COMPOUND AND METHOD FOR REDUCING INFLAMMATION, PAIN, ALLERGY, FLU AND COLD SYMPTOMS
20180271924 ยท 2018-09-27
Inventors
Cpc classification
A61P1/04
HUMAN NECESSITIES
A61K47/46
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61K9/0053
HUMAN NECESSITIES
A61K9/0014
HUMAN NECESSITIES
International classification
A61K36/24
HUMAN NECESSITIES
A61K9/00
HUMAN NECESSITIES
A61P29/00
HUMAN NECESSITIES
A61P1/04
HUMAN NECESSITIES
Abstract
The present invention relates to pharmaceutical and nutraceutical compounds and methods for reducing inflammation, blood sugar, gastric acid, symptoms of allergy, common cold and flu, as well as treating infections and pain associated with trauma, medical procedure, and diseases and disorders in subjects in need thereof. The compounds and methods proposed by this invention are related to essentially a mixture of naturally accruing and/or synthetic substances in certain ratios, administration protocols, and delivery systems that amplify their medicinal qualities and reduce side effects, making their clinical application feasible.
Claims
1. A method for reducing inflammation and pain in subjects in need thereof, the method comprises of administering to the subject at least once in 24 hours at least 1.5 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound, comprising of an extract of Picralima nitida plant and at least one pharmacologically inactive substance; and where said extract contains at least one of not less than 0.02% of akuammine or not less than 0.02% of dihydroakuammine, or not less than 0.001% of vincamajoridine, or not less than 0.001% of akuammidine or not less than 0.001% of pseudoakuammigine, or not less than 0.001% of akuammicine.
2. A method for reducing symptoms associated with an upper respiratory tract infection (common cold), a seasonal allergy reaction, or an acute respiratory illness (flu) of viral or bacterial origin in subjects in need thereof, the method comprises of administering to the subject at least once in 24 hours at least 0.5 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound, comprising of at least 5% of an extract of Picralima nitida plant and at least one pharmacologically inactive substance.
3. A method for producing antitussive, expectorant, and bronchodilating effects in subjects in need thereof, the method comprises of administering to the subject at least once in 24 hours at least 1.5 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound, comprising of an extract of Picralima nitida plant and at least one pharmacologically inactive substance; and where said extract contains at least one of not less than 0.02% of akuammine or not less than 0.02% of dihydroakuammine, or not less than 0.001% of vincamajoridine, or not less than 0.001% of akuammidine, or not less than 0.001% of pseudoakuammigine, or not less than 0.001% of akuammicine or not less than 0.001% of psychotridine; and where said compound contains at least a trace amount of saponins.
4. A method for reducing dermatophytosis and dermatomycosis in subjects in need thereof the method comprises of topically administering to the subject at least once in 24 hours at least 1.5 mg of compound in 24 hours, containing at least 3% of crude extract of Picralima nitida plant, and where said compound contains at least one pharmacologically inactive substance and a humectant.
5. A method for reducing phytosis and mycosis of at least of the following types: superficial, cutaneous, subcutaneous systemic due to primary pathogens, and subcutaneous systemic due to opportunistic pathogens in subjects in need thereof, the method comprises of administering orally or by injection to the subject at least once in 24 hours at least 3 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours, a compound containing at least 5% of Picralima nitida plant extract, and where said compound contains at least one pharmacologically inactive substance.
6. A method for reducing obesity and body weight in subjects in need thereof the method comprises of administering to the subject at least once in 24 hours at least 1.5 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound comprising of an extract of Picralima nitida plant and at least one pharmacologically inactive substance; and where said extract contains at least 0.001% of akuammine or vincamajoridine.
7. A method for symptomatic treatment of diabetes in subjects in need thereof the method comprises of administering to the subject at least once in 24 hours at least 0.8 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound, comprising of at least one pharmacologically inactive substance, and at least 5% of a glycosides extract of Picralima nitida plant or an alkaloid extract of Picralima nitida plant.
8. A method for reducing gastritis, acid overproduction, acid reflux, and peptic ulcers in subjects in need thereof the method comprises of administering to the subject at least once in 24 hours at least 0.5 mg by dry mass per one kg of body weight in 24 hours, but not more than 16,000 mg by dry mass per one kg of body weight in 24 hours of a compound comprising of at least 3% extract of Picralima nitida plant and where said compound contains at least one pharmacologically inactive substance.
9. A compound for reducing symptoms associated with an upper respiratory tract infection (common cold), a seasonal allergy reaction, or an acute respiratory illness (flu) of viral or bacterial origin in subjects in need thereof, comprising of an extract of Picralima nitida plant and at least one pharmacologically inactive substance; and where said extract contains at least one of not less than 0.001% of akuammine, dihydroakuammine, akuammidine, pseudoakuammigine, akuammicine, vincamajoridine alkaloids; and where said compound contains at least a trace amount of one or more other plurality of alkaloids.
10. A compound for at least one of reducing inflammation and pain; reducing symptoms associated with an upper respiratory tract infection (common cold), a seasonal allergy reaction, or an acute respiratory illness (flu) of viral or bacterial origin; producing antitussive, expectorant, and bronchodilating effects; reducing dermatophytosis and dermatomycosis; reducing phytosis and mycosis of at least of the following types: superficial, cutaneous, subcutaneous systemic due to primary pathogens, and subcutaneous systemic due to opportunistic pathogens; reduction of obesity and body weight; producing hypoglycemic effect; reducing gastritis, acid overproduction, acid reflux, and peptic ulcers in subjects in need thereof, comprising of an extract of Picralima nitida plant and at least one pharmacologically inactive substance; and where said compound contains at least 0.001% of total compound of at least one of Mitragyna speciose extract, Cannabis sativa extract, Psychotria species plant extract.
11. A compound for at least one of reducing inflammation and pain; reducing symptoms associated with an upper respiratory tract infection (common cold), a seasonal allergy reaction, or an acute respiratory illness (flu) of viral or bacterial origin; producing antitussive, expectorant, and bronchodilating effects; reducing dermatophytosis and dermatomycosis; reducing phytosis and mycosis of at least of the following types: superficial, cutaneous, subcutaneous systemic due to primary pathogens, and subcutaneous systemic due to opportunistic pathogens; reduction of obesity and body weight; producing hypoglycemic effect; reducing gastritis, acid overproduction, acid reflux, and peptic ulcers in subjects in need thereof, comprising of at least one pharmacologically inactive substance; and at least 0.001% of total compound a natural or synthetic or semi-synthetic at least one of akuammine, dihydroakuammine, akuammidine, pseudoakuammine, akuammicine, akuammigine, pseudoakuammigine, akuammiline and akuammenine, picraphylline, picracine, picraline, picralicine, picratidine, picranitine, burnamine, pericalline and pericineby, reserpinine, majoridine, vincamajoridine, vincamine, vincamajine, perivincine, pubescine, vinine, vincawajine, majorinine, 10-methoxyvinorineor; and where said compound contains at least 0.01% of total compound a natural or synthetic or semi-synthetic at least one of indole monoterpene-type alkaloid, pyrrolidinoindoline-type alkaloid, mitragynine, pseudoindoxyl, 7-hydroxymitragynine.
12. The compound of claim 9, where said compound is for at least one of reducing inflammation and pain; producing antitussive, expectorant, and bronchodilating effects; reducing dermatophytosis and dermatomycosis; reducing phytosis and mycosis of at least of the following types: superficial; cutaneous, subcutaneous systemic due to primary pathogens, and subcutaneous systemic due to opportunistic pathogens; reducing obesity and body weight; producing hypoglycemic effect; reducing gastritis, acid overproduction, acid reflux, and peptic ulcers in subjects in need thereof.
13. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said pharmacologically inactive substance is at least one of a medically acceptable carrier, a skin penetration enhancer, an absorption enhancer, a stabilizer, a solvent, pharmaceutically acceptable fixed oil, a lipid carrier, a polymer, a stabilizing agent, a disintegrant, a lubricant, a diluent, an adjuvant, an emulsifier, a preservative, a colorant, a flavor imparting agent, an acid, a Tris base, sodium carbonate, or a combination thereof.
14. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is administered in a sustained release, or extended release, or a combined sustained release and extended release dosage forms, or in an immediate release dosage forms, or a combined sustained release and immediate release dosage forms, or a combination thereof.
15. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is administered by a route selected from the group consisting of oral, intranasal, inhalation, transdermal, topical, rectal, vaginal, buccal, injection, sublingual, or combination thereof.
16. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is administered in a dosage form selected from the group consisting of a tablet, a liquid dosage form, a hard gelatin capsule, a soft gelatin capsule, an HPMC capsule, an inhalant, an injectable, a transdermal, a buccal, a sublingual, and a rectal or a vaginal suppository, a skin cleanser, a skin toner, a skin moisturizer, a topical skin mask, a topical skin composition.
17. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is administered in combination and/or includes one or more other medications, dietary supplements or food products.
18. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is used for treating of at least one of upper respiratory tract infection (common cold) or an acute respiratory illness (flu) of viral or bacterial origin, acid refluxing, phytosis and mycosis, gastric and duodenal ulcers, Huntington's Disease; Wilson's Disease; Parkinson's Disease; chronic cough; cough associated with Asthma, allergic reaction, respiratory disease, gastro-oesophageal reflux disease (GORD) and post nasal drip syndrome (PNDS); obesity and body weight reduction; diabetes; metabolic and endocrine diseases and disorders; autoimmune system responses (allergic reactions), athetosis-related to damage or degeneration of basal ganglia; gastritis; acid overproduction; acid reflux; peptic ulcers; minor tranquilizers, alcohol, cocaine, (meta)amphetamine, and opioid withdrawal syndromes; symptoms or side effects associated with anti-retroviral therapy, chemotherapy and radiation therapy; AIDS; rheumatoid arthritis; osteoarthritis; fibromyalgia; pain and spasticity symptoms associated with Multiple Sclerosis, Neuromuscular Junction Disorder, autoimmune diseases and disorders, motor neuron diseases and disorders, neurodegenerative diseases and disorders; pain associated with cancer; trauma; athletic performance; migraine; surgical intervention or medical treatment; stroke; heart attack; dental and gum pain; abdominal pain; bone pain, muscle pain; neurological pain; stomach ulcers-related pain; gallbladder disease-related pain; Central Pain Syndrome (CPS); sports trauma; chronic pain disorder (nociceptive pain, neuropathic pain, chronic back or leg pain, painful neuropathies, Complex Regional Pain Syndrome), and acute pain.
19. The method and compound of claims 1, 3, 6, 7, 9 and 11, where said akuammine, dihydroakuammine, akuammidine, pseudoakuammine, akuammicine, akuammigine, pseudoakuammigine, akuammiline and akuammenine, picraphylline, picracine, picraline, picralicine, picratidine, picranitine, burnamine, pericalline and pericineby, reserpinine, majoridine, vincamajoridine, vincamine, vincamajine, perivincine, pubescine, vinine, vincawajine, majorinine, 10-methoxyvinorineor, indole monoterpene-type alkaloids, pyrrolidinoindoline-type alkaloids, mitragynine, pseudoindoxyl, 7-hydroxymitragynine alkaloids are one or more of (i) natural substance that has been purified or modified; (ii) synthetically derived substance, not extracted from a plant; (iii) semi-synthetic substance; (iv) esterified substance; (v) active metabolites of any of the foregoing, (vi) pro-drugs of any of the foregoing; (vii) analogs of any of the foregoing; (viii) derivatives of any of the foregoing; (ix) and mixtures thereof.
20. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, where said extract of Picralima nitida plant is the extract of Vinca major plant.
21. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, where said extract is obtained from any part of the plant by distillation, or solvent extraction, or maceration, or enfleurage, or cold-press extraction, or fractioning, or a combination thereof.
22. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is dispersed in an inert water-soluble carrier at solid (solid dispersion) or liquid state and/or incorporated into a lipid carrier.
23. The method and compound of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, where said compound is an ingestible preparation, where the pharmacologically inactive substance is a food product or a food additive.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0091] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate aspects of the present teachings and together with the description, serve to explain principles of the present teachings.
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DESCRIPTION OF EMBODIMENTS
[0108] Reference will now be made to embodiments, examples of which are illustrated in the accompanying material. In the following description, some details are set forth in order to provide understanding of the proposed invention. However, it will be apparent to one of ordinary skill in the art that the present invention may be practiced without these details. In other instances, well-known methods, procedures, components, circuits, and networks have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.
[0109] It will also be understood that, although the terms first, second, etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first contact could be termed a second contact, and, similarly, a second contact could be termed a first contact, without departing from the scope of the present invention. The first contact and the second contact are both contacts, but they are not the same contact.
[0110] The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms a, an, and the are intended to include the plural forms as well, unless the context clearly indicates otherwise. Moreover, the term or is intended to mean an inclusive or rather than an exclusive or. That is, unless specified otherwise, or clear from the context, the phrase X employs A or B is intended to mean any of the natural inclusive permutations. It will also be understood that the term and/or as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms comprises and/or comprising, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
[0111] As used herein, the term if may be construed to mean when or upon or in response to determining or in response to detecting, depending on the context. Similarly, the phrase if it is determined or if is detected may be construed to mean upon determining or in response to determining or upon detecting (the stated condition or event) or in response to detecting (the stated condition or event), depending on the context.
[0112] As used herein, the terms related, in connection, or associated, or relevant, and similar, depending on the context, means any association, whether direct or indirect, by any applicable criteria as the case may be.
[0113] The word exemplary is used herein to mean serving as an example, instance, or illustration. And no aspect of this disclosure shall be construed as preferred or advantageous over other aspects or designs unless expressly stated.
[0114] The term cannabinoid(s) represents cannabinoid receptor agonists and a group of C21 terpenophenolic compounds found in Cannabis sativa L, as well as synthetic or semisynthetic cannabinoids, for instance, without limitation: nabilone, dexanabinol, ajulemic acid; and cannabinoid receptor ligands that are chemically different endocannabinoids, for instance, without limitation: anandamide; 2-arachidonoylglycerol; and other phytocannabinoids; levonantradol; CP 47,497; (C6)-CP 47,497; (C8)-CP 47,497; (C9)-CP 47,497; CP 50,556-1; CP 55,244; CP 55,940; CP-945,598; HHC; O-1871; AMG-36; AMG-41; AM-694; AM-906; AM-1235; AM-2232; AM-2233; AM-2389 O-1812; THJ-2201; JWH-018 and others.
[0115] The compounds used in the method of the present invention may be in a salt form. As used herein, a salt is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols; alkali or organic salts of acidic residues such as carboxylic acids. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali metal salts, sodium, potassium or lithium.
[0116] As used herein, treating means preventing, slowing, halting, or reversing the progression of a disease or infection. Treating may also mean improving or attempting to improve one or more symptoms of a disease or infection
[0117] As used herein, trace amount means as practiced in analytical chemistryaverage concentration is less than 100 parts per million (ppm) measured in atomic count or less than 100 micrograms per gram.
[0118] As used herein, extract in reference of amounts or proportions is contemplated to be a dried organic layer in solid state with solvents and water not present beyond a trace amount unless explicitly specified otherwise.
[0119] As used herein, a pharmacologically inactive substance means a chemical substance which does not significantly increase or affect the therapeutic action of the active ingredient.
[0120] The term subject or patient refers to a mammal in need of treatment or undergoing treatment using the inventive compounds described herein. Mammalian subjects include without limitation humans, dog, cat, horse or any other animal in need of treatment.
[0121] As used herein, the percent by mass of a mixture is obtained by dividing the mass of each component by the total mass and multiply by 100 (Percent by mass=mass of component/total mass100%). For example, a mixture that contains 1.203 g CaCO.sub.3 and 1.797 g NaCl is equal to CaCO.sub.3=40.10% and NaCl=59.90%.
[0122] The compounds used in the method of the present invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
[0123] As used herein, a acceptable carrier is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.
[0124] The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
[0125] The present invention provides a number of pharmaceutical compounds that represent a stable, fast-acting formulations of naturally occurring substances or their analogs (for the purpose of this document, may be used interchangeably). An analog herein refers to a compound that is derived by chemical, biological, genetic or synthetic transformation of the naturally occurring substances of Picralima nitida, Mitragyna speciose, Cannabis sativa and Psychotria species plants. The plant extract, referred herein, unless otherwise specified, means an extract from any part of the plant.
[0126] The natural alkaloid and other substances are readily obtained from plant tissue by suspending the tissue in an appropriate solvent to extract alkaloid compounds and other tissue components. Analytical purification of such an extract provides pharmaceutical grade alkaloid compounds and other substances. It was reported, for example, that the most abundant opioid alkaloid in the crude extract of Picralima nitida is akuammine at 0.56% of dry mass of the total crude extract, which was isolated and partially characterized in the 1920s (Menzies, Paterson, Duwiejua, & Corbett, 1998). Akuammidine and akuammigine are found in much smaller amounts, 0.034% and 0.01% dry mass of total crude extract, respectively. And akuammicine with pseudoakuammigine are found at 0.006% dry mass of the total crude extract.
[0127] There are many reports and techniques of Picralima nitida extraction and its constituents' isolation. Menzies et al., (1998) reports that dried and powdered seeds were treated first with n-hexane (extracting mainly terpenoids and some alkaloids), then with ethyl acetate. The ethyl acetate fractions were applied to alumina columns (Al.sub.2O.sub.3, Spence type H) from which the alkaloids were isolated by elution in n-hexane:ethyl acetate (1:1). The identities and purities of the dried, isolated alkaloids were confirmed by H-Nuclear Magnetic Resonance spectroscopy. Using this method each alkaloid sample was shown to have purity 98% (Menzies, Paterson, Duwiejua, & Corbett, 1998).
[0128] Koffi et al., (2014) reports preparation of plant extract in the laboratory, where one thousand grams of the fresh seeds of Picralima nitida were rinsed then introduced in 4 liters of distilled water. The mixture was boiled for 45 minutes, then it was wrung in a cloth square, filtered successively twice on absorbent cotton and on Wattman 3 mm paper. The volume of the filtrate obtained was concentrated with Rotavapor and evaporated in a drying oven at 60 C. for 2 days. The pulverized crystals made it possible to obtain a fine powder (41 g) used for the experimentation (Koffi, Emma, & Stephan, 2014).
[0129] Another extraction performed by Igwe et al., (2014) involved extracting with 2 liters of ethanol 3 times for 8 hours at 30 C. 500 g of the powdered Picralima nitida plant leaves. The extract was concentrated under reduced pressure and the supernatant leaf (7.35 g) extract was decanted after complete removal of the solvent. The extract was centrifuged at 10,000 rpm for 20 minutes and the clear supernatant extract was subjected to systematic GC-MS analysis. The components of the ethanolic extract of leaves were identified by matching the peaks with Wiley MS libraries and they were confirmed by comparing mass spectra of the peaks and those from the literature (Igwe & Mgbemena, 2014).
[0130] Another extraction and purification were performed by Tane et al., (2002) where dried powdered seeds of Picralima nitida (2.0 kg) were extracted sequentially with ethanol, and the extract obtained was concentrated under vacuum to yield 97 g of residue. This extract was triturated with 0.1 N HCl and the combined acidic solution was exhaustively partitioned with CH.sub.2Cl.sub.2 to give 17 g of CH.sub.2Cl.sub.2 extract. The aqueous layer was adjusted to pH 9 with a solution of 10% NH.sub.3 and the precipitate was filtered to obtain alkaloids that were dissolved in CH.sub.2Cl.sub.2 and washed several times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated to give 54 g of alkaloid. It was then subjected to chromatographic separation over a column of Al.sub.2O.sub.3. Elution was performed with a mixture of hexane-ethyl acetate with increasing polarity. Fractions of 250 mL were collected and monitored by TLC with appropriate solvent system to give three main portions. The portion eluted with hexane/ethyl acetate (7/3) contained a mixture of picratidine and pseudoakuammine purified by a second column chromatography followed by recrystallization. Akuammicine, which was the main constituent of fractions collected with hexane/ethyl acetate (6/4), was purified by recrystallization to give 33 mg of the product. Portions collected with 50% and 70% of ethyl acetate in hexane contained picranitine, akuammine and akuammidine were regrouped and subjected to column chromatography and pure product obtained by fractional recrystallization to yield 60 mg of picranitine, 23 mg of akuammine and 70 mg of akuammidine (Tane, Tene, & Sterner, 2002).
[0131] Another extraction and purification was performed by Ubulom et al., (2012) where Picralima nitida leaves were first air-dried on laboratory tables at room temperature (28+2 C.). This was followed by pulverization using the crusher machine, where 500 g of the pulverized leaves were macerated separately in distilled water and 50% ethanol for 72 hours, with periodic stirring. Each extract was filtered repeatedly using muslin cloth, non-absorbent cotton wool and Whatman No. 1 filter paper. This was done to get rid of the marc. The aqueous filtrate was concentrated using a lyophiliser, while the ethanolic filtrate was first concentrated in vacuo at 40 C. using a rotary evaporator, after which it was freeze-dried using the lyophiliser (Ubulom, Imandeh, Udobi, & IIya, 2012).
[0132] Another extraction and purification were performed by Erharuyi et al., (2012) where the preparation of extract involved the following: Powdered plant material (3.2 kg) was extracted with 14 liters of methanol by maceration at room temperature for two weeks. The extract was concentrated to dryness using a rotary evaporator at reduced pressure. The concentrated extract was weighed and stored in an air-tight container and kept in the refrigerator at 4 C. The fractionation of extract was performed as follows: The crude methanol extract was subjected to prefractionation/partitioning using different solvents. The crude extract (230 g) was first defatted with 7.5 liters of petroleum ether; the ether insoluble portion was extracted with 16 liters of chloroform followed by 7.5 liters of ethyl acetate. The various fractions were concentrated to dryness, weighed and kept at 4 C. in an air-tight container (Erharuyi & Falodun, 2012).
[0133] Another extraction and purification were performed by Dapaah et al., (2016) where the pods of Picralima nitida were opened, and the seeds removed, air-dried, and milled into powder. A 3 kg quantity of the powder was extracted with 70% ethanol by cold maceration over a 72 hours period. The extract obtained was concentrated at 40 C. and under low pressure using a rotary evaporator to a syrupy mass. The syrupy mass obtained was then dried in a hot air oven maintained at 40 C. to obtain 0.389 kg (yield: 12.9%) of a solid mass of Picralima nitida extract (PNE) (Dapaah, Koffuor, Mante, & Ben, 2016).
[0134] Phytochemical tests were performed on PNE by Dapaah et al., (2016) to determine the presence of tannins, saponins, glycosides, alkaloids, flavonoids, steroids and terpenoids. The following procedures were used. Glycosides were tested as follows: About 200 mg of PNE was warmed with 5 ml dilute H.sub.2SO.sub.4 on a water bath for 2 minutes. It was then cooled and filtered. The filtrate was made alkaline with 2 to 5 drops of 20% NaOH and 1 ml each of Fehlings solution A and B was then added to the filtrate and heated on the water bath for 2 minutes and observed for the appearance of a brick-red precipitate. Saponins were tested as follows: An amount of 0.2 g of PNE was shaken with few milliliters of water and the mixture observed for the presence of a froth which does not readily break upon standing. Tannins were tested as follows: About 0.5 g of PNE was boiled with 25 ml of water for 5 minutes. It was then cooled, filtered and the volume of the filtrate adjusted to 25 ml with water. To 1 ml of the filtrate, 10 ml of water and 5 drops of 1% lead acetate was added. The color and amount of precipitate, if any, was noted and recorded. The procedure was repeated using 5 drops of 1% ferric chloride. Terpenoids were tested as follows: An amount of 0.5 g of PNE was extracted with 2 ml of chloroform in a test tube followed by addition of 1 ml of concentrated sulfuric acid. The presence of terpenoids was identified by appearance of a reddish-brown coloration at the interface. Steroids were tested as follows: About 0.5 g PNE was extracted with 2 ml of chloroform in a test tube followed by addition of acetic anhydride. Concentrated sulfuric acid was added to the walls of the test tube. Appearance of a blue color at the interface indicates the presence of steroids. Flavonoids were tested as follows: About 0.5 g of PNE was extracted with 2 ml of chloroform in a test tube and 2 ml of methanol added to dissolve it. Concentrated hydrochloric acid was then added together with four pieces of magnesium ribbons. A reddish or pink color indicates the presence of flavonoids. Anthraquinones were tested as follows: About 0.5 g of PNE was each extracted separately with 10 ml of benzene and filtered. About 5 ml of 10% ammonia was added to the filtrate and shaken. A reddish or pink coloration is a positive test for anthraquinones. Alkaloids were tested as follows: About 0.5 g of PNE was boiled with 10 ml of dilute HCl in a test tube for 5 minutes. The supernatant was filtered and 3 drops of Dragendorff s reagent (potassium bismuth iodide solution) added to 1 ml of the filtrate in the test tube. The mixture was then shaken and observed for the appearance of an orange-red precipitate (Dapaah, Koffuor, Mante, & Ben, 2016).
[0135] Singh et al., (2017) reports preparation of Vinca major plant extract, where the 5 g of shade dried flowers were grounded, suspended in 100 ml petroleum ether and extracted overnight. Next day, petroleum ether layer was collected and evaporated at 37 C. to yield the ether fraction (31 mg; 0.62% percent extractive). Remaining residue was then extracted overnight with 100 ml benzene and fraction was collected by evaporation (34 mg; 0.68% percent extractive). Likewise, chloroform, acetone, methanol and water extracts were also obtained. The process resulted in completely dried 59 mg chloroform extract (1.18% percent extractive), 42 mg acetone extract (0.84% percent extractive), 88 mg methanol extract (1.76% percent extractive) and 107 mg aqueous extract (2.14%) from the Vinca major flowers (Singh, Jarial, & Kanwar, 2013).
[0136] Amador et al., (1996) reports a preparation of Psychotria colorata alkaloid extracts, where the dried milled leaves (515 g) or flowers (64 g) were wetted with 6 N NH.sub.4OH and extracted with ethanol in a Soxhlet apparatus. After distillation of solvent, the crude ethanol extract was poured into a 2% acetic acid solution, left for 12 hours in refrigerator and filtered. The clear acidic solution was extracted with chloroform (residue discarded). The aqueous phase was adjusted to pH 7 with NaHCO.sub.3 pH 7.0 and extracted with chloroform; the organic layer washed, dried (Na.sub.2SO.sub.4) and evaporated. TLC analysis showed a very similar composition for both alkaloid extracts. The HPLC/MS analyses identified a mixture of pyrrolidinoindoline alkaloids (e.g., quadrigemine C, calycanthine, isocalycanthine, among others) (Amador, Elisabetsky, & Onofre de Souza, 1996).
[0137] Another extraction and purification were performed by Both et al., (2002) where 100 g of dried Psychotria umbellata leaves were extracted with EtOH at room temperature 3-times, each for a week. The extract was concentrated under vacuum at 40 C. to a dark green syrup. The syrup was dissolved in HCl 2% (0.51) and partitioned with CH.sub.2Cl.sub.2. The acid solution was alkalinized with NH.sub.4OH 25% until pH=10 and extracted with CH.sub.2Cl.sub.2. From the CH.sub.2Cl.sub.2 extract 954 mg of a colorless amorphous compound was precipitated. Purity of the compound was checked by TLC with silica gel 60 F254 (CHCl.sub.3MeOH/NH.sub.3 vapor85:15RF=0.2) and HPLC (column: NOVAPACK Cis 150 mm3.9 mmWaters; MeOH:H.sub.2O50:50 as eluent and a Photo Diode Array as detector; Rt=2.13 min) (Both, Kerber, Henriques, & Elisabetsky, 2002).
[0138] Chittrakarn, et al. (2010), had performed extraction and isolation of Kratom alkaloids from leaves red vein type Kratom. Air-dried leaves were pulverized by grinding and then macerated, at room temperature, with absolute methanol for 7 days, twice, while stirring 2-3 times/day. The extracts were mixed, filtered and concentrated using a rotary evaporator and then they were freeze-dried. The yield was 7.92% (w/w) (Chittrakarn, Keawpradub, Sawangjaroen, Kansenalak, & Benjamas, 2010). According to Chittrakarn, et al., (2010) the isolation of crude alkaloids from the methanolic extract of Kratom leaves was made by dissolving it in 10% acetic acid solution. This solution was shaken and left overnight. The acidic filtrate was washed with petroleum ether, adjusted to pH 9 with 25% ammonia solution, and then extracted with chloroform. The chloroform extract was washed with distilled water, dried over anhydrous sodium sulfate and evaporated to yield a dry crude alkaloid extract. According to the isolation procedure, Chittrakarn, et al., (2010) report that the yield of crude alkaloid extract was approximately 0.25% based on fresh weight of Mitragyna speciosa. An aliquot (2.5 g) was then subjected to silica gel column chromatography, eluted with 5% methanol in chloroform to obtain a major alkaloid (1.25 g), which appeared as a single spot on TLC analysis (four different solvent systems). Over all, the yield of mitragynine in the methanolic extract was approximately 1.56% (Chittrakarn, Keawpradub, Sawangjaroen, Kansenalak, & Benjamas, 2010).
[0139] It is preferable, in one embodiment, that the extraction/production method yields substantially the mitragynine and 7-hydroxymitragynine that are believed to be the most effective alkaloids for pain management. There are also various other techniques that are known for extracting and isolating mitragynine and 7-hydroxymitragynine from Mitragyna speciosa plant. For example, Pat. No. CN 102,048,857, describes a method for extracting alkaloids from Kratom (CN Patent No. 102,048,857, 2009).
[0140] The natural CB compounds are also readily obtained from plant tissue by suspending the tissue in an appropriate solvent to extract CB compounds and other tissue components. Analytical purification of such an extract provides pharmaceutical grade CB compounds. Alternatively, CB compounds are extracted from plant tissue under supercritical conditions. Solvents used for supercritical extraction of CBs include, for instance: carbon dioxide, or other gases in isolation or combination with or without solvent modifiers, selected from ethanol, propanol, butanol, hexane, chloroform, dichloromethane, acetone, or any organic solvent capable of extracting CBs, and alcohol-water mixtures, such as water-ethanol or water-butanol mixtures, etc.
[0141] The present invention, in one embodiment, involves a formulation containing an extract from Cannabis plant matter with THC, CBD and optionally the carboxylic acids thereof. In one embodiment, the dried plant matter is ground and subjected to a CO2 extraction and the primary extract obtained is separated. Specifically, ground Cannabis plant material is compressed and charged into an extraction vessel. CO2 is then introduced, having been brought to a temperature, in one embodiment, of approximately 60 C. and to a pressure of approximately 250 bars. When the CO2 enters into contact with the material to be extracted, it extracts the desired CB components, in particular comprising 9-THC and CBD, as well as the carboxylic acids thereof. In one embodiment, the extraction method permits extracting various isomers of THC, selectively obtained from industrial hemp and from drug-producing hemp, also separating undesirable waxes and removing the solvent.
[0142] The CBs, including THC, can be isolated from Cannabis plants using extraction methods or can be made synthetically or semi-synthetically. It is preferable, in one embodiment, that the extraction/production method yields substantially the ()-.sup.9-trans-THC isomer that is the most active isomer of THC. There are also various techniques that are known for isolating and separating the ()-.sup.9-trans-THC isomer from other compounds in THC. For example, U.S. Pat. No. 7,449,589 describes methods for purifying the ()-.sup.9-trans-THC isomer from a mixture of other THC isomers (U.S. Pat. No. 7,449,589, 2004).
[0143] Similar to Cannabis sativa, substances can be extracted from Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants under supercritical conditions. Solvents used for supercritical extraction of alkaloids and other substances include without limitation: carbon dioxide, or other gases in isolation or combination with or without solvent modifiers, selected from ethanol, propanol, butanol, hexane, chloroform, dichloromethane, acetone, or any organic solvent capable of extracting such substances, and alcohol-water mixtures, for instance, water-ethanol or water-butanol mixtures, and others.
[0144] It is not the purpose of this disclosure to provide particulars concerning the attainment of a colloidal formulation that is stable under a range of conditions. However, in one embodiment, the disclosed compound with initial purity (HPLC) of akuammine, 7-hydroxymitragynine, and delta-9-THC being at least 98% by area can achieve stability such that at least 95% by area remains in undegraded form after exposure of the compound to the storage conditions for twelve months, where the ambient temperature is between 20 C. and 40 C. and relative humidity is between 55% and 75%.
[0145] In one embodiment, the stability of said compound is attained by contacting a solution containing akuammine, psychollatine, and delta-9-THC into a solvent such as organic solvents, including acetone, acetic acid, alcohols, chloroform, diethyl ether solvents, and other solvents that can be used to dissolve said alkaloids; and in another embodiment, with addition of pharmaceutically acceptable buffers, stabilizers, and other pharmacologically inactive substances.
[0146] In one embodiment, the compound of this invention is present in the form of micelles or liposomes that encapsulate mitragynine, 7-hydroxymitragynine, THC, CBD, and/or other alkaloids within the membrane of the micelles or liposomes. Within the context of the present technology, the term micelle refers to an aggregate of surfactant molecules dispersed in a liquid colloid, while liposome refers to a vesicle composed of a mono or bilayer lipid.
[0147] In yet another embodiment, other drugs, and pharmaceutically acceptable carriers, if present, may be in the lipophilic membrane or entrapped in the aqueous fluid that forms the core of the liposome. The entrapped alkaloids contribute to the stability of the micelle/liposome membranes, such that the micelle/liposomes formulations may be used as an improved, fast, reliable and efficient system for the oral, enteral, parenteral, intravenous or topical delivery of mitragynine, pseudoindoxyl, 7-hydroxymitragynine, delta-9-THC, and/or other alkaloids, and/or additional drugs to subjects in need thereof
[0148] In another embodiment, unilamellar micelles or liposomes that are thermostable at temperatures greater than 50 C. are used in the manufacture of the compound contemplated by this invention. These micelles or liposomes are obtained by contacting a solution of Mitragyna speciosa and Cannabis sativa plants alkaloids with an appropriate solvent. The mixing of said alkaloid solution occurs in a manner suitable for the rapid dissolution of the alkaloid solution. This can be accomplished through a variety of means including dilution, injection through a small orifice under pressure, and ultrasonic atomization.
[0149] And yet in another embodiment, the disclosed compound has advantageous properties, where the micellar and liposomal compound is stable at high temperatures, exceeding 50 C., is stable to sonication, capable of carrying large payloads of Mitragyna speciosa and Cannabis sativa plants alkaloids as well as other drugs suitable for use in combination therapy and can be stored for extended periods of time, for example greater than 20 weeks at 25 C.
[0150] In certain embodiments, said compound can be in the form of a concentrated, stable colloidal suspension that is obtained by infusing a solvent solution containing the Psychotria umbellata and Picralima nitida plants extract or essentially pure alkaloids into a solvent, with or without buffer. Stabilizing agent, for instance, a polymer or compounds selected from cellulose hyaluronic acid, citric acid, Tris base, sodium carbonate, polyvinyl pyrrolidone (PVP), alginate, chondritin sulfate, poly gamma glutamic acid, gelatin, chitisin, chitosan, corn starch and flour can be used to stabilize the micelle formulations.
[0151] In one embodiment, said compound also exhibits superior systemic delivery and release of Mitragyna speciosa and Cannabis sativa plants alkaloids from the micelle or liposomes used in the manufacture of the contemplated compound. The release of alkaloids from a liposome or micelle of the contemplated compound can be modulated by changing the ratio of the concentration of lipid to the concentration of alkaloids present in the liposome.
[0152] In one embodiment, tissue specific delivery can be achieved by modifying the surface of the liposomes or micelles with compounds that bind specifically to biological macromolecules expressed on cellular surfaces. For instance, the micelle or liposomal surface can be derivatized to display an antibody specific to an antigen expressed on the affected cells.
[0153] According to one embodiment, said compound that is used in the treatment of a disease condition or other therapy is administered to a patient or subject in need of treatment either alone or in combination with other compounds/drugs having similar or different biological activities. For example, said compound may be administered in a combination therapy, i.e., either simultaneously in single or separate dosage forms or in separate dosage forms within hours or days of each other. Examples of compounds/drugs used in such combination therapies include without limitation: chemotherapeutic agents, immunosuppressive agents, immunostimulatory, anti-pyretic, cytokines, opioids, cannabinoids, cytokines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, pro-drug activating enzymes, which may be naturally occurring or produced by recombinant methods, anti-inflammatory agents, antibiotics, protease inhibitors, growth factors, osteo-inductive factors and the like.
[0154] In some embodiments, the compound further contains, in accordance with accepted practices of pharmaceutical compounding, one or more pharmaceutically acceptable excipients, including without limitation: diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents. As stated above, said compounds may contain Cannabis sativa plants alkaloids, their analogs (such as: levonantradol; CP 47,497; (C6)-CP 47,497; (C8)-CP 47,497; (C9)-CP 47,497; CP 50,556-1; CP 55,244; CP 55,940; CP-945,598; HHC; O-1871; AMG-36; AMG-41; AM-694; AM-906; AM-1235; AM-2232; AM-2233; AM-2389 O-1812; THJ-2201; JWH-018 and other cannabinoid receptor agonists), and co-extraction substances, and may be consumed directly or formulated into nutraceutical or pharmaceutically acceptable compounds suitable for oral, enteral, parenteral, intravenous or topical administration.
[0155] The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Dosage forms for oral administration include food, beverages, drinks, soups, baked goods, syrups, oral pharmaceutical compounds, nutraceutical formulations, and the like. Suitable pharmaceutical carriers include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, polymer or the like, which does not significantly interact with other components of the formulations in a deleterious manner.
[0156] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants extracts, the liquid dosage forms can contain inert diluents commonly used in the art. For instance, liquid formulations can contain water, alcohol, polyethylene glycol ethers, and any other pharmaceutically acceptable solvents. Solubilizing agents and emulsifiers such as, without limitation: ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan and mixtures thereof may also be present in said compound.
[0157] Additionally, oral compound of the proposed invention can include, without limitation, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. When formulated as a suspension, said compound may contain the Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants extracts and suspending agents, for example, without limitation: ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof
[0158] In one embodiment, the emulsifier may comprise a mixture of monoglyceride and diglyceride at a total concentration of 1% to 99% w/w and a carrageenan or mixture of carrageenans at a total concentration of 0.01% to 10% w/w. In another embodiment, the emulsifier may be present in a concentration range of 1% to 99%, 5% to 80%, 10% to 35%, 10% to 20%, or about 15%-25%% w/w.
[0159] Solid dosage forms suitable for oral administration include, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants extracts can be used alone or in combination with one or more drugs that are mixed with at least one pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants such as glycerol; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as, for example, acetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, the dosage form can also comprise buffering agents, such as acetic acid and Tris base.
[0160] Micellular or liposomal suspensions can be encapsulated with a variety of polymers, sugars, and chelating agents, to yield stable solid preparation. Encapsulation can take the form of cross linked polymers, trapping of the micells or liposomes within a non-crosslinked polymer network, or dispersed within the crystalline structure of sugar starches or protein molecules. These granules can be further processed to yield sublingual films, suppositories, dispersible powder, tablets, gel capsules, etc.
[0161] Solid dosages in the form of tablets, capsules, pills, and granules can be coated using compounds that accelerate or decrease the release of alkaloids. For instance, the proposed invention also encompasses solid dosage forms having enteric coatings, extended-release coatings, sustained-release coatings, delayed release coatings and immediate-release coatings. Methods used to coat solid dosage forms as well as the materials used to manufacture such coatings are well known in the pharmaceutical formulary art. The solid dosage forms can optionally contain opacity enhancing agents. According to one embodiment, the solid dosage form comprises an enteric coating that permits the release of Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants extracts and/or their respective alkaloids, at a specific location within the gastrointestinal tract, optionally, in a delayed manner. Exemplary of such coating materials include glyceryl monostearate or glyceryl distearate may be employed, polymeric substances and waxes. The compound contemplated by this invention, alone or in combination with one or more drugs, can also be in micro-encapsulated foam, if appropriate, with one or more of the above-mentioned or other excipients.
[0162] In one embodiment, said compound is packaged into a gelatin capsule dosage form. In another embodiment, the compound is packaged into a non-gelatin capsule or an HPMC capsule. Said capsule can be a vegan based capsule or else. The compound disclosed herein includes a sustained release compound, an immediate release compound, or a combined sustained release fraction and immediate release fraction. In one embodiment, the therapeutic effect of the compound has a duration up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, up to 12 hours, up to 14 hours, up to 16 hours, up to 18 hours, or up to 24 hours. In one embodiment, the compound disclosed herein comprises an immediate release fraction and a sustained release fraction, wherein the immediate release fraction contains a therapeutically effective amount of Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants alkaloids and an edible oil; and wherein the sustained release fraction contains a therapeutically effective amount of Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants alkaloids, and a mixture of emulsifiers and other pharmacologically inactive substances.
[0163] In another embodiment, a dietary compound, according to the present invention, is any ingestible preparation that contains the Cannabis sativa, Picralima nitida, Mitragyna speciose, Vinca major, and Psychotria species plants extracts as contemplated by this invention, where the pharmacologically inactive substance is a food product. The food product can be dried, cooked, boiled, lyophilized, baked, frozen, chilled, liquid, semi-liquid or prepared by any preparation used in food processing. Such food product can be, but not limited to: breads, teas, soups, cereals, salads, sandwiches, sprouts, vegetables, animal feed, pills and tablets, soft drinks, instant drinks, and any other human or animal food.
[0164] In yet another embodiment, a compound for parenteral injection comprises pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include, without limitation, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
[0165] In one embodiment, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The compound of the present invention can also contain adjuvants such as, but not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. The compound for parenteral delivery generally includes isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical formulation can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0166] Injectable depot forms are made, in one embodiment, by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the specific polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly-orthoesters and poly-anhydrides. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
[0167] Dosage forms for topical administration include, but are not limited to, ointments, creams, emulsions, lotions, gels, sunscreens and agents that favor penetration within the epidermis. Various additives, known to those skilled in the art, may be included in the topical formulations of the invention. Examples of additives include, but are not limited to, solubilizers, skin permeation enhancers, preservatives (e.g., anti-oxidants), moisturizers, gelling agents, buffering agents, surfactants, emulsifiers, emollients, thickening agents, stabilizers, humectants, dispersing agents and pharmaceutical carriers. Examples of moisturizers include jojoba oil and evening primrose oil.
[0168] Suitable skin permeation enhancers are well known in the art and include lower alkanols, such as methanol ethanol and 2-propanol; alkyl methyl sulfoxides such as dimethylsulfoxide (DMSO), decylmethylsulfoxide (C10 MSO) and tetradecylmethyl sulfoxide; pyrrolidones, urea; N,N-diethyl-m-toluamide; C2-C6 alkanediols; dimethyl formamide (DMF), N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol. Examples of solubilizers include, but are not limited to, hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol) and diethylene glycol monoethyl ether oleate (available commercially as Softcutol); polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, polyethylene glycol (PEG), particularly low molecular weight PEGs, such as PEG 300 and PEG 400, and polyethylene glycol derivatives such as PEG-8 caprylic/capric glycerides (available commercially as Labrasol); alkyl methyl sulfoxides, such as DMSO; pyrrolidones, DMA, and mixtures thereof.
[0169] Prevention and/or treatment of a broader spectrum of infections can be achieved by inclusion of other antibiotics or anti-inflammatory agents or other active ingrediants, as well as other antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like, in the compounds of the invention.
[0170] One of ordinary skill will appreciate that effective amounts of the agents in the compound used in the methods of the invention can be determined empirically. It will be understood that, when administered to a patient, the total daily usage of the compound of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any patient will depend upon a variety of factors: the type and degree of the response to be achieved; the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the duration of the treatment; drugs used in combination or coincidental with the method of the invention; and like factors well known in the medical arts. An overview of the plants, their constituents, safety and efficacy are provided below.
[0171] There are certain side effects that were reported in connection with Picralima nitida and some other active ingredients employed in the proposed formulations. According to Erharuyi et al., (2014) the acute toxicological profile of the methanol fruit rind of Picralima nitida in rats revealed signs of toxic effect on the liver, kidneys and the lungs after prolonged exposure at high doses (1.5-6 g/kg) with LD50 values of 14.5 and 12.5 g/kg for male and female rats respectively. These effects were characterized by marked elevation in serum aspartate amino-transferase (AST), alanine amino-transferase (ALT), glucose, creatinine, total cholesterol and protein (Mabeku, Kouam, Paul, & Etoa, 2008).
[0172] Acute intraperitoneal toxicity tests of the basic alkaloidal fraction of Picralima nitida stem bark showed a dose-dependent toxicity characterized by inflammation and necrosis of the hepatocytes accompanied by reduction in neutrophilic count and a corresponding increase in lymphocytic count. Conjunctiva application showed no sign of reddening or irritation and dermal tests also showed no sensitization, inflammation or death in the animal models used (Fakeye, et al., 2004).
[0173] The acute and sub-chronic toxicity studies of the hydroethanol extract of Picralima nitida leaves (1-5 g/kg p.o. in mice) was carried out by Ilodigwe et al, (2012) the result of the study showed that Picralima nitida leaf extract caused no physical sign of toxicity within 24 hours after prolonged administration, assessment of hematological parameters showed that there was no significant elevation of hemoglobin concentration, packed cell volume and red blood cell count at lower doses. While at higher doses, there was a significant (P<0.05) elevation of white blood cell count and biochemical studies revealed a dose-and time-dependent elevation of serum AST, ALT, and serum alkaline phosphatase and a concomitant degeneration and rupture of the hepatocytes (Ilodigwe, Okoye, Mbagwu, Agbata, & Ajaghaku, 2012). Acute toxicity of the methanol pulp, seed and fruit rind extract of Picralima nitida on rats revealed a mild toxic effect with LD50 values of 7,071.0 mg/kg, 6,948.68 mg/kg and 1,364.91 mg/kg, respectively (Okonta & Aguwa, 2007).
[0174] Although Kratom seems to be safe when administered at 1-10 mg/kg doses (which represents a sub-chronic dose), according to Pantano (2016), after prolonged exposure to a 100 mg/kg dose, as demonstrated in the experiments on Sprague-Dawley rats conducted by Sabetghadam et al. (2013), it causes biochemical and hematological changes with histopathological alterations in several tissues (liver, kidney and brain). Another study reported that Kratom users consume about 67.5-75 mg of Kratom per day and that no adverse effects were shown while only after prolonged exposure to a higher dose of Kratom, clinical signs of toxicity were highlighted (Vicknasingam B. , Narayanan, Beng , & Mansor, 2010). Only a few papers (Kapp, Maurer, Auwarter, Winkelmann, & Hermann-Clausen, 2011), according to Pantano (2016), report liver damages or hepatotoxic sequelae related to Kratom use, and also in these cases, the authors highlighted the difficulties of a correlation between Kratom consumption and hepatic injuries, which was more likely to be associated with the extraction process of the alkaloids or to the presence of contaminants in the herbal products (Raffa, 2014). Moreover, causality has not yet been accurately established for Kratom, as CIOMS scale (RUCAM) has not been applied to suspected cases (Pantano, et al., 2016).
[0175] The pharmacological effects of Kratom are mainly attributed to its principal alkaloid mitragynine and 7-hydroxymitragynine. Mitragynine is the most abundant alkaloid in the leaves. Being a potent atypical opioid, it does have some liability of addiction. A study (Trakulsrichai, et al., 2013) was conducted to identify the characteristics of Kratom poisoning and withdrawal cases from Kratom exposure cases in Ramathibodi Poison Center (RPC), Thailand, during a five-year period. The study provides a retrospective review of Kratom exposure cases from the RPC toxic surveillance system. A total of 52 Kratom exposure cases were identified. There were Kratom poisoning cases (76.9%) and withdrawal cases (23.1%). Common presenting symptoms in the poisoning group were palpitation (22.5%), followed by seizure (17.5%). For the withdrawal group, the common presenting symptoms were myalgia (33.3%), insomnia (16.67%), fatigue (16.67%), and chest discomfort (16.67%). Trakulsrichai, et al., (2013) notes that there was a case of baby with withdrawal symptoms who was delivered from a chronic Kratom-abusing mother, suggesting possible exposure via the transplacental route. There were no deaths in either group. Kratom abuse can cause either poisoning or withdrawal. Most cases in both groups had good prognostic outcome (Trakulsrichai, et al., 2013).
[0176] According to Ramanathan, et al. (2015), several pharmacological studies were undertaken on rodents specifically for mitragynine. However, the mitragynine dose employed in these studies varied largely across rodent species, showing the following characteristics: analgesic (30-200 mg/kg), pharmacokinetics (20-50 mg/kg), toxicity (200-477 mg/kg). Others reported no toxicity even at mitragynine dose levels of 800-900 mg/kg in rodents. However, a study by Janchawee et al. (2007) demonstrated lethal effects after an oral administration of 200 mg/kg mitragynine in rats. The similar fatal effect was also observed after administration of 200 mg/kg alkaloid extract of Kratom to rats (Azizi, Ismail, Mordi, & Ramanathan, 2010).
[0177] It was also reported in a different study that a man who tried to abstain from Kratom had difficulty sleeping, wriggling sensation in the shoulders and the back, dragging sensation in the hips, bitemporal headache, became extremely weak and also had difficulty walking (Thuan, 1957). A study by Vicknasingam and colleagues (2010) also revealed that kratom produced mild side effects such as loss of weight, dehydration, constipation but no other medical problems were reported. However, prolonged use of kratom was reported to cause adverse effects which include nausea, diarrhea, vomiting, hallucinations, psychosis, agitation, dizziness, itching, sweating, dry mouth, respiratory depression, constipation, anorexia, increased urination, palpitations and weight loss (Suwanlert, 1975) (Jansen & Prast, 1988) (Babu, McCurdy, & Boyer, 2008) (Adkins, Boyer, & McCurdy, 2011). Other than adverse effects, there are no reports of mortalities following mitragynine or Kratom consumption alone, even after chronic and high dosage consumption (Ramanathan & Mansor, 2014).
[0178] In a series of 9 lethal cases from Sweden, both mitragynine (0.02-0.18 g/g) and O-desmethyltramadol (0.4-4.3 g/g) were detected in the post mortem blood samples of Krypton (powdered Kratom mixed with the u-opioid receptor agonist, O-desmethyltramadol, an active metabolite of Tramadol) users over a 1-year time. It was suggested that the addition of both, u-opioid receptor agonists, mitragynine and O-desmethyltramadol, to the herbal mixture may have caused the unintentional death. However, since no data for lethal doses in humans are available yet, the contribution of mitragynine to polytoxic causes of death is currently hard to estimate (Holler, et al., 2011).
[0179] In another embodiment of the proposed invention, the following preparation is made to treatment chronic pain: Dry solid ethanolic extract of Picralima nitida was pulverized and dispersed in diethyl ether in order to separate the polar from non-polar constituents. This non-polar solvent was meant to dissolve out the lipophilic constituents while leaving behind the hydrophilic ones (diethyl ether insoluble). Upon filtration the insoluble hydrophilic constituents were separated from the lipophilic constituents. The diethyl ether was evaporated off to recover the extract. The extracts were stored in the desiccator for one week.
[0180] The chitosan microspheres were prepared as follows: A quantity of chitosan powder was dissolved in a vessel containing acetic acid and Tween 80. Distilled water was added, and the solution was stirred vigorously. Sodium sulphate (Na.sub.2SO.sub.4) was then added to the chitosan solution with continuous stirring. Sonication for 15 min and 30 min centrifugation at 5,000 rpm respectively were subsequently carried out and the supernatant discarded. The sediment was re-suspended in distilled water 3 times to get rid of left-over acetic acid. The supernatant was decanted, and the sediment stored. Ethanolic extract of Picralima nitida was used instead of diethyl ether extract because it contained all the aqueous constituents. Picralima nitida powder was dispersed in equal weight of water prior to mixing with chitosan microspheres at a weight ratio of 1:6 and then sonicated for 30 minutes for complete interaction with the microspheres.
[0181] Granules were produced by wet granulation method using Carbosil as a bulking agent. Some quantity of Picralima nitida microspheres was mixed with some Carbosil and blended together. The mixture was thoroughly kneaded with mortar and pestle, screened through sieve 1.7 mm and the wet granules dried in a hot air oven at 50 C. for 1 hour. The dry granulation was obtained by screening the granules through 1.0 mm sieve. Hard gelatin capsules (no. 2) were automatically filled with 500 mg of granulation and stored in an amber bottle. Said process generally shows good granulation flow characteristics. The in-vitro drug release of Picralima nitida from the granulated microspheres showed a consistent pattern. The T50 and T85 values were 42 and 96 min respectively. The presence of Carbosil and microspheric entrapment were responsible for the slight slow release. Said preparation was used, in one embodiment, to treat moderate pain. One 500 mg pill was given to patients every 6 hours to manage pain.
[0182] In another embodiment of the proposed invention, the following topical preparation is made to treat fungal nail infection. Cream formulation with 10% concentration of Picralima nitida extract was prepared using Aqueous Cream BPC as base material and 10% Propylene Glycol (PG) as humectant. This formulation appeared to generally have the highest effectiveness against the microorganisms. Said cream had also exhibited high effectiveness against bacterial infections of skin when applied 4 times a day, with most of the signs/symptoms disappearing after 2-3 weeks of medication.
[0183] The potential commercial uses of the disclosed preparations include, for example, protective/prophylactic and medical uses. The compounds of the invention can also be administered by a variety of other routes, including mucosal, subcutaneous and intramuscular administration, and may comprise a variety of carriers or excipients known in the formulary art, such as, non-toxic solid, semisolid or liquid filler, diluent, encapsulating material and formulation auxiliaries that are pharmaceutically acceptable.
[0184] The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or system for attaining the disclosed result, as appropriate, may separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof.
[0185] While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined in the appended claims. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments but should be defined in accordance with the following claims and their equivalents.
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