Pharmaceutical composition and method for improving the solubility of poorly soluble pharmaceutical active ingredients

Abstract

The present invention relates to a pharmaceutical composition using a polymer as an excipient. In particular, the present invention relates to a pharmaceutical composition containing polyvinyl alcohol, which is suitable for increasing the solubility of a poorly soluble active pharmaceutical ingredient in an aqueous medium. The present invention also relates to a method for improving the solubility of a poorly soluble active pharmaceutical ingredient.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition using a polymer as an excipient. In particular, the present invention relates to a pharmaceutical composition containing polyvinyl alcohol suitable for enhancing the solubility of a poorly soluble pharmaceutical active ingredient in an aqueous medium. The present invention also relates to a method for enhancing the solubility of a poorly soluble pharmaceutical active ingredient.

[0002] State of the Art The use of hydrophilic polymers such as polyvinyl alcohol (PVA) as excipients in pharmaceutical compositions has been widely described. WO 2018 / 083285 discloses powdered PVA having improved properties as a polymer matrix in pharmaceutical compositions containing an active ingredient, particularly in compressed tablets forming an amorphous solid dispersion with a poorly soluble pharmaceutical active ingredient (API).

[0003] The formulation of amorphous solid dispersions is a well-known strategy for improving the bioavailability of poorly water-soluble drugs. Although the amorphous form exhibits high solubility, it is quite unstable and tends to recrystallize and precipitate due to pH changes immediately after dissolution or when changing from an acidic gastric environment to a more neutral intestine. The recrystallized fraction of the API cannot be absorbed. Since drug absorption mainly occurs in the intestine, in pharmaceutical formulations that cannot maintain a high concentration of the API in the intestinal solution, the improvement in bioavailability usually remains slight. Undesirable recrystallization rather decreases the bioavailability of the API. Low bioavailability is a major problem encountered in the development of pharmaceutical compositions, particularly those containing APIs with low water solubility.

[0004] The effect of low-solubility compounds on supersaturation is described in Gift et al.'s "Influence of polymeric excipients on crystal hydrate formation kinetics in aqueous slurries" (J. Pharm. Sci., 2008, 97(12):5198-211). Polyvinyl alcohol successfully demonstrated its ability to suppress crystal formation of model compounds such as caffeine. The PVA grade used in these data is described as polyvinyl alcohol (PVA) with an average molecular weight of 47,000. No further specification or evaluation regarding the degree of hydrolysis is provided.

[0005] Another study using PVA to enhance the supersaturation of the model compound tacrolimus is described in Overhoff et al.'s "Effect of Stabilizer on the Maximum Degree and Extent of Supersaturation and Oral Absorption of Tacrolimus Made By Ultra-Rapid Freezing" (Pharmaceutical Research, 2008, 25(1):167-75). The solid dispersion was prepared by ultra-rapid freeze-drying. The PVA grade used is described as poly(vinyl) alcohol (PVA, Mw 13,000-23,000, 87-89% hydrolyzed). PVA was successfully used as a stabilizer.

[0006] The use of polyvinyl alcohol for hot-melt extrusion was previously described by de Jaeghere et al. in "Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications" (Int. J. Pharm., 2015;492(1-2):1-9). The use of partially hydrolyzed PVA grade as a carrier for oral immediate-release formulations was evaluated. While the effect on release rate was observed, no direct correlation was found between the degree of hydrolysis and supersaturation potential.

[0007] In "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 (February 1, 2016), Brough et al. investigated specific PVA grades, including PVA4-75, PVA4-88, PVA4-98, and PVA4-38, using a non-sink gastric transfer dissolution method. It was found that the solubility of itraconazole, a weakly basic model API, rapidly decreased after a pH shift from 1.2 to 6.8. PVA grades 4-88 were determined to have the effect of improving the solubility and bioavailability of itraconazole, the model API. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2018 / 083285 [Overview of the project] [Problems that the invention aims to solve]

[0009] In particular, there remains a need for excipients with improved solubilization properties after a pH change from an acidic medium to a more neutral medium. [Means for solving the problem]

[0010] [Overview of the prefecture] Surprisingly, in pharmaceutical compositions containing an amorphous solid dispersion of APIs in a polymer matrix, polyvinyl alcohol with a degree of hydrolysis of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C was found to be particularly suitable as a polymer for improving the supersaturation properties after dissolution of poorly water-soluble APIs. [Effects of the Invention]

[0011] Unexpectedly, it was found that there is an optimal range of hydrolysis degree and viscosity in aqueous media that is more likely to supersaturate poorly soluble APIs compared to existing commonly used PVA grades. PVA grades within this optimal range exhibit excellent supersaturation properties in acidic aqueous media, particularly for weakly basic APIs. Surprisingly, the supersaturation properties remain significantly improved even after shifting to nearly neutral aqueous media, compared to standard PVA grades such as PVA with hydrolysis degrees outside the 72%–85% range and viscosities outside the 2mPas–4mPas range. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 is a table summarizing the extrusion parameters for preparing model extrusion matrix systems using itraconazole (ITZ) as a lipophilic model API, with varying grades of PVA. [Figure 2] Figure 2 shows the dissolution profiles of extrusion matrices containing different PVA grades and itraconazole (ITZ). [Figure 3] Figure 3 is a table summarizing the extrusion parameters for preparing a model extrusion matrix system using dipyridamole as a lipophilic model API, with different grades of PVA. [Figure 4] Figure 4 shows the dissolution profiles of extrusion matrices containing different PVA grades and dipyridamole. [Modes for carrying out the invention]

[0013] In a preferred embodiment of the present invention, the PVA has a degree of hydrolysis of 80% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C.

[0014] The most preferred PVA according to the present invention has a degree of hydrolysis of 80% to 83% and a viscosity of 3 mPas for a 4% solution at 20°C, and is particularly PVA3-80 and PVA3-83.

[0015] In another preferred embodiment of the present invention, an amorphous solid dispersion of the API is obtained by combining PVA with optionally further pharmaceutically acceptable components to obtain a polymer matrix, and then mixing the polymer matrix with the API at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient. Preferably, the temperature is at least the melting temperature of the API.

[0016] In another embodiment, the present invention provides oral dosage forms comprising a pharmaceutical composition according to the present invention in the form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels, and films.

[0017] A further aspect of the present invention relates to a method for enhancing the solubility of an API in an aqueous medium, the method comprising mixing at least one poorly soluble pharmaceutical active ingredient with polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 4% solution at 20 °C of 2 mPas to 4 mPas at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the pharmaceutical active ingredient. Preferably, the solubility of the pharmaceutical active ingredient in the aqueous medium is improved as compared to the solubility of the pharmaceutical active ingredient in an amorphous solid dispersion containing polyvinyl alcohol having a degree of hydrolysis outside the range of 72% to 85% and / or a viscosity outside the range of 2 mPas to 4 mPas. The method can be applied under acidic conditions or gastric conditions having a pH of 1 to 2, particularly 1 to 1.2. The method is particularly suitable for enhancing the solubility of the API in a neutral medium having a pH of 6 to 8, particularly pH 6.5 to 7.5.

[0018] [Detailed Description of the Invention] The present invention discloses a pharmaceutical composition comprising an amorphous solid dispersion of at least one pharmaceutical active ingredient in a polymer matrix, wherein the pharmaceutical active ingredient is preferably poorly soluble and the polymer is polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 4% solution at 20 °C of 2 mPas to 4 mPas.

[0019] The pharmaceutical active ingredient (API) of the pharmaceutical composition according to the present invention is dispersed in the polymer matrix. The API is a physiologically active substance in the form of a weak base, a weak acid, or a neutral molecule. The API may be in the form of one or more of its pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates. The pharmaceutical composition may contain a plurality of APIs.

[0020] In this specification, the terms “poorly soluble API,” “poorly water-soluble API,” and “lipophilic API” refer to APIs whose maximum therapeutic dose administered to an individual is so soluble that it cannot be dissolved in 250 ml of aqueous medium in the pH range of 1–8, according to the definition of poor solubility in Biopharmaceutical Classification System (BCS) Classes 2 and 4. Poorly soluble APIs having weakly basic or weakly acidic properties have a pH-dependent solubility profile and can have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs corresponding to BCS Class 2 or 4 are well known to those skilled in the art, respectively.

[0021] In this specification, the term "weakly basic API" means a basic active pharmaceutical ingredient (API) that does not completely ionize in water.

[0022] According to one embodiment of the present invention, the API contained in the pharmaceutical composition of the present invention is present in an amount sufficient to be therapeutically effective. 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 composition in a weight ratio of API to polymer matrix in the range of 1:99 to (90:10), preferably 5:95 to 60:40, and most preferably 10:90 to 30:70.

[0023] Polyvinyl alcohol (PVA) has the ideal formula [CH2CH(OH)] nPVA is a synthetic water-soluble polymer represented by [formula]. It possesses good film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the functional acetate groups are partially or completely hydrolyzed to form alcohol functional groups. If not completely hydrolyzed, PVA is a random copolymer consisting 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 molecular properties of PVA are determined by the degree of hydrolysis and molecular weight. 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, also increase. However, at high degrees of hydrolysis exceeding 88%, the solubility of PVA decreases again. PVA is generally soluble in water, but is practically insoluble in most organic solvents, with the exception of some ethanols.

[0024] Typical PVA nominations indicate the viscosity of a 4% solution at 20°C and the degree of hydrolysis of the polymer. For example, PVA3-83 is a PVA grade with a viscosity of 3 mPas, 83% hydrolyzed, i.e., having 83% vinyl alcohol repeating units and 17% vinyl acetate repeating units. Those skilled in the art will recognize that the 83% degree of hydrolysis and viscosity of 3 mPas include calculated values ​​of 82.50% to 83.49% degree of hydrolysis and 2.50 mPas to 3.49 mPas% viscosity, respectively, using common rounding methods. The viscosity according to the present invention is measured by the Viscosity-Rotational method (912), as described in the monograph "Polyvinyl Alcohols" of USP39.

[0025] The degree of hydrolysis according to the present invention is measured by determining the saponification value of polyvinyl alcohol, as described, for example, in the monograph "Degree of Hydrolysis" of USP39 "Polyvinyl Alcohol":

[0026] Sample: 1g of polyvinyl alcohol, pre-dried at 110°C and brought to a fixed weight. analysis: Transfer the sample to a wide-mouthed 250 ml conical flask fitted with a reflux condenser using a suitable glass joint. Add 35 ml of diluted methanol (3 / 5, 3 in 5) and mix gently until the solid is completely wetted. Add 3 drops of phenolphthalein TS and neutralize with 0.2 N hydrochloric acid or 0.2 N sodium hydroxide, if necessary. 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 washing solution in the flask and let it cool, then titrate with 0.2 N hydrochloric acid VS. Simultaneously, perform a blank measurement using the same method with the same volume of 0.2 N sodium hydroxide VS.

[0027] Calculation of saponification value: Calculate the saponification value:

[0028] Result=[(V B -V S ) × N × M r ] / W

[0029] V B = Volume (ml) of 0.2N hydrochloric acid VS consumed in the titration of the blank. V S = Volume (ml) of 0.2N hydrochloric acid VS consumed in the titration of the sample solution N = Actual normality of hydrochloric acid VS M r = Molecular weight of potassium hydroxide, 56.11 W = Weight (g) of the extracted polyvinyl alcohol portion.

[0030] Calculation of the degree of hydrolysis: Calculate the degree of hydrolysis, which is expressed as the percentage of hydrolysis of polyvinyl acetate:

[0031] Result=100-[7.84×S / (100-0.075×S))

[0032] S = Saponification value of polyvinyl alcohol

[0033] According to the present invention, surprisingly, PVA with a degree of hydrolysis in the range of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C exhibits superior performance in extending the supersaturated state of poorly soluble APIs. Experiments have shown, unexpectedly, that PVA with a degree of hydrolysis greater than 85% or less than 78% and a viscosity of greater than 4 mPas in a 4% solution at 20°C does not exhibit comparable performance in supersaturating model APIs, particularly under near-neutral pH conditions of pH 6.8.

[0034] By changing the hydrolysis grade of PVA, a PVA is provided in which the ratio of hydrogen bond-donating hydroxyl groups can be adjusted, and it is expected that this can function as a dissolution accelerator for sparingly soluble APIs, particularly weakly basic sparingly soluble APIs, regardless of environmental pH conditions.

[0035] Preferred PVAs have a degree of hydrolysis of 80% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C. Particularly preferred PVAs have a degree of hydrolysis of 80% to 83% and a viscosity of 3 mPas in a 4% solution at 20°C. The most preferred PVAs are PVA3-80 and PVA3-83.

[0036] We found that PVA having the viscosity and hydrolysis grade described above ensures and stabilizes the release and supersaturation of poorly soluble APIs in aqueous media, thereby preventing crystallization and phase separation. Since low water solubility of APIs generally leads to low bioavailability after administration as a pharmaceutical formulation, the compositions according to the present invention also contribute to improving the bioavailability of poorly soluble APIs, particularly weakly basic APIs. Surprisingly, the improvement in the degree of API supersaturation was also significant in nearly neutral aqueous media, reflecting the more neutral environment in the intestines.

[0037] In this specification, "bioavailability" refers to the extent to which an API becomes available to target tissue after being administered into a patient's body.

[0038] The use of the PVA grade according to the present invention in polymer matrices for pharmaceutical compositions is of interest for the formulation of solid oral pharmaceutical dosage forms having instantaneous, immediate, or long-term API release.

[0039] In preferred embodiments of the present invention, the polymer matrix can be combined with other pharmaceutically acceptable excipients. In particular, the pharmaceutical composition according to the present invention may contain additional pharmaceutically acceptable hydrophilic or lipophilic polymers. The pharmaceutical composition may also contain flow control agents such as silicon dioxide, fillers, plasticizers, surfactants, and other suitable components well known to those skilled in the art. To avoid doubt, other suitable components, such as flow control agents such as silicon dioxide, are not required to obtain the beneficial properties of the present invention, such as improving the bioavailability of poorly water-soluble APIs, particularly weakly basic APIs. However, these components can be used for other purposes, for example, to optimize the manufacturing process of the pharmaceutical composition or oral dosage form according to the present invention.

[0040] As used herein, the expression "pharmaceutically acceptable" refers to all compounds, such as solvents, dispersions, flow regulators, excipients, carriers, coatings, activators, isotonic agents, and absorption retarders, that do not generally cause allergic reactions or similar unpleasant reactions when administered to humans. The use of such media and agents in pharmaceutical compositions is well known in the art.

[0041] As used herein, the term “amorphous solid dispersion” refers to a dispersion of amorphous API in a polymer 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. Formulations containing amorphous solid dispersions may have higher solubility in aqueous media than crystalline APIs upon dissolution.

[0042] According to one embodiment of the present invention, preferred methods for preparing a pharmaceutical composition include, but are not limited to, hot-melt extrusion, injection molding, compression molding, and additive manufacturing, with hot-melt extrusion being the most preferred method.

[0043] According to a preferred embodiment of the present invention, an amorphous solid dispersion can be obtained by mixing at least one pharmaceutically active ingredient, polyvinyl alcohol, and optionally further pharmaceutically acceptable ingredients at a temperature above the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the pharmaceutically active ingredient. Preferably, the temperature is at least the melting temperature of the API to promote a uniform distribution of the amorphous API throughout the polymer matrix.

[0044] According to the present invention, the minimum working temperature for obtaining an amorphous solid dispersion of API is above the temperature at which PVA is molten, i.e., generally above the glass transition temperature or melting temperature of PVA. To facilitate the formation of a uniform distribution of API, preferably in amorphous form, within the polymer matrix, the working temperature is preferably at least the melting temperature of the API. If the API is solubilized in the molten polymer matrix, the working temperature may also be below the melting temperature of the API.

[0045] The pharmaceutical composition according to the present invention can be incorporated into an oral dosage form in the form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels, or films.

[0046] The polymer matrix of the orally administered dosage form, once ingested, swells and disintegrates in the aqueous environment of gastrointestinal fluid, thereby releasing the API. While the salt form of the weakly basic API can improve the initial aqueous 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. The PVA contained in the dosage form according to the present invention has been shown to maintain a higher concentration of the API in model solutions simulating acidic and neutral gastrointestinal fluids compared to commonly used PVA. Therefore, the pharmaceutical composition according to the present invention has been shown to have the potential to provide improved bioavailability of poorly soluble APIs when administered as an orally administered dosage form. The improved solubility form of the API in the presence of PVA grade according to the present invention provides a higher concentration of the API in gastric fluid or simulated gastric fluid than the concentration of the API provided in the presence of commonly used PVA grade.

[0047] Further embodiments of the present invention are methods for increasing the solubility of a pharmaceutical active ingredient in an aqueous medium, the methods comprising mixing at least one poorly soluble pharmaceutical active ingredient with a polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C, at a temperature exceeding the glass transition temperature or melting temperature of a polymer matrix, thereby forming an amorphous solid dispersion of the pharmaceutical active ingredient.

[0048] According to a preferred embodiment of the present invention, the solubility of the active pharmaceutical ingredient in an aqueous medium is improved compared to the solubility of the active pharmaceutical ingredient in an amorphous solid dispersion containing polyvinyl alcohol having a degree of hydrolysis outside the range of 72% to 85% and / or a viscosity outside the range of 2 mPas to 4 mPas.

[0049] Improved solubility of the active pharmaceutical ingredient in an aqueous medium is preferably observed at acidic and neutral pH levels. The acidic pH according to the present invention is a pH range of less than 7, particularly 1 to 2, and more particularly 1 to 1.2. More preferably, solubility is improved at neutral pH. The neutral pH according to the present invention is a pH range of 6 to 8, and more preferably 6.5 to 7.5.

[0050] Oral pharmaceutical compositions containing amorphous solid dispersions are first exposed to stomach acid after entering the gastrointestinal tract, and then to a more neutral fluid within the intestinal tract. The solubility of the amorphous solid dispersion is further improved after a pH shift in an aqueous medium, from a pH between 1 and 2 to a pH between 6 and 8, preferably from a pH between 1 and 1.2 to a pH between 6.5 and 7.5.

[0051] In the context of the present invention, improved solubility also covers the effects of extending the solubility of the active pharmaceutical ingredient, improving and / or extending the degree of supersaturation, and reducing precipitation, preferably after a pH shift from an acidic medium to a neutral medium. These effects can be confirmed, for example, in dissolution experiments as shown in Figures 2 and 4. According to the present invention, these effects can be used interchangeably.

[0052] Therefore, one embodiment of the present invention is a method for increasing the solubility of a pharmaceutical active ingredient in an aqueous medium using a pharmaceutical composition comprising an amorphous solid dispersion of at least one pharmaceutical active ingredient in a polymer matrix, wherein the polymer is polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C.

[0053] Preferably, the aqueous medium has a pH of 6 to 8.

[0054] In a preferred embodiment, solubility improves after a pH shift from a medium having an acidic pH to a medium having a neutral pH. More preferably, the medium having an acidic pH has a pH between 1 and 2, and the medium having a neutral pH has a pH between 6 and 8.

[0055] A further embodiment of the present invention is the method described above, wherein the polyvinyl alcohol has a degree of hydrolysis of 80% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C. Preferably, the polyvinyl alcohol has a degree of hydrolysis of 80% to 83% and a viscosity of 3 mPas in a 4% solution at 20°C. More preferably, the polyvinyl alcohol is PVA3-80, PVA3-82, or PVA3-83.

[0056] In a further embodiment of the present invention, the active pharmaceutical ingredient is poorly soluble.

[0057] Further embodiments of the present invention are the methods according to any one of claims 1 to 8, wherein the amorphous solid dispersion is obtained by mixing at least one pharmaceutically active ingredient, polyvinyl alcohol, and optionally further pharmaceutically acceptable ingredients at a temperature above the glass transition temperature or melting temperature of a polymer matrix, thereby forming an amorphous solid dispersion of the pharmaceutically active ingredient. Preferably, the temperature is at least the melting temperature of the pharmaceutically active ingredient.

[0058] A further embodiment of the present invention is a pharmaceutical composition obtained by the method described above.

[0059] Further embodiments of the present invention are oral dosage forms comprising the above-mentioned pharmaceutical composition in the form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels, or films.

[0060] Further embodiments of the present invention are methods for preparing the above-mentioned pharmaceutical compositions, comprising the steps of: mixing a poorly soluble pharmaceutical active ingredient, a polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C, and optionally further pharmaceutically acceptable components, at a temperature exceeding the glass transition temperature or melting temperature of a polymer matrix; and thereby forming an amorphous solid dispersion of the pharmaceutical active ingredient. Preferably, the polyvinyl alcohol has a degree of hydrolysis of 80% to 83% and a viscosity of 3 mPas in a 4% solution at 20°C. More preferably, the temperature is at least the melting temperature of the pharmaceutical active ingredient.

[0061] In a preferred embodiment of the present invention, a method for increasing the solubility of a pharmaceutical active ingredient in an aqueous medium contains polyvinyl alcohol having a degree of hydrolysis of 80% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C. More preferably, the polyvinyl alcohol has a degree of hydrolysis of 80% to 83% and a viscosity of 3 mPas in a 4% solution at 20°C. Most preferably, the PVA is PVA3-80 or PVA3-83.

[0062] Further embodiments of the present invention are methods for preparing the above-mentioned pharmaceutical composition, comprising the steps of: mixing a poorly soluble pharmaceutical active ingredient, polyvinyl alcohol having a degree of hydrolysis of 72% to 85% and a viscosity of 2 mPas to 4 mPas in a 4% solution at 20°C, and optionally further pharmaceutically acceptable components, at a temperature exceeding the glass transition temperature or melting temperature of a polymer matrix; and thereby forming an amorphous solid dispersion of the pharmaceutical active ingredient. Preferably, the temperature is at least the melting temperature of the pharmaceutical active ingredient. [Examples]

[0063] [Example 1: Preparation of a PVA matrix supported with ITZ] Nine samples of PVA matrices containing 88 wt% PVA of different PVA grades, 2 wt% silicon dioxide, and 10 wt% itraconazole (ITZ) (BCS class 2) were prepared by hot-melt extrusion as follows:

[0064] For the preparation of the ITZ-supported PVA matrix, one of the following PVA grades was used: PVA5-74, PVA3-80, PVA5-82, PVA3-83, PVA5-88, PVA3-88, PVA4-88 (Parteck MXP), PVA4-98, and PVA18-88.

[0065] Each PVA sample, placed in a porcelain dish, was dried in a vacuum drying oven at 85°C and 100 mbar for 1 hour. The PVA was then cooled rapidly. PVA, ITZ, and silicon dioxide were weighed into a 1 L mixing container according to the weight ratios shown in Figure 1 and mixed for 5 minutes using a tubular mixer. Because itraconazole, the model API, has low fluidity, silicon dioxide was added to the powder mixture as a fluidity modifier. The powder mixture was then loaded into a gravimetric twin-screw feeder of a Brabender KETSE 12 / 36 extruder to determine the maximum feed rate.

[0066] The heating zones were heated until they reached the respective target temperatures shown in Figure 1.

[0067] After the heating zones reached their respective temperatures, the speed and, similarly, the injection rate of the powder mixture were gradually increased in increments of 50 until the target speed and injection rate of 200 rpm and 200.0 g / h were reached, respectively. The extruded material was discarded for approximately 5 minutes until the nozzle pressure and torque stabilized. The extruded material was then transported to the pelletizer by cooling on a conveyor belt at room temperature, where it was crushed into 1.5 mm pellets using a Bravender pelletizer. This process continued until the powder mixture in the feeder was used up, which was reflected in the initial incipient fluctuations of the injection rate.

[0068] The extruded samples obtained in this way were used in dissolution experiments.

[0069] [Example 2: Dissolution profile of PVA matrix supported with 10% ITZ] The dissolution behavior of the extruded material was evaluated according to the pH shift method originally described in Pharmacopoea Europaea 9.0 to test the gastric acid tolerance of the oral formulation.

[0070] Sample preparation: The extruded material was ground in an IKA Tubemill 100 using a 40 ml disposable grinding cup at 25,000 rpm for 20 seconds. Three samples were prepared for each extruded material. For each sample, 375 mg of the extruded material, equivalent to 37.5 mg of ITZ, was weighed out.

[0071] Dissolving method: The dissolution rate of ITZ from extruded material was measured using a Sotax AT7 smart measurement system equipped with a fraction collector and buffer station. Samples were added to a dissolution vessel containing 750 mL of 0.1 M HCl while rotating the paddle at 50 rpm. After 120 minutes, 250 mL of preheated (37°C ± 0.5) 0.2 M Na3PO4x12H2O was added via the buffer station to a total volume of 1000 mL. 2.5 mL samples were taken at 30, 60, 120 minutes, and after a pH shift to pH 6.8, at 135, 150, 180, 240, and 300 minutes.

[0072] HPLC conditions: The soluble samples obtained in this manner were analyzed using an Agilent 1260 Infinity or 1260 Infinity II system equipped with a Chromolith® Performance RP-18e 100-4.6 mm column (Merck) and a UV detector. The HPLC system was operated under isocratic conditions using itraconazole mobile phase (450 / 450 / 200, tetrabutylammonium bisulfate (TBAHS) in Molecula 1.7 g / 1000 mL, acetonitrile Merck LiChrosolv® Reag. Ph Eur for HPLC, and methanol LiChrosolv® Reag. Ph Eur for HPLC). The dissolved sample was filtered, directly diluted 1:1 with itraconazole mobile phase and mixed, and analyzed by HPLC with the following parameters: Runtime: 7 minutes Flow rate: 2.1ml Detection wavelength: 254nm Injection volume: 15μl Column oven temperature: 30℃ Peak retention time: 4 minutes

[0073] The results are shown in Figure 2. The weakly basic API, ITZ, was found to exhibit excellent solubility in acidic solutions in the presence of PVA3-80, PVA3-83, PVA3-88, PVA5-82, and PVA4-88. However, after a pH shift to neutral conditions at 120 minutes, PVA3-80 and PVA3-83 showed superior performance compared to PVA4-88, PVA5-88, PVA18-88, PVA5-74, and PVA4-98, maintaining a sufficient level of release of free base form ITZ. PVA3-88 and PVA5-82 showed only moderate performance.

[0074] [Example 3: Preparation of a PVA matrix supported with dipyridamole] Four samples of PVA matrix containing 90% by weight of PVA with different PVA grades and 10% by weight of dipyridamole (BCS class 2) were prepared by hot-melt extrusion as follows:

[0075] One of the following PVA grades was used to prepare dipyridamole-supported PVA matrices: PVA3-80 (Poval 3-80, Kuraray Europe GmbH), PVA3-83 (Poval 3-83, Kuraray Europe GmbH), and PVA4-88 (Parteck MXP, Merck KGaA).

[0076] Each PVA sample, placed in a porcelain dish, was dried in a vacuum drying oven at 85°C and 100 mbar for 1 hour. The PVA was then cooled rapidly. PVA and dipyridamole were weighed into 1 L containers according to the weight ratios shown in Figure 3 and mixed for 5 minutes using a tubular mixer. The powder mixture was then loaded into a gravimetric twin-screw feeder of a Thermo Fisher Pharma11 extruder, and the maximum feed rate was determined.

[0077] The heating zones were heated until they reached the respective target temperatures shown in Figure 1.

[0078] After the heating zones reached their respective temperatures, the speed and, similarly, the powder mixture dispensing rate were gradually increased in increments of 50 until the target speed and dispensing rate of 200 rpm and 200.0 g / h were reached, respectively. The extruded material was discarded for approximately 5 minutes until the nozzle pressure and torque stabilized. The extruded material was then transported to the pelletizer by cooling on a conveyor belt at room temperature, where it was crushed into 1.5 mm pellets using a Bravender pelletizer. This process continued until the powder mixture in the feeder was used up, which was reflected in the initial fluctuations in the dispensing rate.

[0079] The extruded samples obtained in this way were used in dissolution experiments.

[0080] [Example 4: Dissolution profile of PVA matrix supported with 10% dipyridamole] The dissolution behavior of the extruded material was evaluated according to the pH shift method originally described in Pharmacopoea Europaea 9.0 to test the gastric acid tolerance of the oral formulation.

[0081] Sample preparation: The extruded material was ground in an IKA Tubemill 100 using a 40 ml disposable grinding cup at 25,000 rpm for 20 seconds. Three samples were prepared from each extruded material. For each sample, 500 mg of the extruded material, equivalent to 50 mg of dipyridamole, was weighed out.

[0082] Dissolving method: The dissolution rate of ITZ from extruded material was measured using a Sotax AT7 smart measurement system equipped with a fraction collector and buffer station. Samples were added to a dissolution vessel containing 750 mL of 0.1 M HCl while rotating the paddle at 50 rpm. After 120 minutes, 250 mL of preheated (37°C ± 0.5) 0.2 M Na3PO4x12H2O was added via the buffer station to a total volume of 1000 mL. 2.5 mL samples were taken at 30 minutes, 60 minutes, 120 minutes, and after a pH shift to pH 6.8, at 135 minutes, 150 minutes, 180 minutes, 240 minutes, and 300 minutes.

[0083] HPLC conditions: The soluble samples obtained in this manner were analyzed using an Agilent 1260 Infinity or 1260 Infinity II system equipped with a Chromolith® Performance RP-18e 100-4.6 mm column (Merck) and a UV detector. The HPLC system was operated under isocratic conditions using dipyridamole mobile phase (450 / 450 / 200, tetrabutylammonium bisulfate (TBAHS) in Molecula 1.7 g / 1000 mL, acetonitrile Merck LiChrosolv® Reag. Ph Eur for HPLC, and methanol LiChrosolv® Reag. Ph Eur for HPLC).

[0084] The dissolved sample was filtered, directly diluted 1:1 with the mobile phase dipyridamole, mixed, and analyzed by HPLC with the following parameters: Runtime: 7 minutes Flow rate: 2.1ml Detection wavelength: 254nm Injection volume: 15μl Column oven temperature 30℃ Peak retention time: 3.0 minutes

[0085] The results are shown in Figure 4. Dipyridamole, a weakly basic API, showed excellent solubility in acidic solutions in the presence of PVA3-80, PVA3-83, and PVA4-88, with PVA4-88 being found to release dipyridamole most rapidly and almost completely. After a pH shift to neutral conditions at 120 minutes, PVA3-80 and PVA3-83 showed significantly better performance than PVA4-88 in maintaining a high level of release of the free base form of dipyridamole.

Claims

1. A method for increasing the solubility of a weakly basic pharmaceutical active ingredient in an aqueous medium using a pharmaceutical composition comprising an amorphous solid dispersion of at least one weakly basic pharmaceutical active ingredient in a polymer matrix, wherein the polymer is polyvinyl alcohol having a degree of hydrolysis of 80% to 83% and a viscosity of a 4% solution at 20°C with a viscosity of 3 mPa·s.

2. The method according to claim 1, wherein the aqueous medium has a pH of 6 to 8.

3. The method according to claim 1, wherein solubility is improved after a pH shift from a medium having an acidic pH to a medium having a neutral pH.

4. The method according to claim 3, wherein the acidic medium has a pH between 1 and 2, and the neutral medium has a pH between 6 and 8.

5. The method according to any one of claims 1 to 4, wherein the polyvinyl alcohol is PVA3-80, PVA3-82, or PVA3-83.

6. The method according to any one of claims 1 to 5, wherein the weakly basic active pharmaceutical ingredient is poorly soluble.

7. The method according to any one of claims 1 to 6, wherein the amorphous solid dispersion is obtained by mixing the at least one weakly basic pharmaceutical active ingredient, the polyvinyl alcohol, and optionally further pharmaceutically acceptable components at a temperature exceeding the glass transition temperature or melting temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the weakly basic pharmaceutical active ingredient.

8. The method according to claim 7, wherein the temperature is at least the melting temperature of the weakly basic active pharmaceutical ingredient.

9. A method for preparing a pharmaceutical composition, comprising the steps of: mixing a poorly soluble weak basic pharmaceutical active ingredient, polyvinyl alcohol having a degree of hydrolysis of 80% to 83% and a viscosity of a 4% solution at 20°C with 3 mPa·s, and optionally further pharmaceutically acceptable components at a temperature exceeding the glass transition temperature or melting temperature of a polymer matrix; and thereby forming an amorphous solid dispersion of the weak basic pharmaceutical active ingredient.

10. The method according to claim 9, wherein the temperature is at least the melting temperature of the weakly basic active pharmaceutical ingredient.

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