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    • 专利摘要:
    The present invention provides an oral dosage form comprising a granular phase and a non-granular phase, said granular phase consisting of a therapeutically effective amount of a pharmaceutically active substance, a gas-forming substance and a hydrophilic polymer. Such dosages have been found to offer a fast dissolution rate for ingredients with low water solubility. In addition, the present invention provides a method for the preparation thereof.
    公开号:BE1025229B1
    申请号:E2018/5468
    申请日:2018-07-04
    公开日:2018-12-17
    发明作者:Bart Rossel
    申请人:Oystershell Nv；
    IPC主号:
    专利说明:

    ORAL DOSING FORM FOR IMPROVED SOLUBILITY OF ONE
    WEAK SOLELY, ACTIVE SUBSTANCE AND PREPARATION METHOD
    TECHNICAL FIELD
    The present invention relates to the field of oral dosage forms for the improved solubility of pharmaceutical, sparingly soluble active ingredients. The present invention relates more particularly to the field of oral dosage forms comprising one or more insoluble or sparingly soluble active ingredients, wherein the oral dosage form provides an improved dissolution profile.
    PREFACE
    Oral administration of pharmaceutically active compounds or nutritional supplements is one of the most suitable methods for treating a condition in a human or animal body. However, efficient absorption of the active ingredient through the gastrointestinal tract of the treated body is a requirement for such administration methods.
    To this end, the prior art has oral dosage forms with controlled release profiles. WO 01/15665 is directed to a pharmaceutical composition, preferably in the form of a tablet comprising a therapeutically effective amount of a drug in a carrier comprising a water-insoluble polymer and a water-insoluble inorganic salt.
    WO 2005/097078 offers an oral solid compressed composition comprising a magnesium salt. The composition provides a rapid dissolution of the magnesium salt, with no less than 75% of the magnesium salt dissolving within 45 minutes after placement in hydrochloric acid (0.1 N, 900 ml) according to USP method <711>. In a particular embodiment, the magnesium salt is an inorganic salt such as MgO, Mg (OH) 2, MgCb, and others. The composition can be prepared by dry granulation, direct compression or another suitable process. The composition provides a substantially stable dissolution profile for the magnesium salt, so that the dissolution profile changes only minimally even after a long storage period under pharmaceutically acceptable conditions
    BE2018 / 5468 when it is packaged in a sealed system surrounded by a container. The solid composition can also exclude a cellulose-based composition.
    The compressed composition can be prepared and stored under anhydrous conditions.
    WO 2009/150323 relates to the use of a matrix for oral administration, in tablet form, of gradual continuous release of Mg provided with a protective coating which delays the dissolution in the stomach of Mg, the said matrix being characterized in that, for the administration (A) of 90 to 110 parts by weight of magnesium, the following ingredients comprise: (B1) 180 to 190 parts by weight of hydroxypropyl methyl cellulose; (B2) 19.8 to 22.2 particles by weight of glyceryl behenate; (Cl) 10 to 12 particles by weight of lactose; and (C2) 10 to 12 particles by weight of colloidal silica. The invention also relates to the gradual release composition comprising said matrix and the coating thereof.
    The prior art has attempted to promote bioresorption of such weakly water-soluble or water-insoluble compounds by providing sustained-release dosage forms. However, a problem is that the dosage of the pharmaceutically active compound administered can coagulate in the stomach of the patient, thereby limiting the bioavailability of the active ingredient for bioresorption. It is an object of the present invention to provide oral dosage forms that exhibit rapid and quantitative dissolution profiles.
    SUMMARY OF THE INVENTION
    In a first aspect, the present invention provides an oral dosage form comprising a granular phase and a non-granular phase, wherein said granular phase consists of a pharmaceutically active substance, a gas-forming substance and a hydrophilic polymer.
    The granular phase is provided to allow the oral dosage form to surface and float on the gastric fluid upon ingestion of the oral dosage form. Because of this floating and prolonged residence of the pharmaceutically active ingredient in the stomach in a non-coagulated form, the dissolution can occur quickly and quantitatively.
    BE2018 / 5468
    In a second aspect, the present invention provides a method for preparing an oral dosage form, comprising the following steps:
    - mixing a pharmaceutically active substance, a gas-forming substance and a hydrophilic polymer in the presence of water, whereby a hydrated mixture is obtained;
    - drying said hydrated mixture, whereby grains are obtained;
    - mixing said granules in a non-granular powder; and
    compressing said granules into said non-granular powder, thereby obtaining an oral dosage form comprising a granular phase and a non-granular phase.
    The preparation of the granular phase granules in the presence of water provides a pre-treated hydrophilic polymer. Such pretreatment allows an improved wetting of the hydrophilic polymer and consequently an improved water inflow from the granular phase during contact with the gastric fluid.
    The present invention also provides an oral dosage form according to the first aspect of the invention or obtained by a method according to the second aspect of the invention, comprising a mineral for the treatment, prevention or after-treatment of mineral deficiencies in a human or animal body, preferably in mammals.
    DESCRIPTION OF THE FIGURES
    Furthermore, the figures are included to better understand the description of the present invention. Such figures are intended to aid in the description of the invention and are in no way intended as a limitation of the invention described herein.
    The figures and symbols incorporated herein have the meaning that will usually be understood by those skilled in the art to which this invention belongs.
    Figure 1 shows the amount of elemental magnesium dissolved in a 0.1 N HCl solution, expressed as a percentage of the amount of elemental magnesium in the respective dosage forms, as a function of time (min.).
    BE2018 / 5468
    Figure 2 shows the absolute amount of elemental magnesium dissolved in a 0.1
    N HCl solution, as a function of time (min.).
    DETAILED DESCRIPTION OF THE INVENTION
    Unless defined otherwise, all terms used in the description of the invention, including technical and scientific terms, have the meaning generally understood by one skilled in the art to which this invention relates. Furthermore, the definitions of the terms are included to better understand the description of the present invention.
    As used herein, the following terms have the following meaning:
    One, the and the as used herein refer to both the singular and the plural, unless the context indicates otherwise. A compartment refers, by way of example, to one or more than one compartment.
    Approximately as used herein, which refers to a measurable value such as a parameter, an amount, a duration, and the like, is intended to include variations of +/- 20% or less, preferably +/- 10% or less, more at preferably +/- 5% or less, even more preferably +/- 1% or less, and even more preferably +/- 0.1% or less of the specified value, insofar as such variations are suitable for performing in the described invention. It will be clear, however, that the value to which the modifier roughly refers is also specifically described.
    Including, including and including, and consisting of as used herein, are synonymous with containing, containing or containing, and are inclusive or open terms specifying the presence of what follows, for example, a component and the presence of additional, non-named components, features, do not exclude elements, parts, steps that are well known in the art or described therein.
    Quoting numeric ranges by end points includes all numbers and fractions included within that range, as well as the specified end points. All percentages are to be understood as a percentage by weight and are abbreviated as% by weight, unless otherwise defined or unless a different opinion is given
    BE2018 / 5468 is clear to those skilled in the art from its use or in the context in which it is used.
    The present invention provides a solution to at least one of the above problems by providing a foamed oral dosage form for controlled release and preparation method.
    The term pharmaceutically acceptable is used herein to refer to the compounds, materials, compositions and / or dosage forms which, within the field of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problem or complication, with a reasonable benefit / risk ratio.
    The term elemental additive, elemental mineral, quantity element or trace element refers to the elements of the periodic table of chemical elements: boron, sodium, magnesium, aluminum, silicon, potassium, calcium, vanadium, chromium, manganese, iron, cobalt, nickel, copper , zinc, selenium, molybdenum and barium, and more particularly: boron, magnesium, silicon, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium and molybdenum.
    A formula according to the invention may comprise a sparingly soluble inorganic salt of an elemental additive, such as magnesium, present in an effective amount. A formula according to the invention may comprise a sparingly soluble organic salt of an elemental additive, such as magnesium, present in an effective amount. A formula according to the invention may comprise a sparingly soluble inorganic salt or a sparingly soluble organic salt of an elemental additive, such as magnesium, present in an effective amount. By the term effective amount is meant the number or amount of the elemental additive salt sufficient to induce the required or desired reaction, or in other words, the amount sufficient to induce a noticeable biological reaction when it is administered to a patient. When formulated in a dosage form, the composition may be present in a tablet, capsule, pill, pastille, stick, pellet, pellet or powder.
    BE2018 / 5468
    As used herein, the terms patient or individual are to be understood as warm-blooded animals such as mammals, e.g., cats, dogs, mice, guinea pigs, horses, bovine cows, sheep, and humans.
    In the context of the present invention, hydrophilic polymers are used to improve the performance of the solid oral composition. Examples of hydrophilic polymers suitable for use in an insoluble pharmaceutically active ingredient, such as magnesium oxide, are described in, for example, Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA, 1990, pp. 2,91294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea & Febinger, Philadelphia, PA, 1983, pp 592-638.); AT Florence and D. Altwood, Physicochemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pp. 281-334; RC Rowe, PJ Sheskey, and PJ Weller (eds.), Handbook of Pharmaceutical Excipients, 4th edition, Pharmaceutical Press, London, 2003. The complete disclosures of the references cited herein are hereby incorporated by reference. Still other suitable polymers include water-soluble natural polymers, water-soluble semisynthetic polymers (such as the water-soluble derivatives of cellulose) and water-soluble synthetic polymers. The natural polymers include polysaccharides such as inulin, pectin, algin derivatives (e.g., sodium alginate) and agar, and polypeptides such as casein and gelatin. The semisynthetic polymers include cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, their mixed ether such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose and hydroxypropylethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts, especially sodium carboxymethyl. The synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinyl pyrrolidone and polystyrene sulfonate) and various copolymers of acrylic acid (e.g., carbomer). Other natural, semi-synthetic, and synthetic polymers that are not mentioned herein and that meet the criteria of water solubility, pharmaceutical acceptability, and pharmacological inactivity are also considered as part of the scope of the present invention.
    BE2018 / 5468 The term granular phase is to be understood as a phase within an oral dosage form consisting of granules or multiple solid-state particles with an average particle size and a particle size distribution. In the context of the present invention, such granules are prepared by fluidized bed granulation processes in an aqueous environment.
    In a first aspect, the present invention provides an oral dosage form such as a tablet comprising a granular phase and a non-granular phase, said granular phase consisting of a therapeutically effective amount of a pharmaceutically active substance, a gas-forming substance and a hydrophilic polymer.
    When it enters the acidic environment of the stomach, the non-granular phase of the oral dosage form dissolves rapidly and water spreads into the granules of the granular phase. The hydrophilic polymer in the granular phase absorbs the water and forms a hydrogel. At the same time, the gastric fluid activates the gas-forming agent to form a gas, i.e., carbon dioxide is formed from sodium bicarbonate. Since the gas is formed within the granular phase, gas bubbles become trapped within the hydrogel and reduce the density of the tablet. Consequently, the tablet comes to the surface of the stomach contents where the pharmaceutically active substance can dissolve in the gastric fluid without coagulation of the pharmaceutically active substance and / or early release of such coagulated phase into the intestines. Due to an extended stay of the pharmaceutically active ingredient in the stomach in a non-coagulated form, the dissolution can occur quickly and completely.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, consisting of at least 25% by weight of granular phase, relative to the total weight of the oral dosage form. More preferably, said oral dosage form consists of at least 35% by weight of granular phase and at most 90% by weight of granular phase, and even more preferably 40% by weight to 99% by weight of granular phase. Most preferably, said oral dosage form consists of between 45 and 75% by weight of granular phase, and particularly preferably 46, 48, 50, 52, 54, 56, 58 or 60% by weight of granular phase. A sufficiently large granular phase makes it possible to offer a high content of the pharmaceutically active ingredient.
    BE2018 / 5468 In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, consisting of at least 1 wt% non-granular phase, relative to the total weight of the oral dosage form. More preferably, said oral dosage form consists of at least 10% by weight or more preferably at least 25% by weight of non-granular phase, and even more preferably from 35% to 60% by weight of non-granular phase. Most preferably, said oral dosage form consists of between 40 and 55% by weight of non-granular phase and particularly preferably 40, 42, 44, 46, 48, 50, 52 or 54% by weight of non-granular phase. A sufficiently large non-granular phase contributes to the rapid disintegration of the tablet within the stomach fluid.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said granular phase is prepared by a fluid-based water-based granulation process.
    This is advantageous since pre-treatment of the hydrophilic polymer with water improves its wetting, thereby providing a better inflow of water into the granular phase during the dissolution in the gastric fluid. Since water inflow into the granular phase is an important step in the release of the pharmaceutically active ingredient, an effective water inflow is an important factor that contributes to the rapid release process.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said hydrophilic polymer is included in said granular phase in an amount of at least 5.0% by weight, and preferably in an amount of 10.0% by weight % to 25.0% by weight relative to the total weight of said granular phase. More preferably, said hydrophilic polymer is included in an amount of 10, 12, 14, 16, 18, 20 or 22% by weight, or any amount in between. A sufficiently high amount of hydrophilic polymer is required to provide a sufficiently large hydrogel upon water inflow, in which hydrogel the gas bubbles formed can be trapped.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said hydrophilic polymer is selected from the group comprising methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.
    BE2018 / 5468 In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said gas-forming agent is included in said granular phase in an amount of 10.0 wt% to 25.0 wt% with respect to the total weight of said granular phase. More preferably, said gas-forming agent is included in an amount of 10, 12, 14, 16, 18, 20 or 22% by weight, or any amount in between. A sufficiently high amount of gas-forming agent is required to provide a sufficiently large amount of gas bubbles that can be trapped within the hydrogel formed from said hydrophilic polymer upon water inflow.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said gas-forming agent is an agent that releases CO2. More preferably, said gas-forming agent is included in an amount of 10, 12, 14, 16, 18, 20 or 22% by weight, or any amount in between. The term CO2 releasing agent is to be understood as a substance which, upon contact with an acidic solution, releases CCb gas, such as carbonate or bicarbonate salts of sodium, potassium, calcium, etc. The said CO2 releasing agent is included in the granular phase in an amount of 5 to 10% by weight, more preferably in an amount of 7.0 to 8.5% by weight. Still preferably, said CO2 releasing agent is included in said granular phase in a ratio of about 1: 3 relative to the total amount of hydrophilic polymers in said granular phase. The CO2 released from the composition can thus be optimally embedded in the polymer matrix for an optimum floating effect.
    In a preferred embodiment, said gas-forming agent is a carbon dioxide-forming agent such as sodium bicarbonate, and said oral dosage form further comprises a gas-activating agent, which acts as a catalyst or reagent for releasing carbon dioxide. More preferably, said gas activating agent is an acidifying agent and is provided within the non-granular phase of the tablet. As used herein, the term acidifying agent is intended to designate a compound used to provide an acidic medium for product stability. Such compounds include, by way of example and without limitation, acetic acid, acetic amino acids, citric acid, tartaric acid and other α-hydroxy acids,
    BE2018 / 5468 hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and other edible acids which are well known to those skilled in the art.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said non-granular phase comprises one or more disintegrating agents in an amount of at least 5% by weight relative to the total weight of the staple granular phase. Such disintegrating agents promote the disruption of the solid mass in small particles that are more easily dispersed or dissolved. Examples of disintegrating agents include, for example and without limitation, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clay, bentonite, microcrystalline cellulose (e.g., Avicel), carboxymethylcellulose calcium, croscarmellose sodium, alginic acid, sodium alginate, cellulose polyacrilin potassium (e.g., Amberlite), alginates, sodium starch glycollate, gums, agar, guar, carob, karaya, pectin, tragacanth, crospovidone and other materials well known to those skilled in the art.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said pharmaceutically active substance has a low solubility and / or a low dissolution rate in water. By the term low solubility is meant that the solubility of the pharmaceutically active substance is lower than 0.1 g / 100 ml of water, and more particularly lower than 0.01 g / 100 ml of water, and even more preferably lower than 0.001 g / 100 mL of water.
    Said pharmaceutically active substance preferably comprises an inorganic salt of an elemental additive. Said pharmaceutically active substance more preferably comprises an inorganic salt of boron, magnesium, silicon, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium and / or molybdenum. Such oral dosage forms make it possible to provide additional amounts of quantity elements and / or essential trace elements for the mammal's body and to prevent and treat diseases and disorders.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said granular phase comprises one or more inorganic salts comprising one or more
    BE2018 / 5468 elemental additives, preferably selected from the group comprising boron, magnesium, silicon, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium and / or molybdenum. In a more preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein the anion of said inorganic salt is selected from the group consisting of oxides, carbonates, hydroxides, fluorides, chlorides, iodides, (dibasic) phosphates and sulfates of an elemental additive. Said inorganic salt is more preferably selected from the group consisting of magnesium, oxide, magnesium carbonate, magnesium hydroxide, magnesium fluoride and magnesium chloride. These salts offer a high fractional content of the elemental additive. The said inorganic salt is most preferably magnesium oxide. The present invention also encompasses all of the non-hydrated, hydrated and polymorphic forms of the salts identified above. Suppliers often use different processes to make such salts and most particularly magnesium salts. I.e. MgO from one supplier will probably have a different particle size, bulk density and / or porosity than MgO from another supplier. The present invention includes magnesium salts that are available in any range of pharmaceutically acceptable particle sizes. The magnesium salts of the invention will have a bulk density and / or porosity suitable for use in the formulation and processing of the invention. It is known that the different magnesium and other elemental salts have different solubility in water. Said one or more inorganic salts are preferably included in said granular phase in an amount of 10 to 60% by weight, more preferably in an amount of 20 to 45% by weight and even more preferably in an amount of 25 up to 40% by weight. Most preferably, said one or more inorganic salts are included in said granular phase in an amount of 26, 28, 30, 32, 34, 36, 38 or 40% by weight, or any amount in between.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said non-granular phase comprises one or more inorganic salts comprising an elemental additive, preferably selected from the group comprising boron, magnesium, silicon, vanadium , chromium, manganese, iron, cobalt, nickel, copper, iron, selenium and / or molybdenum. In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said non-granular phase comprises one or more organic salts
    BE2018 / 5468 comprising an elemental additive, preferably selected from the group comprising boron, magnesium, silicon, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium and / or molybdenum, the anion being selected from the group comprising gluconates, aspartates, citrates, glycinates, glycophosphates, amino acid chelates, ascorbates, α-keto glutarates, taurinates, tartrates, fumarates, maleates, lactates, stearates and oxalate dehydrates. More preferably, said organic salt is selected from the group consisting of magnesium gluconate, magnesium aspartate, magnesium citrate, magnesium glycinate, magnesium glycophosphate, magnesium amino acid chelate, magnesium ascorbate, magnesium α-keto glutarate, magnesium taurinate, magnesium tartrate, magnesium fumarate, magnesium lactate, magnesium magnesium hydrate.
    In a preferred embodiment, the invention provides a dosage form according to the first aspect of the invention, wherein said dosage form is a tablet that has a thickness, a length and a width and wherein the length to width ratio is greater than 1.1. The inventors have found that a larger ratio of length to width offers a rapid rise from the tablet to the surface of the aqueous solution liquid. A faster rise in the tablet ensures better contact and disintegration of the tablet, and consequently a faster release of the pharmaceutically active substance. More preferably, said length to width ratio is greater than 1.5 and even more preferably between 1.5 and 4.0. Most preferably, the said ratio is equal to 1.8, 2.0, 2.3, 2.5, 2.8, 3.0, 3.3, 3.5 or 3.8, or any value between them.
    The formulation of the present invention may further include an adsorbent, acidifying agent, anti-stick agent, binder, antioxidant, buffering agent, diluent (filler), alkalizing agent, bulk agent, colorant, plasticizer, stabilizer, flavoring agent, sweetener, disintegrating agent, lubricant, lubricant, opaquant, polishing agent, aroma, surfactant and / or other excipients that are well known to those skilled in the art for use in formulations, or a combination thereof.
    As used herein, the term adsorbent is intended to indicate an agent that can hold other molecules on its surface by physical or chemical (chemisorption) agents. Such compounds include, by way of example
    BE2018 / 5468 of example and without limitation, charcoal in powder form and activated charcoal and other materials well known to those skilled in the art.
    As used herein, the term anti-adhesive is intended to indicate an agent that prevents the ingredients of the solid dosage formula from sticking to needles and dies in a tablet forming machine during production. Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid, and other materials well known to those skilled in the art.
    As used herein, the term binder is intended to indicate a substance used to cause adhesion of powder particles in solid dosage formulas. Such compounds include, by way of example and without limitation, acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, and pregelatinized starch. Other examples of binders include acacia, tragacant, gelatin, starch, cellulose materials such as methylcellulose and sodium carboxymethylcellulose, alginic acids and salts thereof, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (Lutrol ™ F68, Lutrol ™ F127, collage) , gelatin, celluloses in non-aqueous solvents, combinations thereof and others well known to those skilled in the art. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene esters, polyethylene oxide, combinations thereof, and other materials well known to those skilled in the art.
    As used herein, the term diluent is intended to designate another inverted substance that is used as a filler to create the desired bulk, flow properties, and compression properties in the preparation of solid dosage forms. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch and other materials well known to those skilled in the art .
    As used herein, the term antioxidant is intended to indicate an agent that inhibits oxidation and is therefore used to prevent
    BE2018 / 5468 deterioration of preparations by the oxidative process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid , EDTA, pentetate, and sodium metabisulphite and others well known to those skilled in the art.
    As used herein, the term buffering agent is intended to designate a compound that is used to withstand change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid, tartaric acid, potassium metaphosphate, sodium potassium phosphate, sodium , sodium bicarbonate, tris-sodium tartrate and sodium citrate anhydrous and dihydrate and others well known to those skilled in the art.
    As used herein, an aroma is a relatively volatile substance or combination of substances, or one or more water-soluble edibility agents that produces a detectable aroma, taste, odor or odor, or that masks an undesirable taste. Examples of aromas include those that are generally accepted as FD&C.
    As used herein, the term lubricant is intended to indicate an agent used in solid dosage formulas to promote the flowability of the solid mass. Such compounds include, by way of example and without limitation, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicone, tribasic calcium phosphate, silicone hydrogel, and others well known to those skilled in the art.
    As used herein, the term lubricant is intended to indicate a substance used in solid dosage formulas for reducing friction during compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, PEG, talc, mineral oil, stearic acid, and zinc stearate, and other materials well known to those skilled in the art.
    BE2018 / 5468
    As used herein, the term acidifying means is intended to designate a compound used to opaque a coating or composition. Opaquants can be used alone or in combination with a colorant. Such compounds include, by way of example and without limitation, titanium dioxide, talc, and other materials well known to those skilled in the art.
    As used herein, the term polishing agent is intended to designate a compound used to impart an attractive luster to solid dosage forms. Such compounds include, by way of example and without limitation, camauba wax, white wax and other materials well known to those skilled in the art.
    As used herein, the term stabilizer is intended to designate a compound used to stabilize the therapeutic agent against physical, chemical, or biochemical processes that would reduce the therapeutic activity of the agent. Such stabilizer include, for example and without limitation, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols, sodium caprylate and sodium saccharide and others well known. are with the skilled person.
    The formula of the invention may also include oils, for example, solid oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids such as oleic acid, stearic acid and isostearic acid; and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glyceride and acetylated fatty acid glycerides. It may also include alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol; glycerol ketals, such as 2,2-dimethyl, 3-dioxolane-4-methanol; ethers such as polyethylene glycol 450; petroleum hydrocarbons such as mineral oil and petrolatum; or mixtures thereof.
    The present invention further provides an oral dosage form comprising a granular phase and a non-granular phase, said granular phase consisting of an effervescent material comprising a pharmaceutically active substance. It is advantageous that the effervescent material provides a matrix resting on a stomach fluid while the pharmaceutically active substance can be dissolved by
    BE2018 / 5468 the gastric fluid. In this way the pharmaceutically active substance is prevented from coagulating at the bottom of the stomach and is transported through the intestinal tract in a non-bio-absorbable form. The oral dosage form is preferably provided such that the dosage form can float on top of the gastric fluid for at least 2 minutes, preferably at least 4 minutes and more preferably at least 6 minutes, at least 8 minutes or at least 10 minutes. This ensures sufficient time for the dissolution of the water-insoluble, pharmaceutically active substance.
    In a second aspect, the present invention provides a method for preparing an oral dosage form, comprising the following steps:
    - mixing a pharmaceutically active substance, a gas-forming substance and a hydrophilic polymer in the presence of water, whereby a hydrated mixture is obtained;
    - drying said hydrated mixture, whereby grains are obtained;
    - mixing said granules in a non-granular powder; and
    compressing said granules into said non-granular powder, thereby obtaining an oral dosage form comprising a granular phase and a non-granular phase.
    The preparation of the granular phase granules in the presence of water provides a pre-treated hydrophilic polymer within the granular phase. Such pretreatment allows an improved wetting of the hydrophilic polymer and consequently an improved water inflow from the granular phase during contact with the gastric fluid.
    In a preferred embodiment, the invention provides a method according to the second aspect of the invention, wherein said granules are prepared by fluidized granulation.
    In a preferred embodiment, the invention provides a method according to the second aspect of the invention, wherein said oral dosage form is provided with a thickness, a length and a width and wherein the length to width ratio is greater than 1.1. More preferably, said length to width ratio is greater than 1.2 and even more preferably greater than 1.5. Most preferably the said ratio is equal to 1.6, 1.7, 1.8, 1.9, 2.0, 2.2, 2.4, 2.6 or 2.8. The inventors have surprising
    BE2018 / 5468 found that tablets with a length to width ratio greater than
    1.1 rise faster to the level of the gastric fluid.
    In a third aspect, the present invention provides an oral dosage form obtained by a method according to the second aspect of the invention.
    In a fourth aspect, the present invention provides an oral dosage form according to the first aspect of the invention, comprising a mineral for the treatment, prevention or after-treatment of mineral deficiencies in a human or animal body, preferably in mammals.
    In a fifth aspect, the present invention provides an oral dosage form according to the third aspect of the invention, comprising a mineral for the treatment, prevention or after-treatment of mineral deficiencies in a human or animal body, preferably in mammals.
    EXAMPLES
    The following example is intended to further explain the present invention, and is in no way intended to limit the scope of the present invention.
    EXAMPLE 1
    Magnesium oxide is mixed with a CO2-releasing salt sodium bicarbonate, a hydrophilic polymer, hydroxypropyl methylcellulose, a binder polyvinylpyrrolidone and a microcrystalline cellulose, and water-soluble polymers in a ratio as shown in Table 1.
    Table 1: Composition of granular phase.
    Ingredients weight% * magnesium oxide 20 hydroxypropyl methylcellulose (HPMC) 8 sodium bicarbonate 8 microcrystalline cellulose 12 polyvinylpyrrolidone 7
    * weight content expressed as a percentage relative to the total weight of the tablet.
    BE2018 / 5468
    The magnesium oxide is granulated in an HPMC hydrogel in a fluid bed reactor. The formation of magnesium oxide granules is achieved by mixing magnesium oxide, hydropropyl methylcellulose (HPMC), sodium bicarbonate, microcrystalline cellulose and an aqueous 22.9% by weight of polyvinylpyrrolidone solution in a fluid bed reactor. Air with a temperature of 60 ° C is introduced into the reactor at a speed of 500 m 3 / h and discharged at a temperature of 29 ° C for a period of approximately 3 hours. The granules obtained are then dried at an air temperature of 70 ° C to a moisture content of less than 1.2% by weight. The correspondingly obtained granular phase is isolated from the reactor.
    The resulting granular phase is then mixed with a catalyst citric acid, a lubricant in the form of organic magnesium salts, a disintegrating agent, binder and additives according to the composition in Table
    2.
    Table 2: Composition of magnesium tablet.
    Ingredients weight% * granular phase 55 citric acid 7 hydroxypropyl methylcellulose 5 magnesium glycerophosphate 28 vitamin B6 0.5 magnesium stearate 0.5 polyvinylpyrrolidone 4
    * weight content expressed as a percentage relative to the total weight of the tablet.
    The mixture with composition according to Table 2 is then pushed into a tablet at a light supply pressure so as not to break the granular phase. In this way, tablets can be obtained with a rubability / brittleness of less than 3%, a hardness of approximately 135 N and a moisture content of less than 3%.
    Tests show that the obtained tablets float within a period of 120 seconds in a medium of 0.1 N HCl and that complete dissolution in a medium of 0.1 N HCl occurs with light stirring (100 rpm) at 36.5 ° C within a period of 45 to 60 minutes.
    BE2018 / 5468
    Magnesium tablets were prepared according to the method described above, wherein the tablets contained 150 mg elemental magnesium as magnesium oxide and 40 mg elemental magnesium as magnesium glycerophosphate. Test results (according to USP method, <711) show that a high initial release of elemental magnesium is obtained, i.e. about 100 mg of magnesium is released within 10 minutes in solution. The tablet then releases the remaining amount of magnesium at a substantially constant rate. The total amount of elemental magnesium in the tablet is released into the solution within about 20 minutes.
    This can be explained as follows. The non-granular phase allows rapid penetration of water into the tablet as soon as the tablet enters the aqueous medium of the stomach. Accordingly, the non-granular phase rapidly decomposes and has the granular phase as granules. Water then penetrates the granular phase and hydrates HPMC, as a result of which HPMC swells and forms a hydrogel.
    The water, and more particularly the acidic gastric fluid, also activates the CO2-releasing agent in the granules, so that the CO2 released is kept in the hydrogel. The tablet floats through the enclosed gas volumes in the aqueous medium and releases granules into the aqueous medium. However, while it floats in the aqueous medium, the tablet absorbs less water and when a certain amount of CO2 is activated and released, the tablet will sink again and activate a new CO2 releasing agent. The composition and structure of the tablet thus controls the residence time of the tablet and the release efficiency of magnesium in the stomach. In this way an improved solubility of magnesium in the gastric fluid can be achieved, and a better absorption of magnesium in the body.
    The composition and oral dosage form of the present invention is therefore extremely suitable for rapid, initial absorption and, consequently, gradual and complete absorption of elemental magnesium in a human or animal body.
    The oral dosage form of Example 1 was tested for dissolution rate in the gastrointestinal tract using USP method <711>. To this end, a dose was subjected to a 0.1 N HCl solution and the
    BE2018 / 5468 concentration of dissolved elemental magnesium monitored over time. The results were also compared to oral dosage forms for supplemental magnesium well known in the market, as described in comparative examples 1 to 3.
    Table 3. Oral dosage form of comparative examples.
    COMPARATIVEEXAMPLE 1 Powder containing 3 g of magnesium gluconate (corresponding to 162 mg of elemental magnesium), macrogel 6000 and colloidal silica. COMPARATIVEEXAMPLE 2 Capsule containing 450 mg elemental magnesium. COMPARATIVEEXAMPLE 3 Tablet containing 900 mg magnesium glycerofofate (corresponding to 100 mg elemental magnesium), 1 mg vitamin B6, 12.5 pg vitamin B12, 100 pg vitamin B9, 150 mg taurine and 12.5 pg vitamin D.
    The results are shown in Figures 1 and 2. Figure 1 shows the amount of elemental magnesium dissolved in the 0.1 N HCl solution, expressed as a percentage of the amount of elemental magnesium in the respective oral dosage forms, as a function of time (min.). Figure 2 shows the absolute amount of elemental magnesium dissolved in a 0.1 N HCl solution, as a function of time (min.).
    The results show that the tablet of Example 1 shows complete solubility of 80% of all elemental magnesium within 10 minutes, see Figure 1. This corresponds to approximately 160 mg, see Figure 2.
    The results further show that comparative example shows an almost complete solubility of the elemental magnesium. This can easily be explained by the fact that the powder of comparative example 1 consists of an organic magnesium salt, in an uncompressed powder formula that is known to offer faster dissolution rates. However, such dosage forms have a relatively low magnesium content and are inconvenient to use because the user must take different doses per day in the case of compressed or encapsulated dosage forms or in the case of dosage forms in powder form, these must be taken as a water-soluble powder in bulk bags. or stick packs.
    BE2018 / 5468 When we compare the behavior of an inorganic magnesium tablet according to example 1 with the behavior of an inorganic magnesium tablet according to comparative example 1, this leads to the conclusion that the tablet according to the invention shows comparable efficiency in supplying elemental magnesium in a fluid.
    The tablet in comparative example 3 comprises an organic magnesium salt, such as the powder of comparative example 1. The results in figures 1 and 2 clearly show that the tablet dosage form exhibits a slower solubility of elemental magnesium. This can be easily understood by the fact that the tablet matrix must be at least partially dissolved before the organic magnesium salt can come into contact with water and be dissolved therein.
    The capsule according to comparative example 2, on the other hand, offers a significantly lower release of elemental magnesium and has less than 10% of its total elemental magnesium released within one hour. This means that the capsule will have left the mag before the elemental magnesium can be dissolved.
    Finally, tablets can be considered as a preferred oral dosage form since they are easy to use and offer accurate and high amounts of nutrients, elements or active substances. However, the tablet form generally delays the release of the nutrient, element or active substance into the gastric fluid. Consequently, the tablet runs the risk of being emptied from the stomach to the intestinal tract before it is completely dissolved, thereby limiting its bio-accessibility.
    The use of a tablet comprising a non-granular matrix comprising effervescent granules of active substances allows the intake of a tablet that can be dissolved in the gastric fluid in a manner similar to bulk powder dosages.
    权利要求:
    Claims (12)
    [1]
    CONCLUSIONS
    An oral dosage form comprising a granular phase and a non-granular phase, said granular phase comprising magnesium oxide in an amount of 10 to 60% by weight relative to the total weight of said granular phase, a gas-forming substance selected from a carbonate or bicarbonate salt, and a hydrophilic polymer in an amount of at least 5.0% by weight relative to the total weight of said granular phase.
    [2]
    An oral dosage form according to claim 1, wherein said granular phase is prepared by a fluidized bed water-based granulation process.
    [3]
    The oral dosage form according to claim 1 or 2, wherein said hydrophilic polymer is included in said granular phase in an amount of 10.0% to 25.0% by weight relative to the total weight of said granular phase.
    [4]
    The oral dosage form of any one of claims 1 to 3, wherein said gas-forming substance is included in said granular phase in an amount of 10.0% to 25.0% by weight relative to the total weight of said granular phase.
    [5]
    The oral dosage form according to any of claims 1 to 4, wherein said hydrophilic polymer is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
    [6]
    The oral dosage form according to any of claims 1 to 5, wherein said dosage form has a thickness, a length and a width and wherein the length to width ratio is greater than 1.1.
    [7]
    A method for preparing an oral dosage form comprising a granular phase and a non-granular phase comprising the following steps:
    mixing magnesium oxide in an amount of 10 to 60% by weight relative to the total weight of said
    BE2018 / 5468 granular phase, a gas-forming substance selected from a carbonate or bicarbonate salt and a hydrophilic polymer in an amount of at least 5.0% by weight relative to the total weight of said granular phase in the presence of water, whereby a hydrated mixture is obtained ;
    drying said hydrated mixture, thereby obtaining granules;
    mixing said granules in a non-granular powder; and compressing said granules into said non-granular powder, thereby obtaining an oral dosage form comprising a granular phase and a non-granular phase.
    [8]
    The method of claim 7, wherein said granules are prepared by fluidized granulation.
    [9]
    A method according to claim 7 or 8, wherein said oral dosage form is provided with a thickness, a length and a width and wherein the length to width ratio is greater than 1.1.
    [10]
    An oral dosage form obtained by a method according to any of claims 7 to 9.
    [11]
    The oral dosage form according to any of claims 1 to 6, comprising a mineral for the treatment, prevention or after-treatment of mineral deficiencies in a human or animal body.
    [12]
    The oral dosage of claim 10, comprising a mineral for the treatment, prevention, or after-treatment of mineral deficiencies in a human or animal body.
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    同族专利:
    公开号 | 公开日
    BR112019013995A2|2020-02-11|
    EP3345591A1|2018-07-11|
    EP3565525A1|2019-11-13|
    US20190343849A1|2019-11-14|
    BE1025229A9|2019-01-03|
    BE1025229A1|2018-12-10|
    BE1024879A9|2018-08-21|
    ES2870011T3|2021-10-26|
    BE1024879B9|2018-08-29|
    EP3565525B1|2021-03-17|
    BE1024879A1|2018-07-31|
    BE1025229B9|2019-01-08|
    BE1024879B1|2018-08-06|
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    法律状态:
    2019-01-16| FG| Patent granted|Effective date: 20181217 |
    优先权:
    申请号 | 申请日 | 专利标题
    EP17150552.2|2017-01-06|
    EP17150552.2A|EP3345591A1|2017-01-06|2017-01-06|Oral dosage form for enhanced solubilization of a poorly soluble active agent and method of preparation|
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