Composition for improving mucosal penetration

Abstract

This specification provides compositions and methods relating to solid dosage forms containing absorption enhancers. These compositions improve mucosal penetration and absorption of active ingredients.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 505,344, filed on 31 May 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Drug delivery via mucosal surfaces such as the airways, gastrointestinal (GI) tract, and reproductive tract can provide a desirable route of administration for delivering a wide range of drugs. Mucosal surfaces are often highly angiogenic, allowing drugs to bypass first-pass metabolism in the gastrointestinal tract and liver. Furthermore, mucosal administration can enable a faster onset of action than oral administration. Mucosal delivery is a favorable option, especially for drugs where rapid therapeutic action is important, in order to achieve rapid and efficient systemic drug absorption. [Overview of the project]

[0003] Mucosal administration offers an alternative to invasive and typically painful delivery by injection, potentially improving drug delivery to the brain by helping to overcome the difficulties associated with crossing the blood-brain barrier. Despite recent advances in drug discovery science, the development of formulations with enhanced mucosal penetration or absorption remains challenging. For example, many nasal formulations face challenges related to solubility, mucosal adhesion, and mucosal penetration. Therefore, the development of novel formulations for use in nasal administration is needed.

[0004] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a) an active ingredient or a pharmaceutically acceptable salt thereof, b) an absorption enhancer comprising a choline ester, and c) an excipient comprising microcrystalline cellulose, the pharmaceutical composition being formulated into a solid dosage form. In some embodiments, the choline ester is represented by the formula [(CH3)3N+CH2CH2OR]X-, where X is a pharmaceutically acceptable counterion. In some embodiments, X comprises a chloride. In some embodiments, R is selected from the group consisting of C2-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, and C2-C20 heteroalkyl. In some embodiments, the choline ester includes C8-C20 alkanoylcholine selected from the group consisting of arachidoylcholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), caproylcholine (C10), and capryloylcholine (C8), and any combination thereof. In some embodiments, the choline ester includes palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12). In some embodiments, the pharmaceutical composition further includes further excipients. In some embodiments, the further excipients include chitosan, lactose, croscarmellose sodium, tricalcium phosphate, or any combination thereof.

[0005] In some embodiments, the pharmaceutical composition has improved mucosal absorption rate compared to a corresponding pharmaceutical composition without an absorption enhancer, as measured by the pharmacokinetic (PK) parameters of the active ingredient or its metabolites. In some embodiments, the PK parameters of the active ingredient or its metabolites are improved by at least about 15% compared to a corresponding composition without an absorption enhancer. In some embodiments, the pharmacokinetic (PK) parameters of the active ingredient or its metabolites are improved by at least about 20%, 50%, 80%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, or 800% compared to a corresponding composition without an absorption enhancer. In some embodiments, the improvement in PK parameters includes an increase in peak blood drug concentration (Cmax). In some embodiments, the improvement in PK parameters includes a reduction in time to reach Cmax (Tmax). In some embodiments, the pharmaceutical composition has a Tmax of less than 10 minutes or less than 20 minutes. In some embodiments, improvement of the PK parameter includes an improvement in bioavailability (F). In some embodiments, improvement of the PK parameter includes an increase in the area under the curve (AUC). In some embodiments, the AUC includes AUC0-10min, AUC0-20min, AUC0-30min, AUC0-60min, AUC0-90min, AUC0-120min, AUC0-240min, AUC0-480min, or any combination thereof. In some embodiments, improvement of the PK parameter includes an AUC increase of at least about 200%, about 300%, about 400%, about 500%, or about 600% compared to the corresponding pharmaceutical composition without the absorption enhancer. In some embodiments, the PK parameter is measured from plasma or cerebrospinal fluid (CSF). In some embodiments, the PK parameter is measured by methods including high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MSI), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), or any combination thereof.

[0006] In some embodiments, the excipient is present in an amount of at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, or at least about 70 mg. In some embodiments, the pharmaceutical composition provided herein contains about 10 mg to about 60 mg of the excipient. In some embodiments, the pharmaceutical composition contains at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, or at least about 80% by weight of the excipient. In some embodiments, the pharmaceutical composition contains about 40% by weight to about 65% by weight of the excipient. In some embodiments, the pharmaceutical composition contains about 70% by weight to about 95% by weight of the excipient. In some embodiments, the microcrystalline cellulose has an average particle size of about 10 μm to about 100 μm. In some embodiments, the microcrystalline cellulose is present in an amount of about 40% of the total weight of the pharmaceutical composition. In some embodiments, the microcrystalline cellulose is present in an amount of about 90% of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises a further excipient, the further excipient comprising croscarmellose sodium or tricalcium phosphate.

[0007] In some embodiments, the active ingredient comprises a peptide. In some embodiments, the peptide comprises a dipeptide, tripeptide, oligopeptide, polypeptide, or cyclic peptide. In some embodiments, the active ingredient comprises a small molecule drug. In some embodiments, the active ingredient comprises a nucleic acid molecule. In some embodiments, the nucleic acid molecule comprises an antisense oligonucleotide. In some embodiments, the active ingredient comprises a medium molecule drug. In some embodiments, the active ingredient comprises epinephrine, baclofen, levodopa, calcitonin, cyclosporine A, an antisense oligonucleotide, or any combination thereof. In some embodiments, the active ingredient comprises epinephrine or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the active ingredient comprises baclofen or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient comprises levodopa or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient comprises calcitonin or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient comprises cyclosporine A or a pharmaceutically acceptable salt thereof. In some embodiments, the active ingredient or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, the active ingredient or a pharmaceutically acceptable salt thereof is crystalline.

[0009] In some embodiments, the pharmaceutical composition contains about 0.05 mg to about 30 mg of the active ingredient. In some embodiments, the pharmaceutical composition contains an absorption enhancer to microcrystalline cellulose weight ratio of about 1:1 to about 1:100. In some embodiments, the pharmaceutical composition contains an absorption enhancer to microcrystalline cellulose weight ratio of about 1:3 to about 1:15. In some embodiments, the pharmaceutical composition contains about 0.2 mg to about 20 mg of the absorption enhancer. In some embodiments, the pharmaceutical composition contains about 1.5 mg to about 10 mg of the absorption enhancer. In some embodiments, the pharmaceutical composition contains at least about 0.2 mg, at least about 0.5 mg, at least about 1 mg, at least about 1.25 mg, at least about 1.5 mg, at least about 2 mg, at least about 2.5 mg, at least about 3 mg, at least about 3.5 mg, at least about 4 mg, at least about 4.5 mg, or at least about 5 mg of the absorption enhancer.

[0010] In some embodiments, the absorption enhancer is present in an amount of about 1% to about 20% of the total weight of the pharmaceutical composition. In some embodiments, the absorption enhancer is present in an amount of about 6% to about 15% of the total weight of the pharmaceutical composition. In some embodiments, the unit dose of the pharmaceutical composition is about 20 mg to about 250 mg by weight. In some embodiments, the unit dose of the pharmaceutical composition is about 20 mg to about 80 mg by weight. In some embodiments, the unit dose of the pharmaceutical composition is about 60 mg by weight. In some embodiments, the unit dose of the pharmaceutical composition is about 80 mg by weight.

[0011] In some embodiments, the pharmaceutical composition comprises about 1–5 mg of epinephrine or a pharmaceutically acceptable salt thereof, about 2–6 mg of choline ester, and about 51–55 mg of microcrystalline cellulose. In some embodiments, the choline ester is lauroylcholine chloride. In some embodiments, the pharmaceutical composition has a Cmax of epinephrine or its metabolite that is at least about 150%, 250%, 350%, 450%, 550%, or 600% higher than the corresponding pharmaceutical composition that does not contain the choline ester. In some embodiments, the pharmaceutical composition has an area under the curve (AUC) of epinephrine or its metabolite that is at least about 200%, 300%, 400%, 500%, 600%, 700%, or 750% higher than the corresponding pharmaceutical composition that does not contain the choline ester. In some embodiments, the AUC is 0-20min AUC 0-30min AUC 0-60min AUC 0-90min AUC 0-120min , or any combination thereof.

[0012] In some embodiments, the pharmaceutical composition comprises about 3–7 mg of baclofen or a pharmaceutically acceptable salt thereof, about 2–6 mg of choline ester, and about 49–53 mg of microcrystalline cellulose. In some embodiments, the choline ester is lauroylcholine chloride. In some embodiments, the pharmaceutical composition has a Cmax of baclofen or its metabolite that is at least about 200%, 300%, or 400% higher than the corresponding pharmaceutical composition that does not contain choline ester. In some embodiments, the pharmaceutical composition has an AUC of baclofen or its metabolite that is at least about 200%, 300%, 400%, or 500% higher than the corresponding pharmaceutical composition that does not contain choline ester. In some embodiments, the AUC is... 0-20min AUC 0-30min , or AUC 0-240min , or any combination thereof.

[0013] In some embodiments, the pharmaceutical composition comprises about 18 to 28 mg of levodopa or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of choline ester, and about 20 to 50 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 18 to 28 mg of levodopa or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of choline ester, about 20 to 50 mg of microcrystalline cellulose, and optionally about 1 to 3 mg of croscarmellose sodium. In some embodiments, the choline ester is lauroylcholine chloride. In some embodiments, the pharmaceutical composition has a Cmax of levodopa or its metabolite that is at least about 300%, 400%, 500%, or 600% higher compared to a corresponding pharmaceutical composition without choline ester. In some embodiments, the pharmaceutical composition has an AUC of levodopa or its metabolite that is at least about 300%, 400%, 500%, or 600% higher compared to a corresponding pharmaceutical composition without choline ester. In some embodiments, the AUC is AUC 0-20min AUC 0-30min AUC 0-60min or any combination thereof.

[0014] In some embodiments, the pharmaceutical composition comprises about 0.1 to 0.2 mg of calcitonin or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of choline ester, and about 54 to 57 mg of microcrystalline cellulose. In some embodiments, the choline ester is lauroylcholine chloride. In some embodiments, the pharmaceutical composition has a Cmax of calcitonin or its metabolite that is at least about 250% higher compared to a corresponding pharmaceutical composition without choline ester. In some embodiments, the pharmaceutical composition has an AUC of calcitonin or its metabolite that is at least about 100%, 150%, 200%, 250%, or 300% higher compared to a corresponding pharmaceutical composition without choline ester. In some embodiments, the AUC is AUC 0-20min AUC 0-30min AUC 0-120min or any combination thereof.

[0015] In some embodiments, the pharmaceutical composition comprises about 28–32 mg of cyclosporine A or a pharmaceutically acceptable salt thereof, about 2–6 mg of choline ester, and about 24–28 mg of microcrystalline cellulose. In some embodiments, the choline ester is lauroylcholine chloride. In some embodiments, the pharmaceutical composition has an AUC of cyclosporine A or its metabolites that is at least about 600%, 700%, 800%, or 900% higher than the corresponding pharmaceutical composition that does not contain choline ester. In some embodiments, the AUC is 0-20min AUC 0-30min AUC 0-480min , or any combination thereof.

[0016] In some embodiments, the pharmaceutical composition contains about 20-25 mg of antisense oligonucleotide, about 7-10 mg of choline ester, about 32-38 mg of microcrystalline cellulose, and about 0.3-0.6 mg of tricalcium phosphate. In some embodiments, the pharmaceutical composition has a nucleic acid molecule Cmax that is at least about 150% higher than the corresponding pharmaceutical composition that does not contain choline ester. In some embodiments, the pharmaceutical composition has a nucleic acid molecule AUC that is at least about 200% higher than the corresponding composition that does not contain choline ester. In some embodiments, the AUC is... 0-20min AUC 0-30min AUC 0-60min AUC 0-480min , or any combination thereof.

[0017] In some embodiments, the pharmaceutical composition is formulated for mucosal administration. In some embodiments, mucosal administration includes buccal administration, sublingual administration, oral administration, ocular administration, intranasal administration, rectal administration, or vaginal administration. In some embodiments, the pharmaceutical composition is formulated for intranasal administration. In some embodiments, the solid dosage form includes powder, tablet, patch, or capsule. In some embodiments, the solid dosage form includes powder.

[0018] Another aspect of this disclosure includes pharmaceutical compositions provided herein for use in the prevention, diagnosis, or treatment of central nervous system disorders. In some embodiments, the pharmaceutical compositions are for use in preoperative or pre-examination procedures related to central nervous system disorders. In some embodiments, the pharmaceutical compositions are for use in the prevention, diagnosis, or treatment of systemic diseases. In some embodiments, the pharmaceutical compositions are for use in the prevention, diagnosis, or treatment of infections.

[0019] Another aspect of this disclosure includes a method for treating a disorder in a subject requiring treatment, comprising administering a pharmaceutical composition provided herein to the subject. In some embodiments, the disorder includes central nervous system (CNS) disorders. In some embodiments, CNS disorders include cerebral hemorrhage, cerebral infarction, central nervous system infection, brain tumor, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, multiple sclerosis, schizophrenia, depression, bipolar disorder, dysthymia, adjustment disorder, anxiety disorder, agitation, panic disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, sleep disorders, insomnia, traumatic brain injury, glioma, pain, migraine, or any combination thereof. In some embodiments, the disorder includes systemic disorders. In some embodiments, systemic disorders include anaphylaxis, fever, pain, inflammation, rheumatism, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory and metabolic disorders, muscle tone disorders, autonomic neuropathy, dizziness, migraine, hypertension, angina pectoris, arrhythmia, cardiovascular disease, allergies, asthma, bronchospasm, respiratory diseases, peptic ulcers, gastrointestinal disorders, diarrhea, indigestion, gout, hyperuricemia, dyslipidemia, diabetes, hormonal disorders, pituitary hormone disorders, corticosteroid disorders, sex hormone disorders, uterine-related diseases, osteoporosis, bone metabolic diseases, obesity, vitamin deficiencies, malnutrition, intoxication, cancer, hyperimmunity, autoimmune disorders, ear, nose, and throat-related diseases, oral-related diseases, urinary / genitourinary diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related diseases, drug addiction, lifestyle-related diseases, or any combination thereof. In some embodiments, the disorders include Parkinson's disease, pain, migraine, anaphylaxis, epilepsy, anxiety, agitation, obesity, glioma, or Alzheimer's disease. In some embodiments, the subjects include humans or non-human primates. In some embodiments, the pharmaceutical composition is administered intranasally to the subjects.

[0020] Another aspect of this disclosure includes a method for improving the absorption rate of an active ingredient or a pharmaceutically acceptable salt thereof, which involves administering a pharmaceutical composition provided herein to a subject. In some embodiments, the administration includes intranasal administration.

[0021] Another aspect of this disclosure provides a method for preparing a pharmaceutical composition provided herein, comprising granulating a mixture of the active ingredient of the pharmaceutical composition and an absorption enhancer.

[0022] Another aspect of this disclosure provides a method for treating a disease or illness in a subject requiring treatment, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an activator for treating Parkinson's disease and an absorption enhancer comprising a choline ester. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, the solid dosage form is in powder form. In some embodiments, the administration comprises intranasal administration. In some embodiments, the disease or illness includes Parkinson's disease. In some embodiments, the activator for treating Parkinson's disease comprises levodopa. In some embodiments, the administration comprises a time of less than 20 minutes. max This occurs. In some embodiments, administration results in a T time of less than 15 minutes. max This occurs. In some embodiments, administration results in a T time of less than 10 minutes. max This occurs. In some embodiments, administration results in an AUC exceeding 12000 ng × min / mL. In some embodiments, administration results in a C of at least 300 ng / mL. max This occurs. In some embodiments, administration results in at least 500 ng / mL of C max This occurs.

[0023] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually incorporated by reference. [Brief explanation of the drawing]

[0024] Novel features of this disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description and accompanying drawings, which describe illustrative embodiments in which the principles of this disclosure are utilized.

[0025] [Figure 1A] Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1A shows the plasma epinephrine concentrations after intranasal administration of preparations containing epinephrine alone or in combination with an absorption enhancer. [Figure 1B] Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1B shows the plasma epinephrine concentrations after intranasal administration of preparations containing epinephrine alone or in combination with excipients. [Figure 1C] Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1C shows the plasma epinephrine concentration after intranasal administration of preparations containing epinephrine, an absorption enhancer, and an excipient, or preparations containing either epinephrine and either an absorption enhancer or an excipient. [Figure 1D] Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1D shows the plasma epinephrine concentrations after administration of a liquid preparation containing epinephrine and lauroylcholine chloride (LCC), a powder preparation containing epinephrine and chitosan, and a powder preparation containing epinephrine, LCC, and chitosan. [Figure 1E] Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1E shows the plasma epinephrine concentrations after administration of preparations containing epinephrine and LCC, or preparations containing epinephrine, LCC, and lactose. [Figure 1F]Figures 1A to 1F show the plasma epinephrine concentration-time profiles after intranasal administration of several different epinephrine preparations. Figure 1F shows the plasma epinephrine concentrations after administration of 1) preparations containing epinephrine, choline esters (e.g., LCC, PCC, or MyCC), and MCC, 2) epinephrine and MCC, or 3) preparations containing epinephrine, butyrylcholine iodide (BCI), and MCC. [Figure 2A] Figures 2A to 2E show the plasma baclofen concentration-time profiles after intranasal administration of baclofen preparations. Figure 2A shows the plasma baclofen concentrations after intranasal administration of Comparative Examples 12 to 16. Comparative Example 12 is a liquid baclofen preparation that does not contain an absorption enhancer or MCC. Comparative Examples 13 to 16 are liquid or powder preparations containing baclofen and an absorption enhancer. [Figure 2B] Figures 2A to 2E show the plasma baclofen concentration-time profiles after intranasal administration of baclofen preparations. Figure 2B shows the plasma baclofen concentrations after intranasal administration of preparations containing baclofen alone, baclofen and MCC, or baclofen and lactose. [Figure 2C] Figures 2A to 2E show the plasma baclofen concentration-time profiles after intranasal administration of baclofen preparations. Figure 2C shows the plasma baclofen concentrations after administration of different baclofen preparations (e.g., baclofen preparations containing both absorption enhancers and excipients (e.g., MCCs), or baclofen preparations containing either absorption enhancers or MCCs). [Figure 2D] Figures 2A to 2E show the plasma baclofen concentration-time profiles after intranasal administration of baclofen preparations. Figure 2D shows the plasma baclofen concentrations after intranasal administration of baclofen preparations containing both an absorption enhancer (e.g., LCC) and an excipient (e.g., lactose), or containing either LCC or lactose. [Figure 2E]Figures 2A to 2E show the plasma baclofen concentration-time profiles after intranasal administration of baclofen preparations. Figure 2E shows the plasma baclofen concentration after intranasal administration of preparations containing baclofen and an absorption enhancer, baclofen and an excipient, or baclofen, an absorption enhancer, and an excipient. [Figure 3] Figure 3 shows the plasma levodopa concentration-time profiles after intranasal administration of various levodopa formulations (e.g., levodopa compositions containing absorption enhancers and excipients, or levodopa compositions containing excipients but not absorption enhancers). [Figure 4] Figure 4 shows the plasma calcitonin concentration-time profiles after intranasal administration of various calcitonin preparations (e.g., calcitonin compositions containing absorption enhancers and excipients, or calcitonin compositions containing excipients but not absorption enhancers). [Figure 5] Figure 5 shows the blood cyclosporine A concentration-time profiles after intranasal administration of various cyclosporine A formulations (e.g., cyclosporine compositions containing absorption enhancers and excipients, or cyclosporine compositions containing excipients but not absorption enhancers). [Figure 6] Figure 6 shows the plasma antisense oligonucleotide concentration-time profiles after intranasal administration of two antisense oligonucleotide formulations (e.g., antisense oligonucleotide compositions containing antisense oligonucleotides (ASOs), absorption enhancers, and excipients, or antisense oligonucleotide compositions containing ASOs and excipients but without absorption enhancers). [Modes for carrying out the invention]

[0026] Drug delivery via mucosal surfaces such as the airways, gastrointestinal (GI) tract, and reproductive tract offers an alternative to invasive delivery by injection. Mucosal administration can offer several advantages, such as reduced manufacturing and administration costs, potentially improved patient adherence (especially in subjects suffering from needle phobia), and a reduced risk of infection. Furthermore, mucosal drug delivery via the nose, lungs, oral cavity, and reproductive tract can help bypass first-pass metabolism in the liver. While mucosal surfaces are usually highly angiogenic and easily accessible, drug delivery can be hindered by mucus, a complex viscoelastic gel that covers much of the soft tissue in the human body. The mucus layer, containing large amounts of mucin (polymeric proteins densely decorated with negatively charged glycosaminoglycans), forms a highly intertwined network with glycoproteins, lipids, and DNA. This network can prevent the entry of pathogens, but it can also hinder the rapid and sufficient absorption of therapeutic agents. This slow absorption can prolong the period during which the subject can benefit from a drug administered through the mucosal surface. Therefore, there is a need for mucosal compositions that can help overcome the challenges associated with impaired absorption.

[0027] In some embodiments, pharmaceutical compositions and methods relating to solid dosage forms having improved mucosal penetration and / or absorption of the active ingredient are provided herein. In some embodiments, the composition comprises an active ingredient or a pharmaceutically acceptable salt thereof, and an absorption enhancer, the absorption enhancer comprising a choline ester derived from a carboxylic acid. In some embodiments, the composition comprises an active ingredient or a pharmaceutically acceptable salt thereof, an absorption enhancer, and an excipient comprising microcrystalline cellulose. In some embodiments, the solid dosage form is a powder dosage form. The absorption enhancer of the composition may comprise a choline ester derived from a carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the choline ester comprises alkanoylcholines of various chain lengths. The alkanoylcholine may include palmitoylcholine (PC), myristoylcholine (MyC), or lauroylcholine (LC), or a pharmaceutically acceptable salt thereof. In some embodiments, the excipient comprises microcrystalline cellulose (MCC). In some embodiments, the absorption enhancer is not derived from phosphatidic acid. In some embodiments, the absorption enhancer does not contain a phosphate group. In some embodiments, the absorption enhancer is not didecylphosphatidylcholine, lysolauroylphosphatidylcholine, dioctanoylphosphatidylcholine, dilauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0028] Absorption enhancer In some embodiments, the pharmaceutical composition includes an absorption enhancer. The absorption enhancer may be a compound that promotes the absorption of the active ingredient. The term absorption enhancer may also refer to a drug that increases absorption by improving membrane penetration rather than by increasing solubility. Thus, absorption enhancers are sometimes called penetration enhancers.

[0029] Absorption enhancers can improve mucosal penetration and / or absorption of active ingredients through mucous membranes, such as those found in the nose, cheeks, sublingual, rectum, oral cavity, lungs, or vaginal mucosa. In some embodiments, absorption enhancers improve the penetration and / or absorption of active ingredients through the nasal mucosa. In some embodiments, absorption enhancers increase the rate of mucosal absorption. In some embodiments, absorption enhancers improve the potency, onset of action, half-life, or amount of active ingredients absorbed through mucous membranes.

[0030] In some embodiments, the absorption enhancer includes a group of compounds such as fatty acids, choline esters, surfactants, chelating agents, sugars, or any combination thereof.

[0031] In some embodiments, the absorption enhancer comprises a choline ester or a pharmaceutically acceptable salt thereof. The choline ester or a pharmaceutically acceptable salt thereof is of the formula [(CH3)3N + The formula may include a choline ester having CH2CH2OR]X, where X is a pharmaceutically acceptable counterion such as chloride, sulfate, nitrate, perchlorate, bromide, iodide, phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate, lactate, maleate, fumarate, benzylate, cansylate, ethanesulfonate, gluceptate, mesylate, napsylate, and R is an acyl group. In some embodiments, the acyl group is derived from a carboxylic acid. In some embodiments, the acyl group is C2-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkinyl, C2-C 20 Heteroalkyl, C3-C 20 Cycloalkyl, C3-C 20 Includes heterocycloalkyl, aryl, heteroaryl, or any combination thereof. In some embodiments, the acyl group is C2-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkinyl, C2-C 20 Heteroalkyl, C3-C20 Cycloalkyl, C3-C 20 The group is selected from heterocycloalkyl, aryl, heteroaryl, and any combination thereof. In some embodiments, the choline ester includes acylcholine. In some embodiments, the absorption enhancer does not contain a phosphate group. In some embodiments, the absorption enhancer is not didecylphosphatidylcholine, lysolauroylphosphatidylcholine, dioctanoylphosphatidylcholine, dilauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not derived from phosphatidic acid. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0032] In some embodiments, the choline ester is derived from a carboxylic acid. In some embodiments, the choline ester includes an acyl group from a carboxylic acid, and the acyl group is C2-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkinyl, C2-C 20 Heteroalkyl, C3-C 20 Cycloalkyl, C3-C 20 It includes heterocycloalkyl, aryl, heteroaryl, or any combination thereof. In some embodiments, the choline ester is C2-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkinyl, C2-C 20 Heteroalkyl, C3-C 20 Cycloalkyl, C3-C 20 The group comprises a group selected from the group consisting of heterocycloalkyl, aryl, heteroaryl, and any combination thereof. In some embodiments, the choline ester is a C2-C group selected from the group consisting of hexanoyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, or stearoyl. 20Contains alkyl. In some embodiments, the choline ester contains one or more double bonds including 2-hexenoyl, 9-decenoyl, 9-hexadecenoyl, palmitoyl, oleioyl, myristreyl, 9,12-hexadecadienoyl, linoleyl, α-linoleyl, γ-linolenoyl, arachidyl, or eicosapentaenoyl C2-C 20 Contains alkenyls.

[0033] In some embodiments, the choline ester comprises an unsubstituted or substituted acyl group. In some embodiments, the acyl group is substituted with at least one hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, or haloalkoxy group.

[0034] In some embodiments, the choline ester comprises alkanoylcholine or a pharmaceutically acceptable salt thereof. In some embodiments, the alkanoylcholine is C8-C selected from the group consisting of arachidoylcholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), caproylcholine (C10), capryloylcholine (C8), and pharmaceutically acceptable salts thereof. 20 Contains alkyl. In some embodiments, alkanoylcholine is C 10 -C 18 Contains alkyl. In some embodiments, alkanoylcholine is C 12 -C 16 It contains alkyl. In some embodiments, preferred alkanoylcholines include palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12), or pharmaceutically acceptable salts thereof. In some embodiments, the most preferred alkanoylcholine is lauroylcholine (C12) or a pharmaceutically acceptable salt thereof. In some embodiments, the preferred pharmaceutically acceptable salt of the absorption enhancer is a chloride salt.

[0035] In some embodiments, the absorption enhancer (e.g., choline ester) comprises alkenoylcholine or a pharmaceutically acceptable salt thereof. In some embodiments, the alkenoylcholine comprises C2-C 20 Contains alkenyls.

[0036] In some embodiments, the pharmaceutical compositions provided herein contain one or more absorption enhancers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions provided herein contain at least one, two, three, four, five, or more absorption enhancers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions provided herein contain up to one, two, three, four, or five absorption enhancers or pharmaceutically acceptable salts thereof.

[0037] In some embodiments, preferred pharmaceutical compositions include palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12), or pharmaceutically acceptable salts thereof. In some embodiments, preferred absorption enhancers include palmitoylcholine chloride, myristoylcholine chloride, or lauroylcholine chloride (LCC). In some embodiments, the absorption enhancer includes LCC. In some embodiments, the absorption enhancer includes palmitoylcholine chloride (PCC). In some embodiments, the absorption enhancer includes myristoylcholine chloride (MyCC).

[0038] In some embodiments, the pharmaceutical composition contains at least about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, or about 20 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition contains up to about 1 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, or about 20 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition contains about 5 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition contains about 10 mg of an absorption enhancer.

[0039] In some embodiments, the pharmaceutical composition contains about 0.1 mg to about 30 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition contains about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg to about 2.5 mg, about 1.5 mg to about 20 mg, about 1.5 mg to about 15 mg, about 1.5 mg to about 10 mg, about 1.5 mg to about 5 mg, about 1.5 mg to about 2.5 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 5 mg, about 2 mg to about 2.5 mg, about 3 mg to about 20 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about 5 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, or about 5 mg to about 10 mg of an absorption enhancer.

[0040] In some embodiments, the absorption enhancer of the pharmaceutical composition is present in an amount of at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or at least about 20% of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the enhancer of the pharmaceutical composition is present in an amount of up to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or up to about 20% of the total weight (w / w%) of the pharmaceutical composition.

[0041] In some embodiments, the absorption enhancer of the pharmaceutical composition is present in amounts of approximately 1% to 20%, 1% to 18%, 1% to 15%, 1% to 12%, 1% to 10%, 1% to 8%, 1% to 5%, 3% to 20%, 3% to 18%, 3% to 15%, 3% to 12%, 3% to 10%, 3% to 8%, 3% to 5%, 6% to 20%, and 6% to 18% of the total weight (w / w%) of the pharmaceutical composition. They exist in the following proportions: %, approximately 6% to 15%, approximately 6% to 12%, approximately 6% to 10%, approximately 6% to 8%, approximately 8% to 20%, approximately 8% to 18%, approximately 8% to 15%, approximately 8% to 12%, approximately 8% to 10%, approximately 12% to 20%, approximately 12% to 18%, approximately 12% to 15%, approximately 14% to 20%, approximately 14% to 18%, approximately 14% to 15%, approximately 16% to 20%, approximately 16% to 18%, or approximately 18% to 20%.

[0042] In some embodiments, the absorption enhancer constitutes at least about 3% (e.g., 3.7%) of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the absorption enhancer constitutes at least about 6% (e.g., 6.2%, 6.7%, etc.) of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the absorption enhancer constitutes at least about 8% (e.g., 8%) of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the absorption enhancer constitutes at least about 10% (e.g., 13.3%) of the total weight (w / w%) of the pharmaceutical composition.

[0043] In some embodiments, pharmaceutical compositions comprising carboxylic acid-derived choline esters (e.g., LCCs) and excipients (e.g., microcrystalline cellulose (MCCs)) exhibit improved pharmacokinetic parameters compared to corresponding pharmaceutical compositions comprising another class of absorption enhancers (e.g., surfactants or sugars).

[0044] active ingredient The pharmaceutical compositions provided herein comprise one or more active ingredients or pharmaceutically acceptable salts thereof.

[0045] In some embodiments, the active ingredient of the pharmaceutical composition may be a peptide drug or a peptide-related drug. In some embodiments, the peptide drug includes a dipeptide, tripeptide, oligopeptide, polypeptide, or cyclic peptide. In some embodiments, the peptide-related drug includes a peptide mimetic, peptide analog, or drug-peptide conjugate. In some embodiments, the peptide or peptide-related drug has a molecular weight of about 10,000 Datons (Da) or less, about 20,000 Da or less, about 30,000 Da or less, about 40,000 Da or less, or about 50,000 Da or less.

[0046] In some cases, peptides or peptide-related drugs include insulin, human growth hormone, calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34), glucagon-like peptide-1 (GLP-1), interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-releasing hormone, angiotensin, and prolactin. This includes luteinizing hormone, gastric suppressor polypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide, carperitide, plumrintide, lanreotide, eptifibatide, albiglutide, pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide, diconotide, ecalantide, mifamultide, nesiritide, peg-linesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, ventricolamide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, their peptide analogs, or any combination thereof.

[0047] In some embodiments, the active ingredient includes a non-peptide drug.

[0048] In some embodiments, the active ingredient comprises a small molecule drug. In some embodiments, the small molecule drug has a molecular weight of about 1000 g / mol, about 750 g / mol, or less than about 500 g / mol. In some embodiments, the small molecule drug comprises epinephrine, baclofen, or levodopa, or pharmaceutically acceptable salts thereof, or any combination thereof.

[0049] In some embodiments, the active ingredient comprises a medium-molecule drug having a molecular weight of approximately 500 g / mol to approximately 50,000 g / mol. In some embodiments, the medium-molecule drug comprises a polysaccharide, protein, or nucleic acid molecule. In some embodiments, the medium-molecule drug comprises calcitonin, cyclosporine A, or antisense oligonucleotides, or pharmaceutically acceptable salts thereof, or any combination thereof.

[0050] In some embodiments, the active ingredient comprises a drug having a molecular weight greater than 50,000 g / mol, which includes an antibody or a fragment thereof.

[0051] In some embodiments, the active ingredient comprises a nucleic acid molecule. In some embodiments, the nucleic acid molecule may be of various sizes and may include oligonucleotides, polynucleotides, or plasmids. In some embodiments, the nucleic acid molecule may be a chemically modified nucleic acid comprising a modified backbone, a modified sugar moiety, or a combination thereof.

[0052] In some embodiments, the nucleic acid molecule comprises an antisense oligonucleotide (e.g., an antisense oligomer or ASO). As used herein, the terms “ASO” and “antisense oligomer” are used interchangeably and refer to an oligomer, such as a polynucleotide, comprising nucleic acid bases that hybridize to a target nucleic acid (e.g., premRNA or mRNA) sequence by Watson-Crick base pairing or fluctuation base pairing (GU).

[0053] In some embodiments, the antisense oligonucleotide comprises a phosphorothioate bond or a phosphorodiamidate bond. In some embodiments, the internucleotide bond of each antisense oligonucleotide is a phosphorothioate bond. In some embodiments, the antisense oligonucleotide comprises a phosphorodiamidate morpholino, locked nucleic acid, peptide nucleic acid, a 2'-O-methyl moiety, a 2'-fluoro moiety, a 2'-O-methoxyethyl moiety, or a 2'-NMA moiety. In some embodiments, the antisense oligonucleotide comprises at least one modified sugar moiety. In some embodiments, each nucleotide of the antisense oligonucleotide comprises a modified sugar moiety. In some embodiments, each nucleotide of the antisense oligonucleotide comprises a 2'-O-methoxyethyl moiety. In some embodiments, the antisense oligonucleotide comprises at least one modified nucleic acid base. In some embodiments, the antisense oligonucleotide comprises hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, or 5-hydroxymethylcytosine (hydroxymethoylcytosine).

[0054] In some embodiments, the antisense oligonucleotides are 8-50 nucleic acid bases, 8-40 nucleic acid bases, 8-30 nucleic acid bases, 8-25 nucleic acid bases, 8-20 nucleic acid bases, 8-15 nucleic acid bases, 10-50 nucleic acid bases, 10-40 nucleic acid bases, 10-30 nucleic acid bases, 10-25 nucleic acid bases, 10-20 nucleic acid bases, 10-15 nucleic acid bases, 12-50 nucleic acid bases, 12-40 nucleic acid bases, 12-30 nucleic acid bases, 12- It consists of 25 nucleic acid bases, 12-20 nucleic acid bases, 12-15 nucleic acid bases, 15-50 nucleic acid bases, 15-40 nucleic acid bases, 15-30 nucleic acid bases, 15-25 nucleic acid bases, 15-20 nucleic acid bases, 15-19 nucleic acid bases, 15-18 nucleic acid bases, 15-16 nucleic acid bases, 16-20 nucleic acid bases, 16-19 nucleic acid bases, 16-18 nucleic acid bases, 17-20 nucleic acid bases, 17-19 nucleic acid bases, or 18-20 nucleic acid bases.

[0055] In some embodiments, the active ingredient is acyclovir, adrenaline, alirocumab, allergen extract powder, amantadine, amphetamine, ampicillin, adalimumab, apomorphine, aripiprazole, atomoxetine, baclofen, beclomethasone, berimumab, betahistine, blonanserin, brexpiprazole, bromovalerylurea, buprenorphine, butorphanol, cabergoline, calcitonin, canakinumab, cannabide, cannabinol Ido, carbamazepine, carboplatin, cefaclor, ceftazidime, chimeric antibody absiximab, chloral hydrate, chlorpheniramine, chlorpromazine, cisplatin, clonazepam, codeine, cyanocobalamin, cyclophosphamide, cyclosporine A, cyclosporine, dantrolene, delaviridine, denosumab, desmopressin, dexamethasone, dextromethorphan, diazepam, didanosine, digoxin, dihydroergotamine, diltiazem, dimethyl fumarate, donepezil, droxidopa, edaravone, enoxacin, epinephrine Flulin, erenumab, erythropoietin, ethosuximide, etizolam, etoposide, evolocumab, fentanyl, fesoterodine, finasteride, fluorodeoxyglucose, fluorothymidine, fluphenazine, follicle-stimulating hormone, homivirsen, fremanezumab, gabapentin, galantamine, galcanezumab, ganciclovir, ghrelin, glucagon, glucagon-like peptide-1 (GLP-1), golimumab, granisetron, granulocyte colony-stimulating factor, growth hormone-releasing peptide, growth hormone, guanfasin, Haloperidol, humanized antibody bevacizumab, hydromorphone, ibuprofen, ifosfamide, imidafenacin, indinavir, indisetron, insulin, insulin-like growth factor-1 (IGF-1), interferon, interleukin, iopamidol, ipilimumab, keratinocyte growth factor (KGF), laxibacumab, L-dopa, leptin, leuprorelin, levetiracetam, levodopa, loperamide, lormetazepam, low molecular weight heparin, loxoprofen, luteinizing hormone, manganese, melatonin,Memantine, menopausal gonadotropic hormone, methylphenidate, midazolam, mipomersen, mirabegron, morphine, mouse antibody burinatumomab, naloxone, naphazoline, natalizumab, nelfinavir, nerve growth factor (NGF), necitumumab, nevirabine, nevirapine, nitrazepam, nivolumab, nusinersen, ofatumumab, olanzapine, ondansetron, oxybutynin, oxyco Don, oxytocin, ozagrel, palonosetron, panipenem / betamipron, panitumumab, pentobarbital, phenobarbital, phenytoin, piperiden, piperiden, pembrolizumab, placental gonadotropin, primidone, progesterone, prolactin, propiverine, parathyroid hormone (PTH), PTH-related peptide, quetiapine, ramucirumab, remimazolam, Ribavirin, rilmazaphone, risperidone, ritonavir, rivastigmine, rizatriptan, saquinavir, secukinumab, selective thrombin inhibitors, sildenafil, silodosin, simeprevir, sodium valproate, solifenacin, spiperone, stem cell growth factor (SCGF), sumatriptan, tacrolimus, tadalafil, tamsulosin, technetium, telaprevir, temozolomide, thallium, tiaprevir This includes tissue plasminogen activator, tolterodine, topiramate, tramadol, tranilast, triazolam, trihexyphenidyl, tropisetron, valganciclovir, vancomycin, vardenafil, vasopressin, vidarabine, vincristine, zalcitabine, zidovudine, zolmitriptan, zolpidem, zonisamide, zopiclone, 5-FU, or pharmaceutically acceptable salts thereof, or combinations thereof.

[0056] In some embodiments, the active ingredient includes epinephrine, baclofen, levodopa, calcitonin, cyclosporine A, or an antisense oligonucleotide, or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0057] In some embodiments, the active ingredient includes a drug that has bioactivity to the central nervous system (CNS). In some embodiments, the active ingredient includes a drug that is effective for the prevention or treatment of CNS diseases, for the examination or diagnosis of CNS diseases, or for preoperative or pre-examination treatment of CNS diseases. In some embodiments, the drug that has bioactivity to the CNS includes levodopa or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0058] In some embodiments, the activator is not glucagon. In some embodiments, if the absorption enhancer is phosphatidylcholine, the activator is not glucagon. In some embodiments, the absorption enhancer is not derived from phosphatidic acid. In some embodiments, the absorption enhancer does not contain a phosphate group. In some embodiments, the absorption enhancer is not didecylphosphatidylcholine, lysolauroylphosphatidylcholine, dioctanoylphosphatidylcholine, dilauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0059] Baclofen In some embodiments, the active ingredient comprises an activator for reducing muscle spasms. In some embodiments, the active ingredient comprises a skeletal muscle relaxant. In some embodiments, the skeletal muscle relaxant is administered to treat spasticity originating from the spinal cord (e.g., spinal cord injury, multiple sclerosis, etc.). In some embodiments, the skeletal muscle relaxant is administered to treat spasticity originating from the brain (e.g., the cerebrum (e.g., cerebral palsy, traumatic brain injury, etc.)). In some embodiments, the skeletal muscle relaxant is administered to treat multiple sclerosis. In some embodiments, the skeletal muscle relaxant is administered to treat spinal cord injury or spinal cord disease. In some embodiments, the skeletal muscle relaxant is administered to treat dystonia. In some embodiments, the skeletal muscle relaxant is administered to treat spasticity associated with cerebral palsy. In some embodiments, the skeletal muscle relaxant is administered to treat trigeminal neuralgia. In some embodiments, the skeletal muscle relaxant is administered to treat complex regional pain syndrome. In some embodiments, the skeletal muscle relaxant comprises baclofen.

[0060] In some embodiments, the active ingredient includes a drug for treating pain. In some embodiments, the drug for treating pain includes baclofen.

[0061] Levodopa In some embodiments, the active ingredient includes an activator for treating Parkinson's disease. In some embodiments, the active ingredient includes an activator for treating post-encephalitis-induced Parkinsonian syndrome or symptomatic Parkinsonian syndrome. In some embodiments, the active ingredient includes an activator for treating fluctuations in motor symptoms (e.g., off-periods in progressive Parkinson's disease). In some embodiments, the active ingredient includes a neurotransmitter precursor. In some embodiments, the active ingredient includes a dopamine precursor. In some embodiments, the activator includes a dopamine agonist. In some embodiments, the active ingredient includes levodopa.

[0062] Epinephrine In some embodiments, the active ingredient includes an activator for treating type I allergic reactions such as anaphylaxis. In some embodiments, the active ingredient includes an activator for treating hypotension associated with septic shock. In some embodiments, the active ingredient includes an activator that increases mean arterial pressure and / or induces bronchodilation. In some embodiments, the active ingredient includes a cardiac stimulant or inotropic agent such as an adrenergic agonist. In some embodiments, the active ingredient includes epinephrine.

[0063] Calcitonin In some embodiments, the active ingredient comprises a hormone. The hormone may be recombinantly synthesized (e.g., insulin) or purified from a natural source (e.g., salmon calcitonin). In some embodiments, the hormone may be used to treat bone-related disorders such as back pain, osteoporosis, or menopausal symptoms. In some embodiments, the active ingredient comprises salmon calcitonin or a pharmaceutically acceptable salt thereof.

[0064] Cyclosporine A In some embodiments, the active ingredient includes an immunosuppressant. In some embodiments, the immunosuppressant is for treating autoimmune disorders such as psoriasis, rheumatoid arthritis, or Crohn's disease. In some embodiments, the immunosuppressant is for treating rejection after organ transplantation. In some embodiments, the immunosuppressant includes a calcineurin inhibitor, a corticosteroid, or an antimetabolite. In some embodiments, the immunosuppressant includes cyclosporine A.

[0065] In some embodiments, the pharmaceutical compositions provided herein contain at least about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or more of the active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein contain up to about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of the active ingredient or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the pharmaceutical compositions provided herein contain about 0.05 mg to about 50 mg of the active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein contain about 0.05 mg to about 40 mg, about 0.05 mg to about 30 mg, about 0.1 mg to about 40 mg, about 0.1 mg to about 30 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 30 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 10 mg, about 1 mg to about 30 mg, and about 1 mg Contains approximately 25 mg of the active ingredient or a pharmaceutically acceptable salt thereof, approximately 1 mg to 20 mg, approximately 1 mg to 15 mg, approximately 1 mg to 10 mg, approximately 1 mg to 9 mg, approximately 1 mg to 8 mg, approximately 1 mg to 7 mg, approximately 1 mg to 6 mg, approximately 1 mg to 5 mg, approximately 2 mg to 10 mg, approximately 2 mg to 9 mg, approximately 2 mg to 8 mg, approximately 2 mg to 7 mg, approximately 2 mg to 6 mg, or approximately 2 mg to 5 mg.

[0067] In some embodiments, the total weight of the pharmaceutical composition contains at least about 0.05%, about 0.1%, about 0.15%, about 0.2%, 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, or more, of the active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of the pharmaceutical composition contains up to about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 5%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of the active ingredient or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the total weight of the pharmaceutical composition contains about 1% to about 60%, about 1% to about 50%, about 1% to about 40%, about 1% to about 30%, about 2% to about 50%, about 2% to about 40%, about 2% to about 30%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 7.5% to about 50%, about 7.5% to about 40%, about 7.5% to about 30%, about 7.5% to about 20%, about 7.5% to about 15%, about 7.5% to about 10%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 40%, or about 20% to about 35% of the active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of the pharmaceutical composition contains about 0.05% to about 0.4%, about 0.05% to about 0.35%, about 0.05% to about 0.3%, about 0.05% to about 0.25%, about 0.05% to about 0.2%, about 0.05% to about 0.15%, or about 0.05% to about 0.1% of the active ingredient or a pharmaceutically acceptable salt thereof.

[0069] Excipients In some embodiments, the pharmaceutical compositions provided herein include excipients. In some embodiments, the pharmaceutical compositions include microcrystalline cellulose (MCC). In some embodiments, the pharmaceutical compositions include at least one, two, three, four, five, or more excipients or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions include up to one, two, three, four, or five excipients or pharmaceutically acceptable salts thereof.

[0070] In some embodiments, the pharmaceutical composition contains at least about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg or more of an excipient or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains about 50 mg to about 90 mg of an excipient. In some embodiments, the pharmaceutical composition contains about 60 mg to about 80 mg of an excipient (e.g., MCC). In some embodiments, the pharmaceutical composition contains about 50 mg, about 60 mg, about 70 mg, or about 80 mg of an excipient.

[0071] In some embodiments, the pharmaceutical composition comprises an excipient or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 15 mg to about 80 mg, about 15 mg to about 70 mg, about 15 mg to about 60 mg, about 15 mg to about 50 mg, or about 15 mg to about 40 mg.

[0072] In some embodiments, the total weight of the pharmaceutical composition contains at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more of an excipient or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of the pharmaceutical composition contains up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, up to about 90%, or up to about 95% of an excipient or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the total weight of the pharmaceutical composition comprises about 30% to about 95%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 30% to about 50%, about 40% to about 95%, about 40% to about 90%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 95%, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, about 50% to about 60%, about 60% to about 95%, about 60% to about 90%, about 60% to about 80%, or about 60% to about 70% of an excipient or a pharmaceutically acceptable salt thereof. In some embodiments, the excipient (e.g., MCC) makes up about 40% to about 70% of the pharmaceutical composition. In some embodiments, the excipient makes up about 50% to about 60% of the pharmaceutical composition. In some embodiments, the excipient makes up about 50% of the pharmaceutical composition. In some embodiments, the excipient makes up about 55% of the pharmaceutical composition. In some embodiments, the excipient makes up about 60% of the pharmaceutical composition.

[0074] In some embodiments, the pharmaceutical composition includes an excipient. In some embodiments, the pharmaceutical composition includes one excipient. In some embodiments, the pharmaceutical composition includes one or more excipients. In some embodiments, the pharmaceutical composition includes two or more excipients. In some embodiments, the pharmaceutical composition includes three or more excipients. In some embodiments, the pharmaceutical composition includes two excipients. In some embodiments, the pharmaceutical composition includes three excipients.

[0075] In some embodiments, the excipient comprises a carbohydrate molecule or a pharmaceutically acceptable salt thereof. In some embodiments, the carbohydrate molecule comprises a polysaccharide, oligosaccharide, or disaccharide. In some embodiments, the carbohydrate molecule comprises chitosan, microcrystalline cellulose (MCC), croscarmellose, starch, or lactose. In some embodiments, the carbohydrate molecule comprises MCC. In some embodiments, the excipient comprises a sweetener. In some embodiments, the sweetener comprises a disaccharide, monosaccharide, or sugar alcohol. In some embodiments, the sweetener comprises lactose. In some embodiments, the excipient comprises a binder, anti-caking agent, emulsifier, bulking agent, or leavening agent. In some embodiments, the binder, anti-caking agent, emulsifier, bulking agent, or leavening agent comprises MCC.

[0076] In some embodiments, the excipient includes a phosphate. In some embodiments, the phosphate includes calcium phosphate. In some embodiments, the calcium phosphate includes tricalcium phosphate.

[0077] In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose, chitosan, lactose, croscarmellose sodium, tricalcium phosphate, or any combination thereof.

[0078] In some embodiments, the pharmaceutical composition includes microcrystalline cellulose (MCC). Acceptable MCC may include MCC obtained by decomposing cellulosic material such as pulp by either or both acid hydrolysis and / or alkali hydrolysis, then purifying the hydrolysate and grinding or pulverizing it before, during, or after drying. MCC of a selected average particle size may be obtained, for example, by appropriate processing, such as fine grinding using a high-speed rotary impact mill or air attrition mill as needed, and particle size sorting. In some embodiments, the MCC of the pharmaceutical composition presented herein is CEOLUS® PH-F20JP (e.g., average particle size about 20-23 microns, bulk density about 0.23 g / cm³). 3(Angle of repose 60 degrees or more), CEOLUS® PH-301 (for example, average particle size approximately 50 microns, bulk density approximately 0.41 g / cm³) 3 (Angle of repose approximately 41 degrees), CEOLUS® PH-101 (for example, average particle size approximately 50 microns, bulk density approximately 0.29 g / cm³, angle of repose approximately 45 degrees), CEOLUS® PH-102 (for example, average particle size approximately 90 microns, bulk density approximately 0.3 g / cm³) 3 (angle of repose approximately 42 degrees), and CEOLUS® PH-302 (available from Asahi Kasei, for example, average particle size approximately 90 microns, bulk density approximately 0.43 g / cm³). 3 (angle of repose approximately 38 degrees), and AVICEL® PH-105 (for example, average particle size approximately 20 microns, bulk density approximately 0.20~0.30 g / cm³) 3 ), AVICEL (registered trademark) PH-101 (for example, average particle size approximately 50 microns, bulk density approximately 0.26~0.31 g / cm³) 3 ), AVICEL (registered trademark) PH-102 (for example, average particle size approximately 100 microns, bulk density approximately 0.28~0.33 g / cm³) 3 ), AVICEL (registered trademark) PH-301 (for example, average particle size approximately 50 microns, bulk density approximately 0.34~0.45 g / cm³) 3 ), and AVICEL® PH-302 (available from FMC Biopolymer Corporation, for example, with an average particle size of approximately 100 microns and a bulk density of approximately 0.35-0.46 g / cm³). 3 This includes products available under the trade names of ). In some embodiments, the pharmaceutical composition includes CEOLUS® PH-F20JP and CEOLUS® PH-301. In some embodiments, the pharmaceutical composition containing MCC shows improved pharmacokinetic parameters compared to the corresponding pharmaceutical composition containing another excipient (e.g., lactose, chitosan).

[0079] The average particle size of microcrystalline cellulose (MCC) in the pharmaceutical composition may be determined using standard techniques, such as laser diffraction particle size distribution analyzers or sorting methods. In some embodiments, the MCC is approximately 10 μm to 100 μm, approximately 10 μm to 80 μm, approximately 10 μm to 60 μm, approximately 10 μm to 40 μm, approximately 15 μm to 100 μm, approximately 15 μm to 80 μm, approximately 15 μm to 60 μm, approximately 15 μm to 40 μm, approximately 15 μm to 25 μm, approximately 20 μm to 100 μm, approximately 20 μm to 80 μm, and approximately 20 The average particle size is approximately μm to 60 μm, approximately 20 μm to 40 μm, approximately 30 μm to 100 μm, approximately 30 μm to 80 μm, approximately 30 μm to 60 μm, approximately 40 μm to 100 μm, approximately 40 μm to 80 μm, approximately 40 μm to 60 μm, approximately 50 μm to 100 μm, approximately 50 μm to 80 μm, approximately 50 μm to 70 μm, or approximately 65 μm to 75 μm.

[0080] In some embodiments, the microcrystalline cellulose (MCC) has an average particle size of at least about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 90 μm, or about 100 μm or more. In some embodiments, the pharmaceutical composition comprises MCC having an average particle size of up to about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 90 μm, or about 100 μm.

[0081] In some embodiments, the total weight of the pharmaceutical composition is approximately 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 40% to 95%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, % It contains approximately 50% to 95%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 95%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to 90%, 80% to 90%, 85% to 95%, or 90% to 95% microcrystalline cellulose.

[0082] In some embodiments, the total weight of the pharmaceutical composition contains at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more microcrystalline cellulose (MCC). In some embodiments, the total weight of the pharmaceutical composition contains up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, up to about 90%, or up to about 95% MCC.

[0083] In some embodiments, microcrystalline cellulose (MCC) is present in an amount of at least 0.1, at least 0.2, at least 0.3, at least 0.4, at least 0.5, at least 0.6, or at least 0.7 g / cm³ 3 It has a bulk density of . In some embodiments, the pharmaceutical composition has a maximum of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7 g / cm³. 3 It contains MCC having a bulk density of . In some embodiments, the MCC is about 0.1 to 0.5 g / cm³ 3 Approximately 0.1-0.4 g / cm³ 3 , about 0.1~0.3g / cm 3 , about 0.1~0.2g / cm 3 , about 0.2~0.5g / cm 3 Approximately 0.2-0.4 g / cm³ 3 , about 0.2~0.3g / cm 3 , about 0.3~0.5g / cm 3 Approximately 0.3-0.4 g / cm³ 3 , or approximately 0.4-0.5 g / cm³ 3 It has a bulk density of .

[0084] In some embodiments, the pharmaceutical compositions provided herein include weight ratios of absorption enhancers (e.g., choline esters) to excipients (e.g., microcrystalline cellulose) of at least about 5:1, about 2:1, 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, and about 1:100. In some embodiments, the pharmaceutical compositions provided herein include weight ratios of absorption enhancers (e.g., choline esters) to excipients (e.g., microcrystalline cellulose) up to about 5:1, about 2:1, 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, and about 1:100. In some embodiments, the absorption enhancer and excipient (e.g., MCC) are present in the pharmaceutical composition in a ratio of about 1:10 (absorption enhancer:excipient). In some embodiments, the absorption enhancer and excipient (e.g., MCC) are present in the pharmaceutical composition in a ratio of about 1:13 (absorption enhancer:excipient). In some embodiments, absorption enhancers and excipients (e.g., MCCs) are present in the pharmaceutical composition in a ratio of approximately 1:15 (absorption enhancer:excipient).

[0085] In some embodiments, the pharmaceutical compositions provided herein are in ratios of approximately 1:1 to approximately 1:100, approximately 1:1 to approximately 1:90, approximately 1:1 to approximately 1:80, approximately 1:1 to approximately 1:70, approximately 1:1 to approximately 1:60, approximately 1:1 to approximately 1:50, approximately 1:1 to approximately 1:40, approximately 1:1 to approximately 1:30, approximately 1:1 to approximately 1:20, and approximately 1:1 to approximately 1:10. , approximately 1:2~1:50, approximately 1:2~1:40, approximately 1:2~1:30, approximately 1:2~1:20, approximately 1:2~1:10, approximately 1:3~1:50, approximately 1:3~1:40, approximately 1:3~1:30, approximately 1:3~1:20, approximately 1:3~1:10, approximately 1:3~1:5, approximately 1:5~1:50, approximately 1:5~1:5 :40, approx. 1:50~1:50, approx. 1:50~1:20, approx. 1:50~1:10, 1:10~1:100, approx. 1:10~1:90, approx. 1:10~1:80, approx. 1:10~1:70, approx. 1:10~1:60, approx. 1:10~1:50, approx. 1:20~1:90, approx. 1:20~1:80, approx. 1:20~ Includes weight ratios of absorption enhancer (e.g., choline ester) to excipient (e.g., microcrystalline cellulose) of approximately 1:70, approximately 1:20 to approximately 1:60, or approximately 1:20 to approximately 1:50, approximately 1:30 to approximately 1:90, approximately 1:30 to approximately 1:80, approximately 1:30 to approximately 1:70, approximately 1:30 to approximately 1:60, or approximately 1:30 to approximately 1:50.

[0086] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more excipients. In some embodiments, one or more excipients comprise croscarmellose sodium (CCS), tricalcium phosphate (TCP), or a combination thereof.

[0087] Pharmaceutical composition Some aspects of this disclosure provide pharmaceutical compositions having improved mucosal penetration and / or absorption of the active ingredient compared to corresponding pharmaceutical compositions that do not contain absorption enhancers. The pharmaceutical compositions may have improved mucosal penetration and / or absorption of the active ingredient through multiple mucous membranes, such as the nasal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa, oral mucosa, pulmonary mucosa, vaginal mucosa, or a combination thereof. In some embodiments, the pharmaceutical composition improves the penetration and / or absorption of the active ingredient through the nasal mucosa.

[0088] In some embodiments, the pharmaceutical composition improves mucosal penetration and / or absorption of the active ingredient compared to a corresponding pharmaceutical composition that does not contain a choline ester (e.g., lauroyl choline chloride (LCC)). In some embodiments, the pharmaceutical composition improves mucosal penetration and / or absorption of the active ingredient compared to a corresponding pharmaceutical composition that contains the active ingredient but does not contain an excipient (e.g., microcrystalline cellulose (MCC)). In some embodiments, the pharmaceutical composition comprising the active ingredient, a choline ester (e.g., LCC), and an excipient (e.g., MCC) exhibits improved pharmacokinetic parameters (e.g., improved Cmax, improved AUC). In some embodiments, the pharmaceutical composition comprising the active ingredient, a choline ester (e.g., LCC), and MCC exhibits improved pharmacokinetic parameters compared to a corresponding pharmaceutical composition comprising another class of absorption enhancer (e.g., surfactant or sugar). In some embodiments, the pharmaceutical composition comprising the active ingredient, a choline ester (e.g., LCC), and MCC exhibits improved pharmacokinetic parameters compared to a corresponding pharmaceutical composition comprising another excipient (e.g., lactose, chitosan). In some embodiments, the pharmaceutical compositions provided herein exhibit improved pharmacokinetic parameters compared to liquid pharmaceutical compositions containing an absorption enhancer (e.g., LCC).

[0089] The improvement of mucosal penetration and / or absorption of the active ingredient may be measured by a number of mechanisms, including through pharmacokinetic (PK) parameters. The PK parameters may be one or more of several PK parameters, such as drug concentration (C), Cmax, Cmin, Tmax, half-life (t1 / 2), bioavailability (F), or area under the curve (AUC). Bioavailability may be calculated based on the dose of the administered pharmaceutical composition and the area under the curve. The PK parameters may be obtained at any point in time after the administration of the pharmaceutical composition. In some embodiments, drug concentration, bioavailability, and AUC are obtained at least about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 120 minutes, about 180 minutes, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks after administration of the pharmaceutical composition. Subscripts may be used to specify the PK measurement time. For example, C 30min F 0-30min , and AUC 0-30min These are the drug concentration, bioavailability, and AUC obtained approximately 30 minutes after administration of the pharmaceutical composition, respectively.

[0090] In some embodiments, PK parameters are measured from a blood or plasma sample of the subject. In some embodiments, PK parameters are measured from a non-blood sample of the subject, such as amniotic fluid, aqueous humor, bile, breast milk, lymph, mucus, urine, or cerebrospinal fluid. In some embodiments, PK parameters are measured in a target tissue, such as cerebrospinal fluid (CSF) or brain parenchyma of the subject. In some embodiments, PK parameters (e.g., drug concentration) are measured by liquid chromatography (LC), mass spectrometry (MS), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), or any combination thereof (e.g., LC / MS / MS).

[0091] In some embodiments, a pharmaceutical composition (e.g., comprising an active ingredient and a choline ester) provides improved pharmacokinetic (PK) parameters of the activator (e.g., to the subject to whom the pharmaceutical composition is administered) compared to a corresponding pharmaceutical composition (e.g., containing the same active ingredient) that does not contain a choline ester (e.g., LCC). Improvements in PK parameters may include improved bioavailability, increased AUC, extended half-life, increased Cmax, shortened Tmax, or any combination thereof. In some embodiments, a pharmaceutical composition (e.g., comprising an active ingredient and an excipient) provides improved pharmacokinetic (PK) parameters of the activator compared to a pharmaceutical composition (e.g., MCC) that does not contain an excipient, including improved bioavailability, increased AUC, extended half-life, increased Cmax, shortened Tmax, or any combination thereof. In some embodiments, a pharmaceutical composition comprising an active ingredient, an excipient, and an absorption enhancer provides improvements to the pharmacokinetic (PK) parameters of the active ingredient, including improved bioavailability, increased AUC, extended half-life, improved Cmax, shortened Tmax, or any combination thereof, compared to a pharmaceutical composition that does not contain either an excipient (e.g., MCC) or a choline ester (e.g., LCC).

[0092] In some embodiments, a pharmaceutical composition (e.g., comprising an active ingredient and an absorption enhancer) improves the PK parameter of the active ingredient by at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 600%, about 700%, about 800%, about 900%, about 1000%, about 1100%, about 1200%, about 1300%, about 1400%, about 1500%, or about 2000% compared to a pharmaceutical composition (e.g., comprising the same active ingredient) that does not contain a choline ester (e.g., LCC).

[0093] In some embodiments, the improvement of the PK parameter includes the AUC parameter. In some embodiments, the improvement of the AUC parameter includes the AUC0-10min 、AUC 0-30min 、AUC 0-60min 、AUC 0-90min 、AUC 0-120min 、AUC 0-150min 、AUC 0-240min 、AUC 0-300min 、AUC 0-480min 、 or any combination thereof. In some embodiments, improvement of the AUC parameter is AUC 0-10minを含む。 In some embodiments, improvement of the AUC parameter is AUC 0-30min including. In some embodiments, improvement of the AUC parameter is AUC 0-60minを含む。 In some embodiments, improvement of the AUC parameter is AUC 0-90min including. In some embodiments, improvement of the AUC parameter is AUC 0-120min including. In some embodiments, improvement of the AUC parameter is AUC 0-150min including. In some embodiments, improvement of the AUC parameter is AUC 0-240min including. In some embodiments, improvement of the AUC parameter is AUC 0-300min including. In some embodiments, improvement of the AUC parameter is AUC 0-480min including.

[0094] In some embodiments, the pharmaceutical composition has an AUC improved by at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200% compared to the corresponding pharmaceutical composition without an absorption enhancer (e.g., LCC). 0-30min including. In some embodiments, the pharmaceutical composition has an AUC improved by at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to the corresponding pharmaceutical composition without a choline ester (e.g., LCC). 0-60min including.

[0095] In some embodiments, the pharmaceutical composition has an improvement in AUC when measured at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 2 hours, at least 3 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 2 weeks, or longer after the pharmaceutical composition has been administered to a subject.

[0096] In some embodiments, the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, lauroyl chorinchloride, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises a) about 1 to 5 mg of epinephrine or a pharmaceutically acceptable salt thereof, b) about 2 to 6 mg of lauroyl chorinchloride, and c) about 51 to 55 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 3 mg of epinephrine or a pharmaceutically acceptable salt thereof, b) about 4 mg of lauroyl chorinchloride, and c) about 53 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, upon administration of the pharmaceutical composition, the Cmax of epinephrine is improved by at least about 300%, 400%, 500%, 600%, 700%, or 800% compared to a corresponding pharmaceutical composition containing epinephrine but not lauroyl chorinchloride. In some embodiments, when the pharmaceutical composition is administered, the AUC of epinephrine 0-30min This provides at least approximately 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200% improvement compared to a corresponding pharmaceutical composition containing epinephrine but not lauroylcholine chloride.

[0097] In some embodiments, the pharmaceutical composition comprises baclofen or a pharmaceutically acceptable salt thereof, lauroylcholine chloride, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises a) about 3–7 mg of baclofen or a pharmaceutically acceptable salt thereof, b) about 2–6 mg of lauroylcholine chloride, and c) about 49–53 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 5 mg of baclofen or a pharmaceutically acceptable salt thereof, b) about 4 mg of lauroylcholine chloride, and c) about 51 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, upon administration of the pharmaceutical composition, the Cmax of baclofen is improved by at least about 300%, 400%, or 500% compared to a corresponding pharmaceutical composition containing baclofen but not lauroylcholine chloride. In some embodiments, upon administration of the pharmaceutical composition, the AUC of baclofen is improved. 0-30min This represents an improvement of at least approximately 300%, 400%, or 500% compared to a corresponding pharmaceutical composition containing baclofen but not lauroylcholine chloride.

[0098] In some embodiments, the pharmaceutical composition comprises levodopa or a pharmaceutically acceptable salt thereof, lauroyl chorinchloride, microcrystalline cellulose, and croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises a) about 18–28 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 2–6 mg of LCC, c) about 25–50 mg of MCC, and optionally d) about 0.5–3 mg of croscarmellose sodium, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 18–22 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 2–6 mg of LCC, c) about 22–28 mg of MCC, and optionally d) about 1–2 mg of croscarmellose sodium, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 20 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 4 mg of LCC, c) about 34.2 mg of MCC, and d) about 1.8 mg of croscarmellose sodium, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 26.7 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 5.3 mg of LCC, c) about 45.6 mg of MCC, and d) about 2.4 mg of croscarmellose sodium, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 20 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 4 mg of LCC, and c) about 36 mg of MCC, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 26.7 mg of levodopa or a pharmaceutically acceptable salt thereof, b) about 5.3 mg of LCC, and c) about 48 mg of MCC, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, upon administration of the pharmaceutical composition, the Cmax of levodopa is improved by at least about 300%, 400%, 500%, 600%, or 700% compared to a corresponding pharmaceutical composition without LCC. In some embodiments, upon administration of the pharmaceutical composition, the AUC of levodopa is improved. 0-30minThis provides at least about 300%, 400%, 500%, 600%, or 700% improvement compared to a corresponding pharmaceutical composition that does not contain LCC. In some embodiments, the pharmaceutical composition contains about 20 mg to about 100 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 10 mg to about 100 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 60 mg to about 80 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 20 mg to about 40 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 20 mg to about 30 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 20 mg of the active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition contains about 30 mg of the active ingredient (e.g., levodopa).

[0099] In some embodiments, the pharmaceutical composition comprises calcitonin or a pharmaceutically acceptable salt thereof, lauroylcholine chloride, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises a) about 0.1–0.2 mg of calcitonin or a pharmaceutically acceptable salt thereof, b) about 2–6 mg of lauroylcholine chloride, and c) about 54–57 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 0.12 mg of calcitonin or a pharmaceutically acceptable salt thereof, b) about 4 mg of lauroylcholine chloride, and c) about 55.88 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, upon administration of the pharmaceutical composition, the Cmax of calcitonin is improved by at least about 200%, 300%, or 400% compared to a corresponding pharmaceutical composition containing calcitonin but not lauroylcholine chloride. In some embodiments, when the pharmaceutical composition is administered, the AUC of calcitonin increases. 0-30min This provides at least approximately 100%, 200%, or 300% improvement compared to a corresponding pharmaceutical composition containing calcitonin but not lauroylcholine chloride.

[0100] In some embodiments, the pharmaceutical composition comprises cyclosporine A or a pharmaceutically acceptable salt thereof, lauroyl chorinchloride, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises a) about 28–32 mg of cyclosporine A or a pharmaceutically acceptable salt thereof, b) about 2–6 mg of lauroyl chorinchloride, and c) about 24–28 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the pharmaceutical composition comprises a) about 30 mg of cyclosporine A or a pharmaceutically acceptable salt thereof, b) about 4 mg of lauroyl chorinchloride, and c) about 26 mg of microcrystalline cellulose, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, when the pharmaceutical composition is administered, the AUC of cyclosporine A 0-30min This provides at least approximately 400%, 500%, 600%, 700%, or 800% improvement compared to a corresponding pharmaceutical composition containing cyclosporine A but not lauroylcholinchloride.

[0101] In some embodiments, the pharmaceutical composition comprises a) a nucleic acid molecule or a pharmaceutically acceptable salt thereof, and b) an absorption enhancer comprising a choline ester, and the pharmaceutical composition is formulated into a solid dosage form. In some embodiments, the choline ester comprises palmitoylcholine (PC) or a pharmaceutically acceptable salt thereof, myristoylcholine (MyC) or a pharmaceutically acceptable salt thereof, or lauroylcholine (LC) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises an excipient comprising microcrystalline cellulose. In some embodiments, upon administration of the pharmaceutical composition, the Cmax of the nucleic acid molecule is improved by at least about 50%, 80%, 100%, or 200% compared to a corresponding pharmaceutical composition containing a nucleic acid molecule but without an absorption enhancer. In some embodiments, upon administration of the pharmaceutical composition, the AUC of the nucleic acid molecule is improved. 0-30min This represents an improvement of at least approximately 100%, 200%, or 300% compared to a corresponding composition containing nucleic acid molecules but without absorption enhancers.

[0102] In some embodiments, the pharmaceutical composition comprises a nucleic acid molecule or a pharmaceutically acceptable salt thereof, lauroylcholine, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 10 mg of a nucleic acid molecule or a pharmaceutically acceptable salt thereof, about 4 mg of lauroylcholine or a pharmaceutically acceptable salt thereof, and about 13 mg of microcrystalline cellulose. In some embodiments, the nucleic acid molecule comprises an antisense oligonucleotide.

[0103] In some embodiments, the pharmaceutical composition is for mucosal administration, including buccal, sublingual, oral, ocular, intranasal, rectal, and vaginal administration. In some embodiments, the pharmaceutical composition is for intranasal administration.

[0104] The pharmaceutical compositions provided herein are formulated into solid dosage forms, including powders, tablets, patches, or capsules. In some embodiments, the pharmaceutical compositions exhibit improved pharmacokinetic parameters (e.g., improved Cmax, improved AUC) compared to liquid dosage forms. Solid dosage forms may also be characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. While we do not wish to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, tackiness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make a particular solid form suitable for the manufacture of a solid dosage form. Such properties may be determined using certain analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis) described herein and known in the art.

[0105] In some embodiments, the unit dose of the pharmaceutical composition contains a weight of about 20 mg to about 250 mg. In some embodiments, the unit dose of the pharmaceutical composition contains a weight of at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 100 mg, at least about 120 mg, at least about 150 mg, at least about 180 mg, at least about 200 mg, or at least about 225 mg or more.

[0106] Manufacturing method Several aspects of this disclosure relate to methods for producing pharmaceutical compositions. In some embodiments, the production method includes mixing, grinding, granulation, drying, or any combination thereof. In some embodiments, mixing includes mixing in a container (e.g., a bag) or high-shear mixing in a granulator. In some embodiments, grinding includes mortar grinding. In some embodiments, granulation includes agitation granulation, extrusion granulation, fluid bed granulation, high-shear granulation, or a combination thereof. In some embodiments, granulation includes passing a solid pharmaceutical composition through a sieve. In some embodiments, drying includes freeze-drying, lyophilization, spray drying, or spray freeze-drying.

[0107] Treatment method Several aspects of this disclosure relate to methods for treating disorders, comprising administering a pharmaceutical composition provided herein to a subject in need of treatment. In some embodiments, the method includes administering the pharmaceutical composition via buccal, sublingual, oral, ocular, intranasal, rectal, or vaginal administration. In some embodiments, a preferred method includes intranasal administration of the pharmaceutical composition.

[0108] In some embodiments, the methods provided herein include the use of a pharmaceutical composition in the diagnosis, prevention, or treatment of a disorder.

[0109] In some embodiments, the method involves using a pharmaceutical composition to treat a disorder of the central nervous system (CNS). In some embodiments, the CNS disorder includes cerebral hemorrhage, cerebral infarction, CNS infection, brain tumor, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, multiple sclerosis, schizophrenia, depression, bipolar disorder, dysthymia, adjustment disorder, anxiety disorder, agitation, panic disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, sleep disorders, insomnia, traumatic brain injury, glioma, pain, and / or migraine. In some embodiments, CNS disorders include tumors of the CNS, such as meningiomas, pituitary adenomas, craniopharyngiomas, schwannomas, nasopharyngeal angiofibromas, choroid plexus tumors, germinal dysplastic neuroepithelial tumors, neurofibromas, hemangioblastomas, chondromas, giant cell tumors, osteomas, gliomas (e.g., astrocytoma, oligodendroglioma, or glioblastoma), ependymal tumors, hemangiocarcinomas, germ cell tumors, or pineal gland tumors, chordomas, chondrosarcomas, medulloblastomas, olfactory neuroblastomas, lymphomas, gliosarcomas, rhabdomyosarcomas, paranasal sinus cancers, or atypical teratomatous / rhabdoid tumors.

[0110] In some embodiments, the method involves using a pharmaceutical composition to treat a systemic disorder. In some embodiments, the systemic disorder includes anaphylaxis, fever, pain, inflammation, rheumatism, hypnotic / sedative, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory and metabolic disorders, muscle tone disorders, autonomic neuropathy, dizziness, migraine, hypertension, angina pectoris, arrhythmia, cardiovascular disease, allergy, bronchiectasis / asthma, respiratory disease, peptic ulcer, gastrointestinal disorder, diarrhea, indigestion, gout, hyperuricemia, dyslipidemia, diabetes, hormonal disorders, pituitary hormone disorders, corticosteroid disorders, sex hormone disorders, uterine disorders, osteoporosis, bone metabolic disorders, obesity, vitamin deficiencies, malnutrition, intoxication, cancer, hyperimmunity, autoimmune disorders, ear, nose, and throat disorders, oral disorders, urinary / genital disorders, hemorrhoids, skin diseases, hematopoietic / blood coagulation disorders, drug addiction, and lifestyle-related diseases.

[0111] In some embodiments, the method includes using a pharmaceutical composition to diagnose a disorder. In some embodiments, the method includes using a pharmaceutical composition for preoperative or pre-examination treatment. In some embodiments, the preoperative or pre-examination treatment includes a radiopharmaceutical for imaging.

[0112] In some embodiments, the method includes using a pharmaceutical composition to treat a disorder associated with muscle spasms. In some embodiments, the disorders associated with muscle spasms include multiple sclerosis, spinal cord injury, dystonia, spasticity associated with cerebral palsy, trigeminal neuralgia, and focal pain syndromes. In some embodiments, the method includes using a pharmaceutical composition to treat a pain disorder. In some embodiments, the method includes using a pharmaceutical composition to treat Parkinson's disease. In some embodiments, the method includes using a pharmaceutical composition to treat post-encephalitis-related Parkinsonian syndrome, symptomatic Parkinsonian syndrome, or fluctuations in motor symptoms. In some embodiments, the method includes using a pharmaceutical composition to treat a type I allergic reaction such as anaphylaxis. In some embodiments, the method includes using a pharmaceutical composition to treat hypotension associated with septic shock. In some embodiments, the method includes using a pharmaceutical composition to treat bone-related disorders such as lower back pain, osteoporosis, or menopausal disorders. In some embodiments, the method includes using a pharmaceutical composition to treat autoimmune disorders such as psoriasis, rheumatoid arthritis, or Crohn's disease. In some embodiments, the method includes using a pharmaceutical composition to treat post-organ transplant rejection reactions such as graft-versus-host disease.

[0113] In some embodiments, the herein provides a method for treating a disease or illness in a subject requiring treatment, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an activator for treating Parkinson's disease and an absorption enhancer comprising a choline ester. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition is a solid dosage form. The solid dosage form includes a powder formulation for intranasal administration. In some embodiments, the activator for treating Parkinson's disease comprises levodopa. In some embodiments, administration results in a Tmax of less than 20 minutes. In some embodiments, administration results in a Tmax of less than 15 minutes. In some embodiments, administration results in a Tmax of less than 10 minutes. In some embodiments, administration results in an AUC greater than 10,000 ng × min / mL. In some embodiments, administration results in an AUC greater than 12,000 ng × min / mL. In some embodiments, administration results in an AUC greater than 15,000 ng × min / mL. In some embodiments, administration results in a Cmax of at least 300 ng / mL. In some embodiments, administration results in a Cmax of at least 500 ng / mL.

[0114] In some embodiments, administration of a pharmaceutical composition (e.g., comprising an active ingredient and an absorption enhancer) results in an improvement in the pharmacokinetic (PK) parameters of the active ingredient compared to a corresponding pharmaceutical composition (e.g., containing the same active ingredient) that does not include an absorption enhancer (e.g., LCC). The improvement in PK parameters may include an increase in bioavailability, an increase in AUC, an increase in half-life, an increase in Cmax, or a decrease in Tmax, or any combination thereof.

[0115] In some embodiments, administering a pharmaceutical composition provides improvements to the pharmacokinetic (PK) parameters of an activator, including increased bioavailability, increased AUC, increased half-life, increased Cmax, or shortened Tmax, or any combination thereof, compared to a pharmaceutical composition without excipients (e.g., MCC). In some embodiments, a pharmaceutical composition comprising an active ingredient, excipients, and absorption enhancers provides improvements to the pharmacokinetic (PK) parameters of an activator, including increased bioavailability, increased AUC, increased half-life, increased Cmax, or shortened Tmax, or any combination thereof, compared to a pharmaceutical composition without both excipients (e.g., MCC) and absorption enhancers (e.g., LCC).

[0116] In some embodiments, administering a pharmaceutical composition results in an improvement in the AUC parameter. In some embodiments, the improvement in the AUC parameter is AUC 0-10min AUC 0-20min AUC 0-30min AUC 0-60min AUC 0-90min AUC 0-120min AUC 0-150min AUC 0-240min AUC 0-300min AUC 0-480min This includes, or any combination thereof. In some embodiments, improvement of the AUC parameter is AUC 0-10min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-20min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-30min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-60min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-90min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-120min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-150min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-240minThis includes. In some embodiments, the improvement of the AUC parameter is AUC 0-300min This includes. In some embodiments, the improvement of the AUC parameter is AUC 0-480min Includes.

[0117] In some embodiments, the nucleic acid-containing pharmaceutical composition is administered intranasally as a solid formulation. In some embodiments, the nucleic acid-containing pharmaceutical composition can be reconstituted with a pharmaceutically acceptable diluent and then administered by injection. In some embodiments, the injection is intramuscular, subcutaneous, intravenous, or intradermal.

[0118] In some embodiments, administering the pharmaceutical composition results in an AUC improvement of at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200% compared to administering the corresponding pharmaceutical composition without an absorption enhancer (e.g., LCC). 0-30min In some embodiments, administering the pharmaceutical composition results in an AUC improvement of at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to administering the corresponding pharmaceutical composition without an absorption enhancer (e.g., LCC). 0-60min It brings about.

[0119] In some embodiments, administering a pharmaceutical composition results in an improvement in AUC when measured at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 2 hours, at least 3 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 15 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days, at least 2 weeks, or longer after administration of the pharmaceutical composition to the subject.

[0120] In some embodiments, the methods provided herein include administering an effective amount of a pharmaceutical composition. In some embodiments, the effective amount of a pharmaceutical composition contains a lower dose of the active ingredient compared to different formulations comprising the active ingredient. In some embodiments, the effective amount of a pharmaceutical composition contains a dose that is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more less than the dose of the active ingredient in different formulations comprising the active ingredient.

[0121] In some embodiments, the methods provided herein involve less toxicity. In some embodiments, toxicity includes toxicity of the active ingredient, side effects, or adverse drug events.

[0122] The singular forms "a," "an," and "the" include the plural form unless otherwise clearly indicated by the context. Therefore, for example, a reference to "a drug" includes references to one or more such drugs, and a reference to "an excipient" includes references to one or more such excipients. Where the term "range" is used herein, it is intended to include all combinations and partial combinations of the range and any particular embodiment within that range. The term "about," when referring to a number or numerical range, means that the number or numerical range referred to is an approximation within experimental variation (or statistical experimental error), and therefore the number or numerical range varies by 1% to 15% of the stated number or numerical range.

[0123] The terms “formulation” and “composition,” as used herein, are interchangeable and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms “formulation” and “composition” may be used to refer to a mixture of one or more activators with a carrier or other excipient.

[0124] The terms “activator,” “active ingredient,” “active drug,” and “drug,” and their variations, are used interchangeably to refer to drugs or substances that have a specific or selected physiological activity that can be measured when administered to a subject in a significant or effective amount. These terms are intended to encompass both parent drugs and prodrugs.

[0125] The terms “effective dose” or “therapeutically effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that reduces, to some extent, one or more of the symptoms of the disease or illness being treated. This may result in a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing a compound as disclosed herein that is necessary to clinically and significantly reduce the disease. The appropriate “effective” dose in any individual case may be determined using techniques such as dose escalation studies.

[0126] It is understood that the substituents and substitution patterns in the compounds of the present invention can be selected by those skilled in the art to provide chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art, by the methods described below. If the substituent itself is substituted with more than one group, it is understood that these groups may be on the same carbon or different carbons, as long as a stable structure is obtained. As used herein, the term “optionally substituted” means replacing one to six hydrogen radicals in a given structure with radicals of specified substituents, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CEh-O-alkyl, -0P(0)(0-alkyl)2, or -CH2-0P(0)(0-alkyl)2. Preferably, “optionally substituted” means replacing one to four hydrogen radicals in a given structure with the substituents described above. More preferably, one to three hydrogen radicals are replaced with the substituents described above. It is understood that these substituents may be further substituted.

[0127] As used herein, “absorption enhancer” refers to a compound that helps the movement of an active ingredient across the epithelial barrier (for example, in drug delivery). Absorption enhancers are functional excipients included in a formulation to improve the absorption of the active ingredient. The term absorption enhancer usually refers to agents that increase absorption by improving membrane penetration rather than by increasing solubility; therefore, such agents may be more specifically called penetration enhancers.

[0128] As used herein, “small molecule drug” refers to an active pharmaceutical ingredient having a molecular weight of less than approximately 1000 grams / mol (g / mol, or daltons / Da). In some embodiments, small molecule drugs have a molecular weight of less than approximately 500 Da. Small molecule drugs (e.g., insulin, aspirin, and antihistamines) constitute about 90% of pharmaceuticals. Small molecule drugs also include biomolecules such as fatty acids, glucose, amino acids, and cholesterol, as well as secondary metabolites such as lipids, glycosides, alkaloids, and natural phenols. Small molecules may include peptide drugs or non-peptide drugs. Small molecules do not include larger molecules such as polysaccharides, proteins, and nucleic acids.

[0129] As used herein, “medium-molecule drugs” refers to active pharmaceutical ingredients having a molecular weight of approximately 500 Da to approximately 50,000 Da. Medium-molecule drugs include biomolecules such as polysaccharides, proteins, and nucleic acids.

[0130] As used herein, the terms “ASO,” “antisense oligomer,” and “antisense oligonucleotide” are used interchangeably and refer to oligomers such as polynucleotides that contain nucleic acid bases that hybridize to a target nucleic acid (e.g., premRNA or mRNA) sequence by Watson-Crick base pairing or fluctuation base pairing (GU).

[0131] As used herein, the term “excipient” refers to an excipient suitable for use in a solid dosage form. The term “excipient” may be used interchangeably with “carrier” when referring to a non-water-soluble polysaccharide or oligosaccharide. The term “excipient” may be used interchangeably with “viscosity agent” when referring to a water-soluble polysaccharide or oligosaccharide. [Examples]

[0132] The following examples are provided to further illustrate some embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Their exemplary nature will make it clear that other procedures, methodologies, or techniques known to those skilled in the art may be used instead.

[0133] Example 1: Preparation of powder composition The following materials were used in the preparation of the powder formulations of the examples, which included active pharmaceutical ingredients, absorption enhancers, and excipients. The active ingredients used were epinephrine, baclofen, levodopa, salmon calcitonin, cyclosporine A, and MALAT-1 ASO:5'- CTA GTTCACTGAA TGC -3' is one example. Absorption enhancers used include lauroylcholine chloride (LCC), palmitoylcholine chloride, myristoylcholine chloride, butyrylcholine iodide, sodium lauryl sulfate, and n-dodecyl-β-d-maltoside. Excipients used include microcrystalline cellulose (e.g., CEOLUS® PH-F20JP and CEOLUS PH-301), chitosan, chitosan II, lactose, respitose sv003, tricalcium phosphate, croscarmellose sodium, and KICCOLATE® ND-200.

[0134] The physical properties of the main excipients were measured. The average primary particle size was measured using a particle size distribution analyzer based on laser diffraction (Mastersizer 3000, Malvern Instruments) at a dispersion pressure of 2 bar.

[0135] Based on the powder property measurement method of the Japanese Pharmacopoeia's general test methods, the volume of each powder preparation with a known mass was measured when placed in a graduated cylinder, and the bulk density was calculated by dividing the mass by the volume.

[0136] Table 1 shows the average particle size and bulk density. MCC-1 is CEOLUS PH-F20JP, and MCC-2 is CEOLUS PH-301. As shown in Table 1, the microcrystalline cellulose (MCC) used in the present invention has an average primary particle size of approximately 15-70 μm and a bulk density of approximately 0.25-0.45 g / cm³. 3 The average primary particle size of MCC is similar to that of lactose. The bulk density of MCC is similar to that of chitosan.

[0137] [Table 1]

[0138] The powder compositions of this disclosure may be prepared by mixing, grinding, stirring granulation, fluid bed granulation, extrusion granulation, or freeze-drying of the components. As shown in Table 2, 13 exemplary compositions (Examples 1-13) and 21 control compositions (Comparative Examples 1-21) were prepared using the following protocols.

[0139] For Examples 1-6 and 8-14, as well as Comparative Examples 7-9, 11, 17, 20, 22, and 23, the active ingredients, absorption enhancers, and excipients were weighed according to the percentage (wt%) of the total weight of each component listed in Table 2. The total weight of each composition was 10 g. To prepare the first stage mixture, the active ingredients, absorption enhancers, and excipients were weighed, placed in a polybag, and pre-mixed. To prepare the second stage mixture, the first stage mixture was mixed for 3 minutes using a mixing granulator (VGmm model, Powrex) at a stirring speed of 800 rpm and a shearing speed of 3000 rpm. To prepare the third stage mixture, the second stage mixture was further mixed while adding 3-7 mL of water over 1 minute, and then mixed for another minute. To prepare the fourth-stage mixture, the third-stage mixture was removed from the granulator, passed through a 1.7 mm mesh screen (JIS Z8801 (manufactured by Tokyo Screen Co., Ltd.)), and then dried at 50°C for more than 2 hours using a low-temperature thermostat (NDO-450SD, manufactured by Tokyo Rikakikai Co., Ltd.). Finally, the fourth-stage mixture was classified by the powder formulation that remained on a 32 μm sieve screen (JIS Z8801, manufactured by Iida Seisakusho) but passed through a 180 μm sieve screen (JIS Z8801, manufactured by Iida Seisakusho).

[0140] For Example 7 and Comparative Example 24, the active ingredients, absorption enhancers, and excipients listed in Table 2 were weighed according to the percentage of the total weight of each ingredient. The total weight of each composition was 120 mg. Powder formulations were prepared by mixing each weighed ingredient with mortar for 5 minutes.

[0141] For Comparative Examples 1 and 3, the active ingredients and absorption enhancers were weighed according to the weight percentage of the total weight of each component listed in Table 2. The total volume of each composition was 1 mL. Liquid formulations were prepared by dissolving each weighed component in 1 mL of buffer solution at pH 4.01 using a vortex mixer and an ultrasonic cleaner.

[0142] For Comparative Example 2, the active ingredient and absorption enhancer were weighed according to the weight percentage of the total weight of each ingredient listed in Table 2. The total volume of the composition was 10 mL. A liquid formulation was prepared by dissolving each weighed ingredient in 10 mL of buffer solution at pH 4.01 using a vortex mixer and an ultrasonic cleaner.

[0143] For Comparative Examples 4-6, the active ingredients and excipients were weighed according to the percentage of the total weight of each ingredient listed in Table 2. The total weight of each composition was 70 mg. Powder formulations were prepared by mixing each weighed ingredient in a bottle for 1 minute using a vortex mixer.

[0144] For Comparative Example 10, the active ingredient and absorption enhancer were weighed according to the percentage of the total weight of each ingredient listed in Table 2. The total weight of the composition was 2 g. A powder formulation was prepared by mixing each weighed ingredient in a bottle for 1 minute using a vortex mixer.

[0145] For Comparative Examples 12-14, the active ingredients and absorption enhancers were weighed according to the weight percentage of the total weight of each ingredient listed in Table 2. The total volume was 1 mL. Liquid formulations were prepared by dissolving each weighed ingredient in 1 mL of physiological saline using a vortex mixer and an ultrasonic cleaner.

[0146] For Comparative Examples 15 and 16, the active ingredients and absorption enhancers were weighed according to the percentage of the total weight of each ingredient listed in Table 2. The total weight of each composition was 90 mg. Powder formulations were prepared by mixing each weighed ingredient in a bottle for 1 minute using a vortex mixer.

[0147] For Comparative Examples 18 and 19, the active ingredient, absorption enhancer, and excipient were weighed according to the percentage of the total weight of each ingredient listed in Table 2. The total weight of each composition was 1 g. Powder formulations were prepared by mixing each weighed ingredient in a bottle for 1 minute using a vortex mixer.

[0148] For Comparative Example 21, the active ingredient, absorption enhancer, and excipient were weighed according to the percentage of the total weight of each component listed in Table 2. The total weight of each composition was 300 g. To prepare the first stage mixture, the active ingredient, absorption enhancer, and excipient were weighed, placed in a poly bag, and pre-mixed. To prepare the second stage mixture, the first stage mixture was mixed for 1 minute at a stirring speed of 400 rpm and a shearing speed of 1500 rpm using a high-speed mixing granulator (FS-GS-5 model, manufactured by Fukae Powtech Co., Ltd.). To prepare the third stage mixture, the second stage mixture was further mixed while adding 250 mL of water over 3 minutes, and then mixed for another minute. To prepare the fourth stage mixture, the third stage mixture was removed from the granulator and dried in a shelf dryer (NDO-450SD, manufactured by Tokyo Rikakikai Co., Ltd.) at 50°C for 2 hours or more. Finally, the fourth-stage mixture remained on a 32 μm sieve screen (JIS Z8801, manufactured by Iida Seisakusho), but was classified by the powder formulation that passed through a 180 μm sieve screen (JIS Z8801, manufactured by Iida Seisakusho).

[0149] [Table 2-1]

[0150] [Table 2-2]

[0151] [Table 2-3]

[0152] [Table 2-4]

[0153] Abbreviations in Table 2: ASO = MALAT-1 antisense oligonucleotide; LCC = Lauroylcholinchloride; PCC = Palmitoylcholinchloride; MyCC, Myristoylcholinchloride; EPI, Epinephrine; LEVO, Levodopa; Cyclo, Cyclosporine; Calci, Calcitonin; BCI, Butyrylcholine iodide; SLS, Sodium lauryl sulfate; DDM, n-Dodecyl-β-D-Maltoside; MCC-1, CEOLUS PH-F20JP; MCC-2, CEOLUS PH-301; TCP, Tricalcium phosphate; CCS, Croscarmellose sodium. Example 2: Evaluation of the absorption of an epinephrine intranasal powder composition in monkeys Table 3 shows the pharmacokinetic profiles of the epinephrine compositions after intranasal administration. Examples 1, 2, 8, and 9 (60 mg), Comparative Examples 7-11, and Comparative Examples 4-6 (7 mg) were each delivered into the right nostril of conscious male cynomolgus monkeys (with an epinephrine dose equivalent to 3 mg) using an intranasal delivery device for powder formulations. The intranasal delivery device comprises a nozzle, a container for the unit dose powder formulation, and an air generating unit (manufactured by Shin Nippon Biomedical Laboratories, Ltd.). Comparative Examples 1-3 (100 μL) were each delivered into the right nostril of conscious male cynomolgus monkeys (with an epinephrine dose equivalent to 3 mg) using a mucosal spray device (MAD).

[0154] [Table 3-1]

[0155] [Table 3-2]

[0156] [Table 3-3]

[0157] [Table 3-4]

[0158] To measure plasma epinephrine concentrations, blood was collected from the femoral vein and placed in a test tube containing EDTA-2K. Plasma epinephrine concentrations were measured by HPLC.

[0159] The plasma epinephrine concentration-time profiles, as well as the corresponding plasma epinephrine concentrations and PK parameters, are shown in Figures 1A to 1F and Table 3, respectively.

[0160] As shown in Figure 1A, the compositions of Comparative Examples 2-6, which contained absorption enhancers (e.g., LCC, SLS, or DDM), showed equivalent or higher epinephrine concentrations compared to the composition without an absorption enhancer (Comparative Example 1). As shown in Figure 1B, the epinephrine compositions of Comparative Examples 7 and 8 contained excipients (MCC or chitosan) but did not contain absorption enhancers. These compositions had equivalent PK profiles compared to the epinephrine composition of Comparative Example 1. As shown in Figure 1C, the compositions of Examples 1 and 2 contained a combination of LCC and MCC, which dramatically increased plasma epinephrine concentrations compared to the use of LCC or MCC alone. The combination of LCC and MCC in the composition has a remarkable synergistic effect on plasma epinephrine concentration. The improvement in absorption of epinephrine compositions containing LCC and MCC (e.g., Examples 1 or 2) is far greater than the combined improvement in absorption of epinephrine compositions containing either LCC or MCC alone (Comparative Examples 2 and 7). Figure 1D shows plasma epinephrine concentrations after administration of liquid formulations containing epinephrine and lauroylcholine chloride (LCC), powder formulations containing epinephrine and chitosan, and powder formulations containing epinephrine, LCC, and chitosan. Figure 1E shows plasma epinephrine concentrations after administration of formulations containing epinephrine and LCC, or formulations containing epinephrine, LCC, and lactose. Figure 1F shows plasma epinephrine concentrations after administration of formulations containing 1) epinephrine, choline ester (e.g., LCC, PCC, or MyCC), and MCC, 2) epinephrine and MCC, or 3) epinephrine, butyrylcholine iodide (BCI), and MCC.

[0161] As shown in Figure 1F, the composition of Comparative Example 11, which had a combination of butyrylcholine (BCI) and MCC, did not increase plasma epinephrine concentration, but the epinephrine composition containing both LCC and MCC showed the greatest improvement in absorption in this example.

[0162] AUC 0-20min and AUC 0-30minThe value indicates the initial absorption rate after administration. As shown in Table 3, the AUC of epinephrine compositions containing both alkanoylcholine (e.g., LCC) and MCC (e.g., Examples 1 and 2) 0-20min and AUC 0-30min This is the AUC of a composition containing MCC but not any alkanoylcholine (Comparative Example 7). 0-20min and AUC 0-30min It was dramatically higher than the previous example. AUC of Example 1 0-30min This is the AUC of Comparative Example 7. 0-30min It was approximately 4.6 times. AUC of Example 1 0-20min This is the AUC of Comparative Example 7. 0-20min It was approximately 6.4 times. AUC of Example 2 0-30min This is the AUC of Comparative Example 7. 0-30min It was approximately 5.2 times. AUC of Example 2 0-20min This is the AUC of Comparative Example 7. 0-20min It was approximately 7.7 times. In some embodiments, LCC is a preferred alkanoylcholine absorption enhancer. Cmax and AUC (AUC) observed at later time points. 0-60min AUC 0-90min Other PK parameters, such as ), are much higher in epinephrine compositions containing both alkanoylcholine (e.g., LCC) and MCC compared to other compositions. In short, alkanoylcholine, when combined with MCC, is an excellent absorption enhancer for epinephrine.

[0163] Example 3: Evaluation of the absorption of baclofen intranasal powder composition in monkeys Table 4 shows the pharmacokinetic profiles of baclofen after intranasal administration of various baclofen compositions. Examples 3, 10, and 11 (60 mg), Comparative Examples 17-20 (60 mg), and Comparative Examples 15 and 16 (9 mg), each (equivalent to a 5 mg dose of baclofen), were delivered into the right nostril of conscious male cynomolgus monkeys using an intranasal delivery device for powder formulations. The device consists of a nozzle, a container for a unit dose of powder formulation, and an air generating unit. Comparative Examples 12-14 (100 μL), each (equivalent to a 5 mg dose of baclofen), were delivered into the right nostril of conscious male cynomolgus monkeys using an MAD device.

[0164] [Table 4-1]

[0165] [Table 4-2]

[0166] [Table 4-3]

[0167] To measure plasma baclofen concentrations, blood was collected from the femoral vein and placed in test tubes containing EDTA-2K. Plasma baclofen concentrations were measured by LC-MS / MS.

[0168] The plasma baclofen concentration-time profiles, as well as the corresponding plasma baclofen concentrations and PK parameters, are shown in Figures 2A to 2E and Table 4, respectively. As shown in Figure 2A, the baclofen compositions of Comparative Examples 13 to 16, which contained absorption enhancers, had higher baclofen concentrations than the composition of Comparative Example 12, which did not contain an enhancer. The absorption enhancers of Comparative Examples 13 to 16 had equivalent effects on absorption enhancement. As shown in Figure 2B, a slight effect of MCC on absorption enhancement was observed in Comparative Example 17. No effect of lactose on absorption enhancement was observed in Comparative Example 18. As shown in Figure 2C, the baclofen compositions of Examples 3, 10, and 11, which had combinations of alkanoylcholine (e.g., LCC, PCC, or MyCC) and MCC, showed a dramatic increase in plasma baclofen concentration. As shown in Figure 2D, the baclofen preparation of Comparative Example 19, which contained LCC and lactose, showed a lower increase in plasma baclofen concentration than the composition containing LCC and MCC. As shown in Figure 2E, the composition containing both SLS and MCC (Comparative Example 20) also showed improved baclofen absorption, albeit to a lower degree than the formulation containing LCC and MCC. The baclofen composition containing both LCC and MCC showed the greatest improvement in absorption in this example.

[0169] As shown in Table 4, the AUC of the baclofen composition containing both alkanoylcholine (e.g., LCC) and MCC was much higher than the AUC of the other compositions that did not contain the combination of alkanoylcholine and MCC. AUC of the composition of Example 3 0-20min and AUC 0-30min These represent the AUC of the composition of Comparative Example 17, respectively. 0-20min and AUC 0-30min These were approximately 5.4 times and 4.4 times Cmax and AUC(AUC) observed at later time points. 0-60min AUC 0-90min AUC 0-240min Other PK parameters, such as ), are much higher in baclofen compositions containing both alkanoylcholine (e.g., LCC) and MCC compared to other compositions.

[0170] Example 4: Evaluation of the absorption of levodopa intranasal powder composition in monkeys

[0171] [Table 5-1]

[0172] [Table 5-2]

[0173] Table 5 shows examples containing levodopa. Using an intranasal delivery device for powder formulations consisting of a nozzle, a container for unit-dose powder formulations, and an air generating unit, 50 mg of Examples 4, 12-14 was delivered into the right nostril of conscious male cynomolgus monkeys [50 mg (equivalent to 20 mg of levodopa) / nostril / body], and 100 mg of Comparative Example 21 was delivered into both nostrils of conscious male cynomolgus monkeys [100 mg (equivalent to 50 mg of levodopa) / both nostrils / body = 50 mg (equivalent to 25 mg of levodopa) / nostril × both nostrils]. To measure plasma levodopa concentration, blood was collected from the femoral vein and placed in a test tube containing EDTA-2K. 25% sodium pyrosulfite solution and plasma were mixed in a volume ratio of 1:50. Plasma levodopa concentration was measured by LC-MS / MS.

[0174] The plasma levodopa concentration-time profiles, as well as the corresponding plasma levodopa concentrations and PK parameters, are shown in Figure 3 and Table 5, respectively. As shown in Figure 3, the levodopa compositions of Examples 4, 12-14, which included a combination of choline esters (e.g., LCC, PCC, or MyCC) and MCC, dramatically increased plasma levodopa concentrations compared to the composition of Comparative Example 21, which contained only MCC. This significant increase in plasma concentration was observed despite the levodopa dose being 20 mg (representing 40% of the administered 50 mg powder composition) in Example 4, compared to 50 mg (50% of the administered 100 mg powder composition) in Comparative Example 21.

[0175] AUC0-20min and AUC 0-30min The value indicates the initial absorption rate after administration. As shown in Table 5, AUC in levodopa compositions containing MCC and LCC. 0-20min and AUC 0-30min This is the AUC of a levodopa composition that does not contain LCC. 0-20min and AUC 0-30min These figures were dramatically higher, at 7.7 times and 6.1 times, respectively, in levodopa compositions containing choline esters PCC and MCC. 0-20min and AUC 0-30min The Cmax and AUC (AUC) observed at later time points were approximately 3.4 times higher than those of the levodopa composition without PCC. 0-60min AUC 0-90min AUC 0-240min , and AUC 0-480min Other PK parameters, such as those mentioned above, are much higher in levodopa compositions containing both alkanoylcholine and MCC compared to those containing MCC alone.

[0176] The levodopa concentration may be measured in the cerebrospinal fluid (CSF) of the subject. The CSF sample may be obtained from the cerebellar-medulla oblongata of an animal (e.g., a cynomolgus monkey) under isoflurane anesthesia. The CSF sample may also be obtained from a human subject by spinal puncture. Similarly, the levodopa concentration in the CSF may be measured by LC-MS / MS.

[0177] Example 5: Evaluation of the absorption of a calcitonin intranasal powder composition in monkeys Table 6 shows examples containing calcitonin. Using an intranasal delivery device for powder formulations, 60 mg of Example 5 and Comparative Example 22 (equivalent to 0.1 mg of calcitonin) were delivered into the right nostril of conscious male cynomolgus monkeys. To measure plasma calcitonin concentration, blood was collected from the femoral vein and placed in a test tube containing EDTA-2K. Plasma calcitonin concentration was measured by ELISA.

[0178] [Table 6]

[0179] The plasma calcitonin concentration-time profiles, as well as the corresponding plasma calcitonin concentrations and PK parameters, are shown in Figure 4 and Table 6, respectively.

[0180] As shown in Figure 4, the calcitonin composition of Example 5, which contained a combination of LCC and MCC, dramatically increased the plasma calcitonin concentration compared to the composition of Comparative Example 22, which contained only MCC.

[0181] As shown in Figure 6, the AUC in Example 5, which consists of calcitonin, LCC, and MCC 0-20min and AUC 0-30min The Cmax and AUC observed at later time points were dramatically higher than in Comparative Example 22, which consisted only of calcitonin and MCC (approximately 2.6 times and 2.3 times higher, respectively). 0-60min AUC 0-90min AUC 0-240min AUC 0-480min Other PK parameters, such as those mentioned above, are significantly higher in calcitonin compositions containing both LCC and MCC compared to other compositions.

[0182] Example 6: Evaluation of the absorption of cyclosporine A intranasal powder composition in monkeys Table 7 shows examples containing cyclosporine A. Using an intranasal delivery device, 60 mg of Example 6 and Comparative Example 23 (equivalent to a 30 mg dose of cyclosporine A) were delivered into the right nostril of conscious male cynomolgus monkeys. To measure plasma cyclosporine A concentrations, blood was collected from the thigh and placed in test tubes containing EDTA-2K. Blood cyclosporine A concentrations were measured by LC-MS / MS.

[0183] [Table 7]

[0184] The plasma cyclosporine A concentration-time profile, as well as the corresponding plasma cyclosporine A concentration and PK parameters, are shown in Figure 5 and Table 7, respectively. As shown in Figure 5, the cyclosporine A composition of Example 6, which contained a combination of LCC and MCC, dramatically increased the plasma cyclosporine A concentration up to 240 minutes after administration compared to Comparative Example 23.

[0185] As shown in Table 7, the AUC in Example 6, which consists of cyclosporine A, LCC, and MCC 0-20min and AUC 0-30min The values ​​were dramatically higher (approximately 11.6 times and 6.9 times, respectively) than in Comparative Example 23, which consisted of cyclosporine A and MCC (without alkanoylcholine). Cmax and AUC (AUC) observed at later time points. 0-60min AUC 0-90min AUC 0-240min AUC 0-480min Other PK parameters, such as those mentioned above, are much higher in cyclosporine A compositions containing both LCC and MCC compared to other compositions.

[0186] Example 7: Evaluation of the absorption of an antisense oligomer intranasal powder composition in monkeys Table 8 shows examples containing antisense oligonucleotides. Using an intranasal delivery device for powder formulations, 70 mg of Example 7 and Comparative Example 24, each containing an antisense oligonucleotide (equivalent to a 23 mg dose of antisense oligonucleotide), were delivered into the right nostril of conscious male cynomolgus monkeys. To measure plasma antisense oligonucleotide concentrations, blood was collected from the femoral vein at different time points and placed in test tubes containing EDTA-2K. Plasma antisense oligonucleotide concentrations were measured by LC-MS / MS.

[0187] [Table 8]

[0188] The plasma antisense oligonucleotide concentration-time profiles, as well as the corresponding plasma calcitonin concentrations and PK parameters, are shown in Figure 6 and Table 8, respectively. As shown in Figure 6, the composition of Example 7, which included a combination of LCC and MCC, dramatically increased plasma antisense oligonucleotide concentrations after administration compared to Comparative Example 24, which contained MCC and TCP.

[0189] As shown in Table 8, the AUC in Example 7, which consists of antisense oligonucleotides, LCCs, MCCs, and TCPs, is 0-30min The value was dramatically higher (2.1 times) than in Comparative Example 24, which consisted of antisense oligonucleotides (without alkanoylcholine), MCC, and TCP. AUC in Example 7 0-20min This was also dramatically higher (2.1 times) than in Comparative Example 24.

[0190] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will now be able to conceive of numerous variations, modifications, and substitutions without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure may be adopted in the practice of the present disclosure. The following claims define the scope of the present disclosure, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed by the following claims.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition is a) Active ingredient or a pharmaceutically acceptable salt thereof b) Absorption enhancers containing choline esters, and c) Excipients containing microcrystalline cellulose Includes, The aforementioned pharmaceutical composition is formulated into a solid dosage form.

2. The aforementioned choline ester is given by formula [(CH ３ ) ３ N ＋ CH ２ CH ２ OR]X － It is expressed as, in the formula, X － The pharmaceutical composition according to claim 1, wherein is a pharmaceutically acceptable counterion.

3. The pharmaceutical composition according to claim 2, wherein X comprises chloride.

4. R is C ２ -C ２０ alkyl, C ２ -C ２０ alkenyl, C ２ -C ２０ alkynyl, and C ２ -C ２０ The pharmaceutical composition according to claim 2, which is selected from the group consisting of heteroalkyl.

5. The choline ester is selected from the group consisting of arachidoylcholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), caproylcholine (C10), and capryloylcholine (C8), and any combination thereof. ８ -C ２０ A pharmaceutical composition according to any one of claims 1 to 4, comprising alkanoylcholine.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the choline ester comprises palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12).

7. A pharmaceutical composition according to any one of claims 1 to 6, further comprising an additional excipient.

8. The pharmaceutical composition according to claim 7, wherein the further excipient comprises chitosan, lactose, croscarmellose sodium, tricalcium phosphate, or any combination thereof.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein, when measured by the pharmacokinetic (PK) parameters of the active ingredient or its metabolite, it has an improved mucosal absorption rate compared to a corresponding pharmaceutical composition that does not contain the absorption enhancer.

10. The pharmaceutical composition according to claim 9, wherein the PK parameter of the active ingredient or its metabolite is improved by at least about 15% compared to the corresponding composition that does not contain the absorption enhancer.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmacokinetic (PK) parameters of the active ingredient or its metabolites are improved by at least about 20%, 50%, 80%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, or 800% compared to the corresponding composition without an absorption enhancer.

12. The pharmaceutical composition according to claim 11, wherein the improvement of the PK parameter includes an improvement in the maximum blood drug concentration (Cmax).

13. The pharmaceutical composition according to claim 11, wherein the improvement of the PK parameter includes shortening the time to reach Cmax (Tmax).

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition has a Tmax of less than 10 minutes or less than 20 minutes.

15. The pharmaceutical composition according to claim 11, wherein the improvement of the PK parameter includes an improvement in bioavailability (F).

16. The pharmaceutical composition according to claim 11, wherein the improvement of the PK parameter includes an increase in the area under the curve (AUC).

17. The aforementioned AUC is AUC ０－１０ｍｉｎ AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－６０ｍｉｎ AUC ０－９０ｍｉｎ AUC ０－１２０ｍｉｎ AUC ０－２４０ｍｉｎ AUC ０－４８０ｍｉｎ The pharmaceutical composition according to claim 16, comprising, or any combination thereof.

18. The pharmaceutical composition according to any one of claims 9 to 17, wherein the improvement in the PK parameter includes an AUC increase of at least about 200%, about 300%, about 400%, about 500%, or about 600% compared to the corresponding pharmaceutical composition without an absorption enhancer.

19. The pharmaceutical composition according to any one of claims 9 to 18, wherein the PK parameter is measured from plasma or cerebrospinal fluid (CSF).

20. The pharmaceutical composition according to any one of claims 9 to 19, wherein the PK parameter is measured by a method comprising high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MSI), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), or any combination thereof.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the excipient is present in an amount of at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, or at least about 70 mg.

22. A pharmaceutical composition according to any one of claims 1 to 21, comprising approximately 10 mg to approximately 60 mg of the excipient.

23. A pharmaceutical composition according to any one of claims 1 to 22, comprising at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, and at least about 80% by weight of the excipients.

24. A pharmaceutical composition according to any one of claims 1 to 23, comprising approximately 40% to approximately 65% ​​by weight of the excipient.

25. A pharmaceutical composition according to any one of claims 1 to 23, comprising approximately 70% to approximately 95% by weight of the excipient.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the microcrystalline cellulose has an average particle size of about 10 μm to about 100 μm.

27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the microcrystalline cellulose is present in an amount of about 40% of the total weight of the pharmaceutical composition.

28. The pharmaceutical composition according to any one of claims 1 to 26, wherein the microcrystalline cellulose is present in an amount of about 90% of the total weight of the pharmaceutical composition.

29. The pharmaceutical composition according to any one of claims 1 to 28, further comprising a further excipient, wherein the further excipient comprises croscarmellose sodium or tricalcium phosphate.

30. The pharmaceutical composition according to any one of claims 1 to 29, wherein the active ingredient comprises a peptide.

31. The pharmaceutical composition according to claim 30, wherein the peptide comprises a dipeptide, a tripeptide, an oligopeptide, a polypeptide, or a cyclic peptide.

32. The pharmaceutical composition according to any one of claims 1 to 29, wherein the active ingredient includes a small molecule drug.

33. The pharmaceutical composition according to any one of claims 1 to 29, wherein the active ingredient comprises a nucleic acid molecule.

34. The pharmaceutical composition according to claim 33, wherein the nucleic acid molecule comprises an antisense oligonucleotide.

35. The pharmaceutical composition according to any one of claims 1 to 30, wherein the active ingredient comprises a medium-molecule drug.

36. The pharmaceutical composition according to any one of claims 1 to 35, wherein the active ingredient comprises epinephrine, baclofen, levodopa, calcitonin, cyclosporine A, antisense oligonucleotide, or any combination thereof.

37. The pharmaceutical composition according to claim 36, wherein the active ingredient comprises epinephrine or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition according to claim 36, wherein the active ingredient comprises baclofen or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition according to claim 36, wherein the active ingredient comprises levodopa or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition according to claim 36, wherein the active ingredient comprises calcitonin or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition according to claim 36, wherein the active ingredient comprises cyclosporine A or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition according to any one of claims 1 to 39, wherein the active ingredient or a pharmaceutically acceptable salt thereof is amorphous.

43. The pharmaceutical composition according to any one of claims 1 to 39, wherein the active ingredient or a pharmaceutically acceptable salt thereof is crystalline.

44. A pharmaceutical composition according to any one of claims 1 to 43, comprising approximately 0.05 mg to approximately 30 mg of the active ingredient.

45. A pharmaceutical composition according to any one of claims 1 to 44, comprising a weight ratio of the absorption enhancer to the microcrystalline cellulose of approximately 1:1 to approximately 1:

100.

46. The pharmaceutical composition according to claim 45, comprising a weight ratio of the absorption enhancer to the microcrystalline cellulose of approximately 1:3 to approximately 1:

15.

47. A pharmaceutical composition according to any one of claims 1 to 46, comprising approximately 0.2 mg to approximately 20 mg of the absorption enhancer.

48. The pharmaceutical composition according to claim 47, comprising approximately 1.5 mg to approximately 10 mg of the absorption enhancer.

49. A pharmaceutical composition according to any one of claims 1 to 46, comprising at least about 0.2 mg, at least about 0.5 mg, at least about 1 mg, at least about 1.25 mg, at least about 1.5 mg, at least about 2 mg, at least about 2.5 mg, at least about 3 mg, at least about 3.5 mg, at least about 4 mg, at least about 4.5 mg, or at least about 5 mg of the absorption enhancer.

50. The pharmaceutical composition according to any one of claims 1 to 46, wherein the absorption enhancer is present in an amount of about 1% to about 20% of the total weight of the pharmaceutical composition.

51. The pharmaceutical composition according to claim 50, wherein the absorption enhancer is present in an amount of about 6% to about 15% of the total weight of the pharmaceutical composition.

52. The pharmaceutical composition according to any one of claims 1 to 51, wherein the unit dose of the pharmaceutical composition is about 20 mg to about 250 mg by weight.

53. The pharmaceutical composition according to claim 51, wherein the unit dose of the pharmaceutical composition is about 20 mg to about 80 mg by weight.

54. The pharmaceutical composition according to claim 51, wherein the unit dose of the pharmaceutical composition is approximately 60 mg by weight.

55. The pharmaceutical composition according to claim 51, wherein the unit dose of the pharmaceutical composition is approximately 80 mg by weight.

56. The pharmaceutical composition according to claim 37, comprising about 1 to 5 mg of epinephrine or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of the choline ester, and about 51 to 55 mg of the microcrystalline cellulose.

57. The pharmaceutical composition according to claim 56, wherein the choline ester is lauroylcholine chloride.

58. The pharmaceutical composition according to claim 56, wherein the Cmax of epinephrine or its metabolite is at least about 150%, 250%, 350%, 450%, 550%, or 600% higher than the corresponding pharmaceutical composition that does not contain the choline ester.

59. The pharmaceutical composition according to any one of claims 56 to 58, wherein the area under the curve (AUC) of epinephrine or its metabolites is at least about 200%, 300%, 400%, 500%, 600%, 700%, or 750% higher than the corresponding pharmaceutical composition that does not contain the choline ester.

60. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－６０ｍｉｎ AUC ０－９０ｍｉｎ AUC ０－１２０ｍｉｎ The pharmaceutical composition according to claim 59, comprising, or any combination thereof.

61. The pharmaceutical composition according to claim 38, comprising about 3 to 7 mg of baclofen or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of the choline ester, and about 49 to 53 mg of the microcrystalline cellulose.

62. The pharmaceutical composition according to claim 61, wherein the choline ester is lauroylcholine chloride.

63. The pharmaceutical composition according to claim 61, wherein the Cmax of baclofen or its metabolite is at least about 200%, 300%, or 400% higher than that of a corresponding pharmaceutical composition that does not contain choline esters.

64. The pharmaceutical composition according to any one of claims 61 to 63, wherein the AUC of baclofen or its metabolites is at least about 200%, 300%, 400%, or 500% higher than that of a corresponding pharmaceutical composition that does not contain choline esters.

65. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ , or AUC ０－２４０ｍｉｎ The pharmaceutical composition according to claim 64, comprising, or any combination thereof.

66. The pharmaceutical composition according to claim 39, comprising about 18 to 28 mg of the levodopa or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of the choline ester, and about 20 to 50 mg of the microcrystalline cellulose.

67. The pharmaceutical composition according to claim 39, comprising about 18 to 28 mg of levodopa or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of the choline ester, about 20 to 50 mg of the microcrystalline cellulose, and optionally about 1 to 3 mg of croscarmellose sodium.

68. The pharmaceutical composition according to claim 67, wherein the choline ester is lauroylcholine chloride.

69. The pharmaceutical composition according to claim 67, wherein the Cmax of levodopa or its metabolite is at least about 300%, 400%, 500%, or 600% higher than that of the corresponding pharmaceutical composition that does not contain the choline ester.

70. The pharmaceutical composition according to claim 67, wherein the AUC of the levodopa or its metabolite is at least about 300%, 400%, 500%, or 600% higher than that of the corresponding pharmaceutical composition that does not contain the choline ester.

71. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－６０ｍｉｎ The pharmaceutical composition according to claim 70, comprising, or any combination thereof.

72. The pharmaceutical composition according to claim 40, comprising about 0.1 to 0.2 mg of the calcitonin or a pharmaceutically acceptable salt thereof, about 2 to 6 mg of the choline ester, and about 54 to 57 mg of the microcrystalline cellulose.

73. The pharmaceutical composition according to claim 72, wherein the choline ester is lauroylcholine chloride.

74. The pharmaceutical composition according to claim 72, wherein the Cmax of the calcitonin or its metabolite is at least about 250% higher than that of the corresponding pharmaceutical composition that does not contain the choline ester.

75. The pharmaceutical composition according to claim 72, wherein the AUC of the calcitonin or its metabolites is at least about 100%, 150%, 200%, 250%, or 300% higher than the corresponding pharmaceutical composition that does not contain the choline ester.

76. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－１２０ｍｉｎ The pharmaceutical composition according to claim 75, comprising, or any combination thereof.

77. The pharmaceutical composition according to claim 41, comprising approximately 28 to 32 mg of cyclosporine A or a pharmaceutically acceptable salt thereof, approximately 2 to 6 mg of the choline ester, and approximately 24 to 28 mg of the microcrystalline cellulose.

78. The pharmaceutical composition according to claim 77, wherein the choline ester is lauroylcholine chloride.

79. The pharmaceutical composition according to claim 77, wherein the AUC of cyclosporine A or its metabolites is at least about 600%, 700%, 800%, or 900% higher than that of the corresponding pharmaceutical composition that does not contain the choline ester.

80. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－４８０ｍｉｎ The pharmaceutical composition according to claim 79, comprising, or any combination thereof.

81. The pharmaceutical composition according to claim 34, comprising approximately 20 to 25 mg of the antisense oligonucleotide, approximately 7 to 10 mg of the choline ester, approximately 32 to 38 mg of the microcrystalline cellulose, and approximately 0.3 to 0.6 mg of tricalcium phosphate.

82. The pharmaceutical composition according to claim 81, wherein the Cmax of the nucleic acid molecule is at least about 150% higher than that of the corresponding pharmaceutical composition that does not contain the choline ester.

83. The pharmaceutical composition according to claim 81, wherein the AUC of the nucleic acid molecule is at least about 200% higher than that of the corresponding composition that does not contain the choline ester.

84. The aforementioned AUC is AUC ０－２０ｍｉｎ AUC ０－３０ｍｉｎ AUC ０－６０ｍｉｎ AUC ０－４８０ｍｉｎ The pharmaceutical composition according to claim 83, comprising, or any combination thereof.

85. The pharmaceutical composition according to any one of claims 1 to 84, which is formulated for mucosal administration.

86. The pharmaceutical composition according to any one of claims 1 to 85, wherein mucosal administration includes buccal administration, sublingual administration, oral administration, ocular administration, intranasal administration, rectal administration, or vaginal administration.

87. The pharmaceutical composition according to claim 86, wherein the pharmaceutical composition is formulated for intranasal administration.

88. The pharmaceutical composition according to any one of claims 1 to 87, wherein the solid dosage form includes a powder, a tablet, a patch, or a capsule.

89. The pharmaceutical composition according to claim 88, wherein the solid dosage form includes a powder dosage form.

90. A pharmaceutical composition according to any one of claims 1 to 89, for use in the prevention, diagnosis, or treatment of central nervous system diseases.

91. A pharmaceutical composition according to any one of claims 1 to 89, for use in preoperative or pre-examination procedures related to central nervous system diseases.

92. A pharmaceutical composition according to any one of claims 1 to 89, for use in the prevention, diagnosis, or treatment of a systemic disease.

93. A pharmaceutical composition according to any one of claims 1 to 89, for use in the prevention, diagnosis, or treatment of infectious diseases.

94. A method for treating a disorder in a subject requiring treatment, the method comprising administering a pharmaceutical composition according to any one of claims 1 to 93 to the subject.

95. The method according to claim 94, wherein the disorder includes a central nervous system (CNS) disorder.

96. The method according to claim 95, wherein the CNS disorder includes cerebral hemorrhage, cerebral infarction, central nervous system infection, brain tumor, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Lewy body dementia, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia, multiple sclerosis, schizophrenia, depression, bipolar disorder, dysthymia, adjustment disorder, anxiety disorder, agitation, panic disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, sleep disorder, insomnia, traumatic brain injury, glioma, pain, migraine, or any combination thereof.

97. The method according to claim 94, wherein the disorder includes a systemic disorder.

98. The method according to claim 97, wherein the systemic disorder includes anaphylaxis, fever, pain, inflammation, rheumatism, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory and metabolic disorders, muscle tone disorders, autonomic neuropathy, dizziness, migraine, hypertension, angina pectoris, arrhythmia, cardiovascular disease, allergy, asthma, bronchospasm, respiratory disease, peptic ulcer, gastrointestinal disorder, diarrhea, indigestion, gout, hyperuricemia, dyslipidemia, diabetes, hormonal disorders, pituitary hormone disorders, corticosteroid disorders, sex hormone disorders, uterine-related diseases, osteoporosis, bone metabolic diseases, obesity, vitamin deficiencies, malnutrition, poisoning, cancer, hyperimmunity, autoimmune disorders, ear, nose, and throat-related diseases, oral-related diseases, urinary / genitourinary diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related diseases, drug addiction, lifestyle-related diseases, or any combination thereof.

99. The method according to claim 94, wherein the disorder includes Parkinson's disease, pain, migraine, anaphylaxis, epilepsy, anxiety, restlessness, obesity, glioma, or Alzheimer's disease.

100. The method according to any one of claims 94 to 99, wherein the subject includes humans or non-human primates.

101. The method according to any one of claims 94 to 100, wherein the pharmaceutical composition is administered intranasally to the subject.

102. A method for improving the absorption rate of an active ingredient or a pharmaceutically acceptable salt thereof, comprising administering the pharmaceutical composition described in any one of claims 1 to 93 to a subject.

103. The method according to claim 102, wherein the administration includes intranasal administration.

104. A method for preparing a pharmaceutical composition according to any one of claims 1 to 93, comprising granulating a mixture of the active ingredient of the pharmaceutical composition according to any one of claims 1 to 93 and the absorption enhancer.

105. A method for treating a disease or illness in a subject requiring treatment, the method comprising administering a pharmaceutical composition to the subject, The pharmaceutical composition comprises an activator for treating Parkinson's disease and an absorption enhancer containing a choline ester, and the method thereof.

106. The method according to claim 105, further comprising microcrystalline cellulose in the pharmaceutical composition.

107. The method according to claim 105, wherein the pharmaceutical composition is in solid dosage form.

108. The method according to claim 107, wherein the solid dosage form is a powder.

109. The method according to claim 105, wherein the administration includes intranasal administration.

110. The method according to claim 105, wherein the disease or illness includes Parkinson's disease.

111. The method according to claim 105, wherein the activator for treating Parkinson's disease comprises levodopa.

112. By administering the above, T10 minutes less than 20 minutes ｍａｘ The method according to any one of claims 105 to 111, wherein the result is obtained.

113. By administering the above, T15 minutes less than 15 minutes ｍａｘ The method according to claim 112, wherein the result is obtained.

114. By administering it, T10 minutes less ｍａｘ The method according to claim 112, wherein the result is obtained.

115. The method according to any one of claims 105 to 111, wherein the administration results in an AUC exceeding 12,000 ng × min / mL.

116. By administering the above, at least 300 ng / mL of C is obtained. ｍａｘ The method according to any one of claims 105 to 111, wherein the result is obtained.

117. By administering the above, at least 500 ng / mL of C is obtained. ｍａｘ The method according to any one of claims 105 to 111, wherein the result is obtained.

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