Compositions for enhancing mucosal penetration

Abstract

Provided herein are compositions and methods relating to solid dosage forms comprising an absorption enhancer. The composition enhances mucosal penetration and absorption of the active ingredient.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 505,344, filed May 31, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Drug delivery via mucosal surfaces (including the airways, gastrointestinal tract (GI), and reproductive tract) offers a desirable route of administration for a wide range of drugs. Mucosal surfaces are typically highly vascularized and can bypass first-pass metabolism in the gastrointestinal tract and liver. Furthermore, mucosal delivery allows for a faster onset of action compared to oral administration. Mucosal delivery is a superior option for achieving rapid and efficient systemic absorption of drugs, especially crucial for medications requiring rapid therapeutic action. Summary of the Invention

[0003] Mucosal administration offers an alternative to the invasive and often painful delivery method of injection, and can improve drug delivery to the brain by helping to overcome challenges associated with crossing the blood-brain barrier. Despite recent advances in pharmaceutical science, developing formulations with enhanced mucosal penetration or absorption remains challenging. For example, many nasal formulations face challenges related to solubility, mucosal adhesion, and mucosal penetration (to name just a few). Therefore, there is a need to develop novel formulations for nasal administration.

[0004] In some aspects, this disclosure provides a pharmaceutical composition comprising: a) an active ingredient or a pharmaceutically acceptable salt thereof; b) an absorption enhancer comprising choline esters; and c) an excipient comprising microcrystalline cellulose; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, the choline ester is of the formula [(CH3)3N+CH2CH2OR]X - The expression indicates that X is a pharmaceutically acceptable counterion. In some embodiments, X comprises chloride. In some embodiments, R is selected from C2-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, and C2-C20 heteroalkyl. In some embodiments, the choline ester comprises C8 to C20 alkylylcholine selected from: arachidocholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), hexanoylcholine (C10), and capryloylcholine (C8) and any combination thereof. In some embodiments, the choline ester comprises palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12). In some embodiments, the pharmaceutical composition further comprises additional excipients. In some implementations, additional excipients include chitosan, lactose, croscarmellose sodium, tricalcium phosphate, or any combination thereof.

[0005] In some embodiments, the pharmaceutical composition has improved mucosal absorption compared to a corresponding pharmaceutical composition that does not contain an absorption enhancer, the improved mucosal absorption being measured by pharmacokinetic (PK) parameters of the active ingredient or its metabolite. In some embodiments, the PK parameters of the active ingredient or its metabolite are improved by at least about 15% compared to a corresponding composition that does not contain an absorption enhancer. In some embodiments, the pharmacokinetic (PK) parameters of the active ingredient or its metabolite 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 that does not contain an absorption enhancer. In some embodiments, the improved PK parameters include a higher maximum plasma concentration (Cmax). In some embodiments, the improved PK parameters include a shorter 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, improved PK parameters include higher bioavailability (F). In some embodiments, improved PK parameters include a larger area under the curve (AUC). In some embodiments, AUC includes AUC0. 0-10min AUC 0-20min AUC 0-30min AUC 0-60min AUC 0-90min AUC 0-120min AUC 0-240min AUC 0-480min Or any combination thereof. In some embodiments, the improved PK parameter compared to a corresponding pharmaceutical composition not containing an absorption enhancer includes an increase in AUC of at least about 200%, about 300%, about 400%, about 500%, or about 600%. 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-MS), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), or any combination thereof.

[0006] In some embodiments, the excipient is present in amounts 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 comprises about 10 mg to about 60 mg of excipient. In some embodiments, the pharmaceutical composition comprises at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% of excipient by weight. In some embodiments, the pharmaceutical composition comprises about 40% to about 65% of excipient by weight. In some embodiments, the pharmaceutical composition comprises about 70% to about 95% of excipient by weight. In some embodiments, the microcrystalline cellulose has an average particle size of about 10 μm to about 100 μm. In some embodiments, microcrystalline cellulose is present at approximately 40% of the total weight of the pharmaceutical composition. In some embodiments, microcrystalline cellulose is present at approximately 90% of the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises additional excipients, wherein the additional excipients include croscarmellose sodium or tricalcium phosphate.

[0007] In some embodiments, the active ingredient includes a peptide. In some embodiments, the peptide includes a dipeptide, tripeptide, oligopeptide, polypeptide, or cyclic peptide. In some embodiments, the active ingredient includes a small molecule drug. In some embodiments, the active ingredient includes a nucleic acid molecule. In some embodiments, the nucleic acid molecule includes an antisense oligonucleotide. In some embodiments, the active ingredient includes a medium molecule drug. In some embodiments, the active ingredient includes epinephrine, baclofen, levodopa, calcitonin, cyclosporine A, an antisense oligonucleotide, or any combination thereof. In some embodiments, the active ingredient includes 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 comprises about 0.05 mg to about 30 mg of the active ingredient. In some embodiments, the pharmaceutical composition comprises an absorption enhancer and microcrystalline cellulose in a weight ratio of about 1:1 to about 1:100. In some embodiments, the pharmaceutical composition comprises an absorption enhancer and microcrystalline cellulose in a weight ratio of about 1:3 to about 1:15. In some embodiments, the pharmaceutical composition comprises about 0.2 mg to about 20 mg of the absorption enhancer. In some embodiments, the pharmaceutical composition comprises about 1.5 mg to about 10 mg of the absorption enhancer. In some embodiments, the pharmaceutical composition comprises 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. In some embodiments, the unit dose of the pharmaceutical composition is about 20 mg to about 80 mg. In some embodiments, the unit dose of the pharmaceutical composition is about 60 mg. In some embodiments, the unit dose of the pharmaceutical composition is about 80 mg.

[0011] In some embodiments, the pharmaceutical composition comprises about 1-5 mg of adrenaline 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 Cmax of the adrenaline or its metabolite in the pharmaceutical composition is at least about 150%, 250%, 350%, 450%, 550%, or 600% higher than that of a corresponding pharmaceutical composition not containing said choline ester. In some embodiments, the area under the curve (AUC) of the adrenaline or its metabolite in the pharmaceutical composition is at least about 200%, 300%, 400%, 500%, 600%, 700%, or 750% higher than that of a corresponding pharmaceutical composition not containing said choline ester. In some embodiments, AUC includes AUC 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 Cmax of baclofen or its metabolite in the pharmaceutical composition is at least about 200%, 300%, or 400% higher than that of a corresponding pharmaceutical composition not containing choline ester. In some embodiments, the AUC of baclofen or its metabolite in the pharmaceutical composition is at least about 200%, 300%, 400%, or 500% higher than that of a corresponding pharmaceutical composition not containing choline ester. In some embodiments, AUC includes AUC0.05. 0-20min AUC 0-30min or AUC 0-240min Or any combination thereof.

[0013] In some embodiments, the pharmaceutical composition comprises about 18-28 mg of levodopa or a pharmaceutically acceptable salt thereof, about 2-6 mg of cholinesterase, and about 20-50 mg of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 18-28 mg of levodopa or a pharmaceutically acceptable salt thereof, about 2-6 mg of cholinesterase, about 20-50 mg of microcrystalline cellulose, and optionally about 1-3 mg of croscarmellose sodium. In some embodiments, the cholinesterase is lauroylcholine chloride. In some embodiments, the Cmax of levodopa or its metabolite in the pharmaceutical composition is at least about 300%, 400%, 500%, or 600% higher than that of a corresponding pharmaceutical composition not containing cholinesterase. In some embodiments, the AUC of levodopa or its metabolite in the pharmaceutical composition is at least about 300%, 400%, 500%, or 600% higher than that of a corresponding pharmaceutical composition not containing cholinesterase. In some embodiments, AUC includes AUC 0-20min AUC 0-30min AUC 0-60min , or any combination thereof.

[0014] In some embodiments, the pharmaceutical composition comprises about 0.1-0.2 mg of calcitonin or a pharmaceutically acceptable salt thereof, about 2-6 mg of cholinesterase, and about 54-57 mg of microcrystalline cellulose. In some embodiments, the cholinesterase is lauroylcholine chloride. In some embodiments, the Cmax of calcitonin or its metabolite in the pharmaceutical composition is at least about 250% higher than that of a corresponding pharmaceutical composition not containing cholinesterase. In some embodiments, the AUC of calcitonin or its metabolite in the pharmaceutical composition is at least about 100%, 150%, 200%, 250%, or 300% higher than that of a corresponding pharmaceutical composition not containing cholinesterase. In some embodiments, AUC includes AUC0-20min 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 lauroyl choline chloride. In some embodiments, the AUC of cyclosporine A or its metabolite in the pharmaceutical composition is at least about 600%, 700%, 800%, or 900% higher than that of a corresponding pharmaceutical composition not containing choline ester. In some embodiments, the AUC includes AUC0.05. 0-20min AUC 0-30min AUC 0-480min , or any combination thereof.

[0016] In some embodiments, the pharmaceutical composition comprises about 20-25 mg of antisense oligonucleotide, about 7-10 mg of cholinesterol, about 32-38 mg of microcrystalline cellulose, and about 0.3-0.6 mg of tricalcium phosphate. In some embodiments, the Cmax of the nucleic acid molecule in the pharmaceutical composition is at least about 150% higher than that of a corresponding pharmaceutical composition not containing cholinesterol. In some embodiments, the AUC of the nucleic acid molecule in the pharmaceutical composition is at least about 200% higher than that of a corresponding composition not containing cholinesterol. In some embodiments, AUC includes AUC0.05. 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 a powder, tablet, patch, or capsule. In some embodiments, the solid dosage form includes a powder.

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

[0019] Another aspect of this disclosure includes a method of treating a condition in a subject in need, the method comprising administering a pharmaceutical composition provided herein to the subject. In some embodiments, the condition includes a central nervous system (CNS) condition. In some implementation schemes, CNS conditions include cerebral hemorrhage, cerebral infarction, infections of the central nervous system, 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, and anxiety. Disorders, agitation, panic disorder, obsessive-compulsive disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, sleep disorder, insomnia, traumatic brain injury.Injury, glioma, pain, migraine, or any combination thereof. In some implementations, the condition includes systemic symptoms. In some implementation schemes, systemic symptoms include anaphylaxis, defervescence, pain, inflammation, rheumatism, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory metabolic disorder, muscle tone disorder, autonomic neuropathy, dizziness, migraine, hypertension, angina, arrhythmia, cardiovascular diseases, allergies, asthma, bronchoconstriction, respiratory diseases, peptic ulcer, and gastrointestinal disorders. Disorders, diarrhea, indigestion, gout, hyperuricemia, dyslipidemia, diabetes, hormonal disorders, pituitary hormone disorder, corticosteroid disorder, sex hormone disorder, uterine-related diseases, osteoporosis, bone metabolism disordersDiseases, including obesity, vitamin deficiency, malnutrition, poisoning, cancer, hyperimmunity, autoimmune disorders, otolaryngology-related diseases, mouth-related diseases, urinary / genital diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related diseases, narcotic dependence, lifestyle-related diseases, or any combination thereof. In some embodiments, the conditions include Parkinson's disease, pain, migraine, allergic reactions, 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 to the subject via intranasal administration.

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

[0021] Another aspect of this disclosure provides a method for preparing the 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 condition in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an active agent for treating Parkinson's disease and an absorption enhancer, the absorption enhancer comprising choline esters. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition is a solid dosage form. In some embodiments, the solid dosage form is a powder. In some embodiments, the administration comprises intranasal administration. In some embodiments, the disease or condition includes Parkinson's disease. In some embodiments, the active agent for treating Parkinson's disease includes levodopa. In some embodiments, the administration produces T... maxLess than 20 minutes. In some implementations, the generated T is applied. max Less than 15 minutes. In some implementations, the generated T is applied. max Less than 10 minutes. In some embodiments, the AUC produced by administration is greater than 12000 ng x min / mL. In some embodiments, the C... max The concentration is at least 300 ng / mL. In some embodiments, the generated C is applied. max The concentration should be at least 500 ng / mL. Incorporation

[0023] All publications, patents and patent applications mentioned in this specification are incorporated by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Attached Figure Description

[0024] The novel features of this disclosure are 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 illustrate embodiments utilizing the principles of this disclosure, in which: Figures 1A to 1F Plasma adrenaline concentration-time curves were plotted after intranasal administration of various adrenaline preparations. Figure 1A The study showed plasma epinephrine concentrations after intranasal administration of formulations containing epinephrine alone or in combination with an absorption enhancer. Figure 1B The study showed plasma epinephrine concentrations after intranasal administration of formulations containing epinephrine alone or in combination with excipients. Figure 1C The study showed plasma epinephrine concentrations following intranasal administration of a formulation containing epinephrine, an absorption enhancer, and an excipient, or containing epinephrine and an absorption enhancer or an excipient. Figure 1D Plasma epinephrine concentrations after administration of the following formulations are shown: liquid formulations containing epinephrine and lauroyl choline chloride (LCC), powder formulations containing epinephrine and chitosan, and powder formulations containing epinephrine, LCC, and chitosan. Figure 1E The study showed plasma adrenaline concentrations after administration of a formulation containing adrenaline and LCC, or a formulation containing adrenaline, LCC, and lactose. Figure 1F The plasma epinephrine concentrations following administration of formulations containing the following substances are shown: 1) epinephrine, choline esters (e.g., LCC, PCC, or MyCC) and MCC; 2) epinephrine and MCC; or 3) epinephrine, butyryl iodinated choline (BCI) and MCC.

[0025] Figures 2A to 2E The plasma baclofen concentration-time curves after intranasal administration of baclofen were plotted. Figure 2A The plasma baclofen concentrations after intranasal administration of Comparative Examples 12-16 are shown. Comparative Example 12 is a liquid baclofen formulation without an absorption enhancer or MCC. Comparative Examples 13-16 are liquid or powder formulations containing baclofen and an absorption enhancer. Figure 2B The plasma baclofen concentrations were shown after intranasal administration of formulations containing baclofen alone, baclofen and MCC, or baclofen and lactose. Figure 2C The plasma baclofen concentrations after administration of different baclofen formulations are shown (e.g., baclofen formulations containing both an absorption enhancer and an excipient (e.g., MCC), and baclofen formulations containing either an absorption enhancer or MCC). Figure 2D The plasma baclofen concentrations were shown after intranasal administration of a baclofen formulation containing both an absorption enhancer (e.g., LCC) and an excipient (e.g., lactose), or containing either LCC or lactose. Figure 2E The plasma baclofen concentrations following intranasal administration of formulations containing baclofen and an absorption enhancer, baclofen and an excipient, or baclofen, an absorption enhancer, and an excipient are shown.

[0026] Figure 3 Plasma levodopa concentration-time curves were depicted after intranasal administration of various levodopa formulations (e.g., levodopa compositions containing absorption enhancers and excipients, or levodopa compositions containing excipients but without absorption enhancers).

[0027] Figure 4 Plasma calcitonin concentration-time curves were depicted after intranasal administration of various calcitonin formulations (e.g., calcitonin compositions containing absorption enhancers and excipients, or calcitonin compositions containing excipients but without absorption enhancers).

[0028] Figure 5 Blood cyclosporine A concentration-time curves were plotted after intranasal administration of various cyclosporine formulations (e.g., cyclosporine compositions containing absorption enhancers and excipients, or cyclosporine compositions containing excipients but without absorption enhancers).

[0029] Figure 6 Plasma antisense oligonucleotide concentration-time curves were depicted after intranasal administration of two antisense oligonucleotide formulations (e.g., an antisense oligonucleotide composition containing antisense oligonucleotide (ASO), an absorption enhancer, and an excipient, or an antisense oligonucleotide composition containing ASO and an excipient but without an absorption enhancer). Detailed Implementation

[0030] Drug delivery via mucosal surfaces (including the airways, gastrointestinal tract (GI), and genital tract) is an alternative to invasive delivery via injection. Mucosal application offers several advantages, such as reduced manufacturing and administration costs; potentially improved patient compliance—especially for those with a fear of needles; and reduced risk of infection. Furthermore, mucosal drug delivery via the nose, lungs, mouth, and genital tract can help bypass first-pass metabolism in the liver. Mucosal surfaces are generally highly vascularized and easily accessible; however, drug delivery can be hindered by mucus—a complex viscoelastic gel covering much of the body's soft tissue. The mucus layer contains a large amount of mucin (polymeric proteins densely decorated with negatively charged glycosaminoglycans), forming a highly entangled network with glycoproteins, lipids, and DNA. This network can prevent pathogen invasion but may also hinder the rapid and adequate absorption of therapeutic agents. This slow absorption can prolong the time it takes for a subject to benefit from drugs administered via mucosal surfaces. Therefore, there is a need for mucosal compositions that can help overcome problems associated with absorption barriers.

[0031] In some embodiments, this document provides pharmaceutical compositions and methods relating to solid dosage forms having improved mucosal penetration and / or absorption of an active ingredient. In some embodiments, the composition comprises an active ingredient or a pharmaceutically acceptable salt thereof and an absorption enhancer, wherein the absorption enhancer comprises 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 alkylcholines of various chain lengths. Alkylcholines may comprise 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 dicofylphosphatidylcholine, lysolauroylphosphatidylcholine, dicoctanoylphosphatidylcholine, diclauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0032] Absorption enhancer In some respects, pharmaceutical compositions contain absorption enhancers. Absorption enhancers can be compounds that enhance the absorption of the active ingredient. The term absorption enhancer can refer to an agent whose function is to improve absorption by enhancing membrane permeability rather than by increasing solubility. Therefore, absorption enhancers are sometimes also called permeation enhancers.

[0033] Absorption enhancers can improve the mucosal penetration and / or absorption of active ingredients via mucous membranes, such as those present in the nasal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa, ocular mucosa, pulmonary mucosa, or vaginal mucosa. In some embodiments, absorption enhancers improve the mucosal penetration and / or absorption of the active ingredient via the nasal mucosa. In some embodiments, absorption enhancers increase the mucosal absorption rate. In some embodiments, absorption enhancers improve potency, time to onset of action, half-life, or the amount of active ingredient absorbed via the mucosa.

[0034] In some implementations, the absorption enhancer includes a group of compounds such as fatty acids, choline esters, surfactants, chelating agents, sugars, or any combination thereof.

[0035] In some embodiments, the absorption enhancer comprises choline esters or pharmaceutically acceptable salts thereof. Choline esters or pharmaceutically acceptable salts thereof include those having the formula [(CH3)3N] ＋ Choline esters of [CH2CH2OR]X, wherein X is a pharmaceutically acceptable counterion, such as chloride, sulfate, nitrate, perchlorate, bromide, iodide, phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate, lactate, maleate, fumarate, benzenesulfonate, camphorsulfonate, ethanesulfonate, gluconate, methanesulfonate, naphthalenesulfonate, etc.; and wherein R is an acyl group. In some embodiments, the acyl group is derived from a carboxylic acid. In some embodiments, the acyl group includes C2-C... 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C2-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, aryl, heteroaryl, or any combination thereof. In some embodiments, the acyl group is selected from C2-C. 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C2-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, aryl, heteroaryl, or 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 dicofylphosphatidylcholine, lysolauroylphosphatidylcholine, dicoctanoylphosphatidylcholine, diclauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not derived from phosphatidic acid. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0036] In some embodiments, choline esters are derived from carboxylic acids. In some embodiments, choline esters contain an acyl group derived from the carboxylic acid, wherein the acyl group comprises C2-C... 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C2-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, aryl, heteroaryl, or any combination thereof. In some embodiments, the choline ester comprises a group selected from the following: C2-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl group, C2-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, aryl, heteroaryl, or any combination thereof. In some embodiments, the choline ester comprises C2-C... 20 Alkyl, the C2-C 20 The alkyl group is selected from alkyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, or stearyl. In some embodiments, the choline ester comprises a C2-C bond containing one or more double bonds. 20 alkenyl, the C2-C 20 Alkenyl groups include 2-hexenoyl, 9-decenoyl, 9-hexadecenoyl, palmitoyl, oleoyl, myristenoyl, 9,12-hexadecadienoyl, linoleoyl, α-linoleoyl, γ-linolenicoyl, arachidoyl, or eicosapridenoyl.

[0037] 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, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, or haloalkoxy group.

[0038] In some embodiments, the choline ester comprises alkyl choline or a pharmaceutically acceptable salt thereof. In some embodiments, the alkyl choline comprises C8 to C94 esters. 20 Alkyl, C8 to C 20 The alkyl group is selected from: arachidocholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), hexanoylcholine (C10), and capryloylcholine (C8), and pharmaceutically acceptable salts thereof. In some embodiments, the alkylylcholine includes C... 10 To C 18 Alkyl group. In some embodiments, alkyl choline includes C 12 To C16 Alkyl group. In some embodiments, preferred alkyl choline includes palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12), or a pharmaceutically acceptable salt thereof. In some embodiments, the most preferred alkyl choline is lauroylcholine (C12), or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutically acceptable salt of the preferred absorption enhancer is a hydrochloride salt.

[0039] In some embodiments, the absorption enhancer (e.g., choline ester) comprises diethylcholine or a pharmaceutically acceptable salt thereof. In some embodiments, diethylcholine comprises C2-C... 20 Alkenyl groups, including 2-hexenoyl, 9-decenoyl, 9-hexadecenoyl, palmitoyl, oleoyl, myristenoyl, 9,12-hexadecadienoyl, linoleoyl, α-linoleoyl, γ-linolenicoyl, arachidoyl, or eicosapridenoyl.

[0040] In some embodiments, the pharmaceutical compositions provided herein comprise one or more absorption enhancers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions provided herein comprise at least one, two, three, four, five, or more absorption enhancers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions provided herein comprise up to one, two, three, four, or five absorption enhancers or pharmaceutically acceptable salts thereof.

[0041] In some embodiments, preferred pharmaceutical compositions comprise palmitoylcholine (C16), myristoylcholine (C14), or lauroylcholine (C12), or a pharmaceutically acceptable salt thereof. In some embodiments, preferred absorption enhancers include palmitoylcholine chloride (PCC), myristoylcholine chloride, or lauroylcholine chloride (LCC). In some embodiments, the absorption enhancer comprises LCC. In some embodiments, the absorption enhancer comprises palmitoylcholine chloride (PCC). In some embodiments, the absorption enhancer comprises myristoylcholine chloride (MyCC).

[0042] In some embodiments, the pharmaceutical composition comprises 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 comprises 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 comprises about 5 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition comprises about 10 mg of an absorption enhancer.

[0043] In some embodiments, the pharmaceutical composition comprises about 0.1 mg to about 30 mg of an absorption enhancer. In some embodiments, the pharmaceutical composition comprises 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.

[0044] In some embodiments, the absorption enhancer of the pharmaceutical composition is present 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 absorption enhancer of the pharmaceutical composition is present at most: 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 most about 20% of the total weight (w / w) of the pharmaceutical composition.

[0045] In some embodiments, the absorption enhancer of the pharmaceutical composition comprises, by weight (w / w%) of about 1% to about 20%, about 1% to about 18%, about 1% to about 15%, about 1% to about 12%, about 1% to about 10%, about 1% to about 8%, about 1% to about 5%, about 3% to about 20%, about 3% to about 18%, about 3% to about 15%, about 3% to about 12%, about 3% to about 10%, about 3% to about 8%, about 3% to about 5%, about 6% to about 20%, about 6% to about 1% of the total pharmaceutical composition. 8%, about 6% to about 15%, about 6% to about 12%, about 6% to about 10%, about 6% to about 8%, about 8% to about 20%, about 8% to about 18%, about 8% to about 15%, about 8% to about 12%, about 8% to about 10%, about 12% to about 20%, about 12% to about 18%, about 12% to about 15%, about 14% to about 20%, about 14% to about 18%, about 14% to about 15%, about 16% to about 20%, about 16% to about 18%, or about 18% to about 20% are present.

[0046] In some embodiments, the absorption enhancer comprises at least about 3% (e.g., 3.7%) of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the absorption enhancer comprises 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 comprises at least about 8% (e.g., 8%) of the total weight (w / w%) of the pharmaceutical composition. In some embodiments, the absorption enhancer comprises at least about 10% (e.g., 13.3%) of the total weight (w / w%) of the pharmaceutical composition.

[0047] In some embodiments, pharmaceutical compositions containing choline esters derived from carboxylic acids (e.g., LCC) and excipients (e.g., microcrystalline cellulose (MCC)) exhibit enhanced pharmacokinetic parameters compared to corresponding pharmaceutical compositions containing another class of absorption enhancers (e.g., surfactants or sugars).

[0048] Active ingredients The pharmaceutical compositions described herein contain one or more active ingredients or pharmaceutically acceptable salts thereof.

[0049] 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 mimic, peptide analog, or pharmaceutical peptide conjugate. In some embodiments, the peptide or peptide-related drug has a molecular weight of about 10,000 Daltons (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.

[0050] In some cases, peptides or peptide-related drugs include insulin, human growth hormone, calcitonin, glucagon, 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 formation-stimulating factor, and parathyroid hormone. Hormone, thyroid-stimulating hormone-releasing hormone, angiotensin, prolactin, luteinizing hormone, and gastric inhibitory polypeptide.GIP, C-peptide, cyclosporine, FK-506, octreotide, carperitide, pramlintide, lanreotide, eptifibatide, albiglutide, pasireotide, teriparatide, exenatide, liraglutide, emfuvirtide, ziconotide, ecallantide, mifamurtide, nesiritide, peg-linesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, their peptide analogs, or any combination thereof.

[0051] In some implementations, the active ingredient includes a non-peptide drug.

[0052] In some embodiments, the active ingredient comprises a small molecule drug. In some embodiments, the small molecule drug has a molecular weight of less than about 1000 g / mol, about 750 g / mol, or about 500 g / mol. In some embodiments, the small molecule drug comprises adrenaline, baclofen, or levodopa or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0053] In some embodiments, the active ingredient comprises a medium-molecule drug having a molecular weight of about 500 g / mol to about 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 an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0054] In some embodiments, the active ingredient includes a drug with a molecular weight exceeding 50,000 g / mol, which includes an antibody or a fragment thereof.

[0055] In some embodiments, the active ingredient includes a nucleic acid molecule. In some embodiments, the nucleic acid molecule can be of different sizes, including oligonucleotides, polynucleotides, or plasmids. In some embodiments, the nucleic acid molecule can be a chemically modified nucleic acid, which includes a modified backbone, a modified sugar moiety, or a combination thereof.

[0056] In some implementations, the nucleic acid molecule includes antisense oligonucleotides (e.g., antisense oligomers or ASOs). As used herein, the terms “ASO” and “antisense oligomer” are used interchangeably and refer to oligomers such as polynucleotides that include nucleobases that hybridize with the sequence of a target nucleic acid (e.g., pre-mRNA or mRNA) via Watson Crick base pairing or swing base pairing (GU).

[0057] In some embodiments, the antisense oligonucleotide comprises a phosphate thioester bond or a phosphoryldiamine bond. In some embodiments, each nucleotide in the antisense oligonucleotide is a phosphate thioester bond. In some embodiments, the antisense oligonucleotide comprises phosphoryldiamine morpholine, locked nucleic acid, peptide nucleic acid, a 2'-O-methyl moiety, a 2'-fluorine moiety, a 2'-O-methoxyethyl moiety, or a 2'-NMA moiety. In some embodiments, the antisense oligonucleotide contains at least one modified sugar moiety. In some embodiments, each nucleotide of the antisense oligonucleotide contains a modified sugar moiety. In some embodiments, each nucleotide of the antisense oligonucleotide contains a 2'-O-methoxyethyl moiety. In some embodiments, the antisense oligonucleotide contains at least one modified nucleobase. In some embodiments, the antisense oligonucleotide comprises hypoxanthine, xanthine, 7-methylguanine, 5,6-dihydrouracil, 5-methylcytosine, or 5-hydroxymethylcytosine.

[0058] In some implementations, the antisense oligonucleotide comprises 8 to 50 nucleotides, 8 to 40 nucleotides, 8 to 30 nucleotides, 8 to 25 nucleotides, 8 to 20 nucleotides, 8 to 15 nucleotides, 10 to 50 nucleotides, 10 to 40 nucleotides, 10 to 30 nucleotides, 10 to 25 nucleotides, 10 to 20 nucleotides, 10 to 15 nucleotides, 12 to 50 nucleotides, 12 to 40 nucleotides, 12 to 30 nucleotides, 12 to 25 nucleotides. Composed of 12 to 20 nucleosides, 12 to 15 nucleosides, 15 to 50 nucleosides, 15 to 40 nucleosides, 15 to 30 nucleosides, 15 to 25 nucleosides, 15 to 20 nucleosides, 15 to 19 nucleosides, 15 to 18 nucleosides, 15 to 16 nucleosides, 16 to 20 nucleosides, 16 to 19 nucleosides, 16 to 18 nucleosides, 17 to 20 nucleosides, 17 to 19 nucleosides, or 18 to 20 nucleosides.

[0059] In some implementations, the active ingredients include acyclovir, adrenaline, alirocumab, allergen extract powder, amantadine, amphetamine, ampicillin, adalimumab, apomorphine, aripiprazole, atomoxetine, baclofen, beclomethasone, beriimumab, betahistine, blonanserin, and brexpiprazole. azole), bromoxynil, buprenorphine, butorphanol, cabergoline, calcitonin, canakinumab, cannabide, cannabinoid, carbamazepine, carboplatin, cefaclor, ceftazidime, chimeric abciximab antibody abciximab, chloral hydrate, chlorpheniramine, chlorpromazine, cisplatin, clonazepam, codeine, cyanocobalamin, cyclophosphamide, cyclosporine A, cyclosporine, dantrolene, delavirdine, denosumab, desmopressin, dexamethasone, dextromethorphan, diazepam, didanosine, digoxin, dihydroergotamine, diltiazem, dimethyl fumaratefumarate, donepezil, droxidopa, edaravone, enoxacin, epinephrine, erenumab, erythropoietin, ethosuximide, etizolam, etoposide, evolocumab, fentanyl, fesoterodine, finasteride, fluorodeoxyglucose, fluorothymidine, fluphenazine, follicle-stimulating hormone (FSH). Hormone, fomivirsen, 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 bevacizumab, hydromorphone, ibuprofen, ifosfamide, imidafenacin, indinavir, indisetron, insulin, insulin-like growth factor-1Factor-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 gonadotropin. Hormone, methylphenidate, midazolam, mipomersen, mirabegron, morphine, mouse antibody burinatumomab, naloxone, naphazoline, natalizumab, nelfinavir, nerve growth factorFactor, NGF), nucitumumab, nevirabine, nevirapine, nitrazepam, nivolumab, nusinersen, ofatumumab, olanzapine, ondansetron, oxybutynin, oxycodone, oxytocin, ozagrel, palonosetron, panipenem-betamipron, panitumumab, pentobarbital, phenobarbital, phenytoin, piperiden, piperidene, pembrolizumab, placental gonadotropichormone, 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. Valproate, Solifenacin, Spiperone, Stem Cell Growth FactorFactor, SCGF), sumatriptan, tacrolimus, tadalafil, tamsulosin, technetium, telaprevir, temozolomide, thallium, tiapride, tissue plasminogen activator Activators), 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 any combination thereof.

[0060] In some embodiments, the active ingredient includes adrenaline, baclofen, levodopa, calcitonin, cyclosporine A, or an antisense oligonucleotide or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0061] In some embodiments, the active ingredient includes a pharmaceutical agent that is biologically active against the central nervous system (CNS). In some embodiments, the active ingredient includes a pharmaceutical agent that is effective in preventing or treating CNS diseases, examining or diagnosing CNS diseases, or used for preoperative or pre-examination treatment of CNS diseases. In some embodiments, the pharmaceutical agent that is biologically active against the CNS includes levodopa or a pharmaceutically acceptable salt thereof; or any combination thereof.

[0062] In some embodiments, the active agent is not glucagon. In some embodiments, when the absorption enhancer is phosphatidylcholine, the active ingredient 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 dicofylphosphatidylcholine, lysolauroylphosphatidylcholine, dicoctanoylphosphatidylcholine, diclauroylphosphatidylglycerol, or phosphatidylcholine. In some embodiments, the absorption enhancer is not phosphatidylcholine.

[0063] Baclofen In some embodiments, the active ingredient includes an active agent for reducing muscle spasms. In some embodiments, the active ingredient includes a skeletal muscle relaxant. In some embodiments, the skeletal muscle relaxant is administered to treat spasms arising from the spinal cord (e.g., spinal cord injury, multiple sclerosis, etc.). In some embodiments, the skeletal muscle relaxant is administered to treat spasms arising from the brain (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 spasms 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 syndromes. In some embodiments, the skeletal muscle relaxant includes baclofen.

[0064] In some embodiments, the active ingredient includes a drug for treating pain. In some embodiments, the drug for treating pain includes baclofen.

[0065] Levodopa In some embodiments, the active ingredient includes an active agent for treating Parkinson's disease. In some embodiments, the active ingredient includes an active agent for treating postencephalitic parkinsonism or symptomatic parkinsonism. In some embodiments, the active ingredient includes an active agent for treating motor fluctuations (e.g., the "off" phase, such as in advanced Parkinson's disease). In some embodiments, the active ingredient includes a precursor of a neurotransmitter. In some embodiments, the active ingredient includes a dopamine precursor. In some embodiments, the active agent includes a dopamine agonist. In some embodiments, the active ingredient includes levodopa.

[0066] adrenaline In some embodiments, the active ingredient includes an active agent for treating type I hypersensitivity reactions, such as anaphylactic reactions. In some embodiments, the active ingredient includes an active agent for treating hypotension associated with septic shock. In some embodiments, the active ingredient includes an active agent that increases mean arterial blood pressure and / or induces bronchodilation. In some embodiments, the active ingredient includes a cardiac stimulant or a positive inotropic agent, such as an adrenergic agonist. In some embodiments, the active ingredient includes adrenaline.

[0067] Calcitonin In some embodiments, the active ingredient includes a hormone. The hormone may be synthesized via recombinant synthesis (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 conditions such as, for example, lower back pain, osteoporosis, or menopause. In some embodiments, the active ingredient includes salmon calcitonin or a pharmaceutically acceptable salt thereof.

[0068] Cyclosporin A In some embodiments, the active ingredient includes an immunosuppressant. In some embodiments, the immunosuppressant is used to treat autoimmune diseases such as psoriasis, rheumatoid arthritis, or Crohn's disease. In some embodiments, the immunosuppressant is used to treat rejection after organ transplantation. In some embodiments, the immunosuppressant includes calcineurin inhibitors, corticosteroids, or antimetabolites. In some embodiments, the immunosuppressant includes cyclosporine A.

[0069] In some embodiments, the pharmaceutical compositions provided herein comprise 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 an active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein comprise 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 an active ingredient or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the pharmaceutical compositions provided herein comprise 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 comprise 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, about 1 mg to about 25 mg, 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 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, or about 2 mg to about 5 mg of an active ingredient or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the total weight of the pharmaceutical composition comprises 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 an 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.

[0072] In some embodiments, the total weight of the pharmaceutical composition comprises 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 an active ingredient or a pharmaceutically acceptable salt thereof. In some embodiments, the total weight of the pharmaceutical composition comprises 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.

[0073] excipient In some embodiments, the pharmaceutical compositions provided herein comprise excipients. In some embodiments, the pharmaceutical compositions comprise microcrystalline cellulose (MCC). In some embodiments, the pharmaceutical compositions comprise at least one, two, three, four, five, or more excipients or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions comprise up to one, two, three, four, or five excipients or pharmaceutically acceptable salts thereof.

[0074] In some embodiments, the pharmaceutical composition comprises 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 comprises about 50 mg to about 90 mg of an excipient. In some embodiments, the pharmaceutical composition comprises about 60 mg to about 80 mg of an excipient (e.g., MCC). In some embodiments, the pharmaceutical composition comprises about 50 mg, about 60 mg, about 70 mg, or about 80 mg of an excipient.

[0075] In some embodiments, the pharmaceutical composition comprises an excipient or a pharmaceutically acceptable salt thereof 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.

[0076] In some embodiments, the total weight of the pharmaceutical composition comprises 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%, or at least about 95% or more of excipients or pharmaceutically acceptable salts thereof. In some embodiments, the total weight of the pharmaceutical composition comprises at most about 30%, at most about 40%, at most about 50%, at most about 60%, at most about 70%, at most about 80%, at most about 90%, or at most about 95% of excipients or pharmaceutically acceptable salts thereof.

[0077] In some embodiments, the total weight of the pharmaceutical composition comprises about 30% to about 95%, about 30% to 90%, about 30% to about 80%, about 30% to 70%, about 30% to about 60%, about 30% to 50%, about 40% to about 95%, about 40% to 90%, about 40% to about 80%, about 40% to 70%, about 40% to about 60%, about 40% to 50%, about 50% to about 95%, about 50% to about 80%, about 50% to 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 70% of an excipient or a pharmaceutically acceptable salt thereof. In some embodiments, the excipient (e.g., MCC) comprises about 40% to about 70% of the pharmaceutical composition. In some embodiments, the excipient comprises about 50% to about 60% of the pharmaceutical composition. In some embodiments, the excipient comprises about 50% of the pharmaceutical composition. In some embodiments, the excipient comprises about 55% of the pharmaceutical composition. In some embodiments, the excipient comprises about 60% of the pharmaceutical composition.

[0078] In some embodiments, the pharmaceutical composition comprises an excipient. In some embodiments, the pharmaceutical composition comprises one excipient. In some embodiments, the pharmaceutical composition comprises one or more excipients. In some embodiments, the pharmaceutical composition comprises two or more excipients. In some embodiments, the pharmaceutical composition comprises three or more excipients. In some embodiments, the pharmaceutical composition comprises two excipients. In some embodiments, the pharmaceutical composition comprises three excipients.

[0079] 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, filler, or extender. In some embodiments, the binder, anti-caking agent, emulsifier, filler, or extender comprises MCC.

[0080] 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.

[0081] In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose, chitosan, lactose, croscarmellose sodium, tricalcium phosphate, or any combination thereof.

[0082] In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose (MCC). Acceptable MCC may include MCC obtained by decomposing cellulose materials (such as pulp) through either acid hydrolysis or alkaline hydrolysis, followed by purification of the hydrolysis products, and then pulverizing or grinding them before, during, or after drying. For example, MCC with a selected average particle size can be obtained through appropriate processing, such as fine grinding using a high-speed rotary impact mill or an air mill, and size sorting as needed. In some embodiments, the MCC of the pharmaceutical compositions provided herein includes products available under the trade name CEOLUS® PH-F20JP (e.g., with an average particle size of about 20-23 micrometers and a bulk density of about 0.23 g / cm³). 3 (Angle of repose not less than 60 degrees), CEOLUS® PH-301 (e.g., average particle size of approximately 50 micrometers, bulk density of approximately 0.41 g / cm³). 3(with an angle of repose of approximately 41 degrees), CEOLUS® PH-101 (e.g., an average particle size of approximately 50 micrometers and a bulk density of approximately 0.29 g / cm³). 3 (with an angle of repose of approximately 45 degrees), CEOLUS® PH-102 (e.g., an average particle size of approximately 90 micrometers and a bulk density of approximately 0.3 g / cm³). 3 (with an angle of repose of approximately 42 degrees) and CEOLUS® PH-302 (purchased from Asahi Kasei Corporation, for example, with an average particle size of approximately 90 micrometers and a bulk density of approximately 0.43 g / cm³). 3 (with an angle of repose of approximately 38 degrees) and AVICEL® PH-105 (e.g., an average particle size of approximately 20 micrometers and a bulk density of approximately 0.20-0.30 g / cm³). 3 AVICEL® PH-101 (for example, with an average particle size of approximately 50 micrometers and a bulk density of approximately 0.26-0.31 g / cm³). 3 AVICEL® PH-102 (e.g., average particle size of approximately 100 micrometers, bulk density of approximately 0.28-0.33 g / cm³) 3 AVICEL® PH-301 (for example, with an average particle size of approximately 50 micrometers and a bulk density of approximately 0.34-0.45 g / cm³). 3 ) and AVICEL® PH-302 (purchased from FMC Biopolymer Corporation, for example, with an average particle size of about 100 micrometers and a bulk density of about 0.35-0.46 g / cm³). 3 In some embodiments, the pharmaceutical composition comprises CEOLUS® PH-F20JP and CEOLUS® PH-301. In some embodiments, the pharmaceutical composition comprising MCC exhibits enhanced pharmacokinetic parameters compared to a corresponding pharmaceutical composition comprising another excipient (e.g., lactose, chitosan).

[0083] The average particle size of microcrystalline cellulose (MCC) in a pharmaceutical composition can be determined using standard techniques, such as laser diffraction particle size distribution analyzers or sieving methods. In some embodiments, the average particle size of the MCC is about 10 μm to about 100 μm, about 10 μm to about 80 μm, about 10 μm to about 60 μm, about 10 μm to about 40 μm, about 15 μm to about 100 μm, about 15 μm to about 80 μm, about 15 μm to about 60 μm, about 15 μm to about 40 μm, about 15 μm to about 25 μm, about 20 μm to about 100 μm, about 20 μm to about 80 μm, about 20 μm to about 60 μm, about 20 μm to about 40 μm, about 30 μm to about 100 μm, about 30 μm to about 80 μm, about 30 μm to about 60 μm, about 40 μm to about 100 μm, about 40 μm to about 80 μm, about 40 μm to about 60 μm, about 50 μm to about 100 μm, about 50 μm to about 80 μm. μm, approximately 50 μm to approximately 70 μm or approximately 65 μm to approximately 75 μm.

[0084] In some embodiments, the average particle size of the microcrystalline cellulose (MCC) is 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 larger. In some embodiments, the pharmaceutical composition comprises MCC having an average particle size of at most: 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.

[0085] In some embodiments, the total weight of the pharmaceutical composition comprises about 30% to about 95%, about 30% to 90%, about 30% to about 80%, about 30% to 70%, about 30% to about 60%, about 30% to 50%, about 40% to about 95%, about 40% to 90%, about 40% to about 80%, about 40% to 70%, about 40% to about 60%, about 40% to 50%, about 50% to about 95%, about 50% to 90%, about 50% to about 80%, about 50% to 70%, about 50% to about 60%, about 60% to about 95%, about 60% to 90%, about 60% to about 80%, about 60% to 70%, about 70% to 90%, about 80% to 90%, about 85% to 95%, or about 90% to 95%.

[0086] In some embodiments, the total weight of the pharmaceutical composition comprises 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%, or at least about 95% or more of microcrystalline cellulose (MCC). In some embodiments, the total weight of the pharmaceutical composition comprises 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 MCC.

[0087] In some embodiments, the bulk density of microcrystalline cellulose (MCC) is 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 In some embodiments, the pharmaceutical composition comprises MCC having a bulk density of up to 0.1, up to 0.2, up to 0.3, up to 0.4, up to 0.5, up to 0.6, or up to 0.7 g / cm³. 3 In some implementations, the bulk density of MCC is about 0.1 to 0.5 g / cm³. 3 Approximately 0.1 to 0.4 g / cm³ 3 Approximately 0.1 to 0.3 g / cm³ 3 Approximately 0.1 to 0.2 g / cm³ 3 Approximately 0.2 to 0.5 g / cm³ 3 Approximately 0.2 to 0.4 g / cm³ 3 Approximately 0.2 to 0.3 g / cm³ 3 Approximately 0.3 to 0.5 g / cm³ 3 Approximately 0.3 to 0.4 g / cm³ 3 Or approximately 0.4 to 0.5 g / cm³ 3 .

[0088] In some embodiments, the pharmaceutical compositions provided herein comprise an absorption enhancer (e.g., cholinesterol) and an excipient (e.g., microcrystalline cellulose) in a weight ratio 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, or about 1:100. In some embodiments, the pharmaceutical compositions provided herein comprise an absorption enhancer (e.g., cholinesterol) and an excipient (e.g., microcrystalline cellulose) in a weight ratio of 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, or about 1:100. In some embodiments, the absorption enhancer and excipient (e.g., MCC) are present in the pharmaceutical composition at 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 at a ratio of about 1:13 (absorption enhancer: excipient). In some embodiments, the absorption enhancer and excipient (e.g., MCC) are present in the pharmaceutical composition at a ratio of about 1:15 (absorption enhancer: excipient).

[0089] In some embodiments, the pharmaceutical compositions provided herein comprise, by weight ratios of about 1:1 to about 1:100, about 1:1 to about 1:90, about 1:1 to about 1:80, about 1:1 to about 1:70, about 1:1 to about 1:60, about 1:1 to about 1:50, about 1:1 to about 1:40, about 1:1 to about 1:30, about 1:1 to about 1:20, about 1:1 to about 1:10, about 1:2 to about 1:50, about 1:2 to about 1:40, about 1:2 to about 1:30, about 1:2 to about 1:20, about 1:2 to about 1:10, about 1:3 to about 1:50, about 1:3 to about 1:40, about 1:3 to about 1:30, about 1:3 to about 1:20, about 1:3 to about 1:10, about 1:3 to about 1:5, about 1:5 to about 1: 50. Absorption enhancers (e.g., choline esters) and excipients (e.g., microcrystalline cellulose) of about 1:5 to about 1:40, about 1:5 to about 1:50, about 1:5 to about 1:20, about 1:5 to about 1:10, 1:10 to about 1:100, about 1:10 to about 1:90, about 1:10 to about 1:80, about 1:10 to about 1:70, about 1:10 to about 1:60, about 1:10 to about 1:50, about 1:20 to about 1:90, about 1:20 to about 1:80, about 1:20 to about 1:70, about 1:20 to about 1:60 or about 1:20 to about 1:50, about 1:30 to about 1:90, about 1:30 to about 1:80, about 1:30 to about 1:70, about 1:30 to about 1:60 or about 1:30 to about 1:50.

[0090] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more excipients. In some embodiments, one or more excipients include croscarmellose sodium (CCS), tricalcium phosphate (TCP), or a combination thereof.

[0091] Pharmaceutical Composition Some aspects of this disclosure provide a pharmaceutical composition that improves mucosal penetration and / or absorption of the active ingredient compared to a corresponding pharmaceutical composition without an absorption enhancer. The pharmaceutical composition can improve mucosal penetration and / or absorption of the active ingredient through various mucous membranes, such as, for example, nasal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa, ocular mucosa, pulmonary mucosa, vaginal mucosa, or any combination thereof. In some embodiments, the pharmaceutical composition improves mucosal penetration and / or absorption of the active ingredient through the nasal mucosa.

[0092] In some embodiments, the pharmaceutical composition improves mucosal penetration and / or absorption of the active ingredient compared to corresponding pharmaceutical compositions that do not contain choline esters (e.g., lauroylcholine chloride (LCC)). In some embodiments, the pharmaceutical composition improves mucosal penetration and / or absorption of the active ingredient compared to corresponding pharmaceutical compositions that contain the active ingredient but do not contain excipients (e.g., microcrystalline cellulose (MCC)). In some embodiments, pharmaceutical compositions containing the active ingredient, choline esters (e.g., LCC), and excipients (e.g., MCC) exhibit enhanced pharmacokinetic parameters (e.g., higher Cmax, higher AUC). In some embodiments, pharmaceutical compositions containing the active ingredient, choline esters (e.g., LCC), and MCC exhibit enhanced pharmacokinetic parameters compared to corresponding pharmaceutical compositions containing another class of absorption enhancers (e.g., surfactants or sugars). In some embodiments, pharmaceutical compositions containing the active ingredient, choline esters (e.g., LCC), and MCC exhibit enhanced pharmacokinetic parameters compared to corresponding pharmaceutical compositions containing another excipient (e.g., lactose, chitosan). In some embodiments, the pharmaceutical compositions provided herein exhibit enhanced pharmacokinetic parameters compared to liquid pharmaceutical compositions containing absorption enhancers (such as LCC).

[0093] Improved mucosal penetration and / or absorption of the active ingredient can be measured through a variety of mechanisms, such as pharmacokinetic (PK) parameters. PK parameters can 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 can be calculated based on the dose of the drug composition administered and the area under the curve. PK parameters can be obtained at any time after administration of the drug 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 drug composition. Subscripts can be used to specify the time of PK measurement. 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 drug composition.

[0094] 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 target tissues, such as the subject's cerebrospinal fluid (CSF) or brain parenchyma. 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).

[0095] In some embodiments, compared to a corresponding pharmaceutical composition that does not contain choline esters (e.g., LCC) (e.g., contains the same active ingredient), the pharmaceutical composition (e.g., containing both the active ingredient and choline esters) provides (e.g., to a subject who has received the pharmaceutical composition) improved pharmacokinetic (PK) parameters of the active agent. Improved PK parameters may include higher bioavailability, a larger AUC, a longer half-life, a higher Cmax, or a shorter Tmax, or any combination thereof. In some embodiments, compared to a pharmaceutical composition that does not contain excipients (e.g., MCC), the pharmaceutical composition (e.g., containing both the active ingredient and excipients) provides improved pharmacokinetic (PK) parameters of the active agent, including higher bioavailability, a larger AUC, a longer half-life, a higher Cmax, or a shorter Tmax, or any combination thereof. In some embodiments, a pharmaceutical composition containing an active ingredient, excipients, and an absorption enhancer provides improved pharmacokinetic (PK) parameters of the active agent compared to a pharmaceutical composition that does not contain excipients (e.g., MCC) or choline esters (e.g., LCC), including higher bioavailability, greater AUC, longer half-life, higher Cmax, or shorter Tmax, or any combination thereof.

[0096] In some embodiments, compared to a pharmaceutical composition that does not contain choline esters (e.g., LCC) (e.g., contains the same active ingredient), the pharmaceutical composition (e.g., contains the active ingredient and an absorption enhancer) improves the PK parameters of the active agent 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 600%, about 700%, about 800%, about 900%, about 1000%, about 1100%, about 1200%, about 1300%, about 1400%, about 1500%, or about 2000%.

[0097] In some implementations, the improved PK parameter includes the AUC parameter. 0-10min 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 implementations, the improved AUC parameter includes AUC 0-10min In some implementations, the improved AUC parameter includes AUC 0-30min In some implementations, the improved AUC parameter includes AUC 0-60min In some implementations, the improved AUC parameter includes AUC 0-90min In some implementations, the improved AUC parameter includes AUC 0-120min In some implementations, the improved AUC parameter includes AUC 0-150min In some implementations, the improved AUC parameter includes AUC 0-240min In some implementations, the improved AUC parameter includes AUC 0-300min In some implementations, the improved AUC parameter includes AUC 0-480min .

[0098] In some embodiments, the pharmaceutical composition comprises an AUC improved by at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200% compared to a corresponding pharmaceutical composition that does not contain an absorption enhancer (e.g., LCC). 0-30min In some embodiments, the pharmaceutical composition comprises an AUC improved by at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000% compared to a corresponding pharmaceutical composition that does not contain choline esters (e.g., LCC). 0-60min .

[0099] In some embodiments, the pharmaceutical composition has an improved AUC that is 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 a subject.

[0100] In some embodiments, the pharmaceutical composition comprises epinephrine or a pharmaceutically acceptable salt thereof, lauroyl choline chloride, and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises: a) about 1-5 mg of epinephrine or a pharmaceutically acceptable salt thereof; b) about 2-6 mg of lauroyl choline chloride; and c) about 51-55 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as 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 choline chloride; and c) about 53 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, compared to a corresponding pharmaceutical composition containing epinephrine but not lauroyl choline chloride, when this pharmaceutical composition is administered, the Cmax of epinephrine is improved by at least about: 300%, 400%, 500%, 600%, 700%, or 800%. In some embodiments, when the pharmaceutical composition is administered, the AUC of adrenaline is higher than that of a corresponding pharmaceutical composition containing adrenaline but not lauroyl choline chloride. 0-30min Improvements of at least approximately: 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200%.

[0101] In some embodiments, the pharmaceutical composition comprises baclofen or a pharmaceutically acceptable salt thereof, lauroyl choline 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 lauroyl choline chloride; and c) about 49-53 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as 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 lauroyl choline chloride; and c) about 51 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, when this pharmaceutical composition is administered, the Cmax of baclofen is improved by at least about 300%, 400%, or 500% compared to a corresponding pharmaceutical composition that contains baclofen but does not contain lauroyl choline chloride. In some embodiments, when the pharmaceutical composition is administered, the AUC of baclofen is higher than that of a corresponding pharmaceutical composition containing baclofen but not lauroyl choline chloride. 0-30min The improvement is at least approximately 300%, 400%, or 500%.

[0102] In some embodiments, the pharmaceutical composition comprises levodopa or a pharmaceutically acceptable salt thereof, lauroyl choline chloride, 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; wherein the pharmaceutical composition is formulated as 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; wherein the pharmaceutical composition is formulated as 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; wherein the pharmaceutical composition is formulated as 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; wherein the pharmaceutical composition is formulated as 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; wherein the pharmaceutical composition is formulated as 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; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, when the pharmaceutical composition is administered, the Cmax of levodopa is improved by at least about: 300%, 400%, 500%, 600%, or 700% compared to a corresponding pharmaceutical composition that does not contain LCC. In some embodiments, when the pharmaceutical composition is administered, the AUC of levodopa is... 0-30minThe improvement is at least about 300%, 400%, 500%, 600%, or 700%. In some embodiments, the pharmaceutical composition comprises about 20 mg to about 100 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 10 mg to about 100 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 60 mg to about 80 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 20 mg to about 40 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 20 mg to about 30 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 20 mg of an active ingredient (e.g., levodopa). In some embodiments, the pharmaceutical composition comprises about 30 mg of an active ingredient (e.g., levodopa).

[0103] In some embodiments, the pharmaceutical composition comprises calcitonin or a pharmaceutically acceptable salt thereof, lauroyl choline 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 lauroyl choline chloride; and c) about 54-57 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as 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 lauroyl choline chloride; and c) about 55.88 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, when this pharmaceutical composition is administered, the Cmax of calcitonin is improved by at least about: 200%, 300%, or 400% compared to a corresponding pharmaceutical composition that comprises calcitonin but does not contain lauroyl choline chloride. In some embodiments, when the pharmaceutical composition is administered, the AUC of calcitonin is higher than that of a corresponding pharmaceutical composition containing calcitonin but not lauroyl choline chloride. 0-30min The improvement is at least approximately 100%, 200%, or 300%.

[0104] In some embodiments, the pharmaceutical composition comprises cyclosporine A or a pharmaceutically acceptable salt thereof, lauroyl choline chloride, 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 choline chloride; and c) about 24-28 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as 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 choline chloride; and c) about 26 mg of microcrystalline cellulose; wherein the pharmaceutical composition is formulated as a solid dosage form. In some embodiments, when this pharmaceutical composition is administered, the AUC of cyclosporine A is higher than that of a corresponding pharmaceutical composition containing cyclosporine A but not lauroyl choline chloride. 0-30min Improvement of at least approximately: 400%, 500%, 600%, 700%, or 800%.

[0105] 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; wherein the pharmaceutical composition is formulated as 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, when the pharmaceutical composition is administered, the Cmax of the nucleic acid molecule is improved by at least about: 50%, 80%, 100%, or 200% compared to a corresponding pharmaceutical composition comprising a nucleic acid molecule but not comprising an absorption enhancer. In some embodiments, when the pharmaceutical composition is administered, the AUC of the nucleic acid molecule is improved compared to a corresponding composition comprising a nucleic acid molecule but not comprising an absorption enhancer. 0-30min The improvement is at least approximately 100%, 200%, or 300%.

[0106] 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.

[0107] In some embodiments, the pharmaceutical composition is used for mucosal application, including buccal, sublingual, oral, ocular, intranasal, rectal, and vaginal application. In some embodiments, the pharmaceutical composition is used for intranasal application.

[0108] The pharmaceutical compositions provided herein are formulated into solid dosage forms, including powders, tablets, patches, or capsules. In some embodiments, the pharmaceutical compositions exhibit enhanced pharmacokinetic parameters (e.g., higher Cmax, larger AUC) compared to liquid dosage forms. Solid dosage forms can be characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. While not wishing to be limited to any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, adhesion, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence specific processing methods (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization), thereby making certain solid forms suitable for the preparation of solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analytical techniques as described herein and well known in the art (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0109] In some embodiments, the unit dose of the pharmaceutical composition comprises about 20 mg to about 250 mg by weight. In some embodiments, the unit dose of the pharmaceutical composition comprises 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 higher by weight.

[0110] Preparation method Some aspects of this disclosure relate to methods for preparing pharmaceutical compositions. In some embodiments, the preparation method includes blending, grinding, granulation, drying, or any combination thereof. In some embodiments, blending includes in-vessel mixing (e.g., bag mixing) or high-shear mixing in a granulator. In some embodiments, grinding includes mortar grinding. In some embodiments, granulation includes stirred granulation, extrusion granulation, fluidized bed granulation, high-shear granulation, or combinations thereof. In some embodiments, granulation includes sieving a solid pharmaceutical composition. In some embodiments, drying includes freeze drying, lyophilization, spray drying, or spray freeze-drying.

[0111] Treatment Some aspects of this disclosure relate to a method of treating a condition, comprising administering the pharmaceutical composition provided herein to a subject in need. In some embodiments, the method includes administering the pharmaceutical composition via the cheek, sublingually, orally, ocularly, intranasally, rectally, or vaginally. In some embodiments, a preferred method includes administering the pharmaceutical composition via intranasal administration.

[0112] In some implementations, the methods provided herein include using the pharmaceutical composition in the diagnosis, prevention, or treatment of a condition.

[0113] In some implementations, the method includes treating a condition of the central nervous system (CNS) with a pharmaceutical composition. In some implementation schemes, CNS disorders include cerebral hemorrhage, cerebral infarction, CNS infections, brain tumors, 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 disorders, agitation, and panic disorder. Disorders, obsessive-compulsive disorder, autism spectrum disorder, attention deficit / hyperactivity disorder, sleep disorder, insomnia, traumatic brain injury, glioma, pain, and / or migraine.In some implementations, CNS conditions include tumors of the CNS, including meningioma, pituitary adenoma, craniopharyngioma, schwannoma, nasopharyngeal angiofibroma, choroid plexus tumors, dysembryoplastic neuroepithelial tumors, neurofibroma, hemangioblastoma, chondroma, giant cell tumor, osteoma, glioma (e.g., astrocytomas, oligodendrogliomas, or glioblastomas), ependymal tumors, hemangiopericytoma, and germ cell tumors. Tumors, or pineal tumors, chordomas, chondrosarcomas, medulloblastomas, olfactory neuroblastomas, lymphomas, gliosarcomas, rhabdomyosarcomas, paranasal sinus cancers, or atypical teratoid / rhabdoid tumors.

[0114] In some embodiments, the method includes treating systemic symptoms with a pharmaceutical composition. In some embodiments, systemic symptoms include anaphylaxis, defervescence, pain, inflammation, rheumatism, hypnosis / sedation, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory metabolic disorder, muscle tone disorder, autonomic neuropathy, dizziness, migraine, hypertension, angina, arrhythmia, cardiovascular diseases, allergies, bronchodilation / asthma, respiratory diseases, peptic ulcer, and gastrointestinal disorders. Disorders, diarrhea, indigestion, gout, hyperuricemia, dyslipidemia, diabetes, hormonal disorders, pituitary hormone disorder, corticosteroid disorder, sex hormone disorder, uterine-related diseases, osteoporosis, bone metabolism diseases, obesity, vitamin deficiency, malnutrition, poisoning, cancer, hyperimmunity, autoimmune diseases.Disorders, otorhinolaryngology-related diseases, mouth-related diseases, urinary / genital diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related diseases, narcotic dependence, and lifestyle-related diseases.

[0115] In some embodiments, the method includes diagnosing a condition using a pharmaceutical composition. In some embodiments, the method includes preoperative or pre-examination treatment using a pharmaceutical composition. In some embodiments, the preoperative or pre-examination treatment includes a radioactive reagent for imaging.

[0116] In some embodiments, the method includes using a pharmaceutical composition to treat a condition associated with muscle spasms. In some embodiments, conditions associated with muscle spasms include multiple sclerosis, spinal cord injury, dystonia, spasticity associated with cerebral palsy, trigeminal neuralgia, and regional pain syndrome. 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 Parkinson's disease, symptomatic Parkinson's disease, or motor fluctuations. In some embodiments, the method includes using a pharmaceutical composition to treat type I hypersensitivity reactions, such as anaphylactic reactions. 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 skeletal conditions, such as, for example, lower back pain, osteoporosis, or menopause. In some embodiments, the method includes using a pharmaceutical composition to treat autoimmune diseases, such as psoriasis, rheumatoid arthritis, or Crohn's disease. In some embodiments, the method includes using a pharmaceutical composition to treat rejection reactions after organ transplantation, such as graft-versus-host disease.

[0117] In some aspects, this document provides a method for treating a disease or condition in a subject of need, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an active agent for treating Parkinson's disease and an absorption enhancer, the absorption enhancer comprising choline esters. In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, the pharmaceutical composition is in a solid dosage form. Solid dosage forms include powder formulations for intranasal administration. In some embodiments, the active agent for treating Parkinson's disease comprises levodopa. In some embodiments, the administration produces a Tmax of less than 20 minutes. In some embodiments, the administration produces a Tmax of less than 15 minutes. In some embodiments, the administration produces a Tmax of less than 10 minutes. In some embodiments, the administration produces an AUC greater than 10,000 ng x min / mL. In some embodiments, the administration produces an AUC greater than 12,000 ng x min / mL. In some embodiments, the administration produces an AUC greater than 15,000 ng x min / mL. In some embodiments, the administration produces a Cmax of at least 300 ng / mL. In some implementations, the Cmax generated by the application is at least 500 ng / mL.

[0118] In some embodiments, administration of the pharmaceutical composition (e.g., containing both the active ingredient and an absorption enhancer) results in improved pharmacokinetic (PK) parameters of the active agent compared to a corresponding pharmaceutical composition (e.g., containing the same active ingredient) that does not contain an absorption enhancer (e.g., LCC). Improved PK parameters may include increased bioavailability, increased AUC, increased half-life, increased Cmax, or a shorter Tmax, or any combination thereof.

[0119] In some embodiments, administration of the pharmaceutical composition provides improved pharmacokinetic (PK) parameters of the active agent compared to a pharmaceutical composition not containing an excipient (e.g., MCC), including increased bioavailability, increased AUC, increased half-life, increased Cmax or shorter Tmax, or any combination thereof. In some embodiments, a pharmaceutical composition containing an active ingredient, an excipient, and an absorption enhancer provides improved pharmacokinetic (PK) parameters of the active agent compared to a pharmaceutical composition not containing an excipient (e.g., MCC) or an absorption enhancer (e.g., LCC), including improved bioavailability, increased AUC, increased half-life, increased Cmax or shorter Tmax, or any combination thereof.

[0120] In some embodiments, administration of the pharmaceutical composition results in an improved AUC parameter. In some embodiments, the improved AUC parameter includes AUC 0-10min AUC 0-20min AUC 0-30minAUC 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 implementations, the improved AUC parameter includes AUC 0-10min In some implementations, the improved AUC parameter includes AUC 0-20min In some implementations, the improved AUC parameter includes AUC 0-30min In some implementations, the improved AUC parameter includes AUC 0-60min In some implementations, the improved AUC parameter includes AUC 0-90min In some implementations, the improved AUC parameter includes AUC 0-120min In some implementations, the improved AUC parameter includes AUC 0-150min In some implementations, the improved AUC parameter includes AUC 0-240min In some implementations, the improved AUC parameter includes AUC 0-300min In some implementations, the improved AUC parameter includes AUC 0-480min .

[0121] In some embodiments, the nucleic acid-containing pharmaceutical composition is administered intranasally in solid dosage form. In some embodiments, the nucleic acid-containing pharmaceutical composition may be reconstituted in a pharmaceutically acceptable diluent and subsequently administered by injection. In some embodiments, the injection may be intramuscular, subcutaneous, intravenous, or intradermal.

[0122] In some embodiments, administration of this pharmaceutical composition results in AUC compared to administration of a corresponding pharmaceutical composition that does not contain an absorption enhancer (e.g., LCC). 0-30min Improvement of at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, or 1200%. In some embodiments, application of this pharmaceutical composition results in AUC compared to application of a corresponding pharmaceutical composition that does not contain an absorption enhancer (e.g., LCC). 0-60min Improvement of at least 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, or 1000%.

[0123] In some embodiments, administration of the pharmaceutical composition results in an improved AUC, which is 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.

[0124] In some embodiments, the methods provided herein include administering an effective amount of the pharmaceutical composition. In some embodiments, the effective amount of the pharmaceutical composition comprises a lower dose of the active ingredient compared to different formulations of the active ingredient. In some embodiments, the effective amount of the pharmaceutical composition comprises a dose that is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more lower than the dose of the active ingredient in different formulations of the active ingredient.

[0125] In some embodiments, the methods provided herein include lower toxicity. In some embodiments, toxicity includes the toxicity of the active ingredient, side effects, or adverse drug events.

[0126] Unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include plural referents. Thus, for example, referring to “a drug” includes referring to one or more such drugs, and referring to “an excipient” includes referring to one or more such excipients. When a range is used herein, it is intended to include all combinations and subcombinations of that range, as well as specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the number or numerical range mentioned is an approximation within experimental variability (or statistical experimental error), and therefore the number or numerical range may vary between 1% and 15% of that number or numerical range.

[0127] As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some respects, the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipient.

[0128] The terms “active agent,” “active ingredient,” “active pharmaceutical preparation,” “drug,” and their variants are used interchangeably to refer to a pharmaceutical preparation or substance that has measurable specific or selected physiological activity when administered to a subject in a significant or effective amount. These terms are intended to encompass both parent drugs and prodrugs.

[0129] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate quantity of a drug or compound administered that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or the production of any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compounds disclosed herein required to achieve a clinically significant reduction in a certain disease. In any individual case, the appropriate "effective" amount can be determined using techniques such as dose escalation studies.

[0130] It should be understood that the substituents and substitution methods on the compounds of the present invention can be selected by those skilled in the art to obtain chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If a substituent is substituted by more than one group, it should be understood that these multiple groups may be located on the same carbon or on different carbons, as long as a stable structure is obtained. As used herein, the term "optionally substituted" means that one to six hydrogen atoms in a given structure are substituted by a group of a specific substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CEh-O-alkyl, OP(O)(O-alkyl)2 or CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen atoms in a given structure are substituted by the above substituents. More preferably, one to three hydrogen atoms are substituted by the above substituents. It should be understood that the substituent can be further replaced.

[0131] As used herein, “absorption enhancer” refers to a compound that facilitates the crossing of an active ingredient across the epithelial barrier (e.g., in drug delivery). Absorption enhancers are functional excipients included in formulations to improve the absorption of the active ingredient. The term absorption enhancer generally refers to an agent whose function is to improve absorption by enhancing membrane permeability rather than increasing solubility; therefore, such agents are sometimes more specifically referred to as permeation enhancers.

[0132] As used herein, "small molecule drug" refers to an active pharmaceutical ingredient having a molecular weight of less than about 1000 g / mol (or Daltons / Da). In some embodiments, the small molecule drug has a molecular weight of less than about 500 Da. Small molecule drugs (e.g., insulin, aspirin, and antihistamines) constitute about 90% of the drug. 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 molecule drugs may include peptide drugs or non-peptide drugs. Small molecules do not include macromolecules such as polysaccharides, proteins, and nucleic acids.

[0133] As used herein, "medium-molecular-weight drug" refers to an active pharmaceutical ingredient having a molecular weight of approximately 500 Da to approximately 50,000 Da. Medium-molecular-weight drugs include biomolecules such as polysaccharides, proteins, and nucleic acids.

[0134] As used herein, the terms “ASO,” “antisense oligomer,” and “antisense oligonucleotide” are used interchangeably and refer to oligomers such as polynucleotides containing nucleobases that hybridize with the sequence of a target nucleic acid (e.g., pre-mRNA or mRNA) via Watson-Crick base pairing or swing base pairing (GU).

[0135] As used herein, the term "excipient" refers to an excipient applicable to solid dosage forms. When the term "excipient" refers to a water-insoluble polysaccharide or oligosaccharide, it may be used interchangeably with "carrier." When the term "excipient" refers to a water-soluble polysaccharide or oligosaccharide, it may be used interchangeably with "thickener."

[0136] Example The following embodiments are provided to further illustrate some implementations of this disclosure, but are not intended to limit the scope of this disclosure; it should be understood that, given the exemplary nature of these embodiments, those skilled in the art may alternatively use other known procedures, methods or techniques.

[0137] Example 1: Preparation of powder composition In the powder formulation prepared in the examples comprising an active pharmaceutical ingredient, an absorption enhancer, and an excipient, the following materials were used. The active ingredients used included adrenaline, baclofen, levodopa, salmon calcitonin, cyclosporine A, and MALAT-1 ASO: 5'- CTA GTTCACTGAA TGC-3'. The absorption enhancers used include lauroyl choline chloride (LCC), palmitoyl choline chloride, myristoyl choline chloride, butyryl iodide choline, sodium lauryl sulfate, and n-dodecyl-β-D-maltose. The excipients used include microcrystalline cellulose (e.g., CEOLUS (registered trademark) PH-F20JP and CEOLUS PH-301), chitosan, chitosan 11, lactose, respitose sv003, tricalcium phosphate, croscarmellose sodium cellulose, and KICCOLATE (registered trademark) ND-200.

[0138] 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 2000, Malvern Instrument Ltd.) at a dispersion pressure of 2 bar.

[0139] Based on the powder property measurement method in the Japanese Pharmacopoeia General Testing Method, each powder preparation with known mass is placed in a graduated cylinder, its volume is measured, and the bulk density is calculated by dividing the mass by the volume.

[0140] Table 1 shows the average particle size and bulk density. MCC-1 is CEOLUS PH-F20JP; MCC-2 is CEOLUS PH-301. As shown in Table 1, the average primary particle size of the microcrystalline cellulose (MCC) used in this invention is about 15 to 70 μm, and the bulk density is about 0.25 to 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.

[0141]

[0142] MCC-1=CEOLUS PH-F20JP; MCC-2=CEOLUS PH-301.

[0143] The powder compositions disclosed herein can be prepared by blending, grinding, stirring and granulating, fluidized 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 methods.

[0144] For Examples 1-6 and 8-14, and 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-step mixture, the active ingredients, absorption enhancers, and excipients were weighed, placed in a plastic bag, and initially mixed. To prepare the second-step mixture, the first-step mixture was mixed for 3 minutes using a mixing granulator (VGmm type, Powrex Corporation) at a stirring speed of 800 rpm and a chopping speed of 3000 rpm. To prepare the third-step mixture, 3 to 7 mL of water was added to the second-step mixture over 1 minute while further mixing, followed by another minute of mixing. In preparing the fourth-step mixture, the third-step mixture was removed from the granulator and passed through a 1.7 mm mesh sieve (JIS Z 8801, Tokyo Screen Co., Ltd.), followed by drying at 50°C for more than 2 hours in a cryogenic oven (NDO-450SD, Tokyo Rikakikai Co., Ltd.). Finally, the fourth-step mixture was graded into a powder formulation, which passed through a 180 μm sieve (JIS Z 8801, Iida-Seisakusho Japan Corporation) but remained on a 32 μm sieve (JIS Z 8801, Iida-Seisakusho Japan Corporation).

[0145] 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 component. The total weight of each composition was 120 mg. The weighed components were mixed for 5 minutes using a mortar and pestle to prepare a powder formulation.

[0146] For Comparative Examples 1 and 3, the active ingredients and absorption enhancers were weighed according to the weight percentages 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 the weighed components in 1 mL of a buffer solution at pH 4.01 using a vortex mixer and an ultrasonic cleaner.

[0147] For Comparative Example 2, the active ingredient and absorption enhancer were weighed according to the weight percentages of the total weight of each component listed in Table 2. The total volume of the composition was 10 mL. The liquid formulation was prepared by dissolving the weighed components in 10 mL of a buffer solution with pH 4.01 using a vortex mixer and an ultrasonic cleaner.

[0148] For Comparative Examples 4 to 6, the active ingredients and excipients were weighed according to the percentage of the total weight of each component listed in Table 2. The total weight of each composition was 70 mg. The powder formulation was prepared by mixing the weighed components in a bottle for 1 minute using a vortex mixer.

[0149] For Comparative Example 10, the active ingredient and absorption enhancer were weighed according to the percentage of the total weight of each component listed in Table 2. The total weight of the composition was 2 g. The powder formulation was prepared by mixing the weighed components in a bottle for 1 minute using a vortex mixer.

[0150] For Comparative Examples 12 to 14, the active ingredient and absorption enhancer were weighed according to the weight percentage of each component listed in Table 2. The total volume was 1 mL. The weighed components were dissolved in 1 mL of saline solution using a vortex mixer and an ultrasonic cleaner to prepare the liquid formulation.

[0151] For Comparative Examples 15 and 16, the active ingredients and absorption enhancers were weighed according to the percentage of total weight of each component listed in Table 2. The total weight of each composition was 90 mg. The powder formulation was prepared by mixing the weighed components in a bottle using a vortex mixer for 1 minute.

[0152] For Comparative Examples 18 and 19, the active ingredient, absorption enhancer, and excipient were weighed according to the percentage of total weight of each component listed in Table 2. The total weight of each composition was 1 g. The powder formulation was prepared by mixing the weighed components in a bottle using a vortex mixer for 1 minute.

[0153] For Comparative Example 21, the active ingredient, absorption enhancer, and excipient were weighed according to the percentage of total weight of each component listed in Table 2. The total weight of each composition was 300 g. To prepare the first-step mixture, the active ingredient, absorption enhancer, and excipient were weighed, placed in a plastic bag, and initially mixed. To prepare the second-step mixture, the first-step mixture was mixed for 1 minute at a stirring speed of 400 rpm and a chopping speed of 1500 rpm using a high-speed mixing granulator (FS-GS-5 type, FUKAE Powtec Corporation). To prepare the third-step mixture, 250 mL of water was added to the second-step mixture after 3 minutes of further mixing, followed by another minute of mixing. To prepare the fourth-step mixture, the third-step mixture removed from the granulator was dried at 50°C for more than 2 hours in a tray dryer (NDO-450SD, Tokyo Rikakikai Co., Ltd.). Finally, the mixture from the fourth step is graded into a powder formulation that passes through a 180 μm sieve (JIS Z 8801, Iida-Seisakusho Japan Corporation) but is retained on a 32 μm sieve (JIS Z 8801, Iida-Seisakusho Japan Corporation).

[0154] Table 2. Compositions of Powder Formulations

[0155] Abbreviations in Table 2: ASO = MALAT-1 antisense oligonucleotide; LCC = lauroyl choline chloride; PCC = palmitoyl choline chloride; MyCC, myristoyl choline chloride; EPI, adrenaline; LEVO, levodopa; Cyclo, cyclosporine; Calci, calcitonin; BCI, butyryl iodide choline; SLS, sodium lauryl sulfate; DDM, n-dodecyl-β-D-maltose; MCC-1, CEOLUS PH-F20JP; MCC-2, CEOLUS PH-301; TCP, tricalcium phosphate; CCS, croscarmellose sodium cellulose.

[0156] Example 2: Evaluation of the absorption of intranasal adrenaline powder composition in monkeys Table 3 shows the pharmacokinetic characteristics of the epinephrine compositions after intranasal administration. 60 mg of each of Examples 1, 2, 8, and 9, Comparative Examples 7 to 11, and 7 mg of Comparative Examples 4 to 6 were delivered into the right nasal cavity of conscious male cynomolgus monkeys using an intranasal delivery device (equivalent to 3 mg epinephrine) for the powder formulation. This intranasal delivery device included a nozzle, a container for the unit dose of the powder formulation, and a gas generating unit (SNBL, Ltd.). 100 μL of each of Comparative Examples 1-3 were delivered into the right nasal cavity of conscious male cynomolgus monkeys using a mucosal nebulizer (MAD) (equivalent to 3 mg epinephrine).

[0157]

[0158] To measure plasma adrenaline concentration, blood was collected from the femoral vein and placed in a test tube containing EDTA-2K. Plasma adrenaline concentration was then measured using HPLC.

[0159] Figure 1A-1F Tables 1 and 3 show the plasma adrenaline concentration-time curves and the corresponding plasma adrenaline concentrations and PK parameters, respectively.

[0160] like Figure 1A As shown, compared with the composition without an absorption enhancer (Comparative Example 1), the compositions in Comparative Examples 2-6 containing an absorption enhancer (e.g., LCC, SLS, or DDM) exhibited comparable or higher adrenaline concentrations. Figure 1B As shown, the adrenaline compositions of Comparative Examples 7 and 8 contain excipients (MCC or chitosan) and do not contain absorption enhancers. These compositions have comparable PK characteristics to the adrenaline composition of Comparative Example 1. Figure 1C As shown, the compositions in Examples 1 and 2, having a combination of LCC and MCC, significantly increased plasma adrenaline concentrations compared to using LCC or MCC alone. A surprising synergistic effect on plasma adrenaline concentrations was observed when LCC and MCC were combined in the composition. The adrenaline compositions containing both LCC and MCC (e.g., Examples 1 or 2) showed a much greater improvement in absorption than the sum of the absorption improvements of adrenaline compositions containing only LCC or only MCC (comparing Examples 2 and 7). Figure 1D Plasma epinephrine concentrations after administration of the following formulations are shown: liquid formulations containing epinephrine and lauroyl choline chloride (LCC), powder formulations containing epinephrine and chitosan, and powder formulations containing epinephrine, LCC, and chitosan. Figure 1EThe study showed plasma adrenaline concentrations after administration of a formulation containing adrenaline and LCC, or a formulation containing adrenaline, LCC, and lactose. Figure 1F The plasma epinephrine concentrations following administration of formulations containing the following substances are shown: 1) epinephrine, choline esters (e.g., LCC, PCC, or MyCC), and MCC; 2) epinephrine and MCC; or 3) epinephrine, butyryl iodinated choline (BCI), and MCC.

[0161] like Figure 1F As shown, the composition containing butyrylcholine (BCI) and MCC in Comparative Example 11 did not increase plasma adrenaline concentration, while the adrenaline composition containing both LCC and MCC in this example showed the best absorption improvement effect.

[0162] AUC 0-20min and AUC 0-30min The values ​​indicate the absorption capacity in the early stages after administration. As shown in Table 3, the AUC values ​​of adrenaline compositions (e.g., Examples 1 and 2) containing both alkylcholine (e.g., LCC) and MCC are... 0-20min and AUC 0-30min The AUC was significantly higher than that of the composition containing MCC but without any alkylcholine (Comparative Example 7). 0-20min and AUC 0-30min AUC of Example 1 0-30min For comparison, the AUC of Example 7 0-30min Approximately 4.6 times. AUC of Example 1 0-20min For comparison, the AUC of Example 7 0-20min Approximately 6.4 times. AUC of Example 2 0-30min For comparison, the AUC of Example 7 0-30min Approximately 5.2 times that of Example 2. 0-20min For comparison, the AUC of Example 7 0-20min Approximately 7.7 times higher. In some embodiments, LCC is a preferred alkylcholine absorption enhancer. For adrenaline compositions comprising both alkylcholine (e.g., LCC) and MCC, factors such as Cmax and AUC observed at later time points are important. 0-60min AUC 0-90min The other PK parameters of this combination are much higher than those of other combinations. In summary, alkylcholine, when combined with MCC, is an excellent adrenaline absorption enhancer.

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

[0164]

[0165] To measure plasma baclofen concentration, blood was collected from the femoral vein and placed in a test tube containing EDTA-2K. Plasma baclofen concentration was measured by LC-MS / MS.

[0166] Figures 2A-2E Tables 1 and 4 show the plasma baclofen concentration-time curves and the corresponding plasma baclofen concentrations and PK parameters, respectively. Figure 2A As shown, the baclofen compositions in Comparative Examples 13-16 containing absorption enhancers have higher baclofen concentrations than the compositions in Comparative Example 12 without enhancers. The absorption enhancers in Comparative Examples 13-16 are quite effective in enhancing absorption. Figure 2B As shown, in Comparative Example 17, MCC had a slight effect on enhancing absorption. In Comparative Example 18, no effect of lactose on enhancing absorption was observed. Figure 2C As shown, the baclofen compositions in Examples 3, 10, and 11, which combine alkylcholine (e.g., LCC, PCC, or MyCC) with MCC, significantly increased plasma baclofen concentrations. Figure 2D As shown, the baclofen composition containing LCC and lactose in Comparative Example 19 increased plasma baclofen concentration to a lesser extent than the composition containing LCC and MCC. Figure 2E As shown, the composition containing both SLS and MCC (Comparative Example 20) also enhanced baclofen absorption to a lesser extent than the formulation containing both LCC and MCC. In this example, the baclofen composition containing both LCC and MCC exhibited the most significant absorption improvement.

[0167] As shown in Table 4, the AUC of baclofen compositions containing both alkylcholine (e.g., LCC) and MCC is significantly higher than that of other compositions not containing the combination of alkylcholine and MCC. AUC of the compositions in Example 3 0-20minand AUC 0-30min The AUC values ​​of the compositions in Comparative Example 17 are respectively. 0-20min and AUC 0-30min Approximately 5.4 times and 4.4 times. For baclofen compositions containing both alkylcholine (e.g., LCC) and MCC, factors such as Cmax and AUC observed at later time points are also relevant. 0-60min AUC 0-90min AUC 0-240min The other PK parameters of this composition are much higher than those of other compositions.

[0168] Example 4: Evaluation of the absorption of levodopa intranasal powder composition in monkeys Table 5: Plasma levodopa concentrations and pharmacokinetic parameters after intranasal administration of levodopa preparations

[0169] Table 5 shows the examples containing levodopa. 50 mg of the powder formulation from Examples 4, 12 to 14 was delivered into the right nostril of conscious male cynomolgus monkeys using an intranasal delivery device consisting of a nozzle, a container for the unit dose of powder formulation, and a gas generating unit [50 mg (equivalent to 20 mg 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 levodopa) / both nostrils / body = 50 mg (equivalent to 25 mg levodopa) / nostril x both nostrils]. To measure plasma levodopa concentration, blood was collected from the femoral vein and placed in a tube containing EDTA-2K. A 25% sodium metabisulfite solution was mixed with the plasma at a volume ratio of 1:50. Plasma levodopa concentration was measured by LC-MS / MS.

[0170] Figure 3 Tables 1 and 5 show the plasma levodopa concentration-time curves and the corresponding plasma levodopa concentrations and p-values, respectively. Figure 3 As shown, compared to the composition in Comparative Example 21 which only contained MCC, the levodopa compositions in Examples 4, 12 to 14, which included a combination of choline esters (e.g., LCC, PCC, or MyCC) and MCC, significantly increased plasma levodopa concentrations. Although the levodopa dose in Example 4 was 20 mg (40% of the 50 mg powder composition) compared to the 50 mg dose in Comparative Example 21 (50% of the 100 mg powder composition administered), a significant increase in plasma concentrations was observed.

[0171] AUC 0-20min and AUC0-30min The values ​​indicate the absorption capacity in the early stages after administration. Table 5 shows the AUC values ​​of levodopa compositions containing MCC and LCC. 0-20min and AUC 0-30min AUC compared to LCC-free levodopa compositions 0-20min and AUC 0-30min Significantly higher than 7.7 times and 6.1 times. AUC of levodopa compositions containing choline esters PCC and MCC. 0-20min and AUC 0-30min AUC compared to PCC-free levodopa compositions 0-20min and AUC 0-30min Up to approximately 3.4 times. For levodopa compositions containing both alkylcholine and MCC, parameters such as Cmax and AUC observed at later time points (AUC) are also significant. 0-60min AUC 0-90min AUC 0-240min and AUC 0-480min The other PK parameters are much higher than those of levodopa compositions that contain only MCC.

[0172] Levodopa concentrations can also be measured in the cerebrospinal fluid (CSF) of the subject. CSF samples can be obtained from the cerebellomedullary cistern of animals (e.g., cynomolgus monkeys) under isoflurane anesthesia. CSF samples can be obtained from human subjects via spinal cord puncture. Similarly, CSF levodopa concentrations can be measured by LC-MS / MS.

[0173] Example 5: Evaluation of the absorption of calcitonin intranasal powder composition in monkeys Table 6 shows the examples containing calcitonin. 60 mg of each of the powdered formulations (equivalent to 0.1 mg calcitonin) were delivered into the right nasal cavity of conscious male cynomolgus monkeys using an intranasal delivery device. To measure plasma calcitonin concentration, blood was collected from the femoral vein and placed in a tube containing EDTA-2K. Plasma calcitonin concentration was measured by ELISA.

[0174] Table 6: Plasma calcitonin concentrations and pharmacokinetic parameters after intranasal administration of calcitonin preparations

[0175] Figure 4 Tables 1 and 6 show the plasma calcitonin concentration-time curves and the corresponding plasma calcitonin concentrations and PK parameters, respectively.

[0176] like Figure 4 As shown, the calcitonin composition in Example 5 contains a combination of LCC and MCC and significantly increases plasma calcitonin concentration compared to the composition in Comparative Example 22, which contains only MCC.

[0177] As shown in Table 6, the AUC of Example 5, which consists of calcitonin, LCC, and MCC, is... 0-20min and AUC 0-30min The AUC was significantly higher (approximately 2.6 times and 2.3 times higher, respectively) than that of Comparative Example 22, which consisted only of calcitonin and MCC. 0-20min and AUC 0-30min For calcitonin compositions containing both LCC and MCC, factors such as Cmax and AUC observed at later time points are important. 0-60min AUC 0-90min AUC 0-240min AUC 0-480min The other PK parameters of this composition are much higher than those of other compositions.

[0178] Example 6: Evaluation of the absorption of cyclosporine A intranasal powder composition in monkeys Table 7 shows the examples containing cyclosporine A. 60 mg of each of Example 6 and Comparative Example 23 were delivered into the right nostril of conscious male cynomolgus monkeys using an intranasal delivery device (equivalent dose of 30 mg cyclosporine A). To measure plasma cyclosporine A concentrations, blood was collected from the femur and placed in tubes containing EDTA-2K. Blood cyclosporine A concentrations were measured by LC-MS / MS.

[0179] Table 7: Plasma cyclosporine A concentration and pharmacokinetic parameters after intranasal administration of cyclosporine A preparations

[0180]

[0181] Figure 5 Tables 1 and 7 show the blood cyclosporine A concentration-time curves and the corresponding blood cyclosporine A concentrations and PK parameters, respectively. Figure 5 As shown, the cyclosporine A composition in Example 6 comprises a combination of LCC and MCC and significantly increases plasma cyclosporine A concentration within 240 minutes after administration compared to Comparative Example 23.

[0182] As shown in Table 7, the AUC of Example 6, which consists of cyclosporine A, LCC, and MCC, is... 0-20min and AUC 0-30min Significantly higher (approximately 11.6 times and 6.9 times higher, respectively) than the AUC of Comparative Example 23, which consisted of cyclosporine A and MCC (without alkylcholine). 0-20min and AUC 0-30min For cyclosporine A compositions containing both LCC and MCC, factors such as Cmax and AUC observed at later time points are important. 0-60minAUC 0-90min AUC 0-240min AUC 0-480min The other PK parameters of this composition are much higher than those of other compositions.

[0183] Example 7: Evaluation of the absorption of the antisense oligomer intranasal powder composition in monkeys Table 8 shows the examples containing antisense oligonucleotides. 70 mg of each of the antisense oligonucleotides from Example 7 and Comparative Example 24 were delivered into the right nasal cavity of conscious male cynomolgus monkeys using an intranasal delivery device for the powder formulation (equivalent dose of 23 mg antisense oligonucleotide). To measure plasma antisense oligonucleotide concentrations, blood was collected from the femoral vein at different time points and collected into tubes containing EDTA-2K. Plasma antisense oligonucleotide concentrations were measured by LC-MS / MS.

[0184] Table 8: Plasma antisense oligonucleotide concentrations and pharmacokinetic parameters after intranasal administration of antisense oligonucleotide formulations

[0185] Figure 6 Tables 1 and 8 show the plasma antisense oligonucleotide concentration-time curves and the corresponding plasma calcitonin concentrations and p-values, respectively. Figure 6 As shown, compared with Comparative Example 24 which contains MCC and TCP, the composition in Example 7, which contains a combination of LCC and MCC, significantly increased plasma antisense oligonucleotide concentrations after administration.

[0186] As shown in Table 8, the AUC of Example 7, which consists of antisense oligonucleotides, LCC, MCC, and TCP, is... 0-30min The value was significantly higher (up to 2.1 times higher) than that of Comparative Example 24, which consisted of antisense oligonucleotides, MCC, and TCP (excluding alkylcholine). 0-30min Value. AUC of Example 7 0-20min It was also significantly higher (up to 2.4 times) than the AUC of Comparative Example 24. 0-20min .

[0187] While preferred embodiments of this disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will now be conceived by those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments of this disclosure may be employed in the practice of this disclosure. The appended claims are intended to define the scope of this disclosure and therefore cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A pharmaceutical composition comprising: a) The active ingredient or a pharmaceutically acceptable salt thereof; b) Absorption enhancers containing choline esters; and c) Excipients containing microcrystalline cellulose; The pharmaceutical composition is formulated as a solid dosage form.

2. The pharmaceutical composition according to claim 1, wherein the choline ester is composed of formula [(CH3)3N ＋ CH2CH2OR]X - It means that X - It is a pharmaceutically acceptable counterion.

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

4. The pharmaceutical composition according to claim 2, wherein R is selected from C2-C 20 Alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl and C2-C 20 Heteroalkyl groups.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the choline ester comprises C8 to C96. 20 Alkylcholine, the C8 to C999 20 Alkylcholine is selected from: arachidocholine (C20), stearoylcholine (C18), palmitoylcholine (C16), myristoylcholine (C14), lauroylcholine (C12), hexanoylcholine (C10) and octanoylcholine (C8) and any combination thereof.

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. The pharmaceutical composition according to any one of claims 1 to 6, further comprising additional excipients.

8. The pharmaceutical composition of claim 7, wherein the additional 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 the pharmaceutical composition has an improved mucosal absorption rate compared with a corresponding pharmaceutical composition not containing the absorption enhancer, the improved mucosal absorption rate being measured by pharmacokinetic (PK) parameters of the active ingredient or its metabolite.

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

12. The pharmaceutical composition of claim 11, wherein the improved PK parameters include a higher maximum plasma concentration (Cmax).

13. The pharmaceutical composition of claim 11, wherein the improved PK parameters include a shorter time to reach Cmax (Tmax).

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

15. The pharmaceutical composition of claim 11, wherein the improved PK parameter includes higher bioavailability (F).

16. The pharmaceutical composition of claim 11, wherein the improved PK parameter includes a larger area under the curve (AUC).

17. The pharmaceutical composition of claim 16, wherein the AUC comprises AUC 0-10min AUC 0-20min AUC 0-30min AUC 0-60min AUC 0-90min AUC 0-120min AUC 0-240min AUC 0-480min , or any combination thereof.

18. The pharmaceutical composition according to any one of claims 9 to 17, wherein the improved PK parameter, compared to a corresponding pharmaceutical composition not containing an absorption enhancer, comprises an increase in AUC of at least about 200%, about 300%, about 400%, about 500%, or about 600%.

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-MS), 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. The pharmaceutical composition according to any one of claims 1 to 21, comprising about 10 mg to 60 mg of the excipient.

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

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

25. The pharmaceutical composition according to any one of claims 1 to 23, comprising about 70% to about 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 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 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 an additional excipient, wherein the additional 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 of 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 comprises 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 of 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-molecular-weight drug.

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

37. The pharmaceutical composition of claim 36, wherein the active ingredient comprises adrenaline or a pharmaceutically acceptable salt thereof.

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

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

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

41. The pharmaceutical composition of 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. The pharmaceutical composition according to any one of claims 1 to 43, comprising about 0.05 mg to about 30 mg of the active ingredient.

45. The pharmaceutical composition according to any one of claims 1 to 44, comprising the absorption enhancer and microcrystalline cellulose in a weight ratio of about 1:1 to about 1:

100.

46. ​​The pharmaceutical composition of claim 45, comprising the absorption enhancer and microcrystalline cellulose in a weight ratio of about 1:3 to about 1:

15.

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

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

49. The 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 of 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 a unit dose of the pharmaceutical composition weighs about 20 mg to about 250 mg.

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

54. The pharmaceutical composition according to claim 51, wherein a unit dose of the pharmaceutical composition weighs about 60 mg.

55. The pharmaceutical composition according to claim 51, wherein a unit dose of the pharmaceutical composition weighs about 80 mg.

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

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

58. The pharmaceutical composition of claim 56, wherein the Cmax of adrenaline or its metabolites in the pharmaceutical composition is at least about 150%, 250%, 350%, 450%, 550%, or 600% higher than that in a corresponding pharmaceutical composition not containing the choline ester.

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

60. The pharmaceutical composition of claim 59, wherein the AUC comprises AUC 0-20min AUC 0-30min AUC 0-60min AUC 0-90min AUC 0-120min , or any combination thereof.

61. The pharmaceutical composition according to claim 38, comprising 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.

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

63. The pharmaceutical composition of claim 61, wherein the Cmax of baclofen or its metabolites in the pharmaceutical composition is at least about 200%, 300% or 400% higher than that of a corresponding pharmaceutical composition not containing cholinesterase.

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

65. The pharmaceutical composition of claim 64, wherein the AUC comprises AUC 0-20min AUC 0-30min or AUC 0-240min , or any combination thereof.

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

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

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

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

70. The pharmaceutical composition of claim 67, wherein the AUC of levodopa or its metabolites in the pharmaceutical composition is at least about 300%, 400%, 500%, or 600% higher than that of a corresponding pharmaceutical composition not containing the choline ester.

71. The pharmaceutical composition of claim 70, wherein the AUC comprises AUC 0-20min AUC 0-30min AUC 0-60min , or any combination thereof.

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

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

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

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

76. The pharmaceutical composition of claim 75, wherein the AUC comprises AUC 0-20min AUC 0-30min AUC 0-120min , or any combination thereof.

77. The pharmaceutical composition according to claim 41, comprising 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.

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

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

80. The pharmaceutical composition of claim 79, wherein the AUC comprises AUC 0-20min AUC 0-30min AUC 0-480min , or any combination thereof.

81. The pharmaceutical composition according to claim 34, comprising 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.

82. The pharmaceutical composition of claim 81, wherein the Cmax of the nucleic acid molecules in the pharmaceutical composition is at least about 150% higher than that of a corresponding pharmaceutical composition not containing the choline ester.

83. The pharmaceutical composition of claim 81, wherein the AUC of the nucleic acid molecules in the pharmaceutical composition is at least about 200% higher than that of a corresponding composition not containing the choline ester.

84. The pharmaceutical composition of claim 83, wherein the AUC comprises AUC 0-20min AUC 0-30min AUC 0-60min AUC 0-480min , or any combination thereof.

85. The pharmaceutical composition according to any one of claims 1 to 84, wherein the pharmaceutical composition is formulated for mucosal application.

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

87. The pharmaceutical composition of 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 comprises a powder, tablet, patch, or capsule.

89. The pharmaceutical composition of claim 88, wherein the solid dosage form comprises a powder dosage form.

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

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

92. Use of the pharmaceutical composition according to any one of claims 1 to 89 in the prevention, diagnosis or treatment of systemic diseases.

93. Use of the pharmaceutical composition according to any one of claims 1 to 89 in the prevention, diagnosis or treatment of infection.

94. A method of treating a symptom in a subject in need, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 93.

95. The method of claim 94, wherein the condition includes a central nervous system (CNS) condition.

96. The method of claim 95, wherein the CNS condition 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, dysphoric disorder, 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 of claim 94, wherein the condition includes systemic conditions.

98. The method of claim 97, wherein the systemic symptoms include allergic reactions, fever, pain, inflammation, rheumatism, anxiety, psychosis, depression, epilepsy, Parkinson's disease, cerebral circulatory metabolic disorders, dystonia, autonomic neuropathy, dizziness, migraine, hypertension, angina pectoris, arrhythmia, cardiovascular disease, allergy, asthma, bronchoconstriction, 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 deficiency, malnutrition, poisoning, cancer, hyperimmune diseases, autoimmune diseases, otolaryngological diseases, oral diseases, urinary / genital diseases, hemorrhoids, skin diseases, hematopoietic / blood coagulation-related diseases, narcotic dependence, lifestyle-related diseases, or any combination thereof.

99. The method of claim 94, wherein the condition includes Parkinson's disease, pain, migraine, allergic reaction, epilepsy, anxiety, agitation, obesity, glioma, or Alzheimer's disease.

100. The method according to any one of claims 94 to 99, wherein the object includes a human or a non-human primate.

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

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

103. The method of claim 102, wherein the application comprises intranasal application.

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 condition in a subject, the method comprising administering a pharmaceutical composition to the subject, The pharmaceutical composition comprises an active agent for treating Parkinson's disease and an absorption enhancer, wherein the absorption enhancer comprises choline esters.

106. The method of claim 105, wherein the pharmaceutical composition further comprises microcrystalline cellulose.

107. The method of claim 105, wherein the pharmaceutical composition is a solid dosage form.

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

109. The method of claim 105, wherein the application comprises intranasal application.

110. The method of claim 105, wherein the disease or condition includes Parkinson's disease.

111. The method of claim 105, wherein the active agent for treating Parkinson's disease comprises levodopa.

112. The method according to any one of claims 105 to 111, wherein the application of the generated T max Less than 20 minutes.

113. The method of claim 112, wherein the application of the generated T max Less than 15 minutes.

114. The method of claim 112, wherein the application of the generated T max Less than 10 minutes.

115. The method according to any one of claims 105 to 111, wherein the application produces an AUC greater than 12000 ng x min / mL.

116. The method according to any one of claims 105 to 111, wherein the application of the generated C max The concentration should be at least 300 ng / mL.

117. The method according to any one of claims 105 to 111, wherein the application of the generated C max The concentration should be at least 500 ng / mL.

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