EP2897645A1 - Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif - Google Patents

Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif

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Publication number
EP2897645A1
EP2897645A1 EP13755955.5A EP13755955A EP2897645A1 EP 2897645 A1 EP2897645 A1 EP 2897645A1 EP 13755955 A EP13755955 A EP 13755955A EP 2897645 A1 EP2897645 A1 EP 2897645A1
Authority
EP
European Patent Office
Prior art keywords
formulation according
magnesium hydroxide
hydroxide carbonate
active ingredient
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP13755955.5A
Other languages
German (de)
English (en)
Inventor
Guenter Moddelmog
Roberto Ognibene
Thorsten Wedel
Dieter Lubda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Priority to EP13755955.5A priority Critical patent/EP2897645A1/fr
Publication of EP2897645A1 publication Critical patent/EP2897645A1/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds

Definitions

  • Magnesium hydroxide carbonate as a carrier material in active substance-containing preparations
  • the present invention relates to solid formulations containing at least one porous carrier and one or more functional substances, and to their use.
  • Active ingredients for use in pharmaceutical
  • Dosage forms must on the one hand have useful processing properties for the pharmaceutical practice, so that the active ingredient is at all suitable for the further processing of pharmaceuticals to the final dosage form.
  • an inert excipient it is also possible to prepare problematic active components to be processed into patient-appropriate formulations, such as e.g. Transfer powder, granules, capsules or tablets.
  • the carriers used for such purposes must have special physical or chemical properties in order to compensate for the processing deficiencies of the API.
  • the active ingredient is particularly fine-grained and / or must be used in low doses.
  • carrier material to submit a metered amount of powder can.
  • a problem in this context is that the carrier material and the powdery active substance must not segregate for a permanently uniform dosage. This is special during storage and handling of the powder formulation, if the active ingredient is present in substantially smaller particles than that
  • microcrystalline cellulose which is prepared from pulp or crude cellulose by heating with mineral acids and then brought into a finely particulate form by mechanical comminution of the cellulose aggregates. This cellulose shows plastic flow during compression and is one of the viscoelastic
  • Microcrystalline cellulose is used as a filler and dry binder in direct tableting.
  • plastic carrier and filling material is starch, preferably water-soluble, directly tablettable starch which has both plastic and elastic (viscoelastic) deformation behavior.
  • Lactose can be used both as a monohydrate and in an anhydrous form. In addition, it lies, depending on
  • spray-dried lactose containing a high amorphous content can be prepared as directly tablettable
  • Lactose variants are offered by the various suppliers in a variety of particle sizes and grain morphologies for a variety of applications.
  • sugar alcohols such as mannitol, sorbitol and xylitol have become increasingly important as tableting aids with the function of carriers and fillers.
  • inorganic salts for tableting preferably those which are well tolerated and themselves show no side effects when used in the usual amounts.
  • Di-Cafos ® Calciumhydrogenphosphat- dihydrate So is distributed as tableting aids under the brand name Di-Cafos ® Calciumhydrogenphosphat- dihydrate. It is made by reacting calcium hydroxide with phosphoric acid at temperatures below 40 ° C. This produces the monoclinic dihydrate, which occurs in nature as a brushite (Gmelin's Handbook of Inorganic
  • Di-Cafos ® is used as a filling and dry binders in the direct, as Flow regulator in capsule formulations and as abrasive component in toothpastes.
  • Fujicalin ® is anhydrous calcium hydrogen phosphate sold for the production of tablets.
  • Calcium hydrogen phosphate is produced industrially by reacting calcium hydroxide with phosphoric acid at temperatures above 75 ° C (Toy ADF, Walsh EN in: “Phosphorus Chemistry in Everyday Living", 2nd Edition American Chemical Society, Washington, DC (1987)) Tableting finds
  • Anhydrous calcium hydrogen phosphate usually used as a filler and binder, as a Ca 2+ supplier in mineral preparations or as an abrasive in dentifrices.
  • Fujicalin ® crystal growth is limited (Takami K., Machimura is; H., Takado K .; Inagaki M .; Kawashima Y .; in "Novel preparation of free flowing spherically granulated dibasic calcium phosphate anhydrous for direct tabletting" , Chem. Pharm. Bull., 44 (4), 868-870 (1996)), thereby reducing the size of the crystallites as compared to other methods of preparation.
  • this product has a surface area 90 times larger than the Di-Cafos ® .
  • Sodium carbonate, sodium bicarbonate, calcium carbonate or corresponding potassium carbonates used as well as acid components citric acid, tartaric acid or ascorbic acid.
  • inorganic salts are used, the magnesium salts instead of the calcium, Sodium or potassium salts as filler and carrier material included. This applies not only to the mentioned effervescent formulations but also to other mixtures, granules or conventional tablets.
  • Pretreatment can be used as a carrier or tableted directly. It is basic magnesium hydroxide carbonate with the chemical composition 4MgC0 3 xMg (OH) 2 x5H 2 O. It is formed from aqueous solution only if it contains a lot of excess carbon dioxide. Magnesium carbonate can crystallize with 5, 3 and 1 mol of water of crystallization and gradually becomes basic when boiled with water
  • the present invention is based on the object, a
  • powdery carrier material optionally also in a good
  • the object is surprisingly achieved by solid formulations which are characterized in that they
  • a) comprise at least one porous support consisting of
  • Corresponding formulations comprise ordered mixtures consisting of 50 to 99.9% by weight of magnesium hydroxide carbonate and 50 to 0.1% by weight of at least one micronized functional component. Preferably, it is included
  • Magnesium hydroxide carbonate to a material having a BET surface area in the range 25 to 70 m 2 / g, preferably greater 44 n 7g, and a
  • corresponding formulations may contain at least one functional component from the pharmaceutical field
  • Active ingredients, diagnostics, dietary supplements, cosmetics, herbicides, fungicides, reagents, dyes, minerals or catalysts also contain enzymes or microorganisms.
  • these formulations are ordered mixtures containing from 50 to 99.9% by weight
  • these formulations contain, apart from at least one functional component, active ingredients and excipients selected from the group consisting of flow improvers, binders, lubricants, sweeteners and polymers.
  • active ingredients and excipients selected from the group consisting of flow improvers, binders, lubricants, sweeteners and polymers.
  • these mixtures may be formulated as a powder or tablet.
  • the ordered mixture is resistant to long-term powder and retains its homogeneous distribution of active ingredients even after mechanical stress, such as by transport or in required processing steps, even if the pharmaceutical agent is low doses in it.
  • the formulations according to the invention are distinguished by the fact that the porous magnesium hydroxide carbonate contained as carrier together with one or more functional substances form a stable ordered mixture with particularly good homogeneity, which have particularly low separation tendencies.
  • the present object is also achieved by the use of the described formulations for the preparation of mixtures in solid, semisolid and liquid form, which are used, for example, for the preparation of active ingredient-containing tablets, capsules, powders, ointments, creams, suspensions, dispersions. According to the invention, they can also be advantageously used for the preparation of pharmaceutical formulations for oral or dermal application.
  • the formulations are also well suited for the production of cosmetic, agricultural and technical formulations or food preparations and formulations for food supplementation.
  • the object of the invention is also achieved in particular by a process for the preparation of the described formulations, wherein at least one porous carrier consisting of
  • Magnesium hydroxide carbonate, and at least one functional substance in the form of a micronized powder in a mixer selected from the group of tumble mixer, screw-cone mixer, compulsory mixer, agitator, high-speed mixer and fluidized bed mixer are mixed thoroughly.
  • Tablets containing the active ingredient (s) always in the same concentration. But that's not all.
  • the active ingredient must also be evenly distributed in each individual tablet, so that the user, when dividing the tablet, the same in each part of the tablet
  • Drug concentration finds and can dose accurately. Depending on the physical properties of the active ingredient or the active ingredients that are to be formulated as tablets, this results in different requirements, especially when low-dose tablets are to be formulated.
  • the active ingredient is in liquid form, e.g. as an oil, dissolved in aqueous or organic solvents or as a dispersion or emulsion, it must be in a solid state before being used
  • Dosage form first be converted into a powder, which can be further processed.
  • Measures may be taken, whereby the uniform distribution in the solid pharmaceutical dosage form can be ensured. The same applies if the active ingredient in such a small
  • Grain size is present that it can not be sufficiently stable mixed for further tabletting with the other ingredients of the formulation. So tend some drugs because of their
  • the magnesium hydroxide carbonate described in WO 2011/095269 is distinguished by a special particle morphology, combined with a particularly large BET surface area and a high pore volume.
  • the magnesium hydroxide carbonate thus characterized is easily soluble in an acidic and aqueous environment such as gastric juice due to its porous structure and releases CO2 gas.
  • this magnesium hydroxide carbonate can be used as a carrier material or filler, which quickly disintegrate when administered in the mouth or for the preparation of active ingredient-containing
  • Dosage forms consisting predominantly of porous magnesium hydroxide carbonate as a carrier, in the absence of solvents by simple intensive mixing, when the sparingly soluble active ingredient is present as ultrafine powder.
  • Magnesium hydroxide carbonate particles becomes a so-called stable
  • Organic mixture of porous magnesium hydroxide carbonate as a carrier and at least one functional component, which means that the very dilute component present in the mixture can be uniformly dosed so that variations in the weight of the formulation result in smaller variations in dosage under these conditions as if the functional component
  • single-dose pharmaceutical dosage forms of considerable importance such as: in the filling of sacchets with powders or in the filling of the matrices of tableting machines with the mixture to be tableted.
  • Plant treatment agents such as herbicides or fungicides, reagents, diagnostics and feed and also as dyes, minerals or catalysts are suitable. These include, for example, tablets of any shape, pellets or granules and powder mixtures.
  • magnesium hydroxide carbonate is a substance listed in all pharmacopoeias, no additional requirements have to be met with regard to the registration of the filling and carrier material.
  • the magnesium hydroxide used in the invention is directly tablettierbar, can in the active ingredient-containing solid
  • Magnesium hydroxide carbonate as carrier according to the invention may be included. This may include, among others
  • Flavor enhancers such as lubricants and lubricants, and the like can act. Possible additions are, for example
  • thermoplastic polymers lipids, sugar alcohols,
  • thermoplastic polymers are, for example
  • Polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone and vinyl acetate or vinyl propionate, copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol,
  • Methylcellulose and ethylcellulose hydroxyalkylcelluloses, in particular hydroxypropylcellulose (HPC), hydroxyalkyl-alkylcelluloses, in particular hydroxypropylmethylcellulose (HPMC), cellulose esters such as
  • Cellulose phthalates in particular cellulose acetate phthalate,
  • HPMCAS Hydroxypropylmethylcellulose acetate succinate
  • sugars such as sucrose, glucose, maltose, xylose, Fructose, ribose, arabinose, galactose, trehalose, but also
  • Suitable sugar alcohols are sorbitol, xylitol, mannitol, maltitol; a suitable sugar alcohol derivative is also isomalt.
  • Additives can be commercially available in different qualities
  • Suitable lipids are fatty acids, such as stearic acid; Fatty alcohols, such as cetyl or stearyl alcohol; Fats, such as animal or vegetable fats;
  • Waxes such as carnauba wax; or mono- and / or diglycerides or phosphatides, especially lecithin.
  • the fats preferably have a melting point of at least 50 ° C.
  • Preferred are triglycerides of C 2 -, CM-, C 16- and cis-fatty acids.
  • galenic adjuvants whose total amount may amount to up to 20% by weight, preferably less than 10% by weight, in particular less than 5% by weight, based on the dosage form,
  • Extenders or fillers such as lactose, cellulose, silicates or
  • Lubricants such as magnesium and calcium stearate
  • Dyes such as azo dyes, organic or inorganic pigments or dyes of natural origin
  • Stabilizers such as antioxidants, light stabilizers, hydroperoxide killers, radical scavengers, preservatives and microbial attack stabilizers;
  • active substances are to be understood as meaning all substances having a desired physiological action on the human or animal body or plants. It is about
  • active ingredient in particular pharmaceutical active substances.
  • the amount of active ingredient per Dose can vary within wide limits. It is usually chosen so that it is sufficient to achieve the desired effect. Also drug combinations can be used. Active substances in the sense of
  • the vitamins include the vitamins of the A group, the B group, which in addition to Bi, B 2 , B 6 and B12, in a broader sense also nicotinic acid and nicotinamide are understood, as well as biotin, folic acid, but also compounds with vitamin-like Properties such. Adenine, choline, pantothenic acid,
  • Active substances within the meaning of the invention also include peptide therapeutics and proteins.
  • Magnesium hydroxide carbonate for example, be used for processing the following active ingredients in a suitable method:
  • Aminoacetic acid amiodarone, amitriptyline, amlodipine, amoxicillin,
  • Betamethasone bezafibrate, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine, budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin, cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone, Cefuroxime, celediline, chloramphenicol, chlorhexidine, chloropheniramine, chlorthalidone, choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomibramine,
  • Cromoglycinic acid cyanocobalamin, cyproterone, desogestrel,
  • Pantothenic acid paracetamol, penicillin G, penicillin V, phenobarbital, phenoxifylline, phenoxymethylpenicillin, phenylephrine, phenylpropanolamine, phenytoin, piroxicam, polymyxin B, povidone-iodine, pravastatin, prazepam, prazosin, prednisolone, prednisone, promocriptine, propafenone, propranolol, proxyphylline, pseudoephedrine , Pyridoxine, quinidine, ramipril, ranitidine, reserpine, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, simvastatin, somatropin, sotalol, spironolactone, sucralfate, sulbactam, sulf
  • finely particulate active ingredients can be incorporated using magnesium hydroxide carbonate in a formulation and, if desired, be tabletted.
  • the carrier and the active ingredients are mixed intensively with one another in an appropriate quantitative ratio, preferably in a suitable mixer.
  • the active ingredients are, if they are not already present as a super fine powder before the
  • the active ingredient is micronized and then has average particle sizes of a few micrometers, or in the nanometer range.
  • the active compounds are preferably used as functional components in the form of micronized substances having an average particle size (laser, D 50 ) in the range from 1 to 20 ⁇ m, preferably in the range from 1 to 10 ⁇ m.
  • the magnesium hydroxide carbonate which can be used according to the invention is a porous material having a BET surface area in the range from 25 to 70 m 2 / g, preferably greater than 44 m 2 / g, particularly preferably greater than 50 m 2 / g, and a bulk density in the range from 0.40 to 0.60 g / ml, and a tamped density in the range of 0.50 to 0.80 g / ml, which can be obtained as described in WO 2011/095669.
  • powdered magnesium hydroxide carbonate as a carrier and the finely divided active ingredient are initially introduced in a suitable quantitative ratio and mixed thoroughly with one another. But it is also possible to gradually meter in the active ingredient during mixing, in order to achieve in this way a uniform distribution of the active ingredient on the carrier.
  • the mixing of the two components can be carried out in devices that are known to those skilled in the art for this purpose. Preferably, the mixing takes place under mild conditions in a tumble mixer; Screw-cone mixer, compulsory mixer, high-speed mixer,
  • Propeller mixer or in a fluidized bed mixer make it possible to evenly mix liquid active ingredients with the solid carrier material.
  • Magnesium hydroxide carbonate preferably has particle diameters (laser, D 50 ) in the range between 10 and 60 ⁇ m, particularly preferably between 20 and 60 ⁇ m.
  • Homogeneity of the distribution of the active ingredient on the substrate is characterized.
  • the active ingredient-containing powder according to the invention which consists essentially of magnesium hydroxide carbonate as a carrier material and the selected active ingredient, has very good porosity
  • Tablettiereigenschaften has particle diameter (laser, D 5 o) in the range between 10 and 60 pm, preferably between 20 and 60 pm.
  • the advantage of the preparations provided by the present invention is that finely particulate or low-dose active ingredients are present homogeneously distributed bound to a carrier, whereby the production of low-dose preparations is possible, which would tend under normal conditions for segregation.
  • the mixture according to the invention is a product which, even under mechanical stress, is replaced by a pronounced homogeneity and stability of the mixture.
  • the functional component and the magnesium hydroxide carbonate used as the carrier may contain active substances and adjuvants selected from the group of flow improvers, binders, lubricants, sweeteners and polymers.
  • the active ingredient which is optionally present as a pure substance in the form of an oil, by binding to the porous, powdery
  • Magnesium hydroxide carbonate can be provided as a low-dose powder. Due to the porous properties, if desired, this powder can be directly tabletted, thereby obtaining tablets wherein the active ingredient is homogeneously distributed. As in the active ingredient-containing powder is in the tablet produced the
  • the active substance-containing powder can advantageously be used for the production of active ingredient-containing tablets, capsules, powders, ointments, creams, suspensions, dispersions, in particular for the production of pharmaceutical formulations for oral or dermal application or of pharmaceutical, cosmetic, agricultural and technical formulations,
  • Dry dispersion Mastersizer 2000 with dispersing unit Scirocco 2000 (Malvern Instruments Ltd. UK), determinations at 1, 2 and 3 bar counter-pressure; Evaluation Fraunhofer; Dispersant Rl: 1,000,
  • Dispersant R1 1,330; Pump Speed: 2000 rpm; Stirrer Speed: 2000 rpm;
  • Ultrasonic Duration 1 sec; Ultrasonic Level: 100%; Tray Type: General Purpose; Background Time: 7500 msec; Measurement Time: 7500 msec; Obscuration Limits: 10.0-20.0% l; Execution in accordance with ISO 13320-1 and the specifications of the technical manual and the specifications of the equipment manufacturer; Data in% by volume Particle size determination by dry sieving over a sieving tower: Retsch AS 200 control, Fa.Retsch (Germany); Substance quantity: approx. 110.00 g; Sieving time: 30 minutes; Amplitude intensity: 1mm; Interval: 5 seconds; Test sieves with metal wire mesh according to DIN ISO 3310;
  • the sample (amount of sample depends on the ascorbic acid content in the mixture) is placed in a 100 ml beaker and slurried with about 10 ml of demineralized water. Over a
  • the piston stroke pipette is gently shaken with 25%
  • Mixtures the implementation consists of the steps of creating a calibration curve, control by photometric measurement of a standard riboflavin substance known content, photometric
  • the sample (amount of sample is determined by the amount of riboflavin in the mixture) is placed in a 500 ml amber glass volumetric flask, slurried with 5 ml of demineralised water and then with 5 ml
  • Sample B NutriMag MC DC magnesium carbonate heavy, pharm., Gran. i. d. Reinh. BP, USP, Ph Eur; CALMAGS GmbH, Lüneburg (Germany);
  • Table 4 Particle distribution of micronized ascorbic acid determined by laser diffraction with dry dispersion (various pressure conditions):
  • Model active substance riboflavin micronised Milling of a commercially available powdered riboflavin with a purity according to Ph Eur, BP, USP, E 504 on an Aeroplex spiral jet mill Type 200 AS from Hosokawa Alpine, Augsburg (Germany) under nitrogen as protective gas; the
  • Target particle size D (50) measured by laser diffraction
  • Dry dispersion is in the range of 1, 5pm to 2.5pm -
  • the more accurate particle distribution of the material used is shown in the following table:
  • Table 5 Particle distribution of the micronized riboflavin determined by laser diffraction with dry dispersion (various
  • Example 1 Determination of the loading capacity and the homogeneity of various amounts of micronized ascorbic acid on samples A and B after mixing in a tumble mixer
  • the material After mixing, the material is spread on an area of 21x30 cm with the same thickness as possible and sampled at 6 different locations, their ascorbic acid content determined and the standard deviations calculated.
  • Pattern A shows a lower relative for all blends
  • sample A or sample B are micronized with 1.5 g each
  • Puncture density described; for use comes on page 430 under Fig. 2.9.34-3 shown tamping volumeter for powder samples with a fixed drop height of 3 +/- 0.2 mm. Notwithstanding the number of ramming movements specified there, the sample is subjected to 2500 strokes. Then the material is carefully placed on a surface of 21x30 cm with the same thickness as possible laid out and at 6 different places samples on their
  • g ' the sample is spread on the sieve bottom (200 mm) and moved for 60 minutes at an amplitude of 1.5 mm (without interval). Subsequently, 6 samples are taken directly at different points of the sieve bottom, the ascorbic acid content is determined and the standard deviation is calculated.
  • Table 8 Content and S (rel) of ascorbic acid before and after a mechanical load in the tamping volumeter after 2500 impacts
  • Table 9 Content and S (rel) of ascorbic acid before and after a mechanical load in the tamping volumeter after 20,000 impacts
  • Pattern A shows a lower relative for all blends
  • Example 3 Determination of the loading capacity and the homogeneity of various amounts of micronized riboflavin on samples A and B after mixing in a tumble mixer
  • the DC magnesium hydroxide carbonate samples A and B are each added to the amounts of micronized riboflavin indicated in the table and in a laboratory tumble mixer (Turbula T2A, Fa. Willy A. Bachofen, Switzerland) mixed. After a mixing time of 1 minute, the material is deposited over a 1 mm sieve without mechanical stress and any loose agglomerates which may be present are carefully passed through with a paper sheet
  • the material After mixing, the material is spread on an area of 21 ⁇ 30 cm with the same thickness as possible and at 6 different locations samples are determined for their ascorbic acid content and the standard deviations are calculated.
  • Pattern A shows a lower relative for all blends
  • the 5% and 10% mixed riboflavin samples from Example 3 are subjected to mechanical stress for 60 minutes by means of a tower screening machine from Retsch (Germany) type AS 200 control, g '. For this, the samples are placed on the sieve bottom (200 mm) at an amplitude of 1, 5 mm moves without interval switching. Subsequently, 6 samples are taken directly at different points of the sieve, the
  • Table 13 Content and S (rel) of riboflavin before and after mechanical stress in a sieving tower; Nominal load of 10%
  • Pattern A shows a lower relative for all blends

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Cette invention concerne des formulations solides comportant au moins un excipient poreux et une ou plusieurs substances fonctionnelles dans un mélange stable, et leur utilisation.
EP13755955.5A 2012-09-18 2013-08-19 Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif Ceased EP2897645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP13755955.5A EP2897645A1 (fr) 2012-09-18 2013-08-19 Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP12006551 2012-09-18
EP13000730 2013-02-13
PCT/EP2013/002490 WO2014044342A1 (fr) 2012-09-18 2013-08-19 Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif
EP13755955.5A EP2897645A1 (fr) 2012-09-18 2013-08-19 Carbonate d'hydroxyde de magnésium en tant qu'excipient dans des préparations renfermant un principe actif

Publications (1)

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EP2897645A1 true EP2897645A1 (fr) 2015-07-29

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US (1) US20150273062A1 (fr)
EP (1) EP2897645A1 (fr)
JP (1) JP6244363B2 (fr)
KR (1) KR20150058427A (fr)
CN (1) CN104640569A (fr)
BR (1) BR112015005621A2 (fr)
CA (1) CA2885105A1 (fr)
IL (1) IL237741A0 (fr)
WO (1) WO2014044342A1 (fr)

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US10723807B2 (en) 2017-03-31 2020-07-28 Shin-Etsu Chemical Co., Ltd. Method for producing hydroxyalkyl alkyl cellulose
JP6423481B1 (ja) * 2017-04-28 2018-11-14 神島化学工業株式会社 炭酸マグネシウム
CN113518609B (zh) * 2019-02-25 2024-04-30 破坏性材料运营公司 粒状无定形介孔碳酸镁材料
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US20150273062A1 (en) 2015-10-01
KR20150058427A (ko) 2015-05-28
JP6244363B2 (ja) 2017-12-06
WO2014044342A8 (fr) 2015-02-12
IL237741A0 (en) 2015-05-31
JP2015530393A (ja) 2015-10-15
CA2885105A1 (fr) 2014-03-27
WO2014044342A1 (fr) 2014-03-27
CN104640569A (zh) 2015-05-20
BR112015005621A2 (pt) 2017-07-04

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