KR20200082006A - Extended release formulation containing tofacitinib or pharmaceutically acceptable salts thereof as an active ingredient and the preparation method for the same - Google Patents

Abstract

The present invention relates to a sustained-release preparation comprising tofacitinib or a pharmaceutically acceptable salt thereof, a release sustaining agent, and a hydrophilic binder. More specifically, disclosed is a sustained-release preparation in a hydrophilic matrix formulation form which exhibits the same effect as an immediate-release preparation in vivo at a lower dose than the content of currently commercialized sustained-release products, that is, at a dose of 10 mg, and which has a relatively simple manufacturing process, thereby having excellent productivity and economic feasibility.

Description

EXTENDED RELEASE FORMULATION CONTAINING TOFACITINIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS AN ACTIVE INGREDIENT AND THE PREPARATION METHOD FOR THE SAME}

The present invention relates to a sustained release preparation containing tofacitinib or a pharmaceutically acceptable salt thereof and a method for preparing the same. Specifically, it relates to a sustained release preparation comprising a hydrophilic base as tofacitinib or a pharmaceutically acceptable salt and sustained release agent thereof. Such sustained-release preparations can stably and continuously release the drug in vivo, thereby obtaining a desired therapeutic effect by taking only once a day. More specifically, a content lower than that of a commercially available sustained release product, i.e., 10 mg, may have an effect equivalent to that of an immediate release preparation in vivo, and the manufacturing process is also simpler than that of a commercially available sustained release product. It is also characterized by having an advantage.

Tofacitinib, an active ingredient of the present invention, has a compound name of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4- 1)-Amino]-piperidin-1-yl}-3-oxo-propionitrile, and has a structure represented by Formula 1 below.

Tofacitinib represented by Chemical Formula 1 is disclosed in International Publication No. WO2001/042246 as having inhibitory activity of protein kinase, such as Janus Kinas3 (JAK3) enzyme, organ transplantation, xenograft, Lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type I diabetes and diabetes complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and immunosuppression It is known to be useful as an immunosuppressant for other diseases.

In addition, the formula I and their pharmaceutically acceptable salt thereof is disclosed in International Patent Publication WO2002 / 096909, gel janjeu ^® (Xeljanz) defining a main component topa City nip citrate salt are currently commercially available in Korea, International It is specifically disclosed in published patent WO2003/048162. Gel is janjeu ^® (Xeljanz) Chung rheumatoid arthritis, psoriatic arthritis or ulcerative colitis to treatment, topa City nip sheet in immediate release formulation containing the citrate salt 5mg (1 twice-daily dose).

Usually, extended release form releases the drug for a certain period of time in the body compared to immediate release form, so it occurs by maintaining the effective blood concentration of the drug for a long time and frequently administering the immediate release agent. By reducing the amplitude of the blood concentration and reducing side effects accordingly, it is possible to improve patient compliance by reducing the frequency of administration. In addition, when a drug requiring a low dosage such as tofacitinib is prepared as a tablet, since the amount of the additive is greater than that of the active ingredient, it is difficult to ensure uniformity of the content of the active ingredient for each individual tablet, and thus, a higher content is contained. Sustained-release preparations may also be required in terms of securing more uniformity of content.

Regarding sustained-release preparations using tofacitinib as an active ingredient, it is mentioned in WO2012/100949 that tofacitinib can be formulated as a release-controlling agent, and matrix systems (tablets or multiples) are disclosed in WO2014/147526. Particles), osmotic systems, storage systems, etc., mentioning that it is possible to manufacture sustained-release preparations using tofacitinib as an active ingredient using techniques for preparing sustained-release preparations, and describe extruded core systems using osmotic systems as representative examples. Doing. However, in the case of tofacitinib, the bioavailability decreases as the release duration is extended, and thus, when a sustained release preparation is prepared at a daily dosage of 10 mg, as in International Publication Patent WO2012/100949, pharmacokinetic equivalence with the immediate release preparation is secured In order to solve this problem, the international publication patent WO2014/147526, which discloses a sustained-release preparation prepared in an excess dose (11mg), solves this problem. Within the reference range, the bioavailability equivalent to the immediate release formulation was shown, but in the case of the hydrophilic matrix system, the bioavailability equivalent to the excess dose was not secured. A (Osmotic Controlled-release Oral Delivery) OROS formulation of the product that is sold under the trade name of gel janjeu ^® XR (XR Xeljanz) in the United States contains a physical dose of 11mg beyond the immediate release formulation daily dosage dose of 10mg. However, the OROS formulation has a disadvantage in that its manufacturing process is complicated and productivity and economic efficiency are poor.

International Publication Patent Publication WO2012/100949 International Publication Patent Publication WO2014/147526

Thus, the present inventors have studied in order to solve the above problems, and when using a hydrophilic binder in addition to the sustained release agent, the drug is stable and sustained release even with a daily dose of the immediate release preparation, so that the bioequivalent to the immediate release preparation It was confirmed that a sustained release formulation capable of securing a utilization rate could be prepared, and the present invention was completed.

The present invention is to solve the problem of providing a sustained release preparation for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, contains tofacitinib as an active ingredient, and is effective by using a hydrophilic binder in addition to a sustained release agent. A specific solution is to provide a sustained release formulation that is stable and continuously released in a form in which the powder is dispersed in a hydrophilic matrix.

Furthermore, the present invention uses two or more hydrophilic bases and exhibits an equivalent effect to a rapid release preparation in vivo despite the lower content of tofacitinib or a pharmaceutically acceptable salt thereof than a commercially available sustained release product. It is a special problem of the present invention to provide a sustained release preparation of a hydrophilic matrix formulation that is excellent in productivity and economic efficiency due to a simple manufacturing process.

In order to solve the above problems, the present invention discloses the following means.

In one aspect, the present invention discloses a sustained release preparation comprising tofacitinib or a pharmaceutically acceptable salt, sustained release agent and hydrophilic binder.

In the sustained release formulation, the tofacitinib or a pharmaceutically acceptable salt thereof is a citrate salt, aspartate, succinate, orotate, palmitate, stearate, benzoate, ascorbate, and oleate. Acid salts, sulfonates, sulfates, dodecyl sulfates, cyclamates, edisylates, nitrates, maleates or phosphates.

In the sustained release preparation, the sustained release agent can be used as long as it is a pharmaceutically acceptable sustained release base, preferably polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropyl Methylcellulose phthalate, methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose, hydroxypropylcellulose (HPC), pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG), ethyl It may be one or more selected from the group consisting of cellulose (EC) and gelatin. More preferably, HPMC can be used.

The hydrophilic binder may be used as long as it is a pharmaceutically acceptable hydrophilic binder, preferably microcrystalline cellulose, sucrose, titanium oxide, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), corn starch. And it may be one or two or more selected from the group consisting of lactose hydrate. Preferably it may be HPC, PVP or a combination thereof.

When combining two types of the hydrophilic binder, the mixing ratio of the two selected types may be 1:4 to 4:1.

In the sustained release preparation, tofacitinib may be included 10mg.

In the sustained release formulation, the hydrophilic binder may be included in an amount of 5.0 to 20.0 wt% based on the total weight of the formulation.

In the sustained release formulation, the tofacitinib may be in a form dispersed in a hydrophilic matrix.

In another aspect, the invention provides tofacitinib or a pharmaceutically acceptable salt thereof; Hydroxypropyl methylcellulose (HPMC) as a sustained release agent; Hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) as hydrophilic binders; Lactose monohydrate as a diluent; And a sustained release formulation comprising magnesium stearate as a lubricant.

In another aspect, the present invention comprises the steps of preparing a mixture by mixing the main component tofacitinib or a pharmaceutically acceptable salt and other additives thereof; Compressing and sizing the mixture to granulate; Tableting the granules; And it discloses a method for producing a sustained release preparation comprising the step of coating the tablet.

The sustained-release preparations according to the present invention show the prevention or treatment effect of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. More specifically, by using a hydrophilic binder in addition to a sustained release agent, the active ingredient exhibits a stable and sustained release, and thus, an equivalent bioavailability can be exhibited only with the same amount as the daily dosage of the immediate release preparation. In particular, compared to a commercially available OROS product, the manufacturing process is relatively simple, thereby providing a sustained release preparation excellent in productivity and economic efficiency.

1 is a graph comparing the dissolution rate of the sustained-release preparation of the present invention, a sustained-release preparation containing only one hydrophilic binder and a commercially available sustained-release product.
Figure 2 is a graph comparing the PK profile of the sustained-release preparations and commercially-released products of the present invention.
Figure 3 is a graph comparing the PK profile before and after meal of the sustained-release preparation of the present invention.

In the present invention, in the case of the known tofacitinib sustained-release preparation, the content of the immediate-release preparation exceeds the daily dosage, and the manufacturing process is a complicated OROS formulation, whereas the hydrophilic matrix is added using a hydrophilic binder in addition to the sustained release agent. By adjusting the viscosity of the immediate-release preparation is made on the basis that the sustained-release preparation that can exhibit the same effect with only the same amount as the daily dosage is produced through a simple manufacturing process.

In particular, when only one type of hydrophilic binder is used, the elution is too late or the initial elution proceeds too quickly, whereas a combination of two or more hydrophilic binders such as hydroxypropylcellulose (HPC) and polyvinylpyrrolidone (PVP) When combined, it is based on the fact that the active ingredient tofacitinib from the hydrophilic matrix is stable and can continuously elute.

According to the present invention, sustained-release preparations for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis include tofacitinib or a pharmaceutically acceptable salt thereof, a sustained release agent and a hydrophilic binder.

According to the present invention, high-performance liquid chromatography (HPLC) after filtering the eluate obtained at a suitable time at pH 6.8 and 37° C. with 900 ml potassium phosphate buffer according to the second method paddle method (50 rpm) according to the United States Pharmacopeia (USP) When measured by ), the sustained release formulation of the present invention has a drug dissolution rate from the formulation at 2 hours of 45% or less, and a drug dissolution rate from the formulation at 3 hours of 55% or more and 80% or less.

The tofacitinib usable in the present invention is tofacitinib free base or a pharmaceutically acceptable acid addition salt (hereinafter, unless indicated otherwise, in the specification, tofacitinib or a pharmaceutically acceptable salt thereof is referred to as'topa Cytinib'), for example, citrate salt, aspartate, Succinate, orotate, palmitate, stearate, benzoate, ascorbate, oleate, sulfonate, sulfate, dodecyl sulfate, cyclamate, edisylate, nitrate, maleate, phosphate Citrate salt is the most preferred.

The sustained-release agent used in the sustained-release preparation of the present invention can be used as long as it is a pharmaceutically acceptable sustained-release agent, preferably polyvinylpyrrolidone (PVP), a cellulose polymer, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose or hydroxypropylcellulose (HPC), pectin, cyclodextrins, galactomannan, It may be one or more selected from the group consisting of polyethylene glycol (PEG), ethyl cellulose (EC) and gelatin. More preferably, HPMC can be used.

The hydrophilic binder may be used as long as it is a pharmaceutically acceptable hydrophilic binder, preferably microcrystalline cellulose, sucrose, titanium oxide, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), corn starch. And it may be one or two or more selected from the group consisting of lactose hydrate. Preferably it is HPC, PVP, and the like, and most preferably, it may be a combination of HPC and PVP. Particularly, when a low viscosity HPC is used, a more preferable sustained effect can be obtained, and the viscosity measured by using a 2% aqueous solution at 20°C using a Brookfield viscometer is 6.0-10.0 mPa*s.

The sustained release preparation of the present invention is a form in which tofacitinib is dispersed in a hydrophilic matrix, and a hydrophilic matrix reacts with a water-soluble medium in the digestive tract in vivo to form a gel layer film from the outer outer layer of the tablet, and through this gel layer film, tofacitinib It is released slowly over a period of time. The sustained-release preparation of the present invention is capable of releasing topacitinib as an active ingredient at a stable and constant rate by using a hydrophilic binder in addition to a sustained release agent.

The hydrophilic binder may be included in 5.0 to 20.0% by weight based on the total weight of the formulation, preferably 10.0 to 17.5% by weight. When the hydrophilic binder is less than 5.0% by weight, it is insufficient to adjust the viscosity of the hydrophilic matrix to enable continuous elution, and when it exceeds 20.0% by weight, it is uneconomical, and excessive amounts of the hydrophilic binder may cause problems in the manufacturing process of granules. This is because the total weight of the unit dosage form increases, causing inconvenience to taking. Moreover, when mixing 2 or more types of the said hydrophilic binder, the mixing ratio is preferably 1-4:4-1. In particular, the mixing ratio is most preferably 2:3.

The sustained release preparations of the present invention may additionally include pharmaceutically acceptable additives such as diluents, colorants, sweeteners, surfactants, lubricants, stabilizers, and the like.

The diluent may include lactose, microcrystalline cellulose, starch, etc., specifically, lactose includes lactose monohydrate, lactose anhydride, spray dried lactose monohydrate, etc., and microcrystalline cellulose Cellulose, silicate microcrystalline cellulose, and the like, corn starch, pregelatinized starch, and the like, but are not limited thereto.

The colorant may include one or more selected from titanium oxide, iron sulfate, or pigments recommended by FD&C.

The sweetener may include one or more selected from sucralose, sucrose, dextrose, fructose, glucose, liquid glucose or maltose.

As the lubricant, talc, stearyl fumarate, magnesium stearate, or hydrogenated castor oil may be used.

The sustained release formulation of the present invention may include a pharmaceutically usable film coating. The film coating is one or more of the additives commonly used in the coating of oral preparations such as hypromellose, titanium dioxide, PEG, iron oxide, and talc. You can choose and use.

The sustained release preparations of the present invention can be prepared in various dosage forms. For example, it may be formulated into tablets, powders, granules or capsules, such as tablets, coated tablets, multilayer tablets or nucleated tablets, and preferably tablets.

The sustained release preparations of the present invention may include about 5 to 15 mg of tofacitinib, preferably 10 mg of tofacitinib, and the route of administration may be appropriately controlled, but may preferably be administered orally.

The present invention also provides a method for preparing a sustained release preparation. In one embodiment, the method of preparing the sustained release formulation of the present invention

(1) mixing the main component tofacitinib or a pharmaceutically acceptable salt and other additives to prepare a mixture;

(2) compacting and granulating the mixture;

(3) tableting the granules; And

(4) may include the step of coating the tablet.

Hereinafter, the present invention will be described in detail by examples. However, the following examples are only to illustrate the present invention, the content of the present invention is not limited to the following examples.

Example 1 to 4

According to the composition of Table 1, the main components of tofacitinib aspartate, diluent lactose monohydrate, sustained release agent HPMC (Methocel K100LV CR ^® ) and two hydrophilic binders (HPC-L and PVP K30) were mixed and then lubricated Jane magnesium stearate was further added and mixed. This mixture was compressed and granulated in a dry granulator to prepare a dry granulated product, and then compressed and compressed into 1 tablet portions in a rotary tableting machine.

Example 1 Example 2 Example 3 Example 4 Tofacitinib
Aspartate 14.26mg 14.26mg 14.26mg 14.26mg Lactose monohydrate 63.85% 63.85% 63.85% 63.85% Methocel K100LV CR 15% 15% 15% 15% HPC-L 10% 7.5% 5% 2.5% PVP K30 2.5% 5% 7.5% 10% Magnesium stearate 2% 2% 2% 2% Sum 100% 100% 100% 100%

Comparative example 1 and 2

According to the composition of Table 2, the main component of tofacitinib aspartate, diluent lactose monohydrate, sustained release agent HPMC (Methocel K100LV CR ^® ) and one hydrophilic binder (HPC-L or PVP K30) are mixed and then lubricated Jane magnesium stearate was further added and mixed. This mixture was compressed and granulated in a dry granulator to prepare a dry granulated product, and then compressed and compressed into 1 tablet portions in a rotary tableting machine.

Comparative Example 1 Comparative Example 2 Tofacitinib
Aspartate 14.26mg 14.26mg Lactose monohydrate 63.85% 63.85% Methocel K100LV CR 15% 15% HPC-L 12.5% - PVP K30 - 12.5% Magnesium stearate 2% 2% Sum 100% 100%

Experimental Example 1. Elution Profile Experiment

The sustained-release preparations prepared in Examples 1 to 4 and Comparative Examples 1 and 2 and the currently available gelzand XR tablets (control, 11 mg as tofacitinib) were tested for dissolution in the United States Pharmacopoeia (USP). It was performed on the device. Specifically, the speed of the paddle is rotated at 50 rpm, 900 mL of pH 6.8 potassium phosphate buffer is used as the dissolution medium, and the temperature of the buffer is maintained at 37° C., while the eluate obtained at the appropriate time during the test is filtered and then subjected to high performance liquid chromatography Analysis of the tofacitinib released by (HPLC) investigated the dissolution characteristics and the results are shown in Table 3 and FIG. 1.

Time(min) 30 60 120 150 180 210 240 360 Reference 0.25 5.20 34.85 49.41 63.97 71.08 78.19 92.80 Comparative Example 1 8.53 16.97 33.80 41.59 49.37 56.32 63.27 84.67 Comparative Example 2 10.72 23.10 50.62 60.91 71.19 76.84 82.48 89.27 Example 1 9.89 18.15 36.88 45.74 54.60 62.12 69.63 87.95 Example 2 10.54 17.32 41.30 51.44 61.57 67.13 73.69 88.47 Example 3 8.69 18.97 41.18 53.41 63.19 69.27 75.89 90.20 Example 4 10.04 21.41 44.78 54.41 64.04 71.38 78.71 88.91

Tofacitinib is a drug of BCS Class 3, and since the drug has high solubility and low biomembrane permeability, absorption of the drug in vivo is determined by the rate of permeation of the drug itself. When the additives that may affect the biomembrane permeability, such as the sustained-release preparation, are not included, in vivo permeation is dependent on the physicochemical properties of tofacitinib, so the degree of in vivo release can be predicted according to the results of in vitro dissolution. . The Tmax of the currently available Gelzanz XR tablets is 3 to 4 h, and in order to be released in vivo at an equivalent level, it is important to dissolve at a time of 2 to 4 h in an in vitro dissolution experiment, suitably 20 to 42% at 2 h, 2.5 h Elution of 33-56%, 46-65% at 3h, 55-70% at 3.5h, and 72-76% at 4h.

Looking at the dissolution results in Table 3 and Figure 1, in the case of Examples 1 to 4, which is a sustained release formulation of the present invention, the dissolution rate (within ± 10%) similar to that of the gelz XR tablet as a control drug was exhibited at 2 to 4 h. However, in the case of Comparative Example 1 using only the hydrophilic binding agent HPC, the drug release rate was kept constant, but dissolution was delayed when viewed as a whole compared to the control drug. As the drug was released, the release rate tended to be slower with time, and as a whole, it was confirmed that the elution proceeded faster than the control drug. Through this, it was confirmed that the sustained-release preparation of the present invention was able to secure a desired dissolution pattern by mixing HPC and PVP, which are hydrophilic binders, in an appropriate ratio.

Experimental Example 2.PK profile test ( Gel glasses IR tablet 5mg BID vs slow release formulation of the present invention QD )

Randomized, open-label, single dose, two-period, two-treatment, four-cross studies were conducted in healthy men. Subjects received Example X of the present invention, a sustained release formulation of tofacitinib having a 7-day washout period between doses, and Gelzand IR tablets, an immediate release tablet formulation. Sustained release formulations were provided as a single 10 mg dose, and immediate release formulations were provided as two 5 mg tablets in a single dose, the PK profiles were compared and the results are shown in FIG. 2. As shown in the graph of FIG. 2, when the sustained-release preparation of the present invention containing 10 mg of tofacitinib is taken once a day in vivo, it is equivalent to the case of taking 5 mg of Gelzanz IR tablet twice a day. It was confirmed that Cmax and AUC were shown.

Experimental Example 3. PK profile test before/after meal (sustained release preparation of the present invention QD Before and after meals)

Evaluation of the dietary effect of the same sustained-release preparation of the present invention was performed, and the results are shown in Table 4 and FIG. 3.

Cmax AUC 90% CI T/R ratio 90% CI T/R ratio ceremony 94-118 105 92 ∼ 110 100 After meal 116 ∼ 147 76 97 ∼ 108 98

As shown in the graphs of Table 4 and FIG. 3, the pre-prediction vs post-prandial AUC value of the sustained-release preparation of the present invention exhibited an equivalent level, and the sustained-release preparation was not affected by the diet in the case of the sustained-release preparation of the present invention. It means that you have secured the standards you must have.

The sustained-release preparation according to the present invention exhibits a preventive or therapeutic effect on rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, and thus can be used as a pharmaceutical in the pharmaceutical industry and the medical field.

Claims (12)

Sustained release formulation comprising tofacitinib or a pharmaceutically acceptable salt, sustained release agent and hydrophilic binder Tofacitinib or a pharmaceutically acceptable salt thereof, a sustained release agent, and a hydrophilic binder, wherein the drug dissolution rate from the formulation is 45% or less at 2 hours, and the drug dissolution rate from the formulation is 50% or more and 80% or less at 3 hours. Sustained release preparations The method of claim 1 or 2, wherein the tofacitinib or a pharmaceutically acceptable salt thereof is citrate salt, aspartate salt, succinate salt, orotate salt, palmitate salt, stearate salt, benzoate salt, and ascorbine. Sustained-release preparations selected from acid salts, oleate salts, sulfonate salts, sulfate salts, dodecyl sulfate salts, cyclam salt salts, edisyl salt salts, nitrate salts, maleate salts or phosphate salts According to claim 1 or claim 2, wherein the sustained release agent is polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate, methyl cellulose (MC), sodium carboxymethyl cellulose ( CMC-Na), hydroxyethylcellulose, hydroxypropylcellulose (HPC), pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG), ethylcellulose (EC), and at least one selected from the group consisting of gelatin. Sex preparations The method according to claim 1 or 2, wherein the hydrophilic binder is selected from the group consisting of microcrystalline cellulose, sucrose, titanium oxide, hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), corn starch and lactose hydrate. Sustained-release preparations in one or more combinations The sustained release preparation according to claim 5, wherein the hydrophilic binder is selected from hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), or a combination thereof. The sustained-release preparation according to claim 5, wherein the mixing ratio of the two selected hydrophilic binders is 1:4 to 4:1. The sustained release preparation according to claim 1, wherein 10 mg of tofacitinib is included. The sustained release preparation according to claim 1, wherein the hydrophilic binder is included in an amount of 5.0 to 20.0 wt% based on the total weight of the preparation. The sustained-release preparation according to claim 1, wherein the sustained-release preparation further comprises at least one selected from diluents, colorants, sweeteners, surfactants, lubricants and stabilizers. The sustained release preparation according to claim 1, wherein the tofacitinib is dispersed in a hydrophilic matrix. Tofacitinib or a pharmaceutically acceptable salt thereof; Hydroxypropyl methylcellulose (HPMC) as a sustained release agent; Hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) as hydrophilic binders; Lactose monohydrate as a diluent; And sustained-release preparation comprising magnesium stearate as a lubricant

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