Oral terpene cyclodextrin inclusion vehicle

Abstract

The present invention provides oral terpene cyclodextrin inclusion complex delivery vehicles, including formulations in which a cyclodextrin inclusion complex is provided with an enzyme having cyclodextrin-degrading activity capable of digesting cyclodextrin, wherein upon delivery of the delivery vehicle to a target, the cyclodextrin-degrading activity is activated, releasing the guest molecule from the cavity of the cyclodextrin. In another aspect, these cyclodextrin inclusion complex delivery vehicles are provided, for example, in the form of a sustained-release formulation, for example, for the treatment of airway mucus disorders. Formulations are also provided with erectile effects.

Description

[Technical Field]

[0001] The present invention is in the field of biochemical constructs for the delivery of bioactive terpenes, including camphene, as inclusion complexes within cyclodextrins in oral formulations that may include enzymes with cyclodextrin degrading activity. [Background technology]

[0002] Cyclodextrins are non-reducing cyclic glucose oligosaccharides, often the product of the catalytic degradation of starch by cyclomaltodextrin glucanotransferase (EC 2.4.1.19; CGTase). Cyclodextrins can have a variety of structures, including three common cyclodextrins (α-, β-, and γ-cyclodextrin, respectively) with six, seven, or eight D-glucopyranosyl residues linked within the ring by 1,4-glucosidic bonds (see Saenger et al., Chem. Rev. 98 (1998) 1787-1802). The truncated cone shape of cyclodextrins forms a cavity or lumen, with different diameters depending on the number of glucose units. A structural hierarchy of selected cyclodextrins (CDs) is shown in Table 1. Larger cyclodextrins such as cyclomaltononaose (δ-CD) and cyclomaltodecaose (ε-CD) are also possible, as well as supramolecular structures based on various cyclodextrins (see Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug; 65(9): 1215-33).

[0003] [Table 1]

[0004] Cyclodextrins are generally amphiphilic, with a wide edge of the cavity displaying the 2-OH and 3-OH groups and a narrow edge displaying the 6-OH group. These hydrophilic hydroxyl groups are therefore located on the exterior of the cavity, while the interior surface is generally hydrophobic, with anomeric oxygen atoms and C3-H and C5-H hydrogen atoms lined along the interior surface. In aqueous solution, this hydrophobic cavity can contain water molecules, e.g., approximately 3 (α-CD), 7 (β-CD), or 9 (γ-CD), which are slightly confined but have low entropy and are relatively easily displaceable. Alternatively, hydrophilic cyclodextrins can bind and retain one or more appropriately sized molecules within or partially within the CD cavity to form cyclodextrin inclusion complexes or clathrates. For example, cyclodextrins can bind nonpolar aliphatic and aromatic compounds, including drugs such as fat-soluble drugs, increase the water solubility of normally hydrophobic compounds, or minimize undesirable properties such as odor or taste in certain food additives. For this reason, cyclodextrin inclusion complexes are widely used in the pharmaceutical, food, and cosmetic fields (see Hedges, Chem. Rev. 98 (1998) 2035-2044). Cyclodextrins have been used in various sustained-release pharmaceutical formulations, such as inclusion complexes of pharmaceutical compounds with hydrophobic cyclodextrin derivatives (US Pat. No. 4,869,904).

[0005] Cyclodextrins can be chemically modified in various ways to alter their inclusion specificity, physical, and chemical properties. For example, the hydroxyl groups of CDs can be derivatized. For example, two modified CDs are used in numerous pharmaceutical products: SBE-β-CD, a polyanionic, variably substituted sulfobutyl ether of β-CD (Captisol), and HP-β-CD, a modified CD commercially developed by Janssen. Additional CD derivatives include Sugammadex, or Org-25969, in which the 6-hydroxyl group of γ-CD is replaced by a carboxythioacetate ether bond and hydroxybutenyl-β-CD. Other forms of cyclodextrin include 2,6-di-O-methyl-β-CD (DIMEB), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated β-cyclodextrin (RAMEB), sulfobutylether-β-cyclodextrin (SBE-β-CD), sulfobutylether-γ-cyclodextrin (SBE-γ-CD), sulfobutylated β-cyclodextrin sodium salt, sulfobutylated β-cyclodextrin sodium salt, (2-hydroxypropyl)-α These include cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, DIMEB-50, heptakis(2,6-di-O-methyl)-β-cyclodextrin, TRIMEB, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, methyl-β-cyclodextrin, octakis(6-deoxy-6-iodo)-γ-cyclodextrin, and octakis(6-deoxy-6-bromo)-γ-cyclodextrin. Although CDs with favorable pharmacological and toxicological profiles have been developed, residual CDs may disrupt the pharmacokinetics of drugs, including co-administered drugs, especially after parenteral administration (see Stella and He, Toxicol Pathol, January 2008, vol. 36 no. 1, 30-42).

[0006] Cyclodextrins are variably susceptible to enzymatic digestion. For example, γ-CD is relatively easily hydrolyzed by α-amylase, whereas α-cyclodextrin is hydrolyzed less readily. CD-based therapeutics generally rely on the activity of endogenous amylase to digest CD. However, there is significant variation in amylase activity among patients. For example, patients with pancreatic insufficiency, cystic fibrosis, celiac disease, or Crohn's disease may lack normal amounts of amylase. Similarly, patients, particularly geriatric patients, may have insufficient gastric acid production, thereby failing to create adequate low pH conditions in the duodenum to adequately trigger the release of pancreatic amylase. Similar effects may occur with the general increased use of antacids, histamine-2 blockers, proton pump inhibitors, or alternative acid blockers.

[0007] Various microbial cyclodextrin-digesting enzymes have been identified. CD-degrading enzymes include cyclomaltodextrinase (or cyclodextrinase, or CDase, EC 3.2.1.54), maltogenic amylase (EC 3.2.1.313), and neopullulanase (EC 3.2.1.135), which have been reported to be capable of hydrolyzing CD and, in some cases, additional substrates such as pullulan and starch. Cyclodextrinase (CDase) catalyzes the hydrolysis of CD to form α-1,4-linked linear oligosaccharides, thereby releasing the material from the CD inclusion complex. CDase from Bacillus macerans was reported in 1968. Since then, many bacterial CDases have been characterized, including enzymes from Bacillus sp., Thermoanaerobacter ethanolicus strain 39E, Flavobacterium sp., and Klebsiella oxytoca strain M5a1. Archaea CDases from Archaeoglobus fuigidus, Thermococcus sp. B1001, Thermococcus sp. CL1, Thermofilum pendens, and Pyrococcus furiosus have been characterized. The structure of a CDase from Fiavobacterium sp. has been characterized in detail (see Sun et al., Archaea, Volume 2015 (2015), Article ID 397924, reporting the identification of the gene encoding the cyclodextrinase from Thermococcus kodakarensis KOD1 (CDase-Tk)).

[0008] Camphene is a monoterpene with a bicyclic skeleton: a bicyclo[2.2.1]heptane substituted with a geminal methyl group at the 2-position and a methylidene group at the 3-position. Camphene is a natural product found widely in many essential oils, typically as a racemic mixture of D- and L-camphene in varying proportions (Ochocka et al., 2002, Pharmaceutical Biology, 40:5, 395-399). It is widely used as a flavoring and fragrance. Camphene has also been described to have various physiological effects, including hypolipidemic effects (Vaillianou et al., PLoS One, 2011; 6(11) e20516).

[0009] Airway mucus dysfunction contributes to or is symptomatic of a wide variety of airway diseases and conditions (see, e.g., Fahy & Dickey, 2010), often manifesting as cough or difficulty breathing. Diseases characterized by airway mucus dysfunction include cystic fibrosis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, panbronchiolitis, and various immunodeficiency states. Conditions associated with airway mucus dysfunction can include disruption of normal lung mechanics, for example, in intubated, paralyzed, immobilized, or post-surgical patients. These problems may be related to retained mucus. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US4869904 [Non-patent literature]

[0011] [Non-Patent Document 1] Chem. Rev. 98 (1998) 1787-1802 [Non-patent document 2] Adv Drug Deliv Rev. 2013 Aug; 65(9): 1215-33 [Non-patent document 3] Chem. Rev. 98 (1998) 2035-2044 [Non-patent document 4] Toxicol Pathol January 2008 vol. 36 no. 1 30-42 [Non-patent document 5] Archaea, Volume 2015 (2015), Article ID 397924 [Non-patent document 6] 2002, Pharmaceutical Biology, 40:5, 395-399 [Non-Patent Document 7] PLoS One, 2011; 6(11) e20516 Summary of the Invention [Means for solving the problem]

[0012] For example, camphene-containing cyclodextrin inclusion complex delivery vehicles are provided for use in treating airway mucus dysfunction or for providing an erectogenic effect in male subjects. In addition to camphene, the formulations can include additional inclusion complex guest molecules, including additional terpenes, such as plant terpenes. Additional guest molecules include, for example, eucalyptol (i.e., 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; CAS No. 470-82-06; 1,8-cineole; 1,8-epoxy-p-menthane), guaiol (i.e., 2-[(3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-azulenyl]-2-propanol; CAS No. 489-86-1; champacol), and / or delta-3-carene (i.e., 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; CAS No. 13466-78-9). Additional guest molecules can be provided in CD inclusion complexes of plant extracts or compositions, such as peppermint compositions and / or fenugreek compositions, e.g., peppermint oil or fenugreek powder.

[0013] A biologically acceptable carrier can be provided in the cyclodextrin inclusion complex, and the guest molecule is stably held by the cyclodextrin within the biologically acceptable carrier. An enzyme having cyclodextrin-degrading activity that can digest the cyclodextrin that holds the guest molecule can also be provided in the vehicle. The enzyme can be formulated so that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to the target, releasing the guest molecule from the cyclodextrin cavity.

[0014] In another aspect of the delivery vehicle, the enzyme may be formulated with the cyclodextrin inclusion complex or the enzyme may be packaged with the cyclodextrin inclusion complex in the delivery vehicle, and if the enzyme is packaged with the cyclodextrin inclusion complex, the delivery vehicle may further include a biochemically acceptable carrier for the enzyme.

[0015] The enzyme may be, for example, amylase, cyclodextrinase, maltogenic amylase, or neopullulanase. The amylase may be, for example, mammalian salivary amylase, mammalian pancreatic amylase, or microbial amylase. The cyclodextrinase may be, for example, microbial cyclodextrinase.

[0016] The cyclodextrin may be a CD derivative, such as, for example, a hydrophobic alkylated cyclodextrin or a mixed methylated / ethylated cyclodextrin.

[0017] The ratio of the cyclodextrin to the guest molecule may be, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5, although a wide range of alternative values ​​for this parameter are possible, including non-integer ratios.

[0018] The cyclodextrin may be, for example, α-, β- or γ-cyclodextrin, and a wide variety of alternative CD structures may also be used.

[0019] In selected embodiments, additional guest molecules, such as drugs or prodrugs, PDE5 inhibitors, flavonoids (quercetin), cannabinoids, or anti-inflammatory agents (including acetaminophen), may be provided. In this context, the biologically acceptable carrier may advantageously be a pharmaceutically acceptable carrier. The delivery vehicle may be formulated for sustained release of the guest molecule.

[0020] Thus, the present invention provides other embodiments in which the CD delivery vehicle can be used as a pharmaceutical.

[0021] Methods are provided for treating patients with airway mucus dysfunction that is a symptom of diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, panbronchiolitis, or immunodeficiency states. Alternatively, airway mucus dysfunction can be a symptom of conditions associated with disruption of lung mechanics, such as intubation, paralysis, immobilization, or surgical trauma.

[0022] Also provided are methods of providing erectile benefits to a male subject, for example, a male over the age of 50, 60, or 70, or a male subject suffering from erectile dysfunction. DETAILED DESCRIPTION OF THE INVENTION

[0023] Specific formulations of delivery vehicles can include cyclodextrin inclusion complex formulations made by combining cyclodextrin inclusion complexes prepared from a number of sources, including, for example, natural plant extract sources, such as formulations that combine CD inclusion complexes prepared from two, three, four, five, or six of the following, either in a single formulation or in separate formulations provided in combination: an extract of Eucalyptus (Myrtaceae) in a CD inclusion complex, e.g., in a β-CD or γ-CD inclusion complex (e.g., standardized with 6 mg or 4-8 mg of eucalyptol); and / or an extract of Syncarpia glomlifera in a CD inclusion complex, e.g., in a β-CD inclusion complex or a γ-CD inclusion complex (e.g., standardized to 6 mg camphene, or 4-8 mg camphene), and / or 6 mg, or 4 to 8 mg, of peppermint (Mentha piperita) oil in a CD inclusion complex, for example, in a β-CD or γ-CD inclusion complex, and / or an extract of Pinus genus (Pinus pinaster and / or Pinus elliotii and / or Pinus sylvestris) in a CD inclusion complex, e.g., in a β-CD or γ-CD inclusion complex (e.g., standardized to 4 mg, or 2 to 6 mg, of delta-3-carene); and / or Fenugreek extract, for example fenugreek absolute (Trigonella foenum-graecum) 4 mg or 2 to 6 mg in a CD inclusion complex, for example in a β-CD inclusion complex or a γ-CD inclusion complex, and / or An extract of Bulnesia sarmientoi (e.g., standardized with 4 mg, or 2-6 mg, of guaiol) in a CD inclusion complex, e.g., a β-CD inclusion complex or a γ-CD inclusion complex.

[0024] For example, various ratios of ingredients can be provided, with doses ranging from 5 to 250 mg per dose of any one clathrate. The selected formulation may be entirely plant-derived active ingredients. A specific dosage form may be, for example, a single sustained-release capsule, as shown below. extracts of Eucalyptus (Myrtaceae) in a CD inclusion complex, e.g., in a β-CD or γ-CD inclusion complex (e.g., standardized with 6 mg, or 4-8 mg, of eucalyptol); an extract of Syncarpia glomlifera in a CD inclusion complex, e.g., in a β-CD inclusion complex or a γ-CD inclusion complex (e.g., standardized to 6 mg camphene, or 4 to 8 mg camphene); 6 mg, or 4 to 8 mg, of peppermint (Mentha piperita) oil in a CD inclusion complex, for example, in a β-CD inclusion complex or a γ-CD inclusion complex; an extract of the genus Pinus (Pinus pinaster and / or Pinus elliotii and / or Pinus sylvestris) in a CD inclusion complex, e.g., in a β-CD inclusion complex or a γ-CD inclusion complex (e.g., standardized to 4 mg, or 2 to 6 mg, of delta-3-carene); Fenugreek extract in a CD inclusion complex, for example, in a β-CD inclusion complex or a γ-CD inclusion complex, for example, 4 mg or 2 to 6 mg of fenugreek absolute (Trigonella foenum graecum); an extract of Bulnesia sarmientoi (e.g., standardized with 4 mg, or 2-6 mg, of guaiol) in a CD inclusion complex, e.g., a β-CD inclusion complex or a γ-CD inclusion complex; K250 extended release agent 80mg, Amylase 7 mg, and Calcium laurate 5mg.

[0025] The peppermint oil used in the formulations herein can be an extract of the peppermint plant: Mentha piperita. Peppermint oil composition varies, but is characterized as containing menthol (40.7%), menthone (23.4%), (±)-menthyl acetate, 1,8-cineole, limonene, β-pinene, and β-caryophyllene (Schmidt et al., 2009, Nat Prod Commun 4(8): 1107; CAS No. 8006-90-4, MDL No. MFCD00147870).

[0026] Fenugreek (Trigonella foenum graecum) compositions are widely known and are understood to contain various alkaloids, amino acids, saponins, steroidal sapinogenes, and flavonoids (Wani and Kumar, 2018, J. of the Saudi Society of Agricultural Sciences 17(2): 97). For example, fenugreek extract can be produced by solvent extraction of Trigonella foenum graecum seeds and is sometimes identified as fenugreek absolute (CAS No. 84625-40-1, FEMA No. 2486, EC No. 283-415-1, MDL No. MFCD01772302).

[0027] In selected embodiments, the guest molecule may be provided in the form of a plant extract, such as eucalyptol from the genus Eucalyptus (e.g., eucalyptus oil, CAS number 8000-48-4, FEMA number 2466, EC number 283-406-2), camphene from the genus Syncarpia, delta-3-carene (δ-3-carene) from pine trees (e.g., species: Pinus pinaster, Pinus elliotii, Pinus sylvestris, cedar, basil, pine, rosemary, pepper), guaiol (sesquiterpenoid alcohol, also found in cypress pine and guaiacum) from Bulnesia sarmientoi, peppermint oil containing menthol, or fenugreek extract from the seeds of Trigonella foenum-graecum. Other embodiments may include extracts, terpenes, or oils from, for example, Eucalyptus (Myrtaceae), Syncarpia glomlifera, Pinus (Pinus pinaster and / or Pinus elliotii and / or Pinus sylvestris) and Bulnesia sarmientoi, peppermint (Mentha piperita), and fenugreek (Trigonella foenum graecum). These extracts may be formulated in beta- and gamma-dextrin fiber matrices with, for example, high and low viscosity hydroxypropyl methylcellulose (sustained release), hypromellose (cellulose-derived) capsules, cellulose, calcium laurate, and amylase (such as a plant or microbial amylase).

[0028] In selected embodiments, the formulation may include, for example, the following ingredients in, for example, a vegetable cellulose capsule: 75 mg of eucalyptol (10% by weight) in β-CD inclusion complex, Camphene in β-CD inclusion complex (10 wt%) 75 mg, 50 mg of delta-3-carene (10% by weight) in β-CD inclusion complex; 50 mg of guaiol (10 wt%) in γ-CD inclusion complex, 50 mg of peppermint oil (15% by weight) in β-CD inclusion complex; 50 mg of fenugreek absolute (oil) (10% by weight) in γ-CD inclusion complex, K250 sustained release 80mg, Amylase 5 mg, and Calcium laurate 5mg.

[0029] A wide variety of biologically active compounds may be included in the delivery vehicles of the present invention, for example in the form of pharmaceutical compositions, as additional distinct components and / or as additional guest molecules. Examples include docetaxel (US 2014-0336149, US 2013-0296268), carbamazepine (US 2014-0080812), rifampicin (US 7001893), cardiac glycosides, in particular digoxin (US 4555504), progesterone (see Zoppetti et al., Journal of Inclusion Phenomena and Macrocyclic Chemistry, April 2007, Volume 57, Issue 1, pp 111-115). 283-288), albendazole, mebendazole, ricobendazole, fenoprofen, ketoprofen, cocaine, gliclazide, digitoxin, macrocyclic compounds (MCCs), ibuproxam, prochloromethazine, DY-9760e, NSC-639829, ETH-615, piroxicam, levemopamil hydrochloride, ziprasidone mesylate, sulindac, phenolphthalein, danazol (see, Challa et al., 2005, AAPS PharmSciTech 2005; 6 (2) Article 43), itraconazole, nelfinavir mesylate, telmisartan, 5-fluorouracil and other nucleoside analogues, camptothecin, humulene (also known as α-humulene or α-caryovirene), or flavonoids.

[0030] Selected embodiments are medicated food compositions comprising: 75 mg of eucalyptol (e.g., about 10% by weight) in a β-CD inclusion complex; 75 mg of camphene (e.g., about 10% by weight) in a β-CD inclusion complex; 50 mg of delta-3-carene in a β-CD inclusion complex (e.g., about 10% by weight); 50 mg of guaiol (e.g., about 10% by weight) in a γ-CD inclusion complex; 50 mg of peppermint oil in a β-CD inclusion complex (e.g., about 15% by weight); 50 mg of fenugreek absolute (oil) in a γ-CD inclusion complex (e.g., about 10% by weight), and Humulen.

[0031] In selected embodiments, the enzyme contained in the vehicle may be formulated so that upon delivery of the vehicle to the target, the cyclodextrin-degrading activity is activated, releasing the guest molecule from the cyclodextrin cavity. For example, in pharmaceuticals for oral delivery, enzyme activation can be achieved in a dry dosage form, such as a capsule or tablet, into which the enzyme is mixed, so that the enzyme is not active until activated by moisture in the host's gastrointestinal tract. Similarly, a wide variety of time-release matrices and formulations are known, which can be adapted for use in CD delivery vehicles to orchestrate the appropriate activation of the CD-degrading enzyme upon delivery to the target.

[0032] In various aspects, the CD delivery vehicle may have the enzyme formulated with a cyclodextrin inclusion complex, for example, as described above, or the enzyme may be packaged with the cyclodextrin inclusion complex in the delivery vehicle. When packaged together, the delivery vehicle may include, for example, a biochemically acceptable carrier for the enzyme, different from the carrier for the CD inclusion complex. For example, the delivery vehicle may be provided with separate compartments containing the CD inclusion complex and the CD-degrading enzyme, such that the delivery vehicle is composed of a CD inclusion complex compartment linked to a CD-degrading enzyme compartment. A mechanism for combined release of the CD inclusion complex and the CD-degrading enzyme from each compartment in the delivery vehicle can be provided. For example, a syringe with such separate compartments may be provided, and can be ejected by a conventional ejection mechanism, for example, a mechanism that coordinately moves pistons in each compartment, to eject aliquots of the CD inclusion complex and the CD-degrading enzyme, thereby mixing the enzyme and the CD inclusion complex and activating the enzymatic release of the guest molecule from the CD. Vehicles of this type may be used, for example, to disperse topical creams or other surface-active formulations. A wide variety of delivery vehicles of this type may be adapted from devices known as dispersible two-part compositions, such as epoxy resins, two-part pharmaceutical or dental formulations, as described, for example, in US4538920, US8100295, US8308340, US8875947, US8499976, WO2007 / 041266, and WO2000 / 021842.

[0033] Various techniques are available for preparing CD inclusion complexes, as described, for example, in Chaudhary & Patel, IJPSR, 2013; Vol. 4(1): 68-78; Carneiro et al., 2019, Int. J. Mol. Sci. 2019, 20, 642; US2009-0029020; US2009-0214446; US5070081; US5552378; US5674854; and US8658692. A common kneading method involves mixing CDs with water or aqueous alcohol to obtain a paste. Bioactive molecules can then be added to the paste and kneaded for a specific time. The kneaded mixture can then be dried and, if necessary, passed through a sieve. Alternatively, the slurry method involves the following steps: mixing the bioactive molecule and cyclodextrin, adding an appropriate amount of water to the mixture until a paste or slurry is formed, typically with vigorous mixing; continuing mixing for an appropriate period of time, such as 15 minutes, adding more water as needed to maintain the consistency of the paste or slurry, to form the inclusion complex; and drying the product of this final step. Other ingredients, such as emulsifiers, can facilitate the formation of the inclusion complex. For example, this process involves the following steps: dry-mixing the cyclodextrin with an emulsifier (e.g., pectin); combining the dry mixture of cyclodextrin and emulsifier with a solvent, such as water, in a reactor and stirring; adding the guest molecule and stirring (e.g., for about 5-8 hours); cooling the reaction mixture with stirring, if necessary; and emulsifying the mixture and drying the cyclodextrin inclusion complex to form a powder. Other known approaches to preparing cyclodextrin inclusion complexes include freeze-drying, microwave irradiation, and supercritical fluid antisolvent techniques.

[0034] The CD delivery vehicles of the present invention can be provided alone or in combination with other compounds (e.g., nucleic acid molecules, small molecules, peptides, or peptide analogs) in the presence of carriers such as liposomes, adjuvants, or any other pharmaceutically or biologically acceptable carrier. Selected embodiments include drugs in a form suitable for administration to an animal host, such as a mammal, e.g., a human. As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Carriers can be suitable for any appropriate mode of administration, including topical, subcutaneous, intradermal, intravenous, parenteral, intraperitoneal, intramuscular, sublingual, inhalation, intratumoral, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the biologically active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0035] Conventional pharmaceutical practice can be used to provide a suitable formulation or composition for administering the delivery vehicle to a subject. Any suitable route of administration can be used, such as parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intraarticular, intrathecal, intrathecal, intracapsular, intraperitoneal, intranasal, inhalation, aerosol, topical, intratumoral, sublingual, or oral. The therapeutic formulation can be in the form of a liquid solution or suspension. For oral administration, the formulation can be in the form of a tablet or capsule. For nasal drops, the formulation can be in the form of a powder, intranasal drops, or aerosol. For sublingual formulations, the formulation can be in the form of drops, aerosol, or tablets.

[0036] Cyclodextrin-degrading or digestive enzymes can be formulated, for example, for oral delivery. For example, enteric enzyme formulations, such as submicron particle formulations prepared by emulsification-solvent evaporation (Sharma et al., Pharm Dev Technol. 2013 May-Jun: 18(3): 560-9), can be provided. Similarly, delivery vehicles can be formulated as hydrogels (see US2014-0094433) or medicated gums (see US2013-0022652).

[0037] Methods well known in the art for preparing formulations can be found, for example, in "Remington's Pharmaceutical Sciences" (20th edition), ed. A. Gennaro, 2000, Mack Publishing Company, Easton, PA. Formulations for parenteral administration can contain, for example, excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation can contain excipients such as lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or can be oily solutions for administration in the form of nasal drops or as a gel.

[0038] The pharmaceutical compositions of the present invention may be in any form that allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid, or gas (aerosol). Typical routes of administration include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, epidural, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present invention are formulated so that the active ingredients contained in the composition are bioavailable upon administration to a patient. The composition administered to a patient may be in the form of one or more dosage units; for example, a tablet, capsule, or cachet may be a single dosage unit, and a container of the compound in aerosol form may contain multiple dosage units.

[0039] Materials used to prepare pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The compositions of the present invention may contain one or more compounds (active ingredients) known for a particular desired effect. It will be apparent to those skilled in the art that the optimal dosage of the active ingredient in a pharmaceutical composition depends on various factors. Relevant factors include, but are not limited to, the type of subject (e.g., human), the specific form of the active ingredient, the method of administration, and the composition used.

[0040] Generally, pharmaceutical compositions comprise the delivery vehicle of the present invention described herein mixed with one or more carriers.The carrier can be particulate, so that the composition is, for example, in the form of a tablet or powder.For example, when the composition is an oral syrup or an injection solution, the carrier can be liquid.In addition, the carrier can be gaseous, for example, to provide an aerosol composition useful for inhalation administration.

[0041] When intended for oral administration, the composition is preferably either solid or liquid, with semi-solid, semi-liquid, suspension and gel forms being included within the forms considered herein as either solid or liquid.

[0042] As a solid composition for oral administration, the composition may be formulated into a powder, granules, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenge, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. Additionally, one or more of the following adjuvants may be present: binders such as syrup, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrin; disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch, and the like; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, and the like; wetting agents such as sodium lauryl sulfate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavor; and coloring agents.

[0043] When the composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0044] The compositions may be in the form of a liquid, such as an elixir, syrup, solution, aqueous or oily emulsion or suspension, or a dry powder that can be reconstituted with water and / or other liquid media before use. The liquid may be for oral administration or for delivery by injection, as two examples. For oral administration, preferred compositions contain, in addition to the compound, one or more of a sweetener, a thickener, a preservative (e.g., alkyl p-hydroxybenzoate), a dye / colorant, and a flavor enhancer (flavoring). In compositions administered by injection, one or more of a surfactant, a preservative (e.g., alkyl p-hydroxybenzoate), a wetting agent, a dispersing agent, a suspending agent (e.g., sorbitol, glucose, or other sugar syrup), a buffer, a stabilizer, and an isotonic agent may be included. The emulsifier may be selected from lecithin and sorbitol monooleate.

[0045] Liquid pharmaceutical compositions of the present invention may be in the form of a solution, suspension, or other similar form and may contain one or more of the following adjuvants: sterile diluents such as water for injection, saline, preferably physiological saline, Ringer's solution, or isotonic sodium chloride; fixed oils such as synthetic mono- or diglycerides, polyethylene glycols, glycerin, propylene glycol, or other solvents, which serve as solvents or suspending media; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and tonicity adjusters such as sodium chloride or dextrose. Parenteral formulations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0046] The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream, or gel base. The base may comprise, for example, one or more diluents such as petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, water, and alcohol, as well as emulsifiers and stabilizers. A thickener may also be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the biologically active compound of about 0.1 to about 25% w / v (weight per unit volume).

[0047] The composition can be intended for rectal administration, for example, in the form of a suppository that melts in the rectum to release the drug.The composition for rectal administration may contain an oily base as a suitable non-irritating excipient.Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.Low-melting waxes are preferred for preparing suppositories, and a mixture of fatty acid glycerides and / or cocoa butter is a suitable wax.The wax is melted and stirred to uniformly disperse the aminocyclohexyl ether compound.The molten homogeneous mixture is then poured into molds of convenient size and allowed to cool and solidify.

[0048] The composition may contain various substances that modify the physical form of the solid or liquid dosage unit.For example, the composition may contain a material that forms a coating shell around the active ingredient.The coating shell material is typically inert and can be selected from, for example, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredient may be placed in a gelatin capsule or cachet.

[0049] The pharmaceutical composition of the present invention may be comprised of a gaseous dosage unit, e.g., in the form of an aerosol. The term aerosol is used to refer to a variety of systems, ranging from colloidal to pressurized packaging systems. Delivery can be achieved by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredient. Aerosols of the compounds of the present invention can be delivered in single-phase, two-phase, or three-phase systems to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, subcontainers, etc., which can be combined to form a kit.

[0050] The biologically active compounds may be in the form of a free base or a pharmaceutically acceptable salt such as hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate, or other salts known in the art. For appropriate embodiments (e.g., oral or parenteral administration routes), an appropriate salt is selected that enhances the bioavailability or stability of the compound.

[0051] Compositions intended for administration by injection can be prepared by combining the delivery vehicle of the present invention with water and preferably a buffer to form a solution. The water is preferably sterile, pyrogen-free water. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with the aminohexyl ether compound to promote dissolution or uniform suspension of the aminohexyl ether compound in an aqueous delivery system. Because the aminocyclohexyl ether compounds according to the present invention can be hydrophobic, it is desirable for a surfactant to be present in the aqueous composition of the present invention. Other carriers for injection include, but are not limited to, sterile, peroxide-free ethyl oleate, dehydrated alcohol, propylene glycol, and mixtures thereof.

[0052] Suitable pharmaceutical adjuvants for injection solutions include stabilizers, solubilizers, buffers, and viscosity adjusters. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffer, citrate buffer, and high-molecular-weight polyethylene oxide viscosity adjusters. These pharmaceutical preparations can be injected intramuscularly, epidurally, intraperitoneally, or intravenously.

[0053] The present invention also provides a kit comprising a pharmaceutical composition comprising one or more delivery vehicles. The kit also includes instructions for use of the pharmaceutical. Preferably, the commercial package contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient for the preparation of an intravenous injection. It will be apparent to those skilled in the art that light-sensitive and / or air-sensitive compounds require special packaging and / or formulation. For example, packages that are opaque to light and / or sealed from contact with ambient air and / or formulated with appropriate coatings or excipients can be used.

[0054] An "effective amount" of a CD inclusion complex delivery vehicle according to the present invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount of a delivery vehicle can vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the compound to elicit a desired response in the individual. Dosage regimens can be adjusted to provide the optimal therapeutic response. A therapeutically effective amount may also be one in which toxic or detrimental effects of the delivery vehicle or active compound outweigh any therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to or at an early stage of disease, whereby a prophylactically effective amount may be less than a therapeutically effective amount. For any particular subject, the timing and dosage of treatment can be adjusted over time (e.g., daily, every other day, weekly, monthly) according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0055] In selected embodiments, the present invention provides compositions or pharmaceutical preparations containing one or more biologically active compounds selected from biologically active compounds, their solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, mixtures of stereoisomers, geometric isomers, crystalline forms, amorphous forms, metabolites, metabolic precursors or prodrugs, isolated enantiomers, diastereomers and geometric isomers, and mixtures thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient. Additionally, the present invention provides methods for preparing such compositions or pharmaceutical preparations.

[0056] While various embodiments of the present invention are disclosed herein, many adaptations and modifications can be made within the scope of the invention in accordance with the common general knowledge of one skilled in the art. Such modifications include the substitution of known equivalents for any aspect of the invention to achieve the same result in substantially the same way. Numerical ranges include the numbers defining the range. The term "comprising" is used herein as an open-ended term substantially equivalent to the phrase "including but not limited to," and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes a plural of that thing.

[0057] The citation of a reference herein is not an admission that such reference is prior art to the present invention. Any priority documents and all publications, including but not limited to patents and patent applications, cited herein are incorporated herein by reference. All documents cited or referenced in the documents cited herein, together with any manufacturer's instructions, manuals, product specifications, and product sheets for any products described herein or in any document incorporated herein by reference, are incorporated herein by reference or may be used in the practice of the present invention. More specifically, all referenced publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference or fully described herein. The present invention includes all embodiments and variations thereof substantially as described above, and reference is made to the examples and drawings.

[0058] In some embodiments, the present invention excludes steps involving medical or surgical procedures. [Example]

[0059] Example 1: Mucus Formulation I A cyclodextrin inclusion complex of camphene was prepared using food-grade camphene from Vigon Corporation at a camphene to α-cyclodextrin molar ratio of 1:2 using a slurry method. Sustained-release capsules of this camphene inclusion complex (6.5%) were made with the following formulation per capsule: Camphene clathrate 400mg (net 26mg) K-100M Cellulose (Colorcon) 80mg E4M cellulose (Colorcon) 20mg Amylase enzyme 4mg Calcium laurate (flow enhancer) 4mg

[0060] Example 2: Mucus Formulation II An additional cyclodextrin inclusion formulation was prepared for addition to mucus formulation I as follows. Peppermint oil (NOW Foods) inclusion complexes were prepared using a slurry method with a molar ratio of peppermint oil to γ-cyclodextrin of 1:4. Eucalyptol (Vigon) inclusion complexes were prepared using a slurry method with a molar ratio of eucalyptol to α-cyclodextrin of 1:1.

[0061] The above peppermint oil inclusion complex preparation and eucalyptol inclusion complex preparation were added to the ingredients of mucus preparation I to provide capsules of mucus preparation II. Camphene inclusion complex (6.5%) 150mg (net 10mg) Eucalyptol inclusion complex (10%) 135mg (net 13.5mg) Peppermint oil inclusion complex (15%) 46mg (net 7mg) K-100M Cellulose (Colorcon) 70mg E4M cellulose (Colorcon) 17mg Amylase enzyme 4mg

[0062] Example 3: Mucositis associated with nonalcoholic steatohepatitis (NASH) Subject BC had a history of liver cancer and consequent mucositis associated with nonalcoholic steatohepatitis (NASH, a progressive subset of nonalcoholic fatty liver disease) and cirrhosis. BC underwent liver surgery for intrahepatic cholangiocarcinoma and subsequent cancer treatment, including chemotherapy and radiation therapy. A side effect of radiation was the development of mucositis (excessive mucus production), which was refractory to conventional treatments.

[0063] Subject BC began treatment with mucus formulation II of Example 2 on day 1 at a dose of 3 capsules three times daily. By day 5, respiratory mucus dramatically improved, and pulmonary congestion significantly improved, although the patient still had a persistent cough. By day 10 of capsule treatment, the symptoms of excess respiratory mucus virtually disappeared, and the cough was largely resolved. Continued capsule treatment resulted in a lasting improvement in mucositis symptoms, providing evidence of its remarkable effectiveness in treating airway mucus dysfunction, including its antitussive effect.

[0064] Example 4: Bronchiectasis Subject D, 50 years old, had a long-standing diagnosis of severe, refractory bronchiectasis and had pulmonary sputum positive for Pseudomonas for approximately 20 years. The patient was treated with Augmentin (amoxicillin and clavulanate), nebulized hypersol, albuterol, and colistin antibiotics (28 days on, then 28 days off) for a sinus infection.

[0065] The patient began treatment with Mucus Preparation II on June 11 at a dose of four capsules twice daily. On June 14, the dosage was increased to six capsules twice daily, which was accompanied by a transition to sleeping through the night. This was attributed to the resolution of a long-standing cough associated with prone or prone positioning. By June 17, D was sleeping well with continued improvement in airway mucus. This result was attributed by the patient to the resolution of pulmonary congestion mediated by Mucus Preparation II treatment. By June 19, D reported continued improvement and consistently slept through the night. On June 20, D reported an expectorant effect, with thinning of airway mucus, increased ease of expectoration throughout the day, and mucus turning clear from light green. This was true even during the worst part of the "28-day off" portion of the nebulized antibiotic treatment cycle (during the last two weeks of that cycle, D typically experienced a change in airway mucus to dark green). D reported decreased chest tightness, a productive cough, and the ability to sleep on his side through the night. D slept through the night starting June 12, the first day he took Mucus Preparation II. This was a remarkable result, regardless of sleep position or incline, given what had been a consistent, chronic history of only sleeping 2-3 hours at a time before being woken by coughing. This was a dramatic and consistent change after years of intermittent sleeping in a recliner.

[0066] On June 30th, D. Mucus Preparation II +Treatment continued with a switch to Mucus Preparation II, which contains guaiol and fenugreek oil, called 'Diabetes Mellitus'. By July 3, D reported continued significant improvement in his airway mucus dysfunction, with less cough, a more productive cough, and less mucus. Improvements included a decrease in cough frequency, duration, and intensity, with a more productive cough, but overall less mucus to process. At this point, Patient D was two weeks into the "on" portion of a 28-day on, 28-day off antibiotic cycle. His mucus was white, occasionally a light yellow. Typically, at this point in the antibiotic cycle, mucus becomes yellow to light yellow (never clear / white). D continued to sleep through the night. By July 10, at the beginning of the fourth week of the "on" portion of the antibiotic cycle, continued improvement was observed, with D reporting he was able to sleep on his back for the first time in many years, and his mucus was white (no yellow) and less mucus. It had a noticeable expectorant effect and I was able to move much more easily than I had the previous week.

[0067] This example demonstrates the effective treatment of airway mucus dysfunction with oral camphene cyclodextrin formulations, including formulations further containing guaiol and fenugreek oil.

[0068] Example 5: Viral pneumonia, mucus activation effect A composition containing the following CD clathrate combination was provided in capsule form for oral administration. Eucalyptus (Myrtaceae) extract standardized to 6 mg eucalyptol (in β-CD inclusion complex), extract of Syncarpia glomlifera standardized with 6 mg of camphene (in β-CD inclusion complex); Peppermint (Mentha piperita) oil 6 mg (in β-CD inclusion complex), an extract of Pinus genus (Pinus pinaster and / or Pinus elliotii and / or Pinus sylvestris) standardized for 4 mg of delta-3-carene (in a β-CD or γ-CD inclusion complex); Fenugreek (Trigonella foenum-graecum) extract (fenugreek absolute) 4 mg (in gamma-CD inclusion complex), Extract of Bulnesia sarmientoi standardized with 4 mg of guaiol (in γ-CD inclusion complex); K250 extended release agent 80mg, Amylase 7 mg, and Calcium laurate 5mg.

[0069] An adult male patient was diagnosed with a viral infection and presented with a dry, unproductive cough that required vomiting. The patient began treatment with the above preparation at 4 capsules twice daily for 2 days. The patient's cough became productive, with a clear mucoactive effect from the preparation, leading to an improvement in the patient's sense of well-being.

[0070] Example 6: Erectile effect Male subject A began taking Mucus Preparation I at a dose of three capsules twice daily. Within 48 hours, respiratory mucus was significantly reduced, and breathing with exercise significantly improved. Within 48 hours of the first dose of Mucus Preparation I, the 67-year-old subject noticed the onset of nocturnal penile erections, something he had not experienced for some time. The subject increased his dose of Mucus Preparation I to four capsules twice daily, with the immediate effect of significantly improving nocturnal penile erections and sensitivity to daytime or nocturnal erectile stimulation. The subject measured the erectile effect, which was equivalent to 70-85% of the erectile effect of a 25-50 mg dose of sildenafil. The subject further discovered that when administered four capsules twice daily of Viscous Formulation I, a dose of 5 mg of sildenafil achieved substantially the same erectile enhancement as previously administered with 25-50 mg of sildenafil, without any of the side effects previously experienced with 25-50 mg of sildenafil (e.g., headache, flushing, upset stomach, blurred vision, stuffy or runny nose, back pain, muscle pain, and nausea).

Claims

1. A cyclodextrin (CD) inclusion complex formulation, Eucalyptol β-CD inclusion complex; camphene β-CD inclusion complex; delta-3-carene β-CD inclusion complex; a guaiol γ-CD inclusion complex; Peppermint oil β-CD inclusion complex, Fenugreek γ-CD inclusion complex; A CD inclusion complex formulation containing a cyclodextrin-degrading enzyme.

2. A CD inclusion complex formulation as described in claim 1, further containing humulene.

3. Eucalyptol (5 to 15% by weight) in the eucalyptol β-CD inclusion complex; Camphene (5 to 15 wt%) in the camphene β-CD inclusion complex; delta-3-carene (5 to 15 wt%) in the delta-3-carene β-CD inclusion complex; guaiol (5 to 15% by weight) in the guaiol γ-CD inclusion complex; Peppermint oil (10-20% by weight) in the peppermint oil β-CD inclusion complex; 3. The CD inclusion complex preparation according to claim 1, further comprising a fenugreek extract (5 to 15% by weight) in the fenugreek γ-CD complex.

4. Eucalyptol (10% by weight) in the eucalyptol β-CD inclusion complex; Camphene (10% by weight) in the camphene β-CD inclusion complex; delta-3-carene (10% by weight) in the delta-3-carene β-CD inclusion complex; Guaiol (10% by weight) in the guaiol γ-CD inclusion complex; Peppermint oil (15% by weight) in the peppermint oil β-CD inclusion complex; The CD inclusion complex preparation according to any one of claims 1 to 3, comprising a fenugreek extract (10% by weight) in the fenugreek γ-CD complex.

5. The following active ingredients: Eucalyptol (10% by weight) in the eucalyptol β-CD inclusion complex in an amount of 50-100 mg; camphene (5-15 wt%) in the camphene β-CD inclusion complex in an amount of 50-100 mg; delta-3-carene (5-15 wt%) in the delta-3-carene β-CD inclusion complex in an amount of 25-75 mg; guaiol (5-15 wt%) in the guaiol γ-CD inclusion complex in an amount of 25-75 mg; Peppermint oil (10-20% by weight) in the peppermint oil β-CD inclusion complex in an amount of 25-75 mg; 5. The CD inclusion complex formulation according to claim 1, wherein the ratio of active ingredients in the fenugreek γ-CD inclusion complex is substantially equivalent to the ratio of active ingredients in a formulation containing 25 to 75 mg of fenugreek extract (5 to 15% by weight).

6. The CD inclusion complex formulation according to any one of claims 1 to 5, further comprising a sustained-release agent.

7. The CD inclusion complex formulation according to any one of claims 1 to 6, wherein the cyclodextrin-degrading enzyme is amylase.

8. The CD inclusion complex formulation according to any one of claims 1 to 7, further comprising a pharmaceutically acceptable carrier.

9. The CD inclusion complex formulation described in Claim 8, wherein the pharmaceutically acceptable carrier is calcium laurate.

10. Eucalyptol (10% by weight) in the eucalyptol β-CD inclusion complex in an amount of 75 mg; Camphene (10 wt%) in the camphene β-CD inclusion complex in an amount of 75 mg; delta-3-carene (10% by weight) in the delta-3-carene β-CD inclusion complex in an amount of 50 mg; guaiol (10% by weight) in the guaiol γ-CD inclusion complex in an amount of 50 mg; Peppermint oil (15% by weight) in the peppermint oil β-CD inclusion complex in an amount of 50 mg; 10. The CD inclusion complex preparation according to claim 1, comprising 50 mg of fenugreek absolute (oil) (10% by weight) in the fenugreek γ-CD inclusion complex.

11. The CD inclusion complex formulation described in claim 10, further comprising 80 mg of a sustained-release agent.

12. The CD inclusion complex formulation according to claim 10 or 11, further comprising 5 mg of amylase.

13. The CD inclusion complex formulation according to any one of claims 10 to 12, further comprising 5 mg of calcium laurate.

14. The CD inclusion complex formulation according to any one of claims 1 to 13, for use in the oral treatment of airway mucus dysfunction in human patients.

15. an extract of Eucalyptus (Myrtaceae) in a CD inclusion complex; an extract of Syncarpia glomlifera containing camphene in a CD inclusion complex; Peppermint (Mentha piperita) oil in a CD inclusion complex; an extract of Pinus containing delta-3-carene in a CD inclusion complex; Fenugreek extract in a CD inclusion complex; and an extract of Bulnesia sarmientoi containing guaiol in a CD inclusion complex.

16. 16. The formulation of claim 15, further comprising a sustained release agent.

17. 17. The formulation of claim 15 or 16, further comprising a cyclodextrin-degrading enzyme.

18. The formulation of claim 17, wherein the cyclodextrin-degrading enzyme comprises amylase, cyclodextrinase, maltogenic amylase, neopullulanase, mammalian salivary amylase, mammalian pancreatic amylase, or microbial amylase.

19. The formulation according to any one of claims 15 to 18, wherein the cyclodextrin (CD) in each inclusion complex is α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.

20. The formulation of any one of claims 15 to 19, further comprising calcium laurate.

21. the extract of Eucalyptus (Myrtaceae) contains about 4-8 mg of eucalyptol; and / or the extract of Syncarpia glomlifera contains about 4-8 mg of camphene; and / or The peppermint (Mentha piperita) oil is provided in an amount of about 4 to 8 mg in the CD inclusion complex; and / or the Pinus extract contains about 2-6 mg delta-3-carene; and / or The fenugreek extract is provided in the CD inclusion complex at about 2 to 6 mg; and / or 21. The formulation of any one of claims 15 to 20, wherein the extract of Bulnesia sarmientoi contains about 2 to 6 mg of guaiol.

22. The Eucalyptus (Myrtaceae) extract CD inclusion complex comprises a eucalyptol β-CD inclusion complex; and / or The CD inclusion complex of the extract of Syncarpia glomlifera comprises a camphene β-CD inclusion complex, and / or the peppermint (Mentha piperita) oil is provided at least in part in a β-CD inclusion complex; and / or the Pinus extract CD inclusion complex comprises a delta-3-carene β-CD inclusion complex; and / or the fenugreek extract is at least partially provided in a γ-CD inclusion complex, and / or The preparation according to any one of claims 15 to 20, wherein the Bulnesia sarmientoi extract CD inclusion complex comprises a guaiol γ-CD inclusion complex.

23. 21. The formulation of any one of claims 15 to 20, further comprising humulene.

24. A formulation according to any one of claims 15 to 23 for use as a mucoactive agent for treating an airway disorder in a subject in need thereof.

25. 25. The formulation of claim 24, wherein the airway disorder is a respiratory disease or condition characterized by hypersecretion or drying of mucus.

26. 26. The formulation of claim 24 or 25, wherein the airway disorder is asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), CF-related bronchiectasis, non-CF-related bronchiectasis, viral bronchiolitis, bacterial bronchiolitis, or a microbial infection.

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