Oral terpene cyclodextrin inclusion complex vehicle

Abstract

The present invention provides oral terpene cyclodextrin inclusion compound delivery vehicles, including formulations in which the cyclodextrin inclusion compound is provided together with an enzyme having cyclodextrin degradation activity, capable of hydrolyzing the cyclodextrin, so that once the vehicle is delivered to the target, the enzyme is activated and the guest molecule is released from the cyclodextrin cavity. In alternative aspects, for example, these cyclodextrin inclusion compound delivery vehicles are provided in the form of extended release formulations, for example, for the treatment of airway mucus dysfunction. Formulations with erectile efficacy are also provided.

Description

Technical Field

[0001] The present invention is in the field of biochemical constructs for delivering bioactive terpenes, including camphene, as inclusions within cyclodextrins in oral formulations that may include enzymes having cyclodextrin degrading activity. Background Art

[0002] Cyclodextrin is a non-reducing cyclic glucose oligosaccharide, usually the product of starch degradation catalyzed by cyclomaltodextrin glucanotransferase (EC2.4.1.19; CGTase). Cyclodextrin can have a variety of structures (see Saenger et al., Chem. Rev. 98 (1998) 1787-1802), including three common cyclodextrins (α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, respectively) with 6, 7 or 8 D-pyranogluconate residues connected into a ring by α-1,4 glycosidic bonds. The truncated conical shape of cyclodextrin forms a cavity or inner cavity, and the cavity has different diameters depending on the number of glucose units. The size of the selected cyclodextrin (CD) structure is listed in Table 1. It is also possible that it is larger cyclodextrins, such as cyclomaltononaose (δ-CD) and cyclomaltodecanoose (ε-CD), as well as a variety of cyclodextrin-based supramolecular structures (see Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug; 65(9): 1215-33).

[0003] Table 1: Cyclodextrin structures

[0004]

[0005] Cyclodextrins are generally amphiphilic, with the wider edge of their lumen showing 2-OH and 3-OH groups and the narrower edge showing 6-OH. Thus, these hydrophilic hydroxyl groups are located on the outside of the lumen, while the inner surface is generally hydrophobic and is arranged with anomeric oxygen atoms and C3-H and C5-H hydrogen atoms. In aqueous solution, the hydrophobic lumen may contain water molecules, for example, about 3 (α-CD), 7 (β-CD) or 9 (γ-CD) unstable accommodation but low entropy, and therefore relatively easy to displace water molecules. Thus, hydrophilic cyclodextrins may bind and retain one or more molecules of suitable size within or partially within the CD lumen, thereby forming cyclodextrin inclusion bodies or complexes. For example, non-polar aliphatic and aromatic compounds, including drugs, such as lipophilic drugs, may be combined to increase the water solubility of normally hydrophobic compounds, or to minimize undesirable properties such as odor or taste in certain food additives. For this reason, cyclodextrin inclusions are widely used in the fields of medicine, food and cosmetics (see Hedges, Chem. Rev. 98 (1998) 2035-2044). For example, cyclodextrin has been used in a variety of sustained-release drug formulations, such as inclusion complexes of medicinal compounds and hydrophobic cyclodextrin derivatives (U.S. Pat. No. 4,869,904).

[0006] Cyclodextrins can be chemically modified in a variety of ways. For example, to change the inclusion specificity, physical and chemical properties of cyclodextrins. For example, the CD hydroxyl group can be derivatized. For example, two modified CDs have been used in a variety of drug products: SBE-β-CD or captisol (a polyanionic variably substituted sulfobutyl ether of β-CD), and HP-β-CD (a modified CD commercially developed by Janssen). Other CD derivatives include sugammadex or Org-25969, in which the 6-hydroxyl group on γ-CD is replaced by a carboxythioacetic acid ether bond, and hydroxybutenyl-β-CD. Alternative forms of cyclodextrin include: 2,6-di-O-methyl-β-CD (DIMEB), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated-β-cyclodextrin (RAMEB), sulfobutyl ether β-cyclodextrin (SBE-β-CD) and sulfobutyl ether-γ-cyclodextrin (SBEγCD), sulfobutylated β-cyclodextrin sodium salt, sulfobutylated β-cyclodextrin sodium salt, (2 -hydroxypropyl)-α-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, DIMEB-50 heptath (2,6-di-O-methyl)-β-cyclodextrin, TRIMEB heptath (2,3,6-tri-O-methyl)-β-cyclodextrin, methyl-β-cyclodextrin, octa (6-deoxy-6-iodo)-γ-cyclodextrin and octa (6-deoxy-6-bromo)-γ-cyclodextrin. Although CDs such as these have been developed to have good pharmacological and toxicological profiles, there is still the possibility that, after administration, residual CDs may interfere with the pharmacokinetic properties of drugs, including co-administered drugs, particularly after parenteral administration (see Stella and He, Toxicol Pathol January 2008, Vol. 36, No. 1, 30-42).

[0007] There are differences in the sensitivity of cyclodextrins to enzymatic digestion. For example, γ-CD is relatively easily hydrolyzed by α-amylase, while α-cyclodextrin is less susceptible to hydrolysis. CD-based therapeutics generally depend on the activity of endogenous amylase to digest CD. However, there is significant variability in amylase activity between patients. For example, patients with pancreatic insufficiency, cystic fibrosis, celiac disease, or Crohn's disease may lack normal amounts of amylase. Similarly, patients, especially aging patients, may have insufficient gastric acid production and are therefore unable to create the appropriate low pH conditions in the duodenum to properly trigger the release of pancreatic amylase. Increasing the regular use of antacids, histamine-2 blockers, proton pump inhibitors, or alternative acid blockers can produce similar effects.

[0008] A variety of microbial cyclodextrin digestive enzymes have been identified. CD degrading enzymes include cyclomaltodextrinase (or cyclodextrinase or CDase, EC 3.2.1.54), maltogenic amylase (EC 3.2.1.133), neopullulanase (EC 3.2.1.135), which have been reported to hydrolyze CD and, in some cases, other substrates such as pullulan and starch. Cyclodextrinase (CDase) catalyzes the hydrolysis of CD to form linear oligosaccharides with α-1,4-linkages, and thus it can release substrates from CD inclusion complexes. The CD enzyme from Bacillus macerans was reported in 1968, and a variety of CD enzymes from bacteria have been identified since then, such as enzymes from Bacillus sp., Thermoanaerobacter ethanolicus strain 39E, Flavobacterium sp., and Klebsiella oxytoca strain M5a1. Archaeobacterial CD enzymes from Archaeoglobus fulgidus, Thermococcus sp. B1001, Thermococcus sp. CL1, Thermofilum pendens, and Pyrococcus furiosus have been identified. The structure of the CDase from Flavobacterium sp. has been identified in detail (see Sun et al., Archaea, Vol. 2015 (2015), Article No. 397924, which reports the identification of the gene encoding the cyclodextrinase (CDase-Tk) from Thermococcus kodakarensis KOD1).

[0009] Camphene is a monoterpene with a bicyclic skeleton, which is a bicyclo[2.2.1]heptane substituted by a geminal methyl group at the 2-position and by a methylene group at the 3-position. It is a widely distributed natural product that is usually present in a variety of essential oils as a racemic mixture of D-camphene and L-camphene in different proportions (Ochocka et al., 2002, Pharmaceutical Biology, 40:5, 395-399). It has been widely used as a flavoring agent and fragrance. Camphene has also been described as having a variety of physiological effects, such as hypolipidemic effects (Vaillianou et al., PLoS One, 2011; 6(11)e20516).

[0010] Airway mucus dysfunction contributes to or is a symptom of a variety of airway diseases and conditions (see Fahy & Dickey, 2010), which often manifest as cough or wheezing. Diseases characterized by airway mucus dysfunction include cystic fibrosis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, panbronchiolitis, and a variety of immunodeficiency conditions. Conditions associated with airway mucus dysfunction can include a variety of disruptions in normal lung mechanics, for example, in intubated, paralyzed, comatose, or postoperative patients, where the problem may be related to retained mucus. Summary of the invention

[0011] Camphene-containing cyclodextrin inclusion compound delivery vehicles are provided, for example, for treating airway mucus dysfunction, or for providing erectile effects in male subjects. In addition to camphene, the formulation can include other inclusion compound guest molecules, including other terpenes, such as plant terpenes. Other guest molecules may, for example, include: eucalyptol (i.e., 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; CAS 470-82-06; eucalyptol; 1,8-epoxy-p-menthane); guaiacol (i.e., 2-[(3S,5R,8S)-3,8-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-azulenyl]-2-propanol; CAS 489-86-1; flavonol), and / or delta-3 carene (i.e., 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; CAS 13466-78-9). Other guest molecules may, for example, be provided in CD inclusions of plant extracts or compositions, such as peppermint and / or fenugreek compositions, such as peppermint oil or fenugreek powder.

[0012] A biologically acceptable carrier can be provided for the cyclodextrin inclusion complex, so that the guest molecule is stably retained in the biologically acceptable carrier by the cyclodextrin. An enzyme having a cyclodextrin degrading activity capable of hydrolyzing the cyclodextrin retaining the guest molecule can also be provided in the vehicle. The enzyme can be formulated so that the cyclodextrin degrading activity is activated when the vehicle is delivered to the target, thereby releasing the guest molecule from the cyclodextrin cavity.

[0013] In alternative aspects of the delivery vehicle, the enzyme can be co-formulated with a cyclodextrin inclusion compound, or the enzyme can be co-packaged with a cyclodextrin inclusion compound in a delivery vehicle. When the enzyme is co-packaged, the delivery vehicle can also include a biochemically acceptable carrier of the enzyme.

[0014] The enzyme may for example be an amylase, a cyclodextrinase, a maltogenic amylase or a neopullulanase. The amylase may for example be a mammalian salivary amylase or a pancreatic amylase, or an amylase of fungal or bacterial origin. The cyclodextrinase may for example be a microbial cyclodextrinase.

[0015] The cyclodextrin may, for example, be a CD derivative such as a hydrophobic alkylated cyclodextrin or a mixed methylated / ethylated cyclodextrin.

[0016] The ratio of cyclodextrin to guest molecule can 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.

[0017] The cyclodextrin may, for example, be alpha, beta or gamma cyclodextrin, although a very wide range of alternative CD structures may be used.

[0018] In selected embodiments, other guest molecules may be provided, for example, such as drugs or prodrugs, PDE5 inhibitors, flavonoids (quercetin), cannabinoids, or anti-inflammatory agents (including acetaminophen). In this case, the biologically acceptable carrier may advantageously be a pharmaceutically acceptable carrier. The delivery vehicle may be formulated for sustained release of the guest molecule.

[0019] In this manner, the present invention provides an alternative embodiment in which a CD delivery vehicle can be used as a medicament.

[0020] Methods are provided for treating patients with airway mucus dysfunction as a symptom of a disease such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, primary ciliary dyskinesia, non-cystic fibrosis bronchiectasis, panbronchiolitis, or an immunodeficiency condition. Alternatively, the airway mucus dysfunction may be a condition associated with a disruption of lung mechanics, e.g., a symptom of intubation, paralysis, coma, or surgical trauma.

[0021] Also provided are methods for providing an erection in a male subject, eg, a male older than 50, 60, or 70 years of age or a male subject suffering from erectile dysfunction. DETAILED DESCRIPTION

[0022] Specific formulations of delivery vehicles may, for example, include cyclodextrin inclusion compound formulations prepared by combining cyclodextrin inclusion compounds prepared from a number of sources, including natural plant extract sources. For example, a formulation of CD inclusion compounds prepared from 2, 3, 4, 5 or 6 of the following may be combined in, for example, a single formulation or in different formulations provided in combination:

[0023] Eucalyptus (Myrtaceae) extract (e.g., standardized to 6 mg, or 4-8 mg, for example, eucalyptol) in a CD inclusion, e.g., in a βCD or γCD inclusion; and / or

[0024] Syncarpia glomulifera extract (e.g., standardized to 6 mg, or 4-8 mg, of camphene) in a CD inclusion, e.g., in a βCD or γCD inclusion; and / or

[0025] In CD inclusions, for example, in βCD or γCD inclusions, peppermint ( Menthapiperita ) oil 6 mg, or 4-8 mg; and / or

[0026] In a CD inclusion, e.g., in a βCD or γCD inclusion, a Pinus (e.g., Pinus spp. and / or Elliotii and / or Sylvestris spp.) extract (e.g., Carene δ3 standardized to 4 mg, or 2-6 mg); and / or

[0027] In CD inclusions, for example, in βCD or γCD inclusions, fenugreek extract, for example, fenugreek absolute (Trigonella foenum-graecum) 4 mg, or 2-6 mg; and / or

[0028] In a CD inclusion, for example, in a βCD or γCD inclusion, Bulnesia sarmientoi extract (eg, standardized to 4 mg, or 2-6 mg, of guaiacol).

[0029] Different ratios of ingredients can be provided, for example, at 5-250 mg of any one inclusion compound per dose. The selected formulation can be only the plant-derived active ingredient. The specific dosage form can be, for example, as shown below, as a single sustained-release capsule:

[0030] In a CD inclusion, e.g., in a βCD or γCD inclusion, an eucalyptus (Myrtaceae) extract (e.g., standardized to 6 mg, or 4-8 mg, of eucalyptol);

[0031] In a CD inclusion, e.g., in a βCD or γCD inclusion, a pine knotwood extract (e.g., camphene standardized to 6 mg, or 4-8 mg);

[0032] In CD inclusions, for example, in βCD or γCD inclusions, peppermint (menthol) oil 6 mg, or 4-8 mg;

[0033] In a CD inclusion, e.g., in a βCD or γCD inclusion, a Pinus [e.g., maritime pine and / or elliottii pine and / or Scots pine] extract (e.g., standardized to 4 mg, or 2-6 mg, of carene delta 3);

[0034] In CD inclusions, for example, in βCD or γCD inclusions, fenugreek extract, for example, fenugreek absolute (Trigonella foenum-graecum) 4 mg, or 2-6 mg;

[0035] In a CD inclusion, e.g., in a βCD or γCD inclusion, a Jade Sandalwood extract (e.g., standardized to 4 mg, or 2-6 mg, of guaiacol);

[0036] K250 extended release 80 mg;

[0037] Amylase 7mg;

[0038] Ca laurate 5mg.

[0039] As used in the formulations herein, peppermint oil may be an extract of the peppermint plant Mentha piperita. The composition of peppermint oil varies, but has been identified as containing menthol (40.7%) and 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).

[0040] The composition of fenugreek (Trigonella foenum-graecum) is generally known and is understood to contain a variety of alkaloids, amino acids, saponins, steroid sapogenins and flavonoids (Wani and Kumar, 2018, J. of the Saudi society of Agricultural Sciences 17 (2): 97). For example, fenugreek seeds can be extracted by solvent to produce fenugreek extract, which is sometimes identified as fenugreek absolute (CAS No. 84625-40-1, FEMA No. 2486, EC No. 283-415-1, MDL No. MFCD01772302).

[0041] In selected embodiments, the guest molecule may be provided in the form of a plant extract, for example, eucalyptol from eucalyptus (e.g., eucalyptus oil, CAS No. 8000-48-4, FEMA No. 2466, EC No. 283-406-2); camphene from Syncarpia; delta-3-carene (delta-3-carene) from pine (e.g., species: maritime pine; slash pine; European red pine, cedar, basil, pine, rosemary and bell pepper); guaiacol (sesquiterpene alcohol, also found in cypress pine and guaiac); peppermint oil containing menthol; fenugreek extract from fenugreek seeds. Alternative embodiments may, for example, include extracts, terpenes or oils from: eucalyptus (Myrtaceae), pine knotwood, pine (maritime pine and / or slash pine and / or European red pine) and slash pine, peppermint (peppermint) and fenugreek. These extracts can be formulated in a beta and gamma dextrin fiber matrix with high and low viscosity hydroxypropyl methylcellulose (slow release), hypromellose (derived from cellulose) capsules, cellulose, calcium laurate, and an amylase (such as a plant or microbial amylase).

[0042] In selected embodiments, the formulation may, for example, comprise, in a plant cellulose capsule:

[0043] In the βCD inclusion, eucalyptol (10 wt % (weight percentage)) 75 mg;

[0044] In the βCD inclusions, camphene (10 wt%) 75 mg;

[0045] In the βCD inclusions, carene δ3 (10 wt%) 50 mg;

[0046] In the γCD inclusions, guaiacol (10 wt%) 50 mg;

[0047] In the βCD inclusions, peppermint oil (15 wt%) 50 mg;

[0048] In the γCD inclusions, fenugreek absolute oil (oil) (10 wt%) 50 mg;

[0049] K250 extended release 80 mg;

[0050] Amylase 5 mg; and

[0051] Ca laurate 5mg.

[0052] The delivery vehicle of the present invention may be used as other different components and / or as other guest molecules, for example, in the form of a pharmaceutical composition comprising a variety of biologically active compounds, such as: docetaxel (US Patent Publication Nos. 20140336149, 20130296268); carbamazepine (US Patent Publication No. 20140080812); rifampicin (US Patent No. 7001893); cardiac glycosides, specifically digoxin (US Patent No. 4555504); progesterone (see Zoppetti et al., Journal of Inclusion Phenomena and Macrocyclic Chemistry, April 2007, Vol. 57, No. 1, pp. 283-288); albendazole; mebendazole; albendazole sulfoxide (ricobendazole); fenoprofen; ketoprofen; cocaine; gliclazide; digitoxin; macrocyclic compound (MCC); ibuproxen; prochloro-methazine; DY-9760e; NSC-639829; ETH-615; piroxicam; levofloxacin HCl; ziprasidone mesylate; sulindac; mebendazole; sulindac; phenolphthalein; danazol (see Challa et al., 2005, AAPS PharmSciTech 2005; 6(2) Paper No. 43); itraconazole; nelfinavir mesylate; telmisartan; 5-fluorouracil and other nucleoside analogs; camptothecin; humulene (also known as α-humulene or α-caryophyllene); or flavonoids.

[0053] A selected embodiment is a pharmaceutical food composition comprising, in βCD inclusions, eucalyptol (e.g., ~10 wt%) 75 mg; in βCD inclusions, camphene (e.g., ~10 wt%) 75 mg; in βCD inclusions, carene δ3 (e.g., ~10 wt%) 50 mg; in γCD inclusions, guaiacol (e.g., ~10 wt%) 50 mg; in βCD inclusions, peppermint oil (e.g., ~15 wt%) 50 mg; in γCD inclusions, fenugreek absolute (oil) (e.g., ~10 wt%); and humulene.

[0054] In selected embodiments, the enzyme provided in the vehicle can be formulated so that the cyclodextrin degrading activity is activated when the vehicle is delivered to the target, thereby releasing the guest molecule from the cyclodextrin cavity. For example, enzyme activation can be accomplished in a dry dosage form, such as a capsule or tablet, for example, for oral delivery, where the enzyme is mixed so that the enzyme is not active until activated by moisture in the host's gastrointestinal tract. Similarly, a variety of delayed release matrices and formulations are known that can be suitable for use in CD delivery vehicles to coordinate appropriate activation of CD-degrading enzymes when delivered to the target.

[0055] In many aspects, for the examples discussed above, the CD delivery vehicle can have an enzyme co-formulated with a cyclodextrin inclusion compound, or the enzyme can be co-packaged with the cyclodextrin inclusion compound in a delivery vehicle. For co-packaging, the delivery vehicle can, for example, include a biochemically acceptable carrier of the enzyme, which is different from the carrier of the CD inclusion compound. For example, the delivery vehicle can be provided with a separate compartment containing a CD inclusion compound and a CD-degrading enzyme, so that the delivery vehicle will consist of a CD inclusion compound compartment connected to a CD-degrading enzyme compartment. A mechanism for releasing the CD inclusion compound and the CD-degrading enzyme from the respective compartment combinations in the delivery vehicle can be provided. For example, a syringe with such different compartments can be provided, which is discharged by a common discharge mechanism, such as a mechanism by cooperatively moving a piston in each compartment to discharge equal parts of the CD inclusion compound and the CD-degrading enzyme, so that the enzyme and the complex can then be mixed to activate the enzymatic release of the guest molecule from the CD. Such vehicles can, for example, be used to distribute topical creams or other surface active preparations. A variety of such delivery vehicles can be adapted from known devices for dispensing two-component compositions, such as epoxies, two-component medicaments or dental preparations, for example, as disclosed in U.S. Pat. Nos. 4,538,920, 8,100,295, 8,308,340, 8,875,947, 8,499,976 and International Patent Publications WO2007041266 and WO2000021842.

[0056] There are a variety of techniques that can be used to prepare CD inclusion complexes, for example, as described in: Chaudhary & Patel, IJPSR, 2013, Volume 4 (1): 68-76; Carneiro et al., 2019, Int. J. Mol. Sci. 2019, 20, 642; U.S. Patent Publication Nos. US20090029020; US20090214446; US Patent Nos. 5,070,081; 5,552,378; 5,674,854 and 8,658,692. A common method is called kneading, which includes mixing CD with water or aqueous alcohol to provide a paste. The bioactive molecule can then be added to the paste and kneaded for a specified time. The kneaded mixture can then be dried and sieved as needed. Alternatively, the slurry method includes the following steps: mixing the bioactive molecule and cyclodextrin, adding an appropriate amount of water to the mixture, usually vigorously mixing until a paste or slurry is formed; continuing to mix for a suitable period of time, such as 15 minutes, and if necessary, further adding water to maintain the paste or slurry viscosity to form an inclusion complex; and drying the product of this final step. Other ingredients, such as emulsifiers, can help form inclusion complexes, for example, a method including the following steps: dry mixing cyclodextrin and emulsifier (e.g., pectin); mixing the dry mixture of cyclodextrin and emulsifier with a solvent, such as water, in a reactor and stirring; adding a guest molecule and stirring (e.g., about 5 to 8 hours); optionally, cooling the reaction mixture while stirring; and emulsifying the mixture to form a powder before drying the cyclodextrin inclusion complex. Other known methods for preparing CD inclusions include freeze drying, microwave irradiation, and supercritical fluid antisolvent technology.

[0057] The CD delivery vehicle 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 a carrier, such as a liposome, an adjuvant or any pharmaceutically or biologically acceptable carrier. The selected embodiment includes a medicament in a form suitable for administration to an animal host, such as a mammal, for example, a human. As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. The carrier may be suitable for any appropriate form 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 immediate preparation of sterile injectable solutions or dispersions. The use of such vehicles and medicaments for pharmaceutically active substances is well known in the art. Except for any conventional vehicles or agents that are incompatible with the biologically active compounds, their use in the pharmaceutical compositions of the present invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0058] Conventional pharmaceutical practices can be used to provide suitable formulations or compositions for administering the delivery vehicle to a subject. Any suitable route of administration can be used, for example, parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ocular, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhaled, aerosol, topical, intratumoral, sublingual or oral administration. 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 intranasal formulations, in the form of powders, nasal drops or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets.

[0059] Cyclodextrin degradation or digestive enzymes can be (for example) formulated for oral delivery. For example, intestinal enzyme preparations can be provided, such as submicron particle preparations prepared by emulsion solvent evaporation (Sharma et al., Pharm Dev Technol. 2013 May-Jun; 18 (3): 560-9). Similarly, the delivery vehicle can be formulated as a hydrogel (see US Patent Publication 20140094433), or a pharmaceutical gum (see US Patent Publication 20130022652).

[0060] Methods for preparing formulations well known in the art can be found in, for example, "Remington's Pharmaceutical Sciences" (20th edition), edited by A. Gennaro, 2000, Mack Publishing Company, Easton, PA. Formulations for parenteral administration may contain, for example, excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of plant origin, or hydronaphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyethylene oxide-polypropylene oxide copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate, and deoxycholate, or may be oil solutions for administration in the form of nasal drops, or as a gel.

[0061] The pharmaceutical compositions of the present invention may be in any form that allows 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, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, epidural, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present invention are formulated so as to allow the active ingredients contained therein to be bioavailable once the composition is administered to a patient. The composition to be administered to a patient may be in the form of one or more dosage units, wherein, for example, a tablet, capsule, or cachet may be a single dosage unit, and a container of the compound in aerosol form may accommodate multiple dosage units.

[0062] The materials used in the preparation of the pharmaceutical composition should be pharmaceutically pure and nontoxic in the amount used. The composition of the present invention may include one or more compounds (active ingredients) known for a particularly desired effect. It will be apparent to those skilled in the art that the optimal dose of the active ingredient in the pharmaceutical composition will depend on a variety of factors. Related factors include, without limitation, the type of subject (e.g., human), the specific form of the active ingredient, the mode of administration, and the composition used.

[0063] Typically, the pharmaceutical composition comprises a delivery vehicle of the invention as described herein mixed with one or more carriers. The carrier can be particles so that the composition is in, for example, tablet or powder form. The carrier can be a liquid, where the composition is, for example, an oral syrup or an injectable liquid. Additionally, the carrier can be a gas to provide an aerosol composition useful, for example, in inhalation administration.

[0064] When intended for oral administration, the composition is preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms included within the forms considered herein as solid or liquid.

[0065] As a solid composition for oral administration, the composition can be formulated into the form of powders, granules, tablets, pills, capsules, cachets, chewing gums, wafers, lozenges, etc. Such solid compositions will usually contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as syrup, gum arabic, sorbitol, polyvinyl pyrrolidone, carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth or gelatin and mixtures thereof; excipients such as starch, lactose or dextrin, disintegrants such as alginic acid, sodium alginate, sodium carboxymethyl starch, corn starch, etc.; 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, silicon dioxide, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin, flavorings such as peppermint, methyl salicylate or orange flavoring and coloring agents.

[0066] When the composition is in the form of a capsule, for example a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0067] The composition can be in liquid form, such as elixir, syrup, solution, water or oil emulsion or suspension, or even a dry powder that can be reconstituted with water and / or other liquid vehicles before use. As two examples, the liquid can be used for oral administration or for delivery by injection. When it is expected to be used for oral administration, in addition to the compound of the present invention, the preferred composition contains one or more of sweetener, thickener, preservative (e.g., p- hydroxybenzoic acid alkyl ester), dye / colorant and flavor enhancer (flavor). In the composition expected to be used by injection, one or more of surfactant, preservative (e.g., p- hydroxybenzoic acid alkyl ester), wetting agent, dispersant, suspending agent (e.g., sorbitol, glucose or other syrups), buffer, stabilizer and isotonic agent can be included. Emulsifier can be selected from lecithin or sorbitol monooleate.

[0068] Whether they are solutions, suspensions or other similar forms, the liquid pharmaceutical compositions of the present invention may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension vehicles, such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multidose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0069] The pharmaceutical composition can be expected to be used for topical application, in which case the carrier can suitably include a solution, emulsion, ointment, cream or gel base. For example, the base can include one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. Thickeners can be present in the pharmaceutical composition for topical application. If it is expected to be used for transdermal application, the composition can include a transdermal patch or an iontophoresis device. Topical preparations can contain a concentration of the biologically active compound of about 0.1 to about 25% w / v (weight per unit volume).

[0070] The composition can be expected to be used for rectal administration, and it is in the form of a suppository that (for example) will melt in the rectum and release the medicine. The composition for rectal administration can contain an oily base as a suitable non-irritating excipient. These bases include lanolin, cocoa butter and polyethylene glycol without restriction. Low melting point wax is preferred for the preparation of suppositories, and a mixture of fatty acid glycerides and / or cocoa butter is a suitable wax. The wax can be melted, and the aminocyclohexyl ether compound is uniformly dispersed therein by stirring. Then, the molten homogeneous mixture is poured into a mold of appropriate size, cooled and thus solidified.

[0071] The composition can include a variety of materials that change the physical form of the solid or liquid dosage unit. For example, the composition can include materials that form a coating shell around the active ingredient. The materials forming the coating shell are generally inert and can be selected from, for example, sugar, shellac and other enteric coating agents. Alternatively, the active ingredient can be encapsulated in a gelatin capsule or cachet.

[0072] Pharmaceutical composition of the present invention can be made up of gas dosage unit, for example, it can be in the form of aerosol.The term aerosol is used to represent a variety of systems from those with colloidal properties to systems consisting of pressurized packaging.Can be delivered by liquefied or compressed gas or by a suitable pump system for distributing active ingredient.Can deliver the aerosol of the compound of the present invention in a single phase, two phase or three phase system to deliver the active ingredient.The delivery of aerosol includes necessary containers, triggers (activator), valves, sub-containers, etc., which can form a test kit together.

[0073] The biologically active compound can be in the form of a free base or in the form of a pharmaceutically acceptable salt, such as hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. For suitable modes of use (e.g., oral or parenteral administration routes), a suitable salt will be selected to improve the bioavailability or stability of the compound.

[0074] 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. Surfactants can be added to help form a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with aminocyclohexyl ether compounds, thereby helping aminocyclohexyl ether compounds to dissolve or evenly suspend in an aqueous delivery system. It is desirable to have a surfactant in the aqueous composition of the present invention because the aminocyclohexyl ether compounds according to the present invention can be hydrophobic. Other injection carriers include, without limitation, sterile peroxide-free ethyl oleate, anhydrous alcohol, propylene glycol, and mixtures thereof.

[0075] Pharmaceutical adjuvants suitable for injection solutions include stabilizers, solubilizers, buffers and viscosity modifiers. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers and high molecular weight polyethylene oxide viscosity modifiers. These pharmaceutical preparations can be injected intramuscularly, epidurally, intraperitoneally or intravenously.

[0076] The present invention also provides a kit comprising a pharmaceutical composition comprising one or more delivery vehicles. The kit also includes instructions for using the drug. Preferably, the commercial package will contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose can be an amount sufficient to prepare an intravenous injection. It will be apparent to one of ordinary skill in the art that photosensitive and / or gas-sensitive compounds may require special packaging and / or formulations. For example, a package that is opaque to light, and / or sealed to avoid contact with ambient air, and / or formulated with a suitable coating or excipient can be used.

[0077] The "effective amount" of the CD inclusion compound delivery vehicle according to the present invention includes a therapeutically effective amount or a preventive effective amount. "Therapeutically effective amount" refers to an amount effective for achieving the desired therapeutic result at the required dosage and duration. The therapeutically effective amount of the delivery vehicle can be changed according to factors such as the disease state, the age, sex and weight of the individual, and the ability of the compound to cause the desired response in the individual. The dosage regimen can be adjusted to provide the optimal therapeutic response. The therapeutically effective amount can also be an amount in which the therapeutic beneficial effect is greater than any toxic or adverse effect of the delivery vehicle or active compound. "Preventive effective amount" refers to an amount effective for achieving the desired preventive result at the required dosage and duration. Usually, a preventive dose is used in a subject before the disease or in the early stages of the disease, so that the preventive effective amount can be less than the therapeutically effective amount. For any particular subject, the timing and dosage of treatment can be adjusted over time (for example, the time can be daily, every other day, weekly, monthly) according to the professional judgment of the person who administers or supervises the administration of the composition.

[0078] In selected embodiments, the present invention provides a composition or medicament comprising one or more biologically active molecules selected from the group consisting of: a biologically active compound or solvate, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, mixture of stereoisomers, geometric isomer, crystalline or amorphous form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomers, diastereomers and geometric isomers thereof, and mixtures of the above substances, in combination with a pharmaceutically acceptable carrier, diluent or excipient, and also provides a method for preparing such a composition or medicament.

[0079] Although various embodiments of the present invention are disclosed herein, various improvements and modifications can be made within the scope of the present invention according to the general knowledge of those skilled in the art. These modifications include the replacement of any aspect of the present invention by known equivalents, thereby achieving the same results in substantially the same manner. Numerical ranges include numerical values ​​that limit the range. The word "comprising" is used as an open term in this article, which is substantially equivalent to the term "including (but not limited to)" and the word "comprising" has a corresponding meaning. Unless the context clearly provides, as used herein, the singular forms "a" and "the" include plural objects. Therefore, for example, reference to "a thing" includes more than one of the things.

[0080] The citation of references herein is not an admission that these references are prior art of the present invention. Any prior documents and all patent disclosures cited in this specification, including, but not limited to, patents and patent applications, are incorporated herein by reference. All documents cited or referenced in the documents cited herein and any manufacturer's instructions, descriptions, product specifications, and product pages for any product mentioned in this article or in any document incorporated herein by reference are hereby incorporated herein by reference and can be used in the practice of the present invention. More specifically, all referenced documents are specifically and individually indicated to be incorporated herein by reference and are incorporated by reference to the same extent as fully described herein with each individual publication. The present invention includes all embodiments and variations substantially as described above and with reference to the examples and drawings.

[0081] In some embodiments, the present invention does not include steps involving medical or surgical treatment.

[0082] Example

[0083] Example 1: Mucus Formulation I

[0084] Cyclodextrin inclusion complex of camphene was prepared using a slurry method with food grade camphene from Vigon Corporation at a molar ratio of camphene to alpha cyclodextrin of 1:2. Sustained release capsules of this camphene inclusion complex (6.5%) were prepared with the following formulations per capsule:

[0085] Camphene content.............400mg (net content 26mg)

[0086] K-100M cellulose (Colorcon)...80mg

[0087] E4M cellulose (Colorcon)......20mg

[0088] Amylase...................4mg

[0089] Calcium laurate (flow enhancer)..4mg

[0090] Example 2: Mucus Formulation II

[0091] Other cyclodextrin inclusion complex formulations were prepared for addition to mucus formula I as follows: Peppermint oil (NOW Foods) at a molar ratio of oil to gamma cyclodextrin 1:4 using a slurry method. Eucalyptol (Vigon) at a molar ratio of eucalyptol to alpha cyclodextrin 1:1 using a slurry method.

[0092] The peppermint oil and eucalyptol inclusion complex formulation described above was added to the components of mucus formulation I to provide capsules of mucus formulation II:

[0093] Camphene content (6.5%)...150mg (10mg net content)

[0094] Eucalyptol content (10%)...................135mg (13.5mg net content)

[0095] Peppermint oil content (15%).............46mg (7mg net content)

[0096] K-100M cellulose (Colorcon)...............70mg

[0097] E4M cellulose (Colorcon)...................17mg

[0098] Amylase................................4mg

[0099] Example 3: Mucositis associated with nonalcoholic steatohepatitis (NASH)

[0100] Subject BC had liver cancer, and the resulting mucositis associated with nonalcoholic steatohepatitis (NASH, a subtype of the progressive form of nonalcoholic fatty liver disease), combined with a history of cirrhosis. BC had undergone liver surgery for intrahepatic hepatobiliary type liver cancer, and subsequent cancer treatment including chemotherapy and radiation therapy. A side effect of radiation therapy is the development of mucositis (excessive production of mucus), which is resistant to conventional therapy.

[0101] BC was treated with mucus formulation II of Example 2 beginning on day 1 at a dose of 3 capsules 3 times daily. By day 5, respiratory mucus had improved significantly and lung congestion had changed significantly, although a persistent cough was still present. By day 10 of treatment with the capsules, the excess respiratory mucus had virtually disappeared symptomatically and the cough was substantially resolved. Continued treatment with the capsules provided continued improvement in mucositis symptoms, providing evidence of unexpected efficacy in treating airway mucus dysfunction, including antitussive efficacy.

[0102] Example 4: Bronchiectasis

[0103] Subject D, 50 years old, had a diagnosis of long-standing severe and refractory bronchiectasis and had lung sputum positive for Pseudomonas for ~20 years. The patient had undergone treatment with Vogamontin (amoxicillin and clavulanic acid) for sinus infection and nebulized hypersol, salbutamol, and colistin antibiotic therapy (28 days on, then 28 days off).

[0104] The patient began treatment with mucus formula II at 4 capsules twice a day on June 11. On June 14, the dose was increased to 6 capsules twice a day, and this was accompanied by a shift to full-night sleep, which was attributed to the resolution of the chronic cough symptoms associated with prone or supine positions. By June 17, D slept well and airway mucus continued to improve, an outcome attributed to the resolution of the patient's pulmonary congestion mediated by mucus formula II treatment. By June 19, D reported continued improvement, continuous full-night sleep. By June 20, D reported expectorant effect, airway mucus was thinner, easy to cough up all day, and mucus changed from light green to transparent, even in the worst part of the "28-day withdrawal" part of the nebulized antibiotic treatment cycle (the last two weeks of the cycle, during which D usually experienced airway mucus turning into dark green). D reported reduced chest tightness, expectorant cough, and was able to sleep lying flat all night. D slept all night from June 12, the first day of taking mucus formula II. This is an unexpected finding relative to the consistent, chronic history of no more than 2-3 hours of sleep at a time before being awakened by coughing, regardless of sleeping position or inclination. This is a significant and consistent change after years of intermittent sleep in a reclining chair.

[0105] On June 30, D continued treatment and switched to Mucus Formula II with the addition of guaiac and fenugreek oil, which is denoted as Mucus Formula II + . By July 3, D reported continued significant improvement in airway mucus dysfunction, with fewer coughs, more productive coughs and less mucus. Improvements included a decrease in the frequency, duration and intensity of coughs, and the coughs were more productive, but there was less mucus to control overall. At this time, patient D was two weeks into the "on medication" portion of the 28-day medication, i.e., a 28-day off-medication cycle of antibiotics. The mucus was white, and occasionally yellow. Typically, at this point in the antibiotic cycle, the mucus is 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 medication" portion of the antibiotic cycle, improvements continued and D reported being able to sleep supine for the first time in years, with white mucus (no yellow) and less mucus. An expectorant effect was noted, with mucus being easier to move even compared to the previous week.

[0106] This example shows that oral camphene cyclodextrin formulations, including formulations that also contain guaiac and fenugreek oil, are effective in treating airway mucus dysfunction.

[0107] Example 5: Viral pneumonia, mucus activation effect

[0108] A composition comprising a combination of the following CD inclusions is provided for oral administration in capsule form:

[0109] Eucalyptus (Myrtaceae) extract, standardized to 6 mg of cineole (in βCD inclusion complex);

[0110] Pine knotweed extract, standardized to 6 mg camphene (in βCD inclusion complex);

[0111] Peppermint (peppermint) oil 6 mg (in βCD inclusion complex);

[0112] Pinus (Pinus maritime and / or Pinus elliottii and / or Pinus scoparia) extract, standardized to 4 mg of carene delta 3 (βCD or γCD inclusion);

[0113] Fenugreek extract (fenugreek absolute oil) 4 mg (in γCD inclusion complex);

[0114] Jade sandalwood extract, standardized to 4 mg guaiacol (in γCD inclusion complex);

[0115] K250 extended release 80 mg;

[0116] Amylase 7 mg; and

[0117] Ca laurate 5mg.

[0118] An adult male patient was diagnosed with a viral infection and presented with dry mouth and dry cough to the extent of vomiting. The patient started treatment with 4 capsules of the above formulation twice a day for 2 days. The patient's cough became expectorant and the formulation had a significant mucoactive effect, resulting in an improved feeling of well-being for the patient.

[0119] Example 6: Erectile dysfunction

[0120] Male subject A started the dosage of mucus formula I, 3 capsules twice a day. Within 48 hours, exercise breathing was significantly improved and respiratory mucus was significantly reduced. Within 48 hours of the initial dose of mucus formula I, the subject noticed the occurrence of nocturnal penis enlargement, which was not experienced by the 67-year-old subject for some time. The subject increased the dosage of mucus formula I to 4 capsules twice a day, and the effect of nocturnal penis enlargement appeared immediately, and the sensitivity to daytime and nighttime erection stimulation was significantly enhanced. The subject measured that the erection effect was equivalent to 70-85% of the effect of 25-50 mg of sildenafil. The subject also found that when using the mucus formula I dosage of 4 capsules twice a day, 5 mg of sildenafil actually achieved the same erection enhancement as the previous dosage of 25-50 mg of sildenafil, and there was no side effect experienced by the previous use of 25-50 mg of sildenafil (which can (for example) include headache, flushing, stomachache, abnormal vision, stuffy nose or runny nose, backache, muscle pain and nausea).

Claims

1. Use of a cyclodextrin inclusion compound delivery vehicle for preparing a medicament for oral treatment of bronchiectasis, the delivery vehicle comprising: Cyclodextrin, which has a cavity; Camphene, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin to form a cyclodextrin inclusion complex of camphene, wherein the molar ratio of camphene to α-cyclodextrin is 1:2, and the content of the camphene inclusion complex is 150 mg per pellet, providing 10 mg of pure camphene; Eucalyptol, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin, wherein the molar ratio of eucalyptol to α-cyclodextrin is 1:1, and the content of eucalyptol inclusions is 135 mg per capsule, providing 13.5 mg of clean eucalyptol; Peppermint oil, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin, wherein the molar ratio of peppermint oil to gamma-cyclodextrin is 1:4, and the content of peppermint oil inclusions is 46 mg per capsule, providing 7 mg of neat peppermint oil; a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained in the biologically acceptable carrier by the cyclodextrin; Hydroxypropyl methylcellulose ingredient; and Amylase, content is 4 mg per capsule.

2. Use of a cyclodextrin inclusion compound delivery vehicle for formulating a medicament for oral treatment of human male subjects to provide an erectile effect, the delivery vehicle comprising: Cyclodextrin, which has a cavity; Camphene, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin to form a cyclodextrin inclusion complex of camphene, wherein the molar ratio of camphene to α-cyclodextrin is 1:2, the content of the camphene inclusion complex is 400 mg per capsule, and 26 mg of pure camphene is provided; a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained in the biologically acceptable carrier by the cyclodextrin; Hydroxypropyl methylcellulose ingredient; Amylase, 4 mg per capsule; and Calcium laurate, as a flow enhancer, is contained in an amount of 4 mg per capsule.

3. The use according to claim 1 or 2, wherein the amylase has a cyclodextrin degradation activity and is capable of hydrolyzing the cyclodextrin retaining the guest molecule, wherein the amylase is formulated so as to activate the cyclodextrin degradation activity when the vector is delivered to the target, thereby releasing the guest molecule from the cavity of the cyclodextrin. The use according to claim 3, wherein the amylase is co-formulated with the cyclodextrin inclusion complex.

5. The use according to claim 3, wherein the amylase is co-packaged with the cyclodextrin inclusion complex in the delivery vehicle, and the delivery vehicle further comprises a biochemically acceptable carrier for the amylase.

6. The use according to claim 3, wherein the amylase is mammalian salivary amylase, mammalian pancreatic amylase or microbial amylase.

7. The use according to any one of claims 2, 4 to 6, wherein the cyclodextrin is a mixed methylated / ethylated cyclodextrin or a hydrophobic alkylated cyclodextrin.

8. The use according to any one of claims 2, 4 to 6, wherein the delivery vehicle further comprises a drug or prodrug guest molecule.

9. The use according to claim 8, wherein the drug or prodrug guest molecule is a phosphodiesterase type 5 (PDE5) inhibitor.

10. The use according to claim 9, wherein the PDE5 inhibitor is sildenafil, avanafil, lordenafil, milonafil, tadalafil, vardenafil, udenafil, zaprinast, kra-chai-dom, icariin, benzanafil or dasentafil.

11. The use according to any one of claims 2, 4 to 6, 9, 10, wherein the biologically acceptable carrier is a pharmaceutically acceptable carrier.

12. The use according to any one of claims 2, 4 to 6, 9, 10, wherein the delivery vehicle is formulated for sustained release of one or more of the guest molecules.

13. The use according to claim 2, wherein the human male subject suffers from erectile dysfunction.

14. A cyclodextrin inclusion compound delivery vehicle, comprising: Cyclodextrin, which has a cavity; Camphene, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin to form a cyclodextrin inclusion complex of camphene, wherein the molar ratio of camphene to α-cyclodextrin is 1:2, and the content of the camphene inclusion complex is 150 mg per pellet, providing 10 mg of pure camphene; Eucalyptol, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin, wherein the molar ratio of eucalyptol to α-cyclodextrin is 1:1, and the content of eucalyptol inclusions is 135 mg per capsule, providing 13.5 mg of clean eucalyptol; Peppermint oil, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin, wherein the molar ratio of peppermint oil to gamma-cyclodextrin is 1:4, and the content of peppermint oil inclusions is 46 mg per capsule, providing 7 mg of neat peppermint oil; Hydroxypropyl methylcellulose ingredient; Amylase, 4 mg per capsule; PDE5 inhibitors; and A biologically acceptable carrier for the cyclodextrin inclusion complex and the PDE5 inhibitor, wherein the guest molecule is stably retained in the biologically acceptable carrier by the cyclodextrin.

15. A cyclodextrin inclusion compound delivery vehicle, comprising: Cyclodextrin, which has a cavity; Camphene, which is at least partially retained as a guest molecule in the cavity of the cyclodextrin to form a cyclodextrin inclusion complex of camphene, wherein the molar ratio of camphene to α-cyclodextrin is 1:2, the content of the camphene inclusion complex is 400 mg per capsule, and 26 mg of pure camphene is provided; Hydroxypropyl methylcellulose ingredient; Amylase, 4 mg per capsule; Calcium laurate, as a flow enhancer, 4 mg per capsule PDE5 inhibitors; and A biologically acceptable carrier for the cyclodextrin inclusion complex and the PDE5 inhibitor, wherein the guest molecule is stably retained in the biologically acceptable carrier by the cyclodextrin.

16. The delivery vehicle of claim 14 or 15, wherein the PDE5 inhibitor is an attached guest molecule, thereby providing the PDE5 inhibitor as an inclusion complex.

17. The delivery vehicle of claim 14 or 15, wherein the PDE5 inhibitor is sildenafil, avanafil, lordenafil, milonafil, tadalafil, vardenafil, udenafil, zaprinast, kra-chai-dom, icariin, benzanafil, or dasentafil.

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