Cremizole preparations

Abstract

To provide a stable liquid pharmaceutical composition for treating epilepsy disorders. [Solution] A liquid pharmaceutical composition for the treatment of epileptic disorders, comprising cremisole hydrochloride, a solvent, a preservative, and glycerol. The preservative and cremisole hydrochloride are stable during storage. The preservative comprises at least one of methyl parahydroxybenzoate or ethyl parahydroxybenzoate. The solvent is a citrate buffer, and the liquid pharmaceutical composition has a pH of 4-5. A method for preparing a liquid pharmaceutical composition by dissolving cremisole hydrochloride, a preservative, and an excipient in at least one of a solvent, a solubilizer, or a solvent-solubilizer mixed solution. This method further comprises adding glycerol and adjusting the pH to 4-5. A method for treating a subject having an epileptic disorder, comprising administering the liquid pharmaceutical composition.

Description

Technical Field

[0001] The disclosure of this specification relates to an oral formulation of cimetazole hydrochloride that is soluble and stable over time, and a method for preparing such an oral formulation of cimetazole hydrochloride.

Background Art

[0002] Cimetazole hydrochloride is the hydrochloride form of cimetazole, a first-generation histamine receptor (H1) antagonist, a class of drugs shown to have anti-allergic activity. However, cimetazole also acts as an anti-epileptic drug and inhibits behavioral and electrographic seizure activity. This anti-seizure-like activity is thought to be partially regulated by the role of cimetazole in the regulation of serotonin (5-HT) receptor signaling.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Serotonin (5-HT) receptor signaling has also been shown to play a role in anti-seizure activity, including Dravet syndrome, a severe childhood epilepsy syndrome associated with early-onset seizures, severe cognitive deficits, language delay, and motor development delay. Attenuation of seizure activity can be achieved with certain treatments, but a general broad and effective treatment is still needed.

Means for Solving the Problems

[0004] In one aspect, the present invention relates to a liquid pharmaceutical formulation comprising, consisting essentially of, or consisting of cimetazole hydrochloride, a solvent, a preservative, glycerol, a flavoring agent, a sweetening agent, and a solubilizing agent. In one aspect, the cimetazole hydrochloride formulation is stable and retains its solubility over at least a certain prescribed period. Cimetazole hydrochloride has a solubility of 1 mg / ml to 30 mg / ml in solution. In one embodiment, the present invention relates to a liquid pharmaceutical formulation having a pH of 4.5 and comprising, essentially comprising, or consisting thereof, cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, sweetener, flavoring agent, solubilizer (polyethylene glycol (PEG)-400), and preservative (methyl parahydroxybenzoate and ethyl parahydroxybenzoate). In one embodiment, the cremisole hydrochloride and preservative are stable for up to 36 months.

[0005] In one embodiment, the present invention relates to a method for producing a liquid pharmaceutical formulation of cremiso hydrochloride, comprising, essentially comprising, or comprising: dissolving at least one preservative in a solution containing at least one solvent, solubilizer, or mixed solvent-solubilizer solution; dissolving cremiso hydrochloride in a solution containing at least one solvent, solubilizer, or mixed solvent-solubilizer solution; dissolving a plurality of excipients in a solution containing at least one solvent, solubilizer, or mixed solvent-solubilizer solution; adding glycerol; and adjusting the pH such that the final concentration of cremiso hydrochloride in the liquid pharmaceutical composition is in the range of 1 mg / ml to 30 mg / ml and the formulation is soluble and stable over time. In one embodiment, cremisole hydrochloride and a preservative are stable for up to 36 months. In one embodiment, the present invention relates to a method for producing a liquid pharmaceutical formulation of cremisole hydrochloride, comprising, essentially comprising, or comprising, dispensing PEG400 into a beaker, adding ethyl parahydroxybenzoate, adding methyl parahydroxybenzoate (to ensure that the first preservative is completely dissolved before adding the second preservative), adding pH 4.5 citrate buffer to a second beaker, adding cremisole hydrochloride to the second beaker containing the buffer and mixing until completely dissolved, adding a solubilizer containing a preservative to the second beaker containing the buffer and cremisole hydrochloride with stirring, adding a sweetener, adding a flavoring after the sweetener is completely dissolved, adding glycerol to ensure that the mixture is homogeneous, measuring the pH and adjusting the pH to 4.5 + / - 0.5, and matching the volumes.

[0006] In one embodiment, the present invention relates to a method for treating a subject having an epileptic disorder, comprising administering a liquid pharmaceutical formulation containing cremisole hydrochloride. In one embodiment, the formulation contains cremisole hydrochloride in a concentration range of 1 mg / ml to 30 mg / ml. In one embodiment, a liquid pharmaceutical preparation of cremisole hydrochloride is prepared by essentially comprising, or by a method comprising: dissolving at least one preservative in a solution comprising at least one solvent, solubilizer, or mixed solvent-solubilizer solution; dissolving cremisole hydrochloride in a solution comprising at least one solvent, solubilizer, or mixed solvent-solubilizer solution; dissolving a plurality of excipients in a solution comprising at least one solvent, solubilizer, or mixed solvent-solubilizer solution; adding glycerol; and adjusting the pH. In one aspect, epileptic disorders include Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonic epilepsy in infants (SMEI), benign neonatal familial conversion (BNFC), infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, migratory partial epilepsy, and infantile It may be epileptic encephalopathy, tuberous sclerosis (TSC), focal cortical dysplasia, type I lissencephaly, Miller-Dicker syndrome, Angelman syndrome, fragile X syndrome, epilepsy in autism spectrum disorder, subcortical ectopic formation, Walker-Warburg syndrome, Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, persistent status epilepticus, abdominal epilepsy, massive bilateral myoclonic menstrual epilepsy, Jackson seizure disorder, Umberlicht-Lundborg disease, or photosensitive epilepsy.

[0007] The details are explained below.

[0008] One embodiment includes a liquid pharmaceutical composition. The liquid pharmaceutical composition may also be used for the treatment of epileptic disorders. In one embodiment, the epileptic disorder may be childhood epilepsy. In one embodiment, epileptic disorders include Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleinfohr syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonic epilepsy in infants (SMEI), benign neonatal familial conversion (BNFC), infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, migratory partial epilepsy, and infantile seizures. The conditions may include childhood epileptic encephalopathy, tuberous sclerosis (TSC), focal cortical dysplasia, type I lissencephaly, Miller-Dicker syndrome, Angelman syndrome, Fragile X syndrome, epilepsy in autism spectrum disorder, subcortical ectopic formation, Walker-Warburg syndrome, Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, persistent status epilepticus, abdominal epilepsy, massive bilateral myoclonic menstrual epilepsy, Jackson seizure disorder, Umberlicht-Lundborg disease, or photosensitive epilepsy. The liquid pharmaceutical composition may contain, essentially consist of, or consist of cremisole hydrochloride, a solvent, a preservative, and a co-solvent. The liquid pharmaceutical composition may have a pH of 4.5. The liquid pharmaceutical composition may have a pH of 4.5+ / -0.5.

[0009] Cremiso hydrochloride may be present in the liquid pharmaceutical composition at concentrations of 1 mg / ml, 1.125 mg / ml, 2.5 mg / ml, 5.0 mg / ml, 7.5 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, or 30 mg / ml. In one embodiment, cremizole hydrochloride may be present in concentrations of 1 mg / ml to 2.5 mg / ml, 2.5 mg / ml to 5.0 mg / ml, 5.0 mg / ml to 7.5 mg / ml, 7.5 mg / ml to 10 mg / ml, 10 mg / ml to 15 mg / ml, 15 mg / ml to 20 mg / ml, 20 mg / ml to 25 mg / ml, 25 mg / ml to 30 mg / ml, or any subrange between any of these concentration ranges. In one embodiment, cremiso hydrochloride may be present in increments of 0.5 mg / ml in the range of 1 mg / ml to 30 mg / ml (i.e., the concentration in the liquid pharmaceutical composition may be 1 mg / ml, 1.5 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 10.5 mg / ml, 11 mg / ml, 11.5 mg / ml, 12 mg / ml, 12.5 mg / ml, 13 mg / ml, 13.5 mg / ml, 14 mg / ml, 14 mg / ml, 14 mg / ml, 14 mg / ml. 5mg / ml, 15mg / ml, 15.5mg / ml, 16mg / ml, 16.5mg / ml, 17mg / ml, 17.5mg / ml, 18mg / ml, 18.5mg / ml, 19mg / ml, 19.5mg / ml, 20mg / ml, 20.5mg / ml, 21mg / ml, 21.5mg / ml, 22mg / ml, 22.5mg / ml, 23mg / ml, 23.5mg / ml, 24mg / ml, 24.5mg / ml, 25mg / ml, 25.5mg / ml, 26mg / ml, 26.5mg / ml, 27mg / ml, 27.5mg / ml, 28mg / ml, 28.5mg / ml, 29mg / ml, 29.5mg / ml, or 30mg / ml). In one embodiment, cremisole hydrochloride may be present in concentrations of 1 mg / ml to 30 mg / ml, or in a subrange thereof. ジレンデシのなるにますたすは、1mg / ml、1.5mg / ml、2.5mg / ml、3mg / ml、3.5mg / ml、4mg / ml、4.5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6.5mg / ml、7mg / ml、 7.5mg / ml、8mg / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12.5mg / ml、13mg / ml、13.5mg / ml、1 4mg / ml、14.5mg / ml、15mg / ml、15.5mg / ml、16mg / ml、16.5mg / ml、17mg / ml、17.5mg / ml、18mg / ml、18.5mg / ml、19mg / ml、19.5mg / ml、20mg / ml l、20.5mg / ml、21mg / ml、21.5mg / ml、22mg / ml、22.5mg / ml、23mg / ml、23.5mg / ml、24mg / ml、24.5mg / ml、25mg / ml、25.5mg / ml、26mg / ml、26.5 mg / ml, 27mg / ml, 27.5mg / ml, 28mg / ml, 28.5mg / ml, 29mg / ml, or 29.5mg / ml. .5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6.5mg / ml、7mg / ml、7.5mg / ml、8mg / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12. 5mg / ml、13mg / ml、13.5mg / ml、14mg / ml、14.5mg / ml、15mg / ml、15.5mg / ml、16mg / ml、16.5mg / ml、17mg / ml、17.5mg / ml、18mg / ml、18.5mg / ml、19mg / ml、19.5mg / ml、20 mg / ml、20.5mg / ml、21mg / ml、21.5mg / ml、22mg / ml、22.5mg / ml、23mg / ml、23.5mg / ml、24mg / ml、24.5mg / ml、25mg / ml、25.5mg / ml、26mg / ml、26.5mg / ml、27mg / ml、27.The selected endpoints are 5 mg / ml, 28 mg / ml, 28.5 mg / ml, 29 mg / ml, 29.5 mg / ml, or 30.0 mg / ml, with the higher endpoint being higher than the lower endpoint. In one embodiment, cremisole hydrochloride may be present at 5.0 mg / ml, 10 mg / ml, or 15 mg / ml. In one embodiment, cremisole hydrochloride may be present at a concentration of 5.0 mg / ml.

[0010] The solvent may be an acidic solution. The solvent may include, essentially consist of, or be composed of, a citrate buffer having an acidic pH, or a 0.1 M HCl solution. In one embodiment, the solvent may be a citrate buffer having a pH of 4.5. In one embodiment, the citrate buffer may have a pH of 4.5 ± 0.5. In one embodiment, the solvent may include, essentially consist of, or be a cosolvent.

[0011] The solubility of cremisole hydrochloride in solvents and / or solvent-cosolvent solutions may range from 1 mg / ml to 30 mg / ml. In one embodiment, the solubility of cremisole hydrochloride in a solvent and / or solvent-cosolvent solution may be selected from 1 mg / ml, 1.5 mg / ml, 2.5 mg / ml to 5.0 mg / ml, 5.0 mg / ml to 7.5 mg / ml, 7.5 mg / ml to 10 mg / ml, 10 mg / ml to 15 mg / ml, 15 mg / ml to 20 mg / ml, 20 mg / ml to 25 mg / ml, 25 mg / ml to 30 mg / ml, or any subrange between any of these concentration ranges. In one embodiment, the solubility of cremiso hydrochloride in a solvent and / or solvent-cosolvent solution can increase in increments of 0.5 mg / ml in the range of 1 mg / ml to 30 mg / ml (i.e., the solubility in the solvent and / or cosolvent is 1 mg / ml, 1.5 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 10.5 mg / ml, 11 mg / ml, 11.5 mg / ml, 12 mg / ml, 12.5 mg / ml, 13 mg / ml, 13.5 mg / ml). ml, 14mg / ml, 14.5mg / ml, 15mg / ml, 15.5mg / ml, 16mg / ml, 16.5mg / ml, 17mg / ml, 17.5mg / ml, 18 mg / ml, 18.5mg / ml, 19mg / ml, 19.5mg / ml, 20mg / ml, 20.5mg / ml, 21mg / ml, 21.5mg / ml, 22mg / ml , 22.5mg / ml, 23mg / ml, 23.5mg / ml, 24mg / ml, 24.5mg / ml, 25mg / ml, 25.5mg / ml, 26mg / ml, 26.5 mg / ml, 27mg / ml, 27.5mg / ml, 28mg / ml, 28.5mg / ml, 29mg / ml, 29.5mg / ml, or 30mg / ml). In one embodiment, the solubility of cremisole hydrochloride in a solvent and / or solvent-cosolvent solution may be 1 mg / ml to 30 mg / ml, or a sub-range thereof. The range of the low end point is、1mg / ml、1.5mg / ml、2.5mg / ml、3mg / ml、3.5mg / ml、4mg / ml、4.5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6.5mg / ml、7mg / ml、7.5mg / ml、8m g / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12.5mg / ml、13mg / ml、13.5mg / ml、14mg / ml、14.5mg / ml、15mg / ml, 15.5mg / ml, 16mg / ml, 16.5mg / ml, 17mg / ml, 17.5mg / ml, 18mg / ml, 18.5mg / ml, 19mg / ml, 19.5mg / ml, 20mg / ml, 20.5mg / ml, 21mg / ml, 21.5mg / ml, 22mg / ml, 22.5mg / ml, 23mg / ml, 23.5mg / ml, 24mg / ml, 24.5mg / ml, 25mg / ml, 25.5mg / ml, 26mg / ml, 26.5mg / ml, 27mg / ml, 27.5mg / ml, 28mg / ml, 28.5mg / ml, 2 9mg / ml、or 29.5mg / mlからますますますますもます、 1.5mg / ml、2.5mg / ml、3mg / ml、3.5mg / ml、4mg / ml、4.5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6 .5mg / ml、7mg / ml、7.5mg / ml、8mg / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12.5mg / ml、13mg / ml、13.5mg / ml、14mg / ml、14.5mg / ml、15mg / ml、15.5mg / ml、16mg / ml、16.5mg / ml、17mg / ml、17.5mg / ml、18mg / ml、18.5mg / ml、19mg / ml、19.5mg / ml、20mg / ml、20.5mg / ml、21mg / ml、21.5mg / ml、22mg / ml、22.5mg / ml、23mg / ml、23.5mg / ml、24mg / ml、24.5mg / ml、25mg / ml、25.5mg / ml、26mg / ml、26.5mg / ml、27mg / ml、27.The dosage may be selected from 5 mg / ml, 28 mg / ml, 28.5 mg / ml, 29 mg / ml, 29.5 mg / ml, or 30 mg / ml, with the higher endpoint selected being higher than the lower endpoint selected. In one embodiment, the solubility of cremisole hydrochloride in the solvent and / or solvent-cosolvent solution may be 5 mg / ml, 10 mg / ml, or 15 mg / ml. In one embodiment, the solubility of cremisole hydrochloride in a solvent and / or solvent-cosolvent solution may be 5 mg / ml.

[0012] In one embodiment, the cosolvent may include, be essentially composed of, or consist of, glycerol, cremofor ELP, cremofor RH40, polysorbate 20, polysorbate 80, polyethylene glycol succinate tocopheryl (TPGS), solutol HS15, polyethylene glycol (PEG)-400, propylene glycol, 2-hydroxypropyl-β-cyclodextrin, sodium lauryl sulfate (10% w / w in water), and sodium docusate (10% w / w in water), or any other suitable cosolvent capable of forming a cosolution having the solubility described in the paragraph above. In one embodiment, the cosolvent may be glycerol.

[0013] In one embodiment, the solvent may be a citrate buffer having a pH of 4.5, and the cosolvent may be glycerol. In one embodiment, the citrate buffer may have a pH of 4.5 ± 0.5. In one embodiment, the ratio of pH 4.5 citrate buffer to glycerol can range from 99% and 1%, respectively, to 70% and 30%, respectively. In one embodiment, the ratio of pH 4.5 citrate buffer to glycerol may be increased by 0.5% in increments, ranging from 70% to 99% for pH 4.5 citrate buffer and from 1% to 30% for glycerol. In one embodiment, the ratios of citrate buffer at pH 4.5 to glycerol are 99% and 1%, 98.5% and 1.5%, 98% and 2%, 97.5% and 2.5%, 97% and 3%, 96.5% and 3.5%, 96% and 4%, 95.5% and 4.5%, 95% and 5%, 94.5% and 5.5%, 94% and 6%, 93.5% and 6.5%, 93% and 7%, and 9%. 2.5% and 7.5%, 92% and 8%, 91.5% and 8.5%, 91% and 9%, 90.5% and 9.5%, 90% and 10%, 89.5% and 10.5%, 89% and 11%, 88.5% and 11.5%, 88% and 12%, 87.5% and 12.5%, 87% and 13%, 86.5% and 13.5%, 86% and 14%, 85.5% and 14.5%, 85% and 15% , 84.5% and 15.5%, 84% and 16%, 83.5% and 16.5%, 83% and 17%, 82.5% and 17.5%, 82% and 18%, 81.5% and 18.5%, 81% and 19%, 80.5% and 19.5%, 80% and 20%, 79.5% and 20.5%, 79% and 21%, 78.5% and 21.5%, 78% and 22%, 77.5% and 22.5%, It could be 77% and 23%, 76.5% and 23.5%, 76% and 24%, 75.5% and 24.5%, 75% and 25%, 74.5% and 25.5%, 74% and 26%, 73.5% and 26.5%, 73% and 27%, 72.5% and 27.5%, 72% and 28%, 71.5% and 28.5%, 71% and 29%, 70.5% and 29.5%, or 70% and 30%. In one embodiment, the ratio of pH 4.5 citrate buffer to glycerol may be 90% and 10%, 80% and 20%, or 70% and 30%, respectively. In one embodiment, the ratio of citrate buffer at pH 4.5 to glycerol may be 80% and 20%, respectively.

[0014] In one embodiment, the viscosity of the solvent-glycerol solution is such that there is at least a moderate continuous flow of the solution through the test oral administration syringe. The test oral administration syringe may be an Adelphi "Elm Tip", code 706100 or an Adelphi Flat Tip, code 90500. In one embodiment, the solvent is a citrate buffer solution with a pH of 4.5.

[0015] In one embodiment, the solubility of clomizole hydrochloride in a citric acid buffer - glycerol solution at pH 4.5 can range from 1 mg / ml to 30 mg / ml. In one embodiment, the solubility of clomizole hydrochloride in a citric acid buffer - glycerol solution at pH 4.5 can be 1 mg / ml to 1.5 g / ml, 2 mg / ml, 2.5 mg / ml to 5.0 mg / ml, 5.0 mg / ml to 7.5 mg / ml, 7.5 mg / ml to 10 mg / ml, 10 mg / ml to 15 mg / ml, 15 mg / ml to 20 mg / ml, 20 mg / ml to 25 mg / ml, 25 mg / ml to 30 mg / ml, or any sub - range between any of these concentration ranges. In one embodiment, the solubility of clomizole hydrochloride in a citric acid buffer - glycerol solution at pH 4.5 may increase by 0.5 mg / ml within the range of 1 mg / ml to 30 mg / ml (i.e., the solubility in the solvent and / or co - solvent may be 1 mg / ml, 1.5 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 10.5 mg / ml, 11 mg / ml, 11.5 mg / ml, 12 mg / ml, 12.5 mg / ml, 13 mg / ml, 13.5 mg / ml, 14 mg / ml, 14.5 mg / ml, 15 mg / ml, 15.5 mg / ml, 16 mg / ml, 16.5 mg / ml, 17 mg / ml, 17.5 mg / ml, 18 mg / ml, 18.5 mg / ml, 19 mg / ml, 19.5 mg / ml, 20 mg / ml, 20.5 mg / ml, 21 mg / ml, 21.5 mg / ml, 22 mg / ml, 22.5 mg / ml, 23 mg / ml, 23.5 mg / ml, 24 mg / ml, 24.5 mg / ml, 25 mg / ml, 25.5 mg / ml, 26 mg / ml, 26.5 mg / ml, 27 mg / ml, 27.5 mg / ml, 28 mg / ml, 28.5 mg / ml, 29 mg / ml, 29 mg / ml, 29.5 mg / ml, or 30 mg / ml). In one embodiment, the solubility of cremisole hydrochloride in a citrate buffer-glycerol solution at pH 4.5 may be 1 mg / ml to 30 mg / ml, or within that subrange. The range of the low end point is、1mg / ml、1.5mg / ml、2.5mg / ml、3mg / ml、3.5mg / ml、4mg / ml、4.5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6.5mg / ml、7mg / ml、7.5mg / ml、8m g / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12.5mg / ml、13mg / ml、13.5mg / ml、14mg / ml、14.5mg / ml、15mg / ml, 15.5mg / ml, 16mg / ml, 16.5mg / ml, 17mg / ml, 17.5mg / ml, 18mg / ml, 18.5mg / ml, 19mg / ml, 19.5mg / ml, 20mg / ml, 20.5mg / ml, 21mg / ml, 21.5mg / ml, 22mg / ml, 22.5mg / ml, 23mg / ml, 23.5mg / ml, 24mg / ml, 24.5mg / ml, 25mg / ml, 25.5mg / ml, 26mg / ml, 26.5mg / ml, 27mg / ml, 27.5mg / ml, 28mg / ml, 28.5mg / ml, 2 9mg / ml、or 29.5mg / mlからますますますますもます、 1.5mg / ml、2.5mg / ml、3mg / ml、3.5mg / ml、4mg / ml、4.5mg / ml、5mg / ml、5.5mg / ml、6mg / ml、6 .5mg / ml、7mg / ml、7.5mg / ml、8mg / ml、8.5mg / ml、9mg / ml、9.5mg / ml、10mg / ml、10.5mg / ml、11mg / ml、11.5mg / ml、12mg / ml、12.5mg / ml、13mg / ml、13.5mg / ml、14mg / ml、14.5mg / ml、15mg / ml、15.5mg / ml、16mg / ml、16.5mg / ml、17mg / ml、17.5mg / ml、18mg / ml、18.5mg / ml、19mg / ml、19.5mg / ml、20mg / ml、20.5mg / ml、21mg / ml、21.5mg / ml、22mg / ml、22.5mg / ml、23mg / ml、23.5mg / ml、24mg / ml、24.5mg / ml、25mg / ml、25.5mg / ml、26mg / ml、26.5mg / ml、27mg / ml、27.It may be selected from 5 mg / ml, 28 mg / ml, 28.5 mg / ml, 29 mg / ml, 29.5 mg / ml, or 30 mg / ml, and the selected higher endpoint is higher than the selected lower endpoint. In one embodiment, the solubility of clermizole hydrochloride in a citric acid buffer-glycerol solution at pH 4.5 can be 5 mg / ml, 10 mg / ml, or 15 mg / ml. In one embodiment, the solubility of clermizole hydrochloride in an 80% citric acid buffer at pH 4.5 - 20% glycerol solution may be 5 mg / ml, 10 mg / ml, or 15 mg / ml.

[0016] In one embodiment, a single clermizole hydrochloride metabolite or related degradation product was not more than 0.5%, and the total of all clermizole hydrochloride metabolites or related degradation products was 3.0% or less. In an embodiment, the increase in any single clermizole hydrochloride metabolite or related degradation product over time during storage was 0.1% or less from the previous time point. The storage time points and conditions are as described herein.

[0017] In one embodiment, the pharmaceutical composition contains a preservative. In one embodiment, the preservative contains, consists essentially of, or consists of at least one of potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate. In one embodiment, the preservative is potassium sorbate. In one embodiment, the preservative contains, consists essentially of, or consists of at least one of sodium methyl parahydroxybenzoate or sodium ethyl parahydroxybenzoate. In one embodiment, the preservative contains, consists essentially of, or consists of at least one of methyl parahydroxybenzoate or ethyl parahydroxybenzoate. In one embodiment, the preservative comprises methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate.

[0018] In one embodiment, the preservative is present in the pharmaceutical solution at a concentration of 0.01-0.5% (w / v). In one embodiment, the preservative may be increased in 0.01% increments within the range of 0.01-0.5% (w / v) in the pharmaceutical solution. In one method, the preservative is used in concentrations of 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.07% (w / v), 0.08% (w / v), 0.09% (w / v), 0.1% (w / v), 0.11% (w / v), and 0.12% (w / v). v), 0.13%(w / v), 0.14%(w / v), 0.15%(w / v), 0.16%(w / v), 0.17%(w / v), 0.18%(w / v), 0. 19%(w / v), 0.2%(w / v), 0.21%(w / v), 0.22%(w / v), 0.23%(w / v), 0.24%(w / v), 0.25%(w / v ), 0.26%(w / v), 0.27%(w / v), 0.28%(w / v), 0.29%(w / v), 0.30%(w / v), 0.31%(w / v), 0.3 2%(w / v), 0.33%(w / v), 0.34%(w / v), 0.35%(w / v), 0.36%(w / v), 0.37%(w / v), 0.38%(w / v ), 0.39%(w / v), 0.4%(w / v), 0.41%(w / v), 0.42%(w / v), 0.43%(w / v), 0.44%(w / v), 0.45%(w / v), 0.46%(w / v), 0.47%(w / v), 0.48%(w / v), 0.49%(w / v), or 0.5%(w / v) may be selected. In one embodiment, the preservative comprises, is essentially, or consists of at least one of methyl p-hydroxybenzoate sodium, ethyl p-hydroxybenzoate sodium, methyl p-hydroxybenzoate, or ethyl p-hydroxybenzoate. In one embodiment, the preservative comprises, essentially comprises, or consists of at least one of 0.2% (w / v) methyl p-hydroxybenzoate sodium or 0.02% (w / v) ethyl p-hydroxybenzoate sodium. In one embodiment, the preservative comprises, essentially comprises, or consists of at least one of 0.1% (w / v) methyl p-hydroxybenzoate sodium or 0.01% (w / v) ethyl p-hydroxybenzoate sodium. In one embodiment, the preservative comprises, essentially comprises, or consists of at least one of 0.2% (w / v) methyl p-hydroxybenzoate or 0.02% (w / v) ethyl p-hydroxybenzoate.

[0019] In one embodiment, the preservative includes potassium sorbate. In one embodiment, potassium sorbate is present in the pharmaceutical composition in an amount ranging from 0.1% to 0.3% (w / v). In one embodiment, potassium sorbate may be present in the pharmaceutical solution in an amount ranging from 0.1% to 0.3% (w / v) in increments of 0.01%. In one embodiment, the preservative may be selected from 0.1%(w / v), 0.11%(w / v), 0.12%(w / v), 0.13%(w / v), 0.14%(w / v), 0.15%(w / v), 0.16%(w / v), 0.17%(w / v), 0.18%(w / v), 0.19%(w / v), 0.2%(w / v), 0.21%(w / v), 0.22%(w / v), 0.23%(w / v), 0.24%(w / v), 0.25%(w / v), 0.26%(w / v), 0.27%(w / v), 0.28%(w / v), 0.29%(w / v), or 0.30%(w / v) in the pharmaceutical composition. In one embodiment, potassium sorbate is present in the pharmaceutical composition at a concentration of 0.2% (w / v).

[0020] In one embodiment, the pharmaceutical composition includes an antioxidant or a component having antioxidant properties. In one embodiment, the antioxidant or component having antioxidant properties comprises, essentially consists of, or comprises at least one of sodium ascorbate, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), or TPGS. In one embodiment, the antioxidant or component having antioxidant properties is ascorbic acid. In one embodiment, the antioxidant or component having antioxidant properties is ascorbic acid and EDTA. In one embodiment, the antioxidant or component having antioxidant properties is sodium ascorbate. In one embodiment, the antioxidant or component having antioxidant properties is sodium ascorbate and EDTA. In one embodiment, the antioxidant or component having antioxidant properties is TPGS.

[0021] In one embodiment, a pharmaceutical composition comprising, essentially consisting of, or containing methyl sodium p-hydroxybenzoate and ethyl sodium p-hydroxybenzoate includes a solubilizer. In one embodiment, the solubilizer may be TPGS, PEG400, or ultra-purified PEG400. In one embodiment, the solubilizer may be TPGS.

[0022] In one embodiment, a pharmaceutical composition comprising methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate, or essentially consisting thereof, comprises a solubilizer. In one embodiment, the solubilizer may be TPGS, PEG400, ultra-purified PEG400, or propylene glycol.

[0023] In one embodiment, the preservative is stable for 1 day to 36 months. In one embodiment, the preservative is stable for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, or any sub-range of the period disclosed in this paragraph. The lower end of the sub-range can be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, or 35 months. The higher-end endpoint in the sub-range may be selected from 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the selected higher-end endpoint is higher than the selected lower-end endpoint. In one embodiment, the preservative is stable for 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or sub-ranges thereof. In one embodiment, the stability of the preservative may be such that more than 95% of the preservative is stable. In one embodiment, the preservative is stable for at least one of the following periods: 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0024] In one embodiment, the preservative is stable for up to 36 months. In one embodiment, the preservative is stable for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, or in a sub-range of any period disclosed in this paragraph. The lower end of the subrange may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, or 35 months, and the higher end of the subrange may be selected from 1 day, 1 week, 1 month You may choose from weeks, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the higher endpoint selected is higher than the lower endpoint selected. The stabilization period can be 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or a sub-range thereof. In one embodiment, the stability of the preservative may be such that more than 95% of the preservative is stable. In one embodiment, the preservative is stable for up to 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0025] In one embodiment, the preservative is stable for at least 36 months. In one embodiment, the preservative is stable for at least 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months. In one embodiment, the preservative is stable over any period within the range of any of the selected periods described in this paragraph. The lower-range endpoints may be selected from 1 day, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the higher-range endpoints selected are higher than the lower-range endpoints selected. The stabilization period can be 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or a sub-range thereof. In one embodiment, the stability of the preservative may be such that more than 95% of the preservative is stable. In one embodiment, the preservative is stable for at least one of the following periods: 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0026] In one embodiment, the stability of the preservative may be such that it is stable at 90% to 100% and does not decompose. In one embodiment, the stability of the preservative may be such that the preservative is stable in 0.5% increments within the range of 90% to 100% (i.e., the preservative is stable and may exist at 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100%). The lower end of the subrange may be selected from 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, while the higher end of the subrange may be selected from 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 100%, with the higher end being selected higher than the lower end being selected. In one embodiment, the stability of the preservative is higher in the presence of an antioxidant.

[0027] In one embodiment, the stability of the preservative may be such that 90% to 100% remains stable after storage for 0 to 3 months, 3 to 6 months, 6 to 12 months, 12 to 24 months, or 24 to 36 months. In one embodiment, the stability of the preservative may be such that 90% to 95% or 95% to 100% of it remains stable after storage for up to 18 months. In one embodiment, the stability of the preservative may be such that 90% to 95% or 95% to 100% is stable after storage for up to 24 months. In another embodiment, the stability of the preservative may be such that 90% to 95% or 95% to 100% is stable after storage for up to 36 months. In one embodiment, the stability of the preservative is higher in the presence of an antioxidant. In one embodiment, the preservation activity did not change by more than 5% over time from the preservation activity determined at the time of initial storage to storage for 0 to 3 months, 3 to 6 months, 6 to 12 months, 12 to 24 months, or 24 to 36 months. The storage period and conditions are as described herein.

[0028] In one embodiment, the preservative is stable at freezing temperatures of 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C. In one embodiment, the preservative is stable at any temperature within the range of any of the temperatures described in this paragraph. The lower endpoints of the subrange may be selected from 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, with the selected higher endpoints being higher than the selected lower endpoints. The lower endpoints of the subrange may be selected from 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, with the selected higher endpoints being higher than the selected lower endpoints. In one embodiment, the preservative is stable at 5°C, 25°C, and 40°C. In one embodiment, the preservative is within a freezing temperature range of ~0°C, 0°C~5°C, 5°C~10°C, 10°C~15°C, 15°C~20°C, 20°C~25°C, 25°C~30°C, 30°C~35°C, 35°C~40°C, 40°C~45°C, 45°C~50°C, or a sub-range.

[0029] In one embodiment, the pharmaceutical composition includes a solubilizing agent. In one embodiment, the solubilizer comprises, essentially consists of, or comprises at least one of TPGS, ultra-purified PEG400, or propylene glycol. In one embodiment, the solubilizer comprises, essentially consists of, or consists of at least one of TPGS or ultra-purified PEG400. In one embodiment, the solubilizer includes ultra-purified PEG400. In one embodiment, the solubilizer includes TPGS.

[0030] In one embodiment, the pharmaceutical composition includes a taste modifier and / or a sweetener. In one embodiment, the taste modifier comprises, essentially consists of, or consists of at least one of the following: a flavoring agent, a sweetener, a liquid cherry flavor, a liquid orange flavor, a liquid strawberry flavor, a liquid vanilla flavor, a powdered cherry flavor, a powdered orange flavor, a powdered strawberry flavor, or a powdered vanilla flavor. In one embodiment, the taste modifier includes powdered cherry flavor. In one embodiment, the sweetener contains, essentially consists of, or consists of sucralose or sodium saccharin. In one embodiment, the sweetener includes sucralose. In one embodiment, the taste test was conducted by a panel of taste testers who evaluated formulations containing Bitrex in comparison to formulations without Bitrex. In one embodiment, there was no discernible difference in terms of palatability between the sweetener and flavoring agent used. In one embodiment, the formulation, including sweeteners, flavoring agents, and glycerol, all have an acceptable taste.

[0031] In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the cremiso hydrochloride remains stable after incubation of the cremiso hydrochloride-solvent solution for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months. In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the cremiso hydrochloride is stable after incubation of the cremiso hydrochloride-solvent solution for any of the selected periods described in this paragraph, or for any sub-range of time between any of the selected periods described in this paragraph. In one embodiment, the stability of cremiso hydrochloride may be such that more than 95% of the cremiso hydrochloride is stable after incubation of the cremiso hydrochloride-solvent solution for any of the selected periods described in this paragraph, or for any sub-range of time between any of the selected periods described in this paragraph. In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the cremiso hydrochloride remains stable after incubation of the cremiso hydrochloride-solvent solution for 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or between these subranges. The lower-range endpoints may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 18 months, or 24 months, and the higher-range endpoints may be selected from 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, 18 months, 24 months, or 36 months, with the selected higher endpoints being higher than the selected lower endpoints. In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the preservative is stable. In one embodiment, cremisole hydrochloride is stable for at least one of the following periods: 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months. In one embodiment, the stability of cremisole hydrochloride may be such that more than 95% of the preservative is stable. After incubation of the cremisole hydrochloride-solvent solution, the endpoints may be 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or sub-ranges thereof. The lower endpoints in the sub-range may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, or 24 months, and the higher endpoints in the sub-range may be selected from 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, or 36 months, with the selected higher endpoint being higher than the selected lower endpoint.

[0032] In one embodiment, cremizole hydrochloride is stable for up to 36 months. In one embodiment, cremizole hydrochloride is stable for 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months. In one embodiment, cremizole hydrochloride is stable over any period within the range of any of the selected periods described in this paragraph. The stabilization period can be 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or a sub-range thereof. The lower-range endpoints may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the higher-range endpoints selected are higher than the lower-range endpoints selected. In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the preservative is stable. In one embodiment, the stability of cremisole hydrochloride may be such that more than 95% of the preservative is stable. In one embodiment, cremisole hydrochloride is stable for 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0033] In one embodiment, cremisole hydrochloride is stable for at least 36 months. In one embodiment, cremizole hydrochloride is stable for at least 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months. In one embodiment, cremizole hydrochloride is stable over any period within the range of any of the selected periods described in this paragraph. The stabilization period can be 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or a sub-range thereof. The lower-range endpoints may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the higher-range endpoints selected are higher than the lower-range endpoints selected. In one embodiment, the stability of cremiso hydrochloride may be such that more than 90% of the preservative is stable. In one embodiment, the stability of cremisole hydrochloride may be such that more than 95% of the preservative is stable. In one embodiment, cremisole hydrochloride is stable for at least one of the following periods: 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0034] In one embodiment, the stability of cremisole hydrochloride in the solvent may be such that it is stable at 90% to 100% and does not decompose. In one embodiment, cremizole hydrochloride can be stable from an increment of 0.5% in the range of 90% to 100% (i.e., cremizole hydrochloride is stable at 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, and 98%). Endpoints may exist at 98.5%, 99%, 99.5%, or 100%. Lower-range endpoints can be selected from 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, or 99.5%. Endpoints may be selected from 90% , 91% , 91.5% , 92% , 92.5% , 93% , 93.5% , 94% , 94.5% , 95% , 95.5% , 96% , 96.5% , 97% , 97.5% , 98% , 98.5% , 99% , 99.5% , or 100%. Endpoints in the lower subrange may be selected from 90% , 90.5% , 91% , 91.5% , 92% , 92.5% , 93% , 93.5% , 94% , 94.5% , 95% , 95.5% , 96% , 96.5% , 97% , 97.5% , 98% , 98.5% , 99% , 99.5% , or 100%, with selected high endpoints being higher than selected low endpoints.

[0035] In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at freezing temperatures of ~0°C, 0°C~5°C, 5°C~10°C, 10°C~15°C, 15°C~20°C, 20°C~25°C, 25°C~30°C, 30°C~35°C, 35°C~40°C, 40°C~45°C, 45°C~50°C, or in a subrange thereof. The lower endpoint of the subrange may be selected from freezing, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, or 49°C, and the higher endpoint of the subrange may be selected from 0°C, The selected range may be 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, with the selected higher endpoint being higher than the selected lower endpoint. In one embodiment, the stability of cremiso hydrochloride in a solvent may be such that more than 95% of the cremiso hydrochloride is stable after incubation of the cremiso hydrochloride-solvent solution for any period of time described herein or at any temperature described in this paragraph.

[0036] In one embodiment, the stability of cremiso hydrochloride in a solvent may be such that more than 90% of the cremiso hydrochloride remains stable after incubation of the cremiso hydrochloride-solvent solution for up to 18 months at a temperature higher than 4°C but lower than 40°C. In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at a temperature higher than 4°C but lower than 40°C for up to 24 months. In one embodiment, the stability of cremiso hydrochloride in a solvent may be such that more than 90% of the cremiso hydrochloride remains stable after incubation of the cremiso hydrochloride-solvent solution at a temperature higher than 4°C but lower than 40°C for up to 36 months. In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at 25°C for up to 18 months. In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at 25°C for up to 24 months. In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at 25°C for up to 36 months. In one embodiment, the stability of cremisole hydrochloride in a solvent may be such that more than 90% of the cremisole hydrochloride remains stable after incubation of the cremisole hydrochloride-solvent solution at 40°C for up to 6 months.

[0037] In one embodiment, the liquid pharmaceutical composition may contain, essentially consist of, or consist of cremisole hydrochloride, pH 4.5 citrate buffer, a preservative, glycerol, a taste modifier, and a sweetener.

[0038] In one embodiment, the liquid pharmaceutical composition comprises cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, a taste modifier, a sweetener, and ultra-purified PEG400, and the preservatives are methyl parahydroxybenzoate and ethyl parahydroxybenzoate.

[0039] In one embodiment, the liquid pharmaceutical composition comprises cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, a taste modifier, a sweetener, and TPGS, and the preservatives are methyl parahydroxybenzoate and ethyl parahydroxybenzoate.

[0040] In one embodiment, the liquid pharmaceutical composition comprises cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, a taste modifier, a sweetener, and TPGS, and the preservatives are sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate.

[0041] In one embodiment, the liquid pharmaceutical composition contains cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, a taste modifier, a sweetener, and TPGS, with potassium ascorbate as the preservative.

[0042] In one embodiment, the liquid pharmaceutical composition comprises cremisole hydrochloride, pH 4.5 citrate buffer, glycerol, a taste modifier, a sweetener, sodium EDTA, and ascorbic acid, with potassium ascorbate as the preservative.

[0043] In one embodiment, the liquid pharmaceutical composition further comprises an antiepileptic drug.

[0044] In one embodiment, the liquid pharmaceutical composition has a continuous flow and can easily pass through a syringe.

[0045] In one embodiment, cremisole hydrochloride is stable during storage. In one embodiment, storage may be in the range of 2°C to 40°C. In one embodiment, storage can last as long as six months. In one embodiment, storage can last as long as 12 months. In one embodiment, storage can last as long as 18 months. In one embodiment, storage can last as long as 24 months. In one embodiment, storage can last as long as 36 months.

[0046] In one embodiment, the preservative is stable during storage. In one embodiment, the storage temperature may be in the range of 2°C to 40°C. In one embodiment, the stability of the preservative may be such that more than 90% or more than 95% of the preservative is stable after incubation for 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 1 month, 1 month to 2 months, 2 months to 3 months, 3 months to 6 months, 6 months to 9 months, 9 months to 12 months, 12 months to 18 months, 18 months to 24 months, 24 months to 36 months, or subranges thereof. The lower end of the sub-range may be selected from 1 day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, or 35 months, and the higher You may choose from days, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months, and the higher endpoint selected is higher than the lower endpoint selected. In one embodiment, the stability of the preservative may be such that more than 90% of the preservative is stable after incubation for at least one of the following periods: 1 day, 1 week, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months. In one embodiment, the stability of the preservative may be such that more than 95% of the preservative is stable after incubation for at least one of the following periods: 1 day, 1 week, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or 36 months.

[0047] In one embodiment, the stability of the preservative in the solution may be such that more than 90% of the preservative remains stable after incubation of the solution at freezing temperatures of ~0°C, 0°C~5°C, 5°C~10°C, 10°C~15°C, 15°C~20°C, 20°C~25°C, 25°C~30°C, 30°C~35°C, 35°C~40°C, 40°C~45°C, 45°C~50°C, or in a subrange thereof. The lower endpoint of the subrange may be selected from freezing, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, or 49°C, and the higher endpoint of the subrange The endpoint may be selected from 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, or 49°C, and the higher endpoints of the sub-range may be 0°C, 1°C, The range may be selected from 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, or 49°C, with the higher endpoints of the sub-range being 0°C, 1°C, 2°C, 3°C, 4°C, and 5°C. The selected endpoint may be 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, with the higher the selected endpoint being higher than the lower the selected endpoint. In one embodiment, the stability of the preservative in the solvent may be such that more than 95% of the preservative is stable after incubation of the solution for any of the periods or temperatures described in this paragraph. In one embodiment, the stability of the preservative in the solvent may be such that more than 90% of the preservative remains stable after incubation of the solution at 2°C to 8°C, 25°C, or 40°C. In one embodiment, the stability of the preservative in the solvent may be such that more than 95% of the preservative remains stable after incubation of the solution at 2°C to 8°C, 25°C, or 40°C. In one embodiment, the stability of the preservative in the solvent may be such that more than 95% of the preservative remains stable over a maximum of 1 day, 1 week, 1 month, 2 months, 3 months, 6 months, 12 months, 24 months, or 36 months, or any sub-range of time between these periods, after incubation of the solution at 2°C to 8°C, 25°C, or 40°C.

[0048] In one embodiment, the liquid pharmaceutical formulation is in the form of an oral formulation. In one embodiment, the oral formulation may further include at least one pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable carrier may comprise one or more agents selected from the group consisting of ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, human serum albumin, buffers, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, electrolytes, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, waxes, polyethylene glycol, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, talc, magnesium carbonate, kaolin, nonionic surfactants, edible oils, physiological saline, bacteriostatic water, polyethoxylated castor oil, phosphate-buffered saline (PBS), complexing agents including but not limited to cyclodextrin, or any other suitable pharmaceutically acceptable carrier.

[0049] In one embodiment, the liquid pharmaceutical formulation comprises further pharmaceutically acceptable excipients. In one embodiment, the pharmaceutically acceptable excipient may include one or more substances selected from the group consisting of acidifying agents, alkalizing agents, anti-sticking agents, anti-caking agents, defoaming agents, antibacterial agents, preservatives, antioxidants, binders, surface finishing agents, colorants, disintegrants, excipients, emulsifiers, sustained-release formulations, fragrances, lubricants, wetting agents, lubricants, ointment bases, preservatives, solubilizers, adsorbents, sustained-release agents, sweeteners, or any other suitable pharmaceutically acceptable excipients.

[0050] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes, essentially, or consists of, dissolving at least one preservative in a solution containing at least one of a solvent, a solubilizer, or a mixed solvent-solubilizer solution; dissolving cremisole hydrochloride in a solution containing at least one of a solvent, a solubilizer, or a mixed solvent-solubilizer solution; dissolving a plurality of excipients in a solution containing at least one of a solvent, a solubilizer, or a mixed solvent-solubilizer solution; adding glycerol; and adjusting the pH. In one embodiment, the solvent contains, is essentially, or consists of a citrate buffer having a pH of 4.5+ / -0.1. In one embodiment, the pH of the liquid pharmaceutical composition is 4.5 (+ / -0.5). In one embodiment, the final concentration of cremisole hydrochloride in the liquid pharmaceutical composition is in the range of 1 mg / mL to 30 mg / mL. In one embodiment, at least one preservative comprises, essentially consists of, or consists of at least one of potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate.

[0051] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes: dissolving at least one preservative in a solubilizer; adding a solvent to the solubilizer-preservative solution; dissolving cremisole hydrochloride in the solubilizer-preservative-solvent solution; dissolving a plurality of excipients in the cremisole hydrochloride-solubilizer-preservative-solvent solution; adding glycerol to the resulting solution; and adjusting the pH to 4.5 (+ / -0.5) to form a liquid pharmaceutical composition. The preservative is at least one of methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate, the solvent is a citrate buffer with a pH of 4.5+ / -0.1, and the solubilizer is ultra-purified PEG400. In one embodiment, the TPGS is melted and kept at approximately 50°C. In one embodiment, the multiple excipients include at least one sweetener and at least one taste modifier.

[0052] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes adding a solubilizer to a solvent; dissolving cremisole hydrochloride in a solvent-solubilizer mixed solution; dissolving at least one preservative in a cremisole hydrochloride-solvent-solubilizer solution; dissolving multiple excipients in a preservative-cremisole hydrochloride-solvent-solubilizer solution; adding glycerol to the resulting solution; and adjusting the pH to 4.5 (+ / -0.5) to form a liquid pharmaceutical composition. The preservative is at least one of methylsodium p-hydroxybenzoate or ethylsodium p-hydroxybenzoate, and the solvent is a citrate buffer having a pH of 4.5+ / -0.1. In one embodiment, the solubilizer is ultra-purified PEG400. In one embodiment, the solubilizer is TPGS, which is melted before being combined with the solvent. In one embodiment, the multiple excipients include at least one sweetener and at least one taste modifier.

[0053] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes adding a solubilizer to a solvent; dissolving at least one preservative in a solvent-solubilizer mixed solution; dissolving multiple excipients in a preservative-solvent-solubilizer solution; adding glycerol to the excipient-preservative-solvent-solubilizer solution; dissolving cremisole hydrochloride in the excipient-preservative-solvent-solubilizer solution; and adjusting the pH to 4.5 (+ / -0.5) to form a liquid pharmaceutical composition. The preservative contains potassium sorbate, the solvent is a citrate buffer with a pH of 4.5+ / -0.1, and the solubilizer is TPGS. In one embodiment, TPGS is melted before being combined with the solvent. In one embodiment, the multiple excipients include at least one sweetener and at least one taste modifier.

[0054] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes: dissolving at least one preservative in a solvent; dissolving an antioxidant in a preservative-solvent solution; dissolving multiple excipients in an antioxidant-preservative-solvent solution; adding glycerol to an excipient-antioxidant-preservative-solvent solution; dissolving cremisole hydrochloride in an excipient-antioxidant-preservative-solvent solution; and adjusting the pH to 4.5 (+ / -0.5) to form a liquid pharmaceutical composition. The solvent is a citrate buffer having a pH of 4.5+ / -0.1, and the antioxidant contains, essentially consists of, or consists of sodium EDTA, sodium ascorbate, or ascorbic acid. In one embodiment, the antioxidant comprises, essentially consists of, or consists of sodium EDTA and ascorbic acid. In one embodiment, the multiple excipients include at least one sweetener and at least one taste modifier.

[0055] In one embodiment, a method for preparing a liquid pharmaceutical formulation includes adding an antiepileptic drug.

[0056] In one embodiment, a method for treating a subject having an epileptic disorder includes administering a liquid pharmaceutical composition of any embodiment described herein. In one embodiment, a liquid pharmaceutical composition of any embodiment described herein can be administered using one or more routes selected from the group consisting of oral, sublingual, sublabial, buccal, and transmucosal administration. In one embodiment, the liquid pharmaceutical formulation is administered orally. In one embodiment, the epileptic disorder is childhood epilepsy.

[0057] In one embodiment, the concentration of cremisole hydrochloride in the liquid pharmaceutical composition may be in the range of 1 mg / mL to 30 mg / mL.

[0058] In one embodiment, the dose of cremisole hydrochloride used to treat the subject may be selected from 0.5 mg / kg to 500 mg / kg. In one embodiment, the dose of cremisole hydrochloride used to treat the subject may be 0.5 mg / kg to 50 mg / kg, 50 mg / kg to 100 mg / kg, 100 mg / kg to 150 mg / kg, 150 mg / kg to 200 mg / kg, 200 mg / kg to 250 mg / kg, 250 mg / kg to 300 mg / kg, 300 mg / kg to 350 mg / kg, 350 mg / kg to 400 mg / kg, 400 mg / kg to 450 mg / kg, 450 mg / kg to 500 mg / kg, or any subrange between any of these dosage ranges. In one embodiment, the amount of cremiso hydrochloride used to treat the subject may be increased in increments of 0.5 mg / kg from 0.5 mg / kg to 500 mg / kg (i.e., the dose used to treat the subject may be 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg...101 mg / kg, 101.5 mg / kg, 102 mg / kg...498 mg / kg, 498.5 mg / kg, 499 mg / kg, 499.5 mg / kg, or 500 mg / kg). In one embodiment, the amount of cremiso hydrochloride used to treat the subject may be 0.5 mg / kg to 500 mg / kg, or a subrange thereof. The lower subrange endpoints may be selected from 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg...101 mg / kg, 101.5 mg / kg, 102 mg / kg...498 mg / kg, 498.5 mg / kg, 499 mg / kg, or 499.5 mg / kg, and the higher subrange endpoints may be selected from 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg...101 mg / kg, 101.5 mg / kg, 102 mg / kg, 102.5 mg / kg, 103 mg / kg...498 mg / kg, 498.5 mg / kg, 499 mg / kg, 499.5 mg / kg, or 500 mg / kg, with the selected higher endpoints being higher than the selected lower endpoints. In one embodiment, the doses of cremisole hydrochloride used to treat the subject are 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, 15 mg / kg, 17.5 mg / kg, 20 mg / kg, 22.5 mg / kg, 25 mg / kg, 27.5 mg / kg, 30 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, 50 mg / kg, 52.5 mg / kg, 55 mg / kg, 57.5 mg / kg, 60 mg / kg, 62.5 mg / kg, 65 mg / kg, 67.5 mg / kg, 70 mg / kg, 72.5 mg / kg, 75 mg / kg, 77.5 mg / kg, 80 mg / kg, and 82 mg / kg. The dosage may be 5 mg / kg, 85 mg / kg, 87.5 mg / kg, 90 mg / kg, 92.5 mg / kg, 95 mg / kg, 97.5 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, 275 mg / kg, 300 mg / kg, 325 mg / kg, 350 mg / kg, 375 mg / kg, 400 mg / kg, 425 mg / kg, 450 mg / kg, 475 mg / kg, or 500 mg / kg. In one embodiment, the dose of cremisole hydrochloride used to treat the subject may be 50 mg / kg, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, or 500 mg / kg. In one embodiment, the subject is a child with epilepsy.

[0059] In one embodiment, a method for treating a subject includes further treating the subject with an antiepileptic drug. In one embodiment, the antiepileptic drug is administered separately from the liquid pharmaceutical composition containing cremiso hydrochloride as described herein. In one embodiment, the antiepileptic drug is administered simultaneously with a liquid pharmaceutical composition containing cremiso hydrochloride as described herein. In one embodiment, the antiepileptic drug is administered sequentially with a liquid pharmaceutical composition containing cremiso hydrochloride as described herein. In one embodiment, the subject is a child with epilepsy.

[0060] In one embodiment, a method for treating a subject includes administering a liquid pharmaceutical composition comprising cremisole hydrochloride as described herein at least once a day. In one embodiment, a method for treating a subject includes administering a liquid pharmaceutical composition containing cremisole hydrochloride as described herein one to four times a day. In one embodiment, a method for treating a subject includes administering a liquid pharmaceutical composition containing cremisole hydrochloride as described herein one to three times a day. In one embodiment, a method of treating a subject includes administering a liquid pharmaceutical composition containing cremiso hydrochloride as described herein once or twice a day, two or three times a day, or three or four times a day. In one embodiment, a method of treating a subject includes administering a liquid pharmaceutical composition containing cremiso hydrochloride as described herein once a day, twice a day, three times a day, or four times a day. In one embodiment, a method for treating a subject includes administering a liquid pharmaceutical composition comprising cremisole hydrochloride as described herein every two days. In one embodiment, a method for treating a subject includes administering a liquid pharmaceutical composition at least every 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, or 24 hours. In one embodiment, a method for treating a subject includes, if necessary, administering a liquid pharmaceutical composition comprising cremisole hydrochloride as described herein. [Modes for carrying out the invention]

[0061] 1. A liquid pharmaceutical composition comprising cremisole hydrochloride; a solvent; and glycerol, wherein the solvent is a citrate buffer, the pH of the liquid pharmaceutical composition is in the range of 4 to 5, and the liquid pharmaceutical composition may contain a preservative, the preservative being at least one of potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate.

[0062] 2. Embodiment 2: The liquid pharmaceutical composition according to Embodiment 1, wherein the concentration of glycerol in the pharmaceutical composition is 10-30% (wt / wt), the concentration of the citrate buffer is 90-70% (wt / wt), and optionally, the concentration of glycerol in the pharmaceutical composition is 20% (wt / wt) and the concentration of the citrate buffer is 80% (wt / wt).

[0063] 3. Embodiment 1: The liquid pharmaceutical composition according to Embodiment 1 or 2, wherein the preservative comprises at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, or potassium sorbate.

[0064] 4. Embodiment 4: The liquid pharmaceutical composition according to Embodiment 3, wherein the preservative has a concentration of 0.01 to 0.5% (w / v).

[0065] 5. A liquid pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the preservative comprises at least one selected from ethyl parahydroxybenzoate or methyl parahydroxybenzoate.

[0066] 6. Embodiment 6: The liquid pharmaceutical composition according to Embodiment 5, wherein the preservative comprises at least one of 0.2% (w / v) methyl parahydroxybenzoate or 0.02% (w / v) ethyl parahydroxybenzoate.

[0067] 7. A liquid pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the liquid pharmaceutical composition further comprises a solubilizer.

[0068] 8. A liquid pharmaceutical composition of Embodiment 126, wherein the solubilizer comprises one of TPGS or ultra-purified PEG400.

[0069] 9. The liquid pharmaceutical composition of Embodiment 8, wherein the solubilizer is ultra-purified PEG400.

[0070] 10. A liquid pharmaceutical composition of Embodiment 8, wherein the solubilizer is TPGS.

[0071] 11. The liquid pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the liquid pharmaceutical composition further comprises a sweetener.

[0072] 12. The liquid pharmaceutical composition of Embodiment 11, wherein the sweetener comprises sucralose or sodium saccharin.

[0073] 13. The liquid pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the liquid pharmaceutical composition further comprises a taste-modifying substance.

[0074] 14. The liquid pharmaceutical composition of Embodiment 13, wherein the taste modifier comprises at least one of the following: flavoring, sweetener, liquid cherry flavor, liquid orange flavor, liquid strawberry flavor, liquid vanilla flavor, powdered cherry flavor, powdered orange flavor, powdered strawberry flavor, and powdered vanilla flavor.

[0075] 15. The liquid pharmaceutical composition according to any one of Embodiments 1 to 14, wherein the liquid pharmaceutical composition further comprises an antioxidant or a component having antioxidant properties.

[0076] 16. The liquid pharmaceutical composition of Embodiment 15, wherein the antioxidant or component having antioxidant properties is selected from at least one of sodium ascorbate, ascorbic acid, or tocopherol polyethylene glycol succinate (TPGS).

[0077] 17. A liquid pharmaceutical composition according to one of Embodiments 15 or 16, comprising ascorbic acid.

[0078] 18. A liquid pharmaceutical composition according to any one of Embodiments 1 to 17, wherein the concentration of cremiso hydrochloride is 1 mg / ml to 30 mg / ml, and optionally, the concentration of cremiso hydrochloride is one of 5 mg / ml, 10 mg / ml, 15 mg / ml, or 16 mg / ml.

[0079] 19. A liquid pharmaceutical composition according to any one of Embodiments 1 to 18, wherein the liquid pharmaceutical composition further comprises an antiepileptic drug.

[0080] 20. The aforementioned epileptic disorders include Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleinfohr syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonic epilepsy in infants (SMEI), benign neonatal familial conversion (BNFC), infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, migratory partial epilepsy, infantile epileptic encephalopathy, tuberous sclerosis ( A liquid pharmaceutical composition according to any one of Embodiments 1 to 19, which is TSC, focal cortical dysplasia, type I lissencephaly, Miller-Dicker syndrome, Angelman syndrome, Fragile X syndrome, epilepsy in autism spectrum disorder, subcortical ectopic formation, Walker-Warburg syndrome, Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonic menstrual epilepsy, Jackson seizure disorder, Umberlicht-Lundborg disease, or photosensitive epilepsy.

[0081] A liquid pharmaceutical composition according to any one of Embodiments 1 to 20, wherein after 21.36 months of storage, there is no substantial increase in cremiso hydrochloride metabolites or related degradation products; the amount of preservative is maintained at substantially 97% or more of the original amount of preservative; there is no substantial change in the pH of the pharmaceutical composition; there is no substantial change in the color of the pharmaceutical composition; and preferably, storage is carried out at at least one of 2-8°C, 25°C, or 40°C.

[0082] 22. A method for preparing a liquid pharmaceutical composition for the treatment of an epileptic disorder, comprising dissolving at least one of a preservative, cremisole hydrochloride, a plurality of excipients, and glycerol in a solution containing at least one of a solvent or a solubilizer to form a liquid pharmaceutical composition, wherein the solvent is a citrate buffer, the pH of the liquid pharmaceutical composition is 4.5 (+ / -0.5), the at least one preservative comprises at least one of potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate, and further comprising adding a solvent when dissolution occurs in the solubilizer, wherein the concentration of cremisole hydrochloride in the liquid pharmaceutical composition is 1 mg / ml to 30 mg / ml.

[0083] 23. A method for preparing a liquid pharmaceutical composition for treating epileptic disorders according to Embodiment 22, wherein dissolving at least one preservative comprises dissolving at least one preservative in a solubilizer to form a solubilizer-preservative solution; adding a solvent comprises adding a solvent to the solubilizer-preservative solution to form a solubilizer-preservative-solvent solution; dissolving a plurality of excipients comprises dissolving a plurality of excipients in the solubilizer-preservative-solvent solution, preferably dissolving glycerol comprises dissolving glycerol in a cremizole hydrochloride-solubilizer-preservative-solvent solution, and the at least one preservative comprises at least one of methyl parahydroxybenzoate or ethyl parahydroxybenzoate.

[0084] 24. A method for preparing a liquid pharmaceutical composition for treating an epileptic disorder according to Embodiment 22, wherein dissolving the cremisole hydrochloride comprises dissolving the cremisole hydrochloride in a mixed solvent-solubilizer containing the solvent and the solubilizer to form a cremisole hydrochloride-solvent-solubilizer solution; dissolving the at least one preservative comprises dissolving the at least one preservative in the cremisole hydrochloride-solvent-solubilizer solution to form a preservative-cremisole hydrochloride-solvent-solubilizer solution; dissolving the plurality of excipients comprises dissolving the at least one preservative in the preservative-cremisole hydrochloride-solvent-solubilizer solution; preferably, dissolving the glycerol comprises dissolving the glycerol in the preservative-cremisole hydrochloride-solvent-solubilizer solution, wherein the at least one preservative comprises at least one of methylsodium parahydroxybenzoate or ethylsodium parahydroxybenzoate.

[0085] 25. A method for preparing a liquid pharmaceutical composition for treating an epileptic disorder according to Embodiment 22, wherein dissolving at least one preservative comprises dissolving at least one preservative in a mixed solvent-solubilizer containing a solvent and a solubilizer to form a preservative-solvent-solubilizer solution; dissolving multiple excipients comprises dissolving multiple excipients in a preservative-solvent-solubilizer solution to form an excipient-preservative-solvent-solubilizer solution; dissolving glycerol comprises dissolving glycerol in an excipient-preservative-solvent-solubilizer solution; and dissolving cremisole hydrochloride comprises dissolving cremisole hydrochloride in an excipient-preservative-solvent-solubilizer solution, wherein at least one preservative comprises potassium sorbate, the solubilizer comprises TPGS, and the TPGS is dissolved before dissolving the TPGS in the solvent.

[0086] 26. A method for preparing a liquid pharmaceutical composition for treating an epileptic disorder according to Embodiment 22, further comprising dissolving an antioxidant in a solution comprising at least one of a solvent or a solubilizer, wherein dissolving at least one preservative comprises dissolving at least one preservative in a solvent to form a preservative-solvent solution, dissolving an antioxidant comprises dissolving an antioxidant in a preservative-solvent solution to form an antioxidant-preservative-solvent solution, dissolving a plurality of excipients comprises dissolving a plurality of excipients in an antioxidant-preservative-solvent solution to form an excipient-antioxidant-preservative-solvent solution, dissolving glycerol comprises dissolving glycerol in an excipient-antioxidant-preservative-solvent solution, and dissolving cremisole hydrochloride comprises dissolving cremisole hydrochloride in an excipient-antioxidant-preservative-solvent solution, wherein at least one preservative comprises potassium sorbate.

[0087] 27. A method for preparing a liquid pharmaceutical composition for treating any one of the epileptic disorders described in Embodiments 22 to 26, further comprising adjusting the pH of the liquid pharmaceutical composition to pH 4.5 (+ / - 0.5).

[0088] 28. A method for preparing a liquid pharmaceutical composition for treating any one of the epileptic disorders of Embodiments 22 to 27, wherein the solubilizer is ultra-purified PEG400 or TPGS, and the TPGS is melted before use and preferably maintained at about 50°C until at least cremiso hydrochloride is dissolved.

[0089] A method for preparing a liquid pharmaceutical composition for treating an epileptic disorder according to any one of Embodiments 22 to 28, wherein, after storage for up to 36 months, there is no substantial increase in cremiso hydrochloride metabolites or related degradation products; the amount of preservative is maintained at substantially 97% or more of the original amount of preservative; there is no substantial change in the pH of the pharmaceutical composition; and there is no substantial change in the color of the pharmaceutical composition, preferably, storage is carried out at at least one of the following temperatures: 2-8°C, 25°C, or 40°C.

[0090] 30. A method for preparing a liquid pharmaceutical composition for treating any one of the epileptic disorders of Embodiments 22 to 30, further comprising adding an antiepileptic drug.

[0091] 31. The liquid pharmaceutical composition is for the treatment of epileptic disorders, preferably childhood epileptic disorders, and preferably the epileptic disorders are Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleinfohr syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonic epilepsy in infants (SMEI), benign neonatal familial conversion (BNFC), infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, migratory partial epilepsy, infantile epileptic encephalopathy. A method for preparing a liquid pharmaceutical composition for treating any one of the epileptic disorders of Embodiments 22 to 30, which is one of the following: epilepsy, tuberous sclerosis (TSC), focal cortical dysplasia, type I lissencephaly, Miller-Dicker syndrome, Angelman syndrome, fragile X syndrome, epilepsy in autism spectrum disorder, subcortical ectopic formation, Walker-Warburg syndrome, Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, persistent status epilepticus, abdominal epilepsy, widespread bilateral myoclonic menstrual epilepsy, Jackson seizure disorder, Umberlicht-Lundborg disease, or photosensitive epilepsy.

[0092] 32. A method for treating a subject having an epileptic disorder, comprising administering a liquid pharmaceutical composition described in any one of Embodiments 1 to 21, or a liquid pharmaceutical composition prepared by the method described in any one of Embodiments 22 to 31, to a subject in need thereof.

[0093] 33. A method for treating a subject having an epileptic disorder according to Embodiment 32, comprising administering a liquid pharmaceutical composition to a subject in need thereof, wherein the administration includes one or more routes selected from oral, sublingual, sublabial, buccal, and transmucosal, preferably the route of administration being oral.

[0094] 34. A method for treating a subject having an epileptic disorder, comprising administering a liquid pharmaceutical composition to the subject in need thereof, wherein the concentration of cremiso hydrochloride in the liquid pharmaceutical composition is between 1 mg / ml and 30 mg / ml, and preferably the dose of cremiso hydrochloride used to treat the subject is about 0.5 mg / kg, 1 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg. mg / kg, 15mg / kg, 17.5mg / kg, 20mg / kg, 22.5mg / kg, 25mg / kg, 27.5mg / kg, 30mg / kg, 40mg / kg, 42.5mg / kg, 45mg / kg, 47.5mg / kg, 50mg / kg, 52.5mg / kg, 55mg / kg, 57.5mg / kg, 60mg / kg, 62.5mg / kg, 65mg / kg, 67.5mg / kg, 70mg / kg, 72.5mg / kg, 75mg / kg, 77.5mg / kg, 80mg / kg, 82.5mg / kg, 85mg / kg, A method for treating a subject having one of the epileptic disorders described in Embodiments 32 to 33, wherein the dosage is 87.5 mg / kg, 90 mg / kg, 92.5 mg / kg, 95 mg / kg, 97.5 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, 275 mg / kg, 300 mg / kg, 325 mg / kg, 350 mg / kg, 375 mg / kg, 400 mg / kg, 425 mg / kg, 450 mg / kg, 475 mg / kg, or 500 mg / kg.

[0095] 35. A method for treating a subject having an epileptic disorder, comprising administering a liquid pharmaceutical composition to a subject in need thereof, wherein the administration is performed at least every 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, or 24 hours, one of the methods from Embodiments 32 to 34.

[0096] 36. A method for treating a subject having one epileptic disorder according to Embodiments 32 to 35, comprising administering a liquid pharmaceutical composition to a subject in need thereof, further comprising administering an antiepileptic drug, preferably the administration of the antiepileptic drug comprising one of the following: administering the liquid pharmaceutical composition separately from the antiepileptic drug, administering the liquid pharmaceutical composition simultaneously with the antiepileptic drug, or administering the liquid pharmaceutical composition sequentially with the antiepileptic drug. [Examples]

[0097] Example 1: Solubility tests of cremiso hydrochloride in compatible solvent systems were conducted to identify buffer systems that solubilize cremiso hydrochloride at the required concentration without any precipitation. The target concentration of 5 mg / ml cremiso hydrochloride was achieved in several solvents tested, as shown in the shaded rows of Table 1 below.

[0098] [Table 1]

[0099] Cremiso hydrochloride achieved its target solubility in 0.1M HCl; pH 4.5 citrate buffer; pH 4.5 citrate buffer - Cremofor ELP; pH 4.5 citrate buffer - Cremofor RH40; pH 4.5 citrate buffer - Polysorbate 20; pH 4.5 citrate buffer - Polysorbate 80; pH 4.5 citrate buffer - TPGS; pH 4.5 citrate buffer, pH 4.5 citrate buffer - Soltol HS15; pH 4.5 citrate buffer - PEG 400; pH 4.5 citrate buffer - Glycerol; pH 4.5 citrate buffer - Propylene Glycol; and pH 4.5 citrate buffer - 2-(hydroxypropyl-β-cyclodextrin). The data indicate that cremiso hydrochloride achieves a target solubility of at least 5 mg / ml in several solvent solution combinations. Table 1 shows the actual solubility values ​​of cremiso hydrochloride in each solvent system.

[0100] Based on observations from the data in Table 1, it was determined that cremizole hydrochloride has a pH solubility profile in which it is more soluble at acidic pH levels (0.1 M HCl and pH 4.5 citrate buffer) than in pH 6.8 phosphate buffer, where it is almost completely insoluble. The addition of cosolvents to pH 6.8 phosphate buffer did not improve solubility. As shown in Table 1, the addition of cosolvents to pH 6.8 phosphate buffer did not improve solubility at this pH. Table 1 also shows that the addition of some cosolvents (glycerol, PEG400, and propylene glycol) increased solubility, albeit not synergistically. Adding cremisole hydrochloride to citrate buffer at pH 4.5 and then adding other co-solvents (cremofor ELP, cremofor RH40, sorbitol HS15, polysorbate 20 and sodium ascorbate, polysorbate 80 and sodium ascorbate, TPGS, and 2-hydroxypropyl-β-cyclodextrin) further improves the solubility of cremisole hydrochloride in citrate buffer at pH 4.5. Additional solvents / co-solvents tested included sodium lauryl sulfate (10% w / w in water) and sodium docusate (10% w / w in water).

[0101] Although not shown in Table 1 above, the solubility of cremisole hydrochloride was increased to 36 mg / ml in a 20% w / w solution of Solutol HS15 at 40°C. Furthermore, freezing and thawing does not appear to reduce the solubility of cremiso hydrochloride, suggesting that cremiso hydrochloride hardly precipitates upon cooling.

[0102] Example 2: In the example based on the results of Example 1, a pH 4.5 citrate buffer was used due to the high solubility of cremisole hydrochloride. Roll was added to help mask the taste and modify the viscosity. The viscosity of the glycerol / citrate buffer was evaluated using a "syringe passability" test to confirm the ease of distribution before the addition of cremiso hydrochloride. Table 2 below lists formulations with selective concentrations of glycerol in pH 4.5 citrate buffer.

[0103] [Table 2]

[0104] The "injectability" of these formulations was evaluated after the addition of viscous glycerol, using two types of oral syringes (Adelphi "Elmtip," code 706100 and Adelphi Flat Tip, code 90500). The needle passability data is summarized in Table 3, where the following codes are applied: 1 = injection impossible (no flow); 2 = injection possible (dripping flow); 3 = needle passability easy (moderate or continuous flow); 4 = injection easy (continuous flow).

[0105] [Table 3]

[0106] Example 3: In one example, the solubility of cremiso hydrochloride in the solvent mixture was evaluated by gradually increasing the dose of cremiso hydrochloride in each formulation in Table 2, confirming that a solubility of 5 mg / ml of cremiso hydrochloride could be achieved. When 20 mg of cremiso hydrochloride was added to each of the solvent mixtures from Table 2 (A1, B1, and C1) to achieve a target concentration of 5 mg / ml of cremiso hydrochloride, complete dissolution was achieved in approximately 4 minutes using a vortex mixer. When 30 mg of cremiso hydrochloride was added to each of the solvent mixtures from Table 2 (A2, B2, and C2) to achieve a target concentration of 7.5 mg / ml of cremiso hydrochloride, complete dissolution was achieved in approximately 4 minutes using a vortex mixer. When 40 mg of cremiso hydrochloride was added to each of the solvent mixtures (A3, B3, and C3) in Table 2 to achieve a target concentration of 10 mg / ml of cremiso hydrochloride, the samples did not completely dissolve after approximately 6 minutes of vortexing. The samples were then placed in an incubator at 25°C overnight, after which the cremiso hydrochloride was completely dissolved. All samples were analyzed for cremiso hydrochloride content after incubation at 25°C overnight. Table 4 lists the measured solubility of cremiso hydrochloride in each sample.

[0107] [Table 4]

[0108] All solubility values ​​were slightly higher than expected, which may be due to inaccuracies in the small-scale measurements used for the study. No related substances exceeding 0.05% were reported for any of the samples. This result confirms that cremisole hydrochloride can be dissolved at concentrations higher than 5 mg / ml containing 20% ​​w / v glycerol.

[0109] Example 4: In one example, various excipients were examined at 14 days (50°C) to guide the decision on the selection of excipients. These are used during formulation development. Table 5 below shows the stability of cremisole hydrochloride at 14 days after incubation in the various formulations listed.

[0110] [Table 5]

[0111] Prototypes W, X, Y, and Z can be found in Table 6 below.

[0112] [Table 6]

[0113] Based on observations from Table 5, the findings were as follows: It was determined that a citrate buffer at pH 4.5 is compatible with cremiso hydrochloride and can achieve a target concentration of at least 5 mg / ml of cremiso hydrochloride. Some of the solubilizers caused stability problems (however, this may have been due to oxidation of cremisole hydrochloride by the presence of peroxides in the excipients); Two excipients (PEG400 and polysorbate 80), which typically have low levels of peroxides, showed higher levels of the relevant substance, which decreased when antioxidants were included. This suggests that cremizole hydrochloride may be susceptible to oxidation; The tested sweeteners and flavorings are suitable and can be used for flavor masking; The preservatives, sodium methyl p-hydroxybenzoate, sodium ethyl p-hydroxybenzoate, and potassium sorbate showed little to no related substances. However, due to the low solubility of ethyl p-hydroxybenzoate, either a solubilizer such as PEG400 or a soluble form of ethyl p-hydroxybenzoate, such as its sodium salt, is required. Glycerol is compatible with cremisole hydrochloride and can be used to improve the taste formulation.

[0114] Example 5: In one example, a placebo formulation was prepared for taste testing. The bitter taste of cremisole hydrochloride was simulated by adding 25 ppbw / v of Bittrex (denatonium benzoate) to the sample as a substitute. Five placebo formulations were prepared according to Table 7. The placebos were also prepared based on the knowledge that glycerol is known to interact over time with paraben preservatives present in the sample as sodium methyl p-hydroxybenzoate and sodium ethyl p-hydroxybenzoate. Therefore, ideally, when parabens are used as preservatives, it is generally preferable to avoid glycerol or polyols. However, when glycerol is required for taste, a reduction in preservative content did not rule out its use.

[0115] [Table 7]

[0116] In the above placebo formulations, when cherry liquid was added, the solution turned amber, and small spheres were present, likely due to triacetin in the flavor formulation. These spheres appeared to disperse in the bulk liquid after being left overnight. When cherry powder was added as a flavoring agent, the cherry powder dissolved, producing a colorless solution. All formulations except placebo 3 required pH adjustment using citric acid, as their pre-adjustment pH was between 5 and 7. A panel of four taste testers evaluated the formulations by comparing five placebo formulations that spiked Bittrex with five placebo formulations that did not spike Bittrex. The results of the taste tests are shown in Table 8.

[0117] [Table 8]

[0118] The results from the taste evaluation confirm the necessity of glycerol in the formulation, based on the fact that at least one out of four taste testers found the taste of placebo formulation 5 to be acceptable. Regarding the selection of sweeteners, there was no discernible difference between placebo 1 (sucralose) and placebo 2 (sodium saccharin). Regarding the selection of cherry flavor, there was no discernible difference between placebo 3 (liquid cherry) and placebo 4 (powdered cherry). Powdered cherry was selected as the flavoring agent in this example because it has a longer shelf life than liquid cherry and its solubility in the formulation is better than that of the liquid form. Sucralose was used as a sweetener in this example because it had been previously used in other pediatric formulations.

[0119] Example 6: One example includes lead formulations from Example 4, as shown in Tables 7 and 8, which were used for larger-scale production and to conduct short-term accelerated stability studies. For each of these formulations, modifications were made, including the addition of antioxidants based on potential requirements for one of the excipients from excipient compatibility studies, considering that cremisole hydrochloride appears to undergo some oxidation in the presence of excipients containing peroxides (i.e., PEG400 and Tween 80); and the use of alternative preservatives due to slightly lower assay results obtained for both preservatives after 14 days at (50°C), as illustrated in Table 5. These assay results were inconsistent with the very small amounts of the relevant substance observed in these samples, and therefore, both preservatives remained as options for progression. Based on the data obtained from the excipient compatibility test in Example 4, prototype batches were manufactured according to Table 9 below. Prototype A contains potassium sorbate as a preservative, and prototype B contains sodium methyl parahydroxybenzoate and sodium parahydroxybenzoate as preservatives. The prototype batches further distinguished between the presence of antioxidants (prototype AO, prototype BO, and both placebos) and the absence of antioxidants (prototypes A and B).

[0120] [Table 9]

[0121] Prototypes B and BO did not proceed due to precipitates formed from the interaction between parabens (sodium methyl p-hydroxybenzoate and sodium ethyl p-hydroxybenzoate) and cremisole hydrochloride. Prototypes A, AO, and a placebo were subjected to stability testing.

[0122] Example 7: In the examples, stability tests were performed on prototypes A, AO, and A1 at various temperatures over a period of 6 months. Samples were tested for appearance, pH, specific gravity, assay (cremiso hydrochloride), related substances, and preservative assay. Table 10 below summarizes the results of the appearance of prototypes stored at temperatures of 2–8°C, 25°C, or 40°C for 2 weeks, 1 month, or 2 months, as shown. These results demonstrate that the formulation remained clear and free of particulate matter throughout the incubation temperature and time.

[0123] [Table 10]

[0124] Table 10 also summarizes the results of the color appearance of the prototypes at temperatures where they were stored for 2 weeks, 1 month, or 2 months as shown, and at 2–8°C, 25°C, or 40°C. The color changes were visually evaluated and quantified using the European Pharmacopoeia color standards (see "BY" for lower numbers indicating darker hues). Based on the results in Table 10, prototype A (without antioxidant) did not discolor as much as prototype A0 (with antioxidant) or prototype A1 (placebo), especially at the high temperatures used. Prototype A (without antioxidant) showed some discoloration at 40°C, but only slight color change at 25°C, and no color change at 2-8°C. In particular, prototype A1 (placebo) did not discolor as much as prototype AO (containing antioxidant), indicating that the discoloration was at least partially due to the presence of the antioxidant (sodium ascorbate). While discoloration of solutions containing sodium ascorbate was not unprecedented, the rate of discoloration was unexpected, as the change was visible in the prototype AO at 25°C after only two weeks.

[0125] Table 11 summarizes the results of chemical characterization ("assays") of prototype cremiso hydrochloride stored at temperatures of 2–8°C, 25°C, or 40°C for 2 weeks, 1 month, or 2 months, as shown. As shown in Table 11, both the prototype A and prototype AO assays were initially low. This may have been due to sieving after distribution during sample preparation, and therefore the loss of cremiso hydrochloride. However, the assay did not change from the initial point for any sample, regardless of storage conditions.

[0126] [Table 11]

[0127] Table 11 also summarizes the results of the chemical characterization of the preservatives ("preservative assays"). As shown in Table 11, both the prototype A and prototype AO assays were initially similarly low. This explanation is not certain. For both prototype A and prototype AO, a decrease was observed over time and temperature; however, this decrease was less pronounced in the presence of antioxidants. For example, prototype AO (without antioxidants) stored at 25°C showed a 3.5% decrease from the initial assay, compared to an 11% decrease for prototype A (without antioxidants). A review of the literature indicates that potassium sorbate can be oxidized to form a carbonyl moiety, and that this process is accelerated at higher temperatures. Therefore, it was not surprising that antioxidants help prevent the loss of preservatives.

[0128] Table 12 summarizes the results of the chemical characterization of the relevant materials of the prototypes stored for 2 weeks, 1 month, or 2 months at temperatures of 2–8°C, 25°C, or 40°C, as shown. The amount of related substances remains unchanged from the initial point, regardless of storage time and temperature, indicating no increase in impurities in terms of stability. In fact, the only actual impurity recorded was present at a low level (0.06%) with a relative retention time (RRT) of 0.40–0.41.

[0129] [Table 12]

[0130] Syringe compatibility and dose uniformity of prototypes A and AO were evaluated. Two different syringes were used: Adelphi "Elm Tip," code 706100 (a 6 ml short-form dispensing pipette), and Adelphi Flat Tip, code 90500 (an oral dispensing pipette). Over a 24-hour period, no actual changes were observed in the cremiso hydrochloride assay for either prototype A or prototype AO in either syringe, suggesting that each syringe type is compatible with both formulations. The "Related Substances" data also verifies compatibility with any of the syringe types.

[0131] Regarding the dosage from the multipurpose container, both syringes met the criteria set according to Ph.Eur 2.9.27. This indicates that both syringes can accurately deliver both prototype A and prototype AO formulations. Table 13 shows delivery data regarding the accuracy of delivering 20 ml and 1 ml doses.

[0132] [Table 13]

[0133] Example 8: We also developed formulations other than prototypes A, AO, B, and BO. Considering the formation of precipitates due to the interaction between parabens (sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate) and cremisole hydrochloride, as observed in prototypes B and BO of Example 6, other formulations were considered by changing the type and amount of preservatives used, the presence or absence of antioxidants, and the presence or absence of solubilizers. Formulation examples C to K are shown in Table 14 below.

[0134] The alarm limits for any potential change in stability may include at least one of the following: with respect to appearance, any change from the initial appearance; with respect to the formation of the relevant substance, a change of + / - 5% from the nominal value or any individual impurities greater than 0.05%; with respect to the stability of the preservative, a change of + / - 5% from the nominal value; with respect to specific gravity, a change of + / - 2% from the initial value; and with respect to pH, any change greater than 0.2 units from the initial value, where potential changes are monitored at sampling intervals.

[0135] [Table 14]

[0136] Example 9: In one example, potassium sorbate was used as the preservative. EDTA was added together with sodium ascorbate, as shown in formulation C. Formulation C was interrupted due to particle formation observed after the addition of cremiso hydrochloride.

[0137] Example 10: In one example, the preservatives used were sodium methyl p-hydroxybenzoate and ethyl sodium p-hydroxybenzoate, as represented by formulation F. Formulation F was discontinued due to the formation of a precipitate observed after the addition of sodium p-hydroxybenzoate.

[0138] Example 11: In one example, the preservatives used were sodium methyl p-hydroxybenzoate and ethyl sodium p-hydroxybenzoate, both at twice the concentration of formulation F. PEG400 was also added, as represented by formulation H. Formulation H was discontinued due to the formation of a precipitate observed after the addition of sodium methyl p-hydroxybenzoate.

[0139] Example 12: In one example, the preservatives used were sodium methyl p-hydroxybenzoate and sodium p-hydroxybenzoate, both at twice the concentration of formulation F. Propylene glycol was also added, as represented by formulation K. Formulation K was discontinued due to the formation of a brownish, viscous precipitate observed after the addition of propylene glycol.

[0140] Example 13: In one example, the preservative used was potassium sorbate. As shown in Formulation D, EDTA was added along with ascorbic acid. Preparation of formulation D did not result in the formation of fine particles or precipitates. Formulation D was evaluated by visual inspection and quantified using European Pharmacopoeia color standards, as shown in Table 15 below. The sample remained transparent and colorless to very pale yellow after the formulation was formed. However, after one month of storage, when stored at 2-8°C, the samples became darker up to BY3 / BY4, and when stored at 25°C or 40°C, they became significantly darker than B1 and BY1. Formulation D has been discontinued.

[0141] Example 14: In one example, potassium sorbate was used as the preservative. A combination of antioxidant and solubilizer TPGS was added, as shown in Formulation E.

[0142] Formulation E was evaluated based on its appearance and quantified using the European Pharmacopoeia color standards, as shown in Table 15 below. Formulation E was pale yellow and did not form any precipitate. Therefore, stability tests were conducted for both 1-month and 2-month storage at 2-8°C, 25°C, and 40°C. Formulation E showed a slight color change after storage, which was consistent under all storage conditions.

[0143] [Table 15]

[0144] The pH value of formulation E remained close to 4.5 under all storage conditions, as shown in Table 16 below.

[0145] [Table 16]

[0146] Table 17 below summarizes the results of chemical characterization ("assays") of cremiso hydrochloride formulations stored for one or two months at temperatures of 2–8°C, 25°C, and 40°C, as shown. As shown in Table 17, the assay for formulation E did not change from the initial time for any sample, regardless of storage time or conditions.

[0147] [Table 17]

[0148] As shown in Table 19 below, there was a slight increase in the relevant substance after storage at 40°C for 1 and 2 months using Formulation E, and after storage at 25°C for 2 months. The RRT values ​​ranged from 0.61 to 1.56.

[0149] Table 18 below summarizes the results of chemical characterization of preservatives ("preservative assays") according to storage at temperatures of 2–8°C, 25°C, and 40°C for 1 month, 2 months, and 3 months. As shown in Table 18, the assay for potassium sorbate did not show any significant loss greater than 5% at all time points and temperatures tested.

[0150] [Table 18]

[0151] Example 15: In one example, the preservatives used are methylsodium p-hydroxybenzoate and ethylsodium p-hydroxybenzoate, in the amounts shown in Table 14. The antioxidant-solubilizer TPGS combination was added as shown in Formulation G. Formulation G was evaluated and quantified by appearance using European Pharmacopoeia color standards, as shown in Table 15 above. Formulation G was pale yellow and did not form any precipitate. Therefore, stability tests were conducted for both 1-month and 2-month storage at 2-8°C, 25°C, and 40°C. Formulation G showed slight color changes, mainly during storage at 40°C.

[0152] The pH value of formulation G remained close to 4.5 under all storage conditions, as shown in Table 16 above.

[0153] Table 17 above summarizes the results of chemical characterization ("assays") of cremiso hydrochloride formulations stored for one or two months at temperatures of 2–8°C, 25°C, and 40°C, as shown. As shown in Table 17, the assay for formulation G did not change from the initial time for any sample, regardless of storage time or conditions.

[0154] As shown in Table 19 below, formulation G showed no increase in the relevant substance after 1 month of storage at 40°C or 2 months of storage at 25°C. A slight increase in the relevant substance was observed after 2 months of storage at 40°C. The RRT values ​​ranged from 0.61 to 1.56.

[0155] Table 18 above summarizes the results of chemical characterization of preservatives after storage for 1 month, 2 months, and 3 months at temperatures of 2–8°C, 25°C, and 40°C ("preservative assay"). As shown in Table 18, the assays for methylsodium p-hydroxybenzoate and ethylsodium p-hydroxybenzoate did not show any significant loss greater than 5% at any time point and temperature tested, and the values ​​for methylsodium p-hydroxybenzoate were slightly higher than those for ethylsodium p-hydroxybenzoate.

[0156] Example 16: In one example, the preservatives used were methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate in the amounts shown in Table 14. The antioxidant-solubilizer TPGS combination was added as shown in Formulation I. Formulation I was evaluated based on its appearance and quantified using the European Pharmacopoeia color standards as described in Table 15. Formulation I was pale yellow and did not form any precipitate. Therefore, stability tests were conducted for both 1-month and 2-month storage at 2-8°C, 25°C, and 40°C. Formulation I showed slight color changes, mainly during storage at 40°C.

[0157] The pH value of formulation I remained close to 4.5 under all storage conditions, as shown in Table 16 above.

[0158] Table 17 above summarizes the results of chemical characterization ("assays") of cremiso hydrochloride formulations stored for one or two months at temperatures of 2–8°C, 25°C, and 40°C, as shown. As shown in Table 17, the assay for Formulation I did not change from the initial time point for any sample, regardless of storage and conditions.

[0159] As shown in Table 19 below, there was a slight increase in the relevant substance after storage at 40°C for 1 and 2 months using Formulation I, as well as after storage at 25°C for 2 months. The RRT values ​​ranged from 0.61 to 1.56.

[0160] Table 18 above summarizes the results of chemical characterization of preservatives after storage for 1 month, 2 months, and 3 months at temperatures of 2–8°C, 25°C, and 40°C ("preservative assay"). As shown in Table 18, the assays for methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate did not show any significant loss greater than 6% at any time point and temperature tested, and the value for ethyl p-hydroxybenzoate was slightly higher than that for methyl p-hydroxybenzoate. A slight decrease in preservative assay values ​​was observed for methyl parahydroxybenzoate at 1 month, but this appears to recover at 2 months across all temperatures used.

[0161] Example 17: In one example, the preservatives used were methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate in the amounts shown in Table 14. As represented by Formulation J, the solubilizer PEG400 was added without the presence of an antioxidant. Formulation J was evaluated by visual inspection and quantified using the European Pharmacopoeia color standards as described above in Table 15. Formulation J showed minimal color change over a 3-month storage period. The appearance remained consistent even at 40°C for one month, although slight changes in appearance were observed after storage for 2-3 months.

[0162] The pH value of formulation J remained close to 4.5 under all storage conditions, as shown in Table 16 above.

[0163] Table 17 above summarizes the results of chemical characterization ("assays") of cremiso hydrochloride formulations stored for one or two months at temperatures of 2–8°C, 25°C, and 40°C, as shown.

[0164] As shown in Table 17, the assay for formulation J remained unchanged from the initial time point for most samples, regardless of storage and conditions, except for a decrease observed after storage at 40°C for two months. Since this decrease was not accompanied by a corresponding increase in the related substance (Table 19 below), the sample was retested. As shown in Table 17, the results suggest that formulation J remained unchanged from the initial point to two months after storage at either 25°C or 40°C.

[0165] As shown in Table 19 below, this decrease in cremizole hydrochloride was not accompanied by a corresponding increase in related substances. After storage at 40°C for two months, the increase in related substances in formulation J had an RRT value of 0.61.

[0166] [Table 19]

[0167] Table 18 above summarizes the results of chemical characterization of preservatives after storage for 1 month, 2 months, and 3 months at temperatures of 2–8°C, 25°C, and 40°C ("preservative assay"). As shown in Table 18, the assays for methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate did not show any significant loss greater than 5% at any time point and temperature tested, and the value of ethyl p-hydroxybenzoate was slightly higher than that of methyl p-hydroxybenzoate. In fact, the value of ethyl parahydroxybenzoate was slightly higher than that of the target, probably due to a slightly higher weight (0.109 g vs. 0.100 g) of the added target. A slight decrease in preservative assay values ​​was observed for methyl parahydroxybenzoate at 1 month, but this appeared to recover at 2 months across all temperatures used.

[0168] Example 18: In one example, taste tests were conducted on formulations E and J, both with either a placebo or Vitrex added. Four participants rated the taste of each formulation on a scale of 1 to 9 (1 = very like, 9 = very dislike). The results are shown in Table 20 below, suggesting that both formulations have an acceptable taste.

[0169] [Table 20]

[0170] Example 19: In one example, formulation J was prepared again and analyzed after storage at 60% relative humidity (RH) and 2–8°C, and at 60% relative humidity (RH) and 25°C for up to 36 months, and at 75% relative humidity (RH) and 40°C for up to 6 months. The stability of the preparation was analyzed at 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months by evaluating appearance, the activity of cresol hydrochloride (activity assay), the formation of substances related to cresol hydrochloride, storage stability, pH, and the presence of microorganisms, as well as density and fill volume.

[0171] The alert limits for any potential changes to stability included at least one of the following: with respect to appearance, any change from the initial appearance; with respect to the activity assay, replicates must agree within 3% of each other, and any change from the initial average must be within 5%; with respect to the confirmation of cresol hydrochloride or preservatives, not being able to meet the specifications based on the retention time of the main peak in the sample chromatogram that matches the retention time of the main peak in the reference standard chromatogram; with respect to the formation of related substances, any increase in any single related substance of 0.1% or more compared to the previous time point; with respect to storage stability, replicates must be within 3% of each other, and any change from the initial average time point must not exceed 5%; with respect to specific gravity, readings and recordings, where potential changes are monitored at sampling intervals; with respect to density, readings and recordings, where potential changes are monitored at sampling intervals; with respect to pH, readings and recordings, where potential changes are monitored at sampling intervals; with respect to the microbial limit, TAMC ≤ 10 3 CFU / ml, TYMC ≤ 10 2 CFU / ml, and no Escherichia coli is present.

[0172] Preparation J was evaluated for the appearance test and quantified using the European Pharmacopoeia color standards as described in Table 21 below. Most of Preparation J showed a slight color change after storage at 40°C for 3 months and returned to a colorless appearance after 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months of storage at 2 - 8°C and 25°C, as well as after 6 months of storage at 40°C. The appearance of the samples under all storage conditions conformed to the specifications from the initial time point to the 36 - month storage time point at all storage temperatures.

[0173]

Table 21

[0174] The pH value of formulation J remained close to 4.5 throughout all storage conditions, as shown in Table 22. The pH value ranged from 4.45 to 4.54. For all storage conditions, no change in pH was detected outside the normal analytical variation for samples from the initial time point to the 36-month time point. The storage temperature and storage period did not appear to affect the pH of the formulation.

[0175]

Table 22

[0176] The following Table 23 summarizes the results of the chemical characterization (“assay”) of clomipramine hydrochloride in the formulation stored for 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months, and at temperatures of 2 - 8 °C, 25 °C, and 40 °C, as shown. The activity of clomipramine hydrochloride met the specifications at all measured time points. The initial average clomipramine hydrochloride activity was 98.3%. The activity remained consistent from the initial time point to the 36-month time point for storage conditions of 2 - 8 °C and 25 °C, and from the initial time point to the 6-month time point for storage conditions of 40 °C. The lowest reported average of clomipramine hydrochloride activity, recorded after storage at 40 °C for 6 months, was reported as 97.3%.

[0177]

Table 23

[0178] As shown in Table 24 below, with a few exceptions, individual related substances were not detected above the reporting limit from the initial period to 36 months. At 25°C, a single related substance was detected at 0.09%, 0.09%, and 0.65% at 18 months, 24 months, and 36 months, respectively. At 40°C, a single related substance was detected at 0.09% and 0.20% after 3 months and 6 months, respectively. With a few exceptions, the total number of related species did not exceed the reporting limit from the initial point to 36 months later. At 25°C, the total amount of related substances increased to 0.14% after 36 months, reaching the warning limit of ≥0.1%. At 40°C, the total amount of related substances increased again to 0.20% after 6 months, reaching the warning limit of ≥0.1%. The total amount of related substances formed during storage at all measured temperatures and at all time points did not exceed the acceptable threshold. There were no impurities exceeding the 3.0% area threshold, nor any individual impurities measured above the 0.5% area threshold.

[0179] [Table 24]

[0180] Tables 25 and 26 below summarize the results of chemical characterization of preservatives after storage for 1 month, 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, and 36 months at temperatures of 2–8°C, 25°C, and 40°C ("preservative assays"). Activity assays performed on both methylparaben and ethylparaben preservatives at all time points and under all storage temperature conditions did not show a decrease beyond an acceptable threshold. As shown in Tables 25 and 26, the assays for methylparaben and ethylparaben did not show a loss of more than 3.2% at any time point and storage temperature tested, respectively.

[0181] [Table 25]

[0182]

Table 26

[0183] The presence of clomizole hydrochloride, ethylparaben, and methylparaben was determined. The retention times of the main peaks in the sample chromatogram corresponded to those of the main peaks in the reference standard chromatogram for each.

[0184] All evaluated storage conditions were within the acceptable limits for microbial detection at all time points. The levels of the detected microorganisms were TAMC < 10 CFU / ml and TYMC < 10 CFU / ml. The presence of Escherichia coli was not detected.

[0185] Example 20: In one example, Formulations C and D were prepared as follows. Excess of each solid excipient containing cherry flavor, sweetener, antioxidant, and preservative was sieved through a 500 μM mesh and then dispensed in individual weighing boats or beakers in the required amounts. pH 4.5 citrate buffer was dispensed into the beakers and the excipients were added to the buffer in the order of preservative, antioxidant, sweetener, and flavor. After each excipient was completely dissolved, the following were added. Then, glycerol was dispensed into the buffer-excipient solution and mixed until the solution appeared homogeneous. Then, clomizole hydrochloride was added and the mixture was ensured to be homogeneous before measuring the pH of the resulting solution. If the pH was not within the target range (4.5 + / - 0.5), the pH was adjusted to within the target by adding 0.5 M citric acid solution or 0.5 M trisodium citrate solution while stirring. The solution was made to a predetermined volume with pH 4.5 citrate buffer.

[0186] Example 21: In one example, formulation E is prepared as follows: Excess solid excipients, including cherry flavor, sweetener, and preservative, are sieved through a 500 μM mesh and then dispensed into individual weighing boats or beakers in the required amounts. The TPGS is first melted in its container in an oven set to 55°C for 1 hour. In a separate beaker, pH 4.5 citrate buffer was dispensed. While stirring, the following excipients were added to the beaker containing the buffer in this order, ensuring that each component was completely dissolved before adding the following: TPGS, preservatives, sweeteners, and flavorings. Next, glycerol was added and mixed until completely homogenized. Next, cremisole hydrochloride was added to the beaker, ensuring the mixture was homogeneous. If the pH was not within the target range (4.5 ± 0.5), the pH was adjusted to the target range by adding 0.5 M citric acid solution or 0.5 M trisodium citrate solution while stirring. The solution was then diluted to the desired volume with pH 4.5 citrate buffer.

[0187] Example 22: In one example, formulations F, G, and H were prepared as follows. The excess solid excipients, including cherry flavor, sweetener, and preservative, were sieved through a 500 μM mesh and then dispensed into individual weighing boats or beakers in the required amounts. The TPGS was first melted in its container in an oven set to 55°C for 1 hour. In a separate beaker, pH 4.5 citrate buffer was dispensed. For formulations G and H, the solubilizer was added to the buffer and mixed until dissolved. For formulations F, G, and H, cremisole hydrochloride was added to the beaker and mixed until completely dissolved. While stirring, the remaining excipients were added in this order, ensuring that each component was completely dissolved before adding the following: sodium ethyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, sweetener, and flavoring. Next, glycerol was added and mixed until completely homogeneous. If the pH was not within the target range (4.5 ± 0.5), the pH was adjusted to the target range by adding 0.5 M citric acid solution or 0.5 M trisodium citrate solution while stirring. The solution was then brought to the desired volume with pH 4.5 citrate buffer.

[0188] Example 23: In one example, formulations F, G, and H were prepared as follows. The excess solid excipients, including cherry flavor, sweetener, and preservative, were sieved through a 500 μM mesh and then dispensed into individual weighing boats or beakers in the required amounts. The TPGS was first melted in its container in an oven set to 55°C for 1 hour. Dispense the solubilizer (TPGS or PEG400) into a separate beaker. If TPGS is used as the solubilizer, the beaker needs to be heated to approximately 50°C on a hot plate before adding the sweetener. Next, ethyl p-hydroxybenzoate, followed by methyl p-hydroxybenzoate, was added, ensuring that the first preservative was dissolved before adding the second preservative. pH 4.5 citrate buffer was dispensed into the second beaker. Next, cremiso hydrochloride was added and dissolved in a second beaker containing pH 4.5 citrate buffer. While stirring, the contents of the first beaker, including TPGS and preservatives, were added to the second beaker containing pH 4.5 citrate buffer and cremiso hydrochloride. Next, the sweetener was added, followed by the cherry flavoring agent, ensuring that the sweetener was completely dissolved before the flavoring agent was added. Next, glycerol was added and mixed until completely homogeneous. If the pH was not within the target range (4.5 ± 0.5), the pH was adjusted to the target range by adding 0.5 M citric acid solution or 0.5 M trisodium citrate solution while stirring. The solution was then brought to the desired volume with pH 4.5 citrate buffer.

[0189] After the preparation of the formulation, tests including stability testing, cremiso hydrochloride assay, preservative assay, and appearance testing were performed.

[0190] Example 24: In the examples, three formulations were prepared. Each of the three formulations was similar to formulation J in that it used methyl parahydroxybenzoate and ethyl parahydroxybenzoate as preservatives and contained the solubilizer PEG400. The amounts of preservatives, PEG 400, flavor (cherry flavor powder), sweetener (sucralose), glycerol, and citrate buffer components (citric acid monohydrate and trisodium citrate dihydrate) were the same among the individual formulations, as shown in Table 27 below. The three formulations shown in Table 27 contained either 5 mg / ml of cremiso hydrochloride, 10 mg / ml of cremiso hydrochloride, or 20 mg / ml of cremiso hydrochloride.

[0191] [Table 27]

[0192] The formulations were assayed for solubility and stability, including appearance (colorless to pale yellow, free of crystalline precipitates), cremiso hydrochloride stability (90.0% to 110.0% recovery rate), formation of substances related to cremiso hydrochloride (+ / - 0.5% change for any individual impurities, or 3.0% change for all related substances), preservative stability (+ / - 10% change from nominal value; 90.0% to 110.0% recovery rate), and pH (any change exceeding 0.2 units from the initial value).

[0193] All three formulations showed high solubility of cremiso hydrochloride. The 20 mg / ml cremiso hydrochloride formulation did not dissolve completely. The formulations were filtered, and a solubility assay was performed on the remaining portion in the solution. Solubility assays for all formulations showed solubility of 102.5%, 103.8%, and 97.6% for the 5 mg / ml, 10 mg / ml, and 20 mg / ml cremiso hydrochloride samples, respectively.

[0194] All three formulations were clear and colorless in appearance and did not contain any crystalline precipitates during formation.

[0195] During the formation process, the pH values ​​of the three formulations were close to 4.5, as shown in Table 28 below.

[0196] [Table 28]

[0197] The cremiso hydrochloride assays for all three formulations were within acceptable specification limits, as shown in Table 29 below.

[0198] [Table 29]

[0199] No related substances were detected in any of the three formulations.

[0200] Preservative assays of the three formulations provided combined results. The assay results for ethyl p-hydroxybenzoate were within the specification limits for all three formulations. The assay results for methyl p-hydroxybenzoate for 5 mg / ml and 20 mg / ml cremiso hydrochloride samples were within the specification limits, as shown in Table 30 below. The assay results for methyl p-hydroxybenzoate for 10 mg / ml cremiso hydrochloride sample were below the specification limit.

[0201] [Table 30]

[0202] Example 25: In the examples, three formulations were prepared according to the formulation of Example 24, except for the cremiso hydrochloride concentration shown in Table 31 below. The three formulations contained either 10 mg / ml of cremisole hydrochloride (Formulation B), 16 mg / ml of cremisole hydrochloride (Formulation D), or 18 mg / ml of cremisole hydrochloride (Formulation E).

[0203] [Table 31]

[0204] The formulations were assayed for solubility and any potential changes from initial formation to 28 days after storage at 25°C or 40°C. Potential changes included appearance (colorless to pale yellow, free from crystalline precipitates), cremiso hydrochloride stability (assay results 90.0%–110.0%), formation of substances related to cremiso hydrochloride (+ / - 0.5% change for any individual impurities, or 3.0% change for all related substances), preservative stability (+ / - 10% change from nominal value), and pH (any change exceeding 0.1 units from initial value).

[0205] The formulation containing 18 mg / ml of cremiso hydrochloride (Formulation D) was unable to solubilize all of the cremiso hydrochloride. During the initial preparation, the formulation containing 10 mg / ml cremisole hydrochloride (Formulation B) showed the formation of undissolved yellowish solid clumps. The formulation was re-prepared and filtered, appearing clear and pale yellow, and free of crystalline precipitates. The formulation containing 16 mg / ml cremisole hydrochloride (Formulation D) appeared clear, colorless, homogeneous, and free of crystalline precipitates. The appearance of both the 10 mg / ml cremisole hydrochloride (Formulation B) and the 16 mg / ml cremisole hydrochloride (Formulation D) remained clear, colorless to pale yellow, and free of precipitates during storage for 7, 14, and 28 days at either 25°C or 40°C.

[0206] The pH values ​​of both formulations remained close to 4.5 throughout all storage conditions, but the results were below the specification limit. The average pH value ranged from 4.23 to 4.32 throughout storage, as shown in Table 32 below.

[0207] [Table 32]

[0208] The cremiso hydrochloride assays for both formulations were within acceptable specification limits under all storage conditions, as shown in Table 33 below.

[0209] [Table 33]

[0210] The formation of related substances remained within the specification limits under all storage conditions, as shown in Table 34 below.

[0211] [Table 34]

[0212] The preservative assays for both ethyl p-hydroxybenzoate and methyl p-hydroxybenzoate were within acceptable limits under all storage conditions, as illustrated in Table 35 below.

[0213] Table 35

Claims

1. A liquid pharmaceutical composition for treating epileptic disorders in a subject, Clemiso hydrochloride (HCl); Citrate buffer; Preservatives that are methyl p-hydroxybenzoate and / or ethyl p-hydroxybenzoate; Ultra-refined PEG400; Sucralose; and Glycerol, Includes, The pH of the liquid pharmaceutical composition is in the range of 4 to 5. Liquid pharmaceutical composition.

2. The concentration of the glycerol is 10-30% (wt / wt), and the concentration of the citrate buffer is 70-90% (wt / wt). The liquid pharmaceutical composition according to claim 1.

3. The liquid pharmaceutical composition according to claim 1 or claim 2, wherein the preservative is present in a concentration of 0.01 to 0.5% (w / v).

4. The liquid pharmaceutical composition according to any one of claims 1 to 3, wherein the preservative comprises methyl parahydroxybenzoate at a concentration of 0.2% (w / v) and ethyl parahydroxybenzoate at a concentration of 0.02% (w / v).

5. The liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the liquid pharmaceutical composition further comprises a taste-modifying substance.

6. The liquid pharmaceutical composition according to any one of claims 1 to 5, wherein the concentration of the hydrochloric acid (HCl) cremisole in the pharmaceutical composition is 1 mg / mL to 30 mg / mL.

7. The liquid pharmaceutical composition according to any one of claims 1 to 6, wherein the concentration of the hydrochloric acid (HCl) cremisole in the pharmaceutical composition is 5 mg / mL, 10 mg / mL, 15 mg / mL, or 16 mg / mL.

8. Epileptic disorders include childhood epileptic disorders, Dravet syndrome, benign Rolandic absence epilepsy, frontal epileptic disorders, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epileptic disorder, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclonic epileptic disorder in infancy (SMEI), benign neonatal familial epilepsy (BNFC), West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, transitional partial epilepsy, infantile epileptic encephalopathy, tuberous sclerosis ( A liquid pharmaceutical composition according to any one of claims 1 to 7, wherein the condition is TSC), focal cortical dysplasia, type I lissencephaly, Miller-Dieker syndrome, Angelman syndrome, fragile X syndrome, epilepsy in autism spectrum disorder, subcortical ectopic epilepsy, Walker-Warburg syndrome, Alzheimer's disease, post-traumatic epilepsy, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, bilateral megamyoclonic catamenial epilepsy, Jacksonian seizure disorder, Unverricht-Lundburg disease, or photosensitive epilepsy.

9. A liquid pharmaceutical composition according to any one of claims 1 to 8, wherein the epileptic disorder is Dravet syndrome.

10. A liquid pharmaceutical composition according to any one of claims 1 to 8, wherein the epileptic disorder is Lennox-Gastaut syndrome.

11. The liquid pharmaceutical composition according to any one of claims 1 to 10, wherein the liquid pharmaceutical composition is administered to a target by an oral administration route.

12. The liquid pharmaceutical composition according to any one of claims 1 to 11, wherein the liquid pharmaceutical composition is administered to a subject to provide a dose of cremiso hydrochloride (HCl) of about 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg.

13. The liquid pharmaceutical composition according to any one of claims 1 to 12, wherein the composition is administered at least every 24 hours.

14. The liquid pharmaceutical composition according to any one of claims 1 to 13, wherein the liquid pharmaceutical composition comprises hydrochloric acid (HCl) cremisole (0.5 w / v%), methyl parahydroxybenzoate (0.2 w / v%), ethyl parahydroxybenzoate (0.02 w / v%), ultra-purified PEG400 (5 w / v%), glycerol (20 w / v%), cherry flavor powder (0.3 w / v%), sucralose (0.2 w / v%), and a citrate buffer solution with a pH of 4.5 (appropriate amount).

15. The liquid pharmaceutical composition according to any one of claims 1 to 13, wherein the liquid pharmaceutical composition comprises hydrochloric acid (HCl) cremisole (0.474 w / v%), methyl parahydroxybenzoate (0.19 w / v%), ethyl parahydroxybenzoate (0.02 w / v%), ultra-purified PEG400 (4.73 w / v%), glycerol (18.94 w / v%), cherry flavor powder (0.28 w / v%), sucralose (0.19 w / v%), and a citrate buffer solution with a pH of 4.5 (appropriate amount).

16. The liquid pharmaceutical composition according to any one of claims 1 to 13, wherein the liquid pharmaceutical composition comprises hydrochloric acid (HCl) cremisole (0.948 w / v%), methyl parahydroxybenzoate (0.19 w / v%), ethyl parahydroxybenzoate (0.02 w / v%), ultra-purified PEG400 (4.73 w / v%), glycerol (18.94 w / v%), cherry flavor powder (0.28 w / v%), sucralose (0.19 w / v%), and a citrate buffer solution with a pH of 4.5 (appropriate amount).

17. The liquid pharmaceutical composition according to any one of claims 1 to 13, wherein the liquid pharmaceutical composition comprises hydrochloric acid (HCl) cremisole (1.897 w / v%), methyl parahydroxybenzoate (0.19 w / v%), ethyl parahydroxybenzoate (0.02 w / v%), ultra-purified PEG400 (4.73 w / v%), glycerol (18.94 w / v%), cherry flavor powder (0.28 w / v%), sucralose (0.19 w / v%), and a citrate buffer solution with a pH of 4.5 (appropriate amount).

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