably a water-insoluble cellulose, a derivative of water-insoluble cellulose, polymethacrylate, polyalkylacrylate and methacrylic acid-ethyl acrylate copolymer Lt; / RTI > The water-insoluble cellulose may preferably be alkylcellulose, more preferably ethylcellulose. The derivative of the water-insoluble cellulose may preferably be at least one selected from the group consisting of cellulose acetate, cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate.

In addition, a plasticizer, such as polyethylene glycol or triacerin, may be included in the coating solution.

Such a coating process can be carried out once or several times, and it is also possible to perform the coating process in the same coating liquid or in a coating liquid prepared using different materials.

Next, the inner granule may be an inner granule containing acetaminophen. The inner granule can be prepared by assembling acetaminophen and a pharmaceutically acceptable excipient using a binding agent in which a binder such as povidone is dissolved in a solvent such as purified water, and drying and sieving.

Particularly, the inner granule is prepared by using acetaminophen as a releasing drug and using lactose, sodium croscarmellose sodium, colloidal silicon dioxide, hydroxypropylcellulose, microcrystalline cellulose, A low-substituted hydroxypropylcellulose, a powdered cellulose, and the like, and then the binder solution may be used to prepare the immediate release granules.

After preparation of the first sustained release granule, the second sustained release granule and the second sustained release granules as described above, the sustained release pharmaceutical composition of the present invention is prepared by filling the capsule with the tramadol and a pharmaceutically acceptable excipient, Can be prepared.

On the other hand, a characteristic aspect of the present invention is that the pharmaceutical composition of the present invention exhibits a specific PK-profile.

That is, the sustained release composition according to the present invention can be used as a conventional sustained-release preparation containing acetaminophen and tramadol, while securing bioequivalence with acetaminophen and ultraset, which is a rapid-acting combination agent of tramadol, And the PK-profile, it is possible to obtain various body-affecting factors influencing drug release in the body, such as changes in the pH and motility of the gastrointestinal tract, increase in digestive enzymes, gastric emptying time ) And GI transit time (gastrointestinal transit time), showing stable release and showing various kinds of adverse reactions when the conventional sustained-release preparation is administered, for example, leukocytopenia, abdominal pain, Headache, vomiting, and the like.

Specifically, the composition according to the present invention satisfied the following PK-profile by single administration in the fasting state.

Geometric Mean Ratio (Test ² / Reference¹) Reference¹ Test ² Point Estimate 90% Confidence Interval Tramadol C _max (ng / mL) 194.039 174.436 0.899 0.834-0.969 AUC _inf (hr * ng / mL) 1975.188 1947.515 0.986 0.943-1.031 M1
C _max (ng / mL) 41.414 38.773 0.936 0.879-0.997 AUC _inf (hr * ng / mL) 567.039 573.033 1.011 0.972-1.050 Acetaminophen
C _max (ng / mL) 5430.842 5171.138 0.952 0.862-1.052 AUC _inf (hr * ng / mL) 34106.595 35074.402 1.029 0.992-1.066 ¹ UltraSET® Constant Speed (idle state) ² Invention Example-1 Slow (fasting state)

At the same time, the composition according to the present invention showed a PK-profile as shown below after a single oral administration.

Geometric Mean Ratio (Test ² / Reference¹) Reference¹ Test ² Point Estimate 90% Confidence Interval Tramadol Cmax (ng / mL) 174.436 225.122 1.291 1.198-1.391 AUC _inf (hr * ng / mL) 1947.515 2043.160 1.049 1.004-1.097 M1
Cmax (ng / mL) 38.773 40.008 1.032 0.969-1.099 AUC _inf (hr * ng / mL) 573.033 562.825 0.982 0.945-1.021 Acetaminophen
Cmax (ng / mL) 5171.138 4866.873 0.941 0.852-1.040 AUC _inf (hr * ng / mL) 35074.402 34290.135 0.979 0.944-1.015 ¹ Invention Example 1 -1 sustained (fasting state) ² Invention Example-1 Slowing (Highland method)

In addition, the following PK-profile was satisfied as compared with the ULTRASET® Constant Speed Constant (fasted state) and the present invention Example-1 slow speed (high speed method).

Geometric Mean Ratio (Test ² / Reference¹) Reference¹ Test ² Point Estimate 90% Confidence Interval Tramadol
Cmax (ng / mL) 193,357 225.038 1.164 1.094-1.239 AUC _inf (hr * ng / mL) 1879.546 1923.813 1.024 0.922-1.136 M1 Cmax (ng / mL) 41.915 40.717 0.971 0.859-1.099 AUC _inf (hr * ng / mL) 546.607 546.003 0.999 0.928-1.075 Acetaminophen Cmax (ng / mL) 5463.354 4936.48 0.904 0.846-0.965 AUC _inf (hr * ng / mL) 33022.714 31931.291 0.967 0.902-1.037 ¹ UltraSET® Constant Speed (idle state) ² Invention Example-1 Slowing (Highland method)

In addition, the composition according to the present invention satisfies the following PK-profile in fasting-single administration after reaching a steady-state by repeated administration.

Geometric Mean Ratio (Test ² / Reference¹) Reference¹ Test ² Point Estimate 90% Confidence Interval Tramadol
Cmax (ng / mL) 293.062 282.670 0.965 0.913-1.019 AUC _inf (hr * ng / mL) 2264.875 2322.609 1.025 0.995-1.057 M1
Cmax (ng / mL) 53.909 51.570 0.957 0.927-0.987 AUC _inf (hr * ng / mL) 483.895 488.515 1.010 0.984-1.035 Acetaminophen Cmax (ng / mL) 5989.294 6261.054 1.045 0.936-1.168 AUC _inf (hr * ng / mL) 31727.139 31482.935 0.992 0.963-1.023 ¹ UltraSET® Constant acceleration (idle after acceleration) ² Invention Example-1 Slow (fasting after resting state)

As can be seen from the above table, the composition of the present invention is characterized by having pharmacokinetic equivalence with the UltraSET constant constancy in a single fasted state. In Example 1 of the present invention, the Cmax of Tramadol was slightly higher than that of the sustained-release administration of the sustained-release formulation. However, in the development of the sustained-release formulation of the highly soluble drug such as tramadol (about 3,000 mg / mL in water) The drug release rate is estimated to be affected by various influencing factors, which is why many developers face the greatest difficulty in developing a sustained-release drug for high-availability drugs.

However, in Example 1 of the present invention, the AUC _inf , T _max , and T _1/2 of tramadol were equally pharmacologically equivalent and slightly increased only in the C _max ,

In the Food Effect of Ryzolt, which is sold in the United States after the FDA approval of the domestic licensing product Tramaconti Surobije, a conventional western blotting agent containing the same active ingredient tramadol, "AUC was not significantly affected , The C _max was significantly lowered by the Food Effect compared to the 67% increase at 300 mg and the 54% increase at 200 mg administration.

In addition, the pharmacokinetic parameters (AUC, C _max ) in Acetaminophen, Tramadol, and M1 were confirmed to be equivalent in both of the fasted fasting of the UltraSET® constant speed infusion and the administration of the present invention Example-1 slow slow down method.

Such a phenomenon has a very large technical meaning in the sustained-release preparation as in the present invention.

In general, when the formulation is changed to a sustained-release formulation, the PK equivalency test in Phase I clinical trials is a test of 20-to 45-year-old healthy men who were given the fasting and post- , And it is conducted by cross-testing the test drug to be developed with the internal fixation as the reference drug.

(AUC, C _max ) of the drug were compared with the control (fasting) vs. test (fasting), test (fasting) vs. test (fasting) The same method), and the result is judged to be 'pharmacokinetic equivalent', assuming that it will be applied in clinical practice.

In practice, however, the situation in which a patient comes across is often different from the setting of this pharmacokinetic equivalence study. For example, instead of a young, healthy man, older people, young people, and those with one or two abnormalities in organ function can take medication, or the absorption patterns of drugs such as elderly people and infants who are separated from the digestive tract function are like healthy young men I can not.

Particularly, in the case of sustained-release preparations, the most significant difference is the change in the drug release environment in the body due to differences in gastrointestinal pH and mobility, differences in digestive enzymes, and methods of administration, It is difficult to guarantee that it will change. If these effects are influenced by the sustained release of the sustained-release formulation, ultimately, the drug will not exhibit a certain pharmacological effect with increased side-effect on dose-dumping. The prominence of this phenomenon in the slow release formulation is reported by clinical pharmacologists.

However, in the case of the present invention, there was no significant change in the dissolution rate difference within a maximum of 5% depending on factors such as the pH of the dissolution test liquid, the paddle rotation rate, the surfactant, and the partitioning of tablets, This is another technical feature of the present invention.

Another aspect of the present invention is that the in vitro dissolution pattern of the drug is not affected even in the in vitro evaluation, taking into consideration various influencing factors affecting the drug release of the sustained-release preparation.

That is, according to the study of the present inventors, it has been found that when the sustained release composition of the present invention is subjected to the elution test paddle method at a rate of 120 to 240 minutes of a test of 900 mL of the eluate of 75 rpm, pH 1.2 and pH 6.8, However, in the case of conventional sustained release preparations containing acetaminophen and tramadol, it was found that differences in the drug release of acetaminophen and tramadol were 20% and 25%, respectively. Such a phenomenon is clinically very significant considering that the sustained-release preparation described above and the drug release after the meal can be greatly changed in the case of the sustained-release preparation described above. Therefore, the substantial pharmacological effect It is very surprising in that it leads.

Further, in the case of the present invention, with the difference of less than 3% in the elution test paddle method, 900 mL of the pH 6.8 eluate, 75 rpm and 100 rpm test in 120 to 240 minutes, compared to the sustained release preparation containing the same conventional active ingredient, It has been proved that the drug dissolution pattern is not influenced by the same dissolution rate in the case of the presence of the surfactant or the cleaved cleavage simultaneously with the change of the release pattern and when compared with the conventional sustained release preparation. In addition, in the case of the conventional sustained-release pharmaceutical composition, there occurs a phenomenon that mutual influences are generated at the interface between the fast and slow portions and the release speed of the early quick release portion is lowered. In the present invention, however, , And it is very different from the conventional sustained-release preparation in that it does not affect the drug release of acetaminophen and tramadol spontaneously due to rapid disintegration of the tablet.

Hereinafter, the composition of the present invention will be described by the following examples. The following examples illustrate specific embodiments of the present invention, and it should be noted that the present invention is not limited by the following examples.

[Example]

Example 1_ Preparation of the composition of the present invention

The raw materials of the sustained-release preparations according to the present invention and their amounts are shown in Table 5 below.

Ingredients Amount (wt%) Acetaminophen 54.2 Tramadol hydrochloride 6.3 Hydroxyethyl cellulose 3.1 Ammonium methacrylic copolymer 5.3 Hypromellose 0.1 Microcrystalline cellulose 2.0 Hydroxypropylcellulose 0.2 Povidone 1.6 Powdered cellulose 6.8 Sodium carboxymethylcellulose sodium 3.1 Sodium lauryl sulfate 0.2 Ethyl Cellulose 9.9 Sodium hydroxide 0.03 Polyethylene glycol 1.4 Triacetin 1.3 Colloidal silicon dioxide 0.2 Talc 0.47 Magnesium stearate 0.5 Opa Dry Yellow (85F12347) 3.3

Manufacturing method

(1) Using a binding liquid prepared by dissolving ethanol and water in hydroxypropyl cellulose and sodium lauryl sulfate, acetaminophen, tramadol hydrochloride, colloidal silicon dioxide, microcrystalline cellulose, croscarmex methylcellulose sodium, hydroxyethyl cellulose Cellulose, and ammonio methacrylic copolymer are combined and dried and formulated to prepare a first western granule.

(2) Polyethylene glycol and triacetin as plasticizers together with ethylcellulose and sodium hydroxide as a release modifier are dissolved in water and ethanol to prepare a coating liquid and sprayed on the first western granule.

(3) A mixture of acetaminophen, colloidal silicon dioxide, and ammonio methacrylic copolymer was combined using a binding solution prepared by dissolving ethanol and water in ethylcellulose, followed by drying and sizing to form a second western granule .

(4) A coating solution is prepared by dissolving ethanol, water, ethylcellulose, polyethylene glycol and triacetin in water, and coating the second western granule.

(5) Using a binding liquid prepared by dissolving povidone in purified water, a mixture of acetaminophen, colloidal silicon dioxide, powdered cellulose and croscarmellose sodium cellulose is combined to produce an immediate granule.

(6) The first Western granule, the second Western granule, the inner granule is mixed with tramadol and magnesium stearate, and the mixture is coated with opaque.

[Comparative Example]

COMPARATIVE EXAMPLE 1_ Preparation of Composition of Comparative Example of the Present Invention

Compared with the composition of Example 1 according to the present invention, acetaminophen and tramadol were respectively prepared as the first sustained-release granule and the second sustained-release granule, and the drug substance and the amount thereof are shown in Table 6 below.

Ingredients Amount (wt%) Acetaminophen 43.3 Tramadol hydrochloride 5.0 Hydroxyethyl cellulose 5.7 Ammonium methacrylic copolymer 5.7 Hypromellose 0.1 Microcrystalline cellulose 5.7 Hydroxypropylcellulose 0.2 Povidone 1.3 Powdered cellulose 5.3 Sodium carboxymethylcellulose sodium 2.7 Sodium lauryl sulfate 0.2 Ethyl Cellulose 14.1 Sodium hydroxide 0.03 Polyethylene glycol 3.0 Triacetin 2.0 Colloidal silicon dioxide 0.3 Talc 0.47 Magnesium stearate 0.9 Opa Dry Yellow (85F12347) 4.0

Manufacturing method

(1) A binding liquid prepared by dissolving ethanol and water in a mixture of hydroxypropyl cellulose and sodium lauryl sulfate was used to prepare tramadol hydrochloride, colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxyethylcellulose and ammonia And a mixture of an omega acrylic copolymer are combined and dried and formulated to prepare a first western granule.

(2) Polyethylene glycol and triacetin as plasticizers together with ethylcellulose and sodium hydroxide as a release modifier are dissolved in water and ethanol to prepare a coating liquid and sprayed on the first western granule.

(3) A mixture of acetaminophen, colloidal silicon dioxide, and ammonio methacrylic copolymer was combined using a binding solution prepared by dissolving ethanol and water in ethylcellulose, followed by drying and sizing to form a second western granule .

(4) A coating solution is prepared by dissolving ethanol, water, ethylcellulose, polyethylene glycol and triacetin in water, and coating the second western granule.

(5) Using a binding liquid prepared by dissolving povidone in purified water, a mixture of acetaminophen, colloidal silicon dioxide, powdered cellulose and croscarmellose sodium cellulose is combined to produce an immediate granule.

(6) The first Western granule, the second Western granule, the inner granule is mixed with tramadol and magnesium stearate, and the mixture is coated with opaque.

Consideration of Example 1 and Comparative Example 1

Example 1 demonstrates the relatively low water solubility (about 10 mg / mL in water) and the high content (650 mg) of the drug acetone, which are relatively water soluble (about 3,000 mg / mL in water) and low (75 mg) drug tramadol, Aminophen was used to reduce the mass of 20% relative to the composition according to Comparative Example 1. This can be evaluated as a new and advanced new concept of drug release control technology that releases one pharmacologically active ingredient and controls release of another pharmacologically active ingredient, thereby achieving a sustained release. In Comparative Example 1, a first sustained-release granule was prepared using a large amount of a release-controlling agent for releasing a sustained-release drug of tramadol, which is a highly water-soluble drug (about 3,000 mg / mL in water).

[Comparative Example 2]

COMPARATIVE EXAMPLE 2_ Preparation of Composition of Comparative Example of the Present Invention

Compared with the composition of Example 1 according to the present invention, acetaminophen and tramadol were prepared as the first sustained release granule and the second sustained release granule, respectively, and the drug substance and the amount thereof are shown in Table 7 below.

Ingredients Amount (wt%) Acetaminophen 54.2 Tramadol hydrochloride 6.3 Hydroxyethyl cellulose 3.1 Ammonium methacrylic copolymer 5.3 Hypromellose 0.1 Microcrystalline cellulose 2.0 Hydroxypropylcellulose 0.2 Povidone 1.6 Powdered cellulose 6.8 Sodium carboxymethylcellulose sodium 3.1 Sodium lauryl sulfate 0.2 Ethyl Cellulose 9.9 Sodium hydroxide 0.03 Polyethylene glycol 1.4 Triacetin 1.3 Colloidal silicon dioxide 0.2 Talc 0.47 Magnesium stearate 0.5 Opa Dry Yellow (85F12347) 3.3

Manufacturing method

(1) A binding liquid prepared by dissolving ethanol and water in a mixture of hydroxypropyl cellulose and sodium lauryl sulfate was used to prepare tramadol hydrochloride, colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxyethylcellulose and ammonia And a mixture of an omega acrylic copolymer are combined and dried and formulated to prepare a first western granule.

(2) Polyethylene glycol and triacetin as plasticizers together with ethylcellulose and sodium hydroxide as a release modifier are dissolved in water and ethanol to prepare a coating liquid and sprayed on the first western granule.

(3) A mixture of acetaminophen, colloidal silicon dioxide, and ammonio methacrylic copolymer was combined using a binding solution prepared by dissolving ethanol and water in ethylcellulose, followed by drying and sizing to form a second western granule .

(4) A coating solution is prepared by dissolving ethanol, water, ethylcellulose, polyethylene glycol and triacetin in water, and coating the second western granule.

(5) Using a binding liquid prepared by dissolving povidone in purified water, a mixture of acetaminophen, colloidal silicon dioxide, powdered cellulose and croscarmellose sodium cellulose is combined to produce an immediate granule.

(6) The first Western granule, the second Western granule, the inner granule is mixed with tramadol and magnesium stearate, and the mixture is coated with opaque.

Consideration of Example 1, Comparative Example 1 and Comparative Example 2

Example 1 demonstrates the relatively low water solubility (about 10 mg / mL in water) and the high content (650 mg) of the drug acetone, which are relatively water soluble (about 3,000 mg / mL in water) and low (75 mg) drug tramadol, Aminophen was used to reduce the mass of 20% relative to the composition according to Comparative Example 1. In Comparative Example 2, acetaminophen and tramadol, which are the production methods of Comparative Example 1, were prepared from the same first and second western granules by using the same 'raw material drug and its amount' as in Example 1. This can be evaluated as a new and advanced new concept of drug release control technology that releases one pharmacologically active ingredient and controls release of another pharmacologically active ingredient, thereby achieving a sustained release. In Comparative Example 1, a first sustained-release granule was prepared using a large amount of a release-controlling agent for releasing a sustained-release drug of tramadol, which is a highly water-soluble drug (about 3,000 mg / mL in water).

[Experimental Example]

The following experiment was conducted on Example 1, Comparative Example 1, and commercially available ultracet ER tablets. The dissolution test was carried out in accordance with the Notification of Drug Administration (Pharmaceutical Equivalence Test Management Regulation) and the Korean Pharmacopoeia (dissolution test in the General Test Methods). The dissolution test was carried out on the basis of the second method (paddle method), 75 rpm, pH 6.8, The change in pH and paddle rotation rate and the dissolution rate according to the addition of surfactant were evaluated and the dissolution rate according to the division of the sustained-release preparation (tablet) by referring to the 'Guideline on tablet scoring (division) from FDA in August 2011' . The following experimental results are shown in Figs. 3 to 14, and the YJAT-SR in the figure shows Embodiment 1 of the present invention.

EXPERIMENTAL EXAMPLE 1 Evaluation of dissolution rate according to pH change of eluent in elution test

The purpose of this experiment is to evaluate the in vitro dissolution rate change of gastrointestinal tract pH,

The results are shown in FIGS. 3 and 4.

EXPERIMENTAL EXAMPLE 2 Evaluation of dissolution rate according to rotation speed change of paddles in elution test

The purpose of this experiment is an in vitro evaluation of the change of the dissolution rate according to the change of the gastrointestinal motility (activity), and the results are attached to FIG. 5 and FIG. 6.

EXPERIMENTAL EXAMPLE 3 Evaluation of dissolution rate according to presence / absence of surfactant in eluent in elution test

The purpose of this experiment is an in vitro evaluation of the change of the dissolution rate according to the increase or decrease of the digestive enzymes of the intestine, and the results are shown in FIGS. 7 and 8.

EXPERIMENTAL EXAMPLE 4 Evaluation of dissolution rate according to division of tablets in dissolution test

The purpose of this experiment is an in vitro evaluation of the dissolution rate change of the matrix type sustained-release preparation according to the in-vivo tablet disintegration and erroneous dosing methods, and the results are shown in FIGS. 9 and 10.

Experimental Example 5 _ Evaluation of dissolution rate of Example 1 and Comparative Example 1

The purpose of this experiment is a dissolution rate comparison between Example 1 and Comparative Example 1, and the results are shown in FIGS. 11 and 12.

EXPERIMENTAL EXAMPLE 6 ______________________________________ Evaluation of three microemulsions

The purpose of this experiment was to compare the dissolution rate of the composition prepared in Example 1 in a half volume, and the results were shown in FIGS. 13 and 14.

Experimental Example 7_ Evaluation of dissolution rate of Example 1 and Comparative Example 2

The purpose of this experiment is to compare the dissolution rates of Example 1 and Comparative Example 2, and the results are shown in FIGS. 15 and 16.

[Clinical trial of composition according to the present invention]

Phase 1 clinical trial (PART 1)

(Hereinafter referred to as "test drug") according to Example 1 of the present invention and a generic (immediate-release) formulated drug having a license as shown in FIG. 1 (indicated by YJAT SR in FIG. 1 as Example 1) Clinical trials were conducted to compare the pharmacokinetic and pharmacological properties of the drug with the Ultraset ® tablet (hereinafter referred to as the 'reference drug'). Specifically, the pharmacokinetic characteristics of the test drug (once / 12 hours) and the control drug (2 times / 12 hours) were orally administered in a fasting state, Method to determine the effect of food on the bioavailability of the test drug by comparing the pharmacokinetic characteristics of the latter.

The clinical trial protocol was randomly assigned to each of the three order groups (order 1 (ABC), order 2 (BCA), order 3 (CAB)) according to the order of administration. For volunteers, screening tests such as questionnaires, physical examinations, and clinical laboratory tests are conducted within 3 weeks (-21d to -2d) from the first clinical test date (1d) Randomization was performed between screening and 1 day before (-1d) administration of the first clinical trial. After that, the subjects were admitted to the Clinical Trial Center by 6:00 pm on the afternoon of the day.

On the day after the first hospitalization (1d), around 8:00 am (0h), one treatment in the fasting state according to the order group, one treatment in the fasting state (Treatment B) (Treatment C) One of the tablets was orally administered. For the reference drug, take 1 tablet twice every 6 hours, and 1 tablet for test drug. He then proceeded to the first clinical trial according to the planned schedule and discharged from the room 2d am. Thereafter, blood samples should be collected once at the time of administration of the control drug and twice at the time of administration of the test drug. For the second clinical trial after the 4-day withdrawal period, the subjects were admitted to the clinical trial center one day before the administration of the second clinical trial drug (4d) at 6:00 pm, Fasting.

5d At around 8:00 am (0h), the corresponding clinical trial drug was administered according to the order of the second clinical trial. (6d). The patient was taken to the clinical examination center one day before (6d), and the patient was admitted to the clinical examination center one day before the administration of the clinical trial drug to perform the third clinical trial through the 4-day abstinence period. After 10 o'clock, we excluded drinking water and fasted.

9d At around 8:00 am (0h), the corresponding clinical trial drug was administered according to the order group, and the third clinical trial was performed and discharged at 10d am and outpatient visits. Subjects who had completed all clinical trials were selected from 15d to 17d and visited a clinical trial center for post study visit testing.

Phase 1 clinical trial (PART 2)

(Hereinafter referred to as "test drug") according to the first embodiment of the present invention and a generic (immediate-release) formulation that is licensed as shown in FIG. 2 (YJAT SR in FIG. 2 indicates Example 1) Clinical trials were conducted to compare the pharmacokinetic and pharmacological properties of the drug with the Ultraset ® tablet (hereinafter referred to as the 'reference drug'). Specifically, the main pharmacokinetic parameters ( _{Cmax, ss} , AUC _{0-12h, ss} ) of the two clinical trial drugs in the fasting state were obtained after the test drug and the reference drug were repeatedly orally administered and reached _steady- The pharmacokinetic properties were compared and compared.

Clinical trial protocols were randomly assigned to each of the two ordering groups (order 1 (AB), order 2 (BA)) according to the order of administration of each phase of the clinical trial drug.

For volunteers, screening tests such as interviews, physical examinations, and clinical laboratory tests are conducted within three weeks (-21d to -2d) from the first day of administration (1d) to select subjects who are deemed suitable for the clinical trial, And 1 day before the administration of the first clinical trial (-1d). After that, the subjects were admitted to the Clinical Trial Center by 6:00 pm on the afternoon of the day, and after 10 o'clock they were fasted except for drinking water. On the following day (1d), about 8 am (0h), all subjects were orally given one treatment group (Treatment A) or one treatment group (Treatment B) In the case of the reference drug, one tablet was administered four times a day at intervals of 6 hours. In the case of the test drug, one tablet was administered twice a day at intervals of 12 hours. After 3 days of repeated dosing for 2 days (1d ~ 2d), 3 doses were taken in 3d, which was twice daily in 6 hour intervals for the reference drug and 1 tablet for the test drug. Thereafter, the clinical trial was carried out according to the planned schedule, and one outpatient visit was made once the patient was discharged from 4d am. For the second clinical trial after the 4-day abstinence period, the subjects were admitted to the clinical trial center one day before the first administration of the second clinical trial drug (7d) until 6:00 pm, And fasted.

On the next day of hospitalization (8d) at around 8 am (0h), the corresponding clinical trial drug was administered to the first phase of the second phase in accordance with the order of the first clinical trial.

All meals were provided as standard and regardless of the type of medication used for clinical trials, on the day of the clinical study (3d, 10d), lunch (4h) and dinner (10h) (1h, 2d, 1d, 4d, 8d, 9d, 11d) for breakfast (1h) ), Lunch (4h), and evening meal (10h).

After the completion of all clinical trials, a post-study visit test was performed after a certain period of time.

Clinical Phase 1 Results (PART 1)

1) Stability and tolerability evaluation

After single administration of Example-1 of the present invention to healthy male subjects and oral administration of Ultraset® tablets,

12.5% in the UltraSET® treatment group (fasting state treatment)

8.7% in the Invention Example-1 (slow-release) treatment group (fasting state dose)

0.0% in Example-1 (sustained-release) treatment group (after high-dosage treatment)

As a result, it was found that the side effects of the formulation of the present invention were significantly reduced as compared with the Ultraset® tablet.

2) Pharmacokinetic assessment

Invention Example 1 In the case of administration of UltraSET® Pureborn, the point estimate and the 90% confidence interval of the fasting fasting rate of the sustained-release tablet according to the present invention Example 1 Inventive Example 1 in the fast-slow tablet administration Example 1 The results of the point estimate of the ratio and the 90% confidence interval are shown in Table 1, Table 2, and Table 3.

The formulation of Example 1 of the present invention showed that AUC and C _max were pharmacokinetic equivalent in both Ultraset® and acetaminophen, tramadol and Ml when administered at fasting and that the formulation of Example 1 was in the fasting state that and is equivalent to the pharmacokinetic in both AUC, C _max of tramadol AUC, of acetaminophen AUC, C _max, M1, except that Figure only slightly higher C _max of tramadol in comparison to when administered in conjunction with administration of a fat I could confirm.

In addition, when the formulation of Example 1 was administered with the high fat diet and when the Ultraset® tablets were fasted, it was confirmed that the AUC and C _max were pharmacokinetic equivalent in both acetaminophen, tramadol and M1 there was.

Clinical Phase 1 Results (PART 2)

1) Stability and tolerability evaluation

After repeated administration of Example-1 of the present invention to healthy male subjects and oral administration of Ultraset® tablets,

34.8% in the Ultraset® treatment group,

Invention Example-1 (Seojungjeong) Invention group 22.7%

As a result, it was found that the side effects of the formulation of the present invention were significantly reduced as compared with the Ultraset® tablet.

 2) Pharmacokinetic assessment

The results of the percentage point estimate and the 90% confidence interval for repeated administration of Example-1 of the present invention for the repeated administration of UltraSET® are given in Table 4.

The formulation of Example 1 of the present invention can confirm the pharmacokinetic equivalence of AUC and C _max in both Ultraset® and acetaminophen, tramadol and Ml in a single fasted state after reaching repeated administration steady state.

From the results of the first phase of the above clinical tests, Example 1 of the present invention was found to be pharmacologically equivalent to the conventional formulation (Ultra-Phase), Ultraset®, It is shown in Table 8 and Table 9 that the effect that the volatility is very low and the side effect is remarkably reduced.

Clinical phase 1 trial adverse events (part 1, 2 composite) Example-1 according to the present invention [ UltraSET® Constant Constant 10.4% (7 persons / 67 persons) 23.4% (11 persons / 47 persons) spandrel After meals repeat spandrel repeat 2 people / 23 people 0 people / 22 people 5 people / 22 people 3 people / 24 people 8 people / 23 people

Clinical trial abnormal results of conventional slow-release preparation 'patient subjects' 83.2% (104 patients / 125 patients) of the "UltraSET® Bleeding"

Claims (15)

A first sustained release granule comprising acetaminophen and tramadol; And
Tramadol's internal preservation
Wherein said acetaminophen controls the release of tramadol and said composition is administered at a single dose after fasting and after a high fat diet for an average of 0.5 to 3 hours following administration and an average maximum blood serum of 4,400 to 7,000 ng / And provides an average maximum blood concentration of tramadol of 150 to 250 ng / mL at an average of 1.5 to 5 hours after administration. The sustained release pharmaceutical composition of claim 1, further comprising a second sustained release granule comprising acetaminophen. The sustained release pharmaceutical composition according to claim 1, further comprising a granule containing acetaminophen. A sustained release pharmaceutical composition comprising acetaminophen and tramadol,
A first sustained release granule comprising acetaminophen and tramadol;
A second western granule comprising acetaminophen;
An inner granule containing acetaminophen; And
Wherein the composition provides an average maximum blood concentration of acetaminophen of from 4,400 to 7,000 ng / ml at an average of 0.5 to 3 hours after administration when the composition is single administered in the fasting state, And provides an average maximum blood concentration of tramadol of 150 to 250 ng / ml at an average of 1.5 to 5 hours. The method according to claim 4, wherein when the composition is repeatedly administered every 12 hours, an average maximum blood concentration of acetaminophen of 5,000 to 7,800 ng / mL is provided at an average of 0.17 to 4 hours, and an average of 0.5 to 5 hours ≪ / RTI > provides an average maximum blood concentration of tramadol of 240 to 380 ng / mL. 5. The method according to claim 4, wherein when the composition is administered once in the fasting state, the AUC _inf for acetaminophen and tramadol are in the categories of 28,000 to 44,000 hr * ng / ml and 1,600 to 2,500 hr * ng / ml, respectively ≪ / RTI > or a pharmaceutically acceptable salt thereof. The composition according to claim 5, wherein when the composition is repeatedly administered every 12 hours, AUC _{0-12, ss} for acetaminophen and tramadol of 26,000 to 40,000 hr * ng / ml and 1,800 to 3,000 hr * ng / Lt; RTI ID = 0.0 > of: < / RTI > The sustained release pharmaceutical composition according to claim 4, wherein the composition comprises 75 mg of tramadol and 650 mg of acetaminophen per unit dosage form. 5. The sustained release pharmaceutical composition of claim 4, wherein the first sustained release granule or the second sustained release granule is coated with a release modifying polymer. 5. The sustained release pharmaceutical composition according to claim 4, wherein the composition has a dissolution rate of 15% or less in dissolution test for both pH 1.2 and pH 6.8 for both acetaminophen and tramadol.  5. The sustained release pharmaceutical composition of claim 4, wherein the composition has a dissolution rate difference of less than 15% in a dissolution test at 50 rpm and 100 rpm for both acetaminophen and tramadol. A method for preparing a sustained release pharmaceutical composition comprising acetaminophen and tramadol,
(a) preparing a first sustained release granule comprising acetaminophen, tramadol and a pharmaceutically acceptable excipient;
(b) preparing a second western granule comprising acetaminophen and a pharmaceutically acceptable excipient;
(c) preparing acetaminophen and a pharmaceutical granule comprising a pharmaceutically acceptable excipient;
(d) post-mixing the first sustained release granule, the second sustained release granule, the immediate release granules with tramadol and a pharmaceutically acceptable excipient; And
(e) filling the resultant of step (d) with a tablet or a capsule, thereby preparing a sustained release pharmaceutical composition comprising acetaminophen and tramadol. 13. The method of claim 12, wherein the first and second western granules of step (a) and step (b) are coated with a release modifying polymer.  The method of claim 9, wherein the surface of the western granule is at least one selected from the group consisting of water-insoluble cellulose, derivatives of water-insoluble cellulose, polymethacrylate, polyalkyl acrylate or methacrylic acid- Wherein the sustained-release pharmaceutical composition is coated with an insoluble polymer. The sustained release pharmaceutical composition according to claim 4, wherein the composition comprises 37.5 mg of tramadol and 325 mg of acetaminophen per unit dosage form.

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