Antiviral prodrug formulations

Abstract

In part of this specification, a pharmaceutical composition containing an antiviral prodrug and a method of using the drug in the treatment of a viral infection are disclosed.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 491,002, filed on March 17, 2023, which is hereby incorporated by reference in its entirety.

Background Art

[0002] In the present specification, in certain embodiments, a pharmaceutical composition comprising an antiviral prodrug and a cryoprotective substance is disclosed.

Summary of the Invention

[0003] In the present specification, in certain embodiments, (i)

Chemical Formula

[0004] In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the pharmaceutical composition contains about 25% to about 45% by weight of the crystalline form, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and a surfactant. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm.In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.25 to approximately 0.35.

[0005] In this specification, in one embodiment, (i) [ka] A mixture of crystalline forms of compounds represented by; and (ii) cryoprotectants; A pharmaceutical composition (e.g., an aqueous suspension) containing the above is described.

[0006] In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the mixture of crystalline forms of the compound has two crystalline forms. In some embodiments, one of the two crystalline forms is present in about 10% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 90% by weight of the mixture. In some embodiments, one of the two crystalline forms is present in about 15% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 85% by weight of the mixture. In some embodiments, the mixture of crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°. In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°.In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 17.8°, approximately 21.6°, and approximately 23.6°. In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 14.0°, approximately 16.3°, approximately 16.8°, approximately 17.8°, approximately 21.6°, approximately 23.6°, approximately 24.3°, and approximately 26.1°. In some embodiments, the crystalline mixture of the compound is substantially characterized by the XRPD pattern shown in Figure 2. In some embodiments, the pharmaceutical composition contains approximately 25% to approximately 45% by weight of the crystalline mixture of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline mixture of the compound. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the surfactant. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound, the surfactant, and the polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is approximately 250 nm to approximately 650 nm, the particle size distribution (D50) is approximately 350 nm to approximately 900 nm, and the particle size distribution (D90) is approximately 600 nm to approximately 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.25 to approximately 0.35.

[0007] This specification describes a method for treating, suppressing, and / or preventing a viral infection in a patient who requires treatment, suppression, and / or prevention of a viral infection, the method comprising administering an effective amount of a pharmaceutical composition described herein to the patient.

[0008] In some embodiments, the viral infection is a retroviral infection. In some embodiments, the viral infection is an HIV infection. In some embodiments, the method includes administering the pharmaceutical composition intramuscularly.

[0009] In this specification, in one embodiment, (i) [ka] The crystalline form of the compound represented by; and (ii) cryoprotectants; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing the crystalline form of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods including the following will be described.

[0010] In some embodiments, the suspension comprises one or more excipients selected from the group consisting of polyethylene glycol, surfactants, and combinations thereof. In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the suspension further comprises a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the suspension further comprises polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the method comprises mixing the ball-milled mixture and the cryoprotective substance with a phosphate buffer. In some embodiments, the pH of the composition is approximately 6.0 to approximately 7.5. In some embodiments, the pH of the composition is approximately 7.0. In some embodiments, the pharmaceutical composition contains approximately 25% to approximately 45% by weight of the crystalline form, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and the surfactant. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol.In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is approximately 250 nm to approximately 650 nm, the particle size distribution (D50) is approximately 350 nm to approximately 900 nm, and the particle size distribution (D90) is approximately 600 nm to approximately 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles in the pharmaceutical composition is approximately 0.25 to approximately 0.35.

[0011] In this specification, in one embodiment, (i) [ka] A mixture of crystalline forms of compounds represented by; and (ii) cryoprotectants; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing a mixture of the crystalline forms of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods including the following will be described.

[0012] In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the mixture of crystalline forms of the compound has two crystalline forms. In some embodiments, one of the two crystalline forms is present in about 10% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 90% by weight of the mixture. In some embodiments, the mixture of crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°. In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°. In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 7.4°, about 17.8°, about 21.6°, and about 23.6°.In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern at 2θ of about 7.0°, about 7.4°, about 14.0°, about 16.3°, about 16.8°, about 17.8°, about 21.6°, about 23.6°, about 24.3°, and about 26.1°. In some embodiments, the mixture of crystalline forms of the compound is substantially characterized by the XRPD pattern shown in FIG. 2. In some embodiments, the pharmaceutical composition comprises from about 25% to about 45% by weight of the mixture of crystalline forms of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and the surfactant. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound and polyethylene glycol. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the mixture of crystalline forms of the compound, the surfactant, and polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is from about 250 nm to about 650 nm, the particle size distribution (D50) is from about 350 nm to about 900 nm, and the particle size distribution (D90) is from about 600 nm to about 1300 nm. In some embodiments, the z-average particle size of the plurality of nanoparticles is from 200 nm to 900 nm. In some embodiments, the z-average particle size of the plurality of nanoparticles is from 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is from about 0.15 to about 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is from about 0.25 to about 0.35.

Brief Description of the Drawings

[0013] [Figure 1] FIG. 1 shows a histogram of the particle size distribution of formulation F16 after exposure to gamma-ray irradiation.

[0014] [Figure 2]Figure 2 shows an example of the XRPD pattern of a mixture of crystal forms of M2CAB (crystal forms 1 + 4) in the pharmaceutical composition of the present disclosure.

Mode for Carrying Out the Invention

[0015] Definitions As used herein, the term "a" or "an" may mean one or more. In this specification, when the term "a" or "an" is used in conjunction with the term "comprising", it may mean one or more. As used herein, the term "another" may mean at least a second or subsequent one. Further, the terms "having", "including", "containing", and "comprising" are interchangeable, and those skilled in the art recognize that these are open-ended terms. Some embodiments of the present disclosure may consist of or consist essentially of one or more elements, method steps, and / or methods of the present disclosure. It is contemplated that any method, compound, or composition described herein may be applicable to any other method, compound, or composition described herein.

[0016] The terms "about" and "approximately" generally mean the degree of error allowed in the measured quantity in light of the nature or accuracy of the measurement. The degree of error is, for example, within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%.

[0017] Unless otherwise evident from the context, all numerical values ​​or numerical ranges used herein include integers within or encompassing the range, as well as fractions of values ​​or integers within or encompassing the range. Therefore, for example, when referring to the range 90–100%, it includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc. As another example, if we refer to the range of 1 to 5000 times, it includes 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, etc., as well as 1.1x, 1.2x, 1.3x, 1.4x, 1.5x, etc., and 2.1x, 2.2x, 2.3x, 2.4x, 2.5x, etc.

[0018] As used herein, the term “pharmaceutically acceptable excipient” refers to any substance in a pharmaceutical preparation other than the active pharmaceutical ingredient. Typical excipients include those that assist in the manufacturing process, protect, support, or improve stability, increase bioavailability, or enhance patient acceptability. They may also assist in product identification or improve the overall safety or function of the product during storage or use.

[0019] As used herein, the “subject” to which administration is intended includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (infants, children, adolescents, etc.) or adult subjects (young adults, middle-aged adults, or elderly adults, etc.)) and / or non-human animals, e.g., primates (crab-eating macaques, rhesus macaques, etc.), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs and other mammals. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” “subject,” and “individual” are used interchangeably herein. None of these terms require active supervision by a healthcare professional.

[0020] In this specification, the terms “disease,” “disorder,” and “condition” are used interchangeably.

[0021] Unless otherwise specified, the terms “treat,” “treating,” and “treatment” as used herein refer to actions taken when a subject has a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or reverse or delay the progression of the disease, disorder, or condition (also known as “therapeutic measures”).

[0022] Generally, the “effective dose” of a compound means the amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective dose of a compound in this disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, weight, health, and condition of the subject. The “therapeutic effective dose” of a compound is the amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or sufficient to delay or minimize one or more symptoms associated with the disease, disorder, or condition. The therapeutic effective dose of a compound means the amount of therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic effective dose” may include amounts that improve overall treatment, reduce or avoid symptoms or causes of a disease or condition, or enhance the therapeutic effectiveness of other therapeutic agents. The “preventive effective dose” of a compound is the amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or sufficient to prevent their recurrence. The prophylactic effective dose of a compound refers to the amount of therapeutic agent, either alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent. “Prophylactic treatment” refers to any action taken before a subject begins to develop a particular disease, disorder, or condition.

[0023] As used herein, "M2CAB" refers to the following structure: [ka] This refers to compounds that possess [a certain characteristic].

[0024] Pharmaceutical composition In this specification, in some embodiments, (a) M2CAB in crystalline solid form; and (b) Pharmacologically acceptable excipients; A pharmaceutical composition containing the above is disclosed.

[0025] In this specification, in one embodiment, (i) [ka] The crystalline form of the compound represented by; and (ii) cryoprotectants; A pharmaceutical composition (e.g., an aqueous suspension) containing the above is described.

[0026] In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the pharmaceutical composition contains about 25% to about 45% by weight of the crystalline form, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and the surfactant. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm.In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.25 to approximately 0.35.

[0027] In this specification, in one embodiment, (i) [ka] A mixture of crystalline forms of compounds represented by; and (ii) cryoprotectants; A pharmaceutical composition containing [the specified ingredient] is described.

[0028] In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the mixture of crystalline forms of the compound has two crystalline forms. In some embodiments, one of the two crystalline forms is present in about 10% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 90% by weight of the mixture. In some embodiments, one of the two crystalline forms is present in about 15% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 85% by weight of the mixture. In some embodiments, the mixture of crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°. In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°.In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 17.8°, approximately 21.6°, and approximately 23.6°. In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 14.0°, approximately 16.3°, approximately 16.8°, approximately 17.8°, approximately 21.6°, approximately 23.6°, approximately 24.3°, and approximately 26.1°. In some embodiments, the crystalline mixture of the compound is substantially characterized by the XRPD pattern shown in Figure 2. In some embodiments, the pharmaceutical composition contains approximately 25% to approximately 45% by weight of the crystalline mixture of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline mixture of the compound. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the surfactant. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound, the surfactant, and the polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is approximately 250 nm to approximately 650 nm, the particle size distribution (D50) is approximately 350 nm to approximately 900 nm, and the particle size distribution (D90) is approximately 600 nm to approximately 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.25 to approximately 0.35.

[0029] In some embodiments, the pharmaceutical composition is an aqueous suspension.

[0030] In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 3% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 4% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 6% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 7% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 8% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 9% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

[0031] In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 1% to about 10% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 3% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 4% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition.

[0032] In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 1% to about 10% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 3% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 4% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition.

[0033] In some embodiments, the pharmaceutical composition contains about 10% to about 45% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 25% to about 45% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 25% to about 40% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 25% to about 35% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 25% to about 30% by weight of the crystalline form of the compound. In some embodiments, the pharmaceutical composition contains about 30% to about 45% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 30% to about 40% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 35% to about 45% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 25% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 30% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 35% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 40% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 45% by weight of the crystalline form of the compound, based on the total weight of the pharmaceutical composition.

[0034] In some embodiments, the composition has a physiologically acceptable pH (e.g., a pH in the range of about 3 to about 11, or a pH in the range of about 3 to about 7, depending on the formulation and route of administration). In some cases, the pH is about 5.0 to about 8.

[0035] The pharmaceutical compositions disclosed herein are administered by any suitable route through which effective treatment is achieved in the subject. In some embodiments, the pharmaceutical compositions disclosed herein are administered systemically. In some embodiments, the pharmaceutical compositions disclosed herein are administered topically. Routes of administration of the pharmaceutical compositions include, but are not limited to, enteral, gastrointestinal, oral, transdermal, subcutaneous, nasal, intravenous, intravenous bolus, intravenous drip, intra-arterial, intramuscular, transmucosal, inhalation, sublingual, oral, conjunctival, and cutaneous administration. Modes of administration include injection, infusion, drip administration, and / or oral ingestion. "Injection" includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intradermal, intraperitoneal, transtracheal, and subcutaneous injections. In some embodiments, the route is intramuscular administration. In some embodiments, the route is subcutaneous administration.

[0036] How to use This specification discloses, in several embodiments, methods for treating HIV-1 infection in individuals requiring treatment. Furthermore, this specification discloses, in several embodiments, methods for preventing HIV-1 infection in individuals requiring prevention. In addition, this specification discloses, in several embodiments, methods for preventing the transmission of the HIV-1 virus from one individual to another (for example, transmission from a pregnant woman to her child, for example, during childbirth or breastfeeding).

[0037] This specification describes a method for treating, suppressing, and / or preventing a viral infection in an individual requiring treatment, suppression, and / or prevention of a viral infection, the method comprising administering an effective amount of a pharmaceutical composition described herein to the individual.

[0038] In this specification, in one embodiment, a method for treating, suppressing, and / or preventing a viral infection in an individual requiring treatment, suppression, and / or prevention of a viral infection, [ka] A method is disclosed comprising administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising an effective amount of the crystalline form of a compound represented by and a pharmaceutically acceptable excipient.

[0039] In some embodiments, the viral infection is a retroviral infection. In some embodiments, the viral infection is an HIV infection. In some embodiments, the method includes intramuscular administration of the pharmaceutical composition to the individual. In some embodiments, the method includes subcutaneous administration of the pharmaceutical composition to the individual.

[0040] In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once a month. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every two months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every three months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every six months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every nine months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every twelve months.

[0041] In this specification, in one embodiment, a method for treating HIV-1 infection in an individual requiring treatment for HIV-1 infection, [ka] A method is disclosed comprising administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a therapeutically effective amount of the crystalline form of a compound represented by and a pharmaceutically acceptable excipient. Furthermore, in some embodiments herein, a method for preventing HIV-1 infection in an individual requiring prevention of HIV-1 infection is disclosed, [ka] A method is disclosed herein that includes administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a prophylactic effective amount of the crystalline form of a compound represented by and a pharmaceutically acceptable excipient. In addition, in some embodiments herein, a method is disclosed for preventing the transmission of the HIV-1 virus from one individual to another (e.g., transmission from a pregnant woman to her child, for example, during childbirth or lactation), [ka] A method is disclosed comprising administering to the individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a prophylactic effective amount of the crystalline form of a compound represented by and a pharmaceutically acceptable excipient.

[0042] In this specification, in one embodiment, a method for treating HIV-1 infection in an individual requiring treatment for HIV-1 infection, [ka] A method is disclosed herein that includes administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a therapeutically effective amount of a mixture of crystalline forms of a compound represented by and a pharmaceutically acceptable excipient. Furthermore, in some embodiments herein, a method for preventing HIV-1 infection in an individual requiring prevention of HIV-1 infection is disclosed, [ka] A method is disclosed herein that includes administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a prophylactic effective amount of a mixture of crystalline forms of a compound represented by and a pharmaceutically acceptable excipient. In addition, in some embodiments herein, a method is disclosed for preventing the transmission of the HIV-1 virus from one individual to another (e.g., transmission from a pregnant woman to her child, for example, during childbirth or lactation), [ka] A method is disclosed comprising administering to an individual a pharmaceutical composition (e.g., the pharmaceutical composition described herein) comprising a prophylactic effective amount of a mixture of crystalline forms of a compound represented by and a pharmaceutically acceptable excipient.

[0043] In some embodiments, the viral infection is a retroviral infection. In some embodiments, the viral infection is an HIV infection. In some embodiments, the method includes intramuscular administration of the pharmaceutical composition to the individual. In some embodiments, the method includes subcutaneous administration of the pharmaceutical composition to the individual.

[0044] In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once a month. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every two months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every three months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every six months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every nine months. In some embodiments, the method includes administering a mixture of the crystalline form of the compound to the individual once every twelve months.

[0045] In some embodiments, the crystalline form of M2CAB described herein, a mixture of the crystalline forms of M2CAB described herein, or a pharmaceutical composition described herein is administered in combination with additional agents to treat the diseases described herein.

[0046] Manufacturing method In this specification, in one embodiment, (i) [ka] The crystalline form of the compound represented by; and (ii) cryoprotectants; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing the crystalline form of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods including the following will be described.

[0047] In some embodiments, the suspension contains polyethylene glycol. In some embodiments, the suspension contains a surfactant. In some embodiments, the suspension contains one or more excipients selected from the group consisting of polyethylene glycol, surfactants, and combinations thereof. In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the suspension further contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the suspension further contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the method comprises mixing the ball-milled mixture and the cryoprotectant with a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the pharmaceutical composition contains about 25% to about 45% by weight of the crystalline form, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound and the surfactant. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising the crystalline form of the compound, the surfactant, and the polyethylene glycol.In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is approximately 250 nm to approximately 650 nm, the particle size distribution (D50) is approximately 350 nm to approximately 900 nm, and the particle size distribution (D90) is approximately 600 nm to approximately 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles in the pharmaceutical composition is approximately 0.25 to approximately 0.35.

[0048] In this specification, in one embodiment, (i) [ka] A mixture of crystalline forms of compounds represented by; and (ii) cryoprotectants; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing a mixture of the crystalline forms of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods including the following will be described.

[0049] In some embodiments, the suspension contains polyethylene glycol. In some embodiments, the suspension contains a surfactant. In some embodiments, the cryoprotective substance is a sugar. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof. In some embodiments, the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol. In some embodiments, the cryoprotective substance is trehalose. In some embodiments, the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a surfactant. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the surfactant based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains polyethylene glycol. In some embodiments, the pharmaceutical composition contains about 3% to about 5% by weight of the polyethylene glycol based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a phosphate buffer. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the pH of the composition is about 7.0. In some embodiments, the mixture of crystalline forms of the compound has two crystalline forms. In some embodiments, one of the two crystalline forms is present in about 10% to about 30% by weight of the mixture, and the other crystalline form is present in about 70% to about 90% by weight of the mixture. In some embodiments, the mixture of crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°. In some embodiments, the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°.In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 17.8°, approximately 21.6°, and approximately 23.6°. In some embodiments, the crystalline mixture of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 14.0°, approximately 16.3°, approximately 16.8°, approximately 17.8°, approximately 21.6°, approximately 23.6°, approximately 24.3°, and approximately 26.1°. In some embodiments, the crystalline mixture of the compound is substantially characterized by the XRPD pattern shown in Figure 2. In some embodiments, the pharmaceutical composition contains approximately 25% to approximately 45% by weight of the crystalline mixture of the compound, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition contains a plurality of nanoparticles comprising the crystalline mixture of the compound. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the surfactant. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound and the polyethylene glycol. In some embodiments, the pharmaceutical composition comprises a plurality of nanoparticles comprising a crystalline mixture of the compound, the surfactant, and the polyethylene glycol. In some embodiments, the particle size distribution (D10) of the plurality of nanoparticles is approximately 250 nm to approximately 650 nm, the particle size distribution (D50) is approximately 350 nm to approximately 900 nm, and the particle size distribution (D90) is approximately 600 nm to approximately 1300 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 200 nm to 900 nm. In some embodiments, the z-mean particle size of the plurality of nanoparticles is 275 nm to 425 nm. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.15 to approximately 0.4. In some embodiments, the polydispersity index of the plurality of nanoparticles is approximately 0.25 to approximately 0.35. [Examples]

[0050] Abbreviations: API: Active pharmaceutical ingredient; DP: Pharmaceutical product; DS: Active pharmaceutical ingredient; NT: Not tested; ND: Not measured; PSD: Particle size distribution; QS: Quantum satis (sufficient amount). Example 1: DP process for manufacturing M2CAB pharmaceutical products; F1 formulation [Table 1] [Table 2] [Table 3] [Table 4]

[0051] procedure Preparation of PBS: Approximately 1.6 g of potassium dihydrogen phosphate, 8 g of sodium chloride, and 2 g of potassium chloride were added to a glass bottle containing approximately 790 g of deionized water. After dissolution, the pH of the solution was measured, and sodium hydroxide was added to adjust the pH to 7. Deionized water was added to bring the total volume to 1000 g.

[0052] Preparation of pharmaceutical products Approximately 645 mg of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) was added to a 20 mL glass vial using a pipette, followed by 642 mg of PEG-3350 polymer and 10 mL of PBS (pH 7.0). The solution was gently mixed using a magnetic stirrer at 300 rpm (to avoid air bubbles) for 20 minutes to completely dissolve the polymer. Approximately 4500 mg of M2CAB powder was transferred to the glass vial in several portions. The mixture was gently mixed using a magnetic stirrer at 700 rpm (700 rpm) to completely and uniformly disperse the M2CAB (for approximately 18 hours). In-process confirmation was performed by visual observation and microscopic imaging until few or no aggregates were observed. After the M2CAB was uniformly dispersed, the following bead beating process was carried out.

[0053] 0.25 mL of 0.4 mm zirconium oxide beads and 1 mL of the formulation were added to a microcentrifuge tube. Shaking was started at 4800 rpm for 2 minutes (initial temperature: 23°C; final temperature: 36°C), and after 1 minute, a 1 minute pulse was applied. After bead beating, the suspension was placed in a pre-set and washed high-shear homogenizer (5-30 psi) and passed through a high-pressure chamber until the particle size (Z mean) was 400 nm or less. In-process verification was performed using an analyzer. Once the particle size (Z mean) was less than 400 nm, the sample was collected in a 20 mL glass vial, and its appearance, pH, and osmolality were tested and recorded in the table below. [Table 5] [Table 6] [Table 7] [Table 8]

[0054] Consideration After 2 minutes of bead beating, the Z-mean (particle size distribution, i.e., PSD) of F1 decreased to 624 nm. After passing through a high-shear homogenizer once following bead beating, the Z-mean was 363 nm. After 18 hours of stirring, the nano-suspended formulation of F1 became more viscous and difficult to transfer with a pipette. Example 2. Gamma-ray irradiation vs. X-ray irradiation of F1 formulation, and 17-day stability. Objective: To analyze the appearance, particle size distribution, and zeta potential of the F1 formulation after gamma-ray and X-ray irradiation, and to evaluate the 17-day stability of the F1 formulation. In the irradiation test, the target dose was 25 kGy. The actual dose from gamma-ray irradiation was 26.8–27.2 kGy, and the total exposure time was 519 minutes. In the X-ray irradiation, the actual dose was 30.6–31.0 kGy, and the total exposure time was 125 minutes. [Table 9] result [Table 10] [Table 11] [Table 12] [Table 13]

[0055] Consideration The results indicated that the F1 formulation was unstable. Specifically, the F1 formulation transformed into a cake-like state at 25°C, while F1 stored at 2–8°C maintained its fluidity. Furthermore, after both gamma ray and X-ray treatment, the F1 formulation exhibited a cake-like physical form. In the cake-like samples, the particle size distribution (PSD) measured at D(10), D(50), and D(90) was significantly increased. Example 3. M2CAB nano-suspension formulation by ball milling. [Table 14] [Table 15]

[0056] procedure Preparation of a 5% trehalose solution (200 mL) Approximately 10 g of trehalose was added to 200 g of deionized water in a glass container and mixed to obtain a clear solution.

[0057] Preparation of pharmaceutical products Approximately 10 g of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) and 10 g of PEG-3350 polymer were added to a 500 mL glass bottle. 110 g of 5% trehalose solution was transferred to a glass vial and mixed at 700 rpm for 10 minutes until completely dissolved. Next, the solution was mixed at 5000 rpm using a high-shear mixer under ice cooling. Approximately 10 g of M2CAB powder was added to the solution and mixing was resumed at 5000 rpm for 2 minutes. The above procedure was repeated, and the weight transferred, mixing speed, and mixing time were recorded in the table below. [Table 16]

[0058] The solution was slowly mixed under high shear pressure while ice-cold to completely and uniformly disperse the M2CAB.

[0059] Ball milling process: Using a supply funnel, approximately 140-150 mL of milling beads (0.4 mm zirconium oxide beads) were added to the mill's grinding chamber, and the mill was moved to the horizontal operating position. The F13 formulation was added to the mill's recovery container. Overhead stirring was turned on, the cooling water cock was opened, and the product pump was started at the minimum flow rate. As soon as the product flowed out of the outlet into the recovery container, the ball mill was started at the minimum speed (10 Hz or 600 rpm) and increased to 2400 rpm in less than 1 minute. The F13 formulation was ground in the mill at 2400 rpm, and the circulation flow rate of the F13 formulation was gradually increased while maintaining the pressure not to exceed 10. Samples were taken at the points shown in the table below, and the particle size distribution (PSD) was measured. [Table 17]

[0060] The F13 formulation was crushed until a particle size (D50) plateaued, and then collected in a glass bottle. Buffering agent was added, and the mixture was stirred or mixed using an overhead mixer. The pH was adjusted with 1N NaOH or HCl as needed. [Table 18] Example 4. M2CAB nano-suspension formulation by ball milling. [Table 19] [Table 20] [Table 21]

[0061] Procedure: Preparation of the formulation Approximately 11 g of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) and 11 g of PEG-3350 polymer were transferred to a glass bottle. 119 g of water was added, and the solution was slowly mixed at 700 rpm for 15 minutes using a magnetic stirrer to completely dissolve the polymer. Then, 62 g of M2CAB powder was gradually transferred to the glass bottle. The solution was slowly mixed at 1200 rpm for 80 hours using a magnetic stirrer (high shear treatment was used to ensure uniformity of the formulation, and stirring was continued even after the high shear treatment was completed) to completely and uniformly disperse the M2CAB. Then, the remaining M2CAB was added to the glass bottle in stages.

[0062] High shear process The suspension sample was placed in an ice bath and homogenized using a Polytron high-shear mixer at 1200 rpm at 2-8°C for 20 minutes. In-process checks were performed every 5 minutes using an analyzer (approximately 5 μL was sampled each time), and the results were recorded in the table below. The process was stopped if the particle size was in the range of 800-900 nm. [Table 22]

[0063] Ball milling process: Using the supply funnel, 140 mL of milling beads (0.4 mm zirconium oxide beads) were added to the mill's grinding chamber, and the mill was moved to the horizontal operating position. The F14 formulation was added to the mill's recovery container, the mill was started, and the overhead stirrer was activated. The cooling water cock was opened, and the product pump was started at the minimum flow rate.

[0064] As soon as the product flowed out of the outlet into the recovery container, the ball mill was started at the minimum speed (10 Hz or 600 rpm) and increased to 2400 rpm in less than one minute. The F14 formulation was ground at 2400 rpm. With pump setting 4, the circulation rate of the F14 formulation was gradually increased while maintaining a pressure of 10 or less. Samples were taken at the points shown in the table below, and the particle size distribution (PSD) was measured. [Table 23]

[0065] The F14 formulation was ground until the particle size reached approximately 300 nm. The ball-milled samples were collected in bottles, and the ground F14 formulation was stored at 2-8°C. The appearance was observed visually and under an optical microscope, and the particle size distribution was tested. [Table 24]

[0066] Furthermore, no clogging was observed during the process.

[0067] Example 5. Freeze-thaw test of F14 The cryoprotective substances of formulation F14 were screened using particle size distribution (PSD) measurement, as described below.

[0068] procedure 3% trehalose Approximately 30 mg of trehalose and 1 mL of F14 were added to the vial. The vial was thoroughly vortexed, sealed, and crimped. The particle size distribution (PSD) was measured, and the vial was stored at -20°C.

[0069] 5% Trehalose Approximately 50 mg of trehalose and 1 mL of F14 were added to the vial. The vial was thoroughly vortexed, sealed, and crimped. The particle size distribution (PSD) was measured, and the vial was stored at -20°C.

[0070] 10% Trehalose Approximately 100 mg of trehalose and 1 mL of F14 were added to the vial. The vial was thoroughly vortexed, sealed, and crimped. The particle size distribution (PSD) was measured, and the vial was stored at -20°C.

[0071] 3% Mannitol Approximately 30 mg of mannitol and 1 mL of F14 were added to the vial. The vial was vortexed thoroughly, sealed, and crimped. The PSD was measured, and the vial was stored at -20°C.

[0072] 5% Mannitol Approximately 50 mg of mannitol and 1 mL of F14 were added to the vial. The vial was vortexed thoroughly, sealed, and crimped. The PSD was measured, and the vial was stored at -20°C.

[0073] test An osmometer was used, and after performing the initialization procedure with a sample tube filled with 0.25 mL of deionized water according to the instructions, the osmolality was tested. After the instrument was initialized, calibration was confirmed by measuring 200 μL of Clinitrol 290 mOsm standard solution. The result was recorded as 288 mOsm. When the osmometer reached 290 mOsm ± 2, the probe was washed with deionized water and lightly dried with a wipe. Next, the sample tube was replaced with a new one containing 200 μL of sample, and the results were recorded. result [Table 25] [Table 26] Consideration After three freeze-thaw cycles, the particle size remained the same for all three concentrations of trehalose (no significant changes were observed). After three freeze-thaw cycles, no significant changes in particle size were observed for either of the two mannitol concentrations.

[0074] Example 6. Freeze-thaw test of F14 Objective: To introduce a buffering agent into the F14 formulation.

[0075] procedure 3% trehalose-containing buffer Approximately 31 mg of trehalose and 0.78 mg of sodium dihydrogen phosphate monohydrate were added to the vial. 1 mL of F14 was added to the vial, and the solution was vortex-mixed. PSD and osmolality were measured. The vial was sealed, crimped, and stored at -20°C.

[0076] 5% trehalose-containing buffer solution Approximately 50 mg of trehalose and 0.76 mg of sodium dihydrogen phosphate monohydrate were added to the vial. 1 mL of F14 was added to the vial, and the solution was vortex-mixed. PSD and osmolality were measured. The vial was sealed, crimped, and stored at -20°C. result [Table 27] [Table 28]

[0077] After three cycles of freeze-thawing, the particle size remained identical for both concentrations of trehalose containing the buffer (no significant changes were observed).

[0078] Example 7. M2CAB nano-suspension formulation by ball milling. Another 200mL-scale ball milling batch (named F15) was prepared with a higher proportion of surfactant. [Table 29] [Table 30]

[0079] Procedure: Preparation of the formulation Approximately 15 g of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) and 15 g of PEG-3350 polymer were added to a glass bottle. 99 g of water was added, and the solution was slowly mixed at 700 rpm for 10 minutes using a magnetic stirring bar to completely dissolve all components.

[0080] Next, the solution was mixed at 5000 rpm using a high-shear mixer under ice cooling. 10 g of M2CAB powder was transferred to the solution, and the solution was mixed at 8000 rpm for 2 minutes to form a homogeneous, fluid suspension. The above process was repeated, and the weight transferred, mixing speed, and time were recorded in the table below. [Table 31]

[0081] High shear process The suspension sample was placed in an ice bath and homogenized at high speed (12,000 rpm, 2-8°C, 15 minutes) using a high-shear mixer. Particle size was checked every 5 minutes during the process (approximately 5 μL was sampled each time), and the results were recorded in the table below. If the particle size could not be reduced further, the process was stopped. [Table 32]

[0082] Ball milling process: Using a supply funnel, 140-150 mL of milling beads (0.4 mm zirconium oxide beads) were added to the mill's grinding chamber, and the mill was moved to the horizontal operating position. The F13 formulation was added to the mill's recovery container, and the overhead stirrer was started. The cooling water cock was opened, and the product pump was started at the minimum flow rate. As soon as the product flowed out of the outlet into the recovery container, the ball mill was started at the minimum speed (10 Hz or 600 rpm) and increased to 2400 rpm in less than one minute.

[0083] The F13 formulation was ground at 2400 rpm. With pump setting 4 (recorded), the circulation rate of the F13 formulation was gradually increased while maintaining a pressure of 10 or less. Samples were taken at the points shown in the table below, and the PSD was measured. [Table 33] result [Table 34]

[0084] Example 8. Comparison of viscosity and analysis of F13, F14, F15, and F15 (diluted). Viscosity, analysis, and impurity tests were performed on F13, F14, F15, and F15 (diluted). [Table 35]

[0085] Viscosity Test Procedure To test viscosity: 0.5 mL of each sample was placed in a cone-plate rheometer. After reaching equilibrium at 25°C, measurements were taken and the values ​​were recorded. result [Table 36] [Table 37]

[0086] Example 9. Filling a syringe with the formulation and testing the injection force. Injection force tests were conducted for F14, F13, and F15. [Table 38]

[0087] procedure 5 mL syringes fitted with needles of various gauges Two 5 mL syringes were labeled with the formulation code, lot number, syringe size, and needle information. Each formulation was thoroughly mixed, and 5 mL of the formulation was drawn into each syringe using an 18 G needle. Then, the appropriate needle was attached to each syringe.

[0088] The sample was placed in a force meter, and the injection force was measured immediately after filling with the following parameters: syringe inner diameter (ID) (10.39 mm for 5 mL, 8.19 mm for 3 mL); sample volume; rate = 2 mL / min.

[0089] The injected samples were collected in 5 mL glass vials, and the injection force (in Newtons) for each sample was recorded. result [Table 39]

[0090] With a 5 mL syringe, the required injection force for F14 was low during manual injection using a 23G x 1 needle. The injection force was measured at an injection rate of 2 mL / min, and the result was close to the recommended maximum target value of 20 N. Overall, F13 showed considerably high resistance when injected through a 23G needle in a 5 mL syringe. With a 23G x 1 needle in a 3 mL syringe, the required injection force for F13 was lower, and the value was close to the recommended maximum target value of 20 N. A 3 mL syringe is recommended for injecting F13.

[0091] Example 10. Preparation of test samples F13, F14, and F15 containing buffer and 5% trehalose. pH and osmolality tests were conducted on F13, F14, and F15, which contain a buffer and 5% trehalose. [Table 40] Procedure: Sample preparation F13 sample containing buffer and 5% trehalose: See Example 3 above.

[0092] F14 sample containing buffer and 5% trehalose: Approximately 50 mg of trehalose and 1.1 mg of sodium dihydrogen phosphate monohydrate were added to the vial. 1 mL of F14 was added to the vial, then the vial was sealed, crimped, and vortex-mixed.

[0093] F15 sample containing buffer and 5% trehalose Approximately 51 mg of trehalose and 1.0 mg of sodium dihydrogen phosphate monohydrate were added to the vial. 1 mL of F15 was added to the vial, then the vial was sealed, crimped, and vortex-mixed. result [Table 41] [Table 42] Example 11. M2CAB nano-suspension formulation by ball milling. [Table 43] [Table 44]

[0094] Preparation of F16 formulation 11 g of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) and 11 g of PEG-3350 polymer were transferred to a glass bottle. 110 g of water was transferred to a glass vial, and the solution was slowly mixed at 700 rpm for 10 minutes under ice cooling using a magnetic stirrer to completely dissolve all components and obtain a clear solution.

[0095] Approximately 10 g of M2CAB powder was transferred to the solution, and mixing was then resumed at 600 rpm for 2 minutes to form a homogeneous, fluid suspension.

[0096] The above procedure was repeated, and the addition weight, mixing rate, and time were recorded as follows: [Table 45]

[0097] The mixture was slowly mixed at 600 rpm using a propeller agitator to completely and uniformly disperse the M2CAB. The agitation process was carried out under ice cooling conditions.

[0098] High shear process The suspension sample was placed in an ice bath and homogenized at high speed using a Polytron high-shear mixer. In-process particle size checks were performed every 5 minutes (approximately 5 μL was taken each time), and the results were recorded in the table below. The process was stopped when the particle size could not be reduced any further. The high-shear rate was recorded as 8000 rpm, the temperature as 2-8°C, and the time as 15 minutes. [Table 46]

[0099] Ball milling process: Using a supply funnel, 140-150 mL of milling beads (0.4 mm zirconium oxide beads) were added to the mill's grinding chamber. The grinding chamber was closed, and the mill was moved to the horizontal operating position. The F16 formulation was added to the mill's recovery container, and the overhead stirrer was started. The cooling water cock was opened, and the product pump was started at the minimum flow rate.

[0100] As soon as the product flowed out of the outlet into the recovery container, the mill was started at the minimum speed (10Hz or 600rpm) and increased to 2400rpm in less than one minute. The F16 formulation was ground at 2400rpm. With pump setting 4, the circulation rate of the F16 formulation was gradually increased while maintaining a pressure of 10 or less.

[0101] Samples were collected at the points shown in the table below, and the particle size distribution (PSD) was measured. [Table 47]

[0102] The F16 formulation was ground until the particle size was less than 400 nm. The ball-milled sample was collected in a glass bottle. The final weight was 253.804 g and the volume was 145.979 g. The required amount of trehalose was calculated and added by weight. The mixture was stirred with an overhead mixer. The pH was checked and adjusted to 7.0-7.4 with 1N NaOH or HCl as needed.

[0103] Filling process The bulk suspension was agitated with a propeller at a speed of 600 rpm. Using a repeater pump, the bulk product was placed into 10 mL vials at a filling setting of 5.5 mL, for a total of approximately 19 units. Each vial was sealed and crimped, and the formulations were stored at 2–8°C.

[0104] test Appearance, pH, osmolality, PSD, and HPLC analysis / impurities, as well as homogeneity, were tested and recorded in the table below (multiple units were tested using 2 mL packed samples). [Table 48] [Table 49]

[0105] Example 12. Filling a syringe with F16 and testing the injection force. Objective: To conduct an injection force test on F16. [Table 50]

[0106] procedure Two 5mL syringes fitted with needles of various gauges were labeled, including the formulation code, lot number, syringe size, and needle information. Each formulation was thoroughly mixed, and 5mL of the formulation was drawn into each syringe and then connected to a needle. The needle size was recorded.

[0107] Each sample was measured using a force meter immediately after filling. For the measurement, the filled syringe was placed in the force meter, and the force meter was started with the following parameters: syringe inner diameter (ID) (10.39 mm for 5 mL), corresponding sample volume, and rate = 5 mL / min.

[0108] The injected sample was collected in a 5 mL glass vial. To test the syringe force of the formulation, the above procedure was repeated with different needle sizes. result [Table 51] Example 13. DP process for manufacturing M2CAB pharmaceutical product F16 formulation [Table 52] [Table 53]

[0109] Preparation of pharmaceutical products Approximately 14g of Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) and 14g of PEG-3350 polymer were added to a glass bottle. 143g of water was added to a glass vial.

[0110] The solution was slowly mixed at 600 rpm using a magnetic stirring bar to completely dissolve all components (for approximately 15 minutes). The stirring process was stopped once a clear solution was obtained.

[0111] The solution was slowly mixed again at 600 rpm under ice-cooled conditions using a propeller stirrer. 10 g of M2CAB powder was added to the solution. The mixer was reinserted and mixing was resumed at 600 rpm for 2 minutes to form a uniform, fluid suspension.

[0112] The above process was repeated, and the added weight, mixing speed, and time were recorded in the table below. [Table 54]

[0113] The solution was slowly mixed at 600 rpm under ice-cooled conditions using a propeller agitator to completely and uniformly disperse the M2CAB (12-24 hours). High shear process [Table 55]

[0114] Ball milling process: Using a supply funnel, 140-150 mL of milling beads (0.4 mm zirconium oxide beads) were added to the mill's grinding chamber. The grinding chamber was closed, and the mill was moved to the horizontal operating position. The F16 formulation was added to the mill's recovery container, and the overhead stirrer was started. The cooling water cock was opened, and the product pump was started at the minimum flow rate.

[0115] As soon as the product flowed out of the outlet into the recovery container, the mill was started at the minimum speed (10 Hz or 600 rpm) and increased to 2400 rpm in less than one minute. The F16 formulation was ground at 2400 rpm. With pump setting 4, the circulation rate of the F16 formulation was gradually increased while maintaining a pressure of 10 or less. Samples were taken at the points shown in the table below, and the PSD was measured. [Table 56]

[0116] Filling process The bulk suspension was continuously stirred or mixed, and 6 mL of the bulk product was added to approximately 30–36 vials using a manual / repeater pump. Each vial was crimped and stored at 2–8°C.

[0117] test Appearance, pH, osmolality, particle size distribution (PSD), HPLC analysis / impurities, and uniformity were tested (multiple units were tested using 6 mL filled samples). Filled vials were gamma sterilized. result [Table 57] Example 14: Before and after gamma ray irradiation of F16 The F16 formulation was compared before and after gamma ray irradiation. The target gamma ray dose was 25 kGy, the actual dose delivered was 27.9 kGy to 28.5 kGy, and the total exposure time was 581 minutes. result [Table 58]

[0118] Figure 1 shows the histogram of the particle size distribution (PSD) of F16 after gamma-ray irradiation.

[0119] Example 15. Stability of F16 at 40°C The stability of the F16 formulation was measured over 41 days under accelerated conditions (40°C). result [Table 59]

[0120] Example 16: Example of manufacturing procedure for M2CAB formulation F16 This is the preparation procedure for formulation F16. Add Tween® 20 (polyoxyethylene (20) sorbitan monolaurate) to the first container. Transfer PEG3350 to the container using a sterile scoop and record the result. Then add water for injection (WFI) to the container. Next, place a stirring bar in the first container and stir at approximately 600-800 rpm for about 10 minutes to obtain a visually clear solution. Then remove the stirring bar. Place the container in an ice bath. Using an overhead mixer, slowly mix the solution at 500-700 rpm. Transfer the total weight of M2CAB to the first container in stages, approximately 10-20% of the total weight at each stage, stirring before adding M2CAB each time to ensure a well-dispersed suspension of the sample. Continue mixing in the first container with an overhead mixer at 500-700 rpm for about 1-2 hours to obtain a homogeneous suspension. Record the rpm, temperature, and completion time. The container is kept in an ice bath, and the suspension inside the container is mixed using a Silverson high-shear mixer at 8000±500 rpm for approximately 15-30 minutes to further disperse the formulation.

[0121] The first cycle of ball milling is initiated. The procedure is as follows: a. Cool the ball mill system to 5°C. b. Insert the overhead mixer into the first container and agitate the mixture at 400±40 rpm to prevent sedimentation of the suspension. c. If necessary, scrape the bottom of the first container with a spatula to resuspend all large particles. d. Insert the ball mill inlet tube into the first container and the outlet tube into the second container. e. Start the peristaltic pump at minimum flow rate and allow the suspension to flow into the grinding chamber. f. Start the ball mill rotor at minimum speed (10 Hz or 600±60 rpm) and increase the speed to 2400±240 rpm within 2 minutes. g. Gradually increase the pump flow rate so that the pressure in the grinding chamber is less than 15 PSI. h. Once all the suspension has passed through the grinding chamber, stop the pump and take approximately 0.2 mL of sample with a sterile pipette. j. Measure the particle size distribution of the collected sample. Continue the process until the average particle size of the pulverized material is less than 400 nm.

[0122] To reduce particle size, continue the ball mill cycle. The procedure is as follows: a. Gently shake the second container. Then pour the solution into the first container. Return the outlet tube to the second container. b. Activate the peristaltic pump and gradually increase the flow rate until the pressure in the grinding chamber is less than 15 PSI. c. After each cycle, take a 1 mL sample using a sterile pipette for particle size distribution (PSD) measurement. f. Repeat the procedure until the average particle size of the grinding material is less than 400 nm.

[0123] In the subsequent steps, maintain stirring of the nano-suspension in the second container while minimizing foaming and generating a vortex using an overhead mixer. Transfer the trehalose to a weighing dish using a sterile scoop and then transfer it to the second container. Transfer the sodium dihydrogen phosphate monohydrate to a weighing dish using a sterile scoop and then transfer it to the second container. Transfer the disodium hydrogen phosphate heptahydrate to a weighing dish using a sterile scoop and then transfer it to the second container. If necessary, add 1N NaOH / HCl to adjust the pH to 7.0±0.2. The acceptable pH range is 6.8~7.2. Stop stirring the nano-suspension in the second container and record the end time. Insert the overhead mixer into the nano-suspension and maintain stirring at 600~800 rpm. Record the stirring speed and start time. Adjust the stirring speed to the extent that a vortex is generated without excessive foaming. Maintain stirring of the suspension with the overhead mixer. Then, fill the final product into 10 mL Type 1 glass vials using a repeater pump. After filling the vials, immediately seal each vial with an 18mm sterile stopper in a biosafety cabinet. Crimp each vial with a 20mm cap. Place the vials in a secondary carton. Store the carton at 2-8°C and record the storage time.

[0124] Example 17. Crystalline form of M2CAB in the composition The crystalline forms of M2CAB in the compositions of this disclosure are shown. The M2CAB present in the compositions (e.g., formulations F13-F16) are characterized by a mixture of crystalline forms of M2CAB (crystalline form 1+4) and have the powder X-ray diffraction patterns shown in Figure 2. A list of exemplary peaks is shown in Table 23 below.

[0125] XRPD patterns were acquired using a T2 high-throughput XRPD setup. The plates were mounted on a Bruker General Area Detector Diffraction System (GADDS) equipped with a VANTEC-500 gas area detector with intensity and geometric variation correction. Measurement accuracy (peak position) was calibrated using the NIST SRM1976 standard (corundum).

[0126] Data acquisition was performed at room temperature using monochromatic Cu Kα radiation in the 2θ region of 1.5° to 41.5°, which is the most characteristic part of the XRPD pattern. Diffraction patterns from each well were collected in two 2θ ranges (1st frame: 1.5° ≤ 2θ ≤ 21.5°, 2nd frame: 19.5° ≤ 2θ ≤ 41.5°), with an exposure time of 90 seconds for each frame. Background subtraction and curve smoothing were not applied to the XRPD patterns. [Table 60-1] [Table 60-2]

Claims

1. (i) 【Chemistry 1】 The crystalline form of the compound represented by; and (ii) Freezing Protective substances; A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the cryoprotective substance is a sugar.

3. The pharmaceutical composition according to claim 2, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cryoprotective substance is trehalose.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cryoprotective substance is contained in an amount of about 3% to about 10% by weight, based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, comprising about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

7. A pharmaceutical composition according to any one of claims 1 to 6, comprising a surfactant.

8. The pharmaceutical composition according to claim 7, wherein the surfactant is contained in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

9. A pharmaceutical composition according to any one of claims 1 to 8, comprising polyethylene glycol.

10. The pharmaceutical composition according to claim 9, wherein the polyethylene glycol is contained in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

11. A pharmaceutical composition according to any one of claims 1 to 10, comprising a phosphate buffer.

12. A pharmaceutical composition according to any one of claims 1 to 11, wherein the pH is approximately 6.0 to approximately 7.

5.

13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the pH is approximately 7.

0.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the crystalline form is contained in an amount of about 25% to about 45% by weight, based on the total weight of the pharmaceutical composition.

15. The pharmaceutical composition according to any one of claims 1 to 14, comprising a plurality of nanoparticles containing the crystalline form of the compound.

16. A pharmaceutical composition according to any one of claims 7 to 15, comprising a plurality of nanoparticles containing the crystalline form of the compound and the surfactant.

17. A pharmaceutical composition according to any one of claims 7 to 16, comprising a plurality of nanoparticles containing the crystalline form of the compound and the polyethylene glycol.

18. A pharmaceutical composition according to any one of claims 7 to 17, comprising a plurality of nanoparticles containing the crystalline form of the compound, the surfactant, and the polyethylene glycol.

19. The pharmaceutical composition according to any one of claims 15 to 18, wherein the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm.

20. The pharmaceutical composition according to any one of claims 15 to 19, wherein the z-average particle size of the plurality of nanoparticles is 200 nm to 900 nm.

21. The pharmaceutical composition according to any one of claims 15 to 20, wherein the z-average particle size of the plurality of nanoparticles is 275 nm to 425 nm.

22. The pharmaceutical composition according to any one of claims 15 to 21, wherein the polydispersity index of the plurality of nanoparticles is about 0.15 to about 0.

4.

23. The pharmaceutical composition according to any one of claims 15 to 22, wherein the polydispersity index of the plurality of nanoparticles is about 0.25 to about 0.

35.

24. (i) 【Chemistry 2】 A mixture of crystalline forms of compounds represented by; and (ii) Freezing Protective substances; A pharmaceutical composition containing the following:

25. The pharmaceutical composition according to claim 24, wherein the cryoprotective substance is a sugar.

26. The pharmaceutical composition according to claim 24 or 25, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.

27. The pharmaceutical composition according to any one of claims 24 to 26, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol.

28. The pharmaceutical composition according to any one of claims 24 to 27, wherein the cryoprotective substance is trehalose.

29. The pharmaceutical composition according to any one of claims 24 to 28, wherein the cryoprotective substance is contained in an amount of about 3% to about 10% by weight, based on the total weight of the pharmaceutical composition.

30. The pharmaceutical composition according to any one of claims 24 to 29, comprising about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

31. A pharmaceutical composition according to any one of claims 24 to 30, comprising a surfactant.

32. The pharmaceutical composition according to claim 31, wherein the surfactant is contained in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

33. A pharmaceutical composition according to any one of claims 24 to 32, comprising polyethylene glycol.

34. The pharmaceutical composition according to claim 33, wherein the polyethylene glycol is contained in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

35. A pharmaceutical composition according to any one of claims 24 to 34, comprising a phosphate buffer.

36. A pharmaceutical composition according to any one of claims 24 to 35, wherein the pH is approximately 6.0 to approximately 7.

5.

37. A pharmaceutical composition according to any one of claims 24 to 36, wherein the pH is approximately 7.

0.

38. The pharmaceutical composition according to any one of claims 24 to 37, wherein the mixture of crystalline forms of the compound has two crystalline forms.

39. The pharmaceutical composition according to any one of claims 24 to 38, wherein one of the two crystalline forms is present in the mixture in an amount of about 10% to about 30% by weight, and the other crystalline form is present in the mixture in an amount of about 70% to about 90% by weight.

40. The pharmaceutical composition according to any one of claims 24 to 39, wherein the mixture of crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°.

41. The pharmaceutical composition according to any one of claims 24 to 40, wherein the mixture of crystalline forms of the compound is characterized by having characteristic peaks in a powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°.

42. The pharmaceutical composition according to any one of claims 24 to 41, wherein the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is about 7.0°, about 7.4°, about 17.8°, about 21.6°, and about 23.6°.

43. The pharmaceutical composition according to any one of claims 24 to 42, wherein the mixture of crystalline forms of the compound is characterized by having characteristic peaks in the powder X-ray diffraction pattern where 2θ is approximately 7.0°, approximately 7.4°, approximately 14.0°, approximately 16.3°, approximately 16.8°, approximately 17.8°, approximately 21.6°, approximately 23.6°, approximately 24.3°, and approximately 26.1°.

44. The pharmaceutical composition according to any one of claims 24 to 43, wherein a mixture of crystalline forms of the compound is substantially characterized by the XRPD pattern shown in Figure 2.

45. The pharmaceutical composition according to any one of claims 24 to 44, comprising about 25% to about 45% by weight of a mixture of the crystalline form of the compound, based on the total weight of the pharmaceutical composition.

46. The pharmaceutical composition according to any one of claims 24 to 45, comprising a plurality of nanoparticles containing a mixture of crystalline forms of the compound.

47. A pharmaceutical composition according to any one of claims 31 to 46, comprising a plurality of nanoparticles containing a mixture of the crystalline form of the compound and the surfactant.

48. The pharmaceutical composition according to any one of claims 31 to 47, comprising a plurality of nanoparticles containing a mixture of the crystalline form of the compound and the polyethylene glycol.

49. A pharmaceutical composition according to any one of claims 31 to 48, comprising a mixture of crystalline forms of the compound, the surfactant, and a plurality of nanoparticles containing polyethylene glycol.

50. The pharmaceutical composition according to any one of claims 46 to 49, wherein the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm.

51. The pharmaceutical composition according to any one of claims 46 to 50, wherein the Z-average particle size of the plurality of nanoparticles is 200 nm to 900 nm.

52. The pharmaceutical composition according to any one of claims 46 to 51, wherein the z-average particle size of the plurality of nanoparticles is 275 nm to 425 nm.

53. The pharmaceutical composition according to any one of claims 46 to 52, wherein the polydispersity index of the plurality of nanoparticles is about 0.15 to about 0.

4.

54. The pharmaceutical composition according to any one of claims 46 to 53, wherein the polydispersity index of the plurality of nanoparticles is about 0.25 to about 0.

35.

55. A method for treating, suppressing, and / or preventing a viral infection in a patient requiring treatment, suppression, and / or prevention of a viral infection, comprising administering an effective amount of a pharmaceutical composition according to any one of claims 1 to 54 to the patient.

56. The method according to claim 55, wherein the viral infection is a retroviral infection.

57. The method according to claim 55 or 56, wherein the viral infection is HIV infection.

58. The method according to any one of claims 55 to 57, comprising intramuscular administration of the pharmaceutical composition to the individual.

59. (i) 【Transformation 3】 The crystalline form of the compound represented by; and (ii) Freezing Protective substances; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing the crystalline form of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods that include...

60. The method according to claim 59, wherein the suspension comprises one or more excipients selected from the group consisting of polyethylene glycol, surfactants, and combinations thereof.

61. The method according to claim 59 or 60, wherein the cryoprotective substance is a sugar.

62. The method according to any one of claims 59 to 61, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.

63. The method according to any one of claims 59 to 62, wherein the cryoprotective substance is trehalose.

64. The method according to any one of claims 59 to 63, wherein the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

65. The method according to any one of claims 59 to 64, wherein the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

66. The method according to any one of claims 51 to 65, wherein the pharmaceutical composition comprises a surfactant.

67. The method according to any one of claims 66, wherein the pharmaceutical composition contains the surfactant in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

68. The method according to any one of claims 51 to 59, wherein the pharmaceutical composition comprises polyethylene glycol.

69. The method according to claim 68, wherein the pharmaceutical composition contains approximately 3% to 5% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition.

70. The method according to any one of claims 59 to 69, wherein the ball-milled mixture and the cryoprotective substance are mixed with a phosphate buffer.

71. The method according to any one of claims 59 to 70, wherein the pH of the composition is about 6.0 to about 7.

5.

72. The method according to any one of claims 59 to 71, wherein the pH of the composition is about 7.

0.

73. The method according to any one of claims 59 to 72, wherein the pharmaceutical composition contains about 25% to about 45% by weight of the crystalline form, based on the total weight of the pharmaceutical composition.

74. The method according to any one of claims 59 to 73, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing the crystalline form of the compound.

75. The method according to any one of claims 66 to 74, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing the crystalline form of the compound and the surfactant.

76. The method according to any one of claims 66 to 75, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing the crystalline form of the compound and the polyethylene glycol.

77. The pharmaceutical composition according to any one of claims 66 to 76, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing the crystalline form of the compound, the surfactant, and the polyethylene glycol.

78. The method according to any one of claims 74 to 77, wherein the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm.

79. The method according to any one of claims 74 to 78, wherein the z-average particle size of the plurality of nanoparticles is 200 nm to 900 nm.

80. The method according to any one of claims 74 to 79, wherein the z-average particle size of the plurality of nanoparticles is 275 nm to 425 nm.

81. The method according to any one of claims 74 to 80, wherein the polydispersity index of the plurality of nanoparticles is about 0.15 to about 0.

4.

82. The method according to any one of claims 74 to 81, wherein the polydispersity index of the plurality of nanoparticles in the pharmaceutical composition is about 0.25 to about 0.

35.

83. (i) 【Chemistry 4】 A mixture of crystalline forms of compounds represented by; and (ii) Freezing Protective substances; A method for preparing a pharmaceutical composition containing, (a) To provide a suspension containing a mixture of the crystalline forms of the compound; (b) Mixing the suspension using a ball mill rotor to prepare a ball-milled mixture; and (c) Mixing the ball-milled mixture with the cryoprotective substance to prepare the pharmaceutical composition; Methods that include...

84. The method according to claim 83, wherein the cryoprotective substance is a sugar.

85. The method according to claim 83 or 84, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, mannitol, and any combination thereof.

86. The method according to any one of claims 83 to 85, wherein the cryoprotective substance is selected from the group consisting of trehalose, sucrose, and mannitol.

87. The pharmaceutical composition according to any one of claims 83 to 86, wherein the cryoprotective substance is trehalose.

88. The method according to any one of claims 83 to 87, wherein the pharmaceutical composition contains about 3% to about 10% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

89. The method according to any one of claims 83 to 88, wherein the pharmaceutical composition contains about 5% by weight of the cryoprotective substance based on the total weight of the pharmaceutical composition.

90. The method according to any one of claims 83 to 89, wherein the pharmaceutical composition comprises a surfactant.

91. The method according to claim 90, wherein the pharmaceutical composition contains the surfactant in an amount of about 3% to about 5% by weight, based on the total weight of the pharmaceutical composition.

92. The method according to any one of claims 83 to 91, wherein the pharmaceutical composition comprises polyethylene glycol.

93. The method according to claim 92, wherein the pharmaceutical composition contains approximately 3% to 5% by weight of polyethylene glycol based on the total weight of the pharmaceutical composition.

94. The method according to any one of claims 83 to 93, wherein the pharmaceutical composition comprises a phosphate buffer.

95. The method according to any one of claims 83 to 94, wherein the pH of the composition is about 6.0 to about 7.

5.

96. The method according to any one of claims 83 to 95, wherein the pH of the composition is about 7.

0.

97. The method according to any one of claims 83 to 96, wherein the mixture of crystalline forms of the compound has two crystalline forms.

98. The method according to any one of claims 83 to 97, wherein one of the two crystalline forms is present in the mixture in an amount of about 10% to about 30% by weight, and the other crystalline form is present in the mixture in an amount of about 70% to about 90% by weight.

99. The method according to any one of claims 83 to 98, wherein a mixture of the crystalline forms of the compound is characterized by having a characteristic peak in the powder X-ray diffraction pattern where 2θ is about 21.6°.

100. The method according to any one of claims 83 to 99, wherein a mixture of crystalline forms of the compound is characterized by having characteristic peaks in a powder X-ray diffraction pattern where 2θ is about 7.0°, about 17.8°, and about 21.6°.

101. The method according to any one of claims 83 to 100, wherein a mixture of crystalline forms of the compound is characterized by having characteristic peaks in a powder X-ray diffraction pattern where 2θ is about 7.0°, about 7.4°, about 17.8°, about 21.6°, and about 23.6°.

102. The method according to any one of claims 83 to 101, wherein a mixture of the crystalline forms of the compound is characterized by having characteristic peaks in a powder X-ray diffraction pattern where 2θ is about 7.0°, about 7.4°, about 14.0°, about 16.3°, about 16.8°, about 17.8°, about 21.6°, about 23.6°, about 24.3°, and about 26.1°.

103. The method according to any one of claims 83 to 102, wherein a mixture of crystalline forms of the compound is substantially characterized by the XRPD pattern shown in Figure 2.

104. The method according to any one of claims 83 to 103, wherein the mixture of the crystalline form of the compound is contained in an amount of about 25% to about 45% by weight, based on the total weight of the pharmaceutical composition.

105. The method according to any one of claims 83 to 104, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing a mixture of crystalline forms of the compound.

106. The method according to any one of claims 83 to 105, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing a mixture of the crystalline form of the compound and the surfactant.

107. The method according to any one of claims 90 to 106, wherein the pharmaceutical composition comprises a plurality of nanoparticles containing a mixture of the crystalline form of the compound and polyethylene glycol.

108. The method according to any one of claims 90 to 107, wherein the pharmaceutical composition comprises a plurality of nanoparticles comprising a mixture of crystalline forms of the compound, the surfactant, and the polyethylene glycol.

109. The method according to any one of claims 90 to 108, wherein the particle size distribution (D10) of the plurality of nanoparticles is about 250 nm to about 650 nm, the particle size distribution (D50) is about 350 nm to about 900 nm, and the particle size distribution (D90) is about 600 nm to about 1300 nm.

110. The method according to any one of claims 105 to 109, wherein the z-average particle size of the plurality of nanoparticles is 200 nm to 900 nm.

111. The method according to any one of claims 105 to 110, wherein the z-average particle size of the plurality of nanoparticles is 275 nm to 425 nm.

112. The method according to any one of claims 105 to 111, wherein the polydispersity index of the plurality of nanoparticles is about 0.15 to about 0.

4.

113. The method according to any one of claims 105 to 112, wherein the polydispersity index of the plurality of nanoparticles is about 0.25 to about 0.35.

Images