Difelikefalin oral pharmaceutical composition

Abstract

A difelikefalin oral pharmaceutical composition. The pharmaceutical composition comprises difelikefalin, a delivery agent, an auxiliary agent, and optionally a pharmaceutically acceptable non-active ingredient, and may have good bioavailability and reduced variability in drug effectiveness.

Description

An oral pharmaceutical composition of difaxian Technical Field

[0001] The present application relates to the field of medical technology, and in particular to an oral pharmaceutical composition of difacoum. Background Art

[0002] Diphenhydramine is an opioid receptor agonist. Currently marketed products are injectable medications, primarily administered by physicians, which is extremely inconvenient for patients. Oral formulations, on the other hand, can be self-administered by patients without directly damaging the skin and mucous membranes, alleviating pain and improving patient compliance. However, as a polypeptide, diphenhydramine is easily degraded by proteolytic enzymes in the digestive tract and does not readily penetrate the gastrointestinal mucosa. Therefore, if diphenhydramine is formulated for oral administration, a delivery agent would be required to facilitate its absorption across the gastrointestinal mucosa.

[0003] However, the absorption of oral difacillin formulations containing delivery agents is highly dependent on the difacillin, the delivery agent, and the formulation, resulting in high variability in the effective concentration or bioavailability of difacillin in vivo. Therefore, there is a need for an oral difacillin formulation that can reduce the variability in the effective concentration or bioavailability of difacillin in vivo and improve its bioavailability. Summary of the Invention

[0004] The embodiment of the present application provides an oral pharmaceutical composition of difacillin, comprising difacillin, a delivery agent, an adjuvant, and optional pharmaceutically acceptable inactive ingredients.

[0005] In some embodiments, the oral pharmaceutical composition of diphenhydramine includes diphenhydramine, wherein the mass content of diphenhydramine is about 0.05 wt% to about 5 wt% based on the total mass of the pharmaceutical composition; a delivery agent, wherein the mass content of the delivery agent is about 15 wt% to about 75 wt% based on the total mass of the pharmaceutical composition; an auxiliary agent, wherein the mass content of the auxiliary agent is about 5 wt% to about 70 wt% based on the total mass of the pharmaceutical composition; and an optional pharmaceutically acceptable inactive ingredient, wherein the mass content of the optional pharmaceutically acceptable inactive ingredient is about 20 wt% to about 60 wt% based on the total mass of the pharmaceutical composition.

[0006] In some embodiments, the delivery agent can be selected from one or more of N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC), N-[6-(2-hydroxybenzoyl)amino]hexanoic acid (NAH), N-[10-(2-hydroxybenzoyl)amino]decanoic acid (NAD), N-[8-(5-chlorosalicyloyl)amino]octanoic acid (5-CNAC), N-[8-(2-hydroxy-4-methoxybenzoyl)amino]octanoic acid (4-MOAC), N-[4-(2-hydroxy-4-chlorobenzoyl)amino]butyric acid (4-CNAB) and pharmaceutically acceptable salts thereof.

[0007] In some embodiments, the delivery agent can be further selected from one or more of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), potassium N-[8-(2-hydroxybenzoyl)amino]caprylate and / or calcium N-[8-(2-hydroxybenzoyl)amino]caprylate.

[0008] In some embodiments, the delivery agent may preferably be SNAC.

[0009] In some embodiments, the mass ratio of the delivery agent to the dimethoate can be from about 5:1 to about 500:1.

[0010] In some embodiments, the adjuvant may include one or more of the following compounds: sodium phosphate, disodium hydrogen phosphate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, hydrotalcite, and other pharmaceutically acceptable salts of the same acid radical.

[0011] In some embodiments, the mass ratio of the delivery agent to the auxiliary agent can be about 0.5:1 to about 10:1.

[0012] In some embodiments, the pharmaceutical composition may include one type of particle. Alternatively, in some embodiments, the pharmaceutical composition may be made of two or more particles having different compositions.

[0013] In some embodiments, the pharmaceutical composition may include a first particle and a second particle, wherein the first particle may include difacoum and an optional pharmaceutically acceptable inactive ingredient, and the second particle may include a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient.

[0014] In some embodiments, the present application provides an oral pharmaceutical composition of difacoum, comprising an outer layer and a core tablet, wherein the outer layer wraps the core tablet, wherein the core tablet comprises difacoum and a delivery agent; and the outer layer comprises a delivery agent.

[0015] In some embodiments, the tablet core may further include an adjuvant. In some embodiments, the tablet core may further include a diluent. In some embodiments, the tablet core may further include one or more of a lubricant, a disintegrant, and a binder. In some embodiments, the tablet core includes difacialis, a delivery agent, and an adjuvant, as well as one or more of a diluent, a lubricant, a disintegrant, and a binder.

[0016] In some embodiments, the outer layer may further include an adjuvant. In some embodiments, the outer layer may further include a diluent. In some embodiments, the outer layer may further include one or more of a lubricant, a disintegrant, and a binder. In some embodiments, the outer layer includes a delivery agent and one or more of the following: an adjuvant, a diluent, a lubricant, a disintegrant, and a binder.

[0017] In some embodiments, the pharmaceutical composition may include an outer layer and a core tablet, wherein the outer layer does not contain difacillin, the outer layer may include a delivery agent, an adjuvant and an optional pharmaceutically acceptable inactive ingredient, and the core tablet may include difacillin and an optional pharmaceutically acceptable inactive ingredient.

[0018] In some embodiments, the core may further include a delivery agent and / or an adjuvant. In some embodiments, the core may further include a delivery agent and an adjuvant. In some embodiments, the core may further include a lubricant.

[0019] In some embodiments, the core may further include a diluent.

[0020] In some embodiments, based on the mass of the core, the mass content of the diluent in the core is 5wt%-86wt%, 5wt%-80wt%, 5wt%-75wt%, 5wt%-70wt%, 5wt%-75wt%, 5wt%-60wt%, 15wt%-60wt%, 20wt%-60wt%, 5wt%-40wt%, 25wt%-55wt%, 10wt%-35wt%, 30wt%-50wt%, 15wt%-30wt%, 18wt%-28wt%, 35wt%-45wt%, 20wt%-25wt%, 25wt%-30wt%, 30wt%-35wt%, 35wt%-40wt%, 40wt%-45wt%, 45wt%-50wt%, 50wt%-55wt%, 55wt%-60wt%.

[0021] In some embodiments, based on the mass of the core, the mass content of the diluent in the core is 5wt%-40wt%, 10wt%-35wt%, 15wt%-30wt%, 18wt%-28wt%, 20wt%-25wt%.

[0022] In some embodiments, the tablet core may further include a disintegrant and / or a binder.

[0023] In some embodiments, based on the mass of the tablet core, the mass content of the disintegrant in the tablet core is 0.5wt%-10wt%, 1wt%-9.5wt%, 1.5wt%-9wt%, 2wt%-8.5wt%, 2.5wt%-8wt%, 3wt%-7.5wt%, 3.5wt%-7wt%, 4wt%-6.5wt%, 4.5wt%-6wt%, 5wt%-6.5wt%, 5.5wt%-7.5wt%, 6wt%-9wt%, 1.5wt%-6wt%, 2wt%-5.5wt%, 2.5wt%-5wt%, 1.5wt%-4.5wt%.

[0024] In some embodiments, the mass content of the disintegrant in the tablet core is 2wt%-10wt%, 2wt%-9.5wt%, 2wt%-9wt%, 2wt%-8.5wt%, 2wt%-8wt%, 2wt%-7.5wt%, 2wt%-7wt%, 2wt%-6.5wt%, 2wt%-6wt%, 2wt%-5.5wt%, 2wt%-5wt%, 2wt%-4.5wt%, 2wt%-4wt%, 2wt%-3.5wt%, 2wt%-3wt% or 2.5wt%-3wt%, based on the mass of the tablet core.

[0025] In some embodiments, based on the mass of the core, the mass content of the binder in the core is 0.5wt%-7.5wt%, 1wt%-7wt%, 1.5wt%-6.5wt%, 2wt%-6wt%, 2.5wt%-5.5wt%, 3wt%-5wt%, 2.5wt%-4.5wt%, 2wt%-4wt%, 1.5wt%-3.5wt%, 1wt%-3wt%, 0.5wt%-2.5wt%, 3.5wt%-5.5wt%, 4wt%-6wt%, 4.5wt%-6.5wt%, 5wt%-7wt%, 6.5wt%-7.5wt%.

[0026] In some embodiments, based on the mass of the core, the mass content of the binder in the core is 1wt%-7.5wt%, 1wt%-7wt%, 1.5wt%-6.5wt%, 1.5wt%-6wt%, 1.8wt%-5.5wt%, 1.8wt%-5wt%, 2wt%-4.5wt%, 2wt%-4wt%, 2wt%-3.5wt%, 2wt%-3wt%, 2wt%-2.5wt%, 1wt%-2.5wt%, 2.5wt%-5.5wt%, 3wt%-6wt%, 3.5wt%-6.5wt%, 4wt%-6wt%.

[0027] In some embodiments, the outer layer further comprises a diluent. In some embodiments, the outer layer further comprises a lubricant.

[0028] In some embodiments, the outer layer further comprises a disintegrant and / or a binder.

[0029] In some embodiments, the diluent is selected from any one of microcrystalline cellulose, lactose, mannitol, etc. and compound excipients containing any one or more of microcrystalline cellulose, lactose, mannitol, etc., or any combination thereof.

[0030] In some embodiments, the diluent may preferably be microcrystalline cellulose or a microcrystalline cellulose-mannitol compound excipient.

[0031] In some embodiments, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, low-substituted hydroxypropyl cellulose and sodium starch glycolate, and the binder is selected from one or more of hydroxypropyl cellulose, povidone, copovidone, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and ethyl cellulose.

[0032] In some embodiments, the disintegrant may preferably be crospovidone, and the binder may preferably be hydroxypropyl cellulose.

[0033] The present application provides an embodiment of the use of a pharmaceutical composition as described in any embodiment of the present disclosure in the preparation of a medicament for treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, or atopic dermatitis. Alternatively, the present application provides an embodiment of the present application provides a method for treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, or atopic dermatitis in a patient in need thereof, comprising: administering to the patient a therapeutically effective amount of the pharmaceutical composition as described in any embodiment of the present disclosure.

[0034] The embodiments of the present application provide a method for treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, and atopic dermatitis, which comprises orally administering the pharmaceutical composition as described in any embodiment of the present disclosure to a subject in need thereof.

[0035] The embodiments of the present application provide a pharmaceutical composition as described in any embodiment of the present disclosure for treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, and atopic dermatitis. DETAILED DESCRIPTION

[0036] In order to more clearly illustrate the technical solution of the present invention, the technical solution of the present invention will be described using embodiments below. It should be understood that the description of the embodiments is only for the purpose of facilitating the understanding of the technical solution, and is not intended to limit the present invention to the specific embodiments shown. The titles in this application are provided for convenience only and should not be construed as limiting the present invention in any way. The embodiments shown under any title may be combined with the embodiments shown under any other title. For those of ordinary skill in the art, various modifications, improvements and revisions may be made to these embodiments without paying creative work. Therefore, such modifications, improvements and revisions still fall within the spirit and scope of the exemplary embodiments of the present disclosure.

[0037] The present application provides an oral pharmaceutical composition of difelikefalin. In some embodiments, the pharmaceutical preparation (i.e., oral pharmaceutical composition) may include difelikefalin, a delivery agent and an adjuvant. In some embodiments, the pharmaceutical preparation may include difelikefalin, a delivery agent, an adjuvant and optional pharmaceutically acceptable inactive ingredients. In some embodiments, the oral pharmaceutical composition may include difelikefalin, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the oral pharmaceutical composition may include difelikefalin, a delivery agent, an adjuvant, a disintegrant and at least one of a binder, a diluent and a lubricant. In some embodiments, the oral pharmaceutical composition may include difelikefalin, a delivery agent, an adjuvant, a disintegrant, a diluent and a lubricant. In some embodiments, the oral pharmaceutical composition may include difelikefalin, a delivery agent, an adjuvant, a disintegrant, a diluent and a lubricant.

[0038] The term "diffusion" as used herein refers to D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid]-OH, also known as CR845. Diffusions useful in the present invention may be used or prepared in alternative forms. For example, difusions may be used or prepared as pharmaceutically acceptable salts. Typically, such salts improve separation and handling properties. For example, depending on the reagents and reaction conditions, the difusions described herein may be in the form of pharmaceutically acceptable acid salts, such as sulfates, citrates, acetates, oxalates, hydrochlorides, etc. , hydrobromide, nitrate, phosphate, lactate, citrate, tartrate, fumarate are used or prepared. Isostructural crystalline forms, hydrates, solvates and acid salt hydrates are also expected to be within the scope of this application. The drug target of CR845 is a kappa opioid receptor agonist. The pharmaceutical preparation of the present application can be used to treat or prevent conditions that can be alleviated by activating kappa opioid receptors, including conditions such as pain, inflammation, itching, hyponatremia, hypokalemia, congestive heart failure, cirrhosis, nephrotic syndrome, hypertension, edema, intestinal obstruction, cough and glaucoma.

[0039] In some embodiments, the pharmaceutical composition of the present application can be used to treat or prevent chronic kidney disease-related pruritus, chronic liver disease-related pruritus, and atopic dermatitis.

[0040] In some embodiments, the pharmaceutical composition of the present application can be used to prepare drugs for treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, and atopic dermatitis.

[0041] In some embodiments, the method of treating and / or preventing chronic kidney disease-related pruritus, chronic liver disease-related pruritus, and atopic dermatitis of the present application may comprise orally administering the pharmaceutical composition of the present application to a subject in need thereof. The term "treatment" in relation to a given disease or condition includes, but is not limited to, inhibiting the disease or condition, such as preventing the development of the disease or condition; alleviating the disease or condition, such as causing regression of the disease or condition; or alleviating the condition caused by the disease or condition, such as alleviating, preventing or treating the symptoms of the disease or condition. The term "prevention" in relation to a given disease or condition refers to preventing the onset of disease development if it has not already occurred, preventing the occurrence of the disease or condition in a subject who may be susceptible to the disease or condition but has not yet been diagnosed with the disease or condition, and / or preventing further disease / condition development if it already exists.

[0042] In some embodiments, the pharmaceutical compositions of the present application may be co-administered with one or more other therapeutic compounds or adjuvants. The one or more other therapeutic compounds or adjuvants include, but are not limited to, other opioids, cannabinoids, antidepressants, anticonvulsants, tranquilizers, antihistamines, acetaminophen, corticosteroids, ion channel blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), and diuretics, many of which have synergistic effects with the pharmaceutical compositions of the present application.

[0043] In some embodiments, the pharmaceutical composition may be in the form of tablets, pills, capsules, granules, oral solutions or suspensions, etc. In some embodiments, the pharmaceutical composition may preferably be in the form of tablets.

[0044] In some embodiments, the unit mass of the pharmaceutical composition may be about 50 mg to about 2000 mg. In some embodiments, the unit mass of the pharmaceutical composition may preferably be about 100 mg to about 600 mg.

[0045] In some embodiments, difacillin is present in the unit dosage form of the pharmaceutical composition of the present application in an amount of about 0.05 mg to about 30 mg. In some embodiments, difacillin is preferably present in the unit dosage form of the pharmaceutical composition of the present application in an amount of about 0.1 mg to about 10 mg.

[0046] In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of dimethoate can be about 0.01 wt% to about 10 wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of dimethoate can be about 0.01 wt% to about 10 wt%, about 0.01 wt% to about 9 wt%, about 0.01 wt% to about 8 wt%, about 0.01 wt% to about 7 wt%, about 0.01 wt% to about 6 wt%, about 0.01 wt% to about 5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 1 wt%, about 0.05 wt% to about 10 wt%, about 0.08 wt% to about 10 wt%, about 0.1 wt% to about 10 wt%, about 0.2 wt% to about 10 wt%, about 0.5 wt% to about 1 % to about 10 wt%, about 1 wt% to about 10 wt%, about 2 wt% to about 10 wt%, about 3 wt% to about 10 wt%, about 4 wt% to about 10 wt%, about 5 wt% to about 10 wt%, about 6 wt% to about 10 wt%, about 7 wt% to about 10 wt%, about 8 wt% to about 10 wt%, about 9 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 2 wt% to about 7 wt%, about 2 wt% to about 6 wt%, about 2 wt% to about 5 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 3 wt%, about 3 wt% to about 6 wt%, about 3.0 wt% to about 5 wt%, about 3 wt% to about 4 wt%, or about 4 wt% to about 5 wt%. In some embodiments, the mass content of dimethoate can be about 0.1 wt% to about 10 wt% based on the total mass of the pharmaceutical composition.In some embodiments, based on the total weight of the pharmaceutical composition, the mass content of dimethoate can be about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 9 wt%, about 0.1 wt% to about 8 wt%, about 0.1 wt% to about 7 wt%, about 0.1 wt% to about 6 wt%, about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 1 wt%, about 0.2 wt% to about 10 wt%, about 0.3 wt% to about 10 wt%, about 0.4 wt% to about 10 wt%, about 0.5 wt% to about 10 wt%, about 0.6 wt% to about 10 wt%, about 0.7 wt% to about 10 wt%, about 0.8 wt% to about % to about 10wt%, about 1wt% to about 10wt%, about 2wt% to about 10wt%, about 3wt% to about 10wt%, about 4wt% to about 10wt%, about 5wt% to about 10wt%, about 6wt% to about 10wt%, about 7wt% to about 10wt%, about 8wt% to about 10wt%, about 9wt% to about 10wt%, about 1wt% to about 9wt%, about 1wt% to about 8wt%, about 2wt% to about 7wt%, about 2wt% to about 6wt%, about 2wt% to about 5wt%, about 2wt% to about 4wt%, about 2wt% to about 3wt%, about 3wt% to about 6wt%, about 3.0wt% to about 5wt%, about 3wt% to about 4wt% or about 4wt% to about 5wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of dimethoate can be about 0.05 wt% to about 5 wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of dimethoate can be about 0.05 wt% to about 5 wt%, about 0.05 wt% to about 4 wt%, about 0.05 wt% to about 3 wt%, about 0.05 wt% to about 2 wt%, about 0.05 wt% to about 1 wt%, about 0.06 wt% to about 5 wt%, about 0.07 wt% to about 5 wt%, about 0.08 wt% to about 5 wt%, about 0. % to about 4.5 wt%, about 1.0 wt% to about 4 wt%, about 1.5 wt% to about 3.5 wt%, or about 2.0 wt% to about 3 wt%. In some embodiments, the mass content of dimethoate based on the total mass of the pharmaceutical composition may be about 0.1 wt% to about 2 wt%. In some embodiments, the mass content of dimethoate based on the total mass of the pharmaceutical composition may be about 0.1 wt% to about 2 wt%. In some embodiments, the mass content of dimethoate based on the total mass of the pharmaceutical composition may be about 0.1 wt% to about 2.5 wt%.In some embodiments, based on the total weight of the pharmaceutical composition, the mass content of dimethoate can be about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 2.2 wt%, about 0.1 wt% to about 2 wt%, about 0.1 wt% to about 1.9 wt%, about 0.1 wt% to about 1.8 wt%, about 0.1 wt% to about 1.7 wt%, about 0.1 wt% to about 1.6 wt%, about 0.1 wt% to about 1.5 wt%, or about 0.1 wt% to about 1.9 wt%. t%, about 0.2wt% to about 1.5wt%, about 0.3wt% to about 1.5wt%, about 0.4wt% to about 1.5wt%, about 0.5wt% to about 1.5wt%, about 0.5wt% to about 1.4wt%, about 0.5wt% to about 1.3wt%, about 0.5wt% to about 1.2wt%, about 0.5wt% to about 1.1wt%, about 0.5wt% to about 1.0wt%, about 0.5wt% to about 0.9wt%, about 0.5wt% to about 0.8wt%, about 0.5wt% to about 0.7wt%, about 0.5wt% to about 0.6wt%, about 0.6wt% to about 1.0wt%, about 0.6wt% to about 0.9wt%, about 0.6wt% to about 0.8wt%, about 0.6wt% to about 0.7wt%, about 0.7wt% to about 1.0wt%, about 0.7wt% to about 0.9wt%, about 0.7 % to about 0.8 wt%, about 0.8 wt% to about 1.0 wt%, about 0.8 wt% to about 0.9 wt%, or about 0.9 wt% to about 1.0 wt%, about 1.0 wt% to about 2.5 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 2.2 wt%, about 1.8 wt% to about 2.5 wt%, about 1.8 wt% to about 2.2 wt%, about 2.0 wt% to about 2.5 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the mass content of difayanide can be about 0.1 wt% to about 1 wt%, about 0.2 wt% to about 0.9 wt%, or about 0.25 wt% to about 2.5 wt%. In some embodiments, the mass content of difacaline in the core tablet can be about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 1 wt%, about 0.2 wt% to about 0.9 wt%, or about 0.2 wt% to about 2.5 wt%, based on the total mass of the pharmaceutical composition.

[0047] The "mass of difacillin" mentioned herein refers to the mass of difacillin free base when the substance providing difacillin to the composition is a pharmaceutically acceptable salt of difacillin.

[0048] In some embodiments, the delivery agent can be selected from one or more of N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC), N-[6-(2-hydroxybenzoyl)amino]hexanoic acid (NAH), N-[10-(2-hydroxybenzoyl)amino]decanoic acid (NAD), N-[8-(5-chlorosalicyloyl)amino]octanoic acid (5-CNAC), N-[8-(2-hydroxy-4-methoxybenzoyl)amino]octanoic acid (4-MOAC), N-[4-(2-hydroxy-4-chlorobenzoyl)amino]butyric acid (4-CNAB) and pharmaceutically acceptable salts thereof. In some embodiments, the delivery agent may be preferably selected from one or more of N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC), N-[6-(2-hydroxybenzoyl)amino]hexanoic acid (NAH), N-[10-(2-hydroxybenzoyl)amino]decanoic acid (NAD) and pharmaceutically acceptable salts thereof. In some embodiments, the delivery agent may be preferably selected from one or more of N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC) and pharmaceutically acceptable salts thereof. The above-mentioned pharmaceutically acceptable salts are selected from sodium salts, potassium salts or calcium salts. In some embodiments, the delivery agent is preferably sodium N-[8-(2-hydroxybenzoyl)amino]octanoate, hereinafter referred to as SNAC. In some embodiments, the delivery agent is preferably potassium N-[8-(2-hydroxybenzoyl)amino]octanoate. In some embodiments, the delivery agent is preferably calcium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0049] In some embodiments, the delivery agent may be present in a unit dosage form of the pharmaceutical composition of the present application in an amount of about 50 mg to about 500 mg. In some embodiments, the amount of delivery agent can be about 60 mg to about 500 mg, about 70 mg to about 500 mg, about 80 mg to about 500 mg, about 90 mg to about 500 mg, about 100 mg to about 500 mg, about 100 mg to about 450 mg, about 100 mg to about 440 mg, about 100 mg to about 430 mg, about 100 mg to about 420 mg, about 100 mg to about 410 mg, about 100 mg to about 400 mg, about 110 mg to about 400 mg, about 120 mg to about 400 mg, about 130 mg to about 400 mg, about 140 mg to about 400 mg, about 150 mg to about 400 mg, about 160 mg to about 400 mg, about 170 mg to about 400 mg, about 180 mg to about 400 mg, about 190 mg to about 400 mg, or about 200 mg to about 400 mg. In some embodiments, the amount of delivery agent may preferably be from about 200 mg to about 400 mg, from about 210 mg to about 390 mg, from about 220 mg to about 380 mg, from about 230 mg to about 370 mg, from about 240 mg to about 360 mg, from about 250 mg to about 350 mg, from about 260 mg to about 340 mg, from about 270 mg to about 330 mg, from about 270 mg to about 320 mg, from about 270 mg to about 310 mg, from about 270 mg to about 300 mg, from about 280 mg to about 300 mg, from about 280 mg to about 310 mg, from about 280 mg to about 320 mg, from about 280 mg to about 330 mg, from about 290 mg to about 330 mg, from about 290 mg to about 320 mg, from about 290 mg to about 310 mg, or from about 290 mg to about 300 mg. In some embodiments, the amount of delivery agent may preferably be from about 200 mg to about 350 mg, from about 200 mg to about 300 mg, from about 200 mg to about 250 mg, from about 200 mg to about 220 mg, from about 200 mg to about 210 mg, from about 210 mg to about 350 mg, from about 210 mg to about 300 mg, from about 210 mg to about 250 mg, from about 210 mg to about 220 mg, from about 250 mg to about 350 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg.

[0050] In some embodiments, the mass content of the delivery agent can be about 15 wt% to about 75 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the delivery agent can be about 12 wt%-75 wt%, 12 wt%-70 wt%, 12 wt%-65 wt%, 12 wt%-60 wt%, 12 wt%-55 wt%, 12 wt%-50 wt%, 12 wt%-45 wt%, 12 wt%-40 wt%, 12 wt%-35 wt%, 12 wt%-30 wt%, 12 wt%-25 wt%, 12 wt%-20 wt%, 15 wt% to about 75 wt%, about 15 wt% to about 70 wt%, about 15 wt% to about 65 wt%, about 15 wt% to about 60 wt%, about 15 wt% to about 50 wt%, about 15 wt% to about 60 wt%, about 15 wt% to about 75 wt%. % to about 55wt%, about 15wt% to about 50wt%, about 15wt% to about 45wt%, about 15wt% to about 40wt%, about 15wt% to about 35wt%, about 15wt% to about 30wt%, about 15wt% to about 25wt%, about 15wt% to about 20wt%, about 16wt% to about 75wt%, about 17wt% to about 75wt%, about 18wt% to about 75wt%, about 19wt% to about 75wt%, about 20wt% to about 75wt%, about 20wt% to about 74wt%, about 20wt% to about 73wt%, about 20wt% to about 72wt%, about 20wt% to about 71wt%, about 20 wt% to about 70wt%, about 20wt% to about 65wt%, about 20wt% to about 60wt%, about 20wt% to about 55wt%, about 20wt% to about 50wt%, about 20wt% to about 45wt%, about 20wt% to about 40wt%, about 20wt% to about 35wt%, about 20wt% to about 30wt%, about 21wt% to about 70wt%, about 22wt% to about 70wt%, about 23wt% to about 70wt%, about 24wt% to about 70wt%, about 25wt% to about 70wt%, about 25wt% to about 69wt%, about 25wt% to about 68wt%, about 25wt% to about 67wt%, about 25wt% to about 66wt%, about 25wt% to about 65wt%, about 25wt% to about 60wt%, about 25wt% to about 55wt%, about 25wt% to about 50wt%, about 25wt% to about 45wt%, about 25wt% to about 40wt%, about 25wt% to about 35wt%, about 26wt% to about 65wt%, about 27wt% to about 65wt%, about 28wt% to about 65wt%, about 29wt% to about 65wt%, about 30wt% to about 65wt%, about 30wt% to about 65wt%, about 30wt% to about 64wt%, about 30wt% to about 63wt%, about 30wt% to about 62wt%, about 30wt% to about 61wt%,About 30 wt% to about 60 wt%, about 30 wt% to about 55 wt%, about 30 wt% to about 50 wt%, about 30 wt% to about 45 wt%, about 30 wt% to about 40 wt%, or about 30 wt% to about 35 wt%.

[0051] In some embodiments, the mass content of the delivery agent may be preferably about 30 wt % to about 60 wt % based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the delivery agent may be about 31 wt % to about 60 wt %, about 32 wt % to about 60 wt %, about 33 wt % to about 60 wt %, about 34 wt % to about 60 wt %, about 35 wt % to about 60 wt %, about 35 wt % to about 59 wt %, about 35 wt % to about 58 wt %, about 35 wt % to about 57 wt %, about 35 wt % to about 56 wt %, about 35 wt % to about 55 wt %, about 35 wt % to about 50 wt %, about 35 wt % to about 45 wt %, about 35 wt % to about 40 wt %, about 36wt% to about 55wt%, about 37wt% to about 55wt%, about 38wt% to about 55wt%, about 39wt% to about 55wt%, about 40wt% to about 55wt%, about 40wt% to about 54wt%, about 40wt% to about 53wt%, about 40wt% to about 52wt%, about 40wt% to about 51wt%, about 40wt% to about 50wt%, about 40wt% to about 49wt%, about 40wt% to about 48wt%, about 40wt% to about 47wt%, about 40wt% to about 46wt%, about 40wt% to about 45wt%, about 40wt% % to about 44wt%, about 40wt% to about 43wt%, about 40wt% to about 42wt%, about 45wt% to about 60wt%, about 45wt% to about 59wt%, about 45wt% to about 58wt%, about 45wt% to about 57wt%, about 45wt% to about 56wt%, about 45wt% to about 55wt%, about 45wt% to about 54wt%, about 45wt% to about 53wt%, about 45wt% to about 52wt%, about 45wt% to about 51wt%, about 45wt% to about 50wt%, about 45wt% to about 49wt%, about 45wt% to about 4 8wt%, about 45wt% to about 47wt%, about 45wt% to about 57wt%, about 50wt% to about 60wt%, about 50wt% to about 59wt%, about 50wt% to about 58wt%, about 50wt% to about 57wt%, about 50wt% to about 56wt%, about 50wt% to about 55wt%, about 50wt% to about 54wt%, about 50wt% to about 53wt%, about 50wt% to about 52wt%, about 55wt% to about 60wt%, about 55wt% to about 59wt%, about 55wt% to about 58wt% or about 55wt% to about 57wt%.

[0052] In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the dimethoate can be about 5:1 to about 500:1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the dimethoate can be about 5:1 to about 500:1, about 10:1 to about 500:1, about 15:1 to about 500:1, about 20:1 to about 500:1, about 25:1 to about 500:1, about 30:1 to about 500:1, about 35:1 to about 500:1, about 40:1 to about 500:1, about 45:1 to about 500:1, about 50:1 to about 50 0:1, about 50:1 to about 490:1, about 50:1 to about 480:1, about 50:1 to about 470:1, about 50:1 to about 460:1, about 50:1 to about 450:1, about 50:1 to about 440:1, about 50:1 to about 430:1, about 50:1 to about 420:1, about 50:1 to about 410:1, about 50:1 to about 400:1, about 60:1 to about 400:1, about 70:1 to about 400:1, About 80:1 to about 400:1, about 90:1 to about 400:1, about 100:1 to about 400:1, about 100:1 to about 390:1, about 100:1 to about 380:1, about 100:1 to about 370:1, about 100:1 to about 360:1, about 100:1 to about 350:1, about 110:1 to about 350:1, about 120:1 to about 350:1, about 130:1 to about 350:1, about 140:1 to about 350:1, about 150:1 to about 350:1, about 150:1 to about 340:1, about 150:1 to about 330:1, about 150:1 to about 320:1, about 150:1 to about 310:1, about 150:1 to about 300:1, about 160:1 to about 300:1, about 170:1 to about 300:1, about 180:1 to about 300:1, about 190:1 to about 300:1 or about 200:1 to about 300:1.

[0053] In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the delfalin may preferably be about 10:1 to about 300:1, about 20:1 to about 270:1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the delfalin may preferably be about 200:1 to about 300:1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the delfalin may preferably be about 210:1 to about 300:1, about 220:1 to about 300:1, about 230:1 to about 300:1, about 240:1 to about 300:1, about 250:1 to about 300:1, about 260:1 to about 300:1, about 270:1 to about 300:1, about 280:1 to about 300:1, about 290:1 to about 300:1, about 210 :1 to about 290:1, about 220:1 to about 290:1, about 230:1 to about 290:1, about 240:1 to about 290:1, about 250:1 to about 290:1, about 260:1 to about 290:1, about 270:1 to about 290:1, about 280:1 to about 290:1, about 210:1 to about 280:1, about 220:1 to about 280:1, about 230:1 to about 280:1, about 240:1 to about 280:1, about 25 0:1~about 280:1, about 260:1~about 280:1, about 270:1~about 280:1, about 210:1~about 270:1, about 220:1~about 270:1, about 230:1~about 270:1, about 240:1~about 270:1, about 250:1~about 270:1, about 260:1~about 270:1, about 210:1~about 260:1, about 220:1~about 260:1, about 230:1~about 260:1, about 240:1 to about 260:1, about 250:1 to about 260:1, about 210:1 to about 250:1, about 220:1 to about 250:1, about 230:1 to about 250:1, about 240:1 to about 250:1, about 210:1 to about 240:1, about 220:1 to about 240:1, about 230:1 to about 240:1, about 210:1 to about 230:1, about 220:1 to about 230:1, or about 210:1 to about 220:1.

[0054] In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the diflucan may be preferably about 20:1 to about 200:1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the diflucan may be preferably about 25:1 to about 200:1, about 30:1 to about 200:1, about 35:1 to about 200:1, about 40:1 to about 200:1, about 50:1 to about 200:1, about 60:1 to about 200:1, about 70:1 to about 200:1, about 80:1 to about 200:1, about 90:1 to about 200:1, about 100:1 to about 200:1, about 20:1 to about 190:1, about 30:1 to about 190:1, about 40:1 to about 190:1, about 50:1 to about 190:1, about 60:1 to about 190:1, about 70:1 to about 190:1, about 80:1 to about 190:1, about 20:1 to about 180:1, about 30:1 to about 180:1, about 40:1 to about 180:1, about 50:1 to about 180: 1. About 60:1 to about 180:1, about 70:1 to about 180:1, about 20:1 to about 170:1, about 30:1 to about 170:1, about 40:1 to about 170:1, about 50:1 to about 170:1, about 60:1 to about 170:1, about 20:1 to about 160:1, about 30:1 to about 160:1, about 40:1 to about 160:1, about 50:1 to about 160:1, about 20:1 to about 15 0:1, about 30:1 to about 150:1, about 40:1 to about 150:1, about 20:1 to about 140:1, about 30:1 to about 140:1, about 20:1 to about 130:1, about 20:1 to about 120:1, about 20:1 to about 100:1, about 20:1 to about 80:1, about 20:1 to about 60:1, about 20:1 to about 50:1, about 20:1 to about 40:1 or about 20:1 to about 30:1.

[0055] In some embodiments, the mass content of the delivery agent in the tablet core can be about 8 wt% to about 50 wt%, about 10 wt% to about 45 wt%, about 10 wt% to about 40 wt%, about 11 wt% to about 40 wt%, about 12 wt% to about 35 wt%, about 12 wt% to about 32 wt%, or about 10 wt% to about 32 wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the mass ratio of the delivery agent to the dimethoate in the tablet core can be about 20:1 to about 150:1, about 30:1 to about 120:1, about 35:1 to about 110:1, or about 36:1 to about 100:1.

[0056] In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the delivery agent in the outer layer can be about 15wt% to about 55wt%, about 18wt% to about 50wt%, about 20wt% to about 45wt%, about 22wt% to about 45wt%.

[0057] In some embodiments, the mass ratio of the delivery agent to the difficile in the pharmaceutical composition of the present application may preferably be about 20:1 to about 50:1. In some embodiments, the mass ratio of the delivery agent to the difficile in the pharmaceutical composition of the present application may preferably be about 200:1 to about 250:1. In some embodiments, the mass ratio of the delivery agent to the difficile in the pharmaceutical composition of the present application may preferably be about 220:1 to about 250:1.

[0058] In some embodiments, the adjuvant may include, but is not limited to, phosphates (including hydrogen phosphates), tartrates, acetates, citrates, glutamates, carbonates (e.g., bicarbonates, such as bicarbonates containing aluminum and an alkaline earth metal), or any combination thereof. In some embodiments, the adjuvant may include, but is not limited to, any one or combination of sodium phosphate, disodium hydrogen phosphate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, sodium carbonate, anhydrous calcium hydrogen phosphate, magnesium aluminum carbonate, and other pharmaceutically acceptable salts of the same acid radical. In some embodiments, the adjuvant may also include any one or combination of anhydrous disodium hydrogen phosphate, anhydrous calcium hydrogen phosphate, anhydrous sodium carbonate, and other pharmaceutically acceptable salts of the same acid radical. The other pharmaceutically acceptable salts of the same acid radical mentioned above may be selected from sodium salts, potassium salts, or calcium salts. Compared to oral preparations without adjuvants, oral preparations with adjuvants added can reduce the variability of the in vivo drug effectiveness (especially the maximum blood drug concentration) of difacillin among the individuals to whom the adjuvant is added.

[0059] In some embodiments, the adjuvant can be present in the unit dosage form of the pharmaceutical composition of the present application in an amount of about 10 mg to about 1500 mg. In some embodiments, the amount of the adjuvant can be about 10 mg to about 1000 mg, 20 mg to about 1000 mg, about 30 mg to about 800 mg, about 40 mg to about 600 mg, about 50 mg to about 500 mg, about 60 mg to about 400 mg, about 70 mg to about 300 mg, about 80 mg to about 200 mg, about 90 mg to about 100 mg. In some embodiments, the amount of adjuvant can be from about 50 mg to about 200 mg, from about 50 mg to about 150 mg, from about 50 mg to about 100 mg, from about 55 mg to about 200 mg, from about 55 mg to about 150 mg, from about 55 mg to about 100 mg, from about 60 mg to about 200 mg, from about 60 mg to about 150 mg, from about 60 mg to about 100 mg, from about 70 mg to about 200 mg, from about 70 mg to about 150 mg, from about 70 mg to about 100 mg, from about 70 mg to about 90 mg, from about 70 mg to about 85 mg, from about 70 mg to about 80 mg, from about 75 mg to about 200 mg, from about 75 mg to about 150 mg, from about 75 mg to about 100 mg, or from about 75 mg to about 90 mg.

[0060] In some embodiments, a unit dosage form of a pharmaceutical composition of the present application can contain at least about 10 mg, at least 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 500 mg, at least about 750 mg, or at least about 1000 mg of an adjuvant. In some embodiments, the unit dosage form of the pharmaceutical composition of the present application may contain no more than 200 mg, no more than 250 mg, no more than 300 mg, no more than 400 mg, no more than 500 mg, no more than 1000 mg, or no more than 1500 mg of an auxiliary agent.

[0061] In some embodiments, the mass content of the auxiliary agent may be about 5 wt % to about 70 wt % based on the total mass of the pharmaceutical composition. In some embodiments, based on the total weight of the pharmaceutical composition, the mass content of the auxiliary agent can be about 5 wt% to about 65 wt%, about 5 wt% to about 60 wt%, about 5 wt% to about 55 wt%, about 5 wt% to about 50 wt%, about 5 wt% to about 45 wt%, about 5 wt% to about 40 wt%, about 5 wt% to about 35 wt%, about 6 wt% to about 70 wt%, about 7 wt% to about 70 wt%, about 8 wt% to about 70 wt%, about 9 wt% to about 70 wt%, about 10 wt% to about 70 wt%, about 10 wt% to about 69 wt%, about 10 wt% to about 68 wt%, about 10 wt% to about 67 wt%, about 10 wt% to about 66 wt%, about 10 wt% to about 65 wt%, about 11 wt% to about 65 wt%, about 12 wt% to about 65 wt%, % to about 60 wt%, about 20 wt% to about 60 wt%, about 20 wt% to about 55 wt%, about 20 wt% to about 50 wt%, about 20 wt% to about 45 wt%, about 20 wt% to about 40 wt%, about 25 wt% to about 40 wt%, about 25 wt% to about 35 wt%, or about 30 wt% to about 35 wt%.

[0062] In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the auxiliary agent may preferably be about 10 wt% to about 40 wt%, about 6 wt% to about 25 wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the auxiliary agent may preferably be about 11 wt% to about 40 wt%, about 12 wt% to about 40 wt%, about 13 wt% to about 40 wt%, about 14 wt% to about 40 wt%, about 15 wt% to about 40 wt%, about 15 wt% to about 39 wt%, about 15 wt% to about 38 wt%, about 15 wt% to about 37 wt%, about 15 wt% to about 36 wt%, About 15wt% to about 35wt%, about 16wt% to about 35wt%, about 17wt% to about 35wt%, about 18wt% to about 35wt%, about 19wt% to about 35wt%, about 20wt% to about 35wt%, about 20wt% to about 34wt%, about 20wt% to about 33wt%, about 20wt% to about 32wt%, about 20wt% to about 31wt%, about 20wt% to about 30wt%, about 21wt% % to about 30wt%, about 22wt% to about 30wt%, about 23wt% to about 30wt%, about 24wt% to about 30wt%, about 25wt% to about 30wt%, about 25wt% to about 29wt%, about 25wt% to about 28wt%, about 25wt% to about 27wt%, about 10wt% to about 35wt%, about 10wt% to about 30wt%, about 10wt% to about 25wt%, about 10wt% to about 2 0wt%, about 10wt% to about 15wt%, about 15wt% to about 30wt%, about 15wt% to about 25wt%, about 15wt% to about 20wt%, about 20wt% to about 40wt%, about 20wt% to about 25wt%, about 25wt% to about 40wt%, about 25wt% to about 35wt%, about 30wt% to about 40wt%, about 30wt% to about 35wt% or about 35wt% to about 40wt%.In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of the auxiliary agent may preferably be about 10 wt% to about 30 wt%, about 12 wt% to about 30 wt%, about 13 wt% to about 30 wt%, about 14 wt% to about 30 wt%, about 15 wt% to about 30 wt%, about 15 wt% to about 29 wt%, about 15 wt% to about 28 wt%, about 15 wt% to about 27 wt%, about 15 wt% to about 26 wt%, about 15 wt% to about 25 wt%. t%, about 16wt% to about 25wt%, about 17wt% to about 25wt%, about 18wt% to about 25wt%, about 18wt% to about 24wt%, about 18wt% to about 23wt%, about 18wt% to about 22wt%, about 18wt% to about 21wt%, about 18wt% to about 20wt%, about 19wt% to about 25wt%, about 20wt% to about 25wt%, about 20wt% to about 24wt%, about 20wt% to about 23wt %, about 20wt% to about 22wt%, about 20wt% to about 21wt%, about 21wt% to about 30wt%, about 22wt% to about 30wt%, about 23wt% to about 30wt%, about 24wt% to about 30wt%, about 25wt% to about 30wt%, about 25wt% to about 29wt%, about 25wt% to about 28wt%, about 25wt% to about 27wt%, about 10wt% to about 25wt%, about 10wt% to about 20wt% %, about 10 wt % to about 19 wt %, about 10 wt % to about 18 wt %, about 10 wt % to about 16 wt %, about 10 wt % to about 15 wt %, about 10 wt % to about 20 wt %, about 10 wt % to about 15 wt %, about 15 wt % to about 30 wt %, about 15 wt % to about 25 wt %, about 15 wt % to about 20 wt %, about 20 wt % to about 30 wt %, about 20 wt % to about 25 wt % or about 25 wt % to about 30 wt %. In some embodiments, the mass content of the excipients may be preferably 25 wt % to about 30 wt % based on the total mass of the pharmaceutical composition.

[0063] In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the auxiliary agent in the core can be about 0wt% to about 20wt%, about 2wt% to about 20wt%, about 3wt% to about 18wt%, about 4wt% to about 15wt%, about 4wt% to about 14wt%, about 0wt% to about 18wt%, about 0wt% to about 15wt%, about 0wt% to about 13wt%, about 4wt% to about 13wt%.

[0064] In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the auxiliary agent in the outer layer can be 0 wt% to about 20 wt%, about 2 wt% to about 20 wt%, about 3 wt% to about 19 wt%, about 5 wt% to about 18 wt%, about 0 wt% to about 19 wt%, about 0 wt% to about 18 wt%, or about 0 wt% to about 13 wt%.

[0065] In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the excipient may be about 0.5: 1 to about 10: 1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the excipient may be about 1: 1 to about 10: 1, about 1: 1 to about 9: 1, about 1: 1 to about 8: 1, about 1: 1 to about 7: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, about 1: 1 to about 2: 1, about 2: 1 to about 5: 1, about 2: 1 to about 4: 1, or about 2: 1 to about 3: 1.

[0066] In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the auxiliary agent may be preferably about 1: 1 to about 3: 1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the auxiliary agent may be preferably about 1: 1 to about 3: 1, about 1.1: 1 to about 2.9: 1, about 1.2: 1 to about 2.8: 1, about 1.3: 1 to about 2.7: 1, about 1.4: 1 to about 2.6: 1, about 1.5: 1 to about 2.5: 1, about 1.6: 1 to about 2.4: 1, about 1.7: 1 to about 2.3: 1, about 1.8: 1 to about 2.2: 1, about 1.9: 1 to about 2.1: 1, about 2: 1 to about 3: 1, about 2: 1 to about 2.9: 1, about 2: 1 to about 2.8:1, about 2:1 to about 2.7:1, about 2:1 to about 2.6:1, about 2:1 to about 2.5:1, about 2:1 to about 2.4:1, about 2:1 to about 2.3:1, about 2:1 to about 2.2:1, about 2:1 to about 2.1:1, about 2.5:1 to about 3:1, about 2.5:1 to about 2.9:1, about 2.5:1 to about 2.8:1, about 2.5:1 to about 2.7:1, about 2.5:1 to about 2.6:1, about 2.7:1 to about 3:1, about 2.7:1 to about 2.9:1, about 2.7:1 to about 2.8:1. In some embodiments, in the pharmaceutical composition of the present application, the mass ratio of the delivery agent to the auxiliary agent may be preferably about 1:1 to about 2.5:1, about 1:1 to about 2.0:1, about 1:1 to about 1.5:1, about 1.1:1 to about 1.5:1, about 1.2:1 to about 1.5:1, about 1.3:1 to about 1.5:1, about 1.4:1 to about 1.5:1, about 1.5:1 to about 2.5:1, about 1.5:1 to about 2.0:1, about 1.6:1 to about 2.0:1, about 1.7:1 to about 2.0:1, about 1.8:1 to about 2.0:1, about 1.9:1 to about 2.0:1, about 2.0:1 to about 2.5:1, about 2.0:1 to about 2.4:1, about 2.0:1 to about 2.3:1, about 2.0:1 to about 2.2:1, about 2.0:1 to about 2.1:1.

[0067] In some embodiments, the molar ratio of the delivery agent to the auxiliary agent in the pharmaceutical composition of the present application may be about 0.2: 1 to about 6: 1. In some embodiments, the molar ratio of the delivery agent to the auxiliary agent in the pharmaceutical composition of the present application may be about 0.5: 1 to about 6: 1, about 1: 1 to about 6: 1, about 1: 1 to about 5: 1, about 1: 1 to about 4: 1, about 1: 1 to about 3: 1, about 1: 1 to about 2: 1, about 2: 1 to about 5: 1, about 2: 1 to about 4: 1, about 2: 1 to about 3: 1, about 3: 1 to about 6: 1, about 3: 1 to about 5: 1, about 3: 1 to about 4: 1, about 4: 1 to about 6: 1, about 4: 1 to about 5: 1, or about 5: 1 to about 6: 1. In some embodiments, the molar ratio of the delivery agent to the auxiliary agent in the pharmaceutical composition of the present application may preferably be about 0.5: 1 to about 3: 1. In some embodiments, in the pharmaceutical composition of the present application, the molar ratio of the delivery agent to the auxiliary agent may be preferably about 0.5:1 to about 3:1, about 0.5:1 to about 2.5:1, about 0.5:1 to about 2:1, about 0.5:1 to about 1.5:1, about 0.5:1 to about 1:1, about 0.6:1 to about 1:1, about 0.7:1 to about 1:1, about 0.8:1 to about 1:1, about 0.9:1 to about 1:1, about 1:1 to about 3:1, about 1:1 to about 2.5:1, about 1:1 to about 2:1, about 1:1 to about 1.5:1, about 1.1:1 to about 1.5:1, about 1.2:1 to about 1.5:1, about 1.3:1 to about 1.5:1, about 1. 1 to about 4:1, about 1.5:1 to about 3:1, about 1.5:1 to about 2.5:1, about 1.5:1 to about 2:1, about 1.6:1 to about 2:1, about 1.7:1 to about 2:1, about 1.8:1 to about 2:1, about 1.9:1 to about 2:1, about 2:1 to about 3:1, about 2:1 to about 2.5:1, about 2.1:1 to about 2.5:1, about 2.2:1 to about 2.5:1, about 2.3:1 to about 2.5:1, about 2.4:1 to about 2.5:1, about 2.5:1 to about 3:1, about 2.6:1 to about 3:1, about 2.7:1 to about 3:1, about 2.8:1 to about 3:1, or about 2.9:1 to about 3:1.

[0068] The "pharmaceutically acceptable inactive ingredients" herein refer to pharmaceutically acceptable inactive ingredients other than the delivery agents and adjuvants described herein, including diluents, disintegrants, binders, lubricants, protease inhibitors, glidants, wetting agents, flavoring agents, fragrances, sweeteners, colorants, fillers, granulating agents, anti-caking agents, and preservatives. Those skilled in the art can routinely select and adjust these ingredients based on the formulation's formability requirements.

[0069] In some embodiments, the pharmaceutical composition described herein may further include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants. In some embodiments, the mass content of the above-mentioned one or more inactive ingredients may be about 0.1 wt% to about 60 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the above-mentioned one or more inactive ingredients may be about 0.1 wt% to about 81 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the above-mentioned one or more inactive ingredients may be about 10 wt% to about 50 wt%, about 20 wt% to about 60 wt%, or about 24 wt% to about 37 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the above-mentioned one or more inactive ingredients in the core may be about 5 wt% to about 30 wt%, about 6 wt% to about 25 wt%, about 8 wt% to about 20 wt%, or about 8 wt% to about 18 wt% based on the total mass of the pharmaceutical composition. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the one or more inactive ingredients in the outer layer can be about 5 wt% to about 35 wt%, about 8 wt% to about 30 wt%, about 10 wt% to about 30 wt%, or about 12 wt% to about 28 wt%.

[0070] The term "diluent" as used in the present disclosure refers to any pharmaceutically acceptable diluent that can be used to practice the present disclosure. Examples of pharmaceutically acceptable diluents include, but are not limited to, talc, calcium carbonate, calcium hydrogen phosphate, microcrystalline cellulose, powdered cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, maltodextrin, cross-linked polyvinylpyrrolidone, and mixtures thereof. In certain embodiments, exemplary diluents may include, but are not limited to, microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, maltodextrin, pregelatinized starch, and any one or any combination thereof of compound excipients comprising any one or more of microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, maltodextrin, pregelatinized starch, and the like. Exemplary compound excipients can include but are not limited to microcrystalline cellulose-dicalcium phosphate compound excipients, microcrystalline cellulose-polyvidone compound excipients, microcrystalline cellulose-crosslinked polyvidone compound excipients, microcrystalline cellulose-mannitol compound excipients, microcrystalline cellulose-lactose compound excipients, microcrystalline cellulose-pregelatinized starch compound excipients, pregelatinized starch-dicalcium phosphate compound excipients, pregelatinized starch-polyvidone compound excipients, pregelatinized starch-crosslinked polyvidone compound excipients, pregelatinized starch-mannitol compound excipients, pregelatinized starch-lactose compound excipients, etc. In certain embodiments, exemplary diluents can include but are not limited to any one or more of microcrystalline cellulose, powdered cellulose, maltodextrin, mannitol, and microcrystalline cellulose-mannitol compound excipients. In certain embodiments, based on the gross mass of the pharmaceutical composition, the mass content of the diluent can be about 20wt% to about 60wt%, about 16wt% to about 32wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the diluent in the core can be about 0wt% to about 20wt%, about 0wt% to about 15wt%, about 5wt% to about 20wt%, about 6wt% to about 15wt%. In some embodiments, based on the total mass of the pharmaceutical composition, the mass content of the diluent in the outer layer can be about 5wt% to about 30wt%, about 8wt% to about 26wt%. In some embodiments, the diluent in the pharmaceutical composition can include microcrystalline cellulose. In some embodiments, the diluent in the pharmaceutical composition can include microcrystalline cellulose and mannitol. In some embodiments, the diluent in the pharmaceutical composition can include a microcrystalline cellulose-mannitol compound excipient.

[0071] The term "disintegrant" as used in the present disclosure refers to any pharmaceutically acceptable disintegrant that can be used to practice the present disclosure. Examples of pharmaceutically acceptable disintegrants include, but are not limited to: agar, calcium carbonate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, povidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, clay, other celluloses, gums, or mixtures thereof. In some embodiments, exemplary disintegrants may include, but are not limited to, any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, etc., or any combination thereof. In some embodiments, exemplary disintegrants may include, but are not limited to, cross-linked polyvinylpyrrolidone, or mixtures thereof. In some embodiments, the pharmaceutical composition described herein may not include a disintegrant. In some embodiments, the pharmaceutical composition described herein may include a disintegrant. In some embodiments, the mass content of the disintegrant may be about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 4.4 wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the disintegrant in the core tablet can be about 0 wt% to about 5 wt%, about 0 wt% to about 2 wt%, about 0.8 wt% to about 2 wt%, or about 0 wt% to about 1.5 wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the disintegrant in the outer layer can be about 0 wt% to about 5 wt%, about 0 wt% to about 4 wt%, or about 0.8 wt% to about 4 wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the disintegrant in the pharmaceutical composition can include crospovidone.

[0072] The term "binding agent" used in the present disclosure represents any pharmaceutically acceptable binding agent that can be used to practice the present disclosure. The example of pharmaceutically acceptable binding agent includes, but is not limited to: starch (for example, corn starch, potato starch and pregelatinized starch and other starches), maltodextrin, gelatin, natural and synthetic gums such as gum arabic, guar gum, cellulose and its derivatives (for example, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose), polyvinyl alcohol, polyvinyl pyrrolidone and its mixture. In certain embodiments, exemplary binding agent can include but is not limited to any one or any combination of polyvidone, copolyvidone, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose etc. In certain embodiments, pharmaceutical composition described herein may not include binding agent. In certain embodiments, pharmaceutical composition described herein may include binding agent. In some embodiments, the mass content of the binder can be about 0.1wt% to about 4wt%, about 0.5wt% to about 4.5wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the binder in the core can be about 0wt% to about 5wt%, about 0wt% to about 3wt%, about 0wt% to about 2.5wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the binder in the outer layer can be about 0wt% to about 5wt%, about 0wt% to about 3wt%, about 0wt% to about 2.5wt%, based on the total mass of the pharmaceutical composition. In some embodiments, the binder in the pharmaceutical composition can include povidone (e.g., povidone K90). In some embodiments, the binder in the pharmaceutical composition can include hydroxypropyl cellulose.

[0073] The term "lubricant" used in the present disclosure represents any pharmaceutically acceptable lubricant that can be used to practice the present disclosure. The example of pharmaceutically acceptable lubricant includes, but is not limited to: calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, syloid silica gel and mixtures thereof. In certain embodiments, exemplary lubricants can include but are not limited to any one or any combination thereof in magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol etc. In certain embodiments, exemplary lubricants can include but are not limited to magnesium stearate, stearic acid, calcium stearate or its any combination. In certain embodiments, pharmaceutical composition described herein can not include lubricant. In some embodiments, the pharmaceutical composition described herein may include a lubricant. In some embodiments, the mass content of the lubricant may be about 1 wt% to about 6 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the lubricant in the core may be about 0 wt% to about 3 wt%, about 0 wt% to about 1.5 wt%, or about 0 wt% to about 1.4 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the lubricant in the outer layer may be about 0 wt% to about 3 wt%, about 0 wt% to about 2.5 wt%, or about 0 wt% to about 2 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the lubricant in the pharmaceutical composition may include magnesium stearate.

[0074] In some embodiments, the mass content of difacaline in the core tablet may be about 0.1 wt% to about 1 wt%, or about 0.2 wt% to about 0.9 wt%, based on the total mass of the pharmaceutical composition.

[0075] In some embodiments, the pharmaceutical composition described herein may further include a protease inhibitor. Exemplary protease inhibitors may include, but are not limited to, any one of casein hydrolysate, edetate disodium, pepsin inhibitors, trypsin inhibitors, or any combination thereof. In some embodiments, the mass content of the protease inhibitor may be 0.2 wt % to 10 wt % based on the total mass of the pharmaceutical composition.

[0076] In some embodiments, the pharmaceutical composition described herein may further include a glidant. Exemplary glidants may include, but are not limited to, any one of colloidal silicon dioxide, talc, or the like, or any combination thereof. In some embodiments, the glidant may be present in an amount of 0.5 wt % to 5 wt % based on the total weight of the pharmaceutical composition.

[0077] In some embodiments, the pharmaceutical composition described herein may further include a wetting agent. Exemplary wetting agents may include, but are not limited to, any one or any combination of polyethylene glycol, poloxamer, phospholipids, Tween 80, Span 40, propylene glycol monolaurate, sodium lauryl sulfate, and the like. In some embodiments, the wetting agent may be present in an amount of 0.2 wt % to 2 wt % based on the total weight of the pharmaceutical composition.

[0078] In certain embodiments, the pharmaceutical composition described herein may further include flavoring agents. Exemplary flavoring agents may include, but are not limited to, breath freshening compounds such as menthol, spearmint, and cinnamon, spices such as fruit flavorings (e.g., cherry, orange, grape, etc.), active substances for tooth and oral cleaning (e.g., quaternary ammonium bases), and sweeteners. Exemplary sweeteners may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame potassium and its various salts, aspartame, neotame, sodium cyclamate, saccharin and its various salts, stevioside, neohesperidin dihydrochalcone, mogrosides, and sucrose chlorine derivatives such as sucralose. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin, monoammonium glycyrrhizate, stevioside, natural fortified sweeteners such as monk fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, etc.

[0079] In some embodiments, the pharmaceutical composition described herein may include dimethoate, a pharmaceutically acceptable salt of NAC, an adjuvant, and a diluent. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of dimethoate may be about 0.1 wt% to about 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be about 15 wt% to about 75 wt%, the weight content of the adjuvant may be about 5 wt% to about 70 wt%, and the weight content of the diluent may be about 20 wt% to about 60 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of dimethoate may be about 0.1 wt% to about 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be about 12 wt% to about 75 wt%, the weight content of the adjuvant may be about 5 wt% to about 70 wt%, and the weight content of the diluent may be about 8 wt% to about 80 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of diflucan can be about 0.1 wt% to about 2 wt%, the weight content of the pharmaceutically acceptable salt of NAC can be about 15 wt% to about 75 wt%, the weight content of the excipient can be about 5 wt% to about 70 wt%, and the weight content of the diluent can be about 20 wt% to about 60 wt%. In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: excipient: diluent can be 1: (5-500): (2-300): (5-200). In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: excipient: diluent can be 1: (50-300): (50-200): (50-200). In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: excipient: diluent can be 1: (200-300): (100-150): (50-100). In some embodiments, the pharmaceutically acceptable salt of NAC can be sodium NAC, potassium NAC, or calcium NAC. In some embodiments, the adjuvant can be disodium hydrogen phosphate. In some embodiments, the diluent can include microcrystalline cellulose. In some embodiments, the diluent can include microcrystalline cellulose and mannitol. In some embodiments, the diluent can include microcrystalline cellulose and a microcrystalline cellulose-mannitol combination excipient.

[0080] In some embodiments, the pharmaceutical composition described herein may include dimethoate, a pharmaceutically acceptable salt of NAC, an adjuvant, a diluent, and a lubricant. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of dimethoate may be about 0.1 wt% to about 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be about 15 wt% to about 75 wt%, the weight content of the adjuvant may be about 5 wt% to about 70 wt%, the weight content of the diluent may be about 20 wt% to about 60 wt%, and the weight content of the lubricant may be about 1 wt% to about 6 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of dimethoate may be about 0.1 wt% to about 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be about 12 wt% to about 75 wt%, the weight content of the adjuvant may be about 5 wt% to about 70 wt%, the weight content of the diluent may be about 8 wt% to about 80 wt%, and the weight content of the lubricant may be about 1 wt% to about 6 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of diflucan can be about 0.1 wt% to about 2 wt%, the weight content of the pharmaceutically acceptable salt of NAC can be about 15 wt% to about 75 wt%, the weight content of the excipient can be about 5 wt% to about 70 wt%, the weight content of the diluent can be about 20 wt% to about 60 wt%, and the weight content of the lubricant can be about 1 wt% to about 6 wt%. In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: excipient: diluent: lubricant can be 1: (5-500): (2-300): (5-200): (2-20). In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: excipient: diluent: lubricant can be 1: (50-300): (50-200): (50-200): (2-20). In some embodiments, the weight ratio of dimethoate: pharmaceutically acceptable salt of NAC: adjuvant: diluent: lubricant can be 1: (200-300): (100-150): (50-100): (3-10). In some embodiments, the pharmaceutically acceptable salt of NAC can be sodium NAC, potassium NAC, or calcium NAC. In some embodiments, the adjuvant can be disodium hydrogen phosphate. In some embodiments, the diluent can include microcrystalline cellulose. In some embodiments, the diluent can include microcrystalline cellulose and mannitol. In some embodiments, the diluent can include microcrystalline cellulose and a microcrystalline cellulose-mannitol compound. In some embodiments, the lubricant can include magnesium stearate.

[0081] In some embodiments, the pharmaceutical compositions described herein may include difluprednate, a pharmaceutically acceptable salt of NAC, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of difluprednate may be approximately 0.1 wt% to approximately 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be approximately 15 wt% to approximately 75 wt%, the weight content of the adjuvant may be approximately 5 wt% to approximately 70 wt%, the weight content of the diluent may be approximately 20 wt% to approximately 60 wt%, the weight content of the lubricant may be approximately 1 wt% to approximately 6 wt%, and the weight content of the binder may be approximately 0.1 wt% to approximately 4 wt%. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of diflucan may be about 0.1 wt% to about 10 wt%, the weight content of the pharmaceutically acceptable salt of NAC may be about 12 wt% to about 75 wt%, the weight content of the adjuvant may be about 5 wt% to about 70 wt%, the weight content of the diluent may be about 8 wt% to about 80 wt%, the weight content of the lubricant may be about 1 wt% to about 6 wt%, and the weight content of the binder may be about 0.1 wt% to about 4 wt%. In some embodiments, the pharmaceutical composition described herein may include diflucan, a pharmaceutically acceptable salt of NAC, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, based on the total weight of the pharmaceutical composition, the weight content of dimethoate can be about 0.1 wt% to about 2 wt%, the weight content of the pharmaceutically acceptable salt of NAC can be about 15 wt% to about 75 wt%, the weight content of the excipient can be about 5 wt% to about 70 wt%, the weight content of the diluent can be about 20 wt% to about 60 wt%, the weight content of the lubricant can be about 1 wt% to about 6 wt%, and the weight content of the binder can be about 0.1 wt% to about 4 wt%. In some embodiments, the weight ratio of dimethoate: pharmaceutically acceptable salt of NAC: excipient: diluent: lubricant: binder can be 1: (5-500): (2-300): (5-200): (2-20): (0.5-20). In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: adjuvant: diluent: lubricant: binder can be 1: (50-300): (50-200): (50-200): (5-20): (1-6). In some embodiments, the weight ratio of diflucan: pharmaceutically acceptable salt of NAC: adjuvant: diluent: lubricant: binder can be 1: (200-300): (100-150): (100-150): (5-15): (1-4). In some embodiments, the pharmaceutically acceptable salt of NAC can be sodium, potassium, or calcium. In some embodiments, the adjuvant can be disodium hydrogen phosphate. In some embodiments, the diluent can include microcrystalline cellulose.In some embodiments, the diluent may include pregelatinized starch, microcrystalline cellulose-calcium phosphate compound excipients. In some embodiments, the lubricant may include magnesium stearate. In some embodiments, the binder may be povidone. In some embodiments, the binder may be hydroxypropyl cellulose. In some embodiments, the pharmaceutical composition may further include a disintegrant. In some embodiments, the disintegrant may be cross-linked polyvinylpyrrolidone. In some embodiments, the weight ratio of difluprednate to disintegrant may be 1:10 to 1:40. In some embodiments, the weight ratio of difluprednate to disintegrant may be 1:15 to 1:30.

[0082] In some embodiments, the pharmaceutical composition may include a particle. The particle may include dimethoate, a delivery agent, and an adjuvant. Optionally, the particle may also include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants. In some embodiments, the particle may include dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the particle may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant can be granulated after uniform mixing. Granulation methods may include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0083] In some embodiments, the pharmaceutical composition can be made of two or more particles with different compositions. In some embodiments, the pharmaceutical composition can include a first particle and a second particle.

[0084] In some embodiments, the first particle may include dimethoate. In some embodiments, the first particle may include dimethoate and an optional pharmaceutically acceptable inactive ingredient. In some embodiments, the first particle may include dimethoate and a delivery agent. In some embodiments, the first particle may include dimethoate, a delivery agent, and an adjuvant. In some embodiments, the second particle may include a delivery agent. In some embodiments, the second particle may include a delivery agent, an adjuvant. In some embodiments, the second particle may include a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient.

[0085] In some embodiments, the first granules may include thiamethoxam and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include thiamethoxam and a diluent. In some embodiments, the first granules may include thiamethoxam, a diluent, and a lubricant. In some embodiments, the first granules may include thiamethoxam, a diluent, a binder, and a lubricant. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include one or more of a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and a diluent. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the first granules may include dimethoate, a delivery agent, and an adjuvant, and the second granules may include one or more of the delivery agent, adjuvant, diluent, disintegrant, binder, and lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and one or more selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant, and the second granules may include one or more selected from the group consisting of a delivery agent, an adjuvant, diluent, disintegrant, binder, and lubricant. In some embodiments, dimethoate and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent, adjuvant, and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules and then granulated. In some embodiments, a lubricant may be added during the mixing of the first and second granules. In some embodiments, dimethoate and one or more inactive ingredients may be uniformly mixed to form the first granules, which may then be uniformly mixed with the delivery agent, adjuvant, and one or more inactive ingredients and then granulated. In some embodiments, the delivery agent, adjuvant, and one or more inactive ingredients may be uniformly mixed to form the second granules, which may then be uniformly mixed with the dimethoate and one or more inactive ingredients and then granulated. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0086] In some embodiments, the first granules may include dimethoate, an adjuvant, and optional pharmaceutically acceptable inactive ingredients. In some embodiments, the first granules may include dimethoate, an adjuvant, and one or more inactive ingredients selected from a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the first granules may include dimethoate, an adjuvant, and a diluent. In some embodiments, the first granules may include dimethoate, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and one or more inactive ingredients selected from a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and a diluent. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the dimethoate, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added when mixing the first and second granules. In some embodiments, dimethoate, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form first granules, which may then be uniformly mixed with a delivery agent, an adjuvant, and one or more inactive ingredients before granulation. In some embodiments, a delivery agent, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form second granules, which may then be uniformly mixed with dimethoate, an adjuvant, and one or more inactive ingredients before granulation. Granulation methods may include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0087] In some embodiments, the first granules may include dimethoate, a delivery agent, and optional pharmaceutically acceptable inactive ingredients. In some embodiments, the first granules may include dimethoate, a delivery agent, and one or more inactive ingredients selected from a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and one or more inactive ingredients selected from a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and a diluent. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a binder. In some embodiments, dimethoate, a delivery agent, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added when mixing the first and second granules. In some embodiments, the first granules may be uniformly mixed with the dimethoate, a delivery agent, and one or more inactive ingredients, and then uniformly mixed with the delivery agent, an adjuvant, and one or more inactive ingredients before granulation. In some embodiments, the second granules may be uniformly mixed with the dimethoate, a delivery agent, and one or more inactive ingredients before granulation. Granulation methods may include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0088] In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and a diluent. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, a disintegrant, and a binder. In some embodiments, dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a first granule, and the delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a second granule. The first granule can be uniformly mixed with the second granule and then granulated. In some embodiments, a lubricant can be added when the first granule and the second granule are mixed. In some embodiments, dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a first granule, and then the delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a second granule, and then the delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a second granule. The granulation method can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0089] In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the second granules may include an adjuvant and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include an adjuvant and a diluent. In some embodiments, the second granules may include an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include an adjuvant, a diluent, and a binder. In some embodiments, dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the adjuvant and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added during the mixing of the first and second granules. In some embodiments, difluprednisolone, a delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a first granule, which can then be uniformly mixed with the adjuvant and one or more inactive ingredients before granulation. In some embodiments, the adjuvant and one or more inactive ingredients can be uniformly mixed to form a second granule, which can then be uniformly mixed with difluprednisolone, a delivery agent, an adjuvant, and one or more inactive ingredients before granulation. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0090] In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include a delivery agent and a diluent. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a binder. In some embodiments, dimethoate, a delivery agent, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added during the mixing of the first and second granules. In some embodiments, difluprednisolone, a delivery agent, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a first granule, which can then be uniformly mixed with the delivery agent and one or more inactive ingredients before granulation. In some embodiments, the delivery agent and one or more inactive ingredients can be uniformly mixed to form a second granule, which can then be uniformly mixed with difluprednisolone, a delivery agent, an adjuvant, and one or more inactive ingredients before granulation. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0091] In some embodiments, the first granules may include dimethoate, an adjuvant, and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, an adjuvant, and a diluent. In some embodiments, the first granules may include dimethoate, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include a delivery agent and a diluent. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a binder. In some embodiments, dimethoate, an adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added when the first granules and the second granules are mixed. In some embodiments, difluprednisolone, an adjuvant, and one or more inactive ingredients can be uniformly mixed to form a first granule, which can then be uniformly mixed with a delivery agent and one or more inactive ingredients before granulation. In some embodiments, a delivery agent and one or more inactive ingredients can be uniformly mixed to form a second granule, which can then be uniformly mixed with difluprednisolone, an adjuvant, and one or more inactive ingredients before granulation. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0092] In some embodiments, the first granules may include dimethoate, a delivery agent, and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, a delivery agent, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, a binder, and a lubricant. The second granules may include an adjuvant and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include an adjuvant and a diluent. In some embodiments, the second granules may include an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include an adjuvant, a diluent, and a binder. In some embodiments, dimethoate, a delivery agent, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the adjuvant and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added when the first granules and the second granules are mixed. In some embodiments, difluprednisolone, a delivery agent, and one or more inactive ingredients can be uniformly mixed to form a first granule, which can then be uniformly mixed with an adjuvant and one or more inactive ingredients before granulation. In some embodiments, an adjuvant and one or more inactive ingredients can be uniformly mixed to form a second granule, which can then be uniformly mixed with difluprednisolone, a delivery agent, and one or more inactive ingredients before granulation. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0093] In some embodiments, the first granules may include dimethoate, a delivery agent, and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include dimethoate, a delivery agent, and a diluent. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, and a lubricant. In some embodiments, the first granules may include dimethoate, a delivery agent, a diluent, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent and one or more inactive ingredients selected from the group consisting of diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include a delivery agent and a diluent. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, a diluent, and a binder. In some embodiments, dimethoate, a delivery agent, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent and one or more inactive ingredients may be uniformly mixed to form the second granules. The first granules may be uniformly mixed with the second granules to form granules. In some embodiments, a lubricant may be added when the first granules and the second granules are mixed. In some embodiments, difluprednisolone, a delivery agent, and one or more inactive ingredients can be uniformly mixed to form a first granule, which can then be uniformly mixed with the delivery agent and one or more inactive ingredients before granulation. In some embodiments, the delivery agent and one or more inactive ingredients can be uniformly mixed to form a second granule, which can then be uniformly mixed with difluprednisolone, a delivery agent, and one or more inactive ingredients before granulation. Granulation methods can include dry granulation, wet granulation, extrusion granulation, centrifugal granulation, and spray drying granulation.

[0094] In some embodiments, the first granules may include thiamethoxam and a delivery agent. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, and a diluent. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the first granules may include thiamethoxam, a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include one or more of a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants. In some embodiments, the second granules may include a delivery agent, an adjuvant, and one or more inactive ingredients selected from a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, and a diluent. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the second granules may include a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the dimethoate, the delivery agent, the adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and one or more of the delivery agent, adjuvant, diluent, disintegrant, binder, and lubricant may be uniformly mixed to form the second granules. In some embodiments, the dimethoate, the delivery agent, the adjuvant, and one or more inactive ingredients may be uniformly mixed to form the first granules, and the delivery agent, the adjuvant, and one or more inactive ingredients may be uniformly mixed to form the second granules. In some embodiments, the pharmaceutical composition is a tablet comprising: a tablet core obtained by compressing the first granules, and an outer layer encapsulating the tablet core and obtained by compressing the second granules.

[0095] In some embodiments, the present application provides an oral pharmaceutical composition of difacoum, comprising an outer layer and a core tablet, wherein the outer layer wraps the core tablet, wherein the core tablet comprises difacoum and a delivery agent; and the outer layer comprises a delivery agent.

[0096] In some embodiments, the pharmaceutical composition may include an outer layer and a core tablet, with the outer layer surrounding the core tablet.

[0097] In some embodiments, difluprednate is not included in the outer layer. In some embodiments, difluprednate or a pharmaceutically acceptable salt thereof is the only active ingredient in the pharmaceutical composition.

[0098] In some embodiments, the outer layer may include an optional pharmaceutically acceptable inactive ingredient, and the core may include difacillin and an optional pharmaceutically acceptable inactive ingredient. In some embodiments, the outer layer may include a delivery agent and, optionally, one or more selected from an adjuvant, a diluent, a disintegrant, a binder, and a lubricant, and the core may include difacillin and a delivery agent. In some embodiments, the outer layer may include a delivery agent and an adjuvant, and the core may include difacillin, a delivery agent, and an adjuvant.

[0099] In some embodiments, the outer layer may include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0100] In some embodiments, the outer layer may include an optional pharmaceutically acceptable inactive ingredient and the core may include difacillin, a delivery agent, and an optional pharmaceutically acceptable inactive ingredient.

[0101] In some embodiments, the outer layer may include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine, a delivery agent, and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0102] In some embodiments, the outer layer may include optional pharmaceutically acceptable inactive ingredients, and the core may include difacaine, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0103] In some embodiments, the outer layer may include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine, adjuvants, and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0104] In some embodiments, the outer layer may include optional pharmaceutically acceptable inactive ingredients, and the core may include difacaine, a delivery agent, an adjuvant, and optional pharmaceutically acceptable inactive ingredients.

[0105] In some embodiments, the outer layer may include one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0106] In some embodiments, the outer layer may include a delivery agent and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin and optional pharmaceutically acceptable inactive ingredients.

[0107] In some embodiments, the outer layer may include a delivery agent and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacillin and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0108] In some embodiments, the outer layer may include a delivery agent and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, a delivery agent, and optional pharmaceutically acceptable inactive ingredients.

[0109] In some embodiments, the outer layer may include a delivery agent and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacillin, a delivery agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0110] In some embodiments, the outer layer may include a delivery agent and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0111] In some embodiments, the outer layer may include a delivery agent and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine, adjuvants, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0112] In some embodiments, the outer layer may include a delivery agent and optional pharmaceutically acceptable inactive ingredients, and the core may include difacoum, a delivery agent, an adjuvant, and optional pharmaceutically acceptable inactive ingredients.

[0113] In some embodiments, the outer layer may include a delivery agent and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0114] In some embodiments, the outer layer may include adjuvants and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin and optional pharmaceutically acceptable inactive ingredients.

[0115] In some embodiments, the outer layer may include an adjuvant and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0116] In some embodiments, the outer layer may include adjuvants and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, a delivery agent, and optional pharmaceutically acceptable inactive ingredients.

[0117] In some embodiments, the outer layer may include an adjuvant and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacillin, a delivery agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0118] In some embodiments, the outer layer may include adjuvants and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0119] In some embodiments, the outer layer may include an adjuvant and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaline, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0120] In some embodiments, the outer layer may include adjuvants and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, a delivery agent, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0121] In some embodiments, the outer layer may include an adjuvant and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0122] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient, and the core may include difacillin and optionally a pharmaceutically acceptable inactive ingredient.

[0123] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0124] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient, and the core may include difacillin, a delivery agent, and optionally a pharmaceutically acceptable inactive ingredient.

[0125] In some embodiments, the outer layer may include a delivery agent, an auxiliary agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine, a delivery agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0126] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient, and the core may include difacillin, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0127] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacaine, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0128] In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient, and the core may include difacillin, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0129] In some embodiments, the outer layer may include one or more of a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, a binder, and a lubricant, and the core may include dimethoate, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, a binder, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a binder, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a disintegrant, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the core may include dimethoate, a delivery agent, an adjuvant, a diluent, a disintegrant, and a lubricant. In some embodiments, the core may include dimethoate, a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a binder, and a lubricant, and the core may include dimethoate, a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a disintegrant, and a lubricant, and the core may include dimethoate, a delivery agent, an adjuvant, a diluent, a disintegrant, and a lubricant. In some embodiments, the outer layer may include a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant, and the core may include dimethoate, a delivery agent, an adjuvant, a diluent, a disintegrant, a binder, and a lubricant.

[0130] In some embodiments, the outer layer is composed of a pharmaceutically acceptable inactive ingredient and the core is composed of difacillin and an optional pharmaceutically acceptable inactive ingredient.

[0131] In some embodiments, the outer layer is composed of a pharmaceutically acceptable inactive ingredient and the core is composed of difacillin, a delivery agent, and optionally a pharmaceutically acceptable inactive ingredient.

[0132] In some embodiments, the outer layer is composed of pharmaceutically acceptable inactive ingredients, and the core is composed of difacaline, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0133] In some embodiments, the outer layer is composed of pharmaceutically acceptable inactive ingredients, and the core is composed of difacaline, a delivery agent, an adjuvant, and optional pharmaceutically acceptable inactive ingredients.

[0134] In some embodiments, the outer layer consists of a delivery agent and a pharmaceutically acceptable inactive ingredient, and the core consists of difacillin and an optional pharmaceutically acceptable inactive ingredient.

[0135] In some embodiments, the outer layer consists of a delivery agent and a pharmaceutically acceptable inactive ingredient, and the core consists of difafarin, a delivery agent, and optionally a pharmaceutically acceptable inactive ingredient.

[0136] In some embodiments, the outer layer is composed of a delivery agent and a pharmaceutically acceptable inactive ingredient, and the core is composed of difacaine, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0137] In some embodiments, the outer layer is composed of a delivery agent and a pharmaceutically acceptable inactive ingredient, and the core is composed of difacillin, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0138] In some embodiments, the outer layer is composed of adjuvants and pharmaceutically acceptable inactive ingredients, and the core is composed of difacaline and optional pharmaceutically acceptable inactive ingredients.

[0139] In some embodiments, the outer layer is composed of adjuvants and pharmaceutically acceptable inactive ingredients, and the core is composed of difacaine, a delivery agent, and optional pharmaceutically acceptable inactive ingredients.

[0140] In some embodiments, the outer layer is composed of adjuvants and pharmaceutically acceptable inactive ingredients, and the core is composed of difacaline, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0141] In some embodiments, the outer layer is composed of an adjuvant and a pharmaceutically acceptable inactive ingredient, and the core is composed of difacaine, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0142] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a pharmaceutically acceptable inactive ingredient, and the core is composed of difacillin and optional pharmaceutically acceptable inactive ingredients.

[0143] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a pharmaceutically acceptable inactive ingredient, and the core is composed of difacillin, a delivery agent, and optional pharmaceutically acceptable inactive ingredients.

[0144] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a pharmaceutically acceptable inactive ingredient, and the core is composed of difafarin, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0145] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a pharmaceutically acceptable inactive ingredient, and the core is composed of difafarin, a delivery agent, an adjuvant, and optionally a pharmaceutically acceptable inactive ingredient.

[0146] In some embodiments, the outer layer comprises ground ferns.

[0147] In some embodiments, the outer layer may include difacoum and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0148] In some embodiments, the outer layer may include difacaine and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0149] In some embodiments, the outer layer may include difacoum, a delivery agent, and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0150] In some embodiments, the outer layer may include difacialin, a delivery agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0151] In some embodiments, the outer layer may include difacial, adjuvants, and optional pharmaceutically acceptable inactive ingredient compositions, and the core may include a delivery agent, adjuvants, and optional pharmaceutically acceptable inactive ingredient compositions.

[0152] In some embodiments, the outer layer may include difacialin, adjuvants, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include a delivery agent, adjuvants, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0153] In some embodiments, the outer layer may include difacialin, a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0154] In some embodiments, the outer layer may include difacialin, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0155] In some embodiments, the outer layer may include difacillin and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include difacillin, a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0156] In some embodiments, the outer layer may include difacoum and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0157] In some embodiments, the outer layer may include difacillin, a delivery agent, and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include difacillin, a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0158] In some embodiments, the outer layer may include difacoum, a delivery agent, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0159] In some embodiments, the outer layer may include difacillin, adjuvants, and optional pharmaceutically acceptable inactive ingredients, and the core may include difacillin, a delivery agent, adjuvants, and optional pharmaceutically acceptable inactive ingredients.

[0160] In some embodiments, the outer layer may include difacoum, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0161] In some embodiments, the outer layer may include difacillin, a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition, and the core may include difacillin, a delivery agent, an adjuvant, and an optional pharmaceutically acceptable inactive ingredient composition.

[0162] In some embodiments, the outer layer may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants, and the core may include difacoum, a delivery agent, an adjuvant, and optionally one or more inactive ingredients selected from diluents, disintegrants, binders, and lubricants.

[0163] In some embodiments, the outer layer consists of a delivery agent. In some embodiments, the outer layer consists of a delivery agent and an adjuvant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a disintegrant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a binder. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, a binder, and a disintegrant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder.

[0164] In some embodiments, the tablet core consists of dimethoate and a delivery agent. In some embodiments, the tablet core consists of dimethoate, a delivery agent, and an adjuvant. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, and a disintegrant. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, and a binder. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, a binder, and a disintegrant. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the tablet core consists of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant, and a binder.

[0165] In some embodiments, the outer layer consists of a delivery agent, and the core consists of dimethoate and a delivery agent. In some embodiments, the outer layer consists of a delivery agent, and the core consists of dimethoate, a delivery agent, and an adjuvant. In some embodiments, the outer layer consists of a delivery agent and an adjuvant, and the core consists of dimethoate and a delivery agent. In some embodiments, the outer layer consists of a delivery agent and an adjuvant, and the core consists of dimethoate, a delivery agent, and an adjuvant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent, and the core consists of dimethoate, a delivery agent, an adjuvant, and a diluent. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent, and the core consists of dimethoate, a delivery agent, an adjuvant, and a disintegrant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent, and the core consists of dimethoate, a delivery agent, an adjuvant, and a disintegrant. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent, and the core consists of dimethoate, a delivery agent, an adjuvant, and a binder. In some embodiments, the outer layer consists of a delivery agent, an adjuvant, and a diluent, and the core consists of dimethoate, a delivery agent, an adjuvant, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a diluent, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a diluent, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a diluent, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, and a diluent, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant.

[0166] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an auxiliary agent, and a disintegrant, and the core is composed of difalin, a delivery agent, an auxiliary agent, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an auxiliary agent, and a disintegrant, and the core is composed of difalin, a delivery agent, an auxiliary agent, a diluent, a lubricant, a binder, and a disintegrant.

[0167] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant and a binder, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an auxiliary agent, and a binder, and the core is composed of difacaline, a delivery agent, an auxiliary agent, a diluent, a lubricant, a binder, and a disintegrant.

[0168] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an auxiliary agent, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an auxiliary agent, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an auxiliary agent, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an auxiliary agent, a diluent, a lubricant, a binder, and a disintegrant.

[0169] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent and a lubricant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent, a lubricant and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, and a lubricant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, and a lubricant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant.

[0170] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of a dimethicone, a delivery agent, an adjuvant, and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of a dimethicone, a delivery agent, an adjuvant, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of a dimethicone, a delivery agent, an adjuvant, and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of a dimethicone, a delivery agent, an adjuvant, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of a dimethicone, a delivery agent, an adjuvant, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, and a binder, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant.

[0171] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a diluent and a lubricant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant.

[0172] In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a diluent. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder and a disintegrant, and the core is composed of dimethoate, a delivery agent, an adjuvant, a binder and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, and a binder. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a binder, and a disintegrant. In some embodiments, the outer layer is composed of a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant, and the core is composed of difalin, a delivery agent, an adjuvant, a diluent, a lubricant, a binder, and a disintegrant.

[0173] In some embodiments, the mass content of the core tablets is 10 wt%-60 wt% based on the total mass of the pharmaceutical composition. In some embodiments, the mass content of the core tablets is 10 wt%-60 wt%, 12 wt%-58 wt%, 15 wt%-55 wt%, 18 wt%-53 wt%, 20 wt%-50 wt%, 22 wt%-48 wt%, 25 wt%-45 wt%, 28 wt%-42 wt%, 30 wt%-40 wt%, 33 wt%-45 wt%, 35 wt%-50 wt%, 37 wt%-52 wt%, 40 wt%-55 wt%, 45 wt%-60 wt% based on the total mass of the pharmaceutical composition.

[0174] In some embodiments, based on the mass of the outer layer, the mass content of the delivery agent in the outer layer can be 30wt%-75wt%, the mass content of the auxiliary agent can be 0wt%-40wt%, the mass content of the diluent can be 1wt%-30wt%, the mass content of the binder can be 0wt%-7.5wt%, the mass content of the lubricant can be 0.5wt%-5wt%, and the mass content of the disintegrant can be 0wt%-10wt%.

[0175] In some embodiments, based on the mass of the outer layer, the mass content of the delivery agent in the outer layer can be 30wt%-76wt%, the mass content of the auxiliary agent can be 0wt%-40wt%, the mass content of the diluent can be 1wt%-97wt%, the mass content of the binder can be 0wt%-7.5wt%, the mass content of the lubricant can be 0.5wt%-5wt%, and the mass content of the disintegrant can be 0wt%-10wt%.

[0176] In some embodiments, based on the mass of the outer layer, the mass content of the delivery agent in the outer layer can be 30wt%-75wt%, 32wt%-73wt%, 35wt%-70wt%, 37wt%-68wt%, 40wt%-65wt%, 43wt%-62wt%, 45wt%-60wt%, 48wt%-55wt%, 50wt%-75wt%, 52wt%-73wt%, 55wt%-70wt%.

[0177] In some embodiments, based on the mass of the outer layer, the mass content of the auxiliary agent in the outer layer can be 0wt%-40wt%, 0wt%-25wt%, 0.1wt%-40wt%, 1wt%-35wt%, 3wt%-32wt%, 5wt%-30wt%, 7wt%-28wt%, 10wt%-25wt%, 12wt%-23wt%, 15wt%-30wt%, 18wt%-27wt%, 20wt%-25wt%.

[0178] In some embodiments, based on the mass of the outer layer, the mass content of the diluent in the outer layer can be 1wt%-97wt%, 1wt%-95wt%, 1wt%-90wt%, 1wt%-85wt%, 1wt%-80wt%, 1wt%-75wt%, 1wt%-70wt%, 1wt%-65wt%, 1wt%-60wt%, 1wt%-55wt%, 1wt%-50wt%, 1wt%-45wt%, 1wt%-40wt%, 1wt%-35wt%, 1wt%-30wt%, 3wt%-28wt%, 5wt%-25wt%, 7wt%-22wt%, 10wt%-20wt%, 12wt%-18wt%, 15wt%-30wt%, 20wt%-30wt%, 16wt%-36wt%.

[0179] In some embodiments, based on the mass of the outer layer, the mass content of the binder in the outer layer can be 0wt%-7.5wt%, 0wt%-4.2wt%, 0.5wt%-7.5wt%, 0.7wt%-7.0wt%, 0.9wt%-6.5wt%, 1.0wt%-6.0wt%, 1.5wt%-5.5wt%, 2.0wt%-5.0wt%, 2.5wt%-4.5wt%, 3.0wt%-6wt%, 3.5wt%-7.0wt%.

[0180] In some embodiments, based on the mass of the outer layer, the mass content of the lubricant in the outer layer can be 0.5wt%-5wt%, 0wt%-3wt%, 0.8wt%-4.7wt%, 1wt%-4.5wt%, 1.2wt%-4.3wt%, 1.5wt%-4.0wt%, 1.8wt%-3.7wt%, 2wt%-3.5wt%, 2.2wt%-3.8wt%, 2.5wt%-4wt%, 2.7wt%-4.3wt%, 3wt%-4.5wt%, 3.5wt%-5wt%.

[0181] In some embodiments, based on the mass of the outer layer, the mass content of the disintegrant in the outer layer can be 0wt%-10wt%, 0wt%-7wt%, 0.1wt%-10wt%, 0.1wt%-9.5wt%, 0.5wt%-9wt%, 1wt%-8.5wt%, 1.5wt%-8wt%, 2wt%-7.5wt%, 2.5wt%-7wt%, 3wt%-6.5wt%, 3.5wt%-6wt%, 4wt%-5.5wt%, 4.5wt%-6wt%, 5wt%-6.5wt%.

[0182] In some embodiments, based on the mass of the tablet core, the mass content of difacaline in the tablet core is 0.1 wt%-20 wt%, the mass content of the delivery agent may be 30 wt%-75 wt%, the mass content of the auxiliary agent may be 0 wt%-40 wt%, the mass content of the disintegrant may be 0 wt%-10 wt%, the mass content of the diluent may be 1 wt%-30 wt%, the mass content of the binder may be 0 wt%-7.5 wt%, and the mass content of the lubricant may be 0.5 wt%-5 wt%.

[0183] In some embodiments, based on the mass of the tablet core, the mass content of difacaline in the tablet core is 0.1 wt%-20 wt%, the mass content of the delivery agent may be 30 wt%-75 wt%, the mass content of the auxiliary agent may be 0 wt%-95 wt%, the mass content of the disintegrant may be 0 wt%-10 wt%, the mass content of the diluent may be 1 wt%-85 wt%, the mass content of the binder may be 0 wt%-7.5 wt%, and the mass content of the lubricant may be 0.5 wt%-5 wt%.

[0184] In some embodiments, based on the mass of the core, the mass content of dimethicone in the core can be 0.1wt%-20wt%, 0.2wt%-19wt%, 0.5wt%-18wt%, 0.7wt%-17wt%, 0.9wt%-16wt%, 1wt%-15wt%, 1.2wt%-14wt%, 1.5wt%-13wt%, 1.7wt%-12wt%, 2wt%-11wt%, 2.2wt%-10wt%, 2.5wt%-9wt%, 3wt%-8wt%, 4wt%-7wt%, 5wt%-6wt%, 0.6wt%-2.2wt%, 0.6wt%-10wt%.

[0185] In some embodiments, based on the mass of the core, the mass content of the delivery agent in the core can be 30wt%-75wt%, 32wt%-72wt%, 35wt%-70wt%, 37wt%-67wt%, 40wt%-65wt%, 42wt%-62wt%, 45wt%-60wt%, 50wt%-65wt%, 55wt%-70wt%, 60wt%-75wt%, 37.5wt%-67wt%, 45wt%-67wt%, 45wt%-63.5wt%.

[0186] In some embodiments, based on the mass of the core, the mass content of the auxiliary agent in the core can be 0wt%-95wt%, 0wt%-90wt%, 0wt%-80wt%, 0wt%-70wt%, 0wt%-60wt%, 0wt%-50wt%, 0wt%-40wt%, 0.1wt%-40wt%, 0wt%-25wt%, 1wt%-38wt%, 3wt%-35wt%, 5wt%-32wt%, 7wt%-30wt%, 8wt%-25wt%, 10wt%-28wt%, 12wt%-25wt%, 15wt%-22wt%, 18wt%-25wt%, 20wt%-28wt%, 23wt%-30wt%, 25wt%-40wt%.

[0187] In some embodiments, based on the mass of the tablet core, the mass content of the disintegrant in the tablet core can be 0wt%-10wt%, 0.5wt%-10wt%, 1wt%-9.5wt%, 1.5wt%-9wt%, 2wt%-8.5wt%, 2.5wt%-8wt%, 3wt%-7.5wt%, 3.5wt%-7wt%, 4wt%-6.5wt%, 4.5wt%-6wt%, 5wt%-6.5wt%, 5.5wt%-7.5wt%, 6wt%-9wt%, 1.5wt%-6wt%, 2wt%-5.5wt%, 2.5wt%-5wt%, 1.5wt%-4.5wt%, 0wt%-5wt%, 0wt%-6wt%, 0wt%-8wt%, 0wt%-4.2wt%.

[0188] In some embodiments, based on the mass of the core, the mass content of the diluent in the core can be 1wt%-85wt%, 2wt%-80wt%, 5wt%-75wt%, 10wt%-70wt%, 15wt%-65wt%, 20wt%-60wt%, 25wt%-55wt%, 30wt%-50wt%, 35wt%-45wt%, 1wt%-70wt%, 1wt%+60wt%, 1wt%+100wt%, 10wt%+15 ... t%-50wt%, 1wt%-40wt%, 1wt%-30wt%, 2wt%-28wt%, 5wt%-25wt%, 7wt%-23wt%, 10wt%-20wt%, 12wt %-18wt%, 15wt%-20wt%, 17wt%-31wt%, 17wt%-22wt%, 20wt%-25wt%, 23wt%-28wt%, 25wt%-30wt%.

[0189] In some embodiments, based on the mass of the core, the mass content of the binder in the core can be 0wt%-7.5wt%, 0wt%-4.5wt%, 0.5wt%-7.5wt%, 1wt%-7wt%, 1.5wt%-6.5wt%, 2wt%-6wt%, 2.5wt%-5.5wt%, 3wt%-5wt%, 2.5wt%-4.5wt%, 2wt%-4wt%, 1.5wt%-3.5wt%, 1wt%-3wt%, 0.5wt%-2.5wt%, 3.5wt%-5.5wt%, 4wt%-6wt%, 4.5wt%-6.5wt%, 5wt%-7wt%, 6.5wt%-7.5wt%.

[0190] In some embodiments, based on the mass of the core, the mass content of the lubricant in the core can be 0.5wt%-5wt%, 0.8wt%-4.7wt%, 1wt%-4.5wt%, 1.2wt%-4.3wt%, 1.5wt%-4.0wt%, 1.8wt%-3.7wt%, 2wt%-3.5wt%, 2.2wt%-3.8wt%, 2.5wt%-4wt%, 2.7wt%-4.3wt%, 3wt%-4.5wt%, 3.5wt%-5wt%.

[0191] In some embodiments, the delivery agent can be sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC). In some embodiments, the adjuvant can be disodium hydrogen phosphate. In some embodiments, the diluent can include microcrystalline cellulose or mannitol. In some embodiments, the diluent can be microcrystalline cellulose and mannitol. In some embodiments, the binder can be hydroxypropyl cellulose or povidone. In some embodiments, the binder can be hydroxypropyl cellulose. In some embodiments, the lubricant can be magnesium stearate. In some embodiments, the disintegrant can be cross-linked polyvinylpyrrolidone.

[0192] In some embodiments, the core and the outer layer are pressed together, and the outer layer completely wraps the core. In some embodiments, the core can be pressed first, and then the outer layer is wrapped around the core for compression molding. In some embodiments, the outer layer can be formed by pressing at least two tablets or granules up and down, the core is located in the center of the outer layer, and the outer surface of the core fits tightly against the inner wall of the outer layer, forming two parts with completely separated material components. In some embodiments, the core can be a solid body of any shape, including but not limited to at least one of a sphere, a cube, a cuboid, a cylinder, a cone, a truncated cone, a prism, a pyramid, a polyhedron, an ellipse, and a capsule. In some embodiments, the outer layer can be a hollow body of any shape, including but not limited to at least one of a hollow sphere, a hollow cube, a hollow cuboid, a hollow cylinder, a hollow cone, a hollow truncated cone, a hollow prism, a hollow prism, a hollow pyramid, a hollow polyhedron, a hollow ellipsoid, and a hollow capsule.

[0193] In some embodiments, the components included in the core can be uniformly mixed to prepare the first particles. In some embodiments, the components included in the outer layer can be uniformly mixed to prepare the second particles. In some embodiments, the first particles can be compressed by at least two second particles. In some embodiments, the first particle can be placed between two second particles for compression. In some embodiments, a second particle can be pre-compressed to obtain a pre-compressed tablet, a first particle can be placed at the center of the pre-compressed tablet as the core, and another second particle can be placed on the core and compressed to obtain a tablet. In some embodiments, a second particle can be pre-compressed to obtain a pre-compressed tablet, a first particle can be placed at the center of the pre-compressed tablet as the core, and another second particle can be placed on the core on the opposite side of the pre-compressed tablet and compressed to obtain a tablet.

[0194] In some embodiments, for a pharmaceutical composition comprising an outer layer and a core tablet, the release onset of the outer layer may be earlier than the release onset of the core tablet. In some embodiments, the release onset of the outer layer or core tablet is the point in the dissolution profile of the pharmaceutical composition at which the outer layer or core tablet begins to dissolve and release. In some embodiments, the outer layer is not completely dissolved when the core tablet begins to dissolve. In some embodiments, the release onset of the core tablet is 8-35 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 9-33 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 10-30 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 12-28 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 15-25 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 18-23 minutes later than the release onset of the outer layer. In some embodiments, the release onset of the core tablet is 10-20 minutes later than the release onset of the outer layer.

[0195] As used herein, "release point" refers to the time when the drug ingredient begins to dissolve and release.

[0196] As used herein, "about" refers to any value within a ±20% variation, such that "about 10" would include 8 to 12. Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0197] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that can produce a desired response (including preventing or slowing the occurrence of a disease, reducing the severity of a disease, improving the patient's condition, inducing an immune response, delaying or at least slowing the progression of a disease, or curing the disease) in a patient or individual in need thereof, and can be determined by those skilled in the art based on the patient's or individual's age, sex, weight, physical condition, family history, risk of disease, etc. in combination with the contents of this disclosure.

[0198] "Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur. "Optionally includes" means that the subject matter modified may or may not be included. For example, "the particles may include an optional pharmaceutically acceptable inactive ingredient" means that the particles may or may not include the pharmaceutically acceptable inactive ingredient.

[0199] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0200] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0201] The use of any and all examples, or exemplary language, provided herein is intended merely to illustrate certain materials and methods and does not limit the scope. No language in the specification should be construed as indicating any non-claimed element as essential to practice the disclosed materials and methods.

[0202] As shown in this application and claims, unless the context clearly indicates an exception, the words "a", "an", "an" and / or "the" do not specifically refer to the singular and may also include the plural. In general, the terms "comprise", "comprises" and "comprising" and "contain", "contains", "containing" or their equivalents (include, include, including) only indicate that the steps and elements specifically identified are included, and these steps and elements do not constitute an exclusive list. The method or composition may also include other steps or elements. Examples

[0203] The specific embodiments of the present invention will now be described with reference to the following examples. It should be understood that these examples are disclosed only by way of illustration of the present invention and should not limit the scope of the present invention in any way. Unless otherwise stated, the reagents, consumables, instruments, etc. involved in the following examples are all commercially available or can be obtained according to common knowledge in the art. Example 1 - Tablet Composition A

[0204] Weigh 0.1 g of difacillin acetate (calculated as difacillin content, approximately 80%), 0.2 g of povidone K90, 6 g of microcrystalline cellulose, and 0.5 g of magnesium stearate. About one-third of the microcrystalline cellulose and difacillin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Then, povidone K90, magnesium stearate, and the remaining two-thirds of the microcrystalline cellulose were added sequentially and mixed in three dimensions for 10 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0205] 30g of SNAC, 15g of anhydrous disodium hydrogen phosphate, 6g of microcrystalline cellulose, and 0.8g of magnesium stearate were weighed respectively. Anhydrous disodium hydrogen phosphate, magnesium stearate, SNAC, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 20min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 2-5 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0206] 6.8 g of the above-mentioned Granule 1, 38.8 g of Granule 2, and 0.1 g of magnesium stearate were mixed in three dimensions for 5 minutes and tableted using a single punch tablet press to obtain tablets weighing approximately 550 mg. Each tablet contained approximately 1 mg of difazoline. Example 2 - Tablet Composition B

[0207] Weigh 0.1 g of difacillin acetate (calculated as difacillin content, approximately 80%), 0.2 g of povidone K90, 6 g of microcrystalline cellulose, and 0.5 g of magnesium stearate. About one-third of the microcrystalline cellulose and difacillin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Then, povidone K90, magnesium stearate, and the remaining approximately two-thirds of the microcrystalline cellulose were added in sequence and mixed three-dimensionally for 10 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0208] 30g of SNAC, 6g of microcrystalline cellulose, and 0.8g of magnesium stearate were weighed respectively. Magnesium stearate, SNAC, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 20min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 2-5 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0209] 6.8 g of the above-mentioned Granule 1, 25.2 g of Granule 2, and 0.1 g of magnesium stearate were three-dimensionally mixed for 5 minutes and tableted using a single punch tablet press to obtain tablets weighing about 400 mg. The content of difacillin in each tablet was about 1 mg.

[0210] Tablet compositions A and B differ in that tablet composition B does not contain anhydrous disodium hydrogen phosphate. Example 3 - Tablet composition C

[0211] Weigh 0.13 g of difacillin acetate (calculated as difacillin content, approximately 80%), 30 g of SNAC, 15 g of anhydrous disodium hydrogen phosphate, 12 g of microcrystalline cellulose, and 1 g of magnesium stearate. Manually stir and mix approximately 1 / 3 of the microcrystalline cellulose and difacillin acetate for 30 seconds and pass through a No. 4 standard sieve once; then, add SNAC, anhydrous disodium hydrogen phosphate, magnesium stearate, and the remaining approximately 2 / 3 of the microcrystalline cellulose in sequence, and mix three-dimensionally for 10 minutes. Use a single-punch tablet press to compress the tablets to obtain tablets weighing approximately 550 mg, with each tablet containing approximately 1 mg of difacillin. Example 4 - Tablet Composition D

[0212] Weigh 0.1 g of difacillin acetate (calculated as difacillin content, approximately 80%), 0.2 g of povidone K90, 6 g of microcrystalline cellulose, and 0.5 g of magnesium stearate. About one-third of the microcrystalline cellulose and difacillin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Then, povidone K90, magnesium stearate, and the remaining two-thirds of the microcrystalline cellulose were added sequentially and mixed in three dimensions for 10 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0213] 30g of SNAC, 15g of anhydrous disodium hydrogen phosphate, 6g of microcrystalline cellulose, and 0.8g of magnesium stearate were weighed respectively. Anhydrous disodium hydrogen phosphate, magnesium stearate, SNAC, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 20min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 2-5 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0214] 6.8 g of the above-mentioned Granule 1, 38.53 g of Granule 2, and 0.1 g of magnesium stearate were mixed in three dimensions for 5 minutes and tableted using a single punch tablet press to obtain tablets weighing approximately 140 mg. The content of difacillin in each tablet was approximately 0.25 mg. Example 5 - Tablet Composition E

[0215] Weigh 0.1 g of difacillin acetate (calculated as difacillin content, approximately 80%), 0.2 g of povidone K90, 6 g of microcrystalline cellulose, and 0.5 g of magnesium stearate. About one-third of the microcrystalline cellulose and difacillin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Then, povidone K90, magnesium stearate, and the remaining two-thirds of the microcrystalline cellulose were added sequentially and mixed in three dimensions for 10 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0216] 30g of SNAC, 6g of microcrystalline cellulose, and 0.8g of magnesium stearate were weighed respectively. Magnesium stearate, SNAC, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 20min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 2-5 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0217] 6.8 g of the above-mentioned Granule 1, 25.6 g of Granule 2, and 0.1 g of magnesium stearate were three-dimensionally mixed for 5 minutes and tableted using a single punch tablet press to obtain tablets with a tablet weight of about 100 mg. The content of difacillin in each tablet was about 0.25 mg.

[0218] Tablet compositions D and E differ in that Tablet composition E does not contain anhydrous disodium hydrogen phosphate. Example 6 - Tablet composition F

[0219] SNAC (6 g), difalin acetate (approximately 80% difalin content, calculated as difalin) (0.125 g), hydroxypropyl cellulose (0.1 g), microcrystalline cellulose (3 g), crospovidone (0.5 g), anhydrous disodium hydrogen phosphate (3 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, SNAC, anhydrous disodium hydrogen phosphate, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow-concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0220] 14 g of SNAC, 3.5 g of anhydrous disodium hydrogen phosphate, 8 g of microcrystalline cellulose, 0.2 g of hydroxypropyl cellulose, and 0.6 g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30 min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0221] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0222] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 180 mg of Granules 2 are weighed again and added to the mold and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 7 - Tablet Composition G

[0223] SNAC (6 g), hydroxypropyl cellulose (0.1 g), microcrystalline cellulose (3 g), crospovidone (0.5 g), anhydrous disodium hydrogen phosphate (3 g), and magnesium stearate (0.5 g) were weighed separately. SNAC, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, magnesium stearate, crospovidone, and microcrystalline cellulose were added sequentially to a blender and mixed in three dimensions for 15 minutes. Dry granulation was simulated using a single-punch tablet press with a 6x12 mm capsule-shaped, shallow concave tablet die. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0224] 14 g of SNAC, 0.095 g of difalin acetate (calculated as difalin content, approximately 80%), 3.5 g of anhydrous disodium hydrogen phosphate, 8 g of microcrystalline cellulose, 0.2 g of hydroxypropyl cellulose, and 0.6 g of magnesium stearate were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 30 minutes. Dry granulation was simulated using a single-punch tablet press with a 20 mm flat tablet die. The charge was adjusted between 1 and 2 g and the tablet hardness between 1 and 3 kg. After tableting, the mixture was roller compacted, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 2.

[0225] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0226] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 180 mg of Granules 2 are weighed again and added to the mold and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 8 - Tablet Composition H

[0227] SNAC (8 g), difalin acetate (approximately 80% content calculated as difalin), 0.125 g, 0.1 g, 2.8 g, 0.5 g, and 0.5 g of magnesium stearate were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, SNAC, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow-concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0228] 12g of SNAC, 7g of anhydrous disodium hydrogen phosphate, 8g of microcrystalline cellulose, 0.3g of hydroxypropyl cellulose, and 0.7g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0229] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 120 mg.

[0230] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 140 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 140 mg of Granules 2 are weighed again and added to the mold and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 9 - Tablet Composition I

[0231] Weigh 0.125 g of difalin acetate (calculated as difalin content, approximately 80%), 0.5 g of crospovidone, and 11.4 g of anhydrous calcium hydrogen phosphate. Pass the difalin acetate through a No. 4 standard sieve once. Then, add the crospovidone and anhydrous calcium hydrogen phosphate sequentially, and mix three-dimensionally for 15 minutes. Simulate dry granulation using a single-punch tablet press with a 6x12 mm capsule-shaped shallow concave tablet die. Adjust the tableting weight to between 100 and 300 mg and the tableting hardness to between 5 and 10 kg. After tableting, crush the mixture, and collect qualified granules with a particle size between No. 2 and No. 5 standard sieves, designated as Granule 1.

[0232] 20g of SNAC, 4g of anhydrous calcium hydrogen phosphate, 3.5g of microcrystalline cellulose, and 0.5g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0233] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 120 mg.

[0234] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 140 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 140 mg of Granules 2 are weighed again and added to the mold and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 10 - Tablet Composition J

[0235] Weigh 0.125 g of difamoyl acetate (approximately 80% difamoyl acetate content), 0.5 g of hydroxypropyl cellulose, 11 g of microcrystalline cellulose, 1 g of crospovidone, and 0.3 g of magnesium stearate. About one-third of the microcrystalline cellulose and difamoyl acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, and the remaining microcrystalline cellulose were then added in sequence and mixed three-dimensionally for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow-concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0236] 16g of SNAC, 6g of anhydrous disodium hydrogen phosphate, 4.9g of microcrystalline cellulose, 0.5g of hydroxypropyl cellulose, and 0.6g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0237] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 120 mg.

[0238] The tablet core is compressed using the aforementioned Granules 2. Specifically, approximately 140 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 140 mg of Granules 2 are weighed again, added to the mold, and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 11 - Tablet Composition K

[0239] SNAC (6 g), difalin acetate (approximately 80% content calculated as difalin), 0.121 g, 0.09 g, hydroxypropyl cellulose, 2.4 g, 0.6 g, 3 g, and 0.24 g of magnesium stearate were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, SNAC, anhydrous sodium hydrogen phosphate, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6×12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was roller compacted, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0240] 14 g of SNAC, 7 g of anhydrous sodium carbonate, 5.6 g of microcrystalline cellulose, and 0.56 g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous sodium carbonate, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30 min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0241] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 125 mg.

[0242] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 138 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 135 mg of Granules 2 are weighed again and added to the mold and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 12 - Tablet Composition L

[0243] Weigh 0.125 g of difalin acetate (calculated as difalin with approximately 80% content), 0.3 g of hydroxypropyl cellulose, and 13.3 g of anhydrous calcium hydrogen phosphate. Manually stir approximately one-third of the anhydrous calcium hydrogen phosphate with the entire difalin acetate for 30 seconds and pass it through a No. 4 standard sieve. Then, sequentially add the hydroxypropyl cellulose and the remaining anhydrous calcium hydrogen phosphate, and mix three-dimensionally for 15 minutes. Simulate dry granulation using a single-punch tablet press with a 6x12 mm capsule-shaped, shallow concave tablet die. Adjust the tableting weight to between 100 and 300 mg and the tableting hardness to between 5 and 10 kg. After tableting, crush the mixture, and collect qualified granules with a particle size between No. 2 and No. 5 standard sieves and designate them as Granule 1.

[0244] 20g of SNAC, 6g of microcrystalline cellulose, and 0.6g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0245] The above-mentioned Granules 1 and 2 were used to compress a three-layer tablet. Specifically, approximately 133 mg of Granule 2 was weighed and pre-compressed in a single-punch tablet press. Then, 134 mg of Granule 1 was weighed and pre-compressed in a single-punch tablet press. Finally, 133 mg of Granule 2 was weighed and compressed in a single-punch tablet press. The three resulting tablets were then combined to form a three-layer tablet. Example 13 - Tablet Composition M

[0246] SNAC (10 g), difalin acetate (approximately 80% content calculated as difalin), crospovidone (0.5 g), anhydrous sodium hydrogen phosphate (3 g), mannitol (6 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the mannitol and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. SNAC, magnesium stearate, crospovidone, anhydrous sodium hydrogen phosphate, and the remaining mannitol were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6×12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0247] 12g of SNAC, 2g of anhydrous disodium hydrogen phosphate, 2g of microcrystalline cellulose, 2.5g of mannitol, 1g of crospovidone, and 0.5g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, crospovidone, anhydrous disodium hydrogen phosphate, mannitol, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation, and the tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0248] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 200 mg.

[0249] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 100 mg of Granules 2 is weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 100 mg of Granules 2 is weighed again and added to the mold and compressed into a tablet. The finished tablet consists of an outer layer formed by Granules 2 and a tablet core formed by Granules 1, wherein the outer layer completely encapsulates the tablet core. Example 14 - Tablet Composition N

[0250] SNAC (10 g), difalin acetate (approximately 80% content calculated as difalin), crospovidone (0.5 g), anhydrous sodium hydrogen phosphate (3 g), mannitol (6 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the mannitol and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. SNAC, magnesium stearate, crospovidone, anhydrous sodium hydrogen phosphate, and the remaining mannitol were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6×12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0251] 12g of SNAC, 2g of anhydrous disodium hydrogen phosphate, 2g of microcrystalline cellulose, 2.5g of mannitol, 1g of crospovidone, and 0.5g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, crospovidone, anhydrous disodium hydrogen phosphate, mannitol, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation, and the tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0252] 20 g of the above-mentioned Granule 1 and 20 g of Granule 2 were three-dimensionally mixed for 5 minutes and tableted using a single punch tablet press to obtain tablets weighing about 400 mg. The content of difacillin in each tablet was about 1 mg.

[0253] The difference between Tablet Compositions M and N is that Tablet Composition N is a common tablet formed by uniformly mixing Granules 1 and 2 and then pressing them. Example 15 - Tablet Composition O

[0254] SNAC (10 g), difaline acetate (approximately 80% difaline content calculated), povidone K90 (0.5 g), microcrystalline cellulose (4.6 g), anhydrous disodium hydrogen phosphate (5 g), and magnesium stearate (0.3 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difaline acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, povidone K90, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. Dry granulation was simulated using a single-punch tablet press with a 6×12 mm capsule-shaped, shallow concave tablet die. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0255] SNAC 9g, anhydrous disodium hydrogen phosphate 5g, 4g, crospovidone 1.4g, magnesium stearate 0.6g were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, crospovidone and mannitol were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0256] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 200 mg.

[0257] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 100 mg of Granules 2 is weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 100 mg of Granules 2 is weighed again, added to the mold, and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, wherein the outer layer completely encapsulates the core. Example 16 - Tablet Composition P

[0258] SNAC (10 g), difalin acetate (approximately 80% difalin content) (0.24 g), hydroxypropyl cellulose (0.8 g), mannitol (1.8 g), microcrystalline cellulose (1.8 g), anhydrous disodium hydrogen phosphate (5 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, mannitol, magnesium stearate, SNAC, anhydrous disodium hydrogen phosphate, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. Dry granulation was simulated using a single-punch tablet press with a 6×12 mm capsule-shaped, shallow concave tablet die. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was roller compacted, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0259] 10 g of SNAC, 5 g of anhydrous disodium hydrogen phosphate, 1.8 g of microcrystalline cellulose, 1.8 g of mannitol, 0.8 g of hydroxypropyl cellulose, and 0.6 g of magnesium stearate were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, mannitol, and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30 min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0260] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 200 mg.

[0261] The tablet core is compressed using the aforementioned Granule 2. Specifically, approximately 100 mg of Granule 2 is weighed and pre-compressed in a single-punch tablet press. A core tablet is then placed in the center of the pre-compressed tablet. Another approximately 100 mg of Granule 2 is weighed, added to the mold, and compressed into a finished tablet. The finished tablet consists of an outer layer formed by Granule 2 and a core formed by Granule 1, with the outer layer completely encapsulating the core tablet. Each tablet contains approximately 2 mg of difazolin. Example 17 - Tablet Composition Q

[0262] Weigh 7.3 g of SNAC, 0.25 g of difacillin acetate (content calculated based on difacillin is about 80%), 1 g of mannitol, 1 g of microcrystalline cellulose, 1 g of anhydrous disodium hydrogen phosphate, 0.5 g of povidone K90, 0.2 g of crospovidone, and 0.3 g of magnesium stearate respectively. About 1 / 3 of microcrystalline cellulose and difacillin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve once; then mannitol silicon dioxide, magnesium stearate, SNAC, anhydrous disodium hydrogen phosphate, povidone K90, cross-linked povidone and the remaining microcrystalline cellulose were added in sequence and mixed in three dimensions for 15 minutes; a single-punch tablet press was used to simulate dry granulation, and the tableting mold was a 6×12mm capsule-shaped shallow concave tablet. The filling amount was adjusted within the range of 100-300 mg and the tableting hardness was within the range of 5-10 kg. After the tableting was completed, the mixture was crushed and qualified particles with a particle size between the No. 2 and No. 5 standard sieves were collected and recorded as particle one.

[0263] SNAC 6g, anhydrous disodium hydrogen phosphate 3g, microcrystalline cellulose 1g, silicon dioxide 1g, povidone K90 0.5g, crospovidone 0.2g, magnesium stearate 0.3g were weighed respectively. SNAC, magnesium stearate, anhydrous disodium hydrogen phosphate, povidone K90, crospovidone, silicon dioxide and microcrystalline cellulose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0264] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 120 mg.

[0265] The tablet core is compressed using the aforementioned Granules 2. Specifically, approximately 60 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press. A tablet core is then placed in the center of the pre-compressed tablet. Another approximately 60 mg of Granules 2 is weighed and added to the mold and compressed. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1. The outer layer completely encapsulates the core. Each tablet contains approximately 2 mg of difazolin. Example 18 - Tablet Composition R

[0266] SNAC (6 g), difalin acetate (approximately 80% difalin content calculated), 0.12 g, hydroxypropyl cellulose (0.1 g), microcrystalline cellulose (3 g), crospovidone (0.5 g), anhydrous disodium hydrogen phosphate (3 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, SNAC, anhydrous disodium hydrogen phosphate, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6×12 mm capsule-shaped, shallow-concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0267] Weigh 3.5g of anhydrous disodium hydrogen phosphate, 11g of microcrystalline cellulose, 11g of mannitol, 0.2g of hydroxypropyl cellulose, and 0.6g of magnesium stearate. Add magnesium stearate, anhydrous disodium hydrogen phosphate, hydroxypropyl cellulose, mannitol, and microcrystalline cellulose to the mixer in sequence and mix them in three dimensions for 30min. Use a single punch tablet press to simulate dry granulation, and the tableting mold is For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0268] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0269] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 180 mg of Granules 2 are weighed again and added to the mold and compressed into a tablet. The finished tablet consists of an outer layer formed by Granules 2 and a tablet core formed by Granules 1, with the outer layer completely encapsulating the tablet core. Example 19 - Tablet Composition S

[0270] SNAC (6 g), difalin acetate (approximately 80% difalin content calculated), 0.12 g, hydroxypropyl cellulose (0.1 g), microcrystalline cellulose (3 g), crospovidone (0.5 g), anhydrous disodium hydrogen phosphate (3 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, crospovidone, SNAC, anhydrous disodium hydrogen phosphate, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6×12 mm capsule-shaped, shallow-concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0271] Weigh 12g of microcrystalline cellulose, 12g of mannitol, 0.2g of hydroxypropyl cellulose, and 0.6g of magnesium stearate respectively. Add magnesium stearate, hydroxypropyl cellulose, mannitol, and microcrystalline cellulose to the mixer in sequence and mix them in three dimensions for 30min. Use a single punch tablet press to simulate dry granulation. The tableting mold is For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0272] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0273] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 180 mg of Granules 2 are weighed again and added to the mold and compressed into a tablet. The finished tablet consists of an outer layer formed by Granules 2 and a tablet core formed by Granules 1, with the outer layer completely encapsulating the tablet core. Example 20 - Tablet Composition T

[0274] SNAC (6 g), difalin acetate (approximately 80% difalin content, calculated as difalin) (0.125 g), maltodextrin (4 g), and anhydrous disodium hydrogen phosphate (3 g) were weighed separately. Approximately one-third of the maltodextrin and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. SNAC, anhydrous disodium hydrogen phosphate, and the remaining maltodextrin were then added sequentially and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0275] 14 g of SNAC, 3.5 g of anhydrous disodium hydrogen phosphate, and 8 g of maltodextrin were weighed respectively. SNAC, anhydrous disodium hydrogen phosphate, and maltodextrin were added to the mixer in sequence and mixed in three dimensions for 30 min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0276] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0277] The tablet core is compressed using the above-mentioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press; a tablet core is then placed in the center of the pre-compressed tablet; approximately 180 mg of Granules 2 are weighed again and added to the mold and compressed into a tablet. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core. Example 21 - Tablet Composition U

[0278] SNAC (6 g), difalin acetate (approximately 80% difalin content calculated), 0.125 g, hydroxypropyl cellulose (0.1 g), lactose (3 g), crospovidone (0.5 g), anhydrous disodium hydrogen phosphate (3 g), and sodium stearyl fumarate (0.5 g) were weighed separately. Approximately one-third of the lactose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, sodium stearyl fumarate, crospovidone, SNAC, anhydrous disodium hydrogen phosphate, and the remaining lactose were then added in sequence and mixed in three dimensions for 15 minutes. A single-punch tablet press was used to simulate dry granulation, using a 6x12 mm capsule-shaped, shallow concave tablet mold. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was crushed, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0279] 14g of SNAC, 8g of lactose, 0.2g of hydroxypropyl cellulose, and 0.6g of sodium stearyl fumarate were weighed respectively. SNAC, sodium stearyl fumarate, hydroxypropyl cellulose, and lactose were added to the mixer in sequence and mixed in three dimensions for 30min. A single punch tablet press was used to simulate dry granulation. The tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0280] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0281] The tablet core is compressed using the aforementioned Granules 2. Specifically, approximately 180 mg of Granules 2 are weighed and pre-compressed in a single-punch tablet press. A core tablet is then placed in the center of the pre-compressed tablet. Another approximately 180 mg of Granules 2 is weighed and added to the mold and compressed. The finished tablet consists of an outer layer formed by Granules 2 and a core formed by Granules 1, with the outer layer completely encapsulating the core tablet. Example 22 - Tablet Composition V

[0282] SNAC (6 g), difalin acetate (approximately 80% difalin content) (1.6 g), hydroxypropyl cellulose (0.1 g), microcrystalline cellulose (2 g), mannitol (2 g), croscarmellose sodium (0.8 g), anhydrous disodium hydrogen phosphate (3 g), and magnesium stearate (0.5 g) were weighed separately. Approximately one-third of the microcrystalline cellulose and difalin acetate were manually stirred and mixed for 30 seconds and passed through a No. 4 standard sieve. Hydroxypropyl cellulose, magnesium stearate, croscarmellose sodium, SNAC, anhydrous disodium hydrogen phosphate, mannitol, and the remaining microcrystalline cellulose were then added in sequence and mixed in three dimensions for 15 minutes. Dry granulation was simulated using a single-punch tablet press with a 6×12 mm capsule-shaped, shallow concave tablet die. The tableting weight was adjusted to between 100 and 300 mg, and the tableting hardness was between 5 and 10 kg. After tableting, the mixture was roller compacted, and qualified granules with a particle size between No. 2 and No. 5 standard sieves were collected and designated as Granule 1.

[0283] 14 g of SNAC, 4 g of microcrystalline cellulose, 4 g of mannitol, 0.2 g of hydroxypropyl cellulose, 0.6 g of magnesium stearate, 5 g of anhydrous disodium hydrogen phosphate, and 1.2 g of cross-linked sodium carboxymethyl cellulose were weighed respectively. SNAC, magnesium stearate, hydroxypropyl cellulose, microcrystalline cellulose, anhydrous disodium hydrogen phosphate, cross-linked sodium carboxymethyl cellulose, and mannitol were added to the mixer in sequence and mixed in three dimensions for 30 min. A single punch tablet press was used to simulate dry granulation, and the tableting mold was For flat tablets, adjust the loading amount to be within the range of 1-2 g and the tableting hardness to be within the range of 1-3 kg. After tableting, crush the mixture and collect qualified particles with a particle size between No. 2 and No. 5 standard sieves, which are recorded as particles 2.

[0284] The above granules were compressed into tablets using a single punch tablet press to obtain tablet cores with a tablet weight of about 140 mg.

[0285] The above-mentioned granules 2 are used to compress the above-mentioned tablet core. The specific operation is to weigh about 180 mg of granules 2 and pre-compress them in a single-punch tablet press; then place a tablet core at the center of the pre-compressed tablet; weigh about 180 mg of granules 2 again, add them to the mold and compress them into shape. The finished tablet consists of an outer layer formed by granules 2 and a tablet core formed by granules 1, and the outer layer completely wraps the tablet core inside.

[0286] Example 23 - Animal Pharmacokinetic Experiment

[0287] Healthy male beagle dogs were selected as test animals and randomly divided into groups before the experiment. The housing and experimental environment: temperature 20-26°C (diurnal temperature range ≤ 4°C), relative humidity 40-70%, artificial lighting with 12 / 12 hour light / dark alternation. Animals were allowed to acclimate to the environment for at least 5 days before the experiment.

[0288] Beagle dogs in Group A were administered tablet composition D, beagle dogs in Group B were administered tablet composition E, beagle dogs in Group C were administered tablet composition F, and beagle dogs in Group D were administered tablet composition G. Each animal was administered one tablet at a time. Administration was via oral gavage. Specifically, the tablet was placed in the dog's throat, the mouth was sealed, and 10 mL of purified water was immediately administered after the dog swallowed it. The dog was restrained in a standing position before administration and released 1 hour after administration.

[0289] Fasting: The animals were fasted overnight on the day of the experiment (T1), starting at least 8 hours before dosing and feeding for the first time 4 hours after dosing. Water deprivation: Water deprivation was started at least 1 hour before dosing and free access to water was restored 2 hours after dosing.

[0290] Observation during the feeding and testing process: including but not limited to the animal's physical signs, coat, general behavior, mental state, glandular secretions, skin and mucous membrane color, respiratory status, fecal characteristics, genitals, death, etc. If any abnormality is found, it is necessary to determine whether to terminate the test.

[0291] Sampling was performed 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 12 hours after administration. The sampling site was the forelimb vein, and no less than 0.5 mL of plasma was collected per time point (approximately 1 mL of blood was collected at each time point, and no less than 0.5 mL of plasma was obtained after anticoagulation and centrifugation for blood drug concentration testing). The anticoagulant EDTA was added to the sample. After sample collection at each time point, the sample was centrifuged at approximately 3000 rpm for 10 minutes to separate the plasma, and the concentration of difacillin in the plasma was measured.

[0292] The maximum blood drug concentration (C max ), time to peak blood concentration (T max ), area under the curve (AUC last) are shown in Tables 1 to 4 below, along with the individual data, relative variability (RSD), and absolute bioavailability (F%).

[0293] Table 1 - Tablet Composition D - Strength 0.25 mg

[0294] Table 2 - Tablet Composition E - Strength 0.25 mg

[0295] Table 3 - Tablet Composition F - Strength 1.0 mg

[0296] Table 4 - Tablet Composition G (API in Outer Layer) - Strength 1.0 mg

[0297] Comparing Tables 1 and 2, we can see that C in Table 1 max The RSD variability is lower than that of C in Table 2 max The absolute bioavailability in Table 1 is higher than the absolute bioavailability F% in Table 2. Therefore, compared with the beagle dogs given the drug without the adjuvant (i.e., sodium hydrogen phosphate) in Table 2, the variability of the peak plasma concentration of difacillin Cmax among the beagle dogs given the drug containing the adjuvant in Table 1 is reduced, and the absolute bioavailability F% is improved. It can be seen that when difacillin, the delivery agent and the adjuvant are taken as a combination, the peak plasma concentration of difacillin Cmax among individuals can be effectively reduced compared with the combination of difacillin and the delivery agent without the adjuvant. max The variability of the absolute bioavailability is increased by F%. That is, the adjuvant in the present disclosure can effectively reduce the peak blood concentration of FALIN between individuals. max The variability of the drug content was increased by F%.

[0298] Comparing Tables 1 and 3, we can see that C in Table 1 max The RSD variability was 63.2%, and the AUC last The RSD variability was 65.3% and the absolute bioavailability was 9.22%. max The RSD variability was reduced to 28.9%, and the AUC last The RSD variability was reduced to 33.8% and the absolute bioavailability was 15.87%. Therefore, compared with the beagle dogs given the ordinary tablets in Table 1, the drug given in Table 3 is the tablet with a specific structure (including the outer layer and the core) of the present disclosure. After administration, the peak blood concentration of difacillin between the beagle dogs was C max and bioavailability AUC lastThe variability of the drug composition was significantly reduced, and the absolute bioavailability F% was significantly improved. It can be seen that compared with the pharmaceutical composition in the form of ordinary tablets, the pharmaceutical composition with a specific structure disclosed in the present invention can effectively reduce the peak blood concentration of the drug C between individuals. max and bioavailability AUC last The variability of the drug composition disclosed herein can effectively reduce the peak blood concentration of FALIN between individuals. max and bioavailability AUC last The variability of the drug content was increased by F%.

[0299] Comparing Tables 3 and 4, we can see that C max The RSD variability was 85.5%, and the AUC last The RSD variability was 54.1%, the absolute bioavailability F% was 4.70%, and the C max The RSD variability was reduced to 28.9%, and the AUC last The RSD variability was reduced to 33.8% and the absolute bioavailability F% was 15.87%. Therefore, the peak plasma concentration of difacillin in beagle dogs given the drug in which difacillin was disposed in the outer layer in Table 4 was significantly lower than that in beagle dogs given the drug in which difacillin was disposed in the core tablet in Table 3. max and bioavailability AUC last The variability of the drug composition with an outer layer and a core tablet structure is significantly reduced, and the absolute bioavailability F% is significantly improved. Therefore, it can be seen that for a drug composition with an outer layer and a core tablet structure, compared with a drug composition with difacillin disposed in the outer layer, when taking a drug composition with difacillin disposed in the core tablet, the peak blood concentration C of difacillin between individuals can be effectively reduced. max and bioavailability AUC last The variability of difacillin can improve the absolute bioavailability by F%. That is, the pharmaceutical composition of difacillin provided in the core of the tablet in the present disclosure can effectively reduce the peak plasma concentration of difacillin between individuals. max and bioavailability AUC last The variability of the product can improve the absolute bioavailability by F%.

[0300] The pharmacokinetic test method of Example 20 was used to test the compositions H, I, J, K, L, M, N, O, P, Q, R, S and T prepared above. The experimental results showed that, similar to the differences in bioavailability and variability between tablet composition D (ordinary tablet) and tablet composition F (tablet with a specific structure of the present disclosure), the absolute bioavailability F% of tablet compositions M, O, P and Q (tablet with a specific structure of the present disclosure) was 15.5%-17.2%, which was significantly improved by at least 60% compared with tablet composition N (ordinary tablet), and the AUC of tablet compositions M, O, P and Q was 1.5%-1.7%.last The variability was reduced by 27.4% to 57.2% compared to the variability of tablet composition N. In addition, the AUC of tablet composition H (with a delivery agent but no excipient in the core and a delivery agent and excipient in the outer layer) was significantly lower than that of tablet composition F. last The RSD variability was basically unchanged, and the absolute bioavailability F% decreased by 16.2%. The AUC of tablet composition K (the outer layer auxiliary agent is anhydrous sodium carbonate) last The RSD variability was 45% and the absolute bioavailability F% was 4.5%. The AUC of tablet composition L (three-layer tablet structure) last The RSD variability was 54.1% and the absolute bioavailability F% was only 3.73%. The AUC of tablet composition I (tablet core without delivery agent but with excipient, outer layer with delivery agent and excipient) last The RSD variability was 78.6% and the absolute bioavailability F% was 5.03%. The AUC of tablet composition J (tablet core without delivery agent and auxiliary agent, outer layer with delivery agent and auxiliary agent) last The RSD variability was 84% ​​and the absolute bioavailability F% was 3.92%. The AUC of tablet composition R (tablet core with adjuvant and delivery agent, outer layer without delivery agent but with adjuvant) last The RSD variability was 41% and the absolute bioavailability F% was 6.34%. The AUC of tablet composition S (tablet core with delivery agent and auxiliary agent, outer layer without delivery agent and auxiliary agent) last The RSD variability was 49% and the absolute bioavailability F% was 4.18%. The AUC values ​​for tablet composition T (core tablet containing only difacoum, delivery agent, adjuvant and diluent, outer layer containing only delivery agent, adjuvant and diluent), tablet composition U (core tablet containing delivery agent and adjuvant, outer layer containing delivery agent but no adjuvant) and tablet composition V were 2.37 ± 0.13, 1.37 ± 0.17, and 1.37 ± 0.16, respectively. last The RSD variability and absolute bioavailability F% were substantially comparable to those of tablet compositions F, M, O, P, and Q. Example 24 - Animal Efficacy Study

[0301] Male C57BL / 6J mice were acclimated to the environment for at least 7 days before the experiment and randomly divided into 4 groups: negative control group (administered with normal saline, without modeling), pruritus model group (administered with normal saline, with modeling), commercially available difacillin injection group (0.25 mg / kg, calculated as difacillin, the trade name of which is KORSUVA TMThe animals were divided into two groups (prepared according to the formulation of Tablet Composition F, 24 mg / kg, calculated as difacillin, administered orally for modeling), with 12 animals in each group. Animals were first dosed according to group, and approximately 15 minutes after dosing, modeling was initiated (itching was induced by subcutaneous injection of 0.3 mg / kg 5'GNTI behind the neck). After modeling, each animal was videotaped for 30 minutes, and the number of scratching behaviors caused by itch within 30 minutes was manually counted (rapid scratching of the ears, neck, and flanks by lifting the hind paw, with each scratch counted as one hind paw drop or nibbling). Compared with the untreated itch model group, scratching was suppressed in animals that had been pre-administered difacillin, either orally or by injection. The lower the average number of scratches within 30 minutes in each group, the stronger the drug's anti-itching efficacy.

[0302] Results: The average number of scratching in the negative control group was 20±17 times (n=12), and the average number of scratching in the pruritus model group was 345±168 times (n=12), which was significantly higher than that in the negative control group (P<0.001), indicating that the model was successfully established.

[0303] When commercially available difacillin injection was given to itchy mice 15 minutes in advance, the average number of scratching decreased to 144±166 times, which was significantly lower than that of the itchy model group (P<0.01), indicating that difacillin can significantly inhibit the itching of mice through intravenous injection.

[0304] When oral administration of difacillin to pruritus mice 15 minutes in advance, the average number of scratching decreased to 110±119 times (P<0.01), indicating that oral administration of difacillin can achieve similar efficacy as difacillin injection. Table 5 Results of animal pruritus model test Note: The data in the table are expressed as mean ± standard deviation (Mean ± SD). Compared with the negative control group, ###P<0.001; compared with the model group, **P<0.01, ***P<0.001.

[0305] While the basic concepts have been described above, it will be apparent to those skilled in the art that the detailed disclosure is merely illustrative and does not limit the present disclosure. Although not explicitly stated herein, those skilled in the art may make various modifications, improvements, and revisions to the present disclosure. Such modifications, improvements, and revisions are suggested in the present disclosure and remain within the spirit and scope of the exemplary embodiments of the present disclosure.

[0306] At the same time, the present disclosure uses specific words to describe the embodiments of the present disclosure. For example, "in certain embodiments," "in various embodiments," "one embodiment," "an embodiment," and / or "some embodiments" refer to a certain feature, structure, or characteristic related to at least one embodiment of the present disclosure. Therefore, it should be emphasized and noted that "in certain embodiments," "in various embodiments," "one embodiment," "an embodiment," and / or "some embodiments" mentioned twice or more in different locations in the present disclosure do not necessarily refer to the same embodiment. In addition, certain features, structures, or characteristics in one or more embodiments of the present disclosure may be appropriately combined.

[0307] Although the above disclosure discusses some presently useful embodiments of the invention through various examples, it should be understood that such details are for illustrative purposes only and the appended claims are not limited to the disclosed embodiments. On the contrary, the claims are intended to cover all modifications and equivalent combinations that are consistent with the spirit and scope of the embodiments of the present disclosure.

[0308] Similarly, it should be noted that in order to simplify the description of the present disclosure and facilitate understanding of one or more embodiments of the invention, the foregoing description of the embodiments of the present disclosure sometimes combines multiple features into a single embodiment. However, this disclosure method does not mean that the present disclosure requires more features than those mentioned in the claims.

[0309] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0310] Finally, it should be understood that the embodiments described in this disclosure are intended only to illustrate the principles of the embodiments of the present disclosure. Other variations may also fall within the scope of this disclosure. Therefore, by way of example and not limitation, alternative compositions of the embodiments of the present disclosure may be considered consistent with the teachings of this disclosure. Accordingly, the embodiments of the present disclosure are not limited to the embodiments explicitly described and illustrated in this disclosure.

Claims

1. An oral pharmaceutical composition of difelikefalin, comprising an outer layer and a tablet core, the outer layer wrapping the tablet core, wherein, the tablet core comprises difelikefalin and a delivery agent; the outer layer comprises a delivery agent.

2. The pharmaceutical composition according to claim 1, wherein, The tablet core further comprises an adjuvant, and / or the outer layer further comprises an adjuvant.

3. An oral pharmaceutical composition of difelikefalin, wherein, The pharmaceutical composition comprises an outer layer and a tablet core, the outer layer wrapping the tablet core, wherein, the outer layer does not contain difelikefalin, the outer layer comprises a delivery agent, an adjuvant and optionally a pharmaceutically acceptable inactive ingredient; and the tablet core comprises difelikefalin and optionally a pharmaceutically acceptable inactive ingredient.

4. The pharmaceutical composition according to claim 3, wherein, The tablet core further comprises a delivery agent and / or an adjuvant.

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The tablet core further comprises a diluent.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The tablet core further comprises a lubricant.

7. The pharmaceutical composition according to any one of claims 1-6, wherein, The tablet core further comprises a disintegrant and / or a binder.

8. The pharmaceutical composition according to any one of claims 1-7, wherein, The tablet core comprises difelikefalin, a delivery agent and an adjuvant, and one or more of a diluent, a lubricant, a disintegrant and a binder; and / or the outer layer comprises a delivery agent and one or more of the following: an adjuvant, a diluent, a lubricant, a disintegrant and a binder.

9. The pharmaceutical composition according to any one of claims 1-8, wherein, The delivery agent is one or more selected from N-[8-(2-hydroxybenzoyl)amino]octanoic acid (NAC), N-[6-(2-hydroxybenzoyl)amino]hexanoic acid (NAH), N-[10-(2-hydroxybenzoyl)amino]decanoic acid (NAD), N-[8-(5-chlorosalicyl)amino]octanoic acid (5-CNAC), N-[8-(2-hydroxy-4-methoxybenzoyl)amino]octanoic acid (4-MOAC), N-[4-(2-hydroxy-4-chlorobenzoyl)amino]butyric acid (4-CNAB) and pharmaceutically acceptable salts thereof.

10. The pharmaceutical composition according to any one of claims 1-9, wherein, The delivery agent is one or more selected from sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC), potassium N-[8-(2-hydroxybenzoyl)amino]octanoate and / or calcium N-[8-(2-hydroxybenzoyl)amino]octanoate.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, The delivery agent is SNAC.

12. The pharmaceutical composition according to any one of claims 1-11, wherein, The adjuvant comprises one or more of the following compounds: sodium phosphate, disodium hydrogen phosphate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, hydrotalcite and other pharmaceutically acceptable salts with the same acid radical.

13. Use of a pharmaceutical composition according to any one of claims 1-12 in the preparation of a medicament for treating and / or preventing pruritus associated with chronic kidney disease, pruritus associated with chronic liver disease, atopic dermatitis.

14. A method for treating and / or preventing pruritus associated with chronic kidney disease, pruritus associated with chronic liver disease, atopic dermatitis, the method comprising orally administering a pharmaceutical composition according to any one of claims 1-12 to a subject in need thereof.

15. A pharmaceutical composition according to any one of claims 1-12 for treating and / or preventing pruritus associated with chronic kidney disease, pruritus associated with chronic liver disease, atopic dermatitis.

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