WO2016017993A1 - Pharmaceutical formulation comprising amorphous or thermodynamically metastable rivaroxaban - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation including, as an active ingredient, a high dose (preferably, 15 or 20 mg) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl]-2-thiophene carboxamide (rivaroxaban) having increased solubility in an amorphous or thermodynamically metastable crystal form, wherein the pharmaceutical drug has reduced variation in absorption (bioavailability) depending on food intake.

Description

Pharmaceutical formulations comprising amorphous or thermodynamic quasi-stable ribaroxaban

The present invention relates to an active ingredient in a high dose (e.g. 15 or 20 mg) formulation with an effect on diet, comprising an amorphous and / or thermodynamically metastable crystal of Rivaroxaban solid dispersion. The present invention relates to a pharmaceutical preparation that can release phosphorus ribaroxane rapidly but improve the dietary effect and thus have the same effect regardless of the meal.

This application claims the priority based on Korea Patent Application No. 10-2014-0099174 filed on August 1, 2014, all the contents disclosed in the specification and drawings of the application is incorporated in this application.

5-Chloro-N-({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidin-5-yl of the formula } - methyl] thiophene-2-carboxamide (hereinafter referred to as rivaroxaban, the active component (I)) is a drug which is administered orally rivaroxaban is on the market under the name of party relto ^{TM (TM} Xarelto And three commercially available polymorph forms, polymorph form I. Rivaroxaban is used for various thromboembolic diseases and their secondary treatment and / or prophylaxis depending on the dose. Low molecular weight inhibitor of coagulation factor Xa (WO2001 / 147919).

Commercially available Rivaroxaban is designed in a dosage form that can reach 100% bioavailability with or without meals for a 10 mg dose. However, 15 mg and 20 mg must be taken mid-meal to achieve the desired effect (high doses (15 mg and 20 mg) of Rivaroxaban for health care professionals at the US FDA with dinner. Taking warnings to prevent potential decreased efficacy). Such high doses of ribaroxaban formulations present a hassle in taking the desired effect. In particular, food intake is indicated as a general cause of drugs in which blood concentrations differ depending on whether food is taken (Xia et al., British Journal of Clinical Pharmacology, 2009, 68: 1, p77-88). This causes a decrease in the efficacy of patients who eat irregular meals, and makes the patient feel uncomfortable in taking the drug. This is presumed to be due to the difference in solubility of Rivaroxaban, and Rivaroxaban, which has a solubility in water (37 ° C) of 9 μg / ml, dissolves 90% or more in the general eluate volume (900 ml) for 10 mg. can see. On the other hand, in case of 20 mg, only 50% can be dissolved, and due to this low solubility, the bioavailability of about 66% is shown in pre-meal administration. Therefore, the remaining insoluble drugs are absorbed by surfactants such as bile acids secreted in the body and the oil component present in the food when taken with the food to reach the bioavailability of 100% (Samama et al. Thrombosis Journal 2013, 11:11, p 1-7).

In order to solve this problem, the solubilization of ribaroxaban is made to have high bioavailability even when taken regardless of meal, so that the patient can have the same effect no matter how and when it is taken, and provide the patient with higher convenience of taking the drug. And, as a result, it is essential to develop a formulation that will have higher medication compliance.

Various methods are known for solubilizing poorly soluble ribaroxaban. In particular, by causing a change in the thermodynamic state of a compound for solubilization, it is not a thermodynamically stable crystalline form, but a thermodynamically unstable form, i.e. a thermodynamic metastable state that is an amorphous or incomplete crystalline state between an amorphous and a crystalline state, that is, a non-crystal state. It can be prepared as.

In particular, by using the solid dispersion technology known in the field of the present invention, it is possible to prepare a ribaxaban solid dispersion with improved solubility, and to produce such amorphous or thermodynamic metastable ribaroxaban solid dispersion. As a method, for example, a method (manufactured by using a high temperature melting method or a melt extrusion method with various polymers) and a method for preparing by dissolving in a suitable solvent and various polymers (prepared by coprecipitation) International Patent Publication WO2014 / 016842) and the like can be used.

Therefore, the problem to be solved by the present invention is a pharmaceutical formulation containing a high dose (so greater than 10 mg 20 mg or less, preferably 15 or 20 mg) of solubilized ribaroxaban, regardless of whether a high-fat diet, fasting and eating It is to provide a pharmaceutical formulation that can exhibit the same or similar bioavailability.

In order to solve the above problems, the present invention comprises more than 10 mg of ribaroxaban, which is an amorphous or thermodynamic metastable crystalline form (preferably 15 or 20 mg, more preferably 20 mg), pharmaceutically acceptable In a formulation for oral administration of rivaroxaban containing possible excipients, the pharmaceutical formulation is characterized in that the value of the specific gravity of the formulation is one or more.

In the present invention, specific gravity is used as follows. Specific gravity is the ratio of the mass of a substance to the mass of a standard substance with the same volume. Specific gravity, unlike density, has no units. As a standard for comparison with unknown samples, water at 4 ° C (density 0.999973 g / cm ³ ) for liquids and air at 0 ° C and 1 atm is generally used. Specific gravity depends on temperature and pressure (in the case of gases). In general, specific gravity corresponds to density for solids and liquids up to five decimal places, so specific gravity and density may be considered equal. To determine the specific gravity of a formulation, it is calculated by weight and volume in the finished form as it is prepared without breaking the formulation.

In the formulation of formulations, specific gravity is a very important factor in various respects. In the preparation of the formulation, a certain level or more of specific gravity is required for smooth operation. Surprisingly, the study found that drugs that must be assessed for bioavailability using a high-fat diet, such as 15 mg and 20 mg of ribaroxaban, which are affected by food, have a higher specific gravity than fat. It has been found that the formulation with which to have has to be designed.

In order to control the specific gravity of the formulation, it is possible to mix pharmaceutically acceptable excipients which can generally increase the specific gravity, and also increase the specific gravity through the process.

For example, excipients that can increase such pharmaceutically acceptable specific gravity are described in the article Pharmaceutical Technology, Vol. Excipients having one or more specific gravity may be added to the formulations of the present invention as described in 27 (4), p64-80 (2003). Specifically, excipients having a specific gravity such as magnesium oxide of 3.5 or more may be used.

In addition, the process can be changed in another way to increase specific gravity. For example, densification such as granulation, roller compaction and coating of metal oxides (iron oxide, titanium dioxide, etc.) having a specific gravity higher than 4 may be applied.

When manufacturing through the formulation of a single component, it is possible to design a formulation with a high specific gravity (3 or more), but usually because only one component is used in the formulation preparation, and various excipients are mixed, It is virtually difficult to manufacture with the high specific gravity of a single excipient. In addition, since an excessive increase in specific gravity in the properties of the formulation acts as a factor that prevents the release of the drug due to the disintegration of the formulation, the specific gravity of the formulation being designed is difficult to exceed two. However, the present invention is not limited to this theoretical mechanism.

Preferably, the specific gravity of the pharmaceutical formulation is 1 to 3.6, more preferably 1 to 2.

The inventors have prepared a solid or thermodynamically metastable crystal of Rivaroxaban solid dispersion that solubilizes poorly soluble Rivaroxaban in various forms of formulation, for example, capsules, tablets, etc. A pharmacokinetic study was conducted. Unexpectedly, Jarelto ^TM, taken with a high-fat diet when taking solubilized Rivaroxaban before meals, unexpectedly Despite boyeoteum equal pharmacokinetic results and 20 mg, and if hayeoteul taken with high fat diet pharmacokinetic parameter of the solubilized rivaroxaban were rather chair relto ^TM A decrease of 20 mg of C _max and AUC was observed. It was also found that this is an effect of the specific gravity of the formulation, and surprisingly, the absorption of the drug was not smooth when the formulation was taken with a high fat diet. In other words, when a high-fat diet is ingested, a low specific gravity is caused by the oil-derived food layer, and as a result, it is assumed that the formulation loses disintegration or dissolving power due to poor contact with moisture. Thus, the absorption of Rivaroxaban is one of several important factors that has a specific gravity higher than the specific gravity value of the oil that can form a layer inside the stomach (e.g., the typical specific gravity is 0.8). Will be important for high doses of Rivaroxaban formulation with high fat diets. However, the effect of the formulation of the present invention is not limited to this theoretical conjecture.

As a result, when the specific gravity is low, the preparation reaches the absorption site without the disintegration or dissolution of the amorphous or thermodynamic metastable Rivaroxaban preparation after the water has passed through the small intestine or is absorbed by the gastric emptying time. It is believed that the absorption of the drug does not occur, but the present invention is not limited to this theoretical mechanism.

Looking at the US FDA's Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies, if different results are obtained by food in drug absorption, bioavailability experiments and post-prandial bioequivalence effects of food effects, In order to maximize gastrointestinal motility and to maximize drug delivery into the blood, foods with a high fat content of approximately 50% in calories of 800 to 1000 calories are recommended as a dietary diet (FDA Guidance; We recommend that food-). effect BA and fed BE studies be conducted using meal conditions that are expected to provide the greatest effects on GI physiology so that systemic drug availability is maximally affected.A high-fat (approximately 50 percent of total caloric content of the meal and high-calorie (approximately 800 to 1000 calories) meal is recommended as a test meal for food-effect BA and fed BE studies. Diet can be given as shown in Table 1 below.

High-fat diets taken to see how food intake affects the absorption of ribaroxanban Weight (g) Calorie (kcal) egg 54 106.3 bacon 50 155.0 Hash Brown Potato 56. 123.8 toast 56 155.2 milk 226.8 136.1 butter 34.0 254 Total 477.52 930.4 Fat percentage (%) 59.3 References: Pharmacokinetics of Celecoxib after Oral Administration in Dogs and Humans: Effect of Food and Site of Absorption, The Journal of Pharmacology and Experimental Therapeutics, 297 (2), 638-645 (2001)

Preferably, in the present invention, the pharmaceutical formulation is a tablet or capsule formulation, more preferably a tablet formulation.

Preferably, the pharmaceutical formulation of the present invention contains solubilized ribaroxaban, and more preferably comprises ribaroxaban, prepared as a solid dispersion and maintained in the form of an amorphous or thermodynamic metastable form.

Thus, preferably, the present invention provides a pharmaceutical formulation, wherein the pharmaceutical formulation comprises a solid dispersion of a hydrophilic excipient and ribaroxaban, wherein the formulation is prepared using a hydrophilic excipient.

The solid dispersion may be prepared through a conventional melt extrusion method or a co-precipitation method, preferably through a melt extrusion method.

Specifically, the Rivaroxaban solid dispersion is dissolved in a variety of excipients and methods using high temperature melting or melt extrusion methods (International Patent Publication WO2007 / 039122) and various excipients and suitable solvents. After the method is prepared by coprecipitation (International Patent Publication WO2014 / 016842) and the like can be used, but the present invention is not limited to such a manufacturing method. The international patent publications WO2007 / 039122 and WO2014 / 016842 are incorporated herein in their entirety.

Examples of hydrophilic excipients used in the preparation of the solid dispersion according to the present invention include urea, citric acid, benzoic acid, maleic acid, fumaric acid, sugars, sugar alcohols, polyethylene glycol (PEG), polyethylene oxide, polyoxyethylene-polyoxy Propylene block copolymers, vinylpyrrolidone-vinylacetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers, polyvinylpyrrolidone, hydroxypropylcellulose (HPC), saturated polyglycolated glycerides (e.g. For example, Gelucire ^™ , or mixtures thereof, may be used, in particular for the purposes of the present invention vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate aerials Preference is given to coalescing or mixtures thereof.

By way of example, the solid dispersions of the present invention may comprise (S1) (a) ribaroxaban and (b) vinylpyrrolidone-vinyl acetate copolymers, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymers, or these Mixing a polymer selected from the mixture of (preferably vinylpyrrolidone-vinyl acetate copolymer) in a ratio of 1: 0.5 to 1: 9, preferably in a ratio of 1: 3 to 1: 5 Step, and (S2) melt extrusion of the mixture at 100 to 230 ° C, preferably melt extrusion at 130 to 180 ° C, the water solubility is more than 18 ug / ml It can be prepared by a process for the preparation of the composition comprising the loxaban in the form of amorphous and / or thermodynamic metastable crystalline forms.

Preferably, in the above production method according to the present invention, the content (weight) ratio of Rivaroxaban and the polymer is 1: 0.5 to 1: 9 (Rivaroxaban: total polymer content).

The pharmaceutical formulation of the present invention may further include pharmaceutically acceptable additives for preparing the pharmaceutical formulation in addition to the solid dispersion comprising the active ingredient ribaroxaban. Such additives may include pharmaceutically acceptable diluents, binders, disintegrants, carriers, solubilizers, crystallization retardants, glidants, or mixtures thereof, but the invention is not limited to these additional additives.

For example, diluents that may be additionally included include pharmacological activities such as starch, sorbitol, citric acid, mannitol, sucrose, colloidal silica, spray dried lactose, anhydrous lactose, calcium dihydrogen phosphate, anhydrous dibasic calcium phosphate and microcrystalline cellulose. And low cost components may be used alone or in combination. However, the present invention is not limited to the above-mentioned diluent.

For example, a disintegrant which may be additionally included may include lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or a mixture of two or more thereof, but the present invention may It is not limited.

For example, binders that may additionally be included include hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (sodium salt and calcium salt), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxy Polymers of propylcellulose (HPC), L-HPC (HPC of low degree of substitution), polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid and salts thereof, gelatin, guar gum, partially hydrolyzed starch, alginate or xanthan Or a mixture thereof may be used, but the present invention is not limited thereto.

For example, the lubricant may be additionally included colloidal silica (Aerosil), talc, magnesium stearate, a mixture of two or more thereof, and the like, but the present invention is not limited thereto.

For example, solubilizers that may additionally be included include sodium salts of fatty alcohol sulfates such as sodium lauryl sulfate, sulfosuccinates such as sodium dioctyl sulfosuccinate, partially fatty acid esters of polyhydric alcohols, such as Glycerol monostearate, sorbitan esters, for example polyethylene glycol sorbitan monolaurate, monostearate or monooleate, polyhydroxyethylene fatty alcohol ethers, polyhydroxyethylene fatty acid esters, ethylene oxide-propylene Oxide block copolymers (Pluronic ^™ ) or Gelucire or mixtures thereof may be used, but the present invention is not limited thereto.

The present invention contains high doses of solubilized ribaroxaban (above 10 mg up to 20 mg, preferably 15 or 20 mg), and have the same or similar bioavailability (eg, C _max and AUC _last ) are provided.

The following drawings, which are attached to this specification, illustrate preferred embodiments of the present invention, and together with the contents of the present invention serve to further understand the technical spirit of the present invention, the present invention is limited to the matters described in such drawings. It should not be construed as limited.

Figure 1 is a graph showing the change in blood concentration after taking Comparative Example 1 fasted (fed) or between (fed).

Figure 2 is a graph showing the release of the drug appearing after the test of Comparative Example 2 and Example 1 in various pH dissolution medium.

Figure 3 is Comparative Example 1 is taken between meals, Comparative Example 2 is a graph showing the change in blood concentration after taking between fasting or between meals.

Figure 4 is a graph showing the release of drugs appearing after the dissolution test in Comparative Examples 1 and 2 and Example 1 in a specific dissolution medium.

FIG. 5 is a graph showing changes in blood concentration after Comparative Example 1 is taken between meals and Example 1 is taken on an empty stomach or between meals.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the present invention should not be construed as limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

Comparative Example 1: Jarelto ^TM 20 mg

Comparative Example 2: Formulation of Specific Gravity 0.8 Containing 20 mg of Solubilized Rivaroxaban

A solid dispersion comprising Rivaroxaban, either amorphous or thermodynamic metastable, was prepared first. Rivaroxaban and the vinylpyrrolidone-vinyl acetate copolymer were prepared by melt extrusion at a temperature ratio of 1: 3 at a temperature in the range of 130 to 220 ° C. using a solid extrusion method. Thereafter, microcrystalline cellulose, crospovidone, Aerosil, and magnesium stearate, which are commonly known excipients, were mixed with the solid dispersion and filled into capsules to prepare a formulation having a specific gravity of 0.8.

Example 1 Formulation of Specific Gravity 1 or More with 20 mg of Solubilized Amorphous Rivaroxaban

A solid dispersion comprising Rivaroxaban, either amorphous or thermodynamic metastable, was prepared first. Rivaroxaban and the vinylpyrrolidone-vinyl acetate copolymer were prepared by melt extrusion at a temperature ratio of 1: 3 at a temperature in the range of 130 to 220 ° C. using a solid extrusion method. Thereafter, microcrystalline cellulose, crospovidone, Aerosil, and magnesium stearate, which are commonly known excipients, were mixed with the solid dispersion. This mixture was then compressed to prepare a tablet, which had a specific gravity of 1.24.

Experimental Example 1: Pharmacokinetic Evaluation of Pre-Meal and Inter-Meal Medication in Comparative Example 1

Comparative Example 1 The pharmacokinetic evaluation of the formulation was made. Three patients per group were divided into two groups, and Comparative Example 1 was dosed with fasting and between meals, and blood was collected at predetermined time intervals. Each pharmacokinetic profile was identified and the results are shown in Table 2 and FIG. 1. For reference, Comparative Example 1, which contains 20 mg of active ingredient (I), is recommended to be administered with meals because of low bioavailability when fasting administration ( The Journal of Clinical Pharmacology , 46, 549-558, 2006). ).

C _max (ng / ml) AUC _last (hr * ng / ml) Comparative Example 1 Fasted 239.8 2402.3 Comparative Example 1 Fed 501.2 4027.4

Experimental results showed that the bioavailability was reduced by more than 40% when the active ingredient (I) was not taken with meals. Therefore, as many papers and the FDA recommend, the doses (20 mg and 15 mg) must be taken with meals.

Experimental Example 2: Measurement of specific gravity of Comparative Example 2 and Example 1

Each specific gravity is measured and shown in Table 3 below.

Formulation Weight (mg) Formulation Volume (ml) Specific gravity (density) Comparative Example 2 290 0.37 0.8 Example 1 217.5 0.18 1.24

Experimental Example 3: in-vitro test results of Comparative Example 2 and Example 1

In-vitro eluate pH 1.2, pH 4.0, pH6.8, 900ml, 37 ° C, 75 ° C elution was performed by comparing the respective dissolution profiles to summarize the difference in dissolution rate between formulations at a certain time in Table 4 The overall dissolution profile is shown in FIG. 2.

Dissolution Rate Difference (%) between Comparative Example 2 and Example 1 15 minutes 30 minutes 60 minutes pH1.2 3 2 2 pH4.0 One One 2 pH6.8 6 One 2

As summarized in Table 4, Comparative Example 2 and Example 1 can be confirmed that the dissolution rate difference between the two formulations within 15%, 15 minutes, 30 minutes, 60 minutes difference is less than 15%.

Experimental Example 4: Pharmacokinetic Evaluation of Comparative Example 1 and Comparative Example 2

Pharmacokinetic evaluations of the Comparative Example 1 and Comparative Example 2 formulations were made. Four groups per group were divided into three groups, Comparative Example 1 was fed to the fast (Fed), Comparative Example 2 was fasted (Fasted) and the drug (Fed) was administered the drug and the blood was collected at a predetermined time interval. Each pharmacokinetic profile was identified and the results are shown in Table 5 and FIG. 3.

C _max (ng / ml) AUC _last (hr * ng / ml) Comparative Example 1 Fed 516.5 4048.4 Comparative Example 2 Fasted 559.2 4020.9 Comparative Example 2 Fed 406.3 3282.1

From the results of FIG. 3 and Table 5, Comparative Example 2 of the solubilized active ingredient (I) was found to have the same level of Cmax and AUClast as Comparative Example 1, which must be administered with a meal despite being administered on an empty stomach. It became. On the other hand, when Comparative Example 2 was administered with a meal, it was confirmed that Cmax and AUClast showed about 14% lower results than Comparative Example 1 administered between meals.

Experimental Example 5: Dissolution test (milk 200 ml + distilled water 240 ml + olive oil 10 ml)

Experimental Method: The amount of liquid to be eaten when a high fat diet was ingested, and 200 ml of milk, 10 ml of oil (predicted value), and 240 ml of distilled water for dosing were mixed, and the degree of drug release was evaluated at 75 rpm at 37 ° C. Shown in In the case of the formulation having a small specific gravity in the milk, oil, and water mixture, it can be confirmed that it is present in the eluate in a floating state at the beginning of the dissolution test. In particular, Comparative Example 2 is suspended for about 1 hour and shows a significantly slow elution pattern.

Experimental Example 6: Pharmacokinetic Evaluation of Comparative Example 1 and Example 1

Pharmacokinetic evaluations of the Comparative Example 1 and Example 1 formulations were made. The group was divided into three groups of four people per group, Comparative Example 1 was fed to the fast (Fed), Example 1 was fasted (Fasted) and between the (Fed) the drug was administered and the blood was collected at a predetermined time interval. Each pharmacokinetic profile was identified and the results are shown in Table 6 and FIG. 5.

C _max (ng / ml) AUC _last (hr * ng / ml) Comparative Example 1 Fed 472.0 3918.2 Example 1 Fed 495.7 3922.9 Example 1 Fasted 484.8 3975.6

As shown in the results of FIG. 5 and Table 6, tablets having a specific gravity of 0.8 mg or more of solubilized amorphous ribaroxaban 20 mg or more when administered between meals, C _max and AUC equivalent to those of Comparative Example 1 administered between meals. was found to have _last . In addition, even when Example 1 was administered on an empty stomach, it was confirmed that C _max and AUC _last showed the same result as Example 1 administered between meals.

Claims (11)

In a formulation for oral administration of rivaroxaban containing more than 10 mg of rivaroxaban, which is an amorphous or thermodynamic metastable crystalline form, Pharmaceutical formulation, characterized in that the specific gravity of the formulation is one or more. The pharmaceutical formulation according to claim 1, wherein the specific gravity of the formulation for oral administration comprising ribaroxaban, which is an amorphous or thermodynamic metastable crystalline form, is 1 to 3.6. The pharmaceutical formulation according to claim 2, wherein the specific gravity of the formulation is 1 to 2. 2. The pharmaceutical formulation of claim 1, wherein the formulation contains 15 or 20 mg of ribaroxaban, an active ingredient. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a tablet or capsule. 6. The pharmaceutical formulation of claim 5, wherein the formulation is in tablet form. The pharmaceutical formulation according to any one of claims 1 to 6, wherein the formulation comprises a solid dispersion of a hydrophilic excipient and ribaroxaban, prepared using a hydrophilic excipient. The pharmaceutical formulation of claim 7, wherein the solid dispersion is prepared by melt extrusion or coprecipitation. The pharmaceutical formulation of claim 8, wherein the solid dispersion is prepared by melt extrusion. 8. The hydrophilic excipient according to claim 7, wherein the hydrophilic excipient is urea, citric acid, benzoic acid, maleic acid, fumaric acid, sugars, sugar alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene-polyoxypropylene block copolymers, vinylpyrrolidone- A pharmaceutical formulation, characterized in that it is a vinyl acetate copolymer, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropylcellulose, saturated polyglycolated glycerides, or mixtures thereof. The pharmaceutical formulation of claim 10, wherein the hydrophilic excipient is vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol-polyvinyl caprolactam-polyvinyl acetate copolymer, benzoic acid, or mixtures thereof.

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