JP2010515773A - Treatment with non-steroidal anti-inflammatory drugs and omega-3 fatty acids and combination products thereof - Google Patents

Abstract

  The present invention provides a combination of one or more NSAIDs and a mixture of omega-3 fatty acids, a method of administering such a combination, and a unit dosage form of such a combination.

Description

  The present invention includes one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic disease, fever, painful pain or other symptoms, painful menstruation , Fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any symptoms mediated by COX, and / or combinations thereof To a combination of one or more non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 fatty acids, or a unit dosage form of the combination, to treat any condition effective for treatment with .

  The present invention also relates to a combination product of one or more NSAIDs and omega-3 fatty acids.

  Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to lower fever, relieve pain, and reduce inflammation and swelling. One mechanism that NSAIDs are thought to act on is thought to reduce the amount of inflammatory chemicals by reducing the enzymatic biosynthesis of inflammatory chemicals, ie prostaglandins and leukotrienes. . It has been clarified that inhibition of the enzyme, cyclooxygenase (COX) can suppress the production of prostaglandins, and the suppression of the production is not limited, but osteoarthritis, rheumatoid arthritis, acute Explain its pharmacological effects observed in a variety of inflammatory conditions including musculoskeletal pain, toothache, dysmenorrhea, migraine, postoperative pain and familial adenomatous polyposis (FAP).

  Various types of NSAID agents have been developed and used in mammalian systems, including but not limited to the following representative examples: ibuprofen, naproxen, ketoprofen, oxaprozin, diclofenac, indomethacin, sulindac, Piroxicam, meclofenamate, mefanamic acid, nabumetone, etoradolac, ketorolac, choline magnesium trisalicylate, aspirin, diflunisal, salsalate, fenoprofen, flurbiprofen, pyrprofen, thiaprofenic acid, loxoprofen, indoprofen, fenbufen, carprofen , Suprofen, celecoxib, valdecoxib, rofecoxib, parecoxib, deracoxib, luminacoxib, etoroxixib and meloxicam.

  Marine oil, also called fish oil, has been found to be an excellent source of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and to control lipid metabolism. Omega-3 fatty acids have been found to have beneficial effects on cardiovascular disease risk factors, mild hypertension, hypertriglyceridemia, and particularly excellent effects on coagulation factor VII phospholipid complex activity . Omega-3 fatty acids increase serum HDL-cholesterol, lower serum triglycerides, alter serum LDL-cholesterol particle size pattern, lower systolic and diastolic blood pressure and pulse rate, blood coagulation factor VII -Reduce the activity of the phospholipid complex. Furthermore, omega-3 fatty acids are well tolerated without causing any severe side effects.

One form of omega-3 fatty acid is a concentrate of omega-3, long chain polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark LOVAZA ^™ . Such forms of omega-3 fatty acids are described, for example, in US Pat. Nos. 5,520,077, 5,656,667 and 5,698,594, each of which is hereby incorporated by reference.

  US Patent Publication No. 2005/0101563 discloses a method for preventing or treating pain or inflammation in a subject by administering a COX-2 inhibitor and a polyunsaturated fatty acid, optionally glucosamine and / or chondroitin. . US Patent Publication No. 2005/0101563 also discloses pharmaceutical compositions that generally comprise a COX-2 inhibitor and a polyunsaturated fatty acid, optionally glucosamine and / or chondroitin.

  US Patent Publication No. 2006/0024356 discloses the bones of dogs and other animals by administering a diet containing long chain n-3 fatty acids, optionally other components such as glucosamine, chondroitin, antioxidants and NSAIDs. Disclosed are methods for treating arthritis and methods for preventing or delaying its onset.

US Pat. No. 5,050,077 US Pat. No. 5,656,667 US Pat. No. 5,698,594 US Patent Publication No. 2005/0101563 US Patent Publication No. 2006/0024356

  There is a need for combination therapy of one or more NSAIDs and omega-3 fatty acids. In addition, there is a need for a single dose or unit dosage form of a combination of one or more NSAIDs and omega-3 fatty acids. Such combinations may include one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic diseases, fever, pain secondary to pain disorder or other symptoms, dysmenorrhea , Fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any symptoms mediated by COX, and / or combinations thereof It enables new and more effective pharmaceutical treatment for any symptom effective for treatment.

  A method for administering separate products or unit dosage forms comprising one or more NSAIDs and omega-3 fatty acids that combine one or more NSAIDs with omega-3 fatty acids to provide specific therapeutic properties There are also unmet requirements in the field.

  The present invention includes one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic disease, fever, painful disorder or other symptoms, painful menstruation , Fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any symptoms mediated by COX, and / or combinations thereof Administering one or more NSAIDs and omega-3 fatty acids together, or administering a unit dosage form thereof that may provide effective pharmaceutical treatment for any other condition that is effective for treatment with To meet unmet requirements in this and other areas.

  Other embodiments of the invention are directed to combination products, such as unit dosage forms, comprising one or more NSAIDs and omega-3 fatty acids. In one embodiment of the present invention, the combination product may have one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic diseases, fever, pain disorders or other symptoms Secondary pain, dysmenorrhea, fibromyalgia, acute musculoskeletal pain, chronic musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, cholesterol and triglyceride levels , COX mediated symptoms, and / or any other symptom effective for treatment with this combination.

  Other embodiments of the invention are secondary to one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic diseases, fever, pain disorders or other symptoms Pain, dysmenorrhea, fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any symptoms mediated by COX, And / or any other method of treatment that is effective for treatment with the combination, comprising administering one or more NSAIDs and omega-3 fatty acids in combination.

  Other features and advantages of the present invention will become apparent to those skilled in the art upon examination or practice of the following description of the invention.

The present invention includes one or more of the following symptoms: arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic disease, fever, painful disorder or other symptoms, painful menstruation , Fibromyalgia, musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any symptoms mediated by COX, and / or combinations thereof A combination product or unit that utilizes one or more NSAIDs and omega-3 fatty acids, preferably LOVAZA ^TM omega-3 fatty acids, to treat any other condition effective for treatment with It is intended that the dosage form comprises one or more NSAIDs and one or more omega-3 fatty acids.

  In a preferred embodiment, the present invention provides a novel combination product for treating osteoarthritis.

In another preferred embodiment, the administration comprises omega-3 fatty acids, preferably in the form of LOVAZA ^TM omega-3 fatty acids, and one or more NSAIDs, wherein the omega-3 fatty acids are one or more It is administered simultaneously with multiple NSAIDs.

In other embodiments, the administration comprises omega-3 fatty acids, preferably in the form of LOVAZA ^TM omega-3 fatty acids, and one or more NSAIDs, wherein the omega-3 fatty acids are one or more NSAIDs. Are administered separately. For example, one or more NSAIDs may be administered once a day and omega-3 fatty acids may be administered twice a day. Those of ordinary skill in the art who benefit from this disclosure will determine the exact dosage of omega-3 fatty acids and one or more NSAIDs and their dosage regimen depending on a variety of factors, such as the route of administration and the severity of the symptoms. You will understand that.

  The present invention may incorporate currently known NSAIDs or future NSAIDs in amounts that are generally understood to be safe. In a more preferred embodiment, the NSAID is: ibuprofen, naproxen, ketoprofen, oxaprozin, diclofenac, indomethacin, sulindac, piroxicam, meclofenamate, mephanamic acid, nabumetone, etorborak, ketorolac, choline magnesium trisalicylate, aspirin, Diflunisal, salsalate, fenoprofen, flubiprofen, pyrprofen, thiaprofenic acid, loxoprofen, indoprofen, fenbufen, carprofen, suprofen, celecoxib, valdecoxib, rofecoxib, parecoxib, delacoxib, lumiracoxib, all of ethlicoxib and meloxicam .

  As used herein, the term “omega-3 fatty acids” refers to natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (eg, Zaloga et al., US Patent Application Publication Number). 2004/0254357, and Horrobin et al., US Pat. No. 6,245,811, each of which is hereby incorporated by reference), precursors or salts thereof, or mixtures thereof. Examples of omega-3 fatty acids include omega-3 polyunsaturated long chain fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and α-linolenic acid, mono-, di- and omega-3 fatty acids and glycerol. -And esters such as tri-glycerides; esters of omega-3 fatty acids and primary, secondary or tertiary alcohols such as, but not limited to, fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long chain fatty acids such as EPA or DHA, their triglycerides, their ethyl esters and mixtures thereof. Omega-3 fatty acids or esters, derivatives, conjugates, precursors, salts and mixtures thereof are used in their pure form or as components of oils such as fish oils, preferably highly refined fish oil concentrates be able to. Commercially available omega-3 fatty acids suitable for use in the present invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, UK), EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX4510TG, EPAX4510TG , K85TG, K85EE, K80EE and EPAX7010EE (Norway, 1326 Lysaker, EPAX AS).

  Preferred forms of omega-3 fatty acids are shown in US Pat. Nos. 5,520,077, 5,656,667 and 5,698,694, the contents of which are hereby incorporated by reference.

  Another preferred composition comprises omega-3 fatty acids at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80%. Includes blends at a concentration of weight percent, or more specifically, at least 90 weight percent. It is preferred that the omega-3 fatty acid comprises at least 50% by weight, more preferably at least 60% by weight, even more preferably at least 70% by weight, most preferably at least 80%, for example about 84% by weight EPA and DHA. . Preferably, the omega-3 fatty acid comprises about 5 to about 100% by weight of EPA, more preferably about 25 to about 75% by weight, more preferably about 40 to about 55% by weight, and most preferably about 46% by weight. . It is preferred that the omega-3 fatty acid comprises about 5 to about 100 wt% DHA, more preferably about 25 to about 75 wt%, more preferably about 30 to about 60 wt%, most preferably about 38 wt%. . All the above percentages are by weight compared to the total fatty acids contained in the composition, unless otherwise specified. The weight percent is preferably based on the form of the ethyl ester of omega-3 fatty acid, even if other forms other than the ethyl ester according to the invention are utilized, but based on the form of its free acid or ester. can do.

  The ratio of EPA: DHA is 99: 1 to 1:99, preferably 4: 1 to 1: 4, more preferably 3: 1 to 1: 3, most preferably 2: 1 to 1: 2. The omega-3 fatty acid may contain pure EPA or pure DHA.

  Omega-3 fatty acid oils may optionally include antioxidants such as alpha tocopherol, oils such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin, and mixtures thereof. .

The most preferred form of omega-3 fatty acid is LOVAZA ^™ omega-3 fatty acid (K85EE: Norway, Lysaker, Pronova Biocare AS), which preferably has the following properties (per dosage form):

  One or more NSAID and omega-3 fatty acid combination products can be administered by means known in the art. Such means include oral, rectal, nasal, topical (including cutaneous, buccal and sublingual) or parenteral (subcutaneous, intramuscular, intraarticular and intradermal) administration. These compositions are preferably administered orally.

  The dose of the active ingredient in the composition of the present invention is variable, but it is essential that the amount of the active ingredient is such that an appropriate dosage form can be obtained. The choice of dosage depends on the required therapeutic action, on the mode of administration and on the duration of treatment.

  One or more NSAID and omega-3 fatty acid combination products may be used in capsules, tablets, powders that can be dispersed in beverages, solutions, soft gelatin capsules, or other known in the art, such as liquid solutions in oral capsules. It may be administered in a conventional dosage form. In certain embodiments, the capsule is made of hard gelatin. The combination product may also be contained in a liquid suitable for injection or infusion.

  The active ingredients of the invention, one or more NSAIDs and omega-3 fatty acids are also administered in combination with one or more non-active pharmaceutical ingredients (generally also known as “excipients” herein). May be. Non-active ingredients are used, for example, to solubilize, suspend, thicken, dilute, emulsify, stabilize, store, protect, color, and flavor the active ingredients, making the active ingredients safe and convenient. It helps to build an applicable and effective formulation that is acceptable for use. In certain embodiments, the excipient is a surfactant, such as propylene glycol monocaprylate, a mixture of long chain fatty acids and esters of glycerol and polyethylene glycol, polyethoxylated castor oil, glycerol esters, oleoyl macrogol gluceride. , Propylene glycol monolaurate, propylene glycol dicaprylate / dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate; co-solvents such as ethanol, glycerol, polyethylene glycol, and propylene glycol; and / or coconut Oils such as olive or safflower oil. The use of surfactants, co-solvents, oils or combinations thereof is generally known in the pharmaceutical arts and, as one skilled in the art will appreciate, any suitable excipient may be used in the present invention and its It can be used in connection with embodiments.

  The omega-3 fatty acid can be administered in a daily dosage of about 0.1 g to about 10 g, more preferably about 0.5 g to about 8 g, and most preferably about 0.75 g to about 4 g. Preferably, in unit dosage form, the omega-3 fatty acid is formulated in an amount of about 0.1 g to about 2 g, preferably about 0.5 g to about 1.5 g, more preferably about 1 g.

  In one embodiment of the present invention, the one or more NSAIDs may generally be formulated in an amount of about 0.5 mg to about 1000 mg. In embodiments where the NSAID is meloxicam, meloxicam is generally formulated in an amount of about 1 mg to about 50 mg, preferably about 3.25 mg to about 22.5 mg, more preferably 7.5 mg to about 15 mg in a daily dose. obtain.

  In certain variations of the invention, a combination of one or more NSAIDs and omega-3 fatty acids is formulated in a single dose or unit dose.

  Daily dosages of one or more NSAIDs and omega-3 fatty acids can be administered together in 1 to 10 dosages, with a preferred number of administrations of 1 to 6 times per day. Administration is preferably oral administration; however, other dosage forms that provide unit doses of one or more NSAIDs and omega-3 fatty acids may be used.

  In certain preferred embodiments, soft gelatin capsules are used. The production of soft gelatin capsules is well known to those skilled in the art. See, for example, Ebert (1978), “Soft Gelatin Capsules: A Unique Dosage Form”, Pharmaceutical Technology 1 (5). This content is hereby incorporated by reference. In certain embodiments, one or more NSAIDs and / or omega-3 fatty acids are formulated in a soft gelatin capsule. In certain embodiments, the active ingredients of a soft gelatin capsule are combined with a solubilizer. Solubilizers include surfactants, hydrophilic or hydrophobic solvents, oils or combinations thereof.

  One type of solubilizer that may be used is a vitamin E substance. This group of solubilizers includes α-, β-, γ-, δ-, ζ1-, ζ2- and η-tocopherols, their dl, d and l forms, and their structural analogs such as tocotrienol. And the corresponding derivatives thereof, for example esters formed with organic acids; and mixtures thereof. Preferred vitamin E substance solubilizers are tocopherol, tocotrienol, and acetic acid, propionic acid, bile acid, lactic acid, pyrivic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Tocopherol derivatives with organic acids such as benzoic acid, cinnamic acid, mandelic acid, polyethylene glycol succinate and salicylic acid are included. Particularly preferred vitamin E substance solubilizers include alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl acid succinate, alpha-tocopheryl polyethylene glycol 1000 succinate or mixtures thereof.

  Another group of solubilizers is an organic acid ester of a monohydric alcohol. The monohydric alcohol is, for example, ethanol, isopropanol, t-butanol, fatty alcohol, phenol, cresol, benzyl alcohol or cycloalkyl alcohol. Organic acids include, for example, acetic acid, propionic acid, butyric acid, fatty acids having 6 to 22 carbon atoms, bile acids, lactic acid, pyrivic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid Acids, benzoic acid, cinnamic acid, mandelic acid and salicylic acid. Preferred solubilizers within this group include trialkyl citrates, lower alcohol fatty acid esters and lactones. Preferred trialkyl citrates include triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate and mixtures thereof. Triethyl citrate is particularly preferred. Particularly preferred lower alcohol fatty acid esters include ethyl oleate, ethyl linoleate, ethyl caprylate, ethyl caprate, isopropyl myristate, isopropyl palmitate and mixtures thereof. Lactones may also serve as solubilizers. Examples include ε-caprolactone, δ-valenolactone, β-butyrolactone, isomers thereof and mixtures thereof.

The solubilizer may be a nitrogen-containing solvent. Preferred nitrogen-containing solvents include dimethylformamide, dimethylacetamide, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, and mixtures thereof. Here, alkyl is C _1-12 branched or straight chain alkyl. Particularly preferred nitrogen-containing solvents include N-methyl 2-pyrrolidone, N-ethyl 2-pyrrolidone or a mixture thereof. The nitrogen-containing solvent may be in the form of a polymer such as polyvinyl pyrrolidone.

  Another group of solubilizers includes phospholipids. Preferred phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithin, lysolecithin, lysophosphatidylcholine, polyethylene glycolated phospholipid / lysophospholipid, lecithin / lysolecithin and mixtures thereof.

  Another group of preferred solubilizers are glycerol acetate and acetylated glycerol fatty acid esters. Preferred glycerol acetates include acetin, diacetin, triacetin, and mixtures thereof. Triacetin is particularly preferred. Preferred acetylated glycerol fatty acid esters include acetylated monoglycerides, acetylated diglycerides and mixtures thereof.

  In addition, the solubilizer may be a glycerol fatty acid ester. The fatty acid component has about 6-22 carbon atoms. Glycerol fatty acid esters can be monoglycerides, diglycerides, triglycerides or mixtures thereof. Preferred glycerol fatty acid esters include monoglycerides, diglycerides, medium chain triglycerides with fatty acids having about 6-12 carbons, or mixtures thereof. Particularly preferred glycerol fatty acid esters include medium chain monoglycerides with fatty acids having about 6-12 carbons, medium chain diglycerides with fatty acids having about 6-12 carbons, or mixtures thereof.

  The solubilizer may be a propylene glycol ester. Preferred propylene glycol esters include propylene carbonate, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol fatty acid ester, acetylated propylene glycol fatty acid ester, or mixtures thereof. Alternatively, the propylene glycol fatty acid ester may be a propylene glycol fatty acid monoester, a propylene glycol fatty acid diester or a mixture thereof. Fatty acids have about 6-22 carbon atoms. It is particularly preferred that the propylene glycol ester is propylene glycol monocaprylate (CAPRYOL®). Other preferred propylene glycol esters include propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylate / dicoupler, or mixtures thereof.

  Another group of solubilizers are ethylene glycol esters. Examples of the ethylene glycol ester include monoethylene glycol monoacetate, diethylene glycol ester, polyethylene glycol ester, or a mixture thereof. Further examples include ethylene glycol monoacetate, ethylene glycol diacetate, ethylene glycol fatty acid monoester, ethylene glycol fatty acid diester, or mixtures thereof. Furthermore, ethylene glycol esters include polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, or mixtures thereof. Again, the fatty acid component will contain about 6-22 carbon atoms. Particularly preferred ethylene glycol esters are those marketed under the trade names LABRAFIL® and LABRASOL®.

  For example, polyoxyethylene-sorbitan having a alkylene moiety of 4 to 25, such as the known types of mono- and tri-lauryl, palmityl, stearyl and oleyl esters, marketed under the trade name TWEEN® Fatty acid esters (also called polysorbates) are also suitable as surfactants.

Usable hydrophilic solvents include alcohols such as water miscible alcohols such as absolute ethanol, or glycerol. Other alcohols include any glycol that can be obtained from glycols, such as oxides such as ethylene oxide, such as 1,2-propylene glycol. Other examples are polyols such as polyalkylene glycols such as poly (C _2-3 ) alkylene glycol. A typical example is polyethylene glycol. Further, the hydrophilic component N- alkylpyrrolidones, for example _{N- (C 1-14} alkyl) pyrrolidone, specifically N- methylpyrrolidone, tri _{(C 1-4} alkyl) citrate, specifically triethyl citrate, It preferably contains dimethyl isosorbide, (C ₅ -C ₁₃ ) alkanoic acid, such as caprylic acid, or propylene carbate.

The hydrophilic solvent may comprise a main component or a single component, for example an alcohol, for example a C _1-4 alcohol, specifically ethanol, or alternatively a component selected from co-components, for example a partial lower ether or a lower alkanol. . Preferred partial ethers include, for example, TRANSCUTOL® (represented by the formula: C ₂ H ₅ — [O— (CH ₂ ) ₂ ] ₂ —OH), GLYCOFUROL® (tetrahydrofurfuryl alcohol polyethylene glycol) Also known as ethers) or lower alkanols such as ethanol.

  In an embodiment of the present invention, the unit dosage form pharmaceutical composition consists of an essentially homogeneous solution, which consists essentially of a solvent system in which one or more NSAIDs comprise omega-3 fatty acids (ie, Less than 10%, preferably less than 5% remain undissolved). The one or more NSAIDs are substantially dissolved in the omega-3 fatty acid oil to provide a substantially homogeneous composition. In preferred embodiments, the one or more NSAIDs are completely dissolved. The one or more NSAIDs are preferably blended in the pharmaceutical composition without using a large amount of solubilizer (except for omega-3 fatty acids). In a preferred embodiment, if formulated, solubilizers other than omega-3 fatty acids are 50% w / w or less, preferably 40% or less, based on the total weight of the solvent system in the dosage form. Preferably, it is blended in an amount of 30% or less, more preferably 20% or less, even more preferably 10% or less, and most preferably 5% or less. In certain embodiments, the solvent system does not include solubilizers other than omega-3 fatty acids. As used herein, the term “solvent system” generally includes omega-3 fatty acids in the form of oils. In other preferred embodiments, the weight ratio of omega-3 fatty acids to other solubilizers is at least 0.5: 1, more preferably at least 1: 1, even more preferably at least 5: 1, most preferably at least 10: 1.

  In a preferred embodiment, the omega-3 fatty acid is at least 30% weight / weight, more preferably at least 40%, even more preferably at least 50%, most preferably at least 60, based on the total weight of the solvent system in the dosage form. It is blended in the amount of%. In certain embodiments, the loading can be at least 70%, at least 80%, or at least 90%.

The dosage form comprising the substantially homogeneous solution is at room temperature (about 23 ° C. to 27 ° C., preferably about 25 ° C.) and 60% relative humidity for a period of at least 1 month, preferably at least 6 months, more preferably at least 1 Must be stable for a year, most preferably for at least 2 years. A substantially homogeneous solution is preferably prepared using omega-3 fatty acids in the LOVAZA ^™ form. The term “stable” means, according to the applicant, that one or more dissolved NSAIDs do not precipitate out of solution and to a significant extent, for example in an amount of less than 10%, preferably less than 5%. It means that it is not chemically modified.

In addition, dosage forms containing essentially homogeneous solutions must prevent degradation of one or more NSAIDs. Certain embodiments include unit dosage forms of one or more NSAIDs and omega-3 fatty acids, wherein at least an initial amount measured at an initial time (t ₀ ) of one or more NSAIDs in the dosage form. 90% should be stored at room temperature and 60% relative humidity and maintained for a period of at least 1 month, preferably at least 6 months, more preferably at least 1 year, most preferably at least 2 years.

  The combination product is obtained by combining one or more NSAIDs with omega-3 fatty acids and optionally one or more hydrophilic solvents, surfactants, other solubilizers, and / or other excipients. Can be produced by methods known to those skilled in the art.

  Other embodiments of the invention are directed to suspensions of one or more NSAIDs in omega-3 fatty acids. In some embodiments, the suspension consists of one or more NSAID solid crystalline particles, solid amorphous particles, or mixtures thereof in omega-3 fatty acids. Another embodiment is a pharmaceutical composition comprising a suspension of one or more NSAIDs in omega-3 fatty acids, wherein a portion of the one or more NSAIDs is solubilized in a solvent system. Is included. For example, in certain embodiments, the invention is a pharmaceutical composition comprising an omega-3 fatty acid and one or more NSAIDs, wherein about 1-15% by weight of the one or more NSAIDs are present in the solution, while A pharmaceutical composition is provided wherein the rest of the NSAID is present in the suspension.

  In another embodiment, the invention provides a pharmaceutical composition comprising an omega-3 fatty acid and one or more NSAIDs, wherein at least about 80% by weight of the one or more NSAIDs, preferably about 85%, more Preferably, a pharmaceutical composition is provided wherein about 90%, even more preferably about 95%, most preferably about 99% is present in the suspension as solid particles.

  Another preferred embodiment of the present invention is directed to soft gelatin capsules coated with one or more NSAIDs. In such embodiments, the at least one coating applied to the outside of the soft gelatin capsule includes one or more NSAIDs, a coating material such as a film-forming material and / or a binder, and optionally a lubricant, filling. And other conventional additives such as antioxidants and antioxidants. Preferred coating materials include antioxidants, solubilizers, chelating agents and / or absorption enhancers. Surfactants act as both solubilizers and absorption enhancers.

  The coating agent may be applied by conventional means such as pan coating, fluid bed coating or spray coating. The coating agent can be applied as a suspension, spray, dust or powder. The coating agent may be formulated to provide immediate, delayed / enteric release or sustained release of one or more NSAIDs according to methods well known in the art. Conventional coating techniques are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed. (1990), the contents of which are hereby incorporated by reference.

  Immediate release coatings are typically used to improve the accuracy of product release, as a moisture barrier, and to mask odors. It is important that the film rapidly disintegrates in the gastric juice to lead to effective dispersion and dissolution. EUDRAGIT RD100 (Rohm) is an example of such a coating agent. The material is a combination of a water-insoluble cationic methacrylate copolymer and a water-soluble cellulose ether. The material in powder form is easily dispersed in an easily sprayable suspension and forms a flat film upon drying. Of course, other suitable immediate release coating agents may be utilized in accordance with the present invention. Such films rapidly disintegrate in aqueous media at a constant rate regardless of pH and film thickness.

  The protective coating layer (ie, seal coat) may be applied by conventional coating methods such as pan coating or fluidized bed coating using a solution of the polymer in water or a suitable organic solvent, if necessary, or using an aqueous polymer dispersion. You may apply by. Suitable materials for the protective layer include cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, ethylcellulose aqueous dispersant and the like. The protective coating layer includes an antioxidant, a chelating agent, a colorant and a pigment.

  Enteric coating layers can be prepared by conventional coating methods such as pan coating or fluidized bed coating with a solution of the polymer in water or in a suitable organic solvent, with or without a seal coating agent, or by using an aqueous polymer dispersion. It may be applied on the core. All commercially available pH sensitive polymers are included. The pharmaceutically active ingredient is not limited to this value, but is not released in the acidic environment of the stomach where the pH is below about 4.5. When the pH sensitive layer dissolves at a higher pH, the pharmaceutically active ingredient becomes available after a certain period of time or after the unit dosage form has passed through the stomach. A preferred delay time is in the range of 1 to 6 hours.

  Enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid / methacrylic acid methyl ester, for example, trade name EUDRAGIT L12 .5, L100 or EUDRAGIT S12.5, S100 or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersants or redispersants such as EUDRAGIT L30D-55, EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm Pharma); AQUATERIC, AQUACOAT CPD30 (FMC); KOLLICOAT MAE 30D and 30DP ( BASF); EASTACRYL 30D (Eastman Chemical) can also be applied.

  The sustained release film coat can be a wax or wax-like substance, fatty alcohol, shellac varnish, zein, hydrogenated vegetable oil, water-insoluble cellulose, acrylic acid and / or methacrylic acid polymer, any other slowly digested known in the art. Includes possible or dispersible solids. The solvent for the hydrophobic coating material may be either an organic solvent or an aqueous solvent. Preferably, the hydrophobic polymer is selected from (i) a water-insoluble cellulosic polymer such as alkali cellulose, preferably ethyl cellulose; (ii) an acrylic polymer; or (iii) a mixture thereof. In another preferred embodiment of the invention, the hydrophobic material comprising the controlled release coating agent is an acrylic polymer. Pharmaceutically acceptable acrylic polymers can be used for the purposes of the present invention. The acrylic polymer may be any of a cationic, anionic or nonionic polymer, may be an acrylate, a methacrylate, and may be formed from methacrylic acid or a methacrylic acid ester. Examples of suitable acrylic acid polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, methyl methacrylate, aminoalkyl methacrylate. Copolymers, poly (acrylic acid), poly (methacrylic acid), alkyl methacrylate amine copolymers, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polymethacrylate, methyl methacrylate copolymer, poly (methyl methacrylate) Acrylate) copolymers, polyacrylamides, poly (methacrylic anhydride) and glycidyl methacrylate copolymers.

  A barrier coat may be included between the outer coat and the soft gelatin shell. The barrier coat may consist of an enteric / delayed release coat (above) or a barrier (non-functional) layer that serves as a protective coat and prevents the pharmaceutically active ingredient from leaching out of the shell or vice versa. To prevent.

  In one embodiment of the invention, one or more NSAIDs are divided into a first part and a second part, one part being placed on the coating and the other part being placed in a soft gelatin capsule. In one embodiment, the dosage form has a time lag between administration of the first portion and administration of the second portion by providing an enteric coating as a barrier layer. In other embodiments, the first portion may be released immediately, followed by a delayed or sustained release of the second portion. In further embodiments, the first portion may be delayed released, followed by the bolus administration of the second portion.

  For example, soft gelatin capsules, although coating techniques are widely used in the pharmaceutical industry for applying functional or non-functional coats to a single dosage form and for depositing pharmacologically active bulk powder on sugar beads There are also a number of challenges that may be encountered during the coating. These challenges are often attributed to the properties of gelatin and dosage forms. Soft gelatin capsules generally contain a medicament dissolved or dispersed in an oil or hydrophilic liquid (fill liquid). The inherent softness of soft gelatin capsules is due to the presence of plasticizer and residual moisture in the capsule shell. Thus, soft gelatin capsules are a more dynamic system than conventional or hard gelatin capsules. Atmospheric moisture may penetrate into the capsule shell or into the filling liquid. The drug or filling liquid may move into the capsule shell, while the plasticizer or remaining aqueous gelatin may move into the filling liquid. Volatile components in soft gelatin capsules may escape into the atmosphere.

  As described above, the polymeric coating is generally applied as an aqueous solution, organic solution or dispersion, in which case the polymer-containing droplets are atomized with a gas and sprayed onto the substrate. The coating apparatus may be heated to promote solvent evaporation and film formation. In the case of soft gelatin capsules, the processing parameters of spray speed and bed temperature must be controlled. Since gelatin is water soluble, spraying aqueous polymer material at high speed can result in solubilization of the gelatin and aggregation of the capsules. High bed temperature evaporates the remaining moisture from the capsule shell, making the capsule brittle. Accordingly, the present invention includes a method for coating soft gelatin capsules that avoids these results.

  In addition, the deposition of small amounts of one or more NSAIDs on the surface of soft gelatin capsules can be affected by several factors. The accuracy of the deposition needs to be demonstrated by evaluating the coating invariance, including the mass dispersion of the coated capsules and the content mismatch of the coated NSAID (s).

  The present invention is a method of coating a soft gelatin capsule comprising omega-3 fatty acids with a coating material and a coating agent comprising one or more NSAIDs, controlling the rate at which the coating agent is deposited on the soft gelatin capsule, A method is provided for controlling the temperature during the coating process to produce physically and chemically stable coated gelatin capsules.

  In another embodiment, the coating agent of the present invention may also be applied on hard capsules or tablets. Hard gelatin capsules may contain powders, beads or microtablets instead of liquids (eg, a system similar to US Pat. No. 5,681,588, hereby incorporated by reference).

Another embodiment of the invention is a unit dosage form of one or more NSAIDs and omega-3 fatty acids, the initial time measured at the initial time (t ₀ ) of the one or more NSAIDs in the dosage form. At least 90% of the quantity is maintained after 1 month storage (preferably 6 months storage, more preferably 1 year storage, most preferably 2 years storage) at room temperature and 60% relative humidity Including unit dosage forms.

  In certain embodiments, the formulations of the present invention improve the metabolic action and / or efficacy of one or both active ingredients, preferably one or both administered in their conventional intact amounts, and their metabolic action and / or It improves the efficacy. In other embodiments, the formulations of the present invention are capable of reducing the dose of one or more NSAIDs and / or omega-3 fatty acids compared to prior art formulations, yet each active ingredient The efficacy of is maintained or even improved.

  This combination of one or more NSAIDs and omega-3 fatty acids allows for an effect that is greater than the combined or additive effects that are conceivable with the two drugs alone. Thus, the combination therapy of the two active ingredients, either separately or via the novel combination product of the present invention, can increase efficacy at the standard dose of the two active ingredients or decrease the dose of the ingredients. It can lead to an unexpected increase in the action of the active ingredient, which makes it possible to maintain its efficacy. Improvements in the bioavailability or efficacy of drugs or other active ingredients will reduce some daily doses and are well tolerated in pharmaceutical practice. Undesirable side effects are also reduced as a result of reduced dose and reduced excipients.

  All references cited in this specification are hereby incorporated by reference in their entirety.

Example

  A test was conducted to determine if a solution could be prepared with a number of non-steroidal anti-inflammatory drugs (NSAIDs) in omega-3 polyunsaturated fatty acids. Non-steroidal anti-inflammatory drugs tested were acetaminophen, ibuprofen, meloxicam, piroxicam and naproxen. The omega-3 polyunsaturated fatty acid tested was omega-3 polyunsaturated fatty acid triacylglycerol (EPAX® 6000TG). Experiments show that it is difficult to make solutions in the form of triacylglycerols of NSAIDs and omega-3 polyunsaturated fatty acids.

Example 1

The solubility of each NSAID was tested at the recommended target “dose”. The target dose was equivalent to 25% of the recommended daily maximum dose and assumed that four 1000 mg EPAX® capsules were consumed per day. Target doses for study NSAID were: acetaminophen 800 mg, ibuprofen 300 mg, meloxicam 4 mg, naproxen 150 mg and piroxicam 5 mg.

  Initial solubility results indicated that acetaminophen, ibuprofen and meloxicam did not dissolve in EPAX®. At the target concentrations of three NSAIDs at about 25 ° C. and about 40 ° C., a high viscosity paste is observed with acetaminophen; a high viscosity suspension turbid with ibuprofen is observed; A turbid liquid was observed. When heated to about 70 ° C., a clear clear solution with a precipitate at the bottom was observed with meloxicam, and this phenomenon was maintained unchanged upon cooling to room temperature. When heated to about 70 ° C., a clear solution was observed with ibuprofen, but upon cooling to room temperature, precipitation of ibuprofen occurred.

  An initial solubility result for piroxicam was observed at 70 ° C. for a clear solution, but upon cooling to room temperature a turbid suspension was formed. As a result of the initial solubility of naproxen, a turbid suspension was observed both at 70 ° C. and at room temperature.

Example 2

  Experiments were performed to determine the concentration at which the NSAID dissolved and formed a solution. The amount of each NSAID was weighed in a separate vial, followed by the weighed amount of EPAX® 6000TG. The vial was capped and then sonicated for 5 minutes to bake. If the NSAID did not dissolve, the preparation was placed in a 40 ° C./75% RH stability chamber for about 1.5 hours. If a clear solution was not obtained, then additional weights of EPAX® were added stepwise. Each preparation was sonicated for about 15 minutes, and EPAX® was added to each. The results are shown in Table 1.

  The preparation of 10 mg ibuprofen and 1 g EPAX® (1000 mg) was clear, but the dose of ibuprofen was well below the target dose of 300 mg. A preparation of 2 mg of piroxicam and 1 g of EPAX® (1000 mg) appeared to dissolve when heated to 40 ° C., but the dose of piroxicam was below the target dose of 5 mg. A meloxicam 2 mg and EPAX® 15 g (15000 mg) preparation was observed to dissolve, while the meloxicam dose was below the 4 mg target dose and the EPAX® dose was 1 g. Well above the target dose of (1000 mg). The preparation of naproxen 75 mg and EPAX® 10 g (10000 mg) appeared to be dissolved, but this dosage form of naproxen was below the target dose of 150 mg / g EPAX®.

Claims (16)

a. A unit dosage form comprising omega-3 fatty acids and optionally solubilizing agents;
b. One or more outer coating agents on the unit dosage form, wherein at least one outer coating agent comprises one or more NSAIDs;
c. One or more barrier coatings may be included between the unit dosage form and one or more outer coatings,
d. A seal coating agent may be included on the unit dosage form.
Pharmaceutical composition.   2. The pharmaceutical composition of claim 1, wherein the one or more outer coating agents are formulated for immediate release, delayed / enteric release, or sustained release of one or more NSAIDs.   The pharmaceutical composition according to claim 1, wherein the one or more barrier coating agents are formulated for enteric / delayed release of omega-3 fatty acids or as a non-functional protective layer.   The pharmaceutical composition according to claim 1, wherein the unit dosage form is a soft gelatin capsule, a hard gelatin capsule or a tablet.   One or more NSAIDs are ibuprofen, naproxen, ketoprofen, oxaprozin, diclofenac, indomethacin, sulindac, piroxicam, meclofenamate, mefanamic acid, nabumetone, etodolac, ketorolac, choline magnesium trisalicylate, aspirin, diflunisal, salsalate, The medicament according to claim 1, wherein the drug is selected from profen, flubiprofen, pyrprofen, thiaprofenic acid, loxoprofen, indoprofen, fenbufen, carprofen, suprofen, celecoxib, valdecoxib, rofecoxib, parecoxib, deracoxib, lumiracoxib, etoroxib or meloxicam Composition.   2. The pharmaceutical composition of claim 1, wherein the omega-3 fatty acid contains at least about 70% EPA and DHA.   The pharmaceutical composition of claim 1 comprising from about 0.1 g to about 10 g of omega-3 fatty acid.   At least one outer coating comprising one or more NSAIDs is sprayed onto the unit dosage form, controlling the deposition rate of the coating and controlling the temperature during the coating process, both physically and chemically. 2. A pharmaceutical composition according to claim 1 which produces a stable coated unit dosage form.   Arthritis, osteoarthritis, rheumatoid arthritis, autoimmune disorders, sudden recurrence of chronic diseases, fever, pain secondary to pain disorder or other symptoms, dysmenorrhea, fibromyalgia, acute musculoskeletal pain, chronic Musculoskeletal pain, toothache, postoperative pain, familial adenomatous polyposis, other neoplastic disease symptoms, reduced cholesterol and triglyceride levels, any COX mediated symptoms, and / or NSAIDs and omega-3 fatty acids A method of treating a subject having one or more symptoms selected from the group consisting of any other symptoms effective for combination therapy, comprising administering the pharmaceutical composition of claim 1 to the subject Including the method.   The method of treating a subject according to claim 9, wherein the symptom is osteoarthritis.   The method of treating a subject according to claim 9, wherein the symptom is rheumatoid arthritis.   The method of treating a subject according to claim 9, wherein the symptom is dysmenorrhea.   The method of treating a subject according to claim 9, wherein the symptom is fibromyalgia.   The method of treating a subject according to claim 9, wherein the symptom is chronic musculoskeletal pain.   The method of treating a subject according to claim 9, wherein the symptom is a neoplastic disease.   10. The method of treating a subject according to claim 9, wherein the symptom is familial adenomatous polyposis.