Capric acid and myristic acid compositions for treating conditions

Abstract

Provided herein are compositions, articles of manufacture, food products, and methods for treating certain conditions, such as fibrotic disease (e.g., asthma). For example, in certain embodiments, provided herein are food products (e.g., that are ketogenic) that contain high levels (e.g., at least 10% by weight of the food product) of capric acid (C10), myristic acid (C14), or combination thereof (e.g., as free fatty acids or as triglycerides). In other embodiments, methods are provided for receiving an order for such a food product, and shipping the food product to a subject with fibrotic disease (e.g., after receiving or verifying prescription information). In some embodiments, methods are provided of administering or providing a composition to a subject such that the subject receives at least 50 grams per day (e.g., 200 grams per day), on multiple days, of capric acid (C10), myristic acid (C14), or combination thereof.

Claims

1. A composition comprising: carbohydrates, proteins, and fats, wherein at least 30% by weight of the composition comprises the fats, and wherein at least 50% by weight of the fats are a combination of capric acid (C10) and myristic acid (C14), and wherein the ratio of C10 to C14 is: 80:20-90:10.

2. The composition of claim 1, wherein the capric acid (C10) and the myristic acid (C14) are provided in a form selected from the group consisting of: free fatty acids, esters, diglycerides, glycolipids, and phospholipids.

3. The composition of claim 1, wherein at least 60% by weight of the composition comprises the fats.

4. The composition of claim 1, wherein the capric acid (C10) and the myristic acid (C14) are in the form of triglycerides.

5. The composition of claim 1, wherein at least 10% by weight of the composition comprises the proteins.

6. The composition of claim 1, wherein less than 15% by weight of the composition comprises the carbohydrates.

7. The composition of claim 1, wherein the composition is in a form selected from the group consisting of: liquid emulsion, powder, spray dried powder, freeze dried powder, and a liquid drink.

8. The composition of claim 1, wherein the composition is detectably free of at least one of the following: eggs, peanuts, tree nuts, soy, wheat, fish, shellfish, and sulfites.

9. The composition of claim 1, wherein the composition provides 90-500 Calories.

10. The composition of claim 1, wherein the composition comprises at least 10 grams of: the combination of the capric acid (C10) and the myristic acid (C14).

11. The composition of claim 1, wherein at least 10% by weight of the composition comprises said carbohydrates.

12. An article of manufacture comprising a food product comprising: carbohydrates, proteins, and fats, wherein at least 65% by weight of the food product comprises the fats, and wherein at least 60% by weight of the fats are a combination of capric acid (C10) and myristic acid (C14), and wherein the ratio of C10 to C14 is: 80:20-90:10.

13. The article of claim 12, wherein said food product is in the form of a powder.

14. The article of claim 13, wherein said powder is a spray dried powder or a freeze dried powder.

15. The article of claim 12, wherein said food product is in the form of a liquid.

16. The article of claim 12, wherein at least 10% by weight of the food product comprises the proteins.

17. The article of claim 12, wherein the capric acid (C10) and the myristic acid (C14) are in the form of triglycerides.

18. An article of manufacture comprising a food product comprising: carbohydrates, proteins, and fats, wherein said foot food product is in the form of a powder, wherein at least 65% by weight of the food product comprises the fats, and wherein at least 60% by weight of the fats are a combination of capric acid (C10) and myristic acid (C14), wherein the ratio of C10 to C14 is: 80:20-90:10, and wherein the capric acid (C10) and the myristic acid (C14) are in the form of triglycerides.

19. The article of claim 18, further comprising a packaging component, wherein the food product is located inside the packaging component, and wherein food product is sealed inside the packaging component in a sterile manner.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows the effects of standard diet C10 and C14 on overall airway constriction.

(2) FIG. 2 shows effects of standard diet C10 and C14 on lung compliance.

(3) FIG. 3 shows effects of standard diet C10 and C14 on lung stiffness.

(4) FIG. 4 shows effects of standard diet C10 and C14 on forced expiratory lung volume.

(5) FIG. 5 shows experimental design of animals fed with various dosages of coconut oil in a mouse house dust mite model.

(6) FIG. 6A shows overall airway constriction.

(7) FIG. 6B shows central airway constriction.

(8) FIG. 6C shows peripheral airway constriction.

(9) FIG. 6D shows lung compliance.

(10) FIG. 6E shows peripheral lung tissue elastance.

(11) FIG. 6F shows lung elastance.

DEFINITIONS

(12) To facilitate an understanding of the present technology, a number of terms and phrases are defined below. Additional definitions are set forth throughout the detailed description.

(13) Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrase “in one embodiment” as used herein does not necessarily refer to the same embodiment, though it may. Furthermore, the phrase “in another embodiment” as used herein does not necessarily refer to a different embodiment, although it may. Thus, as described below, various embodiments of the technology may be readily combined, without departing from the scope or spirit of the technology.

(14) In addition, as used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and/or” unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.”

(15) The term “medical food,” as used herein, is as defined by the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) of 1988, which is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”

(16) As used herein, the terms “subject” and “patient” refer to any animal, such as a mammal like a dog, cat, bird, livestock, and preferably a human (e.g., a human with a disease such as asthma, a fibrotic disease, obesity, etc.).

(17) As used herein, the term “administration” refers to the act of giving a drug, prodrug, or other agent (e.g., food product), or therapeutic treatment to a subject. Exemplary routes of administration to the human body can be through the mouth (oral), skin (transdermal, topical), nose (nasal), lungs (inhalant), oral mucosa (buccal), by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.), and the like.

DETAILED DESCRIPTION

(18) Provided herein are compositions, articles of manufacture, food products, and methods for treating certain conditions, such as fibrotic disease (e.g., asthma). For example, in certain embodiments, provided herein are food products (e.g., that are ketogenic) that contain high levels (e.g., at least 10% by weight of the food product) of capric acid (C10), myristic acid (C14), or combination thereof (e.g., as free fatty acids or as triglycerides). In other embodiments, methods are provided for receiving an order for such a food product, and shipping the food product to a subject with fibrotic disease (e.g., after receiving or verifying prescription information). In some embodiments, methods are provided of administering or providing a composition to a subject such that the subject receives at least 40 grams or at least 50 per day (e.g., 200 grams per day), on multiple days, of capric acid (C10), myristic acid (C14), or combination thereof.

(19) In certain embodiments, the food products described herein are formulated as a smoothie or similar edible food product. In certain embodiments, the food products described herein (e.g., smoothie, or bar) are accompanied by caloric restriction (e.g., to treat asthma).

(20) In certain embodiments, a protocol is employed to explore the effects of calorie restriction on asthma health, and metabolic parameters of mitochondria UCP-2 expression and ROS generation in relation to asthma. This protocol calls for alternate-day calorie restriction to 5.5 kcal/kg (−400 kcal/day for a 70 kg individual) and will provide a formula for subjects to consume (e.g., the food products described herein) on their restriction days to enhance compliance. Because of the high level of dietary regulation of UCP-2 expression, the selection of this formula may have a significant impact on outcomes. In an animal-model study, Sullivan at al demonstrated that a ketogenic diet increases UCP-2 expression resulting in a decrease in ROS expression (Sullivan et al., Ann Neurol. 2004 April; 55(4):576-80). Since, in some embodiments, the subjects will already be restricting intake, selecting a formula to encourage ketosis will likely enhance UCP-2 expression.

(21) The traditional formula used for inducing ketosis in ketogenic diet treatment of epilepsy is KetoCal. But this formula would only provide 8 grams of protein per 400 kcals (or 0.11 g/kg). This level of protein would likely lead to negative nitrogen balance which is not desired. Alternatively, it has been shown that ketosis in humans can be initiated in a less restricted diet with a significant portion of calories coming from medium-chain triglycerides (Liu, Epilepsia. 2008 November; 49 Suppl 8:33-6, which is herein incorporated by reference in its entirety). It has also been demonstrated in humans that higher fat diets correlate to increased expression of UCPs 2 and 3 (Schrauwen, et al., Int. J. Obes. Relat. Metab. Disord. 2001 April; 25(4):449-56). Therefore, in some embodiments, an exemplary formula has been developed to provide optimal protein levels while limiting carbohydrates and maximizing medium-chain triglycerides and total fat content in order to encourage UCP expression and support study outcomes.

(22) The role of UCP-1 in the brown adipose tissue of rodents is well known to play a role in thermoregulation by dissipating the proton motive force as thermal energy. Because of the similar mechanism of action of UCP-2 in human adipose, it is expected that increased expression of UCP2 will lead to an increase in body temperature. Therefore, it is recommended, in some embodiments, that subjects' body temperature as well as urinary ketone levels (which will determine if the formula successfully induces ketosis) be measured periodically to examine both diet efficacy and compliance. A third measure of dietary compliance is the respiratory exchange ratio. This measure can be compared to the predicted respiratory exchange ratio (or food quotient) from the formula to test for non-compliance.

(23) An exemplary recipe for a food product (smoothie) is as shown in Table 1 below:

(24) TABLE-US-00001 TABLE 1 Ingredient Amount (grams) Coconut milk 395.67 Yogurt, plain, whole milk* 450.2 Strawberries, frozen 122.13 Mango, frozen 48.57 BeneProtein** 80.3 Papaya, fresh 54.46 Vanilla extract, imitation 7.25 Ascorbic acid, crystals 1.12 Splenda 14.0 *The yogurt used in the taste panel was a mixture (approx. 50/50) of plain low-fat and vanilla low-lat. The analyses included in this document use plain, whole milk as in the above recipe. **Nestle's brand whey protein powder.

(25) In certain embodiments, the invention addresses the potential corollary between calorie restriction on asthma health, and metabolic parameters of mitochondria UCP-2 expression and ROS generation in relation to asthma. Both the smoothie and the frozen smoothie were significantly (P<0.05) better than the Atkins shake in the qualities of taste, texture, and mouthfeel using a student's T-Test, and the frozen smoothie also has significantly better aftertaste.

(26) A nutritional approach to treat asthma to help patients breathe better is provided herein. In certain embodiments, a proprietary formula is provided which is based on a ketogenic diet which includes medium chain triglyceride (MCTs) formulation (e.g., C10 and C14 fatty acids). Evidence suggests that altered cellular metabolism plays a role in asthma, and that obesity and asthma are derived from common pathway(s) that promote inflammation and adiposity. A proprietary formula for a shake/smoothie or other food product as described herein (e.g., as an alternate-day calorie restriction) is provided herein to increases UCP-expression which results in a decrease in reactive oxygen species (ROS) expression which has a profound effect on asthma health. Mitochondrial function is central in regulating metabolism and susceptibility to allergic and immunologic diseases. In the mechanism and function of mitochondria, ATP is generated via cellular respiration through the electron transport chain. In this process some reactive oxygen species (ROS) are formed which are crucial in immune signal transduction and in pathological inflammation

(27) In certain embodiments, provided herein are food products (as described herein) that provide certain generally optimum protein levels while limiting carbohydrates, maximizing medium chain triglycerides (MCTs) (e.g., that provide C10 and C14 fatty acids) and total fat content. While the present invention is not limited to any particular mechanism, and an understanding of the mechanism is not necessary to practice the invention, is it believed that such food product encourage mitochondrial uncoupling protein 2 (UCP expression-2) which in-turn attenuates mitochondrial ROS production that could alleviate symptoms of asthma (e.g., determination of inflammation by noninvasive biomarker such as urinary bromotyrosine and exhaled NO).

(28) In some embodiments, the C10 and C14 fatty acids in the food product and compositions are esterified to a triglyceride, diglyceride, monoglyceride or phospholipid molecule. In some embodiments, the C10 and/or C14 fatty acids in the food product and compositions are provided as ethyl esters. In some embodiments, the capric acid (C10), myristic acid (C14), or combination thereof are provided in an oral delivery vehicle, food product, nutritional supplement, dietary supplement or functional food. In some embodiments, the administration of the capric acid (C10), myristic acid (C14), or combination thereof is oral, topical, parenteral, enteral, transdermal, intradermal, intraocular, intravitreal, sublingual, or intravaginal and may preferably comprise an effective amount of the composition.

(29) In certain embodiments, the capric acid (C10), myristic acid (C14) (or combination thereof) compositions according to the present technology comprises or consists of a pharmaceutically acceptable carrier, diluent, or excipient (including combinations thereof). Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient, or diluent is selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical comprise as, or in addition to, the carrier, excipient, or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilizing agent(s). This pharmaceutical composition will desirably be provided in a sterile form. It may be provided in unit dosage form and will generally be provided in a sealed container. A plurality of unit dosage forms may be provided.

(30) Pharmaceutical compositions within the scope of the present technology may include one or more of the following: preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, odorants, and/or salts. Compounds of the present technology may themselves be provided in the form of a pharmaceutically acceptable salt. In addition, embodiments may comprise buffers, coating agents, antioxidants, suspending agents, adjuvants, excipients, and/or diluents. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid.

(31) They may also contain other therapeutically active agents in addition to compounds of the present technology. Where two or more therapeutic agents are used they may be administered separately (e.g., at different times and/or via different routes) and therefore do not always need to be present in a single composition. Thus, combination therapy is within the scope of the present technology.

(32) The routes for administration (delivery) include, but are not limited to, one or more of: oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, via the penis, vaginal, epidural, sublingual. It is to be understood that not all of the agent need be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes.

(33) If the C10 and/or C14 agent of the present technology is administered parenterally, then examples of such administration include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrastemally, intracranially, intramuscularly, or subcutaneously administering the agent; and/or by using infusion techniques.

(34) In some embodiments, pharmaceutical compositions adapted for oral administration are provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions. Tablets or hard gelatin capsules may comprise lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Soft gelatin capsules may comprise vegetable oils, waxes, fats, semi-solid, or liquid polyols etc. Solutions and syrups may comprise water, polyols and sugars. For the preparation of suspensions, oils (e.g., vegetable oils) may be used to provide oil-in-water or water-in-oil suspensions. An active agent intended for oral administration may be coated with or admixed with a material that delays disintegration and/or absorption of the active agent in the gastrointestinal tract (e.g., glyceryl monostearate or glyceryl distearate may be used). Thus, the sustained release of an active agent may be achieved over many hours and, if necessary, the active agent can be protected from being degraded within the stomach. Pharmaceutical compositions for oral administration may be formulated to facilitate release of an active agent at a particular gastrointestinal location due to specific pH or enzymatic conditions.

(35) Alternatively, the C10 and/or C14 agent of the present technology may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The agent of the present technology may also be dermally or transdermally administered, for example, by the use of a skin patch. For application topically to the skin, the agent of the present technology can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. If the agent of the present technology is administered parenterally, then examples of such administration include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrastemally, intracranially, intramuscularly or subcutaneously administering the agent; and/or by using infusion techniques.

(36) For parenteral administration, the agent is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

(37) Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of that compound; the age, body weight, general health, sex, diet, mode and time of administration; rate of excretion; drug combination; the severity of the particular condition; and the individual undergoing therapy. The agent and/or the pharmaceutical composition of the present technology may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day. For oral and parenteral administration to human patients, the daily dosage level of the agent may be in single or divided doses.

(38) Depending upon the need, the agent may be administered at a dose of from 1 g/kg to 10/kg body weight, per day. Naturally, the dosages mentioned herein are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.

(39) “Therapeutically effective amount” refers to the amount of the therapeutic agent that is effective to achieve its intended purpose, i.e., treating symptoms of asthma or a reduction of inflammation and associated symptoms. The methods described herein may employ a daily therapeutically effective amount. While individual patient needs may vary, determination of optimal ranges for effective amounts of the compounds related to the technology is within the skill of the art. Generally, the dosage regimen for treating a condition with the compounds and/or compositions of this technology is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient; the severity of the dysfunction; the route of administration; pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used; whether a drug delivery system is used; and whether the compound is administered as part of a drug combination and can be adjusted by one skilled in the art. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the exemplary dosage regimens set forth herein.

EXAMPLES

Example 1

Capric Acid (C10) and Myristic Acid (C14) Improve Symptoms of Asthma

(40) Medium chain fatty acid (MCF) composition of natural coconut oil is shown in the table below Table 1 below.

(41) TABLE-US-00002 TABLE 1 C8:0 5-9% C16:0 8-11% C10:0 4-10% C18:0 8-14% C12:0 44-52% C18:1 1.5% max C14:0 13-21% C18:2 0.5% max
Mice were fed with standard, coconut oil or MCF supplemented diets starting six weeks before allergen sensitization. Isofluorane anesthetized mice received 100 ug house dust mite (D. pteronyssinus) extract (HDME) (Greer Labs, NC) in 50 ug saline by nasal aspiration. Five days later mice were challenged daily with 10 ug HDME for 5 days. Three days, after the last HDME exposure, airway hyper-reactivity is measured and lungs collected for analysis. The diets were 15 kcal % fat at a dose of 21 g coconut oil or purified MCF per kg diet. Based on the daily food intake of 4.75 g/day/25 g mouse, each mouse consumes 100 mg of coconut oil or MCF per day.

(42) TABLE-US-00003 TABLE 2 Daily Intake per Natural Coconut Oil mouse fed with Daily Intake per mouse fed MCF MCF Composition coconut oil with purified MCF diet C8  5-9% 5-9 mg 100 mg (4 g/kg body weight) C10  4-10% 4-10 mg 100 mg (4 g/kg body weight) C12 44-52% 44-52 mg 100 mg (4 g/kg body weight) C14 13-21% 13-21 mg 100 mg (4 g/kg body weight) C12/C14 — — 70/30 mg (2.8 g C12; 1.2 g C14/kg bodyweight)

(43) The results of this examples are shown in FIGS. 1-4, which show the results with the mice treated with the various fatty acids, which are present mainly as triglycerides in coconut oil. FIG. 1 shows that overall airway constriction (Rrs on Y-axis) induced by increasing dose of methacholine, a bronchoconstrictor, (x-axis) is inhibited in animals fed with C10 or C14. FIG. 2 shows that the ability of the lungs to stretch (Crs on Y-axis) in response to an increasing dose of methacholine (x-axis) is improved in animals fed with C10 or C14. FIG. 3 shows that stiffness the lungs (Ers on Y-axis) in response to an increasing dose of methacholine (x-axis) is decreased in animals fed with C10 or C14. FIG. 4 shows that the amount of forcefully exhaled air (FEV on Y-axis) in response to increasing dose of methacholine, (x-axis) is increased in animals fed with C10 or C14.

Example 2

Effect of Coconut Diet on Airway Hyper-Reactivity in a Preclinical Mouse Model of House Dust Mite Induced Asthma

(44) Experimental Outline and Results are as follows. Mice were fed with standard or coconut oil supplemented diets starting six weeks before allergen sensitization. Isofluorane anesthetized mice received 100 ug house dust mite (D. pteronyssinus) extract (HDME) (Greer Labs, NC) in 50 ug saline by nasal aspiration. Five days later mice are challenged daily with 10 ug HDME for 5 days. Three days, after last HDME exposure, airway hyper-reactivity is measured and lungs collected for analysis (FIG. 5).

(45) As shown in FIG. 6A-C, coconut oil diet reduced airway resistance (FIG. 6A-C) in a dose dependent manner: overall, central and peripheral airway hyper-reactivity were decreased. Lung compliance and elastance parameters showed coconut oil dose-dependent decreased of lung stiffness (FIG. 6D-F). The work shown in FIG. 6 was conducted as follows. Measurement of lung mechanics was performed using the FlexiVent ventilator (FlexiVent, Scireq, Montreal, Canada). Airway Hyperresponsiveness and lung mechanics were measured in response to increasing doses of inhaled methacholine. (A-C) Parameters of airway resistance. (D) Tissue compliance, which is inversely related to lung stiffness. (E-F) Lung elastance parameters.

(46) All publications and patents mentioned in the above specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the technology as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the technology that are obvious to those skilled in pharmacology, biochemistry, medical science, or related fields are intended to be within the scope of the following claims.