Oral terpene cyclodextrin inclusion compound vehicle

Abstract

Oral terpene cyclodextrin inclusion delivery vehicles are provided that include formulations in which the cyclodextrin inclusion is provided with an enzyme having cyclodextrin degrading activity, capable of hydrolyzing cyclodextrin, to activate the enzyme and release guest molecules from the cyclodextrin cavity upon delivery of the vehicle to a target. In alternative aspects, these cyclodextrin inclusion compound delivery vehicles are provided, for example, in the form of delayed release formulations, for example, for the treatment of airway mucus dysfunction. Formulations having erectile efficacy are also provided.

Description

Technical Field

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

[0002] Cyclodextrins are non-reducing cyclic glucose oligosaccharides, typically the products of starch degradation catalyzed by cyclomaltodextrin glucanotransferase (E.C. 2.4.1.19; CGTase). Cyclodextrins can have a variety of structures (see Saenger et al., Chem. Rev. 98 (1998) 1787-1802), including three common cyclodextrins with 6, 7, or 8 D-glucopyranose residues linked in a ring by α-1,4 glycosidic bonds (α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively). The truncated conical shape of cyclodextrins forms a cavity or inner lumen, which has different diameters depending on the number of glucose units. The sizes of the selected cyclodextrin (CD) structures are listed in Table 1. Larger cyclodextrins, such as cyclononamylose (δ-CD) and cyclodecamylose (ε-CD), as well as a variety of cyclodextrin-based supramolecular structures, are also possible (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 rim of their inner cavity showing 2-OH and 3-OH groups, while the narrower rim shows 6-OH. Thus, these hydrophilic hydroxyl groups are located on the outer side of the inner cavity, while the inner surface is generally hydrophobic and is arranged with anomeric oxygen atoms as well as C3-H and C5-H hydrogen atoms. In aqueous solution, this hydrophobic inner cavity can contain water molecules, for example, about 3 (α-CD), 7 (β-CD), or 9 (γ-CD) water molecules that are unstably accommodated but have low entropy and are thus relatively easily displaced. Therefore, hydrophilic cyclodextrins can bind and retain one or more molecules of appropriate size within or partially within the CD inner cavity, thereby forming cyclodextrin inclusion compounds or complexes. For example, nonpolar aliphatic and aromatic compounds, including drugs such as lipophilic drugs, can be bound, thereby increasing the water solubility of compounds that are hydrophobic under normal circumstances, or minimizing undesired properties such as odor or taste in certain food additives. For this purpose, cyclodextrin inclusion compounds are widely used in the fields of pharmaceuticals, foods, and cosmetics (see Hedges, Chem. Rev. 98 (1998) 2035-2044). For example, cyclodextrins have been used in a variety of sustained-release pharmaceutical formulations, such as inclusion compounds of medical compounds with hydrophobic cyclodextrin derivatives (U.S. Patent No. 4,869,904).

[0006] Cyclodextrins can be chemically modified in a variety of ways. For example, to alter the inclusion specificity, physical, and chemical properties of cyclodextrins. For example, the CD hydroxyl groups can be derivatized. For example, two modified CDs have been used in a variety of pharmaceutical 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-hydroxy group on γ-CD is replaced by a carboxythioacetic acid ether bond, and hydroxybutenyl-β-CD. Alternative forms of cyclodextrins 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), sodium salt of sulfobutylated β-cyclodextrin, sodium salt of sulfobutylated β-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, DIMEB-50 hepta(2,6-di-O-methyl)-β-cyclodextrin, TRIMEB hepta(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 favorable pharmacological and toxicological profiles, there remains 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 susceptibility of cyclodextrins to enzymatic digestion. For example, γ-CD is relatively easily hydrolyzed by α-amylase, while α-cyclodextrin is less easily hydrolyzed. CD-based therapeutic agents generally depend on the activity of endogenous amylase to digest CDs. However, there are significant differences 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, particularly elderly patients, may have insufficient gastric acid production and thus cannot create appropriately low pH conditions in the duodenum to properly trigger the release of pancreatic amylase. The routine use of antacids, histamine-2 blockers, proton pump inhibitors, or alternative acid blockers can have a similar effect.

[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 be able to hydrolyze CDs and, in some cases, other substrates such as pullulan and starch. Cyclodextrinase (CDase) catalyzes the hydrolysis of CDs to form linear oligosaccharides with α-1,4-bonds and thus it can release substrates from CD inclusion complexes. The CD enzyme from Bacillus macerans was reported in 1968 and since then a variety of CD enzymes from bacteria have been identified, such as enzymes from Bacillus sp., Thermoanaerobacter ethanolicus strain 39E, Flavobacterium sp., and Klebsiella oxytoca strain M5a1. Archaeal CD enzymes have been identified from Archaeoglobus fulgidus, Thermococcus sp. B1001, Thermococcus sp. CL1, Thermofilum pendens, and Pyrococcus furiosus. The structure of the CD enzyme from Flavobacterium sp. has been characterized in detail (see Sun et al., Archaea, Volume 2015 (2015), Article ID 397924, which reported the gene identification of 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 with gem-dimethyl at the 2-position and methylene at the 3-position. It is a widely distributed natural product that usually exists as a racemic mixture of D-camphene and L-camphene in various essential oils 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 promotes a variety of airway diseases and conditions or their symptoms (see Fahy & Dickey, 2010), which are typically manifested as coughing 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 various immunodeficiency conditions. Conditions associated with airway mucus dysfunction can include disruptions of various 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] There is provided a camphene cyclodextrin inclusion complex delivery vehicle, for example, for treating airway mucus dysfunction or for providing an erectile effect in male subjects. In addition to camphene, the formulation can include other inclusion complex guest molecules, including other terpenes, such as phytoterpenes. Other guest molecules can (for example) include: eucalyptol (i.e., 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane; CAS 470-82-06; 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 489-86-1; champacol), and / or δ-3-carene (i.e., 3,7,7-trimethylbicyclo[4.1.0]hept-3-ene; CAS 13466-78-9). Other guest molecules can be provided (for example) 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, thereby stably retaining the guest molecule within the biologically acceptable carrier through the cyclodextrin. An enzyme having cyclodextrin-degrading activity capable of hydrolyzing the cyclodextrin retaining the guest molecule can also be provided in the vehicle. The enzyme can be formulated such that the cyclodextrin-degrading activity is activated upon delivery of the vehicle to the target, thereby releasing the guest molecule from the cyclodextrin cavity.

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

[0014] The enzyme can (for example) be amylase, cyclodextrinase, maltogenic amylase, or pullulanase. Amylase can (for example) be mammalian salivary amylase or pancreatic amylase, or amylase from fungal or bacterial sources. Cyclodextrinase can (for example) be microbial cyclodextrinase.

[0015] The cyclodextrin can be, for example, 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 also possible, including non-integer ratios.

[0017] The cyclodextrin can be, for example, α, β or γ cyclodextrin, although a very wide range of alternative CD structures can still be used.

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

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

[0020] A method for treating a patient having 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 is provided. As an alternative, airway mucus dysfunction can be a condition associated with disruption of lung mechanics, for example, symptoms of intubation, paralysis, coma or surgical trauma.

[0021] A method for providing an erection in a male subject, such as a male greater than 50, 60 or 70 years of age or a male subject suffering from erectile dysfunction, is also provided. Detailed Description

[0022] Specific formulations of the delivery vehicle can, for example, include cyclodextrin inclusion complex formulations prepared by incorporating cyclodextrin inclusion complexes prepared from some sources, including natural plant extraction sources. For example, formulations of CD inclusion complexes prepared from 2, 3, 4, 5 or 6 of the following are incorporated in a single formulation or in different formulations provided in combination:

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

[0024] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, Syncarpia glomulifera extract (e.g., camphene standardized to 6 mg, or 4 - 8 mg); and / or in CD inclusion compounds, for example, in βCD or γCD inclusion compounds, peppermint (Mentha piperita) oil 6 mg, or 4 - 8 mg; and / or

[0025] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, Pinus (e.g., Pinaster and / or Elliotii and / or Sylvestris) extract (e.g., carene δ3 standardized to 4 mg, or 2 - 6 mg); and / or

[0026] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, fenugreek extract, such as absolute fenugreek (Trigonella foenum - graecum) 4 mg, or 2 - 6 mg; and / or in CD inclusion compounds, for example, in βCD or γCD inclusion compounds, Bulnesia sarmientoi extract (e.g., guaiol standardized to 4 mg, or 2 - 6 mg).

[0027] The components in different proportions can be provided (e.g.) at 5 - 250 mg per dose of any of the inclusion compounds. The selected formulations can be solely active ingredients of plant origin. Specific dosage forms can be (e.g.) as shown below, as a single 0 sustained - release capsule:

[0028] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, eucalyptus (Myrtaceae) extract (e.g., cineole standardized to 6 mg, or 4 - 8 mg);

[0029] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, Syncarpia glomulifera extract (e.g., camphene standardized to 6 mg, or 4 - 8 mg);

[0030] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, peppermint (Mentha piperita) oil 6 mg, or 4 - 8 mg;

[0031] In CD inclusion compounds, for example, in βCD or γCD inclusion compounds, Pinus [e.g., Pinaster and / or Elliotii and / or Sylvestris] extract (e.g., carene δ3 standardized to 4 mg, or 2 - 6 mg); in CD inclusion compounds, for example, in βCD or γCD inclusion compounds, fenugreek extract, such as absolute fenugreek (Trigonella foenum - graecum) 4 mg, or 2 - 6 mg;

[0032] In a CD inclusion, for example, in a βCD or γCD inclusion, costus root extract (e.g., guaiol standardized to 4 mg, or 2 - 6 mg);

[0033] 80 mg of K250 sustained release agent;

[0034] 7 mg of amylase;

[0035] 5 mg of calcium laurate.

[0036] As used in the formulations herein, peppermint oil can be an extract of the peppermint plant Mentha piperita. The composition of peppermint oil varies, but has been identified 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).

[0037] The composition of fenugreek (Trigonella foenum-graecum) is generally known and is understood to contain various 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 extract can be produced by solvent extraction of fenugreek seeds and is sometimes identified as fenugreek absolute (CAS No. 84625-40-1, FEMA No. 2486, EC No. 283-415-1, MDL No. MFCD01772302).

[0038] In the selected embodiments, the guest molecule can 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; δ-3-carene from pine (e.g., species: Pinus pinaster; Pinus elliottii; Pinus sylvestris, cedar, basil, pine, rosemary, and capsicum); guaiol from amyris (a sesquiterpene alcohol also present in Cupressus and Guaiacum); peppermint oil containing menthol; fenugreek extract from fenugreek seeds. Alternative embodiments can (for example) include extracts, terpenes, or oils from the following: eucalyptus (Myrtaceae), turpentine tree, Pinus (Pinus pinaster and / or Pinus elliottii and / or Pinus sylvestris) and amyris, peppermint (Mentha piperita) and fenugreek. These extracts can be formulated in a β- and γ-cyclodextrin fiber matrix together with high and low viscosity hydroxypropyl methylcellulose (sustained release), hydroxypropyl methylcellulose (cellulose-derived) capsules, cellulose, calcium laurate, and amylase (such as plant or microbial amylase).

[0039] In the selected embodiments, the formulation can (for example) contain, in (for example) a plant cellulose capsule:

[0040] In the β-CD inclusion, 75 mg of eucalyptol (10 wt% (weight percentage));

[0041] In the β-CD inclusion, 75 mg of camphene (10 wt%);

[0042] In the β-CD inclusion, 50 mg of δ3-carene (10 wt%);

[0043] In the γ-CD inclusion, 50 mg of guaiol (10 wt%);

[0044] In the β-CD inclusion, 50 mg of peppermint oil (15 wt%);

[0045] In the γ-CD inclusion, 50 mg of fenugreek absolute (oil) (10 wt%);

[0046] 80 mg of K250 extended release agent;

[0047] 5 mg of amylase; and

[0048] 5 mg of Ca laurate.

[0049] They can be included as other different components and / or as other guest molecules in the delivery vehicle of the present invention, for example, in the form of a pharmaceutical composition containing various biologically active compounds, such as: docetaxel (US Patent Publication 20140336149, 20130296268); carbamazepine (US Patent Publication 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; gliclazide; digitoxin; macrocyclic compound (MCC); ibuprofen; prochloro-methazine; DY-9760e; NSC-639829; ETH-615; piroxicam; levomoracizine HCl; ziprasidone mesylate; sulindac; mebendazole; sulindac; phenolphthalein; danazol (see Challa et al., 2005, AAPS PharmSciTech 2005; 6(2) article number 43); itraconazole; nelfinavir mesylate; telmisartan; 5-fluorouracil and other nucleoside analogs; camptothecin; humulene (also known as α-humulene or α-caryophyllene); or flavonoids.

[0050] The selected embodiment is a nutraceutical composition, which contains 75 mg of cineole (e.g., ~10 wt%) in βCD inclusion; 75 mg of camphene (e.g., ~10 wt%) in βCD inclusion; 50 mg of δ3-carene (e.g., ~10 wt%) in βCD inclusion; 50 mg of guaiol (e.g., ~10 wt%) in γCD inclusion; 50 mg of peppermint oil (e.g., ~15 wt%) in βCD inclusion; fenugreek absolute oil (oil) (e.g., ~10 wt%) in γCD inclusion; and humulene.

[0051] In the selected embodiment, the enzyme provided in the vehicle can be formulated to activate the cyclodextrin degradation activity 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 (e.g.) a medicament for oral delivery, in a dry dosage form such as a capsule or tablet, where the enzyme is mixed so that the enzyme is inactive until it is activated by moisture in the host gastrointestinal tract. Similarly, a variety of sustained-release matrices and formulations are known, which can be suitable for use in the CD delivery vehicle to coordinate the proper activation of the CD-degrading enzyme upon delivery to the target.

[0052] In several aspects, with respect to the examples discussed above, the CD delivery vehicle can have an enzyme co-formulated with the cyclodextrin inclusion complex, or the enzyme can be co-packaged with the cyclodextrin inclusion complex in the delivery vehicle. With respect to co-packaging, the delivery vehicle can (for example) include a biochemically acceptable carrier for the enzyme - a carrier different from the CD inclusion complex. For example, the delivery vehicle can be provided with separate compartments containing the CD inclusion complex and the CD-degrading enzyme, such that the delivery vehicle will consist of a CD inclusion complex compartment connected to a CD-degrading enzyme compartment. An arrangement can be provided for the combined release of the CD inclusion complex and the CD-degrading enzyme from their respective compartments in the delivery vehicle. For example, a syringe with such different compartments can be provided, which is discharged by a common discharge mechanism, such as a mechanism for co-moving pistons in each compartment to discharge aliquots of the CD inclusion complex and the CD-degrading enzyme, such 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 for dispensing topical creams or other surface-active formulations. A variety of such delivery vehicles can be adapted from devices known for dispensing two-component compositions, such as epoxy resins, two-component drugs, or dental formulations, by way of example, as disclosed in U.S. Patent Nos. 4,538,920, 8,100,295, 8,308,340, 8,875,947, 8,499,976 and International Patent Publications WO2007041266 and WO2000021842.

[0053] There are a variety of techniques available for the preparation of CD inclusion complexes. For example, as described in: Chaudhary & Patel, IJPSR, 2013, Vol. 4(1): 68 - 76; Carneiro et al., 2019, Int. J. Mol. Sci. 2019, 20, 642; U.S. Patent Publication US20090029020; US20090214446; U.S. Patent Nos 5,070,081; 5,552,378; 5,674,854 and 8,658,692. A common method is known as the kneading method, which involves mixing CD with water or aqueous alcohol to provide a paste. Then, the bioactive molecule can be added to the paste and kneaded for the specified time. Then, the kneaded mixture can be dried and sieved as required. As an alternative, the slurry method involves the steps of mixing the bioactive molecule and cyclodextrin, adding an appropriate amount of water to the mixture, usually mixing vigorously until a paste or slurry is formed; continuing to mix for a suitable period, such as 15 minutes, and further adding water if necessary to maintain the viscosity of the paste or slurry to form the inclusion complex; and drying the product of this final step. Other ingredients, such as emulsifiers, can assist in the formation of the inclusion complex. For example, a method including the steps of dry - mixing cyclodextrin and an emulsifier (e.g., pectin); mixing the dry - mixture of the cyclodextrin and the emulsifier with a solvent, such as water, in a reactor and agitating; adding the guest molecule and stirring (e.g., for about 5 to 8 hours); optionally, cooling the reaction mixture while stirring; and emulsifying the mixture before drying the cyclodextrin inclusion complex to form a powder. Other known methods for preparing CD inclusion complexes include lyophilization, microwave irradiation, and supercritical fluid anti - solvent techniques.

[0054] 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 liposomes, adjuvants, or any pharmaceutically or biologically acceptable carrier. The selected embodiments include 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 can be suitable for any appropriate mode of administration, including topical, subcutaneous, intradermal, intravenous, parenteral, intraperitoneal, intramuscular, sublingual, inhaled, 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 media and agents for pharmaceutically active substances is well - known in the art. Except insofar as any conventional media or reagent is incompatible with the biologically active compound, its use in the pharmaceutical compositions of the present invention is contemplated. Supplementary active compounds can also be introduced into the compositions.

[0055] 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, inhalation, aerosol, topical, intratumoral, sublingual or oral administration. Therapeutic formulations can be in the form of a liquid solution or suspension; for oral administration, the formulation can be in the form of tablets or capsules; for intranasal formulations, in the form of powders, nasal drops or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets.

[0056] Cyclodextrin-degrading or digestive enzymes can be formulated, for example, for oral delivery. For example, enteric enzyme formulations can be provided, such as submicron particle formulations 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).

[0057] Methods well known in the art for preparing formulations can be found, for example, in "Remington's Pharmaceutical Sciences" (20th Edition), edited by 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 naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or poly(ethylene oxide)-poly(propylene oxide) copolymers can 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 can contain excipients, such as lactose, or can be an aqueous solution containing, for example, poly(ethylene oxide)-9-lauryl ether, glycocholate and deoxycholate, or can be an oil solution for administration in the form of nasal drops, or as a gel.

[0058] The pharmaceutical composition of the present invention can be in any form that permits the composition to be administered to a patient. For example, the composition can be in solid, liquid, or gaseous (aerosol) form. Typical routes of administration include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, epidural, intracardiac injection, or infusion techniques. The pharmaceutical composition of the present invention is formulated so that once the composition is administered to a patient, the active ingredient contained therein is bioavailable. The composition administered to the patient takes the form of one or more dosage units, where, for example, a tablet, capsule, or cachet can be a single dosage unit, and a container of a compound in aerosol form can contain multiple dosage units.

[0059] The materials used in the preparation of the pharmaceutical composition should be pharmaceutically pure and non-toxic in the amounts used. The composition of the present invention can include 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 the pharmaceutical composition will depend on a variety of factors. Relevant 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.

[0060] Typically, the pharmaceutical composition includes the delivery vehicle of the present invention as described herein mixed with one or more carriers. The carrier can be particulate, so that the composition is in, for example, tablet or powder form. The carrier can be liquid, where the composition is, for example, an oral syrup or an injectable liquid. Additionally, the carrier can be gaseous to provide an aerosol composition useful in, for example, inhaled administration.

[0061] When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension, and gel forms are included within the forms considered to be solid or liquid herein.

[0062] As a solid composition for oral administration, the composition can be formulated in the form of powders, granules, tablets, pills, capsules, cachets, chewing gums, wafers, troches, etc. Such solid compositions will generally contain one or more inert diluents or edible carriers. Additionally, one or more of the following adjuvants may be present: binders such as syrup, gum arabic, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum 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, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silica; sweetening agents such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate or orange flavoring and coloring agents.

[0063] When the composition is in the form of a capsule, e.g., a hard gelatin capsule, in addition to materials of the above types, it can contain a liquid carrier such as polyethylene glycol or an oily liquid.

[0064] The composition can be in liquid form, e.g., an elixir, syrup, solution, water or oil emulsion or suspension, or even a dry powder that can be reconstituted with water and / or other liquid vehicle(s) prior to use. As two examples, the liquid can be for oral administration or for delivery by injection. When intended for oral administration, in addition to the compounds of the present invention, the preferred compositions contain one or more of a sweetening agent, a thickening agent, a preservative (e.g., alkyl p-hydroxybenzoates), a dye / coloring agent and a flavor enhancer (flavorant). In compositions intended for administration by injection, one or more of a surfactant, a preservative (e.g., alkyl p-hydroxybenzoates), a wetting agent, a dispersing agent, a suspending agent (e.g., sorbitol, glucose or other syrup), a buffer, a stabilizer and an isotonic agent may be included. The emulsifying agent can be selected from lecithin or sorbitan monooleate.

[0065] Whether they are in solution, suspension 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 methylparaben; 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. The parenteral preparations may be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. Physiological saline is the preferred adjuvant. The injectable pharmaceutical compositions are preferably sterile.

[0066] The pharmaceutical compositions may be intended for topical administration, in which case the carrier may suitably comprise a solution, an emulsion, an ointment, a cream or a gel base. For example, the base may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifying and stabilizing agents. Thickeners may be present in the pharmaceutical compositions for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or an iontophoretic device. The topical preparations may contain a concentration of the biologically active compound of from about 0.1 to about 25% w / v (weight per unit volume).

[0067] The compositions may be intended for rectal administration, which is in the form of, for example, a suppository that will melt in the rectum and release the drug. The compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. These bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. Low melting point waxes are preferred for the preparation of suppositories, and a mixture of fatty acid glycerides and / or cocoa butter is a suitable wax. The wax may be melted and the aminocyclohexyl ether compound uniformly dispersed therein by stirring. Then, the melted and uniform mixture is poured into a mold of appropriate size and allowed to cool and thereby solidify.

[0068] The compositions may include a variety of materials that alter the physical form of the solid or liquid dosage units. For example, the compositions may include materials that form a coating shell around the active ingredient. The materials forming the coating shell are generally inert and may be selected from, for example, sugars, shellac and other enteric coating reagents. As an alternative, the active ingredient may be encapsulated in a gelatin capsule or a cachet.

[0069] The pharmaceutical composition according to the present invention may consist of gas dosage units. For example, it may be in the form of an aerosol. The term "aerosol" is used to denote a variety of systems ranging from those having colloidal properties to systems consisting of pressurized packages. It can be delivered by liquefied or compressed gases or by a suitable pump system for dispensing the active ingredient. The aerosol of the compounds of the present invention can be delivered in a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes the necessary container, activator, valve, sub-container, etc., which can together form a kit.

[0070] The biologically active compound can be in the form of the 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 a suitable mode of use (e.g., oral or parenteral administration route), the appropriate salt will be selected to enhance the bioavailability or stability of the compound.

[0071] The composition 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 and pyrogen-free water. A surfactant can be added to help form a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with the aminocyclohexyl ether compound, thereby helping the aminocyclohexyl ether compound to dissolve or be uniformly suspended in the aqueous delivery system. The presence of a surfactant is desired in the aqueous composition of the present invention because the aminocyclohexyl ether compound according to the present invention can be hydrophobic. Other injectable carriers include, without limitation, sterile peroxide-free ethyl oleate, anhydrous alcohol, propylene glycol and mixtures thereof.

[0072] Pharmaceutical adjuvants suitable for injection solutions include stabilizers, solubilizers, buffers and viscosity regulators. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffer, citrate buffer and high molecular weight polyethylene oxide viscosity regulators. These pharmaceutical formulations can be injected intramuscularly, epidurally, intraperitoneally or intravenously.

[0073] The present invention also provides a kit comprising a pharmaceutical composition comprising one or more delivery vehicles. The kit also comprises 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 those of ordinary skill in the art that photosensitive and / or gas-sensitive compounds may require special packaging and / or formulation. For example, packaging 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.

[0074] The "effective amount" of the CD inclusion complex delivery vehicle according to the present invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" means an amount that is effective, at the required dosage and for the required duration, to achieve the desired therapeutic result. The therapeutically effective amount of the delivery vehicle can vary depending on factors such as the disease state, the age, sex, and weight of the individual, and the ability of the compound to elicit 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 benefit is greater than any toxic or adverse effects of the delivery vehicle or the active compound. A "prophylactically effective amount" means an amount that is effective, at the required dosage and for the required duration, to achieve the desired prophylactic result. Generally, prophylactic dosages are used in a subject before or at an early stage of a disease, such that the prophylactically 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 (e.g., the time can be daily, every other day, weekly, monthly) according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0075] In selected embodiments, the present invention provides a composition or medicament comprising one or more bioactive molecules in combination with a pharmaceutically acceptable carrier, diluent, or excipient, wherein the bioactive molecules are selected from: bioactive compounds or solvates, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, mixtures of stereoisomers, geometric isomers, crystalline or amorphous forms, metabolites, metabolic precursors, or prodrugs thereof, including their isolated enantiomers, diastereomers, and geometric isomers, and mixtures of the foregoing, and also provides a method for preparing such a composition or medicament.

[0076] 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 substitution of any aspect of the present invention with known equivalents, thereby achieving the same result in substantially the same manner. Numerical ranges include the values defining the range. The word "comprising" is used herein as an open term, which is substantially equivalent to the term "including (but not limited to)" and the word "comprising" has the corresponding meaning. Unless the context clearly dictates otherwise, as used herein, the singular forms "a" and "the" include plural objects. Thus, for example, a reference to "a thing" includes more than one such thing.

[0077] The citations to references in this document are not an admission that these references are prior art to the present invention. Any prior document and all patent publications 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 the instructions, descriptions, product specifications, and product pages of any manufacturer of any product mentioned in this document or in any document incorporated herein by reference are hereby incorporated herein by reference and may be used in the practice of the present invention. More specifically, all referenced documents are incorporated by reference to the same extent that each individual publication is specifically and separately indicated as being incorporated by reference herein and is fully described herein. The present invention includes all embodiments and variations substantially as described above and with reference to the embodiments.

[0078] In some embodiments, the present invention does not include steps involving medical or surgical treatment.

[0079] Examples

[0080] Example 1: Mucus formulation I

[0081] Using the slurry method, a cyclodextrin inclusion complex of camphene was prepared from food-grade camphene from Vigon Corporation at a molar ratio of camphene to α-cyclodextrin of 1:2. Sustained-release capsules of this camphene inclusion complex (6.5%) were prepared according to the formulation of each of the following capsules:

[0082] Camphene inclusion... 400 mg (net content 26 mg)

[0083] K-100M cellulose (Colorcon)... 80 mg

[0084] E4M cellulose (Colorcon)... 20 mg

[0085] Amylase... 4 mg

[0086] Calcium laurate (flow enhancer).. 4 mg

[0087] Example 2: Mucus formulation II

[0088] Other cyclodextrin inclusion complex preparations were made for addition to Mucus formulation I as follows: Using the slurry method, peppermint oil (NOW Foods) at a molar ratio of oil to γ-cyclodextrin of 1:4. Using the slurry method, eucalyptol (Vigon) at a molar ratio of eucalyptol to α-cyclodextrin of 1:1.

[0089] The above peppermint oil and eucalyptol inclusion complex preparations were added to the components of Mucus formulation I to provide capsules of Mucus formulation II:

[0090] Camphene inclusion (6.5%)……………150 mg (net content 10 mg)

[0091] Eucalyptol inclusion (10%)………………135 mg (net content 13.5 mg)

[0092] Peppermint oil inclusion (15%)…………46 mg (net content 7 mg)

[0093] K - 100M cellulose (Colorcon)……………70 mg

[0094] E4M cellulose (Colorcon)………………17 mg

[0095] Amylase…………………………4 mg

[0096] Example 3: Mucositis associated with non - alcoholic steatohepatitis (NASH)

[0097] Subject BC had hepatocellular carcinoma and developed mucositis associated with non - alcoholic steatohepatitis (NASH, a subtype of the progressive form of non - alcoholic fatty liver disease), in combination with a history of cirrhosis. BC underwent liver surgery for intrahepatic hilar cholangiocarcinoma and subsequent cancer treatment including chemotherapy and radiotherapy. The side effect of radiotherapy was the appearance of mucositis (excessive mucus production), which was resistant to conventional therapies.

[0098] BC started treatment with the mucus formulation II of Example 2 at a dose of 3 capsules, 3 times a day on day 1. By day 5, respiratory mucus was significantly improved and pulmonary congestion was markedly altered, although there was still a persistent cough. By day 10 of treatment with the capsules, excessive respiratory mucus had virtually disappeared symptomatically and the cough was substantially resolved. Continued treatment with the capsules provided a continuous improvement in mucositis symptoms, thus providing evidence of unexpected efficacy in the treatment of airway mucus dysfunction, including cough - suppressing efficacy.

[0099] Example 4: Bronchodilation

[0100] Subject D, a 50 - year - old, had a diagnosis of long - standing severe and refractory bronchiectasis and had Pseudomonas aeruginosa positive in the lung sputum for ~ 20 years. The patient underwent treatment with Augmentin (amoxicillin and clavulanic acid) for sinus infections and aerosolized hypersol, salbutamol, and polymyxin E antibiotics (treatment for 28 days, then off - drug for 28 days).

[0101] The patient started treatment with 4 capsules twice daily of mucin formulation II on June 11. On June 14, the dose was increased to 6 capsules twice daily, and this was accompanied by a shift to overnight sleep, which was attributed to the resolution of chronic cough symptoms associated with the prone or recumbent position. By June 17, D was sleeping well and airway mucus continued to improve, which was an outcome attributed to the resolution of the patient's pulmonary congestion mediated by mucin formulation II treatment. By June 19, D reported continued improvement with continuous overnight sleep. By June 20, D reported expectorant effects, with airway mucus being thinner, easier to expectorate throughout the day, the mucus changing from light green to transparent, even during the worst part of the "28-day drug holiday" portion of the nebulized antibiotic treatment cycle (the last two weeks of the cycle, during which D typically experiences a change in airway mucus to dark green). D reported decreased chest tightness, productive cough, and was able to sleep flat overnight. D has slept overnight since the first day of taking mucin formulation II, June 12. Regardless of sleep position or inclination, this is an unexpected result compared to a persistent, chronic history of sleep lasting no more than 2 - 3 hours each time before waking due to coughing. After years of intermittent sleep in a recliner chair, this is a significant and persistent change.

[0102] On June 30, D continued treatment and was switched to mucin formulation II with added guaiol and fenugreek oil, designated as mucin formulation II + . By July 3, D reported continued significant improvement in airway mucus dysfunction, with less coughing, more productive cough, and less mucus. The improvement included a decrease in the frequency, duration, and intensity of coughing, and the cough was more productive, but overall there was less mucus to manage. At this time, patient D was two weeks into the "drug" portion of the 28-day medication, i.e., the 28-day drug holiday cycle of the antibiotic. The mucus was white and occasionally yellow. Typically, at this point in the antibiotic cycle, the mucus is yellow to light yellow (never transparent / white). D continued to sleep overnight. By July 10, at the start of the fourth week of the "drug" portion of the antibiotic cycle, improvement continued and D reported being able to sleep supine for the first time in years, with the mucus being white (no yellow) and less mucus. Expectorant effects were noted, with the mucus being more mobile even compared to the previous week.

[0103] This example demonstrates the effective treatment of airway mucus dysfunction with an orally administered camphene cyclodextrin preparation, including preparations further containing guaiol and fenugreek oil.

[0104] Example 5: Viral pneumonia, mucolytic activity

[0105] A composition for oral administration in the form of capsules is provided, comprising a combination of the following CD inclusions:

[0106] Eucalyptus (Myrtaceae) extract, eucalyptol standardized to 6 mg (in the βCD inclusion complex);

[0107] Pinus massoniana Lamb. extract, standardized to 6 mg camphene (in β-CD clathrate);

[0108] Peppermint (Piperita officinalis) oil 6 mg (in β-CD clathrate);

[0109] Pinus L. (Pinus pinaster Ait. and / or Pinus elliottii Engelm. and / or Pinus sylvestris L.) extract, standardized to 4 mg δ3-carene (β-CD or γ-CD inclusion);

[0110] Trigonella foenum-graecum L. extract (Trigonella foenum-graecum L. absolute) 4 mg (in γ-CD clathrate);

[0111] Bulnesia sarmientoi extract, standardized to 4 mg guaiol (in γ-CD clathrate);

[0112] K250 sustained release agent 80 mg;

[0113] Amylase 7 mg; and

[0114] Calcium laurate 5 mg.

[0115] Adult male patients diagnosed with viral infections, showing dry mouth, dry cough to vomiting. The patients started treatment with 4 capsules of the above preparation twice a day for 2 days. The patients' cough became productive, and the preparation had an obvious mucolytic effect, resulting in an improvement in the patients' sense of health.

[0116] Example 6: Erection effect

[0117] Male subject A started the administration of the dose of Mucus Formula I, 3 capsules twice a day. Within 48 hours, the exercise respiration was significantly improved and the respiratory mucus was significantly reduced. Within 48 hours of the initial dose administration of Mucus Formula I, the subject noticed the occurrence of nocturnal penile tumescence, which had not been experienced by the 67-year-old subject for some time. The subject increased the dose of Mucus Formula I to 4 capsules twice a day, and the effect of nocturnal penile tumescence immediately occurred, and the sensitivity to daytime and nocturnal erection stimuli was significantly enhanced. The subject measured that the erection effect was equivalent to 70 - 85% of the effect of 25 - 50 mg dose of sildenafil. The subject also found that when using the dose of Mucus Formula I of 4 capsules twice a day, a 5 mg dose of sildenafil actually achieved the same erection enhancement as the previous dose administration of 25 - 50 mg of sildenafil, and there were no side effects (which may (for example) include headache, flushing, abdominal pain, abnormal vision, nasal congestion or runny nose, back pain, muscle pain, and nausea) experienced with the previous use of 25 - 50 mg of sildenafil.

Claims

1. A cyclodextrin (CD) inclusion complex preparation, comprising: eucalyptol β-CD inclusion complex; camphene β-CD inclusion complex; carene δ3 β-CD inclusion complex; guaiol γ-CD inclusion complex; peppermint oil β-CD inclusion complex; fenugreek extract γ-CD inclusion complex; and cyclodextrin degrading enzyme, optionally further comprising humulene.

2. The CD inclusion complex preparation according to claim 1, comprising: eucalyptol (5-15 wt%) in the eucalyptol β-CD inclusion complex (optionally in an amount of 50-100 mg); camphene (5-15 wt%) in the camphene β-CD inclusion complex (optionally in an amount of 50-100 mg); carene δ3 (5-15 wt%) in the carene δ3 β-CD inclusion complex (optionally in an amount of 25-75 mg); guaiol (5-15 wt%) in the guaiol γ-CD inclusion complex (optionally in an amount of 25-75 mg); peppermint oil (10-20 wt%) in the peppermint oil β-CD inclusion complex (optionally in an amount of 25-75 mg); fenugreek extract (optionally, oil) (5-15 wt%) in the fenugreek γ-CD inclusion complex (optionally in an amount of 25-75 mg).

3. The CD inclusion complex preparation according to claim 1 or 2, comprising: eucalyptol (10 wt%) in the eucalyptol β-CD inclusion complex; camphene (10 wt%) in the camphene β-CD inclusion complex; carene δ3 (10 wt%) in the carene δ3 β-CD inclusion complex; guaiol (10 wt%) in the guaiol γ-CD inclusion complex; peppermint oil (15 wt%) in the peppermint oil β-CD inclusion complex; and fenugreek extract (optionally, oil) (10 wt%) in the fenugreek γ-CD inclusion complex.

4. The CD inclusion complex preparation according to any one of claims 1 to 3, comprising a certain proportion of active ingredients, the proportion being substantially equivalent to the proportion of active ingredients in a preparation comprising the following active ingredients: eucalyptol (10 wt%) in an amount of 50-100 mg in the eucalyptol β-CD inclusion complex; camphene (5-15 wt%) in an amount of 50-100 mg in the camphene β-CD inclusion complex; carene δ3 (5-15 wt%) in an amount of 25-75 mg in the carene δ3 β-CD inclusion complex; guaiol (5-15 wt%) in an amount of 25-75 mg in the guaiol γ-CD inclusion complex; peppermint oil (10-20 wt%) in an amount of 25-75 mg in the peppermint oil β-CD inclusion complex; and fenugreek extract (optionally, oil) (5-15 wt%) in an amount of 25-75 mg in the fenugreek γ-CD inclusion complex.

5. The CD inclusion complex preparation according to any one of claims 1 to 4, further comprising a sustained release agent.

6. The CD inclusion complex according to claim 5, wherein the sustained release agent is K250.

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

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

9. The CD inclusion complex according to claim 8, wherein the pharmaceutically acceptable carrier is calcium laurate.

10. The CD inclusion complex preparation according to any one of claims 1 to 9, comprising: cineole (10 wt%) 75 mg in cineole β-CD inclusion complex; camphene (10 wt%) 75 mg in camphene β-CD inclusion complex; δ3-carene (10 wt%) 50 mg in δ3-carene β-CD inclusion complex; guaiol (10 wt%) 50 mg in guaiol γ-CD inclusion complex; peppermint oil (15 wt%) 50 mg in peppermint oil β-CD inclusion complex; trigonella net (oil) (10 wt%) 50 mg in trigonella γ-CD inclusion complex.

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