DE102007048705A1 - Amorphous formulation - Google Patents

Abstract

The invention relates to an amorphous formulation of at least one solid substance at room temperature, containing cellulose and / or cellulose derivatives and optionally at least one surface-active substance, and a process for their preparation.

Description

The The present invention relates to an amorphous formulation at least a solid at room temperature substance containing cellulose and / or cellulose derivatives and optionally at least one surface-active substance, a process for their preparation by displacement precipitation and their use for the application of the substance contained.

In Water-insoluble substances are strong limited transport from the place of application to the place the effectiveness in the biological system is severely restricted in its efficiency. There are a larger number of approaches the dissolution rate of such substances by suitable To improve formulation.

It is described that by grinding crystalline substances in high-pressure homogenizers into so-called nanosuspensions, the dissolution rate can be improved by specific surface enlargement, by increased saturation solubility, and by shortening of the diffusion distance [ Müller et al., Pharm. Ind. 61, (1): 74-78; 1999 ]. It is also known that an improvement in the dissolution rate of crystalline substances can be achieved by grinding in ball mills to finely divided suspensions [ GG Liversidge et al., Int. J. Pharm. 125: 91; 1995 ]. The increase in the dissolution rate is achieved here essentially by representing higher surface areas per mass, due to the comminution of the crystals.

Furthermore, an increase in the dissolution rate of poorly soluble substances can be achieved by finely divided, X-ray amorphous precipitation. Here, the amorphous particles are stabilized by means of a surrounding shell [ H. Auweter et al., Angew. Chem. Int. Ed. 38 (15): 2188-2191; 1999 ]. The dissolution rate of a substance in the amorphous state is greater than the dissolution rate of the same substance in crystalline form. Thus, the formulation in the amorphous state is an additional advantage to the finely divided formulations described above. Above-mentioned finely divided core-shell particles are also the subject of EP65193A2 and EP932339B1 ,

Envelope layers are often represented in the pharmaceutical industry from derivatives of cellulose. Furthermore, cellulose itself is a common filler in overall formulations, which in WO200565663A1 . WO2003024426A1 . US5417982A and EP838218B1 is disclosed. Here, cellulose and active ingredient are brought into a substantially dry state only in the final formulation in contact. It can not be assumed that a physicochemical interaction takes place from active ingredient to cellulose (derivative). This is a stabilization of u. U. present amorphous structure is not likely. Use find the fillers rather to achieve altered release profiles, eg. B. by swelling of the cellulose (derivatives) and thereby slowed diffusion of the drug in the resulting gel matrix.

A Use of cellulose and / or cellulose derivatives in the course of a Precipitation process are not disclosed.

Underivatized cellulose is insoluble in pure water and pure organic solvents [ SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 ]. However, there are methods of dissolving cellulose using aqueous systems containing bi- or tervalent metals, salts and concentrated acids. [ SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 ] However, due to the increased toxicity of the individual components, these systems render the overall formulation unsuitable for use in the pharmaceutical field.

By a thermal treatment of cellulose in dimethyl sulfoxide (DMSO) / para-formaldehyde (PF) solutions, a homogeneous solution of cellulose can also be represented. [ SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 ]

Cellulose derivative in this context refers to chemical compounds in which further chemical groups are covalently bound to the cellulose backbone. As such, for example, carboxymethylcellulose (a part of the hydroxyl groups of the cellulose is linked as an ether with a -CH ₂ -COOH- (carboxymethyl) group) and hydroxypropylmethylcellulose (a part of the hydroxyl groups of the cellulose is as ether with a -CH ₃ Group linked, other than ether with -CH ₂ -CHOH-CH ₃ ).

It turns out, however, that a finely divided, amorphous state can not be equally easily stabilized for all substances by corresponding shell layers. So z. For example, in Rivaroxaban ^® recrystallization observed after just a few days. In general, it is difficult in many cases to prevent recrystallization of a precipitate with finely divided amorphous property, since the thermodynamically preferred form of the substance is crystalline under normal conditions. [ Angew. Chem. 2001, 113, 4460-4492 ].

It was therefore an object of the present invention to provide a stable, finely divided, amorphous formulation of a thermodynamically preferably crystalline substance which is solid at room temperature and a process for the production thereof which overcomes the disadvantages of the prior art that the substance becomes more available.

It it was surprisingly found that the task was solved can be, by a formulation containing at least one solid at room temperature, which under normal conditions thermodynamic preferably crystalline, cellulose and / or cellulose derivatives, and optionally a surfactant, characterized characterized in that the formulation is more than 50% in amorphous Mixed phase is present, determined by X-ray diffractometry.

in this connection describes stable amorphous mixed phase, the obtained, solid amorphous Condition of the entire formulation over a period of at least two days, proven by powder X-ray diffractometry or differential thermoanalysis.

Amorphous in the sense of the invention means that more than half, preferably more than 75%, particularly preferably more than 90%, of the resulting inventive formulation is present in an amorphous mixed phase. Conversely, measure of amorphicity is the degree of crystallinity that can be determined by X-ray diffractometry by those skilled in the art. Furthermore, the person skilled in the art can ascertain this by differential scanning calorimetry (DSC). A general procedure for determining the amorphicity of a substance or formulation will also be apparent to those skilled in the art DIN EN 13925-1 ,

Prefers is the thermodynamically preferred form of the at least one Solid substance present under normal conditions crystalline. The term normal conditions is in particular a pressure of 1013 hPa and room temperature (20 ° C). Thermodynamically preferred Form is the form in which the substance is stored for a period of more than two days under normal conditions becomes.

Prefers is the at least one at room temperature as a solid Substance is an active substance that can be used pharmaceutically or can be used in crop protection.

Especially Preferably, the at least one is at room temperature as a solid present substance thermodynamically preferred under normal conditions crystalline and it is a pharmaceutical agent, in the field of healing and alleviating diseases of the animal and man can be used, such. B. acidotherapeutic agents, Analeptics / antihypoxema, analgesics / anti-inflammatory drugs, antiallergic drugs, Antianemic, antiarrhythmic, antibiotics / anti-infective, anti-dementia, Antidiabetics, antidotes, antiepileptics, antihypertensives, antihyperglycemics, Antihypotonics, anticoagulants, antifungals, antiparasitic agents, Antiphlogistics, arteriosclerotic agents, broncholytics / antiasthmatics, Cholagoga and biliary therapies, cholinergics, corticoids, Dermatological, diuretic, circulating, medications for the treatment of addictions, enzyme inhibitors, fibrinolytics, Geriatrika, Gout, Gynekologika, Hypatika, Hypnotika / Sedativa, Immunomodulators, cardic, coronary, laxative, lipid-lowering, local anesthetics / neural therapeutics, Gastrointestinal, migraine, muscle relaxants, ophthalmics, Osteoporosis, Otologics, Psychotropic drugs, Rhinologics, Thyroid drugs, Sexual hormones, Anticonvulsants, removers, urologics, veno-therapeutics, vitamins and cytostatics.

When Examples of some of these pharmaceutical agents are Boldin, Quinolones, felodipine, flurbiprofen, ibuprofen, ketoprofen, macrolides, Nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, norfloxacin, Ofloxacin, paclitaxel, rivaroxaban, sulfonamides and tetracyclines called.

Especially the active substances Rivaroxaban, Fluriprofen, Ibuprofen, Ketoprofen nifedipine and nimodpin.

All particularly preferred is the active ingredient rivaroxaban.

Also Preferably, the at least one substance is under normal conditions thermodynamically preferably crystalline in front and it is z. B. the crop protection agents of the classes of herbicides, fungicides, Insecticides, acaricides, nematicides, bird repellents, Plant nutrients and soil conditioners.

Suitable surfactants include those that lower the surface tension of the solvents used to make the formula of the present invention. This preferably comprises the substance classes of the ethoxylated tristyrylphenols or ethylene-propylene block copolymers or polyalkylene glycol ethers. Particularly preferred Soprophor ^® 4D384, Pluronic ^® PE 6800, and Brij ^® 76 find application.

• a) Bereitstellen einer Lösung 1 von Cellulose und/oder Cellulosederivat in einem polaren, hochsiedenden, aprotischen Lösungsmittel oder Lösungsmittelgemisch, gegebenenfalls weiterhin enthaltend mindestens einen (Halb-)acetalbildner
• b) Vollständiges Lösen der bei Raumtemperatur festen Substanz in Lösung 1, gegebenenfalls zusammen mit einer oberflächenaktiven Substanz unter Bildung einer Lösung A.
• c) Bereitstellen eines protischen Verdrängungsmittels (Lösung 2), gegebenenfalls mit einer oberflächenaktiven Substanz, in dem sich die bei Raumtemperatur feste Substanz und die in Lösung 1 enthaltene Cellulose und/oder Cellulosederivate nur in geringem Maße lösen lassen und das sich mit dem Lösungsmittel oder Lösungsmittelgemisch in Lösung 1 mischen lässt, als Lösung B
• d) Vermischen der Lösungen A und B, so dass bei Raumtemperatur feste Substanz und Cellulose und/oder Cellulosederivate sofortig in fester, amorpher Mischphase als Fällprodukt ausfallen.
• e) optional Weiterbehandeln, um die feste Mischphase in trockener Form zu erhalten.

The invention further provides a process for the preparation of a formulation of a solid substance at room temperature, comprising the steps

• a) providing a solution 1 of cellulose and / or cellulose derivative in a polar, high-boiling, aprotic solvent or solvent mixture, optionally further containing at least one (semi-) acetal former
• b) complete dissolution of the solid at room temperature substance in solution 1, optionally together with a surface-active substance to form a solution A.
• c) providing a protic displacement agent (solution 2), optionally with a surface-active substance in which the substance solid at room temperature and the cellulose and / or cellulose derivatives contained in solution 1 can be dissolved only to a small extent and which mixes with the solvent or solvent mixture in solution 1, as solution B
• d) mixing the solutions A and B, so that at room temperature solid substance and cellulose and / or cellulose derivatives precipitate immediately in solid, amorphous mixed phase as a precipitate.
• e) optionally further treating to obtain the solid mixed phase in dry form.

When high boiling point for the purposes of the present invention apply solvents or solvent mixtures whose boiling point is 1013 hPa is above 100 ° C, preferably above 150 ° C, more preferably above 200 ° C.

polar Solvents are solvents or mixtures of solvents, whose dipole moment exceeds 2.5 Debye. Preferably, the dipole moment is above 3 Debye; Especially preferably above 3.5 Debye.

Especially preferred solvents are, for example, dimethyl sulphoxide, Dimethylacetamide, dimethylformamide, N-methylpyrrolidone, N-methylformamide, Nitrobenzene, ethylene glycol and formamide. Very particularly preferred becomes dimethyl sulfoxide (DMSO).

The Providing the solution 1 in step a) can by heating of cellulose and / or cellulose derivatives, in the solvent or solvent mixture, optionally together with a (semi-) acetal former, such as. Paraformaldehyde, acetaldehyde, Acetone, propanone can be achieved. Solution 1 contains preferably between 0.01 and 2% by weight of cellulose and / or cellulose derivative, more preferably between 0.1 and 1% by weight, especially preferred about 1% by weight (in each case based on the solution 1) and optionally at least one (semi-) acetal former.

Becomes in solution 1 uses a (semi-) acetal former, so contains Solution 1 preferably between 1 and 10% by weight of (semi-) acetal former, more preferably between 5 and 9% by weight, especially preferred about 8% by weight.

Of the Proportion of the above-mentioned surfactant the solution A produced in step b) is at most 5% by weight, preferably between 1 and 3% by weight, especially preferably about 2% by weight. The proportion of the dissolved active substance based on solution A is between 1 and 10 Gew%, prefers between 2 and 7 Gew%, particularly prefers about 5% by weight.

at the displacer (solution 2) according to step c) is z. B. protic solvent, or Solvent mixtures of especially water and / or Alcohols (eg, methanol, ethanol, propanol, etc.), or mixtures of other solvents with the polar, aprotic, high-boiling solvents are miscible and with this a homogeneous under the conditions of the invention Form phase. Preferably, solution B then contains less than 5% by weight, more preferably between 1 and 3% by weight, especially preferred about 2% by weight of a surfactant as described above Substance.

The Solubility of the solid at room temperature substance or the cellulose and / or cellulose derivatives contained in solution A. in the displacer "in only a small degree" means in the context of the invention that the displacer dissolves them to less than 1% by weight, preferably to less than 0.5% by weight, more preferably less than 0.1% by weight.

At the Mixing the solutions A and B in step d) have the both solution streams are the same or different Temperatures, preferably different temperatures. Especially Solution A preferably has a temperature between 50 ° C and 100 ° C, while solution B is a temperature between 0 ° C and 30 ° C has. Particularly preferred here Solution A is a temperature of 70 ° C to 90 ° C and solution B is a temperature between 0 ° C and 10 ° C. Most preferably, the temperature is from solution A about 80 ° C and the temperature of Solution B about 5 ° C.

Prefers the mixing of solution A and solution takes place B continuously, more preferably is the Mass flow ratio of solution A to solution B between 0.01 and 1, particularly preferably between 0.1 and 0.5, most preferably about 0.25.

Prefers the continuous mixing takes place by means of a mixing nozzle. Alternatively, the implementation of d), also by strong Stirring or sonication of the solutions A and B conceivable.

If it is desirable to obtain the precipitate in dry form, further treatment in a further step e) by heating and / or treatment with negative pressure in order to achieve this.

Prefers Further processing takes place in two stages. The first step includes preferably filtration, the second step preferably comprises heating, which is particularly preferably carried out under reduced pressure becomes.

Especially Preferably, the filtration is carried out so that at a negative pressure of 0.9 bar over the filter membrane no more permeate can be sucked more. The distance from Liquid by heating preferably finds Heating to 30 ° C-60 ° C, especially preferably at 40 ° C-50 ° C. Especially preferred This is also a negative pressure relative to ambient pressure of 0.2-0.5 bar applied, particularly preferred is a Negative pressure of 0.3 bar applied.

One Another object of the present invention is the use the formulation of the invention as an agent in the pharmaceutical application, or as a herbicide, fungicide, Insecticide, acaricide, nematicide, bird repellant, plant nutrient or soil conditioner improvement agent The invention will be described below explained in more detail with reference to the figures and examples but without restricting it to these.

It demonstrate:

1 the Differential Scanning Calorimetry (DSC) plot of the crystalline rivaroxaban in addition to the formulation prepared according to Example 1, where T is the temperature in degrees Celsius and W is the specific measured heat flow in watts per gram. Furthermore, X denotes a pure active substance (in this case rivaroxaban), while Y denotes its amorphous precipitate which was obtained by the present method,

2 the micrograph of the formulation prepared according to Example 2 at 40X magnification in an optical incident light microscope. The person skilled in the art recognizes the absence of crystalline fractions. To DIN EN 13925-1 one would come to the same conclusion here that an amorphous mixed phase of the formulation is present.

3 the X-ray powder diffractogram of crystalline rivaroxaban (X) next to the formulation (Y) obtained according to Example 1, shown in the obtained intensity (C) over sampled angle 2θ.

Examples:

Example 1:

It was submitted in a vessel, a volume of 1 L DMSO. In the liquid 10 g cellulose (Heweten ^®, microcrystalline cellulose, product of J. Rettenmaier & Söhne GmbH, Rosenberg) dosed and in addition weighed 80 g paraformaldehyde. With vigorous stirring, the resulting suspension was heated to 140 ° C. It was further stirred until the milky color of the suspension disappeared and the reactor contents were largely transparent. Thereafter, the obtained liquid 1 was slowly cooled to 80 ° C. In 845 ml of liquid 1 50 g Rivaroxaban ^® (product of Bayer Healthcare AG) and 20 g of Soprophor 4D384 ^® (obtained from Bayer AG, Agricultural Center Monheim) dissolved.

Furthermore, it was cooled to 5 ° C produced as a displacement means comprises a 2 wt% solution of Soprophor B ^® 4D384 in water. The two solutions were contacted in a mass flow ratio of 3/8 (A / B) in a T-mixer. The result was a white, amorphous precipitate, which was filtered off and dried overnight in a drying oven at 40 ° C and 0.3 bar vacuum. According to 1 , which represents the measurement data of the Mettler-Toledo DSC822 ^e instrument used, is clearly the lack of crystallization point of cellulose-anti-crystallization rivaroxaban conspicuous (see. DIN EN 13925-1 ). The measurement of rivaroxaban / formulation was carried out in a temperature program in which the heating phase of the sample from 25 ° C to 250 ° C / 280 ° C at 5 K / min. was carried out and the cooling back to room temperature at 2 K / min took place.

3 represents the X-ray powder diffraction of the formulation prepared according to Example 1 next to one with the same settings on the same device (transmission diffractometer from STOE & Cie GmbH with linear position sensitive detector (PSD), radiation: copper, K1, wavelength: 1.5406 Å, generator parameters: 45 kV , 35 mA measuring range in 2θ: 2-38 °, increment in 2θ: 0.2 °, measuring time: 10.0 s / step) measured X-ray powder diffractogram of the pure substance rivaroxaban dar. The skilled artisan immediately recognizes the absence of the characteristic pattern in consequence of amorphous structure. This allowed an amorphicity greater than 99% (based on the pure substance after DIN EN 13925-1 ) be determined.

Example 2:

As in Example 1, a solution 1 was prepared. In 845 ml of solution 1, 50 g of rivaroxaban were dissolved. In addition, 20 g of Pluronic ^® PE was 6800 (product of BASF Aktiengesellschaft Germany) herein dissolved. Furthermore, a cooled to 5 ° C, aqueous solution B with 2 wt% Pluronic ^® PE 6800 was prepared. In the mass flow ratio 3/8 (A / B), the solutions were brought into contact with each other analogously to Example 1. Again, a white, amorphous precipitate was formed. 2 shows the amorphous precipitate. The precipitate was filtered off and dried overnight in a drying oven at 40 ° C and 0.3 bar vacuum.

Example 3:

In An Erlenmeyer flask was charged with 1 L DMSO and heated to 80 ° C heated. In the liquid were 10 g of cellulose and 40 g of paraformaldehyde. The following was for Heated to 80 ° C for 1.5 h. After that, as in Example 2 described method. Again a white, amorphous precipitate. The work-up was carried out analogously to Example 1.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - EP 65193 A2 [0004]
• - EP 9323391 B [0004]
• WO 200565663 A1 [0005]
• - WO 2003024426 A1 [0005]
• - US 5417982 A [0005]
• EP 838218 B1 [0005]

Cited non-patent literature

• Müller et al., Pharm. Ind. 61, (1): 74-78; 1999 [0003]
• GG Liversidge et al., Int. J. Pharm. 125: 91; 1995 [0003]
• H. Auweter et al., Angew. Chem. Int. Ed. 38 (15): 2188-2191; 1999 [0004]
• - SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 [0007]
• - SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 [0007]
• - SN Danilov, Russian Chem. Rev. 39 (2): 156-168; 1970 [0008]
• - Angew. Chem. 2001, 113, 4460-4492 [0010]
• - DIN EN 13925-1 [0014]
• - DIN EN 13925-1 [0041]
• - DIN EN 13925-1 [0044]
• - DIN EN 13925-1 [0045]

Claims (16)

Formulation containing at least one solid at room temperature substance which is thermodynamically preferably crystalline under normal conditions, cellulose and / or cellulose derivatives, and optionally a surface-active substance, characterized in that the formulation is present in more than 50% in amorphous mixed phase, determined by X-ray diffractometry. A formulation according to claim 1, characterized in that they contain more than 75% in amorphous mixed phase is present, determined by X-ray diffractometry. A formulation according to any one of the claims 1 or 2, wherein the at least one used at room temperature solid substance, a pharmaceutical agent or a plant protection agent from the class of herbicides, fungicides, insecticides, acaricides, Nematicides, bird repellents, plant nutrients or soil conditioner. Formulation according to one of the preceding Claims, characterized in that the used room temperature solid substance is rivaroxaban. Process for the preparation of a formulation of a solid at room temperature, comprising the steps a) Providing a solution 1 of cellulose and / or cellulose derivative in a polar, high boiling, aprotic solvent or solvent mixture, optionally further containing at least a (semi-) acetal former b) complete release the solid at room temperature substance in solution 1, optionally together with a surfactant to form a solution A. c) Providing a protic Displacer (solution 2), optionally with a surfactant in which the solid at room temperature and those contained in solution 1 Cellulose and / or cellulose derivatives only to a small extent Let it dissolve and deal with the solvent or solvent mixture in solution 1 lets, as solution B d) mixing the solutions A and B, so that solid at room temperature and cellulose and / or Cellulose derivatives immediately in solid, amorphous mixed phase as precipitate fail. e) optional further treatment to the solid mixing phase to obtain in dry form. A method according to claim 5, characterized characterized in that the solvent or solvent mixture in solution 1, a dipole moment greater than 2.5 Debye, preferably greater than 3 Debye, more preferred larger 3.5 Debye has, is aprotic and has a boiling point at 1013 hPa above 100 ° C, preferably above 15 ° C, more preferably above 200 ° C has. A method according to claim 5 or 6, characterized in that the proportion of cellulose and / or Cellulose derivatives in solution 1 between 0.01% by weight and 2 % By weight, preferably between 0.1% by weight and 1% by weight. Method according to one of the claims 5 to 7, characterized in that solution 1 in addition contains a (half) acetal former. Method according to claims 8, characterized in that solution 1 is a (semi-) acetal former in a proportion of 1 to 10% by weight, more preferably between Contains 5 and 9 wt%, particularly preferably about 8 wt%. Method according to one of the claims 5 to 9, characterized in that solution A and / or solution B is a surfactant in a proportion of at most 5% by weight, preferably from 1% by weight to 3% by weight. Method according to one of the claims 5 to 10, characterized in that the mixing of the solutions A and B are continuous. Method according to one of the claims 5 to 11, characterized in that the solutions A and B have different temperatures. Method according to one of the claims 5 to 12, characterized in that the removal of liquid from the precipitate by means of filtration and / or heating he follows. A method according to one of Claims 5 to 10, characterized in that the at least a solid at room temperature, thermodynamically preferred, crystalline Substance is a pharmaceutical agent or a plant protection agent of Class of herbicides, fungicides, insecticides, acaricides, nematicides, Protective substances against bird disease, plant nutrients or soil conditioner. Formulation available after one of Process according to claims 5 to 14th Use of a formulation according to any of claims 1 to 4 or 15 as an agent in the pharmaceutical application, or as a herbicide, fungicide, insecticide, acaricide, nematicide, bird repellant, plant nutrient or soil structure ver bes-improver.