Preparations containing omega-3 fatty acid salts and extracts of gum resin from Boswellia species

Abstract

The present invention relates to a preparation comprising at least one extract of gum resin from Boswellia species and at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Surprisingly, this combination of the extract of gum resin from Boswellia species and polyunsaturated fatty acid salts significantly and unexpectedly enhances the biosynthesis of specific inflammation-resolving lipid mediators (SPMs), helping to resolve inflammatory symptoms.

Description

[Technical Field]

[0001] The present invention provides a preparation comprising an extract of gum resin from Boswellia species in combination with at least one omega-3 fatty acid salt consisting of at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); their use to promote the production of specific inflammation-resolving lipid mediators (SPMs) that actively resolve inflammation; Regarding. [Background technology]

[0002] Dietary intake of omega-3 fatty acids, namely alpha-linolenic acid (ALA), EPA, and DHA, is beneficial to human health, specifically improving rheumatoid arthritis and reducing cardiovascular disease risk factors [1,2]. Although various seafood products are dietary sources of EPA / DHA, their consumption is often insufficient to meet dietary requirements (typically 500 g of EPA and DHA per day) [3]. This gap has been filled by the widespread availability of dietary supplements and fortified foods containing omega-3 fatty acids [4]. Dietary supplements are concentrated sources of nutrients or other substances with nutritional or physiological effects intended to supplement the normal diet (www.efsa.europa.eu / en / topics / topic / food-supplements). For example, omega-3 fatty acid supplements often contain triglycerides or omega-3 ethyl esters of EPA / DHA derived from fish oil, krill oil, or algae.

[0003] Omega-3 fatty acids generally have anti-inflammatory, cardioprotective, and neuroprotective properties [2,5]. Their mechanisms of action include, for example, direct scavenging of reactive oxygen species, alteration of cell membrane fluidity with subsequent influence on cell signaling events, modulation of the activity of transcription factors such as PPARγ and NFkappaB that regulate the biosynthesis of pro- and anti-inflammatory cytokines, and competitive elimination of substrates converted to pro-inflammatory mediators by cyclooxygenase and lipoxygenase.

[0004] Because daily intake of these omega-3 sources from food and dietary supplements is limited, ensuring maximum bioavailability of these fatty acids is important. Because hydrophobic nutrients are often consumed independently of meals in capsule or pill form, their bioavailability from the digestive system is often low, presenting a particular challenge for supplements. Secretion of digestive juices (bile acids, phospholipids, lipase) is rarely or not induced in the fasting state, leading to incomplete enzymatic hydrolysis of oils and fats, low solubilization capacity, and low bioavailability.

[0005] Further challenges to bioavailability arise when advanced formulation techniques are used to release omega-3 fatty acids in the lower digestive system (e.g., small or large intestine), bypassing part of the digestive system. Capsules or tablets coated with release polymers, respectively, can be used for this purpose. In these systems, the natural solubilization mechanisms described above are less effective and reduce bioavailability, so they must be supplemented with appropriate measures.

[0006] The same is true for the application of omega-3 fatty acids to isolated cells and tissues for in vitro culture, for example, as part of a serum-free cell culture medium composition. In these applications, solubilization in the gastrointestinal tract is preferably mimicked by a formulation close to the natural system to maximize biocompatibility and bioavailability. For addition to cell culture media, it is also essential to disperse the fatty acids in the medium so that they can optimally pass through a sterile filter.

[0007] Various approaches have been developed to solve the bioavailability problem by formulating omega-3 fatty acids, chemically modifying them, or both. One promising approach is the hydrolysis of omega-3 fatty acid esters followed by saponification, which mimics part of the natural digestive process and thereby increases solubility. Patent Document 1 describes a composition containing polyunsaturated omega-3 fatty acid salts that can be stabilized against oxidation.

[0008] Lipid mediators (LMs) play an important role in promoting and resolving inflammation, thus regulating various inflammatory and inflammation-related diseases. Among proinflammatory LMs, cyclooxygenase (COX)-derived prostaglandins such as PGE2 and 5-lipoxygenase (LOX)-derived products such as LTB4 are particularly interesting. These proinflammatory eicosanoids are generated from arachidonic acid (AA, 20:4).

[0009] Meanwhile, LOX enzymes, and to some extent COX, can act in concert to convert AA into anti-inflammatory lipoxins or metabolize eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) into inflammation-resolving LMs (so-called "specific inflammation-resolving lipid mediators" or SPMs). Recently, several oxygenated products of ω-3 and ω-6 fatty acids have been identified and functionally positioned as key mediators of the beneficial health effects of these fatty acids, particularly in ameliorating chronic inflammatory conditions. [6] These SPMs include maresins (MaRs), ED-series and D-series resolvins (RvEs and RvDs), protectins, lipoxins, and their precursors, such as 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17,18-epoxyeicosatetraenoic acid (17,18-EEQ). SPMs are endogenously formed by LOX, COX-2, and cytochrome P450 monooxygenases (CYP450) and function as potent agonists of active inflammation resolution, signaling through G protein-coupled receptors at nanomolar concentrations. Rodent studies have demonstrated the efficacy of SPMs against numerous infectious and inflammatory diseases. [6] For example, RvE1, RvD2, protectin D1 (PD1), and LXA4 promote the clearance of pathogenic Pseudomonas gingivalis [7], Escherichia coli [8], Herpes simplex [9], Candida

[10] , and H5N1 influenza

[11] .

[0010] LXA4, LXB4, RvE1, RvE3, RvD1-6, PD1, MaR1, and MaR2 are protective in models of periodontitis, cystic fibrosis, neuroinflammation, ischemic stroke, Alzheimer's disease

[12] , atherosclerosis

[13] , nonalcoholic fatty liver disease

[14] , corneal trauma

[15] , retinopathy

[16] , glaucoma

[17] , colitis

[18] , asthma [19, 20], insulin resistance

[14] , arthritis

[21] , and pain

[22] . Furthermore, some precursors of SPMs have been shown to exert anti-inflammatory effects themselves. For example, 18-hydroxy-eicosapentaenoic acid (18-HEPE) inhibits monocyte adhesion to vascular endothelial cells

[23] and prevents the progression of cardiovascular disease by inhibiting pressure overload-induced maladaptive cardiac remodeling

[24] . Similarly, 17,18-EEQ has cardioprotective, antiarrhythmic, vasodilatory, and anti-inflammatory properties.[5] Paracrine secretion of ARA-derived 15-HETE by enteric glial cells supports intestinal barrier function, a function that is impaired in conditions such as Crohn's disease.

[25]

[0011] However, translating these promising preclinical findings to improve human health has proven challenging. Direct administration of SPMs via intravenous or intraperitoneal injection, as has been done in experimental studies, is not suitable for humans, regardless of its preventative approach. Oral administration of SPM-containing supplements or foods is not rational due to the relatively short half-life of SPMs in body fluids, making them unlikely to reach target tissues. Clinical trials using the SPM precursors EPA / DHA have yielded inconclusive or negative results, particularly in patients with inflammatory bowel disease, asthma, and metabolic syndrome [2]. This lack of benefit in humans contrasts with the effective treatment of various animal disease models with SPMs [6]. We believe that the endogenous conversion of ω-3 (and ω-6) fatty acids to SPMs is a crucial step for successful outcomes from interventions aimed at preventing, curing, or treating inflammatory diseases with polyunsaturated fatty acids (PUFAs). We also believe that the SPM-generating machinery is dysfunctional under certain conditions, a notion supported by findings of decreased (local or circulating) SPM levels in diabetic wounds

[26] , metabolic syndrome

[27] , asthma [19, 28], ulcerative colitis

[29] , Crohn's disease

[25] , and periodontitis

[30] , as well as decreased expression or activity of SPM-generating enzymes in severe asthma

[28] , ulcerative colitis

[29] , cystic fibrosis

[31] , periodontitis

[30] , and Alzheimer's disease

[12] .

[0012] Two major aspects that determine the extent of LM production in cells are the amount and activity of biosynthetic enzymes (COX, LOX, CYP) that can be affected by Boswellia extract and the amount of available substrates (AA, EPA, and DHA). [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2016 / 102323A1 Summary of the Invention [Problem to be solved by the invention]

[0014] It is therefore an object of the present invention to provide a technology that will enhance endogenous SPM production in an organism to benefit humans and animals suffering from the above conditions and who are in need of new strategies to prevent, ameliorate, or cure such similar conditions where omega-3 supplementation alone has had little or no success.

[0015] This object is achieved by the present invention, which provides mixtures of omega-3 fatty acids and / or their salts with extracts of gum resin from Boswellia species and their use for stimulating the production of specific resolution lipid mediators (SPMs) that actively resolve inflammation.

[0016] It has been surprisingly found that the combined supplementation of an omega-3 fatty acid salt consisting of at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid, with an extract of gum resin derived from Boswellia species, synergistically enhances the production of specific inflammation-resolving lipid mediators and their precursors.

[0017] Boswellia, also known as Indian frankincense, is an herbal extract obtained from the gum resin of the Boswellia tree. Resin made from the bark of the Boswellia tree has been used for centuries in Asian and African folk medicine. It is believed to be effective in treating chronic inflammatory diseases and other health conditions. Boswellia preparations are available as resin, pills, or creams. Extracts of gum resin from Boswellia species (Boswellia extracts) have been demonstrated to be effective in reducing inflammation and may be useful in treating many health conditions, including osteoarthritis, rheumatoid arthritis, asthma, and inflammatory bowel disease.

[0018] Boswellia extract has effective anti-inflammatory properties, making it an effective pain reliever and preventing cartilage loss.

[0019] Various tetracyclic and pentacyclic triterpene acids (e.g., boswellic acid, tirucaric acid, lobulic acid, lupeolic acid, and nicantic acid) in Boswellia extracts contribute to their anti-inflammatory properties. In particular, boswellic acids are bioactive and include β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid (KBA), and acetyl-11-keto-β-boswellic acid (AKBA). Boswellic acids are a series of pentacyclic triterpene molecules produced by plants in the Boswellia genus. Like many other terpenes, boswellic acids occur in the resins of plants that exude them; they are estimated to comprise 30% of the ethanolic extract produced from the resin of Boswellia serrata. KBA and AKBA inhibit 5-lipoxygenase (5-LOX), an enzyme that produces leukotrienes. AKBA is believed to be the most potent of the four boswellic acids in inhibiting 5-LOX, although other studies have implicated other boswellic and triterpene acids in the extract's anti-inflammatory properties through inhibition of cathepsin G, LL-37, microsomal prostaglandin E2 synthase (mPGES)-1, and eye kappa B kinase.

[0020] Preparations combining Boswellia extract with omega-3 fatty acids selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be applied, for example, as dietary supplements or orally administered drugs with appropriate coatings, and released in specific regions of the gastrointestinal tract. Furthermore, such compositions formulated with carrier systems (e.g., nanocellulose) can be used topically to treat inflammatory skin conditions.

[0021] Omega-3 fatty acids commonly used in food fortification or dietary supplements are derived from krill oil, fish oil, or ethyl esters derived from the former. Recently, a technique has been reported for stabilizing EPA / DHA-free fatty acids with amino acids, resulting in solid, somewhat inert EPA / DHA salts that can be incorporated into food and supplement preparations. International Publication No. 2016 / 102323A1 describes a composition comprising a polyunsaturated omega-3 fatty acid salt that can be stabilized against oxidation. International Publication No. 2017 / 202935A1 discloses a method for preparing a composition comprising an omega-3 fatty acid salt and an amine, comprising the steps of kneading a paste containing one or more omega-3 fatty acids, one or more basic amines, and 20% or less by weight of water, based on the total weight of the paste, until a homogeneous paste is obtained.

[0022] Therefore, the present invention of a boosting technology for intracellular SPM production opens new opportunities in the prevention and treatment of various inflammatory conditions, including diseases, especially cardiovascular, joint and chronic inflammatory diseases.

[0023] The present invention provides at least one extract of gum resin from Boswellia species; at least one polyunsaturated fatty acid consisting of at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid; The present invention relates to a preparation comprising:

[0024] The extracts according to the present invention are prepared from one or more of the following: Boswellia serrata, Boswellia carterii, Boswellia papyrifera, Boswellia ameero, Boswellia bullata, Boswellia dalzielii, Boswellia dioscorides, Boswellia elongata, Boswellia frereana, Boswellia nana, Boswellia neglecta, Boswellia ogadensis, Boswellia pirottae, Boswellia Boswellia pirottae, Boswellia popoviana, Boswellia rivae, Boswellia sacra, and Boswellia socotrana, preferably Boswellia serrata.

[0025] The extracts are prepared by using hydrodistillation, steam distillation, extraction by percolation, extraction under ultrasound, solvent extraction, Soxhlet extraction, supercritical fluid extraction, or membrane nanofiltration.

[0026] In a preferred embodiment of the present invention, the preparation comprises one or more boswellic acids, preferably one or more boswellic acids selected from β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid (AKBA), α-boswellic acid, 3-O-acetyl-α-boswellic acid, and 3-O-acetyl-β-boswellic acid.

[0027] In another embodiment, the preparation further comprises one or more of the following: acidic resins, gums, tetracyclic and pentacyclic triterpene acids, incensol acetate, phellandrene, (+)-cis- and (+)-trans-olivanic acid.

[0028] According to the invention, the fatty acids are selected from the omega-3 fatty acids EPA and DHA.

[0029] It is preferred if the omega-3 fatty acid salt has an organic counterion selected from lysine, arginine, ornithine, choline, and mixtures thereof.

[0030] It is particularly preferred to use fatty acid salts containing EPA and DHA and having organic counterions selected from lysine, arginine, and ornithine.

[0031] In another configuration, the preparation comprises at least 10% by weight of Boswellia extract, preferably at least 20% by weight, more preferably at least 30% by weight, and most preferably at least 40% by weight.

[0032] In another configuration, the preparation comprises at least 10% by weight, preferably at least 20% by weight, more preferably at least 30% by weight, and most preferably at least 40% by weight of polyunsaturated fatty acid salt.

[0033] It is even more preferred if the preparation comprises at least 40% by weight of Boswellia extract and at least 40% by weight of polyunsaturated fatty acid salts.

[0034] Another preferred aspect of the present invention is the formulation of omega-3 dispersions (possibly liposomes) to further enhance bioavailability. Such dispersions preferably consist of a phospholipid mixture (e.g., deoiled sunflower lecithin) or a specific phospholipid (e.g., dioleylphospatidylcholine (DOPC)). The most preferred form of such dispersions contains free omega-3 fatty acid salts.

[0035] Thus, in a preferred embodiment, the preparation further comprises as phospholipid at least one phospholipid preferably selected from deoiled phospholipids having a phosphatidylcholine content of more than 70% by weight, preferably more than 90% by weight, and a phosphatidylethanolamine content of less than 5% by weight, preferably less than 1% by weight, or non-hydrogenated phospholipids having an oleic acid and / or linoleic acid content of more than 70% by weight of the total fatty acids.

[0036] In a further preferred embodiment, the preparation comprises a dispersion of at least one phospholipid and at least one polyunsaturated fatty acid salt. It is particularly preferred to use omega-3 fatty acids.

[0037] In a further preferred configuration of the invention, the mass ratio of phospholipid to fatty acid salt is greater than 0.001, preferably greater than 0.05, more preferably greater than 0.01, more preferably greater than 0.09, most preferably greater than 0.39.

[0038] In another embodiment, the preparation is in powder or liquid form and when mixed with water at a pH value between 6.5 and 7.5, results in a colloidal dispersion with an average particle size of less than 1 μm, preferably less than 500 nm, most preferably less than 250 nm.

[0039] In another embodiment, both phospholipids and fatty acid salts are present and the components are finely dispersed within each other such that they are detectable in amounts of 100 μg or less.

[0040] In another preferred embodiment, the weight ratio of Boswellia extract to polyunsaturated fatty acid salt is 0.5:1 to 1:0.5.

[0041] Of course, free fatty acids are absorbed in the small intestine and are therefore unavailable to the large intestine. Preferred formulations for intestinal delivery of the preparations of the present invention are those that provide gastric protection, small intestine targeted preparation release, and large intestine targeted preparation release.

[0042] Therefore, another aspect of the present invention is a preparation according to the present invention, further comprising a targeted release formulation. The targeted release formulation according to the present invention is a formulation that ensures delivery of omega-3 fatty acids to a specific target in the body. Preferred formulations of such preparations promote enteral or colonic delivery in the lower small intestine or large intestine. Targeted release formulations can be obtained by adding an enteric polymer to the dosage form matrix or by adding a coating, preferably an enteric coating, to the dosage form matrix.

[0043] Enteric coatings are barriers applied to oral medications to prevent dissolution or disintegration in the gastric environment. Most enteric coatings function by providing a surface that is stable at the highly acidic pH of the stomach but rapidly disintegrates at higher (alkaline) pHs. For example, they do not dissolve in the gastric acid (pH below 3) of the stomach, but dissolve in the alkaline (pH 7-9) environment of the small intestine.

[0044] Thus, in an advantageous configuration, the targeted release formulation comprises a coating, preferably selected from methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, zein.

[0045] As the enteric coating, it is preferable to use a polymer polymerized from 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate, and 5 to 15% by weight of methacrylic acid.

[0046] The disclosed polymer dispersion may preferably contain 15-50 wt% of a polymer polymerized from 20-30 wt% methyl methacrylate, 60-70 wt% methyl acrylate, and 8-12 wt% methacrylic acid. The most preferred polymer is polymerized from 25 wt% methyl methacrylate, 65 wt% methyl acrylate, and 10 wt% methacrylic acid.

[0047] A 30% by weight aqueous dispersion of a polymer polymerized from 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid corresponds to the commercial product EUDRAGUARD® biotic.

[0048] The percentage of monomers totals 100%. Functional polymers are 2-30 mg / cm 2 , preferably 5 to 20 mg / cm 2 is applied in an amount of

[0049] In a preferred configuration, the preparation further comprises one or more of the following: anthocyanins, vitamins, minerals, fiber, fatty acids, amino acids, and proteins.

[0050] In certain configurations, the preparation further comprises a vitamin selected from biotin, vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B9 (artificial folic acid or folic acid), vitamin C (ascorbic acid), vitamin D (calciferol), vitamin E (tocopherols and tocotrienols), and vitamin K (quinones), or a mineral selected from sulfur, iron, chlorine, calcium, chromium, cobalt, copper, magnesium, manganese, molybdenum, iodine, selenium, and zinc.

[0051] A further aspect of the invention relates to tablets, pellets, microparticles or microparticle compositions, or capsules comprising the preparation according to the invention.

[0052] In a particular combination, the present invention relates to a capsule containing the preparation of the present invention. The capsule may contain up to 50% by weight of both an extract of gum resin derived from Boswellia species and a polyunsaturated fatty acid salt. The polyunsaturated fatty acid salt contains at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid. The basic amino acid is preferably selected from lysine, arginine, and ornithine.

[0053] In another particular embodiment, the present invention relates to a tablet containing the preparation of the present invention. The tablet comprises at least 20% by weight of an extract of gum resin from Boswellia species and at least 20% by weight of a polyunsaturated fatty acid salt. The polyunsaturated fatty acid salt comprises at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid. The basic amino acid is preferably selected from lysine, arginine, and ornithine.

[0054] Furthermore, the use of such preparations as feed or nutritional supplements, as medicines or in topical applications is part of the present invention.

[0055] Another aspect of the invention is a preparation as described above for use in the treatment or prevention of chronic inflammatory diseases, preferably asthma, occupational asthma, eczema, bronchitis, hay fever, urticaria, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-articular rheumatism, osteoporosis, coronary heart disease, atherosclerosis, endothelial dysfunction, multiple sclerosis, vasculitis, nephritis, uveitis, glomerulonephritis, systemic lupus erythematosus, restenosis after angioplasty, ulcerative colitis, conjunctivitis, dermatitis, psoriasis, cystic fibrosis, acute respiratory distress syndrome, IBS (inflammatory bowel disease), IBD (inflammatory bowel disease), chronic obstructive pulmonary disease, adult respiratory distress syndrome, allergic rhinitis, gastrointestinal allergies, allergic diseases, lichen simplex chronicus (LSC).

[0056] A further aspect of the present invention is a method for enhancing the production of one or more specific pro-inflammatory lipid mediators (SPMs), comprising: at least one Boswellia extract; at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid selected from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid; The present invention relates to a preparation comprising:

[0057] SPMs are preferably selected from the group consisting of 17-hydroxy-DHA (17-HDHA), 14-hydroxy-DHA (14-HDHA), 13-hydroxy-DHA (13-HDHA), 7-hydroxy-DHA (7-HDHA), 4-hydroxy-DHA (4-HDHA), 18-hydroxy-eicosapentaenoic acid (18-HEPE), 15-hydroxy-eicosapentaenoic acid (15-HEPE), 12-hydroxy-eicosapentaenoic acid (12-HEPE), 11-hydroxy-eicosapentaenoic acid (11-HEPE), 8-hydroxy-eicosapentaenoic acid (8-HEPE), 5-hydroxy-eicosapentaenoic acid (5-HEPE), 15-hydroxy-eicosatetraenoic acid (15-HETE), 12-hydroxy-eicosatetraenoic acid (12-HETE), ), 8-hydroxy-eicosatetraenoic acid (8-HETE), 5-hydroxy-eicosatetraenoic acid (5-HETE), 9-hydroxyoctadecadienoic acid (9-HODE), 13-hydroxyoctadecadienoic acid (13-HODE), 10(S),17(S)-dihydroxy-docosahexaenoic acid (PDX), protectin D1 (PD1), aspirin-induced PD1 (AT-P D1), maresin 1 (MaR1), maresin 2 (MaR2), resolvin D1-6 (RvD1-6), aspirin-induced RvD1 (AT-RvD1), resolvin E1 (RvE1), resolvin E2 (RvE2), resolvin E3 (RvE3), lipoxin A4 (LXA4), lipoxin A5 (LXA5), lipoxin B4 (LXB4), and lipoxin B5 (LXB5).

[0058] Therefore, in a further preferred embodiment, the SPM is selected from 17-HDHA, 14-HDHA, 13-HDHA, 7-HDHA, 4-HDHA, 18-HEPE, 15-HEPE, 12-HEPE, 11-HEPE, 5-HEPE, 15-HETE, 12-HETE, 8-HETE, 5-HETE, 9-HODE, 13-HODE, PDX, PD1, AT-PD1, MaR1, MaR2, RvD1-6, AT-RvD1, RvE1, RvE2, RvE3, LXA4, LXA5, LXB4, LXB5, preferably 17-HDHA, 14-HDHA, 18-HEPE, PDX, PD1, RvD1-6, MaR1. [Brief explanation of the drawings]

[0059] [Figure 1] FIG. 1 shows the stimulation of LM biosynthesis formation in human M1-like macrophages by Boswellia extract. [Figure 2] FIG. 2 shows the stimulation of LM biosynthesis formation in human M2-like macrophages by Boswellia extract. [Figure 3] FIG. 3 shows stimulation of LM biosynthesis in human M1 macrophages. [Figure 4] FIG. 4 shows stimulation of LM biosynthesis in human M2 macrophages. [Figure 5] FIG. 5 shows stimulation of LM biosynthesis formation in human M2 macrophages by omega-3 lysine salt (AvailOm®), arginine salt, and ornithine salt. [Figure 6] FIG. 6 shows the stimulation of LM biosynthesis in human M2 macrophages by omega-3 arginine salts and ornithine salts. [Example]

[0060] Macrophage isolation and culture, and LM metabololipidomic analysis Leukocyte concentrates from freshly collected peripheral blood from healthy adult donors were provided by the Institute of Transfusion Medicine at the University Hospital of Jena, Germany. The experimental protocol was approved by the Ethics Committee of the University Hospital of Jena. All methods were performed in accordance with relevant guidelines and regulations. Peripheral blood mononuclear cells (PBMCs) were isolated using dextran sedimentation and centrifugation on Ficoll-Histopaque 1077-1 (Sigma-Aldrich, Taufkirchen, Germany). Published criteria for differentiation and polarization into M1 and M2 subpopulations were used

[32] . Therefore, monocytes were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, 2 mmol / L l -glutamine (Biochrom / Merck, Berlin, Germany), and penicillin-streptomycin (Biochrom / Merck) with 20 ng / mL GM-CSF (Peprotech, Hamburg, Germany) for 6 days, followed by treatment with 100 ng / mL LPS (Sigma-Aldrich) and 20 ng / mL INF-γ (Peprotech) for an additional 48 hours to generate M1 cells. M2 cells were differentiated by culture with 20 ng / mL M-CSF (Peprotech) for 6 days and then polarized by culture with 20 ng / mL IL-4 (Peprotech) for an additional 48 hours.

[0061] Macrophages (2 × 10 6Boswellia serrata (1 / mL) was cultured in PBS containing 1 mM CaCl2. Extracts of Boswellia serrata or vehicle control (0.1% DMSO) were applied 15 min before E. coli stimulation (E. coli serotypes = O6:K2:H1, ratio = 1:50 (M1 / M2:E. coli) at 37 °C for 180 min). To facilitate quantification, the supernatant was transferred to 2 mL of ice-cold methanol containing 10 μL of deuterium-labeled internal standards (200 nM d8-5S-HETE, d4-LTB4, d5-LXA4, d5-RvD2, d4-PGE2, and 10 μM d8-AA). Deuterated and non-deuterated LM standards were purchased from Cayman Chemical / Biomol GmbH (Hamburg, Germany). Sample preparation was performed by adapting published standards

[33] . Briefly, the sample was kept at -20°C for 60 min to precipitate proteins. After centrifugation (1,200 g, 4°C, 10 min), 8 mL of acidified HO (pH 3.5) was added for solid-phase extraction. Before loading the sample onto the column, a solid-phase cartridge (Sep-Pak® Vac 6 cc, 500 mg / 6 mL C18, Waters, Milford, MA) was equilibrated with 6 mL of methanol and 2 mL of HO. After washing with 6 mL of HO and an additional 6 mL of n-hexane, the LM was eluted with 6 mL of methyl formate. Finally, the sample was dried using an evaporation system (TurboVap LV, Biotage, Uppsala, Sweden) and resuspended in 100 μL of methanol-water (50 / 50, v / v) for automated UPLC-MS-MS injection. LM profiling was analyzed using an Acquit™ UPLC system (Waters, Milford, MA) and a QTRAP 5500 mass spectrometer (ABSciex, Darmstadt, Germany) equipped with a Turbo V™ source and electrospray ionization (ESI).The LM was eluted using an ACQUITY UPLC® BEH C18 column (1.7 μm, 2.1 × 100 mm, Waters, Eschborn, Germany) at a flow rate of 0.3 mL / min at 50 °C and a mobile phase consisting of 42:58:0.01 (v / v / v) methanol-water-acetic acid (v / v / v), ramping to 86:14:0.01 (v / v / v) in 12.5 min and then to 98:2:0.01 (v / v / v) in 3 min (Table S1). The QTrap 5500 was operated in negative ionization mode using scheduled multiple reaction monitoring (MRM) coupled with information-dependent acquisition (IDA). The scheduled MRM window was 60 s, optimized LM parameters (CE, EP, DP, CXP) were employed

[33] , and the curtain gas pressure was set at 35 psi. The retention time and at least six diagnostic ions of each LM were confirmed using external standards (Cayman Chemicals). Quantification was performed using calibration curves for each LM. Linear calibration curves were obtained for each LM. 2 The value was 0.998 or higher (for fatty acids 0.95 or higher).

[0062] Polyunsaturated fatty acid composition In the examples of the present invention, various polyunsaturated fatty acid compositions were used. Various omega-3 fatty acid salts were prepared with organic counterions selected from the basic amino acids lysine, arginine, and ornithine. The omega-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA) are present in a ratio of approximately 2:1 (ratio = EPA:DHA).

[0063] Omega-3 lysine salt (AvailOm®) contains approximately 32% by weight of L-lysine and approximately 65% by weight of polyunsaturated fatty acids. The predominant polyunsaturated fatty acids in the composition are the omega-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA), which together account for approximately 58% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the omega-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0064] Omega-3 arginine salt (ω-3-arg) contains approximately 35% by weight of L-arginine and approximately 64% by weight of polyunsaturated fatty acids. The predominant polyunsaturated fatty acids in the composition are the ω-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA), which together account for approximately 49% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the ω-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0065] Omega-3 ornithine salt (ω-3-orn) contains approximately 29% by weight of L-ornithine and approximately 70% by weight of polyunsaturated fatty acids. The major polyunsaturated fatty acids in the composition are the ω-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA), which together account for approximately 54% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the ω-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0066] Experimental Example 1: Stimulation of LM biosynthesis in Escherichia coli-stimulated human monocyte-derived M1 and M2 macrophages by extracts of gum resin from Boswellia species Human monocyte-derived macrophages were polarized into M1 (Figure 1) or M2 (Figure 2) subspecies for 48 hours and then treated with an extract of gum resin from Boswellia species (Boswellia extract). -BS (Boswellin super®, Sabinsa Corporation (USA), a standardized extract from the gum resin of Boswellia serrata containing a minimum of 10% AKBA and a minimum of 20% total identified boswellic acids), - CAS (Casperome®, Indena, purified extract obtained from the gum resin of Boswellia serrata, containing more than 25% boswellic acids), and - AUR (Aureliasan extract, Boswellia carterii extract) (50 μg / mL each), or -AKBA (10 μM) (In the figure, the gray bars represent the group supplemented with AvailOm®, and the black bars represent the group not supplemented with AvailOm® (3 μg / mL).) After 180 min of incubation at 37°C, lipid mediators were isolated by solid-phase extraction and analyzed by UPLC-MS-MS. Data are means ± SEM, n = 3. One-way ANOVA was performed using log-transformed data (Tukey's post-hoc test; * = # p < 0.05, ** = ## p < 0.01, *** = # # p < 0.005).

[0067] The production of LMs RvD2, RvD4, RvD5, PDX, PD1, MaR1, 17-HDHA, 14-HDHA, 18-HEPE, as well as LTB4 and PGE2 in M1 macrophages is shown in Figure 1, and their production in M2 macrophages is shown in Figure 2.

[0068] In proinflammatory M1 macrophages, which normally produce small amounts of SPM, the addition of AvailOm® only slightly increased LM production, and exposure to Boswellia extract (AUR, BS, or CAS) or AKBA did not significantly enhance LM biosynthesis. However, the combination of AvailOm® with Boswellia extract or AKBA significantly increased EPA- and DHA-derived LMs, particularly RvD5, PD1, PDX, MaR1, and 18-HEPE. In contrast, AA-derived proinflammatory LMs (PGE2 and LTB4) did not increase under any condition. These data suggest that AvailOm® switches LM production in M1 from proinflammatory to inflammation-resolving.

[0069] A more pronounced effect of combining AvailOm® with Boswellia extract (AUR, BS, or CAS) or AKBA on the production of EPA- and DHA-derived LMs was evident in M2 (Figure 2). Surprisingly, while either Boswellia extract or AvailOm® showed a moderate effect, their combination clearly resulted in a synergistic increase in lipid mediators (e.g., RvD5, PD1, PDX, and the precursor 17-HDHA). The same was true for MaR1 and 14-HDHA. The data suggest a synergistic mechanism for SPM production, in which Boswellia extract activates the key enzyme 15-LOX-1 and AvailOm® serves as an available substrate. However, supplementation with EPA and / or DHA (AvailOm®) alone as substrates was not sufficient to result in substantial SPM production compared with their combination with Boswellia extract.

[0070] We conclude that supplementing human M1 and M2 macrophages in vitro with AvailOm® promotes the production of SPMs and their precursors, especially when the cells are stimulated with AKBA (a pharmacological anti-inflammatory agent) or Boswellia extract. These data strongly suggest that combining AKBA or the parent Boswellia extract with AvailOm® promotes the production of inflammation-resolving LMs (i.e., SPMs), thereby resolving inflammatory diseases.

[0071] Experimental Example 2: Effects of EPA / DHA lysine salts and free fatty acids on lipid mediator biosynthesis in human monocyte-derived M1 and M2 macrophages Human monocyte-derived macrophages were polarized into M1 (Figure 3) or M2 (Figure 4) subpopulations for 48 hours and then treated with various sources of ω-3 fatty acids, including: - Omegatex (Omegatex 5723, 57% EPA, 23% DHA), -Omega3 (ω-3-fatty acids, 57% EPA, 23% DHA), AvailOm®, and - Liposomal AvailOm® (corresponding to 3 μg / mL of EPA+DHA) (In the figure, the gray bars represent the group supplemented with AUR, a Boswellia extract, and the black bars represent the group not supplemented with AUR (50 μg / mL).) After 180 min of incubation at 37°C, lipid mediators were isolated by solid-phase extraction and analyzed by UPLC-MS-MS. Data are means ± SEM, n = 3. One-way ANOVA was performed using log-transformed data (Tukey's post-hoc test; * = # p < 0.05, ** = ## p < 0.01, *** = # # p < 0.005).

[0072] The production of LMs RvD2, RvD4, RvD5, PDX, PD1, MaR1, 17-HDHA, 14-HDHA, 18-HEPE, as well as LTB4 and PGE2 in M1 macrophages is shown in Figure 3, and their production in M2 macrophages is shown in Figure 4.

[0073] Comparing various sources of DHA and EPA as SPM / precursor substrates in macrophage supplementation showed that in M1, AvailOm® combined with Boswellia extract AUR produced the most significant increases in RvD5, PD1, PDX, MaR1, and 14-HDHA, followed by liposomal AvailOm®, which produced the highest 17-HDHA production with AUR (Figure 3). Again, the combination of AvailOm® and AUR produced synergistic effects on RvD5, PD1, PDX, MaR1, 17-HDHA, and 14-HDHA, but no apparent stimulatory effects on AA-derived PGE2 and LTB4.

[0074] In M2, which generally has a high SPM-producing capacity due to high expression levels of 15-LOX-1, a key enzyme in SPM biosynthesis, the Boswellia extract AUR, in combination with Omega3, AvailOm®, or liposomal AvailOm®, significantly increased all SPMs and precursors investigated. Again, AUR, or any combination of Omega3, AvailOm®, and liposomal AvailOm®, had only a moderate effect on LTB4 and PGE2 production.

[0075] Experimental Example 3: Effects of EPA / DHA lysine salts and free fatty acids on lipid mediator biosynthesis in human monocyte-derived M1 and M2 macrophages Human monocyte-derived macrophages were polarized to the M2 subpopulation for 48 hours and then treated with various omega-3 fatty acid salts. - omega-3 lysine salt (AvailOm®), - omega-3 arginine salt, and - omega-3 ornithine salt (Gray bars indicate supplementation with AUR, a Boswellia extract; black bars indicate no supplementation with AUR (50 μg / mL).) After 180 min of incubation at 37°C, lipid mediators were isolated by solid-phase extraction and analyzed by UPLC-MS-MS. Data shown in Figures 5 and 6 are mean ± SEM, n = 3. One-way ANOVA was performed using log-transformed data (Tukey's post-hoc test; * = # p < 0.05, ** = ## p < 0.01, *** = # # p < 0.005).

[0076] Table 1 summarizes the stimulation values of LM biosynthesis formation in human M2 macrophages in pg / million cells by Boswellia extract AUR and lysine salts of EPA and DHA (AvailOm®), Table 2 by arginine salts of EPA and DHA, and Table 3 by ornithine salts of EPA and DHA. The "-fold" values indicate the relative fold increase compared to Boswellia extract.

[0077] These values clearly demonstrate the presence of a synergistic effect with Boswellia extract on SPM production, as the measured values for the combination are much higher than the sum of the values for the individual substances for all three omega-3 salts. For example, for all amino acid salts, this effect is dramatic when looking at the SPMs 17-HDHA, 14-HDHA, 7-HDHA, 4-HDHA, 18-HEPE, 15-HEPE, 12-HEPE, 11-HEPE, and 5-HEPE.

[0078] [Table 1]

[0079] [Table 2]

[0080] [Table 3]

[0081] Figure 5 shows the production of LMs RvD2, RvD4, RvD5, PDX, PD1, MaR1, 17-HDHA, 14-HDHA, 18-HEPE, as well as LTB4 and PGE2 in M2 macrophages using ω-3 lysine salt (AvailOm®), arginine salt, and ornithine salt.

[0082] FIG. 6 shows the stimulation of LM biosynthesis in human M2 macrophages by ω-3 arginine salt and ornithine salt.

[0083] Example 4: Capsules containing EPA / DHA lysine salt and Boswellia extract The following ingredients were loaded into HPMC capsules:

[0084] [Table 4]

[0085] The capsule may further comprise an amino acid selected from L-ornithine, L-aspartic acid, L-lysine, and L-arginine.The capsule may further comprise another carbohydrate component selected from arabinoxylan, barley grain fiber, oat grain fiber, rye fiber, wheat bran fiber, inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS), resistant starch, β-glucan, glucomannan, galactoglucomannan, guar gum, and xylooligosaccharides.

[0086] The capsule may further comprise one or more plant extracts selected from ginger, cinnamon, grapefruit, parsley, turmeric, curcuma, olive fruit, ginseng, turmeric, garlic, broccoli, spirulina, pomegranate, cauliflower, kale, coriander, green tea, onion, and milk thistle.The capsule may further comprise charcoal, chitosan, glutathione, monacolin K, plant sterols, plant stanols, sulforaphane, collagen, and hyaluronic acid. The capsule may further comprise a vitamin selected from biotin, vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B9 (artificial folic acid or folic acid), vitamin C (ascorbic acid), vitamin D (calciferol), vitamin E (tocopherol and tocotrienol), and vitamin K (quinone), or a mineral selected from sulfur, iron, chlorine, calcium, chromium, cobalt, copper, magnesium, manganese, molybdenum, iodine, selenium, and zinc.

[0087] Example 5: Enteral capsules containing EPA / DHA lysine salt and Boswellia extract The capsules prepared in Example 3 were coated with an enteric coating composition:

[0088] [Table 5] Coating Composition

[0089] Example 6: Formulation of tablets containing EPA / DHA lysine salt and Boswellia extract The formulations (Table 6) were prepared and used for tableting. Corresponding masses of the tablet core ingredients (except magnesium stearate) in each formulation were blended using a turbo blender. Magnesium stearate was added in a second blending step just prior to the compression step.

[0090] [Table 6]

[0091] Tablet compression was performed on a Korsch XP 1 eccentric press. 21 mm x 9 mm oval biconvex tooling was used to obtain tablets with a target weight of 1,000 mg. A compression of approximately 15 kN was applied to obtain tablets with a hardness (resistance to crushing) of approximately 75 N. Friability was less than 1%, and mass uniformity showed less than 5% variation.

[0092] As a final manufacturing step, the resulting tablets are coated with a EUDRAGUARD Natural-based coating. The coating provides taste and odor masking, a barrier against moisture absorption, and can improve photostability. Coating was performed in an O'Hara Labcoat drum coater equipped with a perforated 15-inch drum. The coating suspension, consisting of EUDRAGUARD Natural, talc, glycerol, and Chlorophyll E 141ii, was applied at 4.0 mg / cm. 2 was applied at an average spray rate of 5.5 g / min / kg.

[0093] The resulting film-coated tablets were intact and free of agglomerates. The characteristic odors of AvailOm® and Boswellia serrata extract were largely masked. The film-coated tablets disintegrated in 0.1 N HCl (pH 1.20) within 30 minutes, exhibiting mass uniformity of less than 5% variation and moisture content of 4-7%.

[0094] The compressed tablets were stable for at least 2 months at 25°C and 60% relative humidity and at 40°C and 75% relative humidity.

[0095] The tablets may further contain a vitamin selected from biotin, vitamin A, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B9 (artificial folic acid or folic acid), vitamin C (ascorbic acid), vitamin D (calciferol), vitamin E (tocopherol and tocotrienol), and vitamin K (quinone), or a mineral selected from sulfur, iron, chlorine, calcium, chromium, cobalt, copper, magnesium, manganese, molybdenum, iodine, selenium, and zinc.

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Claims

1. - at least one extract of gum resin from Boswellia species, at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid chosen from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and at least one basic amino acid, Including, the polyunsaturated fatty acid salt comprises an organic counterion of the omega-3 fatty acid, the organic counterion comprising the basic amino acid selected from lysine, arginine, ornithine, and mixtures thereof; the weight ratio of the extract to the polyunsaturated fatty acid salt is between 0.5:1 and 1:0.5; An anti-inflammatory preparation comprising at least 30% by weight of said extract and at least 30% by weight of said polyunsaturated fatty acid salt.

2. The extract is selected from the group consisting of Boswellia serrata, Boswellia carterii, Boswellia papyrifera, Boswellia ameero, Boswellia bullata, Boswellia dalzielii, Boswellia dioscorides, Boswellia elongata, Boswellia frereana, Boswellia nana, Boswellia neglecta, Boswellia ogadensis, Boswellia pirottae, Boswellia popoviana, Boswellia 2. The anti-inflammatory preparation of claim 1, prepared from one or more of Boswellia popoviana, Boswellia rivae, Boswellia sacra, and Boswellia socotrana.

3. 3. The anti-inflammatory preparation according to claim 1 or claim 2, wherein the extract is prepared by using hydrodistillation, steam distillation, extraction by percolation, extraction under ultrasound, solvent extraction, Soxhlet extraction, supercritical fluid extraction, or membrane nanofiltration.

4. 4. The anti-inflammatory preparation according to any one of claims 1 to 3, comprising one or more boswellic acids selected from β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid (AKBA), α-boswellic acid, 3-O-acetyl-α-boswellic acid, and 3-O-acetyl-β-boswellic acid.

5. 5. The anti-inflammatory preparation of any one of claims 1 to 4, further comprising one or more of the following: acidic resins, gums, tetracyclic and pentacyclic triterpene acids, incensol acetate, phellandrene, (+)-cis- and (+)-trans-olivanic acid.

6. 6. The anti-inflammatory preparation according to any one of claims 1 to 5, further comprising at least one phospholipid selected from deoiled phospholipids having a phosphatidylcholine content of more than 70% by weight and a phosphatidylethanolamine content of less than 5% by weight, or non-hydrogenated phospholipids having an oleic acid and / or linoleic acid content of more than 70% by weight of total fatty acids.

7. 7. The anti-inflammatory preparation of claim 6, wherein the mass ratio of said phospholipid to said polyunsaturated fatty acid salt is greater than 0.

01.

8. 8. The anti-inflammatory preparation of any one of claims 1 to 7, further comprising a targeted release formulation, the targeted release formulation comprising a coating selected from methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, and zein.

9. 9. The anti-inflammatory preparation of any one of claims 1 to 8, further comprising one or more of anthocyanins, vitamins, minerals, fiber, fatty acids, amino acids, and proteins.

10. A tablet, pellet, microparticle or microparticle composition, or capsule comprising the anti-inflammatory preparation according to any one of claims 1 to 9.

11. Use of an anti-inflammatory preparation according to any one of claims 1 to 9 in animals as a feed or nutritional supplement, or as a medicine, or in topical application.

12. 10. The anti-inflammatory preparation according to any one of claims 1 to 9 for use in the treatment or prevention of chronic inflammatory diseases, asthma, occupational asthma, eczema, bronchitis, hay fever, urticaria, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-articular rheumatism, osteoporosis, coronary heart disease, atherosclerosis, endothelial dysfunction, multiple sclerosis, vasculitis, nephritis, uveitis, glomerulonephritis, systemic lupus erythematosus, restenosis after angioplasty, ulcerative colitis, conjunctivitis, dermatitis, psoriasis, cystic fibrosis, acute respiratory distress syndrome, IBS (inflammatory bowel disease), IBD (inflammatory bowel disease), chronic obstructive pulmonary disease, adult respiratory distress syndrome, allergic rhinitis, digestive allergies, allergic diseases, and lichen simplex chronicus (LSC).

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