WO2026015297A1 - Injectable biphasic formulations - Google Patents

Abstract

The present disclosure provides novel compositions for biologically active compounds that are administered through injection. The active compounds include, but are not limited to steroid hormones, diarylheptanoids, and flavonoids. These compositions are distinguished from the prior art through the addition of an oil to the overall composition, which results in a biphasic formulation. The oil serves to enhance the efficiency of delivery of the formulation to a human or animal subject, and reduces discomfort associated with the injection process. Optionally, one or more additional substances, each of which is soluble in oil, can be added to the oil to enable the deliverable of multiple active compounds in a single injection.

Description

PATENT Attorney Docket No.115653-1499537-000510WO INJECTABLE BIPHASIC FORMULATIONS CROSS-REFERENCE TO RELATED APPLICATION [0001] The current application claims priority to US Provisional Patent Application No. 63/668,298, filed July 7, 2024, the content of which is hereby incorporated by reference in its entirety for all purposes. FIELD OF THE DISCLOSURE [0002] The disclosure relates to biphasic formulations of bioactive substances whereby an oil is included as a second component, along with a first solvent, in a formulation to improve the efficiency of administration of the bioactive substance by injection. BACKGROUND [0003] A variety of bioactive compounds, including but not limited to, steroid hormones, curcuminoids, diarylheptanoids, and/or flavonoids are commonly used as therapeutics, taken either as nutritional supplements or prescription drugs, to address a wide range of health problems. It is often desirable to deliver these compounds via injection, dissolved in an aqueous or non-aqueous solvent. However, in many instances subjects report feeling pain at the injection site when the treatment is administered. Herein we disclose biphasic formulations wherein an oil is included as a second phase in the injection formulation to reduce patient discomfort upon administration and/or to enhance delivery of the bioactive molecule, which may also comprise the inclusion of one or more additional active molecules into the oil phase of the formulation. This offers the opportunity to deliver multiple bioactive molecules in a single injection as well as the opportunity to deliver molecules which possess opposing hydrophilic and hydrophobic properties in the same injection formulation. [0004] A particular application of the disclosure is to deliver curcuminoids, such as curcumin, by means of injection, and also for delivery of curcuminoids or flavonoids with other active molecules such as steroids, including but not limited to, the sex hormones e.g., testosterone, estrogen, progesterone, and analogs thereof. Chemically, curcumin is known as diferuloylmethane, and is an active component found in turmeric (Curcuma longa) and in Curcuma xanthorrhiza oil. The molecule is considered to have potential as an anti-inflammatory agent to protect the human body against the effects of inflammation, which has been associated with a range of maladies including of cancer, cardiovascular disease, respiratory disease, age- related diseases, and neurological disorders. However, the use of these molecule classes has hitherto been limited by suboptimal formulations which restrict their modes of delivery. Notably, curcumin has been considered to have low potential as a therapeutic drug due to its low bioavailability and instability (see Nelson et al. (2017), J. Med. Chem. 60: 1620-1637, and Nelson et al. (2017), Med. Chem. Letters. 8: 467–470). The formulations disclosed herein provide an efficient means of delivering curcumin by injection, thus increasing its bioavailability and utility as a therapeutic drug. [0005] Reports on the testosterone market, from as recently as 2021 indicate that there are no significant oral formulations in the market, and the market is divided roughly 50:50 between injectable and topical formulations (see: www.skyquestt.com/report/testosterone-replacement- therapy-market). The injectable formulation typically comprises testosterone dissolved in a non- aqueous solvent such as cotton seed oil or another plant derived oil. However, testosterone use poses an increased risk for cardiovascular disease and has been reported to cause high blood pressure, blood clots, and other serious heart problems. What is needed in the art are new ways to delivery sex hormones such as testosterone as well as other drugs. The current disclosure satisfies these needs and offers other advantages as well. BRIEF SUMMARY [0006] The disclosure provides a biphasic composition, methods for treating various indications and delivery of a therapeutic agent or bioactive substance. The therapeutic agent can be a health supplement product or a prescription drug. Specifically, the composition comprises an oil, which may be a biologically derived oil, such as a vegetable oil e.g., cotton seed oil, or a mineral oil. A particular example comprises a formulation containing curcumin, dissolved in glycerol, combined with an oil. For example, the injectable biphasic formulation disclosed herein, offers a means to co-deliver curcumin and testosterone and/or testosterone analogs (including its esters) by injection. Inclusion of a protective molecule such as curcumin dissolved in a solvent as a second phase to the oil-based testosterone containing phase in the formulation, offers a means to potentially ameliorate the negative side effects of a testosterone injection. [0007] The disclosed method of delivery is superior to the existing modes of delivery, which may omit the oil and which cause severe discomfort to patients upon administration. Combination formulations, including both testosterone and curcumin, wherein the latter is included to protect against inflammation and/or cardiovascular disease, which might otherwise result from artificially elevated testosterone levels, are also disclosed. We further disclose injectable formulations comprising the inclusion of an oil, as a lubricant, in combination with another solvent in which a bioactive component is dissolved. The bioactive component can be an existing drug which is used in humans or animals, including but not limited to, an antimicrobial, an aesthetic, an anticancer drug, an opioid, an antipsychotic, an analgesic, a sex hormone, a blood thinner, a diabetes drug, a flavonoid, a diuretic, an immunosuppressant, or another therapeutic substance. [0008] These and other aspects, objects and embodiments will become more apparent when read with the detailed description and figure that follows. BRIEF DESCRIPTION OF THE DRAWINGS [0009] Figure 1 illustrates an example of a biphasic formulation incorporating oil as a lubricant, ready for injection into a subject. The photograph shows a typical dose of curcumin dissolved in glycerol (darker layer, bottom layer) together with a second phase comprising grape seed oil (top layer). In this example, the total dose is approximately 0.6 ml, comprising approximately 0.3 ml of oil and approximately 0.3 ml of curcumin dissolved in glycerol. The concentration of the curcumin in this example was approximately 40 mg per ml of glycerol, which solution also included sodium carbonate at a level of 20 mg/ml of glycerol. DETAILED DESCRIPTION [0010] This disclosure provides injectable biphasic formulations, which comprise a liquid solvent containing a bioactive or therapeutic molecule of interest. The first phase is a non-oil- based solvent phase. The solvent may be water or a non-aqueous solvent, which is either hydrophilic or hydrophobic in nature. The choice of solvent depends upon the physical chemical properties of the bioactive molecule being used. For example, testosterone and its analogs are poorly soluble in water and are typically delivered in an oil-based solvent, an example of which is cotton seed oil. Glycerol or propan-1,2,3-triol is a three-carbon compound isolated from fats and lipids which possesses three hydroxyl groups; the molecule is especially useful for formulating drugs as it is itself soluble in water, but it can dissolve many compounds which are insoluble in water. Hitherto, a primary limitation on the use of curcumin in injectable form has been its poor solubility in water (Kurien and Scofield,Trends Pharmacol Sci. 2009 Jul; 30(7): 334–335). The second phase of the biphasic composition is the oil phase. [0011] In certain instances, the compositions disclosed herein comprise an injectable formulation whereby curcumin is dissolved in glycerol as the non-oil phase, which also contains a dissolved alkaline salt such as sodium carbonate, as an alternative solvent to water, and oil is added as an additional phase to the formulation. The oil which remains in a separate phase to the glycerol phase in the formulation acts a lubricant, increasing the efficiency of the injection processes and also reducing discomfort to the subject who is injected. [0012] Curcumin and related compounds have previously been delivered in injectable formulations as detailed in US Patent No. 12,128,011, incorporated herein by reference. [0013] The addition of oil provides lubricant and makes the injection easier to perform, enabling a potentially viscous solution (as is the case with glycerol) to enter the tissue more readily. Previously disclosed injectable formulations have been limited by the fact that human subjects report significant pain at the injection site upon injection. Advantageously, subjects report that inclusion of the oil in the formulation disclosed herein significantly reduces the pain associated with the injection. [0014] In certain aspects, upon injection of the biphasic formulation, the oil flows into the injection site first ahead of the glycerol phase in which the curcumin is dissolved and forms an injection site pocket or depot in which the surrounding tissue is initially separated from the glycerol by the oil, thereby reducing tissue damage and/or pain. Following the injection, mechanical movement of the muscle, enables a slower more controlled release and dispersion of the active ingredient into the surrounding tissue. [0015] In a further series of embodiments, the methodologies and compositions herein encompass biphasic formulations whereby an oil is included in an injectable formulation of protective bioactive polyphenolic molecules including those of the flavonoid class. Such molecules include resveratrol and its analogs. Such molecules also include luteolin, kaempferol, apigenin and quercetin and derivatives thereof; the aforementioned four common flavonol glycoside compounds are found in many plants and possess multiple biological activities, including anti-inflammatory and antioxidant activities (Tian et al. (2021) South African J. Bot. 137: 257-264). [0016] Further, the disclosure provides methods of reducing the pain associated with injection of a drug formulation by including an oil as an additional component in the formulation. DEFINITIONS: [0017] “ADHD” means “Attention Deficit Hyperactivity Disorder”. ADHD is a common neurodevelopmental disorder which is often first diagnosed in childhood and often lasts into adulthood. Persons with ADHD may have trouble paying attention, concentrating, controlling impulsive behaviors (may act without thinking about what the result will be), or be overly active. Other features of ADHD may include one or more of the following behaviors: daydreaming, forgetfulness, fidgeting, excessive talking, risk taking, irritability and/or aggression. [0018] “Attentional Control” refers to an individual's capacity to choose what they pay attention to and what they ignore and is also colloquially referred to as “Concentration”. Enhanced attentional control is highly desirable for various occupations including pilots, surgeons, and computer gamers. [0019] “Biologically Derived Oil” means an oil that is extracted or processed from a biological source that comprises a living organism or a recently living organism, as opposed to a fossilized organism. Examples of biologically derived oils include plant oils, animal oils, oils from algae, and oils derived from the fermentation of microbes. Vegetable oils are extracted from various plants and seeds, including fruits, nuts, and grains. Common examples useful in the present disclosure include olive oil, canola oil, soybean oil, sesame seed oil, sunflower oil, coconut oil, cottonseed oil, avocado oil, and peanut oil. Other oils include grapeseed oil, safflower oil, corn oil, palm oil, rice bran oil and wheat germ oil. [0020] A “biphasic system” means a mixture containing two distinct liquid phases, a non-oil phase liquid solvent phase and an oil phase. The biphasic system is not an emulsion. An emulsifying agent is not required. [0021] “Curcumin” refers to the bright yellow chemical which is also known as diferuloylmethane. It is produced by plants of the Curcuma longa species and is the principal curcuminoid of turmeric (Curcuma longa), a member of the ginger family, Zingiberaceae. The compound is often included in herbal supplements, cosmetics ingredient, food flavoring, and is sometimes used as a food coloring. Chemically, curcumin is a diarylheptanoid, a molecule that is a polyphenol, a beta-diketone, an enone, a diarylheptanoid and an aromatic ether. [0022] “Dehydroepiandrosterone” or “DHEA” means the Steroid molecule that has been _{variously referred to as 3 -Hydroxyandrost-5-en-17-one, by its systematic IUPAC name} (3aS,3bR,7S,9aR,9bS,11aS)-7-Hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a- tetradecahydro-1H-cyclopenta[a]phenanthren-1-one, as androstenolone; as prasterone; as _{androst-5-en-3 -ol-17-one; as 5,6-Didehydroepiandrosterone; and/or as} dehydroisoepiandrosterone. The molecule may act as and/or be used as an androgen. [0023] “Estrogen” means the class of female sex hormones that is responsible for the development and regulation of the female reproductive system and secondary sex characteristics. Several types of estrogen molecule are known to have estrogenic hormonal activity, including estrone, estradiol, estriol and estetrol (which is produced during pregnancy). The former molecules are all analogs with substituents of the same four-ring carbon skeleton. [0024] “Flavonoid” means a class of polyphenolic secondary metabolites which possess a characteristic fused ring structure. Chemically, flavonoids have the general structure of a 15- carbon skeleton, have a characteristic defining feature in that they possess two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen). This carbon structure can be abbreviated C6-C3-C6. Flavonoid subtypes include Flavanols, Flavan-3-ols, Flavones, Flavanones, Isoflavones, and Anthocyanins. Flavonoids (also sometimes referred to as bioflavonoids) are categorized as part of the broader class of compounds known as “polyphenols”. The name “Flavonoid” comes from the Latin word “flavus”, meaning yellow, a common color of such compounds in nature and the molecules. The compounds luteolin, kaempferol, apigenin, and quercetin are examples of flavanols, however curcumin, although a phenolic compound, is not a flavonoid, as it lacks the requisite defining fused ring structure. [0025] “Hormone” means a molecule that typically acts as a signaling molecule in a multicellular organism; such a molecule is typically produced and/or secreted in a particular cell or tissue and them moves to a different cell or tissue where it elicits a physiological or developmental effect. Hormones are organic molecules and many different classes have been identified. A well-known example is the class comprising Steroid Hormones (as defined below) which includes the sex hormones testosterone, estrogen, and progesterone. [0026] “Glycerol” which is also known as “Glycerin,” “Glycerine,” “1,2,3- Trihydroxypropane,” means the molecule with the IUPAC name propan-1,2,3-triol. [0027] “IBS” means Irritable Bowel Syndrome; a common disorder that affects the gastrointestinal tract. Typical symptoms include cramping, abdominal pain, bloating, gas, diarrhea, and/or constipation. [0028] “Inflammation” refers to a response of a human or animal body to harmful stimuli, such as pathogens, damaged cells, or chemical stimuli. The response has evolved as a protective mechanism and involves immune cells, blood vessels, and molecular mediators. Inflammation serves to clear out damaged cells and tissues, and initiate tissue repair. Inflammation can be classified as acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement of plasma and leukocytes (in particular granulocytes) from the blood into the injured tissues (Wikipedia). A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells in the injured tissue. Prolonged inflammation, known as chronic or systemic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and involves simultaneous destruction and healing of the tissue. [0029] “Inflammatory disease” or “Inflammation” refers to one or more pathologies that arise due to prolonged inflammation or an overactive inflammation response and may involve the immune system cells attacking the body’s own tissues. Drugs, or stimulants such as alcohol, can produce inflammation; chronic inflammation is often associated with aging and general poor health and has been associated with certain cancers, autoimmune diseases, mental health problems, neurodegenerative diseases, and cardiovascular diseases. [0030] “Lethargy” refers to a condition whereby a human or animal feels, or exhibits symptoms, of fatigue or sluggishness. Lethargy is often associated with changes in mood, reduced mental acuity, decreased alertness, or decreased ability to execute complex tasks. [0031] “Mineral Oil” means an oil that is produced by chemical synthesis or which has been extracted or processed from petroleum or fossilized material. [0032] “Plant Oil” means an oil that is extracted or processed from a photosynthetic organism, or from an alga. Examples include plant seed oils such as grape seed, cotton seed, canola oil, castor oil, and palm oil. [0033] “Polyphenols” refers to the large family of naturally occurring phenols that is abundant in plants and structurally diverse. The term polyphenol is not well-defined, but it is generally agreed that they are natural products that possess one or more hydroxyl groups on aromatic rings and which include four principal classes: phenolic acids, flavonoids, stilbenes, and lignans. [0034] “Progesterone” refers to the steroid molecule that is variously referred to as pregn-4- ene-3,20-dione, (1S,3aS,3bS,9aR,9bS,11aS)-1-Acetyl-9a,11a-dimethyl 1,2,3,3a,3b,4,5,8,9,9a,9b,10,11,11a-tetradecahydro-7H-cyclopenta[a]phenanthren-7-one and or as pregnenedione. The molecule has important endogenous roles in regulating the menstrual cycle, pregnancy, and embryogenesis. It has various medical applications as a drug including uses to mitigate the risk of uterine or cervical cancer, in hormone replacement therapy, in feminizing hormone therapy, and in combination with estrogen as a contraceptive. [0035] “Steroid hormone” refers to a “Steroid” or “Steroid molecule” that acts as a hormone. A “Steroid” or “Steroid molecule” typically means an organic molecule with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Some examples of Steroids are gonane, testosterone, estradiol, progesterone, DHEA, cholic acid, dexamethasone, and lanosterol. [0036] “Testosterone” refers to the steroid molecule that is the primary male sex hormone and _{androgen in male animals, with the chemical formula C19H28O2 and the IUPAC name 17 -} Hydroxyandrost-4-en-3-one. [0037] In certain aspects, the disclosure provides a composition comprising a biphasic injectable formulation that contains a bioactive biomolecule dissolved in a first phase, which is a non-oil-based solvent; and a second phase, which is an oil. [0038] In certain aspects, the composition comprises a biphasic injectable formulation that contains a bioactive biomolecule dissolved in a non-oil-based solvent at a concentration of at least 0.00001 mg/ml, at least 0.0001 mg/ml, at least 0.001 mg/ml, at least 0.01 mg/ml, at least 0.1 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 10 mg/ml, at least 11 mg/ml, at least 12 mg/ml, at least 13 mg/ml, at least 14 mg/ml, at least 15 mg/ml, at least 16 mg/ml, at least 17 mg/ml, at least 18 mg/ml, at least 19 mg/ml, or least 20 mg/ml, or at least 25 mg per ml, or at least 50 mg per ml, or at least 75 mg per ml, at least 100 mg per ml, or at least 1 g/ml of total solution; and an oil that is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400% or at least 500% of the volume of the non-oil-based solution to produce a composition with two separate phases, and whereby the formulation is delivered into a human or animal subject by means of an injection system for therapeutic treatment. [0039] In certain aspects, the first phase, the non-oil phase can be from about 0.01 ml to about 15 ml. In other instances, the non-oil phase can be from about 0.01 ml to about 5 ml. For example, the non-oil phase can be 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 1.1 ml, 1.2 ml, 1.3 ml, 1.4 ml, 1.5 ml, 1.6 ml, 1.7 ml, 1.8 ml, 1.9 ml, 2 ml, 2.1 ml, 2.2 ml, 2.3 ml, 2.4 ml, 2.5 ml, 2.6 ml, 2.7 ml, 2.8 ml, 2.9 ml, 3 ml, 3.1 ml, 3.2 ml, 3.3 ml, 3.4 ml, 3.5 ml, 3.6 ml, 3.7 ml, 3.8 ml, 3.9 ml, 4 ml, 4.1 ml, 4.2 ml, 4.3 ml, 4.4 ml, 4.5 ml, 4.6 ml, 4.7 ml, 4.8 ml, 4.9 or 5.0 ml. [0040] In certain aspects, the non-oil-based solvent is glycerol. [0041] In certain aspects, the glycerol also contains a dissolved alkaline salt. [0042] In certain aspects, the bioactive molecule is curcumin, insulin, resveratrol, quercetin, luteolin, apigenin, kaempferol, or an analog of any one of the foregoing. [0043] In certain aspects, the second phase is an oil phase. The oil phase can be from about at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400% or at least 500% of the volume of the initial non-oil based formulation. For example, if the first non-oil phase is 0.2 ml, the oil phase can be 0.01 ml to 1 ml in volume (5% to 500% of the volume of the first phase). [0044] In certain aspects, the oil phase contains a dissolved second bioactive molecule. [0045] In certain aspects, the second bioactive molecule is a steroid hormone or another therapeutic drug. [0046] In certain aspects, the second bioactive molecule is testosterone, DHEA, or an ester of testosterone, or an analog of testosterone, progesterone or an analog of progesterone, estrogen, or an analog of estrogen. [0047] In certain aspects, the composition is used as a treatment for pain, ADHD, IBS, cancer, respiratory disease, a degenerative disease, diabetes, high blood pressure, cardiovascular disease, inflammation, low libido, hypogonadism, depression, obesity, lethargy, a psychiatric disorder, or to kill or inhibit a microbial parasite, or to kill or inhibit a virus, or to increase attentional control. [0048] In certain aspects, the composition contains a drug approved by the FDA or equivalent regulatory agency. [0049] In certain aspects, the oil that is a plant-derived oil. [0050] In certain aspects, the oil that is a mineral oil. [0051] In certain aspects, the composition further comprises a bioactive molecule that is selected from the group consisting of: a diarylheptanoid, a curcuminoid, a polyphenol, a flavonoid, an antimicrobial, an aesthetic, an anticancer drug, an opioid, an analgesic, a sex hormone, a blood-thinner, a diabetes drug, a diuretic, an immunosuppressant, an RNA molecule, a DNA molecule, an antibody, a peptide, a vaccine, a weight-loss drug, a therapeutic drug that is used to treat a neurogenerative disorder, an antiviral drug, an active component of Ozempic, an active component of Eliquis, an active component of Biktarvy, an active component of Cabenuva, an active component of Aduhelm, choline a choline esterase inhibitor, a benzodiazepine, an antipsychotic, an antidepressant, an active component of Umbilify, a drug containing Lithium, or a therapeutic drug, and a recreational drug. [0052] The active ingredient for Ozempic is semaglutide. [0053] The active ingredient for Eliquis is apixaban. [0054] The active ingredients for Biktarvy are bictegravir, emtricitabine and tenofovir alafenamide. [0055] The active ingredients for Cabenuva are Cabotegravir and Rilpivirine. [0056] The active ingredient for Aduhelm is aducanumab. [0057] The active ingredient for Umbilify is Aripiprazole. [0058] In certain aspects, the disclosure provides a method of increasing the efficiency of, or reducing the pain associated with, the injection of a non-oil based drug formulation, comprising adding a volume of oil to the formulation prior to administering the injection whereby the volume of oil added is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400% or at least 500% of the volume of the initial non-oil based formulation. [0059] In certain aspects, the composition comprises a biphasic injectable formulation that contains a bioactive biomolecule dissolved in a non-oil-based solvent such as glycerol; and oil. By adding 0.1 mg to 20 mg sodium carbonate per milliliter glycerol, it is possible to achieve concentrations of 0-300 mg curcumin per milliliter of glycerol in the glycerol phase. The biphasic formulation also contains oil which remains in a separate phase and acts a lubricant, increasing the efficiency of the injection process and also reducing discomfort to the subject who is injected. In some aspects, the oil phase comprises the active ingredient. [0060] In certain aspects, the present injectable solution allows for a dose of greater than 20 mg of curcuminoid per milliliter of glycerol (typically 20-250 mg of curcuminoid per milliliter of glycerol) which, for example, allows for a high dose intramuscular depot of solution which slowly dissolves in interstitial fluid and into the blood stream over the course of days/weeks, avoiding daily injections/clinic visits. Upon injection of the biphasic formulation, the oil flows into the injection site ahead of the glycerol phase in which the curcumin is dissolved and forms an injection site pocket. [0061] In certain aspects, the present formulation is not aqueous, thereby avoiding problems of curcuminoid precipitation and degradation. Therefore, the present injectable solution can be stored for greater than 24 hours without precipitation or chemical degradation. [0062] According to one aspect, there is provided a method comprising dissolving a curcuminoid in glycerol to make an injectable solution, wherein an alkali salt is added to the glycerol to increase the solubility of the curcuminoid in the glycerol to more than 20 milligrams curcuminoid per milliliter of glycerol, thereafter, this glycerol phase is then added to an oil phase, and followed by therapeutic administration of the injectable solution. [0063] An alkali salt may be added to the glycerol to increase the solubility of the curcuminoid in the glycerol to more than 20 milligrams curcuminoid per milliliter of glycerol, and therapeutic administration of the injectable solution. [0064] More than 1 milligram of alkali salt may be added to the glycerol. [0065] The injectable solution may comprise a concentration of greater than 100 milligrams curcuminoid per milliliter of glycerol. [0066] More than 6 milligrams of alkali salt may be added to the glycerol. [0067] The injectable solution may comprise a concentration of approximately 200 milligrams curcuminoid per milliliter of glycerol. [0068] More than 13 milligrams of alkali salt may be added to the glycerol. [0069] The injectable solution may comprise a concentration of approximately 250 milligrams curcuminoid per milliliter of glycerol. [0070] More than 16 milligrams of alkali salt may be added to the glycerol. [0071] Administration may comprise administration of the injectable solution more than 24 hours after dissolving the curcuminoid in the glycerol. [0072] Administration may comprise administration of the biphasic injectable solution as is. [0073] Administration may comprise administration of the biphasic injectable solution without the addition of water. [0074] The curcuminoid may be at least one of a curcuminoid selected from the group consisting of curcumin, metabolites of curcumin, tetrahydrocurcumin, demethoxycurcumin, bisdemethoxycurcumin and curcumin esters. [0075] The alkali salt may comprise sodium carbonate. [0076] The alkali salt may comprise at least one of calcium hydroxide and calcium carbonate. [0077] The method may further comprise heating the glycerol to between the melting and the boiling point of glycerol. [0078] The method may further comprise filtering the curcuminoid solution to remove any undissolved alkali salt. [0079] The method may further comprise allowing the curcuminoid solution to cool and filtering the curcuminoid solution to remove any undissolved or precipitated curcuminoid. [0080] The method may further comprise antibacterial filtration of the curcuminoid solution through a 0.02-0.22 m filter. [0081] Administration may comprise injection. [0082] Injection may comprise intramuscular injection. [0083] Injection may comprise at least one of subcutaneous, intradermal, intraperitoneal and intra-abdominal injection. [0084] According to another aspect, there is provided an injectable solution comprising curcuminoid dissolved in glycerol, wherein an alkali salt is added to the glycerol so that the curcuminoid dissolves to a concentration of greater than 20 milligrams curcuminoid per milliliter of glycerol. [0085] The injectable solution may comprise a concentration of approximately 200 milligrams curcuminoid per milliliter of glycerol and more than 13 milligrams of alkali salt may be added to the glycerol. EXAMPLES EXAMPLE 1. Inclusion of oil in an injectable formulation [0086] A formulation is prepared by dissolving a bioactive biomolecule in a non-oil-based solvent at a concentration of at least 0.00001 mg/ml, at least 0.0001 mg/ml, at least 0.001 mg/ml, at least 0.01 mg/ml, at least 0.1 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 10 mg/ml, at least 11 mg/ml, at least 12 mg/ml, at least 13 mg/ml, at least 14 mg/ml, at least 15 mg/mg, at least 16 mg/ml, at least 17 mg/ml, at least 18 mg/ml, at least 19 mg/ml, or least 20 mg/ml, or at least 25 mg per ml, or at least 50 mg per ml, or at least 75 mg per ml, at least 100 mg per ml, or at least 1g/ml of total solution. [0087] The non-oil phase solvent formulation is added to a volume of oil that is at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400% or at least 500% of the volume of the non-oil-based solution to produce a formulation with two separate phases. The formulation is injected into a human subject by means of an injection system such as a syringe and needle. [0088] Further instantiations of EXAMPLE 1 include the following: [0089] (i) The formulation of EXAMPLE 1 wherein the bioactive molecule is selected from the list: a diarylheptanoid, a curcuminoid, insulin, an antimicrobial, an aesthetic, an anticancer drug, an opioid, an analgesic, a blood thinner, a diabetes drug, a polyphenol, a flavonoid, a diuretic, an immunosuppressant, an RNA molecule, a DNA molecule, an antibody, a peptide, a vaccine, a weight-loss drug, a therapeutic drug that is used to treat a neurogenerative disorder, an antiviral drug, an active component of Ozempic, an active component of Eliquis, an active component of Biktarvy, an active component of Cabenuva, an active component of Aduhelm, choline a choline esterase inhibitor, a benzodiazepine, an antipsychotic, an antidepressant, an active component of Umbilify, a drug containing Lithium, or a therapeutic drug, or a recreational drug. [0090] (ii) The formulation of EXAMPLES 1 (i) and (ii) where the non-oil-based solvent is glycerol or water. [0091] (iii) The formulation of EXAMPLES 1 (i)-(iii) wherein the oil is a plant oil or another biologically derived oil. [0092] (iv) The formulation of EXAMPLES 1 (i)-(iii) wherein the oil is a mineral oil. [0093] (v) The formulation of EXAMPLES 1 (i)-(iv) wherein the oil contains a dissolved second bioactive molecule. [0094] (vi) The formulation of EXAMPLE 1 (v) wherein the second bioactive molecule a Steroid Hormone or a therapeutic drug. [0095] (vii) The formulation of EXAMPLE 1 (vi) wherein the second bioactive molecule is testosterone, progesterone, estrogen, or an analog of any of the foregoing. [0096] (viii) The formulation of EXAMPLES 1 (i)-(vii) wherein the first bioactive molecule is curcumin, insulin, resveratrol, quercetin, luteolin, apigenin, or kaempferol. [0097] (ix) The formulation of EXAMPLES 1 (i)-(viii) wherein the formulation is used as a vaccine, as a treatment for pain, ADHD, IBS, cancer, respiratory disease, a degenerative disease, diabetes, obesity, high blood pressure, cardiovascular disease, inflammation, low libido, hypogonadism, depression, lethargy, or a psychiatric disorder, or to kill or inhibit a microbial parasite, to kill or inhibit a virus, or to increase Attentional Control. [0098] (x) The formulation of EXAMPLES 1 (i)-(ix) wherein the formulation is used as a treatment for a condition in a non-human animal. [0099] (xi) The formulation of EXAMPLES 1 (i)-(x) wherein the bioactive molecule is a drug approved by a regulatory agency such as the FDA. EXAMPLE 2. Inclusion of oil in an injectable formulation of curcumin [0100] A formulation is prepared by dissolving curcumin in glycerol to which an alkaline salt has been added at a concentration of between 0 – 200 mg of the alkaline salt per ml of glycerol. Curcumin is them add to the glycerol and alkaline salt solution at a concentration of at least 0.1 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 10 mg/ml, at least 11 mg/ml, at least 12 mg/ml, at least 13 mg/ml, at least 14 mg/ml, at least 15 mg/ml, at least 16 mg/ml, at least 17 mg/ml, at least 18 mg/ml, at least 19 mg/ml, or least 20 mg/ml, or at least 25 mg/ml, or at least 50 mg per ml, or at least 75 mg per ml, or at least 100 mg/ml, or at least 250 g per ml of the non-oil phase solution. The formulation is added to a volume of oil that is at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400% or at least 500% of the volume of the non-oil-based solution to produce a formulation with two separate phases. The formulation is injected into a human subject by means of an injection system such as a syringe and needle. [0101] Further instantiations of EXAMPLE 2 include the following: [0102] (i) The formulation of EXAMPLE 2 wherein the alkaline salt is sodium carbonate. [0103] (ii) The formulation of EXAMPLE 2 wherein the oil is a biologically derived oil, a plant oil, a vegetable oil, cotton seed oil, grape seed oil, linseed oil, or a mineral oil. EXAMPLE 3. Inclusion of oil in an injectable formulation of curcumin reduced pain upon administration to a subject [0104] A formulation was prepared by dissolving curcumin in the non-oil based solvent glycerol, containing sodium carbonate at concentration of approximately 16 mg/ml, such that the curcumin was present at a concentration of approximately 50 mg per ml of the total solution. The formulation was injected into a 51-year-old human male subject. The subject reported significant pain and a burning sensation at the site of injection. [0105] An improved formulation was prepared by dissolving curcumin in the non-oil based solvent glycerol, containing sodium carbonate at concentration of approximately 16 mg/ml, such that the curcumin was present at a concentration of approximately 50 mg per ml of the total solution or the non-oil based solvent glycerol phase. Prior to administration the practitioner added a volume of grape seed oil that was approximately 100% of the volume of the non-oil- based solution to produce a formulation with two separate phases, a dark phase containing the curcumin solution and a lighter phase comprising the oil as shown in Figure 1. The new formulation was injected into the same 51-year-old human male test subject. The subject reported no significant level of pain or discomfort with the improved formulation. [0106] An additional panel of combinations of formulations was then tested whereby the sodium carbonate was at 50 mg/ml and 100 mg/ml, the curcumin was at 25 mg/ml and 100 mg/ml and the volume of oil was at 25% and 200% of the formulation respectively. The aforementioned eight combinations were tested on the same subject (over a period of four weeks). In each instance the subject reported that the formulation caused no significant level of discomfort on or after administration.

Claims

WHAT IS CLAIMED IS: 1. A composition comprising a biphasic injectable formulation that contains a bioactive molecule dissolved in a non-oil-based solvent at a concentration of at least 0.00001 mg/ml of the non-oil based solvent and an oil phase that is at least 5%, of the volume of the non- oil-based solution.

2. The composition of claim 1, wherein the bioactive molecule has a concentration of about 0.0001 mg/ml to about 1 g/ml.

3. The composition of claim 1, wherein the volume of the non-oil solvent phase is from about 0.01 ml to about 15 ml.

4. The composition of claim 1, wherein the oil phase has a volume of about 5% to about 500% of the non-oil based solvent.

5. The composition of claim 1, where the non-oil-based solvent is glycerol.

6. The composition of claim 5, wherein the glycerol also contains a dissolved alkaline salt.

7. The composition of claim 1, wherein the bioactive molecule is selected from the group consisting of curcumin, insulin, resveratrol, quercetin, luteolin, apigenin, kaempferol, and an analog of any one of the foregoing.

8. The composition of claim 1, wherein the oil contains a dissolved second bioactive molecule.

9. The composition of claim 8, wherein the second bioactive molecule is a Steroid Hormone or another therapeutic agent.

10. The composition of claim 8, wherein the second bioactive molecule is a member selected from the group consisting of testosterone, DHEA, an ester of testosterone, an analog of testosterone, progesterone, an analog of progesterone, estrogen, and an analog of estrogen.

11. The composition of claim 1, wherein the composition is used as a treatment for pain, ADHD, IBS, cancer, respiratory disease, a degenerative disease, diabetes, high blood pressure, cardiovascular disease, inflammation, low libido, hypogonadism, depression, obesity, lethargy, a psychiatric disorder, or to kill or inhibit a microbial parasite, or to kill or inhibit a virus, or to increase Attentional Control.

12. The composition of claim 1, wherein the composition contains a drug approved by the FDA or equivalent regulatory agency.

13. The composition according to any one of claims 1, 5, or 6, wherein the oil that is a plant-derived oil.

14. The composition according to any one of claims 1, 5, or 6, wherein the oil that is a mineral oil.

15. The composition according to any one of claims 1, 5, or 6, further comprising a bioactive molecule that is selected from the group consisting of: a diarylheptanoid, a curcuminoid, a polyphenol, a flavonoid, an antimicrobial, an aesthetic, an anticancer drug, an opioid, an analgesic, a sex hormone, a blood-thinner, a diabetes drug, a diuretic, an immunosuppressant, an RNA molecule, a DNA molecule, an antibody, a peptide, a vaccine, a weight-loss drug, a therapeutic drug that is used to treat a neurogenerative disorder, an antiviral drug, an active component of Ozempic, an active component of Eliquis, an active component of Biktarvy, an active component of Cabenuva, an active component of Aduhelm, choline a choline esterase inhibitor, a benzodiazepine, an antipsychotic, an antidepressant, an active component of Umbilify, a drug containing Lithium, or a therapeutic drug, and a recreational drug.

16. A method of increasing the efficiency of, or reducing the pain associated with injection, the method comprising administering by injection a biphasic formulation that contains a bioactive molecule dissolved in a non-oil-based solvent at a concentration of at least 0.00001 mg/ml; and an oil that is at least 5% of the volume of the non-oil-based solution.

17. The method of claims 16, wherein the volume of oil in the biphasic formulation is about 5% to about 500% of the volume of the non-oil based solvent.