Method for producing amorphous solid dispersion in submicron range by co-precipitation

Abstract

To provide a method for producing amorphous solid dispersions in microparticle form.SOLUTION: A method comprises: (i) preparing a solution comprising at least one pharmaceutically active compound and a solution comprising at least one stabilizing agent, each solution being prepared using a first solvent; (ii) mixing the solutions with a second solvent which comprises at least one anti-solvent by means of microfluidization or a microreaction to obtain a suspension of amorphous particles by co-precipitation; and (iii) isolating the amorphous particles in a powder form using distillation, drying, spray drying, filtration, or any combination thereof to form amorphous particles having a bulk density in the range of about 0.1 g / ml to about 1.0 g / ml.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] 1. FIELD OF THEINVENTION The present invention relates to molecular contact / interaction within defined reaction chambers or microchannels. In a device that promotes The present invention relates to a method for producing an amorphous solid dispersion by carrying out co-precipitation. Amorphous solids of pharma- ceutical active compounds (APIs) in particulate form with particle sizes in the submicron range. Method for producing amorphous solid dispersions, amorphous solid dispersions obtained by said method, and their uses - Patents.com The method is useful in the pharmaceutical field, particularly for the preparation of active pharmaceutical ingredients, drug product intermediates, or drug production. The methods described herein are suitable for continuous manufacturing. This allows for the synthesis and particle engineering of solid dispersions in a single step. The amorphous microparticles thus produced exhibit advantageous properties in terms of particle size and particle density. [Background technology]

[0002] 2. BACKGROUND OF THEINVENTION Up to 90% of active pharmaceutical substances under development are poorly water-soluble and usually have low biological activity. Overcoming this and successfully converting new chemical entities into pharmaceutical drug products To facilitate this, various engineering and formulation approaches are being developed: particle design and size reduction techniques , self-emulsifying drug delivery systems, cyclodextrin complexes, amorphous solid dispersions, salt forms, and Among the various options, stabilized amorphous solid dispersions have been developed. The use of HIV-1 has become an increasingly popular platform, with numerous drugs on the market. Amorphous solid dispersions consist of at least two components, generally a stabilizer (e.g., a polymer) and The unique advantage of amorphous solid dispersions compared to other formulation strategies is the rapid absorption of the drug. Once the drug begins to dissolve in the field, a state of supersaturation is achieved, i.e., the concentration of the drug The goal is to achieve a value significantly above its intrinsic solubility. (Developability Classification System (DCS), or Biopharmaceutical Class IIa compounds according to the Biopharmaceutics Classification System (BCS) where applicable) and / or by increasing the maximum concentration of the active compound in the solution (D CS (applicable to class IIb compounds) can achieve enhanced bioavailability. When dissolution kinetics are important to achieve bioavailability, the amorphous solid dispersion The product characteristic, particle size, plays a key role in the dissolution profile of a drug product. obtain.

[0003] Various methods have been reported in the literature for the preparation of solid dispersions (e.g. spraying drying, freeze drying, hot melt extrusion) while controlling the particle size in the submicron range. The latest advances in technology that allow for the preparation of solid dispersion particles while at the same time maintaining the amorphous nature of the particles. Spray-dried particles are typically hollow, have low density, and are 2-120 mm in diameter. The particle size of the extrudate obtained by hot melt extrusion is in the micron range. High density, very coarse particles or pellets that require additional downstream processing ( For example, mill grinding).

[0004] One of the objects of the present invention is to use microreactors or microfluidics to produce active ingredients, excipients, Promotes molecular contact or interaction between the flow containing agents, e.g., stabilizers, and solvent / antisolvent systems and to provide an alternative co-precipitation process for producing high density, submicron range amorphous solids. The aim is to obtain a dispersion.

[0005] In the field of inorganic compound applications, Filipa Castro et al.'s Micro Reaction Technology (PhD thesis, "Process Intensification for Hydroxyapatite Nanoparticles Production" "The Production of Hydroxyapatite Nanoparticles", Univ. Minho, 2013) was applied. The production and properties of hydroxyapatite nanoparticles have been improved by using conventional methods such as stirred tanks. Compared with the conventional approach, Filipa Castro et al. report a surface-to-volume ratio that enhances heat and mass transfer. We observed benefits attributable to an increase in

[0006] In the field of application of pharmaceutical compounds, the state of the art includes the processing and / or crystallization of drug-free particles. US 8,367,004 B2 includes several similar approaches in the treatment of volatile substances. Hany Ali et al. disclose a method for producing crystals or polymorphs having particle sizes in the chromatic range. Iranian Journal of Pharmaceutical Research, 13 (3), 2014, 785-795) A bottom-up technique for producing nanocrystals of nido is described. Hong Zhao et al. In the paper (Ind. Eng. Chem. Res., 46 (24), 2007, 8229-8235), the activity of the submicron region was A method for producing single crystal particles of pharmaceutical ingredients has been described. The new setting for the production of the amorphous drug-only microparticle product, cefuroxime axetil The above-mentioned references disclose the details of microfluidization or microreaction and the benefits thereof. Surprisingly, evaluation of the co-precipitation of amorphous solid dispersions provides deep insight into the benefits of This has not been done at all with new technology.

[0007] The term "micro reaction" refers to a micro reactor, a micro mixer, a micro channel, or The physical and / or chemical reactions occurring within any other components contained within the microfluidic field. This document relates to technologies involved in the response.

[0008] The term "microfluidization" refers to Microfluidic Reaction Technology (MRT), which is a device-like This includes both the hardware and the process. and / or minimize diffusion limitations between single-phase and multi-phase reactant flows, thereby facilitating chemical reactions. The technology can achieve high shear, meso-mixing range and micro-mixing. Provides intense and homogeneous mixing in the range and generates nanometer-scale vortices and products The device is involved in continuous fluid processing through a fixed geometry.

[0009] The term "amorphous solid dispersion" refers to a dispersion of at least one drug in an amorphous state in a matrix. The matrix is ​​defined as a dispersion of polymers, surfactants, or mixtures thereof. Also, within the scope of the present invention, the term is used to refer to active It is used to describe a co-precipitate in the form of amorphous nanoparticles that contain both the component and the matrix. It is used.

[0010] In the case of pharmaceutical amorphous solid dispersions, the selection of the ingredients, the solvent and / or the anti-solvent system, the amount of each ingredient, The concentrations of these, as well as the mixing conditions, should be such that the composition of the precipitated particles corresponds to the intended formulation. In this process, it is crucial to the simultaneous precipitation or co-precipitation of all components. Not only does it address the difficulties in producing pharmaceutical amorphous solid dispersions, but it also addresses the problems of producing pharmaceutical amorphous solid dispersions in the submicron range. Therefore, the dissolution rate of the so-called BCS Class II compounds is also addressed. It is reasonable to address pharmaceutical compounds that are limited in both mass and / or solubility.

[0011] He is also a pioneer in the field of submicron particle production through solvent-controlled co-precipitation. There are several significant examples of new technology. US 7,0375,28 B2 uses acidified cold water to Solvent-controlled precipitation using an enteric polymer as a dispersant and The patent discloses a process in which co-precipitated particles are obtained through co-precipitation. Following the co-precipitation step, the patent also discloses a 0. The implementation of a high energy process to obtain particle sizes in the range of 4 μm to 2.0 μm is described. However, the coprecipitated particles produced through this method can be amorphous, crystalline, or semi-crystalline. It does not allow control over the solid state of the material. Furthermore, the use of a third step following the coprecipitation step The use of high-energy conditions suggests that the particle size is stabilized. Another limitation of US 7,037,528 B2 is that it is mandatory to use a surfactant in the formulation. The present invention addresses all of these limitations.

[0012] WO 2013105894A1 describes a method for mixing two streams, spraying the mixture through a nozzle and drying the mixture. A method for producing amorphous hybrid nanoparticles by subjecting the nanoparticles to a process for the preparation of amorphous hybrid nanoparticles is described. Atomizers use a supercritical fluid in one of the streams to precipitate material prior to atomization. The dried particles are collected from the sieve. This method produces amorphous solids having particle sizes in the submicron range. The addition of a compound to the supercritical fluid, typically carbon dioxide, is suitable for producing a dispersion. Treatment of feedstock with high pressure, high temperature gas mixed with supercritical fluids, limited by the solubility of the product This, combined with the challenges of reducing the amount of ethanol produced, poses a serious obstacle to commercial production.

[0013] Therefore, the inventors of the present invention have developed amorphous solid dispersions, particularly those in the submicron range. This recognizes the need to provide a method for producing In the present invention, the production of pharmaceutical amorphous solid dispersion particles with a stable size down to at least 50 nm is achieved. This can be achieved by the method of the present invention, which allows the production of a microreactor or microfluidic device. To obtain dense, submicron-range amorphous solid dispersions of the active ingredient, agglomeration is used. This technique is also suitable for continuous processing. It is possible to synthesize the components in a solvent-based and / or solvent-free manner and is easily scalable to commercial scale. Since the compounds can be dissolved in either the antisolvent system, their solubility constraints are minimized. can be. Summary of the Invention

[0014] (3. SUMMARY OF THEINVENTION) According to one embodiment of the present invention, there is provided a method for producing an amorphous solid dispersion in particulate form, comprising: (i) a solution containing at least one pharma- ceutical active compound and a solution containing at least one stabilizer; preparing solutions, each solution being prepared using a first solvent; and (ii) using microfluidization or microreaction, said solution being mixed with at least one antisolvent; and mixing the amorphous particles with a second solvent containing the amorphous particles to obtain a suspension of amorphous particles by coprecipitation. It will be offered.

[0015] Preferably, the solution containing the at least one pharma- ceutical active compound and the at least one stabilizer are Solutions containing a fixing agent are combined to form a first stream which is then mixed with the second solvent, The second solvent can be a poor solvent for both the pharma- ceutical active ingredient and the stabilizer. Preferably, the solution containing the stabilizer is combined with the second solvent to form a second stream. wherein the second stream comprises an anti-solvent for the pharma- ceutical active compound.

[0016] According to another aspect of the present invention, there is provided a method for producing an amorphous solid dispersion in particulate form, comprising the steps of: (i) a solution of at least one pharma- ceutical active compound in a first solvent, and preparing a solution containing at least one stabilizer using a second solvent; a poor solvent for the pharma- ceutical active compound; and (ii) Mixing the solutions using microfluidization or microreaction to produce amorphous particles by coprecipitation obtaining a suspension of particles.

[0017] The method includes an isolation step of isolating the amorphous particles, preferably in powder form.

[0018] According to another aspect of the present invention, the particulate amorphous solid dispersion obtained by the process of the present invention is The dispersion comprises 5-95% (w / w) of the pharma- ceutical active compound and 95-5% (w / w) of the stabilizer. The stabilizer is preferably at least one surfactant and / or polymer.

[0019] In accordance with another aspect of the present invention, a method for producing a pharmaceutical composition comprising the particulate amorphous solid dispersion as described herein. Pharmaceutical compositions are provided.

[0020] In accordance with another aspect of the present invention, there is provided a method for the preparation of a particulate amorphous solid dispersion for pharmaceutical use comprising the steps of: In particular, pharmaceutical compositions are provided.

[0021] In accordance with another aspect of the present invention, a method for increasing the bioavailability of a pharma- ceutical active compound is provided. For this purpose, a particulate amorphous solid dispersion is provided.

[0022] The above and other features and advantages of the present invention are set forth in the following detailed description of the invention and the accompanying drawings. This will be more readily understood by considering the following drawings. [Brief description of the drawings]

[0023] (4. BRIEF DESCRIPTION OF THE DRAWINGS) These drawings show some specific aspects of the embodiments of the present invention and are intended to be illustrative of the principles of the present invention. It should not be used to limit or define

[0024] [Figure 1] 1 shows a schematic representation of the process of the present invention. [Diagram 2] 1 shows XRPD patterns corresponding to itraconazole:Eudragit® L100 coprecipitates with drug loadings of 10% and 40% by weight (spectra A1 and A2, respectively). [Diagram 3] 1 shows XRPD patterns corresponding to a 10 wt % cinnarizine:Eudragit® L100 co-precipitate isolated by filtration and additionally dried in a tray dryer oven (B1), and isolated by spray drying (B2). [Figure 4]1 shows SEM micrographs at a) 1000×, b) 3000×, c) 10,000×, and b) 30,000× magnification corresponding to a 10 wt % cinnarizine:Eudragit® L100 co-precipitate product isolated by spray drying. [Diagram 5] 1 shows XRPD patterns corresponding to nilotinib:Eudragit® L100 coprecipitates with drug loadings of 10% and 40% by weight (spectra of C1 and C2, respectively). [Figure 6] 1 shows powder dissolution profiles obtained over 240 minutes for a 40% by weight nilotinib:Eudragit® L100 nano-amorphous formulation (A), a 40% by weight nilotinib:Eudragit® L100 micro-amorphous formulation (B), and crystalline nilotinib (C). [Figure 7] 1 shows the XRPD diffractograms corresponding to 20 wt % carbamazepine:Eudragit® L100 after coprecipitation (A) and after isolation by spray drying (B). [Figure 8] 4 shows SEM micrographs at a) 1500x, b) 3000x, c) 10,000x, and d) 40,000x magnification corresponding to a 20 wt% carbamazepine:Eudragit® L100 co-precipitation product. [Figure 9] 4 shows SEM micrographs at a) 500x, b) 1000x, c) 5,000x, and d) 20,000x magnification corresponding to a 20 wt% carbamazepine:Eudragit® L100 spray dried product. [Figure 10] FIG. 1 shows the in vitro dissolution profiles of powders of material produced within the scope of the present invention (nanoamorphous-A) and material produced by spray drying (microamorphous-B). [Figure 11] FIG. 1 shows pharmacokinetic profiles obtained over 180 minutes for formulations with 20% by weight carbamazepine: Eudragit® L100 nano-amorphous (A), micro-amorphous (B), and model carbamazepine in the crystalline state (C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] 5. Detailed Description of the Invention The present invention relates to a pharmaceutical composition comprising at least one pharma- ceutical active compound and at least one stabilizer, The present invention provides a method for producing amorphous solid dispersions in particulate form having particle sizes in the Cron range. do.

[0026] As shown in Figure 1, the manufacturing process can be divided into three stages: Step (i) - Select two solvents (a first solvent and a second solvent), which are compatible with the active pharmaceutical ingredient of interest. The compound is partially soluble in one of the solvents (hereafter simply referred to as the "solvent"); It is practically insoluble in the other solvent (hereafter referred to as the "poor solvent"). In a preferred embodiment, the pharma- ceutical active compound(s) and the stabilizer (i.e., The polymer(s) and / or surfactant(s) are dissolved or partially dissolved in the first solvent. and the second solvent is poorly soluble in both the pharma- ceutical active compound(s) and the stabilizer. In a preferred embodiment, the pharma- ceutical active compound(s) is dissolved in the first solvent; or partially dissolves, the second solvent being a poor solvent for the pharma- ceutical active compound(s). In a preferred embodiment, the stabilizer (i.e., surfactant, polymer) is soluble in the second solvent. and the second solvent is a poor solvent for the pharma- ceutical active compound(s). As used herein, the term "poor solvent" refers to a solvent that is substantially less soluble in the substance / compound(s). Used to describe solvents that exhibit low solubility in water. When mixed with a poor solvent, the substance does not dissolve in it but rather precipitates in the poor solvent, which is preferred. Alternatively, composite particles made of different materials may be formed.

[0027] Preferably, the term "anti-solvent" is used herein to describe a solvent or solvent mixture. wherein the substance exhibits substantially lower solubility compared to the solvent. The term "anti-solvent" is used to refer to a solvent in which the substance is completely insoluble.

[0028] Preferably, the term "solvent" is used herein to describe a solvent or mixture of solvents. is used where the substance exhibits a solubility ratio of up to 50 volume / g of solute. The term "volume / g" is a measure of the number of milliliters of solvent per gram of solute.

[0029] Those skilled in the art will appreciate that a solvent may be used as a solvent for a particular compound and as a poor solvent for another compound. It will be possible to select a solvent that can be used as the solvent.

[0030] Preferably, the term "soluble" means that 10 to 30 parts of a solvent are needed to dissolve 1 part of a solute. It means it will be necessary.

[0031] Preferably, the term "substantially lower solubility" refers to a solubility of 100 to 10% to dissolve a portion of the solute. This means that 00 parts of solvent are required.

[0032] Preferably, the term "substantially insoluble" refers to a degree of insolubility of 1000 to 10,000 times to dissolve a portion of a solute. 000 parts of a solvent are required; and the term "insoluble" means that 1 part of a solute is dissolved This means that more than 10,000 parts of solvent are required to dissolve it.

[0033] The terms "solvent" portion(s) and "solute" portion(s) are expressed in milliliters per gram of solute. This refers to the volume of a suitable solvent in liters.

[0034] In step (i), one or more solvents capable of forming a coprecipitate in at least one solvent / antisolvent system are The pharmaceutical active compound and one or more stabilizers (i.e., polymer(s) and / or surfactants) are A first stream (1) is prepared comprising a solution of one or more medicament active agents. A solution of the compound and one or more stabilizers (i.e., polymer(s) and / or surfactants) Solutions of (a) and (b) are prepared separately and then combined to form the first stream. A second stream (2) is prepared which comprises a second solvent comprising a poor solvent for the pharma- ceutical active compound and the stabilizer. To manufacture.

[0035] In a preferred embodiment, a solution of one or more stabilizers is combined with the second solvent to form the second stream. or the stabilizer can be added directly to the second solvent to form the second stream. In this case, the second solvent acts as a solvent for the stabilizer and for the pharmaceutical agent present in the first stream. It can act as a poor solvent for the pharma- ceutical active compound(s).

[0036] Preferably, the ratio of the pharma- ceutical active compound to the stabilizer present in the solution(s) is is in the range of about 95-5 (% w / w) to about 5-95 (% w / w).

[0037] Step (ii) - Microfluidizing or microreacting said first stream (1) and said second stream (2). Mixing is performed under controlled conditions in a device (3) for carrying out microfluidization. The apparatus for the present invention preferably comprises a highly selective reaction chamber or microchannel. Promoting effective molecular contact / interaction and the formation of amorphous nanoparticles by co-precipitation of materials in the two streams A microreactor or microfluidic reaction technology (MRT) device for forming the suspension (4), or any Preferably, the reaction chamber has a well-defined diameter and size. Preferably, the channel has a diameter of about 10 microns to about 400 microns. More preferably, the diameter is in the range of about 50 microns to about 200 microns. One or more devices, such as microreactor(s) or MRTs, may be used in series or parallel. The process carried in the device is preferably a continuous process. It is a process.

[0038] Preferably, the solution is continuously pumped into the reaction chamber, The solution is mixed and reacted within the reactor (continuous flow reaction).

[0039] The first and second streams are preferably pumped through one or more intensifier pumps at different rates that are individually controlled. to substantially control the interaction between the first and second streams, and thereafter The flow is fed to a device (3) for microfluidization or microreaction. Preferably, The overall flow rate, i.e. including the active substance(s), excipients (stabilizers), solvent, and anti-solvent The flow rates of the two streams are controlled by using at least one booster pump. The flow rate can be up to 50 kg / hour.

[0040] Preferably, the peristaltic pump is adapted to pump at least one of two streams, i.e. the solvent and anti-solvent streams. It can be used to control the flow rate of one stream. The flow rate of both streams can be controlled independently. and thus the flow rate of each stream can be in the range of about 0-50 kg / hr.

[0041] The first and second streams are then pumped to a combined stream using one or more boost pumps. When pressurized and delivered to the device, the first and second stream components are nano / The interaction occurs at a micro-scale level. Preferably, the pressure of this process is not limited thereto. The pressure range is not limited to, but is within the range of about 345 bar (34.5 MPa) to about 3500 bar (350 MPa).

[0042] Optimize the selection of mix ratios, process pressures, and solids concentrations to achieve the desired particle size Preferably, the mixing ratio of the solvent to the poor solvent is, but is not limited to, However, the solids concentration in the solvent mixture is within the range of about 1:2 to 1:50. Although not limited thereto, it is within the range of about 1-30% w / w.

[0043] The coprecipitation and mixing conditions, such as the solvent / antisolvent system, are preferably such that the solid amorphous phase produced is The ratio of solvent to antisolvent determines the nature, particle size, and morphology of the solvent and antisolvent used. It depends on the properties of the substance, such as the supersaturation capacity of the solvent and the precipitation rate of the substance. The ratio of the poor solvent varies from 2 to 30 times the ratio of the solvent.

[0044] Preferably, the temperature control of the solvent and anti-solvent systems is in accordance with the supersaturation capacity and precipitation rate of the material. Both are used to manipulate the solvent system and / or anti-solvent system with the components. The temperature is within the range of -10°C to 50°C, but is not limited thereto.

[0045] Step (iii) - The method of the present invention comprises the steps of: An optional isolation step ( 5). The solvent may be removed by any suitable technique known to those skilled in the art. Preferably The step of removing the solvent may be performed by distillation, drying, spray drying, filtration, or any combination thereof. The morphology of the resulting amorphous solid dispersion particles also varies depending on the parameters of the isolation process. For example, the morphology of the amorphous solid dispersion particles, e.g., the level of agglomeration, can be controlled. , the porosity of the agglomerates, and the bulk density of the powder, preferably used in a spray drying process. and / or drying at a temperature to remove excess residual solvent in the final product. It can be controlled by the process.

[0046] The method of the present invention includes a solution containing at least one pharma- ceutical active compound and at least one The method includes preparing a solution containing a stabilizer. Preferably, both the pharma- ceutical active compound and the stabilizer are A solution is prepared comprising:

[0047] The pharma- ceutical active compound and the stabilizer are non-solvent in at least one solvent and / or anti-solvent system. A crystalloid coprecipitate can be formed. The solution(s) can then be microfluidized or The second solvent is mixed with the second solvent by micro-reaction to obtain a suspension of amorphous particles by co-precipitation. The solvent comprises at least one poor solvent for the pharma- ceutical active compound and / or the stabilizer. The amorphous particles can be isolated in powder form in a known manner. The term "submicron range" in the context of the present invention means nanoparticles. It refers to particle sizes ranging from a few nm to less than 1 mm.

[0048] The particle size of the amorphous nanoparticles is within the range of about 50 nm to about 10 μm; preferably about 50 nm to about 1 μm. and more preferably within the range of about 50 nm to about 500 nm.

[0049] In a preferred embodiment, the method comprises: (i) a solution of at least one pharma- ceutical active compound in a first solvent, and preparing a solution containing at least one stabilizer using a second solvent; a poor solvent for the pharma- ceutical active compound; and (ii) Mixing the solutions using microfluidization or microreaction to produce amorphous particles by coprecipitation obtaining a suspension of the particles.

[0050] In a preferred embodiment, the method comprises: (i) at least one pharma- ceutical active compound and at least one stabilizer using a first solvent; preparing a solution comprising: (ii) using microfluidization or microreaction to the pharma- ceutical active compound and the stabilizer; The solution is mixed with a second solvent containing at least one poor solvent, and amorphous particles are formed by coprecipitation. Obtaining a suspension.

[0051] In a preferred embodiment, the method comprises: (i) a solution containing at least one pharma- ceutical active compound and a solution containing at least one stabilizer; preparing solutions, each solution being prepared using a first solvent; and (ii) subjecting the solution to a reaction using microfluidization or microreaction to the pharma- ceutical active compound and the stabilizer; The mixture is mixed with a second solvent containing at least one poor solvent for the solvent, and the amorphous particles are precipitated by coprecipitation. and obtaining a suspension. Preferably, the solutions are combined to form a single stream, Then it is mixed with the second solvent.

[0052] Preferably, the solution containing the at least one pharma- ceutical active compound and the at least one stable Solutions containing reagents are combined to form a first flow, which is then subjected to microfluidization or microreaction. Preferably, the second solvent is used to mix the pharma- ceutical active ingredient and the stabilizer. It is a poor solvent for both.

[0053] Preferably, the solution containing the stabilizer is combined with the second solvent to form a second stream. The second stream may comprise a poor solvent for the medicament active compound. A solution containing a pharma- ceutical active compound forms a first stream.

[0054] The stabilizer used in the method of the present invention comprises at least one polymer and / or at least The polymer and / or surfactant may comprise at least about 0. The surfactant may be present in an amount ranging from 0.01 to 90% (w / w). The surfactant is preferably: anionic surfactants, cationic surfactants, nonionic surfactants, and combinations thereof. The compound is selected from the group consisting of

[0055] Preferably, at a pressure sufficient to cause interaction of the components of the first and second streams. a first stream containing the pharma- ceutical active compound and the stabilizer, and combining said second stream with said anti-solvent for said component in said stream with said micro- and / or nano-solvent. The reaction chamber is adapted to react on a nanoscale to form a suspension of amorphous nanoparticles by coprecipitation. into the one or more channels in the

[0056] Preferably, at a pressure sufficient to cause interaction of the components of the first and second streams. a first stream containing the pharma- ceutical active compound, the first stream being mixed with the stabilizer and the poor affinity for the pharma- ceutical active compound; and combining said second flow containing a solvent, and said components in said flow being distributed on a micro- and / or nano-scale. reacting said first and second nanoparticles in said reaction chamber to form a suspension of amorphous nanoparticles by coprecipitation. Deliver to the above channels.

[0057] The method of the present invention is characterized in that after the interaction inside the MRT or microreactor, the combined flow The method may further comprise the step of cooling and quenching the reaction mixture.

[0058] The present invention also provides a pharmaceutical composition comprising 5 to 95% (w / w) of a medicament active ingredient and 95 to 5% (w / w), preferably bounded by the bounds of The present invention relates to a particulate amorphous solid dispersion comprising a surfactant and / or a polymeric stabilizer. The microparticles are in the range of about 50 nm to about 10 μm, preferably in the range of about 50 nm to about 10 μm, more preferably Alternatively, the particle size may be within the range of 50 nm to about 500 nm.

[0059] Preferably, the microparticles of the solid dispersion have a bulk density in the range of about 0.1 g / ml to 1.0 g / ml. Yes.

[0060] Organic compounds for use in the process of the present invention may be any compound that exhibits decreasing solubility in different solvents. The organic compound is preferably one or more medicamentously active compounds. Examples of preferred pharma- ceutical active compounds include, but are not limited to, poorly soluble Active compounds, thermolabile compounds with poor stability, or compounds requiring small particle size and high density Drug products may be mentioned.

[0061] In a preferred embodiment, the terms "low solubility," "poorly soluble," and "poorly water soluble" are used. The definition of the compound corresponds to that of the Biopharmaceutical Classification System (BCS). According to the BCS, a compound is They can be divided into four classes with regard to solubility (according to the United States Pharmacopoeia) and intestinal permeability Class I compounds have high permeability and high solubility, while Class II compounds have high permeability and Class III compounds are characterized by low permeability and high solubility; and Class IV compounds have low permeability and low solubility. Class II and Class IV.

[0062] Examples of poorly soluble compounds include, but are not limited to: intraconazole (intraconazole) Antifungal drugs such as traconazole or related drugs, e.g. fluoconazole ), terconazole, ketoconazole, and saperconazole; anti-infectives, e.g., gliocorticoids, Theofulvin and related compounds (e.g., griseoverdin); antimalarial Drugs (e.g., atovaquone); afatinib, axitinib, bosutinib, cetuximab , crizotinib, dasatinib, erlotinib, fostamatinib, gefitinib, ibrutinib nib, imatinib, zemurasenib, lapatinib, lenvatinib, mubritinib, or nilo Protein kinase inhibitors such as tinib; immune system modulating drugs (e.g., cyclosporine); Cardiovascular drugs (e.g., digoxin and spironolactone); ibuprofen; sterols or steroids; danazol, acyclovir, dapsone, indinavir, nifedipine, Nitrofurantion, phentytoin, ritonavir, Quinavir, sulfamethoxazole, valproic acid, trimethoprin, Cetazolamide, azathioprine, iopanoic acid, nalidixic acid, nevirapine, prazicanthe rifampicin, albendazole, amitruptyline, artemidine , lumefantrine, chloropromazine, ciprofloxacin , clofazimine, efavirenz, iopinavir, folic acid, glibencla amide, haloperidol, ivermectin, mebendazole, niclosamide, pyrantel, Pyrimethamine, retinol vitamins, sulfadiazine, sulfasalazine, triclava There are drugs from the group including aztreonam, ...

[0063] A detailed list of preferred groups of poorly soluble compounds includes, but is not limited to, AC E inhibitors, adenohyphoseal hormones, adrenergic neuron blockade Drugs, corticosteroids, inhibitors of corticosteroid biosynthesis, α-adrenergic receptor antagonists α-adrenergic antagonists, selective α2-adrenergic agonists, analgesics , antipyretics and anti-inflammatory drugs, androgens, anesthetics, anti-addictive drugs, antiandrogens, anti-anxiety drugs Arrhythmic drugs, antiasthmatic drugs, anticholinergic drugs, anticholinesterase drugs, anticoagulants, antidiabetic drugs, antidiarrheal drugs Drugs, antidiuretics, antiemetics and intestinal motility stimulants, antiepileptics, antiestrogens, antifungals , antihypertensives, antibacterials, antimigraine drugs, antimuscarinics, anticancer drugs, antiparasitics, antiparkinsonians Anti-inflammatory drugs, antiplatelet drugs, antiprogestin drugs, antithyroid drugs, antitussives, antiviral drugs, antibacterial drugs Antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiazides dide, β-adrenergic agonist, β-adrenergic antagonist, selective β1-adrenergic adrenergic antagonists, selective β2-adrenergic agonists, bile salts, body fluid volume and Agents acting on the composition, butyrophenones, agents acting on calcification, calcium channel blockers Drugs, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic agonists, cholinesterases Enzyme reactivators, dermatological drugs, diphenylbutylpiperidine, diuretics, ergot alkaloids, Estrogens, ganglion blockers, ganglion stimulants, hydantoins, control of gastric acidity and digestive tract Drugs for the treatment of ulcers, hematopoietic drugs, histamine, histamine antagonists, 5-hydroxytryptamine Roxytryptamine antagonists, drugs for the treatment of hyperlipoproteinemia, hypnotics and Sedatives, immunosuppressants, laxatives, methylxanthines, monoamine oxidase inhibitors, neurotransmitters Muscle blockers, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines drugs for the treatment of psychiatric disorders, retinoids, Thorium channel blockers, drugs for spasticity and acute muscle spasms, succinimides, thioxanes Antithrombotic agents, thrombolytic agents, thyroid drugs, tricyclic antidepressants, inhibitors of renal tubular transport of organic compounds, Drugs that act on uterine motility, vasodilators, vitamins, etc., or combinations of these There are a combination of active agents or bioactive compounds.

[0064] Preferably, the pharma- ceutical active compound is a tyrosine kinase inhibitor. For example, it is Xilinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, la Patinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, Selected from the group consisting of sunitinib, vandetanib, vemurafenib, and combinations thereof. It is possible.

[0065] Preferred examples of the pharma- ceutical active compounds include, but are not limited to, itraconazole, These include cinnarizine, nilotinib, carbamazepine, or combinations thereof.

[0066] Preferably, the pharma- ceutical active compound is nilotinib.

[0067] The pharma- ceutical active compound may be present in an amount ranging from about 0.1 to about 95% (w / w) of the dispersion.

[0068] In accordance with the present invention, the solvent used in the method preferably has one or more functional groups of interest. A solvent or solvents in which the organic compound, preferably a medicamentously active compound, is at least partially soluble. Also preferably, the solvent or mixture of solvents contains a stabilizer (polymer / interface The solvent is preferably a solvent in which the excipient (such as the active agent) is at least partially soluble. or an anionic surfactant, a cationic surfactant, or a nonionic surfactant. It can be provided with one or more surface modifiers (surfactants). The surfactants are A compound that reduces surface tension (or interfacial tension) between liquids or between liquids and solids Surfactants also act as cleaning agents, wetting agents, emulsifying agents, foaming agents, and / or dispersing agents. It is also possible.

[0069] Examples of such solvents include, but are not limited to: water, acetone, methyl chloride, dichloromethane, Methylformamide, methanol, ethanol, dimethyl sulfoxide (ethanoldimethy l sulfoxide), methyl ethyl ketone, dimethylacetamide, lactic acid, isopropanol , 3-pentanol, n-propanol, glycerol, butylene glycol, ethylene glycol Coal, propylene glycol, dimethyl isosorbide, tetrahydrofuran, 1,4-diisopropyl alcohol Xanthane, polyethylene glycol (1,4-dioxanepolyethylene glycol), polyethylene Licorice ester, polyethylene glycol sorbitan, polyethylene glycol monoa Alkyl ether, polypropylene glycol, polypropylene alginate, butanediol or mixtures thereof.

[0070] The antisolvent according to the invention may be miscible or immiscible with the solvent and with the substances present. In addition, the poor solvent may show low solubility or complete insolubility when mixed. One or more surface modifiers, such as, but not limited to, anionic surfactants, may be mixed therein. Aqueous solutions that may be provided with an active agent, a cationic surfactant, or a non-ionic surfactant. Preferably, the aqueous solution comprises deionized water.

[0071] Preferably, the at least one surfactant can also be used as a stabilizer. The surfactant may be, but is not limited to, an anionic surfactant, a cationic surfactant, The surfactant may be an ionic surfactant, a nonionic surfactant, or a combination thereof.

[0072] Suitable anionic surfactants include, but are not limited to, potassium laurate, Sodium lauryl sulfate, sodium dodecyl sulfate, alkyl polyoxyethylene sulf ate, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidylcholine lycolin, phosphatidylglycerol, phosphatidylinosine, phosphatidylserine phosphatidic acid and its salts, sodium carboxymethylcellulose, cholesteryl ester and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, glycodeoxycholic acid), and their salts (e.g., sodium deoxycholate, (e.g., smd), or a combination of these.

[0073] Suitable cationic surfactants include, but are not limited to, quaternary ammonium salts. compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, lauryl chloride Dimethylbenzylammonium, acylcarnitine hydrochiorides, or halo There is alkylpyndinium genide.

[0074] Suitable non-ionic surfactants include, but are not limited to, polyoxyethylene fatty acids. Fatty alcohol ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene Glycol, Polypropylene Glycol, Cetyl Alcohol, Cetostearyl Alcohol , stearyl alcohol, aryl alkyl polyether alcohol, polyoxyethylene Polyoxypropylene copolymers (poloxomers), polaxamines , methylcellulose, hydroxycellulose, hydroxypropylcellulose, hydroxy Dipropyl methylcellulose, noncrystalline cellulose, polyvinyl alcohol, glyceryl esters, and polyvinylpyrrolidone, or combinations thereof.

[0075] Preferably, a pH adjuster can be added to the anti-solvent solution. Examples of pH adjusters include These include, but are not limited to, sodium hydroxide, hydrochloric acid, Tris buffer or citrate, acetic acid Salts, lactates, meglumine, etc.

[0076] Also preferably, at least one polymer is used for stabilization of the amorphous form. Suitable polymers for use in the formulations of the present invention include, but are not limited to, However, cellulose esters, cellulose ethers, polyalkylene oxides, poly Acrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, acetic acids Vinyl polymers, oligosaccharides, polysaccharides, hydroxypropyl cellulose, polyvinylpyrrolide Hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, hydroxy Dipropyl methylcellulose, cellulose phthalate, cellulose succinate, phthalic acetate Acid cellulose, Hydroxypropyl methylcellulose phthalate, Hydroxypropyl methylcellulose Chilled cellulose acetate succinate, polyethylene oxide, polypropylene oxide , copolymers of ethylene oxide and propylene oxide, methacrylic acid / acrylic acid Ethyl Copolymer, Methacrylic Acid / Methyl Methacrylate Copolymer, Hydroxypropyl Methylcellulose succinate, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylate), gelatin, copolymer of gelatin, vinyl acetate and crotonic acid, moiety Hydrolyzed polyvinyl acetate, carrageenan, galactomannan, high viscosity gum or xanthan gum gum, or a combination of these.

[0077] In addition to the active compound and the stabilizer, the mixture may also contain additional These may include, but are not limited to, plasticizing agents. Compounds that have the effect or property of improving the dissolution profile of an active substance may include.

[0078] The particles obtained by the method of the present invention can be formulated into a pharmaceutical composition. Examples of pharmaceutical forms for administration of the amorphous solid dispersions synthesized via the methods described herein include: and solid dosage forms, such as tablets, capsules, granules, pellets, or powders. The resulting compositions have, but are not limited to, supersaturation, improved dissolution rate, controlled The composition may have enhanced properties including controlled release or taste masking.

[0079] The present invention generally provides a method for producing an amorphous solid dispersion in particulate form, comprising: At least one active pharmaceutical ingredient capable of forming an amorphous coprecipitate in a solvent and a stable preparing a solution containing the agent; The solution is mixed with at least one anti-solvent using a microreactor to produce amorphous nanoparticles. obtaining a suspension of the particles by coprecipitation, optionally followed by isolating the particles in powder form. The method may further comprise the step of: The interactions are useful in defining the amorphous nature of the nanosuspension. Mixing is enhanced using microfluidization and cavitation. and the mixing of the anti-solvent is carried out at high pressure.

[0080] Compared to conventional methods for producing amorphous solid dispersions known in the prior art, the present invention The method exhibits several advantages: it is easier to prepare solid amorphous dispersions than conventional methods, such as Spray drying and hot melt extrusion have low solubility in volatile organic solvents and / or The method of the present invention is not suitable for producing compounds having high melting points or high processing temperatures. A wide range of solvent / anti-solvent systems can be used while avoiding the need for mixing energies. Processing and formulation conditions such as grease, solvent / anti-solvent ratio, temperature, residence time, composition, and concentration to achieve desired particle properties, e.g., powder density, particle size, surface area, and dissolution rate. The suspended particles obtained by the method of the present invention are consistently in an amorphous solid state. In addition, the fine particle amorphous solid dispersions produced by the method of the present invention are in the submicron range. It is stable and has a high density.

[0081] Furthermore, the amorphous solid dispersion obtained by the method of the present invention has a stable fine particle morphology, A subsequent stabilization step is avoided.

[0082] The particle size of the nanoparticles obtained by the method of the present invention is in the submicron range and the subsequent solidification Avoid high energy processing, e.g. milling, high shear mixing, which may result in changes in the bulk state .

[0083] In addition, in the present invention, the isolation of particles can be carried out while maintaining the powder characteristics. Additionally, isolation of the particles can be performed to tailor / improve powder properties. The advantage is that the process is adaptable to continuous processing and can be easily scaled up. be.

[0084] The present invention also relates to a pharmaceutical composition comprising a particulate amorphous solid dispersion according to the present invention.

[0085] The present invention also relates to a particulate amorphous solid dispersion according to the invention for use as a medicament. The present invention relates to a pharmaceutical composition comprising:

[0086] The present invention also relates to a microparticle formulation for use in increasing the bioavailability of a pharma- ceutical active compound. This relates to amorphous solid dispersions. EXAMPLES

[0087] It is intended only to suggest a method of practicing the invention and does not serve to limit the scope of the invention. Suitable examples are described below:

[0088] Example 1 Itraconazole (BCS / DCS class IIb, Tm / Tg ~1.32, Log P 4.4) and 1:1 methacrylamide Acid-methyl methacrylate copolymer (Eudragit® L100, Evonik Rohm GmbH, D Two separate solutions of 10:90 (total mass 2 g) and 40:6 Both components (total mass 1 g) were dissolved in separate mixtures of ethanol / acetone in a volume ratio of 1:1. The total volume of the solvent was 100 mL, so each solid concentration of one of the solutions was The solid concentration in one was ~2.5 wt.%, while the solid concentration in the other was ~1.3 wt.%. The amount of deionized water used was 10 times the amount of the solvent. The pH of the water was adjusted using a hydrochloric acid solution (37%). The pH was adjusted to 2.10 and the temperature was reduced to 5 ± 2°C.

[0089] The coprecipitates were then placed in a chamber with a 75 μm diameter reaction channel followed by a 200 μm diameter reaction PureNano™ Microfluidic Reaction Technology (Model MRT The peristaltic pump was set to maintain a 1:10 ratio of solvent and antisolvent. The boost pump was set to apply a pressure of approximately 20 kPsi (138 MPa).

[0090] After the coprecipitation process, the resulting suspension was filtered using vacuum and the wet cake was dried in a tray dryer. The powder was dried in an oven at a temperature of about 70 °C for ~48 h. At the end of the drying process, the powder was submitted for solid state analysis. X-ray powder diffraction (XRPD) to assess the potential presence of crystalline material. Further analysis.

[0091] FIG. 2 shows the drug loading of itraconazole at 10% and 40% by weight: Eudragit® L10 The XRPD patterns corresponding to the 0 coprecipitates are shown (spectra A1 and A2, respectively). 8 Advance Bruker AXS Theta-2Theta diffractometer with a copper radiation source (Cu Kalpha2, wavelength = 1.5406 The measurements were performed at 2θ intervals of 3–70°, with a voltage of 40 kV and a filament emission of 35 mA. The measurements were performed with a step size of 0.017° and a step time of 50 seconds.

[0092] Both formulations exhibited the halo characteristic of the amorphous form. The characteristic peaks in the XRPD profile of were not observed in the freshly prepared product. These results indicate that itraconazole can be amorphized successfully by using the method according to the present invention. Furthermore, due to the presence of the polymer, which also provides stabilization, Amorphous formulations with drug loadings of % by weight could be produced.

[0093] Example 2 Cinnarizine (BCS class II, Tm / Tg ~1.40, Log P ~5.77) and 1:1 methacrylate-methacrylate Methyl acrylate copolymer (Eudragit® L100, Evonik Rohm GmbH, Darmst adt, Germany) was prepared. Both components in a weight ratio of 10:90 (total mass 2 grams) were mixed by volume It was dissolved in a 1:1 mixture of ethanol / acetone. The total volume of the solvent was 100 mL, so The solid concentration in the solution was 2.5% by weight. As a poor solvent, the amount of the solvent was 10 times that of the solvent. The pH of the water was adjusted to 2.10 with hydrochloric acid (37%) and the temperature was The temperature was lowered to 5 ± 2 °C. The isolation process may affect the solid state and physical stability of the final drug. To demonstrate that further treatment of the solution does not affect the The resulting suspension was divided into two equal parts - one part of the suspension was filtered and dried in a tray dryer oven. The second part was dried (under the same conditions as in Example 1) and then mixed with a laboratory-scale As in Example 1, except that the drying was performed in a spray dryer (Buchi, model B-290). The procedure was the same as described above. The spray drying unit was operated in open cycle mode ( (i.e., without recirculation of drying gas). The drying unit was stabilized with nitrogen and maintained at a stable inlet temperature (T_in = 141°C) and outlet temperature (T_out After stabilization, the suspension was pumped to the nozzle using a peristaltic pump (F _Feed = 0.44 kg / hr) and atomized at the tip of the nozzle (F_Fine = 1.4 kg / hr). The droplets were dried in a spray drying chamber with a co-current nitrogen flow (F_drying = 35 kg / h). The productive stream was directed into a cyclone and collected at the bottom. The products were analyzed by XRPD (same experimental method as in Example 1), and only the spray-dried suspension was analyzed by scanning electron microscopy. The crystals were analyzed by scanning electron microscope (SEM).

[0094] FIG. 3 shows that the granules were isolated by filtration and then dried in a tray dryer oven (B1) and sprayed. (B2), 10% by weight cinnarizine:Eudragit® L100 co-precipitation, isolated by fog drying The XRPD patterns corresponding to the samples are shown in Table 1. No significant differences were observed between both XRPD patterns. As in Example 1, both products exhibited halos characteristic of amorphous morphology, and the pure No characteristic peaks were observed in the XRPD profile of pure crystalline cinnarizine. The results show that (1) the method described in the present invention can be applied to various therapeutic agents having different physicochemical properties. (2) the ability to produce amorphous dispersions / solutions of molecules; and This suggests that the solid state is independent of the isolation process chosen. Spray drying of the suspension Drying serves as a simple method to separate particles, thus preserving the solid state and physical properties of the drug in the formulation. 4a-4d show 10 wt % cinnarizine isolated by spray drying: 1000×, 3000×, 10,000×, and 10,000×, respectively, corresponding to the Eudragit® L100 coprecipitation product. The SEM micrographs at 30,000x and 30,000x magnifications are shown in Figs. 4c and 4d. It was clear that the agglomerates consisted of individual particles, most of which had a diameter of about 100 nm. It became so.

[0095] Example 3 Nilotinib (BCS class IV, Tm / Tg ~1,28, cLog P ~4.8) and 1:1 methacrylate-methacrylate Methyl acrylate copolymer (Eudragit® L100, Evonik Rohm GmbH, Darmstad) Two separate solutions were prepared: 10:90 (total mass 2 g) and 40:60 (total mass 100 g). Both components (amount 1 g) were dissolved in separate solutions of pure ethanol (total volume of solvent was 1 00 mL, so that the solids concentration in one of the solutions is ∼2.5 wt.%, while The other solid concentration was set to 1.3 wt.%. As a poor solvent, a solution equivalent to 10 times the amount of the solvent was used. The pH of the water was adjusted to 2.10 with hydrochloric acid (37%) and the temperature was The temperature was lowered to 5 ± 2°C. Further processing of the solution was carried out according to the procedure applied in Examples 1 and 2. The process was the same as that described above, followed by vacuum filtration and a simple drying step. The resulting products were then characterized by XRPD according to the experimental methods described in the previous examples. Ta.

[0096] FIG. 5 shows Nilotinib:Eudragit® L100 co-precipitation at drug loadings of 10% and 40% by weight. The XRPD patterns corresponding to the products (spectra of C1 and C2, respectively) are shown in FIG. As in Example 2, both formulations exhibited the halo characteristic of the amorphous form, with no clear evidence of pure crystalline nilotinium. The characteristic peaks in the XRPD profile of the brew were not observed in the freshly prepared product. .

[0097] Example 4 In addition, experiments using 40% by weight nilotinib and 60% by weight Eudragit® L100 showed that The coprecipitation was carried out according to the conditions described above. The powder produced was isolated by spray drying, due to the submicron size of the particles. Hereafter, we will refer to this as nano-amorphous.

[0098] For comparison purposes, the same nilotinib-based formulation was prepared using a conventional approach by spray drying. The powder produced was subsequently referred to as micron-scale because its particles are on the micron scale. The experimental conditions were the same as those presented in Example 2.

[0099] Both powders were compared in terms of their in vitro dissolution profiles. The dissolution profile of the powder was evaluated using a USP Type II apparatus (DIS 900 mL of FaSSIF bioreleven was cultured using a 30-mL PBS (Copley Scientific, Nottingham, UK). The cells were incubated at 37 ± 100°C in t medium (pH 6.5) (biorelevant, Croydon, UK) at a paddle speed of 100 rpm. Dissolution experiments were performed using a thermostatic bath at 0.5 °C. The study was carried out with a loading of 200 mg of the target drug nilotinib. Aliquots (15 mL) of the samples were dissolved in dissolution medium Aliquots were taken at various time points (15, 30, 60, 120, and 240 min) without exchange. The pellet was immediately filtered through a 0.45 μm filter (A with a 0.45 μm hydrophilic polypropylene (GHP) membrane). The solution was filtered using a crodisc® 25 mm syringe filter, and 4.5 mL of the filtrate was subsequently diluted with 0. The filtrates were diluted with 0.5 mL of ethanol. In all cases, the filtrates were visually inspected prior to quantification. The amount of nilotinib in the medium was determined using Beer's law and the A Hitachi U-2000 double-beam UV / Vis spectrophotometer (Hitachi, Tokyo, Japan) was used to measure the The measurement was performed at 65 nm.

[0100] Prior to analysis of the in vitro dissolution results, density measurements were performed using graduated cylinders to determine the Both bulk and tap density values ​​of the microamorphous powders were obtained. The bulk densities were approximately twice as high as those previously reported (i.e., 0.432 g / mL vs. 0.215 g / mL, respectively). / mL, and tap density of 0.480 g / mL vs. 0.239 g / mL) were observed.

[0101] Spray drying is known to produce hollow particles that exhibit low density and poor flowability. The powders produced within the scope of the present invention are solid / compact and have high bulk. It has good density and good flow properties, making it ideal for downstream processing, i.e. tableting, capsule filling. I did.

[0102] FIG. 6 shows 40 wt% nilotinib: Eudragit® L100 nanoamorphous formulation (A); % Nilotinib: Eudragit® L100 micro amorphous formulation (B) and crystalline Nilotinib Shown is the powder dissolution profile of rotinib (C) obtained over a period of 240 minutes. As shown, the nano-amorphous and micro-amorphous formulations showed higher dissolution rates relative to the crystalline reference product. The solution rate was shown.

[0103] When comparing nanoamorphous vs. microamorphous, the former formulation outperformed the latter at 15 minutes. It was observed that significantly higher supersaturation levels could be reached by the solvent-controlled precipitation process. Due to the high surface area of ​​the produced nanoparticles, the increase in dissolution rate was observed in amorphous micro-solid dispersions. This favors the creation of higher levels of supersaturation when compared to

[0104] Example 5 Carbamazepine (BCS / DCS class IIa, Tm / Tg ~1,4, Log P ~2,6) and 1:1 methacrylamide Acid-methyl methacrylate copolymer (Eudragit® L100, Evonik Rohm GmbH, D A solution of 100g of 100% ethanol (Armstadt, Germany) was prepared. The weight ratio of both components was 20:80 (total mass 3 grams). The solids were dissolved in pure methanol (total volume of solvent was 44 mL, so the concentration of solids in solution was 8 The amount of deionized water used as the poor solvent was 10 times the amount of the solvent. The pH of the water was adjusted to 2.10 with hydrochloric acid (37%) and the temperature was reduced to 5±2°C. Further treatment of the solution was identical to the experimental procedures applied in the previous examples, This was followed by a spray drying step to isolate the particles. The spray drying unit was an open-sided The suspension was pumped through the nozzle in a circular mode (i.e., without recirculation of the drying gas). Prior to feeding, the spray drying unit was stabilized with nitrogen and maintained at a stable inlet temperature (T_in = ∼15 The suspension was then pumped through a peristaltic pump to ensure a stable flow rate and a stable temperature at the outlet (T_out = 6°C) and outlet temperature (T_out = ∼80°C). (F_supply = 0.81 kg / hr) was fed to the nozzle and atomized at the tip of the nozzle (atomization The droplets were then sprayed in a spray-drying chamber with a co-current nitrogen flow (F The flow containing the dried particles was directed into a cyclone. At the end of the process, the material produced was characterized by XRPD and SEM. The amorphous content is confirmed in Figure 7A. As in the previous experiment, the formulation exhibited a halo characteristic of the amorphous form. No sign of carbamazepine crystallinity was observed. Figure 8 shows SEM micrographs at various magnifications. A photograph is shown. Similar to the particles in Example 2, agglomerated particles and spherical particles were obtained. However, However, in terms of particle size number distribution, the particle size distribution is about 100 nm. A larger number of particles with larger particle sizes were observed compared to Example 2, in which Ta.

[0105] In vitro properties of amorphous nanocomposite particles produced by the methods disclosed herein To evaluate the potency of the powder, powder dissolution experiments were performed.

[0106] For comparison purposes, a formulation with 20% by weight carbamazepine: Eudragit® L100 was It was produced according to the conventional approach by spray drying. The process conditions were kept constant. A similar XRPD diffractogram was obtained, as shown in FIG. 7B. As in Example 4, spray drying was performed. The typical particle size of amorphous solid dispersions produced by drying is limited to the micron size range. This was done (Figure 9).

[0107] FIG. 10 shows the composition of the material produced within the scope of the present invention (nanoamorphous-A) and the composition produced by spray drying. The powder in vitro dissolution profile for the selected material (microamorphous-B) is presented. The dashed line at 50 min corresponds to the pH shift.

[0108] Powder dissolution profiles were obtained using a microcentrifuge pH shift dissolution method. The experiments were performed at 37°C. The experiment was carried out in a 2 mL microcentrifuge tube in a water bath at 37 °C. The simulated gastric phase was 0.9 mL 0.01N The simulated intestinal phase consisted of 0.9 mL FaSSIF biorelevent medium in a separate volume of 0.9 mL HCl (pH = 2). The combined pH values ​​were pH 6.5 (biorelevant, Croydon, UK). The pH was confirmed using test strips (pH 6-6.5). Both media were degassed and preheated to 37°C before use. Dissolution experiments were performed under non-precipitation conditions with a loading of 850 μg of the target drug under study, carbamazepine. This was performed by measuring the equilibrium concentrations of carbamazepine in the gastric and intestinal phases, respectively. Aliquots of the samples were diluted at various time points ( Samples were taken at time points (10, 20, 35, 60, 90, 150, and 180 min). The pH shift occurred at 50 min. Preparation of the test tubes for sampling consisted of removing the more recent from the water bath and Centrifuge at 13,000 rpm for 1 minute using a Hitachi Koki mac microcentrifuge CT15RE. Subsequently, 25 μL of the supernatant was aliquoted, with only 10 μL being the low volume insert. The remaining solution was diluted 15-fold in methanol in an HPLC vial containing 150 μL of the product. The test tube was vortexed for a few seconds until complete redispersion of the precipitate was observed. The water bath was then placed back in and placed at the next time point. The amount of carbamazepine dissolved in the medium was An HPLC system (Model 2695) equipped with an rs photodiode array detector (Model 2996) was used. The column used was Zorbax (registered trademark) XDB-C18 (4.6 mm × 150 mm, 3.5 μm The mobile phase was 60:40% v / v methanol and water, respectively. The injection volume was 10 μL. The flow rate was kept constant at 1 mL / min. UV absorption was measured at 285 nm. The column temperature was maintained at 25°C. Chromatographs were collected and integrated using Empower Version 2.0. Drug amounts were measured relative to standard single point injections.

[0109] As with the previous example, due to the high surface area of ​​the amorphous nanoparticles produced within the scope of the present invention, The dissolution rate was maximized compared to microamorphs produced by spray drying.

[0110] Understanding synergistic effects (nano + amorphous) on absorption and bioavailability of DCS class IIa drugs To investigate the effect of nano-amorphous and micro-amorphous formulations on the pharmacokinetics of morphine in mice, The study was carried out in.

[0111] Adult CD1 female mice (22-24 g) were purchased from Charles River (Barcelona, ​​Spain). Animals were fed standard laboratory chow and water ad libitum. All animal experiments were conducted in accordance with the local animal ethics committee. With the approval of the Commission, Portuguese Laws DR n° 31 / 92, DR 153 IA 67 / 92 and all compliant On the day of dosing, the animals were fasted for approximately 6 hours before starting the experiment. This period was considered sufficient to empty the stomach of the mice (Lab Anim. 2013, 47(4), 225-40). Mice were administered equal doses of each formulation by oral gavage, with a mean of 7.4 mg / kg body weight. Carbamazepine was administered (n = 3). The vehicle was acidified water (0.01N HCl, pH ~2). The concentration of the suspension was adjusted to contain the appropriate dose in 0.35 mL of suspension. Gastric capacity is approximately 0.4 mL, so 0.35 mL would be sufficient without overloading gastric capacity and / or This was considered to be an ideal oral administration volume to avoid reflux into the esophagus (J Pharm Pharmacol. 2008, 60(1), 63-70). The time interval between preparation of the suspension and administration of the medication was approximately 30 seconds. After dosing, mice were kept in restraining cages with free access to water. Blood samples (~1 aliquots) were administered into the retro-orbital plexus ( Blood samples were centrifuged and serum samples were kept refrigerated until assay. Serum carbamazepine concentrations were measured using the IMMULITE 2000® XPi immunoassay system. The assay was performed using a system (Siemens Healthcare Diagnostics). This assay combines chemiluminescence and immunoassay reactions. Direct conjugation of the phosphatase (ALP)-catalyzed group to the target The reaction is based on the measurement of the light produced by the dephosphorylation of the protein. Therefore, the light produced in this reaction is It is proportional to the amount of drug in the sample.

[0112] Pharmacokinetic profiles obtained over 180 min are shown in FIG. ), microamorphous (B), and crystalline states of carbamazepine (C). corresponds to the limit of quantification (LOQ) of the immunoassay method, which is 1.25 mg / L. Therefore, the LOQ of this method is Serum samples with amounts of carbamazepine below Q were processed by liquid-liquid extraction and analyzed using HPLC. Serum aliquots were transferred to 2 mL microcentrifuge tubes. 4 v / v methanol was added to each tube and mixed by vortexing for 5 min. A cloudy solution was formed due to precipitation of proteins. The samples were then centrifuged at 2,000 rpm for 5 min. The supernatant was extracted and transferred directly to an HPLC vial equipped with a low volume insert (150 μL). Each sample was analyzed using the HPLC conditions described above. The dashed and dotted line in Figure 11 indicates the extraction process. The carbamazepine concentration obtained in serum samples assuming a 60% yield from the This average yield value corresponds to the maximum value of the positive samples, i.e., above the LOQ of the immunoassay. The determination was made by applying the extraction method to the circulating sample. The nanoamorphous systems produced according to the scope of the present invention show a significantly improved drug delivery in mice compared to crystalline drugs. Enhanced bioavailability was observed in

[0113] The observed differences can be explained by the difference in particle size between the formulations. The high surface area of ​​the nano-amorphous particles It results in a very fast dissolution rate when exposed to gastrointestinal fluids, thus resulting in a larger amount in solution. of carbamazepine.

Claims

1. 1. A method for producing an amorphous solid dispersion in particulate form comprising: (i) a solution containing at least one pharma- ceutical active compound and a solution containing at least one stabilizer; preparing solutions, each solution being prepared using a first solvent; and (ii) using microfluidization or microreaction, said solution being mixed with at least one antisolvent; and mixing the resulting solution with a second solvent containing the amorphous particulates to obtain a suspension of amorphous particulates by co-precipitation.

2. A solution containing the at least one pharma- ceutically active compound and the at least one stabilizer.

2. The method of claim 1, wherein the first stream is formed by combining the solutions containing the first solvent and then mixing the solutions with the second solvent. method.

3. The second solvent is a poor solvent for both the pharma- ceutical active ingredient and the stabilizer. The method described in item 2.

4. 12. The method of claim 1, wherein the solution containing the stabilizer is combined with the second solvent to form a second stream. The method described.

5. The method of claim 4 , wherein the second stream comprises an anti-solvent for the pharma- ceutical active compound.

6. 6. The method of claim 4 or 5, wherein the solution containing the pharma- ceutical active compound forms a first stream.

7. 1. A method for producing an amorphous solid dispersion in particulate form comprising: (i) a solution of at least one pharma- ceutical active compound in a first solvent, and preparing a solution containing at least one stabilizer using a second solvent; a poor solvent for the pharma- ceutical active compound; and (ii) Mixing the solutions using microfluidization or microreaction to produce amorphous particles by coprecipitation obtaining a suspension of the particles.

8. 8. The method according to claim 1, further comprising an isolation step of isolating the amorphous particles in powder form. The method described in section .

9. The amorphous particles are formed by distillation, drying, spray drying, filtration, or any combination thereof. The method of claim 8, wherein the compound is isolated.

10. 10. The method of claim 1, wherein the amorphous particles are nanoparticles having a particle size in the submicron range. The method according to any one of the preceding claims.

11. 11. The method of claim 10, wherein the particle size is in the range of about 50 nm to about 10 μm.

12. 10. The method of claim 1, wherein the particle size is in the range of about 50 nm to about 1 μm, or in the range of 50 nm to about 500 nm.

1. The method described in claim 1.

13. The stabilizer is at least one polymer and / or at least one surfactant. The method according to any one of claims 1 to 12.

14. The polymer and / or surfactant are in the range of about 0.001 to 90% (w / w) of the dispersion.

14. The method of claim 13, wherein said compound is present in an amount of

15. The polymer is: cellulose ester, cellulose ether, polyalkylene oxide , polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol , vinyl acetate polymers, oligosaccharides, polysaccharides, hydroxypropyl cellulose, polyvinylpyrrolidone rolidone, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, Hydroxypropyl methylcellulose, cellulose phthalate, cellulose succinate, acetic acid Cellulose Phthalate, Hydroxypropyl Methylcellulose Phthalate, Hydroxypropyl Pyrmethylcellulose acetate succinate, polyethylene oxide, polypropylene Oxide, copolymers of ethylene oxide and propylene oxide, methacrylic acid / acrylic acid Ethyl methacrylate copolymer, methacrylic acid / methyl methacrylate copolymer, hydroxypropyl propyl methylcellulose succinate, butyl methacrylate / 2-dimethyl methacrylate Aminoethyl copolymer, poly(hydroxyalkyl acrylate), poly(hydroxya Copolymer of vinyl acetate, gelatin, crotonic acid, partially hydrolyzed Degraded polyvinyl acetate, carrageenan, galactomannan, high viscosity gum or xanthan 15. The method of claim 13 or 14, wherein the active ingredient is selected from the group consisting of: gum, and combinations thereof.

16. The surfactant may be an anionic surfactant, a cationic surfactant, or a non-ionic surfactant.

15. The method of claim 13 or 14, further comprising a surfactant.

17. The anionic surfactant is: potassium laurate, sodium lauryl sulfate, dodecyl sulfate, Sodium alginate, Sodium dimethyl ether sulfate, Sodium polyoxyethylene sulfate, Dioctyl sodium sulfosuccinate, phosphatidylcholine, phosphatidylglycerol rol, phosphatidylinosine, phosphatidylserine, phosphatidic acid, and the like salts, sodium carboxymethylcellulose, cholic acid, deoxycholic acid, glycosyltransferase Cholic acid, taurocholic acid, glycodeoxycholic acid, and their salts, deoxycholic acid 17. The method of claim 16, wherein the hydroxypropyl phosphate group is selected from the group consisting of sodium phosphate, sodium phosphate dihydrate ...

18. The cationic surfactant is: a quaternary ammonium compound (benzalkonium chloride), Cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride, acyl carnitine hydrochloride, or alkylpindinium halide, and combinations thereof.

17. The method of claim 16, wherein the compound is selected from the group consisting of:

19. The nonionic surfactant is: polyoxyethylene fatty alcohol ether, polyoxyethylene fatty alcohol ether, Diethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, sorbitan Esters, glycerol monostearate, polyethylene glycol, polypropylene glycol Recall, Cetyl Alcohol, Cetostearyl Alcohol, Stearyl Alcohol, Ali alkyl polyether alcohol, polyoxyethylene-polyoxypropylene copolymer poloxomer, polaxamine, methylcellulose, hydroxycellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Amorphous cellulose polyvinyl alcohol, glyceryl esters, and polyvinylpyrrolidone, and The method of claim 15, wherein the compound is selected from the group consisting of a combination of:

20. Any of claims 1 to 19, wherein the first solvent may be the same or different for each solution. The method according to any one of claims 1 to 10.

21. 21. Any one of claims 1 to 20, wherein the first solvent and / or the second solvent comprises a solvent mixture. The method described in section .

22. 22. Any one of claims 1 to 21, wherein the first and second solvents may be the same or different. The method described.

23. The first and / or second solvent is: water, acetone, methylene chloride, dimethylformamide, Methanol, ethanol, dimethyl sulfoxide, methyl ethyl ketone, dimethylacetone Amides, lactic acid, isopropanol, 3-pentanol, n-propanol, glycerol, Ethylene glycol, ethylene glycol, propylene glycol, dimethyl isosorbide , tetrahydrofuran, 1,4-dioxane, polyethylene glycol, polyethylene glyco esters, polyethylene glycol sorbitan, polyethylene glycol monoalkyl ether, polypropylene glycol, polypropylene alginate, butanediol, 23. The method of any one of claims 1 to 22, wherein the compound is selected from the group consisting of: and mixtures thereof.

24. The method of any one of claims 1 to 23, wherein the anti-solvent comprises an aqueous solution.

25. 25. The method of claim 24, wherein the aqueous solution is deionized water.

26. The method according to any one of claims 1 to 25, further comprising adding a pH adjuster to the anti-solvent. method.

27. The pH adjuster is: sodium hydroxide, hydrochloric acid, Tris buffer, or citrate, acetate, 27. The method of claim 26, wherein the compound is selected from the group consisting of lactate, meglumine, and combinations thereof. Law.

28. 28. The method according to claim 1, wherein the medicament is a tyrosine kinase inhibitor. Method of posting.

29. The tyrosine kinase inhibitor is: axitinib, crizotinib, dasatinib, erlotinib, Nib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, and 29. The method of claim 28, selected from the group comprising combinations thereof.

30. The method of any one of claims 1 to 29, wherein the pharma- ceutical active compound is nilotinib.

31. the pharma- ceutical active compound is present in an amount ranging from about 0.1 to about 95% (w / w) of the dispersion; The method of any one of claims 1 to 30.

32. A plasticizing compound is added to improve the dissolution profile of the pharma- ceutical active compound. The method according to any one of claims 1 to 31.

33. The microfluidization or microreaction may be carried out using at least one microfluidic reaction technique (MRT 33. The method of any one of claims 1 to 32, wherein the method is accomplished using a microreactor.

34. 34. The method of claim 33, wherein the MRT and the microreactor comprise a reaction chamber.

35. The reaction chamber comprises one or more channels, each of which has a diameter of about 10 microns to about 400 microns.

35. The method of claim 34, having a diameter in the micron range.

36. 36. The method of claim 35, wherein the channel has a diameter in the range of about 50 microns to about 200 microns. method.

37. 37. The method according to claim 31, wherein the MRT or the microreactor is arranged in series or in parallel. The method according to any one of the preceding claims.

38. Any one of claims 33 to 37, wherein the MRT or the microreactor is a continuous flow reactor. The method described in section .

39. The solution is continuously pumped into the reaction chamber, and the solution is continuously pumped into the reaction chamber. The method of any one of claims 33 to 38, wherein the liquids are mixed and reacted (continuous flow reaction).

40. said pharmaceutical agent at a pressure sufficient to cause interaction of the components of said first and second streams; The first stream containing an active compound and the stabilizer is subjected to a pressure change test for the pharma- ceutical active compound and the stabilizer. and combining said second stream with said anti-solvent to react and co-precipitate the components in said stream into a non-aqueous solution. into the one or more channels in the reaction chamber to form a suspension of crystalloid particles. The method of any one of claims 31 to 39.

41. said pharmaceutical agent at a pressure sufficient to cause interaction of the components of said first and second streams; The first stream containing the active compound is mixed with the stabilizer and the poorly soluble solubility agent for the pharma- ceutical active compound. and combining said second stream containing a solvent, and the components in said stream react to form amorphous particles by coprecipitation. into the one or more channels in the reaction chamber to form a suspension.

40. The method according to any one of items 33 to 39.

42. 40. The method of claim 40, wherein the pressure is in the range of about 345 bar (34.5 MPa) to about 3500 bar (350 MPa). Or the method described in 41.

43. Cooling the combined stream after interaction within the MRT and / or microreactor.

43. The method of any one of claims 33 to 42, further comprising:

44. 5-95% (w / w) of said pharmaceutical active ingredient and 95-5% (w / w) of said stabilizer.

44. A particulate amorphous solid dispersion obtainable by the process according to any one of items 1 to 43.

45. The stabilizer comprises at least one surfactant and / or at least one polymer.

45. The particulate amorphous solid dispersion of claim 44.

46. 44. The method of claim 43, wherein the microparticles comprise nanoparticles having a particle size in the range of about 50 nm to about 10 μm.

45. A fine particle amorphous solid dispersion according to claim 45.

47. Claim 4, wherein the particle size is in the range of about 50 nm to about 1 μm; or in the range of 50 nm to about 500 nm.

7. The particulate amorphous solid dispersion according to claim 6.

48. 45. The method of claim 44, wherein the microparticles have a bulk density in the range of about 0.1 g / ml to about 1.0 g / ml. Fine particle amorphous solid dispersions.

49. 49. A pharmaceutical composition comprising the particulate amorphous solid dispersion of any one of claims 44 to 48.

50. A particulate amorphous solid dispersion according to any one of claims 44 to 48 for use as a medicament. A pharmaceutical composition comprising the product.

51. Any of claims 44 to 48 for use in increasing the bioavailability of a medicament active compound.

3. The particulate amorphous solid dispersion according to claim 1.

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