Methods and pharmaceutical compositions for treating diseases

Abstract

The present application relates to new polymorphs of (R)-praziquantel, anhydride (R)-2(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH), compositions containing said polymorphs, and methods for preparing pharmaceutical formulations containing said polymorphs. The invention also provides improved methods of their use for controlling, treating and preventing zoonotic and parasitic diseases in humans and animals, which comprises administering to a subject in need thereof a therapeutically effective amount of an active agent using the pharmaceutical formulations of the invention.

Description

Technical Field

[0001] The present invention generally relates to new polymorphs of (R)-praziquantel, anhydrous (R)-2(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH), compositions containing such polymorphs, methods for manufacturing pharmaceutical formulations containing such polymorphs, and methods for their use in the treatment of diseases.

Background Art

[0002] Parasitic flatworms of the phylum Platyhelminthes infect (endoparasitize) and parasitize (epiparasitize) vertebrates, showing a diverse spectrum of organisms. In addition to common parasitic and zoonotic infections in humans, pet animals, and production animals, farmed animals including fish have been functioning as definitive and intermediate hosts for various flatworm parasites. It is estimated that more than 500 million people worldwide are suffering from or at risk of many parasitic zoonotic infections, posing a major threat to global health for both humans and animals.

[0003] Praziquantel is a synthetic pyrazine-isoquinoline derivative, a white or off-white crystalline powder with a bitter taste. This agent is recognized worldwide as an anti-parasitic drug that is very effective and has a broad spectrum against a wide variety of tapeworms (cestodes) and flukes (trematodes). Praziquantel is an important anti-flatworm parasite therapeutic drug in both human and veterinary medicine. It is widely used in the treatment of diseases such as Schistosoma japonicum infection, schistosomiasis, Schistosoma mansoni infection, clonorchiasis, paragonimiasis, Fasciolopsis buski infection, echinococcosis, taeniasis, and cysticercosis. It is also widely used not only for human use but also for anti-parasitic treatment of animals such as poultry farming and aquaculture.

[0004] Currently available praziquantel is a racemic compound containing 50% each of the (R)-praziquantel and (S)-praziquantel isomers. Scientists have isolated and obtained both pure optical isomers from racemic praziquantel and, in preclinical and preliminary clinical trials, have found the following: (R)-praziquantel is the effective parasitic component of praziquantel, while (S)-praziquantel is inactive or even harmful. Therefore, the development of (R)-praziquantel has potential clinical value in terms of higher efficacy, fewer side effects, and better medical compliance.

[0005] Many small molecule drugs and active pharmaceutical ingredients (APIs) are known to exist in different crystalline forms, i.e., polymorphs. In particular, when water is incorporated into the crystal lattice and crystalline hydrates are formed, the thermodynamic uncertainty can lead to drug substances that are difficult to formulate. In addition to variability in hydrate stability, the presence of both stoichiometric and non-stoichiometric behaviors presents further problems, requiring non-trivial solutions. Polymorphs can unexpectedly affect solubility, stability, and bioavailability, and may exhibit undesirable physical, chemical, and pharmaceutical properties. The unpredictability of such polymorphic crystalline forms or mixtures can affect the safety and efficacy of these drugs when administered to humans or animals. Therefore, the physicochemical properties, manufacturing, shelf life, and physiological activity of APIs and pharmaceuticals are strictly regulated by regulatory agencies worldwide, including the U.S. Food and Drug Administration.

[0006] (R)-praziquantel is generally known to exist as a hemihydrate or monohydrate (Meyer et al., 2009 and Cedillo-Cruz et al., 2014). The theoretical weight loss of this molecule is estimated to be 5.7% for the monohydrate and 2.8% for the hemihydrate. Chinese invention patent CN104327077A discloses a crystalline form of (R)-praziquantel, and its X-ray diffraction pattern (Cuk α emission) shows the following seven diffraction peaks: 2θ 6.9±0.2°, 8.3±0.2°, 15.1±0.2°, 19.8±0. 2°, 21.9±0.2°, 24.3±0.2°. However, there are no reports yet on formulations containing specific (R)-praziquantel crystals or their storage stability.

[0007] Because active pharmaceutical ingredients are stored under various conditions such as temperature, solvent, and humidity, they are susceptible to degradation. Therefore, controlling potential changes in hydrates and chiral drug molecules during processing and storage of pharmaceuticals, as well as in the development of the final formulation, is a challenge. Consequently, it is desirable to identify and characterize novel crystalline forms of (R)-praziquantel that offer advantages compared to other solid forms in the manufacture, processing, formulation, or administration of the compound. Furthermore, the reliable production of selected polymorphs is a crucial factor in determining the success of the final pharmaceutical product.

[0008] We have recently discovered that (R)-praziquantel exists as an extremely stable anhydrous crystal. This unusually stable form exhibits desirable physicochemical and pharmaceutical properties, resulting in reproducibly high drug purity and enabling its development as a pharmaceutical product on an industrial scale. [Overview of the project]

[0009] One aspect of this disclosure provides a novel polymorph of (R)-praziquantel, namely form B.

[0010] In one embodiment, form B is (R)-praziquantel anhydride, which has a characteristic peak in the XRPD pattern at a 2θ value of 13.1±0.2°, preferably 13.1±0.1°. As used herein, the term “anhydride” refers to a crystalline form of the compound containing 0.2 moles or less of water per molecule of the compound, and can be expressed as substantially anhydride.

[0011] In a further embodiment, form B is an anhydrous (R)-praziquantel having a water content between 0 and about 1% w / w (0.17 mol water equivalent) as measured by a standard Karl Fischer detection procedure, preferably between about 0 and about 0.6%, more preferably between about 0 and about 0.5%. In a detailed embodiment, form B is an anhydrous (R)-praziquantel having a water content of about 0.26% ((R)-praziquantel:water ratio of 20:1 or less).

[0012] In one embodiment, the B-form crystals of the present invention are substantially isolated. "Substantially isolated" means that a particular crystalline form of the compound of formula B is at least partially isolated from impurities. For example, in some embodiments, the B-form crystals contain less than about 1% or less than about 0.5% impurities. The impurities generally include, for example, other crystalline forms and other substances and their optical isomers, which are not substantially isolated crystalline forms.

[0013] In one embodiment, (R)-praziquantel B is (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one, and the water of crystallization content is less than 0.2 mol per molecule.

[0014] In one embodiment, (R)-praziquantel B is (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one, with a crystal water content of approximately 0.1 mol per molecule.

[0015] In one embodiment, (R)-praziquantel B is (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one, and no water of crystallization is present.

[0016] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 8.6 ± 0.2° at 100% relative intensity.

[0017] In further embodiments, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 13.1±0.2° with a relative intensity of 3% or more. In some preferred embodiments, the relative intensity of the diffraction peak at 13.1±0.2° is less than 7%. In even more preferred embodiments, the relative intensity of the diffraction peak at 13.1±0.2° is less than 5%.

[0018] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 17.9 ± 0.2°.

[0019] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 19.3 ± 0.2°.

[0020] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 20.1 ± 0.2°.

[0021] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 20.9 ± 0.2°.

[0022] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 22.3 ± 0.2°.

[0023] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 24.8 ± 0.2°.

[0024] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 27.8 ± 0.2°.

[0025] In a further embodiment, the X-ray diffraction pattern of (R)-praziquantel B (Cuk α emission) shows a diffraction peak at 31.2 ± 0.2°.

[0026] In a further aspect, the X-ray diffraction pattern (CuK α radiation) of the (R)-praticantel B form shows diffraction peaks at 34.5 ± 0.2°.

[0027] In some aspects, the X-ray diffraction pattern (CuK α radiation) of the (R)-praticantel B form shows diffraction peaks at 7.2 ± 0.2°, 8.6 ± 0.2°, 13.1 ± 0.2°, 15.3 ± 0.2°, 20.1 ± 0.2°, 19.3 ± 0.2°, 24.1 ± 0.2°, and 24.8 ± 0.2°.

[0028] In another aspect, the X-ray diffraction pattern (CuK α radiation) of the (R)-praticantel B form shows diffraction peaks at 7.2 ± 0.2°, 8.6 ± 0.2°, 13.1 ± 0.2°, 13.8 ± 0.2°, 14.4 ± 0.2°, 15.3 ± 0.2°, 16.0 ± 0.2°, 16.9 ± 0.2°, 17.9 ± 0.2°, 18.2 ± 0.2°, 19.3 ± 0.2°, 20.1 ± 0.2°, 20.9 ± 0.2°, 22.3 ± 0.2°, 24.1 ± 0.2°, 24.8 ± 0.2°, 25.8 ± 0.2°, 27.8 ± 0.2°, and 31.2 ± 0.2°.

[0029] In another aspect, the X-ray diffraction pattern (CuK α radiation) of the (R)-praticantel B form shows diffraction peaks at 7.2 ± 0.2°, 8.6 ±​​​​​Diffraction peaks are observed at °, 16.9±0.2°, 17.9±0.2°, 18.2±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.8±0.2°, 27.8±0.2°, 31.2±0.2°, and 34.5±0.2°.

[0031] In some embodiments, the moisture content of (R)-praziquantel B is less than 0.6% (w / v). In some other embodiments, the moisture content of (R)-praziquantel B is less than 0.3% as measured by a standard Karl Fischer detection procedure.

[0032] Physically, anhydrous crystals according to one aspect of the present disclosure are obtained as a white powder consisting of aggregates of birefringent rod-shaped or needle-shaped crystals.

[0033] As a typical example, the X-ray diffraction pattern (Cuk α emission) of (R)-praziquantel B is substantially identical to that of Figure 1.

[0034] As a typical example, anhydrous type B crystals are characterized by differential scanning calorimetry thermograms that exhibit endothermic properties with a peak temperature of approximately 112.5°C.

[0035] The novel B-form crystals of (R)-praziquantel have a significantly lower water content compared to all known hemihydrate and monohydrate crystal forms. Remarkably, it also exhibits long-term stability under a variety of storage conditions.

[0036] One aspect of this disclosure is to provide pharmaceutical formulations comprising one or more crystalline forms of (R)-praziquantel, particularly form B, having advantageous therapeutic effects. Related objectives include providing compositions and methods for enabling formulations of (R)-praziquantel to induce and maintain a desired pharmacokinetic response in subjects requiring it. The crystals of the present invention can be administered alone or in the form of pharmaceutical compositions in combination with pharmaceutically acceptable carriers or excipients, the proportion and properties thereof determined by the solubility and chemical properties of the selected compound, the selected route of administration, and standard pharmaceutical practice. Another objective of this disclosure is to provide methods for treating schistosomiasis and other disorders transmitted by infections caused by trematodes, tapeworms, and other parasites using such formulations. Preferably, the subject may be an animal, more preferably a warm-blooded animal, even more preferably a mammal, such as a human or non-human mammal or a fish.

[0037] For oral administration, the composition may be formulated as tablets, capsules, pills, chewable tablets, dragees, lozenges, liquids, semi-solid gels and pastes, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated.

[0038] Furthermore, for intravenous or subcutaneous administration, the composition can be formulated in a solution, preferably a physiologically suitable buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulations such as suspensions, stabilizers, and / or dispersants. In certain embodiments, the composition is formulated in a sterile solution.

[0039] The composition may further contain a pharmaceutically acceptable carrier. The term "carrier" refers to a diluent, excipient, or hibicle (solvent) for administering the therapeutic agent. The carrier or excipient may be a solid, semi-solid, or liquid material and may function as a solvent or hibicle for the active ingredient. In addition to the formulations described above, this composition may also be formulated as a depot formulation. Such formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intravascular or intramuscular injection.

[0040] Furthermore, the composition is a semipermeable matrix of solid polymers containing the composition, such as a sustained-release cis It can be delivered using Tem.

[0041] For oral administration, the pharmaceutical composition may take the form of tablets, capsules, or chews or pastes prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pre-gelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid or semi-solid formulations for oral administration may take the form of solutions, syrups, or suspensions, or may be presented as soft chews or paste products to be combined with water or other suitable vehicles before use. Such liquid formulations may contain pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible oils); emulsifiers (e.g., It can be prepared using lecithin or acacia; a solubilizer (e.g., cyclodextrin); a non-aqueous vehicle (e.g., hydrogenated vegetable oil, almond oil, oily ester or ethyl alcohol); and a preservative (e.g., methyl or propyl p-hydroxybenzoate, sorbic acid, benzyl alcohol, sodium benzoate, potassium sorbate).

[0042] In accordance with this disclosure, one embodiment provides a tablet having the pharmaceutical formulation of (R)-praziquantel B according to this disclosure.

[0043] In further embodiments, the pharmaceutical formulation comprises (R)-praziquantel B and a pharmaceutically acceptable excipient. In one preferred embodiment, the pharmaceutical formulation comprises 40-80% by weight of (R)-praziquantel B and 20-60% by weight of a pharmaceutically acceptable excipient. In another preferred embodiment, the pharmaceutical formulation comprises 50-70% by weight of (R)-praziquantel B and 30-50% by weight of a pharmaceutically acceptable excipient.

[0044] Furthermore, excipients include disintegrants, binders, fillers, surfactants / solubilizers, lubricants, flavoring agents, diluents, anti-adhesion agents, lubricants, and coating agents.

[0045] Examples of disintegrants include hydroxypropyl cellulose (HPC), low-density HPC, sodium carboxymethyl starch, carboxymethyl cellulose (CMC), sodium CMC, calcium CMC, carboxymethyl starch, hydroxypropyl starch, modified starch; crystalline cellulose, sodium starch glycolate (CMS-Na), one or more, but not limited to these; calcium carbonate, sodium croscarmellose, crospovidone, gum, magnesium aluminum silicate, methylcellulose, potassium polariphosphate, sodium alginate, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone hydroxypropyl cellulose, sodium starch glycolate, and starch.

[0046] Preferably, the disintegrant may be present in an amount ranging from about 2% to about 30% by weight of the formulation. More preferably, the disintegrant may be present in an amount ranging from about 2% to about 10% by weight of the formulation.

[0047] In a preferred embodiment, the disintegrant is sodium starch glycolate (CMS-Na), and its content is 2-8%.

[0048] Examples of binders include one or more polyvinylpyrrolidones (also known as povidone), povidone K 30, polyethylene glycol, acacia, alginic acid, agar, calcium carrageenan, cellulose derivatives such as ethylcellulose, methylcellulose, and hydroxycellulose. Examples of binders include, but are not limited to, propylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or mixtures thereof. Preferably, the binder may be present in an amount ranging from about 1% to about 20% by weight of the formulation.

[0049] In a preferred embodiment, the binder is povidone K30, and its content is 2-8%.

[0050] Examples of diluents or fillers include one or more lactoses available under the Tablettose trademark (e.g., spray-dried lactose, α-lactose, β-lactose), various grades of lactose available under the Pharmatose trademark, lactitol, saccharose, sorbitol, mannitol, dextrate, dextrin, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (e.g., microcrystalline cellulose (MCC) available under the trademark "Avicel"), microcrystalline cellulose PH 101, hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substitution), hydroxypropyl methylcellulose (HPMC), and methylcellulose polymers (e.g., Methocel A, Methocel A 4C, Methocel A 15C, Methocel A 4C). Examples of such materials include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose, non-pareile seed, sugar globules and other cellulose derivatives, soy protein powder, starch or turbid starch (including potato starch, corn starch, maize starch and rice starch) and mixtures thereof. Preferably, carriers, diluents or fillers may be present in an amount ranging from about 2 to about 50% by weight of the composition.

[0051] In one preferred embodiment, the diluent or filler is MCC, and its content is 35-45%.

[0052] Examples of surfactants or solubilizers include polysorbate (tween80), sodium dodecyl sulfate (sodium lauryl sulfate, SLS), oaryldimethylamine oxide, sodium doxate, poloxamer (poloxamer 188), cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohol, polyoxyethylene sorbitan monooleate, octoxynol, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, polyoxyethylene 10-lauryl ether, brij, bile salts (sodium deoxycholate, sodium cholate), polyoxyl castor oil, 2-hydroxylpropyl-β-cyclodextrin (HPβCD), β-cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD). , lecithin, methylbenzethonium chloride, carboxylic acid esters, sulfonates, petroleum sulfonates, alkylbenzene sulfonates, naphthalene sulfonates, olefin sulfates, alkyl sulfates, sulfates, sulfated natural oils and fats, sulfate esters, sulfated alkanolamides, alkylphenols, ethoxylated & sulfated, ethoxylated aliphatic alcohols, polyoxyethylene surfactants, carboxylic acid esters, polyethylene glycol esters, anhydrous sorbitol esters & ethoxylated derivatives, glycol esters of fatty acids, carboxylic acid amides, monoalkanolamine condensates, polyoxyethylene fatty acid amides, quaternary ammonium salts, amines with amide bonds, polyoxyethylene alkyl & alicyclic amines, N, N, It comprises, but is not limited to, one or more selected from the group consisting of N-tetrakis-substituted ethylenediamine 2-alkyl-1-hydroxyethyl-2-imidazoline, N-coco-3-aminopropionic acid / sodium salt, N-talou-3-iminodipropionate disodium salt, N-carboxymethyl n-dimethyl n-9-octadecenylammonium hydroxide, n-cocoamidetil n-hydroxyethylglycine sodium salt, or mixtures thereof.

[0053] Preferably, a surfactant or solubilizer may be present in an amount ranging from about 0.5% to about 10% by weight of the formulation.

[0054] In one preferred embodiment, the surfactant or solubilizer is SLS, and its content is 1-3%. More preferably, the SLS content in the tablet is 0.9-1%.

[0055] Preferably, lubricants, anti-adhesion agents and lubricants are incorporated into the pharmaceutical formulations of the present disclosure, including stearic acid and its pharmaceutically acceptable salts or esters (e.g., magnesium stearate, calcium stearate, sodium stearyl fumarate or other metal stearates), talc, waxes (e.g., , and glycerides), light mineral oil, PEG, silicic acid or its derivatives or salts (e.g., silicates, silicon dioxide, colloidal silicon dioxide and its polymers, crospovidone, magnesium aluminosilicate and / or magnesium aluminometasilicate), sucrose esters of fatty acids, hydrogenated vegetable oils (e.g., hydrogenated castor oil), or mixtures thereof. Preferably, lubricants, anti-adhesion agents and lubricants may be present in amounts ranging from about 0.1 to about 6% by weight of the formulation. More preferably, lubricants, anti-adhesion agents and lubricants may be present in amounts ranging from about 0.1 to about 5% by weight of the formulation or a suitable mixture thereof.

[0056] In one preferred embodiment, the lubricant is colloidal silicon dioxide, and its content is 0.3 to 2%.

[0057] In a preferred embodiment, the lubricant is magnesium stearate, and its content is 0.25 to 5%.

[0058] In one preferred embodiment, the lubricant is sodium stearyl fumarate, with a content of 0.3-3%. Tests have shown that no color change was observed when sodium stearyl fumarate was used as the lubricant, however, certain lubricants (e.g., magnesium stearate) may have the problem of changing color when stored at high temperatures (e.g., 60°C).

[0059] In yet another embodiment, the pharmaceutical preparation is a tablet, comprising 2-10% by weight of a disintegrant, 2-30% by weight of a binder, 2-40% by weight of a filler, 0.5-2% by weight of a surfactant (or stabilizer / solubilizer), and 0.3-0.8% of a lubricant.

[0060] In another embodiment, 2-10% by weight of the tablet is a disintegrant, 2-10% is a binder, 30-40% is a filler, and 0.3-3% is a lubricant.

[0061] In yet another embodiment, the excipient comprises povidone K30. In yet another embodiment, 1 to 4% by weight of the tablet is povidone K30. In yet another embodiment, one tablet contains 10 to 600 mg of (R)-praziquantel form B, preferably 50 to 600 mg, preferably 20 to 300 mg, more preferably 50 to 300 mg, and more preferably 50 to 150 mg.

[0062] In a preferred embodiment, the tablet contains, by weight: 40-80% (R)-praziquantel type B, 30-50% MCC, 0.5-2% SLS, 2-8% CMS-Na, 1-8% povidone K30, 0.3-2% colloidal silicon dioxide, and 0.1-5% sodium stearyl fumarate.

[0063] In another preferred embodiment, the tablet contains, by weight: 40-60% (R)-praziquantel type B, 30-50% MCC, 0.5-2% SLS, 5-8% CMS-Na, 1-5% povidone K30, 0.3-1% colloidal silicon dioxide, and 0.3-3% sodium stearyl fumarate.

[0064] In another preferred embodiment, the tablet contains, by weight: 40-60% (R)-praziquantel type B, 30-50% MCC, 0.5-2% SLS, 5-8% CMS-Na, 1-5% povidone K30, 0.3-1% colloidal silicon dioxide, and 2-5% sodium stearyl fumarate.

[0065] Furthermore, the particle size of (R)-praziquantel B is less than 150 microns, preferably at least 90% of the particles have a particle size of less than about 100 microns, more preferably less than about 50 microns, and even more preferably less than about 20 microns. In another embodiment, particularly more preferably, at least 90% of the particles have a particle size of less than about 0.2 microns.

[0066] In addition, the present invention also provides a semi-solid oral alloantimicrobial formulation for the treatment, control, and prevention of endoparasitic and extrinsic parasitic infections in warm-blooded animals, particularly companion animals such as cats and dogs. This soft oral composition or pasta, basically comprising (R)-praziquantel type B and at least one of benzimidazole (albendazole) or macrocyclic lactones (moxidectin and ivermectin) or tripenzimidine or milbemycin oxime or other antiparasitic agents, may further contain veterinarily acceptable inert components, such as thickeners, humectants, preservatives, pH adjusters, colorants, fragrances, binders, fillers, viscosity modifiers and opacifiers or dispersants, antioxidants and buffers.

[0067] The solvent used in the homogeneous paste of the present invention is a polar solvent that dissolves both the first anthelmintic agent (R)-praziquantel and at least one benzimidazole (albendazole) or tripenzimidine, or a macrolide anthelmintic compound (milbemycin oxime). Examples of such solvents include propylene glycol, polyethylene glycol, glycerol former, 1-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO).

[0068] The thickeners intended in this invention are well known to those skilled in the art. Examples of compounds that function as thickeners include cellulose, starch, natural gum, monothioglycerol, synthetic polymers, such as polymers and copolymers of polyvinylpyrrolidone or (meth)acrylate. Particularly preferred thickeners are hydroxypropyl cellulose, xanthan gum, and hydroxyethyl starch. The thickener may be present in an amount of about 3 to about 30%.

[0069] Opaquers can be added to absorb and / or reflect the energy of specific light and / or specific wavelengths, and thus can improve the stability of the formulation. Opaquers include, for example, zinc oxide or titanium dioxide, and can be present in amounts of about 0.5 to about 2.5%. Titanium dioxide is particularly preferred. These compounds are well known to those skilled in the art.

[0070] Wetting agents that may be used in the composition include, but are not limited to, glycerol (also known herein as glycerin), propylene glycol, cetyl alcohol, and glycerol monostearate. Various grades of polyethylene glycol can also be used as humectants.

[0071] Many flavorings may be used in the formulations of this disclosure to improve the palatability of oral animal formulations. Preferred flavorings are those not derived from animal sources. In various embodiments, flavorings derived from fruits, meats (including, but not limited to, pork, beef, chicken, fish, etc.), vegetables, cheese, bacon, cheese-bacon, and / or artificial flavorings may be used.

[0072] The formulation of the present invention may contain other inert components, such as antioxidants. These compounds are well known in formulation technology. Antioxidants can be added to the composition of the present invention to suppress the degradation of the activator. Suitable antioxidants include ascorbic acid, f Examples include, but are not limited to, malic acid, sodium ascorbate, and BHA (butylated hydroxyanisole). Antioxidants are generally added to the formulation in an amount of about 0.01 to about 2.0% (w / w) based on the total weight of the formulation, with about 0.05 to about 1.0% being particularly preferred.

[0073] In accordance with this disclosure, another embodiment provides a method for treating a parasitic disease in a human or animal. This method includes administering the aforementioned formulation to a subject suffering from a parasitic disease.

[0074] Furthermore, formulations containing (R)-praziquantel show promising prospects for the treatment of many zoonotic and parasitic diseases, including but not limited to schistosomiasis, hepatochomycosis, pulmonary paragonimus, or phylloheliditis, tapeworm infections, cysticercosis, and hydatiditis, and may be used in particular for the treatment of infections caused by species of schistosomiasis, such as Schistosoma mekongii, Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haeformis; infections caused by hepatochomycosis, Opisthotis vivellini, or gastrointestinal infections caused by tapeworms, including Dipyridinium canis or Teniaeformis. The pharmaceutical formulations can be used for the treatment of cysticercosis and neurocysticercosis (NCC). The pharmaceutical formulations are also useful for the treatment of health conditions, which can be treated in combination with other anthelmintics, anticystosomar, and antirematosids. Furthermore, the pharmaceutical formulations may be used in veterinary medicine, for example, in dogs and cats, for the elimination of tapeworms, and in combination with benzimidazole or tripendimidine or microlide compounds (moxidectin, selamectin, milbemycin oxime) and cyclooctadepsipeptide (emodepside), for the elimination of various types of hookworms, roundworms, whipworms, and filarial worms such as Dyrofilaria immitis. The pharmaceutical formulations may also be used to eliminate tapeworms in humans, buffalo, sheep, pigs, horses, ferrets, birds, chinchillas, mice, rats, hamsters, gerbils, and guinea pigs, and furthermore, the pharmaceutical formulations may be used in aquaculture and fish to eliminate tapeworms and fructosis in reptiles and various fish.

[0075] In some embodiments, the parasite is a tapeworm, a flattened, segmented worm that lives in the intestines of mammals. During infection, live tapeworm larvae are grouped together within a cyst. Once inside the digestive tract, the larvae grow into large adults that can cause symptoms in the host. Tapeworms can cause gastrointestinal infections. For example, cysticercosis is one disease in which tapeworm larvae are involved in the human body. Tapeworms include Taenia solium, Taenia saginata, Hymenolepis nana (dwarf tapeworm), Dipylidium caninum, and Taenia feline.

[0076] In some embodiments, the parasites are monogenean aquatic animals such as European catfish, yellowtail, black clapperfish, spotted eagle ray, goldfish, guppies, sticklebacks, blue snapper, and silver perch, including ancylodiscoides vistulensis, Benedenia seriolae, Cleidodiscus sp., Clemacotyle australis, Dactylogyrus sp., Gyrodactylus aculeati, Gyrodactylus turnbulli, Haliotrema abaddon and Lepidotrema bidyanain, and digenean aquatic animals such as Clinostomum complanatum, Clinostomum marginatum and Diplostomum spathaceum insunshine. This includes tapeworms (Bothriocephalus acheilognathi) that parasitize bass, channel catfish, grass carp, silver carp, and bonytail chub, channel catfish, red shiner, and red snapper, as well as schistosomiasis such as Cardicola forsteri and Cardicola oentalis that parasitize bluefin tuna, southern bluefin tuna, Atlantic bluefin tuna, and bluefin tuna. However, according to some embodiments, additional suitable antiparasitic agents that can be combined with (R)-praziquantel type B crystals for human and animal use are one or more selected from the group consisting of tinidazole, metronidazole, and melarsoprol. Eflornithine, rifampin, amphotericin B, pentamidine, stivogluconate sodium, meglumine antimonite, fluconazole, artesunate, artemether, and dihydroartemisinin, quinine, quinidine, chloroquine, atovaquone proguanil, artemether lumefantrine, meflocine, doxycycline, clindamycin, paromomycin, atovaquone, nitazocine Sanid, azithromycin, fumagiline, paromomycin, diloxanide, levamisol, sekinidazole, ornidazole, iodoquinol, flutidylxanide, clindamycin, atovaquone, azithromycin, diminazene, trypan blue, oxamnikinin, niclozamide, emodepside, albendazole, fenbendazole, mebendazole, tripenzimidine, thiabendazole, pyrantel, fenbentel, morantel, monepantel, dercantel, diethylcarbamazine, milbemycin oxime, ivermectin, eprinomectin, selamectin, doramectin, moxidectin, abamectin.

[0077] In accordance with this disclosure, in yet another embodiment, a method is provided for modulating the response of blasphemous and inflammatory cytokines and chemokines in subjects suffering from cytokine-mediated disorders during the course of chronic schistosomiasis or other diseases. The method comprises administering the aforementioned formulations to a subject. Examples of such cytokines include integrins, fibronectin, interferon-γ, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, TNF-α, and TGF-β1 produced by host immune cells. Examples of such disorders include inflammatory and autoimmune diseases due to chronic schistosomiasis, regenerative diseases, and hepatic fibrosis. The method comprises administering a (R)-praziquantel B-type crystalline formulation to a subject.

[0078] The treatment, comprising (R)-praziquantel crystals, is effective across a wide dosage range. Typical dosing forms, comprising the (R)-praziquantel crystal form provided herein, range from approximately 0.1 mg to approximately 3000 mg / day and are administered once daily in the morning or in divided doses throughout the day with meals. Dosage units can be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 300, 350, 400, 450, 500, or 1000 mg of the active compound.

[0079] In yet another embodiment, the method further comprises administering one or more formulations to a subject once or more times daily, wherein the total daily intake of (R)-praziquantel formulation B is greater than 10 mg / kg in humans and 1 mg / kg in dogs or cats. In some embodiments, the formulation is a tablet. In other embodiments, the formulation is a capsule, a chewable or paste.

[0080] In various embodiments, the attending physician may modify the dosage, route of administration, and administration regimen in consideration of the subject's age, health condition, sex, and the severity of the disease; therefore, the above dosage range is not intended to limit the scope of the present invention in any way. The pharmaceutical composition will typically be administered daily or consecutively, alone, or in several divided doses.

[0081] In accordance with this disclosure, in yet another embodiment, tablets and other formulation compositions having an effective amount of (R)-praziquantel form B and pharmaceutically acceptable excipients are provided. For example, tablets administered to a subject can sustain a measurable pharmacokinetic response. The pharmacokinetic response is characterized by a shortened Tmax and increased plasma exposure (AUC and Cmax values) (see Example 8) compared to an equivalent dose of (R)-PZQ orally dispersible tablets or capsules, or a commercially available racemic praziquantel tablet containing 50% (R)-PZQ as the active isomer and another 50% (S)-PZQ as the inactive bitter isomer.

[0082] In various embodiments, therapeutic methods involving the administration of such tablets and other formulation compositions are provided for subjects (patients or animals) suffering from schistosomiasis and hepatic and pulmonary influenza infections and zoonotic diseases such as neurocystic disease, teniasis, and hidachidosis, as well as for other autoimmune diseases and inflammatory fibrotic disorders mediated by parasite-specific cytokines during the course of infection.

[0083] In various embodiments, a therapeutic method is provided for administering such active pharmaceutical ingredients to subjects (patients or animals) suffering from zoonotic parasitic diseases in warm-blooded animals, particularly cats, dogs, horses, chickens, pigs, sheep, cattle, and birds.

[0084] In various embodiments, a therapeutic method for administering such active pharmaceutical ingredients is provided by a bath therapy for aquaculture, including commercial and ornamental fish, that suffer from diseases such as skin diseases caused by zoonotic parasitic infections.

[0085] In various embodiments, methods of administering such active pharmaceutical ingredients are provided by oral intubation or medicated fish feed for aquaculture, using production fish and ornamental fish, including but not limited to European catfish, yellowtail, cownose ray, black crappie, great white eagle, ray, goldfish, guppy stickleback, rainbow trout, Western Australian pufferfish, taki pufferfish, silver perch, rockfish, Pacific bluefin tuna, sunshine bass, channel catfish, grass carp, silver carp, bluegill, kona, bonito tail chub, red shiner, red snapper, and turbon, as the final / intermediate hosts.

[0086] In one embodiment, the present disclosure refers to a method for preparing (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one crystalline form B, the method comprising: a) Dissolve the compound in at least one solvent at around 45°C to form a solution; b) Add another solvent to the solution and cool to form a solid; c) Isolate the solid by filtration; d) Dry the solid under vacuum (≤-0.08 MPa) at 35±5℃ for at least 10 hours to obtain type B.

[0087] Preferably, one solvent is an anhydrous solvent. More preferably, one solvent is selected from acetone, acetonitrile, chloroform, dichloromethane, dimethyl sulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, ethanol, ethyl acetate, isopropyl acetate, isopropyl alcohol, methanol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl tert-butyl ether, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, toluene, and the antisolvent is n-heptane, n-hexane, and Petroleum Aether Luna It is either selected from one of these options, or a combination of them.

[0088] Preferably, in step b), the mixture is cooled at 0-5°C, preferably 3°C, for at least 5 hours. [Brief explanation of the drawing]

[0089] The above and other aspects, features and advantages of this disclosure will become more apparent from the following detailed description taken in conjunction with the accompanying drawings, in which: [Figure 1] Figure 1 shows a typical X-ray powder diffraction (XRPD) pattern of (R)-praziquantel B. In this figure, the counts per 2 seconds (linear scale) are shown on the Y axis, and the value of 2θ (degrees) is shown on the X axis. [Figure 2] Figure 2 shows a typical thermogravimetric analysis (TGA) curve and a typical differential scanning calorimeter (DSC) thermogram for Form B, with the temperature in °C on the X axis. The right vertical axis (lower curve) shows heat flow (W / g), and the left vertical axis (upper curve) shows weight loss (%). [Figure 3] Figure 3 shows the mean (R)-praziquantel plasma concentration time-course profiles of healthy human subjects after a single dose of TL-010 at 20 mg / kg, 30 mg / kg, and 40 mg / kg administered orally in tablet form, according to Example 8 of this disclosure. [Figure 4] Figure 4 shows the temporal profile of mean (R)-praziquantel plasma concentrations in a crossover study design according to Example 8 of this disclosure, after single administration of 20 mg / kg TL-010 tablets and 40 mg / kg reference drug racemicraziquantel tablets (Biltricide®) to healthy human subjects, respectively. [Modes for carrying out the invention]

[0090] Detailed description of the invention The following describes various embodiments of this specification. The embodiments and terminology used herein are not intended to limit the technology described herein to any particular embodiment, and the embodiments and terminology include modifications, equivalents, and / or substitutes relating to the corresponding embodiments described herein.

[0091] Explanation of related terms Throughout this disclosure, the terms used are to be understood in accordance with their typical meanings established in the relevant technologies, namely, the technologies of medicinal chemistry, medicine, biology, parasitology, genetics, molecular biology, biochemistry, physiology, and pharmacy. However, certain terms have been further clarified and explained as follows:

[0092] As used herein and in the claims, the terms “comprise,” “comprising,” “include,” and “including” are intended to specify the presence of a described feature, integer, component, or step, but not to exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0093] In this specification, the term “approximately” when used with respect to the peak position of an X-ray powder diffraction pattern refers to the inherent variation of the peak, for example, depending on the calibration of the instrument used, the process used to manufacture the polymorph, the age of the crystallized material, etc. In this case, the instrument measurement variation was approximately 0.2 degrees 2θ. A person skilled in the art who is interested in this disclosure will understand the use of “approximately” in this context. The term “approximately” with respect to other defined parameters, such as moisture content, C, t, AUC, intrinsic dissolution rate, temperature, and time, indicates, for example, the inherent variability in the measurement of the parameter or the achievement of the parameter. A person skilled in the art who is interested in this disclosure will understand the variability of the parameter as implied by the use of the word “approximately.”

[0094] The term "chiral" refers to a molecule that possesses the property of being non-superimposed mirror images of each other. "Enantiomers" are two stereoisomers of a compound that are non-superimposed mirror images of each other. Many organic compounds exist as optically active compounds, possessing the ability to rotate the plane of polarized light. When describing optically active compounds, the prefixes L and D, or R and S, are used to indicate the absolute configuration of the molecule with respect to the chiral center. The prefixes L and D, R and S, or (-) and (+) are used to indicate the sign of the rotation of plane-polarized light by the compound, with L, R, or (-) meaning the compound is revorotatory. Compounds with D, S, or (+) are dextrotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Certain stereoisomers are sometimes called enantiomers, and mixtures of such isomers are generally called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0095] As used herein, “polymorphism” refers to the occurrence of different crystalline forms of a compound. Crystalline forms have different arrangements and / or conformations of molecules in the crystal lattice. A solvate is a crystalline form containing a stoichiometric or non-stoichiometric amount of solvent. A “solvate” usually refers to a form of a compound that has bonded with a solvent through a solvation reaction. This physical bond may include hydrogen bonds. Conventional solvents include water, methanol, and ethanol. Examples include acetic acid, DMSO, THF, and diethyl ether. Therefore, various polymorphs can arise from a single compound, and each polymorph has different physical properties such as solubility profile, melting point temperature, hygroscopicity, particle shape, density, flowability, moldability, and X-ray diffraction peaks. Since the solubility of each polymorph differs, confirming the presence of polymorphs in a pharmaceutical is essential to providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid forms of a pharmaceutical containing polymorphs and determine the stability, solubility, and flow properties of each polymorph. Polymorphs of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy and other methods.

[0096] XRPD stands for X-ray powder diffraction, an analytical technique that measures X-ray diffraction in the presence of solid components. Crystalline materials with regularly repeating atomic arrangements yield characteristic powder patterns. Materials with similar unit cells produce powder patterns with similar positions measured in 2θ units. Solvates exhibiting this property are called isostructural solvates or isomorphic solvates. The intensity of reflection varies depending on the electron density causing diffraction, the sample, sample preparation, and instrument parameters. Analysis of XRPD data is based on the general appearance of the measured powder pattern and the known response of the X-ray diffractometer used for data acquisition. The position, shape, width, and relative intensity distribution of diffraction peaks in the powder pattern can be used to characterize the type of solid order in the powder sample. Additionally, the position, shape, and intensity of broad diffuse scattering (halo) above the instrument background can be used to characterize the level and type of solid disorder. XRPD was performed using a Bruker D2 phasor diffractometer. Approximately 10 mg of the compound was uniformly dispersed on a single-crystal silicon plate. Instrument parameters are shown in Table 1 below: [Table 1]

[0097] Differential scanning calorimetry (DSC) measures the difference in thermal energy between a solid sample and a suitable reference sample as the temperature rises. The DSC thermogram is characterized by an endotherm (showing energy uptake) and an exotherm (showing energy release), which typically change as the sample is heated. The DSC thermograph was obtained using a TA Discovery 2500 from TA-Instruments. The sample was weighed (approximately 3 mg) into a standard aluminum TA-Instruments sample pan closed with a suitable cover. The following parameters were used: initial temperature: 25°C, heating rate: 10°C / min; final temperature: 300°C; nitrogen flow: 50 ml / min. For any given example, the observed endothermic values ​​may also vary from instrument to instrument; however, if the instruments are similarly calibrated, they should generally be within the range defined herein.

[0098] Thermogravimetric analysis (TGA) is a test method that records the change in weight of a sample by heating it in air or a controlled atmosphere such as nitrogen. The thermogravimetric curve (thermogram) provides information about the solvent or water content and the thermal stability of the material. TGA was performed using a TA Discovery TGA 5500 thermogravimeter with the following parameters: Initial temperature: room temperature; Heating rate: 10°C / min; Final condition: 350°C

[0099] The "subjects" under consideration for administration include humans (i.e., males or females of any age group, e.g., pediatric subjects (adolescents) or adult subjects (e.g., young adults, middle-aged adults, elderly adults)) and / or other non-human animals, e.g., mammals (commercially relevant mammals such as cats and / or dogs, horses, cattle, buffalo, pigs, sheep, goats) and birds. This includes, but is not limited to, species (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be male or female at any stage of development. The animal may be a transgenic animal or a genetically modified animal. In certain embodiments, the subject is a non-human animal. In certain embodiments, the animal is a fish.

[0100] "Parasitic diseases" refer to infections or illnesses caused or transmitted by parasites. Examples of parasitic diseases include schistosomiasis, clonorchiosis, opisthorchiosis, paragonimiosis and cestodiasis, fasciolopsyosis, lymphatic filariasis, onchocerciasis, drakuncliosis, trichoryosiosis, strongiliosis, trichomoniasis, toxoplasmosis, malaria, African trypanosoma, Chagas disease, leishmaniasis, amphibia and giardiasis.In another embodiment, parasitic diseases are parasitic diseases of humans or animals, and these include tapeworm-tapeworm infection, diphyllotriasis-tapeworm, echinococcosis-tapeworm, hymenococcussis, bovine tapeworm, cysticercosis-swine tapeworm, bertierosis, sparganosis, clonorchiosis, lancet liver flu, liver flu-fasciolosis, fasciolopsis-intestinal flu, metagonimiasis-intestinal flu, metruchiosis, Chinese liver flu, paragonimiasis, pulmonary influenza, schistosomiasis-birhurziasis, birhurziasis or snail fever (all types), enteric schistosomiasis, urinary schistosomiasis, schistosomiasis by Japanese schistosomiasis, Asian enteric schistosomiasis, swimmer's switch Hookworm infection, hookworm infection, anisakiasis, roundworm parasitic pneumonia, roundworm baylissarciosis, roundworm lymphatic filariasis, dioctophim renal infection, guinea pig draculasis, pinworm enteritis, pinworm enteritis, Harrisfarobias, loaloa filariasis, calabarta, mansonellosis, filariasis, river blindness, onchocerciasis, stroniroidosis parasitic pneumonia, theradidosis, toxocariosis, trichineosis, whiplash, elephantiasis lymphatic filariasis. Acanthocephaliosis, Harzon syndrome, Miaasis, Screwworm, Cocriomiya, Flea, Bed bug, Firefly, Head lice-pedicula, Carapaceous lice-pedicula, Crab lice-pedicula, Demodex-Demodix, Scabiosa, "Thigger" (trombiculidae-trombiculosis), Fleas, Cigarette beetles, Ticks, Granulomatous amoeba encephalitis (eye infection), Acanthamoeba keratitis, Granulomatous amoeba encephalitis (skin infection), Babesiosis, Balantidiasis, Blastocystosis, Cryptosporidius, Cyclosporidius, This includes, but is not limited to, diamebiasis, amoebiasis, giardiasis, isosporiasis, leishmaniasis, primary amoebic meningoencephalitis (PAM), malaria, rhinosporidiosis, sarcocystosis, toxoplasmosis (acute and latent), trichomoniasis, sleeping sickness, and Chagas disease.

[0101] The terms pharmaceutical, medicinal product, medicinal chemical, medicinal compound, compound, and chemical substance are used interchangeably throughout this disclosure. API, as used herein, refers to a medicinal active ingredient. In various embodiments of this disclosure, unless otherwise specified, the API of a capsule, tablet, or other formulation is (R)-praziquantel B, also designated TL-010. The terms pharmaceutically acceptable excipient, pharmaceutically compatible excipient, and excipient are used interchangeably throughout this disclosure. These refer to non-API substances such as disintegrants, binders, fillers, and lubricants, solubilizers, etc., used in pharmaceutical formulations. These are generally safe for administration to humans and animals in accordance with established regulatory standards, including those published by the U.S. Food and Drug Administration.

[0102] As used herein, "tablet" generally refers to a safe, easily dissolvable container for transporting a particular drug.

[0103] As used herein, capsules generally refer to safe, easily dissolvable enclosures for carrying specific pharmaceuticals. In one embodiment, the capsule is made of gelatin. The size is generally between 1 and 4.

[0104] Other suitable matrix materials, such as totally synthetic polymer chemicals having gelatin-like properties, can be used to manufacture TL-010 tablets or capsules, or liquid or semi-solid formulations such as soft chews or pastes, according to alternative embodiments of this disclosure.

[0105] As used herein, AUC refers to the area under the curve representing the change in blood concentration of TL-010 over time.

[0106] When used herein, Cmax refers to the maximum blood concentration shown on a curve representing the change in blood concentration of TL-010 over time.

[0107] As used herein, Tmax refers to the time at which the blood concentration reaches its maximum value, as shown on the curve representing the change in blood concentration of TL-010 over time.

[0108] As used in this disclosure, T1 / 2 refers to the time it takes for the blood concentration of TL-010 to decrease to half of its maximum value.

[0109] AUC, Cmax, Tmax, and T1 / 2 are key pharmacokinetic parameters that characterize the pharmacokinetic response of certain drugs, such as TL-010, in animals or humans, and are therefore used collectively.

[0110] Tablet formulations of praziquantel for human and animal use (R) To those skilled in the art of pharmaceutical research and manufacturing, it is generally known that tablet formulations allow for the generous addition of non-API components, including excipients and coatings, particularly high-concentration fillers. However, the addition of non-API components can limit the amount of API supported in each tablet.

[0111] This disclosure provides a novel (R)-praziquantel tablet formulation named TL-010, comprising (R)-praziquantel form B and certain pharmaceutically acceptable excipients.

[0112] According to one embodiment, this novel tablet is capable of eliciting favorable pharmacokinetic responses in human and animal subjects. In another embodiment, this novel tablet formulation facilitates dissolution and improves fluidity during the tablet manufacturing process.

[0113] Furthermore, these tablets contain 100-400 mg of TL-010 as the active pharmaceutical ingredient.

[0114] In various embodiments, one or more pharmaceutically acceptable excipients are added. For example, in one embodiment, 2-10% by weight of the tablet is a disintegrant, 2-30% is a binder, 2-40% is a filler, 0.3-3% is a lubricant, 0.5-2% is a surfactant, and 0.1-0.8% is a lubricant. As stated at the beginning of this detailed description, a number of substances can be suitably included as disintegrants, binders, fillers, surfactants, stabilizers, and lubricants. Examples include sodium stearyl fumarate as a lubricant, microcrystalline cellulose as a filler, and CMC-Na as a disintegrant. In certain embodiments, the tablet formulation further contains povidone K30 as a binder. By weight, povidone K30 may account for 1-4% of the tablet.

[0115] In preferred embodiments, the relative proportions (by weight) of the formulation components are as follows. Referring to Table 2 below, as the active pharmaceutical ingredient (API), tablets of groups A and B contain (R)-praziquantel form B alone, while tablets of groups C to I are prepared by combining (R)-praziquantel with any other anthelmintic substance for human and animal use. With a certain ratio of API mixture (TL-010:X), the relative proportions (by weight) of the API and other components are as follows: [Table 2]

[0116] Precautions 1. Notation for X in the above groups: Group A, Group B: (R)-praziquantel alone, Group C: albendazole, Group D: tripenzimidine, Group E: ivermectin, Group F: milbemycin oxime, Group G: moxidectin, Group H: pyrantel pamoate, Group I: fenbentyl 2. Subjects H: Human, P: Dog, Cat, Horse

[0117] The formulations of the present invention can be prepared by various techniques recognized in the art.

[0118] The manufacture of TL-010 tablets based on various embodiments of tablet formulations involves a series of steps. These steps include TL-010 granulation, fluid bed drying, grinding, lubrication compounding, encapsulation, and preparation for bulk packaging.

[0119] The granules of TL-010 can be prepared in the following order: First, povidone K30 is mixed with water and dissolved using an overhead mixer. Second, TL-010 is pulverized together with microcrystalline cellulose PH-101, sodium lauryl sulfate, and CMS-Na to break down any clumps. Third, the pulverized TL-010, microcrystalline cellulose PH-101, sodium lauryl sulfate, and CMS-Na are placed in a high-shear granulator and mixed. Fourth, povidone and aqueous solution are added and mixed. Fifth, after the povidone and aqueous solution have been completely added, the TL-010 granules are mixed for a certain period of time.

[0120] The fluidized bed drying process may be carried out in a fluidized bed dryer with an inlet temperature of 45°C or lower, and the grinding process may be carried out using a suitable grinder such as Quadro Comil® or Airjet Mill. The lubricant compounding process can be carried out by adding appropriate amounts of CMS-Na(ext), colloidal silicon dioxide, and sodium stearyl fumarate. The granules of TL-010 can be further blended at this point. For tablets, the final blend is compressed into 15.0 mm*6.0 mm tablets. The target weight of the tablets is 300 mg and the target hardness is 100 N. The tablets can then be coated using a film coating pan. In a preferred embodiment, a dose of 200-300 mg can be obtained. To complete the tablet manufacturing process, the finished tablets can be packaged in protected 45 ml HDPE bottles and stored at a controlled room temperature.

[0121] Those skilled in the art of drug research and drug manufacturing will understand that some of the steps described above may be modified or omitted, and additional steps may be included, without substantially altering the outcome of the manufacturing process.

[0122] According to some embodiments, the tablet formulation has good physical and chemical stability, This results in a shelf life of 12 to 36 months.

[0123] As described in Table 8 of Example 3 and Example 4, exemplary compositions and storage stability of TL-010 formulation-containing tablets were prepared and investigated. Representative batches of TL-010 / excipient formulations were prepared using routine wet formulation methods.

[0124] (R)-Praziquantel capsule formulation In general, capsule formulations are known to easily contain high concentrations of APIs without or with the use of pharmaceutical excipients. Capsules may be able to contain more binders instead of the fillers that are more commonly used in tablets. When a high concentration of API is desired and no specific excipients are known to be essential, capsule formulations are often adopted.

[0125] In the case of capsule formulations, the capsule shell may be made of hard gelatin in one embodiment. The shell may be transparent or opaque, white or colored in various embodiments. The capsule is preferably size 3 or 4 to yield 150 mg of the desired neat TL-010 active pharmaceutical ingredient (API). Other sizes may be employed in alternative embodiments. For example, to further improve the flowability of the powder, TL-010 granules containing an excipient such as sodium lauryl sulfate (SLS) may be encapsulated in two-piece, size 1, gelatin capsules using a suitable encapsulating agent to obtain a desired TL-010 dose of 150-300 mg, preferably using size 2 capsules for a 150 mg API containing the excipient.

[0126] Furthermore, (R)-praziquantel, form B can be formulated for oral administration in capsules containing 200 mg of (R)-praziquantel, form B. For these experiments, (R)-praziquantel, form B with a D90 particle size between approximately 5 and 150 microns may be used. All inactive 200 mg components may be GRAS and USP / NF excipients. Strength manufacturing processes may include wet granulation using a high-shear mixer / granulator and filling into hard gelatin capsules.

[0127] Semi-solid oral formulations for veterinary animals This disclosure also provides a soft, oral, homogeneous anthelmintic veterinary formulation for the treatment, control, and prevention of internal and external parasitic infections in warm-blooded animals, particularly companion animals such as cats and dogs. This semi-solid oral composition or paste formulation is essentially composed of (R)-praziquantel alone or in combination with at least one benzimidazole (albendazole), tripenzimidine, or tripenzimidine, or a macrolide anthelmintic (milbemycin oxime or moxidectin), a solvent for dissolving (R)-praziquantel with benzimidazole or tripenzimidine, or milbemycin oxime or moxidectin, and at least one filler, at least one surfactant, at least one fragrance, at least one thickener, at least one binder, at least one lubricant, at least one humectant, at least one preservative, at least one opacifier, and at least one antimicrobial agent.

[0128] In some preferred embodiments, Table 3 shows various compositions of soft oral anthelmintic formulations for pet animals (dogs and cats). The oral formulation compositions include API(R)-praziquantel type B and benzimidazole, or tripendimidine, or Mackintosh. Alternatively, they may contain tripendimidine, macrolide compounds, milbemycin oxime, etc., and can be used in warm-blooded animals such as dogs and cats. [Table 3]

[0129] In some other preferred embodiments, the soft oral formulation or pasta of the present invention may be prepared by a process comprising, for example, dissolving at least two different anthelmintic agents, e.g., (R)-praziquantel and a macrolide compound or benzimidazole or tripenzimidine, dissolving a thickener or drug in a solvent, and forming a thickened solution. Other inactive ingredients such as artificial beef flavoring, zinc oxide, polyvinylpyrrolidone K 30, and at least one compound selected from the group consisting of surfactants, preservatives or antioxidants are added and mixed well until a soft, homogeneous pasta formulation is formed, but here the manufacturing method does not involve the addition of water, as shown in Table 4. [Table 4]

[0130] Another soft oral anthelmintic composition of the present invention is, in addition, an aqueous-based paste and may further contain veterinarily acceptable inert components, such as solubilizers, colorants, humectants, and buffers, as shown in Example 5 and Table 11. The veterinarily acceptable components are known to those skilled in the art of veterinary formulation technology.

[0131] The moisture content of the paste-like formulation of the present invention is, for example, 30% by weight, preferably 20% by weight, and particularly 10% by weight, based on the total weight of the formulation.

[0132] The solvent used in the flexible oral formulation of the present invention is a polar solvent capable of dissolving both the first anthelmintic (R)-praziquantel and at least one benzimidazole (albendazole) or tripenzimidine. Alternatively, it can dissolve tripenzimidine and at least one macrolide compound (milbemycin oxime or moxidectin). Examples of such solvents include propylene glycol, polyethylene glycol, and glycerol.

[0133] Humectants may consist of multiple oils, including but not limited to natural and synthetic fats or oils. Typical sources of animal fats include fish oil, chicken fat, animal tallow, choice white grease, prime steam lard, and mixtures thereof. Humectants may typically be present in the composition at a concentration of about 1% to about 25% (w / w).

[0134] The thickeners intended in this invention are well known to those skilled in the art. Examples of compounds that function as thickeners include cellulose, starch, natural gum, monothioglycerol, polyvinylpyrrolidone, and synthetic polymers such as polymers and copolymers of (meth)acrylates. Particularly preferred thickeners are microcrystalline cellulose (Avicel), hydroxypropyl cellulose, xanthan gum, and hydroxyethyl starch. The thickener may be present in an amount of about 1 to about 30%.

[0135] Opaquers can be added to absorb and / or reflect the energy of specific light and / or specific wavelengths, and thus improve the stability of the formulation. Opaquering agents include, for example, zinc oxide and titanium dioxide, which can be present in amounts of about 0.5 to 2.5%. Titanium dioxide is particularly preferred. These compounds are well known to those skilled in the art.

[0136] The resulting soft paste is filled into toothpaste-like, squeezeable soft tubes using a filling machine, with different dosage units ranging from approximately 0.5 to 10 g / mL for animals of different sizes. These cap-sealed, toothpaste-like tubes are made of plastic with volumetric scoring, are single-use, and have a total volume size of 0.5 mL to 10 mL. These soft tubes offer advantages such as accurate dosage and storage stability. Filling the required amount of paste into a toothpaste-like container and applying the paste directly to the oral cavity ensures that the animal is ingesting the correct amount. The prerequisites for using the soft oral paste formulation of this invention, particularly in household medicinal paste tubes, are its excellent stability and shelf life.

[0137] The soft oral composition or pasta formulation of the present invention is preferably applied to warm-blooded animals by small, easy-to-squeeze travel-size toothpaste tubes. Examples of warm-blooded animals include all ruminants, horses, dogs, and cats. Particularly preferred are dogs, cats, cattle, sheep, pigs, and horses. The amounts of each anthelmintic compound are well known to those skilled in the art. For pet animals such as dogs and cats, preferred amounts of (R)-praziquantel include, for example, about 0.3 mg / kg to about 20 mg / kg of animal body weight, with the range of about 1 mg / kg to about 3 mg / kg or 1.5 mg / kg of animal body weight being particularly preferred. The most particularly preferred amount is about 3 mg / kg of animal body weight. Preferred ranges for anthelmintic macrolide compounds such as moxidectin are, for example, about 0.1 to about 0.6 mg / kg, with about 0.3 to about 0.5 mg / kg being particularly preferred. A preferred range for anthelmintic benzimidazole compounds such as albendazole is 1 to 60 mg / kg of animal body weight. A preferred range for anthelmintic tripenzimidine compounds is 1 to 60 mg / kg of animal body weight. The most particularly preferred amount of albendazole or tripenzimidine is about 50 mg / kg of animal body weight. A preferred range for anthelmintic milbemycin oxime compounds includes 0.1 to 40 mg / kg of animal body weight. The most particularly preferred amount is about 0.5 mg / kg of animal body weight. In one embodiment, dogs receive 3 mg / kg of (R) per animal body weight. To provide doses of praziquantel and 0.3 mg / kg moxidectin or 0.5 mg / kg milbemycin oxime, 2 g of a soft paste composition containing (R)-praziquantel type B and moxidectin or milbemycin oxime, as described in Tables 3, 4, and 11, was administered.

[0138] Preferred embodiments of the semi-solid oral formulations of the anthelmintic according to the present invention are described in Tables 3, 4, and 11, respectively, for oil- and aqueous-based compositions of paste formulations containing (R)-praziquantel B and other compounded veterinary drugs, as well as inactive components.

[0139] In one embodiment, the oral animal composition is a paste-like composition. In another embodiment, the oral animal composition is in the form of tablets or chews manufactured using a molding machine, as shown in Table 2.

[0140] The soft oral composition or pasta formulation of the present invention is suitable for controlling pathogenic endoparasites in companion animals, particularly warm-blooded animals such as dogs or especially cats, and has a favorable safety profile for warm-blooded animals, in particular, with the removal of (S)-praziquantel, which accounts for 50% of the components causing bitterness and malodor, and the potential toxic components in racemicpraziquantel used in commercially available compounded animal drugs. The agent is effective against all or individual stages of the pest development. Examples of pathogenic endoparasites include tapeworms, trematodes, nematodes, and Acantocephala.

[0141] Liquid composition and solid preparation containing (R)-Praziquantel B for farmed fish Fish, the world's most economically important food source, like other vertebrates, suffer production problems such as health, welfare, and feed efficiency when infected with helminth parasites. Fish are parasitized by both larval and adult forms of tapeworms and pendulum worms. In aquaculture, processing the fish is necessary to prevent economic losses. Furthermore, larvae that parasitize fish can infect humans, requiring treatment. In addition, fish kept in aquariums and as ornamental fish may also require treatment.

[0142] Parasitically effective amounts of (R)-praziquantel B may be present in formulations acceptable to fish.

[0143] Generally, (R)-praziquantel B, used to control fish ectoparasites such as monodinians, is used in the form of a liquid composition, in its pure form, and / or as a solid active substance (e.g., (R)-praziquantel B with a specific particle size, preferably 0.1 to 150 microns, more preferably 0.5 to 10 microns) for bath treatment. For example, by placing fish in a "medicinal bath" and keeping them there for a certain period of time (several minutes to several days, preferably 1 hour to 48 hours, more preferably 5 hours to 24 hours), for example, when moving fish from one rack or tank to another, for example, by placing them in a rack where fish are kept, an entire pond, a tank or aquarium. The active pharmaceutical ingredient can be prepared or formulated in any suitable form, e.g., powder, granules, solution, emulsion, micro / nano emulsion, emulsified concentrate, suspension, nanosuspension, or suspension concentrate, tablet, or simply pure (R)-praziquantel B itself. For example, a suitable formulation may be one in which (R)-praziquantel type B is dispersed in water containing fish to a final concentration of 1 to 50 mg / L, and then diluted to 10 mg / L over a period of up to 96 hours, preferably 1 to 48 hours, and more preferably 6 to 24 hours.

[0144] For internal parasites in fish, oral administration of a formulation containing (R)-praziquantel type B is a preferred method. The form may be, for example, 1) feed additive: pellets, powders, premixes, granules, solutions, emulsions, micro / nano emulsions, emulsifiable concentrates, suspensions, nanosuspensions, or suspension concentrates homogeneously mixed with feed as a feed additive, or 2) tablets: powders, premixes, granules, solutions, emulsions, micro / nano emulsions, emulsifiable concentrates, suspensions, nanosuspensions, or suspensions administered in tablet form, the outer layer of which may consist of, for example, a fish feed composition that completely covers the active substance.

[0145] Preferably, the (R)-praziquantel B formulation may contain at least one adjuvant conventionally used in formulation technology, such as a solvent, excipient, or solubilizer. The formulation can be prepared by methods known to the extent of the invention, typically by mixing, granulating, and / or compressing (R)-praziquantel B with a solid or liquid carrier, and optionally adding further adjuvants such as emulsifiers or dispersants, stabilizers, colorants, antioxidants, and / or preservatives.

[0146] More preferably, the medicinal fish feed may be used in the form of fish feed granules or pellets having a coating of (R)-praziquantel. Preferably, the fish feed comprises (R)-praziquantel and at least one of corn starch, pre-gelatinized corn starch, protein, nutrients, vegetable oil and / or fish oil. Alternatively, commercially available fish pellets or granules may be coated with (R)-praziquantel and a premix comprising one or more suitable excipients such as starch, fumed silica (Aerosil®), microcrystalline cellulose, and lactose.

[0147] (R)-Praziquantel B may be in the form of medicated fish feed or administered by intubation via the esophagus. For example, the medicated fish feed may be in the form of fish feed granules or pellets having a coating made of (R)-Praziquantel B. To coat the pellets, 25g of gelatin (Davis Gelatine, New Zealand) was dissolved in 625ml of hot tap water (50°C) using a magnetic heater / stirrer. After dissolution, this gelatin solution was poured into a rotary cement mixer containing 25kg of pellets and the required amount of (R)-praziquantel. Mixing was continued for a further 5 minutes to ensure uniform coating of gelatin and (R)-praziquantel. The pellets were then removed from the mixer, spread thinly, and placed in a cool room at 8°C to allow the gelatin to solidify. After setting, the pellets were returned to the feed bag until use.

[0148] The intubation vehicle was prepared by heating 60 g of food starch (Solamyl) in 1 L of H2O to 100°C, cooling, and then mixing the vehicle with (R)-praziquantel type B at doses of 5 mg / kg, 50 mg / kg, and 200 mg / kg body weight. The administration method was 5 to 200 mg / kg body weight, as a single dose or once daily for 3 to 20 days, preferably a single dose of 200 mg / kg body weight, and more preferably a single dose of 50 to 100 mg / kg body weight daily for 3 to 5 days.

[0149] Furthermore, (R)-praziquantel B can be formulated in combination with other active agents that can treat parasitic infections in fish.

[0150] The following examples illustrate a typical preparation method, formulation composition, API, and physicochemical properties and stability of the formulation according to the present invention, as well as the therapeutic results. [Examples]

[0151] Example 1: Manufacture of (R)-Praziquantel Type B A scale-up procedure and preferred process parameters for the production of the anhydrous form B of (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one on its own have been identified.

[0152] A solution of approximately 1.5 kg of (R)-praziquantel dissolved in ethyl acetate was concentrated and then concentrated under reduced pressure in a 50-liter jacketed reactor (approximately 5 v / w). The solution was placed in the 50-liter jacketed reactor and maintained under vacuum (≤0.08 MPa) with the jacket temperature between 25°C and 45°C. The resulting mixture was exchanged twice with isopropanol (4.6 kg / batch) to a concentration of approximately 3 v / w. n-heptane (21 kg) was added to the batch while increasing the batch temperature to 40°C-50°C. The resulting mixture was stirred for approximately 1 hour. The batch temperature was cooled to 0-5°C over approximately 3 hours, and the mixture was stirred for a further 2 hours between 0-5°C. The mixture was filtered, and the cake was washed with n-heptane (5.1 kg). The isolated moist (R)-praziquantel was dried in a vacuum (≤0.08 MPa) oven at 35 ± 5°C for at least 10 hours.

[0153] A white solid was sampled for XRPD, KF, and HPLC. Purity and gravimetric tests were performed by HPLC. Weight: 1.2 kg, Assay: 100%, HPLC purity: 99.9% (214 nm), Chiral Purity: 100%.

[0154] Recrystallization with isopropanol / n-heptane and drying under vacuum at 35±5°C for at least 10 hours are crucial steps for efficiently removing unbound water from (R)-2-(cyclohexanecarbonyl)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinoline-4(11bH)-one type B, thereby ensuring that the high purity of the pharmaceutical active ingredient meets industrial GMP standards.

[0155] The XRPD spectrum of (R)-praziquantel B is shown in Figure 1, and the XRPD data is shown in Table 5. The DSC / TGA spectrum is shown in Figure 2. [Table 5]

[0156] Example 2: Evaluation of the physicochemical properties and stability of anhydrous form B of (R)-praziquantel Type B is reliably manufactured using an industrial crystallization method with a purity of 99.0% or higher, impurities of 0.15% or less, and moisture content of 0.5% or less. Detailed test results are shown in Table 6. [Table 6]

[0157] Moisture content according to the Karl Fischer method Accurately weigh approximately 0.1-0.5 g of type B sample, transfer it to a KF titration vessel (aldehyde ketone volume method), and then use USP <921> Measure in accordance with the standard.

[0158] Differential Scanning Calorimetry (DSC) Weigh approximately 2-3 mg of the compound into an open aluminum pan and press the lid tightly. Heat the sample at 25°C to 300°C. Heat at a rate of 10°C / min until [a certain temperature is reached]. Integrate all endothermic and exothermic phenomena and report onset, peak, and melting / crystallization heats.

[0159] Thermogravimetric analysis (TGA) Weigh approximately 10 mg of the compound into a platinum pan. Heat the sample from room temperature to 300°C at a rate of 10°C / min with a sample purge flow rate of 60 mL / min and a balance purge flow rate of 40 mL / min.

[0160] The data is presented as a plot of weight percentage change against temperature. The weight loss is determined as the temperature at which endothermic / exothermic phenomena were observed in DSC, or as a predetermined weight loss between room temperature and 120°C.

[0161] For R)-praziquantel B, a melting point of 112.5°C was observed. DSC data showed a strong, sharp endothermic reaction at 109°C (onset), corresponding to the weight loss in TGA, followed by another strong endothermic reaction at 112°C, presumably indicating the melting of B. In the DSC thermogram of anhydrous crystalline PZQ (Figure 2), no phase transition was observed from 109°C to melting at 112°C. In TGA, desolvation and dehydration were completed within 15 minutes at 100°C and within 40 minutes at 60°C. A weight loss of approximately 1.5% was observed in the TGA thermogram when heated from room temperature to 90°C, which is attributed to the decomposition of volatile substances.

[0162] In summary, the B-type sample from Example 1 is an anhydrous crystalline solid containing approximately 0.1 mol of water (<0.5% w / v). The DSC thermogram showed endothermic activity between approximately 105°C and 115°C, with endothermic activity occurring at approximately 112°C. It is also slightly hygroscopic.

[0163] Type B active pharmaceutical ingredients (APIs) were stored for 18 months under different storage conditions: 25°C, 60% relative humidity; 30°C, 65% relative humidity; and 40°C, 75% relative humidity, in both sealed and open conditions. The results demonstrated good stability over time under various storage conditions. In some embodiments, under various storage conditions, the anhydrous APIs provided herein may have stability and moisture content controlled to 0.5% or less by KF for at least, or at least about, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months. For example, under storage conditions of 25°C and 60% relative humidity, the tablets and APIs provided herein may be stable for at least, or at least about, 3 months, 6 months, 9 months, 12 months, and 18 months.

[0164] The long-term stability and moisture content of (R)-praziquantel type B (API) provided herein at 25°C and 60% relative humidity have been demonstrated by the results shown in Table 6 above.

[0165] The accelerated solid stability of TL-010 anhydrous (Type B) and hemihydrate (R)-praziquantel under open and closed conditions was investigated. Under open conditions of 45°C and 75% relative humidity, the accelerated stability of TL-010 anhydrous and (R)-praziquantel hemihydrate was compared. The results showed that impurities were present in the hemihydrate after 3 months of storage. The results are shown in Table 7 below.

[0166] Hemihydrate (R)-praziquantel was prepared according to the reported method (see Myer, et al).

[0167] The accelerated solid stability of anhydrous and hemihydrate (R)-praziquantel was measured by placing approximately 1.0 g of the material in a glass dish and storing it for 3 months under two conditions: a) 45°C / 75% (RH) in a closed state, and b) 45°C / 75% relative humidity (RH) in an open state. The final content and decomposition products of this material were determined by KF, TGA, and HPLC.

[0168] Results: a) Closed conditions: No significant degradation was observed (HPLC assay 99.9% initial). In the KF test of the anhydrous product, the water absorption rate did not exceed 0.3%. b) Opened condition: Significant degradation was observed in the anhydrous product. No degradation was observed (HPLC measurement 99.9% initial). However, two impurity peaks were found in the hemihydrate, and the total amount of impurities was more than 0.3%. On the other hand, in the KF test of the anhydrous form, when left at 75% RH and 45°C for 3 months, the water absorption rate increased from the initial 1.3% to approximately 2.5%, and no impurity peaks were observed (Table 7). From this, it was found that the anhydrous form is stable even under accelerated conditions and does not undergo significant degradation. [Table 7]

[0169] Overall, remarkably, an extremely stable anhydrous crystalline(R)-praziquantel B-form was discovered that retains the desired physical appearance and analytical chemical properties over longer periods. Due to its exceptionally high purity and remarkable stability, anhydrous crystalline(R)-praziquantel appears to be advantageous for use in pharmaceutical formulation development on an industrial scale.

[0170] Example 3: Composition, stability, and dissolution profile of tablets containing type B The following formulation (see Table 8) was used to prepare tablets that provided the final dosage form, i.e., 150 mg of TL-010. [Table 8]

[0171] In addition to the therapeutic benefits of the TL-010 formulations provided herein, these tablet formulations exhibit good stability over time under various storage conditions. In some embodiments, under various storage conditions, the TL-010 formulations provided herein may be stable for at least, or at least about 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, or 48 months. For example, under storage conditions of 25°C and 60% relative humidity, the tablets and TL-010 formulations provided herein may be stable for at least, or at least about 3 months, 6 months, 9 months, 12 months, and 18 months. It can be stable.

[0172] In another example, under storage conditions of 40°C and 75% relative humidity, the tablets and TL-010 formulations provided herein can be stable for at least, or at least about, three to six months.

[0173] In some embodiments, the stability of the tablets and TL-010 formulations provided herein is determined by measuring the dissolution rate of the stored tablets and / or TL-010 formulations. To evaluate the stability of TL-010 tablet formulations, any of the various dissolution methods provided herein or otherwise known in the art can be performed. Dissolution measurement is an in vitro method known in the art as a powerful indicator of in vivo pharmacokinetic performance. Thus, the stability of TL-010 tablet formulations measured by dissolution methods will indicate the in vivo Tmax and AUC values ​​of the subject when the TL-010 formulation is stored, for example, for the indicated time, under the exemplified conditions described above. Typically, dissolution levels that indicate an acceptable level of stability are dissolution of at least, or at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher, of TL-010 in the tablets provided herein. To determine the stability of the TL010 formulation, any of the various dissolution methods provided herein or otherwise known in the art may be employed. For example, dissolution may be determined according to the pharmacopoeia dissolution methods specified in USPII.

[0174] The 300 mg TL-010 tablet formulation from Example 3 was stored for 24 months under two different storage conditions: 25°C, 60% relative humidity, and 40°C, 75% relative humidity. The results showed that the tablets did not change significantly over the 24-month period. The amount of TL-010 formulation eluted at 40°C, 75% relative humidity did not change significantly during the first 6 months. Dissolution analysis was performed using water as the solvent and an Apparatus 2 (paddle) according to the pharmacopoeia dissolution method specified in USPII, at a Q ~75% specification of the label claim over 30 minutes. The total impurity level of each formulation measured by HPLC was less than 0.1% over the 24-month period. Finally, the percentage of TL-010 in each sample determined by HPLC did not show any significant degradation over the 24-month period.

[0175] Table 9 shows the long-term stability and dissolution profile of TL-010 tablet formulations containing (R)-praziquantel B type at 25°C and 60% relative humidity. [Table 9]

[0176] As can be seen from Tables 6 and 9, the unusual stability of anhydrous crystalline (R)-praziquantel results in highly reproducible batches and better storage characteristics. No chemical degradation or enantiomer conversion was observed by standard analytical methods during the storage period of the API and tablets, and consistent results were obtained in solubility, dissolution, and pharmacokinetic studies in humans and animals, further providing strong evidence that anhydrous form B of (R)-praziquantel is an excellent candidate for manufacturing process scale-up and clinical development.

[0177] Example 4: Alternative composition for tablets containing type B Tablets containing 150 mg of TL-010 were prepared using the following formulation (see Table 10). [Table 10]

[0178] Example 5: Flexible oral composition or pasta formulation containing R)-praziquantel type B Table 11 shows the composition of a soft oral anthelmintic formulation for pet animals (dogs and cats). The oral formulation contains API (R)-praziquantel B and benzimidazole (albendazole), tripenzimidine, macrolide compounds, or milbemycin oxime, and can be used in warm-blooded animals such as dogs and cats. [Table 11]

[0179] As an example, a homogeneous aqueous suspension paste for oral administration can be prepared by the following process: Prepare a solution by adding propylene glycol or HBβCD to 1.0.01 M citrate buffer and microcrystalline cellulose. 2. Dissolve (R)-praziquantel type B and albendazole (or tripenzimidine), and milbemycin oxime or at least one macrolide anthelmintic compound, or the compound with a thickener and filler or drug in a solution and mix well at ambient temperature. 3. Add other inactive ingredients such as artificial beef flavoring, titanium dioxide, polyvinylpyrrolidone K30, and at least one compound selected from the group consisting of surfactants, preservatives, or antioxidants, and mix until homogeneously dispersed. 4. Finally, add the remaining buffer to the mixture in a blender and mix well to obtain a soft, homogeneous paste. 5. The resulting semi-solid formulation is then filled into toothpaste-tube-like, squeezeable soft tubes using a filling machine, in different dosage units ranging from approximately 0.5 to 10 g / mL for animals of different sizes.

[0180] Example 6: Experimental study of the clinical pharmacokinetics and pharmacodynamics of (R)-praziquantel A (reported in CN104327077A) in the treatment of schistosomiasis japonica. One exploratory clinical trial was conducted involving eight patients with chronic schistosomiasis japonica using a single dose of (R)-praziquantel 30 mg / kg. These adult patients (4 males, 4 females) were selected from endemic areas using the fecal miracle hatching method and admitted to local hospitals. During hospitalization, they were provided with a standard diet, alcohol was prohibited, and unrelated medications were discontinued. Three of the eight patients were diagnosed with mild hepatomegaly, and two with mild ascites. Most clinical chemistry tests showed no abnormalities in liver or kidney function. (R)-praziquantel is a white crystalline powder and was prepared as neat API (Type A) in gelatin capsules (200 mg / capsule, 2 capsules). On day 1, all patients received a single dose of (R)-praziquantel 30 mg / kg, followed by oral administration of approximately 200 mL of drinking water.

[0181] Clinical observation: Each patient was carefully observed after drug administration, focusing on their complaints and signs. All patients experienced mild and transient side effects, and the treatment was well tolerated. No significant changes were observed in electrocardiograms before administration, 2 hours after administration, and 24 hours after administration. Clinical chemistry tests for liver and kidney function in blood and urine also showed no changes before and after administration.

[0182] For pharmacokinetic analysis, blood samples were collected from the cubital vein before administration and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. The blood samples were processed to obtain serum, which was stored in a -40°C freezer until analysis. Serum concentrations were measured using our proprietary reverse-phase high-performance liquid chromatography (HPLC) system. 60 minutes after oral ingestion of the capsule, the mean serum concentration of (R)-praziquantel reached 0.13 μg / mL. The mean serum concentration was measured at 0.15 μg / mL at 2 hours and 0.09 μg / mL at 8 hours. The pharmacokinetic results of capsule therapy in this study are shown in Table 12.

[0183] Therapeutic effect: Six months after treatment, each patient underwent three consecutive fecal occult blood tests. A 100% negative rate for fecal occult blood was achieved, confirming that all eight patients were completely cured.

[0184] Example 7: Report on the pharmacokinetic study of (R)-praziquantel orally dispersed tablets (ODT) Two pharmacokinetic studies in healthy adult males have been reported (Bagchus et al, 2019 Relative Bioavailability of Orally Dispersible Tablet (ODT) Formulations of Levo- and Racemic Praziquantel: Two Phase I Trials Clin Transl Sci. 2019 Jan;12(1):66-76. Merck KGaA, Darmstadt, Germany, hereafter referred to as "Bagchus 2019").

[0185] In this study, levopraziquantel (i.e., (R)-PZQ) was administered orally to 17 healthy adult subjects (Group D) at a dose of 30 mg / kg in an orally disintegrating tablet (ODT) formulation. Plasma samples were collected before administration and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours after administration. Plasma (R)-PZQ concentrations were measured using a valid enantioselective LC / MS assay. The obtained pharmacokinetic parameter values ​​are shown in Table 12. The ODT formulation contained 150 mg of the active ingredient (R)-PZQ, along with certain undisclosed pharmaceutically acceptable excipients, mannitol, and a sweetener to mask the taste. For comparison at the same oral dose level of 30 mg / kg, the pharmacokinetic results between the ODT, the capsules of Example 6, and the TL-010 table of Example 8 are summarized in Table 12 below.

[0186] Example 8: Pharmacokinetic study of the current TL-010 tablets of (R)-praziquantel from Example 3 in humans. The first study shown in Figure 3 shows the mean change in plasma concentration over time in three groups of healthy human subjects who received a single dose of TL-010 tablet formulations at different dose levels. The three plasma drug concentration-time curves in this graph represent three different dose groups of subjects: A, 20 mg / kg; B, 30 mg / kg; C, 40 mg / kg. As shown in Figure 3, a dose-proportional increase in (R)-praziquantel exposure (AUC and Cmax) was observed, suggesting linear pharmacokinetics of TL-010 over the dose range of 20–40 mg / kg in healthy subjects.

[0187] In another pharmacokinetic study, 23 fasted healthy human subjects were divided into two groups and conducted in a crossover design. One group (Group I) received TL-010 tablets at 20 mg / kg, while the other group (Group II) received the reference drug, Biltricide® tablets at 40 mg / kg. Plasma concentrations of (R)-praziquantel were 0.25, 0.5, and 1 before and after administration. Chiral LC / MS / MS was used to measure levels at 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Figure 4 is a plot of the time course of plasma(R)-praziquantel levels summarizing this study. As shown in Figure 4, the maximum plasma(R)-praziquantel level was reached 1.5 hours after administration in both groups. Surprisingly, however, as shown in the plot, the mean Cmax was approximately 75% higher in the TL-010 tablet group than in the same subjects who received the reference compound Biltricide®. It's very high.

[0188] To compare with previous results from Example 7, the report by Bagchus et al. 2019 using orally disintegrating tablet (ODT) formulations, and Example 6 using neat (R)-praziquantel powder in capsules without excipients, pharmacokinetic comparisons were summarized in Table 12 for three (R)-praziquantel oral formulations (current TL-010 tablets, ODTs, and capsules) at the same single oral dose level of 30 mg / kg under feeding conditions. The AUC of TL-010 tablets was found to be significantly higher (approximately 125% and 19% increases) than that of capsules and ODTs. AUC values ​​were calculated on a time axis from zero to infinity. The Tmax values ​​were shorter for TL-010 tablets than for ODTs and capsule formulations. Overall, TL-010 tablets demonstrated faster oral absorption and greater plasma exposure of (R)-praziquantel compared to ODTs and capsules. [Table 12]

[0189] As shown in Table 13, a similar trend was observed when comparing the plasma exposure (AUC) of the 40 mg / kg group of TL-010 tablets with the results of the same dose group of (R)-praziquantel ODT under rapid conditions reported in Bagchus 2019. Unexpectedly, the mean AUC value of TL-010 tablets was found to be approximately 3.68 times higher than that of the group using ODT. [Table 13] Example 9: Pharmacokinetic study of the current (R)-praziquantel tablets of Example 3 in dogs. A pilot crossover pharmacokinetic study was conducted in dogs orally administered with the TL-010 tablets described herein. In male beagle dogs, pharmacokinetic and relative bioavailability studies of (R)-praziquantel (R-PZQ) were performed after oral administration of half the dose of TL-010 (150 mg / tablet) versus commercially available PZQ tablets (Biltricide®, the same amount of (R)-praziquantel (150 mg / tablet) and 600 mg / tablet containing the S-isomer). The PK values ​​obtained for these groups are summarized in Table 14. Plasma R-PZQ in dogs administered with TL-010 tablets had a shorter Tmax and higher Cmax and AUC than in dogs administered with racemic PZQ tablets. The results showed that racemic PZQ resulted in much higher blood concentrations of S-PZQ and its metabolite, S-hydroxyisoquaronine, and that its potential components induce drug interactions between isomers, potentially raising safety concerns when administered with other drugs in combination therapy. When R-PZQ was administered alone, the S-isomer and other No metabolites, nor the conversion of the S-isomer and its metabolites to R-PZQ, were detected, indicating a relatively safe profile for animals. [Table 14]

[0190] The increased PK values, particularly Cmax and AUC, of ​​these results shown in Examples 6-9 indicate relatively high bioavailability of the (R)-PZQ tablets according to this disclosure. As a result, these tablets can sustain a superior therapeutic effect in subjects (patients or animals). It should be noted that the drug formulations in these previously reported studies differed. Bagchus 2019 in Example 7 used an orally disintegrating tablet (ODT) formulation containing 150 mg of the active ingredient (R-PZQ) and certain undisclosed pharmaceutical excipients, as well as mannitol and sweeteners for taste masking, while Example 6 used 200 mg of neat (R)-praziquantel A in a capsule without excipients. Therefore, compared to the 100% A in capsule used in Example 6 and the ODT tablet in Example 7, the current tablets with anhydrous B and excipients are advantageously administered to subjects in need, thereby eliciting the desired pharmacokinetic response from the subjects. While such desirable PK reactions are unexpected and surprising results, it is conceivable that the specific composition and amounts of the disintegrant CMS-Na (sodium starch glycolate) and excipients such as the lubricant and sodium stearyl fumarate, as well as binders such as microcrystalline cellulose and povidone K30, may play some role in favorably interacting with the (R)-praziquantel molecule.

[0191] Example 10: Therapeutic Indications One embodiment of the present disclosure provides a method for treating diseases such as schistosomiasis japonica, schistosomiasis, schistosomiasis mansoni, hepatoparasitic fluke, lung fluke, sparganosis mansoni, hypertrophic fluke, echinococcosis, tapeworm infection, and cysticercosis, including neurocysticercosis.

[0192] These methods involve administering the TL-010 tablets of this disclosure to patients suffering from a parasitic infection or a cytokine-mediated disorder. Administration may be once, twice, or three times daily, with one or more tablets administered per dose. According to a particular embodiment, the total daily dose is at least 1500 mg for human subjects or at least 1 mg / kg for warm-blooded animals such as dogs and cats.

[0193] The total daily intake may vary depending on the patient's demographic characteristics, physiological and genetic status, and disease prognosis, among other factors, as well as their overall profile. For example, children or elderly individuals may be given a lower daily dose than that given to a typical adult.

[0194] The antiparasitic activity of (R)-praziquantel has been demonstrated in various in vivo animal models, as well as in in vitro culture studies using various adult parasites, including schistosomiasis, liver flukes, and tapeworms. These data suggest that (R)-praziquantel is effective in treating parasitic infections caused by diseases such as schistosomiasis japonica, schistosomiasis mansoni, liver flukes, lung flukes, sparganosis mansoni, hypertrophic flukes, echinococcosis, tapeworm infections, and cysticercosis.

[0195] Clinical findings in humans following treatment with (R)-praziquantel are consistent with the anti-cystosoma effect observed in experimental animals. A pilot open clinical trial of oral administration of (R)-praziquantel is underway. The study was conducted on patients with schistosomiasis japonica, schistosomiasis, schistosomiasis nicolai, and schistosomiasis narcosis.

[0196] One of the clinical benefits of (R)-praziquantel is that it has been shown to improve medical compliance by removing the S-isomer, which is 50% of the active ingredient in commercially available racemic praziquantel tablets and has a very unpleasant odor and bitter taste. This removal may also eliminate safety and drug (or isomer) interaction concerns due to the high plasma concentrations of the S-isomer and its hydroxylated metabolites. At the same dose, (R)-praziquantel is known to have superior anthelmintic effects compared to praziquantel, while (S)-praziquantel is known to be almost inactive. (R)-praziquantel shows lower cardiotoxicity in isolated rat atria and conscious rabbits compared to (S)-praziquantel. TL-010 tablets are small, tasteless tablets with low doses and high safety, making them particularly effective for treating pediatric patients and pet animals such as dogs and cats who are sensitive to smells and tastes.

[0197] Thus, antiparasitic activity was demonstrated in clinical trials using both controlled protocol designs and open-label studies. Side effects observed with oral administration were relatively mild (drowsiness, stomach discomfort, photosensitive rash). No serious side effects were reported.

[0198] In summary, based on clinical data on the anthelmintic activity and efficacy of racemic praziquantel in animals and patients, and preliminary reports by others on (R)-praziquantel and this disclosure, (R)-praziquantel clearly demonstrates clinical benefits when used in humans or animals.1) 1) 1) 2 Parasitic infections such as various schistosomiasis, hepatochomidosis and opisthochiosis, hypertrophic fluke infection, lung fluke infection, tapeworm infection, cysticercosis, echinococcosis / hydatid infection, heterophydia, echinostomydiosis, neodiprostomydiosis, gymnophagoidosis, diphyllobothrium cephalocephali infection and membranous tapeworm infection; and more. These are commonly seen in various animals, including pet animals (dogs and cats), agricultural and economic animals (beef, lamb / sheep, pigs, horses), as well as zoonotic diseases in aquaculture and fisheries.

[0199] 1) Parasitic infections such as various types of schistosomiasis, hepatochomiasis and opisthochiasis, hypertrophic trematodesis, lung paragonimiasis, tapeworm infection, cysticercosis, echinococcosis / hydatidosis, heterophydia, echinostomydiosis, neodiprostomydiosis, gymnophagoidosis, diphyllobothrium cephalocephali and membranous tapeworm infections; etc. 2) Commonly seen in various animals are zoonotic diseases in pet animals (dogs and cats), agricultural and economic animals (beef, lamb / sheep, pigs, horses), as well as in aquaculture and fisheries. 3) Based on the potential antifibrotic activity of (R)-praziquantel, the TL-010 tablet formulation of this disclosure may be administered according to other embodiments to prevent or treat subjects suffering from cytokine-mediated hepatic fibrosis, inflammation, and tissue regeneration associated with chronic schistosomiasis.

[0200] The descriptions, examples, and data, while illustrating exemplary embodiments, are provided for illustrative purposes only and are not intended to limit the various embodiments of this disclosure. All references cited herein, for whatever reason, are incorporated specifically and fully by reference. This description of embodiments is solely for the purpose of aiding the understanding of the methods and core concepts of this disclosure. Those skilled in the art can make various improvements and modifications to this disclosure without departing from the technical principles thereof, and these improvements and modifications... Please note that this also falls within the scope of protection of this disclosure.

Claims

1. Anhydrous B-type crystals of (R)-praziquantel, characterized by X-ray powder diffraction patterns including 2θ values ​​of 8.6±0.2°, 13.1±0.2°, 17.9±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, and 24.8±0.2°, wherein the anhydrous B-type crystals have a water content between 0 and 1% w / w as measured by a standard Karl Fischer detection procedure, or the anhydrous B-type crystals contain less than 0.2 mol of crystalline water per molecule.

2. The aforementioned X-ray powder diffraction pattern includes a 2θ value of 13.1 ± 0.1°; Alternatively, the water content of the anhydrous type B crystals is 0–0.6% w / w as measured by the standard Karl Fischer detection procedure; Alternatively, the anhydrous type B crystal contains less than 0.1 mol of crystalline water per molecule; Alternatively, the anhydrous type B crystals are free of impurities; Alternatively, the X-ray powder diffraction pattern includes a 2θ value of 8.6 ± 0.2° at 100% relative intensity; Alternatively, the X-ray powder diffraction pattern includes a 2θ value of 13.1 ± 0.2° at a relative intensity of 3% or more; and / or, the X-ray powder diffraction pattern includes a 2θ value of 13.1 ± 0.2° at a relative intensity of less than 7%; Alternatively, it is a white powder consisting of aggregates of birefringent rod-shaped or needle-shaped crystals; Alternatively, the anhydrous type B crystal is characterized by a differential scanning calorimetry thermogram having an endothermic peak temperature of 112.5°C; Alternatively, the purity of the anhydrous type B crystal is 99.0% or higher; Alternatively, the particle size of the B-type crystal is less than 150 microns. An anhydrous B-type crystal according to claim 1, characterized by the above.

3. The X-ray powder diffraction pattern includes at least one 2θ value selected from 27.8±0.2°, 31.2±0.2°, and 34.5±0.2°; Alternatively, the X-ray powder diffraction patterns are 7.2±0.2°, 8.6±0.2°, and 13.1°. Includes 2θ values ​​of ±0.2°, 15.3±0.2°, 17.9±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 24.1±0.2°, and 24.8±0.2°; Alternatively, the X-ray powder diffraction pattern includes 2θ values ​​of 7.2±0.2°, 8.6±0.2°, 13.1±0.2°, 13.8±0.2°, 14.4±0.2°, 15.3±0.2°, 16.0±0.2°, 16.9±0.2°, 17.9±0.2°, 18.2±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.8±0.2°, 27.8±0.2°, and 31.2±0.2°; Alternatively, the X-ray powder diffraction pattern includes 2θ values ​​of 7.2±0.2°, 8.6±0.2°, 13.1±0.2°, 15.3±0.2°, 16.0±0.2°, 17.9±0.2°, 18.2±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 24.1±0.2°, 24.8±0.2°, 27.8±0.2°, 31.2±0.2°, and 34.5±0.2°; Alternatively, the X-ray powder diffraction pattern includes 2θ values ​​of 7.2±0.2°, 8.6±0.2°, 13.1±0.2°, 13.8±0.2°, 14.4±0.2°, 15.3±0.2°, 16.0±0.2°, 16.9±0.2°, 17.9±0.2°, 18.2±0.2°, 19.3±0.2°, 20.1±0.2°, 20.9±0.2°, 22.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.8±0.2°, 27.8±0.2°, 31.2±0.2°, and 34.5±0.2°; Alternatively, the water content of the anhydrous type B crystals is 0–0.5% w / w as measured by a standard Karl Fischer detection procedure; Alternatively, the anhydrous type B crystal does not contain crystalline water; Alternatively, the impurity content of the anhydrous type B crystal is less than 1%; Alternatively, the X-ray powder diffraction pattern includes a 2θ value of 13.1 ± 0.2° with a relative intensity of less than 5%; Alternatively, the purity of the anhydrous type B crystal is 99.9% or higher; Alternatively, at least 90% of the anhydrous type B crystals have a particle size of less than 100 microns; the anhydrous type B crystal according to claim 1.

4. The impurity content of the aforementioned anhydrous type B crystals is less than 0.5%; Alternatively, at least 90% of the anhydrous type B crystals have a particle size of less than 50 microns; Anhydrous B-type crystal according to claim 1.

5. At least 90% of the anhydrous type B crystals have a particle size of less than 20 microns; Anhydrous B-type crystal according to claim 1.

6. At least 90% of the anhydrous type B crystals have a particle size of less than 0.2 microns; Anhydrous B-type crystal according to claim 1.

7. A pharmaceutical composition comprising a therapeutically effective amount of anhydrous form B crystals of (R)-praziquantel as described in any one of claims 1 to 6, and a pharmaceutically or veterinarily acceptable carrier.

8. The pharmaceutical composition is formulated as an oral preparation, an injectable preparation, a depot preparation, a semi-solid preparation, or a topical preparation; Alternatively, the pharmaceutical composition may be formulated as a tablet, capsule, granule, chewable, dragee, lozenge, liquid, gel, paste, solution, syrup, slurry, granule, powder, premix, or suspension; Alternatively, the carrier may be a solid, semi-solid, or liquid; Alternatively, the pharmaceutical composition may be delivered using a sustained-release system; The pharmaceutical composition according to claim 7.

9. The pharmaceutical composition may be in the form of tablets or chewable preparations or capsules or granules prepared with pharmaceutically acceptable excipients, or semi-solid pastes or liquid formulations prepared with pharmaceutically acceptable excipients; Alternatively, the pharmaceutical composition may be delivered using a sustained-release system, the sustained-release delivery system being a semipermeable matrix of a solid polymer; The pharmaceutical composition according to claim 7.

10. The pharmaceutical composition according to claim 9, wherein the excipient comprises one or more selected from the group consisting of binders, fillers, lubricants, disintegrants, surfactants, solubilizers, lubricants, flavoring agents, diluents, anti-adhesion agents, coating agents, wetting agents, or combinations thereof; and / or, the additive comprises one or more selected from the group consisting of suspending agents, emulsifiers, solubilizers, non-aqueous vehicles, preservatives, or combinations thereof.

11. The pharmaceutical composition is a tablet or chewable tablet comprising 40 to 80% by weight of anhydrous type B crystals and 20 to 60% by weight of a pharmaceutically acceptable excipient; and / or the pharmaceutical composition comprises 10 to 300 mg of anhydrous type B crystals per tablet; and / or the pharmaceutical composition according to claim 9, wherein each tablet comprises 10 to 600 mg of anhydrous type B crystals.

12. The disintegrant comprises one or more selected from the group consisting of hydroxypropylcellulose, low-density hydroxypropylcellulose, sodium carboxymethyl starch, carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethyl starch, hydroxypropyl starch, modified starch, crystalline cellulose, sodium starch saccharidone, calcium carbonate, sodium croscarmellose, crospovidone, gum, aluminum magnesium silicate, methylcellulose, potassium polaritrin, sodium alginate, low-substituted hydroxypropylcellulose, cross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starch saccharidone, starch, or combinations thereof; and / or, the binder comprises one or more selected from the group consisting of polyvinylpyrrolidone, povidone K30, polyethylene glycol, acacia, alginic acid, agar, calcium carrageenan, cellulose derivatives, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, or combinations thereof; and / or, the diluent or filler comprises one or more selected from the group consisting of lactose, various grades of lactose, lactitol, saccharose, sorbitol, mannitol, dextrin, dextrin, dextrin, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose, microcrystalline cellulose PH 101, hydroxypropyl cellulose, L-hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose polymer, hydroxyethyl cellulose, carboxymethyl cellulose sodium, carboxymethylene, carboxymethyl hydroxyethyl cellulose, non-pareile seed, sugar globules and other cellulose derivatives, starch, turbid starch, or combinations thereof; and / or, the surfactant or solubilizer is polysorbate, sodium dodecyl sulfate, lauryldimethylamine oxide, sodium docusate, polyoxomer, cetyltrimethylammonium bromide, polyethoxylated alcohol, polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, polyoxyl 10 lauryl ether, bile salt, polyoxyl castor oil, 2-hydroxypropyl-β-cyclodextrin β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, RMβCD, lecithin, methylbenzethonium chloride, carboxylate, sulfonate, petroleum sulfonate, alkylbenzene sulfonate, naphthalene sulfonate, olefin sulfonate, alkyl sulfate, sulfate, sulfated natural oils and fats, sulfated ester, sulfated alkanolamide, alkylphenol, ethoxylated / sulfated aliphatic alcohol, polyoxyethylene surfactant, carboxylic acid ester, polyethylene glycol ester, anhydrosorbitol ester and its ethoxylated derivative, glycol ester of fatty acids The following are included:

1. Carboxamide, monoalkamino complex, polyoxyethylene fatty acid amide, quaternary ammonium salt, amine having an amide bond, polyoxyethylene alkyl and alicyclic amine, N,N,N,N tetrakis-substituted ethylenediamine 2-alkyl 1-hydroxyethyl 2-imidazoline, N-coco-3-aminopropionic acid / sodium salt, N-tarou-3-iminodipropionate disodium salt, N-carboxymethyl N-dimethyl N-9 octadecenylammonium hydroxide, N-cocoamidemethyl N-hydroxyethylglycine sodium salt, or one or more selected from the group consisting of these; and / or, the lubricant, anti-adhesion agent and lubricant comprises one or more selected from the group consisting of stearic acid and pharmaceutically acceptable salts or esters, talc, wax, glycerides, light mineral oil, PEG, silicic acid or its derivatives or salts, sucrose esters of fatty acids, hydrogenated vegetable oils, or combinations thereof; and / or the disintegrant is present in an amount of 2 to 30% by weight; and / or the disintegrant is sodium starch glycolate; and / or the binder is present in an amount ranging from 1 to 20% by weight; and / or the binder is povidone K 30; and / or the carrier, diluent, or filler is present in an amount ranging from 2 to 50% by weight; and / or the diluent or filler is microcrystalline cellulose; and / or the surfactant or solubilizer is present in an amount ranging from 0.5 to 10% by weight; and / or the surfactant or solubilizer is sodium lauryl sulfate; and / or the lubricant, anti-adhesion agent, or lubricant is present in an amount ranging from 0.1 to 6% by weight; and / or, the lubricant is colloidal silicon dioxide, with a content of 0.3 to 2%; and / or, the lubricant is sodium stearyl fumarate, with a content of 0.3 to 5%; or, the lubricant is magnesium stearate, with a content of 0.25 to 5%. The pharmaceutical composition according to claim 10.

13. The pharmaceutical composition comprises 50 to 70% by weight of anhydrous type B crystals and 30 to 50% by weight of a pharmaceutically acceptable excipient; Alternatively, each tablet contains 20-300 mg of anhydrous type B crystals; Alternatively, the disintegrant is present in an amount ranging from 2% to 10% by weight; Alternatively, the binder may be present in an amount ranging from 2% to 8% by weight; Alternatively, the carrier, diluent, or filler may be present in an amount ranging from 17.5% to 45% by weight; Alternatively, the surfactant or solubilizer may be present in an amount ranging from 1% to 3% by weight; Alternatively, the lubricant, anti-adhesion agent, or lubricant may be present in an amount ranging from 0.1 to 5% by weight; Alternatively, the lubricant content is 0.3 to 3%; The pharmaceutical composition according to claim 10.

14. Each tablet contains 50-150 mg of anhydrous type B crystals; The disintegrant is present in an amount ranging from 2% to 8% by weight; Alternatively, the carrier, diluent, or filler may be present in an amount ranging from 35% to 45% by weight; Alternatively, the surfactant or solubilizer may be present in an amount ranging from 0.9% to 1% by weight; The pharmaceutical composition according to claim 10.

15. The pharmaceutical composition according to claim 7, characterized in that the pharmaceutical composition is a tablet and contains 40 to 80% by weight of type B crystals, 30 to 50% by weight of microcrystalline cellulose, 0.5 to 2% by weight of sodium lauryl sulfate, 2 to 8% by weight of sodium starch glycolate, 1 to 8% by weight of povidone K30, 0.3 to 2% by weight of colloidal silicon dioxide, and 0.1 to 5% by weight of sodium stearyl fumarate.

16. The pharmaceutical composition according to claim 15, characterized in that the pharmaceutical composition is a tablet and contains 40 to 60% by weight of type B crystals, 30 to 50% by weight of microcrystalline cellulose, 0.5 to 2% by weight of sodium lauryl sulfate, 5 to 8% by weight of sodium starch glycolate, 1 to 5% by weight of povidone K30, 0.3 to 1% by weight of colloidal silicon dioxide, and 0.3 to 3% by weight of stearyl fumarate.

17. The pharmaceutical composition is a semi-solid, granular, or chewable oral alloantigenic anthelmintic formulation for the treatment, control, and prevention of internal and external parasitic infections in animals, wherein the semi-solid oral alloantigenic, granular, or chewable alloantigenic anthelmintic formulation comprises only anhydrous type B crystals, or in combination therewith, abamectin, selamectin, moxidectin, ivermectin, emamectin, doramectin, eprinomectin, pyrantel, amitraz, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, febantel, octadepsipeptide, oxfendazole, oxybendazole, The formulation comprises at least one veterinary drug or a mixture thereof selected from paraherbicamide, parbendazole, thiabendazole, tetramizole, triclabendazole, rebamizole, oxantel, novalon, morantel, milbemycin, milbemycin oxime, cyclooctadepsipeptide, demiditraz, diethylcarbamazine, fipronil, hydroprene, quinoprene, methoprene, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen, spinosad, aminoacetonitrile derivatives, pyrantel, benzimidazoles, febantherezoles, tripenzimidine, and a veterinarily acceptable inactive component; Alternatively, the pharmaceutical composition may contain the following effective medicinal ingredients: 1.5% of the (R)-praziquantel anhydrous form B crystals, or plus 0.15% moxidectin, or plus 0.2% milbemycin oxime, or plus 25% tripendimidine, or plus albendazole; and / or the pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a semi-solid paste comprising 1 to 6% by weight of anhydrous type B crystals and 20 to 60% by weight of a pharmaceutically acceptable excipient.

18. Veterinary-acceptable inert ingredients include one or more selected from the group consisting of fillers, thickeners, flavoring agents, binders, colorants or opacifiers, humectants, preservatives, antioxidants, cyclodextrins, buffers, viscosity modifiers, solubilizers, surfactants, lubricants, antimicrobial agents, solvents, or combinations thereof; The filler is present in an amount ranging from 1 to 40% by weight, and / or the filler is selected from one or more of the group consisting of corn starch, soy protein powder, microcrystalline cellulose, or a combination thereof; and / or, the thickener is present in an amount ranging from 1 to 30% by weight, and / or, the thickener is hydroxypropyl cellulose, microcrystalline cellulose, corn starch, xanthan gum, polyvinylpyrrolidone, hydroxyethyl starch, or a combination thereof. One or more are selected from the group consisting of; and / or, the flavoring agent is present in an amount ranging from 10 to 25% by weight; and / or the binder is present in an amount ranging from 2 to 8% by weight; and / or the binder is selected from one or more of the group consisting of polyvinylpyrrolidone K 30, crosslinked polyvinylpyrrolidone, PEG 4000, or combinations thereof; and / or the coloring agent or opacifying agent is present in an amount ranging from 0 to 2% by weight; and / or the humectant is present in an amount ranging from 1 to 25% by weight; and / or the humectant is one or more selected from the group consisting of glycerol, animal fat, fish oil, propylene glycol, or a combination thereof; and / or the preservative is present in an amount ranging from 0.3 to 1.4% by weight; and / or the preservative is selected from one or more of the group consisting of benzyl alcohol, sodium benzoate, potassium sorbate, or combinations thereof; and / or the antioxidant is present in an amount ranging from 0.01 to 7% by weight; and / or the antioxidant is selected from one or more of the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, or combinations thereof; and / or the buffer is HCl or citrate; and / or the viscosity modifier is present in an amount ranging from 1% to 10% by weight; and / or the viscosity modifier is selected from one or more of the group consisting of hydrogenated castor oil, corn oil, olive oil, or combinations thereof; and / or the solubilizer is present in an amount ranging from 1 to 5% by weight; and / or the solubilizer is HPβCD; and / or the surfactant is present in an amount ranging from 1 to 5% by weight; and / or the surfactant is sodium lauryl sulfate; and / or the solvent is present in an amount ranging from 1 to 10% by weight; and / or the solvent is propylene glycol, polyethylene glycol, or glycerol; and / or the lubricant is present in an amount ranging from 1 to 10% by weight; and / or the lubricant is a hydrogenated vegetable oil; and / or the antimicrobial agent is present in an amount ranging from 1 to 10% by weight; and / or the antimicrobial agent is benzyl alcohol; and / or, the semi-solid oral equivalent is an oil-based paste, and the veterinarily acceptable inert component is one or more selected from the group consisting of fillers, surfactants, flavoring agents, thickeners, binders, solvents, lubricants, preservatives, antimicrobial agents, antioxidants, opacifiers, or combinations thereof; and / or, semi-solid oral allogenes are aqueous-based pastes, and veterinarily acceptable inert ingredients are selected from the group consisting of fillers, colorants or opacifiers, solubilizers, flavoring agents, binders, humidifiers, preservatives, buffers, or combinations thereof; The pharmaceutical composition according to claim 17, wherein the buffer is a citrate.

19. The aforementioned pharmaceutical composition includes tinidazole, metronidazole, melarsoprol, eflunithine, rifampin, amphotericin B, pentamidine, sodium stivogluconate, meglumine antimonia, fluconazole, artesunate, artemether, dihydroartemisinin, quinine, quinidine, chloroquine, atobacuon proguanil, artemether lumefantrine, mefloquine, doxycycline, clindamycin, paromomycin, atobacuon, nitazoxanide, azithromycin, fumagiline, and paromomycin. Diloxanide, Secnidazole, Ornidazole, Iodoquinol, Diloxanide Furoate, Clindamycin, Atovaquone, Azithromycin, Diminazene, Trypan Blue Oxamnikinin, Emodepside, Tribendimidine, Fenbentyl, Monepantel, Delcantel, Diethylcarbamazine, Abamectin, Selamectin, Moxidectin, Ivermectin, Evamectin, Doramectin, Eprinomectin, Pyrantel, Amitraz, Albendazole, Cambendazole, Fenbendazole, Flubendazole The pharmaceutical composition according to claim 7, further comprising one or more selected from the group consisting of mebendazole, febantel, octadepsipeptide, oxfendazole, oxybendazole, paraherbicamideparbendazole, thiabendazole, tetramisole, triclabendazole, rebamisole, oxantel, novalon, morantel, milbemycin, milbemycin oxime, demiditraz, diethylcarbamazine, fipronil, hydroprene, quinoprene, methoprene, metaflumizone, niclosamide, permethrin, pyrethrin, pyrantel pamoate, pyriproxyfen, spinosad, and aminoacetonitrile derivatives.

20. A method for preventing or treating a subject suffering from a parasitic infection and related disease, including schistosomiasis, clonorchiosis, opistolchiosis, paragonimiasis, fasciolopsyosis, teniasis (tapeworm infection), cysticercosis, echinococcosis, heterophysiosis, echinostomiasis, neodyprostomiasis, gymnophagoidosis, diphyllobothriasis, bertieriasis, sparganosis, or hymenorepiasis, comprising administering anhydrous form B crystals of (R)-praziquantel as described in any one of claims 1 to 6 and / or a pharmaceutical composition as described in any one of claims 4 to 19 to a subject suffering from a parasitic disease (provided the subject is not human).

21. The subjects include cats, dogs, horses, chickens, pigs, sheep, and cattle. and / or the dosage is in the range of 0.1 to 3,000 mg per day; and / or the method involves administering one or more of the formulation to a subject once or more times a day such that the total daily intake of type B crystals to the animal is 1 mg / kg or more; and / or administering it on a daily basis; and / or the method according to claim 20, wherein the subject is a non-human mammal or a fish.

22. A method for treating infections caused by fish parasites, including tapeworms and hyacinths (monogenes, digenes, and cestodes), in aquaculture animals and fish, using the anhydrous crystalline form B described in any one of claims 1 to 6 or the pharmaceutical composition described in any one of claims 7 to 19.

23. Fish parasites, Ancylodiscoides vistulensis, Benedenia seriolae, Cleidodiscus sp., Clemacotyle australis, Dactylogyrus sp., Gyrodactylus aculeati, Gyrodactylus turn bulli, Haliotrema abaddon, or Lepidotrema bidyanaiin (Target: European catfish, yellowtail, black clapperfish, spotted eagle ray, goldfish, guppy, stickleback, Western Australian jewfish, or silver perch) Clinostomum complanatum, Clinostomum marginatum, or Diplostomum spathaceum (target species: sunshine bass, channel catfish, grass carp, or silver carp) ; including Bothriocephalus acheilognath (applicable to Bonytail chub, grass carp, red shiner, or red snapper), or aporocotylid blood flukes (applicable to bluefin tuna, Cardicola forsteri, Southern bluefin tuna (Thunnus maccoyii), Atlantic bluefin tuna (Thunnus thynnus), bluefin tuna (Thunnus orientalis), or Cardicola orientalis); and / or the method includes a medicated bath, a medicated feed, or oral intubation; And / or, in the case of a medicated bath, the final concentration of anhydrous type B crystals in the water is 1 mg / L to 50 mg / L, for a maximum of 96 hours; and / or, oral administration of a formulation containing the anhydrous form B crystals of (R)-praziquantel is used in the form of fish feed granules, pellets, or tablets, or a powder containing feed additives, together with feed additives; The method according to claim 22, and / or, the amount of the anhydrous form B crystals of (R)-praziquantel is in the range of 5 to 200 mg / kg (body weight), administered as a single dose, twice daily, or daily for up to 20 days.

24. The amount of (R)-praziquantel anhydrous form B crystals is in the range of 50 to 100 mg / kg (body weight) and is administered as a single dose; Alternatively, the amount of (R)-praziquantel anhydrous form B crystals is in the range of 50 to 100 mg / kg (body weight), administered as a single dose once a day for 2 to 5 consecutive days. The method according to claim 23.

25. a) Dissolve the (R)-praziquantel compound in at least one solvent at 45°C to form a solution; b) Add another solvent to the solution and cool the mixture at 0-5°C for at least 5 hours to form a solid, where the other solvent is n-heptane; c) Isolate the solid by filtration; d) Dry the solid under vacuum (≤-0.08 MPa) at 35±5°C for at least 10 hours to obtain anhydrous B-type crystals. A method for producing anhydrous B-type crystals of (R)-praziquantel according to any one of claims 1 to 6, including the method described in any one of claims 1 to 6.

26. The manufacturing method according to claim 25, wherein the at least one solvent is an anhydrous solvent, and the one solvent is one or more selected from the group consisting of acetone, acetonitrile, chloroform, dichloromethane, dimethyl sulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, ethanol, ethyl acetate, isopropyl acetate, isopropyl alcohol, methanol, methyl isobutyl ketone, 2-methyltetrahydrofuran, methyl tert-butyl ether, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, and toluene.

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