RU2748311C1 - Pharmaceutical composition containing solid dispersions of amorphous cladribine and pharmaceutically acceptable water-soluble carrier - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: group of inventions relates to a pharmaceutical composition of cladribine. Cladribine pharmaceutical composition contains a solid dispersion of amorphous cladribine and a pharmaceutical acceptable water-soluble carrier, wherein the pharmaceutically acceptable water-soluble carrier used is maltodextrin spray dried maltodextrin from high amylose peas and wherein the weight ratio of cladribine and the pharmaceutically acceptable water-soluble carrier in the solid dispersion is not lower than 1:3. Also disclosed is a method of preparing the composition and a solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier.

EFFECT: group of inventions provides high stability at low pH and high bioavailability of cladribine.

13 cl, 2 dwg, 1 tbl, 3 ex

Description

The present invention relates to a pharmaceutical composition comprising a solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier. The pharmaceutically acceptable water soluble carrier can be spray dried maltodextrin from high amylose peas. The pharmaceutical composition can be used as a drug, especially for the treatment of multiple sclerosis.

Background of the present invention

Cladribine (2-CdA), 2-chloro-2'-deoxyadenosine, formula 1,

is an antineoplastic agent that is used in the treatment of lymphoproliferative diseases, including hairy cell leukemia (SCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), Langerhans cell histiocytosis, non-Hodgkin's lymphomas, macroglobulin-vascular remnant remittance (RMS), and Valcidinemia remission 2-CdA is a prodrug that is converted to the corresponding nucleotide (an essential requirement for cytotoxicity). The triphosphate analog inhibits various processes involved in the synthesis of DNA and RNA. Moreover, the effect of the nucleoside analogue on leukemic cells may imply modulation of apoptosis pathways, cell cycle control, or signal transduction pathways.

Cladribine can be injected or taken orally. However, the physicochemical properties of cladribine make it difficult to obtain a finished dosage form for oral administration. First, only negligible solubility in water is observed at room temperature. Therefore, oral absorption is limited by dissolution rate, and dissolution assistance and dissolution rate are required to increase oral bioavailability. Secondly, cladribine is sensitive to low pH environments. At acidic pH, degradation increases markedly over time, even at physiological temperatures. At pH 2 and a temperature of 37 °, after 6 h, only 13% 2-CdA remains in the solution; at pH 1 after 2 hours at 37 ° C, the 2-CdA content is only 2%; the calculated half-life T1 / 2 is 1.6 h (pH 2, 37 ° C) and 0.37 h (pH 1, 37 ° C) (Tarasiuk A, Skierski J, Kazimierczuk Z, Stability of 2-chloro-2 ' -deoxyadenosine at various pH and temperature Arch Immunol Ther Exp (Warsz) 1994; 42 (1): 13-5).

Accordingly, both low solubility and low pH value of cladribine significantly complicate the development of a finished dosage form for oral administration.

The main obstacles to the successful development of a finished dosage form of cladribine for oral administration are the combination of the following: a) a narrow absorption window in the upper part of the small intestine, where cladribine enters the tissues through nucleoside transport proteins scattered along the intestinal epithelial lining, and undergoes intracellular phosphorylation to active forms, 2-CdA triphosphate, with the participation of deoxycytidine kinase in target cells; and b) destruction under the influence of low pH and with the participation of certain enzymes, for example, purine nucleoside phosphorylase, produced by the microbial microflora.

Thus, if the drug is not rapidly released in the upper small intestine, it will be characterized by low bioavailability and will undergo rapid degradation; it is these concerns that make the release profile so important.

Solubility and dissolution rate are two important parameters that must be considered in order to achieve the therapeutic efficacy of a drug when taken orally. Poor water solubility and dissolution profile of insoluble drugs remain a serious problem in the formulation and development of finished oral dosage forms.

In an attempt to improve the solubility and increase the dissolution rate of poorly dissolving drugs, various techniques have been used, including solid dispersion (TD), micronization, lipid-based forms, micronized forms, and complexation. TD and complexation using hydrophilic carriers have shown promise in improving the solubility and dissolution of poorly soluble drugs. The improved solubility and dissolution profiles of the forms based on TD and complexation can be explained by a decrease in particle size, a change in the crystalline form of the drug to an amorphous form, the solubilizing effect of hydrophilic carriers, and better wettability of the drug surrounded by carriers.

The complex of hypophilic drug and hydrophilic carrier (inclusion complexes) can be obtained by simply mixing the drug and excipients, which will provide improved solubilization of the substance. Inclusion complexes are obtained by introducing a non-polar molecule (guest molecule) into the cavity of another molecule (host molecule). Cyclodextrins are most commonly used as the host molecule.

Cyclodextrin complexation has advantages due to low hygroscopicity, low toxicity, high fluidity, excellent compatibility and compressibility, which increases the stability of the drug substance and increases shelf life.

Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a hydrophobic central cavity. This molecular structure gives cyclodextrins some unique properties. The hydrophilic outer surface of the molecule makes it soluble in water, and the hydrophobic cavity creates a microenvironment for non-polar molecules of the appropriate size. In aqueous solutions, cyclodextrins are capable of forming inclusion complexes with many medicinal substances, absorbing the entire molecule of the substance or, more precisely, some non-polar part of the molecule into the cavity.

The term "solid dispersion" refers to a group of solid preparations, which include at least two different components, usually a hydrophilic matrix and a hydrophobic drug.

Several solid dispersion methods are described in the literature: solvent evaporation, kneading, melting or coalescence, melt extrusion, co-precipitation, coevaporation, spray drying, gel encapsulation, supercritical fluid technology, lyophilization.

Speaking about the dispersion of components, when a system is chemically and physically homogeneous or homogeneous, or consists of one phase (in terms of thermodynamics), a solid dispersion is called "solid solution" or "smooth solution". Such systems do not contain any significant amount of active ingredients in crystalline or microcrystalline form, as evidenced by the results of thermal analysis (differential scanning calorimetry) or X-ray structural analysis (wide angle X-ray scattering).

One of the fundamental principles for the preparation of solid dispersions is to obtain an amorphous state, which is considered more soluble in comparison with the crystalline state, since in the amorphous state, energy is not required to destroy the crystal lattice, unlike the crystalline form.

In US Pat. No. 6,194,395 (priority dated February 25, 1999), 2-hydroxypropyl-β-cyclodextrin (HPBCD) was used to improve the solubility of cladribine in water and sensitivity to low pH.

Later, in the patent US 8785415 (priority dated 03.28.2003), the formation of a complex from amorphous cladribine and cyclodextrin was described as a mixture of an amorphous inclusion complex of cladribine with amorphous cyclodextrin, a mixture of amorphous free cladribine bound to amorphous cyclodextrin as a non-inclusion complex and amorphous free cladribine, and their effect on the absorption of cladribine when taken orally.

The authors of the above patent have described only one method for preparing the cladribine-cyclodextrin complex (freeze-drying). According to US Pat. No. 8,785,415, manipulation with a large amount of water and long-term complexation are necessary to obtain the shape due to the limited solubility of cladribine. To obtain a finished dosage form, expensive processes, equipment, and a large amount of energy and time are required.

In fact, the finished dosage form prepared according to the aforementioned patent is a mixture of complex and absorbed API in a ratio of 30-40% to 70-60%, respectively, which significantly complicates the control and predictability of the process and can affect the solubility and degradation of the API in the stomach. with low absorption of 2-CdA. In addition, there is no direct evidence of a positive effect of 30-40% 2-CdA in the inclusion complex on the remaining absorbed molecules on the surface of the carrier.

Thus, in view of the above, there is still a need for alternative, improved pharmaceutical formulations containing amorphous cladribine that are stable, simple, and inexpensive to prepare, while still being commercially available. Based on this, it is desirable to obtain a stable amorphous cladribine and find a reliable process for obtaining such a stable amorphous cladribine.

Summary of the invention

The present invention relates to a pharmaceutical composition comprising a solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier.

It has been found that a solid dispersion of amorphous cladribine and a water-soluble carrier provides high stability at low pH and high bioavailability.

The pharmaceutically acceptable water soluble carrier can be spray dried maltodextrin from high amylose peas. Spray-dried maltodextrin from high amylose peas can be obtained by partial hydrolysis of the carrier pea starch. Such a carrier offers a new technical approach in the preparation of a stable solid dispersion with amorphous cladribine, which would be suitable for the preparation of finished dosage forms for oral administration. The solid dispersion improves the overall drug release characteristics of the poorly soluble cladribine.

The weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier in the solid dispersion may not be less than 1: 3, more preferably 1: 4.

The weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier can be from 1: 3 to 1:20, preferably from 1: 4 to 1:15, more optimally from 1: 5 to 1:15, and most preferably from 1: 5 to 1:10.

The solid dispersion may contain a residual solvent in an amount of not more than 10% by weight of the solid dispersion, preferably not more than 9%, preferably not more than 7%, even better not more than 5%, but most optimally not more than 2%.

The pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients.

The pharmaceutical composition can take the form of a tablet or capsule.

The pharmaceutical composition can be used as a drug, especially for the treatment of multiple sclerosis.

The following describes the use of the pharmaceutical composition for oral administration and / or parenteral administration.

The present invention also relates to a two-step process for preparing a solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier:

- preparing a solution containing cladribine and a pharmaceutically acceptable water-soluble carrier in a solvent or mixture of solvents, and

- removing the solvent from the solution, preferably by vacuum evaporation, spray drying or freeze drying.

Cladribine can be crystalline, polymorphic, or amorphous and dissolved in a solvent or solvent mixture to form a solution.

The pharmaceutically acceptable water soluble carrier can be spray dried maltodextrin from high amylose peas. The weight ratio of cladribine to pharmaceutically acceptable water-soluble carrier in solution may be at least 1: 3, more preferably 1: 4.

The weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier can be from 1: 3 to 1:20, preferably from 1: 4 to 1:15, more optimally from 1: 5 to 1:15, and most preferably from 1: 5 to 1:10.

The solution is prepared using at least one solvent: water and alcohol C1-C4, preferably water, ethanol, methanol and isopropanol and mixtures thereof, more preferably the solvent is a mixture of water and ethanol or water and isopropanol.

The water content is possible at a level of at least 70% (w / w) of the finished solvent. The solvent can be a water-alcohol solution.

After removing the solvent or solvent mixture from the solution, the resulting solid can be dried. The dried solid may contain residual solvent in an amount of not more than 10% by weight of the solid dispersion, preferably not more than 9%, preferably not more than 7%, even better not more than 5%, but most optimally not more than 2%.

Brief Description of Drawings

The invention is further described with reference to the figures:

FIG. 1 a, b X-ray diffraction images of cladribine complexes in the implementation of the present invention and standards;

Fig. 2 Behavior of cladribine API and solid dispersion in HCl buffer at pH 1.4.

Detailed description of the invention

The implementation and variations of the present invention are described in more detail below. However, it should be emphasized that the present invention is not limited to such implementation and variations. It is also mentioned that it is possible to describe only certain scenarios for implementing the invention. However, an experienced person will understand that the properties described in relation to such an implementation can be combined in different ways and that individual characteristics can be omitted if this is acceptable in a particular case.

The present invention relates to a pharmaceutical composition comprising a solid dispersion of amorphous cladribine and a pharmaceutically acceptable carrier.

However, a description is given of a method for preparing a solid dispersion of amorphous cladribine, in accordance with one implementation scenario, using at least the following:

a. obtaining a solution containing cladribine and a pharmaceutically acceptable carrier in a solvent or mixture of solvents;

b. removing the solvent from solution a);

c. Optional drying of the solid obtained in b) to obtain the desired solid dispersion of cladribine.

Cladribine in the form of an amorphous premix for the described use is sufficiently stable and suitable for use in pharmaceutical compositions intended for the treatment of diseases, including, inter alia, multiple sclerosis.

The following describes a method for preparing amorphous cladribine: removing the solvent from the cladribine solution and the pharmaceutically acceptable carrier. Also described is a method for preparing a solid dispersion consisting of amorphous cladribine: removing the solvent from the cladribine solution with the addition of a pharmaceutically acceptable carrier.

A solution of cladribine can be prepared by dissolving cladribine in a solvent or mixture of solvents. Any polymorphic form can be used to prepare a solution, for example, crystalline forms, including solvates and hydrates.

In an effort to find potential new cladribine solubilizers that could be used in the commercial production of amorphous cladribine, spray dried maltodextrin from high amylose peas Kleptose® Linecaps was tested.

Kleptose® Linecaps (maltodextrin from pea starch) are rich in unbranched and soluble amylose. This amylose fraction provides inclusion compounds required for taste masking and other applications. Amylose exists in the form of helical structures, and, like cyclodextrin, they have a hydrophilic outer surface and a hydrophobic inner cavity created by glycosidic ester bonds that form a cavity that allows amylose to encapsulate certain drugs.

The encapsulating ability of amylose can also improve the solubility of certain drug molecules in cold water. However, to match the solubilization capacity of cyclodextrins, more Kleptose® Linecaps by weight (about 10 times more) are required due to their high molecular weight. In terms of molar characteristics, Kleptose® Linecaps and cyclodextrins have similar effects.

According to the information provided, Kleptose Linecaps should dissolve by forming a CLD inclusion complex only at high Linecaps: API ratios. For cladribine, the ratio should be close to 1: 100.

Surprisingly, when Linecaps was reconstituted in an aqueous alcohol solution, its effect on solubility was unexpectedly improved. It was found that the use of an aqueous alcoholic solution leads to a significant reduction in the amount of pea maltodextrin required to dissolve and stabilize cladribine in solution, and after evaporation, a stable amorphous solid dispersion is obtained, suitable for finished dosage forms for oral administration with acceptable stability and dissolution profile.

The present invention is based on the conclusion that the combination of spray dried maltodextrin from high amylose peas, obtained by partial hydrolysis of pea starch, as a carrier and an aqueous alcohol solution, offers a new technical approach to obtaining a stable solid dispersion with amorphous API of cladribine, suitable for the production of ready-to-use dosage forms for oral administration.

Cladribine and Kleptose Linecaps can be dissolved with the same solvent or different solvents and then mixed. In carrying out the invention, the disclosed solid dispersion comprises cladribine and the carrier in weight ratios ranging from about 1: 3 to about 1:15, preferably from 1: 5 to 1:10.

As solvents for dissolving cladribine and the carrier, a mixture of water and organic solvents, for example C1-C4 alcohols, can be used, among others. Examples of organic solvents that can be used in the present invention include ethanol, methanol, isopropanol, and mixtures thereof. The amount of solvent used for dissolution depends on the type of solvent and the dissolution temperature.

Linecaps are poorly soluble in water solution: EtOH. When Linecaps are dissolved in water, followed by the addition of EtOH in a ratio of up to 1: 1 (v / v), it remains soluble, while dissolved cladribine remains stable for several days.

The dissolution temperature can range from about 35 ° C to about 60 ° C, depending on the type of solvent used for solubilization. Any other temperature is also allowed, provided that a clear solution is obtained.

If desired, the resulting solution can be filtered to remove undissolved particles prior to further processing. Undissolved particles can be removed by filtration, centrifugation, settling, and other methods. Filtration of the solution is carried out through paper, fiberglass or other membrane material.

The solvent can be removed by suitable means, for example, atmospheric evaporation or vacuum evaporation. Such methods include vacuum evaporation, spray drying, and freeze drying (lyophilization).

The solvent can be evaporated under vacuum, for example below 100 mm Hg. or below 600 mm Hg at a temperature from about -20 ° C to 70 ° C. Various temperatures and vacuum values can be used, provided that the amount of impurities in the preparation does not increase.

For example, spray drying or evaporation in a Buki rotary evaporator is more suitable for industrial scale production in batches of about 100 g, 1 kg or more. In accordance with the present invention, the amorphous form obtained by spray drying or Buki evaporator dissolves rapidly from the pharmaceutical composition.

The resulting amorphous material can be collected from equipment, for example, by scraping or by other methods suitable for a particular device, it is possible in a nitrogen atmosphere.

If desired, the drying of the solid preparation can be carried out under suitable conditions to obtain the desired solid dispersion of cladribine in amorphous form, practically free of solvents. In embodiments of the present invention, the solid dispersion of cladribine contains residual solvents in an amount of not less than 1%, but not more than 10% by weight of the solid dispersion. In one particular application, the solid dispersion contains a residual solvent in an amount of not more than 2% by weight. In another application, the solid dispersion contains residual solvent in an amount of 4% to 7% by weight.

Drying can be continued until the amount of residual solvent reaches the desired value, for example, the range defined by the International Conference on the Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use. The recommended solvent value depends on the type of solvent, but should not exceed 5000 ppm, or about 4000 ppm, or about 3000 ppm.

Drying can take place under reduced pressure, for example below 650 mm Hg. or below 50 mm Hg, at a temperature of 35 ° C to 70 ° C. Drying can last for a sufficient period of time to obtain the desired result, for example, from 1 hour to 20 hours, and longer. Drying times can be longer or shorter, depending on the product specification.

For drying, suitable equipment can be used, for example, a shelf dryer, a vacuum oven, an oven, a fluidized bed dryer, or the like.

Cladribine and its impurities can be analyzed by HPLC.

The present invention also describes a method for preparing pharmaceutical compositions containing amorphous cladribine and one or more pharmaceutically acceptable excipients. The method may involve mixing or granulating an amorphous solid dispersion of cladribine with one or more pharmaceutically acceptable excipients, followed by tabletting or encapsulation using well known equipment and methods.

Pharmaceutical compositions within the scope of the present invention have a dissolution profile typical of immediate release formulations. Upon preparation and storage, the pharmaceutical compositions of the present invention remain in amorphous form.

The pharmaceutical compositions of the present invention can be packaged in a blister material. The blister material used in the present invention can be any blister material known to the mid-level specialist. The blister material of the present invention is selected from the following materials: PTFE, PVC / aluminum, duplex / aluminum, triplex / aluminum, and aluminum / aluminum. To provide protection of the compositions of the present invention, for example, from moisture, thereby preventing transition to the polymorphic form, it is preferable to choose polytetrafluoroethylene, triplex / aluminum and aluminum / aluminum.

The pharmaceutical composition of the present invention can be used as a medicine. Typically, the pharmaceutical composition is for the treatment of multiple sclerosis.

The present invention is illustrated by the following examples.

Example 1: Cladribine: Linecaps 1:10 by weight

5.0 g Linecaps were dissolved in 25 ml of distilled water with stirring at room temperature, after which 10 ml of ethanol was added. 0.5 g of cladribine was suspended in Linecaps: water: ethanol solution and heated to 50 ° C. After the solution became clear and the spray dryer was heated, the solution was pumped to the spray dryer where the solvent was evaporated and the solid was collected.

A similar process was carried out using isopropanol instead of ethanol.

The results of powder X-ray diffraction analysis of the samples were recorded (Fig. 1). Control sample a) is the linecaps powder used to prepare the above cladribine: linecaps composition. Sample b) is a solid dispersion of cladribine: linecaps at a weight ratio of 1:10 in water / ethanol as described above. Control c) is a physical mixture of cladribine and linecaps in a weight ratio of 1:10, i.e. not in the form of a solid dispersion of amorphous cladribine. Sample d) is a solid dispersion of cladribine-linecaps in a weight ratio of 1:10 in water / isopropanol as described above.

The X-ray diffraction results of sample b) and sample d) show that the isolated solid dispersion is completely amorphous. The same results were achieved using vacuum evaporation or spray drying to dry / remove the solvent (not shown).

In comparison, solution c) (physical mixture of cladribine and linecaps) shows that the compound cladribine is at least partially in crystalline form.

Example 2: Behavior of Clodribine API and Solid Dispersion in HCl Buffer at pH 1.4

The effect of the solid dispersion on the stability of cladribine was tested at pH 1.4 and 37 ° C.

10 mg of API cladribine (control sample) or 10 mg of a solid dispersion of cladribine according to the present invention, for example, obtained as described in example 1 above, was dissolved in a buffer solution of HCl at pH 1.4. The time when the solid dispersion was completely dissolved was taken as the reference point. Both samples were placed in an autosampler and the concentrations of cladribine were determined over a period of 105 minutes. As can be seen from Fig. 2, the solid dispersion of cladribine was significantly more stable at pH

1.4 compared to pure API cladribine. When expressed in terms of relative area comparison, the concentration of the solid dispersion of cladribine was about 75% higher than the concentration of cladribine after 105 minutes. The area curve was calculated using the trapezoidal formula.

Example 3: Cladribine Tablets

Cladribine tablets were prepared by direct compression. 110.0 g of solid dispersion of cladribine-linecaps in a ratio of 1:10 (55% of the total weight) according to the present invention, for example, obtained as described in example 1 above, was sieved and then mixed with 78.0 g of microcrystalline cellulose (39% of the total weight) and 10 g croscarmellose sodium (5% of the total weight), then added 2 g of magnesium stearate (1% of the total weight).

The resulting powder mixture was tableted into 200 mg tablets containing 10 mg of cladribine. The measured dissolution profiles in pH 4.5 buffer are shown in the table below:

The results show that the studied tablets dissolved quickly, complete dissolution was achieved after 10 minutes, and the dissolution requirements for rapidly dissolving drugs were met.

Claims (16)

1. A pharmaceutical composition of cladribine containing a solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier, wherein spray-dried maltodextrin from high-amylose peas is used as a pharmaceutically acceptable water-soluble carrier, and wherein the weight ratio of cladribine and pharmaceutically acceptable water-soluble carrier in the solid dispersion is at least 1: 3: ... 2. The pharmaceutical composition of cladribine according to claim 1, wherein the weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier in the solid dispersion is not more than 1: 4. 3. The pharmaceutical composition of cladribine according to claim 1, wherein the weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier is from 1: 3 to 1:20, preferably from 1: 4 to 1:15, more optimally from 1: 5 to 1:15 and better just from 1: 5 to 1:10. 4. The pharmaceutical composition of cladribine according to any one of paragraphs. 1-3, where the solid dispersion contains a residual solvent in an amount of not more than 10% by weight of the solid dispersion, preferably not more than 9%, preferably not more than 7%, even better not more than 5%, but most optimally not more than 2%. 5. The pharmaceutical composition of cladribine according to any one of paragraphs. 1-4, also containing one or more pharmaceutically acceptable excipients. 6. The pharmaceutical composition of cladribine according to any one of paragraphs. 1-5, in the form of a tablet or capsule. 7. The pharmaceutical composition of cladribine according to any one of paragraphs. 1-6 for oral and / or parenteral administration. 8. A method of obtaining a composition according to claim 1, which proceeds in two stages: - preparing an aqueous-alcoholic solution containing cladribine and a pharmaceutically acceptable water-soluble carrier in a solvent or mixture of solvents, and - removal of the solvent from the solution by vacuum evaporation, spray drying or freeze drying, wherein spray dried maltodextrin from high amylose peas is used as the pharmaceutically acceptable water-soluble carrier, and wherein the weight ratio of cladribine to the pharmaceutically acceptable water-soluble carrier in the solid dispersion is not less than 1: 3. 9. The method of claim 8, wherein the cladribine is in crystalline, polymorphic, or amorphous form and is dissolved in a solvent or solvent mixture to form a solution. 10. The method according to PP. 8, 9, where the solution is prepared using at least one solvent: water and alcohol C1-C4, preferably water, ethanol, methanol and isopropanol and mixtures thereof, more preferably the solvent is a mixture of water and ethanol or water and isopropanol. 11. The method according to PP. 8-10, where the water content is at least 50%, more preferably at least 60%, even better at least 70% (w / w) of the total solvent. 12. The method according to PP. 8-11, where after removing the solvent or solvent mixture from the resulting solution, the solid is dried. 13. Solid dispersion of amorphous cladribine and a pharmaceutically acceptable water-soluble carrier obtained according to claims. 8-12.

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