Black seed oil preparation

Abstract

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

Description

Technical Field

[0001] The presently disclosed subject matter relates to black seed oil formulations. Background Art

[0002] Black seed oil has been observed to have a variety of beneficial health effects, such as reducing high blood pressure, inflammation, allergies, asthma, and antiviral and anticancer properties. Unfortunately, some patients taking black seed oil have reported negative gastric side effects. Therefore, there remains a need for new methods to administer black seed oil while reducing negative gastric side effects. Summary of the Invention

[0003] One aspect of the present disclosure provides a black seed oil formulation comprising an enteric-coated capsule and black seed oil contained therein. In an exemplary embodiment, the enteric-coated capsule comprises a coating comprising an enteric component applied thereto. In alternative or further embodiments, the enteric-coated capsule comprises an enteric component incorporated directly into the capsule itself (e.g., incorporated into a matrix layer of the capsule).

[0004] In an exemplary embodiment, the enteric capsule comprises an acid-insoluble polymer. In an exemplary embodiment, the enteric capsule comprises a film-forming polymer. In an exemplary embodiment, the enteric capsule comprises hydroxypropyl methylcellulose phthalate (HPMCP) and / or the enteric capsule comprises a hydroxypropyl methylcellulose (HPMC) matrix layer.

[0005] In an exemplary embodiment, the black seed oil formulation comprises a banding solution applied thereto. In an exemplary embodiment, the banding solution comprises a second enteric component. In a specific embodiment, the enteric component (e.g., HPMCP) and the second enteric component (e.g., HPMCP) are the same.

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

[0007] In an exemplary embodiment, the black seed oil formulation remains intact in gastric acid (e.g., endogenous or simulated gastric acid) at a pH of 3 or less. 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 gastric discomfort that may occur with administration of 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 digestive tract, such as in the duodenum, jejunum, and / or colon. For example, in one exemplary embodiment, the black seed oil formulation dissolves or disintegrates at a pH of about 6 to about 7, while remaining intact at a pH below about 5.5, for targeting the jejunum, or dissolves or disintegrates at a pH above 7, while remaining intact at a pH below about 6.0, for targeted delivery to the ileum and colon.

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

[0010] By reference to the following description (including examples), the present invention can be more fully understood. Unless otherwise defined, all technical and scientific terms used herein all have the identical meaning commonly understood by those of ordinary skill in the art. Although methods and materials similar or equivalent to those methods and materials described herein can be used when practicing or testing the present invention, suitable methods and materials are described herein. In addition, the materials, methods and examples are only illustrative and are not intended to be limiting.

[0011] Terms and Definitions

[0012] As used herein, the term "about" or "approximately" means within an acceptable range of a particular value determined by one skilled in the art, and may depend in part on how the value is measured or determined, such as limitations of the measurement system or technology. For example, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% or less on either side of a given value. Alternatively, with respect to biological systems or processes, the term "about" can mean within an order of magnitude, within 5 times, or within 2 times of a value on either side. Unless otherwise indicated, the numerical values ​​given herein are approximate, which means that the term "about" or "approximately" can be inferred when not explicitly stated.

[0013] In order to provide a more concise description, some of the quantitative expressions given herein are not limited by the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each amount given herein is intended to refer to the actual given value and the approximate value of this value that can be reasonably inferred based on the ordinary skills in the art, including equivalent values ​​and approximate values ​​derived due to the experimental and / or measurement conditions of this given value. Whenever a yield is given as a percentage, this yield refers to the mass of the entity given by the yield relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Unless otherwise indicated, concentrations given as a percentage refer to mass ratios.

[0014] As used herein, unless expressly stated otherwise, the terms "a / kind" and "the" are to be understood to refer to both the singular and the plural. Thus, "a / kind" and "the" (and appropriate grammatical variations thereof) refer to one or more.

[0015] Unless expressly stated otherwise, a group of items linked with the conjunction "and" should not be read as requiring that each of those items be present in the grouping, but rather should be read as "and / or." Similarly, a group of items linked with the conjunction "or" should not be read as requiring mutual exclusivity among the grouping, but rather should be read as "and / or," unless expressly stated otherwise. Furthermore, although items, elements, or components of the invention may be described or claimed in the singular, the plural is contemplated within the scope thereof unless limitation to the singular is explicitly stated.

[0016] The terms "comprise" and "include" are used in this document in an open, non-restrictive sense. Unless expressly stated otherwise, other terms and phrases used in this document and variations thereof should be interpreted as open and not restrictive. Thus, the term "example" is used to provide an illustrative example of the item being discussed, rather than an exhaustive or limiting list thereof. Similarly, adjectives such as "conventional," "traditional," "normal," "standard," "known," and terms of similar meaning should not be interpreted as limiting the item in question to items available at a given time period or at a given time, but should be interpreted as covering conventional, traditional, normal, or standard technology that is available or known at any time now or in the future. Similarly, when this document refers to technology that is obvious or known to a person of ordinary skill in the art, such technology covers technology that is obvious or known to a person of ordinary skill in the art at any time now or in the future.

[0017] In some cases, expanded words and phrases (such as "one or more," "at least," "but not limited to," or other similar phrases) should not be interpreted as meaning that narrower circumstances are intended or required in the absence of these expanded phrases. As will become apparent to one of ordinary skill in the art after reading this document, the illustrative embodiments and their various alternatives may be implemented without limitation to the illustrative examples.

[0018] 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 edition, Lippincott Williams & Wilkins (2005).

[0019] As used herein, the term "formulation" is the form in which a dosage is administered to a subject or patient. The black seed oil extract can be administered as part of a formulation containing inactive agents, such as an enteric (eg, enteric-coated) capsule.

[0020] The term "pharmaceutically acceptable," as used in connection with the formulations of the present disclosure, means that the molecular entities and other ingredients of such formulations are physiologically tolerable and do not generally produce adverse reactions when administered to animals (e.g., humans) according to their intended mode of administration (e.g., oral).

[0021] A "pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and biologically suitable substance (such as an inert substance) that is added to a pharmacological formulation or otherwise used as a vehicle, carrier, or diluent to facilitate administration of the agent and is compatible therewith. Suitable pharmaceutical carriers include those described in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005).

[0022] As used herein, the term "inert" refers to any inactive ingredient of the formulation. As used herein, the definition of "inactive ingredient" follows the definition of the U.S. Food and Drug Administration in 21 CFR 201.3(b)(8), i.e., any component of a drug product other than the active ingredient.

[0023] As used herein, "suitable for oral administration" refers to a sterile drug product, such as a product manufactured according to good manufacturing practices (GMP) as understood in the art, that is suitable for administration to a subject (eg, a human subject).

[0024] As used herein, the term "disorder" is used interchangeably with "disease" or "condition." For example, a pulmonary disorder also means a pulmonary disease or pulmonary condition.

[0025] The term "treating" encompasses therapeutic approaches to a disease state in a subject and includes: (i) preventing the disease state from occurring, particularly where the subject is susceptible to the disease state but has not yet been diagnosed with the disease state; (ii) inhibiting the disease state, e.g., arresting its development (progression) or delaying its onset; and (iii) relieving the disease state, e.g., causing regression of the disease state, until a desired endpoint is reached. These terms also include ameliorating symptoms of the disease (e.g., relieving pain, discomfort, or disability), where such improvement may directly affect the disease (e.g., affecting the cause, spread, or manifestations of the disease) or not directly affect the disease.

[0026] As used in this disclosure, the term "effective amount" is interchangeable with "therapeutically effective amount" and refers to the amount or dosage of thymoquinone and / or other active ingredients in black seed oil that is effective to treat the specific diseases, disorders, or conditions disclosed herein, and thus "treating" includes producing the desired preventive, inhibitory, alleviating, or ameliorative effect. In the treatment methods according to the present invention, an "effective amount" of any of the presently described formulations is administered to a subject (e.g., a mammal). The "effective amount" will vary 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 on a case-by-case basis.

[0027] The terms "individual," "subject," and "patient" are used interchangeably herein and may refer to vertebrates, particularly mammals, more particularly primates (including non-human primates and humans), and include experimental animals in the context of clinical trials or screening or activity experiments. Thus, as will be readily appreciated by those skilled in the art, the formulations of the present invention are particularly suitable for administration to any vertebrate, particularly mammals, more particularly humans.

[0028] Reference will now be made to embodiments of the present invention, examples of which will be described and illustrated in conjunction with the accompanying examples. Although certain embodiments are described herein, it should be understood that the embodiments are not intended to limit the scope of the present invention. On the contrary, this disclosure is intended to encompass alternatives, modifications, and equivalents, all of which may be included within the present invention as defined by the appended claims.

[0029] In an exemplary embodiment, the black seed oil formulations of the present disclosure are formulated into capsules that, when ultimately formulated for oral administration, 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 break down (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). It has been previously shown that at pH values ​​greater than 5.5, substantially all of the drug is released (e.g., 90% solubility for the formulation at pH 6.8), while no drug is released at lower pH values. This can improve the bioavailability of black seed oil and target drug delivery to areas of the intestine, making it useful for treating specific 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, 12(3), 219, which is hereby incorporated by reference.

[0030] More specifically, the formulations of the present disclosure can allow the formulation to remain intact and not dissolve or disintegrate at low pH (e.g., about 3 or lower pH) when it enters the stomach, but dissolve at a pH targeting the duodenum, jejunum, or ileum and colon. For example, in certain embodiments, the formulation can dissolve at a pH higher than 5.5 (duodenal targeting) or pH 6-7 (jejunum targeting) or higher than 7 pH (ileum and colon targeting), while remaining intact and / or not dissolving or disintegrating under lower pH conditions further upstream in the digestive tract. This can be achieved, for example, based on the capsule, enteric coating, and / or sealing solution employed. As used herein, and for the purpose of brevity, the term "enteric" refers to any of such formulations.

[0031] In certain embodiments, whether a formulation is considered intact, dissolved, or disintegrated is determined by USP <711> To determine: dissolution in either or both of apparatus 1 (basket stirring element) and / or apparatus 2 (paddle stirring element).

[0032] In embodiments, the black seed oil formulations of the present disclosure are formulated to provide the enteric properties of the present disclosure by using capsules that are enteric in nature, or by using capsules that are not initially enteric but have been modified with an enteric coating prior to loading with black seed oil, thereby providing an enteric formulation for administration to a subject. In such embodiments, the enteric coating applied to the capsules may also serve as a sealing solution. Alternatively, the sealing solution may be applied separately as a separate step.

[0033] The example of enteric coating that can be used according to the present disclosure includes enteric components known in the art, including acid-insoluble polymers and film-forming polymers. In an exemplary embodiment, the acid-insoluble polymer can also be selected from the group consisting of: acrylic acid and methacrylic acid copolymers, cellulose acetate, such as phthalates, butyrates, hydroxypropyl methylcellulose phthalate and salts thereof. In an exemplary embodiment, the film-forming polymer is selected from the group consisting of: cellulose acetate phthalate, cellulose acetate trimellitate (cellulose acetate tremellitate), HPMCP, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate (PVAP) and methacrylic acid copolymers.

[0034] For example, HPMCP is a phthalate ester of hydroxypropyl methylcellulose and is included in the United States National Pharmacopoeia (US / NF). Capsules to which enteric coatings such as HPMCP have been applied are available from, for example, CapsCanada. ® (Dania Beach, FL) and SETylose GmbH & Co. KG (Wiesbaden, Germany).

[0035] The threshold pH at which enteric-coated capsules containing HPMCP dissolve, for example, can be controlled, for example, by varying the phthalyl content. In certain exemplary embodiments, the formulation dissolves at, for example, a pH greater than 5.5 (duodenal targeting), or pH 6-7 (jejunum targeting), or greater than 7 (ileum and colon targeting).

[0036] Another enteric coating that can be used in accordance with the present disclosure includes a coating comprising a polymer having methyl acrylate as a monomer (e.g., a methyl acrylate copolymer) having various acidic or basic groups to allow the formulation to remain intact and not dissolve or disintegrate at low pH, but to dissolve at, for example, a pH above 5.5 (duodenal targeting) or pH 6-7 (jejunal targeting) or a pH above 7 (ileum and colon targeting). Methyl acrylate enteric coatings as described above are commercially available (e.g., Eudragit® polymers for delayed release, such as Eudragit® L 30 D-55, Eudragit® FS 30 D, Eudragit® L, and Eudragit® S polymers, which are commercially available from Evonik Industries AG (Essen, Germany)).

[0037] In certain exemplary embodiments, hard capsule is provided.Alternatively, in certain exemplary embodiments, soft capsule is provided.In either case, in exemplary embodiments, with one or more layers of known enteric properties can be given material or composition coating the surface of the capsule manufactured in advance (for example, spraying or film coating manufactured capsule), described material or composition such as but not limited to the composition comprising HPMCP or methacrylate copolymer.Alternatively, in other exemplary embodiments, enteric components (for example, HPMCP, methyl acrylate copolymer and other acid-insoluble polymers) are directly incorporated into hard capsule or soft capsule (that is, when initially preparing hard capsule or soft capsule, introduce enteric polymer) when initial manufacturing.Therefore, in this technology, the giving of enteric properties occurs during the manufacturing process, rather than processing preformed capsule.

[0038] In certain exemplary embodiments, film-forming polymers known to those of ordinary skill in the art may also be incorporated to provide an enteric coating in the black seed oil formulations of the present disclosure.

[0039] A sealing solution can be applied to the formulations of the present disclosure. Conventionally, capsules are composed of two halves. If one half of the capsule is filled with the formulation containing black seed oil, the other half of the capsule is joined to the filled half to encapsulate the formulation. A sealing solution can be applied to the joined capsules to promote sustained and long-term bonding of the capsules. In certain embodiments, the sealing solution contains an enteric component, which can be the same enteric component incorporated into the enteric coating and / or the capsule itself.

[0040] In certain embodiments, the amount of thymoquinone present in the administered black seed oil formulation is at least 0.25%, or at least 0.5%, or at least 0.75%, or at least 1%, or at least 1.25%, or at least 1.5%, at least 1.6%, or at least 1.75%, at least 2%, at least 2.1%, or at least 2.5%, 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 thymoquinone concentration in the administered black seed oil formulation.

[0041] The presently disclosed black seed oil formulations can be administered to treat any indication or condition in a subject, or to a healthy subject seeking to maintain good health. In certain exemplary embodiments, the presently disclosed formulations are administered to a subject (e.g., orally to a human subject) to treat an inflammatory disease or condition. For example, the presently disclosed formulations can be administered to treat an inflammatory disease or condition selected from the group consisting of 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, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejection.

[0042] The following examples are included to demonstrate certain non-limiting aspects of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in practice. However, in light of this disclosure, it will be appreciated by those skilled in the art that many changes may be made in the specific embodiments disclosed and still achieve similar or similar results without departing from the spirit and scope of the present invention.

[0043] Example

[0044] Example 1: Oral Black Seed Oil Formulation

[0045] Black seed oil (BSO) was filled into size 00 HPMC hard shell enteric coated capsules (500 mg BSO / capsule), which are available under the trade name AR-CAPS ® From CapsCanada ® (Dania Beach, FL). HPMC capsules are coated with hydroxypropyl methylcellulose phthalate (HPMCP) to provide enteric-coated capsules. The capsules are supplied in two pieces, into which black seed oil is placed, and the two pieces are joined together. In a separate procedure, a liquid formulation of HPMCP is applied as a sealing solution to the area where the top and bottom of the capsule meet to seal the capsule. The filled and sealed capsules are then inspected for leaks and dried.

[0046] For the sake of brevity, all publications, including patent applications, patents, and other citations mentioned herein are incorporated 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 by reference. However, the citation of any such publication should not be construed as an admission that it is prior art to the present invention.

[0047] Although the present invention has been particularly shown and described with reference to its preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention as encompassed by the claims. In addition, all embodiments included herein are given for illustrative purposes only and are not to be construed as limiting the present invention, as various changes may be made thereto without departing from the spirit and scope of the invention.

Claims

1. A black seed oil preparation, comprising an enteric-coated capsule and black seed oil contained therein.

2. The black seed oil formulation of claim 1, wherein the enteric-coated capsule comprises a coating comprising an enteric component applied thereto.

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

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

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

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

7. The black seed oil preparation of claim 1, wherein the enteric-coated capsule comprises a hydroxypropyl methylcellulose (HPMC) matrix layer.

8. The black seed oil preparation of claim 2 or 3, further comprising a sealing solution applied thereto.

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

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

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

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

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

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

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

5.

16. The black seed oil formulation of claim 12, wherein the formulation dissolves or disintegrates at a pH of about 6 to about 7 while remaining intact at a pH below about 5.

5.

17. The black seed oil formulation of claim 12, wherein the formulation dissolves or disintegrates at a pH above 7 while remaining intact at a pH below about 6.

0.

18. A black seed oil preparation comprising: Enteric-coated capsules comprising a hydroxypropyl methylcellulose (HPMC) matrix layer and an enteric coating comprising hydroxypropyl methylcellulose phthalate (HPMCP); and Black seed oil is contained in the enteric-coated capsule, wherein the black seed oil comprises at least 1.5 wt % thymoquinone based on the total weight of the black seed oil in the formulation.

19. The black seed oil formulation of claim 18, further comprising a sealing solution applied thereto, the sealing solution comprising hydroxypropyl methylcellulose phthalate (HPMCP).

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