Combination of beta-lactam compound and probenecid and use thereof

Abstract

The present disclosure provides a combination of a beta-lactam compound and probenecid and uses thereof. The present disclosure relates to a bilayer tablet comprising a second layer comprising a beta-lactam compound or a pharmaceutically acceptable salt thereof; and a first layer, the first layer comprising probenecid or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treating or preventing disease using the bilayer tablets.

Description

[0001] This application is a divisional application of the invention application with the application date of December 23, 2019, the Chinese national application number of 201980045618.0, and the invention name of "Combination of β-lactam compounds and probenecid and use thereof". Technical Field

[0002] The present application relates to drug combinations and therapeutic uses for controlling infection and mitigating or eliminating antibiotic resistance. Background Art

[0003] β-lactam compounds are a class of antibiotics that have a β-lactam ring in their molecular structure. β-lactam compounds have been used to treat diseases associated with Gram-positive and Gram-negative bacteria. The mechanism of action of these β-lactam compounds optimally requires that the concentration of the antibiotic be maintained at or above a specific inhibition threshold called the 'minimum inhibitory concentration (MIC)' in order to be effective. Keeping these antibiotic concentrations high also helps to avoid the possibility of antibacterial activity due to selection of bacteria with higher MICs. Therefore, there is a need for compositions and methods associated with β-lactam antibiotics that optimize their tissue concentrations in order to improve their ability to control infections and mitigate or eliminate the possibility of antibiotic resistance. Summary of the invention

[0004] The present disclosure particularly provides a bilayer tablet, the bilayer tablet comprising:

[0005] A first layer comprising probenecid or a pharmaceutically acceptable salt thereof; and

[0006] The second layer comprises a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0007] In some aspects, the present disclosure provides a method of preparing a bilayer tablet, the method comprising:

[0008] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force, thereby forming a pre-compressed first layer;

[0009] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0010] iii) compressing said pre-compressed first layer and said second granular material with a second force, thereby forming a pre-coated bi-layer tablet.

[0011] In some aspects, the present disclosure provides a bilayer tablet prepared by the method disclosed herein.

[0012] In some aspects, the present disclosure provides a method of treating or preventing a disease, the method comprising administering a bilayer tablet described herein to a subject in need thereof.

[0013] In some aspects, the present disclosure provides a bilayer tablet as described herein for use in treating or preventing a disease in a subject in need thereof.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present disclosure belongs. In this specification, unless the context clearly specifies otherwise, the singular form also includes the plural. Although methods and materials similar or equivalent to the methods and materials described herein can be used to practice or test the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. It is not recognized that the references listed herein are prior art of the claimed invention. In the event of a conflict, this specification (including definitions) will prevail. In addition, materials, methods and embodiments are only illustrative and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure will prevail.

[0015] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a diagram depicting an exemplary process for preparing a granular material of probenecid.

[0017] Figure 2 is a diagram depicting an exemplary process for preparing a particulate material of Compound III-2b.

[0018] Figure 3 is a diagram describing an exemplary process for preparing a bilayer tablet of the present disclosure.

[0019] 4A to 4D is a set of graphs comparing the in vitro release characteristics of exemplary batches of bilayer tablets of the present disclosure and comparable compositions. Figure 4A is a graph comparing the in vitro release of probenecid from batches 1 to 3 of bilayer tablets and comparable commercial probenecid tablets. Figure 4B It is a graph showing the in vitro release of the β-lactam compound (Compound III-2b) and probenecid from the fourth batch of bilayer tablets. Figure 4C It is a graph showing the in vitro release of the β-lactam compound (Compound III-2b) and probenecid of the fifth batch of bilayer tablets. Figure 4D It is a graph showing the in vitro release of the β-lactam compound (Compound III-2b) and probenecid of the sixth batch of bilayer tablets.

[0020] FIG. 5A to FIG. 5G is a set of graphs comparing several physical properties and in vitro release characteristics of bilayer tablets prepared with various first and second compression forces. Figure 5A is a graph comparing the total volume of bilayer tablets. Figure 5B is a graph comparing the porosity of bilayer tablets. Figure 5C is a graph comparing the total pore surface area of ​​bilayer tablets. Figure 5D is a graph comparing the total pore counts of bilayer tablets. Figure 5E It is a graph comparing the volume of the largest pores of the bilayer tablets. Fig. 5F is a graph comparing the volume ratio between the largest pore and the total pores of a bilayer tablet. Figure 5G is a graph showing the in vitro release profile of an exemplary batch of bilayer tablets prepared by high compression force.

[0021] Figure 6 is a graph showing the effect of administration of a β-lactam compound (Compound III-2b) and probenecid in the form of a bilayer tablet (compared to individual formulations) on the plasma levels of a β-lactam compound (Compound IIb) in the fasting state.

[0022] Figure 7 is a graph showing the effect of administration of a β-lactam compound (Compound III-2b) and probenecid in a bilayer tablet form (compared to individual formulations) on the plasma levels of a β-lactam compound (Compound IIb) in the fed state.

[0023] Figure 8 is a graph showing the effect of administration of a β-lactam compound (Compound III-2b) and probenecid in a bilayer tablet form (compared to individual formulations) on the area under the curve (AUC) of a β-lactam compound (Compound IIb).

[0024] Fig. 9 The maximum plasma concentration (C max )’s effect. DETAILED DESCRIPTION

[0025] The present disclosure particularly provides a bilayer tablet, the bilayer tablet comprising:

[0026] a second layer comprising a β-lactam compound or a pharmaceutically acceptable salt thereof; and

[0027] The first layer comprises probenecid or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the first layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the second layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the first layer comprises about 500±1000 mg, about 500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about 500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±500 mg, about 500±600 mg, about 500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±500 mg. 0±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg probenecid or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the second layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof; and the first layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the second layer comprises about 500±1000 mg, about 500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about 500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg, about 500±90 mg, About 500±80mg, about 500±70mg, about 500±60mg, about 500±50mg, about 500±45mg, about 500±40mg, about 500±35mg, about 500±30mg, about 500±25mg, about 500±20mg, about 500±15mg, about 500±10mg, or about 500±5mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the first layer comprises about 500±1000 mg, about 500±900 mg, about 500±800 mg, about 500±700 mg, about 500±600 mg, about 500±500 mg, about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg. , about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg of probenecid or a pharmaceutically acceptable salt thereof; and the second layer comprises about 500±100 0mg, about 500±900mg, about 500±800mg, about 500±700mg, about 500±600mg, about 500±500mg, about 500±450mg, about 500±400mg, about 500±350mg, about 500±300mg, about 500±250mg, about 500±200mg, about 500±150mg, about 500±100mg, about 500±90mg, about 500±80mg, about 500±70mg, about 500±60mg, about 500±50mg, about 500±45mg, about 500±40mg, about 500±35mg, about 500±30mg, about 500±25mg, about 500±20mg, about 500±15mg, about 500±10mg, or about 500±5mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the first layer comprises about 500 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the second layer comprises about 500 mg of a β-lactam compound (eg, Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the first layer of the bilayer tablet comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g of probenecid.

[0037] In some embodiments, the first layer of the bilayer tablet comprises about 500 mg probenecid.

[0038] In some embodiments, the second layer comprises about 500 mg of a β-lactam compound (eg, Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof; and the first layer comprises about 500 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the second layer comprises:

[0040]

[0041] In some embodiments, the second layer comprises Compound III-2.

[0042] In some embodiments, the second layer comprises Compound III-2a.

[0043] In some embodiments, the second layer comprises Compound III-2b.

[0044] In some embodiments, the second layer of the bilayer tablet contains about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g of Compound III-2, Compound III-2a, or Compound III-2b.

[0045] In some embodiments, the second layer of the bilayer tablet contains about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g of Compound III-2.

[0046] In some embodiments, the second layer of the bilayer tablet contains about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g of Compound III-2a.

[0047] In some embodiments, the second layer of the bilayer tablet comprises about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1 g of Compound III-2b.

[0048] In some embodiments, the second layer of the bilayer tablet comprises about 500 mg of Compound III-2, Compound III-2a, or Compound III-2b.

[0049] In some embodiments, the second layer of the bilayer tablet comprises about 500 mg of Compound III-2.

[0050] In some embodiments, the second layer of the bilayer tablet comprises about 500 mg of Compound III-2a.

[0051] In some embodiments, the second layer of the bilayer tablet comprises about 500 mg of Compound III-2b.

[0052] In some embodiments, the bilayer tablet further comprises one or more pharmaceutical excipients.

[0053] In some embodiments, the one or more pharmaceutical excipients are selected from cellulose, croscarmellose sodium, magnesium stearate, lactose monohydrate, and hydroxypropyl cellulose.

[0054] In some embodiments, the bilayer tablet further comprises about 227±200 mg, about 227±150 mg, about 227±100 mg, about 227±90 mg, about 227±80 mg, about 227±70 mg, about 227±60 mg, about 227±50 mg, about 227±40 mg, about 227±30 mg, about 227±20 mg, about 227±15 mg, about 227±10 mg, or about 227±5 mg of microcrystalline cellulose (e.g., about 227 mg microcrystalline cellulose).

[0055] In some embodiments, the bilayer tablet further comprises about 225±200 mg, about 225±150 mg, about 225±100 mg, about 225±90 mg, about 225±80 mg, about 225±70 mg, about 225±60 mg, about 225±50 mg, about 225±40 mg, about 225±30 mg, about 225±20 mg, about 225±15 mg, about 225±10 mg, or about 225±5 mg microcrystalline cellulose (e.g., about 225 mg microcrystalline cellulose).

[0056] In some embodiments, the bilayer tablet further comprises about 56±50 mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about 56±30 mg, about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10 mg, about 56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg of cross-linked sodium carboxymethylcellulose (e.g., about 56 mg cross-linked sodium carboxymethylcellulose).

[0057] In some embodiments, the bilayer tablet further comprises about 3.3±3 mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg, about 3.3±1.6 mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg, about 3.3±0.9 mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg, about 3.3±0.5 mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg, or about 3.3±0.1 mg intragranular magnesium stearate (e.g., about 3.3 mg intragranular magnesium stearate).

[0058] In some embodiments, the bilayer tablet further comprises about 6.9±3 mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg, about 6.9±1.6 mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg, about 6.9±0.9 mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg, about 6.9±0.5 mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg, or about 6.9±0.1 mg extragranular magnesium stearate (e.g., about 6.9 mg extragranular magnesium stearate).

[0059] In some embodiments, the bilayer tablet further comprises about 70±50 mg, about 70±45 mg, about 70±40 mg, about 70±35 mg, about 70±30 mg, about 70±25 mg, about 70±20 mg, about 70±15 mg, about 70±10 mg, about 70±5 mg, about 70±4 mg, about 70±3 mg, or about 70±2 mg of lactose 316 monohydrate (e.g., about 70 mg of lactose 316 monohydrate).

[0060] In some embodiments, the bilayer tablet further comprises about 69±50 mg, about 69±45 mg, about 69±40 mg, about 69±35 mg, about 69±30 mg, about 69±25 mg, about 69±20 mg, about 69±15 mg, about 69±10 mg, about 69±5 mg, about 69±4 mg, about 69±3 mg, or about 69±2 mg of lactose 316 monohydrate (e.g., about 69 mg of lactose 316 monohydrate).

[0061] In some embodiments, the bilayer tablet further comprises about 21±20 mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about 21±4 mg, about 21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg, about 21±1.4 mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about 21±0.8 mg, about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg hydroxypropyl cellulose (e.g., about 21.4 mg hydroxypropyl cellulose).

[0062] In some aspects, the present disclosure provides a bi-layer tablet comprising:

[0063] A first layer comprising about 500 mg of probenecid; and

[0064] The second layer contained about 500 mg of Compound III-2b.

[0065] In some embodiments, the bilayer tablet further comprises:

[0066] about 227±200 mg, about 227±150 mg, about 227±100 mg, about 227±90 mg, about 227±80 mg, about 227±70 mg, about 227±60 mg, about 227±50 mg, about 227±40 mg, about 227±30 mg, about 227±20 mg, about 227±15 mg, about 227±10 mg, or about 227±5 mg microcrystalline cellulose;

[0067] about 56±50 mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about 56±30 mg, about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10 mg, about 56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg croscarmellose sodium;

[0068] about 3.3±3 mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg, about 3.3±1.6 mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg, about 3.3±0.9 mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg, about 3.3±0.5 mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg, or about 3.3±0.1 mg intragranular magnesium stearate;

[0069] about 6.9±3 mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg, about 6.9±1.6 mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg, about 6.9±0.9 mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg, about 6.9±0.5 mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg, or about 6.9±0.1 mg extragranular magnesium stearate;

[0070] about 70±50 mg, about 70±45 mg, about 70±40 mg, about 70±35 mg, about 70±30 mg, about 70±25 mg, about 70±20 mg, about 70±15 mg, about 70±10 mg, about 70±5 mg, about 70±4 mg, about 70±3 mg, or about 70±2 mg lactose monohydrate 316; and

[0071] About 21±20 mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about 21±4 mg, about 21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg, about 21±1.4 mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about 21±0.8 mg, about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg hydroxypropyl cellulose.

[0072] In some embodiments, the bilayer tablet further comprises:

[0073] about 225±200 mg, about 225±150 mg, about 225±100 mg, about 225±90 mg, about 225±80 mg, about 225±70 mg, about 225±60 mg, about 225±50 mg, about 225±40 mg, about 225±30 mg, about 225±20 mg, about 225±15 mg, about 225±10 mg, or about 225±5 mg microcrystalline cellulose;

[0074] about 56±50 mg, about 56±45 mg, about 56±40 mg, about 56±35 mg, about 56±30 mg, about 56±25 mg, about 56±20 mg, about 56±15 mg, about 56±10 mg, about 56±5 mg, about 56±4 mg, about 56±3 mg, or about 56±2 mg croscarmellose sodium;

[0075] about 3.3±3 mg, about 3.3±2.5 mg, about 3.3±2 mg, about 3.3±1.8 mg, about 3.3±1.6 mg, about 3.3±1.4 mg, about 3.3±1.2 mg, about 3.3±1 mg, about 3.3±0.9 mg, about 3.3±0.8 mg, about 3.3±0.7 mg, about 3.3±0.6 mg, about 3.3±0.5 mg, about 3.3±0.4 mg, about 3.3±0.3 mg, about 3.3±0.2 mg, or about 3.3±0.1 mg intragranular magnesium stearate;

[0076] about 6.9±3 mg, about 6.9±2.5 mg, about 6.9±2 mg, about 6.9±1.8 mg, about 6.9±1.6 mg, about 6.9±1.4 mg, about 6.9±1.2 mg, about 6.9±1 mg, about 6.9±0.9 mg, about 6.9±0.8 mg, about 6.9±0.7 mg, about 6.9±0.6 mg, about 6.9±0.5 mg, about 6.9±0.4 mg, about 6.9±0.3 mg, about 6.9±0.2 mg, or about 6.9±0.1 mg extragranular magnesium stearate;

[0077] about 69±50 mg, about 69±45 mg, about 69±40 mg, about 69±35 mg, about 69±30 mg, about 69±25 mg, about 69±20 mg, about 69±15 mg, about 69±10 mg, about 69±5 mg, about 69±4 mg, about 69±3 mg, or about 69±2 mg lactose monohydrate 316; and

[0078] About 21±20 mg, about 21±15 mg, about 21±10 mg, about 21±5 mg, about 21±4 mg, about 21±3 mg, about 21±2 mg, about 21±1.8 mg, about 21±1.6 mg, about 21±1.4 mg, about 21±1.2 mg, about 21±1 mg, about 21±0.9 mg, about 21±0.8 mg, about 21±0.7 mg, about 21±0.6 mg, or about 21±0.5 mg hydroxypropyl cellulose.

[0079] In some embodiments, the bilayer tablet further comprises:

[0080] about 220 mg to about 230 mg microcrystalline cellulose;

[0081] about 50 mg to about 60 mg croscarmellose sodium;

[0082] about 3 mg to about 4 mg intragranular magnesium stearate;

[0083] about 6 mg to about 8 mg extragranular magnesium stearate;

[0084] about 65 mg to about 75 mg lactose monohydrate 316; and

[0085] About 20 mg to about 23 mg hydroxypropyl cellulose.

[0086] In some embodiments, the bilayer tablet further comprises:

[0087] About 227 mg microcrystalline cellulose;

[0088] About 56 mg croscarmellose sodium;

[0089] About 3.3 mg of intragranular magnesium stearate;

[0090] About 6.9 mg extragranular magnesium stearate;

[0091] about 70 mg lactose monohydrate 316; and

[0092] About 21.4 mg hydroxypropyl cellulose.

[0093] In some embodiments, the bilayer tablet further comprises:

[0094] About 225 mg microcrystalline cellulose;

[0095] About 56 mg croscarmellose sodium;

[0096] About 3.3 mg of intragranular magnesium stearate;

[0097] About 6.9 mg extragranular magnesium stearate;

[0098] about 69 mg lactose monohydrate 316; and

[0099] About 21.4 mg hydroxypropyl cellulose.

[0100] In some embodiments, a bilayer tablet is prepared by the methods disclosed herein.

[0101] In some aspects, the present disclosure provides a bilayer tablet prepared by the methods disclosed herein.

[0102] Physical properties of bilayer tablets

[0103] In some embodiments, the bi-layer tablet is formulated to have white, yellow, pink, or any color in between.

[0104] In some embodiments, the bi-layer tablet is configured to have an oval shape.

[0105] In some embodiments, the bilayer tablet is configured to have a length of about 19±10 mm, about 19±9 mm, about 19±8 mm, about 19±7 mm, about 19±6 mm, about 19±5 mm, about 19±4 mm, about 19±3 mm, about 19±2 mm, about 19±1 mm, about 19±0.8 mm, about 19±0.6 mm, about 19±0.5 mm, about 19±0.4 mm, about 19±0.3 mm, about 19±0.2 mm, or about 19±0.1 mm (e.g., about 19 mm).

[0106] In some embodiments, the bilayer tablet is configured to have a width of about 10.3±20 mm, about 10.3±18 mm, about 10.3±16 mm, about 10.3±14 mm, about 10.3±12 mm, about 10.3±10 mm, about 10.3±9 mm, about 10.3±8 mm, about 10.3±7 mm, about 10.3±6 mm, about 10.3±5 mm, about 10.3±4 mm, about 10.3±3 mm, about 10.3±2 mm, about 10.3±1 mm, about 10.3±0.8 mm, about 10.3±0.6 mm, about 10.3±05 mm, about 10.3±0.4 mm, about 10.3±0.3 mm, about 10.3±0.2 mm, or about 10.3±01 mm (e.g., about 10.3 mm).

[0107] In some embodiments, the bilayer tablet is configured to have a thickness of about 8.2±20 mm, about 8.2±18 mm, about 8.2±16 mm, about 8.2±14 mm, about 8.2±12 mm, about 8.2±10 mm, about 8.2±9 mm, about 8.2±8 mm, about 8.2±7 mm, about 8.2±6 mm, about 8.2±5 mm, about 8.2±4 mm, about 8.2±3 mm, about 8.2±2 mm, about 8.2±1 mm, about 8.2±0.8 mm, about 8.2±0.6 mm, about 8.2±0.5 mm, about 8.2±0.4 mm, about 8.2±0.3 mm, or about 8.2±0.2 mm.

[0108] In some embodiments, the bilayer tablet is configured to have a hardness greater than about 80N, greater than about 85N, greater than about 90N, greater than about 95N, greater than about 100N, greater than about 105N, greater than about 110N, greater than about 115N, greater than about 120N, greater than about 125N, greater than about 130N, greater than about 140N, greater than about 150N, greater than about 160N, greater than about 170N, greater than about 180N, greater than about 190N, greater than about 200N, greater than about 220N, greater than about 240N, greater than about 260N, greater than about 270N, greater than about 280N, greater than about 290N, or greater than about 300N.

[0109] In some embodiments, the bilayer tablet is configured to have a hardness greater than about 120N.

[0110] In some embodiments, the bi-layer tablet is configured to have a hardness of less than 300N.

[0111] In some embodiments, the bilayer tablet is configured to have a hardness greater than about 120N and less than 300N.

[0112] In some embodiments, the bilayer tablet is configured to have a friability of less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1%.

[0113] In some embodiments, the bilayer tablet is configured to have a friability of less than about 0.1%, less than about 0.09%, less than about 0.08%, less than about 0.07%, less than about 0.06%, less than about 0.05%, less than about 0.04%, less than about 0.03%, less than about 0.02%, or less than about 0.01%.

[0114] In some embodiments, the bilayer tablet is configured to have a diameter less than 2000 mm. 3 , less than about 1900mm 3 , less than about 1800mm 3 , less than about 1700mm 3 , less than about 1600mm 3 , less than about 1500mm 3 , less than about 1400mm 3 , less than about 1300mm 3 , less than about 1250mm 3 , less than about 1240mm 3 , less than about 1230mm 3 , less than about 1220mm 3 , less than about 1210mm 3 , less than about 1200mm 3 , less than about 1190mm 3 , less than about 1180mm 3 , less than about 1170mm 3 , less than about 1160mm 3 , less than about 1150mm 3 , less than about 1140mm 3 , less than about 1130mm 3 , less than about 1120mm 3 , less than about 1110mm 3, less than about 1100mm 3 , less than about 1080mm 3 , less than about 1060mm 3 , less than about 1040mm 3 , less than about 1020mm 3 , or less than about 1010mm 3 total volume.

[0115] In some embodiments, the bilayer tablet is configured to have a diameter of about 1150 ± 300 mm 3 , about 1150±250mm 3 , about 1150±200mm 3 、About 1150±180mm 3 , about 1150±160mm 3 , about 1150±150mm 3 , about 1150±140mm 3 , about 1150±120mm 3 , about 1150±100mm 3 、About 1150±90mm 3 、About 1150±80mm 3 、About 1150±70mm 3 、About 1150±60mm 3 , about 1150±50mm 3 、About 1150±45mm 3 , about 1150±40mm 3 , about 1150±35mm 3 , about 1150±30mm 3 , about 1150±25mm 3 , about 1150±20mm 3 , about 1150±15mm 3 , about 1150±10mm 3 、About 1150±9mm 3 、About 1150±8mm 3 、About 1150±7mm 3 、About 1150±6mm 3 、About 1150±5mm 3 、About 1150±4mm 3 , or about 1150±3mm 3 (For example, about 1148mm 3 )’s total volume.

[0116] In some embodiments, the bilayer tablet is configured to have a diameter of about 1050 ± 300 mm 3 , about 1050±250mm3 , about 1050±200mm 3 , about 1050±180mm 3 , about 1050±160mm 3 , about 1050±150mm 3 , about 1050±140mm 3 , about 1050±120mm 3 , about 1050±100mm 3 , about 1050±90mm 3 , about 1050±80mm 3 , about 1050±70mm 3 , about 1050±60mm 3 , about 1050±50mm 3 , about 1050±45mm 3 , about 1050±40mm 3 , about 1050±35mm 3 , about 1050±30mm 3 , about 1050±25mm 3 , about 1050±20mm 3 , about 1050±15mm 3 , about 1050±10mm 3 , about 1050±9mm 3 、About 1050±8mm 3 、About 1050±7mm 3 、About 1050±6mm 3 、About 1050±5mm 3 , about 1050±4mm 3 , about 1050±3mm 3 , about 1050±2mm 3 , or about 1050±1mm 3 (e.g. about 1050mm 3 )’s total volume.

[0117] In some embodiments, the bilayer tablet is configured to have a porosity of less than about 20%, less than about 15%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1.8%, less than about 1.6%, less than about 1.4%, less than about 1.2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1%.

[0118] In some embodiments, the bilayer tablet is configured to have a porosity of about 0.73±0.5%, about 0.73±0.45%, about 0.73±0.4%, about 0.73±0.35%, about 0.73±0.3%, about 0.73±0.25%, about 0.73±0.2%, about 0.73±0.15%, about 0.73±0.1%, about 0.73±0.09%, about 0.73±0.08%, about 0.73±0.07%, about 0.73±0.06%, about 0.73±0.05%, about 0.73±0.04%, about 0.73±0.03%, about 0.73±0.02%, or about 0.73±0.01% (e.g., about 0.73%).

[0119] In some embodiments, the bilayer tablet is configured to have a diameter of less than about 5,000,000 mm 2 、less than about 4,000,000mm 2 、less than about 3,000,000mm 2 、less than about 2,000,000mm 2 , less than about 1,000,000mm 2 、less than about 900,000mm 2 , less than about 800,000mm 2 、less than about 700,000mm 2 , less than about 600,000mm 2 , less than about 500,000mm 2 , less than about 400,000mm 2 、less than about 300,000mm 2 , less than about 200,000mm 2 , less than about 100,000mm 2 、less than about 90,000mm 2 、less than about 80,000mm 2 、less than about 70,000mm 2 、less than about 60,000mm 2 、less than about 50,000mm 2 、less than about 40,000mm 2 、less than about 30,000mm 2 、less than about 20,000mm 2 、less than about 10,000mm 2 、less than about 9,000mm 2 、less than about 8,000mm 2 、less than about 7,000mm 2 、less than about 6,000mm 2 、less than about 5,000mm2 , less than about 4900mm 2 , less than about 4800mm 2 , less than about 4700mm 2 , less than about 4600mm 2 , less than about 4500mm 2 , less than about 4400mm 2 , less than about 4300mm 2 , less than about 4200mm 2 , less than about 4100mm 2 、less than about 4,000mm 2 , less than about 3900mm 2 , less than about 3800mm 2 , less than about 3700mm 2 , less than about 3600mm 2 , less than about 3500mm 2 , less than about 3400mm 2 , less than about 3300mm 2 , less than about 3200mm 2 , less than about 3100mm 2 、less than about 3,000mm 2 , less than about 2900mm 2 , less than about 2800mm 2 , less than about 2700mm 2 , less than about 2600mm 2 , less than about 2500mm 2 , less than about 2400mm 2 , less than about 2300mm 2 , less than about 2200mm 2 , less than about 2100mm 2 、less than about 2,000mm 2 , less than about 1900mm 2 , less than about 1800mm 2 , less than about 1700mm 2 , less than about 1600mm 2 , less than about 1500mm 2 , less than about 1400mm 2 , less than about 1300mm 2 , less than about 1200mm 2 , less than about 1100mm 2 , or less than about 1,000mm 2 total pore surface area.

[0120] In some embodiments, the bilayer tablet is configured to have a diameter of less than about 3,000 mm.2 total pore surface area.

[0121] In some embodiments, the bilayer tablet is configured to have a diameter of about 2050 ± 1000 mm 2 、About 2050±950mm 2 , about 2050±900mm 2 、About 2050±850mm 2 , about 2050±800mm 2 、About 2050±750mm 2 、About 2050±700mm 2 、About 2050±650mm 2 , about 2050±600mm 2 、About 2050±550mm 2 , about 2050±500mm 2 , about 2050±450mm 2 , about 2050±400mm 2 , about 2050±350mm 2 , about 2050±300mm 2 , about 2050±250mm 2 , about 2050±200mm 2 , about 2050±150mm 2 , about 2050±100mm 2 、About 2050±90mm 2 、About 2050±80mm 2 、About 2050±70mm 2 , about 2050±60mm 2 、About 2050±50mm 2 , about 2050±40mm 2 , about 2050±30mm 2 , about 2050±20mm 2 , about 2050±10mm 2 , or about 2050±5mm 2 (For example, about 2045mm 2 )’s total pore surface area.

[0122] In some embodiments, the bilayer tablet is configured to have about 1,000,000 or less, about 900,000 or less, about 800,000 or less, about 700,000 or less, about 600,000 or less, about 500,000 or less, about 400,000 or less, about 390,000 or less, about 380,000 or less, about 370,000 or less, about 360,000 or less, about 3 or less, about 50,000 or less, about 340,000 or less, about 330,000 or less, about 320,000 or less, about 310,000 or less, about 300,000 or less, about 290,000 or less, about 280,000 or less, about 270,000 or less, about 260,000 or less, about 250,000 or less, about 240,000 or less, about 230,000 or less, about 220,000 or less, about 210,000 or less, about 200,000 or less, about 190,000 or less, about 180,000 or less, about 170,000 or less, about 160,000 or less, about 150,000 or less, about 140,000 or less, about 130,000 or less, about 120,000 or less, about 110,000 or less, about 100,000 or less, A total pore count of about 90,000 or less, about 80,000 or less, about 70,000 or less, about 60,000 or less, about 50,000 or less, about 40,000 or less, about 30,000 or less, about 20,000 or less, about 10,000 or less, about 9,000 or less, about 8,000 or less, about 7,000 or less, about 6,000 or less, or about 5,000 or less.

[0123] In some embodiments, the bilayer tablet is configured to have a total pore count of about 255,000±200,000, about 255,000±150,000, about 255,000±100,000, about 255,000±90,000, about 255,000±80,000, about 255,000±70,000, about 255,000±60,000, about 255,000±50,000, about 255,000±40,000, about 255,000±30,000, about 255,000±20,000, or about 255,000±10,000.

[0124] In some embodiments, the bilayer tablet is configured to have a thickness of about 10 mm. 3 Or smaller, about 9mm 3 Or smaller, about 8mm 3 Or smaller, about 7mm 3Or smaller, about 6mm 3 Or smaller, about 5mm 3 or smaller, about 4mm 3 Or smaller, about 3mm 3 or smaller, about 2mm 3 Or smaller, about 1.9mm 3 Or smaller, about 1.8mm 3 Or smaller, about 1.7mm 3 Or smaller, about 1.6mm 3 Or smaller, about 1.5mm 3 Or smaller, about 1.4mm 3 Or smaller, about 1.3mm 3 Or smaller, about 1.2mm 3 Or smaller, about 1.1mm 3 Or smaller, about 1.0mm 3 Or smaller, about 0.95mm 3 Or smaller, about 0.90mm 3 Or smaller, about 0.85mm 3 Or smaller, about 0.80mm 3 Or smaller, about 0.75mm 3 Or smaller, about 0.70mm 3 Or smaller, about 0.65mm 3 Or smaller, about 0.60mm 3 Or smaller, about 0.55mm 3 Or smaller, about 0.50mm 3 Or smaller, about 0.45mm 3 Or smaller, about 0.40mm 3 Or smaller, about 0.35mm 3 Or smaller, about 0.30mm 3 Or smaller, about 0.25mm 3 Or smaller, about 0.20mm 3 Or smaller, about 0.15mm 3 Or smaller, about 0.10mm 3 Or smaller, about 0.09mm 3 Or smaller, about 0.08mm 3 Or smaller, about 0.07mm 3 Or smaller, about 0.06mm 3 Or smaller, about 0.05mm 3 Or smaller, about 0.04mm 3 Or smaller, about 0.03mm 3 Or smaller, about 0.02mm 3 or smaller, or about 0.01mm 3 The maximum pore volume.

[0125] In some embodiments, the bilayer tablet is configured to have a thickness of about 0.84 ± 0.5 mm 3 , about 0.84±0.45mm 3 , about 0.84±0.4mm 3 , about 0.84±0.35mm 3 , about 0.84±0.3mm 3 , about 0.84±0.25mm 3 , about 0.84±0.2mm 3 , about 0.84±0.15mm 3 , about 0.84±0.1mm 3 , about 0.84±0.09mm 3 , about 0.84±0.08mm 3 、About 0.84±0.07mm 3 , about 0.84±0.06mm 3 , about 0.84±0.05mm 3 , about 0.84±0.04mm 3 , about 0.84±0.03mm 3 , about 0.84±0.02mm 3 , or about 0.84±0.01mm 3 The maximum pore volume.

[0126] In some embodiments, the bilayer tablet is configured so that the ratio between the maximum pore volume and the total pore volume is about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less.

[0127] In some embodiments, the bilayer tablet is configured such that the ratio between the maximum pore volume and the total pore volume is about 10±9%, about 10±8%, about 10±7%, about 10±6%, about 10±5%, about 10±4.5%, about 10±4%, about 10±3.5%, about 10±3%, about 10±2.5%, about 10±2%, about 10±1.9%, about 10±1.8%, about 10±1.7%, about 10±2.5 ... About 10±1.6%, about 10±1.5%, about 10±1.4%, about 10±1.3%, about 10±1.2%, about 10±1.1%, about 10±1.0%, about 10±0.9%, about 10±0.8%, about 10±0.7%, about 10±0.6%, about 10±0.5%, about 10±0.4%, about 10±0.3%, about 10±0.2%, or about 10±0.1%.

[0128] Physicochemical properties of bilayer tablets

[0129] It is to be understood that the bi-layer tablets of the present disclosure may have one or more of the physicochemical properties disclosed herein.

[0130] In vitro release of β-lactam compounds or pharmaceutically acceptable salts thereof

[0131] In some embodiments, the bilayer tablet is configured to release about 40±20%, about 40±18%, about 40±16%, about 40±14%, about 40±12%, about 40±10%, about 40±9%, about 40±8%, about 40±7%, about 40±6%, about 40±5%, about 40±4%, about 40±3%, about 40±2%, or about 40±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0132] In some embodiments, the bilayer tablet is configured to release about 63±20%, about 63±18%, about 63±16%, about 63±14%, about 63±12%, about 63±10%, about 63±9%, about 63±8%, about 63±7%, about 63±6%, about 63±5%, about 63±4%, about 63±3%, about 63±2%, or about 63±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0133] In some embodiments, the bilayer tablet is configured to release about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0134] In some embodiments, the bilayer tablet is configured to release about 80±10%, about 80±9%, about 80±8%, about 80±7%, about 80±6%, about 80±5%, about 80±4%, about 80±3%, about 80±2%, or about 80±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes as determined by the test methods described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0135] In some embodiments, the bilayer tablet is configured to release about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes, as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0136] In some embodiments, the bilayer tablet is configured to release about 91±5%, about 91±4%, about 91±3%, about 91±2%, or about 91±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 45 minutes, as measured by the test methods described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0137] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0138] releasing about 40±20%, about 40±18%, about 40±16%, about 40±14%, about 40±12%, about 40±10%, about 40±9%, about 40±8%, about 40±7%, about 40±6%, about 40±5%, about 40±4%, about 40±3%, about 40±2%, or about 40±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0139] releasing about 63±20%, about 63±18%, about 63±16%, about 63±14%, about 63±12%, about 63±10%, about 63±9%, about 63±8%, about 63±7%, about 63±6%, about 63±5%, about 63±4%, about 63±3%, about 63±2%, or about 63±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0140] Release about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 15 minutes;

[0141] Release about 80±10%, about 80±9%, about 80±8%, about 80±7%, about 80±6%, about 80±5%, about 80±4%, about 80±3%, about 80±2%, or about 80±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes;

[0142] Releases about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes; and

[0143] About 91±5%, about 91±4%, about 91±3%, about 91±2%, or about 91±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 45 minutes.

[0144] In some embodiments, the bilayer tablet is configured to release about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0145] In some embodiments, the bilayer tablet is configured to release about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0146] In some embodiments, the bilayer tablet is configured to release about 82±10%, about 82±9%, about 82±8%, about 82±7%, about 82±6%, about 82±5%, about 82±4%, about 82±3%, about 82±2%, or about 82±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by the test methods described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0147] In some embodiments, the bilayer tablet is configured to release about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0148] In some embodiments, the bilayer tablet is configured to release about 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes, as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0149] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0150] releasing about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0151] Release about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0152] Release about 82±10%, about 82±9%, about 82±8%, about 82±7%, about 82±6%, about 82±5%, about 82±4%, about 82±3%, about 82±2%, or about 82±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes;

[0153] Releases about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 20 minutes; and

[0154] About 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 30 minutes.

[0155] In some embodiments, the bilayer tablet is configured to release about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <811> Test method) measured in vitro.

[0156] In some embodiments, the bilayer tablet is configured to release about 70±20%, about 70±18%, about 70±16%, about 70±14%, about 70±12%, about 70±10%, about 70±9%, about 70±8%, about 70±7%, about 70±6%, about 70±5%, about 70±4%, about 70±3%, about 70±2%, or about 70±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <811> Test method) measured in vitro.

[0157] In some embodiments, the bilayer tablet is configured to release about 81±10%, about 81±9%, about 81±8%, about 81±7%, about 81±6%, about 81±5%, about 81±4%, about 81±3%, about 81±2%, or about 81±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by the test methods described herein (e.g., in accordance with USP <811> Test method) measured in vitro.

[0158] In some embodiments, the bilayer tablet is configured to release about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes as determined by a test method described herein (e.g., in accordance with USP <811> Test method) measured in vitro.

[0159] In some embodiments, the bilayer tablet is configured to release about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes, as measured by the test methods described herein (e.g., in accordance with USP <811> Test method) measured in vitro.

[0160] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <811> The bilayer tablets were configured to release:

[0161] releasing about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0162] releasing about 70±20%, about 70±18%, about 70±16%, about 70±14%, about 70±12%, about 70±10%, about 70±9%, about 70±8%, about 70±7%, about 70±6%, about 70±5%, about 70±4%, about 70±3%, about 70±2%, or about 70±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0163] Release about 81±10%, about 81±9%, about 81±8%, about 81±7%, about 81±6%, about 81±5%, about 81±4%, about 81±3%, about 81±2%, or about 81±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 15 minutes;

[0164] releases about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 20 minutes; and

[0165] About 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 30 minutes.

[0166] In some embodiments, the bilayer tablet is configured to release about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0167] In some embodiments, the bilayer tablet is configured to release about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0168] In some embodiments, the bilayer tablet is configured to release about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by the test methods described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0169] In some embodiments, the bilayer tablet is configured to release about 92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about 92±5%, about 92±4%, about 92±3%, about 92±2%, or about 92±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0170] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0171] releasing about 47±20%, about 47±18%, about 47±16%, about 47±14%, about 47±12%, about 47±10%, about 47±9%, about 47±8%, about 47±7%, about 47±6%, about 47±5%, about 47±4%, about 47±3%, about 47±2%, or about 47±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0172] Release about 71±20%, about 71±18%, about 71±16%, about 71±14%, about 71±12%, about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0173] Releases about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 15 minutes; and

[0174] About 92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about 92±5%, about 92±4%, about 92±3%, about 92±2%, or about 92±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 20 minutes.

[0175] In some embodiments, the bilayer tablet is configured to release about 52±20%, about 52±18%, about 52±16%, about 52±14%, about 52±12%, about 52±10%, about 52±9%, about 52±8%, about 52±7%, about 52±6%, about 52±5%, about 52±4%, about 52±3%, about 52±2%, or about 52±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0176] In some embodiments, the bilayer tablet is configured to release about 74±20%, about 74±18%, about 74±16%, about 74±14%, about 74±12%, about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0177] In some embodiments, the bilayer tablet is configured to release about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by the test methods described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0178] In some embodiments, the bilayer tablet is configured to release about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0179] In some embodiments, the bilayer tablet is configured to release about 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes, as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0180] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0181] releasing about 52±20%, about 52±18%, about 52±16%, about 52±14%, about 52±12%, about 52±10%, about 52±9%, about 52±8%, about 52±7%, about 52±6%, about 52±5%, about 52±4%, about 52±3%, about 52±2%, or about 52±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0182] releasing about 74±20%, about 74±18%, about 74±16%, about 74±14%, about 74±12%, about 74±10%, about 74±9%, about 74±8%, about 74±7%, about 74±6%, about 74±5%, about 74±4%, about 74±3%, about 74±2%, or about 74±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0183] Release about 84±10%, about 84±9%, about 84±8%, about 84±7%, about 84±6%, about 84±5%, about 84±4%, about 84±3%, about 84±2%, or about 84±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 15 minutes;

[0184] Releases about 89±10%, about 89±9%, about 89±8%, about 89±7%, about 89±6%, about 89±5%, about 89±4%, about 89±3%, about 89±2%, or about 89±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 20 minutes; and

[0185] About 95±5%, about 95±4%, about 95±3%, about 95±2%, or about 95±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 30 minutes.

[0186] In some embodiments, the bilayer tablet is configured to release about 53±20%, about 53±18%, about 53±16%, about 53±14%, about 53±12%, about 53±10%, about 53±9%, about 53±8%, about 53±7%, about 53±6%, about 53±5%, about 53±4%, about 53±3%, about 53±2%, or about 53±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0187] In some embodiments, the bilayer tablet is configured to release about 77±20%, about 77±18%, about 77±16%, about 77±14%, about 77±12%, about 77±10%, about 77±9%, about 77±8%, about 77±7%, about 77±6%, about 77±5%, about 77±4%, about 77±3%, about 77±2%, or about 77±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0188] In some embodiments, the bilayer tablet is configured to release about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0189] In some embodiments, the bilayer tablet is configured to release about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes, as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0190] In some embodiments, the bilayer tablet is configured to release about 98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%, about 98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%, about 98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about 98±0.1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 30 minutes as determined by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0191] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0192] releasing about 53±20%, about 53±18%, about 53±16%, about 53±14%, about 53±12%, about 53±10%, about 53±9%, about 53±8%, about 53±7%, about 53±6%, about 53±5%, about 53±4%, about 53±3%, about 53±2%, or about 53±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 5 minutes;

[0193] releasing about 77±20%, about 77±18%, about 77±16%, about 77±14%, about 77±12%, about 77±10%, about 77±9%, about 77±8%, about 77±7%, about 77±6%, about 77±5%, about 77±4%, about 77±3%, about 77±2%, or about 77±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 10 minutes;

[0194] Release about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in a bilayer tablet within about 15 minutes;

[0195] Releases about 93±5%, about 93±4%, about 93±3%, about 93±2%, or about 93±1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 20 minutes; and

[0196] About 98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%, about 98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%, about 98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about 98±0.1% of the β-lactam compound (e.g., Compound III-2, Compound III-2a or Compound III-2b) or a pharmaceutically acceptable salt thereof in the bilayer tablet is released within about 30 minutes.

[0197] In vitro release of probenecid or its pharmaceutically acceptable salt

[0198] In some embodiments, the bilayer tablet is configured to release about 25±20%, about 25±18%, about 25±16%, about 25±14%, about 25±12%, about 25±10%, about 25±9%, about 25±8%, about 25±7%, about 25±6%, about 25±5%, about 25±4%, about 25±3%, about 25±2%, or about 25±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0199] In some embodiments, the bilayer tablet is configured to release about 66±20%, about 66±18%, about 66±16%, about 66±14%, about 66±12%, about 66±10%, about 66±9%, about 66±8%, about 66±7%, about 66±6%, about 66±5%, about 66±4%, about 66±3%, about 66±2%, or about 66±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0200] In some embodiments, the bilayer tablet is configured to release about 92±20%, about 92±18%, about 92±16%, about 92±14%, about 92±12%, about 92±10%, about 92±9%, about 92±8%, about 92±7%, about 92±6%, about 92±5%, about 92±4%, about 92±3%, about 92±2%, or about 92±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0201] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0202] releases about 25±10%, about 25±9%, about 25±8%, about 25±7%, about 25±6%, about 25±5%, about 25±4%, about 25±3%, about 25±2%, or about 25±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0203] releases about 66±10%, about 66±9%, about 66±8%, about 66±7%, about 66±6%, about 66±5%, about 66±4%, about 66±3%, about 66±2%, or about 66±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0204] About 92±2%, about 92±1.8%, about 92±1.6%, about 92±1.4%, about 92±1.2%, about 92±1%, about 92±0.9%, about 92±0.8%, about 92±0.7%, about 92±0.6%, about 92±0.5%, about 92±0.4%, about 92±0.3%, about 92±0.2%, or about 92±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0205] In some embodiments, the bilayer tablet is configured to release about 28±20%, about 28±18%, about 28±16%, about 28±14%, about 28±12%, about 28±10%, about 28±9%, about 28±8%, about 28±7%, about 28±6%, about 28±5%, about 28±4%, about 28±3%, about 28±2%, or about 28±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0206] In some embodiments, the bilayer tablet is configured to release about 71 ± 20%, about 71 ± 18%, about 71 ± 16%, about 71 ± 14%, about 71 ± 12%, about 71 ± 10%, about 71 ± 9%, about 71 ± 8%, about 71 ± 7%, about 71 ± 6%, about 71 ± 5%, about 71 ± 4%, about 71 ± 3%, about 71 ± 2%, or about 71 ± 1% of the probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0207] In some embodiments, the bilayer tablet is configured to release about 94±20%, about 94±18%, about 94±16%, about 94±14%, about 94±12%, about 94±10%, about 94±9%, about 94±8%, about 94±7%, about 94±6%, about 94±5%, about 94±4%, about 94±3%, about 94±2%, or about 94±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0208] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0209] releases about 28±10%, about 28±9%, about 28±8%, about 28±7%, about 28±6%, about 28±5%, about 28±4%, about 28±3%, about 28±2%, or about 28±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0210] releases about 71±10%, about 71±9%, about 71±8%, about 71±7%, about 71±6%, about 71±5%, about 71±4%, about 71±3%, about 71±2%, or about 71±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0211] About 94±2%, about 94±1.8%, about 94±1.6%, about 94±1.4%, about 94±1.2%, about 94±1%, about 94±0.9%, about 94±0.8%, about 94±0.7%, about 94±0.6%, about 94±0.5%, about 94±0.4%, about 94±0.3%, about 94±0.2%, or about 94±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0212] In some embodiments, the bilayer tablet is configured to release about 30±20%, about 30±18%, about 30±16%, about 30±14%, about 30±12%, about 30±10%, about 30±9%, about 30±8%, about 30±7%, about 30±6%, about 30±5%, about 30±4%, about 30±3%, about 30±2%, or about 30±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0213] In some embodiments, the bilayer tablet is configured to release about 72±20%, about 72±18%, about 72±16%, about 72±14%, about 72±12%, about 72±10%, about 72±9%, about 72±8%, about 72±7%, about 72±6%, about 72±5%, about 72±4%, about 72±3%, about 72±2%, or about 72±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0214] In some embodiments, the bilayer tablet is configured to release about 94±20%, about 94±18%, about 94±16%, about 94±14%, about 94±12%, about 94±10%, about 94±9%, about 94±8%, about 94±7%, about 94±6%, about 94±5%, about 94±4%, about 94±3%, about 94±2%, or about 94±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0215] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0216] releases about 30±10%, about 30±9%, about 30±8%, about 30±7%, about 30±6%, about 30±5%, about 30±4%, about 30±3%, about 30±2%, or about 30±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0217] releases about 72±10%, about 72±9%, about 72±8%, about 72±7%, about 72±6%, about 72±5%, about 72±4%, about 72±3%, about 72±2%, or about 72±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0218] About 94±2%, about 94±1.8%, about 94±1.6%, about 94±1.4%, about 94±1.2%, about 94±1%, about 94±0.9%, about 94±0.8%, about 94±0.7%, about 94±0.6%, about 94±0.5%, about 94±0.4%, about 94±0.3%, about 94±0.2%, or about 94±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0219] In some embodiments, the bilayer tablet is configured to release about 41±20%, about 41±18%, about 41±16%, about 41±14%, about 41±12%, about 41±10%, about 41±9%, about 41±8%, about 41±7%, about 41±6%, about 41±5%, about 41±4%, about 41±3%, about 41±2%, or about 41±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0220] In some embodiments, the bilayer tablet is configured to release about 87±20%, about 87±18%, about 87±16%, about 87±14%, about 87±12%, about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0221] In some embodiments, the bilayer tablet is configured to release about 96±20%, about 96±18%, about 96±16%, about 96±14%, about 96±12%, about 96±10%, about 96±9%, about 96±8%, about 96±7%, about 96±6%, about 96±5%, about 96±4%, about 96±3%, about 96±2%, or about 96±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0222] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0223] releases about 41±10%, about 41±9%, about 41±8%, about 41±7%, about 41±6%, about 41±5%, about 41±4%, about 41±3%, about 41±2%, or about 41±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0224] releases about 87±10%, about 87±9%, about 87±8%, about 87±7%, about 87±6%, about 87±5%, about 87±4%, about 87±3%, about 87±2%, or about 87±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0225] About 96±2%, about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%, about 96±1%, about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%, about 96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about 96±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0226] In some embodiments, the bilayer tablet is configured to release about 43±20%, about 43±18%, about 43±16%, about 43±14%, about 43±12%, about 43±10%, about 43±9%, about 43±8%, about 43±7%, about 43±6%, about 43±5%, about 43±4%, about 43±3%, about 43±2%, or about 43±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0227] In some embodiments, the bilayer tablet is configured to release about 86±20%, about 86±18%, about 86±16%, about 86±14%, about 86±12%, about 86±10%, about 86±9%, about 86±8%, about 86±7%, about 86±6%, about 86±5%, about 86±4%, about 86±3%, about 86±2%, or about 86±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0228] In some embodiments, the bilayer tablet is configured to release about 98±20%, about 98±18%, about 98±16%, about 98±14%, about 98±12%, about 98±10%, about 98±9%, about 98±8%, about 98±7%, about 98±6%, about 98±5%, about 98±4%, about 98±3%, about 98±2%, or about 98±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 15 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0229] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0230] releases about 43±10%, about 43±9%, about 43±8%, about 43±7%, about 43±6%, about 43±5%, about 43±4%, about 43±3%, about 43±2%, or about 43±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0231] releases about 86±10%, about 86±9%, about 86±8%, about 86±7%, about 86±6%, about 86±5%, about 86±4%, about 86±3%, about 86±2%, or about 86±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0232] About 98±2%, about 98±1.8%, about 98±1.6%, about 98±1.4%, about 98±1.2%, about 98±1%, about 98±0.9%, about 98±0.8%, about 98±0.7%, about 98±0.6%, about 98±0.5%, about 98±0.4%, about 98±0.3%, about 98±0.2%, or about 98±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0233] In some embodiments, the bilayer tablet is configured to release about 75±20%, about 75±18%, about 75±16%, about 75±14%, about 75±12%, about 75±10%, about 75±9%, about 75±8%, about 75±7%, about 75±6%, about 75±5%, about 75±4%, about 75±3%, about 75±2%, or about 75±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 10 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0234] In some embodiments, the bilayer tablet is configured to release about 37±20%, about 37±18%, about 37±16%, about 37±14%, about 37±12%, about 37±10%, about 37±9%, about 37±8%, about 37±7%, about 37±6%, about 37±5%, about 37±4%, about 37±3%, about 37±2%, or about 37±1% of probenecid or a pharmaceutically acceptable salt thereof in the bilayer tablet within about 5 minutes as measured by a test method described herein (e.g., in accordance with USP <711> Test method) measured in vitro.

[0235] In some embodiments, as determined by the test methods described herein (e.g., in accordance with USP <711> The bilayer tablets were configured to release:

[0236] releases about 37±10%, about 37±9%, about 37±8%, about 37±7%, about 37±6%, about 37±5%, about 37±4%, about 37±3%, about 37±2%, or about 37±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 5 minutes;

[0237] releases about 75±10%, about 75±9%, about 75±8%, about 75±7%, about 75±6%, about 75±5%, about 75±4%, about 75±3%, about 75±2%, or about 75±1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet in about 10 minutes; and

[0238] About 96±2%, about 96±1.8%, about 96±1.6%, about 96±1.4%, about 96±1.2%, about 96±1%, about 96±0.9%, about 96±0.8%, about 96±0.7%, about 96±0.6%, about 96±0.5%, about 96±0.4%, about 96±0.3%, about 96±0.2%, or about 96±0.1% of probenecid or a pharmaceutically acceptable salt thereof in a bilayer tablet is released in about 15 minutes.

[0239] Test methods for physicochemical properties of bilayer tablets

[0240] It will be appreciated that the physicochemical properties, such as the in vitro release characteristics of the bilayer tablets, can be determined using methods commonly used in the art (e.g., in accordance with USP <711> Test method) measured in vitro.

[0241] In some embodiments, the USP <711> The method is performed using a paddle apparatus, basket apparatus, reciprocating cylinder or flow cell as described in the method.

[0242] In some embodiments, the USP <711> The method was performed using a paddle apparatus as described in Methods.

[0243] In some embodiments, the USP <711> The method is carried out at a temperature of about 37±10°C, about 37±8°C, about 37±6°C, about 37±5°C, about 37±4°C, about 37±3°C, about 37±2°C, about 37±1°C, or about 37±0.5°C. In some embodiments, the method is carried out in accordance with USP <711> The method is carried out at a temperature of about 37°C.

[0244] In some embodiments, the USP <711> The method is performed with a sampling volume of about 2.5±2mL, about 2.5±1.8mL, about 2.5±1.6mL, about 2.5±1.4mL, about 2.5±1.2mL, about 2.5±1mL, about 2.5±0.9mL, about 2.5±0.8mL, about 2.5±0.7mL, about 2.5±0.6mL, about 2.5±0.5mL, about 2.5±0.4mL, about 2.5±0.3mL, about 2.5±0.2mL, or about 2.5±0.1mL. In some embodiments, the method is performed in accordance with USP <711> The method is performed with a sample volume of approximately 2.5 mL.

[0245] In some embodiments, the USP <711> The method is carried out at a rotation speed of about 75±50 rpm, about 75±40 rpm, about 75±30 rpm, about 75±20 rpm, about 75±15 rpm, about 75±10 rpm, or about 75±5 rpm. In some embodiments, the method is carried out at a rotation speed of about 75±50 rpm, about 75±40 rpm, about 75±30 rpm, about 75±20 rpm, about 75±15 rpm, about 75±10 rpm, or about 75±5 rpm. <711> The process was carried out at a rotation speed of about 75 rpm.

[0246] In some embodiments, the USP <711> The method is carried out at a medium volume of about 900±500mL, about 900±450mL, about 900±400mL, about 900±350mL, about 900±300mL, about 900±250mL, about 900±200mL, about 900±150mL, about 900±100mL, about 900±90mL, about 900±80mL, about 900±70mL, about 900±60mL, about 900±50mL, about 900±40mL, about 900±30mL, about 900±20mL, or about 900±10mL. In some embodiments, the method is carried out at a medium volume of about 900±500mL, about 900±450mL, about 900±400mL, about 900±30mL, about 900±20mL, or about 900±10mL. <711> The method was carried out in a medium volume of about 900 mL.

[0247] In some embodiments, the USP <711> The method is carried out at a pH of about 6.8±3, about 6.8±2.8, about 6.8±2.6, about 6.8±2.4, about 6.8±2.2, about 6.8±2, about 6.8±1.8, about 6.8±1.6, about 6.8±1.4, about 6.8±1.2, about 6.8±1, about 6.8±0.9, about 6.8±0.8, about 6.8±0.7, about 6.8±0.6, about 6.8±0.5, about 6.8±0.4, about 6.8±0.3, about 6.8±0.2, or about 6.8±0.1. In some embodiments, the method is carried out at a pH of about 6.8±3, about 6.8±2.8, about 6.8±1.6, about 6.8±1.4, about 6.8±1.2, about 6.8±1, about 6.8±0.9, about 6.8±0.8, about 6.8±0.7, about 6.8±0.6, about 6.8±0.5, about 6.8±0.4, about 6.8±0.3, about 6.8±0.2, or about 6.8±0.1. <711> The method is carried out at a pH of about 6.8.

[0248] In some embodiments, the USP <711> The method is performed by HPLC (eg, HPLC-UV) analysis.

[0249] β-lactam compounds

[0250] In some embodiments, the β-lactam compound is a monobactam or a prodrug thereof.

[0251] In some embodiments, the β-lactam compound is aztreonam, tigemonam, carumonam, nocardicin A, a prodrug thereof, an analog thereof, or a derivative thereof.

[0252] In some embodiments, the β-lactam compound is a penem, a carbapenem, a clavam, or a prodrug thereof.

[0253] In some embodiments, the β-lactam compound is benzylpenicillin, benzathinebenzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin, propicillin, pheneticillin, azidocillin, clometocillin, penamcillin, cloxacillin (e.g., dicloxacillin or flucloxacillin), oxacillin, nafcillin, methicillin, amoxicillin, ampicillin (e.g., pivampicillin), phenoxymethylpenic ... lin), hetacillin, bacampicillin, metampicillin, talampicillin), epicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam (e.g., pivmecillinam), sulbenicillin, or a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0254] In some embodiments, the β-lactam compound is a penem, a carbapenem, or a prodrug thereof.

[0255] In some embodiments, the β-lactam compound is a thiopenem, oxypenem, aminopenem, alkylpenem, arylpenem, or a prodrug thereof.

[0256] In some embodiments, the β-lactam compound is ertapenem, an antipseudomonal carbapenem (e.g., doripenem, imipenem, meropenem), biapenem, panipenem, sulopenem, tebipenem, faropenem, a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0257] In some embodiments, the β-lactam compound is a cephem, a carbacephem, an oxacephem, or a prodrug thereof.

[0258] In some embodiments, the beta-lactam compound is cefazolin, cefalexin, cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine, cefalotin, cefatrizine, cefaclor, cefotetan, a cephamycin (e.g., cefoxitin, cefprozil, cefuroxime, cefuroxime axetil),axetil), cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole), carbacephems (e.g., loracarbef), cefixime, ceftriaxone, antipseudomonal (e.g., ceftazidime, cefoperazone), cefdinir, cefcapene, cefdaloxime, ceftizoxime, cephalosporins cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefodizime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephems (e.g., flomoxef, latamoxef), cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome, cefovecin, or a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0259] In some embodiments, the β-lactam compound is a thiopentylpenicem or a prodrug thereof.

[0260] In some embodiments, the β-lactam compound has formula (I):

[0261]

[0262] Its pharmaceutically acceptable salt, prodrug, analog or derivative thereof, wherein R 1is H or optionally substituted alkyl.

[0263] In some embodiments, the β-lactam compound has formula (Ia):

[0264]

[0265] A pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof or a derivative thereof. In some embodiments, the β-lactam compound has formula (Ib):

[0266]

[0267] or a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof. 1 It's H.

[0268] In some embodiments, the β-lactam compound has formula (II):

[0269]

[0270] A pharmaceutically acceptable salt, a prodrug, an analog or a derivative thereof.

[0271] In some embodiments, the β-lactam compound has formula (IIa):

[0272]

[0273] A pharmaceutically acceptable salt, a prodrug, an analog or a derivative thereof.

[0274] In some embodiments, the β-lactam compound has formula (IIb):

[0275]

[0276] A pharmaceutically acceptable salt, a prodrug, an analog or a derivative thereof.

[0277] In some embodiments, R 1 is optionally substituted alkyl.

[0278] In some embodiments, the β-lactam compound has any one of formula (III), (IIIa), and (IIIb):

[0279]

[0280] Its pharmaceutically acceptable salt, prodrug, analog or derivative thereof, wherein R 2 is H or optionally substituted alkyl.

[0281] In some embodiments, the β-lactam compound is selected from the group consisting of:

[0282]

[0283] Its pharmaceutically acceptable salts, prodrugs, analogs and derivatives.

[0284] In some embodiments, the β-lactam compound is selected from the group consisting of:

[0285]

[0286] Its pharmaceutically acceptable salts, prodrugs, analogs and derivatives.

[0287] In some embodiments, the β-lactam compound is selected from Its pharmaceutically acceptable salts, prodrugs, analogs and derivatives.

[0288] Nitrogen-Containing Compounds of the Disclosure In some embodiments, the β-lactam compound has any one of formula (IV), (IVa), and (IVb):

[0289]

[0290]

[0291] Its pharmaceutically acceptable salt, prodrug, analog or derivative thereof, wherein R 3 is H or optionally substituted alkyl.

[0292] In some embodiments, R 3 It is a C2-C8 alkyl group.

[0293] In some embodiments, R 3 It is CH2CH3, CH2CH2CH3 or CH2CH(CH3)2.

[0294] Preparation method

[0295] In some aspects, the present disclosure provides a method of preparing a bilayer tablet.

[0296] In some embodiments, the bilayer tablets of the present disclosure are prepared by the methods disclosed herein.

[0297] In some embodiments, the method comprises:

[0298] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force, thereby forming a pre-compressed first layer;

[0299] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0300] iii) compressing said pre-compressed first layer and said second granular material with a second force, thereby forming a pre-coated bi-layer tablet.

[0301] In some embodiments, the first particulate material is prepared by a process disclosed herein (e.g., Figure 1 In some embodiments, the first granular material is prepared by granulating a mixture of powder or solid probenecid or a pharmaceutically acceptable salt thereof and one or more excipients.

[0302] In some embodiments, the second particulate material is prepared by a process disclosed herein (e.g., Figure 2 prepared by the process described in .

[0303] In some embodiments, the second particulate material is prepared by granulating a mixture of a powdered or solid β-lactam compound or a pharmaceutically acceptable salt thereof (eg Compound III-2b) and one or more excipients.

[0304] In some embodiments, the granular mixture is further compacted (eg, by one or more rollers), thereby forming a compacted ribbon portion.

[0305] In some embodiments, the compacted strand portion is further pelletized, crushed, and / or screened through one or more appropriately sized screens.

[0306] In some embodiments, the compacting step and the granulating, crushing and / or screening steps are repeated one or more times.

[0307] In some embodiments, the first force is about 20 kN or less, about 19 kN or less, about 18 kN or less, about 17 kN or less, about 16 kN or less, about 15 kN or less, about 14.5 kN or less, about 14 kN or less, about 13.5 kN or less, about 13 kN or less, about 12.5 kN or less, about 12 kN or less, about 11.5 kN or less, about 11 kN or less, about 10.5 kN or less, about 10 kN or less, about 9. 5 kN or less, about 9 kN or less, about 8.5 kN or less, about 8 kN or less, about 7.5 kN or less, about 7 kN or less, about 6.5 kN or less, about 6 kN or less, about 5.5 kN or less, about 5 kN or less, about 4.5 kN or less, about 4 kN or less, about 3.5 kN or less, about 3 kN or less, about 2.5 kN or less, about 2 kN or less, about 1.5 kN or less, about 1 kN or less, or about 0.5 kN or less.

[0308] In some embodiments, the first force is about 11.5 kN or less.

[0309] In some embodiments, the second force is about 50 kN or less, about 45 kN or less, about 40 kN or less, about 39 kN or less, about 38 kN or less, about 37 kN or less, about 36 kN or less, about 35 kN or less, about 34 kN or less, about 33 kN or less, about 32 kN or less, about 31 kN or less, about 30 kN or less, about 29 kN or less, about 28 kN or less, about 27 kN or less, about 26 kN or less, about 25 kN or less, about 20 kN or less, about 15 kN or less, about 10 kN or less, about 9 kN or less, about 8 kN or less, about 7 kN or less, about 6 kN or less, about 5 kN or less, about 4 kN or less, about 3 kN or less, about 2 kN or less, or about 1 kN or less.

[0310] In some embodiments, the second force is about 30 kN or less.

[0311] In some embodiments, the first force is about 11.5 kN or less, and the second force is about 30 kN or less.

[0312] In some embodiments, the method comprises:

[0313] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force of about 20 kN or less, about 19 kN or less, about 18 kN or less, about 17 kN or less, about 16 kN or less, about 15 kN or less, about 14.5 kN or less, about 14 kN or less, about 13.5 kN or less, about 13 kN or less, about 12.5 kN or less, about 12 kN or less, about 11.5 kN or less, about 11 kN or less, about 12.5 kN or less, about 12 kN or less, about 13.5 kN or less, about 13 kN or less, about 14.5 kN or less, about 13.5 kN or less, about 13 kN or less, about 13.5 kN or less, about 13 kN or less, about 12.5 kN or less, about 12 kN or less, about 11.5 kN or less, about 11 kN or less, about 13.5 kN or less, about 13 ....5 kN or less, about 13 kN or less, about 13.5 kN or less, about 13.5 kN or less, about 13.5 kN or less, about 10.5 kN or less, about 10 kN or less, about 9.5 kN or less, about 9 kN or less, about 8.5 kN or less, about 8 kN or less, about 7.5 kN or less, about 7 kN or less, about 6.5 kN or less, about 6 kN or less, about 5.5 kN or less, about 5 kN or less, about 4.5 kN or less, about 4 kN or less, about 3.5 kN or less, about 3 kN or less, about 2.5 kN or less, about 2 kN or less, about 1.5 kN or less, or about 1 kN or less;

[0314] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0315] iii) compressing the pre-compressed first layer and the second particulate material with a second force of about 50 kN or less, about 45 kN or less, about 40 kN or less, about 39 kN or less, about 38 kN or less, about 37 kN or less, about 36 kN or less, about 35 kN or less, about 34 kN or less, about 33 kN or less, about 32 kN or less, about 31 kN or less, thereby forming a pre-coated bi-layer tablet. About 30 kN or less, about 29 kN or less, about 28 kN or less, about 27 kN or less, about 26 kN or less, about 25 kN or less, about 20 kN or less, about 15 kN or less, about 10 kN or less, about 9 kN or less, about 8 kN or less, about 7 kN or less, about 6 kN or less, about 5 kN or less, about 4 kN or less, about 3 kN or less, about 2 kN or less, about 1 kN or less.

[0316] In some embodiments, the method comprises:

[0317] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force of about 11.5 kN or less, thereby forming a pre-compressed first layer;

[0318] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0319] iii) compressing the pre-compressed first layer and the second granular material with a second force of about 30 kN or less, thereby forming a pre-coated bi-layer tablet.

[0320] In some embodiments, the first force is about 1.5±1.2 kN, about 1.5±1.1 kN, about 1.5±1.0 kN, about 1.5±0.9 kN, about 1.5±0.8 kN, about 1.5±0.75 kN, about 1.5±0.7 kN, about 1.5±0.65 kN, about 1.5±0.6 kN, about 1.5±0.55 kN, about 1.5±0.5 kN, about 1.5±0.45 kN, about 1.5±0.4 kN, about 1.5±0.35 kN, about 1.5±0.3 kN, about 1.5±0.25 kN, about 1.5±0.2 kN, about 1.5±0.15 kN, about 1.5±0.1 kN, or about 1.5±0.05 kN.

[0321] In some embodiments, the first force is about 1.5 kN.

[0322] In some embodiments, the first force is about 0.5±0.45 kN, about 0.5±0.4 kN, about 0.5±0.35 kN, about 0.5±0.3 kN, about 0.5±0.25 kN, about 0.5±0.2 kN, about 0.5±0.15 kN, about 0.5±0.1 kN, or about 0.5±0.05 kN.

[0323] In some embodiments, the first force is about 0.5 kN.

[0324] In some embodiments, the second force is about 11.5±10 kN, about 11.5±9 kN, about 11.5±8 kN, about 11.5±7 kN, about 11.5±6 kN, about 11.5±5 kN, about 11.5±4 kN, about 11.5±3 kN, about 11.5±2 kN, about 11.5±1 kN, about 11.5±0.9 kN, about 11.5±0.8 kN, about 11.5±0.7 kN, about 11.5±0.6 kN, about 11.5±0.5 kN, about 11.5±0.4 kN, about 11.5±0.3 kN, about 11.5±0.2 kN, or about 11.5±0.1 kN.

[0325] In some embodiments, the second force is about 11.5 kN.

[0326] In some embodiments, the first force is about 1.5 kN and the second force is about 30 kN.

[0327] In some embodiments, the method comprises:

[0328] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force to form a pre-compressed first layer, wherein the first force is about 1.5±1.2 kN, about 1.5±1.1 kN, about 1.5±1.0 kN, about 1.5±0.9 kN, about 1.5±0.8 kN, about 1.5±0.75 kN, about 1.5±0.7 kN, about 1.5±0.65 kN, about 1.5±0.8 kN, about 1.5±0.9 kN, about 1.5±0.8 kN, about 1.5±0.75 kN, about 1.5±0.8 kN, about 1.5±0.8 kN, about 1.5±0.9 ... about 1.5±0.6 kN, about 1.5±0.55 kN, about 1.5±0.5 kN, about 1.5±0.45 kN, about 1.5±0.4 kN, about 1.5±0.35 kN, about 1.5±0.3 kN, about 1.5±0.25 kN, about 1.5±0.2 kN, about 1.5±0.15 kN, about 1.5±0.1 kN, or about 1.5±0.05 kN;

[0329] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0330] iii) compressing the pre-compressed first layer and the second particulate material with a second force of about 11.5±10 kN, about 11.5±9 kN, about 11.5±8 kN, about 11.5±7 kN, about 11.5±6 kN, about 11.5±5 kN, about 11.5±4 kN, about 11.5±3 kN, about 11.5±2 kN, about 11.5±1 kN, about 11.5±0.9 kN, about 11.5±0.8 kN, about 11.5±0.7 kN, about 11.5±0.6 kN, about 11.5±0.5 kN, about 11.5±0.4 kN, about 11.5±0.3 kN, about 11.5±0.2 kN, or about 11.5±0.1 kN to form a pre-coated bi-layer tablet.

[0331] In some embodiments, the method comprises:

[0332] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force of about 1.5 kN, thereby forming a pre-compressed first layer;

[0333] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0334] iii) compressing the pre-compressed first layer and the second granular material with a second force of about 11.5 kN, thereby forming a pre-coated bi-layer tablet.

[0335] In some embodiments, the first force is about 1.25±1.2 kN, about 1.25±1.1 kN, about 1.25±1.0 kN, about 1.25±0.9 kN, about 1.25±0.8 kN, about 1.25±0.75 kN, about 1.25±0.7 kN, about 1.25±0.65 kN, about 1.25±0.6 kN, about 1.25±0. 55kN, about 1.25±0.5kN, about 1.25±0.45kN, about 1.25±0.4kN, about 1.25±0.35kN, about 1.25±0.3kN, about 1.25±0.25kN, about 1.25±0.2kN, about 1.25±0.15kN, about 1.25±0.1 kN, or about 1.25±0.05kN.

[0336] In some embodiments, the first force is about 1.25 kN.

[0337] In some embodiments, the second force is about 30±20 kN, about 30±15 kN, about 30±10 kN, about 30±9 kN, about 30±8 kN, about 30±7 kN, about 30±6 kN, about 30±5 kN, about 30±4 kN, about 30±3 kN, about 30±2 kN, about 30±1 kN, about 30±0.9 kN, about 30±0.8 kN, about 30±0.7 kN, about 30±0.6 kN, about 30±0.5 kN, about 30±0.4 kN, about 30±0.3 kN, about 30±0.2 kN, or about 30±0.1 kN.

[0338] In some embodiments, the second force is about 30 kN.

[0339] In some embodiments, the first force is about 1.25 kN and the second force is about 30 kN.

[0340] In some embodiments, the method comprises:

[0341] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force, thereby forming a pre-compressed first layer, wherein the first force is about 1.25±1.2 kN, about 1.25±1.1 kN, about 1.25±1.0 kN, about 1.25±0.9 kN, about 1.25±0.8 kN, about 1.25±0.75 kN, about 1.25±0.7 kN, about 1.25±0.65 kN, about 1 .25±0.6 kN, about 1.25±0.55 kN, about 1.25±0.5 kN, about 1.25±0.45 kN, about 1.25±0.4 kN, about 1.25±0.35 kN, about 1.25±0.3 kN, about 1.25±0.25 kN, about 1.25±0.2 kN, about 1.25±0.15 kN, about 1.25±0.1 kN, or about 1.25±0.05 kN;

[0342] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0343] iii) compressing the pre-compressed first layer and the second particulate material with a second force of about 30±20 kN, about 30±15 kN, about 30±10 kN, about 30±9 kN, about 30±8 kN, about 30±7 kN, about 30±6 kN, about 30±5 kN, about 30±4 kN, about 30±3 kN, about 30±2 kN, about 30±1 kN, about 30±0.9 kN, about 30±0.8 kN, about 30±0.7 kN, about 30±0.6 kN, about 30±0.5 kN, about 30±0.4 kN, about 30±0.3 kN, about 30±0.2 kN, or about 30±0.1 kN to form a pre-coated bi-layer tablet.

[0344] In some embodiments, the method comprises:

[0345] i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force of about 1.25 kN, thereby forming a pre-compressed first layer;

[0346] ii) adding a second particulate material comprising a β-lactam compound or a pharmaceutically acceptable salt thereof to the pre-compressed first layer;

[0347] iii) compressing the pre-compressed first layer and the second granular material with a second force of about 30 kN, thereby forming a pre-coated bi-layer tablet.

[0348] In some embodiments, the method further comprises:

[0349] iv) coating the pre-coated bi-layer tablet with a coating agent, thereby forming a bi-layer tablet.

[0350] In some embodiments, the coating agent comprises polyvinyl alcohol (PVA).

[0351] In some embodiments, the coating agent does not contain polyethylene glycol (PEG) or soy lecithin.

[0352] In some embodiments, the coating agent is AMB White 80W68912.

[0353] In some embodiments, the coating agent is Opadry AMB Pink 80W240026.

[0354] How to use

[0355] In some aspects, the present disclosure provides a method of treating or preventing a disease, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a bilayer tablet disclosed herein.

[0356] In some aspects, the present disclosure provides a bilayer tablet disclosed herein for use in treating or preventing a disease in a subject in need thereof.

[0357] Subjects and diseases treated

[0358] In some embodiments, the subject in need thereof is an animal. In some embodiments, the subject in need thereof is a human.

[0359] In some embodiments, the subject in need thereof is a human who is 18 years of age or older.

[0360] In some embodiments, the subject in need thereof is a human less than 18 years old.

[0361] In some embodiments, a disease is associated with an increase or decrease in the population of one or more microorganisms (eg, bacteria) in a subject.

[0362] In some embodiments, the disease is associated with an increase in one or more microorganisms (e.g., bacteria) populations in a subject. In some embodiments, the methods of the present disclosure result in a decrease in one or more microorganisms (e.g., bacteria) populations in a subject.

[0363] In some embodiments, the disease is associated with a decrease in one or more microorganisms (e.g., bacteria) populations in a subject. In some embodiments, the methods of the present disclosure result in an increase in one or more microorganisms (e.g., bacteria) populations in a subject.

[0364] In some embodiments, the disease is associated with an increase or decrease in one or more bacterial populations selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides coprocola, Prevotella capri copri), Porphyromonas asaccharolytica, and Prevotella bivia; or any organism in the following genera: Succinivibrio, Alistipes, Prevotella, Paraprevotella, Parabacteroides, and Odoribacter.

[0365] In some embodiments, the disease is associated with an increase or decrease in one or more bacterial populations selected from Staphylococcus epidermidis, Streptococcus pneumonia, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pyogenes.

[0366] In some embodiments, the disease is associated with an increase or decrease in one or more bacterial populations selected from the group consisting of Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenza, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettageri, Providencia stuartii, and Serratia marcescens.

[0367] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from Bacteroides vulgatus, Clostridium perfringens, and Fusobacterium spp.

[0368] In some embodiments, the disease is associated with an infection. In some embodiments, the infection is a gram-negative infection. In some embodiments, the infection is a gram-positive infection.

[0369] In some embodiments, the infection is resistant to one or more antibiotics when administered without probenecid or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the infection is resistant to the one or more β-lactam compounds when administered without probenecid or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection, and infectious diarrhea.

[0372] In some embodiments, a disease is associated with (eg, caused by) a change in the microbiome in a subject.

[0373] In some embodiments, a disease is associated with (eg, caused by) a change in the microbiome in a human subject.

[0374] In some embodiments, the disease is a neurodegenerative disease.

[0375] In some embodiments, the disease is amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, schizophrenia, or Huntington's disease.

[0376] In some embodiments, the disease is Alzheimer's disease.It is noted that probenecid has been found to increase the concentration of beta-lactam compounds in the cerebrospinal fluid (Ralph G. Dacey and Merle A. Sande, Antimicrobial Agents and Chemotherapy 6:437-441 (1974)). Recently, the bacterial pathogen Porphyromonas gingivalis has been found in the brain associated with pathological damage, which is associated with Alzheimer's disease (Dominy et al., Sci. Adv. 5:eaau3333 (2019), and thiopentane is active against this bacterium (Lois M. Ednie and Peter C. Appelbaum, Antimicrobial Agents and Chemotherapy 53:2163-2170 (2009)). Without wishing to be bound by theory, it is understood that when administered with probenecid, β-lactam compounds (e.g., Compound III-2b) result in more effective treatment of brain infections of this organism relative to thiopentane treatment alone.

[0377] In some embodiments, the disease is cancer.

[0378] In some embodiments, the cancer is a solid cancer, such as ovarian cancer, breast cancer, head and neck cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, or lymphoma, or any combination thereof.

[0379] In some embodiments, the cancer is a sarcoma or carcinoma, such as a fibrosarcoma, a myxosarcoma, a liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphoendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon cancer, a pancreatic cancer, a prostate cancer, a squamous cell carcinoma, a basal cell carcinoma, adenocarcinoma, a sweat gland carcinoma, a sebaceous gland carcinoma, a papillary carcinoma, a papillary gland carcinoma, a Cancer, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Williams tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma.

[0380] In some embodiments, the cancer is a leukemia, such as acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia); or chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia).

[0381] In some embodiments, the cancer is polycythemia vera, lymphoma (Hodgkin's and non-Hodgkin's), multiple myeloma, Waldenstrom's macroglobulinemia ( macroglobulinemia) or heavy chain disease.

[0382] In some embodiments, the disease is inflammatory bowel disease.

[0383] In some embodiments, the inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, irritable bowel syndrome, microscopic colitis, diversion colitis, or Behcet's disease.

[0384] Application

[0385] In some embodiments, the bilayer tablet is administered once daily.

[0386] In some embodiments, the bilayer tablet is administered twice daily.

[0387] In some embodiments, the bilayer tablet is administered three or more times per day.

[0388] In some embodiments, the bilayer tablet is administered for about 1 day.

[0389] In some embodiments, the bilayer tablet is administered for more than about 1 day.

[0390] In some embodiments, the bilayer tablet is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0391] In some embodiments, the bilayer tablet is administered under one or more drug holidays.

[0392] In some embodiments, the bilayer tablet is administered without any drug holiday.

[0393] In some embodiments, the bilayer tablet is administered to the subject with food (eg, the subject eats it).

[0394] In some embodiments, the subject eats within about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 2 days, about 5 days, or about 10 days prior to administration of the bilayer tablet.

[0395] In some embodiments, the subject in need thereof fasts for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 2 days, about 5 days, or about 10 days prior to administration of the bilayer tablet.

[0396] In some embodiments, the subject in need thereof eats within about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 2 days, about 5 days, or about 10 days after administration of the bilayer tablet.

[0397] In some embodiments, the subject in need thereof fasts for about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 24 hours, about 2 days, about 5 days, or about 10 days after administration of the bilayer tablet.

[0398] For AUC and / or C max Role

[0399] In some embodiments, the administration results in an area under the curve (AUC) for plasma concentration of the β-lactam compound in a subject in need thereof that is higher than in a comparable subject receiving administration of a comparable composition.

[0400] In some embodiments, administration results in a maximum plasma concentration (C max ) is substantially the same as compared to comparable subjects receiving administration of comparable compositions.

[0401] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0402] The subject in need thereof has an increase in the area under the curve (AUC) of about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500 or more within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration compared to a comparable subject receiving administration of a comparable composition.

[0403] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0404] the subject in need thereof has an increase in the area under the curve (AUC) within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration as compared to a comparable subject receiving administration of a comparable composition; and

[0405] The maximum plasma concentration (C max ) is about 50% to about 150%, about 60% to about 140%, about 70% to about 130%, about 80% to about 120%, about 90% to about 110%, about 95% to about 105%, or 98% to about 102% of comparable subjects receiving administration of a comparable composition.

[0406] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0407] the subject in need thereof has an increase in the area under the curve (AUC) within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration as compared to a comparable subject receiving administration of a comparable composition; and

[0408] The maximum plasma concentration (C max ) is substantially the same as compared to comparable subjects receiving administration of comparable compositions.

[0409] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0410] The subject in need thereof has an area under the curve (AUC) of about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500 or more within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration compared to a comparable subject who receives administration of the bilayer tablet without food (e.g., the comparable subject is fasting).

[0411] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0412] the subject in need thereof has an area under the curve (AUC) of about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500% or more within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration as compared to a comparable subject who receives administration of the bilayer tablet without food (e.g., the comparable subject is fasting); and

[0413] The maximum plasma concentration (C max ) is about 50% to about 150%, about 60% to about 140%, about 70% to about 130%, about 80% to about 120%, about 90% to about 110%, about 95% to about 105%, or 98% to about 102% as compared to comparable subjects who receive administration of the bi-layer tablet without food (e.g., the comparable subjects are fasting).

[0414] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0415] the subject in need thereof has an area under the curve (AUC) of about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500% or more within about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days from administration as compared to a comparable subject who receives administration of the bilayer tablet without food (e.g., the comparable subject is fasting); and

[0416] The maximum plasma concentration (C max ) is substantially the same as compared to comparable subjects who received administration of the bilayer tablet without food (e.g., the comparable subjects were fasting).

[0417] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0418] The area under the curve (AUC) within about 1 day from the administration was about 4325±3000 ng·h / mL, about 4325±2500 ng·h / mL, about 4325±2000 ng·h / mL, about 4325±1500 ng·h / mL, about 4325±1000 ng·h / mL, about 4325±900 ng·h / mL, about 4325±800 ng·h / mL, about 4325±700 ng·h / mL, about 4325±600 ng·h / mL, about 4325±500 ng·h / mL, about 4325±400 ng·h / mL, About 4325±300 ng·h / mL, about 4325±200 ng·h / mL, about 4325±100 ng·h / mL, about 4325±90 ng·h / mL, about 4325±80 ng·h / mL, about 4325±70 ng·h / mL, about 4325±60 ng·h / mL, about 4325±50 ng·h / mL, about 4325±40 ng·h / mL, about 4325±30 ng·h / mL, about 4325±20 ng·h / mL, or about 4325±10 ng·h / mL (e.g., about 4325 ng·h / mL).

[0419] In some embodiments, the bilayer tablet is administered to a subject in need thereof with food (e.g., the subject eats), and the administration results in a plasma concentration of the β-lactam compound of:

[0420] The area under the curve (AUC) within about 1 day from the administration was about 6600±3000 ng·h / mL, about 6600±2500 ng·h / mL, about 6600±2000 ng·h / mL, about 6600±1500 ng·h / mL, about 6600±1000 ng·h / mL, about 6600±900 ng·h / mL, about 6600±800 ng·h / mL, about 6600±700 ng·h / mL, about 6600±600 ng·h / mL, about 6600±500 ng·h / mL, about 6600±400 ng·h / mL, About 6600±300ng·h / mL, about 6600±200ng·h / mL, about 6600±100ng·h / mL, about 6600±90ng·h / mL, about 6600±80ng·h / mL, about 6600±70ng·h / mL, about 6600±60ng·h / mL, about 6600±50ng·h / mL, about 6600±40ng·h / mL, about 6600±30ng·h / mL, about 6600±20ng·h / mL, or about 6600±10ng·h / mL (e.g., about 6600ng·h / mL).

[0421] In some embodiments, administration results in a plasma concentration of the β-lactam compound that is:

[0422] The area under the curve (AUC) within about 1 day from administration was about 5100±3000 ng·h / mL, about 5100±2500 ng·h / mL, about 5100±2000 ng·h / mL, about 5100±1500 ng·h / mL, about 5100±1000 ng·h / mL, about 5100±900 ng·h / mL, about 5100±800 ng·h / mL, about 5100±700 ng·h / mL, about 5100±600 ng·h / mL, about 5100±500 ng·h / mL, about 5100±400 ng·h / mL, About 5100±300ng·h / mL, about 5100±200ng·h / mL, about 5100±100ng·h / mL, about 5100±90ng·h / mL, about 5100±80ng·h / mL, about 5100±70ng·h / mL, about 5100±60ng·h / mL, about 5100±50ng·h / mL, about 5100±40ng·h / mL, about 5100±30ng·h / mL, about 5100±20ng·h / mL, or about 5100±10ng·h / mL (for example, about 5100ng·h / mL).

[0423] In some embodiments, the bilayer tablet is administered to a subject in need thereof with food (e.g., the subject eats), and the administration results in a plasma concentration of the β-lactam compound of:

[0424] The area under the curve (AUC) within about 1 day from the administration was about 7340±3000 ng·h / mL, about 7340±2500 ng·h / mL, about 7340±2000 ng·h / mL, about 7340±1500 ng·h / mL, about 7340±1000 ng·h / mL, about 7340±900 ng·h / mL, about 7340±800 ng·h / mL, about 7340±700 ng·h / mL, about 7340±600 ng·h / mL, about 7340±500 ng·h / mL, about 7340±400 ng·h / mL, About 7340±300 ng·h / mL, about 7340±200 ng·h / mL, about 7340±100 ng·h / mL, about 7340±90 ng·h / mL, about 7340±80 ng·h / mL, about 7340±70 ng·h / mL, about 7340±60 ng·h / mL, about 7340±50 ng·h / mL, about 7340±40 ng·h / mL, about 7340±30 ng·h / mL, about 7340±20 ng·h / mL, or about 7340±10 ng·h / mL (e.g., about 7340 ng·h / mL).

[0425] definition

[0426] As used herein, "alkyl", "C1, C2, C3, C4, C5 or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl groups include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl or n-hexyl. In certain embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms (e.g., C1-C6 for a straight chain and C3-C6 for a branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms.

[0427] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon monocyclic or polycyclic (eg, fused, bridged, or spiro) system (eg, C3-C4) having 3 to 30 carbon atoms. 12 、C3-C 10 or C3-C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl.

[0428] Unless otherwise indicated, as used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged or spiro), or 11- to 14-membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms (e.g., O, N, S, P or Se), e.g., 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or e.g., 1, 2, 3, 4, 5 or 6 heteroatoms (independently selected from the group consisting of nitrogen, oxygen and sulfur). Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazacycloheptanyl, Heterocycloheptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran ]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]octan-6-yl, etc. In the case of polycyclic non-aromatic rings, only one ring needs to be non-aromatic (e.g. 1,2,3,4-tetrahydronaphthyl or 2,3-dihydroindole).

[0429] As used herein, the term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl groups in which one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone are replaced with specified substituents. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0430] As used herein, the term "alkyl linker" or "alkylene linker" is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, a C1-C6 alkylene linker is intended to include C1, C2, C3, C4, C5 and C6 alkylene linking groups. Examples of alkylene linkers include moieties having one to six carbon atoms such as, but not limited to, methyl (-CH2-), ethyl (-CH2CH2-), n-propyl (-CH2CH2CH2-), isopropyl (-CHCH3CH2-), n-butyl (-CH2CH2CH2CH2-), sec-butyl (-CHCH3CH2CH2-), isobutyl (-C(CH3)2CH2-), n-pentyl (-CH2CH2CH2CH2CH2-), sec-pentyl (-CHCH3CH2CH2CH2-), or n-hexyl (-CH2CH2CH2CH2CH2CH2-).

[0431] As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar to the above-mentioned alkyl groups in length and possible substitution but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyls (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyls. In certain embodiments, the main chain of a straight or branched alkenyl has six or less carbon atoms (e.g., C2-C6 for a straight chain, C3-C6 for a branched chain). The term "C2-C6" includes alkenyls containing two to six carbon atoms. The term "C3-C6" includes alkenyls containing three to six carbon atoms.

[0432] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms replaced with a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0433] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar to the above-mentioned alkyl groups in length and possible substitution but containing at least one triple bond. For example, "alkynyl" includes straight chain alkynyl (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl. In certain embodiments, there are six or less carbon atoms (e.g., C2-C6 for straight chain and C3-C6 for branched chain) in the main chain of the straight or branched chain alkynyl. The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene joints" or "C2-C6 alkynylene joints" are intended to include C2, C3, C4, C5 or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linking groups.

[0434] As used herein, the term "optionally substituted alkynyl" refers to unsubstituted alkynyl groups or alkynyl groups in which one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms are replaced with a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0435] Other optionally substituted parts (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include both unsubstituted parts and parts with one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted by one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0436] As used herein, the term "aryl" includes groups having aromatic character, including groups or polycyclic systems "bound" to one or more aromatic rings and not containing any heteroatoms in the ring structure. Examples include phenyl, naphthyl, etc.

[0437] As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic ring consisting of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, such as 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or such as 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)). p , wherein p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocyclic ring does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0438] In addition, the terms "aryl" and "heteroaryl" include polycyclic aromatic and heteroaryl groups, such as tricyclic, bicyclic aromatic and heteroaryl groups, for example, naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0439] The cycloalkyl, heterocycloalkyl, aryl or heteroaromatic ring may be substituted at one or more ring positions (e.g., a ring carbon or a heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, Alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form a polycyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0440] As used herein, the term "carbocycle" or "carbocyclic ring" is intended to include any stable monocyclic, bicyclic, or tricyclic ring having the specified number of carbon atoms, any of which may be saturated, unsaturated, or aromatic. Carbocycles include cycloalkyl and aryl. For example, C3-C 14Carbocycle is intended to include monocyclic, bicyclic or tricyclic rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms. Examples of carbocycle include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0] bicyclooctane, [4.3.0] bicyclononane and [4.4.0] bicyclodecane and [2.2.2] bicyclooctane. When one or more carbon atoms connect two non-adjacent carbon atoms, a bridged ring is generated. In one embodiment, the bridged ring is one or two carbon atoms. It should be noted that the bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, substituents recited for the ring may also be present on the bridge. Also included are fused rings (eg, naphthyl, tetrahydronaphthyl) and spiro rings.

[0441] As used herein, the term "heterocycle" or "heterocyclic group" includes any ring structure (saturated, unsaturated or aromatic) containing at least one ring heteroatom (e.g., 1 to 4 heteroatoms selected from N, O and S). Heterocycles include heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine and tetrahydrofuran.

[0442] Examples of heterocyclic groups include, but are not limited to, acridinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl yl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolyl, indolizinyl, indolyl, 3H-indolyl, isatoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxol-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2 ,4-oxadiazol-5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthrenyl.

[0443] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced by a selected group in a designated group, with the proviso that the normal valence of the designated atom is not exceeded and that the substitution produces a stable compound. When the substituent is an oxo or keto (i.e., =O), 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean a compound that is sufficiently stable to withstand separation from a reaction mixture to a suitable purity and formulated as an effective therapeutic agent.

[0444] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any atom on the ring. When a substituent is listed without indicating that the substituent is bonded to an atom in the rest of the compound of a specified formula, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0445] When any variable (e.g., R) occurs more than one time in any component or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, then the group may be optionally substituted with up to two R moieties, and R at each occurrence is independently selected from the definition of R. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0446] As used herein, the term "hydroxyl" includes a group having -OH or -O - The group.

[0447] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "perhalogenated" generally refers to a moiety in which all hydrogen atoms are replaced by halogen atoms. The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0448] As used herein, the term "carbonyl" includes compounds and moieties containing a carbon connected to an oxygen atom with a double bond. Examples of carbonyl-containing moieties include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0449] As used herein, the term "carboxyl" refers to -COOH or a C1-C6 alkyl ester thereof.

[0450] As used herein, the term "acyl" includes moieties containing an acyl group (RC(O)-) or a carbonyl group. As used herein, the term "substituted acyl" includes acyl groups in which one or more of the hydrogen atoms are replaced by, for example, alkyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0451] As used herein, the term "aroyl" includes moieties having an aryl or heteroaromatic portion bonded to a carbonyl group. Examples of aroyl include phenylcarboxyl, naphthylcarboxyl, and the like.

[0452] As used herein, the terms "alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" include alkyl groups as described above wherein oxygen, nitrogen, or sulfur atoms are substituted for one or more of the hydrocarbon backbone carbon atoms.

[0453] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy. The alkoxy group may be substituted with, for example, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of alkoxy substituted with halogen include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0454] As used herein, the term "ether" or "alkoxy" includes compounds or moieties containing an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom that is covalently bonded to an alkyl group.

[0455] As used herein, the term "ester" includes compounds or moieties containing carbon or heteroatoms bonded to an oxygen atom (which is bonded to the carbon of a carbonyl group). The term "ester" includes alkoxycarboxyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and the like.

[0456] As used herein, the term "thioalkyl" includes compounds or moieties containing an alkyl group connected to a sulfur atom. The thioalkyl group may be substituted, for example, by groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl or aromatic or heteroaromatic moieties.

[0457] As used herein, the term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties that contain a carbon attached to a sulfur atom with a double bond.

[0458] As used herein, the term "thioether" includes moieties containing a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to, alkylthioalkyl, alkylthioalkenyl, and alkylthioalkynyl. The term "alkylthioalkyl" includes moieties having an alkyl, alkenyl, or alkynyl bonded to a sulfur atom bonded to an alkyl. Similarly, the term "alkylthioalkenyl" refers to a moiety in which an alkyl, alkenyl, or alkynyl is bonded to a sulfur atom covalently bonded to an alkenyl; and "alkylthioalkynyl" refers to a moiety in which an alkyl, alkenyl, or alkynyl is bonded to a sulfur atom covalently bonded to an alkynyl.

[0459] As used herein, the term "amine" or "amino" refers to -NH2. "Alkylamino" includes groups of compounds in which the nitrogen of -NH2 is bound to at least one alkyl group. Examples of alkylamino include benzylamino, methylamino, ethylamino, phenethylamino, and the like.

[0460] As used herein, the term "dialkylamino" includes groups in which the nitrogen of -NH2 is bound to two alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino.

[0461] As used herein, the terms "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.

[0462] As used herein, the terms "aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy groups substituted with an amino group.

[0463] As used herein, the term "alkylarylamino," "alkylaminoaryl," or "arylaminoalkyl" refers to an amino group bound to at least one alkyl group and at least one aryl group.

[0464] As used herein, the term "alkylaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

[0465] As used herein, the term "acylamino" includes groups in which the nitrogen is bonded to an acyl group. Examples of acylamino groups include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido.

[0466] As used herein, the term "amide" or "aminocarboxy" includes compounds or moieties that contain a nitrogen atom bound to the carbon of a carbonyl or thiocarbonyl group.

[0467] As used herein, the term "alkylaminocarboxy" includes an alkyl, alkenyl, or alkynyl group bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.

[0468] As used herein, the term "arylaminocarboxy" includes an aryl or heteroaryl moiety bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.

[0469] As used herein, the terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties in which the alkyl, alkenyl, alkynyl, and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.

[0470] The amide may be substituted with a substituent such as a linear alkyl group, a branched alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group. The substituent on the acylamino group may be further substituted.

[0471] It will be appreciated that probenecid (eg sold under the brand name Probalan) has the following structure:

[0472]

[0473] The nitrogen-containing compounds of the disclosure can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxide) to provide other compounds of the disclosure. Thus, all nitrogen-containing compounds shown and claimed are contemplated to include both the compounds shown and their N-oxide derivatives (which may be represented as N→O or N→O) when valence and structure permit. + -O - ). In addition, in other cases, the nitrogen in the compounds of the present disclosure can be converted into N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine with an oxidant such as m-CPBA. When valence and structure permit, all nitrogen-containing compounds shown and claimed are also considered to cover both the compounds shown and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3- to 14-membered carbocyclic ring or 3- to 14-membered heterocyclic ring) derivatives.

[0474] In this specification, for convenience in some cases, the structural formula of the compound represents a specific isomer, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc., and it should be understood that not all isomers may have the same level of activity. In addition, for compounds represented by various formulas, there may be crystal polymorphism. It should be noted that any crystal form, crystal form mixture or its anhydride or hydrate is included in the scope of the present disclosure.

[0475] As used herein, the term "isomerism" means compounds that have the same molecular formula but differ in the sequence of bonding of the atoms or in the arrangement of the atoms in space. Isomers that differ in the arrangement of the atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture".

[0476] As used herein, the term "chiral center" refers to a carbon atom that is bonded to four different substituents.

[0477] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture". When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of the chiral center. The absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents under consideration attached to the chiral center are ranked according to the ordering rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0478] As used herein, the term "geometric isomers" refers to diastereomers that exist due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are named with the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0479] It should be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has a chiral isomeric form or a geometric isomeric form, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers may have the same level of activity.

[0480] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

[0481] As used herein, the term "atropisomer" is a stereoisomer in which the atoms of the two isomers differ in their arrangement in space. Atropisomers exist because of restricted rotation caused by steric hindrance of rotation of large groups around a central bond. Such atropisomers usually exist as a mixture, however, due to recent advances in chromatographic techniques, it has become possible to separate a mixture of two atropisomers under selected circumstances.

[0482] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form into another isomeric form. This conversion causes the form migration of hydrogen atoms, accompanied by the exchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer sets in solution. In a solution where tautomerization may occur, the chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. In possible various types of tautomerism, two types are usually observed. In keto-enol tautomerism, simultaneous displacement of electrons and hydrogen atoms occurs. The ring-chain tautomerism as shown by glucose occurs because the aldehyde group (-CHO) in the sugar chain molecule reacts with a hydroxyl group (-OH) in the same molecule to provide a cyclic (ring-shaped) form for it.

[0483] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when a compound has a tautomeric form, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a high level of activity compared to other tautomers.

[0484] As used herein, the term "crystalline polymorph", "polymorph" or "crystalline form" means a crystal structure in which a compound (or its salt or solvate) can be crystallized in different crystal packing arrangements, all with the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can make one crystalline form dominant. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0485] It should be understood that, if applicable, compounds of any formula described herein include the compounds themselves, as well as salts thereof, and solvates thereof. For example, salts can be formed between anions on substituted benzene compounds and positively charged groups (e.g., amino groups). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthenate, and acetate (e.g., trifluoroacetate).

[0486] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations on substituted benzene compounds and negatively charged groups (e.g., carboxylates). Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions. Substituted benzene compounds also include those salts containing quaternary nitrogen atoms.

[0487] It should be understood that the compounds of the present disclosure (e.g., salts of the compounds) can exist in hydrated or unhydrated (anhydrous) forms or in the form of solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0488] As used herein, the term "solvate" means a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to entrap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance in which the water retains its molecular state as H2O.

[0489] As used herein, the term "analog" refers to a compound that is similar in structure to another compound but has a slightly different composition (such as due to the replacement of one atom by an atom of a different element or due to the presence of a particular functional group, or the replacement of one functional group by another). Thus, an analog is a compound that is similar or comparable in function and appearance, but not similar or comparable in structure or origin to a reference compound.

[0490] As used herein, the term "derivative" refers to compounds having a common core structure and being substituted with various groups as described herein.

[0491] As used herein, the term "bioisostere" refers to a compound produced by the exchange of one atom or a group of atoms with another atom or another group of atoms that is broadly similar. The purpose of bioisosteric substitution is to produce new compounds with similar biological properties to the parent compound. Bioisosteric substitution can be based on physical chemistry or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0492] It should be understood that the present disclosure is intended to include all isotopes of atoms present in the disclosed compounds. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include C-13 and C-14.

[0493] As used herein, unless otherwise specified, the expressions "one or more of A, B or C", "one or more A, B or C", "one or more of A, B and C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to the selection from the group consisting of A, B and / or C, i.e., one or more A, one or more B, one or more C or any combination thereof.

[0494] It is understood that the present disclosure provides methods for synthesizing compounds of any of the formulae described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the examples.

[0495] It should be understood that throughout the description, when a composition is described as having, including or comprising a particular component, it is contemplated that the composition also consists essentially of or consists of said component. Similarly, when a method or process is described as having, including or comprising a particular process step, the process also consists essentially of or consists of said process step. In addition, it should be understood that the order of steps or the order in which a particular action is performed is not important, as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0496] It should be understood that the synthetic process disclosed herein can tolerate various functional groups and therefore can use various substituted starting materials. The process generally provides the desired final compound at the end or near the end of the entire process, but in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt.

[0497] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, for example, the following classic textbooks are applicable and recognized reference textbooks for organic synthesis known to those skilled in the art: Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), which are incorporated herein by reference.

[0498] Those of ordinary skill in the art should note that during the reaction sequence and synthesis scheme described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. Those of ordinary skill in the art will recognize that certain groups may need to be protected from reaction conditions via the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in molecules. Lists of protecting groups and the introduction and removal of these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0499] It should be understood that, unless otherwise stated, any description of a method of treatment includes the use of the compound to provide such treatment or prevention as described herein, as well as the use of the compound to prepare a medicament for treating or preventing such a disorder. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0500] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or an increased risk of developing a disease. "Subject" includes mammals. The mammal may, for example, be a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In one embodiment, the mammal is a human.

[0501] As used herein, the term "candidate compound" refers to a compound of the present disclosure or a pharmaceutically acceptable salt, polymorph or solvate thereof that has been or will be tested in one or more in vitro or in vivo bioassays to determine whether the compound may elicit a desired biological or medical response in a cell, tissue, system, animal or human being that is being sought by a researcher or clinician. A candidate compound is a compound of the present disclosure or a pharmaceutically acceptable salt, polymorph or solvate thereof. Biological reactions or effects may occur in vitro or in animal models, as well as other biological changes observable in vitro. In vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0502] As used herein, the term "treatment" describes the management and care of a patient for the purpose of combating a disease, disorder or condition, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, disorder or condition, or to eliminate the disease, disorder or condition. The term "treatment" may also include treatment of in vitro cells or animal models.

[0503] As used herein, the term "time proximity" refers to the administration of one therapeutic agent (e.g., a β-lactam compound disclosed herein) before or after the administration of another therapeutic agent (e.g., probenecid) for a period of time, so that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of another therapeutic agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of another therapeutic agent. In some embodiments, "time proximity" means that the administration of one therapeutic agent is performed before or after the administration of another therapeutic agent for a period of time, so that there is a synergistic effect between one therapeutic agent and another therapeutic agent. "Time proximity" can be changed according to various factors, including (but not limited to) the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is to be administered; the disease or disorder to be treated or improved; the therapeutic outcome to be achieved; the dosage, frequency of administration, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route of administration of the therapeutic agent. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within one hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be performed in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary within a treatment cycle or within a dosing regimen.

[0504] It will be appreciated that the disclosed compounds, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may or may also be used to prevent related diseases, disorders or conditions, or to identify suitable candidates for such purposes.

[0505] As used herein, the terms "preventing" or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such disease, disorder or condition.

[0506] It should be understood that for detailed descriptions of known techniques or equivalent techniques discussed herein, those skilled in the art can refer to general reference textbooks. These textbooks include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th Edition (1990), Mandell et al., Principles and Practice of Infectious Diseases, Saunders Publishing (8th Edition, 2014). Of course, these textbooks can also be consulted in making or using aspects of the present disclosure.

[0507] As used herein, the term "combination therapy" or "adjuvant therapy" includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least one second agent as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

[0508] It will be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0509] As used herein, the term "pharmaceutical composition" is a preparation containing the disclosed compounds in a form suitable for application to a subject. In one embodiment, the pharmaceutical composition is in bulk form or in unit dosage form. The unit dosage form is any of various forms, including, for example, a single pump or vial on a capsule, IV bag, tablet, aerosol inhaler. The amount of active ingredient (e.g., a preparation of the disclosed compound or its salt, hydrate, solvate or isomer) in the unit dose of the composition is an effective amount and changes according to the specific treatment involved. It will be appreciated by those skilled in the art that it is sometimes necessary to make routine changes to the dosage according to the age and illness of the patient. The dosage will also depend on the route of administration. Various routes are covered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. The dosage form of the compound of the present disclosure for topical or transdermal administration includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are required.

[0510] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, substances, compositions, carriers and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0511] As used herein, the term "pharmaceutically acceptable excipient" means an excipient suitable for preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in this specification and claims includes one and more than one such excipient.

[0512] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents, such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and tension regulators, such as sodium chloride or dextrose. pH values ​​may be adjusted with acid or alkali, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be packaged in ampoules, disposable syringes, or multidose vials made of glass or plastic.

[0513] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many well-known methods currently used for chemotherapy treatment. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or administered via the skin using a patch. The selected dose should be sufficient to constitute an effective treatment but not yet so high as to produce unacceptable side effects. The patient's disease condition and health status should be closely monitored during and after treatment for a reasonable period of time.

[0514] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates or prevents an identified disease or disorder, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the disorder; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0515] It will be appreciated that for any compound, the therapeutically effective amount can be estimated initially in a cell culture assay, for example, of neoplastic cells, or in an animal model, typically rats, mice, rabbits, dogs or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine doses and routes suitable for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that causes 50% mortality in the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0516] Dosage and administration are adjusted to provide adequate levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state; the general health of the subject; the age, weight, and sex of the subject; diet; time and frequency of administration; drug combination; reaction sensitivity; and tolerance / response to therapy. Depending on the half-life and clearance rate of the particular formulation, the long-acting pharmaceutical composition may be administered every 3 to 4 days, weekly, or once every two weeks.

[0517] Pharmaceutical compositions containing active compounds of the present disclosure can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, making dragees, water milling, emulsifying, encapsulating, coating or lyophilizing processes. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which contain excipients and / or adjuvants that facilitate processing of the active compound into pharmaceutically usable preparations. Of course, appropriate preparations depend on the selected route of administration.

[0518] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluidity should reach the extent of easy injection. It must be stable under manufacturing and storage conditions, and must be preserved to prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using a surfactant. The prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, polyols (such as mannitol and sorbitol) and sodium chloride will preferably be included in the composition. The extended absorption of the injectable composition can be achieved by including a delayed absorption agent (such as aluminum monostearate and gelatin) in the composition.

[0519] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound in an appropriate solvent together with one or a combination of the ingredients listed above, followed by sterilization by filtration as required. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing an alkaline dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0520] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be coated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be combined with an excipient and used in the form of a tablet, lozenge or capsule. Oral compositions can also be prepared using a fluid carrier suitable for use as a mouthwash, wherein the compound in the fluid carrier is orally administered and gargled and spit out or swallowed. Pharmaceutically compatible adhesives and / or adjuvant substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds with similar properties: adhesives, such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; sliding agents, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as peppermint, methyl salicylate or orange flavoring.

[0521] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0522] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art, and for transmucosal administration, include, for example, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved via the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gels, or creams as generally known in the art.

[0523] The active compound can be prepared with a pharmaceutically acceptable carrier that will prevent the compound from being rapidly eliminated from the body, such as a controlled release formulation, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such preparations are obvious to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These substances can be prepared according to methods known to those skilled in the art, such as described in U.S. Patent No. 4,522,811.

[0524] It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unit dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the unit dosage forms of the present disclosure is dictated by and directly dependent upon the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0525] In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure varies according to the following: the medicament, the age, weight and clinical illness of the patient receiving the treatment, and the experience and judgment of the clinician or physician administering the therapy, as well as other factors affecting the selected dosage. In general, the dosage should be sufficient to slow down the symptoms of the disease and preferably subside, and it is also preferred that the disease subsides completely. The dosage may be in the range of about 0.01 mg / kg to about 5000 mg / kg per day. In a preferred aspect, the dosage may be in the range of about 1 mg / kg to about 1000 mg / kg per day. In one aspect, the dosage will be in the range of about 0.1 mg / day to about 50 g / day, about 0.1 mg / day to about 25 g / day, about 0.1 mg / day to about 10 g / day, about 0.1 mg to about 3 g / day, or about 0.1 mg to about 1 g / day, in a single, divided or continuous dose (the dosage may be directed to the patient's weight (in kg), body surface area (in m 2 The effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as indicated by a clinician or other qualified observer. Improvements in survival and growth are indicative of regression. As used herein, the term "dosage effective manner" refers to the amount of active compound that produces a desired biological effect in a subject or cell.

[0526] It will be understood that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0527] It is to be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also encompassed within the scope of the claimed disclosure.

[0528] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure in which the parent compound is modified by making an acid or base salt thereof. In some embodiments, a pharmaceutically acceptable salt of a compound (e.g., a β-lactam compound or probenecid described herein) is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali metal or organic salts of acidic residues (e.g., carboxylic acids); and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, by non-toxic inorganic or organic acids. By way of example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, acid), hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, para-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and commonly present amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0529] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed by replacing acidic protons present in the parent compound with metal ions such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0530] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0531] As used herein, the term "prodrug" refers to any agent that is completely or partially converted into a targeted compound (e.g., a β-lactam compound or probenecid described herein) when administered to a mammal. In some embodiments, a prodrug of a compound (e.g., a β-lactam compound or probenecid described herein) is also a pharmaceutically acceptable salt of the compound.

[0532] It should be understood that the compounds of the present disclosure can also be prepared as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound can be converted into its corresponding ester, such as methyl ester, ethyl ester or other ester. In addition, the alcohol group in the compound can be converted into its corresponding ester, such as acetate, propionate or other ester.

[0533] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, sublingual, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of a particular route of administration.

[0534] The dosing regimen utilizing the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. An ordinary physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0535] Techniques for preparing and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0536] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the various embodiments. The provided embodiments illustrate the various components and methods applicable to practicing the present disclosure. The embodiments do not limit the disclosure claimed. Based on the present disclosure, those skilled in the art may identify and adopt other components and methods applicable to practicing the present disclosure.

[0537] In the synthetic schemes described herein, compounds may be drawn as having one particular configuration for simplicity. Such particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor to exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0538] Once the compounds designed, selected and / or optimized by the above methods are prepared, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have the expected activity, binding activity and / or binding specificity.

[0539] In addition, high throughput screening can be used to accelerate analysis using such assays. Thus, it is possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methods for performing high throughput screening are described in, for example, Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0540] As used herein, the term "granular material" refers to an agglomeration of discrete solid, macroscopic particles. In some embodiments, the granular material is made by granulating a powder or solid substance (e.g., a common granulation process in chemical and pharmaceutical industry technology). In some embodiments, the granulation process involves the aggregation of fine particles into larger particles (e.g., particles with a size range of between 0.2 mm and 4.0 mm). In some embodiments, the granulation process involves shredding or grinding a solid material into finer particles or pellets.

[0541] As used herein, the term "brittleness" refers to the tendency of a solid material to break into smaller pieces under stress or contact. In some embodiments, brittleness is determined by common techniques in the art (e.g., by USP <1216> In some embodiments, friability is measured by using a transparent drum and taking the tablet weight before and after tumbling.

[0542] As used herein, the term "total pore surface area" refers to the total area of ​​the pore surface in an object (e.g., a bilayer tablet of the present disclosure). In some embodiments, the total pore surface area is measured by common techniques in the art (e.g., X-ray computed tomography (X-ray CT)).

[0543] As used herein, the term "total pore count" refers to the total amount of pores in an object (e.g., a bilayer tablet of the present disclosure). In some embodiments, the total pore count is measured by common techniques in the art (e.g., X-ray computed tomography (X-ray CT)).

[0544] As used herein, the term "maximum pore volume" refers to the volume of the largest pores in an object (e.g., a bilayer tablet of the present disclosure). In some embodiments, the maximum pore volume is measured by common techniques in the art (e.g., X-ray computed tomography (X-ray CT)).

[0545] As used herein, the term "total pore volume" refers to the total volume of all pores in an object (e.g., a bilayer tablet of the present disclosure). In some embodiments, the total pore volume is measured by common techniques in the art (e.g., X-ray computed tomography (X-ray CT)).

[0546] As used herein, the term "porosity" refers to the fraction of the volume of void spaces in a material relative to the total volume of the material. In some embodiments, porosity is measured by common techniques in the art (eg, industrial CT scanning).

[0547] In some embodiments, porosity is measured by X-ray computed tomography (X-ray CT). X-ray CT is a non-destructive analytical technique for visualizing and quantifying the interior of a material in 3D. In an exemplary procedure, the tablet is firmly held in an X-ray transparent polystyrene block during scanning. The tablets are individually scanned using a GE V|TOME|X M240kV (GE Sensing and Inspection Technologies, Wunstorf, Germany) X-ray CT system. The X-ray tube energy and current are 80kv and 160μA, respectively. The scan consists of 2400 radiographic images at a resolution of 14 microns (each integrating 8 images to reduce image noise). When reconstructing the data, a digital magnification factor is used to achieve a final resolution of 7.5 microns. Low attenuation materials such as air (voids) appear as dark areas. Higher attenuation materials or denser areas in the sample appear brighter. Images, animations, and microstructure quantification were performed using Volume Graphics VGStudioMAX (v2.2) software (Volume Graphics, GmbH, Germany).

[0548] As used herein, the term "comparable composition" refers to a composition having comparable parameters or being under comparable conditions with a bilayer tablet of the present disclosure. In some embodiments, a comparable composition comprises the same amount of probenecid or a pharmaceutically acceptable salt thereof and / or a β-lactam compound or a pharmaceutically acceptable salt thereof as a bilayer composition of the present disclosure. In some embodiments, a comparable composition comprises probenecid or a pharmaceutically acceptable salt thereof (e.g., a commercial composition of probenecid). In some embodiments, a comparable composition comprises a β-lactam compound or a pharmaceutically acceptable salt thereof (e.g., a commercial composition of compound III-2b). In some embodiments, a comparable composition comprises probenecid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof. In some embodiments, a comparable composition is a comparable tablet, i.e., a tablet having comparable parameters or being under comparable conditions with a bilayer tablet of the present disclosure. In some embodiments, a comparable tablet comprises the same amount of probenecid or a pharmaceutically acceptable salt thereof and / or a β-lactam compound or a pharmaceutically acceptable salt thereof as a bilayer tablet of the present disclosure. In some embodiments, the comparable tablet is a monolayer tablet comprising probenecid or a pharmaceutically acceptable salt thereof (e.g., a commercial tablet of probenecid). In some embodiments, the comparable tablet is a monolayer tablet comprising a β-lactam compound or a pharmaceutically acceptable salt thereof (e.g., a commercial tablet of compound III-2b). In some embodiments, the comparable tablet is a monolayer tablet comprising probenecid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof. In some embodiments, the comparable tablet is a bilayer tablet prepared by a different process than the bilayer tablets of the present disclosure. In some embodiments, the comparable tablet is a bilayer tablet prepared by a process having one or more different conditions (e.g., compression sequence, first force, and / or second force) than the bilayer tablets of the present disclosure.

[0549] In some embodiments, the comparable composition is a suspension or solution having comparable parameters or being under comparable conditions with the bilayer tablet of the present disclosure. In some embodiments, the comparable suspension or solution comprises the same amount of probenecid or a pharmaceutically acceptable salt thereof and / or a β-lactam compound or a pharmaceutically acceptable salt thereof as the bilayer suspension or solution of the present disclosure. In some embodiments, the comparable suspension or solution comprises probenecid or a pharmaceutically acceptable salt thereof (e.g., a commercial suspension or solution of probenecid). In some embodiments, the comparable suspension or solution comprises a β-lactam compound or a pharmaceutically acceptable salt thereof (e.g., a commercial suspension or solution of compound III-2b). In some embodiments, the comparable suspension or solution comprises probenecid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0550] In some embodiments, the comparable composition is a combination of a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof, which is formulated into a separate formulation with comparable parameters or under comparable conditions to the bilayer tablet of the present disclosure. In some embodiments, the comparable composition is a combination of a β-lactam compound or a pharmaceutically acceptable salt thereof (e.g., Compound III-2b) formulated into a first comparable tablet, suspension, or solution and probenecid or a pharmaceutically acceptable salt thereof formulated into a second comparable tablet, suspension, or solution.

[0551] All publications and patent documents cited herein are incorporated herein by reference, just as if each such publication or document was expressly and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not deemed to be an admission that any publication and patent document is relevant prior art, and it does not constitute any admission about its content or date. The present invention has now been described in a written description, and those skilled in the art will recognize that the present invention can be implemented in a variety of embodiments and that the foregoing description and the following examples are for illustrative purposes and do not limit the appended claims.

[0552] Example

[0553] Example 1. Preparation of bilayer tablets

[0554] according to Figures 1 to 3 Various batches of bilayer tablets of the present disclosure containing 500 mg of probenecid and 500 mg of compound III-2b were prepared by the process described in and according to the process described herein.

[0555] Preparation of probenecid bulk granulation material. The probenecid API and excipients (except magnesium stearate) were loaded into a single pot wet granulator bowl and mixed. The granulation solution (IPA: water) was then added with the impeller rotating in unison with the chopper. For wet agglomeration, the impeller was run until the endpoint was reached (currently defined by the operating time). The granulated agglomerate was vacuum dried and heated before sieving the particles in a conical mill equipped with a suitable opening size rasp screen. Magnesium stearate was added and lubricated.

[0556] Preparation of Compound III-2b Bulk Granular Material. Compound III-2b API was mixed with excipients (except magnesium stearate) in an IBC blender and blended. Magnesium stearate was added to the blend and lubricated intragranularly. The lubricated blend was dry granulated via one or more roller compaction to obtain a compacted ribbon portion. In the same equipment, the ribbon was pre-crushed and screened through a screen of a suitable size. Magnesium stearate was added and lubricated via blending.

[0557] Preparation of bilayer tablets. Probenecid and Compound III-2b bulk granules were compressed using a rotary tablet press equipped with a D-type oval die and punch set. The first bulk granular material was added and pre-compressed before adding the second bulk granular material and final compression. Exemplary tablets were manufactured at a target weight of 1381 mg and a target thickness of 8.2 mm. The tablets were coated in a pan with Tablets were coated with AMB White 80W68912 coating. The target coating weight gain was 4% w / w per tablet.

[0558] The composition and physical properties of the prepared tablets are shown in Table 1A and Table 1B below.

[0559] Table 1A

[0560]

[0561]

[0562] a Assuming 100% efficacy

[0563] b Type PH102; Microcrystalline cellulose weight adjusted according to potency correction of active drug substance.

[0564] Table 1B

[0565]

[0566] In-process control. Loss on drying of probenecid granules was performed to ensure complete drying. Granule uniformity was performed on both probenecid and compound III-2b granular materials. Throughout tablet manufacturing, tablet weight uniformity, hardness, thickness and friability were checked to ensure that tablets were manufactured at target weight (monolayer and tablet core), thickness range and hardness suitable for further processing. In addition, tablet cores for content uniformity were also collected at specified intervals during process operation. AQL sampling was used to inspect the appearance and weight gain of coated tablets. The acceptance criteria for in-process control are summarized in Table 2 below.

[0567] Table 2

[0568]

[0569]

[0570] Example 2. In vitro release characteristics of bilayer tablets

[0571] Use in accordance with USP <711> The in vitro release characteristics of the bilayer tablets prepared according to the procedure described in Example 1 were tested by the method of (with the conditions shown in Table 3 below) and analyzed by HPLC-UV (with the HPLC operating conditions shown in Table 4 below).

[0572] Table 3

[0573]

[0574]

[0575] Table 4

[0576]

[0577] The detailed procedures of the test are described below.

[0578] Dissolution medium. Accurately weigh 68 g of potassium dihydrogen phosphate into a 10 L flask and dissolve with an appropriate volume of water. Make up the total volume to 10 L with water and mix thoroughly. Adjust to pH 6.8.

[0579] Standard solution. Accurately weigh 27.5 mg of compound III-2b and 27.5 mg of probenecid reference standard into an amber 50 mL volumetric flask. Add approximately 30 mL of dissolution medium and sonicate the flask until the standard is completely dissolved. Dilute the flask to a certain volume with the dissolution medium and mix thoroughly.

[0580] Test Procedure. Set up the dissolution bath according to Table 3. Transfer 900 mL of dissolution medium to each container and ensure that the dissolution medium is equilibrated to 37°C. Transfer the tablets to each container (N=6) and start dissolution. Remove a certain volume of medium (2.5 mL) from the container at each designated time point according to Table 3. Filter the sample solution and add it to the HPLC vial for analysis against the reference standard solution according to Table 4.

[0581] Calculation. Calculate the response factor (RF) of compound III-2b and probenecid in the standard:

[0582]

[0583] in:

[0584] AR = Area of ​​Compound III-2b or probenecid

[0585] WR = weight of compound III-2b or probenecid standard (mg)

[0586] P = purity of the reference standard in decimal format (e.g., 100.0% = 1.00) D = dilution factor of the standard

[0587] Calculate the content (mg) of compound III-2b and probenecid dissolved at each time point:

[0588]

[0589] in:

[0590] A n = Peak area response of compound III-2b or probenecid in the sample at extraction point "n"

[0591] RFAVG = Average standard response factor of compound III-2b or probenecid from the calibration standards of each sample

[0592] V = initial volume of culture medium = 900 mL

[0593] PV = extraction volume (mL)

[0594] C n =Content (mg)

[0595] The percentage of dissolved Compound III-2b and probenecid at each time point was calculated:

[0596]

[0597] in:

[0598] LC = labeled amount 500 mg of compound III-2b and 500 mg of probenecid

[0599] "Cn" = content of compound III-2b and probenecid at each time point (mg)

[0600] Method Validation. The analysis by HPLC-UV has been validated. The parameters, acceptance criteria and results evaluated are presented in Table 5 and comply with ICH Q2 requirements. The intended purpose of the method was validated.

[0601] Table 5

[0602]

[0603]

[0604] Several exemplary batches of bilayer tablets were prepared by the first and second compression forces shown in Table 6A. The in vitro release characteristics of the exemplary batches of bilayer tablets are shown in Tables 6B and 4A to 4D middle.

[0605] Table 6A

[0606] First compression force (kN) Second compression force(kN) Batch 1 0.94 13.12 Batch 2 0.51 8.34 Batch 3 2.12 12.65 Batch 4 2.77 15.51 Batch 5 2.18 14.27 Batch 6 2.56 13.22

[0607] Table 6B

[0608]

[0609]

[0610] Example 3. Effect of compression force on physical properties of bilayer tablets

[0611] Bilayer tablets were prepared according to the procedure described in Example 1 and with various first and second compression forces (shown in Table 7A below).

[0612] Table 7A

[0613] Tablet Sample# First force (kN) Second force (kN) 1 1.50 11.50 2 11.50 1.50 3 1.25 30.00 4 2.00 20.00 5 1.25 15.00 6 0.50 10.00 7 1.25 5.00

[0614] The table is characterized by X-ray computed tomography (X-ray CT), and the collected data is subsequently quantified. X-ray computed tomography (X-ray CT). X-ray CT is a non-destructive analytical technique for visualizing and quantifying the interior of a material in 3D. The tablets were firmly held in an X-ray transparent polystyrene block during scanning. The tablets were individually scanned using a GE V|TOME|XM 240kV (GE Sensing and Inspection Technologies, Wunstorf, Germany) X-ray CT system. The X-ray tube energy and current were 80kv and 160μA, respectively. The scan consisted of 2400 radiographic images at a resolution of 14 microns (integration of 8 images was performed each to reduce image noise). When reconstructing the data, a digital magnification factor was used to achieve a final resolution of 7.5 microns. Low attenuation materials such as air (voids) appear as dark areas. Higher attenuation materials or denser areas in the sample appear brighter. Images, animations, and microstructural quantification were performed using Volume Graphics VGStudioMAX (v2.2) software (Volume Graphics, GmbH, Germany). The physical characteristics of the tablets are shown in FIG. 5A to FIG. 5F The in vitro release characteristics of an exemplary batch of bilayer tablets (prepared by a first compression force of 2.06 kN and a second compression force of 25.69 kN) are shown in Figure 5G and Table 7B.

[0615] Table 7B

[0616] Sampling time (min) Released compound III-2b (%) Released probenecid (%) 5 36 19 10 60 50 15 72 77 20 79 93 30 86 98 45 91 99 60 94 99

[0617] Example 4: Effects of a beta-lactam compound and probenecid administered by the same route of administration.

[0618] In two separate studies, normal and healthy subjects were administered a β-lactam compound (Compound III-2b; thiopenem prodrug) and probenecid. In Study No. 1, subjects were administered 500 mg of thiopenem prodrug in the form of a powder for oral suspension and simultaneously administered 500 mg of probenecid provided in the form of a monolayer tablet. In Study No. 2, subjects were administered 500 mg of thiopenem prodrug and 500 mg of probenecid in the form of a bilayer tablet. The results of both studies are shown in Figures 6 to 9 and Table 8 below.

[0619] Table 8

[0620]

[0621]

[0622] It was observed that administration of sulopenem prodrug and probenecid in the form of a bilayer tablet resulted in an increase in the amount of sulopenem in the blood relative to administration of each agent as a separate formulation.

[0623] Administration of the combination of sulopenem prodrug and probenecid in a bilayer tablet in the fasting state increased the amount of sulopenem in the blood by 17.9% relative to the same amount of sulopenem prodrug delivered as a powder in a bottle administered with probenecid in a monolayer tablet, as measured by the area under the curve.

[0624] Similarly, administration of the combination of sulopenem prodrug and probenecid in the form of a bilayer tablet in the fed state increased the amount of sulopenem in the blood by 11.3% relative to the same amount of sulopenem prodrug delivered as a powder in a bottle administered with probenecid in a monolayer tablet, as measured by the area under the curve.

[0625] Equivalent

[0626] It should be understood that the present invention may be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the foregoing embodiments should be considered illustrative in all respects, rather than limiting the invention described herein. Therefore, the scope of the present invention is indicated by the appended claims rather than the foregoing description, and all changes within the equivalent meanings and scope of the claims are intended to be included therein.

Claims

1. A double-layer tablet, comprising: A first layer comprising about 500 mg of probenecid or a pharmaceutically acceptable salt thereof; The second layer, which contains about 500 mg of about 220 mg to about 230 mg of microcrystalline cellulose; about 50 mg to about 60 mg of croscarmellose sodium; from about 3 mg to about 4 mg of intragranular magnesium stearate; from about 6 mg to about 8 mg of extragranular magnesium stearate; about 65 mg to about 75 mg of lactose monohydrate; and From about 20 mg to about 23 mg of hydroxypropyl cellulose.

2. A method for preparing the bilayer tablet of claim 1, the method comprising: i) compressing a first particulate material comprising probenecid or a pharmaceutically acceptable salt thereof with a first force, thereby forming a pre-compressed first layer; ii) adding a second particulate material comprising compound III-2 to the pre-compressed first layer; as well as iii) compressing said pre-compressed first layer and said second granular material with a second force, thereby forming a pre-coated bi-layer tablet.

3. A method for treating or preventing a disease, the method comprising administering a pharmaceutically effective amount of the bilayer tablet of claim 1 to a subject in need thereof.

4. The method of claim 3, wherein the subject in need thereof is a human.

5. The method of claim 3, wherein the disease comprises an increase or decrease in a population of one or more bacteria selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, Clostridium fusiformis, Eubacterium tarda, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distachyon, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides monotheca, Porphyromonas insaccharolyticus, Prevotella dirutolyticus, Staphylococcus epidermidis, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Citrobacter freundii, Citrobacter krebs, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Serratia marcescens, Bacteroides vulgaris, Clostridium perfringens, and Fusobacterium species.

6. The method of claim 3, wherein the disease is an infection selected from the group consisting of uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection, and infectious diarrhea.

7. The method of claim 3, wherein the disease is a neurodegenerative disease, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, cancer, or inflammatory bowel disease.

8. The method of claim 3, wherein the bilayer tablet is administered to the subject with food.

9. The method of claim 3, wherein the administration results in an area under the curve (AUC) for plasma concentration of the β-lactam compound in the subject in need thereof that is higher than that of a comparable subject receiving administration of a comparable composition.

10. The method of claim 3, wherein the administration results in a maximum plasma concentration (C max ) is substantially the same as compared to comparable subjects receiving administration of comparable compositions.

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