Spray-dried amorphous solid dispersions and methods of preparation

Abstract

The present invention relates to the use of polyvinyl alcohol for spray drying to form an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix. Furthermore, the present invention relates to a process for producing an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying.

Description

[Technical Field]

[0001] Technical Field The present invention relates to the use of polyvinyl alcohol for spray drying to form an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix. Furthermore, the present invention relates to a process for producing an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying. [Background technology]

[0002] background Drug product formulations must be carefully designed when the active pharmaceutical ingredient (API) exhibits low solubility and / or low bioavailability. The Biopharmaceutical Classification System (BCS) places these APIs in Class II (low solubility) and Class IV (low solubility and low bioavailability). They pose challenges to dissolution from the final formulation, and this challenge affects the majority of formulation efforts, as 40% of marketed products and 70–90% of new chemical entities (NCEs) are classified in Classes II and IV of the BCS. Higher lipophilicity, higher molecular weight, and the resulting lower aqueous solubility are the result of the growing trend in combinatorial chemistry and new drug design.

[0003] Low aqueous solubility is often associated with a stable crystalline state of an API. This state can be overcome by disrupting the crystal lattice and creating an amorphous state. This state represents a higher-energy form than the crystalline counterpart of the same API, but is less stable. Due to this higher-energy state, the amorphous form leads to increased apparent solubility, resulting in supersaturation in the gastrointestinal tract (GIT) and improved bioavailability. This behavior is explained by the spring-parachute analogy: the extra free energy and increased dissolution are known as springs, while the parachutes serve to slow the decline of free dissolved drug. The parachutes are auxiliary materials that additionally serve to stabilize the high-energy amorphous state of the API, prolong storage, and facilitate handling and manufacturing. These materials are known as carriers and can, for example, be polymers. Polymers reduce the molecular mobility of the API, increase the glass transition temperature, protect the API from recrystallization, and, if the polymer itself is water-soluble, can also facilitate wetting during dissolution.

[0004] To produce these polymer amorphous solid dispersions (PASD / ASD), methods involving 1) melting, 2) solvent evaporation, and 3) melt-solvent evaporation can be applied (Kim et al. 2021). Spray drying (SD) can be described as a solvent evaporation method in which a liquid feedstock containing dissolved API and polymer is sent to a drying chamber, atomized to produce dried microparticles, which can then be collected. This technique protects the microparticles during the drying process due to the cooling effect of the liquid vaporization, and it takes only milliseconds, making it the method of choice for heat-sensitive materials. The advantage of this rapid drying is that the drug-polymer system is well mixed within the product. SD can be applied at all development stages, from discovery to development, and can later be scaled up to commercial processes. For commercial drug products, spray drying and hot-melt extrusion are the methods of choice and account for the majority of registered products (Bhujbal, Mitra, et al. 2021).

[0005] To generate droplets from a feedstock, a liquid is transported through a nozzle. In pharmaceutical applications, pneumatic nozzles are primarily used. The liquid is atomized by a gas stream, which can be either air or a select inert gas (Ziaee et al. 2019). Droplets are generated at the tip of the nozzle, where the gas stream disrupts the liquid stream. These nozzles are multi-fluid, with one fixed gas channel and one or more fluid channels. For pharmaceutical applications where the components are not co-soluble in the same solvent system, three-fluid nozzles can utilize two fluid channels, making spray drying possible. This can be used for co-spray drying of two APIs (Focaroli et al. 2020) or ASD, where the polymer and API require different solvent systems (Bhujbal, Su, et al. 2021).

[0006] In a standard spray drying process, select components are often dissolved or dispersed in a common solvent, which acts as the feed solution or suspension. The feedstock is then delivered to a two-fluid nozzle, with one channel holding the liquid and the other holding a pressurized gas (N2 or air). The need for an amorphous form of an API is often based on low water solubility, and therefore the API is dissolved in an organic solvent. To produce an ASD, a polymer is dissolved in the same solvent and spray-dried to yield the desired product. Only if the API is completely dissolved can an amorphous state be produced, leading to an unstable or crystalline product (Bhujbal, Mitra, et al. 2021).

[0007] Although there is a pool of polymers available that are soluble in organic solvents, co-solubility of the API and polymer is not always achievable. For such challenging combinations, a three-fluid nozzle setup, where an additional channel for delivering a second liquid stream is available, could be a solution. This could be applicable to the production of ASDs using an API (naproxen) and a polymer (PVP) (Bhujbal, Su, et al. 2021) or to the development of co-spray-dried formulations for pulmonary delivery of theophylline and salbutamol sulfate (Focaroli et al. 2020).

[0008] The use of hydrophilic polymers, such as PVA, as excipients in pharmaceutical compositions has been widely described. WO 2018 / 083285 A1 discloses powdered PVA with improved properties as a polymer matrix in pharmaceutical compositions containing active ingredients, particularly in compressed tablets, where it forms amorphous solid dispersions with poorly soluble active pharmaceutical ingredients (APIs). ASDs containing PVA as the polymer are known to significantly increase the solubility of poorly water-soluble drugs (Brough et al. 2016). While the preparation of PVA-containing ASDs by melting (e.g., melt or hot-melt extrusion) has been well described, there is little experience with the preparation of PVA-containing ASDs by spray drying. The only publication using PVA for spray drying was published in 2011 and described the application of PVA 22,000 and celecoxib in a suspension delivered through a two-fluid nozzle (Fouad et al. 2011). One disadvantage is that not all products produced are completely amorphous by XRD, making these compositions unsuitable for solubility enhancement and pharmaceutical use. Furthermore, polyvinyl alcohol is not listed as a suitable polymer for ASD production (Hugo, Kunath, and Dressman 2013), and an additional recent review has excluded PVA from the list of polymers for spray-dried dispersions (Bhujbal, Mitra, et al. 2021).

[0009] To ensure a stable, fully amorphous ASD formulation, complete dissolution of the API is one of the critical steps. While PVA is soluble in water (or water-ethanol / water-methanol systems), poorly soluble APIs often require organic solvents. Therefore, co-dissolution is challenging and not feasible to produce a stable ASD using PVA.

[0010] By creating an amorphous solid dispersion, both components, the active ingredient and the polymer, are usually dissolved in a common solvent. This is often a limitation for aqueous polymers such as PVA, and is also the reason they are considered unsuitable for spray drying due to their limited solubility in organic solvents. This often precludes the application of a common solvent for the polymer and the low-solubility active ingredient. In addition, the PVA grade defines the performance of solubility enhancement for poorly soluble APIs, and therefore not all PVA grades are applicable. Furthermore, the aqueous solubility itself strongly depends on the degree of hydrolysis and molecular weight of each PVA grade.

[0011] Currently, spray drying with PVA is rarely applied in pharmaceutical processes because classical PVA grades exhibit limited solubility in common solvents or solvent mixtures.

[0012] Therefore, there is a need for a method for preparing spray-dried ASDs using PVA as a polymer. A further object of the present invention is to find an optimal PVA grade and / or PVA grade range for spray drying to produce ASDs. In addition, to improve the properties of the resulting ASDs, a combination of (i) an optimal PVA grade and / or PVA grade range and (ii) a spray-drying technique is needed. Specific properties to be improved include the degree of amorphization of the API in the ASD, the dissolution behavior of the API, and / or the stability of the amorphous form of the API in the ASD. Summary of the Invention

[0013] Summary of the Invention Surprisingly, it has been found that PVA having a degree of hydrolysis of 90% or less is particularly suitable for the preparation of ASD using spray drying, especially three-fluid spray drying, as it leads to improved amorphization, dissolution and / or stability of the API.

[0014] When dissolving API and PVA in two different solvents and using a setup with a three-fluid nozzle, co-solubility issues become a target, especially when the desired drug loading cannot be achieved in a two-fluid nozzle setup. Additionally, the PVA grade needs to be carefully evaluated. High viscosity values ​​lead to early nozzle clogging, while high hydrolysis grades can lead to PVA solubility issues.

[0015] In a further embodiment of the invention the PVA has a degree of hydrolysis between 74% and 88% and a viscosity of a 4% solution at 20° C. between 3 mPas and 5 mPas, in particular the PVA is PVA 3-82, 4-88 or 5-74.

[0016] A further aspect of the present invention is a process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, comprising: a) preparing a first feed solution comprising at least one active pharmaceutical ingredient; b) preparing a second feed solution comprising polyvinyl alcohol having a degree of hydrolysis of 90% or less; c) spray drying the first and second feed solutions with a three-fluid nozzle; wherein preferably in a three-fluid nozzle, the first feed solution is the internal phase and the second feed solution is the external phase.

[0017] In another aspect, the present invention provides a process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, comprising: a) preparing a feed solution comprising at least one active pharmaceutical ingredient and at least one polyvinyl alcohol having a degree of hydrolysis of 90% or less; b) spray drying the feed solution; The process comprises:

[0018] A further aspect of the present invention relates to an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by the process as defined above.

[0019] A further aspect of the present invention relates to a pharmaceutical dosage form comprising an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by a process as defined above.

[0020] Detailed Description of the Invention One aspect of the present invention is the use of polyvinyl alcohol in a spray drying process to form an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix, wherein the polyvinyl alcohol has a degree of hydrolysis of 90% or less.

[0021] In a specific embodiment, the spray drying is three-fluid nozzle spray drying. Spray drying is a process that converts a liquid into a dry state. The applied solvent can be aqueous or any organic solvent, or a mixture thereof. The liquid form can be a solution, suspension, dispersion, emulsion, or paste, while the resulting dried product can be a powder, aggregate, or granule with various particle morphologies and sizes. Possible resulting particle morphologies include irregular particles, spheres or satellites, hollow spheres and cenospheres, solid particles, wrinkled particles, or encapsulated products. Particle sizes can range from 100 nm to 1000 μm. Spray drying is applied for drying liquids, micronization, encapsulation of liquids and solids, agglomeration, granulation, and the production of amorphous solid dispersions.

[0022] During the drying process, the liquid feedstock is transported through a nozzle, generating fine droplets that are subsequently sprayed into a heated drying chamber. Commonly applied nozzles include rotary atomizers, pressure nozzles, ultrasonic nozzles, and two-fluid and three-fluid nozzles of various diameters. In addition, inkjet, aerosol-assisted, and electrostatic atomizers are also feasible nozzle types. Figure 1 shows schematic diagrams of two-fluid and three-fluid nozzles.

[0023] In the heated drying chamber, the solvent system is completely removed by evaporation. The drying medium can be air or an inert gas that flows uniformly through the spray drying system. The flow of the drying gas can be co-current, counter-current, or mixed mode relative to the nozzle direction.

[0024] To further separate the dry particles from the drying gas, separation devices are used. For this purpose, cyclones, bag filters, wet collectors or electrostatic precipitators can be applied.

[0025] Two-fluid nozzles are a common setup where the liquid and gas come into contact either at the nozzle outlet or inside before exiting the spray zone. In both cases, there is one channel dedicated to the atomizing air and one additional channel for the liquid transported to the nozzle. Peristaltic pumps can be applied in this process. In the following, this method will be referred to as "two-fluid nozzle spray drying".

[0026] A three-fluid nozzle can be applied to independently supply two liquids. This nozzle includes a third channel for the supply of an additional liquid. This setup can be used to co-spray dry a diluent liquid, e.g., an immiscible system, or to facilitate encapsulation. Hereinafter, this method is referred to as "three-fluid nozzle spray drying." According to the present invention, the three-fluid nozzle has two channels for the liquid phase, an inner phase (inner channel) and an outer phase (outer channel), and one peripheral channel for atomizing air. (Bhujbal, Su, et al. 2021)

[0027] Polyvinyl alcohol (PVA) has the ideal formula [CH2CH(OH)] n It is a synthetic water-soluble polymer with excellent film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, in which the acetate functional groups are partially or completely hydrolyzed to alcohol functional groups. When not fully hydrolyzed, PVA is a random copolymer consisting of vinyl alcohol repeating units (CH2CH(OH)) and vinyl acetate repeating units (CH2CH(OOCCH)(III)). PVA's polarity is closely related to its molecular structure. The degree of hydrolysis and molecular weight determine its molecular properties. As the degree of hydrolysis of the acetate groups increases, the polymer's solubility in aqueous media, as well as its crystallinity and melting temperature, increase. However, at a degree of hydrolysis above 88%, the solubility of PVA decreases again. PVA is generally soluble in water but insoluble in almost all organic solvents, except in some cases, ethanol.

[0028] Typical PVA nomenclature indicates the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA 3-83 is a PVA grade that is 83% hydrolyzed and has a viscosity of 3 mPas, i.e., 83% vinyl alcohol repeat units and 17% vinyl acetate repeat units. Those skilled in the art will recognize that, according to common rounding rules, a calculated hydrolysis grade of 83% and a viscosity of 3 mPas encompasses calculated hydrolysis grades of 82.50% to 83.49% and viscosities of 2.50 mPas to 3.49 mPas. Viscosity according to the present invention is measured by the Viscosity Rotation Method (912) as described in USP 39 Monograph under "Polyvinyl Alcohol." The degree of hydrolysis according to the present invention is measured by determining the saponification number of the polyvinyl alcohol, as described, for example, in USP 39 Monograph "Polyvinyl Alcohol" under "Degree of Hydrolysis".

[0029] Sample: 1 g of polyvinyl alcohol previously dried to constant weight at 110°C analysis: The sample is transferred to a wide-mouth 250 ml conical flask attached to a reflux condenser using a suitable glass joint. 35 ml of dilute methanol (3 in 5) is added and gently mixed to ensure the solid is completely wetted. 3 drops of phenolphthalein TS are added and neutralized with 0.2 N hydrochloric acid or 0.2 N sodium hydroxide, if necessary. 25.0 ml of 0.2 N sodium hydroxide VS is added and gently refluxed on a hot plate for 1 hour. The condenser is rinsed with 10 ml of water, and the washings in the flask are collected, cooled, and titrated with 0.2 N hydrochloric acid VS. Concomitantly, a blank determination is performed in the same manner using the same amount of 0.2 N sodium hydroxide VS.

[0030] Calculation of saponification value: Calculate the saponification number: Result=[(VB-VS)×N×Mr] / W VB = volume (ml) of 0.2N hydrochloric acid VS consumed in the blank titration VS = volume (ml) of 0.2N hydrochloric acid VS consumed in titrating the sample solution N = Actual normality of hydrochloric acid VS Mr = molecular weight of potassium hydroxide, 56.11 W = weight of polyvinyl alcohol (g)

[0031] Calculation of the degree of hydrolysis: The degree of hydrolysis, expressed as a percentage of hydrolysis of polyvinyl acetate, is calculated. Result=100-[7.84×S / (100-0.075×S)) S = saponification value of polyvinyl alcohol

[0032] According to the present invention, the PVA grade, PVA3-82, refers to a PVA having the following specifications: pH: 5.0-6.5 Viscosity: 2.55-3.45 Ester value: 180-220

[0033] Ester number I according to Ph.Eur. 10.8 E is the amount of potassium hydroxide in milligrams required to saponify the esters present in 1 g of a substance. It is called the saponification number I s and acid number I A Calculated from: I E =I S -I A

[0034] The use of PVA grades according to the present invention is of interest for the formulation of solid oral pharmaceutical dosage forms with immediate, immediate or extended API release.

[0035] Preferred PVAs have a degree of hydrolysis of 70% to 90%, more preferably 74% to 88%. Regarding the viscosity of PVA grades for use according to the present invention, in principle, all PVA grades with a viscosity suitable for spray drying are applicable to the spray drying method according to the present invention. Those skilled in the art will know how to select a PVA grade with a viscosity suitable for these methods. In a preferred embodiment, the PVA has a viscosity of 20 mPas or less in a 4% solution at 20°C. In a further preferred embodiment, the PVA has a viscosity of 1 to 18 mPas in a 4% solution at 20°C. In an even more preferred embodiment, the PVA has a viscosity of 2 to 10 mPas in a 4% solution at 20°C. More preferably, the PVA has a viscosity of 2 to 5 mPas in a 4% solution at 20°C. Most preferably, the PVA has a viscosity of 3 to 5 mPas in a 4% solution at 20°C.

[0036] In one embodiment, the polyvinyl alcohol has a degree of hydrolysis of 70% to 90% and a viscosity of a 4% solution of 1 to 18 mPas at 20°C. In a preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis of 70 to 90% and a viscosity of a 4% solution of 2 to 10 mPas at 20°C. In a more preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis of 74 to 88% and a viscosity of a 4% solution of 2 to 5 mPas at 20°C. In a most preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis of 74 to 88% and a viscosity of a 4% solution of 3 to 5 mPas at 20°C.

[0037] Preferably, the polyvinyl alcohol is PVA3-80, PVA3-81, PVA3-82, PVA3-83, PVA2-88, PVA3-88, PVA4-88, PVA5-88, PVA2-74, PVA3-74, PVA4-74 or PVA5-74, more preferably PVA3-82, 4-88 or 5-74, most preferably PVA3-82.

[0038] The above PVA, PVA specifications and PVA grades apply equally to (i) the use of polyvinyl alcohol in the processes of spray drying and three-fluid nozzle spray drying, (ii) the processes for producing amorphous solid dispersions of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying and three-fluid spray drying, (iii) the amorphous solid dispersions of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by such processes, and (iv) pharmaceutical dosage forms comprising the amorphous solid dispersions of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by such processes.

[0039] An active pharmaceutical ingredient (API) is a biologically active agent. The API may be a small molecule in the form of a weakly basic, weakly acidic, or neutral molecule, and may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. The ASD of the present invention may contain one or more APIs. In one embodiment, the API is a poorly soluble or lipophilic API.

[0040] As used herein, the terms "poorly soluble API," "poorly water-soluble API," and "lipophilic API" refer to an API that has a solubility such that the highest therapeutic dose of the particular API administered to an individual cannot be dissolved in 250 ml of aqueous medium in the pH range of 1 to 8, according to the definition of low solubility by Biopharmaceutics Classification System (BCS) Classes 2 and 4. Poorly soluble APIs with weakly basic or weakly acidic characteristics have a pH-dependent solubility profile and can have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs that fall into BCS Classes 2 or 4, respectively, are well known to those skilled in the art.

[0041] In one embodiment, the API is a weakly basic API. As used herein, the term "weakly basic API" refers to a basic active pharmaceutical ingredient (API) that does not completely ionize in water.

[0042] In a preferred embodiment, the API is a PROTAC. According to the present invention, a "PROTAC" or "proteolysis-inducing chimera" is a heterobifunctional molecule composed of two active domains and a linker, which is capable of removing specific unwanted proteins. Compared to conventional enzyme inhibitors, PROTACs function by inducing selective intracellular protein degradation, consisting of two covalently linked protein-binding molecules: one capable of binding to an E3 ubiquitin ligase, and the other binding to the target protein intended for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome.

[0043] The API contained in the pharmaceutical dosage forms of the present invention is present in an amount sufficient to exert a therapeutic effect. For a given API, the therapeutically effective amount is generally known or readily accessible to those skilled in the art. Typically, the API may be present in the pharmaceutical dosage form in a weight ratio of API to polyvinyl alcohol of 0.1:99.1 to 60:40, preferably 1:99 to 50:50, more preferably 5:95 to 40:60, and most preferably 10:90 to 30:70.

[0044] According to the present invention, an amorphous solid dispersion of at least one active pharmaceutical ingredient is formed. As used herein, the term "amorphous solid dispersion" or "ASD" refers to a dispersion of at least one amorphous API in a PVA matrix. Preferably, the amorphous API is distributed in a molecularly dispersed state within the polymer matrix. In this case, the solid dispersion is a solid solution. The ASD according to the present invention does not exhibit significant diffraction peaks of the crystalline API in X-ray powder diffraction (XRD) measurements, and does not exhibit a melting peak of the API in differential scanning calorimetry (DSC) measurements. Upon dissolution, a formulation containing the amorphous solid dispersion can achieve a higher solubility in aqueous media than the crystalline API.

[0045] A further aspect of the present invention is a process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, comprising: a) preparing a feed solution comprising at least one active pharmaceutical ingredient and at least one polyvinyl alcohol having a degree of hydrolysis of 90% or less; b) spray drying the feed solution; The process comprises:

[0046] The spray drying can be two-fluid nozzle spray drying or three-fluid nozzle spray drying.

[0047] In a further aspect, it is a process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, comprising: a) preparing a first feed solution comprising at least one active pharmaceutical ingredient; b) preparing a second feed solution comprising polyvinyl alcohol having a degree of hydrolysis of 90% or less; c) spray drying the first and second feed solutions with a three-fluid nozzle; The process comprises:

[0048] Preferably, the first feed solution is the internal phase in the three-fluid nozzle and the second feed solution is the external phase.

[0049] The feed solution is typically prepared by dissolving the required amount of PVA in water. Preferably, deionized water is used. Preferably, the solution is heated to a temperature of 40°C or higher. Each API is dissolved in a suitable solvent under stirring until a solution is obtained. In a two-fluid nozzle setup, the API solution is added to the PVA solution. Alternatively, the feed solution for a two-fluid nozzle setup can be prepared in one step by directly dissolving the API and PVA in a suitable solvent.

[0050] Suitable solvents for preparing the feed solution are solvents commonly used in pharmaceutical and spray drying applications known to those skilled in the art, such as water, methanol, ethanol, acetone or mixtures thereof.

[0051] In further embodiments, the process can include additional steps, such as using a pneumatic pump to feed one or both solutions or suspensions into a two-fluid or three-fluid nozzle, each of which sprays liquid into a hot atomization chamber, where the particles are dried and collected in a separator.

[0052] For the avoidance of doubt, the process according to the present invention encompasses two-fluid nozzle spray drying and three-fluid nozzle spray drying using either PVA, PVA specification or PVA grade as defined above.

[0053] A further aspect of the present invention relates to an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by the process as defined above.

[0054] A further aspect of the present invention relates to a pharmaceutical dosage form comprising an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by a process as defined above.

[0055] For the avoidance of doubt, the amorphous solid dispersions and pharmaceutical dosage forms according to the present invention may comprise either PVA, PVA specification or PVA grade as defined above.

[0056] Surprisingly, it has been found that there is an optimum for a particular specification of PVA grade or range of PVA grades that can be beneficially used in a spray drying process to form an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix.

[0057] It has been found that only PVA grades with a degree of hydrolysis of 90% or less result in spray-dried ASDs with suitable amorphization grades and / or dissolution behavior. The viscosity of the PVA is not critical to ASD formation, as long as the viscosity is low enough for use in the spray-drying process. Suitable viscosities of PVA for the spray-drying process are known to those skilled in the art.

[0058] At a specific API loading in a PVA matrix, spray drying with a three-fluid nozzle yielded an amorphous product, while the commonly used two-fluid nozzle yielded a partially crystalline product (Figures 2-4). Surprisingly, we found that not all PVA grades were suitable for this particular method, as PVA 4-98 and PVA 3-98 exhibited dissolution issues when preparing the spray solution. Furthermore, other PVA grades did not yield the expected amorphized grade (PVA 2-98, Figure 9) and also exhibited poor solubility (Figure 5). Surprisingly, only PVA grades with a degree of hydrolysis below 90% yielded ASDs with favorable amorphized grades and dissolution behavior. PVA grades PVA 3-82, 4-88, and 5-74 showed the best results in both amorphized grades and dissolution. Unexpectedly, PVA 3-82 exhibited a superior dissolution profile compared to all other PVA grades. In addition, a PVA grade, PVA 3-82, was able to stabilize the amorphous form of the API in the ASD formulation during storage at different conditions, without any significant reduction in dissolution enhancement.

[0059] Furthermore, the PVA having the above-identified degree of hydrolysis and / or viscosity ensures and stabilizes the release and supersaturation of APIs, especially poorly soluble APIs, in aqueous media, thereby preventing crystallization and phase separation. Generally, low aqueous solubility of an API is associated with low bioavailability after its administration to pharmaceutical preparations, so the composition according to the present invention also contributes to improving the bioavailability of poorly water-soluble APIs, especially weakly basic APIs.

[0060] As used herein, "bioavailability" is a term that refers to the degree to which an API becomes available to target tissues after administration into a patient's body.

[0061] After dissolution of the pharmaceutical dosage form of the present invention, improved supersaturation is observed, and the API is better maintained in solution. Upon entry into the gastrointestinal tract, the pharmaceutical dosage form swells and disintegrates in the aqueous environment of the gastrointestinal fluid, thereby releasing the API. While salt forms of weakly basic APIs may exhibit improved initial aqueous concentrations in acidic gastric fluid, weakly basic APIs rapidly convert to their free base forms in more neutral intestinal fluids, where the free base form of the API has a significantly lower equilibrium concentration. The PVA of the present invention maintains improved concentrations of the API in model solutions simulating acidic and neutral gastrointestinal solutions compared to PVAs outside the stated specifications. Thus, the pharmaceutical dosage form of the present invention has the potential to improve the bioavailability of low-solubility APIs. The solubility-improved form of an API in the presence of PVA according to the present invention provides a concentration of the API in gastric fluid or simulated gastric fluid that is greater than the concentration of the API provided in the presence of PVAs outside the stated specifications. [Brief explanation of the drawings]

[0062] [Figure 1] FIG. 1 shows a schematic diagram of a two-fluid nozzle and a three-fluid nozzle. [Figure 2] FIG. 2 shows the results of XRD measurement. [Figure 3] FIG. 3 shows a DSC thermogram. [Figure 4] Figure 4 shows a comparison of 30% DL of KETO with 4-88 PVA using a two-fluid nozzle and suspension versus a three-fluid nozzle and solution setup. [Figure 5] FIG. 5 shows the dissolution enhancement in spray-dried ASDs prepared with PVA 4-88, PVA 3-82, PVA 2-98, and PVA 5-74.

[0063] [Figure 6] FIG. 6 shows the dissolution of ritonavir. [Figure 7] FIG. 7 shows the results of XRD measurement. [Figure 8] FIG. 8 shows the results of XRD measurement. [Figure 9] FIG. 9 shows the results of XRD measurement. [Figure 10] FIG. 10 shows the results of XRD measurement.

[0064] [Figure 11] FIG. 11 shows the results of XRD measurement. [Figure 12] FIG. 12 shows the results of XRD measurement. [Figure 13] FIG. 13 shows the results of XRD measurement. [Figure 14] FIG. 14 shows the results of XRD measurement. [Figure 15] FIG. 15 shows the dissolution of ketoconazole.

[0065] [Figure 16] FIG. 16 shows the results of XRD measurement. [Figure 17] FIG. 17 shows the results of XRD measurement. [Figure 18] FIG. 18 shows the molecular formula of PROTAC 1. [Figure 19] FIG. 19 shows the molecular formula of PROTAC 2. [Figure 20] FIG. 20 shows the molecular formula of PROTAC ARV-110.

[0066] [Figure 21] FIG. 21 shows the dissolution of spray-dried dispersions of PROTAC 1 with PVA 3-82 compared to original PROTAC 1 in phosphate buffer at pH 6.8. [Figure 22] FIG. 22 shows the dissolution of spray-dried dispersions of PROTAC 2 with PVA 3-82 compared to original PROTAC 2 in pH 6.8 phosphate buffer. [Figure 23]FIG. 23 shows the dissolution in pH 6.8 phosphate buffer of spray dried dispersions of ARV 110 with PVA 3-82 compared to the original ARV110. [Figure 24] FIG. 24 shows the results of XRD measurement. [Figure 25] FIG. 25 shows the results of XRD measurement.

[0067] [Figure 26] FIG. 26 shows the results of XRD measurement. [Figure 27] FIG. 27 shows the results of dissolution measurements. [Figure 28] FIG. 28 shows the results of dissolution measurements. [Figure 29] FIG. 29 shows the results of XRD measurement. [Figure 30] FIG. 30 shows the results of XRD measurement.

[0068] example: Example 1: Two-fluid nozzle spray drying versus three-fluid nozzle spray drying of solutions and suspensions The properties of products prepared by (i) two-fluid nozzle spray drying and (ii) three-fluid nozzle spray drying were compared using PVA grade, PVA 4-88, and ketoconazole (KETO) as API in solution and suspension.

[0069] spray drying The following feed solutions and suspensions (Table 1) were spray dried using a Büchi spray dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen.

[0070] [Table 1]

[0071] Two-fluid nozzle (i): PVA 4-88 is heated to 60°C at a rotation speed of 200 rpm and dissolved in deionized water on a magnetic stirrer. Ketoconazole is dissolved in the respective ethanol volume and added to the PVA solution. The solution (Formulation No. 1) or suspension (Formulation No. 2) is fed into a Büchi spray dryer. The solution is kept unstirred, while the suspension is stirred during the spraying process to prevent sediment formed during the process from being drawn into the spray chamber.

[0072] Three-fluid nozzle (ii): Prepare a solution of PVA 4-88 in water as described above (Formulation No. 3). Dissolve ketoconazole in methanol (MeOH). The feed solutions are pumped into a 50 mL syringe and inserted into a PHD ULTRA™ syringe pump (Harvard Apparatus, US): PVA 4-88 in water in the outer feed port and ketoconazole in MeOH in the inner feed port.

[0073] The following conditions were applied to the spray drying process: inlet temperature 100°C, outlet temperature 60°C, drying air flow rate 35 m 3 / h, (Aspirator: 100%), and atomization air flow rate 670 L / min (N2: 55 mm). The flow rate of the supply liquid is adjusted according to the outlet temperature.

[0074] PXRD Powder diffraction patterns were measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) with CuKα radiation (λ = 1.54 A). The samples were scanned in reflection mode from 3 to 50°2θ (deg) at a scan rate of 10°2θ (deg) / min and a step size of 0.020°2θ (deg). The results are shown in Figure 2. The accelerating voltage and current were 45 kV and 15 mA, respectively.

[0075] DSC As shown in Figure 3, DSC thermograms of the samples were collected using a DSC 3 (METTLER, US) under a nitrogen gas flow of 50 ml / min. A total of 2–5 mg of sample powder was loaded into an aluminum Tzero pan (40 μL) and sealed with an aluminum Tzero lid. The samples were analyzed at a heating rate of 5°C / min from -25°C to 230°C.

[0076] As can be seen in Figures 2 and 3, spray drying of a suspension of ketoconazole with PVA 4-88 leads to a partially crystalline product, while spraying of the respective solution leads to an amorphous product. In both examples, a two-fluid nozzle setup is used. It can be seen that a drug loading of 14% leads to a completely amorphous product, whereas a drug loading of 30% is not possible using the two-fluid nozzle.

[0077] Sharp signals in the X-ray diffraction of crystalline ketoconazole (Figure 2) can be found at 7.1, 17.4, 23.6, and 27.4° 2θ. These peaks are still visible as major signals in the spray-dried suspension of KETO in 4-88 PVA, but these patterns are not detectable in the XRD of the spray-dried product using each solution. The melting point of ketoconazole is defined as being in the range of 148°C to 150°C, and can be identified in the DSC of the ketoconazole-PVA suspension (Figure 3), but no such peak can be identified in the DSC curve of the spray-dried ketoconazole-PVA solution.

[0078] Increasing the drug loading to the desired 30% DL is not feasible for KETO because the solvent system used yields suspensions with DLs >14%. For higher DLs, a three-fluid nozzle setup is used. Figure 4 shows a comparison of 30% DL for KETO with 4-88 PVA using a two-fluid nozzle and suspension versus a three-fluid nozzle and solution setup. With the three-fluid nozzle setup, no sharp peaks are detectable at 7.1, 17.4, 23.6 and 27.4°2θ.

[0079] Example 2: Dissolution of ASD with different API and PVA grades Dissolution was tested using a three-fluid nozzle spray dryer ASD with indomethacin (INDO), ritonavir (RITO), and ketoconazole (KETO) as APIs and PVA grades PVA 2-98, PVA 3-82, PVA 4-88, and PVA 5-74. Additionally, PVA grades PVA 3-98 and 4-98 were investigated, but the process of spray drying this PVA grade was not feasible due to dissolution issues when preparing the spray solution.

[0080] Spray dried indomethacin ASD The following feed solutions were spray dried using a Büchi spray dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen.

[0081] Due to the different solubilities, a three-fluid nozzle was used. Feed port 1, the internal phase, contained 3 g of indomethacin in 50 mL of a 70:30 volumetric mixture of acetone and deionized water. Feed port 2, the external phase, contained the polymer solution. 7 g of PVA 5-74, PVA 3-82, PVA 4-88, PVA 2-98, PVA 3-98, and PVA 4-98 were dissolved in 50 mL of deionized water by heating on a magnetic stirrer at 60 °C and a rotation speed of 200 rpm. The feed solution was drawn up into a 50 mL syringe and inserted into a PHD ULTRA™ syringe pump (Harvard Apparatus, US).

[0082] The following conditions were applied to the spray drying process: inlet temperature 90°C, outlet temperature 50°C, drying air flow rate 35 m3 / h (Aspirator: 100%), and atomizing air flow rate 670 L / min (N2: 55 mm). The flow rate of the feed liquid is adjusted according to the outlet temperature.

[0083] Drug content determination of indomethacin by RP-HPLC To determine the drug loading, weigh 1 gram of sample into a 250 mL volumetric flask. Add 125 mL of Milli-Q water and stir with a magnetic stir bar at 500 rpm for 45 minutes. After filling the solution to 250 mL with acetonitrile, the sample must be filtered through a 0.45 μm filter and diluted 1:5 with mobile phase.

[0084] The mobile phase consisted of 1000 mL of acetonitrile and 1000 mL of indomethacin buffer USP (0.01 M NaHPO * The mixture is then placed in an ultrasonic bath for 15 minutes.

[0085] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. An LC-18 (Supelco, 4.0 × 300 mm, 5 μm) column was used for quantification, with a column oven temperature of 40°C. The injection volume was 10 μl, and the flow rate was 1 ml / min. The UV detection wavelength was 254 nm, and the retention time was approximately 2.4 min. Duplicate determinations and double injections were performed.

[0086] Dissolution Measurement Indomethacin ASD Dissolution of indomethacin is carried out in a Dissolution Sotax AT7 smart (Sotax AG, Loerrach, Germany) equipped with a fraction collector (Sotax C613) and a UV-visible spectrophotometer (UV-VIS Agilent 8453). Samples (25 mg of IND or 83.3 mg of solid dispersion particles (30% drug loading)) were added to 900 mL of SGFsp for disintegration testing using paddle stirring at a rotation speed of 75 rpm at 37°C. The drug concentration in the medium was measured spectrophotometrically at 318 nm (UV-VIS Agilent 8453). The path length was 10 mm.

[0087] Because indomethacin is poorly soluble at acidic pH, solubility enhancement was investigated using simulated gastric fluid (SGF). Figure 5 shows the dissolution enhancement in spray-dried ASDs prepared with PVA 4-88, PVA 3-82, PVA 2-98, and PVA 5-74. IND-PVA 3-82 exhibited excellent dissolution values, while IND-PVA 4-88 and IND-PVA 5-74 displayed similar dissolution behavior. IND-PVA 2-98 provided sufficient solution upon dissolution and was amenable to the spray-drying process, but the product exhibited unfavorable dissolution behavior. Additionally, PVA 4-98 and 3-98 were investigated, but spray-drying both PVA grades was not feasible due to dissolution issues when preparing the spray solution.

[0088] Spray-dried Ritonavir ASD The following feed solutions were spray dried using a Büchi spray dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen. Due to the different solubilities, a three-fluid nozzle was used. Feed port 1, the internal phase, contains 3 g of ritonavir in 50 mL of ethanol. Feed port 2, the external phase, contains the polymer solution. 7 g of PVA 4-88 or PVA 3-82 is dissolved in 50 mL of deionized water on a magnetic stirrer and heated to 60 °C with a rotation speed of 200 rpm. The feed solution is pumped into a 50 mL syringe and inserted into a PHD ULTRA™ syringe pump (Harvard Apparatus, US).

[0089] The following conditions were applied to the spray drying process: inlet temperature 100°C, outlet temperature 60°C, drying air flow rate 35 m 3 / h, (Aspirator: 100%), and atomization air flow rate 670 L / min (N2: 55 mm). The flow rate of the feed liquid is adjusted according to the outlet temperature.

[0090] Drug content determination of ritonavir by RP-HPLC Weigh 5-10 milligrams into a 50 mL volumetric flask. Add 25 mL of mobile phase and stir at 500 rpm with a magnetic stir bar until a clear solution is obtained. After filling the solution with mobile phase, the sample must be filtered through a 0.45 μm filter.

[0091] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using an RP-C18 (Supelco, 4.6 × 150 mm, 5 μm) column. The injection volume was 20 μl, and the flow rate was 1 ml / min. The mobile phase was a mixture of 2 g / L potassium phosphate monobasic in water and acetonitrile in a volume ratio of 45:55. The mobile phase was adjusted to pH 4.0±0.05 using phosphoric acid. The UV detection wavelength was 215 nm.

[0092] Dissolution Measurement Ritonavir ASD Dissolution of samples was determined in fasted state simulated intestinal fluid V2 (FaSSIF V2, Biorelevant). 20 mg of bulk drug or raw material equivalent was weighed into a 100 ml Erlenmeyer flask, 20 ml of dissolution medium was added, and the mixture was stirred at 200 rpm using a magnetic stir bar.

[0093] Two milliliters of dissolution medium were removed from the dissolution vessel at predetermined time points (5, 10, 20, 40, 60, 90, and 120 minutes) and immediately replaced with 2 milliliters of fresh dissolution medium. The samples were then filtered through a 0.45 μm filter, diluted with acetonitrile, and subsequently filtered again through a 0.45 μm filter. The drug content of the samples was analyzed using RP-HPLC.

[0094] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using an RP-C18 (Supelco, 4.6 × 150 mm, 5 μm) column. The mobile phase contained a mixture of potassium phosphate monobasic 2 g / L in water and acetonitrile in a volume ratio of 45:55. The mobile phase was adjusted to pH 4.0±0.05 using phosphoric acid. The flow rate was 1 ml / min, and the injection volume was 20 μl, with a UV detection wavelength of 215 nm.

[0095] Ritonavir exhibits low solubility and bioavailability values ​​and is therefore classified as BSC Class IV. The dissolution of a spray-dried amorphous solution of ritonavir is improved using PVA, as can be seen in Figure 6. To demonstrate the improved dissolution, a biorelevant medium, FaSSIF (Fasted State Simulated Intestinal Fluid), was used, which mimics the dissolution process of an API in the upper intestine. PVA 4-88 improves the dissolution of the crystalline API by approximately four orders of magnitude. PVA 3-82 performs superiorly, showing a seven order of magnitude improvement in dissolution compared to the crystalline material at 120 minutes.

[0096] Spray dried ketoconazole ASD The following feed solutions were spray dried using a Büchi spray dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen.

[0097] Due to the different solubilities, a three-fluid nozzle was used. Feed port 1, the internal phase, contains 3 g of ketoconazole in 50 mL of ethanol. Feed port 2, the external phase, contains the polymer solution. 7 g of PVA 2-98, PVA 3-82, PVA 4-88, and PVA 5-74 are dissolved in 50 mL of deionized water by heating on a magnetic stirrer at 60 °C and a rotation speed of 200 rpm. The feed solution is drawn up into a 50 mL syringe and inserted into a PHD ULTRA™ syringe pump (Harvard Apparatus, US).

[0098] The following conditions were applied to the spray drying process: inlet temperature 100°C, outlet temperature 60°C, drying air flow rate 35 m 3 / h, (Aspirator: 100%), and atomization air flow rate 670 L / min (N2: 55 mm). The flow rate of the feed liquid is adjusted according to the outlet temperature.

[0099] Dissolution Measurement Ketoconazole ASD Dissolution of ketoconazole is carried out in a Dissolution Sotax AT7 smart (Sotax AG, Lorrach, Germany) equipped with a fraction collector (Sotax C613) and a UV-visible spectrophotometer (UV-VIS specord 200 plus). Samples (400 mg ketoconazole or 1333 mg solid dispersion particles (30% drug loading)) were added to 500 mL of FaSSIF for disintegration testing using paddle stirring at a rotation speed of 50 rpm at 37°C.

[0100] 2 ml samples are taken at 30, 60, 120, 135, 150, 180, 240 and 300 minutes. The sample solution is filtered through a 0.45 μm filter into a vial and diluted 1:1 with ethanol. An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. An LC-18 (Supelco, 4.0 × 300 mm, 5 μm) column was used for quantification, with a column oven temperature of 40°C. The injection volume was 5 μl, and the flow rate was 2 ml / min.

[0101] The mobile phase is split into two eluents (70% eluent A / 30% eluent B). Eluent A is a mixture of 10 mL of diisopropylamine in 5 L of methanol. Eluent B uses 5 g / L of ammonium acetate in Milli-Q water. The UV detection wavelength was 225 nm, and the retention time was approximately 5.7 minutes.

[0102] Figure 15 shows the improved dissolution of 30% (w / w) ketoconazole in FaSSIF as spray-dried ASD containing PVA 4-88, PVA 3-82, PVA 5-74, and PVA 2-98 compared to the crystalline product. PVA 3-82, followed by PVA 4-88, significantly improved ketoconazole dissolution. PVA 2-98 showed improved release within the first 20 minutes, but recrystallization of ketoconazole led to dissolution comparable to that of the crystalline material. PVA 5-74 showed a nearly linear increase in ketoconazole dissolution, reaching the second-best dissolution value at 120 minutes.

[0103] Example 3: XRD of ASD with different API and PVA grades XRD measurements were carried out using a three-fluid nozzle spray dryer ASD of ketoconazole (KETO), ritonavir (RITO) and indomethacin (INDO) as APIs using PVA grades, PVA 2-98, PVA 3-82, PVA 4-88 and PVA 5-74. Spray-dried ASD was prepared as described in Example 2, and XRD measurements were carried out as described in Example 1. The results are shown in Figures 7 to 14.

[0104] XRD measurements (Figures 7-14, 16 and 17) show that spray drying with PVA 3-82, 4-88, and 5-74 leads to products with good amorphization of the API. XRD of spray-dried PVA 2-98 (Figures 9 and 16) shows that the product does not have a completely amorphous state, exacerbating the slower dissolution rate (Figure 5).

[0105] Example 4: Three-fluid nozzle spray drying of ASD using PROTAC as API Spray drying PROTAC ASD The following PROTACs were used: PROTAC 1 (molecular formula see Figure 18), PROTAC 2 (molecular formula see Figure 19) and PROTAC ARV-110 (molecular formula see Figure 20). For PROTACs 1 and 2, the following feed solutions were spray dried using a Büchi spray dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen.

[0106] Due to the different solubilities, a three-fluid nozzle was used. Feed port 1, the internal phase, contains 70 mg of PROTAC in 25 mL of ethanol. Feed port 2, the external phase, contains the polymer solution. 140 mg of PVA 3-82 is dissolved in 25 mL of deionized water on a magnetic stirrer and heated to 60 °C with a rotation speed of 200 rpm. The feed solution is pumped into the spray dryer with the help of a peristaltic pump.

[0107] The following conditions were applied to the spray drying process: inlet temperature 90°C, outlet temperature 50°C, drying air flow rate 35 m3 / h (Aspirator: 100%), and atomizing air flow rate 670 L / min (N2: 55 mm). The flow rate of the feed liquid is adjusted according to the outlet temperature.

[0108] For PROTAC ARV-110, the feed solution below was spray dried using a Büchi Spray Dryer B-290 (Büchi, Switzerland) equipped with a high-efficiency cyclone and a Büchi Inert Loop B-295 (Büchi, Switzerland), and the system was inertized with nitrogen.

[0109] Due to the different solubilities, a three-fluid nozzle was used. Feed port 1, the internal phase, contains 400 mg of PROTAC in 550 mL of DCM:MeOH (40:60). Feed port 2, the external phase, contains the polymer solution. 932 mg of PVA 3-82 is dissolved in 550 mL of deionized water on a magnetic stirrer. The feed solution is pumped into the spray dryer with the help of a peristaltic pump.

[0110] The following conditions were applied to the spray drying process: inlet temperature 80°C, outlet temperature 45°C, drying air flow rate 35 m3 / h (Aspirator: 100%), and atomizing air flow rate 670 L / min (N2: 55 mm). The flow rate of the feed liquid is adjusted according to the outlet temperature.

[0111] Determining the drug content of PROTACs For PROTACs 1 and 2, dissolve 1 mg of sample in 50 ml of DMSO. Samples should be filtered through a 0.45 μm filter.

[0112] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using an RP-C18 (Phenomenex, 4.6 × 250 mm, 5 μm) column. The injection volume was 50 μl, and the flow rate was 1 ml / min. The eluents are made up as follows: Eluent A: 0.1% TFA in water; Eluent B: 0.1% TFA in acetonitrile.

[0113] For PROTAC ARV-110, dissolve 1 mg of sample in 50 ml of DMSO. Samples should be filtered through a 0.45 μm filter.

[0114] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Diode-Array Detector was used. A Waters XBridge Column C8 (4.6 × 50 mm, 3.5 μm) was used for quantification. The injection volume was 5 μl, and the flow rate was 1.7 ml / min. The eluents were as follows: eluent A: 0.1% formic acid in water; eluent B: 0.1% formic acid in acetonitrile.

[0115] Dissolution measurements of PROTAC ASDs For PROTACs 1 and 2, sample dissolution was determined in phosphate buffer, pH 6.8, as the dissolution medium. Five mg of bulk drug or a spray-dried powder sample equivalent to 5 mg of drug was weighed into a 100 ml Erlenmeyer flask. A magnetic stir bar was then added to the Erlenmeyer flask, stirred at 200 rpm, and 25 ml of dissolution medium was then added (concentration: 0.2 mg / ml).

[0116] At predetermined time points (5, 10, 20, 40, 60, 90, and 120 minutes), 500 μl of sample was removed from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolved sample was then filtered through a 0.45 μm filter. Finally, the sample was analyzed for drug content using HPLC.

[0117] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using an RP-C18 (Phenomenex, 4.6 × 250 mm, 5 μm) column. The injection volume was 50 μl, and the flow rate was 1 mL / min. The eluents are composed as follows: Eluent A: 0.1% TFA in water; Eluent B: 0.1% TFA in acetonitrile. The method was as follows: a linear gradient of eluent B from 0 to 100% in 25 minutes.

[0118] For PROTAC ARV-110, sample dissolution was determined at room temperature in phosphate buffer pH 6.8 as the dissolution medium. 5 mg of bulk drug or a spray-dried powder sample equivalent to 5 mg of drug was weighed into a 100 ml Erlenmeyer flask. A magnetic stir bar was then added to the Erlenmeyer flask, stirred at 200 rpm, and 25 ml of dissolution medium was then added (concentration: 0.2 mg / ml).

[0119] At predetermined time points (5, 10, 20, 40, 60, 90, and 120 minutes), 500 μl of sample was removed from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolved sample was then filtered through a 0.45 μm filter. The sample was diluted with eluent B (1:1). Finally, the sample was analyzed for drug content using HPLC.

[0120] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using a C8 column (Waters XBridge Column C8, 4.6 × 50 mm, 3.5 μm). The injection volume was 5 μl, and the flow rate was 1.7 ml / min. The eluents were composed as follows: Eluent A: 0.1% formic acid in water; Eluent B: 0.1% formic acid in acetonitrile. Method: Eluent B was applied at a flow rate of 1.7 mL / min with a linear gradient from 10% to 90% in 2 min.

[0121] Figures 21-23 show the dissolution of spray-dried dispersions of PROTAC 1, PROTAC 2, and ARV110 with PVA 3-82 compared to the original PROTAC 1, PROTAC 2, and ARV110 in phosphate buffer at pH 6.8. It can be seen that none of the original PROTAC 1, PROTAC 2, or ARV110 exhibits measurable dissolution in phosphate buffer over 120 minutes. For all three examples, spray-dried dispersions of PVA 3-82 with the respective PROTAC exhibit improved dissolution. While PROTAC 1 exhibits a significant increase in dissolution with a continuous decrease in release values ​​within the first 30 minutes, for PROTAC 2, the enhanced release stabilizes over the 120-minute period. Additionally, ARV110 is stabilized with a higher level of dissolved drug compared to the crystalline material, demonstrating the rapid onset of the spray-dried dispersion as well as extended release over the entire 120-minute period.

[0122] Powder X-ray diffraction Powder diffraction patterns were measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) with CuKα radiation (λ = 1.54 A). Samples were scanned in reflection mode from 3 to 50°2θ (deg) at a scan rate of 10°2θ (deg) / min and a step size of 0.020°2θ (deg). The accelerating voltage and current were 45 kV and 15 mA, respectively. XRD measurements (Figures 24-25) show that both the raw material and spray-dried PROTAC1 and PROTAC are amorphous. PROTAC ARV-110 is crystalline in the raw material, and the spray-dried dispersion using PVA 3-82 is amorphous (Figure 26).

[0123] Example 5: ASD stability measurement To investigate the stability of the PVA 3-82-ARV110 formulation, the spray dried and raw products were stored using the following conditions and investigated by dissolution experiments and X-ray diffraction after 4 weeks. [Table 2] Samples of spray-dried PVA 3-82 / ARV110 are still amorphous after 4 weeks of storage at either 5°C in a refrigerator (Figure 29) and 25°C at 60% rH (Figure 30). Additionally, the samples do not show a significant reduction in dissolution enhancement compared to dissolutions performed at t=0 (Figures 27 and 28).

[0124] Dissolution measurements of PVA 3-82 / ARV110 from stability studies For PROTAC ARV-110, sample dissolution was determined at room temperature in phosphate buffer pH 6.8 as the dissolution medium. Five mg of bulk drug or spray-dried powder from the stability study, equivalent to 5 mg of drug, was weighed into a 100 ml Erlenmeyer flask. A magnetic stir bar was then added to the Erlenmeyer flask and stirred at 200 rpm. 25 ml of dissolution medium was then added (concentration: 0.2 mg / ml).

[0125] At predetermined time points (5, 10, 20, 40, 60, 90, and 120 minutes), 500 μl of sample was removed from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolved sample was then filtered through a 0.45 μm filter. The sample was diluted with eluent B (1:1). Finally, the sample was analyzed for drug content using HPLC.

[0126] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II Variable Wavelength Detector was used. Quantitative analysis was performed using a C8 column (Waters XBridge column C8, 4.6 × 50 mm, 3.5 μm). The injection volume was 5 μl and the flow rate was 1.7 ml / min. The eluents were composed as follows: Eluent A: 0.1% formic acid in water; Eluent B: 0.1% formic acid in acetonitrile. Method: A linear gradient of eluent B from 10% to 90% in 2 minutes was used at a flow rate of 1.7 mL / min.

[0127] Powder X-ray diffraction Powder diffraction patterns were measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) with CuKα radiation (λ = 1.54 A). Samples were scanned in reflection mode from 3 to 50°2θ (deg) at a scan rate of 10°2θ (deg) / min and a step size of 0.020°2θ (deg). The accelerating voltage and current were 45 kV and 15 mA, respectively.

[0128] literature - Bhujbal, SV, B. Mitra, U. Jain, Y. Gong, A. Agrawal, S. Karki, LS Taylor, S. Kumar, and Q. Tony Zhou. 2021. 'Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies', Acta Pharm Sin B, 11: 2505-36. - Bhujbal, SV, Y. Su, V. Pathak, DY Zemlyanov, AA Cavallaro, EJ Munson, LS Taylor, and QT Zhou. 2021. 'Effect of Storage Humidity on Physical Stability of Spray-Dried Naproxen Amorphous Solid Dispersions with Polyvinylpyrrolidone: Two Fluid Nozzle vs. Three Fluid Nozzle', Pharmaceutics, 13. - Brough et al., Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 1), AAPS PharmSciTech Vol. 17, No.1, p. 176 (01.02.2016) - Focaroli, S., G. Jiang, P. O'Connell, J. V. Fahy, and A. M. Healy. 2020. 'The Use of a Three-Fluid Atomising Nozzle in the Production of Spray-Dried Theophylline / Salbutamol Sulphate Powders Intended for Pulmonary Delivery', Pharmaceutics, 12. - Fouad, E. A., M. El-Badry, G. M. Mahrous, F. K. Alanazi, S. H. Neau, and I. A. Alsarra. 2011. 'The use of spray-drying to enhance celecoxib solubility', Drug Dev Ind Pharm, 37: 1463-72. - Hugo, M., K. Kunath, and J. Dressman. 2013. 'Selection of excipient, solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate', Drug Dev Ind Pharm, 39: 402-12. - Kim, D. H., Y. W. Kim, Y. Y. Tin, M. T. Soe, B. H. Ko, S. J. Park, and J. W. Lee. 2021. 'Recent Technologies for Amorphization of Poorly Water-Soluble Drugs', Pharmaceutics, 13. - Ziaee, A., A. B. Albadarin, L. Padrela, T. Femmer, E. O'Reilly, and G. Walker. 2019. 'Spray-drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches', Eur J Pharm Sci, 127: 300-18.

Claims

1. 1. Use of polyvinyl alcohol in a spray drying process to form an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix, wherein the polyvinyl alcohol has a degree of hydrolysis of 90% or less.

2. 2. The use according to claim 1, wherein the polyvinyl alcohol has a degree of hydrolysis of 74 to 88% and a viscosity of a 4% solution at 20°C of 2 to 5 mPas.

3. 3. The use according to claim 1 or 2, wherein the polyvinyl alcohol is PVA3-80, PVA3-81, PVA3-82, PVA3-83, PVA2-88, PVA3-88, PVA4-88, PVA5-88, PVA2-74, PVA3-74, PVA4-74 or PVA5-74.

4. 4. The use according to any one of claims 1 to 3, wherein the polyvinyl alcohol is PVA 3-82, 4-88 or 5-74.

5. The use according to any one of claims 1 to 4, wherein the polyvinyl alcohol is PVA3-82.

6. 6. The use according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient is a PROTAC.

7. The use according to any one of claims 1 to 6, wherein the process for spray drying is three-fluid nozzle spray drying.

8. 1. A process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, comprising: a) preparing a feed solution comprising at least one active pharmaceutical ingredient and at least one polyvinyl alcohol having a degree of hydrolysis of 90% or less; b) spray drying the feed solution; The process comprising:

9. 1. A process for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, comprising: a) preparing a first feed solution comprising at least one active pharmaceutical ingredient; b) preparing a second feed solution comprising polyvinyl alcohol having a degree of hydrolysis of 90% or less; c) spray drying the first and second feed solutions with a three-fluid nozzle; The process comprising:

10. 10. The process according to claim 8 or 9, wherein the polyvinyl alcohol has a degree of hydrolysis of 74 to 88% and a viscosity of a 4% solution at 20°C of 2 to 5 mPas.

11. 11. The process of any one of claims 8 to 10, wherein the polyvinyl alcohol is PVA 3-82, 4-88 or 5-74.

12. The process according to any one of claims 8 to 11, wherein the polyvinyl alcohol is PVA3-82.

13. 13. The process of any one of claims 8 to 12, wherein the active pharmaceutical ingredient is a PROTAC.

14. 14. An amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by the process according to any one of claims 8 to 13.

15. 15. The amorphous solid dispersion of claim 14, wherein the active pharmaceutical ingredient is a PROTAC.

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