EP2934590A1

EP2934590A1 - Magnesium hydroxide carbonate as excipient in pharmaceutical preparations, having improved release of active ingredient

Info

Publication number: EP2934590A1
Application number: EP13798577.6A
Authority: EP
Inventors: Guenter Moddelmog; Roberto Ognibene; Thorsten Wedel; Dieter Lubda
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2012-12-21
Filing date: 2013-11-22
Publication date: 2015-10-28
Also published as: BR112015014739A2; US20150328316A1; AU2013362269A1; JP6498607B2; IL239393A0; CN104870018A; JP2016503763A; WO2014094956A1; JP2019023246A; CA2895827A1; KR20150100826A

Abstract

The invention relates to pharmaceutical formulations of active ingredients that are not readily soluble in aqueous solutions, having improved release of active ingredient, and to a method for the production thereof. The invention in particular relates to pharmaceutical preparations in which magnesium hydroxide carbonate is used as excipient.

Description

IV magnesium hydroxide carbonate as a carrier in pharmaceutical compositions with improved drug release

The present invention relates to pharmaceutical formulations of drugs poorly soluble in aqueous solutions with improved

Drug release, as well as a process for their preparation.

In particular, these are pharmaceutical preparations in which IVIagnesiumhydroxidcarbonat serves as a carrier. State of the art

Active ingredients (APIs) for use in pharmaceutical preparations must have useful processing properties for the pharmaceutical practice so that a patient-appropriate dosage form can be formulated at all. On the other hand, the active ingredients in the body must be released from these formulations again to their

to develop physiological action. In particular sparingly soluble

Active ingredients cause problems here, as they are per se and also from their own

Formulations are not or only insufficiently quickly soluble, and thus in the body are not sufficiently absorbed to their

to fulfill medical purpose. Through chemical or physical manipulation of the API, by using a

Solution-speeding additive or by the skillful choice of a drug carrier can accelerate the drug release of such poorly soluble problem drugs.

Object of the present invention

It is therefore an object of the present invention to provide formulations and methods whereby sparingly soluble active substances are brought into a form in which they can be made more readily bioavailable after administration to the patient. In particular, the object is a stable connection between a physiologically acceptable, porous IVIagnesiumhydroxidcarbonat in a mold

by which the solubility rate of the

poorly soluble drug improves and releases it Drug forms is accelerated, so that the conditions for improved absorption and bioavailability are given.

Brief description of the invention

The subject of the present invention are in particular

Accelerated release formulations containing high surface area porous magnesium hydroxide carbonate as carrier material and at least one active ingredient. As active ingredients, at least one pharmaceutical active ingredient is preferably contained in the formulation according to the invention. In appropriate

inventive pharmaceutical formulations with better

Bioavailability is at least one sparingly soluble component of BCS

Classes II and IV included.

Surprisingly, the improved release of the sparingly soluble active ingredients is achieved by applying it or by applying it from a solution to the porous magnesium hydroxide carbonate as a carrier material. In this context, the better drug release is achieved satisfactorily when, as

Support material magnesium hydroxide carbonate having a BET surface area of at least 20 m ² / g, preferably of at least 30 m ² / g and particularly preferably of at least 40 m ² / g, is used and from it

corresponding pharmaceutical formulations are produced.

Particularly good properties show in this context

Formulations in which porous magnesium hydroxide carbonate with a BET pore volume of at least 0.1 cm ³ / g is contained as a carrier material.

These formulations of the invention can be prepared according to the invention in a simple process, wherein in a first step, the active ingredient or in a suitable solvent or

Solvent mixture is (are) dissolved, wherein the porous

Magnesium hydroxide carbonate is not soluble. In the following process step, the solution obtained is intimately with the porous

Magnesium hydroxide mixed and then removed the solvent or mixture after mixing again. The removal of the Solvent or mixtures can be made using various convection and contact drying methods. A particularly good connection between the magnesium hydroxide carbonate and the sparingly soluble in aqueous solutions or active ingredient (s) is obtained when the process is carried out using a fluidized bed drying, and the active ingredient solution at low temperature to a submitted in the fluidized bed porous magnesium hydroxide by spraying in intimate contact and dried. However, it has also been shown that a good connection between the carrier and the one or more sparingly soluble in aqueous solutions drug (s) is obtained when the porous magnesium hydroxide in the active ingredient-containing

Suspended solution and then in a spray or

Freeze-drying process is dried. Detailed description

In aqueous solutions sparingly soluble active pharmaceutical active ingredients are generally poorly bioavailable. (In the following, active pharmaceutical agents are referred to as APIs.) Therefore, it is in such

Problem drug is the primary goal to increase the rate of dissolution to release an adequate amount of drug in the body and to provide for absorption. This is the only way to achieve a sufficiently high concentration of active substance at the desired site of action in the body.

The chemical and physical manipulations often used to increase the rate of dissolution often present toxicological and technical problems; as well the use of

solubilizing additives because such additives often show negative physiological interactions with the body tissues.

These problems can be solved by using the

Problem drug rears on a physiologically acceptable porous carrier. Magnesium hydroxide carbonates with a particularly large BET Surface and a high pore volume are particularly suitable for this, since they are considered physiologically largely harmless.

Due to the large surface area and the high pore volume of the magnesium hydroxide carbonate used, it is possible to use the

Distribute problem drug evenly on this surface and in the pores. At the same time, this will make the available

Contact surface for a possible interaction with the

Release medium or the physiological fluids increased. This can be done by preparing a simple physical mixture of the crystalline API with the particular magnesium hydroxide carbonate. This is for a good connection between the

Magnesiumhydroxidcarbonatträger and the crystalline APIs, however, important to present the latter preferably in the form of very small particles, so that by a corresponding physical interaction a

Link between carrier and API can form.

It has now been found through experimentation that a better connection between the magnesium hydroxide carbonate carrier and the sparingly soluble drugs can be produced when the latter are in a suitable state

Solvent are dissolved and this solution is then brought into intimate contact with the porous magnesium hydroxide, so that the surface and the pores of the carrier can be covered or filled with the drug solution. Subsequently, the solvent is removed. This can be achieved by drying the

Solvent a drug magnesium hydroxide carbonate conglomerate form.

Due to the enlargement of the contactable

Drug surface and possibly also due to the forming amorphous structures, especially in the case of poorly soluble in aqueous solution APIs, their rate of release significantly increased. This also provides an essential prerequisite for improved bioavailability of the problematic drug substance. For the preparation of the preparations according to the invention, a magnesium hydroxide carbonate with a special particle morphology is particularly suitable, in particular that in WO 2011/095269 A1

described magnesium hydroxide carbonate. It is characterized by a suitable particle morphology, combined with a particularly large BET surface area and a high pore volume.

The magnesium hydroxide carbonate described herein is easily soluble in an acidic and aqueous environment such as gastric juice due to its porous structure and releases CO2 gas. Depending on the size of one out of this

Magnesium hydroxide carbonate manufactured tablet can this

Magnesium hydroxide carbonate as a carrier material or filler in

Medicament preparations are used, which disintegrate rapidly after oral intake or for the production of medicated effervescent drinks.

Due to the special properties of the in WO 201 1/095269 A1

described Magnesiumhydroxidcarbonate receives the formulator in the pharmaceutical industry, the ability to bring even problematic drugs in a fast drug release form. Particularly interesting is the possibility of influencing the dissolution rate and the solubility (also as supersaturation) and, consequently, influencing the bioavailability of poorly soluble and / or poorly absorbable APIs. It is particularly advantageous that it is at

Magnesium hydroxide carbonate as a carrier is a substance listed in all pharmacopoeias, so that no problems can arise from the registration for the approval of the drugs.

However, not only in the pharmaceutical industry but also in other applications which are confronted with corresponding release problems of active ingredients, this principle may be advantageous, such as e.g. in analytical

Test systems, diagnostics, for the release of agricultural active substances, in veterinary medicine or in body implants.

To prepare the preparations of the invention, a sparingly soluble API, such as fenofibrate, is completely dissolved in a suitable solvent. To prepare this solution becomes a solvent or a solvent mixture used, wherein

Magnesium hydroxide is not or only slightly soluble.

This solution is intimately mixed with a magnesium hydroxide carbonate having a particularly large BET surface area and a large pore volume. Thereafter, the solvent is removed, for example, by evaporation in vacuo, optionally with gentle heating or by freeze-drying. The resulting drug-magnesium hydroxide carbonate conglomerate has, as the further studies have shown, an improved in vitro release behavior, especially when it is further processed into formulations in tablet form.

This type of formulation of poorly soluble active ingredients is particularly advantageous when particularly low-dose preparations of the active ingredient have to be prepared. Due to the firm binding of the active ingredient to the surface of the carrier material, a free-flowing powder is obtained, which, if desired, can be compressed into tablets in which a consistent active ingredient concentration can be reliably guaranteed. The same applies, however, to active substances which are to be administered in low doses and administered in powder form. Since the drug is firmly attached to the carrier, no separation of powdered carrier and drug can take place.

Surprisingly, however, it has also been found that the advantageous properties of being applied to the porous support are retained if the sparingly soluble active compound is applied in relatively high concentration to the porous magnesium hydroxide carbonate as carrier from the solution. Even under these conditions, the drug has improved drug release, although due to the increased concentration in the solution during the removal of the solvent used

It would be assumed that the original physical and chemical properties of the sparingly soluble active substance outweigh and take effect.

In particular, in formulations in which the active ingredient must be administered very low doses, the uniform distribution of the active ingredient is advantageous to bear, because by the firm bond to the carrier Variations in the weight of the formulation lead to smaller variations in dosage than if the functional component were in the form of separate particles. Dosage forms are to be understood as meaning all forms which are suitable for use as medicaments, in particular for oral administration, as well as

Nutritional supplements but also cosmetics,

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, capsules, pellets or granules and powder mixtures.

Although the magnesium hydroxide carbonate used according to the invention can be directly tabletted, auxiliaries may be present in the active substance-containing solid formulations in addition to the active ingredient and the porous magnesium hydroxide carbonate as carrier according to the invention. These may include, but are not limited to flavor enhancers, tableting aids such as lubricants, and the like. Possible additives are, for example, thermoplastic polymers, lipids, sugar alcohols,

Sugar alcohol derivatives, solubilizers, lubricants, and others.

Suitable 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,

Polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates and polymethacrylates (Eudragit types), copolymers of methyl methacrylate and acrylic acid, polyethylene glycols, alkyl celluloses, in particular

Methylcellulose and ethylcellulose, Hydroxyalkylcetlulosen, in particular hydroxypropylcellulose (HPC), hydroxyalkyl-alkylcelluloses, in particular hydroxypropylmethylcellulose (HPMC), cellulose esters such

Cellulose phthalates, in particular cellulose acetate phthalate,

Hydroxypropylmethylcellulose phthalate and

Hydroxypropylmethylcellulose acetate succinate (HPMCAS). The skilled worker is familiar with such thermoplastic polymers. He can depending on select desired properties of the tablets to be produced between the commercially available for this purpose thermoplastic polymers.

But even low molecular weight substances may be included as additional carriers and fillers in the active ingredient-containing formulations. These can be sugars such as sucrose, glucose, maltose, xylose, fructose,

Ribose, arabinose, galactose, trehalose, but also sugar alcohols.

Suitable sugar alcohols are sorbitol, xylitol, mannitol, maltitol; a suitable one

Sugar alcohol derivative is also isomalt. Also suitable may be urea, nicotinamide, amino acids or cyclodextrins. These additives can be obtained commercially in various grades under different trade names.

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 the Ci ₂ , C ₄ , Cie and C-is fatty acids.

In addition, conventional galenic adjuvants whose total amount may be up to 20% by weight, preferably less than 10% by weight, in particular less than 5% by weight, based on the dosage form, can be used. Which includes:

Extenders or fillers, such as lactose, cellulose, silicates, phosphates or silica;

Lubricants, such as magnesium and calcium stearate, sodium stearyl fumarate; plasticizers;

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;

Flavors and odors; Anti adhesive;

disintegrating auxiliaries (disintegrants)

and retarding agents.

For the purposes of the invention, active substances are to be understood as meaning all substances having a desired physiological action on the human or animal body or plants. These are in particular pharmaceutical active ingredients. 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 within the meaning of the invention are also vitamins and minerals as well as peptide therapeutics and proteins.

As sparingly soluble substances in the context of the invention are substances whose saturation solubility at room temperature (20 ° C) in at least one of the following media is less than 1 wt .-%: water, 0.1 molar aqueous hydrochloric acid, aqueous phosphate buffer pH 7, 2, 0.9% by weight aqueous sodium chloride solution.

According to the invention, the sparingly soluble substances are a large number of active substances and effect substances, in particular pharmaceutical or cosmetic active ingredients, active ingredients for dietary supplements or dietary agents or food additives.

Sparingly soluble substances according to the invention are, for example: piroxicam, clotrimazole, carbamazepine, 17-beta-estradiol, sulfathiazole, fenofibrate, benzocaine, lidocaine, dimethindene, biperiden, bisacodyl,

Clioquinol, droperidol, haloperidol, nifedipine, nitrendipine, tetracycline, phenytoin, glafenin, floctafenine, indomethacin, ketoprofen, ibuprofen, dipyridamole, mefenamic acid, amiodarone, felodipine, itraconazole,

Ketoconazole, danazol, furosemide, tolbutamide, ritonavir, lopinavir,

Naproxen, spironolactone, propafenone, progesterone, paclitaxel, docetaxel, theophylline, hydrocortisone, beta carotene, vitamin A, tocopherol acetate, riboflavin, vitamin Q10, vitamin D, vitamin K, disulfiram, nimodipine, chlorothiazide, chlorpropamide, dicoumarol, chloramphenicol, digoxin,

Lonidamine, Pizotifen, Atovaquone, Amprenavir, Bexaroten, Calcitrol, Clofazimine, Doxercalciferol, Dronabinol, Durasteride, Etoposide, Loratadine, Risperidone, Saquinavir, Sirolimus, Valproic Acid, Amphotericin, Alprostadil, Carmustine, Chlordiazepoxide, Fenoldopam, Melphalan, Methocarbamol, Oxytetracycline, Docetaxel, Fulvestrant, Propofol, Voriconazole, Ziprasidone, Leuprolide Acetate, Viadur, Valrubicin, tramadol, celecoxib, etodolac,

Refocoxib, Oxaprozin, Leflunomide, Diclofenac, Nabumetone,, Flurbiprofen, Tetrahydrocannabinol, Capsaicin, Ketorolac, Albendazole, Ivermectin,

Amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutin, rifapentin,

Trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz,

Dicoumarol, Tirofiban, Cilostazol, Ticlidopine, Clopidrogel, Oprevelkin,

Paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol,

Repaglinide, glimepiride, pioglitazone, rosiglitazone, troglitazone, glyburide, glipizide, glibenclamide, fosphenytione, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole,

Miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, lisinopril, benezepril, nifedipine, nisolidipine, telmisartan, irbesartan, eposartan,

Valsartan, candesartan, minoxidil, terazosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizotifen, sumatriptan,

Zolmitriptan, naratriptan, rizatriptan, aminoglutethimide, busulphan,

Cyclosporin, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel,

Tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutamide, bicalutanide, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin,

Beclomethasone, budesonide, betamethasone, prednisolone, cisapride,

Cimetidine, loperamide, famotidine, lansoprazole, rabeprazole, nizatidine, omeprazole, cetirizine, cinnarizine, dexchlorpheniramine, loratadine,

Clemastine, Fexofenadine, Chlorpheniramine, Acutretin, Tazarotene,

Calciprotein, calcitriol, targretin, isotretinoin, tretinoin, calcifediol,

Fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinitrate,

Dihydrotachysterol, essential fatty acids, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydroepiandrosterone,

Medroxyprogesterone, progesterone, rimexolone, megestrol acetate, oestradiol, finasteride, mefepristone, L-thyroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, and theirs Isomers, derivatives, salts or mixtures or other active substances which fulfill the abovementioned definition.

If the release of fenofibrate as a model active substance from a capsule is compared in release experiments, the active ingredient being prepared from an acetone solution on a magnesium hydroxide carbonate according to the invention (sample A) (example 4), it is found that this formulation leads to a significantly improved release of the In comparison to formulations which consist of a mechanical mixture of the active ingredient and the magnesium hydroxide carbonate. The release from this formulation is also more favorable than out

corresponding formulations in which the magnesium hydroxide carbonate has been prepared in a manner other than described in WO 20 1/095269 A1 and accordingly has a lower porosity and lower surface area (Examples 5 and 6, fenofibrate based on the

Magnesium hydroxide carbonate samples B and C).

In summary, it can be seen from the experiments carried out that the application of a sparingly soluble active substance from a solution to magnesium hydroxide carbonate as a carrier for a simple mechanical mixture of the components with respect. Release rate and

Release amount of the drug is superior.

Surprisingly, however, a pattern of the magnesium hydroxide carbonate loaded with fenofibrate (out of solution) shows a significantly improved behavior in terms of rate and extent of drug release (Sample A in Example 4, magnesium hydroxide carbonate prepared according to the process described in WO 2011/095269 A1). This outstanding release behavior of the sample A (Example 4) is found both in the release medium which has been mixed with 1% SDS and with 0.5% SDS.

The magnesium hydroxide carbonate of sample A differs from the other investigated magnesium hydroxide carbonate grades (samples B and C), in particular in the BET surface area. The magnesium hydroxide carbonate of the sample B shows a BET surface area of only about 11.5 m ² / g, that of the sample C at least about 31.6 m ² / g, but the invention

Magnesium hydroxide carbonate of sample A has a BET surface area of 44 _{) has} 4m ² / g. The 31.6m ² / g BET surface area of sample C does not appear to be sufficient for a significant improvement in drug release. The data show that such formulations have a faster and more

more extensive drug release than comparable mechanical

Have mixtures of the components.

The present description enables one skilled in the art to fully embrace the invention. Without further explanation, it is therefore assumed that a person skilled in the art can make the most of the above description.

Any ambiguity goes without saying, the quoted

Publications and patent literature. Accordingly, these documents are considered part of the disclosure of the present application

Description. This applies in particular to the disclosure of the application WO 2011/095269, wherein the preparation of the used

Magnesiumhydroxidcarbonats is described and which is herewith part of the disclosure of the present invention.

For a better understanding and clarification of the invention, examples are given below which are within the scope of the present invention. These examples are also used for

Illustration of possible variants. Due to the general validity of the described principle of the invention, however, the examples are not suitable for reducing the scope of protection of the present application only to these. Furthermore, it is self-evident to the person skilled in the art that both in the given examples and in the remainder of the description, the amounts of components contained in the compositions amount in the sum to only 100% by weight, molar or vol

Aggregate composition and can not exceed it, even if the percentage ranges indicated are higher Could yield values. Unless otherwise stated, therefore,% data are in terms of weight, mol or vol.%.

The temperatures given in the examples and the description as well as in the claims are always in ° C.

Examples

The following materials, equipment and measurement methods were used to carry out the following examples:

Apparatus and method for characterizing the properties of the material

1. Bulk density: according to DIN EN ISO 60: 1999 (German version)

- indication in "g / mr

2nd tamped density: according to DIN EN ISO 787-11: 1995 (German version) - in "g / ml"

3. Surface area determined according to BET: Evaluation and performance according to literature "BET Surface Area by Nitrogen Absorption" by S. Brunauer et al. (Journal of American Chemical Society, 60, 9, 1983) Device: ASAP 2420

Micromeritics Instrument Corporation (USA); Nitrogen; Weighing: approx. 3,0000g; Heating: 50 ° C (5 h); Heating rate 3K / min; Indication of the

arithmetic mean of three determinations

4. Particle Size Determination by Laser Diffraction with Dry Dispersion:

Mastersizer 2000 with dispersing unit Scirocco 2000 (Malvern

Instruments Ltd. UK), determinations at 1 and 2 bar counter pressure;

Evaluation Fraunhofer; Dispersant Rl: 1.000, Obscuration Limits: 0.0- 10.0%, Tray Type: General Purpose, Background Time: 7500 msec, Measurment Time: 7500 msec, Execution according to ISO 3320-1 and the specifications of the technical manual and specifications of the

Equipment manufacturer; Data in Vol%

5. Particle size determination by laser diffraction with wet dispersion: Mastersizer 2000 with wet dispersion unit Hydro 2000S (Malvern Instruments Ltd. UK); Dispersion medium demineralized water;

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; Measure Time: 7500 msec; Obscuration limits: 10.0-20.0%;

Performance in accordance with ISO 13320-1 and in accordance with the specifications of the technical manual and the specifications of the equipment manufacturer; Data in Vol%

, Particle size determination by dry sieving over a sieving tower: Retsch AS 200 control, Fa.Retsch (Germany); Substance quantity: approx. 110.00g; Sieving time: 30 minutes; Amplitude intensity: 1 mm; Interval: 5 seconds; Test sieves with metal wire mesh according to DIN ISO 3310; Screen widths (in mm): 710, 600, 500, 400, 355, 300, 250, 200, 150, 100, 75,

50, 32; Indication of the quantity distribution per sieve fraction in the tables as "wt.% Of the initial weight"

7. Release test: The samples are filled in a hard capsule in an in-vitro release device from ERWEKA

(Heusenstamm, Germany) with the "Appartus 2 (Paddle Apparatus)" described in the USP 35 under <711> and under the conditions described there for "Immediate-release dosage forms" (USP = United States Pharmacopoeia). So that the capsules do not float, they are weighted with a so-called "sinker" (see USP35 under <711> Apparatus 2.) The sampling takes place automatically via a peristaltic pump system with subsequent measurement in a photometer Lambda 35, Perkin Elmer (USA) in one

Thru Cell. The averaged values result from 6 measurements. Measuring equipment and measuring parameters:

Release device ERWEKA DT70 equipped with Apparatus 2

Paddle Apparatus according to USP 35

- Temperature: 37 ° C +/- 0.5 ° C

- Speed of the paddle: 75 rpm

- Volume of release medium per measuring vessel: 1000 ml

- Sample weight per capsule: 500 mg substance

- total running time of the measurement: 120 min. (with sampling at 5, 10, 15, 20, 25, 30, 45, 60, 75, 90 and 120 min.)

- Tube pump for sampling: Ismatec IPC, type ISM 931; App. No.

12369-00031

- Photometer Lambda 35 (Perkin Elmer) - Measurement at 290 nm in a 2mm flow cell

Evaluation via Dissolution Lab Software Version 1.1., Perkin Elmer Inc. (USA)

Composition (% by weight) of the release medium with 0.5% SDS:

Sodium chloride 0.2%

Hydrochloric acid l M 8.1%

SDS (sodium dodecyl sulfate) 0.5%

Demineralized water 91, 2%

Composition (in% by weight) of the release medium with 1% SDS:

Sodium chloride 0.2%

Hydrochloric acid 1M 8.1%

SDS (sodium dodecyl sulfate) 1.0%

Demineralized water 90.7% 8. Content Determination Fenofibrate in the mechanical mixtures or in the fenofibrate / magnesium hydroxide carbonate conglomerates by HPLC over a LiChrospher 100 RP-18e 125-4 column 150828 Merck, Darmstadt (Germany); Guard column: LiChrospher 100 RP-18e 4-4 Art.No. 50962; Eluent: 69.93% by volume acetonitrile 100030 Merck KGaA, Darmstadt, 29.97 Vol% Water LiChrosolv ItemNo. 1 5333 Merck KGaA,

Darmstadt and 0,10 Vol% trifluoroacetic acid Art.No. 108262 Merck KGaA, Darmstadt (Germany), pH ca.1, 5; Flow: 2ml / min .; Pressure: approx. 65 bar; Temperature: 50 ° C; Detection: 286 nm characterization of the materials used

Magnesium hydroxide used:

Sample A: Parteck Mg DC magnesium hydroxide carbonate heavy Ph Eur, BP, USP, E 504, Merck KGaA, Darmstadt (Germany), Art. No. 102440, Batch: K0076840

Sample B: NutriMag MC DC magnesium carbonate heavy, pharm., Gran.

idReinh. BP, USP, Ph Eur; CALMAGS GmbH, Lüneburg (Germany); Batch: 308075060 Sample C: Pharmagnesia MC Type A granules magnesium carbonate heavy Ph Eur, E 504, Lehmann & Voss & Co, Hamburg (Germany), Batch: 0805-089, Delivery Lot: 4500068169 Additional characterization of samples A, B and C with respect to

Bulk density, tamped density, BET surface area, BET pore volume,

Particle distribution by laser diffraction with wet dispersion (in water) and tower sieving:

Table 1: Bulk density, tamped density, BET surface area, BET pore volume (for details on the measuring methods, see Methods)

Table 2: Particle distribution determined by laser diffraction with

Wet dispersion in water

Data in μιη (for details on the measuring method see Methods)

Table 3: Particle distribution determined by tower sieving

Data in% by weight (for details on the measuring method see Methods)

Sample <32μηι 32-50 50-75 75- 100- 150- 200- μιη Mm ΙΟΟμιτι 150μηι 200μΐΎΐ 250μηη

Sample A 12.2 53.4 27.2 6.1 0.2 0.2 0.1

Sample B 0.1 0.3 0.4 1, 1 5.2 10.9 12.4

Sample C 0.0 0.0 0.2 0.9 3.7 12.8 16.5 Sample 250- 300- 355- 400- 500- 600-> 710 m

300μΓη 355μηι 400μπι δθθμιη 600μηη 710μ (

Sample A 0.1 0.1 0.1 ο, ο 0.1 0.2 0.0

Sample B 11, 8 12.5 7.5 21.1 15.3 1, 4 0.0

Sample C 17.8 14.9 13.0 17.8 2.4 0.0 ο, ο

Used Modeling Agent Fenofibrate:

Fenofibrate> = 99% powder, Sigma Aldrich, Buchs (Switzerland), Pcode 101050968, F6020, LOT BCBG3328V

Table 4: Particle distribution determined by laser diffraction with

Dry dispersion (different pressure conditions)

Details in μιτι (for details on the measuring method see Methods)

Acetone used to dissolve the fenofibrate: acetone suitable for use as excipient EMPROVE exp Ph Eur, BP, NF, Merck KGaA, Darmstadt (Germany), Art. No .: 100013, lot: K42947013

Chemicals used to prepare the release media:

Sodium dodecyl sulfate Ph Eur, Merck KGaA, Darmstadt (Germany), Item No .: 817034, Lot: K42572034 (as a short name for

Sodium dodecylsulfate is used in text and tables "SDS") Sodium chloride suitable for use as excipient EMPROVE exp pH Eur, BP, USP, Merck KGaA, Darmstadt (Germany), Art. No .: 106400, Batch: K93205800

Hydrochloric acid c (HCI) = 1 mol / l (1N) TitriPUR, Merck KGaA, Darmstadt

(Germany); Item No .: 109057, Batch: HC247274 Demineralised water (short name: "demineralised water")

Hard capsules used: Capsugel Gr.OO, Product CD: X01E0009, Capsugel Order no. 2159658-1-1, Lot no. 33045581

Magnesium hydroxide carbonate for drug release

Aim: The aim of the experiments is to differentiate the in vitro release behavior of poorly soluble drugs, such as To elucidate fenofibrate from formulations based on different types of magnesium hydroxide carbonate. For this purpose, three different free-flowing and

directly compressible magnesium hydroxide carbonates (especially with

different BET surface areas and pore volume) as well as different incorporation methods of the active ingredient on the carrier: a) simple mechanical mixtures of active ingredient and carrier

across from

b) Active substance applied from solution to the carrier. test results

A) Examples 1-3: Preparation of the mechanical mixtures of fenofibrate and magnesium hydroxide carbonate samples A-C and measurement of fenofibrate release from capsules filled with these mixtures

Principle:

Per 45.0g of Magnesiumhydroxidcarbonatmuster A-C are mixed with 5.0g fenofibrate, mixed and then each 500mg +/- 2mg of these mixtures by hand in hard capsules filled (each 12 capsules per

Mixture). 6 of these capsules are in the paddle apparatus of the company Erweka in the two media (with 1% SDS or 0.5% SDS) on

Speed and extent of fenofibrate release tested.

The measurements in the two release media with different amounts of SDS detergent serve to better discriminate the different fenofibrate release behavior based on the three different magnesium hydroxide carbonates. Mischbedinqunqen:

Mixing vessel: 250ml wide-necked glass bottle, order no. 215-1805, VWR, Germany)

Mixer type: Laboratory tumble mixer TurbulaT2A (Willy A.Bachofen, Switzerland)

Table 5:

Mixture: After 5 min. Mixing the material by a 1mm hand screen (diameter 20mm, Retsch, Haan, Germany) filed and any clumps easily with a plastic spatula by hand through the sieve pressed: Then again for 5 min. mixed.

Content and homogeneity of the mixtures are determined: Determination of the fenofibrate by HPLC from in each case 6 samples of a production whereby the rel. Standard deviation may not be greater than 10%.

Then filling in hard capsules and measuring the release behavior.

Table 6: Results of fenofibrate release from the hard capsules in the release medium with 1% SDS / sodium dodecyl sulfate

(In% by weight of the amount of fenofibrate released relative to a total expected quantity of 50 mg fenofibrate / capsule, measurement of 6 capsules per example)

Fig. 1: It is the Fenofibratfreisetzungsprofile the mechanical

Mixtures based on the three different magnesium hydroxide in the presence of 1% SDS shown (Examples 1, 2 and 3); Amount of fenofibrate released [wt%] as a function of time [min]. Table 7: Results of fenofibrate release from the hard capsules in the release medium with 0.5% SDS / sodium dodecyl sulfate

Fig. 2: It is the Fenofibratfreisetzungsprofile the mechanical

Mixtures based on the three different Magnesiumhydroxidcarbonate in the presence of 0.5% SDS shown (Examples 1, 2 and 3); Amount of fenofibrate released [wt%] as a function of time [min].

Result of the release tests of fenofibrate from physical mixtures with different types of magnesium hydroxide carbonate:

The formulations of Examples 1-3 differ in theirs

Release behavior both in the presence of 1% SDS and in

Presence of 0.5% SDS with each other only slightly. The extent of release after 120 minutes, as expected, tends to be higher for the larger amount of SDS in the release medium (1%) over the lower level (0.5%). A discriminatory influence of the used

Magnesium hydroxide carbonates is not recognizable. B) Examples 4-6: Preparation of magnesium hydroxide carbonate samples AC added with dissolved fenofibrate, removal of the solvent and measurement of fenofibrate release from capsules filled with these fenofibrate / magnesium hydroxide carbonate conglomerates

Principle:

Per 450.0 g of Magnesiumhydroxidcarbonatmuster A-C are mixed with 50.0g of fenofibrate (dissolved in acetone), intimately mixed, the solvent removed and then each 500mg +/- 2mg of these conglomerates by hand in hard capsules filled (12 capsules per production). Each 6 of these capsules are tested in the paddle apparatus of Erweka in both media (with 1% SDS or with 0.5% SDS) on the rate and extent of fenofibrate release.

The measurements in the two release media with different amounts of SDS detergent serve to better discriminate the different fenofibrate release behavior based on the three different magnesium hydroxide carbonates.

production:

Each 450.0 g Magnesiumhydroxidcarbonatmuster A-C are placed in a Hobart mixer N-50 with flat stirrer light metal (Hobart Canada, North York, Ontario, Canada) and 2 min. mixed. Thereafter, the clear, colorless fenofibrate solution (50.0 g of fenofibrate dissolved in 250 g of acetone) is added as quickly as possible within about 10 seconds.

Table 8:

It is again for 2 min. mixed - cover the mixing vessel to avoid evaporation of the acetone as far as possible - then the Switch off the mixer, cover the mixing vessel with a glass and 15

Let stand for minutes. After that, the acetone gets in

Vacuum drying oven Heraeus VT 5050 EK removed (23 hours at 50 ° C, vacuum: 180 mbar), the product is placed on a 1mm sieve and a content and homogeneity test is carried out: Determination of the

Fenofibrats by HPLC from in each case 5 samples of a production whereby the rel. Standard deviation may not be greater than 10%.

Then filling in hard capsules and measuring the release behavior.

Table 9: Results of fenofibrate release from the hard capsules in the release medium with 1% SDS / sodium dodecyl sulfate

(In% by weight of the amount of fenofibrate released relative to a total expected amount of 50 mg fenofibrate / capsule, measurement of 6 capsules per example)

FIG. 3: The release profiles of fenofibrate [% by weight] in FIG

Dependence on time [min] after mounting on different

Magnesium hydroxide carbonate in the medium with 1% SDS shown (Examples 4, 5 and 6).

Table 10: Results of fenofibrate release from the hard capsules in the release medium with 0.5% SDS / sodium dodecyl sulfate (In% by weight of the amount of fenofibrate released relative to a total expected amount of 50 mg fenofibrate / capsule, measurement of 6 capsules per example)

FIG. 4: The release profiles of fenofibrate [% by weight] in FIG

Dependent on time [min] after mounting on various magnesium hydroxide carbonates in the medium with 0.5% SDS

(Examples 4, 5 and 6).

Result of the release tests of fenofibrate grown on different types of magnesium hydroxide carbonate: Both in the

Release medium with 1% SDS as well as with only 0.5% SDS, there is a clear differentiation in the release behavior between the 3

Examples 4-6. Fenofibrate grown on the

Magnesium hydroxide carbonate sample A according to Example 4 exhibits significantly faster and greater drug release both in speed and in extent (after 120 minutes) than the fenofibrate grown on the magnesium hydroxide carbonate samples B and C (Examples 5 and 6).

C) Comparative presentation of the different

Release behavior of fenofibrate from mechanical mixtures (Examples 1-3) and from conglomerates

(recovered by raising dissolved fenofibrate to various magnesium hydroxide carbonates (Examples 4-6), releasing in a medium supplemented with 1% SDS) Fig. 5: The release profiles of fenofibrate after being grown on different magnesium hydroxide carbonates compared to the profiles of the mechanical mixtures in the presence of 1% SDS are shown;

Examples 4-6 compared with Examples 1-3.

Result: In the release medium with 1% SDS as detergent, the fenofibrate formulation of Example 4 (fenofibrate grown on the magnesium hydroxide carbonate sample A) shows the fastest as well as the most quantitative release of the active ingredient. Examples 5 and 6

(Fenofibrate grown on the Magnesiumhydroxidcarbonatmuster B and C) show a significantly slowed down and reduced in extent

Release of fenofibrate. In contrast, the mechanical mixtures are significantly less favorable in their fenofibrate release behavior and also show no discrimination between the 3 used

Magensiumhydroxidcarbonatmustem.

D) Comparative presentation of the different

(recovered by raising dissolved fenofibrate to various magnesium hydroxide carbonates (Examples 4-6); release in one

Medium with addition of 0.5% SDS)

Fig. 6: The release profiles of fenofibrate after mounting on various magnesium hydroxide carbonates compared to the profiles of the mechanical mixtures in the presence of 0.5% SDS are shown; Examples 4-6 compared with Examples 1-3.

Result: In the release medium with only 0.5% SDS as detergent, the fenofibrate formulation of Example 4 (fenofibrate grown on the magnesium hydroxide carbonate sample A) also shows the fastest as well as the most quantitative release of the active ingredient. The

Examples 5 and 6 (fenofibrate grown on the

Magnesium hydroxide carbonate samples B and C) show a clear

slowed and also to the extent reduced release of fenofibrate. In contrast, the mechanical mixtures are in their Fenofibrate release behavior significantly less favorable and also show no discrimination between the 3 used

Magensiumhydroxidcarbonatmustern. E) Conclusion from the experiments

1. Obtaining fenofibrate from a solution on the

Magnesium hydroxide carbonate carrier is superior to a simple mechanical mixture of the components in terms of release rate and release amount of the drug.

2. Mechanical mixtures do not show release differentiation between the tested types of magnesium hydroxide carbonate.

3. Surprisingly, however, a pattern of magnesium hydroxide carbonates loaded with fenofibrate (out of solution) shows a significantly improved behavior in terms of rate and extent of drug release (Sample A in Example 4). This outstanding

Release behavior of Sample A (Example 4) is found in both the release medium with 1% SDS and with 0.5% SDS.

4. Pattern A differs from Patterns B and C especially in the BET surface area; Pattern C shows a BET surface area of only about 1; 5 m ² / g, pattern B of at least about 31, 6m ² / g and of sample A 44,4m ² / g. The

31, 6m ² / g BET surface area of sample C does not appear to be sufficient for a significant release improvement.

The data show that formulations according to the invention have a faster and more extensive release of active ingredient than comparable mechanical mixtures of the components. Furthermore, it is shown that by selecting a Magnesiumhydroxidcarbonats with a particularly large surface area and high pore volume, an additional improvement of the in vitro release behavior of a poorly water-soluble drug can be achieved.

Claims

P A T E N T A N S P R E C H E

1. Formulations with accelerated release of active ingredient, containing

porous magnesium hydroxide carbonate with a high surface area

Carrier material and at least one active ingredient.

A formulation according to claim 1, characterized in that it is a pharmaceutical formulation containing at least one

contains pharmaceutical agent.

A formulation according to claim 1 or 2, comprising at least one sparingly soluble active substance of BCS classes II and IV.

Formulations according to one of claims 1, 2, or 3 obtainable by applying the active substance or the active ingredients from a solution to the porous magnesium hydroxide carbonate as carrier material.

Formulations according to one or more of claims 1 to 4, comprising magnesium hydroxide carbonate having a BET surface area of at least 20 m ² / g, preferably of at least 30 m ² / g and

more preferably at least 40 m ² / g.

Formulations according to one or more of claims 1 to 5, comprising porous magnesium hydroxide carbonate having a BET pore volume of at least 0.1 cm ³ / g as support material.

A process for the preparation of the formulations according to one or more of claims 1 to 6, characterized in that the active substance or substances in a suitable solvent or

Solvent mixture is (are) dissolved, wherein the porous

Magnesium hydroxide carbonate is not soluble, and the resulting solution is intimately mixed with the magnesium hydroxide carbonate and the solvent or mixture is removed again after mixing.

A method according to claim 7, characterized in that the active substance-containing solution at low temperature to a in the Fluidized porous magnesium hydroxide carbonate is brought into intimate contact by spraying and dried.

9. The method according to claim 7, characterized in that the porous magnesium hydroxide carbonate suspended in the active substance-containing solution and then in a spray or

Freeze-drying process is dried.