Black Seed Oil Formulation

Abstract

A black seed oil formulation for administration to a subject, comprising an enteric coated capsule and black seed oil therein.

Description

[Technical Field]

[0001] The subject matter disclosed herein relates to black seed oil formulations. [Background technology]

[0002] Black seed oil has been observed to have many beneficial health effects, including reducing high blood pressure, inflammation, allergies, and asthma, as well as antiviral and anticancer effects. However, some patients who receive black seed oil have reported experiencing negative gastric side effects. Therefore, new methods of administering black seed oil while reducing negative gastric side effects remain needed. Summary of the Invention

[0003] One aspect of the disclosed subject matter is to provide a black seed oil formulation comprising an enteric-coated capsule and black seed oil. In one exemplary embodiment, the enteric-coated capsule comprises a coating thereon comprising an enteric component. In other or further embodiments, the enteric-coated capsule comprises an enteric component incorporated directly into the capsule itself (e.g., incorporated into a substrate layer of the capsule).

[0004] In exemplary embodiments, the enteric capsule comprises an acid-insoluble polymer. In exemplary embodiments, the enteric capsule comprises a film-forming polymer. In exemplary embodiments, the enteric capsule comprises hydroxypropylmethylcellulose phthalate (HPMCP) and / or the enteric capsule comprises a base layer of hydroxypropylmethylcellulose (HPMC).

[0005] In an exemplary embodiment, the black seed oil formulation has a banding solution applied thereto. The banding solution, in an exemplary embodiment, includes a second enteric component. In one particular embodiment, the enteric component (e.g., HPMCP) and the second enteric component (e.g., HPMCP) are the same.

[0006] In exemplary embodiments, the black seed oil comprises at least 0.25 wt%, or at least 0.5 wt%, or at least 0.75 wt%, or at least 1 wt%, or at least 1.25 wt%, or at least 1.5 wt%, at least 1.6 wt%, or at least 1.75 wt%, at least 2 wt%, or at least 2.1 wt%, or at least 2.5 wt%, based on the total weight of black seed oil in the formulation.

[0007] In one exemplary embodiment, the black seed oil formulation remains intact in gastric acid (e.g., endogenous or simulated gastric acid) at a pH below 3. Thus, when administered to a subject, the black seed oil formulation does not dissolve or disintegrate in the subject's stomach, thereby avoiding or reducing the stomach discomfort that can occur when administering other black seed oil formulations.

[0008] In one exemplary embodiment, the black seed oil formulation dissolves or disintegrates at a pH greater than about 5.5. Thus, when administered to a subject, the black seed oil formulation is released in the lower part of the digestive tract, for example, the duodenum, jejunum, and / or colon. For example, in an exemplary embodiment, when targeting the jejunum, the black seed oil formulation dissolves or disintegrates at a pH of about 6 to about 7, but remains intact at a pH less than about 5.5; and when targeting the colon, the black seed oil formulation dissolves or disintegrates at a pH greater than 7, but remains intact at a pH less than about 6.0.

[0009] In one exemplary embodiment, a black seed oil formulation is provided, comprising an enteric capsule comprising a hydroxypropyl methylcellulose (HPMC) base layer and an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP), and black seed oil contained in the enteric capsule, wherein the black seed oil comprises at least 1.5% by weight of thymoquinone, based on the total weight of the black seed oil in the formulation. In one embodiment, the black seed oil formulation further comprises an applied banding solution, wherein the banding solution comprises hydroxypropyl methylcellulose phthalate (HPMCP). In one exemplary embodiment, the black seed oil is in an amount of about 500 mg, although other amounts of the formulation may also be provided. DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention can be more fully understood by referring to the following description, including examples. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used to implement or test the present invention, suitable methods and materials are described herein. Furthermore, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

[0011] Terms and Definitions As used herein, the term "about" or "approximately" refers to a range of tolerance for a particular value, as determined by one of ordinary skill in the art, which may depend in part on how the value is measured or determined, e.g., the limitations of the measurement system or technique. For example, "about" can refer to a range of up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a particular value. Alternatively, with respect to biological systems or processes, the term "about" can mean within an order of magnitude, within 5-fold, or within 2-fold on either side of a value. Numerical values described herein are approximations unless otherwise specified, and the term "about" or "approximately" is inferred even when not explicitly stated.

[0012] For a simpler explanation, some quantitative expressions described herein may not be accompanied by the term "about." However, regardless of whether the term "about" is explicitly used, all numerical values described herein are understood to mean both the actual value and its approximate value that can be reasonably estimated by a person skilled in the art, including equivalents and approximations based on experimental and / or measurement conditions for the given value. When a yield is expressed as a percentage, the yield indicates the mass of the subject substance relative to the maximum amount that can be obtained under specific stoichiometric conditions. When a concentration is expressed as a percentage, it indicates a mass ratio unless otherwise specified.

[0013] As used herein, the terms "a," "an," and "the" should be understood to refer to both the singular and the plural, unless otherwise specified. Thus, "a," "an," and "the" (and grammatical variations thereof, as appropriate) refer to one or more.

[0014] A group of items joined by the conjunction "and" should not be construed as requiring that each and every one of the items be included in the group, but rather should be construed as "and / or" unless otherwise expressly stated. Similarly, a group of items joined by the conjunction "or" should not be construed as requiring that the items in the group be mutually exclusive, but rather should be construed as "and / or" unless otherwise expressly stated. Furthermore, where items, elements, or components of the invention are described or claimed in the singular, the plural is intended to be included in the scope unless limitation to the singular is explicitly stated.

[0015] The terms "comprises" and "includes" are used herein in an open and non-limiting sense. Other terms and phrases used herein, and variations thereof, unless expressly stated otherwise, should be interpreted in an open and non-limiting sense. Thus, the term "example" or "for example" indicates an illustrative instance of the item under discussion, but is not intended to be an exhaustive or exclusive example. Similarly, the adjectives "conventional," "traditional," "usual," "standard," "known," and words of similar import should not be construed to limit what is being described to a particular era or what is available at a particular time, but rather should be interpreted to encompass conventional, traditional, usual, or standard technology available or known at any time now or in the future. Similarly, when this specification refers to technology that would be apparent or known to those of ordinary skill in the art, it encompasses technology that would be apparent or known to those of ordinary skill in the art at any time now or in the future.

[0016] The use of broad terms or phrases such as "one or more," "at least," "not limited to," or other similar terms should not be construed as indicating that a narrower meaning is intended or required in the absence of such broader terms. Those skilled in the art will appreciate after reading this specification that the illustrated embodiment and its various alternatives can be implemented without being limited to the illustrated examples.

[0017] The term "carrier" refers to an adjuvant, vehicle, or excipient with which a compound is administered. In some embodiments, the carrier is a solid carrier. Suitable pharmaceutical carriers include those described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005).

[0018] As used herein, the term "formulation" refers to the form in which the dose administered to a subject or patient is contained. The black seed oil extract may be administered as part of a formulation containing inactive ingredients, such as an enteric-coated capsule (e.g., an enteric-coated capsule).

[0019] The term "pharmaceutically acceptable" as used in connection with the disclosed subject formulations refers to molecular and other components of the formulation that are physiologically tolerable and do not ordinarily produce an untoward reaction when administered to an animal (e.g., a human) according to the intended method of administration (e.g., oral administration).

[0020] A pharmaceutically acceptable excipient refers to a substance that is non-toxic, biologically acceptable, and biologically suitable for administration to a subject, and includes, for example, an inert substance added to a pharmaceutical formulation as a vehicle, carrier, or diluent to facilitate administration of the drug and to be compatible with the drug. Suitable pharmaceutical carriers include those described in "Remington: The Science and Practice of Pharmacy, 21st Edition" (Lippincott Williams & Wilkins, 2005).

[0021] As used herein, the term "inactive" refers to the inactive ingredients of the described formulation. The definition of "inactive ingredient" as used herein is in accordance with the U.S. Food and Drug Administration (FDA) definition as defined in 21 CFR 201.3(b)(8) and is any component of a drug product other than the active ingredient.

[0022] As used herein, the term "suitable for oral administration" refers to a sterile pharmaceutical product, such as a product manufactured under Good Manufacturing Practices (GMP), that is suitable for administration to a subject (e.g., a human subject), as would be understood by one of skill in the art.

[0023] As used herein, the term "disorder" is used interchangeably with "disease" or "condition." For example, "pulmonary disorder" means a lung disease or condition.

[0024] The terms "treat," "treating," and "treatment" include therapy directed at a disease state in a subject, including: (i) preventing the onset of the disease state, particularly when the subject is predisposed to the disease state but has not yet been diagnosed with the disease; (ii) inhibiting the disease state, e.g., halting its progression (development) or delaying its onset; and (iii) mitigating the disease state, e.g., causing it to regress or improve until a desired outcome is achieved. Additionally, these terms include alleviating symptoms of the disease (e.g., reducing pain, discomfort, or impairment), which may or may not directly affect the disease itself (e.g., affecting the cause, transmission, or manifestation of the disease).

[0025] As used herein, the term "effective amount" is used interchangeably with "therapeutically effective amount" and refers to an amount or dosage of thymoquinone and / or other active ingredients contained in black seed oil that is effective in treating a specific disease, condition, or disorder disclosed herein. Therefore, "treating" includes producing the desired preventive, suppressive, palliative, or ameliorative effect. In the treatment methods of the present invention, an "effective amount" of any formulation described herein is administered to a subject (e.g., a mammal). The "effective amount" varies depending on the compound, the disease (and its severity), the desired treatment, the age and weight of the subject, etc., and can be determined by one of ordinary skill in the art depending on the circumstances.

[0026] As used herein, the terms "individual," "subject," and "patient" are used interchangeably and refer to vertebrates, particularly mammals, more particularly primates (including non-human primates and humans), including experimental animals in clinical trials, screening, or activity experiments. Thus, as will be readily understood by those skilled in the art, the formulations of the present invention are particularly suitable for administration to vertebrates, particularly mammals, more particularly humans.

[0027] Embodiments of the present invention will now be illustrated and described with reference to the examples set forth below. While specific embodiments are described herein, they are not intended to limit the scope of the present invention. Rather, the present disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the invention as defined by the appended claims.

[0028] In exemplary embodiments, the black seed oil formulations of the disclosed subject matter are formulated as capsules, ultimately formulated for oral administration, that are stable (i.e., do not dissolve) at pH levels typically found in the stomach (e.g., a pH of about 3 or lower), but readily disintegrate (i.e., dissolve or disintegrate) at higher pH levels typically found in the small intestine and further downstream in the digestive tract (e.g., a pH of about 5.5 to about 9). While it has previously been suggested that substantially all drug is released at a pH of >5.5 (e.g., 90% solubility of the formulation at pH 6.8), it has not been suggested that lower pH levels could increase the bioavailability of black seed oil and target drug delivery to the intestinal region, thereby finding application in certain indications, such as irritable bowel syndrome. See, e.g., Azad et al., Encapsulation of Black Seed Oil in Alginate Beads as a pH-Sensitive Carrier for Intestine-Targeted Drug Delivery: In Vitro, In Vivo and Ex Vivo Study, Pharmaceutics 2020, 72(3), 219 (incorporated herein by reference).

[0029] More specifically, the formulations disclosed herein can be designed to retain their shape and not dissolve or disintegrate at low pHs (e.g., pH of about 3 or lower) such as those encountered in the stomach, while dissolving at pHs targeted to the duodenum, jejunum, ileum, or colon. For example, in certain embodiments, the formulations of the present invention may be designed to dissolve at pHs >5.5 (when targeting the duodenum), pH 6-7 (when targeting the jejunum), or pH >7 (when targeting the ileum and colon), while retaining their shape and / or not dissolving or disintegrating in lower pH environments such as those found in the upper gastrointestinal tract. This can be achieved, for example, based on the capsule, enteric coating, and / or banding solution used. As described herein, and for purposes of brevity, the term "enteric" is used to refer to any of these formulations.

[0030] In certain embodiments, whether the formulation remains in shape or dissolves or disintegrates is determined by the U.S.P. <711> : (Dissolution test in either or both of Apparatus 1 (Basket Stirring Element) and / or Apparatus 2 (Paddle Stirring Element): Dissolution, determined by either or both of Apparatus 1 (Basket Stirring Element) and / or Apparatus 2 (Paddle Stirring Element).

[0031] In embodiments, the black seed oil formulations disclosed herein are formulated to have the enteric properties disclosed herein, either through the use of a capsule that is itself enteric coated, or through the use of a capsule that is not initially enteric coated but that is enteric coated prior to filling with the black seed oil, to provide an enteric formulation for administration to a subject. In such embodiments, the enteric coating applied to the capsule can also function as the banding solution. Alternatively, the banding solution can be applied separately as a separate step.

[0032] Examples of enteric coatings that can be used with the subject matter disclosed herein include enteric components known in the art, including acid-insoluble polymers and film-forming polymers. In exemplary embodiments, the acid-insoluble polymer can also be selected from the group consisting of acrylic and methacrylic acid copolymers, phthalic acid esters, butyric acid esters, cellulose acetate esters such as hydroxypropylmethylcellulose phthalate (HPMCP), and salts thereof. In exemplary embodiments, the film-forming polymer is selected from the group consisting of cellulose acetate phthalate, tremellitate cellulose acetate, HPMCP, hydroxypropylmethylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP), and methacrylic acid copolymers.

[0033] For example, HPMCP is a phthalate ester of hydroxypropyl methylcellulose and is accepted in the US National Formulary (US / NF). Capsules coated with enteric coatings such as HPMCP are commercially available from, for example, CapsCanada® (Dania Beach, Florida) and SE Tylose GmbH & Co. KG (Wiesbaden, Germany).

[0034] For example, the pH threshold at which enteric capsules containing HPMCP dissolve can be controlled by, for example, varying the phthalyl content. In certain exemplary embodiments, formulations of the present invention dissolve at, for example, pH >5.5 (targeting the duodenum), pH 6-7 (targeting the jejunum), or pH above 7 (targeting the ileum and colon).

[0035] Other enteric coatings that can be used with the disclosed subject matter include coatings comprising polymers with methyl acrylate as a monomer (e.g., copolymers of methyl acrylate); such polymers are commercially available with different acidic or alkaline groups, and the formulation retains its shape (does not dissolve or disintegrate) at low pH but dissolves, for example, at pH > 5.5 (targeting the duodenum), or pH 6-7 (targeting the jejunum), or at a pH above 7 (targeting the ileum and colon). The above-mentioned methyl acrylate enteric coatings are commercially available (e.g., Eudagrit® polymers for delayed release, such as Eudragit® L 30 D-55, Eudragit® FS 30 D, Eudragit® L, and Eudragit® S polymers, available from Evonik Industries AG, Essen, Germany).

[0036] In one exemplary embodiment, a hard capsule is provided. Alternatively, in another exemplary embodiment, a soft capsule is provided. In either case, in the exemplary embodiment, the surface of a pre-manufactured capsule is coated (e.g., sprayed or film-coated onto a previously manufactured capsule) with one or more layers of a substance or composition known to impart enteric properties (e.g., a composition including, but not limited to, HPMCP or a methyl acrylate copolymer). Alternatively, in another exemplary embodiment, enteric ingredients (e.g., HPMCP, a methyl acrylate copolymer, and other acid-insoluble polymers) are incorporated directly into the hard or soft capsule during their initial manufacture (i.e., the enteric polymer is introduced when the hard or soft capsule is first prepared). Thus, in this technique, the impartation of enteric properties occurs during the manufacturing process, as opposed to treating an already formed capsule.

[0037] In certain exemplary embodiments, film-forming polymers known to those skilled in the art can be incorporated to provide an enteric coating to the black seed oil formulations disclosed herein.

[0038] A banding solution can be applied to the formulations of the present disclosure. Traditionally, capsules are constructed in two halves, with one capsule half filled with a formulation containing black seed oil and then the other capsule half mated with the filled half to encapsulate the formulation. A banding solution can be applied to the bonded capsules to promote sustained, long-term bonding of the capsules. In some embodiments, the banding solution includes an enteric component, which can be the same enteric component incorporated into the enteric coating and / or the capsule itself.

[0039] In some embodiments, the amount of thymoquinone present in the administered black seed oil formulation is at least 0.25 wt%, or at least 0.5 wt%, or at least 0.75 wt%, or at least 1 wt%, or at least 1.25 wt%, or at least 1.5 wt%, or at least 1.6 wt%, or at least 1.75 wt%, at least 2 wt%, at least 2.1 wt%, or at least 2.5 wt%, based on the total weight of the black seed oil in the formulation. The dosage of black seed oil can be adjusted based on the concentration of thymoquinone in the administered black seed oil formulation.

[0040] The black seed oil formulations disclosed herein can be administered to a healthy subject to treat any indication or condition, or to maintain the subject's good health. In certain exemplary embodiments, the formulations disclosed herein are administered to a subject (e.g., orally to a human subject) to treat an inflammatory disease or condition. For example, the formulations disclosed herein can be administered to treat allergies, asthma, COPD, autoimmune diseases, celiac disease, colitis, irritable bowel syndrome, intestinal hyperplasia, metabolic syndrome, obesity, diabetes, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, or transplant rejection.

[0041] The following examples are included to demonstrate certain non-limiting aspects of the invention. It should be understood by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention. However, those of skill in the art should, in light of the disclosure herein, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. [Example]

[0042] Example 1: Oral Black Seed Oil Formulation Black seed oil (BSO) was filled into size 00 HPMC hard-shell, enteric-coated capsules (500 mg BSO / capsule) commercially available from CapsCanada® (Dania Beach, Florida) under the trade name AR-CAPS®. The HPMC capsules were coated with hydroxypropyl methylcellulose phthalate (HPMCP) to create the enteric-coated capsules. The capsules consisted of two parts; black seed oil was filled into the capsules and the two parts were then combined together. In a separate step, a liquid HPMCP composition was applied as a banding solution to the area where the top and bottom halves of the capsules join to seal the capsules. The filled and sealed capsules were inspected for leaks and then dried.

[0043] For the sake of brevity, all publications mentioned in this specification, including patent applications, patents, and other references, are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference, provided that the citation of such publications shall not be construed as an admission that they are prior art to the present invention.

[0044] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, 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 scope of the invention as encompassed by the claims. Furthermore, all embodiments contained herein are set forth for illustrative purposes only and should not be construed as limitations on the invention, as many variations are possible without departing from the spirit and scope of the invention.

Claims

1. A black seed oil formulation comprising an enteric-coated capsule and black seed oil.

2. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises a coating disposed thereon, the coating comprising an enteric component.

3. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises an enteric ingredient directly incorporated into the capsule.

4. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises an acid-insoluble polymer.

5. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises a film-forming polymer.

6. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises hydroxypropyl methylcellulose phthalate (HPMCP).

7. 10. The black seed oil formulation of claim 1, wherein the enteric capsule comprises a hydroxypropyl methylcellulose (HPMC) base layer.

8. 4. The black seed oil formulation of claim 2 or 3, further comprising a banding solution applied thereon.

9. 9. The black seed oil formulation of claim 8, wherein the banding solution comprises a second enteric component.

10. 10. The black seed oil formulation of claim 9, wherein the enteric component and the second enteric component are the same.

11. 11. The black seed oil formulation of claim 10, wherein the enteric ingredient is hydroxypropyl methylcellulose phthalate (HPMCP).

12. 2. The black seed oil formulation of claim 1, wherein the black seed oil contains at least 1.5% by weight of thymoquinone, based on the total weight of black seed oil in the formulation.

13. 2. The black seed oil formulation of claim 1, wherein the black seed oil contains at least 2% by weight of thymoquinone, based on the total weight of black seed oil in the formulation.

14. 10. The black seed oil formulation of claim 1, wherein the formulation remains intact in stomach acid at a pH of 3 or below.

15. 13. The black seed oil formulation of claim 12, wherein the formulation dissolves or disintegrates at a pH greater than about 5.

5.

16. 13. The black seed oil formulation of claim 12, wherein the formulation remains intact at a pH below about 5.5 and dissolves or disintegrates at a pH of about 6 to about 7.

17. 13. The black seed oil formulation of claim 12, wherein the formulation remains intact at a pH below about 6.0 and dissolves or disintegrates at a pH above 7.

18. an enteric capsule comprising a hydroxypropyl methylcellulose (HPMC) substrate layer and an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP); and 1. A black seed oil formulation in an enteric coated capsule, wherein the black seed oil contains at least 1.5% by weight of thymoquinone based on the total weight of the black seed oil in the formulation. and a black seed oil formulation containing.

19. 20. The black seed oil formulation of claim 18, further comprising a banding solution applied thereon, said banding solution comprising hydroxypropyl methylcellulose phthalate (HPMCP).

20. 20. The black seed oil formulation of claim 18 or 19, wherein the black seed oil is contained in an amount of about 500 mg.

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