WO2022090295A1 - Procédé de production d'une dispersion solide amorphe et composition pharmaceutique pour stabiliser des ingrédients pharmaceutiques actifs - Google Patents

Procédé de production d'une dispersion solide amorphe et composition pharmaceutique pour stabiliser des ingrédients pharmaceutiques actifs Download PDF

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Publication number
WO2022090295A1
WO2022090295A1 PCT/EP2021/079785 EP2021079785W WO2022090295A1 WO 2022090295 A1 WO2022090295 A1 WO 2022090295A1 EP 2021079785 W EP2021079785 W EP 2021079785W WO 2022090295 A1 WO2022090295 A1 WO 2022090295A1
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Prior art keywords
active pharmaceutical
solid dispersion
amorphous solid
pva
pharmaceutical ingredient
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English (en)
Inventor
Thomas KIPPING
Finn BAUER
Nicole DI GALLO
Anja-Nadine KNUETTEL
Alessandro Giuseppe Elia
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Merck Patent GmbH
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polymer matrix.
  • the invention further relates to a pharmaceutical composition using polymers as an excipient and particularly to an improved pharmaceutical composition comprising a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate which is suitable to stabilize active pharmaceutical ingredients.
  • hydrophilic polymers such as polyvinyl alcohol (PVA) in an excipient for pharmaceutical compositions has been widely described.
  • PVA polyvinyl alcohol
  • One approach to enhance the bioavailability of active pharmaceutical ingredients (APIs) involved forming an amorphous solid dispersion of the API in a polymer matrix resulting in stabilization of the more soluble amorphous form and thus to an improvement of solubility and bioavailability of the API.
  • WO 2018/083285 A1 discloses powdered PVA having improved properties as a polymer matrix in pharmaceutical compositions comprising APIs, especially in compressed tablets forming amorphous solid dispersions with poorly soluble active pharmaceutical ingredients (APIs).
  • Hot-melt extrusion is known to be one of the key technologies to create an amorphous solution or dispersion.
  • Novel developments include adding a surfactant to the polymer matrix for improving the solubility and stability of the API (Vo CL, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013;85(3 Pt B):799-813). Due to their high polarity, hydrophilic polymers such as PVA are often not able to keep poorly soluble APIs in solution.
  • a polymer matrix comprising polyvinyl alcohol (PVA) and polyvinyl acetate (P Ac) is particularly suitable for producing an amorphous solid dispersion of an active pharmaceutical ingredient (API) in a melting process.
  • PVA and PVAc exhibit a very good miscibility in the molten state even though the individual polymers have completely different solubility characteristics.
  • the presence of the hydrophilic PVA in combination with the lipophilic PVAc facilitates the formation of an amorphous solid dispersion of the API in the polymer matrix in the molten state.
  • the presence of the lipophilic PVAc does not only improve the formation and the stability of the amorphous solid dispersion of the API in the polymer matrix but also improves desired sustained release properties of an oral dosage form comprising the amorphous solid dispersion.
  • the invention concerns a method for producing an amorphous solid dispersion comprising mixing polyvinyl alcohol, polyvinyl acetate, optionally further pharmaceutically acceptable components and at least one active pharmaceutical ingredient at a temperature above the glass transition temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the API.
  • the temperature is at least the melting temperature of the API.
  • the invention concerns a pharmaceutical composition for oral administration comprising an amorphous solid dispersion of at least one API in a polymer matrix comprising a PVA and a PVAc and wherein the amorphous solid dispersion is obtainable by a method according to the invention.
  • the pharmaceutical composition according to the invention preferably comprises an API that is poorly soluble in water.
  • the presence of the PVAc prolongs the release profile and contributes to preventing phase separation and recrystallization of the poorly soluble API in aqueous solution.
  • the bioavailability of the API for the patient can be enhanced.
  • the invention concerns an oral dosage form comprising the above-mentioned pharmaceutical composition in form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels, films.
  • a further aspect of the invention concerns a method for stabilizing the amorphous form of an active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate, said method comprising a step of mixing polyvinyl alcohol, polyvinyl acetate and the active pharmaceutical ingredient at a temperature above the glass transition temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient, preferably wherein the weight ratio of polyvinyl acetate and polyvinyl alcohol is from 1:3.5 to 8:1.
  • the present invention discloses a method for producing an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate, comprising the step of mixing polyvinyl alcohol, polyvinyl acetate and the at least one active pharmaceutical ingredient at a temperature above the glass transition temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient.
  • the amorphous solid dispersion can optionally contain further pharmaceutically acceptable components.
  • amorphous solid dispersion is a dispersion of an amorphous API in a polymer matrix.
  • the amorphous API is distributed in a molecularly dispersed state within the polymer matrix.
  • the solid dispersion is a solid solution.
  • formulations comprising an amorphous solid dispersion can reach higher solubilities in aqueous media than the crystalline API.
  • Polyvinyl alcohol is a synthetic water-soluble polymer that has the idealized formula [CH2CH(OH)] n . It possesses good film-forming, adhesive, and emulsifying properties. PVA is prepared from polyvinyl acetate, where the functional acetate groups are either partially or completely hydrolysed to alcohol functional groups. If not completely hydrolysed, PVA is a random copolymer consisting of vinyl alcohol repeat units -[CH2CH(OH)]- and vinyl acetate repeat units -[CH2CH(OOCCHs)]-. The polarity of PVA is closely linked to its molecular structure. The hydrolysis degree and the molecular weight determine the molecular properties of PVA.
  • PVA 4-88 is a PVA grade with a viscosity of 4 mPas that is 88 % hydrolysed, i.e. having 88 % of vinyl alcohol repeat units and 12 % of vinyl acetate repeat units.
  • a hydrolysis grade of e.g. 88 % and a viscosity of 4 mPas encompasses calculated hydrolysis grades of 87.50 % to 87.49 % and calculated viscosities of 3.50 mPas to 4.49 mPas % according to common rounding methods.
  • Viscosity according to the invention is measured as stated in USP 39 under Monograph “Polyvinyl Alcohol” with the method Viscosity- Rotational Method (912).
  • the degree of hydrolysis according to the invention is measured by determining the saponification value of the Polyvinyl Alcohol, e.g. as stated in USP 39 under Monograph “Polyvinyl Alcohol” under “Degree of Hydrolysis”:
  • Vs volume of 0.2 N hydrochloric acid VS consumed in the titration of the Sample solution (ml)
  • M r molecular weight of potassium hydroxide, 56.11
  • Polymer matrices according to the present invention can comprise any PVA grade.
  • Preferred PVA grades are selected from the group consisting of PVA 3-74, PVA 3- 80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-84, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-74, PVA 4-85, PVA 4-88, PVA 4-98, PVA 5-72, PVA 5-74, PVA 5-82, PVA 5-88, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVA 13-88, PVA 15-79, PVA 15-99, PVA 18-88, PVA 20-98, PVA 23-88, PVA 26-80, PVA 26-88, PVA 2-98, PVA 28-99, PVA 30-75, PVA 30-92, PVA 30-98, PVA 32-80, PVA 32-88, PVA 40- 88 or any PVA grades in between.
  • More preferred PVA grades are polyvinyl alcohols having a hydrolysis degree of 72 % to 90 %, in particular 74 % to 88 %, and a viscosity of a 4 % solution at 20° C of 2 mPas to 5 mPas, in particular 3 mPas to 5 mPas.
  • Particularly preferred PVA grades are selected from the group consisting of PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-84, PVA 3-85, PVA 3-88, PVA 4-88, and PVA 5-74, in particular PVA 4-88.
  • Further preferred PVA grades have a degree of hydrolysis in the range of greater than 72.2 % according to the requirements of the European Pharmacopoeia, or between 85 - 89 % according to the United States Pharmacopoeia, and a molecular weight in the range of 14 000 g/mol to 250 000 g/mol. With increasing molecular weight, the viscosity of an aqueous solution of the PVA increases.
  • Amorphous solid dispersions and pharmaceutical compositions according to the present invention may comprise PVA, which is composed of one or more grades of PVA of differing molecular weights and of differing grades of hydrolysis.
  • Polyvinyl acetate is an aliphatic synthetic polymer that has the idealized formula [CH2CH(COOCHs)]n. PVAc is prepared by the polymerization of vinyl acetate monomer. The molecular weight of PVAc is typically 10.000 g/mol to 1.500.000 g/mol. Preferred PVAcs according to the invention have an average molecular weight of 10.000 g/mol to 500.0000 g/mol.
  • the method of the invention enables combining PVAc and PVA despite their different hydrophilic/lipophilic properties in the molten state resulting in the formation of a homogenous polymer matrix.
  • PVAc supports and stabilizes the formation of an amorphous solid dispersion of a poorly soluble API in a polymer matrix comprising PVA. It was shown that heating a mixture of API, PVA and PVAc above their glass transition temperature or melting temperature while mixing, e.g. in an extruder, results in a substantially homogenous amorphous solid dispersion.
  • the temperature of the melt is above the melting temperature of the API in order to facilitate a uniform distribution of the API throughout the polymer matrix.
  • Typical working temperatures for obtaining an amorphous solid dispersion of an API in a PVA/PVAc polymer matrix are 140° C to 230° C, particularly 180° C to 200° C.
  • the minimum working temperature for obtaining an amorphous solid dispersion of the API is the temperature above which the polymer matrix comprising polyvinyl alcohol and polyvinyl acetate is in a molten state, i.e. generally a temperature above the glass transition temperature or melting temperatures of the polymer matrix.
  • the working temperature is preferably at least the melting temperature of the API.
  • working temperature can also be below the melting temperature of the API.
  • This method may be employed in commonly known manufacturing methods for producing pharmaceutical compositions for oral dosage forms that include a mixing and heating step that is suitable for producing an amorphous solid dispersion of the API within a polymer matrix, and a subsequent solidifying step. Manufacturing methods employing these steps are e.g. hot-melt extrusion, melt extrusion, injection molding, compression molding, or additive manufacturing.
  • the amorphous solid dispersion may be produced in two separate melting steps. The first step being the mixing of PVAc, PVA and optionally additional pharmaceutically acceptable components at a temperature above the glass transition temperature or melting temperature of the polymer mixture. After solidifying the so obtained polymer mixture is grinded.
  • the second step being the mixing of the solidified and grinded polymer mixture with the API at a temperature above the glass transition temperature or melting temperature of the polymer matrix.
  • the API can optionally be mixed with the solidified and grinded polymer mixture before extrusion or the API can be added during extrusion of the polymer mixture.
  • weight ratios of the lipophilic PVAc to the hydrophilic PVA improve the formation and the stability of the amorphous solid dispersion of the API in the polymer matrix, in particular the amorphous form of the API in the amorphous solid dispersion, obtained by a method according to the present invention.
  • Preferred weight ratios of PVAc to PVA in a polymer matrix for obtaining a stabilizing effect on the amorphous state of the API are in the range from 1:3.5 to 8:1, preferably 1:3.5 to 3.5:1.
  • a polymer matrix comprising certain weight ratios of PVAc to PVA in the polymer matrix of a pharmaceutical composition may have an advantageous influence on the release properties of the API. Accordingly, in a preferred embodiment the PVAc and the PVA are combined in a weight ratio of 1:3.5 to 1:1 for obtaining desirable release properties while maintaining enhanced stabilization of the amorphous solid dispersion of the API.
  • Preferred weight ratios of PVAc to PVA for obtaining a rapid and substantially full release of a poorly soluble API are in the range of 1:3.5 to 1:2. It was shown that higher weight ratios of PVAc to PVA in the range of 1:2 to 1:1 improve the sustained release properties of a poorly soluble API.
  • the invention discloses a pharmaceutical composition for oral administration comprising an amorphous solid dispersion of at least one active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate, wherein the amorphous solid dispersion is obtainable by using a method according to the present invention.
  • a further aspect of the invention relates to an oral dosage form comprising a pharmaceutical composition according to invention in form of tablets, beads, granules, pellets, capsules, suspensions, emulsions, gels, films.
  • the invention provides a method for stabilizing the amorphous form of an active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate, said method comprising a step of mixing polyvinyl alcohol, polyvinyl acetate and the active pharmaceutical ingredient at a temperature above the glass transition temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient.
  • stabilizing the amorphous form of an active pharmaceutical ingredient in a polymer matrix means that the formation and/or the stability of the amorphous solid dispersion of the API in the polymer matrix is increased. In particular, the formation and/or the stability of the amorphous form of the API in the amorphous solid dispersion is improved. According to the invention this stabilizing effect is measured by differential scanning calorimetry measurements as described in Example 3 of the present application, which gives an indication of the presence of crystalline API.
  • the method for stabilizing the amorphous form of an active pharmaceutical ingredient in a polymer matrix comprising polyvinyl alcohol and polyvinyl acetate includes a method for improving stability of an amorphous solid dispersion or a method for forming an amorphous solid dispersion having an improved stability.
  • Differential scanning calorimetry measurements revealed that in the presence of PVAc and PVA in a weight ratio of PVAc to PVA from 1:3.5 to 8:1 , preferably 1:3.5 to 3.5:1 , an amorphous solid dispersion of a poorly soluble API is obtained which is free of any detectable crystalline material.
  • the absence of crystalline API in the polymer matrix is highly desirable for a high absorption of the API in vivo.
  • the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion is enhanced as compared to the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion comprising polyvinyl acetate and polyvinyl alcohol in a weight ratio outside the range from 1:3.5 to 8:1, preferably in a weight ratio outside 1:3.5 to 3.5:1.
  • the temperature is at least the melting temperature of the active pharmaceutical ingredient.
  • the invention provides the use of a polymer mixture comprising polyvinyl alcohol and a polyvinyl acetate for stabilizing the amorphous form of an active pharmaceutical ingredient in an amorphous solid dispersion by mixing polyvinyl alcohol, polyvinyl acetate and the active pharmaceutical ingredient at a temperature above the glass transition temperature of the polymer matrix, thereby forming an amorphous solid dispersion of the active pharmaceutical ingredient, preferably wherein the weight ratio of polyvinyl acetate and polyvinyl alcohol is from 1 :3.5 to 8: 1 , more preferably 1 :3.5 to 3.5: 1.
  • the invention provides the use of a polymer mixture as described above, wherein the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion is enhanced as compared to the stability of the amorphous form of the active pharmaceutical ingredient in the amorphous solid dispersion comprising polyvinyl acetate and polyvinyl alcohol in a weight ratio outside the range from 1:3.5 to 8:1, preferably in a weight ratio outside 1 :3.5 to 3.5: 1.
  • a pharmaceutical composition for oral administration suitable for sustained release of the API comprises weight ratios of PVAc to PVA in the range of 1:2 to 1:1.
  • weight ratios of PVAc to PVA in the range of 1:2 to 1:1 in a polymer matrix comprising an amorphous solid solution is of particular interest for the formulation of solid oral pharmaceutical dosage forms with a prolonged API release.
  • bioavailability is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body of a patient.
  • PVAc and PVA may be combined in a weight ratio of 1:3.5 to 1:1 for obtaining desirable release properties for specific APIs.
  • the invention provides a tool for varying the solubilizing effects of PVAc on poorly soluble APIs in a wide range in order to enhance the stability of the amorphous solid dispersion while maintaining desirable release properties of a specified API in aqueous media. It is assumed that PVAc supports the solubilization of lipophilic APIs in the matrix in order to stabilize the amorphous solid dispersion, whereas PVA assures the release of the API.
  • the polymer matrix comprising PVA and PVAc may be combined with other pharmaceutically acceptable excipients.
  • the pharmaceutical composition according to the invention may comprise additional pharmaceutically acceptable hydrophilic or lipophilic polymers.
  • the pharmaceutical composition may also comprise fillers, plasticizers, surfactants, and other suitable components that are well known to those skilled in the art.
  • pharmaceutically acceptable refers to all compounds, such as solvents, dispersion media, excipients, carriers, coatings, active agents, isotonic and absorption delaying agents, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.
  • solvents such as solvents, dispersion media, excipients, carriers, coatings, active agents, isotonic and absorption delaying agents, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.
  • dispersion media such as solvents, dispersion media, excipients, carriers, coatings, active agents, isotonic and absorption delaying agents, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.
  • active agents such as isotonic and absorption delaying agents, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.
  • isotonic and absorption delaying agents and the like that do not produce an allergic or similar untoward reaction when
  • the active pharmaceutical ingredients (API) of the pharmaceutical compositions according to the invention are biologically active agents in form of a weak base, a weak acid or a neutral molecule.
  • the API may be in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogues, prodrugs, and solvates thereof.
  • the pharmaceutical composition may comprise more than one API.
  • the terms “poorly soluble API”, “poorly water-soluble API” and “lipophilic API” refer to an API having a solubility such that the highest therapeutic dose of the particular API to be administered to an individual cannot be dissolved in 250 ml of aqueous media ranging in pH from 1 to 8 following the definition of low solubility according to the Biopharmaceutics Classification System (BCS) classes 2 and 4. Poorly soluble APIs with weakly basic or weakly acidic characteristics have a pH-dependent solubility profile and can have a wide range of solubility in the aqueous environment of the gastrointestinal tract. APIs falling under BCS classes 2 or 4, respectively, are well known to persons skilled in the art. A typical example for a poorly soluble API of BCS class 2 is itraconazole (ITZ).
  • the API included in the pharmaceutical compositions of the present invention has a sufficient amount to be therapeutically effective.
  • therapeutically effective amounts are generally known or readily accessible by persons skilled in the art.
  • the API may be present in the pharmaceutical composition in a weight ratio of API to the polymeric matrix the range of 1:99 to 90:10, preferably 5:95 to 60:40, most preferably 10:90 to 30:70.
  • Figure 1 shows a table summarizing extrusion parameters for preparing model ternary matrix systems with varying ratios of PVA and PVAc and itraconazole (ITZ) as a lipophilic model API.
  • Figure 2 shows a cyclic DSC scan of itraconazole drug substance.
  • Figure 3 shows differential scanning calorimetry thermograms of respective ternary systems comprising PVA, PVAc and itraconazole as a lipophilic model API.
  • Figure 4 shows differential scanning calorimetry thermograms of the respective ternary systems PVA, PVAc and itraconazole as a lipophilic model API (1st derivative at mesophase region of itraconazole).
  • Figure 5 shows drug release profiles of ternary systems containing PVA, PVAc and itraconazole as a lipophilic model API.
  • the quantities of PVAc, PVA and ITZ required for a total mass of 200 g powder mixture according to the weight ratios shown in Fig. 1 were weighed into a 1 L mixing vessel and then mixed by means of a tubular mixer for 5 min. The powder mixture was then filled into the gravimetric twin-screw feeder of a Brabender KETSE 12/36 extruder and a determination of the maximum feed rate was performed. The heating zones were heated at the respective target temperatures as shown in Fig. 1. After the heating zones had reached their respective temperatures, the speed and, analogously, the dosing rate of the powder mixture was increased step by step in units of 50 until the target speed and target dosing rate of 200 rpm and 200.0 g/h, respectively, were reached.
  • the extrudate was discarded for about 5 minutes until nozzle pressure and torque stabilized.
  • the extrudate was then allowed to cool on the conveyor belt at room temperature and thereby conveyed to the pelletizer, where the extrudate was crushed to 1.5 mm pellets using a Brabender pelletizer.
  • the process was continued until the powder mixture in the feeder was used up. This was reflected in incipient fluctuations in the dosing rate. Afterwards, the dosing was stopped and the screw speed was gradually reduced to 10 rpm and held for another 10 minutes to feed residual polymer from the extruder barrel, which was then discarded.
  • Cyclic DSC experiments were performed on a DSC 3+ instrument (Mettler Toledo) in order to assess the thermal behavior of the API itraconazole (ITZ). 2 mg of the crystalline ITZ was weighed in an aluminium pan. The sample was heated from 25 °C to 180°C at 10 °C/min followed by a cooling step from 180 °C to 25 °C at 10 °C/min. In a second heating step the sample was heated from 25 °C to 220 °C at 10 °C/min.
  • Fig. 2 The results are presented in Fig. 2.
  • a prominent melting peak of crystalline itraconazole can be observed at about 168 °C.
  • mesophase regions of itraconazole can be observed between 70 °C and 90 °C.
  • the material is heated again.
  • mesophase regions of itraconazole can be observed.
  • No additional melting peak is observed indicating the full amorphization of the model drug substance.
  • the mesophase transition is considered to be a good indicator for the distribution of itraconazole within a polymer matrix.
  • micronized ternary composition pellets obtained in Example 1 were weighed into 40 pl aluminium crucibles (standard crucibles). With a load of 10 % ITZ the sample weight was between 5 mg and 7 mg. The samples were sealed. A small hole was pierced in the crucible lid by the autosampler immediately before the measurement or immediately before placing the sample in the heating furnace.
  • the crucible lids are specially provided with a "horn" in order to facilitate piercing without perforating the lid.
  • a temperature profile from 20 °C (room temperature) to 230 °C was chosen for the DSC analysis in order to cover as many effects as possible.
  • a uniform heating rate of 30 °C/min was chosen.
  • N2 was used as the purge gas which was supplied with 50 ml/min (controlled by the DSC instrument).
  • Example 3 Drug release of ternary compositions
  • the ternary composition extrudates were ground in an I KA Tubemill 100 with a 40 ml disposable grinding cup for 20 sec at 25000 rpm. 3 samples of each extrudate were prepared. For each sample, 500 mg of extrudate were weighed corresponding to 50 mg ITZ per sample.
  • the dissolution rates of ITZ from the ternary composition extrudates were measured using a Sotax AT7 smart measuring system equipped with a fraction collector. The samples were placed in dissolution vessels containing 900 mL 0.1M HCI with a paddle rotation of 75 rpm. Samples were taken at 5, 15, 30, 60 and 120 min.
  • the so obtained dissolution samples were analyzed with an Agilent 1260 Infinity or 1260 Infinity II system equipped with a Chromolith® Performance RP-18e 100-4.6 mm column (Merck) and UV detection.
  • the HPLC system was operated under isocratic conditions with Mobile Phase Itraconazole (450/450/200 tetrabutylammonium hydrogen sulfate (TBAHS) of Molecula 1.7 g/1000 mL, acetonitrile Merck LiChrosolv® Reag. Ph Eur for HPLC, and methanol LiChrosolv® Reag. Ph Eur for HPLC.
  • the ternary composition having a weight ratio of PVAc:PVA of 1:1 showed sustained release of the ITZ.
  • higher contents of the lipophilic PVAc can be used to adapt the release kinetics and enable a tailored release formulation while providing enhanced stabilisation of the amorphous solid dispersion.
  • the formulator can flexibly adapt the properties of the polymer matrix to the targeted API.
  • the polarity of the entire polymer matrix is adaptable and the formulator gains the opportunity to define the type of solid dispersion.

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Abstract

La présente invention concerne un procédé de production d'une dispersion solide amorphe d'au moins un ingrédient pharmaceutique actif dans une matrice polymère. L'invention concerne en outre une composition pharmaceutique utilisant des polymères en tant qu'excipient et en particulier une composition pharmaceutique améliorée comprenant une matrice polymère comprenant de l'alcool polyvinylique et de l'acétate de polyvinyle qui est appropriée pour stabiliser des ingrédients pharmaceutiques actifs.
PCT/EP2021/079785 2020-10-28 2021-10-27 Procédé de production d'une dispersion solide amorphe et composition pharmaceutique pour stabiliser des ingrédients pharmaceutiques actifs Ceased WO2022090295A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0852140A1 (fr) * 1995-08-11 1998-07-08 Nissan Chemical Industries, Limited Procedes permettant de rendre amorphes des medicaments peu solubles
WO2018083285A1 (fr) 2016-11-07 2018-05-11 Merck Patent Gmbh Comprimé à libération contrôlée à base d'alcool polyvinylique et sa fabrication
EP2755637B1 (fr) * 2011-09-13 2020-08-12 ISP Investments LLC Dispersion solide de composés peu solubles comprenant une crospovidone et au moins un polymère hydrosoluble

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0852140A1 (fr) * 1995-08-11 1998-07-08 Nissan Chemical Industries, Limited Procedes permettant de rendre amorphes des medicaments peu solubles
EP2755637B1 (fr) * 2011-09-13 2020-08-12 ISP Investments LLC Dispersion solide de composés peu solubles comprenant une crospovidone et au moins un polymère hydrosoluble
WO2018083285A1 (fr) 2016-11-07 2018-05-11 Merck Patent Gmbh Comprimé à libération contrôlée à base d'alcool polyvinylique et sa fabrication

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BROUGH CHRIS ET AL: "Use of Polyvinyl Alcohol as a Solubility-Enhancing Polymer for Poorly Water Soluble Drug Delivery (Part 1)", AAPS PHARMSCITECH, SPRINGER US, NEW YORK, vol. 17, no. 1, 4 December 2015 (2015-12-04), pages 167 - 179, XP036112594, DOI: 10.1208/S12249-015-0458-Y *
NOVOA G A G ET AL: "Physical solid-state properties and dissolution of sustained-release matrices of polyvinylacetate", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 59, no. 2, 1 February 2005 (2005-02-01), pages 343 - 350, XP004719606, ISSN: 0939-6411, DOI: 10.1016/J.EJPB.2004.07.012 *
WLODARSKI KAMIL ET AL: "Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions", PHARMACEUTICAL RESEARCH, SPRINGER NEW YORK LLC, US, vol. 35, no. 1, 5 January 2018 (2018-01-05), pages 1 - 15, XP036404383, ISSN: 0724-8741, [retrieved on 20180105], DOI: 10.1007/S11095-017-2313-1 *

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