Spray-dried amorphous solid dispersions and methods of making

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 invention relates to a method for producing an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying.

Description

Technical Field

[0001] 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 method for producing an amorphous solid dispersion of an active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying. Background Art

[0002] When active pharmaceutical ingredients (APIs) exhibit poor solubility and / or poor bioavailability, careful formulation design of drug products is required. The Biopharmaceutics Classification System (BCS) classifies these APIs into Class II (poor solubility) and Class IV (poor solubility and poor bioavailability). They pose a challenge to the dissolution of the final formulation, and since 40% of marketed products and 70-90% of new chemical entities (NCEs) are classified as Class II and Class IV of the BCS, this challenge affects most formulation efforts. Greater lipophilicity, higher molecular weight, and the resulting poor aqueous solubility stem from the rising trend in combinatorial chemistry and new drug design.

[0003] Poor aqueous solubility is usually associated with a stable crystalline state of the API. This state can be overcome by disrupting the crystal lattice and creating an amorphous state. This state shows a higher energy form, but is not as stable as the crystalline counterpart of the same API. Due to this higher energy state, the amorphous form leads to an increase in apparent solubility, which leads to a supersaturated state and increased bioavailability in the gastrointestinal tract (GIT). This behavior is described in the analogy of a spring-parachute: the additional free energy and increased dissolution are called the spring, while the parachute helps to slow down the reduction of the freely dissolved drug. A parachute is an auxiliary material that additionally helps to stabilize the high-energy amorphous state of the API, prolong storage and facilitate processing and manufacturing. This material is called a carrier and can be, for example, a polymer. The polymer reduces the molecular mobility of the API, increases the glass transition temperature, protects the API from recrystallization, and if the polymer itself is water-soluble, can also promote wetting during dissolution.

[0004] To generate these polymer amorphous solid dispersions (PASD / ASD), methods including 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, as the liquid feedstock in which the API and polymer are dissolved is forwarded and sprayed into a drying chamber to produce dry microparticles, which can then be collected. This technology is the method of choice for heat-sensitive materials, as the cooling effect during the evaporation of the liquid protects the microparticles during the drying process, which also takes only milliseconds. The advantage of this rapid drying is a well-mixed drug-polymer system in the product. SD can be applied in all development stages: from discovery to development, and can later be scaled up to commercial processes. Among marketed pharmaceutical 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 the feedstock, the liquid is delivered through a nozzle. For pharmaceutical applications, pneumatic nozzles are mainly used. The liquid is atomized by a gas flow, which can be air or a selected inert gas (Ziaee et al., 2019). Droplets are produced at the tip of the nozzle, where the liquid stream is disrupted by the gas flow. These nozzles are multifluid, with a 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 make spray drying possible due to the availability of two fluid channels. 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, the selected ingredients are typically dissolved or dispersed in a common solvent that is used as a feed solution or feed suspension. The feedstock is then forwarded to a two-fluid nozzle where one channel holds the liquid and the other holds a pressurized gas (N2 or air). The demand for an amorphous form of the API is typically based on poor water solubility, so the API is dissolved in an organic solvent. To generate an ASD, the polymer is dissolved in the same solvent and spray dried to produce the desired product. An amorphous state can only be produced when the API is completely dissolved, and dispersions or suspensions result in unstable or crystalline products (Bhujbal, Mitra et al., 2021).

[0007] There are many polymers that are soluble in organic solvents, but co-solubility of the API and polymer is not always feasible. For such challenging combinations, a setup using a three-fluid nozzle may be a solution, where an additional channel can be used to forward a second liquid stream. This could be applicable to the generation of ASDs using an API (naproxen) and a polymer (PVP) (Bhujbal, Su et al., 2021) or 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 for 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 formed of amorphous solid dispersions with poorly soluble active pharmaceutical ingredients (APIs). ASDs with PVA as a polymer are known to significantly increase the solubility of poorly water-soluble drugs (Brough et al., 2016). Although the preparation of ASDs containing PVA by melting (e.g., melting or hot melt extrusion) has been well described, there is little or no experience in preparing ASDs containing PVA by spray drying methods. The only publication using PVA in a spray drying application was published in 2011 and describes the use of PVA 22,000 and celecoxib in a suspension fed by a two-fluid nozzle (Fouad et al., 2011). One disadvantage is that not all of the generated products are completely amorphous in XRD, which makes these compositions unsuitable for solubility enhancement and pharmaceutical use. Furthermore, polyvinyl alcohol is not listed as a suitable polymer for producing ASD (Hugo, Kunath, & Dressman, 2013), and another recent review excludes 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 key steps. PVA is only soluble in water (or water-ethanol / water-methanol systems), while poorly soluble APIs usually require organic solvents. Therefore, co-dissolution is challenging and not feasible to generate stable ASD using PVA.

[0010] By creating an amorphous solid dispersion, the two components, drug and polymer, are usually dissolved in a common solvent. This is usually a limitation of water-based polymers such as PVA and is the reason why they are not considered suitable for spray drying due to their limited solubility in organic solvents. This usually excludes the use of common solvents for polymers and poorly soluble drugs. In addition, the PVA grade defines the realization of solubility enhancement of poorly soluble APIs, so not every PVA grade is suitable. In addition, the water solubility itself depends largely on the degree of hydrolysis and molecular weight of the corresponding PVA grade.

[0011] Currently, spray drying of PVA is rarely used in pharmaceutical processes due to the limited solubility of classic PVA grades in common solvents or solvent mixtures.

[0012] Therefore, there is a need for a method for preparing spray-dried ASD using PVA as polymer. Another object of the present invention is to find the best PVA grade and / or PVA grade range suitable for spray drying to make ASD. In addition, a combination of (i) the best PVA grade and / or PVA grade range and (ii) spray drying technology is needed to improve the properties of the resulting ASD. The specific properties to be improved are 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] Surprisingly, it was found that PVA having a degree of hydrolysis of 90% or less is particularly suitable for preparing ASD using spray drying, in particular three-fluid spray drying, as it results in improved amorphization, dissolution and / or stability of the API.

[0014] When dissolving the API and PVA in two different solvents and using a setup with a three-fluid nozzle, target the co-dissolution issue, especially when the required drug loading cannot be achieved in a two-fluid nozzle setup. In addition, the PVA grade needs to be carefully evaluated. While high viscosity values ​​lead to rapid nozzle clogging, highly hydrolyzed grades may cause solubility issues with PVA.

[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 and 5 mPas, in particular the PVA is PVA 3-82, 4-88 or 5-74.

[0016] A further embodiment of the present invention is a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, the method comprising the steps of:

[0017] a) preparing a first feed solution comprising the at least one active pharmaceutical ingredient,

[0018] b) preparing a second feed solution comprising polyvinyl alcohol having a degree of hydrolysis of 90% or less,

[0019] c) spray drying the first and second feed solutions using a three-fluid nozzle, preferably wherein the first feed solution is the inner phase and the second feed solution is the outer phase in the three-fluid nozzle.

[0020] In another aspect, the present invention provides a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, the method comprising the steps of:

[0021] a) preparing a feed solution comprising the at least one active pharmaceutical ingredient and at least one polyvinyl alcohol having a degree of hydrolysis of 90% or less,

[0022] b) spray drying the feed solution.

[0023] 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, which dispersion is obtainable by the process defined above.

[0024] 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, which dispersion is obtainable by the process defined above. DETAILED DESCRIPTION

[0025] An embodiment of the present invention is the use of polyvinyl alcohol in a process for spray drying 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.

[0026] In a specific embodiment, the spray drying is three-fluid nozzle spray drying.

[0027] Spray drying is a method of converting a liquid into a dry state. The solvent used can be aqueous or any organic solvent or a mixture thereof. The liquid form can be a solution, suspension, dispersion, emulsion or paste, and the resulting dry product can be a powder, agglomerate or granules with various particle morphologies and particle sizes. The particle morphologies that may be produced are irregular particles, spheres or satellites, hollow spheres and hollow microbeads, solid particles, shrunken particles or encapsulated products. The particle size range can be from 100nm to 1000μm. Spray drying is suitable for drying, micronization of liquids, encapsulation of liquids and solids, agglomeration, granulation, and the production of amorphous solid dispersions.

[0028] During the drying process, the liquid feed is delivered through a nozzle that produces fine droplets that are subsequently ejected into a heated drying chamber. Commonly used 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 possible nozzle types. Schematics of two-fluid and three-fluid nozzles can be seen in Figure 1 .

[0029] In the heated drying chamber, the solvent system is completely removed by evaporation. The drying medium can be air or an inert gas, which flows through the spray drying system in a uniform manner. The flow of the drying gas can be in co-current, counter-current or mixed mode with the nozzle direction.

[0030] In order to further separate the dried particles from the drying gas, a separation device is used. For this purpose, a cyclone separator, a bag filter, a wet collector or an electrostatic precipitator can be applied.

[0031] The two-fluid nozzle is a common setup in which the liquid and gas come into contact at the outlet of the nozzle or inside and then flow out into the spray area. In both cases, there is a dedicated channel for the atomizing air and an additional channel for the liquid delivered into the nozzle. For this process, a peristaltic pump can be applied. In the following, this method is referred to as "two-fluid nozzle spray drying".

[0032] In order to supply two liquids independently, a three-fluid nozzle can be applied. The nozzle includes a third channel for an additional liquid feed. Using this setup, multiple liquids (e.g., immiscible systems) can be co-spray dried or encapsulated. In the following, 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 phases, namely the inner phase (inner channel) and the outer phase (outer channel), and a surrounding channel for atomizing air (Bhujbal, Su et al., 2021).

[0033] Polyvinyl alcohol (PVA) is a synthetic water-soluble polymer with an idealized molecular formula of [CH2CH(OH)] n. It has good 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. If not completely hydrolyzed, PVA is a random copolymer composed of vinyl alcohol repeating units -[CH2CH(OH)]- and vinyl acetate repeating units -[CH2CH(OOCCH3)]-. The polarity of PVA is closely related to its molecular structure. The degree of hydrolysis and molecular weight determine the molecular properties of PVA. As the degree of hydrolysis of the acetate groups increases, the solubility of the polymer in aqueous media, as well as the crystallinity and melting temperature of the polymer increase. However, at a high degree of hydrolysis of more than 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but is almost insoluble in almost all organic solvents, excluding ethanol in some cases.

[0034] 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 with a viscosity of 3 mPas and 83% hydrolysis, i.e., 83% vinyl alcohol repeating units and 17% vinyl acetate repeating units. The skilled person knows that, according to the common rounding method, an 83% hydrolysis grade and a viscosity of 3 mPas include calculated hydrolysis grades of 82.50% to 83.49% and calculated viscosities of 2.50 mPas to 3.49 mPas. The viscosity according to the invention is measured as described in USP 39 under the monograph "Polyvinyl Alcohol" using the method Viscosity-Rotation (912).

[0035] The degree of hydrolysis according to the invention is measured by determining the saponification value of the polyvinyl alcohol, for example, as described in USP 39 under "Degree of Hydrolysis" in the monograph "Polyvinyl Alcohol":

[0036] Sample: 1g polyvinyl alcohol, dried to constant weight at 110°

[0037] analyze:

[0038] Transfer the sample to a wide-mouthed 250 ml conical flask, which is mounted on a reflux condenser via a suitable glass joint. Add 35 ml of dilute methanol (3 / 5) and mix gently to ensure that the solid is completely wetted. Add 3 drops of phenolphthalein TS and, if necessary, add 0.2 N hydrochloric acid or 0.2 N sodium hydroxide to neutralize. Add 25.0 ml of 0.2 N sodium hydroxide VS and reflux gently on a hot plate for 1 hour. Wash the condenser with 10 ml of water, collect the washings in the flask, cool, and titrate with 0.2 N hydrochloric acid VS. At the same time, perform a blank determination using the same amount of 0.2 N sodium hydroxide VS in the same manner.

[0039] Calculation of saponification value:

[0040] Calculate the saponification value:

[0041] Result = [(VB-VS) × N × Mr] / W

[0042] VB = volume of 0.2N hydrochloric acid VS consumed in blank titration (ml)

[0043] VS = Volume of 0.2N hydrochloric acid VS consumed in the titration of the sample solution (ml)

[0044] N = actual equivalent concentration of hydrochloric acid VS

[0045] Mr = molecular weight of potassium hydroxide, 56.11

[0046] W = weight of the polyvinyl alcohol portion taken (g)

[0047] Calculation of degree of hydrolysis:

[0048] Calculate the degree of hydrolysis, expressed as the percentage of hydrolysis of polyvinyl acetate:

[0049] Result = 100 - [7.84 × S / (100 - 0.075 × S))

[0050] S = saponification value of polyvinyl alcohol

[0051] According to the present invention, PVA grade PVA 3-82 refers to a PVA having the following specifications:

[0052] pH: 5.0-6.5

[0053] Viscosity: 2.55-3.45

[0054] Ester value: 180-220

[0055] According to European Pharmacopoeia 10.8, ester value I E It is a number that expresses in milligrams the amount of potassium hydroxide required to saponify the esters present in 1 gram of a substance. It is determined by the saponification value I S and acid value I A calculate:

[0056] I E =I S -I A

[0057] The use of PVA grades according to the present invention has important implications for the formulation of solid oral pharmaceutical dosage forms with instant, immediate or prolonged API release.

[0058] Preferred PVA has a degree of hydrolysis between 70% and 90%, more preferably between 74% and 88%. Regarding the viscosity of the PVA grades used according to the present invention, in principle all PVA grades with a viscosity suitable for spray drying are suitable for the spray drying method according to the present invention. Those skilled in the art know to select PVA grades with suitable viscosities for these methods. In a preferred embodiment, the PVA has a viscosity of 20 mPas or less for a 4% solution at 20°C, in a further preferred embodiment, the PVA has a viscosity of between 1 and 18 mPas for a 4% solution at 20°C, in a further preferred embodiment, the PVA has a viscosity of between 2 and 10 mPas for a 4% solution at 20°C, more preferably a viscosity of between 2 and 5 mPas for a 4% solution at 20°C, and most preferably a viscosity of between 3 and 5 mPas for a 4% solution at 20°C.

[0059] In one embodiment, the polyvinyl alcohol has a degree of hydrolysis between 70% and 90% and a viscosity of 1 to 18 mPas as a 4% solution at 20° C. In a preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis between 70% and 90% and a viscosity of 2 to 10 mPas as a 4% solution at 20° C. In a more preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis between 74% and 88% and a viscosity of 2 to 5 mPas as a 4% solution at 20° C. In a most preferred embodiment, the polyvinyl alcohol has a degree of hydrolysis between 74% and 88% and a viscosity of 3 to 5 mPas as a 4% solution at 20° C.

[0060] Preferably, the polyvinyl alcohol is PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 2-88, PVA 3-88, PVA 4-88, PVA 5-88, PVA 2-74, PVA 3-74, PVA 4-74 or PVA 5-74, more preferably PVA 3-82, 4-88 or 5-74, most preferably PVA 3-82.

[0061] The above-mentioned PVA, PVA specifications and PVA grades are also applicable to (i) the use of polyvinyl alcohol in methods for spray drying and three-fluid nozzle spray drying, (ii) methods for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying and three-fluid spray drying, (iii) an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by such a method and (iv) a pharmaceutical dosage form comprising an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix obtainable by such a method.

[0062] Active pharmaceutical ingredients (APIs) are bioactive agents. APIs can be small molecules in the form of weak bases, weak acids, or neutral molecules, and can 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 more than one API. In one embodiment, the API is a poorly soluble or lipophilic API.

[0063] As used herein, the terms "poorly soluble API", "poorly water soluble API" and "lipophilic API" refer to APIs having solubility according to Biopharmaceutics Classification System (BCS) Class 2 and Class 4, following the definition of low solubility, such that the highest therapeutic dose of the specific API to be administered to an individual cannot be dissolved in 250 ml of an aqueous medium having a pH of 1 to 8. Poorly soluble APIs having weakly basic or weakly acidic characteristics have a pH-dependent solubility profile and may have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs belonging to BCS Class 2 or Class 4, respectively, are well known to those skilled in the art.

[0064] 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), wherein the basic API does not completely ionize in water.

[0065] In a preferred embodiment, the API is a PROTAC. According to the present invention, a "PROTAC" or "proteolysis targeting chimera" is a heterobifunctional molecule consisting of two active domains and a linker that is capable of removing specific unwanted proteins. Compared to traditional enzyme inhibitors, PROTACs act by inducing selective intracellular proteolysis consisting of two covalently linked protein-binding molecules: one molecule is able to engage the E3 ubiquitin ligase and the other molecule binds to the target protein intended for degradation. Recruiting the E3 ligase to the target protein leads to ubiquitination, followed by degradation of the target protein by the proteasome.

[0066] The API contained in the pharmaceutical dosage form of the present invention has an amount sufficient to be therapeutically effective. For a given API, the therapeutically effective amount is generally known or readily available 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.

[0067] According to the present invention, an amorphous solid dispersion of at least one active pharmaceutical ingredient is formed. The term "amorphous solid dispersion" or "ASD" used herein is 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 show obvious diffraction peaks of the crystalline API in X-ray powder diffraction (XRD) measurements, and does not show melting peaks of the API in differential scanning calorimetry (DSC) measurements. After dissolution, preparations containing amorphous solid dispersions can achieve higher solubility in aqueous media than crystalline APIs.

[0068] A further embodiment of the present invention is a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, the method comprising the steps of:

[0069] a) preparing a feed solution comprising the at least one active pharmaceutical ingredient and at least one polyvinyl alcohol having a degree of hydrolysis of 90% or less,

[0070] b) The feed solution is spray dried.

[0071] The spray drying may be two-fluid nozzle spray drying or three-fluid nozzle spray drying.

[0072] In a further embodiment, it is a method of producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, the method comprising the steps of:

[0073] a) preparing a first feed solution comprising the at least one active pharmaceutical ingredient,

[0074] b) preparing a second feed solution comprising polyvinyl alcohol having a degree of hydrolysis of 90% or less,

[0075] c) spray drying the first and second feed solutions using a three-fluid nozzle.

[0076] Preferably, in the three-fluid nozzle, the first feed solution is an inner phase and the second feed solution is an outer phase.

[0077] The feed solution is typically prepared by dissolving the desired amount of PVA in water. Preferably, deionized water is used. Preferably, the solution is heated to a temperature of 40°C or higher. The respective API is dissolved in a suitable solvent under stirring until a solution is obtained. For 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 dissolving the API and PVA directly in a suitable solvent.

[0078] Suitable solvents for preparing the feed solution are the customary solvents for pharmaceutical and spray drying applications known to the person skilled in the art, such as water, methanol, ethanol, acetone or mixtures thereof.

[0079] In further embodiments, the method may 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. The corresponding nozzle sprays the liquid into a high temperature spray chamber where the particles are dried and collected with a separation device.

[0080] For the avoidance of doubt, the process according to the present invention encompasses two-fluid nozzle spray drying and three-fluid nozzle spray drying with any of the PVA, PVA specifications or PVA grades defined above.

[0081] 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 defined above.

[0082] 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 the process defined above.

[0083] For the avoidance of doubt, the amorphous solid dispersion and pharmaceutical dosage form according to the present invention may comprise any of the PVA, PVA specifications or PVA grades defined above.

[0084] It has surprisingly been found that there is an optimal PVA grade or a range of PVA grades having certain specifications which can be advantageously used in a spray drying process to form an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix.

[0085] It has been found that only PVA grades with a degree of hydrolysis of 90% or less produce spray-dried ASDs with the appropriate degree of amorphization and / or dissolution behavior. The viscosity of the PVA is less important for the formation of the ASD unless the viscosity is low enough for the spray-drying process. Suitable viscosities of PVA for use in spray-drying processes are known to those skilled in the art.

[0086] At a certain API loading in the PVA matrix, three-fluid nozzle spray drying resulted in an amorphous product, whereas the commonly used two-fluid nozzle resulted in a partially crystalline product ( Figure 2-Figure 4 ). It was surprisingly found that not all PVA grades were suitable for this particular process, as PVA 4-98 and PVA 3-98 showed dissolution problems when preparing the spray solution. In addition, other PVA grades did not result in the expected amorphization grade (PVA 2-98, Fig. 9), and also resulted in low dissolution levels ( Figure 5 ). Surprisingly, only PVA grades with a degree of hydrolysis of 90% or less resulted in ASDs with suitable amorphization grade and dissolution behavior. PVA grades PVA 3-82, 4-88 and 5-74 showed the best results in terms of both amorphization grade and dissolution. Surprisingly, PVA 3-82 showed a superior dissolution profile compared to all other PVA grades.

[0087] Furthermore, PVA grade PVA 3-82 was able to stabilize the amorphous form of API in ASD formulations during storage under different conditions and no significant decrease in dissolution enhancement was observed.

[0088] In addition, PVA having the above-mentioned hydrolysis degree and / or viscosity ensures and stabilizes the release and supersaturation of API, especially poorly soluble API, in aqueous media, thereby preventing crystallization and phase separation. Since the low water solubility of API is usually accompanied by its low bioavailability after administration in a pharmaceutical formulation, the composition according to the present invention also helps to improve the bioavailability of poorly water-soluble API, especially weakly basic API.

[0089] As used herein, "bioavailability" is a term referring to the extent to which an API becomes available to target tissues after administration to a patient's body.

[0090] After dissolving the pharmaceutical dosage form of the present invention, improved supersaturation is observed and the API is better maintained in solution. After entering the gastrointestinal tract, the pharmaceutical dosage form swells and disintegrates in the aqueous environment of the gastrointestinal fluid, thereby releasing the API. Although the salt form of the weakly basic API may show an improved initial water concentration in acidic gastric fluid, the weakly basic API is rapidly converted to the free base form in the more neutral intestinal fluid, where the free base form of the API has a significantly lower equilibrium concentration. Compared with PVA outside the above specifications, the PVA according to the present invention maintains an increased API concentration in a model solution simulating acidic and neutral gastrointestinal solutions. Therefore, the pharmaceutical dosage form according to the present invention has the potential to improve the bioavailability of APIs with poor solubility. Compared with the API concentration provided in the presence of PVA outside the specifications, the solubility-improved form of the API in the presence of the PVA according to the present invention provides a greater concentration of the API in gastric fluid or simulated gastric fluid.

[0091] Example:

[0092] Example 1: Two-fluid nozzle spray drying and three-fluid nozzle spray drying of solutions and suspensions

[0093] The properties of products prepared by (i) two-fluid nozzle spray drying and (ii) three-fluid nozzle spray drying were compared using PVA grade PVA4-88 and ketoconazole (KETO) as API in solution and suspension.

[0094] Spray drying

[0095] A Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( The following feed solutions and suspensions (Table 1) were spray dried at 14°C in Switzerland.

[0096] Table 1

[0097]

[0098] Two-fluid nozzle (i): PVA 4-88 was dissolved in deionized water on a magnetic stirrer at 60 °C with heating at 200 rpm. Ketoconazole was dissolved in the corresponding volume of ethanol and added to the PVA solution. The solution (Formulation No. 1) or suspension (Formulation No. 2) was fed into a Büchi spray dryer. The suspension was stirred during spraying, while the solution was kept unstirred to avoid any precipitate formed during the process from being sucked into the spray chamber.

[0099] Three-fluid nozzle (ii): Prepare a solution of PVA4-88 in water as described above (Formulation No. 3). Dissolve ketoconazole in methanol (MeOH). Draw the feed solution with a 50 mL syringe and insert it into the PHD ULTRA TM A syringe pump (Harvard Apparatus, US) was used with PVA 4-88 in water in the external feed and ketoconazole in methanol in the internal feed.

[0100] The following conditions were applied in the spray drying process: inlet temperature 100 °C, outlet temperature 60 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0101] PXRD

[0102] The diffraction pattern of the powder was measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) and CuKα radiation (λ=1.54A). The sample was scanned from 3° to 50° 2θ (degrees) in reflection mode with a scanning speed of 10° 2θ (degrees) / min and a step size of 0.020° 2θ (degrees), and the results are shown in Figure 2 The accelerating voltage and current were 45 kV and 15 mA.

[0103] DSC

[0104] like Figure 3 The DSC thermograms of the samples shown were collected using a DSC 3 (METTLER, US) under a nitrogen flow of 50 ml / min. A total of 2-5 mg of sample powder was filled into an aluminum Tzero pan (40 μL) and sealed with an aluminum Tzero lid. The samples were analyzed from -25°C to 230°C at a heating rate of 5°C / min.

[0105] like Figure 2 and Figure 3 As shown, spray drying of a suspension of ketoconazole and PVA4-88 resulted in a partially crystalline product, whereas spraying of the corresponding solution resulted in an amorphous product.

[0106] In both examples a two-fluid nozzle setup was used. It can be seen that a drug loading of 14% resulted in a completely amorphous product when a two-fluid nozzle was used, whereas a drug loading of 30% was not possible.

[0107] 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 the main signals in the spray-dried suspension of KETO in 4-88 PVA, while these patterns cannot be detected in the XRD of the spray-dried product using the corresponding solution. The melting point of ketoconazole is defined as being in the range of 148°C-150°C and can be detected in the DSC of ketoconazole-PVA suspensions ( Figure 3 ), whereas no such peak could be identified in the DSC curve of the spray-dried ketoconazole-PVA solution.

[0108] In the solvent system used, it was not feasible to increase the drug loading to the required amount for 30% DL for KETO as suspensions were obtained at DL > 14%. For higher DL, a three-fluid nozzle setup was used. Figure 4 A comparison of using a two-fluid nozzle and suspension versus a three-fluid nozzle and solution setup for KETO and 4-88 PVA at 30% DL is shown.

[0109] For the three-fluid nozzle setup, no sharp peaks could be detected at 7.1, 17.4, 23.6 and 27.4° 2θ.

[0110] Example 2: Dissolution of ASDs with Different API and PVA Grades

[0111] The dissolution was tested using a three-fluid nozzle spray-dried ASD with indomethacin (INDO), ritonavir (RITO) and ketoconazole (KETO) as API and PVA grades PVA 2-98, PVA 3-82, PVA4-88 and PVA 5-74. In addition, PVA grades PVA 3-98 and 4-98 were investigated, but the method of spray drying these PVA grades was not feasible due to dissolution issues when preparing the spray solution.

[0112] Spray dried indomethacin ASD

[0113] A Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( Switzerland) the following feed solutions were spray dried.

[0114] Due to the different solubilities, a three-fluid nozzle was used. Feed 1, the internal phase, contained 3 g of indomethacin in 50 mL of a mixture of acetone and deionized water in a volume ratio of 70:30. Feed 2, the external phase, contained the polymer solution. 7 g of PVA 5-74, PVA 3-82, PVA 4-88, PVA 2-98, PVA3-98, and PVA 4-98 were dissolved in 50 mL of deionized water at 60 °C on a magnetic stirrer with heating at 200 rpm. The feed solutions were drawn up with a 50 mL syringe and inserted into the PHDULTRA TM In a syringe pump (Harvard Apparatus, US).

[0115] The following conditions were applied in the spray drying process: inlet temperature 90 °C, outlet temperature 50 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0116] Indomethacin Drug Content Determination by RP-HPLC

[0117] To determine the drug loading, weigh one gram of sample in a 250 mL volumetric flask. Add 125 mL of Milli-Q water and stir at 500 rpm for 45 min on a magnetic stir bar. 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 the mobile phase.

[0118] The mobile phase was a mixture of 1000 mL acetonitrile and 1000 mL indomethacin buffer USP (0.01 M NaH2PO*H2O 1.38 g / L + 0.01 M Na2HPO4 1.41 g / L), and placed in an ultrasonic bath for 15 min.

[0119] Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with Agilent 1260 II variable wavelength detector was used. LC-18 (Supelco, 4.0 x 300 mm, 5 μm) column was used for quantification, and the column heating box temperature was 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 about 2.4 min. Duplex determination and dual injection were performed.

[0120] Dissolution Measurement Indomethacin ASD

[0121] The dissolution of indomethacin was carried out on a Dissolution Sotax AT7 smart (Sotax AG, Germany).

[0122] The 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 with paddle stirring at 75 rpm at 37°C. The drug concentration in the medium was measured spectrophotometrically at 318 nm (UV-VISAgilent 8453). The path length was 10 mm.

[0123] Solubility enhancement was studied using simulated gastric fluid (SGF) since indomethacin is poorly soluble in acidic pH. Figure 5Improved dissolution was shown for spray dried ASD prepared with PVA4-88, PVA 3-82, PVA 2-98 and PVA 5-74. IND-PVA3-82 showed superior dissolution values, while IND-PVA4-88 and IND-PVA 5-74 showed similar dissolution behavior. IND-PVA 2-98 provided adequate solution upon dissolution and was suitable for the spray drying process, but the product showed unfavorable dissolution behavior. In addition, PVA 4-98 and 3-98 were studied, but the method of spray drying the two PVA grades was not feasible due to dissolution issues when preparing the spray solution.

[0124] Spray dried ritonavir ASD

[0125] A Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( Switzerland) the following feed solutions were spray dried.

[0126] Due to the different solubilities, a three-fluid nozzle was used. Feed 1, the internal phase, contained 3 g of ritonavir in 50 mL of ethanol. Feed 2, the external phase, contained the polymer solution. 7 g of PVA4-88 or PVA 3-82 was dissolved in 50 mL of deionized water on a magnetic stirrer at 60 °C with heating at 200 rpm. The feed solutions were drawn up with a 50 mL syringe and inserted into the PHDULTRA TM In a syringe pump (Harvard Apparatus, US).

[0127] The following conditions were applied in the spray drying process: inlet temperature 100 °C, outlet temperature 60 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0128] Ritonavir Drug Content Determination by RP-HPLC

[0129] Weigh 5 to 10 mg in a 50 mL volumetric flask. Add 25 mL of mobile phase and stir at 500 rpm on 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.

[0130] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used. Quantification was performed using a RP-C18 (Supelco, 4.6×150 mm, 5 μm) column. The injection volume was 20 μl and the flow rate was 1 ml / min.

[0131] The mobile phase was a mixture of 2 g / l potassium dihydrogen phosphate in water and acetonitrile in a volume ratio of 45:55. The mobile phase was adjusted to pH 4.0 ± 0.05 with phosphoric acid. The UV detection wavelength was 215 nm.

[0132] Dissolution Measurement of Ritonavir ASD

[0133] The dissolution of the samples was determined in fasting simulated intestinal fluid V2 (FaSSIF V2, Biorelevant). 20 mg of the drug substance or drug substance equivalent was weighed and placed in a 100 ml conical flask, 20 ml of the dissolution medium was added and stirred at 200 rpm using a magnetic stirring bar.

[0134] At predetermined time points, 2 ml of dissolution medium was taken out from the dissolution vessel and immediately replaced with 2 ml of fresh dissolution medium (5, 10, 20, 40, 60, 90, 120 min). The sample was then filtered through a 0.45 μm filter, diluted with acetonitrile, and then filtered again through a 0.45 μm filter. The drug content of the sample was analyzed using RP-HPLC.

[0135] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used. Quantification was performed using a RP-C18 (Supelco, 4.6×150 mm, 5 μm) column.

[0136] The mobile phase contained a mixture of 2 g / l potassium dihydrogen phosphate in water and acetonitrile in a volume ratio of 45:55. The mobile phase was adjusted to a pH of 4.0 ± 0.05 using phosphoric acid. The UV detection wavelength was 215 nm, the flow rate was 1 ml / min, and the injection volume was 20 μl.

[0137] Ritonavir shows low solubility and bioavailability values ​​and is therefore classified as BSC class IV. Figure 6 As shown, the solubility of the spray-dried amorphous solution of ritonavir was improved when PVA was used. To show the dissolution improvement, the biorelevant medium FaSSIF (Fasted State Simulated Intestinal Fluid) was used, which mimics the dissolution process of the API in the upper intestine.

[0138] PVA 4-88 improved the dissolution of the crystalline API by approximately four orders of magnitude. PVA 3-82 performed superiorly and showed a seven-order-of-magnitude dissolution improvement over the crystalline material at 120 minutes.

[0139] Spray dried ketoconazole ASD

[0140] A Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( Switzerland) the following feed solutions were spray dried.

[0141] Due to the different solubilities, a three-fluid nozzle was used. Feed 1, the inner phase, contained 3 g of ketoconazole in 50 mL of ethanol. Feed 2, the outer phase, contained the polymer solution. 7 g of PVA 2-98, PVA 3-82, PVA 4-88, and PVA 5-74 were dissolved in 50 mL of deionized water on a magnetic stirrer at 60 °C with heating at 200 rpm. The feed solutions were drawn up with a 50 mL syringe and inserted into the PHD ULTRA TM Syringe pump (Harvard Apparatus, US).

[0142] The following conditions were applied in the spray drying process: inlet temperature 100 °C, outlet temperature 60 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0143] Dissolution Measurement Ketoconazole ASD

[0144] The dissolution of ketoconazole was carried out on a Dissolution Sotax AT7 smart (Sotax AG, Germany).

[0145] The samples (400 mg ketoconazole or 1333 mg solid dispersion particles (30% drug loading)) were added to 500 mL FaSSIF for disintegration testing with paddle stirring at 50 rpm at 37°C.

[0146] 2 ml samples were collected after 30, 60, 120, 135, 150, 180, 240 and 300 min. The sample solution was filtered through a 0.45 μm filter into a vial and diluted with ethanol at a ratio of 1:1.

[0147] Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with Agilent 1260 II variable wavelength detector was used. LC-18 (Supelco, 4.0 x 300 mm, 5 μm) column was used for quantification, and the column heating box temperature was 40 ° C. The injection volume was 5 μl, and the flow rate was 2 ml / min. The mobile phase was divided into two eluents (70% eluent A / 30% eluent B). Eluent A was a mixture of 10 ml diisopropylamine in 5 L methanol. For eluent B, 5 g / L ammonium acetate in milli-Q water was used.

[0148] The UV detection wavelength was 225 nm, and the retention time was approximately 5.7 min.

[0149] Fig.15 The dissolution of 30% (w / w) ketoconazole as a spray-dried ASD containing PVA4-88, PVA3-82, PVA 5-74 and PVA 2-98 was shown to be improved compared to the crystalline product in FaSSIF. PVA 3-82, followed by PVA4-88, significantly improved the dissolution of ketoconazole. PVA 2-98 showed an improved release within the first 20 minutes, but recrystallization of ketoconazole resulted in a dissolution comparable to the crystalline material. PVA 5-74 showed an almost linear increase in ketoconazole dissolution, reaching the second best dissolution value at the 120 time point.

[0150] Example 3: XRD of ASD with different API and PVA grades

[0151] XRD measurements were performed using ketoconazole (KETO), ritonavir (RITO) and indomethacin (INDO) as APIs and PVA grades PVA 2-98, PVA 3-82, PVA4-88 and PVA 5-74 using a three-fluid nozzle spray drying ASD.

[0152] The spray-dried ASD was prepared as described in Example 2 and the XRD measurements were performed as described in Example 1. Figures 7 to 14 shown.

[0153] XRD measurement ( Figures 7 to 14, 16 and 17) show that spray drying with PVA 3-82, 4-88 and 5-74 leads to products with good API amorphization. The XRD ( Fig. 9 and 16 ) showed that the product did not have a completely amorphous state, which increased the lower dissolution rate ( Figure 5 ).

[0154] Example 4: Three-fluid nozzle spray drying of ASD with PROTAC as API Spray drying of PROTAC ASD

[0155] The following PROTACs were used: PROTAC 1 (molecular formula see Fig.18 )、PROTAC 2 (molecular formula see Fig.19 ) and PROTAC ARV-110 (molecular formula see Fig. 20 ).

[0156] For PROTAC 1 and 2, a Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( Switzerland) the following feed solutions were spray dried.

[0157] Due to the different solubilities, a three-fluid nozzle was used. Feed 1, the inner phase, contained 70 mg PROTAC in 25 mL ethanol. Feed 2, the outer phase, contained the polymer solution. 140 mg PVA 3-82 was dissolved in 25 mL deionized water on a magnetic stirrer at 60 °C with heating at 200 rpm. The feed solutions were pumped into the spray dryer with the help of a peristaltic pump.

[0158] The following conditions were applied in the spray drying process: inlet temperature 90 °C, outlet temperature 50 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0159] For PROTAC ARV-110, a Büchi spray dryer B-290 ( Switzerland) and the Büchi inert loop B-295 ( Switzerland) the following feed solutions were spray dried.

[0160] Due to different solubilities, a three-fluid nozzle was used. Feed 1, the inner phase, contained 400 mg PROTAC in 550 mL DCM:MeOH (40:60). Feed 2, the outer phase, contained the polymer solution. 932 mg PVA 3-82 was dissolved in 550 mL deionized water on a magnetic stirrer. The feed solution was pumped into the spray dryer with the help of a peristaltic pump.

[0161] The following conditions were applied in the spray drying process: inlet temperature 80 °C, outlet temperature 45 °C, drying air flow rate 35 m 3 / h (aspirator: 100%) and atomizing air flow rate 670 L / min (N2: 55 mm). The feed solution flow rate was adjusted according to the outlet temperature.

[0162] Drug content determination of PROTAC

[0163] For PROTAC 1 and 2, 1 mg of sample was dissolved in 50 ml of DMSO. The sample must be filtered through a 0.45 μm filter.

[0164] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used.

[0165] Quantification was performed using a Phenomenex (4.6×250 mm, 5 μm) column. The injection volume was 50 μl and the flow rate was 1 ml / min.

[0166] The eluent compositions were as follows: eluent A: 0.1% TFA in water; eluent B: 0.1% TFA in acetonitrile.

[0167] For PROTAC ARV-110, dissolve 1 mg of sample in 50 ml of DMSO. The sample must be filtered through a 0.45 μm filter.

[0168] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260 II diode array detector was used. Quantification 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 eluent composition was as follows: eluent A: 0.1% formic acid in water; eluent B: 0.1% formic acid in acetonitrile.

[0169] Dissolution Measurement of PROTAC ASD

[0170] For PROTAC 1 and 2, the dissolution of the samples was determined at room temperature in phosphate buffer pH 6.8 as the dissolution medium. 5 mg of the drug substance or a spray-dried powder sample equivalent to 5 mg of the drug was weighed and placed in a 100 ml conical flask, followed by adding a magnetic stir bar to the conical flask and stirring at 200 rpm, and then adding 25 ml of the dissolution medium (concentration: 0.2 mg / ml).

[0171] At predetermined time points (5, 10, 20, 40, 60, 90, 120 min), 500 μl of sample was taken from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolution sample was then filtered through a 0.45 μm filter. Finally, the sample was analyzed for drug content using HPLC.

[0172] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used.

[0173] Quantification was performed using a Phenomenex (4.6×250 mm, 5 μm) column. The injection volume was 50 μl and the flow rate was 1 ml / min.

[0174] The eluent compositions were as follows: eluent A: 0.1% TFA in water; eluent B: 0.1% TFA in acetonitrile. The method was as follows: linear gradient 0-100% eluent B in 25 minutes.

[0175] For PROTAC ARV-110, the dissolution of the sample was measured at room temperature in phosphate buffer pH 6.8 as the dissolution medium. 5 mg of the drug substance or a spray-dried powder sample equivalent to 5 mg of the drug was weighed and placed in a 100 ml conical flask, followed by adding a magnetic stir bar to the conical flask and stirring at 200 rpm, and then adding 25 ml of the dissolution medium (concentration: 0.2 mg / ml).

[0176] At predetermined time points (5, 10, 20, 40, 60, 90, 120 min), 500 μl of sample was taken from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolution sample was then filtered through a 0.45 μm filter. The sample was diluted with eluent B (1:1). Finally, the drug content of the sample was analyzed using HPLC.

[0177] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used. A C8-Column (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.

[0178] The eluent compositions were as follows: eluent A: 0.1% formic acid in water; eluent B: 0.1% formic acid in acetonitrile. Method: Linear gradient from 10% to 90% eluent B in 2 minutes at a flow rate of 1.7 ml / min.

[0179] Figures 21 to 23 The dissolution of spray-dried dispersions of PROTAC 1, PROTAC 2, and ARV 110 with PVA 3-82 is shown compared to the original product PROTAC 1, PROTAC 2, and ARV110 in phosphate buffer at pH 6.8. As can be seen, the original PROTAC 1, PROTAC 2, and ARV110 did not show any measurable dissolution in phosphate buffer over a period of 120 minutes. For all three examples, the spray-dried dispersions of PVA 3-82 and the corresponding PROTAC showed improved dissolution. For PROTAC 1, the dissolution increased significantly within the first 30 minutes, and the release values ​​continued to decrease, while for PROTAC 2, the improved release was stable over a period of 120 minutes. In addition, compared to the crystalline material, ARV110 was stable at high levels of dissolved drug, showing a rapid onset of spray-dried dispersions and extended release over the entire time of 120 minutes.

[0180] X-ray powder diffraction

[0181] The diffraction pattern of the powder was measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) and CuKα radiation (λ=1.54A). The sample was scanned from 3° to 50° 2θ (degrees) in reflection mode with a scanning speed of 10° 2θ (degrees) / min and a step size of 0.020° 2θ (degrees). The accelerating voltage and current were 45 kV and 15 mA.

[0182] XRD measurement ( Figures 24 to 25 ) shows that the raw material and spray-dried PROTAC 1 and PROTAC are amorphous. For PROTAC ARV-110, it can be seen that the raw material is crystalline, while the spray-dried dispersion containing PVA 3-82 is amorphous ( Fig.26 ).

[0183] Example 5: Stability Measurement of ASD

[0184] To investigate the stability of the PVA 3-82–ARV110 formulation, the spray-dried and original products were stored using the following conditions and investigated after 4 weeks in dissolution experiments and X-ray diffraction.

[0185]

[0186] The spray-dried PVA 3-82 / ARV110 samples were stored in a refrigerator at 5°C ( Fig.29 ) and at 25°C, 60% rH ( Fig.30 ) remained amorphous after 4 weeks of storage. In addition, the samples did not show a significant decrease in dissolution enhancement compared to the dissolution performed at t = 0 ( Fig. 27 and 28 ).

[0187] Dissolution Measurements of PVA 3-82 / ARV110 from Stability Studies

[0188] For PROTAC ARV-110, the dissolution of the samples was determined at room temperature in phosphate buffer pH 6.8 as the dissolution medium. 5 mg of the drug substance or the spray-dried powder equivalent to 5 mg of the drug from the stability study was weighed and placed in a 100 ml conical flask, followed by adding a magnetic stir bar to the conical flask and stirring at 200 rpm, and then adding 25 ml of the dissolution medium (concentration: 0.2 mg / ml).

[0189] At predetermined time points (5, 10, 20, 40, 60, 90, 120 min), 500 μl of sample was taken from the dissolution vessel and immediately replaced with 500 μl of fresh dissolution medium. The dissolution sample was then filtered through a 0.45 μm filter. The sample was diluted with eluent B (1:1). Finally, the drug content of the sample was analyzed using HPLC.

[0190] An Agilent 1260 infinity HPLC system (Agilent, Santa Clara, USA) equipped with an Agilent 1260II variable wavelength detector was used. A C8-Column (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.

[0191] The eluent compositions were as follows: eluent A: 0.1% formic acid in water; eluent B: 0.1% formic acid in acetonitrile. Method: Linear gradient from 10% to 90% eluent B in 2 minutes at a flow rate of 1.7 ml / min.

[0192] X-ray powder diffraction

[0193] The diffraction pattern of the powder was measured using a Miniflex 600 X-ray diffractometer (Rigaku, Japan) and CuKα radiation (λ=1.54A). The sample was scanned from 3° to 50° 2θ (degrees) in reflection mode with a scanning speed of 10° 2θ (degrees) / min and a step size of 0.020° 2θ (degrees). The accelerating voltage and current were 45 kV and 15 mA.

[0194] References

[0195] ·Bhujbal, SV, B. Mitra, U. Jain, Y. Gong, A. Agrawal, S. Karki, LSTaylor, S. Kumar, and Q. Tony Zhou. 2021. 'Pharmaceuticalamorphous solid dispersion: A review of manufacturing strategies', ActaPharm Sin B, 11: 2505-36.

[0196] ·Bhujbal, SV, Y.Su, V.Pathak, DYZemlyanov, AACavallaro, EJMunson, LSTaylor, and QTZhou.2021. 'Effect ofStorage Humidity on Physical Stabilityof Spray-Dried NaproxenAmorphous Solid Dispersions with Polyvinylpyrrolidone: Two FluidNozzle vs.Three Fluid Nozzle',Pharmaceutics,13.

[0197] ·Brough et al., Use of Polyvinyl Alcohol as a SolubilityEnhancing Polymer for Poorly Water-Soluble Drug Delivery(Part 1),AAPS PharmSciTechVol.17,No.1,p.176(01.02.2016)

[0198] ·Focaroli,S.,G.Jiang,P.O'Connell,J.V.Fahy,and A.M.Healy.2020.'TheUse of a Three-Fluid Atomising Nozzle in theProduction of Spray-DriedTheophylline / Salbutamol Sulphate PowdersIntended for Pulmonary Delivery',Pharmaceutics,12.

[0199] ·Fouad,E.A.,M.El-Badry,G.M.Mahrous,F.K.Alanazi,S.H.Neau,andI.A.Alsarra.2011.'The use of spray-drying to enhancecelecoxib solubility',Drug Dev Ind Pharm,37:1463-72.

[0200] ·Hugo,M.,K.Kunath,and J.Dressman.2013.'Selection ofexcipient,solventand packaging to optimize the performance ofspray-dried formulations:caseexample fenofibrate',Drug Dev Ind Pharm,39:402-12.

[0201] ·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 ofPoorly Water-Soluble Drugs',Pharmaceutics,13.

[0202] ·Ziaee,A.,A.B.Albadarin,L.Padrela,T.Femmer,E.O'Reilly,andG.Walker.2019.'Spray-drying ofpharmaceuticals andbiopharmaceuticals:Criticalparameters and experimental processoptimization approaches',Eur J Pharm Sci,127:300-18。

Claims

1. Use of polyvinyl alcohol in a process for spray drying 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. The method according to claim 1, wherein the polyvinyl alcohol has a degree of hydrolysis between 74% and 88% and a viscosity of a 4% solution at 20°C between 2 and 5 mPas.

3. The use according to claim 1 or 2, wherein the polyvinyl alcohol is PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 2-88, PVA 3-88, PVA 4-88, PVA 5-88, PVA 2-74, PVA 3-74, PVA 4-74 or PVA 5-74.

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 PVA 3-82.

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

7. Use according to any one of claims 1 to 6, wherein the method used for spray drying is three-fluid nozzle spray drying.

8. A method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by spray drying, the method comprising the steps of: a) preparing a feed solution comprising the 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.

9. A method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polyvinyl alcohol matrix by three-fluid nozzle spray drying, the method comprising the steps of: a) preparing a first feed solution comprising the 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 using a three-fluid nozzle.

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

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

12. The method according to any one of claims 8 to 11, wherein the polyvinyl alcohol is PVA 3-82.

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

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

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

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