Pharmaceutical Formulation with Improved Solubility and Bioavailability

Abstract

The present invention relates to a pharmaceutical formulation comprising at least one active pharmaceutical ingredient (API) having low aqueous solubility or a pharmaceutically acceptable salt thereof in the form of particles of a size between 1 and 800 nm, wherein said particles are encapsulated within a large microparticle of a size between 1 and 100 .Math.m formed by a matrix comprising at least an excipient. Therefore, the API is entrapped or encapsulated in the microparticles of excipients. This pharmaceutical formulation contains the pharmaceutical active ingredient having improved solubility and subsequently supra-bioavailability.

Claims

1. A method to prepare sub-micron particles between 1 and 800 nm of at least one active pharmaceutical ingredient or pharmaceutical acceptable salt thereof encapsulated into microparticles between 1 and 100 .Math.m comprising excipients, the method practiced the method practiced in a facility comprising: an injection unit, a drying unit, which is arranged after the injection unit, and a collection unit, arranged after the drying unit; the method comprises the following stages: a) preparing of an emulsion comprising: at least one active pharmaceutical ingredient or pharmaceutically acceptable salt thereof to be encapsulated, one or more excipients; at least two non-miscible or partially miscible solvents or two miscible solvents that by solubilizing the API or the excipients become non-miscible or partially miscible solvents, b) forming droplets from the solution obtained in stage (a) in the presence of an injection gas flow; c) drying the droplets obtained in stage (b) in the drying unit at a controlled temperature to obtain microparticles; and d) collecting the microparticles obtained in stage (c) by means of the collection unit.

2. The method according to claim 1 wherein the excipient used in stage a) further comprising a surfactant to stabilize the emulsion.

3. The method according to claim 1 wherein the solvents used in step a) are selected from the list consisting of: water, alcohol, toluene, ethyl acetate, methylene chloride, chloroform, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, deep eutectic solvents, natural deep eutectic solvents and combinations thereof.

4. The method according to claim 1 wherein stage c) is carried out at a temperature between 1 and 45ºC.

5. The method according to claim 1, wherein the stage b) of forming droplets is carried out by applying a voltage of between 0.1 kV and 500 kV to the solution and injection gas flow at the outlet of the injection unit.

Description

FIGURES

[0135] FIG. 1. 1a. Shows an exemplary embodiment of the facility for industrial encapsulation of an API (or pharmaceutically acceptable salt thereof) wherein the injection unit (1), drying unit (2) and collection unit (3) can be seen.1b. Shows another exemplary embodiment of the facility for industrial encapsulation of an API (or pharmaceutically acceptable salt thereof) comprising an electric circuit (9) arranged at the droplet outlet (14) of the injection unit (1).

[0136] FIG. 2. Shows the SEM images of HPMC-valsartan microparticles obtained by the electro-nebulizer in example 1.

[0137] FIG. 3: Shows the TEM images of valsartan particles obtained by the electro-nebulizer, after dissolving the polymer in cold water in example 1.

[0138] FIG. 4. Shows the SEM images of HPMC-valsartan microparticles obtained by the electro-nebulizer in example 2.

[0139] FIG. 5. Shows the TEM images of valsartan particles obtained by the electro-nebulizer, after dissolving the polymer in cold water in example 2.

[0140] FIG. 6. Shows the SEM images of HPMC-valsartan microparticles obtained by the electro-nebulizer in example 3.

[0141] FIG. 7. Shows TEM images of valsartan particles obtained by the electro-nebulizer, after dissolving the polymer in cold deionized water in example 3.

[0142] FIG. 8. Shows SEM images of HPMC-valsartan microparticles obtained by the electro-nebulizer in example 4.

[0143] FIG. 9. Shows TEM images of valsartan particles obtained by the electro-nebulizer, after dissolving the polymer in cold deionized water in example 4.

EXAMPLES

[0144] As shown in FIG. 1, the facility for carrying out the method of encapsulation of an API comprises at least: [0145] one injection unit (1) comprising at least one injector with at least one inlet for a emulsion (6) (which already includes valsartan to be encapsulated, the encapsulating material in the case that it is used for an encapsulation process, a solvent and necessary additives), an inlet for the injection gas (8) and an outlet for droplets (14) for the emulsion that exits sprayed in droplets; [0146] one drying unit (2) arranged after the injection unit (1) and comprising at least one drying gas inlet (7) and an inlet for the droplets (11) that exit the injection unit (1); and comprising a longitudinal receptacle (12) which preferably has a cylindrical configuration, and which is arranged with its longitudinal direction horizontal and which has sufficient length to allow the evaporation of all the solvent of the droplets; and has a microparticles and drying gas outlet (13) through which microparticles pass (which are the droplets without the solvent, which has evaporated during its circulation through the drying unit); [0147] one collection unit (3) arranged after the drying unit, which is configured to separate the microparticles generated from the drying gas (it drags the solvent which has evaporated in the drying unit) and comprises an outlet for said generated microparticles (4) and an outlet for the drying gas (5).

[0148] In one exemplary embodiment of the invention, the collection unit further comprises a solvent condensing device (10), arranged at the drying gas outlet (5), downstream from the collection unit (3). In another exemplary embodiment, the facility may comprise a drying gas recirculation device that makes it possible to redirect the drying gas towards the injection unit (1) and/or the drying unit (2).

[0149] In one exemplary embodiment, the injector of the injection unit is a nebuliser consisting of a sprayer such as that described above. The injection gas flow rate, in one exemplary embodiment, is between 1 and 500 L/min. The flow rate of the injected liquid, which is in the form of emulsion, ranges preferably between 1 ml/h and 50 L/h.

[0150] In one exemplary embodiment, the facility additionally comprises a high-voltage electric circuit (9) at the outlet of the injection unit (1). The voltage used in the circuit depends on the flow rate of the injected emulsion and ranges between 100 V and 500 kV. The effect achieved is that of charging the emulsion, focusing the droplet beam and collaborating in the formation of the droplets, improving control over the size thereof. It also influences the monodispersity of the droplets, since it generates a more homogeneous size distribution. A high monodispersity may be essential to the final product, since it enables greater homogeneity in the protection or release of the API that has been encapsulated and, therefore, greater control over the encapsulation process.

[0151] In one exemplary embodiment, the drying gas flow rate ranges between 10 and 100,000 m.sup.3/h.

[0152] To this end, in these cases the facility may additionally comprise a device for pre-drying the drying gas in order for said drying gas introduced in said unit to be drier, thereby increasing the yield of the facility. In those cases where ethanol, isopropanol and other non-aqueous solutions are used drying is easier because the drying gas, typically air, does not include a solvent. Therefore, the drying gas is free from ethanol and, therefore, does not affect the speed of evaporation of the ethanol in the drying unit.

[0153] In order to control the evaporation of the solvent in the facility more efficiently, the drying unit further comprises, in one exemplary embodiment, a pressure control device that makes it possible to work at different pressures, even in a vacuum.

[0154] Preferably, the facility is designed to obtain a microparticle size ranging between 1 and 50 .Math.m in diameter. For typical drying flow rates between 10 and 100,000 m.sup.3/h, the optimum diameters and lengths of the drying unit range between 20 and 200 cm in diameter and between 20 cm and 20 m in length. In an exemplary embodiment detailed below, the drying unit comprises a cylindrical receptacle 60 cm in diameter and 2 m in length with cone-shaped inlets and outlets.

Example 1

HPMC-Valsartan Microparticles (Percentage of API in the Particle is of 30% by Weight)

[0155] In this example, the production of hydroxypropyl methyl cellulose or hypromellose (HPMC) microparticles containing sub-micron sized valsartan particles is described, using the electro-nebulizer technique, with a percentage of API in the particle of 30% by weight.

Emulsion Preparation

[0156] In this case, an oil in water (O/W) emulsion was used, with a ratio organic phase: aqueous phase of 30:70. In a first step, the aqueous phase of the emulsion is prepared. The polymer (HMPC) is dissolved in cold deionized water with a concentration of 20 mg/mL. 10 mg/mL of TEGO (TEGOⓇ SML sorbitan fatty acid ester) is added to this mixture. The organic phase of the emulsion consisted of 30 mg/mL of valsartan in chloroform. The organic phase is slowly added over the aqueous phase and stirred in the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a homogeneous size distribution of the micelles of the emulsion. During the stirring, the emulsion is maintained in a cold bath to prevent emulsion temperature from rising.

Electro-Nebulizer Process

[0157] Once the emulsion has been obtained, it is immediately used to generate microparticles by the electro-nebulizer technology. The emulsion is introduced in the drying chamber by means of the injection equipment at a flowrate of 10 mL/min. This injection equipment has an electro-nebulizer to generate an aerosol of the emulsion and, thus, guarantees an adequate evaporation of the solvent. This electro-nebulizer operates with a compressed air flow rate of 10 L/min and a voltage of 10 kV. The aerosol drops are dried by means of 85 m.sup.3/h of process air, in co-current mode, and at room temperature. The dried microparticles are collected on a cyclone.

Particle Characterization

[0158] The morphology of the microparticles obtained is studied by SEM. The HPMC-valsartan microparticles have a medium size of 4.1 .Math.m (±2.0). They are shown in FIG. 2.

[0159] In order to observe the morphology of the drug inside the HPMC microparticle, the polymer (HMPC) was dissolved in cold deionized water and the morphology of the drug is studied by Transmission Electron Microscopy (TEM). The drug exhibits a submicron size needle shape, shown in FIG. 3.

[0160] The obtained encapsulated Valsartan particles are being used for the finished product manufacturing by usage of conventional pharmaceutical techniques.

Example 2

HPMC-Valsartan Microparticles (Percentage of API in the Particle is of 63% by Weight)

[0161] In this example, the encapsulation of valsartan in HPMC is described, using the electro-nebulizer technique, with a percentage of API in the particle of 63% by weight.

Emulsion Preparation

[0162] An oil in water (O/W) emulsion was used, with a ratio organic phase: aqueous phase of 30:70. In a first step, the aqueous phase of the emulsion is prepared. The polymer is dissolved in cold deionized water with a concentration of 20 mg/mL. 10 mg/mL of TEGO (TEGOⓇ SML sorbitan fatty acid ester) is dissolved in this mixture. The organic phase of the emulsion consisted of 120 mg/mL of valsartan in ethanol 85%. The organic phase is slowly added over the aqueous phase and stirred in the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a homogeneous size distribution of the micelles of the emulsion. During the stirring, the emulsion is maintained in a cold bath to prevent emulsion temperature from rising.

Electro-Nebulizer Process

[0163] Once the emulsion has been obtained, it is immediately used to generate microparticles by the electro-nebulizer method. The emulsion is introduced in the drying chamber by means of the injection equipment at a flowrate of 10 mL/min. This injection equipment has an electro-nebulizer to generate an aerosol of the emulsion and, thus, guarantee an adequate evaporation of the solvent. This electro-nebulizer operates with a compressed air flowrate of 10 L/min and a voltage of 10 kV. The aerosol drops are dried by means of 85 m.sup.3/h of process air in co-current mode at room temperature. The dried microparticles are collected on a cyclone.

Particle Characterization

[0164] The morphology of the microparticles obtained is studied by SEM. The HPMC-valsartan microparticles are spheres with a medium size of 5.0 .Math.m (±4.1). They are shown in FIG. 4.

[0165] In order to observe the morphology of the drug inside the HPMC microparticle, the polymer was dissolved in cold deionized water and the morphology of the drug is observed by TEM. The drug exhibits a submicron size needle shape which is shown in FIG. 5.

[0166] The obtained encapsulated Valsartan particles are being used for the finished product manufacturing by usage of conventional pharmaceutical techniques. The final pharmaceutical formulations is in the form of a tablet, granulate, powder, capsule or other.

[0167] Example of a pharmaceutical composition: [0168] a) encapsulated valsartan 111 mg (microparticles of HPMC encapsulating valsartan) [0169] b) microcrystalline cellulose 40 mg [0170] c) colloidal silicon dioxide 4 mg [0171] d) sodium lauryl sulfate 1 mg [0172] e) magnesium stearate 1.6 mg [0173] f) OpadryⓇ White 5 mg

[0174] A mixture was made of encapsulated valsartan, microcrystalline cellulose, colloidal silicon dioxide, sodium lauryl sulfate with the above-mentioned quantities. The mixture was blended for 20 minutes. Magnesium stearate was sieved and added to the blended mixture and blended for an additional 5 minutes. Thereafter, the mixture was compressed into tablets using a Fette tableting press to have a suitable hardness and a friability of less than 1.0%. The tablet cores were coated with ready to use coating mixture Opadry.

Example 3

HPMC-Valsartan Microparticles (Percentage of API in the Particle is of 82% by Weight)

[0175] In this example, the encapsulation of valsartan in HPMC is described, using the electro-nebulizer, with a percentage of API in the particle of 82% by weight.

Emulsion Preparation

[0176] In this case, an oil in water emulsion (O/W) was used, with a ratio organic phase: aqueous phase is of 30:70. In a first step, the aqueous phase of the emulsion is prepared. The polymer with a concentration of 10 mg/mL was dissolved in cold deionized water. 1 mg/mL of TEGO (TEGOO SML sorbitan fatty acid ester) is dissolved in this mixture. The organic phase of the emulsion consisted of 120 mg/mL of valsartan in ethanol 85%. The organic phase is slowly added over the aqueous phase and stirred in the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a homogeneous size distribution of the micelles of the emulsion. During the stirring the emulsion is maintained in a cold bath, to prevent emulsion temperature from rising.

Electro-Nebulizer Process

[0177] Once the emulsion has been obtained, it is immediately used to generate microparticles by the electro-nebulizer method. The emulsion is introduced in the drying chamber by means of the injection equipment at a flow rate of 10 mL/min. This injection equipment has an electro-nebulizer to generate an aerosol of the emulsion and, thus, guarantee an adequate evaporation of the solvent. This electro-nebulizer operates with a compressed air flow rate of 10 L/min and a voltage of 10 kV. The aerosol drops are dried by means of 85 m.sup.3/h of process air in co-current mode at room temperature. The dried microparticles are collected on a cyclone.

Particle Characterization

[0178] The morphology of the microparticles obtained is studied by SEM. The HPMC-valsartan microparticles are spheres with a medium size of 6.1 .Math.m (±3.3). They are shown in FIG. 6.

[0179] In order to observe the morphology of the drug inside the HPMC microparticle, the polymer was dissolved in cold deionized water and the morphology of the drug is observed by TEM. The drug shows a submicron size needle shape, which is shown in FIG. 7.

[0180] The obtained encapsulated Valsartan particles are being used for the finished product manufacturing by usage of conventional pharmaceutical techniques.

Example 4

HPMC-Valsartan Microparticles (Percentage of API in the Particle is of 71% by Weight)

[0181] In this example, the encapsulation of valsartan in HPMC is described, using the electro-nebulizer, with a percentage of API in the particle of 71% by weight.

Emulsion Preparation

[0182] In this case, an oil in water emulsion (O/W) was used, with a ratio organic phase: aqueous phase of 30:70. In a first step, the aqueous phase of the emulsion is prepared. The polymer with a concentration of 20 mg/mL was dissolved in cold deionized water. 1 mg/mL of TEGO (TEGOO SML sorbitan fatty acid ester) is dissolved in this mixture. The organic phase of the emulsion consisted of 120 mg/mL of valsartan in ethanol 85%. The organic phase is slowly added over the aqueous phase and stirred in the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a homogeneous size distribution of the micelles of the emulsion. During the stirring, the emulsion is maintained in a cold bath to prevent emulsion temperature from rising.

Electro-Nebulizer Process

[0183] Once the emulsion has been obtained, it is immediately used to generate microparticles by the electro-nebulizer. The emulsion is introduced in the drying chamber by means of the injection equipment at a flowrate of 10 mL/min. This injection equipment has an electro-nebulizer to generate an aerosol of the emulsion and, thus, guarantees an adequate evaporation of the solvent. This electro-nebulizer operates with a compressed air flowrate of 10 L/min and a voltage of 10 kV. The drops of the aerosol are dried by means of 85 m.sup.3/h of process air, in co-current mode, and at room temperature. The dried microparticles are collected on a cyclone.

Particle Characterization

[0184] The morphology of the microparticles obtained is studied by SEM. The HPMC-valsartan microparticles are spheres with a medium size of 6.1 .Math.m (±3.3). They are shown in FIG. 8.

[0185] In order to observe the morphology of the drug inside the particles inside the HPMC microparticle, the polymer was dissolved in cold deionized water and the morphology of the drug is observed by TEM. The drug exhibits a submicron size needle shape, which is shown in FIG. 9.

[0186] The obtained encapsulated Valsartan particles are being used for the finished product manufacturing by usage of conventional pharmaceutical techniques.

Example 5

HPMC-Abiraterone Acetate Microparticles (Percentage of API in the Particle is of 63% by Weight)

[0187] In this example, the encapsulation of abiraterone acetate in HPMC is described, using the electro-nebulizer, with a percentage of API in the particle of 63% by weight.

Emulsion Preparation

[0188] An oil in water (O/W) emulsion was used, with a ratio organic phase: aqueous phase of 30:70. In a first step, the aqueous phase of the emulsion is prepared. The polymer is dissolved in cold deionized water with a concentration of 20 mg/mL. 10 mg/mL of TEGO (TEGOⓇ SML sorbitan fatty acid ester) is dissolved in this mixture. The organic phase of the emulsion consisted of 120 mg/mL of abiraterone acetate in ethanol 85%. The organic phase is slowly added over the aqueous phase and stirred in the ultraturrax for 5 min at 17,000 rpm, followed by 1 min of ultrasounds to achieve a homogeneous size distribution of the micelles of the emulsion. During the stirring, the emulsion is maintained in a cold bath to prevent emulsion temperature from rising.

Electro-Nebulizer Process

[0189] Once the emulsion has been obtained, it is immediately used to generate microparticles by the electro-nebulizer. The emulsion is introduced in the drying chamber by means of the injection equipment at a flowrate of 10 mL/min. This injection equipment has an electro-nebulizer to generate an aerosol of the emulsion and, thus, guarantees an adequate evaporation of the solvent. This electro-nebulizer operates with a compressed air flowrate of 10 L/min and a voltage of 10 kV. The drops of the aerosol are dried by means of 85 m.sup.3/h of process air, in co-current mode, and at room temperature. The dried microparticles are collected on a cyclone.

Finished Product

[0190] The tablet was formulated as one swallowable dosage form which is bio-equivalent to two 500 mg tablets of Zytiga Ⓡ reference product or four 250 mg tablets of Zytiga Ⓡ. The smaller strengths might be produced by using the proportional formulation for abiraterone acetate tablets made by the technology described in the present invention.