HK1188130A

HK1188130A - Pharmaceutical compositions

Info

Publication number: HK1188130A
Application number: HK14101215.1A
Authority: HK
Inventors: K．J．贝托弗; J．P．卡特斯特拉; F．盖斯帕
Original assignee: 沃泰克斯药物股份有限公司
Priority date: 2006-03-20
Filing date: 2014-02-11
Publication date: 2014-04-25

Description

Pharmaceutical composition

The present application is a divisional application of an invention patent application having an application date of 2007, 3/19, application No. 200780018279.4 and an invention name of "pharmaceutical composition".

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. application serial No. 60/784, 275 filed on 3/20/2006 and U.S. application serial No. 60/871, 692 filed on 12/22/2006. The disclosure of the prior application is considered part of the disclosure of the present application (and is incorporated herein by reference).

Technical Field

The invention relates to a pharmaceutical composition and a preparation method thereof.

Background

It is known in the pharmaceutical art that low solubility drugs often exhibit poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, dietary status of the patient, and the form of the drug.

Solid dispersions of the drug in the matrix can be prepared as follows: a homogeneous solution or melt of the drug and matrix material is formed and the mixture is then solidified by cooling or removal of the solvent. Solid dispersions of such drugs often exhibit enhanced bioavailability when administered orally as compared to oral compositions comprising undispersed drug.

Spray drying is the most widely used industrial process involving particle formation and drying, and can be used to produce solid dispersions of pharmaceutical compounds. It is very suitable for the continuous production of dry solids in the form of powders, granules or agglomerates from liquid feedstocks such as solutions, emulsions and pumpable suspensions. Spray drying is therefore an ideal process, in which the end product must meet precise quality criteria in terms of particle size distribution, residual water content, bulk density and particle shape.

Spray drying generally involves atomizing a liquid feedstock into a mist of droplets, which are contacted with hot air or gas in a drying chamber. The mist is typically generated by a rotary (wheel) or nozzle atomizer. Under controlled temperature and gas flow conditions, moisture is evaporated from the droplets and dried particles are formed.

Summary of The Invention

The present inventors have discovered that during spray drying of a drug (e.g., VX-950) or other therapeutic agent (e.g., a drug or a solid dispersion of a therapeutic agent), varying the solvent (e.g., including a non-volatile or high boiling point solvent) can improve the properties of the resulting product (e.g., a solid dispersion such as an amorphous solid dispersion of a drug or therapeutic agent). In some instances, the inclusion of a non-volatile or high boiling solvent as a component of the solvent mixture during spray drying may result in an increase in the amount of time required for the resulting particles to solidify and/or dry, thus in some instances providing improved particles, e.g., particles that are larger and/or denser and/or more fluid than the same particles that have been obtained using a solvent system that does not contain a non-volatile or high boiling solvent. In some cases, inclusion of a non-volatile or high boiling point solvent as a component of the solvent mixture during spray drying may aid in dissolving components (e.g., surfactants or polymers) present in the feedstock solution (e.g., the solution or suspension to be spray dried). Spray drying to produce a solid dispersion may be performed, for example, on a homogeneous solution, melt, or suspension of the drug and matrix material, followed by solidification of the mixture by cooling or removal of the solvent.

In one aspect, the methods include a method of spray drying a drug (e.g., VX-950) or other therapeutic agent, the method comprising forming a mixture of the drug in a suitable solvent or combination of solvents, wherein at least one of the solvents is a non-volatile or high boiling solvent, to form a mixture of the drug and the solvent, and then spray drying the mixture to obtain an amorphous drug product. The resulting pharmaceutical product may have a bulk density of, for example, about 0.25 to about 0.50, such as about 0.35 to about 0.45, such as about 0.37 or about 0.41. The resulting pharmaceutical product may have a d50 of, for example, about 35 to about 55, such as about 40 to about 50, such as about 43 or about 47. The mixture may be a solution or a suspension.

In some embodiments, the methods comprise a method of spray drying a drug (e.g., VX-950) or other therapeutic agent, the method comprising, forming a mixture of the drug in a suitable solvent or combination of solvents, wherein at least one of the solvents is a non-volatile or high boiling solvent, to form a mixture of the drug and the solvent, and then spray drying the mixture to obtain an amorphous drug product, with the proviso that the drug is not N- [2, 4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxamide.

In some embodiments, the drug is a small molecule drug, e.g., a drug having a molecular weight of less than about 1000 daltons, e.g., less than about 750 daltons or less than about 500 daltons.

In some embodiments, the drug is a poorly soluble drug.

The drug may be selected from one of the classes of analgesics, anti-inflammatory agents, antihelminthics, antiarrhythmics, antibacterials, antivirals, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastics, erectile dysfunction modifiers, immunosuppressants, antiprotozoals, antithyroids, anxiolytics, sedatives, hypnotics, neuroleptics, beta-blockers, inotropes, corticosteroids, diuretics, antiparkinsonism agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, antianginals, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, antiobesity agents, cognitive enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostatic hypertrophy agents, essential fatty acids, or non-essential fatty acids.

In some preferred embodiments, the medicament is an antiviral agent, e.g., an antiviral agent for the treatment of hepatitis c (HepC), e.g., a HepC protease inhibitor. In some most preferred embodiments, the agent is VX-950:

VX-950。

in some embodiments, the solvent is a combination of solvent components comprising at least one non-volatile solvent. For example, the solvent is a combination of components including a volatile solvent and a non-volatile solvent.

Examples of suitable volatile solvents include solvents that dissolve or suspend the drug, either alone or in combination with another co-solvent. In some preferred embodiments, the solvent or solvent combination completely dissolves the drug.

Examples of volatile solvents include dichloromethane, acetone, chloroform, and THF. Examples of the non-volatile solvent include organic acids such as glacial acetic acid, DMSO, DMF, and water.

In some embodiments, the non-volatile solvent is a component of the solvent system. For example, the non-volatile solvent is present at about 0.1% to about 20% (by weight) (e.g., about 0.5% to about 3%, about 1% to about 5%, about 3% to about 15%, about 4% to about 12%, or about 5% to about 10%) as a component in the solvent.

In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination (e.g., methylene chloride and acetone) and a non-volatile solvent (e.g., glacial acetic acid). For example, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

In some embodiments, the solvent system comprises glacial acetic acid.

In some embodiments, the solvent system comprises glacial acetic acid in combination with at least one volatile solvent such as acetone and/or dichloromethane (e.g., dichloromethane and acetone mixtures).

In some embodiments, the mixture also includes a surfactant, for example, Sodium Lauryl Sulfate (SLS) or vitamin E or a derivative thereof (e.g., vitamin E TPGS).

In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination (e.g., methylene chloride and acetone) and a non-volatile solvent (e.g., water). For example, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% water (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 1% to about 5% water).

In some embodiments, the solvent system comprises water.

In some embodiments, the solvent system comprises water in combination with at least one volatile solvent such as acetone and/or dichloromethane (e.g., a mixture of dichloromethane and acetone).

In another aspect, the spray drying process comprises forming a solid dispersion of a drug (e.g., VX-950) and one or more polymers, comprising forming or providing a mixture of the drug and the polymers in a suitable solvent or solvent combination, wherein at least one solvent is a non-volatile or high boiling point solvent, to form a mixture of the drug, the polymers, and the solvent, and then spray drying the mixture to obtain a solid dispersion drug product. The resulting pharmaceutical product may have a bulk density of, for example, about 0.25 to about 0.50, such as about 0.35 to about 0.45, such as about 0.37 or about 0.41. The resulting pharmaceutical product may have a d50 of, for example, about 35 to about 55, such as about 40 to about 50, such as about 43 or about 47. The mixture may be a solution or a suspension. In a preferred embodiment, the solid dispersion product is an amorphous solid dispersion. For example, an amorphous solid dispersion that is substantially free of crystalline drug product.

Examples of polymers for the solid dispersion include one or more water soluble polymers or partially water soluble polymers. Water soluble or partially water soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC; also known as hypromellose), Hydroxypropylcellulose (HPC)) or ethylcellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), acrylates, such as polymethacrylates (e.g.,E) cyclodextrins (e.g., beta-cyclodextrin) and their copolymers and derivatives, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate).

In some preferred embodiments, the polymer is Hydroxypropylmethylcellulose (HPMC), such as HMPC60SH50, HPMC E50 or HPMCE 15.

In some embodiments, the polymer is a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., Cellulose Acetate Phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS; also known as hypromellose acetate succinate), carboxymethylcellulose (CMC) or salts thereof (e.g., sodium salts such as (CMC-Na)), Cellulose Acetate Trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MC)AP), or polymethacrylates (e.g.,S)。

in some preferred embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), e.g., HMPC AS-HG.

In another embodiment, the polymer is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (e.g., crospovidone).

In another embodiment, the polymer is polyvinylpyrrolidone (PVP).

In some embodiments, the polymer is a mixture of 2 or more polymers (e.g., a combination of 2 cellulosic polymers such as HPMC and HPMCAS).

In some embodiments, the polymer is present in the solid dispersion in an amount of about 30% to about 70% (by weight).

In some embodiments, the drug is a poorly soluble drug.

In some preferred embodiments, the medicament is an antiviral agent, e.g., an antiviral agent for the treatment of HepC, e.g., a HepC protease inhibitor. In some most preferred embodiments, the agent is VX-950:

VX-950。

in some embodiments, the solvent is a combination of solvent components comprising at least one non-volatile solvent. For example, the solvent is a combination of components comprising a volatile solvent and a non-volatile solvent.

In some embodiments, the non-volatile solvent is a component in a solvent system. For example, the non-volatile solvent is present as a component in the solvent in an amount of about 0.1% to about 20% (by weight) (e.g., about 0.5% to about 3%, about 1% to about 5%, about 3% to about 15%, about 4% to about 12%, or about 5% to about 10%).

In some embodiments, the mixture also comprises a surfactant, for example, Sodium Lauryl Sulfate (SLS) or vitamin E or a derivative thereof (e.g., vitamin E TPGS).

In another aspect, the process includes,

a) forming or providing a mixture of a poorly water soluble drug (e.g., VX-950), at least one polymer, and a solvent system comprising at least one non-volatile solvent, and

b) spray-drying the mixture to form a solid dispersion comprising the poorly water-soluble drug to obtain a solid dispersion of the drug.

The resulting dispersion may have a bulk density of, for example, about 0.25 to about 0.50, such as about 0.35 to about 0.45, such as about 0.37 or about 0.41. The resulting dispersion may have a d50 of, for example, about 35 to about 55, such as about 40 to about 50, such as about 43 or about 47.

VX-950。

in some embodiments, the solvent is a solvent combination comprising at least one non-volatile solvent. For example, the solvent is a combination of components including a volatile solvent and a non-volatile solvent.

Examples of volatile solvents include dichloromethane, acetone, chloroform, THF.

Examples of the non-volatile solvent include organic acids such as glacial acetic acid, DMSO, DMF, and water.

In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination (e.g., methylene chloride and acetone) and a non-volatile solvent (e.g., glacial acetic acid). For example, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid). In some preferred embodiments, the solvent mixture comprises from about 40% to about 80% dichloromethane, from about 20% to about 35% acetone, and from about 0.1% to about 15% water (e.g., from about 50% to about 70% dichloromethane, from about 25% to about 30% acetone, and from about 1% to about 5% water).

In a preferred embodiment, the solvent mixture comprises about 75:24:1 weight percent of dichloromethane to acetone to non-volatile solvent.

Examples of polymers for the solid dispersion include one or more water soluble polymers or partially water soluble polymers. Water soluble or partially water soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropyl)Methyl Cellulose (HPMC), hydroxypropyl cellulose (HPC)) or ethyl cellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), acrylates, such as polymethacrylates (e.g.,E) cyclodextrins (e.g., beta-cyclodextrin) and their copolymers and derivatives, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate).

In some preferred embodiments, the polymer is Hydroxypropylmethylcellulose (HPMC), such as HPMC60SH50, HPMC E50 or HPMC E15.

In some embodiments, the polymer is a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., Cellulose Acetate Phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or salts thereof (e.g., sodium salts such as (CMC-Na)), Cellulose Acetate Trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g.,)。

in some preferred embodiments, the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), e.g., HPMC AS-HG.

In another embodiment, the polymer is polyvinylpyrrolidone (PVP).

In some embodiments, the polymer is present in the solid dispersion in an amount of about 30% to about 90% (by weight).

In another aspect, the invention provides a method of preparing a solid dispersion of VX-950, comprising:

a) forming or providing a solution of VX-950, a cellulosic polymer, and a solvent, wherein the solvent comprises at least one non-volatile solvent component (e.g., glacial acetic acid);

b) spray drying the mixture to form a solid amorphous dispersion comprising VX-950 and the cellulosic polymer.

In some embodiments, the polymer is HPMC, HPMCAS, or a mixture thereof. In some preferred embodiments, the polymer is HPMCAS, or a mixture of HPMC and HPMCAS.

In some preferred embodiments, the solvent system is a combination of a volatile solvent or solvent combination (e.g., methylene chloride and acetone) and a non-volatile solvent (e.g., glacial acetic acid or water). For example, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid). For example, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% water (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 1% to about 5% water).

In some embodiments, the solvent comprises a mixture of dichloromethane, acetone, and glacial acetic acid.

In some embodiments, the solvent comprises a mixture of dichloromethane, acetone, and water.

a) forming or providing a mixture of VX-950, at least one cellulosic polymer, and a solvent, wherein the solvent comprises glacial acetic acid, and

b) spray drying the mixture to form a solid dispersion comprising VX-950. The resulting dispersion may have a bulk density of, for example, about 0.25 to about 0.50, such as about 0.35 to about 0.45, such as about 0.37 or about 0.41. The resulting dispersion may have a d50 of, for example, about 35 to about 55, such as about 40 to about 50, such as about 43 or about 47.

a) forming or providing a mixture of VX-950, at least one cellulosic polymer, and a solvent, wherein the solvent comprises water, and

b) spray drying the mixture to form a solid dispersion comprising VX-950.

In some embodiments, the solvent also comprises a volatile solvent, or a combination of solvents that dissolve or suspend the drug and polymer. In some preferred embodiments, the solvent or solvent combination completely dissolves the drug and polymer.

In some preferred embodiments, the solvent comprises a mixture of dichloromethane and acetone. In some embodiments, glacial acetic acid is present in the solvent in an amount of from about 0.1% to about 20% (by weight) (e.g., from about 3% to about 15%, from about 4% to about 12%, or from about 5% to about 10%) as a component.

In some embodiments, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

In some preferred embodiments, the solvent comprises a mixture of dichloromethane and acetone. In some embodiments, water is present in the solvent as a component in an amount of about 0.1% to about 20% (by weight) (e.g., about 3% to about 15%, about 4% to about 12%, or about 1% to about 10%).

In some embodiments, the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% water (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 1% to about 5% water).

In one aspect, the invention provides a product made by the method described herein. Such as a solid dispersion of a drug (e.g., VX-950), such as an amorphous solid dispersion of a drug (e.g., VX-590). For example, amorphous solid dispersions are provided that include a drug (e.g., VX-950), at least one polymer, and optionally one or more solubility enhancing surfactants (e.g., SLS or vitamin E TPGS). The dispersion can improve the aqueous solubility and bioavailability of the drug (e.g., VX-950) upon oral administration of the solid dispersion to a mammal (e.g., rat, dog, or human). In certain aspects, at least a portion of the drug (e.g., VX-950) in the solid dispersion is in an amorphous state (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%). In a preferred embodiment, the solid dispersion is substantially or essentially free of a crystalline drug (e.g., VX-950).

In a preferred embodiment, the solid dispersion prepared by the methods described herein comprises about 45% to about 85% VX-950, about 5% to about 25% of an HPMC polymer, such as HPMC60SH50, about 5% to about 30% of an HPMCAS polymer, such as HPMCAS-HG, and about 0.1% to about 10% of a surfactant, such as SLS or vitamin E or derivatives thereof (e.g., vitamin E TPGS), wherein the HPMC and HPMCAS together comprise about 90%, about 95%, about 98%, about 99%, or about 100% of the total polymer present.

In a preferred embodiment, the solid dispersion prepared by the method described herein exhibits a predetermined level of physical and/or chemical stability. For example, the solid dispersion retains about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99% of amorphous VX-950 when stored at 25 ℃ in a closed, water-tight container (e.g., a brown glass bottle or a High Density Polyethylene (HDPE) container).

It will be appreciated that the spray drying may be carried out in the presence of an inert gas. In some embodiments, the process comprising spray drying can be carried out in the presence of a supercritical fluid (comprising carbon dioxide or a mixture of carbon dioxide).

As used herein, "poorly soluble drug" refers to a drug that is substantially completely water insoluble or water insoluble. The term applies to any beneficial therapeutic agent having a dose (mg) to aqueous solubility (mg/ml) ratio of greater than 100ml, where drug solubility is the solubility of the neutral (e.g., free base or free acid) form in unbuffered water. This definition includes, but is not limited to, drugs that are substantially insoluble in water (less than 1.0 μ g/ml).

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Brief Description of Drawings

Figure 1 is a schematic flow diagram of the spray drying process, control, sampling and testing.

Fig. 2 is an outline of the spray drying process.

The table in fig. 3 provides the properties of a spray-dried VX-950 solid dispersion in an aqueous solvent system.

FIG. 4 is a flow chart of the production process, control, sampling and testing.

Detailed Description

Spray drying method

And (5) spray drying. A preferred embodiment of the present invention comprises an amorphous solid dispersion obtained by spray drying, wherein the solvent mixture of the starting materials comprises at least one non-volatile solvent (e.g., glacial acetic acid or water). Thus, in another embodiment, the present invention provides drying the product obtained by spray drying to remove the solvent.

The pharmaceutical composition can be obtained by spray drying a mixture comprising the drug (e.g., VX-950), a suitable polymer, and a suitable solvent system. Spray drying is a process which involves atomizing a liquid mixture containing, for example, a solid and a solvent, and removing the solvent. Atomization may be achieved by, for example, nozzles or on a rotating disk.

Spray drying is a process of converting a liquid feed into a dry particulate form. Optionally, a secondary drying process, such as fluidized bed drying or vacuum drying, may be used to reduce residual solvent to pharmaceutically acceptable levels. Generally, spray drying involves contacting a highly dispersed liquid suspension or solution with a sufficient volume of hot air or gas to evaporate and dry the liquid droplets. The article to be spray dried may be any solution, suspension, coarse suspension, slurry, colloidal dispersion or paste which may be atomized using the selected spray drying apparatus. In one standard operation, the product is sprayed into a stream of warm filtered air or gas, which evaporates the solvent and transports the dried product to a collector (e.g., a cyclone, or directly to a membrane filter bag). The off-gas is then depleted with solvent or alternatively sent to a condenser for capture and efficient recycling of solvent. Spray drying can be carried out using commercially available types of equipment. For example, commercial spray dryers are produced by Buchi Ltd. and Niro (e.g., PSD series spray dryers produced by Niro) (see, US2004/0105820; US 2003/0144257). For example, a pressure nozzle, a two-fluid electrostatic nozzle, a two-fluid nozzle or a rotary atomizer may be used.

Spray drying typically employs a solids loading of material (i.e., drug and excipients) of about 0.5% to about 30%, preferably at least about 10%. In some embodiments, loadings of less than 10% can result in light or porous dispersions or low bulk densities or unacceptably long run times. Generally, the upper limit of solids loading is determined by the viscosity (e.g., pumpability) of the resulting solution and the solubility of the components in the solution. In general, the viscosity of the solution may determine the size of the particles in the resulting powder product.

Techniques and methods for spray drying can be found in Perry's Chemical engineering handbook, 6 th edition, r.h.perry, d.w.green & J.O. Maloney, eds.), McGraw-Hill book co (1984), and Marshall "organization and spread-Drying" 50, chem.eng.prog.monogr.series2 (1954). Generally, spray drying is carried out with an inlet temperature of from about 40 ℃ to about 200 ℃, e.g., from about 45 ℃ to about 150 ℃, preferably from about 50 ℃ to about 100 ℃, e.g., about 50 ℃. Spray drying is typically carried out with an outlet temperature of from about 15 ℃ to about 100 ℃, e.g., from about 20 ℃ to about 75 ℃, e.g., about 27 ℃.

Removal of the solvent requires subsequent drying steps, such as tray drying, fluidized bed drying (e.g., about room temperature to about 100 ℃, e.g., about 60 ℃), vacuum drying, microwave drying, rotary drum drying, or double cone vacuum drying (e.g., about room temperature to about 100 ℃, e.g., about 60 ℃ or less).

Fluidized spray drying. Another preferred embodiment of the present invention comprises amorphous solid dispersions obtained by fluidized spray drying, wherein the solvent mixture of the starting materials comprises at least one non-volatile solvent (e.g., glacial acetic acid or water). Thus, in another embodiment, the present invention provides drying the product obtained by fluidized spray drying to remove the solvent.

The process of fluidized spray drying combines spray drying and fluidized bed drying techniques. Agglomerated powders are obtained on the basis of an integrated fluidized bed or belt and multistage process, wherein the moist powder produced in the first drying stage forms agglomerates, which are dried and cooled in subsequent stages. Briefly, a pressure nozzle, a two-fluid electrostatic nozzle, a two-fluid nozzle, or a rotary atomizer sprays feed into a fluidized bed into a spray dryer. Agglomeration occurs in the spray dryer incorporating the refined, recycled material and agglomerated particles fall into the bed. The exhaust outlet passes through the ceiling causing further agglomeration in the spray zone. Viscous products can be successfully dried, a process that is ideal for drying heat sensitive products, achieving improved aroma retention. This process produces a lumpy, free-flowing powder with minimal fineness.

As an example, in a spray dryer, the feed is sprayed into the drying air from an atomizing nozzle fixed at the top of the drying chamber and down into the spray chamber. The vigorous fluidization of the moist powder in the fluidized bed at the bottom of the chamber and the recirculation of fines from the cyclone attachment results in spray drying in the powder laden gas. Since the resulting powdering effect overcomes the problem of powder binding, higher water content granules can be processed in the drying chamber. Drying can be carried out at lower power and exhaust gas temperatures, thereby improving product quality while achieving higher thermal efficiency. The degree of agglomeration and particle size distribution can be influenced by varying the operating conditions and the location of reintroduction of fines into the drying chamber. By optimizing the operating conditions, dispersions having properties that are advantageous for downstream processing (e.g., direct compression) can be obtained.

For conventional spray drying, non-volatile solvents (e.g., glacial acetic acid, DMSO, DMF, or water) may be used for the FSD process.

Although embodiments of the present invention relate to the use of non-volatile solvents in spray drying, it should be understood that fluidized spray drying processes are also suitable and may be used in the embodiments described herein.

A detailed description of Fluidized Spray Drying of VX-950 is provided in a provisional application entitled Fluidized Spray Drying filed 2006, 12/22 (attorney docket No. 19079 and 016P 01).

Solvent(s)

In general, there is a direct relationship between bulk density/flowability and residual solvent; the higher the bulk density/better the flowability, the higher the residual solvent. In some cases, the particle size and density can be manipulated by varying the amount of time required for the particles to solidify and/or dry. Thus, inclusion of a non-volatile (or high boiling) solvent in the mixture can provide a particulate product with improved properties. For example, the addition of glacial acetic acid or water to a solvent system comprising a volatile organic solvent can provide larger and/or denser particles than those produced without the use of glacial acetic acid or water. The larger and/or denser particles may have improved flow properties, which may be desirable for downstream formulation of the particles, for example, to form an oral dosage form such as a tablet or capsule. In some embodiments, the solvent system provides particles that solidify after at least about 5 seconds, at least about 7 seconds, at least about 10 seconds, at least about 12 seconds, at least about 15 seconds, at least about 20 seconds, or more.

In addition, it may be advantageous to optimize powder flowability and bulk density and/or to use secondary drying to remove residual solvent. In one embodiment of the invention, the solid dispersion is dried in a fluidized bed. In some embodiments, it has been found that fluidized bed drying at about 40 ℃ to about 80 ℃, e.g., about 40 ℃ to about 60 ℃, e.g., about 45 ℃ for about 8 hours can be effective in providing the best effect of certain solid dispersions of VX-950. In other embodiments, for example, fluid bed drying at 45 ℃ for about 4 hours using HPMCAS as the polymer in the solid dispersion is already effective to provide acceptable levels of residual solvent in the final product.

In a preferred method, the solvent includes a volatile solvent and a non-volatile solvent. In some embodiments, the solvent comprises a mixture of volatile solvents. Preferred solvents include solvents that can dissolve VX-950 and the polymer (when present) and/or the surfactant (when present). Suitable solvents include those described above, for example, dichloromethane, acetone, and the like.

In the embodiment of spray-dried or fluidized spray-dried VX-950, a preferred solvent includes a mixture of dichloromethane, acetone, and glacial acetic acid.

In other embodiments of spray-drying or fluidized spray-drying VX-950, a preferred solvent includes a mixture of dichloromethane, acetone, and water.

In some cases, the solvent may react with the material to be spray dried (e.g., a compound of interest, such as a drug or therapeutic agent). Thus, in some embodiments, when preparing a feed solution containing a compound of interest, a solvent that does not react with the compound is preferred. For example, an alcohol can react with a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) to form a ketal. Thus, when preparing a feed solution containing a target compound, a solvent that does not react with (specifically forming a ketal) the compound (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) is preferred. Such solvents should not contain OH groups or similar reactive moieties. Because of the reactivity of certain compounds (e.g., VX-950), the preferred solvent for use in the solvent system of the present invention for preparing a feed solution containing such compounds is not polyethylene glycol (e.g., PEG8000) (i.e., except for polymers having free hydroxyl moieties).

In another preferred embodiment, the non-volatile solvent is water. Dichloromethane: acetone: an exemplary weight percentage of water is 75:24: 1.

In some cases, the non-volatile solvent (e.g., water) facilitates dissolution of components, such as surfactants (e.g., SLS), present in the mixture undergoing spray drying.

In another preferred embodiment, the non-volatile solvent (e.g., water) has a higher bulk density.

In some embodiments, the non-volatile solvent is a component in a solvent mixture. For example, the non-volatile solvent is present as a component in the solvent in an amount of about 1% to about 20% (by weight) (e.g., about 1% to about 5%, about 3% to about 15%, about 4% to about 12%, or about 5% to about 10%). In other embodiments, the non-volatile solvent (e.g., water) is present in an amount of about 0% to about 5%, such as about 1%.

In some preferred embodiments, the solvent mixture is a combination of a volatile solvent or solvent combination (e.g., methylene chloride and acetone) and a non-volatile solvent (e.g., water or glacial acetic acid). For example, the solvent mixture comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid). As another example, the solvent mixture comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 1% to about 15% water (e.g., about 50% to about 70% dichloromethane, about 25% to about 30% acetone, and about 1% to about 5% water). Dichloromethane: acetone: an exemplary weight percentage of non-volatile solvent (e.g., water) is 75:24: 1.

Because of the reactivity of VX-950, a preferred polymer in embodiments that include VX-950 is not polyethylene glycol (e.g., PEG8000) (i.e., other than a polymer having free hydroxyl moieties).

The solvent, particle size and temperature drying range can be modified to produce the optimum solid dispersion. The skilled person will appreciate that small particle sizes will result in faster solvent removal. The applicant has found that smaller particles can result in loose particles which do not provide an optimum solid dispersion for downstream processing such as tabletting. At higher temperatures, crystallization or chemical degradation of VX-950 may occur. At lower temperatures, a sufficient amount of solvent cannot be removed.

Particle size distribution and density (e.g., bulk density and/or tap density) may be optimized, for example, by varying one or more of the following parameters, outlet temperature and feed pressure. The suitability of the parameter variable can be evaluated. For example, to evaluate the suitability of the outlet temperature, the temperature may be increased (e.g., to 30 ℃) while keeping all other process parameters unchanged. Comparing the properties (e.g., density) of the dispersion obtained using this elevated temperature spray drying with the properties of the dispersion prepared according to the invention (e.g., an outlet temperature of 25 ℃), it can be evaluated whether a change in temperature is beneficial (e.g., a change may be beneficial if the change results in an increase in the desired property (e.g., increased bulk density).

Other parameters that may be varied and optimized during spray drying (e.g., in a similar manner) include the selection of non-volatile solvents, the percentage of non-volatile solvents used, the selection of volatile solvents, the percentage of volatile solvents used (e.g., the total percentage and/or the ratio of each volatile solvent to the other solvent (if more than one volatile solvent is used)), the selection of surfactants, the percentage of surfactants used, the selection of polymers, the percentage of polymers used, the selection of atomizers, the solution feed rate, the cyclone pressure differential, the order of solids addition, the percentage of solids loading, and/or the inlet temperature. If post-spray drying is carried out, the choice of drying process, the duration of the drying process, the speed of the dryer, the drying temperature, the drying pressure, and/or the drying time can be optimized.

The nature of the solvent can be modified to optimize particle size and density. For example, increasing the amount of high boiling (or non-volatile) solvent components in the solvent may increase the length of time required for solidification and/or drying of the resulting spray-dried particles. Thus, where larger and/or denser particles are desired, it is desirable to increase the amount of high boiling (or non-volatile) solvent. The nature of the high boiling or non-volatile solvent may also vary depending on the nature of the dispersed particles and/or the desired properties of the drug. For example, a desirable high boiling or non-volatile solvent increases the solubility of the drug or other component (e.g., surfactant, e.g., SLS; or polymer) in solution, does not chemically react with or promote chemical degradation of the drug (or surfactant or polymer, if present). For example, organic acid solvents are not suitable for drugs that are acid sensitive or have acid sensitive moieties. The process herein provides for optimal particle size and optimal drying temperature.

Examples of volatile solvents include ketones, alcohols, acetonitrile, dichloromethane, acetone, chloroform and THF. The skilled artisan will appreciate that the choice of solvent depends, at least in part, on the solubility of the composition (e.g., drug or other therapeutic agent) in the solvent and/or the reactivity of the composition (e.g., functional group) with the particular solvent.

Examples of the non-volatile solvent include organic acids such as toluene, glacial acetic acid, DMSO, DMF, and water. The choice of solvent depends, at least in part, on the solubility of the composition (e.g., drug or other therapeutic agent) in the solvent and/or the reactivity of the composition (e.g., functional group) with the particular solvent. The term "non-volatile solvent" as used herein refers to a liquid having a boiling point greater than 80 ℃ at 1 atm.

To evaluate the suitability of a solvent, the choice of solvent can be varied while keeping all other process parameters unchanged. Comparing the properties (e.g., density) of the dispersion obtained using this modified solvent spray drying to the properties of the dispersion prepared according to the invention using the solvents described herein (e.g., water as the non-volatile solvent), it can be evaluated whether a change in solvent is beneficial (e.g., a change may be beneficial if the change results in an increase in the desired properties (e.g., increased bulk density)). In a similar manner, the amount of a given solvent (e.g., water as the non-volatile solvent) can also be evaluated, for example, by comparing the resulting product to a product produced using the amount of solvent described herein (e.g., 1% water as the non-volatile solvent).

Polymer and method of making same

The product to be spray dried or fluidized spray dried (e.g., an agglomerated product such as a powder or particle), e.g., a solid dispersion (e.g., an amorphous solid dispersion) comprising a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950), can comprise one or more polymers (or a solid state carrier).

The methods of spray drying and FSD using the nonvolatile solvents described herein can be used to prepare solid dispersions (e.g., amorphous solid dispersions) containing a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950). In addition, the mixture to be dried containing the solvent (e.g., volatile and non-volatile solvents) and the target compound (e.g., drug) may also contain one or more polymers (or solid state carriers).

One or more polymers may be used with the subject compounds as part of an amorphous solid dispersion system. For example, the polymer may be present in a feed solution (e.g., a solution to be dried by fluidized spray drying) with a target compound (e.g., a drug). Without being bound by theory, the presence of the polymer may help prevent, reduce, or slow the amount or rate of crystallization of the target compound (e.g., drug) compared to the amount or rate of crystallization that occurs in the absence of the polymer. For example, the amount of crystallization may be reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or by at least about 99% when the polymer is used, as compared to the amount of crystallization in the absence of the polymer. For example, the one or more polymers may protect the drug from crystallization in aqueous media (e.g., gastric and/or intestinal fluids). For example, HPMC can help reduce (e.g., the amount of a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950)) that crystallizes at low pH (e.g., in gastric fluid). HPMC can provide protection in gastric fluid (e.g., fasted or fed gastric fluid) and simulated gastric fluid ("SGF") (e.g., fasted or fed SGF). As another example, HPMCAS may provide increased physical stability and reduce (e.g., the amount of a compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950)) crystallization in intestinal fluid (e.g., fasting or fed intestinal fluid) and simulated intestinal fluid ("SIF") (e.g., fasting or fed SIF). As a result, one or more of the following may be enhanced: bioavailability, solubility and absorption of a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950).

In addition, by reducing the rate of crystallization, the polymer can increase the storage stability of the composition, e.g., the stability of a dispersion or solid form (e.g., a directly compressed form, e.g., a tablet) containing a compound of interest (e.g., a drug, e.g., a poorly soluble drug, such as VX-950) obtained by spray drying or FSD is increased by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) as compared to the stability of the composition without the use of the polymer. The polymer can increase the stability of the solid dispersion (e.g., when stored at 4 ℃ or at room temperature) by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) as compared to the solid dispersion stored under the same conditions and in the absence of the polymer.

Furthermore, without being bound by theory, the presence of multiple polymers can help prevent, reduce, or slow the amount or rate of crystallization of a compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950) as compared to the amount or rate of crystallization that occurs in the presence of one polymer. For example, the amount of crystallization may be reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% when a plurality of polymers are used, as compared to the amount of crystallization in the presence of one polymer. For example, various polymers may protect the drug from crystallization in aqueous media (e.g., gastric or intestinal fluids). For example, one polymer, e.g., HMPC or HPMCAS, or multiple polymers, e.g., a mixture comprising HPMC and HPMCAS, may provide increased protection for a given dispersion of VX-950: for example, HMPC can protect VX-950 from crystallization in gastric fluid or SGF, while HPMCAS can protect VX-950 from crystallization in intestinal fluid or SIF. As a result, use of the mixture can provide improved bioavailability, solubility, and/or absorption of the compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950). In addition, a plurality of polymers can increase the storage stability of the composition, e.g., the stability of a solid form (e.g., a spray-dried dispersion, a directly compressed dosage form, e.g., a tablet) containing a compound of interest (e.g., a drug, e.g., a poorly soluble drug, e.g., VX-950) is increased by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) as compared to the stability of the composition without the use of the polymer. The plurality of polymers can increase the stability of the solid dispersion (e.g., when stored at 4 ℃ or at room temperature) by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) as compared to a solid dispersion that is stored under the same conditions and does not contain the polymer.

One or more polymers (e.g., comprising one or more cellulosic polymers) can be used to provide a particular form of a compound of interest (e.g., a drug, e.g., a poorly soluble drug, e.g., VX-950) such that, when administered, the area under the curve (AUC) of the compound of interest (e.g., a drug, e.g., a poorly soluble drug, e.g., VX-950) is substantially the same in both fasted and fed subjects, e.g., reducing or substantially eliminating food effects in the subjects.

In one embodiment, one or more polymers, or one or more polymers of the plurality of polymers of the present invention, are capable of being dissolved in an aqueous medium. The solubility of the polymer may be pH independent or pH dependent. The latter includes one or more enteric polymers. The term "enteric polymer" refers to a polymer that is preferentially soluble in the low acid environment of the intestine as compared to the high acid environment of the stomach, e.g., a polymer that is insoluble in acidic aqueous media, but soluble at a pH greater than 5-6. Suitable polymers should be chemically and biologically inert. To improve the physical stability of the solid dispersion, the glass transition temperature (Tg) of the polymer(s) (e.g., the polymers, or one or more of the polymers) should be as high as possible. For example, preferred polymers have a glass transition temperature that is at least equal to or greater than the glass transition temperature of the compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950). Other preferred polymers have glass transition temperatures in the range of about 10 to about 15 ℃ of the target compound (e.g., drug, e.g., poorly soluble drug, e.g., VX-950). Examples of suitable glass transition temperatures for the polymer include at least about 55 ℃, at least about 60 ℃, at least about 65 ℃, at least about 70 ℃, at least about 75 ℃, at least about 80 ℃, at least about 85 ℃, at least about 90 ℃, at least about 95 ℃, at least about 100 ℃, at least about 105 ℃, at least about 110 ℃, at least about 115 ℃, at least about 120 ℃, at least about 125 ℃, at least about 130 ℃, at least about 135 ℃, at least about 140 ℃, at least about 145 ℃, at least about 150 ℃, at least about 155 ℃, at least about 160 ℃, at least about 165 ℃, at least about 170 ℃, or at least about 175 ℃ (measured under dry conditions). Without wishing to be bound by theory, it is believed that the underlying mechanism is that polymers with higher Tg generally have lower molecular mobility at room temperature, which is a key factor in stabilizing the physical stability of amorphous solid dispersions.

In addition, the hygroscopicity of the polymer (or polymers, or one or more of the polymers) should be as low as possible. For comparison purposes herein, the hygroscopicity of a polymer, polymer combination, or composition is characterized by a relative humidity of about 60%. In some preferred embodiments, the polymer has less than about 10% water uptake, e.g., less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% water uptake. Cellulosic polymers typically have about 3% water uptake, while PVP typically has about 9% water uptake. Hygroscopicity can also affect the physical stability of solid dispersions. In general, moisture absorbed in the polymer can greatly reduce the Tg of the polymer and the resulting solid dispersion, which can further reduce the physical stability of the solid dispersion described above.

In one embodiment, the one or more polymers, or one or more of the polymers in the plurality of polymers, are one or more water soluble polymers or partially water soluble polymers. Water soluble or partially water soluble polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC; also known as hypromellose), Hydroxypropylcellulose (HPC)) or ethylcellulose, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), acrylates, such as polymethacrylates (e.g.,E) cyclodextrins (e.g., beta-cyclodextrin) and their copolymers and derivatives, including, for example, PVP-VA (polyvinylpyrrolidone-vinyl acetate). In some preferred embodiments, the polymer or one of the polymers is Hydroxypropylmethylcellulose (HPMC), such as HPMC E50 (e.g., from Dow), HPMCE15 or HPMC60SH5OcP (e.g., Shin-Etsu Metholose, HPMC60SH 50). HPMC is available from Shin-Etsu in various types, including SM, 60SH, 65SH, 90 SH. The difference between each of these types is the viscosity grade and the methoxy and hydroxypropyl contents. One most preferred type for use in spray dispersions is HPMC60SH。

In some embodiments, the one or more polymers, or one or more of the polymers, are pH-dependent enteric polymers. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., Cellulose Acetate Phthalate (CAP)), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate (HPMCA), carboxymethylcellulose (CMC) or salts thereof (e.g., sodium salts such as (CMC-Na)), Cellulose Acetate Trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g.,in some preferred embodiments, the polymer or one of the polymers is hydroxypropylmethylcellulose acetate succinate (HPMCAS). HPMCAS is available from Shin-Etsu in various grades, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. The difference in each of these grades is the percentage of substitution of acetate and succinate. One most preferred grade for use in spray dispersions is AS-HG from Shin-Etsu.

Other polymers of HPMCAS and HPMCA having different degrees and combinations of substitution of hydroxypropyl, methoxy, acetyl and succinyl groups are also known in the art (see, e.g., WO2005/115330), and may be used in the invention described herein. For example, a polymer of HPMCAS in which the degree of substitution of succinyl groups on HPMCAS (DOS) may be used_s) Degree of substitution with acetyl (DOS)_Ac) Is DOS_sGreater than or equal to about 0.02, DOS_AcGreater than or equal to about 0.65 and DOS_Ac+DOS_sGreater than or equal to about 0.85. As another example, a HPMCA polymer in which the degree of substitution of acetyl groups on the polymer (DOS) may be used_Ac) Is about 0.6 or less, or the degree of substitution of acetyl groups on the polymer (DOS)_Ac) Is at least about 0.15. In other placesIn embodiments, HPMCA polymer having a solubility parameter of about 24.0(J/cm) or less may be used.

In another embodiment, the polymer or one or more of the polymers is an insoluble cross-linked polymer, such as polyvinylpyrrolidone (e.g., crospovidone).

In some cases, the polymer may be reacted with the target compound. Thus, in some embodiments, when preparing a feed solution containing a target compound, polymers that do not react with the compound are preferred. For example, an alcohol can react with a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) to form a ketal. Thus, when preparing a feed solution containing a compound of interest, polymers that do not react with (specifically form ketals) the compound (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) are preferred. Such polymers should not contain OH groups or similar reactive moieties. Because of the reactivity of certain compounds (e.g., VX-950), the preferred polymer for use in various polymers or as a polymer of the invention to prepare a feed solution containing such compounds is not polyethylene glycol (e.g., PEG8000) (i.e., other than a polymer having free hydroxyl moieties).

In embodiments where the compound of interest (e.g., a drug, e.g., a poorly soluble drug, e.g., VX-950) and one or more polymers (e.g., VX-950 and an HPMC and/or HPMCAS polymer) form a solid dispersion (e.g., a lumpy product), the total amount of polymer is typically at least about 5% (e.g., about 4% or 6%), at least about 10% (e.g., 9% or 11%), at least about 15% (e.g., 14% or 16%), at least about 20% (e.g., 19% or 21%), and preferably at least about 30% (e.g., about 29% or 31%), e.g., at least about 35% (e.g., about 34% or 36%), at least about 40% (e.g., about 39% or 41%), at least about 45% (e.g., about 44% or 46%), or at least about 50% (e.g., about 49% or 51%), relative to the total weight of the solid dispersion. The amount is generally about 99% or less, preferably about 80% or less, for example about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less. In one embodiment, the amount of polymer is up to about 30% (and more specifically, about 28% to 32%, e.g., about 29%) of the total weight of the dispersion. In one embodiment, the amount of polymer is up to about 35% (and more specifically, about 33% to 37%, e.g., about 34%) of the total weight of the dispersion. In one embodiment, the amount of polymer is up to about 40% (and more specifically, about 38% to 42%, e.g., about 39%) of the total weight of the dispersion. In one embodiment, the amount of polymer is up to about 45% (and more specifically, about 43% to 47%, e.g., about 44%) of the total weight of the dispersion.

Solid dispersions (e.g., agglomerated products) containing a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) can contain a variety of polymers. For example, 2 polymers may be used in the dispersion. In some embodiments, the plurality of polymers may include one or more than one cellulosic polymer. For example, the spray dried dispersion may comprise 2 cellulosic polymers, for example HPMC and HPMCAS. In some embodiments, the solid dispersion comprises a mixture of HPMC and HPMCAS. The amount of each polymer used in the dispersion can vary, as can the ratio of the polymers to each other. For example, the dispersion may comprise from about 0% to about 100% (by weight) of the first polymer (e.g., HPMC) and from about 0% to about 100% (by weight) of the second polymer (e.g., HPMCAS) (where the sum of the percentages (by weight) of the 2 polymers amounts to 100% of the total polymers present in the dispersion). For example, in a solid dispersion of VX-950 containing a polymer, the first polymer is present in an amount of about 33% and the second polymer is present in an amount of about 67% of the total amount of polymer added. In another example, the first polymer is present in an amount of about 55.5% and the second polymer is present in an amount of about 44.5% of the total amount of polymer added. In another example, the first polymer is present in an amount of about 63% and the second polymer is present in an amount of about 37% of the total amount of polymer added. In another example, the first polymer is present in an amount of about 50% and the second polymer is present in an amount of about 50% of the total amount of polymer added. In another example, the first polymer is present in an amount of about 100% and the second polymer is present in an amount of about 0% of the total amount of polymer added.

In one of the various embodiments of the present invention, one of the polymers is polyvinylpyrrolidone (PVP) (e.g., PVP 29/32). PVP may be present in an amount up to about 35%, up to about 40%, up to about 45%, or up to about 50%. Dispersions containing about 50% (e.g., about 49.5%) PVP K29/32 are included in the present invention.

In another embodiment, the invention encompasses solid dispersions (e.g., agglomerated products) of a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) and a cellulosic polymer (e.g., an HPMC or HPMCAS polymer). In some preferred embodiments, the compound (i.e., VX-950) is present in an amount of at least about 50%, such as at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or more of the dispersion. In some preferred embodiments, the drug is present in an amount of about 55% to about 90%, e.g., about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%. The polymer is present in an amount of at least about 5%, at least about 10%, at least about 15%, and preferably at least about 20%, such as at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%. In some embodiments, the amount is generally about 55% or less, and preferably about 50% or less, such as about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, or about 10% or less.

In another embodiment, the invention encompasses solid dispersions (e.g., agglomerated products) of a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) and at least 2 cellulosic polymers (e.g., HPMC and/or HPMCAS polymers). In some preferred embodiments, the compound (i.e., VX-950) is present in an amount of at least about 50%, such as at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or more of the dispersion. In some preferred embodiments, the drug is present in an amount of about 55% to about 70%, e.g., about 55%, about 60%, about 65%, or about 70%. As noted above, the polymer is present in an amount of at least about 15%, and preferably at least about 20%, e.g., at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%. In some embodiments, the amount is generally about 55% or less, and preferably about 50% or less, such as about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, or about 10% or less.

In some preferred embodiments, the dispersion further comprises other minor ingredients, such as surfactants (e.g., SLS or vitamin E TPGS). In some preferred embodiments, the surfactant is present in an amount of less than about 10% (by weight), such as less than about 9% (by weight), less than about 8% (by weight), less than about 7% (by weight), less than about 6% (by weight), less than about 5% (by weight), less than about 4% (by weight), less than about 3% (by weight), less than about 2% (by weight), or about 1% (by weight) of the dispersion.

In a most preferred embodiment, the dispersion comprises about 49.5% VX-950, about 49.5% HPMCAS and about 1% SLS.

The one or more polymers should be present in an amount effective to stabilize the solid dispersion. Stabilization includes inhibiting or reducing crystallization of a compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950). Such stabilization inhibits the conversion of the compound from the amorphous to the crystalline form. For example, the polymer may prevent at least a portion (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more) of the compound from changing from amorphous to crystalline form.

For example, in low pH (e.g., in gastric juice (e.g., fasted gastric juice) or SGF (e.g., fasted SGF)), a compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950) can dissolve, become supersaturated, and then crystallize. The one or more polymers may prevent or reduce crystallization of the compound under such or similar conditions or during storage of a composition containing the compound. Stabilization may be measured, for example, by measuring the glass transition temperature of the solid dispersion, by measuring the relaxation rate of the amorphous material, or by measuring the solubility or bioavailability of the compound.

One or more polymers can be used in formulations with a compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950). One, more than one, or all of the polymers suitable for use in combination with a compound (e.g., to form a solid dispersion (e.g., a agglomerated product), such as an amorphous solid dispersion) should have one or more of the following properties:

1. the glass transition temperature of the polymer or combination of polymers should be less than about 10-15 c below the glass transition temperature of the compound. Preferably, the glass transition temperature of the polymer or combination of polymers is greater than the glass transition temperature of the compound, generally at least 50 ℃ above the desired storage temperature of the pharmaceutical product. For example, at least about 100 deg.C, at least about 105 deg.C, at least about 110 deg.C, at least about 120 deg.C, at least about 130 deg.C, at least about 140 deg.C, at least about 150 deg.C, at least about 160 deg.C or higher.

2. The polymer or combination of polymers should be relatively non-hygroscopic. For example, the polymer should absorb less than about 10% water when stored under standard conditions, e.g., less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, less than about 4%, or less than about 3% water. Preferably, the one or more polymers should not substantially absorb water when stored under standard conditions.

3. The polymer or combination of polymers should have a solubility similar to or better than that of the compound in a solvent suitable for the spray drying process. In a preferred embodiment, the one or more polymers are dissolved in one or more of the same solvents or solvent systems as the compound. Preferably, the one or more polymers are soluble in at least one non-hydroxyl containing solvent, such as methylene chloride, acetone, or a combination thereof.

4. The polymer or polymer combination should increase the solubility of the compound in aqueous and physiologically relevant media when combined with the compound, e.g., in a solid dispersion, relative to the solubility of the compound in the absence of the polymer or relative to the solubility of the compound when combined with a reference polymer. For example, the one or more polymers can increase the solubility of the amorphous compound by reducing the amount of amorphous compound that is converted from the solid amorphous dispersion to the crystalline compound.

5. The polymer or combination of polymers should reduce the relaxation rate of the amorphous material.

6. The polymer or combination of polymers should increase the physical and/or chemical stability of the compound.

7. The polymer or combination of polymers should improve the manufacturability of the compound.

8. The polymer or combination of polymers should enhance one or more of the handling, application, or storage properties of the compound.

9. The polymer or combination of polymers should not adversely interact with other pharmaceutical components such as excipients.

Candidate polymers (or other components) may be tested for suitability using the FSD method described herein to produce compositions containing amorphous compounds. The stability, resistance to crystal formation, or other property of the candidate composition can be compared and compared to a reference formulation, e.g., a formulation described herein, e.g., containing a compound of interest (e.g., a drug, e.g., a poorly soluble drug, e.g., VX-950). For example, about 83% amorphous VX-950, about 17% HPMCAS or crystalline VX-950. For example, a candidate composition can be tested to determine whether it inhibits the onset time of solvent-mediated crystallization, or a percent conversion at a given time under controlled conditions of at least 50%, 75%, 100%, or 110%, and a reference formulation, or a candidate composition can be tested to determine whether it has an increased bioavailability or solubility of VX-950 relative to crystalline VX-950.

Surface active agent

The product to be spray dried or fluidized spray dried (e.g., a agglomerated product such as a powder or particle), e.g., a solid dispersion (e.g., an amorphous solid dispersion) comprising the compound of interest (e.g., a drug, such as a poorly soluble drug, e.g., VX-950) and optionally one or more polymers (or solid state carriers), can comprise a surfactant. The surfactant or surfactant mixture generally reduces the interfacial tension between the solid dispersion and the aqueous medium. Suitable surfactants or surfactant mixtures may also enhance the water solubility and bioavailability of the compound of interest (e.g., a drug, such as a poorly soluble drug, such as VX-950) from a solid dispersion. Surfactants useful in the present invention include, but are not limited to, sorbitan fatty acid esters (e.g., sorbitan fatty acid esters)Polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan fatty acid estersPolysorbate, sodium lauryl sulfate (SLS, also known as SDS or sodium dodecyl sulfate), Sodium Dodecylbenzenesulfonate (SDBS), dioctyl sodium sulfosuccinate (Docusate), sodium Dioxycholate (DOSS), sorbitan monostearate, sorbitan tristearate, cetyltrimethylammonium bromide (HTAB), sodium N-lauroylsarconate, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, Gelucire44/14, ethylenediaminetetraacetic acid (EDTA), vitamin E, or a tocol derivative, such as alpha tocopherol, (e.g., d-alpha tocopherol, d 1-alpha tocopherol, tocopherol succinate), and a tocopherol ester, such as tocopherol acetate, tocopherol succinate, e.g., vitamin E d-alpha tocopherol polyethylene glycol 1000 succinateEsters (TPGS; e.g., vitamin E TPGS from Eastman), lecithin, MW677-692, monosodium glutamate monohydrate, Labrasol, PEG8 glyceryl caprylate/caprate, Transcutol, diethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol/hydroxystearate, taurocholic acid, Pluronic F68, Pluronic F108 and Pluronic F127 (or any other polyoxyethylene-polyoxypropylene copolymer)Or saturated polyglycolyzed glycerides). Specific examples of such surfactants that may be used in the present invention include, but are not limited to, span 65, span 25, tween 20, Capryol90, Pluronic F108, Sodium Lauryl Sulfate (SLS), vitamin E TPGS, pluronics and copolymers, phospholipids such as PC (phosphatidylcholine) (e.g., from egg or soy), PIs (phosphatidylinositol), PAs (phosphatidic acid), PEs (phosphatidylethanolamine), PGs (phosphatidylglycerol). The surfactant may also be a lipid or fatty acid such as dipalmitoyl phosphorylcholine (DPPC) or similar lipids (DAPC, DSPC, DPPG, etc.). Such Lipids may be obtained synthetically, for example, from Genzyme or Avanti Polar Lipids. SLS (e.g., Sigma or Fischer) and vitamin E TPGS are preferred.

The amount of surfactant (e.g., SLS or vitamin E TPGS) can be about 0.1-20% relative to the total weight of the solid dispersion. Preferably, it is about 1% to about 20%, about 1 to about 15%, about 1 to about 10%, more preferably about 1% to about 5%, for example about 1%, about 2%, about 3%, about 4% or about 5%.

In some embodiments, the amount of surfactant is at least about 0.1%, preferably at least about 0.5%, more preferably at least about 1% (e.g., about 1%) relative to the total weight of the solid dispersion. In these embodiments, the amount of surfactant is no more than about 20%, and preferably no more than about 15%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, or about 1%.

Candidate surfactants (or other components) and candidate amounts may be tested for suitability in the present invention in a manner similar to that described for the test solvents.

Composition/packaging/use

In one embodiment, the solid dispersion may be prepared as a pharmaceutical composition, for example, a tablet. According to a preferred embodiment, the solid dispersion is present in an amount effective to have a therapeutic effect in a patient. Alternatively, the compositions of the invention comprise another additive described herein (e.g., to provide a combination therapy). Each component may be present in a separate composition, a combined composition, or a single composition.

Pharmaceutical compositions (e.g. tablets) comprising solid dispersions typically contain a pharmaceutically acceptable carrier, binder/diluent, surfactant, disintegrant, glidant, lubricant or vehicle (or carrier).

For example, a solid dispersion prepared as described herein can be directly compressed into a dosage form. In some embodiments, the dispersion is mixed with one or more excipients prior to compression. As an example, a detailed description of direct override VX-950 is provided in provisional application entitled DIRECTLY COMPRESSEDDOSAGE FORMS filed on 22.2006 (attorney docket No. 19079-017P 01).

The compositions and methods of the present invention may optionally comprise one or more excipients (see U.S. patent No. 6,720,003, U.S. published application No. 2004/0030151, and/or international application WO 99/02542)). Excipients are substances that act as carriers or vehicles in the dosage form or are added to the pharmaceutical composition to improve handling, storage, or preparation of the dosage form. Excipients include, but are not limited to, diluents, disintegrants, adhesives, wetting agents, lubricants, glidants, crystallization inhibitors, surface modifying agents, agents to mask or counteract an unpleasant taste or odor, flavoring agents, dyes, flavors, fillers, binders, stabilizers, and substances to improve the appearance of the composition.

The term "comprising" as used herein is intended to be open-ended, thereby indicating that additional agents may be included in addition to the agents specified.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin.

Pharmaceutical compositions, e.g., solid dispersions, e.g., spray-dried drugs, can be prepared as tablets. For example, a spray dispersion of a drug may be combined with molten particles, one or more diluents, and/or one or more disintegrants, and one or more lubricants, one or more other excipients, vehicles, carriers, and/or fillers, and compressed into a tablet form. The resulting tablets may then be further processed, for example, by coating the tablets with a substance, such as a film or shellac, to help maintain the stability or integrity of the tablet, to facilitate oral administration of the tablets, to mask the taste of the tablets, to add a fragrance, to color the tablets, to modify the release of the drug contained in the tablets upon ingestion and/or to mask the taste of the tablet formulation. Coatings suitable for this purpose (e.g., shellac, enteric coatings for modified release) are known in the art. Certain sweeteners, flavoring agents or coloring agents may also be added to the tablets or coatings if desired. Techniques and compositions for making tablets are described in, for example,Remington's Pharmaceutical Sciencesarthur Osol, eds., pp.1553-1593 (1980).

According to a preferred embodiment, the composition of the invention is formulated for administration to a mammal, preferably a human. While the tablet forms provided herein are preferably formulated for oral administration, other formulations are available.

The invention also provides pharmaceutical packages and kits comprising a tablet formulation of amorphous VX-950 or a pharmaceutical composition according to any embodiment herein.

Pharmaceutical compositions, e.g., containing a solid (e.g., spray-dried) dispersion as described herein, can also be prescribed to a patient in a "patient pack" containing more than one dose, preferably the entire course of treatment, in a single package (e.g., blister pack). Where a traditional prescription pharmacist divides a patient supply from bulk supplies of medication, a patient pack is preferred over traditional prescriptions in that the patient always has access to the package insert contained in the patient pack, which is normally not present in traditional prescriptions. The inclusion of package inserts has been shown to improve patient compliance with physician guidance. Preferably, the medicament is in an oral dosage form, for example in the form of a tablet.

It will be appreciated that administration of the combination of the invention by means of a single patient pack or multiple patient packs of each formulation is an additional feature required by the invention, with instructions contained in the package insert instructing the patient on the correct use of the invention.

In an alternative embodiment of the invention, the pharmaceutical pack further comprises one or more additives as described herein. The one or more additives may be provided in the same package or in separate packages.

According to another aspect of the invention, a pack comprises at least a solid (e.g., spray-dried) dispersion or any tablet form of any composition according to the invention, and an information insert containing instructions on the use of the composition of the invention (or the use of the composition of the invention and a combination of additives as described herein).

Thus, the present invention provides a kit for simultaneous or sequential administration of a solid (e.g. spray-dried) dispersion or any composition according to the invention (and optional additives) or derivatives thereof prepared in a conventional manner. Typically, such kits comprise, for example, a composition of each inhibitor and optional additives (and in one or more pharmaceutical preparations) in a pharmaceutically acceptable carrier and written instructions for simultaneous or sequential administration. Preferably, the medicament is in an oral dosage form, e.g., in the form of a tablet.

In another embodiment, a packaged kit is provided containing one or more dosage forms for self-administration (preferably oral dosage forms); container means, preferably sealed, for containing the dosage forms during storage and prior to use; and instructions for administration of the drug to a patient. The instructions are typically written instructions on the package insert, label, and/or other components of the kit, and the dosage form or form is as described herein. Each dosage form may be individually contained in a sheet of metal foil-plastic sheet, each dosage form being isolated from each other in separate cells or blisters, or the dosage forms may be contained in a single container, in a plastic bottle or vial. Typically, the kits of the present invention will also include a container for packaging the individual kit components, i.e., the dosage form, the containment device, and written instructions for use. Such packaging means may take the form of paperboard or carton, plastic or foil bags and the like.

Embodiments of the invention also include additives. Thus, the method of the present invention comprises the step of applying such additives.

Dosage form

Dosage levels useful for preventing and treating a condition in a subject to be treated are from about 0.01 to about 100mg/kg body weight/day, preferably from about 10 to about 100mg/kg body weight/day of a solid (e.g., spray-dried) dispersion. In some embodiments, a dosage level of about 0.4 to about 10 g/day, e.g., about 1 to about 4 g/day, preferably about 2 to about 3.5 g/day per human (based on the average body weight of the human calculated as about 70 kg) is included. Typically, the administration of the pharmaceutical composition of the invention and according to the invention is from about 1 to about 5 times per day, preferably from about 1 to about 3 times per day, or alternatively a continuous infusion. In some embodiments, the solid (e.g., spray-dried) dispersion or pharmaceutical composition containing it is administered using a controlled release formulation. In some embodiments, this can assist in providing relatively stable blood levels of the solid (e.g., spray-dried) dispersion.

In some embodiments, the dosage of the solid (e.g., spray dried) dispersion is a standard dosage, e.g., from about 1g to about 5 g/day, more preferably from about 2g to about 4 g/day, more preferably from about 2g to about 3 g/day, e.g., about 2.25g or about 2.5 g/day. The dose may be administered, for example, as a spray-dried dispersion or tablet.

Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to form a single dosage form will vary depending upon the subject being treated and the particular mode of administration. Typical formulations contain from about 5% to about 95% active compound (w/w). Preferably, such formulations contain from about 20% to about 80%, from about 25% to about 70%, from about 30% to about 60% active compound.

When the compositions or methods of the present invention comprise a solid (e.g., spray-dried) dispersion in combination with one or more additional therapeutic or prophylactic agents, the dosage levels of both the solid (e.g., spray-dried) dispersion and the additive should be between about 10 and 100%, and more preferably between about 10 and 80%, of the normal dosage administered in a monotherapy regimen.

Once the condition of the patient has improved, a maintenance dose of a compound, composition or combination of the invention can be administered, if necessary. Subsequently, the dose or frequency of administration, or both, can be reduced to, for example, about 1/2 or 1/4 or less of the dose or frequency of administration as a function of the symptoms until a level of improvement in the condition is reached when the symptoms have been alleviated to a desired level, and treatment should be discontinued. However, once any recurrence of disease symptoms occurs, the patient requires intermittent treatment on a long-term basis.

It will also be understood that the specific dose and treatment regimen for any particular patient will vary depending upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the attending physician, and the severity of the particular disease being treated. The amount of active ingredient will also depend on the presence, absence and nature of the additional antiviral agent in the particular compound and composition.

Examples

Example 1

The mixture of the following components was spray dried to provide a solid dispersion of VX-950. VX-950/HPMCAS-HG/SLS were combined in a ratio of 49.5/49.5/1 (weight/weight) and combined at a solids concentration of 10 in a solvent system comprising dichloromethane/acetone/glacial acetic acid in a ratio of 66.6/28.5/5 to provide a product with a bulk density of d50 and 0.37 of 43.03.

Example 2

The mixture of the following components was spray dried to provide a solid dispersion of VX-950. VX-950/HPMCAS-HG/SLS were combined in a ratio of 49.5/49.5/1 (weight/weight) and combined at a solids concentration of 10 in a solvent system comprising dichloromethane/acetone/glacial acetic acid in a ratio of 63/27/10 to provide a product with a d50 of 47.02 and a bulk density of 0.41.

Example 3

Spray-dried dispersions of VX-950 were prepared using multiple VX-950 batches, HPMCAS-HG (hypromellose acetate succinate, HG grade, Shin-Etsu Chemical Co.) polymer, and SLS (sodium lauryl sulfate, Fisher) surfactant. Spray drying was carried out and subsequent after-drying in a double-cone dryer. Producing a dry dispersion with low residual solvent levels and targeted powder properties. Success criteria include having acceptable process yields (>80%) and meeting purity specifications for all target drug products, matching target properties within specified physical characteristics (particle size and bulk density).

Formulation composition and Process overview

The 2 active dispersions are described in table 1 to produce the respective total formulation compositions.

TABLE 12 active dispersions to produce respective formulation compositions (based on 116.25kgVX-950, 13 wt%)

Function of component	Components	Kg
			API	VX-950	116.25
Polymer/dispersant	Hydroxypropyl methylcellulose acetate succinate, NF/JPE (HPMCAS-HG)	116.25
			Surface active agent	Sodium Lauryl Sulfate (SLS)	2.348
Process solvent	Dichloromethane, NF (for Dispersion)	1178.8
			Process solvent	Acetone, NF (for Dispersion)	377.2
Process solvent	DI water	15.7

A schematic flow chart of the production process is given in fig. 1.

The process flow is explained as follows:

A) preparation of solution and spray dryer

1) Dichloromethane was prepared in the equilibrium solvent tank.

2) A predetermined amount of 100kg of acetone was added to the mixing reactor (see Table 1).

3) An appropriate amount (see table 1) of dichloromethane was prepared in the main solution reactor. The pressure differential cell confirms the correct amount of solvent charge.

4) The VX-950 drug substance was loaded into the main solution reactor (see Table 1). The total solids loading was 13 wt%. Sampling was checked by visual inspection to verify that the drug substance was dissolved.

5) HPMCAS-HG was loaded into the main solution reactor (see table 1). The total solids loading was 13 wt%.

6) The remaining predetermined amount of acetone was added to the mixing reactor (see table 1).

7) Acetone, SLS and DI water were charged into the main solution reactor.

8) After dissolution, the resulting batches were tested for appearance and viscosity.

9) The spray system SK-MFP pressure nozzle was installed and tested for correct atomization with the equilibrium solvent. (nozzles 48/21, 50/21, or 52/21 may also be used)

B) Start-up of spray dryer

1) The spray dryer is heated to the appropriate outlet temperature.

2) The equilibrium solvent was sprayed until all parameters were in equilibrium and constant.

3) Once the spray dryer reaches equilibrium, spray drying of the feed solution begins.

4) The dried particles were separated from the process gas by inertia through a cyclone and collected in a polyethylene bag. The process gas is then filtered to obtain fine particles and condensed to remove the process solvent.

5) The original samples were taken and tested for particle size distribution and packing and tap density.

a) If the particle size distribution and density are within the acceptance criteria and close to the target (see table 6), the process continues and samples are taken according to the sampling plan.

b) If the particle size distribution and density are not within the acceptance criteria and are not close to the target (see Table 6), the process is optimized as desired (e.g., by changing one or more of the following: nozzle, outlet temperature, feed pressure). The collection bag is replaced and the powder outside the acceptance criteria is left for inspection. Once the sample is within specification, the process with the current parameters is started.

C) Spray drying is carried out

1) Sampling was performed according to the sampling schedule.

2) Any changes in the process parameters are recorded.

3) Any stops or ends of the continuous operation are recorded.

4) After the end of the spray drying of the feed solution, the solvent was switched to equilibrium and normal shutdown was carried out.

D) Post-drying process

1) The spray-dried dispersion was loaded into a secondary dryer and dried until all residual solvents (dichloromethane, acetone, ethyl acetate and toluene) were below the established specifications.

Device for measuring the position of a moving object

An 8000-L industrial scale reactor equipped with a mechanical stirrer and a thermal loop was used to mix the original solution. An industrial scale spray dryer (Niro pharmaceutical spray dryer FSD12.5CC) was used in a normal direct flow spray drying mode. A pressure nozzle system (Sprayingsystems Maximum Free Passage SK-MFP series variety, orifices 48-54, center 21) was used. A high performance pressure pump with a solvent compatible/resistant gasket pumps the feed solution through the atomizer into the spray drying tank. The inertial cyclone separates the product from the process gas and solvent vapors. The filter bag then collects the fine particles that were not separated by the cyclone. The resulting gas was condensed to remove the process solvent and recycled back to the heater and spray dryer (closed cycle).

FIG. 2 is a schematic diagram of a spray drying process.

The resulting product was transferred to a double cone vacuum dryer to dry the residual solvent.

Critical process control and parameters

Both spray drying and double cone drying processes require critical process controls and parameters. From a prior study batch, the primary process control parameters have been identified.

The key process controls and parameters of the spray drying process that are monitored and recorded throughout the run time are:

mounted atomisers/nozzles

Feed pressure

Inlet temperature

Condenser temperature set point (at about-10 to-15 ℃)

Key process metrics of the spray drying process monitored and recorded throughout the run time are:

solution feed rate

-outlet temperature

Cyclone pressure differential and drying gas flow rate

Table 2 defines spray drying process parameters/metrics, settings/ranges and target guidelines.

TABLE 2 spray drying variables, settings and targets

Variables of	Set/range
		Mounted atomizer	Spray system SK-MFP
Solution feed rate	120-200 kg/hour
		Pressure of feed	20-50bar
Inlet temperature	50-80℃
		Outlet temperature	25-31℃
Pressure differential across cyclone separators	10.5-13.5cm H₂O

Material

All excipients and process solvents used were in accordance with the current version of the european pharmacopoeia, japanese pharmacopoeia or USP/NF, as shown in tables 1 and 3. All excipients and process solvents were purchased from approved suppliers. The manufacturer's certificate of analysis is approved and all material received is tested.

TABLE 3 materials

Variations in production

Production 2 uses a process optimized for dispersion. Most particularly, the dispersion has a particle size and bulk density greater than production 1, as needed for increasing powder flowability and direct compression on high speed tableting machines. Such powders were prepared by varying the spray drying parameters. Changes are also made to tighten the process and avoid possible deviations.

Example 4

Spray-dried dispersions of VX-950 were prepared as described using a solvent system containing water. The solvent system contained 75% dichloromethane, 24% acetone and 1% water (w/w/w). The dispersion contained 49.5% VX-950, 49.5% HPMCAS-HG and 1% SLS (w/w). As shown in fig. 3, different combinations of outlet temperature, feed pressure, cyclone pressure, condenser setpoint temperature, nozzle type, solids loading, and solution feed rate were tested during the spray drying process. As shown in fig. 3, varying these parameters changes the properties of the resulting dispersion (particle size (PS)), span, bulk density, tap density, and level of residual solvent).

Example 5

Goal and success criteria

Producing a dry dispersion with low residual solvent levels and targeted powder properties. Success criteria include having acceptable process yields (>80%) and meeting product purity specifications for all target drugs, matching target properties within specified physical characteristics (particle size and bulk density).

Formulation composition and Process overview

The total formulation composition produced by the 2 active dispersions is described in table 4.

TABLE 4 formulation composition produced by the first active dispersion (15 wt% based on 100kg VX-950)

A schematic flow chart of the production process is given in fig. 4.

The process flow is explained as follows:

A) preparation of solution and spray dryer

1) Dichloromethane was prepared in the equilibrium solvent tank.

2) DI water was charged to the secondary mix tank (see table 4).

3) An appropriate amount (see table 4) of dichloromethane was prepared in the main solution reactor. The pressure differential cell confirms the correct amount of solvent charge.

4) VX-950 drug substance was packed into the main solution reactor (see Table 7). The total solids loading was 15 wt%. Sampling was checked by visual inspection to verify that the drug substance was dissolved.

5) The HPMCAS-HG was loaded into the main solution reactor (see table 4). The total solids loading was 15 wt%.

6) The amount of acetone was added to the mixing reactor (see table 4). Samples were taken to determine if all solids had dissolved.

7) SLS and water were added to the main mixing reactor.

8) The spray system SK-MFP pressure nozzle was installed and tested for correct atomization with the equilibrium solvent.

B) Start-up of spray dryer

1) The spray dryer is heated to the appropriate outlet temperature.

4) The dried particles were separated from the process gas by inertia through a cyclone separator and collected in a polyethylene bag. The process gas is then filtered to obtain fine particles and condensed to remove the process solvent.

a) If the particle size distribution and density are within the acceptance criteria and are close to the target (see table 11), the process continues and samples are taken according to the sampling plan.

b) If the particle size distribution and density are not within the acceptance criteria and are not close to the target (see Table 11), the process is optimized as desired (e.g., by changing one or more of the following: outlet temperature, feed pressure, or condenser temperature). The collection bag is replaced and the powder outside the acceptance criteria is left for inspection. Once the sample is within specification, the process with the current parameters is started.

C) Post-drying process

1) The spray-dried dispersion was charged to a secondary dryer.

2) Continue until all residual solvents (dichloromethane, acetone, ethyl acetate and toluene) are below the established specifications.

D) Testing, shipping

1) Samples of the dispersion were tested for release testing.

Device for measuring the position of a moving object

An 8000-L commercial scale reactor (R240) equipped with a mechanical stirrer and a thermal loop was used to mix the original solution. The reactor (R32) was used for SLS and water mixture. An industrial scale spray dryer (Niro pharmaceutical spray dryer FSD12.5CC) was used in a normal direct flow spray drying mode. A pressure nozzle system (Spraying Systems Maximum FreePassage SK-MFP series species, orifice 54, center 21) was used. A high performance pressure pump with a solvent compatible/resistant gasket pumps the feedstock solution through an atomizer into a spray drying tank. The inertial cyclone separates the product from the process gas and solvent vapors. The filter bag then collects the fine particles that were not separated by the cyclone. The resulting gas was condensed to remove the process solvent and recycled back to the heater and spray dryer (closed cycle).

FIG. 2 is a schematic diagram of a spray drying process.

The resulting product was transferred to a double-cone vacuum dryer (S901) to dry the residual solvent. The dried product was sieved into a nitrogen purged glove box (nitrogen swell glovebox) and packaged.

Critical process control and parameters

mounted atomisers/nozzles

Feed pressure

Inlet temperature

-condenser temperature setpoint

solution feed rate

-outlet temperature

Cyclone pressure differential and drying gas flow rate

Table 5 defines spray drying process parameters/metrics, settings/ranges and target guidelines.

TABLE 5 spray drying variables, settings and targets

Variables of	Set/range
		Mounted atomizer	Spray system SK-MFP
Solution feed rate	130-180 kg/h
		Pressure of feed	40-65bar
Outlet temperature	22-29℃
		Pressure differential across cyclone separators	10.0-12.5cmH₂O

Material

All excipients and process solvents used were in accordance with the current version of the european pharmacopoeia, japanese pharmacopoeia or USP/NF, as shown in tables 4 and 6. All excipients and process solvents were purchased from approved suppliers. The manufacturer's certificate of analysis is approved and all material received is tested.

TABLE 6 materials

Variations in production

Production uses 10% or 30% by weight solutions. Solution production may also be varied. In some batches, the SLS/DI water mixture is added last to the main solution reactor. The inlet temperature of the spray dryer is monitored, but in some production there is no defined range or target. It is recommended to reduce in-process sampling. The polymer was tested for KF prior to loading.

A number of inventive embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

1. A method of spray drying a drug, the method comprising, forming or providing a mixture of the drug in a solvent system comprising a solvent or a combination of components, wherein at least one solvent is a non-volatile solvent, to form a mixture of the drug and the solvent, and spray drying the mixture to obtain an amorphous drug product, with the proviso that the drug is not N- [2, 4-bis (1, 1-dimethylethyl) -5-hydroxyphenyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxamide.

2. The method of claim 1, wherein the mixture comprises a solution or suspension.

3. The method of claim 1, wherein the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons.

4. The method of claim 1, wherein the drug is a poorly soluble drug.

5. The method of claim 1, wherein the drug is selected from one of the classes of analgesics, anti-inflammatory agents, antihelminthics, antiarrhythmics, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastics, erectile dysfunction modifiers, immunosuppressive agents, antiprotozoal agents, antithyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers, inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytic agents, lipid regulating agents, antianginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioids, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, antiobesity agents, cognitive enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostatic hypertrophy agents, essential fatty acids, or non-essential fatty acids.

6. The method of claim 1, wherein the drug comprises an antiviral agent.

7. The method of claim 6, wherein said antiviral agent is used to treat hepatitis C (HepC).

8. The method of claim 7, wherein said antiviral agent comprises a HepC protease inhibitor.

9. The method of claim 8, wherein the HepC protease inhibitor comprises VX-950.

10. The method of claim 1, wherein the solvent system comprises a combination of components comprising at least one non-volatile solvent.

11. The method of claim 10, wherein the combination of components comprises a volatile solvent and a non-volatile solvent.

12. The method of claim 11, wherein the volatile solvent comprises dichloromethane, acetone, chloroform or THF.

13. The method of claim 11, wherein the non-volatile solvent comprises glacial acetic acid, DMSO, DMF, or water.

14. The method of claim 11, wherein the non-volatile solvent is present in an amount of from about 0.1% to about 20% (by weight).

15. The method of claim 11, wherein the solvent system comprises a combination of a volatile solvent and a non-volatile solvent.

16. The method of claim 15, wherein the volatile solvent comprises dichloromethane and acetone.

17. The method of claim 15, wherein the non-volatile solvent comprises glacial acetic acid.

18. The method of claim 15, wherein the solvent system comprises dichloromethane, acetone, and glacial acetic acid.

19. The method of claim 18, wherein the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid.

20. The method of claim 15, wherein the non-volatile solvent comprises water.

21. The method of claim 15, wherein the solvent system comprises dichloromethane, acetone, and water.

22. The method of claim 21, wherein the solvent system comprises from about 40% to about 80% dichloromethane, from about 20% to about 35% acetone, and from about 0.1% to about 15% water.

23. The method of claim 1, wherein the solvent system comprises glacial acetic acid.

24. The method of claim 1, wherein the solvent system comprises water.

25. The method of claim 1, wherein the mixture comprises a surfactant.

26. The method of claim 25, wherein the surfactant comprises Sodium Lauryl Sulfate (SLS) or vitamin E or a derivative thereof.

27. A method of forming a solid dispersion comprising a drug and one or more polymers, the method comprising forming or providing a mixture of the drug and one or more polymers in a solvent or combination of solvents, wherein at least one solvent is a non-volatile solvent, to form a mixture of the drug, one or more polymers and solvent; and spray-drying the mixture to obtain a solid dispersion.

28. The method of claim 27, wherein the mixture is a solution or suspension.

29. The method of claim 27, wherein said solid dispersion is an amorphous solid dispersion.

30. The method of claim 27, wherein the mixture comprises one or more water soluble polymers or partially water soluble polymers.

31. The method of claim 30, wherein the water soluble or partially water soluble polymer is a cellulose derivative; ethyl cellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); an acrylate; or cyclodextrins or copolymers and derivatives thereof.

32. The method of claim 30, wherein the water soluble or partially water soluble polymer is Hydroxypropylmethylcellulose (HPMC).

33. The method of claim 27, wherein the mixture comprises a pH-dependent enteric polymer.

34. The method of claim 33, wherein the pH-dependent enteric polymer is a cellulose derivative; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose acetate succinate (HPMCAS); carboxymethyl cellulose (CMC) or a salt thereof; cellulose Acetate Trimellitate (CAT); hydroxypropyl cellulose acetate phthalate (HPCAP); hydroxypropylmethylcellulose acetate phthalate (HPMCAP); methyl Cellulose Acetate Phthalate (MCAP); or polymethacrylates.

35. The method of claim 34, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS).

36. The method of claim 27, wherein the mixture comprises an insoluble crosslinked polymer.

37. The method of claim 27, wherein the mixture comprises polyvinylpyrrolidone (PVP).

38. The method of claim 27, wherein the mixture comprises a mixture of 2 or more polymers.

39. The method of claim 38, wherein the mixture of 2 or more polymers comprises 2 cellulosic polymers.

40. The method of claim 39, wherein the mixture of 2 or more polymers comprises HPMC and HPMCAS.

41. The method of claim 27, wherein the one or more polymers are present in the solid dispersion in an amount of from about 30% to about 70% (by weight).

42. The method of claim 27, wherein the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons.

43. The method of claim 27, wherein the drug is a poorly soluble drug.

44. The method of claim 27, wherein the drug is selected from one of the classes of analgesics, anti-inflammatory agents, antihelminthics, antiarrhythmics, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungal agents, antigout agents, antihypertensive agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastics, erectile dysfunction modifiers, immunosuppressive agents, antiprotozoal agents, antithyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers, inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytic agents, lipid regulating agents, antianginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioids, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, antiobesity agents, cognitive enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostatic hypertrophy agents, essential fatty acids, or non-essential fatty acids.

45. The method of claim 27, wherein the medicament comprises an antiviral agent.

46. The method of claim 45, wherein said antiviral agent is used to treat hepatitis C (HepC).

47. The method of claim 46, wherein said antiviral agent comprises a HepC protease inhibitor.

48. The method of claim 47, wherein the HepC protease inhibitor comprises VX-950.

49. The method of claim 27, wherein the solvent or solvent combination comprises a combination of components comprising at least one non-volatile solvent.

50. The method of claim 49, wherein the combination of components comprises a volatile solvent and a non-volatile solvent.

51. The method of claim 50, wherein the volatile solvent comprises dichloromethane, acetone, chloroform or THF.

52. The method of claim 50, wherein the non-volatile solvent comprises glacial acetic acid, DMSO, DMF, or water.

53. The method of claim 50, wherein the non-volatile solvent is present in an amount of from about 0.1% to about 20% (by weight).

54. The method of claim 50, wherein the solvent system comprises a combination of a volatile solvent and a non-volatile solvent.

55. The method of claim 54, wherein the volatile solvent comprises dichloromethane and acetone.

56. The method of claim 54, wherein the non-volatile solvent comprises glacial acetic acid.

57. The method of claim 54, wherein the solvent or solvent combination comprises dichloromethane, acetone, and glacial acetic acid.

58. The method of claim 57, wherein the solvent or combination of solvents comprises from about 40% to about 80% dichloromethane, from about 20% to about 35% acetone, and from about 0.1% to about 15% glacial acetic acid.

59. The method of claim 54, wherein the non-volatile solvent comprises water.

60. The method of claim 54, wherein the solvent or solvent combination comprises dichloromethane, acetone, and water.

61. The method of claim 60, wherein the solvent or combination of solvents comprises from about 40% to about 80% dichloromethane, from about 20% to about 35% acetone, and from about 0.1% to about 15% water.

62. The method of claim 27, wherein the solvent or combination of solvents comprises glacial acetic acid.

63. The method of claim 27, wherein the solvent or solvent combination comprises water.

64. The method of claim 27, wherein the mixture comprises a surfactant.

65. The method of claim 64, wherein the surfactant comprises Sodium Lauryl Sulfate (SLS) or vitamin E or a derivative thereof.

66. A method comprising

a) Forming or providing a mixture of a poorly water soluble drug, one or more polymers, and a solvent system comprising at least one non-volatile solvent, and

67. The method of claim 66, wherein the one or more polymers comprise one or more water soluble polymers or partially water soluble polymers.

68. The method of claim 67, wherein the water soluble or partially water soluble polymer is a cellulose derivative; ethyl cellulose; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); an acrylate; or cyclodextrins or copolymers and derivatives thereof.

69. The method of claim 67, wherein the water soluble or partially water soluble polymer is Hydroxypropylmethylcellulose (HPMC).

70. The method of claim 66, wherein the one or more polymers comprise a pH-dependent enteric polymer.

71. The method of claim 70, wherein the pH-dependent enteric polymer is a cellulose derivative; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose acetate succinate (HPMCAS); carboxymethyl cellulose (CMC) or a salt thereof; cellulose Acetate Trimellitate (CAT); hydroxypropyl cellulose acetate phthalate (HPCAP); hydroxypropylmethylcellulose acetate phthalate (HPMCAP); methyl Cellulose Acetate Phthalate (MCAP); or polymethacrylates.

72. The method of claim 71, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS).

73. The method of claim 66, wherein the one or more polymers comprise an insoluble crosslinked polymer.

74. The method of claim 66, wherein the one or more polymers comprise polyvinylpyrrolidone (PVP).

75. The method of claim 66, wherein the mixture comprises a mixture of 2 or more polymers.

76. The method of claim 75, wherein the mixture of 2 or more polymers comprises 2 cellulosic polymers.

77. The method of claim 76, wherein the mixture of 2 or more polymers comprises HPMC and HPMCAS.

78. The method of claim 66, wherein the one or more polymers are present in the solid dispersion in an amount of from about 30% to about 90% (by weight).

79. The method of claim 66, wherein the drug is a small molecule drug, such as a drug having a molecular weight of less than about 1000 daltons.

80. The method of claim 66, wherein the drug is selected from one of the following classes of analgesics, anti-inflammatory agents, antihelminthics, antiarrhythmics, antibacterials, antivirals, anticoagulants, antidepressants, antidiabetics, antiepileptics, antifungals, antigout agents, antihypertensive agents, antimalarials, antimigraine agents, antimuscarinics, antineoplastics, erectile dysfunction modifiers, immunosuppressive agents, antiprotozoal agents, antithyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers, inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytic agents, lipid regulating agents, antianginal agents, Cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioids, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, antiobesity agents, cognitive enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostatic hypertrophy agents, essential fatty acids, or non-essential fatty acids.

81. The method of claim 66, wherein the medicament comprises an antiviral agent.

82. The method of claim 81, wherein said antiviral agent is used to treat hepatitis C (HepC).

83. The method of claim 82, wherein said antiviral agent comprises a HepC protease inhibitor.

84. The method of claim 83, wherein the HepC protease inhibitor comprises VX-950.

85. The method of claim 66, wherein the solvent system comprises a combination of components comprising at least one non-volatile solvent.

86. The method of claim 85, wherein the solvent system comprises a volatile solvent and a non-volatile solvent.

87. The method of claim 86, wherein the volatile solvent comprises dichloromethane, acetone, chloroform or THF.

88. The method of claim 86, wherein the non-volatile solvent comprises glacial acetic acid, DMSO, DMF, or water.

89. The method of claim 86, wherein the non-volatile solvent is present in an amount of from about 0.1% to about 20% (by weight).

90. The method of claim 86, wherein the solvent system comprises a combination of a volatile solvent and a non-volatile solvent.

91. The method of claim 90, wherein the volatile solvent comprises dichloromethane and acetone.

92. The method of claim 91, wherein the solvent system comprises about 75:24:1 weight percent of dichloromethane to acetone to non-volatile solvent.

93. The method of claim 90, wherein the non-volatile solvent comprises glacial acetic acid.

94. The method of claim 90, wherein the solvent system comprises dichloromethane, acetone, and glacial acetic acid.

95. The method of claim 94, wherein the solvent system comprises about 40% to about 80% dichloromethane, about 20% to about 35% acetone, and about 0.1% to about 15% glacial acetic acid.

96. The method of claim 90, wherein the non-volatile solvent comprises water.

97. The method of claim 90, wherein the solvent or solvent combination comprises dichloromethane, acetone, and water.

98. The method of claim 97, wherein the solvent or combination of solvents comprises from about 40% to about 80% dichloromethane, from about 20% to about 35% acetone, and from about 0.1% to about 15% water.

99. The method of claim 66, wherein the solvent or combination of solvents comprises glacial acetic acid.

100. The method of claim 66, wherein the solvent or solvent combination comprises water.

101. The method of claim 66, wherein the mixture comprises a surfactant.

102. The method of claim 101, wherein the surfactant comprises Sodium Lauryl Sulfate (SLS) or vitamin E or a derivative thereof.

103. A method of preparing a solid dispersion of VX-950, the method comprising:

a) forming or providing a solution of VX-950, a cellulosic polymer, and a solvent, wherein the solvent comprises at least one non-volatile solvent component;

104. A method of preparing a solid dispersion of VX-950, the method comprising:

b) spray drying the mixture to form a solid dispersion comprising VX-950.

105. A method of preparing a solid dispersion of VX-950, the method comprising:

b) spray drying the mixture to form a solid dispersion comprising VX-950.

106. The product prepared by the process of claim 1.

107. The product made by the process of claim 27.

108. The product made by the process of claim 66.

109. A product made by the method of claim 103.

110. A product made by the process of claim 104.

111. A product made by the process of claim 105.