Co-crystals of active substances with carbohydrate molecule backbones

Abstract

Co-crystals comprising an API and a molecular scaffold comprising a saccharide are described herein. The co-crystals can be used to improve drug solubility and bioavailability, tailor API release profiles, achieve controlled hydrophilicity and lipophilicity, enhance stability, improve taste and palatability, reduce the need for chemical modifications and process steps, and are applicable to a wide range of APIs. In various embodiments, the APIs include, but are not limited to, stimulants, antibiotics, antiviral drugs, antifungal drugs, and anticancer drugs. The co-crystals provided herein can be prepared by a variety of different methods, and in several embodiments, a variety of APIs can be co-crystallized with a molecular scaffold comprising a saccharide.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 543,472, filed October 10, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to the formulation, synthesis, scale-up preparation, and application of novel solid-state crystalline materials with carefully designed molecular structures suitable for the effective support and delivery of a wide range of active ingredients or combinations thereof. More specifically, this disclosure relates to the formation of cocrystals using a carbohydrate-based molecular framework and the integration of active ingredients suitable for various applications. These active ingredients may include stimulants such as nicotine, various active pharmaceutical ingredients (APIs), supplements, nutritional supplements, dietary supplements, homeopathic ingredients, cosmetic ingredients, and various combinations thereof. In general, API cocrystals can be used for a wide range of therapeutic, preventative, recreational, nutritional, and health and wellness applications. Background Technology

[0004] Active pharmaceutical ingredients (APIs) can exist in a variety of different solid forms, such as polymorphs, solvates, hydrates, salts, eutectics, and amorphous solids. Each form exhibits unique physicochemical properties that can profoundly affect bioavailability, manufacturability, purification, and stability. For a review on this topic, see, for example, AVYadav, “Co-crystals: A novel Approach to Modify Physicochemical Properties of Active Pharmaceutical Ingredients,” Indian J. Pharm. Sci., 71(4), 359-370, 2009.

[0005] Despite researchers' continued efforts to utilize these physical forms to optimize the routes of administration and dosage regimens of various APIs, predicting and optimizing API delivery in different physical forms remains a challenge. Furthermore, the original form of the active ingredient (e.g., pure API) is susceptible to various environmental exposures and conditions that can lead to decomposition of the active ingredient or induce decomposition accompanied by side reactions (forming byproducts or impurities). Such damaging conditions can include oxygen, visible light, ultraviolet light, water or moisture, low or high temperatures, low or high pressure, and the acidity / alkalinity of the local environment.

[0006] Specifically, for (S)-nicotine, the API is an oily, pale yellow liquid that decomposes upon exposure to light and is known to oxidize in air to form reaction products that can further undergo downstream reactions. Although using nicotine salts improves stability compared to free alkaloids, nicotine salts are known to produce a lower pH, leading to corrosion of metal devices and packaging. Furthermore, nicotine salts diminish the throat hit desired by nicotine users from free nicotine; therefore, there remains a need to develop a non-salt crystalline solid form of (S)-nicotine.

[0007] In other examples, the original API components are limited by their inherent low chemical solubility, stability, bioavailability, release profile, and unpleasant taste and palatability. Furthermore, some APIs require chemical modification to alter the molecular structure of their precursors to obtain better physicochemical and pharmacological properties, which is both time-consuming and labor-intensive. Therefore, there is a need to develop novel formulation technologies, such as co-crystallization paradigms, to integrate APIs and address these issues in an efficient, low-cost, and easy-to-operate manner.

[0008] Co-crystallization has been recognized as a promising technique for enhancing the stability and delivery performance of APIs. However, many existing methods face challenges in terms of scaffold and encapsulation capabilities, as well as issues of scalability, predictability, and efficiency when targeting a wide range of active ingredients.

[0009] While contemporary therapeutic, health, and recreational products are diverse, they often face inherent challenges related to optimizing delivery, onset time, release duration, and patient safety. For example, in nicotine delivery, the ongoing pursuit is to develop methods that achieve both rapid onset and prolonged release, while significantly reducing the intake of harmful and potentially harmful substances (HPHCs)—crucial for harm reduction. Similarly, the treatment of serious diseases such as pneumonia, chronic obstructive pulmonary disease (COPD), and lung cancer requires innovations that improve targeting accuracy, regulate release rates (from immediate onset to prolonged duration), and enhance the stability and safety of active pharmaceutical ingredients (APIs). This need extends beyond systemic diseases to localized conditions such as skin and wound infections. The overall goal remains consistent: to maximize therapeutic efficacy and efficiency while minimizing side effects.

[0010] Therefore, there remains a need to continue innovating, developing, and optimizing new solid forms of APIs, including the use of novel excipients to form API eutectics. Summary of the Invention

[0011] According to various embodiments of this disclosure, it has now been surprisingly discovered that carbohydrate molecular backbones can co-crystallize with various APIs to form stable co-crystallizations, and that these co-crystallizations enable predictable and controlled delivery of APIs in a variety of applications.

[0012] Surprisingly, it was also found that by carefully selecting APIs, suitable sugar linkers as building blocks of the molecular skeleton, appropriate solvents and additives, the optional presence of metal ions, and the pH value tailored during the co-crystallization reaction, the long co-crystallization process involving slow and reversible self-assembly and self-correction can be significantly shortened.

[0013] In various embodiments, the cocrystal formed by the active ingredient and the glycosylated molecular backbone can provide improved drug solubility and bioavailability, customizable API release profiles, controllable hydrophilicity and lipophilicity, enhanced stability due to the crystalline form compared to amorphous or liquid forms, improved taste and palatability suitable for oral or oral-related applications, reduced need for chemical modifications and processing steps, and applicability to a wide range of APIs, food additives, preservatives, and pharmaceutical excipients.

[0014] In various embodiments, the carbohydrate molecular skeleton used for co-crystallization with the active ingredient may include, for example, a metal-organic framework (MOF), a covalent organic framework (COF), a hydrogen-bonded organic framework (HOF), a coordination polymer, etc.

[0015] In a more specific example, the carbohydrate molecular skeleton includes a cyclodextrin metal-organic skeleton (CD-MOF).

[0016] In some embodiments, the eutectic comprises (S)-nicotine co-crystallized with a carbohydrate molecular backbone. The carbohydrate molecular backbone may include CD-MOF. This type of (S)-nicotine eutectic is significantly more stable than (S)-nicotine free base.

[0017] In some embodiments, the cocrystal includes the following active ingredients: antibiotics, antiviral agents, antifungal agents, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs, corticosteroids, antihistamines, antidepressants, hallucinogens, analgesics, anesthetics, central nervous system (CNS) depressants, stimulants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, cannabis, herbal extracts or supplements (e.g., phenols, fatty acids, tannins, coumarins, flavonoids, lignans, alkaloids, saponins, terpenoids, polysaccharides, cannabinoids, amino acids, glycosides, esters, steroids, vitamins, antioxidants, etc.).

[0018] Co-crystallization methods based on glycomolecular skeletons are versatile and applicable to a variety of active ingredients, and hold promise for revolutionizing their delivery, efficacy, efficiency, and stability.

[0019] The cocrystals formed by this method are suitable for various routes of administration, including oral, inhalation, transdermal, sublingual, and intravenous administration, thereby expanding their therapeutic applications.

[0020] In several embodiments, a eutectic is provided, comprising an active ingredient (also referred to as an API) and a molecular backbone comprising sugars, wherein the molecular backbone and the active ingredient are present in a common lattice.

[0021] In several embodiments, the active ingredient is selected from stimulants, antibiotics, antiviral agents, antifungal agents, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antihistamines, antidepressants, hallucinogens, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, vasodilators, anticholinergic drugs, vaccines, insulin, sedative-hypnotics, antipsychotics, immunosuppressants, enzymes, anticoagulants, chemotherapeutic drugs, antidiabetic drugs, antiemetics, anticonvulsants, hormones. The group consisting of gene therapy vectors, monoclonal antibodies, antiparasitic agents, antifibrotic agents, antiarrhythmic agents, antiplatelet agents, biological response modifiers, radiopharmaceuticals, penetrants, antituberculosis drugs, antileukotriene agents, antimigraine drugs, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, triterpenes, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and combinations thereof.

[0022] In several embodiments, the active ingredient comprises a stimulant. In several embodiments, the active ingredient comprises an antibiotic. In several embodiments, the active ingredient comprises an antiviral agent. In several embodiments, the active ingredient comprises an antifungal agent. In several embodiments, the active ingredient comprises an anti-inflammatory agent. In several embodiments, the active ingredient comprises a nonsteroidal anti-inflammatory drug (NSAID). In several embodiments, the active ingredient comprises a corticosteroid. In several embodiments, the active ingredient comprises an antihistamine. In several embodiments, the active ingredient comprises an analgesic. In several embodiments, the active ingredient comprises an anesthetic. In several embodiments, the active ingredient comprises a hormone.

[0023] In several embodiments, the active ingredient comprises an alkaloid capable of acting as a stimulant. In several embodiments, the active ingredient comprises (S)-nicotine. In several embodiments, the active ingredient comprises caffeine. In several embodiments, the active ingredient comprises both caffeine and nicotine.

[0024] In several embodiments, the active ingredient comprises an antibiotic. In several embodiments, the active ingredient comprises multiple antibiotics. In several embodiments, when multiple antibiotics are used, the multiple antibiotics are selected from the same class (e.g., the same structure or mechanism of action). In several embodiments, when multiple antibiotics are used, the multiple antibiotics are selected from different classes (e.g., different structures or mechanisms of action). In several embodiments, the antibiotic is selected from the class of antibiotics composed of β-lactams, cephalosporins, carbapenems, monocyclic β-lactams, macrolides, fluoroquinolones, aminoglycosides, tetracyclines, sulfonamides, glycopeptides, oxazolidinones, rifamycins, macrolides, nitroimidazoles, aminoglycosides, cyclic lipopeptides, lincosamides, and combinations thereof.

[0025] In several embodiments, the antibiotic is selected from the group consisting of: benzathine penicillin, benzathine penicillin (penicillin G), benzathine penicillin G, oxazolidin, penicillin V, phenoxymethylpenicillin (penicillin V), procaine penicillin, feneccillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxazolidin, temoxicillin, amoxicillin, ampicillin, mecillin, piperacillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, and combinations thereof.

[0026] In several embodiments, the antibiotic is selected from the group consisting of: cefazolin, cephalexin, cephalosporin C, cefotaxime, cefepime, cefuroxime, cefaclor, cefprozil, cefamandole, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cefpirome, cefuroxime, cefuroxime, cefepime, and combinations thereof.

[0027] In several embodiments, the antibiotic is selected from the group consisting of imipenem, meropenem, biapenem, doripenem, ertapenem, faropenem, panipenem, rezupenem, telbipenem, thiomycin, and combinations thereof.

[0028] In several embodiments, the antibiotic is selected from the group consisting of aztreonam, tegafur, nocamycin A, tabutoxin β-lactam, and combinations thereof.

[0029] In several embodiments, the antibiotic is selected from the group consisting of: erythromycin, azithromycin, clarithromycin, tererythromycin, carbamycin A, josamycin, tylosin, midecamycin / midecamycin acetate, pyruvicin, spiramycin, pyruvicin acetate, tylosin / tylosin, roxithromycin, borobam, and combinations thereof.

[0030] In several embodiments, the antibiotic is selected from the group consisting of: moxifloxacin, ciprofloxacin, levofloxacin, flumethin, oxacrylic acid, rosofaxin, sinofloxacin, nalidixic acid, pyrrolic acid, pipemidic acid, flerofloxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gapafloxacin, pazufloxacin, sparfloxacin, timafloxacin, tosufloxacin, clinfloxacin, gatifloxacin, sitafloxacin, prulifloxacin, besifloxacin, derafloxacin, gemifloxacin, trovafloxacin, ozenafloxacin, danoxacin, difluorofloxacin, enrofloxacin, ibafloxacin, mabofloxacin, obbifloxacin, sarafloxacin, and combinations thereof.

[0031] In several embodiments, the antibiotic is selected from the group consisting of: kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B / C, neomycin E, streptomycin, prazomicin, and combinations thereof.

[0032] In several embodiments, the antibiotic is selected from the group consisting of tetracycline, doxycycline, minocycline, chlortetracycline, oxytetracycline, demethylchlortetracycline, methacycline, rolicycline, tigecycline, eracycline, salazine, omalicycline, and combinations thereof.

[0033] In several embodiments, the antibiotic is selected from the group consisting of: sulfamethoxazole, sulfonamides, sulfasalazine, sulfacetyl, sulfadiazine, sulfadiazine, sulfafuran (sulfaisoxazole), sulfadiazine (sulfaisodimethazine), sulfaguanidine, sulfamozole, sulfanilide, sulfadimethoxypyrimidine, sulfamethoxypyridazine, sulfamethoxydiazine, sulfadoxine, sulfamethopyrazine, terephthalic acid, and combinations thereof.

[0034] In several embodiments, the antibiotic is selected from the group consisting of vancomycin, teicoplanin, tervavancin, ramoranine, decaranine, kobomycin, compstatin, orivancin, dapavancin, and combinations thereof.

[0035] In several embodiments, the antibiotic is selected from the group consisting of linezolid, pofuzumamide, terdizazole, latizazole, cycloserine, contezolid, and combinations thereof.

[0036] In several embodiments, the antibiotic is selected from the group consisting of rifampin, rifabutin, rifapentine, rifaximin, and combinations thereof.

[0037] In several embodiments, the active substance comprises an antifungal agent. In several embodiments, the antifungal agent is selected from the group consisting of: amphotericin B, voriconazole, itraconazole, nystatin, hamycin, natamycin, rimomycin, bifonazole, butonazole, clotrimazole, econazole, fenteconazole, isoconazole, ketoconazole, ruliconazole, miconazole, omeconazole, oxiconazole, sertaconazole, thioconazole, tiaconazole, abaconazole, ciproconazole, ifluconazole, fluconazole, fluconazole, isaconazole, posaconazole, propiconazole, rivanazole, terconazole, abafenoxanazole, butenafine, naftifine, terbinafine, anidoxanazole, carbafenoxanazole, etc. Porfenicol, micafungin, ibuprofen, acricin, amorolfen, oxalones, benzoic acid, flavone, ciclopirox ketone (ciclopirox ketoneamine), cloiodohydroxyquine, coal tar, copper(II) sulfate, crystal violet, chlorhexidine, chlorphenesin, diiodoquinoline (iodoquinol), fluorocytosine (5-fluorocytosine), fumonisin, griseofulvin, haloroside, mitefoxin, nicotinic acid, oromethiophene, piroctone ethanolamine, valerate, potassium iodide, potassium permanganate, selenium disulfide, sodium thiosulfate, sulfur, tonaphthyl ester, triacetin, undecenoic acid, zinc pyrithione and combinations thereof.

[0038] In several embodiments, the active substance comprises an antiviral agent. In several embodiments, the antiviral agent is selected from the group consisting of: oseltamivir, remdesivir, favipiravir, entfuvirtide, amantadine, rimantadine, plelecanidine, acyclovir, zidovudine, lamivudine, raltegravir, erteiravir, dolutegravir, formivavir, zanamivir, sofosbuvir, ledipasvir, velpatasvir, voxiprevir, irbavir, grazoprevir, glucareprevir, pibumetasvir, and combinations thereof.

[0039] In several embodiments, the active substance includes hormones, such as epinephrine.

[0040] In several embodiments, the chemotherapeutic drugs are selected from the group consisting of platinum compounds, anthracyclines, tyrosine kinase inhibitors, taxanes, vinca alkaloids, topoisomerase inhibitors, epidermal growth factor receptor (EGFR) inhibitors, programmed death factor-1 (PD-1) inhibitors, camptothecin (CPT), 9-nitrocamptothecin (9-NC), 5-fluorouracil (5-FU), bevacizumab, temozolomide, and combinations thereof.

[0041] In several embodiments, the chemotherapy drug is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, tetranitrate, phenanthreneplatin, picoplatin, saxaplatin, and combinations thereof.

[0042] In several embodiments, the chemotherapeutic drug is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, penoxorubicin, and combinations thereof.

[0043] In several embodiments, the chemotherapy drug is selected from the group consisting of imatinib, gefitinib, erlotinib, dasatinib, sunitinib, adavosertib, lapatinib, pazopanib, and combinations thereof.

[0044] In several embodiments, the chemotherapy drug is selected from the group consisting of: paclitaxel, docetaxel, taxine A, taxine B, taxine C, baccatin III, 10-deacetylated baccatin, taxine A, taxine B, and combinations thereof.

[0045] In several embodiments, the chemotherapy drug is selected from the group consisting of: vincristine, vinblastine, vinorelbine, vinaminol, vinorelbine, vinbutin, vinpocetine, minocycline, methoxyminocycline, minocycline, vindiflumine, deoxyvinaminol, vinpocetine, and combinations thereof.

[0046] In several embodiments, the chemotherapy drug is selected from the group consisting of topotecan, irinotecan, camptothecin, belotecone, silotecan, indomethacin, topovalle, BE-13793C, indotecan, indimitecan, neomycin, coumarin, nalidixic acid, sinofloxacin, norfloxacin, and combinations thereof.

[0047] In several embodiments, the chemotherapy drug is selected from the group consisting of: gemcitabine, methotrexate, decitabine, nerabine, clofarabine, capecitabine, fludarabine, cradabine, 5-fluorouracil, cytarabine, and combinations thereof.

[0048] In several embodiments, the chemotherapy drug is selected from the group consisting of erlotinib, gefitinib, osimertinib, afatinib, lapatinib, cetuximab, dacomitinib, vandetanib, ometinib, ametinib, panitumumab, icotinib, and combinations thereof.

[0049] In several embodiments, the chemotherapy drug is selected from the group consisting of nivolumab, pembrolizumab, semipril, and combinations thereof.

[0050] In several embodiments, the chemotherapeutic agent is selected from the group consisting of: camptothecin (CPT), 9-nitrocamptothecin (9-NC), 5-fluorouracil (5-FU), bevacizumab, temozolomide, and combinations thereof.

[0051] In several embodiments, the chemotherapy drug is selected from the group consisting of atezolizumab, avelumab, durvalumab, ipilimumab, trimemumab, rilatumab, and combinations thereof.

[0052] In several embodiments, the molecular framework is selected from the group consisting of metal-organic frameworks (MOFs), covalent organic frameworks (COFs), hydrogen-bonded organic frameworks (HOFs), coordination polymers, or other eutectic forms. In several embodiments, the resulting API-CD-MOF is organized in a eutectic form rather than an amorphous form. In several embodiments, the molecular framework comprises a cyclodextrin-based metal-organic framework (CD-MOF). In several embodiments, the CD-MOF comprises cyclodextrin and an alkali metal cation. In several embodiments, the cyclodextrin is selected from α-, β-, or γ-cyclodextrin. In several embodiments, the cyclodextrin comprises α-cyclodextrin. In several embodiments, the cyclodextrin comprises β-cyclodextrin. In several embodiments, the cyclodextrin comprises γ-cyclodextrin. In several embodiments, the alkali metal cation is selected from the group consisting of lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+) ions. In several embodiments, the alkali metal cation comprises lithium (Li+) ions. In several embodiments, the alkali metal cation includes sodium (Na+) ions. In several embodiments, the alkali metal cation includes potassium (K+) ions. In several embodiments, the alkali metal cation includes rubidium (Rb+) ions. In several embodiments, the alkali metal cation includes cesium (Cs+) ions. In several embodiments, the CD-MOF includes β-cyclodextrin and sodium (Na+) ions. In several embodiments, the CD-MOF includes γ-cyclodextrin and potassium (K+) ions.

[0053] According to the embodiments, the API-CD-MOF eutectic provided herein can be prepared by processes selected from spray drying, freeze drying, co-solvent crystallization, cooling crystallization, evaporation crystallization, supercritical fluid crystallization, slurry conversion, liquid antisolvent precipitation, and combinations thereof.

[0054] In several embodiments, a eutectic is provided comprising (S)-nicotine and a cyclodextrin-based metal-organic framework (CD-MOF), wherein the (S)-nicotine and the CD-MOF exist in a common lattice. In several embodiments, the cyclodextrin comprises α-, β-, or γ-cyclodextrin, and the CD-MOF further comprises an alkali metal cation selected from lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+) ions.

[0055] In several embodiments, a eutectic is also provided, comprising (S)-nicotine and a cyclodextrin-based molecular framework, wherein the (S)-nicotine and the molecular framework exist in a common lattice, and the lattice is completely free of metal ions.

[0056] In several embodiments, a method for preparing an API-eutectic solid is provided, the method comprising: preparing a mixture comprising metal ions, cyclodextrin, water, and a first organic solvent; adding a solution of API in a second organic solvent to the mixture; and adding sufficient amounts of the first organic solvent and / or the second organic solvent to the mixture to induce co-crystallization and form an API-eutectic solid. In several embodiments, the first and second organic solvents are selected from the group consisting of ethanol, methanol, acetonitrile, isopropanol, propylene glycol, glycerol, and mixtures thereof. In several embodiments, both the first and second organic solvents are ethanol.

[0057] In several embodiments, a method for preparing an API-eutectic solid is also provided, the method comprising: preparing a solution in a solvent or solvent mixture, the solution comprising (i) an active pharmaceutical ingredient (API), (ii) a cyclodextrin selected from α-, β-, and γ-cyclodextrins, and (iii) at least one alkali metal cation selected from lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+) ions; feeding the solution into a spray drying apparatus; atomizing the solution into droplets in the spray drying apparatus; evaporating the solvent or solvent mixture from the droplets in a drying chamber of the spray drying apparatus under conditions suitable for forming solid particles; and collecting the solid particles from the drying chamber, wherein the solid particles comprise a eutectic of API and a cyclodextrin metal-organic framework (CD-MOF). In several embodiments, the spray drying apparatus is operated under selected conditions to promote the formation of the eutectic by controlling at least one of the following: the temperature inside the drying chamber, the solvent evaporation rate, or the airflow rate through the drying chamber. In several embodiments, the spray drying apparatus promotes eutectic formation by controlling the temperature within the drying chamber. In several embodiments, the spray drying apparatus promotes eutectic formation by controlling the solvent evaporation rate. In several embodiments, the spray drying apparatus promotes eutectic formation by controlling the airflow rate through the drying chamber.

[0058] In several embodiments, the solvent is selected from the group consisting of water, ethanol, methanol, isopropanol, glycerol, propylene glycol, acetone, dimethylformamide (DMF), diethylformamide (DEF), and mixtures thereof. In several embodiments, the solvent is a mixture of ethanol and water. In several embodiments, the water:ethanol ratio may be about 100:1, about 75:1, about 50:1, about 25:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:25, about 1:50, about 1:75, about 1:100, or any ratio between the values ​​listed above. In several embodiments, the ratio of solvent 1 to solvent 2 may be approximately 100:1, approximately 75:1, approximately 50:1, approximately 25:1, approximately 20:1, approximately 15:1, approximately 10:1, approximately 9:1, approximately 8:1, approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, approximately 2:1, approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:6, approximately 1:7, approximately 1:8, approximately 1:9, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:25, approximately 1:50, approximately 1:75, approximately 1:100, or any ratio between the values ​​listed above.

[0059] In several embodiments, the temperature inside the drying chamber is maintained between 50°C and 300°C, including 80°C to 200°C, 50°C to 60°C, 60°C to 70°C, 70°C to 80°C, 80°C to 90°C, 90°C to 100°C, 100°C to 110°C, 110°C to 120°C, 120°C to 130°C, and 130°C to 140°C. 140°C to 150°C, 150°C to 160°C, 160°C to 170°C, 170°C to 180°C, 180°C to 190°C, 190°C to 200°C, 200°C to 225°C, 225°C to 250°C, 250°C to 275°C, 275°C to 300°C, and any temperature range (including the endpoints) between the ranges listed above.

[0060] In some embodiments, the airflow rate through the drying chamber is maintained between 5 and 1000 L / min. In some embodiments, the airflow rate through the drying chamber is maintained between 10 and 500 L / min. In several embodiments, the airflow rate through the drying chamber is maintained within one of the following ranges: 5 to 10 L / min, 10 to 20 L / min, 20 to 30 L / min, 30 to 40 L / min, 40 to 50 L / min, 50 to 60 L / min, 60 to 70 L / min, 70 to 80 L / min, 80 to 90 L / min, 90 to 100 L / min, 100 to 125 L / min, 125 to 150 L / min, 150 to 175 L / min, 175 to 200 L / min, 200 to 225 L / min, 225 to 250 L / min, 250 to 275 L / min, 275 to 300 L / min, 300 to 325 L / min, 325 to 350 L / min, 350 to 375 L / min, 375 to 400 L / min, 400 to 425 L / min. L / min, 425 to 450 L / min, 450 to 475 L / min, 475 to 500 L / min, 500 to 600 L / min, 600 to 700 L / min, 700 to 800 L / min, 800 to 900 L / min, 900 to 1000 L / min, and any airflow rate range (including the endpoints) between the ranges listed above.

[0061] In several embodiments, the atomization of the solution can be achieved by using ultrasonic, pneumatic, pressure atomizers, rotary atomizers, electrostatic, air-assisted, hydraulic, hydraulic and air-driven rotary, or other spray configuration nozzles.

[0062] In some embodiments, the eutectic has a particle size distribution between 0.1 and 300 µm. In some embodiments, the eutectic has a particle size distribution between 0.2 µm and 200 µm. In several embodiments, the grain size distribution of the eutectic may be within one of the following ranges: 0.1 µm to 0.2 µm, 0.2 µm to 0.5 µm, 0.5 µm to 0.75 µm, 0.75 µm to 1 µm, 1 µm to 5 µm, 5 µm to 10 µm, 10 µm to 20 µm, 20 µm to 30 µm, 30 µm to 40 µm, 40 µm to 50 µm, 50 µm to 60 µm, 60 µm to 70 µm, 70 µm to 80 µm, 80 µm to 90 µm, 90 µm to 100 µm, 100 µm to 125 µm, 125 µm to 150 µm, 150 µm to 175 µm, 175 µm to 200 µm, 200 µm to 250 µm, 250 µm to 300 µm. µm, and any particle size range (including the endpoints) between the ranges listed above.

[0063] In several embodiments, the method further includes adjusting the pH of the solution to between 3 and 9 prior to the atomization step. In several embodiments, the pH is adjusted to about 3. In several embodiments, the pH is adjusted to about 4. In several embodiments, the pH is adjusted to about 5. In several embodiments, the pH is adjusted to about 6. In several embodiments, the pH is adjusted to about 7. In several embodiments, the pH is adjusted to about 8. In several embodiments, the pH is adjusted to about 9. In several embodiments, the pH may be adjusted to any pH between the above values.

[0064] In several embodiments, the API and CD-MOF component (α-, β-, or γ-cyclodextrin, and an alkali metal cation selected from Li+, Na+, K+, Rb+, and Cs+ ions) are present in a mass percentage ratio of 10:1 to 1:30 (API:CD-MOF). In several embodiments, the API and CD-MOF component (α-, β-, or γ-cyclodextrin, and an alkali metal cation selected from Li+, Na+, K+, Rb+, and Cs+ ions) are present in a mass percentage ratio of 100:1 to 1:100 (API:CD-MOF), including 100:1, about 75:1, about 50:1, about 25:1, about 20:1, about 15:1, about 10:1, etc. 1. Approximately 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:50, 1:75, 1:100, or any ratio between the values ​​listed above. In several embodiments, the ratio of solvent 1 to solvent 2 may be approximately 100:1, approximately 75:1, approximately 50:1, approximately 25:1, approximately 20:1, approximately 15:1, approximately 10:1, approximately 9:1, approximately 8:1, approximately 7:1, approximately 6:1, approximately 5:1, approximately 4:1, approximately 3:1, approximately 2:1, approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:6, approximately 1:7, approximately 1:8, approximately 1:9, approximately 1:10, approximately 1:15, approximately 1:20, approximately 1:25, approximately 1:50, approximately 1:75, approximately 1:100, or any ratio between the values ​​listed above.

[0065] In several embodiments, a spray drying apparatus configured to perform the methods disclosed herein is provided, comprising a solution feeding system, an atomizer, a drying chamber, a temperature control system for regulating the temperature inside the drying chamber, an airflow system for regulating the airflow rate through the drying chamber, and a particle collection system.

[0066] In several embodiments, a dosage form of an API is provided, comprising: the API co-crystallized in a co-crystallization, the co-crystallization comprising the API and a molecular backbone comprising sugars in a common lattice; at least one excipient; and at least one matrix. In several embodiments, the at least one excipient and / or the at least one matrix contribute to the dosage form or a physical property of the dosage form. In several embodiments, the dosage form is selected from oral pouches (i.e., pouch-shaped dosage forms for placing and delivering active ingredients such as drugs in the oral cavity), dry powder inhalers, nasal inhalers, nasal sprays, transdermal patches, topical creams, tablets, lozenges, capsules, blister packs, gummies, chewing gum, oral dissolving films, oral pouches, chewable tablets or chewable sticks, nebulizer solutions, oral solutions or suspensions, buccal or sublingual tablets or films, effervescent tablets or granules, suppositories or vaginal suppositories, injection solutions or injection suspensions, intramuscular injections, intravenous injections. The group consisting of subcutaneous injection solutions, lyophilized formulations for reconstitution, implantable devices or reservoir formulations, microspheres or nanoparticles, liposome formulations, inhalable aerosol sprays or solutions, ear drops or ophthalmic solutions, microneedle patches, emulsions, microemulsions, nanoemulsions, sustained-release or controlled-release formulations, films or meshes for surgical implantation, powders or granules for reconstitution, orally disintegrating tablets or readily dissolving tablets, vaginal rings or vaginal membranes, anal rings or plugs, mouthwashes or rinsing solutions, subcutaneous or intradermal patches, and sheets.

[0067] In several embodiments, a method is provided for treating a disease in an individual with such need, treating a physical or mental illness in an individual with such need, inducing stimulation in an individual with such need, and / or promoting general health in an individual with such need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active ingredient and a molecular backbone comprising sugars, wherein the molecular backbone and the active ingredient are present in a common crystal lattice.

[0068] In several embodiments, the disease or condition is selected from the group consisting of asthma, cystic fibrosis, chronic sinusitis, allergy, pulmonary hypertension, pulmonary fibrosis, acute respiratory distress syndrome, pulmonary infection, antimicrobial resistant (AMR) pulmonary infection, pneumonia, chronic obstructive pulmonary disease (COPD), lung cancer, pathogenic or neuropathic pain, substance or opioid abuse disorder, addiction, depression, central nervous system (CNS) disease, sleep disorder, skin infection, and wound infection.

[0069] In several embodiments, the active ingredient is selected from the group consisting of stimulants, antibiotics, antiviral agents, antifungal agents, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antihistamines, antidepressants, hallucinogens, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, triterpenes, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and combinations thereof.

[0070] In several embodiments, a method is provided for treating a disease or symptom, inducing stimulation, or promoting the general health of a subject, the method comprising administering to the subject a composition comprising a eutectic or dosage form according to the present disclosure.

[0071] In several embodiments, the use of the eutectic or dosage form according to this disclosure is provided for treating a disease or symptom, inducing stimulation, or promoting the general health of a subject.

[0072] In several embodiments, the use of the cocrystal or dosage form according to the present disclosure in the preparation of a medicament for treating a disease or condition, inducing stimulation, or promoting the general health of a subject is provided.

[0073] This invention pertains to the field of therapeutic and recreational product delivery, proposing a novel cocrystal formulation for the programmable release of active ingredients. At its core, this invention aims to revolutionize the delivery mechanism of substances such as nicotine, focusing on rapid onset of action, prolonged release, and significantly reduced intake of harmful or potentially harmful substances (HPHCs) to improve safety. Furthermore, this innovative embodiment extends to targeted therapy for key health conditions, including local and systemic diseases. From lung cancer, COPD, and pneumonia to localized skin and wound infections, this formulation aims to optimize drug targeting, modulate release patterns, and enhance therapeutic efficacy while reducing side effects. Given its broad applicability, this invention represents a step towards redefining the modern drug delivery paradigm. Attached Figure Description

[0074] The subject matter is specifically pointed out and clearly claimed in the conclusion of the specification. However, a more complete understanding is best obtained by considering the following figures, along with the detailed description and claims:

[0075] Figure 1An implementation scheme for the γ-cyclodextrin-metal-organic framework (Na+ / K+) crystal structure was described, showing the structural unit, the γ-CD-MOF single cell structure, and the γ-CD-MOF 3×3×3 cell structure.

[0076] Figure 2 The illustrations depict the crystallization process over time, emphasizing that typical crystallization is a slow process that requires slow and reversible molecular-molecular interactions, self-assembly, hydrogen bond formation, etc., to allow the lattice to self-correct defects over the long period from initial nucleation to crystal structure growth.

[0077] Figure 3 This indicates that a strong base (such as NaOH) and alkali metal ions (such as Na+) are required to initiate the crystallization of cyclodextrin-based metal-organic frameworks (CD-MOFs), a process that sometimes only produces amorphous powder.

[0078] Figure 4 This demonstrates the use of alkaloids with specific pKb values ​​to provide OH at a much slower rate than strong bases. - The general concept is explained, and it is illustrated how alkaloids and sodium chloride can be used together to replace NaOH in the formation of CD-MOF.

[0079] Figure 5 Non-limiting renderings are provided regarding how alkaloids such as (S)-nicotine are trapped in CD-MOFs to form cocrystals. This description should not be interpreted as providing the only possible mechanism for the formation of alkaloid-CD-MOF cocrystals, as there may be no alkaloid molecules within the cavities of cyclodextrin molecules in CD-MOF cocrystals encapsulated with active ingredients.

[0080] Figure 6 Photographs are provided of three different reaction mixtures capable of forming (S)-nicotine-β-CD-MOF cocrystals (as a non-limiting example of a cocrystal). The opaque / turbid reaction mixtures, due to the addition of ethanol to the aqueous mixture to initiate the cocrystallization process and the insolubility of the resulting cocrystal in aqueous ethanol, indicate that β-cyclodextrin is capable of forming (S)-nicotine-β-CD-MOF cocrystals (left vial), while 2-hydroxypropyl-β-cyclodextrin (middle vial) and methyl-β-cyclodextrin (right vial) cannot produce (S)-nicotine-β-CD-MOF cocrystals under the same reaction conditions.

[0081] Figure 7A , 7B Photographs of actual (S)-nicotine-β-CD-MOF eutectics (as a non-limiting example of a eutectic) produced by combining (S)-nicotine, sodium chloride, and β-cyclodextrin in water and then adding ethanol are provided in 7C.

[0082] Figure 8 Powder X-ray diffraction (XRD) patterns of the separated (S)-nicotine-β-CD-MOF eutectic are presented and compared with theoretical XRD patterns generated by simulation.

[0083] Figure 9A , 9B 9C shows the lattice structure mode of the (S)-nicotine-β-CD-MOF eutectic prepared by the method provided herein.

[0084] Figure 10 A table of chemical properties of the (S)-nicotine-β-CD-MOF eutectic prepared by the method provided herein is presented.

[0085] Figure 11 The experiment described is to demonstrate the presence of encapsulated, embedded, or otherwise “docked” (S)-nicotine molecules within the (S)-nicotine-β-CD-MOF eutectic, which is performed by washing the eutectic and analyzing the supernatant and the washed eutectic.

[0086] Figure 12A-12B Provided from Figure 10 HPLC chromatograms of the supernatant (12A) and the obtained cocrystal (12B) from the washing experiment showed that, although no free (S)-nicotine was released during the final washing, the (S)-nicotine-β-CD-MOF cocrystal digested in PBS buffer showed a strong (S)-nicotine presence signal.

[0087] Figure 13 The dissolution rate comparison between (S)-nicotine-β-CD-MOF eutectic and microcrystalline cellulose carriers loaded with (S)-nicotine was explained.

[0088] Figure 14 Two powder XRD patterns obtained from two independent eutectic preparation experiments are presented and compared with the theoretical patterns simulated for CD-MOF crystals. The top pattern shows that (S)-nicotine-CD-like molecular framework eutectic is formed even in the complete absence of Na+ metal ions.

[0089] Figures 15A-15C HPLC chromatograms are provided, showing the release of various non-limiting API instances from their corresponding β-CD-MOF cocrystals after digestion. Figure 15A shows the release of melatonin. Figure 15B shows the release of 5-hydroxy-L-tryptophan. Figure 15C shows the release of L-tryptophan.

[0090] Figures 16A-16BHPLC chromatograms are provided, showing the release of non-limiting API instances from their corresponding β-CD-MOF cocrystals after digestion. Figure 16A shows the release of benzocaine, and Figure 16B shows the release of acetaminophen.

[0091] Figure 17 A schematic diagram of a non-limiting method for producing API-CD-MOF is shown. As illustrated, API-CD-MOF consists of API (e.g., as provided herein), an alkali metal salt (e.g., potassium chloride, potassium benzoate, etc.), a sugar (e.g., γ-cyclodextrin, β-cyclodextrin, etc.), and a solvent (e.g., water:ethanol in a 1:1 ratio or other suitable ratio, depending on the embodiment). These components are used to prepare a solution in the solvent, which is then fed into a spray drying apparatus. Using this apparatus, the solution is atomized into droplets. Under conditions suitable for forming solid particles, the solvent is evaporated from the droplets in a drying chamber, and the collected solid particles contain a eutectic of API and CD-MOF.

[0092] Figures 18A-18B Non-limiting examples of devices for preparing API-CD-MOFs according to the embodiments provided herein are shown. Figure 18A shows, for example, a device for... Figure 17 A photograph of the spray drying equipment in the schematic depiction of the method is shown in Figure 18B. Figure 18B shows a photograph of API-CD-MOF produced by spray drying. Ciprofloxacin-γ-CD-MOF is depicted as a non-limiting example.

[0093] Figure 19 The structures of non-restrictive antibiotics are shown, which can be used as APIs for generating the API-CD-MOFs provided herein.

[0094] Figure 20 Scanning electron microscope images of micron-sized ciprofloxacin-γ-CD-MOF eutectic are shown.

[0095] Figure 21 Powder XRD of the API-CD-MOF eutectic is shown (ciprofloxacin-γ-CD-MOF is shown here as a non-limiting embodiment). The near-identical overlap between experimental and simulation results validates the method presented herein for generating API-CD-MOF crystal structures.

[0096] Figures 22A-22BThe HPLC spectra of non-limiting examples of digested antibiotic-CD-MOF cocrystals are shown. Figure 22A shows the HPLC spectrum of a single antibiotic cocrystalized with γ-CD-MOF. In this example, the non-limiting example of antibiotic is rifampin, and the sharp HPLC-UV peaks depict successful cocrystalization (note that γ-CD-MOF alone has no HPLC-UV signal). Figure 22B shows the cocrystalization of multiple antibiotics with γ-CD-MOF. The non-limiting example antibiotics used are ciprofloxacin and tetracycline. The presence of two independent sharp HPLC-UV peaks (one for each antibiotic) indicates that both antibiotics were successfully cocrystalized.

[0097] Figure 23 Data related to the antimicrobial efficacy of various antibiotics co-crystallized with γ-cyclodextrin as a non-limiting example are presented. Efficacy was measured against γ-CD-MOF alone (i.e., without antibiotics).

[0098] Figure 24 Data related to the antimicrobial efficacy of ciprofloxacin co-crystallized with γ-CD-MOF (a non-limiting example of an antibiotic) are shown. Efficacy was measured in contrast to ciprofloxacin alone (i.e., without co-crystallization).

[0099] Figures 25A-25B Photographs related to the cocrystal embodiments for dry powder inhalers (DPIs) provided herein are shown. Figure 25A shows a ciprofloxacin-γ-CD-MOF cocrystal placed in a DPI capsule (as a non-limiting embodiment). Figure 25B shows a cocrystal capsule placed in a DPI delivery device configured for drug inhalation administration.

[0100] Figure 26 A schematic diagram illustrating a non-limiting example of the therapeutic use of antibiotic-CD-MOF in treating lung infections, as provided in this article. Detailed Implementation

[0101] The detailed description of non-limiting embodiments is illustrated with reference to the accompanying drawings, which show non-limiting embodiments by way of example and best mode. While these non-limiting embodiments have been described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments can be implemented and logical, chemical, and mechanical changes can be made without departing from the spirit and scope of the invention. Therefore, the detailed description is provided for illustrative purposes only and is not intended to be limiting. For example, unless otherwise stated, the steps described in any method or process description may be performed in any order and are not necessarily limited to the given order. Furthermore, any reference to the singular includes the plural embodiments, and any reference to multiple components or steps may include the singular embodiments or steps. Similarly, any reference to attachment, fixation, connection, or similar terms may include permanent, removable, temporary, partial, full, and / or any other possible attachment options. In addition, any reference to non-contact (or similar phrases) may also include reduced contact or minimal contact.

[0102] In various embodiments of this disclosure, stable sugar-based cocrystals configured for the controlled release of an active pharmaceutical ingredient (API) are disclosed. In various instances, the cocrystal is formed by co-crystallization of the API with a sugar-based molecular backbone. In some instances, the pH of the co-crystallization is adjusted such that, during the co-crystallization process, at least some of the free OH groups of the sugar bind to metal ions and / or positively or partially positively charged API molecules.

[0103] Definitions and Explanations

[0104] As used herein, the terms "pharmaceutical active substance," "bioactive substance," or more simply "active substance" refer to a compound capable of inducing at least some perceptible physiological or psychological effect in an animal (such as a human), including molecules capable of inducing purely sensory effects (such as odor). Active substances may also be referred to as drugs, active pharmaceutical ingredients (APIs), or pharmaceutical products, including herbal medicines, flavorings, flavorings, antimicrobial agents, nutritional supplements, or other natural or synthetic substances that may not be recognized as drugs by the pharmaceutical industry or the medical community and are not, or do not require, registration with any regulatory agency (such as the U.S. Food and Drug Administration, FDA). In various embodiments of this disclosure, active substances can be classified according to their chemical structure as small molecules, such as alkaloids, flavonoids, terpenes, diterpenes, triterpenes, terpenoids, diterpenoid compounds, triterpenoid compounds, amino acids, aldehydes, vitamins, vitamin cofactors, nucleotides, nucleotide analogs, steroids, etc. Active substances as used herein can also be biological agents, such as those comprising proteins, oligonucleotides, mRNA, antibodies, engineered viral particles, etc. Of particular interest in this paper is the use of any subclass of alkaloids as active substances in eutectics.

[0105] As used herein, the term "molecular framework" or more simply "skeleton" refers to any type of two- or three-dimensional molecular structure characterized by having a scaffold and a degree of porosity, whether fully crystalline or characterized by an amorphous, liquid, or glassy structure, including, for example, metal-organic frameworks (MOFs), covalent organic frameworks (COFs), hydrogen-bonded organic frameworks (HOFs), coordination polymers, etc. Molecular frameworks are often self-assembled and can provide a supporting structure for functional molecules such as catalysts. In various embodiments according to this disclosure, the molecular framework is co-crystallized with the active material.

[0106] As used herein, the term "carbohydrates" takes its usual meaning in organic and carbohydrate chemistry. The term can refer to any and all naturally occurring and synthetic sugars, combinations of covalently bound sugars, and polymeric sugars, including monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Of particular interest in this paper are cyclodextrins, which fall within the larger category of polysaccharides.

[0107] As used herein, the term "cyclodextrin" refers to the entire class of cyclic polysaccharides obtained from starch. Unless further specified, the simple term cyclodextrin refers to any and all α-, β-, and γ-forms of cyclodextrin, characterized by having six, seven, and eight glucose subunits, respectively, wherein the subunits are linked by 1,4-glycosidic bonds. At least 150 cyclodextrin compounds are known. Cyclodextrins are known to have a cyclic shape, with an outer surface sufficiently hydrophilic to impart water solubility, and an internal cavity that is less hydrophilic than the outer surface but not completely hydrophobic.

[0108] In various embodiments, cyclodextrins include, but are not limited to, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, hepta(2,6-di-O-)ethyl-β-cyclodextrin, 6-O-α-maltose-β-cyclodextrin, random methylated β-cyclodextrin (RAMEB), sulfonyl butyl ether-β-cyclodextrin, sulfonyl lipid-β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, octa-(6-bromo-6-deoxy)-γ-cyclodextrin, octa-(6-... 8-(6-chloro-6-deoxy)-γ-cyclodextrin, 8-(6-deoxy-6-iodo)-γ-cyclodextrin, 8-(6-deoxy-6-mercapto)-γ-cyclodextrin, 8-(2,3,6-tri-O-methyl)-γ-cyclodextrin, 8-(2,3-diacetyl-6-sulfate)-γ-cyclodextrin, 8-(3-O-butyryl-2,6-di-O-pentyl)-γ-cyclodextrin, 8-6-sulfate-γ-cyclodextrin, and mixtures thereof. In some instances, cyclodextrins are used herein to form molecular backbones, such as, but not limited to, cyclodextrin-based metal-organic frameworks (or CD-MOFs). For reviews on CD-MOF, please see, for example, R. Zhao et al., “Cyclodextrin-based metal-organic framework materials: classification, synthetic strategies and their applications in various delivery systems,” Carbohydrate Polymers, 319, article 121198 (2023).

[0109] As used herein, the terms "eutectic," "API eutectic," or "API-molecular-skeletal eutectic" refer to compounds comprising the active substance as defined herein, bound to at least one other compound, wherein the eutectic exists in a crystalline lattice. Eutectic is distinctly different from ordinary API salts and API complexes without an identifiable lattice. In a eutectic, regardless of whether the bound at least one other compound may be an acid, there is no proton transfer to form a salt in its own sense. The U.S. FDA defines a eutectic as a crystalline material composed of two or more distinct molecules, typically an API and a eutectic form (also known as a "co-formation") existing in the same lattice in a defined stoichiometric ratio. Eutectic differs from salts, polymorphs, solvates, and hydrates, which are typical alternative forms of API.

[0110] As used in this article, the acronym “NCT” refers to (S)-nicotine, such as free alkaloids and (S)-nicotine that may dissociate from salts or complexes of (S)-nicotine. In some instances, the term “NCT” is used to simplify the process of writing the full name (S)-nicotine on a chart axis.

[0111] As used herein, the term "nicotine salt" refers to a compound containing protonated (S)-nicotine and bound with a negatively charged counterion (anion), wherein the counterion is typically the conjugate base of an acid used to protonate the free nicotine alkaloid. Nicotine salts are typically formed by proton transfer between (S)-nicotine and an inorganic or organic acid, or a mixture of acids in any combination, to protonate the free (S)-nicotine alkaloid and form the corresponding salt. (S)-nicotine salts are known and, depending on the acid used to form the salt or mixed salts, other stoichiometry may be formed beyond a 1:1 acid-to-alkaloid ratio. For example, T.A. Perfetti described (S)-nicotine salts made from various organic acids in “Structural Studies of Nicotine Salts,” International Contributions to Tobacco Research, 12(2), 43-54, 1983, where 1:1, 2:1, and 3:1 acid-to-nicotine alkaloid ratios were observed. Perfetti disclosed that nicotine forms a 3:1 acid-base salt with an aliphatic monocarboxylic acid (such as acetic acid), where one acid molecule bonds as in a 1:1 salt, and the other two acid molecules bond to the nitrogen atom of the pyridine ring. Perfetti also observed that nicotine benzoate is a 1:1 acid-base salt, while nicotine citrate is a 2:1 acid-base salt. For example, (S)-nicotine lactate and (S)-nicotine benzoate can be used in electronic cigarettes. Examples of organic acids that can be used to form (S)-nicotine salts include, but are not limited to, formic acid, acetic acid, adipic acid, trifluoroacetic acid, aspartic acid, butyric acid, 2-methylbutyric acid, 3-methylbutyric acid, benzoic acid, caprylic acid, citric acid, crotonic acid, EDTA, fumaric acid, gluconic acid, glutamic acid, glyceric acid, glycolic acid, lactic acid, lauric acid, levulinic acid, maleic acid, L-(-)-malic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, phenylacetic acid, phthalic acid, picric acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tannic acid, L-(+)-tartaric acid, hydroxymalonic acid, valeric acid, vanillic acid, and combinations thereof. Such (S)-nicotine salts can be prepared by reacting a free base of an alkaloid with a suitable acid or mixture of acids in a manner known to those skilled in the art.

[0112] As used herein, the terms “subject,” “individual,” “subject in need,” “individual in need,” “patient,” or “patient in need” refer to any human or non-human animal (e.g., a dog or poultry) that exhibits symptoms of a disease or condition, is diagnosed with such a disease or condition in certain circumstances, or is identified as being at risk of developing the disease (e.g., due to underlying comorbidities or otherwise compromised immune systems, or a genetic predisposition), or that desires to obtain any physicochemical effect (whether physiological or psychogenic) through the application of the product, or that desires to obtain or maintain a particular appearance or health condition. Non-limiting examples of “individual” in this document include humans, dogs, cats, rabbits, cattle, pigs, birds, etc., of any age, sex, and race.

[0113] As used herein, when referring to the treatment of an “individual in need,” the term “treatment” means any type of intervention intended to alter the natural course of an individual’s condition, including alleviating the pathogenesis of a disease or psychosomatic condition, and alleviating signs and symptoms of aging, including skin health and appearance, cognitive decline, arthritis, and other joint and muscle conditions. Treatment includes, but is not limited to, the administration of the cocrystals of this disclosure or the administration of pharmaceutical compositions comprising cocrystals of this disclosure, and may be administered preventively or after a diagnosis of a disease or condition. “Treatment” also includes preventive administration aimed at slowing the progression of the treated disease or condition, delaying the onset of the disease or condition, or reducing the severity of its onset. Treating symptoms of an underlying disease or condition, or prevention (e.g., anticipating the onset of a disease or condition), does not necessarily imply the complete eradication, cure, or prevention of the disease or condition or its associated symptoms.

[0114] As used herein, the term “modulation” includes “increasing” or “decreasing” one or more quantifiable parameters, optionally in a definite and / or statistically significant amount. The terms “increase” or “enhancement,” or “stimulation,” generally refer to the ability of one or more cocrystals of this disclosure or a combination thereof to produce or evoke a physiological or psychological response (i.e., a downstream effect) in a subject in need that is greater than that induced by the absence of the cocrystal of this disclosure (i.e., the absence of the agent) or a control compound. The relevant physiological and psychological responses will be apparent to those skilled in the art and may include physiological responses manifested by a reduction in pathogen or cancer cell counts in tissue or blood samples, tumor shrinkage, or higher scores on psychological tests. The amount of “increase” or “enhancement” is generally a “statistically significant” amount and may include an increase of 1.1, 1.2, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more (e.g., 500, 1000 times) compared to the amount produced by the eutectic (without the pharmaceutical agent) or control compound of this disclosure, including all integers and decimals above 1 (e.g., 1.5, 1.6, 1.7, 1.8).

[0115] The terms “reduction” or “inhibition” can generally refer to the ability of one or more cocrystals or combinations thereof of this disclosure to “reduce” an associated physiological response (e.g., symptoms of a disease or condition as measured by a known medical diagnosis). The associated physiological or psychological response will be apparent to those skilled in the art and may include the reduction of symptoms or pathology of a disease (such as cancer or infection). A “reduction” in response compared to a response produced without application of the compounds of this disclosure or a control composition may be “statistically significant” and may include reductions of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, including all integers therein.

[0116] As used herein, when referring to the administration of a cocrystal or composition thereof according to this disclosure to an individual in need, the term "therapeuticly effective amount" refers to the minimum dose of a cocrystal or composition according to this disclosure that provides the desired therapeutic effect to a subject exhibiting physical or mental symptoms of a disease or condition. Therefore, the therapeutically effective amount for an individual in need of treatment may vary depending on the nature of the subject (human or non-human animal, age, sex, weight, overall health status, presence of comorbidities, etc.), the nature and severity of the current disease state or condition, the specific cocrystal administered, the dosage form of the cocrystal, the dosage form of the composition comprising the cocrystal, the concentration of the API in the cocrystal or composition thereof, and the desired end result, recognizing that the desired end result may be subjectively observed and / or confirmed, or objectively measured and / or confirmed. In various embodiments, the therapeutically effective amount for treating a subject exhibiting a disease or condition may be an amount that results in a reduction of measurable variables obtained from the individual receiving the API cocrystal.

[0117] As used herein, when referring to the administration of a cocrystal or composition thereof according to this disclosure to a subject in need, the term "preventative effective amount" means the minimum dose of the cocrystal or composition according to this disclosure that prevents the onset of a disease or condition (whether physical or mental). In various embodiments, the subject in need may have written proof of exposure to a pathogen or carcinogen, or may simply suspect prior exposure or fear the possibility. Similar to the therapeutic effective amount for treating an existing disease state or condition in an individual, the preventative effective amount also varies depending on the nature of the subject (human, canine, weight, age, overall health condition, comorbidities, etc.), the nature, frequency, and concentration of exposure to a pathogen or carcinogen, the specific cocrystal administered and its purity, the dosage form of the cocrystal, the dosage form of the composition comprising the API-cocrystal, the concentration of the API in the cocrystal or composition thereof, and the desired end result, recognizing that the desired end result may be entirely subjective, such as the absence of an onset of disease or condition despite exposure to or suspected exposure to a pathogen or carcinogen.

[0118] As used herein, the term "dosage form" takes its usual meaning in the pharmaceutical field, referring to the physical form of a cocrystal or composition thereof designed for a specific route of administration. For example, dosage forms include, but are not limited to, injections, infusions, inhaled vapors, nasal sprays, nasal gels, topical preparations (such as transdermal ointments, ointments, and patches), powders, tablets, sublingual tablets, capsules, lozenges, oral films, oral pouches, syrups, chewing gum, etc. In various embodiments, the cocrystals according to this disclosure and compositions containing such cocrystals of interest may, for example, comprise powders, and dosage forms may include capsules containing powdered compounds or compositions encapsulated in a capsule shell, or tablets comprising powdered compounds or compositions compressed into a size and shape suitable for oral swallowing or sublingual dissolution, or compositions encapsulated in nonwoven pouches for oral placement, or oral films, or dosage forms comprising inhaled vapors supplied by an nebulizer, sprayer, or similar device containing a vaporizable liquid. In some implementations, the dosage form is selected from lozenges, dry powder inhalers, nasal inhalers, nasal sprays, transdermal patches, topical creams, tablets, lozenges, capsules, blister packs, gummies, chewing gum, oral dissolving films, lozenges, chewing tablets or chewing sticks, nebulized solutions, oral solutions or suspensions, buccal or sublingual tablets or films, effervescent tablets or granules, suppositories or vaginal suppositories, injectable solutions or suspensions, intramuscular injection solutions, intravenous injection solutions, subcutaneous injection solutions, lyophilized formulations for reconstitution, implantable devices or reservoirs, microspheres or nanoparticles, liposome formulations, inhalable aerosol sprays or solutions, ear drops or ophthalmic solutions, microneedle patches, emulsions, microemulsions, nanoemulsions, sustained-release or controlled-release formulations, films or meshes for surgical implants, powders or granules for reconstitution, oral dispersible or sublingually melting tablets, vaginal rings or films, anal rings or inserts, mouthwashes or rinses, subcutaneous or intradermal patches, and wafers.

[0119] As used herein, the term “about” refers to a quantity, level, value, number, frequency, percentage, size, dimensions, quantity, weight, or length that differs from a reference quantity, level, value, number, frequency, percentage, size, quantity, weight, or length by as much as 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%. For example, a quantity expressed as “about 5 wt.%” includes a range of variation from 4.5 to 5.5 wt.%.

[0120] General Implementation Plan

[0121] In various embodiments, a cocrystal comprises: an active substance; and a molecular framework comprising a sugar; wherein the molecular framework and the active substance reside within a common crystal lattice. In various embodiments, the cocrystal may also comprise a metal ion, wherein the molecular framework comprises a metal-organic framework (MOF). In various examples, the active substance of the cocrystal comprises an alkaloid. In examples where the active substance is an alkaloid, the alkaloid, depending on its pKb value, can provide sufficient basicity in the presence of a metal ion to facilitate MOF formation. In other words, the alkaloid can replace the need to add a strong base when co-crystallizing API with MOF. In various examples, the sugar comprises cyclodextrin. In various examples, the molecular framework comprises a cyclodextrin metal-organic framework (CD-MOF). In various embodiments, the cocrystal comprises a (S)-nicotine-β-CD-MOF cocrystal.

[0122] In various embodiments, a composition comprises: at least one eutectic containing an active substance and a molecular backbone containing sugars; and at least one excipient. In various instances, the excipient determines the physical dosage form of the composition and may include fillers, binders, disintegrants, lubricants, etc. The components present in the eutectic and compositions thereof in this disclosure are discussed in the definitions section and below.

[0123] Active substances

[0124] In various embodiments, the active substances in the eutectic according to this disclosure can be classified according to their end use or their physiological or psychoactive activity. Active substances as used herein include, but are not limited to, antibiotics, antibacterial agents, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, stimulants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs and their extracts, essential oils, vitamins or supplements, antioxidants, etc. In several implementation schemes, the active substance includes, but is not limited to, irritants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, vasodilators, anticholinergic drugs, vaccines, insulin, sedatives and hypnotics, antipsychotics, immunosuppressants, enzymes, anticoagulants, chemotherapeutic drugs, antidiabetic agents, antiemetics, anticonvulsants, hormones, and gene therapy. Carriers, monoclonal antibodies, antiparasitic agents, antifibrotic agents, antiarrhythmic agents, antiplatelet agents, biological response modifiers, radiopharmaceuticals, penetrants, antituberculosis drugs, antileukotriene drugs, antimigraine agents, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof.

[0125] In various embodiments, the active substances in the cocrystals according to this disclosure can be classified according to their chemical categories rather than their biological characteristics or effects, for example, based on identifiable chemical structures, into alkaloids, phenols or polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, triterpenes, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, etc. Alkaloid active substances are of particular interest herein, primarily because certain alkaloids possess a wide range of physicochemical properties and medicinal benefits after application, and also because alkaloids can contribute alkalinity to the cocrystallization process when the molecular backbone contains sugars with free -OH hydroxyl groups. In various embodiments, the cocrystals herein contain alkaloids as APIs.

[0126] Alkaloid active substances include, but are not limited to: pyrrolidines (such as senna), tropanes (such as atropine, scopolamine, and cocaine), pyrrolizidines (such as senna), piperidines (such as sedumine), quinolizidines (such as lupinine), indorazines (such as strychnine), pyridines (such as (S)-nicotine), sesquiterpene pyridine derivatives (such as euonymus), isoquinolines (such as morphine), oxazoles, tyrosine or phenylalanine and their derivatives. Derivatives, isoxazole derivatives (such as muscarinic acid), thiazole derivatives (such as nostoc cyclic peptide), quinazolines (such as haloxyfop-methyl), quinolines (such as cousparin and various quinines), indole alkaloids (such as yohimbine, strychnine, and vinca alkaloids), imidazoles (such as pilocarpine), purine derivatives (such as caffeine), various colchicine alkaloids, various muscarine alkaloids, benzylamines (such as capsaicin), various putrescine alkaloids, and various spermidine alkaloids. This list does not imply any limitation on the properties of the alkaloids contained in the cocrystal. Active substances also include flavonoids, herbal medicines, and other non-alkaloid natural or synthetic substances, such as resveratrol, vitamins and vitamin cofactors (such as coenzyme Q10), quercetin, etc.

[0127] Molecular skeleton

[0128] The cocrystal according to this disclosure comprises a molecular framework, such as a MOF, COF, HOF, or coordination polymer. In various embodiments, the cocrystal comprises a metal-organic framework (MOF), further comprising an alkali metal ion (such as Li+, Na+, K+, Rb+, or Cs+) and cyclodextrin as a sugar. In various embodiments, the cocrystal comprises a cyclodextrin-based metal-organic framework (CD-MOF). In several embodiments, the CD-MOF comprises α-cyclodextrin. In several embodiments, the CD-MOF comprises β-cyclodextrin. In several embodiments, the CD-MOF comprises γ-cyclodextrin.

[0129] CD-MOFs containing cyclodextrins and alkali metals are a class of porous, renewable, and food-safe MOFs. CD-MOFs can be prepared on an industrial scale. CD-MOFs can crystallize into cubic or other symmetrical crystals, although changing the metal ion from Na+ to K+, Rb+, or Cs+ can alter the topology, connectivity, pore shape, and pore size of the resulting CD-MOF crystal. In several embodiments, CD-MOFs contain sodium ions. In several embodiments, CD-MOFs contain potassium ions. In several embodiments, CD-MOFs contain lithium ions. In several embodiments, CD-MOFs contain rubidium ions. In several embodiments, CD-MOFs contain cesium ions. The CD-MOFs provided herein can contain any alkali metal ion having any cyclodextrin to provide the desired pore shape and / or size (or otherwise modified topology) to achieve the desired API release rate from the API-CD-MOF.

[0130] Application of API-eutectic

[0131] In various embodiments, the API-molecular skeleton cocrystals according to this disclosure play a role in a wide range of therapeutic, preventative, and health and wellness applications. For example, the API-molecular skeleton cocrystals of this document can be used in medical applications, clinical treatments, emergency responses, personal care, personal fitness, and personal health. The API-molecular skeleton cocrystals of this disclosure, or compositions thereof, can be used to promote overall human health, promote a healthy immune system, and / or prevent, reduce, or delay the occurrence or recurrence of any human disease or condition, or any effects of daily or event-related stress.

[0132] According to this disclosure, diseases treatable with cocrystals include, but are not limited to, acne vulgaris, asthma, autoimmune diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivity reactions, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, atherosclerosis, allergies, myopathy, leukocyte defects, cancer, endometriosis, and multiple sclerosis. Conditions treatable with cocrystals of this disclosure include, but are not limited to, infections, age spots, skin tags, fine lines and wrinkles, depression, anxiety, bipolar disorder and schizophrenia, eating disorders, psychosis, mood disorders, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and personality disorders. Unhealthy physical conditions may manifest as underweight and mood swings, lethargy, fatigue, multiple chemical allergies, asthma, difficulty breathing, and depression in individuals of this age group.

[0133] In various embodiments, methods for treating diseases in individuals in need include applying a therapeutically effective amount of API-molecular-base cocrystal. In various embodiments, methods for treating physical or mental illnesses in individuals in need include applying a therapeutically effective amount of API-molecular-base cocrystal. In various embodiments, methods for inducing stimulation in individuals in need include applying a therapeutically effective amount of API-molecular-base cocrystal. In various embodiments, methods for promoting the overall health of individuals in need include applying a therapeutically effective amount of API-molecular-base cocrystal. In various embodiments, methods for treating cosmetic conditions in individuals in need include applying a therapeutically effective amount of API-molecular-base cocrystal.

[0134] Eutectic formulation

[0135] API-eutectic solids can be incorporated into compositions that provide specific physical dosage forms, such as tablets, capsules, powders, oral instant films, lozenges, chewing gum, etc. For example, in several embodiments, the dosage form is selected from lozenges, dry powder inhalers, nasal inhalers, nasal sprays, transdermal patches, topical creams, tablets, lozenges, capsules, blister packs, gummies, chewing gum, oral dissolving films, lozenges, chewing tablets or chewing sticks, nebulized solutions, oral solutions or suspensions, buccal or sublingual tablets or films, effervescent tablets or granules, suppositories or vaginal suppositories, injectable solutions or suspensions, intramuscular injection solutions, intravenous injection solutions, subcutaneous injection solutions, lyophilized formulations for reconstitution, implantable devices or reservoirs, microspheres or nanoparticles, liposome formulations, inhalable aerosol sprays or solutions, ear drops or ophthalmic solutions, microneedle patches, emulsions, microemulsions, nanoemulsions, sustained-release or controlled-release formulations, films or meshes for surgical implants, powders or granules for reconstitution, oral dispersible or molten tablets, vaginal rings or films, anal rings or inserts, mouthwashes or rinses, subcutaneous or intradermal patches, and wafers.

[0136] Oral pouches

[0137] In various embodiments, the API-eutectic solid is provided in the form of an oral pouch. An oral pouch is a pouch-shaped dosage form for placing and delivering an active ingredient such as a drug in the oral cavity; when the active ingredient is nicotine, such products may be called nicotine pouches. APIs include, but are not limited to, stimulants (such as nicotine), antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, cannabis, herbal extracts, or supplements (e.g., phenols, fatty acids, tannins, coumarins, flavonoids, lignans, alkaloids, saponins, terpenes, polysaccharides, cannabinoids, amino acids, glycosides, esters, steroids, vitamins, antioxidants, etc.). In several embodiments, the active substance is selected from the above groups and mixtures thereof.

[0138] Dry powder inhaler, nasal inhaler or spray

[0139] In various embodiments, the API-eutectic solid is provided in the form of a dry powder inhaler, nasal inhaler, nebulizer, or other inhalation form (including powder form for nasal and / or pulmonary delivery of API). The selection of APIs and active ingredients is the same as described in the sublingual pouch section.

[0140] Transdermal patches or topical creams

[0141] In various implementation schemes, the API-eutectic solid is provided in the form of a transdermal patch or topical cream containing the API. The selection range of APIs and active ingredients is the same as in the groups described above.

[0142] Tablets, lozenges, capsules or blister packs

[0143] In various implementation schemes, the API-eutectic solid is provided in the form of API tablets, lozenges, capsules, or blister packs. The selection range of APIs and active ingredients is the same as in the groups described above.

[0144] Gummies, chewing gum, or oral instant films

[0145] In various implementation schemes, the API-eutectic solid is provided in the form of API gummies, chewing gum, or oral instant films. The selection range of APIs and active ingredients is the same as in the groups described above.

[0146] General discussion and precautions

[0147] CD-MOFs, due to their high specific surface area, controllable porosity, and biocompatibility, have become a promising approach for various drug delivery applications, such as antimicrobial agents, analgesics, flavoring agents, nutrients, and supplements. Furthermore, as structural units of CD-MOFs, over 130 approved pharmaceutical ingredients have been formulated with CDs to optimize their physicochemical properties. Figure 1 Non-limiting examples of crystal structures of γ-cyclodextrin-metal-organic frameworks (γ-CD-MOFs) with Na+ / K+ metal ions are described. Such crystal structures can provide scaffolds for a variety of APIs and pharmaceutical excipients. Figure 1 It shows how the basic γ-CD-MOF (Na+ / K+) structural unit crystallizes into a single cell and then further crystallizes into a γ-CD-MOF 3×3×3 cell.

[0148] Figure 2 This paper schematically illustrates the traditional crystallization process over time, emphasizing that typical crystallization is a slow process requiring slow and reversible molecular-molecular interactions, self-assembly, hydrogen bond formation, etc., to allow the lattice to self-correct defects over the long period from initial nucleation to crystal structure growth. While traditional crystallization and co-crystallization are very slow and sometimes frustrating processes, often resulting in amorphous powders rather than crystals, a unique method has now been discovered and described in this paper. Co-crystallization times for forming API-molecular framework co-crystallization can now be as short as 30 seconds, instead of hours or days.

[0149] Figure 3 This demonstrates that the presence of a strong base and alkali metal ions is required for the efficient formation and crystallization of cyclodextrin-based metal-organic frameworks (CD-MOFs). The base and alkali metal ions are essential for catalyzing the formation of salts between CD hydroxyl groups and metal cations, and for initiating the formation of ordered CD-MOF crystal structures. In some cases, both the strong base and the metal ions are provided using NaOH.

[0150] In traditional API-molecular backbone synthesis, CD-molecular backbones (such as CD-MOF) are first formed into crystalline substances (see...). Figure 1The process involves adding the API and forcing it to bind with the crystalline CD-MOF. This route is inefficient and complex because the stable CD-MOF crystals must now dissociate to some extent to reach equilibrium with the API. This slow process may only produce amorphous powder instead of an API-CD-MOF eutectic. Overall, this traditional process for forming an API-CD-MOF eutectic results in poor crystallinity and the presence of an amorphous phase, low yield, and is a time-consuming and costly manufacturing process. Furthermore, even after successfully crystallizing the CD-MOF, there remains a separate residual step of loading the API into the CD-MOF crystal structure, which seems counterintuitive to the idea of ​​disrupting the existing CD-MOF crystals.

[0151] Figure 4 This indicates that (S)-nicotine or other suitable alkaloids slowly provide the OH groups required for the formation of the alkaloid and CD-MOF eutectic. - The ability of ions. Despite Figure 5 This disclosure conceptually illustrates one aspect of the formation of a (S)-nicotine-CD-MOF eutectic, but the diagram should not be interpreted literally as meaning that each (S)-nicotine molecule forms an inclusion complex with a cyclodextrin cavity. Rather, the structure is a eutectic that simultaneously contains (S)-nicotine and CD-MOF in a lattice structure. According to this disclosure, co-crystallization of (S)-nicotine with cyclodextrin occurs within approximately 30 seconds in the presence of sodium chloride, resulting in a highly crystalline solid form, improved API stability, programmable API release profiles, and the possibility of integrating multiple components.

[0152] Experimental Section

[0153] Actual experiments provided a eutectic that could be characterized and studied. (S)-nicotine was used both as an API and as a slow-release OH- to provide alkalinity. - Sodium chloride is used as the source of Na+ ions. + The alkali metal ions are sourced from cyclodextrins selected from β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin, which are used as sugars forming the molecular backbone. The reaction is carried out in water, followed by the addition of ethanol to induce co-crystallization. In some experiments, photographs of the co-crystallization and the liquid mixture were taken. It should be noted that successful co-crystallization is characterized by the formation of an opaque or turbid mixture, which is an indication of the formation of insoluble and dispersed co-crystallization. When the reaction mixture remains optically transparent, it is concluded that co-crystallization has not been successful, and only soluble salts are present in the solution. The experimental methods and materials disclosed in conjunction with the examples below are a non-limiting description of methods and apparatus that can be used to generate sugar-based co-crystallizations containing APIs.

[0154] Example 1 – Co-solvent crystallization

[0155] General Procedure

[0156] An aqueous mixture was prepared by combining (S)-nicotine, sodium chloride, and one selected from β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin in water. After a few minutes to ensure homogeneity, ethanol was added to the aqueous mixture to induce co-crystallization of (S)-nicotine with CD-MOF. The presence of turbidity indicated the formation of the co-crystallization. The synthesis was very efficient and simple, carried out in a one-pot reaction, with the co-crystallization occurring in high yield after only about 30 seconds. In other examples, another API can be used instead of (S)-nicotine. If the API is not an alkaloid or other weakly basic substance, it may be necessary to add at least some NaOH to obtain alkalinity, or, for example, replace some of the sodium chloride with NaOH.

[0157] result

[0158] Now for reference Figure 6 Experimental results for each cyclodextrin revealed the importance of having free hydroxyl groups in each monosaccharide of the cyclodextrin oligosaccharide chain. Figure 6 The photographs show that a suspension of (S)-nicotine-β-CD-MOF eutectic can only be obtained when the cyclodextrin used for CD-MOF is β-cyclodextrin. When 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin is used for CD-MOF, only a clear solution is obtained, meaning that no insoluble eutectic is formed, but only a soluble salt is produced. Of the three options—β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin—only β-cyclodextrin has the ability to react with Na+. + Alkali metal cations coordinate to form free -OH groups in CD-MOF. On the other hand, 2-hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin lack available -OH groups at the 6-position of their oligosaccharide chains, thus no eutectic is formed, and the mixture remains optically transparent. Therefore, for the following results, only β-cyclodextrin is used to form a characterizable (S)-nicotine-β-CD-MOF eutectic.

[0159] Figure 7A , 7B Images 7C and 7C show photographs of the actual (S)-nicotine-β-CD-MOF eutectic. The white bars in each of the three images indicate the scale of each image in micrometers. The (S)-nicotine-β-CD-MOF eutectic appears to be cubic or tetragonal in shape, with sizes ranging from about 10 μm to about 20 μm. Figure 8 Actual powder X-ray diffraction analysis of the (S)-nicotine-β-CD-MOF eutectic is provided. The upper spectrum is the actual XRD obtained from the separated (S)-nicotine-β-CD-MOF eutectic, and the lower spectrum is a simulation for comparison purposes. Figure 8As shown, powder XRD results indicate that the obtained (S)-nicotine-β-CD-MOF eutectic has the same crystal structure as theoretically obtained. Figure 9A , 9B 9C shows the details of the molecular crystal structure of the (S)-nicotine-β-CD-MOF eutectic obtained therefrom. Figure 10 The table lists the chemical details of the (S)-nicotine-β-CD-MOF eutectic obtained therefrom.

[0160] Figure 11 Figure 12 illustrates a set of experiments performed to further verify the presence of encapsulated or otherwise encapsulated or crystalline (S)-nicotine in the (S)-nicotine-β-CD-MOF cocrystal. As shown, the suspension of the (S)-nicotine-β-CD-MOF cocrystal in aqueous ethanol was centrifuged to separate the (S)-nicotine-β-CD-MOF cocrystal from the supernatant. The (S)-nicotine-β-CD-MOF cocrystal was then washed three times with clean ethanol, followed by a final centrifugation. As shown in the HPLC results in Figure 12, the final supernatant showed no relevant signal in the HPLC chromatogram, while the (S)-nicotine-β-CD-MOF cocrystal digested in PBS buffer showed a strong (S)-nicotine signal in the HPLC chromatogram. These experiments clearly show that (S)-nicotine is trapped in the (S)-nicotine-β-CD-MOF eutectic structure, possibly as a lattice point in the crystal structure, or partially encapsulated in the CD cavity, or a combination of these structures.

[0161] Figure 13 The results of the dissolution studies conducted are presented. This experiment aimed to compare the dissolution rates of (S)-nicotine-β-CD-MOF cocrystal and (S)-nicotine adsorbed on a microcrystalline cellulose support. Results are shown as the change in weight (mg) of (S)-nicotine in solution over time. The results demonstrate that the release of (S)-nicotine from the (S)-nicotine-β-CD-MOF cocrystal into solution can be controlled to achieve a preferred, programmable release profile.

[0162] Figure 14 Two other experiments were conducted to form CD-MOF eutectics. Figure 14 The powder XRD pattern of the (S)-nicotine-β-CD- molecular framework eutectic is shown. The topmost pattern is formed in a water / ethanol mixture but without the essential Na. +The (S)-nicotine-CD- molecular framework eutectic of alkali metal ions was obtained. The middle spectrum was obtained from the (S)-nicotine-β-CD-MOF eutectic prepared as described above in an aqueous medium containing sodium chloride. The bottom spectrum is a simulated spectrum of theoretically obtainable β-CD-MOF crystals. The formation of a (S)-nicotine-CD-like molecular framework eutectic in the absence of metal ions, as demonstrated by the top XRD pattern, is indeed very remarkable. Therefore, although this eutectic cannot be (S)-nicotine-β-CD-MOF eutectic itself without the presence of any metal ions, it is clear, as demonstrated by the obtained powder XRD pattern, that some type of (S)-nicotine-β-CD- molecular framework eutectic has been formed.

[0163] Figures 15 and 16 illustrate the versatility of APIs used to form CD-molecular framework cocrystals. In these experiments, various API-cocrystals were washed, and then... Figure 11-1 The samples captured in step 2 were digested (using (S)-nicotine). Figure 15 shows that melatonin, 5-hydroxy-L-tryptophan, and L-tryptophan all successfully bound to cyclodextrin to form a cocrystal, as evidenced by the release of each of these active substances upon digestion of the cocrystal. Similarly, Figure 16 shows that benzocaine and acetaminophen each successfully bound to cyclodextrin to form a cocrystal, as evidenced by the release of each of these active substances upon digestion of the cocrystal.

[0164] Example 2 – Spray Drying Crystallization

[0165] General Procedures and Results

[0166] In several implementations, the co-crystallization method provided herein utilizes spray drying. Figure 17A schematic diagram of a non-limiting embodiment of co-crystallization via spray drying is shown. In short, the components used to generate API-CD-MOF include (i) API, (ii) alkali metal salts, (iii) cyclodextrins, and (iv) solvents (or solvent mixtures). As discussed in this article, APIs can be a wide variety of pharmaceutical agents, such as stimulants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof. Alkali metal salts can be ions from any alkali metal, including lithium (Li). + ), sodium (Na + ), potassium (K) + ), Rubidium (Rb + ) and cesium (Cs) + The cyclodextrin is selected from α-, β-, or γ-cyclodextrin, depending on the embodiment. The solvent (or solvent mixture) may be water, ethanol, methanol, isopropanol, glycerol, propylene glycol, acetone, dimethylformamide (DMF), diethylformamide (DEF), or mixtures thereof.

[0167] In this example, a non-limiting example of the API used is the antibiotic ciprofloxacin. 150 mg of ciprofloxacin, 75 mg of potassium chloride, and 150 mg of γ-cyclodextrin were dissolved in a solvent containing 7.5 ml H₂O and 7.5 ml ethanol (although other ratios may be used). The solution was heated to 37°C with stirring and held for 5 minutes. The API-salt-CD solution was introduced into a spray drying apparatus (see Figure 18A). The solution was atomized in the apparatus to form droplets. The spray drying apparatus included a drying chamber in which the droplets were exposed to a temperature of 150°C for 5 minutes, with an airflow rate of 400 CFM flowing through the drying chamber to evaporate the solvent and generate solid particles. The solid particles API-CD-MOF were collected, and Figure 18B shows an example of the resulting particles (ciprofloxacin-γ-CD-MOF). As a non-limiting example, Figure 19 The structures of a selected group of other antibiotics are shown, which can be co-crystallized into the API-CD-MOF provided herein. Figure 20Scanning electron microscopy images of a micrometer-sized ciprofloxacin-γ-CD-MOF eutectic are shown, demonstrating crystal formation. It should be understood that this API-CD-MOF differs from... Figures 7A-7C The examples shown are non-limiting instances of those containing different forms of cyclodextrin (β-CD) and using (S)-nicotine as the API.

[0168] To further evaluate this non-limiting API-CD-MOF, the generated ciprofloxacin-γ-CD-MOF eutectic was analyzed by powder X-ray diffraction. Figure 21 Two data trajectories are displayed. The upper trajectory is the diffraction pattern of the experimentally generated ciprofloxacin-γ-CD-MOF eutectic, and the lower trajectory is the computer-simulated diffraction pattern of the ciprofloxacin-γ-CD-MOF eutectic. As shown in the figure, the two diffraction patterns are basically similar, thus verifying the process of generating the ciprofloxacin-γ-CD-MOF eutectic and the identity of the crystal itself.

[0169] Additional experiments were conducted to co-crystallize and evaluate the properties of other non-limiting API examples. Another co-crystallization of the antibiotic in γ-CD-MOF was performed, this time using rifampin. The procedure was substantially similar to that described above for ciprofloxacin, but with 100 mg of rifampin used in the initial solution. The resulting rifampin-CD-MOF was digested in PBS, and the digested sample was then analyzed by HPLC. Figure 22A shows the HPLC spectrum with a single sharp HPLC-UV peak, indicating successful co-crystallization of a single antibiotic with γ-CD-MOF (note that γ-CD-MOF alone (i.e., without cargo) has no HPLC-UV signal). Similarly, another co-crystallization production run was performed, this time using two separate antibiotics as non-limiting examples of APIs. In this experiment, 50 mg of ciprofloxacin and 50 mg of tetracycline were added to an H2O:ethanol solution containing 75 mg of potassium chloride and 150 mg of γ-CD (in a 1:1 ratio, but other ratios may be used depending on the implementation plan). As with rifampin, the resulting co-crystallization was digested in PBS and analyzed by HPLC. Figure 22B shows the successful co-crystallization of multiple antibiotics within a γ-CD-MOF, evidenced by two independent sharp HPLC-UV peaks (one for each antibiotic). These data demonstrate that different APIs can be successfully co-crystallized into sugar-based MOFs. Notably, these also demonstrate that unrelated APIs can be co-crystallized, enabling customized API delivery in some implementations. As a non-limiting example, the co-crystallization of ciprofloxacin and tetracycline could allow for the use of multi-mechanism approaches to treat infections. Similarly, other co-crystallizations presented herein can utilize synergistic amounts of other APIs, such as analgesics and anti-migraine medications for migraine sufferers, or hormones (e.g., estrogen) and biological response modifiers (skin temperature) for perimenopausal or postmenopausal women.

[0170] Further experiments were conducted to evaluate the functionality of the API-CD-MOFs provided herein. These experiments assessed the antimicrobial efficacy of various antibiotics (as non-limiting examples of APIs). In the first experiment, *Mycobacterium terrae* was inoculated into Middlebrook 7H9 medium and incubated at 37 °C. Various antibiotic-CD-MOFs, including ciprofloxacin-γ-CD-MOF, clofazimine-γ-CD-MOF, rifampin-γ-CD-MOF, tetracycline-γ-CD-MOF, and vancomycin-γ-CD-MOF, were generated according to the methods described herein. These test compounds were compared to individual γ-CD-MOFs (i.e., no cargo). Each test API-CD-MOF (or control) was added at increasing concentrations (ranging from 0.1 ug / mL to 500 ug / mL) to 0.300 mL of *Mycobacterium terrae* aliquots and incubated for 120 h. The optical density (OD) (600 nm) of each test sample was measured to determine whether the microbial growth rate was increasing or decreasing. These data were displayed in... Figure 23 The graph depicts the control γ-CD-MOF as the thickest line, with its OD values ​​around 0.6 at all tested concentrations, indicating a stable population of *Mycobacterium terrestrialum*. In stark contrast, API-CD-MOF showed concentration-dependent reductions in *Mycobacterium terrestrialum* populations for each test, with concentrations of 100 ug / mL (or higher for clofazimine-CD-MOF) effectively killing the entire population. However, even lower concentrations (10 ug / mL or higher for ciprofloxacin-CD-MOF, tetracycline-CD-MOF, rifampin-CD-MOF, and vancomycin-CD-MOF) showed significant antibacterial activity.

[0171] Based on this experiment, a single API (ciprofloxacin, as a non-limiting example) was co-crystallized with γ-CD-MOF or β-CD-MOF and its antibacterial activity was compared with that of ciprofloxacin alone. In this experiment, Mycobacterium abscessus was inoculated into Middlebrook 7H9 medium and incubated at 37 °C. Each test API-CD-MOF (or control) was added to 0.300 ml of Mycobacterium abscessus aliquots at increasing concentrations (ranging from 0.1 ug / mL to 500 ug / mL) and incubated for 120 h. The optical density (OD) (600 nm) of each test sample was measured to determine whether the microbial growth rate increased or decreased. These data were displayed in Figure 24In this context, it is noteworthy that the antibacterial activity exhibited by each API-CD-MOF was similar to that of ciprofloxacin alone. The minimum inhibitory concentrations (MICs) of both γ-CD-MOF and β-CD-MOF were ~8 μg / mL, which showed no detectable difference from ciprofloxacin alone. These data demonstrate that cocrystals of both γ-CD-MOF and β-CD-MOF can be successfully formed, and the APIs they contain remain functional. However, these API-CD-MOFs offer numerous potential advantages over individual APIs, including enhanced stability, improved bioavailability, improved cell targeting and permeability, increased or decreased half-life (as needed), adjustable release profiles, multiple API forms for synergistic effects, configurable dosage forms, and other benefits.

[0172] Regarding dosage forms, many options exist. In several embodiments, the cocrystals provided herein are configured as solid particles (see, for example, Figure 18B). In some embodiments, the cocrystal configuration is used in dry powder inhalers (DPIs). Figure 25A shows a ciprofloxacin-γ-CD-MOF cocrystal placed in a DPI capsule (as a non-limiting embodiment). Figure 25B shows a cocrystal capsule placed in a DPI delivery device configured for drug inhalation administration. In several embodiments, such forms are particularly useful for delivering drugs by inhalation (e.g., for treating or preventing lung infections or diseases). This use is... Figure 26 It is depicted schematically in the middle. Figure 26 A schematic diagram depicts the delivery of an API-CD-MOF to the lungs. As shown, in several embodiments, an antibiotic is used as the API, and the antibiotic-CD-MOF is delivered to the alveoli via a DPI, where it is phagocytosed by alveolar macrophages. Those macrophages infected with bacteria are thus exposed to the antibiotic, thereby treating the lung infection. While the schematic diagram illustrates lung infections (particularly deep lung infections), other diseases / conditions can also be treated, and other areas of the lungs can be treated. For example, in several embodiments, the API-CD-MOF is used to treat asthma, tuberculosis, cystic fibrosis, chronic sinusitis, allergies, pulmonary hypertension, pulmonary fibrosis, acute respiratory distress syndrome, pneumonia, and chronic obstructive pulmonary disease (COPD). In several embodiments, one or more of the trachea, bronchi, bronchioles, and alveoli are treated.

[0173] In the detailed description, references to “various embodiments,” “one embodiment,” “an example embodiment,” etc., indicate that the described embodiments may include specific features, structures, or characteristics, but each embodiment may not necessarily include that specific feature, structure, or characteristic. Furthermore, such phrases do not necessarily refer to the same embodiment. Additionally, when a specific feature, structure, or characteristic is described in connection with an embodiment, it is assumed that implementing such a feature, structure, or characteristic in conjunction with other embodiments (whether explicitly described or not) is within the knowledge of those skilled in the art. Upon reading the description, it will be apparent to those skilled in the relevant art (or more articulations) how this disclosure can be implemented in alternative embodiments. The steps described in any method or process description may be performed in any order and are not necessarily limited to the given order. Furthermore, any reference to the singular includes the plural embodiments, and any reference to multiple components or steps may include a singular embodiment or step. Similarly, any reference to attachment, fixing, connection, coupling, or similar terms may include permanent (e.g., integral), detachable, temporary, partial, complete, and / or any other possible attachment options. Any components may be coupled to each other by friction, snap-fit, sleeve, bracket, clip, or other means now known or hereafter developed in the art. Furthermore, any reference to "no contact" (or similar phrase) may also include "reduced contact" or "minimum contact." Regarding components grouped by function or characterized herein, unless otherwise expressly stated herein, it is not excluded that such components may be grouped with or characterized by another function. For example, a component discussed herein as a solubilizer may also be used as a surfactant, and vice versa. The scope of this disclosure also includes any and all overlapping, subscopes, and combinations thereof. Languages ​​such as "up to," "at least," "greater than," "less than," "between," etc., include the listed figures. Figures beginning with terms such as "about" or "approximately" include the listed figures. For example, "about 90%" includes "90%." Language such as "at least 95% of the active substance bound to a carbohydrate-based molecular backbone" includes 96%, 97%, 98%, 99%, and 100% of the active substance bound to a carbohydrate-based molecular backbone. Any headings or subheadings used herein are for organizational purposes only and should not be used to limit the scope of the embodiments disclosed herein. Benefits, other advantages, and solutions to problems have been described herein in conjunction with specific embodiments. However, any element of benefit, advantage, solution to a problem, and any benefit, advantage, or solution that may lead to or become more apparent should not be construed as a key, essential, or fundamental feature or element of this disclosure. The scope of this disclosure should therefore be limited only by the appended claims, wherein reference to a singular element is not intended to mean “one and only one,” but rather “one or more” unless expressly stated otherwise.Furthermore, when phrases such as “at least one of A, B, and C” or “at least one of A, B, or C” are used in the claims or description, it is intended to be interpreted as indicating that A may be present alone in an embodiment, B may be present alone in an embodiment, C may be present alone in an embodiment, or any combination of elements A, B, and C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C. All structural, chemical, and functional equivalents of the elements of the various embodiments described above, known to those skilled in the art, are expressly incorporated herein by reference and are intended to be included in these claims. Furthermore, no device or component of a device, or method of using a device, is required to solve every problem that this disclosure attempts to address in order to be included in these claims. Moreover, no element, component, or method step in this disclosure is intended to be offered to the public, whether or not it is expressly recited in a claim. No element of any claim is intended to invoke 35 USC 112(f) unless an element is expressly recited using the phrase “means for”. As used herein, the terms “comprising,” “including,” or any other variation thereof are intended to cover non-exclusive inclusion, such that a chemical, chemical composition, process, method, article, or apparatus that includes a list of elements may include not only those elements but also other elements not expressly listed or inherent to such chemical, chemical composition, process, method, article, or apparatus.

[0174] Numbering Implementation Plan

[0175] The implementation plan provided in this article includes:

[0176] 1. A eutectic comprising: an active substance; and a molecular framework comprising sugars; wherein the molecular framework and the active substance exist within a common crystal lattice.

[0177] 2. The cocrystal according to embodiment 1, wherein the active substance is selected from the group consisting of: irritants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof.

[0178] 3. The eutectic according to embodiment 1, wherein the active substance is an alkaloid capable of acting as a stimulant.

[0179] 4. The eutectic according to embodiment 1, wherein the active substance is (S)-nicotine.

[0180] 5. The eutectic according to embodiment 1, wherein the molecular framework is selected from the group consisting of: metal-organic frameworks (MOF), covalent organic frameworks (COF), hydrogen-bonded organic frameworks (HOF), or coordination polymers or other eutectic forms.

[0181] 6. The eutectic according to embodiment 1, wherein the molecular framework comprises a cyclodextrin-based metal-organic framework (CD-MOF).

[0182] 7. The eutectic according to embodiment 6, wherein the CD-MOF comprises α-, β-, or γ-cyclodextrin and a compound selected from Li + Na + K + 、Rb + and Cs + Alkali metal cations.

[0183] 8. A eutectic comprising: (S)-nicotine; and a cyclodextrin-based metal-organic framework (CD-MOF); wherein the (S)-nicotine and the CD-MOF exist within a common lattice.

[0184] 9. The eutectic according to embodiment 8, wherein the cyclodextrin comprises α-, β-, or γ-cyclodextrin, and the CD-MOF further comprises a compound selected from Li. + Na + K + 、Rb + and Cs + Alkali metal cations.

[0185] 10. A eutectic comprising: (S)-nicotine; and a cyclodextrin-based molecular framework; wherein the (S)-nicotine and the molecular framework exist within a common lattice, and wherein the lattice is completely free of metal ions.

[0186] 11. A method for manufacturing an API-eutectic solid, the method comprising: preparing a mixture comprising metal ions, cyclodextrin, water and a first organic solvent; adding a solution of API in a second organic solvent to the mixture; and adding a sufficient amount of at least one of the first or second organic solvent to the mixture to induce co-crystallization and form an API-eutectic solid.

[0187] 12. The method according to embodiment 11, wherein the first and second organic solvents are selected from the group consisting of ethanol, methanol, acetonitrile, isopropanol, propylene glycol, glycerol, and mixtures thereof.

[0188] 13. The method according to embodiment 11, wherein both the first and second organic solvents are ethanol.

[0189] 14. A dosage form of an API comprising: the API crystallized in a eutectic within a common lattice comprising the API and a molecular backbone comprising sugars; at least one excipient; and at least one matrix; wherein the at least one excipient and / or the at least one matrix promotes the dosage form or the physical properties of the dosage form; and wherein the dosage form is selected from lozenges, dry powder inhalers, nasal inhalers, nasal sprays, transdermal patches, topical creams, tablets, lozenges, capsules, blister packs, gummies, chewing gum, oral films, lozenges, chewable tablets or chewable sticks, nebulized solutions, oral solutions or suspensions, buccal or sublingual solutions. Tablets or films, effervescent tablets or granules, suppositories or vaginal suppositories, injectable solutions or suspensions, intramuscular injection solutions, intravenous injection solutions, subcutaneous injection solutions, lyophilized formulations for reconstitution, implantable devices or reservoirs, microspheres or nanoparticles, liposome formulations, inhalable aerosol sprays or solutions, ear drops or ophthalmic solutions, microneedle patches, emulsions, microemulsions, nanoemulsions, sustained-release or controlled-release formulations, films or meshes for surgical implants, powders or granules for reconstitution, oral dispersible or sublingually soluble tablets, vaginal rings or films, anal rings or inserts, mouthwashes or rinses, subcutaneous or intradermal patches, and wafers.

[0190] 15. A method of treating a disease in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

[0191] 16. A method of treating a physical or mental illness in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

[0192] 17. A method for inducing stimulation in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

[0193] 18. A method for promoting the overall health of an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

[0194] 19. The method according to embodiment 15 or 16, wherein the disease or condition is selected from asthma, cystic fibrosis, chronic sinusitis, allergy, pulmonary hypertension, pulmonary fibrosis, acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease (COPD), lung cancer, pathological or neuropathic pain, substance or opioid abuse disorder, addiction, depression, central nervous system (CNS) disease, sleep disorder, skin infection, and wound infection.

[0195] 20. The method according to any one of embodiments 15-19, wherein the active substance is selected from the group consisting of: irritants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof.

Claims

1. A eutectic comprising: an active substance; and a molecular framework comprising sugars; wherein the molecular framework and the active substance exist within a common crystal lattice.

2. The eutectic according to claim 1, wherein the active substance is selected from the group consisting of: stimulants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, hallucinogens, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, vasodilators, anticholinergic drugs, vaccines, insulin, sedatives and hypnotics, antipsychotics, immunosuppressants, enzymes, anticoagulants, chemotherapeutic drugs, antidiabetic drugs, antiemetics, anticonvulsants, and stimulants. Gene therapy vectors, monoclonal antibodies, antiparasitic drugs, antifibrotic drugs, antiarrhythmic drugs, antiplatelet drugs, biological response modifiers, radiopharmaceuticals, penetrants, antituberculosis drugs, antileukotriene drugs, antimigraine drugs, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof.

3. The eutectic according to claim 1, wherein the active substance is an alkaloid capable of acting as a stimulant.

4. The eutectic according to claim 1, wherein the active substance comprises (S)-nicotine.

5. The eutectic according to claim 1, wherein the active substance comprises an antibiotic.

6. The cocrystal according to claim 5, wherein the antibiotic is selected from the antibiotic class, which is selected from the group consisting of: β-lactams, cephalosporins, carbapenems, monocyclic β-lactams, macrolides, fluoroquinolones, aminoglycosides, tetracyclines, sulfonamides, glycopeptides, oxazolidinones, rifamycins, macrolides, nitroimidazoles, aminoglycosides, cyclic lipopeptides, lincosamides, and combinations thereof.

7. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of: benzathine penicillin, benzathine penicillin (penicillin G), benzathine penicillin G, oxazolidin, penicillin V, phenoxymethylpenicillin (penicillin V), procaine penicillin, feneccillin, cloxacillin, dicloxacillin, flucloxacillin, methicillin, nafcillin, oxazolidin, temoxicillin, amoxicillin, ampicillin, mecillin, piperacillin, carbenicillin, ticarcillin, azlocillin, mezlocillin, and combinations thereof.

8. The cocrystal according to claim 5, wherein the antibiotic is selected from the group consisting of: cefazolin, cephalexin, cephalosporin C, cefotaxime, cefepime, cefuroxime, cefaclor, cefprozil, cefamandole, cefotetan, cefoxitin, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, cefepime, cefpirome, cefpirome, cefuroxime, cefuroxime, cefepime, and combinations thereof.

9. The cocrystal according to claim 5, wherein the antibiotic is selected from the group consisting of imipenem, meropenem, biapenem, doripenem, ertapenem, faropenem, panipenem, rezupenem, telbipenem, thiomycin, and combinations thereof.

10. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of aztreonam, tegafur, nocamycin A, tabutoxin β-lactam, and combinations thereof.

11. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of: erythromycin, azithromycin, clarithromycin, tererythromycin, carbamycin A, josamycin, tylosin, midecamycin / midecamycin acetate, pyruvicin, spiramycin, pyruvicin acetate, tylosin / tylosin, roxithromycin, borobamycin, and combinations thereof.

12. The cocrystal according to claim 5, wherein the antibiotic is selected from the group consisting of: moxifloxacin, ciprofloxacin, levofloxacin, flumethin, oxacrylic acid, rosofaxin, sinofloxacin, nalidixic acid, pyrrolic acid, pipemidic acid, flerofloxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin, gapafloxacin, pazufloxacin, sparfloxacin, timafloxacin, tosufloxacin, clinfloxacin, gatifloxacin, sitafloxacin, prulifloxacin, besifloxacin, derafloxacin, gemifloxacin, trovafloxacin, ozenafloxacin, danoxacin, difluorofloxacin, enrofloxacin, ibafloxacin, mabofloxacin, obibixacin, sarafloxacin, and combinations thereof.

13. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of: kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B / C, neomycin E, streptomycin, prazomicin, and combinations thereof.

14. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of tetracycline, doxycycline, minocycline, chlortetracycline, oxytetracycline, demethylchlortetracycline, methacycline, methacycline, rolicycline, tigecycline, eracycline, salazine, omalicycline, and combinations thereof.

15. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of: sulfamethoxazole, sulfonamides, sulfasalazine, sulfacetyl, sulfadiazine, sulfadiazine, sulfafuran (sulfaisoxazole), sulfadiazine (sulfaisodimethazine), sulfaguanidine, sulfamozole, sulfanilide, sulfadimethoxypyrimidine, sulfamethoxypyridazine, sulfadiazine, sulfadoxine, sulfamethoxypyrazine, terephthalic acid, and combinations thereof.

16. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of vancomycin, teicoplanin, tervacin, ramoranine, decarbazin, kobacin, compstatin, orivancin, dapavancin, and combinations thereof.

17. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of linezolid, pofuzolamide, terdizolid, ladizolamide, cycloserine, contezolid, and combinations thereof.

18. The eutectic according to claim 5, wherein the antibiotic is selected from the group consisting of rifampin, rifabutin, rifapentine, rifaximin, and combinations thereof.

19. The eutectic according to claim 1, wherein the active substance comprises an antifungal agent.

20. The eutectic according to claim 19, wherein the antifungal agent is selected from the group consisting of: amphotericin B, voriconazole, itraconazole, nystatin, hamycin, natamycin, rimomycin, bifonazole, butonazole, clotrimazole, econazole, fenteconazole, isoconazole, ketoconazole, ruliconazole, miconazole, omeconazole, oxiconazole, sertaconazole, thioconazole, tiaconazole, abaconazole, ciproconazole, ifluconazole, fluconazole, fluconazole, isaconazole, posaconazole, propiconazole, rivanazole, terconazole, abafenoxam, butenafine, naftifine, terbinafine, etc. Nifentanil, caspofungin, micafungin, ibuprofen, acricin, amorolfen, orconazoles, benzoic acid, fuchsin, ciclopirox ketone (ciclopirox ketoneamine), cloiodohydroxyquine, coal tar, copper(II) sulfate, crystal violet, chlorhexidine, chlorphenesin, diiodoquinoline (iodoquinol), fluorocytosine (5-fluorocytosine), fumonisin, griseofulvin, haloroside, mitefoxin, nicotinic acid, oromethiophene, piroctone ketone ethanolamine, valerate, potassium iodide, potassium permanganate, selenium disulfide, sodium thiosulfate, sulfur, tonaphthyl ester, triacetin, undecenoic acid, zinc pyrithione and combinations thereof.

21. The eutectic according to claim 1, wherein the active substance comprises an antiviral agent.

22. The eutectic according to claim 21, wherein the antiviral agent is selected from the group consisting of: oseltamivir, remdesivir, favipiravir, enfuvirtide, amantadine, rimantadine, prolecanidine, acyclovir, zidovudine, lamivudine, raltegravir, erteiravir, dolutegravir, formivavir, zanamivir, sofosbuvir, ledipasvir, velpatasvir, voxiprevir, irbavir, grazoprevir, glucareprevir, pibumetasvir, and combinations thereof.

23. The eutectic according to claim 1, wherein the active substance comprises a chemotherapeutic drug.

24. The cocrystal according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of platinum compounds, anthracyclines, tyrosine kinase inhibitors, taxanes, vinca alkaloids, topoisomerase inhibitors, epidermal growth factor receptor (EGFR) inhibitors, programmed death factor-1 (PD-1) inhibitors, camptothecin (CPT), 9-nitrocamptothecin (9-NC), 5-fluorouracil (5-FU), bevacizumab, temozolomide, and combinations thereof.

25. The eutectic according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, tetranitrate, phenanthreneplatin, picoplatin, saxaplatin, and combinations thereof.

26. The eutectic according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, penoxorubicin, and combinations thereof.

27. The cocrystal of claim 23, wherein the chemotherapeutic agent is selected from the group consisting of imatinib, gefitinib, erlotinib, dasatinib, sunitinib, adavosertib, lapatinib, pazopanib, and combinations thereof.

28. The cocrystal according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of: paclitaxel, docetaxel, taxine A, taxine B, taxine C, baccatin III, 10-deacetylated baccatin, taxine A, taxine B, and combinations thereof.

29. The eutectic according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of: vincristine, vinblastine, vinorelbine, vinaminol, vinorelbine, vinbutin, vinpocetine, minocycline, methoxyminocycline, minocycline, vindiflumine, deoxyvinaminol, vinpocetine, and combinations thereof.

30. The eutectic according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of: topotecan, irinotecan, camptothecin, belotetan, silotecan, indomethacin, topovalle, BE-13793C, indotecan, indimitecan, neomycin, coumarin, nalidixic acid, sinofloxacin, norfloxacin, and combinations thereof.

31. The cocrystal according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of: gemcitabine, methotrexate, decitabine, nelabine, clofarabine, capecitabine, fludarabine, cradabine, 5-fluorouracil, cytarabine, and combinations thereof.

32. The cocrystal of claim 23, wherein the chemotherapeutic agent is selected from the group consisting of erlotinib, gefitinib, osimertinib, afatinib, lapatinib, cetuximab, dacomitinib, vandetanib, ometinib, ametinib, panitumumab, icotinib, and combinations thereof.

33. The cocrystal of claim 23, wherein the chemotherapeutic agent is selected from the group consisting of nivolumab, pembrolizumab, semipril, and combinations thereof.

34. The cocrystal according to claim 23, wherein the chemotherapeutic agent is selected from the group consisting of: camptothecin (CPT), 9-nitrocamptothecin (9-NC), 5-fluorouracil (5-FU), bevacizumab, temozolomide, and combinations thereof.

35. The cocrystal of claim 23, wherein the chemotherapeutic agent is selected from the group consisting of atezolizumab, avelumab, durvalumab, ipilimumab, trimemumab, renalalimab, and combinations thereof.

36. The eutectic according to any one of claims 1 to 35, wherein the molecular framework is selected from the group consisting of metal-organic frameworks (MOFs), covalent organic frameworks (COFs), hydrogen-bonded organic frameworks (HOFs), or coordination polymers or other eutectic forms.

37. The eutectic according to claim 1, wherein the molecular framework comprises a cyclodextrin-based metal-organic framework (CD-MOF).

38. The eutectic according to claim 37, wherein the CD-MOF comprises cyclodextrin and alkali metal cations.

39. The eutectic according to claim 38, wherein the cyclodextrin is selected from α-, β-, or γ-cyclodextrin.

40. The eutectic according to claim 38, wherein the alkali metal cation is selected from lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+) and cesium (Cs+) ions.

41. The eutectic according to claim 38, wherein the CD-MOF comprises β-cyclodextrin and sodium (Na+) ions.

42. The eutectic according to claim 38, wherein the CD-MOF comprises γ-cyclodextrin and potassium (K+) ions.

43. The eutectic according to any one of claims 1 to 42, wherein the eutectic is produced by a process selected from the group consisting of: spray drying, freeze drying, co-solvent crystallization, cooling crystallization, evaporation crystallization, supercritical fluid crystallization, slurry conversion, liquid antisolvent precipitation, and combinations thereof.

44. A eutectic comprising: (S)-nicotine; and a cyclodextrin-based metal-organic framework (CD-MOF); wherein the (S)-nicotine and the CD-MOF exist within a common lattice.

45. The eutectic according to claim 44, wherein the cyclodextrin comprises α-, β-, or γ-cyclodextrin, and the CD-MOF further comprises an alkali metal cation selected from lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+) ions.

46. ​​A eutectic comprising: (S)-nicotine; and a cyclodextrin-based molecular framework; wherein the (S)-nicotine and the molecular framework are present in a common lattice, and wherein the lattice is completely free of metal ions.

47. A method for manufacturing an API-eutectic solid, the method comprising: Prepare a mixture comprising metal ions, cyclodextrin, water and a first organic solvent; A solution of the API in a second organic solvent is added to the mixture; And add a sufficient amount of at least one of the first or second organic solvents to the mixture to induce co-crystallization and form an API-eutectic solid.

48. The method of claim 47, wherein the first and second organic solvents are selected from the group consisting of ethanol, methanol, acetonitrile, isopropanol, propylene glycol, glycerol, and mixtures thereof.

49. The method of claim 48, wherein both the first and second organic solvents are ethanol.

50. A method for manufacturing an API-eutectic solid, the method comprising: A solution is prepared in a solvent or solvent mixture, the solution comprising (i) an active pharmaceutical ingredient (API), (ii) a cyclodextrin selected from α-, β-, and γ-cyclodextrins, and (iii) at least one alkali metal cation selected from lithium (Li+), sodium (Na+), potassium (K+), rubidium (Rb+), and cesium (Cs+) ions; the solution is fed into a spray drying apparatus; the solution is atomized in the spray drying apparatus to form droplets; the solvent or solvent mixture in the droplets is evaporated in a drying chamber of the spray drying apparatus under conditions suitable for forming solid particles; solid particles are collected from the drying chamber, wherein the solid particles comprise a eutectic of API and a cyclodextrin-metal-organic framework (CD-MOF); and wherein the spray drying apparatus is operated under conditions selected to promote eutectic formation by controlling at least one of the following: the temperature inside the drying chamber, the solvent evaporation rate, or the airflow velocity through the drying chamber.

51. The method of claim 50, wherein the solvent is selected from the group consisting of water, ethanol, methanol, isopropanol, glycerol, propylene glycol, acetone, dimethylformamide (DMF), diethylformamide (DEF), and mixtures thereof.

52. The method according to claim 50 or 51, wherein the temperature inside the drying chamber is maintained between 80°C and 200°C.

53. The method according to any one of claims 50 to 52, wherein the air flow rate through the drying chamber is maintained between 10 and 500 L / min.

54. The method according to any one of claims 50 to 53, wherein the atomization of the solution is achieved using an ultrasonic, pneumatic, pressure atomizer, rotary atomizer, electrostatic, air-assisted, hydraulic, hydraulic and pneumatic rotary or other spray configuration nozzle.

55. The method according to any one of claims 50 to 54, wherein the particle size distribution of the eutectic is between 0.2 μm and 200 μm.

56. The method according to any one of claims 50 to 55, further comprising the step of adjusting the pH of the solution to between 3 and 9 prior to the atomization step.

57. The method according to any one of claims 50 to 56, wherein the API and CD-MOF components (α-, β- or γ-cyclodextrin, and alkali metal cations selected from Li+, Na+, K+, Rb+ and Cs+ ions) are present in a mass percentage ratio of 10:1 to 1:30 (API:CD-MOF).

58. A spray drying apparatus configured to perform the method according to any one of claims 50 to 57, comprising: Solution feeding system; atomizer; Drying chamber; Temperature control system for regulating the internal temperature of the drying chamber; An airflow system used to regulate the airflow velocity through the drying chamber; And particle collection systems.

59. A dosage form of an API comprising: the API crystallized in a eutectic within a common lattice comprising the API and a molecular backbone comprising sugars; at least one excipient; and at least one matrix; wherein the at least one excipient and / or the at least one matrix promotes the dosage form or the physical properties of the dosage form; and wherein the dosage form is selected from lozenges, dry powder inhalers, nasal inhalers, nasal sprays, transdermal patches, topical creams, tablets, lozenges, capsules, blister packs, gummies, chewing gum, oral films, lozenges, chewable tablets or chewable sticks, nebulized solutions, oral solutions or suspensions, buccal or tongue applications. Tablets or films, effervescent tablets or granules, suppositories or vaginal suppositories, injectable solutions or suspensions, intramuscular injection solutions, intravenous injection solutions, subcutaneous injection solutions, lyophilized formulations for reconstitution, implantable devices or reservoirs, microspheres or nanoparticles, liposome formulations, inhalable aerosol sprays or solutions, ear drops or ophthalmic solutions, microneedle patches, emulsions, microemulsions, nanoemulsions, sustained-release or controlled-release formulations, films or meshes for surgical implants, powders or granules for reconstitution, oral dispersible or sublingually soluble tablets, vaginal rings or films, anal rings or inserts, mouthwashes or rinses, subcutaneous or intradermal patches, and wafers.

60. A method of treating a disease in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

61. A method of treating a physical or mental illness in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

62. A method for inducing stimulation in an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

63. A method for promoting the overall health of an individual in need, the method comprising administering a therapeutically effective amount of a cocrystal, the cocrystal comprising an active substance and a molecular backbone comprising sugars, wherein the molecular backbone and the active substance are present within a common crystal lattice.

64. The method according to claim 60 or 61, wherein the disease or condition is selected from asthma, cystic fibrosis, chronic sinusitis, allergy, pulmonary hypertension, pulmonary fibrosis, acute respiratory distress syndrome, lung infection, antimicrobial resistant (AMR) lung infection, pneumonia, chronic obstructive pulmonary disease (COPD), lung cancer, pathological or neuropathic pain, substance or opioid abuse disorder, addiction, depression, central nervous system (CNS) disease, sleep disorder, skin infection, and wound infection.

65. The method according to any one of claims 60 to 64, wherein the active substance is selected from the group consisting of: irritants, antibiotics, antiviral drugs, antifungal drugs, mucolytics, pulmonary surfactants, bronchodilators, anti-inflammatory agents, NSAIDs, corticosteroids, antihistamines, antidepressants, psychedelics, analgesics, anesthetics, central nervous system (CNS) depressants, hallucinogens, dissociative anesthetics, narcotic analgesics, inhalants, herbs, herbal extracts, essential oils, vitamins, supplements, antioxidants, alkaloids, phenols, polyphenols, fatty acids, tannins, lignans, polysaccharides, glycosides, esters, flavonoids, terpenes, diterpenes, diterpenoid compounds, triterpenes, triterpenoid compounds, amino acids, proteins, antibodies, steroids, corticosteroids, cannabinoids, surfactants, saponins, coumarins, and mixtures thereof.

66. A method for treating a disease, condition, inducing stimulation or promoting overall health in a subject, the method comprising administering to the subject a composition comprising a cocrystal according to any one of claims 1-46 or a dosage form according to claim 59.

67. Use of the eutectic according to any one of claims 1-46 or the dosage form according to claim 59 in treating a subject's disease, condition, inducing stimulation, or promoting the subject's overall health.

68. Use of the eutectic according to any one of claims 1-46 or the dosage form according to claim 59 in the preparation of a medicament for treating a disease, symptom, inducing stimulation, or promoting the overall health of a subject.

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