Micronized opicapone

Abstract

The present invention relates to micronized olpinapone, and more particularly to a micronized pharmaceutical product of crystalline olpinapone having a percentage of bunchy agglomerates of less than or equal to 30%. The invention also relates to a process for the production of these micronized pharmaceutical products and to the use of said micronized pharmaceutical products for increasing the bioavailability of olpinapone in the treatment of Parkinson's disease. In addition, the present invention provides methods for calculating the primary particle size distribution and aggregate content of such products.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 2021800207749, application date March 12, 2021, and invention name “Micronized Opicapone”. Field of the Invention

[0002] The present invention relates to micronized pharmaceutical products consisting essentially of crystalline opicapone. The present invention also relates to a method for producing these micronized pharmaceutical products and to the use of said micronized pharmaceutical products for increasing the bioavailability of opicapone in the treatment of Parkinson's disease. In addition, the present invention relates to methods for determining the primary particle size distribution and agglomerate content within such micronized pharmaceutical products. Background Art

[0003] For decades, levodopa (L-DOPA) has been used in clinical practice to treat various diseases including Parkinson's disease. L-DOPA can cross the blood-brain barrier, where it is then converted into dopamine and increases dopamine levels. However, the conversion of L-DOPA to dopamine may also occur in peripheral tissues, which may cause side effects after the administration of L-DOPA. Therefore, the co-administration of peripheral amino acid decarboxylase (AADC) inhibitors such as carbidopa or benserazide has become standard clinical practice, which prevents the dopamine conversion in peripheral tissues. It is also known that inhibitors of catechol-O-methyltransferase (COMT) can provide clinical improvement to patients receiving L-DOPA treatment for Parkinson's disease because COMT catalyzes the degradation of L-DOPA.

[0004] As described in International Publication No. WO 2007 / 013830, the nitrocatechol derivative opicapone has been found to be a potent and long-acting COMT inhibitor. This compound is biologically active, bioavailable, and exhibits low toxicity. Therefore, opicapone has potentially valuable pharmaceutical properties in the treatment of several central and peripheral nervous system disorders, such as mood disorders; movement disorders such as Parkinson's disease, Parkinson's disease, and restless legs syndrome; gastrointestinal disturbances; edema-forming states; and hypertension, where inhibition of catecholamine O-methylation may have therapeutic benefits. The development of the opicapone molecule is described in LEKiss et al., J. Med. Chem., 2010, 53, 3396-3411, and the opicapone molecule was approved for marketing in the European Union as early as June 2016.

[0005] Further research since WO 2007 / 013830 has focused on optimizing opicapone into a stable and bioavailable form. For example, WO 2009 / 116882 describes various polymorphs of opicapone, of which polymorph A is kinetically and thermodynamically stable. WO 2010 / 114404 and WO 2010 / 114405 describe stable opicapone formulations used in clinical trials. WO 2013 / 089573 describes an optimized process for producing opicapone in good yield using simple starting materials. Importantly, WO 2013 / 089573 also discloses that when recrystallized opicapone is ball-milled or micronized in a spiral jet mill, microparticles of a desired size can be obtained for good oral bioavailability. This effect is supported by the poster abstract “Relative Bioavailability of Opicapone from Two Different Formulations in Healthy Subjects: The In Vivo Effect of Particle Size” (R. Lima et al., AAPS Annual Meeting, Orlando, 2015), which describes a study comparing the bioavailability (AUC) of micronized and non-micronized opicapone in healthy volunteers. 0-无限时间 and C 最大 ) is undergoing Phase I clinical trials. WO 2013 / 089573 discloses that micronized opicapone exhibits approximately 2-fold higher bioavailability than its non-micronized equivalent, equivalent circular diameter (ECD) values (D10, D50, and D95). Therefore, the preferred form of opicapone for clinical use is based on a drug product consisting essentially of crystalline opicapone material having the ECD size characteristics described in WO 2013 / 089573.

[0006] Although consistently more bioavailable than the non-micronized form, the inventors later discovered that the final drug product formulation containing micronized crystalline opicapone was superior in its oral bioavailability (e.g., AUC and C 最大 This variability was observed despite the drug product being manufactured according to good manufacturing practices and meeting the ECD size characteristics described in WO 2013 / 089573.

[0007] Therefore, there remains a need for a drug product consisting essentially of crystalline opicapone that can be formulated with suitable pharmaceutical excipients to provide a final drug product having enhanced oral bioavailability and consistent pharmacokinetic parameters (e.g., AUC and C 最大) in order to ensure bioequivalence in humans and / or animal models. Additionally, there remains a need for methods of characterizing drug products consisting essentially of crystalline opicapone that can predict whether the drug product can be formulated with suitable pharmaceutical excipients to provide a final drug product with enhanced oral bioavailability and consistent pharmacokinetic parameters (e.g., AUC and C 最大 ) in order to ensure bioequivalence in humans and / or animal models. Summary of the Invention

[0008] The inventors have now identified previously unknown properties of micronized drug products consisting essentially of crystalline opicapone, as characterized using the standard ECD values (D10, D50 and / or D95) described in WO 2013 / 089573, which may give rise to differences in pharmacokinetic parameters (e.g. AUC and C 最大 ) of biologically significant batch-to-batch variability.

[0009] The inventors have found that when the aggregate distribution of micronized crystalline opicapone is analyzed and the proportion of bundle-like aggregates is low (≤30%), while preferably the proportion of spherical aggregates is high (≥70%), the bioavailability of such products can be improved and biologically significant batch-to-batch variability can be eliminated. In batches that do not meet these criteria, repeated micronization, preferably by jet milling, as described below, can produce a micronized product that meets these criteria.

[0010] Thus, in a first general embodiment, the present invention provides a drug product consisting essentially of crystalline opicapone having the following primary particle size distribution:

[0011] D10 (maximum distance) greater than or equal to 5 μm;

[0012] D50 (maximum distance) of 10 to 70 μm; and

[0013] D90 (maximum distance) less than or equal to 250 μm;

[0014] And has the following agglomerate distribution:

[0015] % of bundle-like agglomerates less than or equal to 30%.

[0016] In a second general embodiment, the present invention provides another drug product comprising the drug product according to the first general embodiment admixed with one or more pharmaceutically acceptable excipients.

[0017] In a third general embodiment, the present invention provides another pharmaceutical product, wherein the pharmaceutical product according to the second general embodiment is granulated.

[0018] In a fourth general embodiment, the invention provides another drug product comprising the drug product according to the third general embodiment admixed with one or more pharmaceutically acceptable excipients.

[0019] In a fifth general embodiment, the invention provides a capsule for oral administration comprising the pharmaceutical product according to any of the second, third or fourth general embodiments.

[0020] In a sixth general embodiment, the invention provides a tablet for oral administration comprising the pharmaceutical product according to any one of the second, third or fourth general embodiments.

[0021] In a seventh general embodiment, the present invention provides a method of manufacturing a pharmaceutical product, the method comprising the steps of:

[0022] a) micronizing a product consisting essentially of crystalline opicapone;

[0023] b) determining the primary particle size distribution and the % of bundle-like agglomerates of the crystalline opicapone in the micronized product;

[0024] c) retaining a micronized product consisting essentially of crystalline opicapone having the following primary particle size distribution:

[0025] D10 (maximum distance) greater than or equal to 5 μm;

[0026] D50 (maximum distance) of 10 to 70 μm; and

[0027] D90 (maximum distance) less than or equal to 250 μm;

[0028] And has the following agglomerate distribution:

[0029] % bundled agglomerates less than or equal to 30%; and

[0030] d) If necessary, repeating steps a) to c) on a micronized product consisting essentially of crystalline opicapone without said primary particle size distribution and said agglomerate distribution as defined in step c) above.

[0031] In an eighth general embodiment, the invention provides the use of a drug product as defined in the first general embodiment in the manufacture of a medicament for increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease as compared to the bioavailability of said opicapone that would be obtained from an equivalent medicament manufactured using the drug product as defined in the first general embodiment except that the percentage of bundled aggregates is greater than 30%.

[0032] In a ninth general embodiment, the present invention provides a medicament comprising a drug product as defined in the first general embodiment for use in increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease as compared to the bioavailability of said opicapone that would be obtained from an equivalent medicament comprising a drug product as defined in the first general embodiment except that the percentage of bundled aggregates is greater than 30%.

[0033] In a tenth general embodiment, the present invention provides a method of increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease, said method comprising administering to said patient a medicament comprising a therapeutically effective amount of a drug product as defined in the first general embodiment, wherein said medicament provides increased bioavailability of opicapone as compared to the bioavailability of opicapone that would be obtained from an equivalent medicament comprising a drug product as defined in the first general embodiment except that the percentage of bundled aggregates is greater than 30%.

[0034] In an eleventh general embodiment, the present invention provides a method for determining the primary particle size distribution of a pharmaceutical product consisting essentially of micronized crystalline opicapone, the method comprising the steps of:

[0035] i) dispersing the drug product in mineral oil in such a manner as to deagglomerate any agglomerates;

[0036] ii) setting up the dispersion for particle size measurement;

[0037] iii) measuring the maximum distance between any two points of a single particle of crystalline opicapone;

[0038] iv) repeating step iii) for at least 100 particles; and

[0039] v) Calculate the D10 (maximum distance), D50 (maximum distance), and D90 (maximum distance) values.

[0040] In a twelfth general embodiment, the present invention provides a method for determining the primary particle size distribution of a pharmaceutical product consisting essentially of micronized crystalline opicapone, the method comprising the steps of:

[0041] i) dispersing the drug product in mineral oil in such a manner as to deagglomerate any agglomerates;

[0042] ii) setting up the dispersion for particle size measurement;

[0043] iii) measuring the total fiber length of individual particles of crystalline opicapone;

[0044] iv) repeating step iii) for at least 100 particles; and

[0045] v) Calculate the D10 (total fiber length), D50 (total fiber length) and D90 (total fiber length) values.

[0046] In a thirteenth general embodiment, the present invention provides a method for determining the agglomerate distribution of a pharmaceutical product consisting essentially of micronized crystalline opicapone, the method comprising the steps of:

[0047] i) conditioning a dried sample of the drug product for aggregate analysis without disaggregating the aggregates;

[0048] ii) determining the percentage of bundle-like aggregates within the sample; and

[0049] iii) determining the percentage of spherical aggregates in the sample.

[0050] Other specific and preferred aspects of these general embodiments are described below. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 A picture showing typical "bundles" located between disaggregated primary particles of crystalline opicapone is shown.

[0052] Figure 2 A picture showing typical "spherical agglomerates" located between deagglomerated primary particles of crystalline opicapone is shown.

[0053] Figure 3 Preferred aspect ratio and solidity values for spherical agglomerates are shown.

[0054] Figure 4 The "equivalent circular diameter" (ECD) of the particles (a) is shown.

[0055] Figure 5 The "maximum distance" of the particles (b) is shown.

[0056] Figure 6 The "total fiber length" of the fiber particles (c) is shown.

[0057] Figure 7 The correlation between the "total fiber length" and the "maximum distance" of the particles is shown.

[0058] Figure 8 The correlation between bundle-like and spherical aggregates is shown.

[0059] Figure 9 Shown are plasma levels of opicapone following single oral administration of various micronized crystalline opicapone samples to male Wistar rats (see Experiment 4.1 below). DETAILED DESCRIPTION

[0060] A. Definition

[0061] Unless otherwise limited in specific instances, the following definitions apply to the terms used throughout this specification.

[0062] A "drug product" is a product that can be used to prepare a final pharmaceutical or drug product suitable for administration to a patient.

[0063] The term "consisting essentially of crystalline opicapone" means that the drug product consists entirely of crystalline opicapone, or that the drug product consists of crystalline opicapone with only minor amounts of other components that do not substantially affect its essential pharmaceutical properties. A drug product consisting essentially of crystalline opicapone will generally contain crystalline opicapone in an amount of at least 95%, preferably at least 97%, more preferably at least 98%, and even more preferably at least 99% by weight, based on the total dry weight of the drug product.

[0064] The term "primary particle" refers to the smallest discrete identifiable crystalline entity of opicapone within a sample of a drug product. A primary particle may consist of a single crystal of opicapone. Figure 1 and Figure 2 In the present invention, the primary particles of crystalline opicapone are generally rod-shaped and / or needle-shaped and / or fiber-shaped.

[0065] An "agglomerate" of crystalline opicapone refers to an aggregate of at least 10 primary particles of crystalline opicapone held together, typically by weak physical interactions. Typically, such an agglomerate contains more primary particles of crystalline opicapone. Agglomerate formation is generally reversible, and an agglomerate can generally be converted into discrete primary particles by applying relatively weak forces.

[0066] "Bundle-like aggregates" of crystalline opicapone are aggregates in which the primary particles are primarily aggregated side by side. Such aggregates may, for example, resemble bundles of corn (see Figure 1). Typically, such agglomerates have at least 60%, more typically at least 70%, still more typically at least 80% of their primary particles aggregated side by side. Unlike most agglomerates, the bundled agglomerates of crystalline opicapone are not easily converted (e.g., deagglomerated) into discrete primary particles. "Bundled agglomerates" can be further defined as having an 'aspect ratio' of less than 0.45 (or alternatively an 'elongation' greater than 0.55, since elongation = 1 - aspect ratio). The "aspect ratio" is equal to the "width" of the agglomerate divided by its "length", where the "length" is calculated by projecting all possible lines from one point on the perimeter of the agglomerate to another point on its perimeter onto the "major axis" (the "major axis" is the axis of minimum rotational energy) and measuring the maximum length of these projections, and the "width" is calculated by projecting all possible lines from one point on the perimeter of the agglomerate to another point on its perimeter onto the "minor axis" (the "minor axis" is the axis of maximum rotational energy) and measuring the maximum length of these projections.

[0067] "Spheroidal aggregates" of crystalline opicapone are aggregates in which the primary particles are arranged in a manner different from "bundle-like aggregates." Typically, this results in essentially spherical or ball-like aggregates (see Figure 2 ). Like most agglomerates, the spherical agglomerates of crystalline opicapone are readily converted into discrete primary particles. "Spherical agglomerates" can be further defined as having an 'aspect ratio' greater than or equal to 0.45 (or alternatively an 'elongation' less than or equal to 0.55, since elongation = 1 - aspect ratio). "Spherical agglomerates" can be further defined as "polygons" having [solidity:aspect ratio] coordinates within the region defined by the vertices [0.23:1], [0.82:0], [1:0], and [1;1] on a graph of solidity (y-axis) versus aspect ratio (x-axis). "Aspect ratio" is as defined above, and "solidity" is equal to the area defined by the actual perimeter of the agglomerate divided by the area defined by its "convex hull perimeter". "Convex hull perimeter" is a well-known parameter that, in simple terms, can be imagined as an imaginary elastic band stretched around the outline of the particle image. Thus, a polygon with an aspect ratio of 1 can have a wide range of compactness (i.e., 0.23 to 1), while a polygon with an aspect ratio approaching 0 must be within a narrow range of compactness (i.e., 0.82 to 1). Of course, spherical agglomerates preferably have an aspect ratio greater than or equal to 0.45. Thus, an agglomerate that meets the polygon criterion does not necessarily qualify as a preferred spherical agglomerate; and a spherical agglomerate that meets the aspect ratio criterion does not necessarily qualify as a polygon. However, particularly preferred spherical agglomerates meet both the aspect ratio criterion and the polygon criterion (see Figure 3 cross-hatched area).

[0068] Spherical agglomerates generally require less energy to convert them into discrete primary particles than bundle-like agglomerates. In other words, a stronger force is generally required to break up bundle-like agglomerates than spherical agglomerates.

[0069] The term "% of bundle-like aggregates" refers to the number of bundle-like aggregates in a drug product expressed as a percentage of the total number of all types of aggregates present in the drug product. Similarly, the term "% of spherical aggregates" refers to the number of spherical aggregates in a drug product expressed as a percentage of the total number of all types of aggregates present in the drug product.

[0070] The "equivalent circular diameter" (ECD) of a particle is the diameter of a circle having the same area A as the projected area of the particle image (see Figure 4 ).

[0071] The "maximum distance" of a particle is the maximum distance between any two points of the particle (see Figure 5 ).

[0072] "Total fiber length" refers to the length of the fiber particle as if it were straightened. This can be assessed by analyzing the fiber skeleton and then deriving its length, also including the branching of the particle (if any) (see Figure 6 ).

[0073] During the research leading to the present invention, the inventors measured both the maximum distance and the total fiber length of different batches of a drug product consisting essentially of crystalline opicapone and surprisingly found that these parameters were directly correlated in a predictable manner (see Figure 7 ). This parameter is preferred due to the fact that maximum distance is faster to measure and less computationally expensive. However, it is also within the scope of the present invention to measure alternative parameters that correlate with maximum distance in a predictable manner. For example, for a micronized drug product consisting essentially of crystalline opicapone, total fiber length can be measured instead and converted approximately to maximum distance by multiplying the total fiber length by 0.8. In order to ensure that conversions between equivalent parameters are predictable, a correlation factor (R) of at least 0.90, preferably 0.95, is required. 2 ).

[0074] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention by studying the disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0075] B. Pharmaceutical Products

[0076] The present invention provides a drug product consisting essentially of crystalline opicapone having a specific primary particle size distribution and a percentage of bundle-like agglomerates less than or equal to 30%.

[0077] The inventors have surprisingly discovered that a drug product having these properties can be used to prepare a final pharmaceutical dose or drug product suitable for administration to a patient that exhibits good oral bioavailability (e.g., AUC and C 最大 ) while reducing batch-to-batch variability. In particular, a drug product having these properties does not result in batches experiencing a significant reduction in bioavailability when formulated into a final dosage form or drug product. In this regard, a "significant reduction in bioavailability" is defined as a change in a specific pharmacokinetic parameter (e.g., AUC and / or C 最大 ) is reduced, such that the final pharmaceutical agent or drug product may no longer be considered bioequivalent to the pharmaceutical agent or drug product approved by the relevant regulatory agency. The term "bioequivalence" is known to the skilled person and generally refers to the bioavailability (e.g., AUC and C 最大 ) is within the range of 80% to 125% of the standard parameters established for the final pharmaceutical dose or drug product as approved by the relevant regulatory authorities.

[0078] Generally speaking, a micronized drug product consisting essentially of crystalline opicapone has the following primary particle size distribution:

[0079] i) D10 (maximum distance) greater than or equal to 5 μm;

[0080] ii) a D50 (maximum distance) of 10 to 70 μm; and

[0081] iii) D90 (maximum distance) less than or equal to 250 μm;

[0082] Thus, in generally preferred embodiments, the drug product consists essentially of crystalline opicapone having the following primary particle size distribution and agglomerate distribution:

[0083] i) D10 (maximum distance) greater than or equal to 5 μm;

[0084] ii) D50 (maximum distance) of 10 to 70 μm;

[0085] iii) a D90 (maximum distance) less than or equal to 250 μm; and

[0086] iv) % bundle-like agglomerates less than or equal to 30%.

[0087] In preferred embodiments, the micronized drug product has a percentage of crystalline opicapone aggregates of less than or equal to 25%, more preferably less than or equal to 20%, even more preferably less than or equal to 15%, and most preferably less than or equal to 10%. These lower levels of aggregates can provide, for example, enhanced bioavailability (e.g., AUC and C) compared to products having greater than 30% aggregates. 最大 ).

[0088] Alternatively or additionally, enhanced bioavailability (e.g., AUC and C 最大 ) and reduced batch-to-batch variability. This is because the inventors have found that the agglomerates in the crystalline opicapone of the micronized drug product consist mainly of bundle-like agglomerates and spherical agglomerates (see Figure 8 ). Thus, a percentage of spherical agglomerates greater than or equal to 70% is equivalent to a percentage of bundle-like agglomerates less than or equal to 30%. Preferably, the micronized drug product has a percentage of crystalline opicapone of spherical agglomerates greater than or equal to 75%, more preferably greater than or equal to 80%, even more preferably greater than or equal to 85%, and most preferably greater than or equal to 90%.

[0089] In a preferred embodiment, the total area occupied by bundle-like agglomerates in a 1 mg sample of the drug product is less than 4.0×10 6 μm 2 / mg, more preferably less than 3.0×10 6 μm 2 / mg, even more preferably less than 2.0×10 6 μm 2 / mg, most preferably less than 1.0×10 6 μm 2 / mg.

[0090] In a preferred embodiment, the total volume occupied by bundle-like agglomerates in a 1 mg sample of the drug product, as determined by particle size measurements (such as the particle size measurements described in Experiment 1 below), is less than 5×10 8 μm 3 / mg, more preferably less than 3.0×10 8 μm 3 / mg, even more preferably less than 2.0×10 8 μm 3 / mg, most preferably less than 1.0×10 8 μm 3 / mg.

[0091] In a more preferred embodiment, the crystalline opicapone has the following primary particle size distribution:

[0092] i) D10 (maximum distance) greater than or equal to 8 μm;

[0093] ii) a D50 (maximum distance) of 20 to 55 μm; and / or

[0094] iii) D90 (maximum distance) less than or equal to 200 μm.

[0095] In an even more preferred embodiment, the crystalline opicapone has the following primary particle size distribution:

[0096] i) D10 (maximum distance) greater than or equal to 9 μm;

[0097] ii) a D50 (maximum distance) of 25 to 50 μm; and / or

[0098] iii) D90 (maximum distance) less than or equal to 180 μm.

[0099] These values are particularly suitable and indicate optimal bioavailability, while bioequivalence was observed, provided that significant amounts of bundle-like aggregates (ie, more than 30%) were not present.

[0100] The drug product of the present invention consists essentially of micronized crystalline opicapone. This is because drug products with significant amounts of impurities and / or other drug components (e.g., pharmaceutical excipients) are not easily amenable to the process of determining the primary particle size distribution, total fiber length distribution, and / or agglomerate distribution of the drug product, as described below. It may not be possible to accurately distinguish the primary particles and / or agglomerates of micronized crystalline opicapone from other particles present. For example, a final medicament or drug product containing 25 to 50 mg of opicapone will be combined with a relatively large amount of pharmaceutical excipients and cannot be analyzed using the methods described below. Therefore, the drug product typically contains crystalline opicapone in an amount of at least 95% by weight, preferably at least 97% by weight, more preferably at least 98% by weight, and even more preferably at least 99% by weight, based on the total dry weight of the drug product. This level of purity makes the drug product particularly suitable for characterization by the methods described below.

[0101] In another preferred embodiment, the crystalline opicapone of the drug product is polymorph A disclosed in WO 2009 / 116882. This polymorph exhibits excellent kinetic and thermodynamic stability, excellent bioavailability, and is particularly suitable for the micronization process described for opicapone.

[0102] C. Manufacturing Method

[0103] Methods for the synthesis, purification, crystallization and micronization of opicapone are known to those skilled in the art and are described in the background section. However, the present invention also provides a method for producing the pharmaceutical product described above, comprising the following steps:

[0104] a) micronizing a product consisting essentially of crystalline opicapone;

[0105] b) determining the primary particle size distribution and the % of bundle-like agglomerates in the micronized product;

[0106] c) retaining a micronized product consisting essentially of crystalline opicapone having the following primary particle size distribution:

[0107] D10 (maximum distance) greater than or equal to 5 μm;

[0108] D50 (maximum distance) of 10 to 70 μm; and

[0109] D90 (maximum distance) less than or equal to 250 μm;

[0110] And has the following agglomerate distribution:

[0111] % bundled agglomerates less than or equal to 30%; and

[0112] d) If necessary, repeating steps a) to c) on a micronized product consisting essentially of crystalline opicapone without the primary particle size distribution and agglomerate distribution defined in step c) above.

[0113] The claimed method allows one skilled in the art to (1) identify drug product batches with suitable bioavailability and reduced batch-to-batch variability, and (2) establish micronization conditions that are well suited for converting micronized opicapone batches with an excessively high percentage of bundle-like agglomerates into drug products according to the present invention.

[0114] The inventors have found that the following micronization method is most suitable for reducing the level of bundle-like agglomerates. Preferably, the micronization is performed by grinding (and / or regrinding) using a jet milling process with a feed rate of between 100 and 400 g / 30 sec and a milling pressure of between 2.0 and 7.0 bar.

[0115] In the case where a large number of bundle-like agglomerates are suspected or known to be present in a batch of micronized crystalline opicapone, the present application also provides a method for manufacturing a drug product, the method comprising the steps of:

[0116] a) jet milling a micronized product consisting essentially of crystalline opicapone having a % of bundle-like agglomerates greater than or suspected to be greater than 30%;

[0117] b) determining the primary particle size distribution and the % of bundle-like agglomerates of crystalline opicapone in the micronized product;

[0118] c) retaining a micronized product consisting essentially of crystalline opicapone having the following primary particle size distribution:

[0119] D10 (maximum distance) greater than or equal to 5 μm;

[0120] D50 (maximum distance) of 10 to 70 μm; and

[0121] D90 (maximum distance) less than or equal to 250 μm;

[0122] And has the following agglomerate distribution:

[0123] % bundled agglomerates less than or equal to 30%; and

[0124] d) If necessary, repeating steps a) to c) on a micronized product consisting essentially of crystalline opicapone without the primary particle size distribution and agglomerate distribution defined in step c) above.

[0125] If the micronized product were analyzed using the process described below, it would be known that the micronized product contained this level of bundled agglomerates. If the micronized product were manufactured using the same process as a batch of micronized product known to contain this level of bundled agglomerates, it would be suspected that the micronized product contained this level of bundled agglomerates.

[0126] Once it has been determined that the drug product complies with the present invention, the drug product can be further processed into a final medicament or drug product, knowing that bioequivalence will be achieved. Thus, in generally preferred embodiments, the micronized drug product retained in step c) of the method described above is combined with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition suitable for oral administration (e.g., a medicament or drug product). Thus, preferred embodiments of the present invention relate to methods of making a pharmaceutical composition comprising (i) a therapeutically effective amount of a drug product as defined above (e.g., an amount providing 25 to 50 mg of opicapone); and (ii) one or more pharmaceutically acceptable excipients.

[0127] Preferably, the method comprises forming a granulate of the drug product and one or more excipients. More preferably, the method comprises forming a unit dose of the granulate. Even more preferably, the unit dose is a capsule or tablet.

[0128] The drug product manufactured according to the method of the present invention can be administered alone or in combination with one or more other pharmaceutical products (e.g., dopamine precursors and / or AADC inhibitors). Generally, the dopamine precursors and / or AADC inhibitors will be administered together with one or more pharmaceutically acceptable excipients as a single formulation and will be administered at least 1 hour before or after the pharmaceutical composition manufactured according to the method of the present invention.

[0129] Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences," 19th edition (Mack Publishing Company, 1995). Particularly suitable excipients include lactose monohydrate, sodium starch glycolate, pregelatinized corn starch, and magnesium stearate. Particularly suitable dosage forms for the pharmaceutical compositions include capsules and tablets.

[0130] The method is particularly suitable for use in the manufacture of pharmaceutical products and pharmaceutical formulations comprising a pharmaceutical product having any or all of the preferred features described above in Section B above.

[0131] D. How to use

[0132] The present invention relates, in part, to the use of a drug product of the present invention in the manufacture of a medicament for increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease, as compared to the bioavailability of opicapone that would be obtained from an equivalent medicament manufactured using the drug product of the present invention except that the percentage of bundled aggregates is greater than 30%.

[0133] The present invention also relates in part to a medicament comprising a drug product of the present invention for use in increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease as compared to the bioavailability of opicapone that would be obtained from an equivalent medicament comprising a drug product of the present invention except that the percentage of bundled aggregates is greater than 30%.

[0134] The present invention also relates in part to a method of increasing the bioavailability of opicapone in a patient suffering from Parkinson's disease, said method comprising administering to said patient a medicament comprising a therapeutically effective amount of a drug product of the present invention, wherein said medicament provides increased bioavailability of opicapone as compared to the bioavailability of opicapone that would be obtained from an equivalent medicament comprising a drug product of the present invention except that the percentage of bundled aggregates is greater than 30%.

[0135] In a preferred aspect of the present invention, the above-described uses, medicaments for use or methods of treatment are to be performed by adjusting the parameters related to the bioavailability of opicapone (e.g., AUC and / or C 最大 The improvement in bioavailability is compared to the bioavailability of opicapone that would be obtained from an equivalent dosage form manufactured using the drug product of the present invention except that the percentage of bundled aggregates is greater than 30%.

[0136] In another preferred aspect of the invention, the medicament for use or the method of treatment described above is co-administered with L-DOPA to a patient suffering from Parkinson's disease. In a more preferred aspect of the invention, L-DOPA is co-administered with an AADC inhibitor such as benserazide or carbidopa.

[0137] E. Procedure for Determining the Aggregate Distribution of Crystalline Opicapone

[0138] As described above, the inventors unexpectedly discovered that certain batches of drug product consisting essentially of micronized crystalline opicapone, despite meeting primary particle size limits according to standard ECD calculations (e.g., D10, D50, and D90), were not bioequivalent when formulated into the final pharmaceutical dosage or drug product.

[0139] After extensive experimentation, the inventors discovered a technique for mounting a dry sample of the drug product onto a solid surface that allowed for the detection of previously unknown agglomerated particles of crystalline opicapone.

[0140] By optimizing the conditions, the inventors identified a reliable and reproducible procedure for determining the aggregate distribution of a pharmaceutical product. The optimal conditions are detailed in Experiment 1 below.

[0141] As will be described below, the inventors identified two distinct types of aggregates—bundle-like aggregates and spherical aggregates. The presence of a large number of bundle-like aggregates was associated with poor bioavailability and non-bioequivalence, while the presence of a large number of spherical aggregates was associated with good bioavailability and bioequivalence.

[0142] Since the inventors have identified the causes of batch-to-batch variability and identified conditions under which different aggregate forms can be distinguished, alternative techniques can be used to visualize and distinguish these aggregates. For example, the inventors have used both optical microscopy and scanning electron microscopy to visualize these aggregates. It is conceivable that at least atomic force microscopy and more specialized light scattering forms (e.g., using combined dynamic and static light scattering to calculate shape factor p and polydispersity) can also be used.

[0143] Thus, the present invention relates in part to a process for determining the agglomerate distribution of a drug product consisting essentially of micronized crystalline opicapone, said process comprising the steps of:

[0144] i) preparing dried samples of drug products for aggregate analysis without disaggregating the aggregates;

[0145] ii) determining the percentage of bundle-like aggregates within the sample; and

[0146] iii) Determine the percentage of spherical aggregates within the sample.

[0147] A convenient way to position a dried sample is by applying moderate pressure. This allows the sample to be positioned for aggregate analysis without disaggregating the aggregates. Thus, in a preferred embodiment, the process for determining the aggregate distribution of a pharmaceutical product includes positioning the dried sample by applying pressure.

[0148] The inventors have found that the dispersion of a pharmaceutical product in a manner that separates agglomerates but does not cause their disaggregation can be optimized by using a specific applied pressure and / or sample size. Therefore, in a more preferred embodiment, the process for determining the agglomerate distribution of a pharmaceutical product comprises placing a dried sample of the pharmaceutical product for agglomeration analysis using an applied pressure between 0.1 bar and 2 bar, preferably between 0.5 bar and 1.5 bar, and more preferably 1 bar. Pressures below this range do not allow for the proper placement of larger amounts of pharmaceutical product for agglomerate analysis because the sample is not sufficiently distributed to visualize the individual agglomerates. Pressures above this range may cause the disaggregation of agglomerates, particularly spherical agglomerates, and this is particularly true when analyzing smaller amounts of pharmaceutical product.

[0149] In another more preferred embodiment, the process for determining the aggregate distribution of the drug product comprises using between 0.1 and 2 mg, preferably between 0.5 and 1.5 mg, and more preferably about 1 mg of dry drug product to prepare a dry sample of the drug product for aggregate analysis. Amounts below this range are more sensitive to the disaggregation of aggregates, while amounts above this range are more difficult to distribute sufficiently to visualize individual agglomerates.

[0150] F. Procedure for Determining the Primary Particle Size Distribution of Crystalline Opicapone

[0151] Once the inventors identified a suitable process for determining the agglomerate distribution of a drug product, they proceeded to identify an orthogonal process for determining the primary particle size distribution of a drug product, namely a process that completely disaggregates all agglomerates while allowing the primary particles of micronized opicapone to remain intact.

[0152] After extensive experimentation, the inventors discovered a technique for dispersing the drug product in mineral oil in a manner that disaggregates any agglomerates and then mounting the dispersion on a solid surface that allows for the measurement of the maximum distance of individual primary particles and / or total fiber length of crystalline opicapone.

[0153] By optimizing the conditions, the inventors identified a reliable and reproducible procedure for determining the primary particle size distribution (ie, maximum distance and / or total fiber length distribution) of pharmaceutical products. The optimized conditions are detailed in Experiment 2 below.

[0154] Thus, the present invention is directed, in part, to a process for determining the primary particle size distribution of a pharmaceutical product consisting essentially of micronized crystalline opicapone, said process comprising the steps of:

[0155] i) dispersing the drug product in mineral oil in such a manner as to deagglomerate any agglomerates;

[0156] ii) setting up the dispersion for particle size measurement;

[0157] iii) measuring the maximum distance between any two points of a single particle of crystalline opicapone;

[0158] iv) repeating step iii) for at least 100 particles; and

[0159] v) Calculate the D10 (maximum distance), D50 (maximum distance), and D90 (maximum distance) values.

[0160] Taking into account that the maximum distance between particles is directly and closely related to the total fiber length, the present invention also relates in part to a process for determining the primary particle size distribution of a pharmaceutical product consisting essentially of micronized crystalline opicapone, said process comprising the steps of:

[0161] i) dispersing the drug product in mineral oil in such a manner as to deagglomerate any agglomerates;

[0162] ii) setting up the dispersion for particle size measurement;

[0163] iii) measuring the total fiber length of individual particles of crystalline opicapone;

[0164] iv) repeating step iii) for at least 100 particles; and

[0165] v) Calculate the D10 (total fiber length), D50 (total fiber length) and D90 (total fiber length) values.

[0166] In a more preferred embodiment, the process for determining the primary particle size distribution of the drug product comprises dispersing a sample of the drug product in mineral oil for particle size analysis using between 0.1 and 2 mg, preferably between 0.5 and 1.5 mg, and more preferably about 1 mg of dry drug product. Amounts below this range are more susceptible to disaggregation of agglomerates, while amounts above this range are extremely difficult to disperse sufficiently to visualize individual particles. It will be apparent to the skilled artisan that larger or smaller amounts of drug product may be utilized in the mineral oil, as long as the relative proportions and concentrations of the suspended drug product remain within this range.

[0167] In another more preferred embodiment, the process for determining the primary particle size distribution of the pharmaceutical product comprises detecting using optical microscopy and / or light scattering techniques (e.g., using combined dynamic and static light scattering to calculate shape factor p and polydispersity). In yet another more preferred embodiment, the process for determining the primary particle size distribution of the pharmaceutical product comprises detecting using optical microscopy.

[0168] G. Examples

[0169] Experiment 1 - "Dry" Process for Aggregate Identification and Characterization

[0170] The measurements were performed by using a Malvern instrument equipped with a sample dispersion unit plate and the Morphologi G3 (MG3) method under the following instrument parameters:

[0171] Sample amount: about 1 mg

[0172] One or more SOP optics: 2.5x

[0173] Light source: reflective (ceiling light)

[0174] Threshold: 0-78

[0175] Scanning area: 64.5×49.0

[0176] Size bar: 81

[0177] Injection pressure: 1 bar

[0178] Fiber width <14μm

[0179] Roundness <0.2

[0180] Additional information on the Morphologi technology and equipment is available from the manufacturer, Malvern Panalytical, or from the following internet addresses: https: / / www.malvernpanalytical.com / en / products / product- range / morphol ogi-range .

[0181] It is important to obtain a uniform dispersion of the sample without agglomerate fragments. This can be achieved by carefully adjusting the sample amount (to aid dispersion on the glass slide) and the injection pressure (to obtain a uniform dispersion without agglomerate fragments).

[0182] Spherical aggregates are identified by the following classifications:

[0183] Polygon: [Compactness; Aspect Ratio] ([0.230; 1]; [0.820; 0]; [1; 0]; [1; 1])

[0185] Elongation ≤ 0.550

[0186] Bundles are identified by the following classifications:

[0187] Elongation>0.550

[0188] The results of the analysis of 5 comparative samples of micronized crystalline opicapone and 7 inventive samples of micronized crystalline opicapone are shown in Table 3 below:

[0189] Table 3

[0190]

[0191] Experiment 2 - "Wet" Process for Determining Primary Particle Size Distribution of Pharmaceutical Products

[0192] Approximately 2 mg of crystalline opicapone was accurately weighed and then transferred to a beaker containing mineral oil. An appropriate amount of the prepared suspension was then collected, spread on a microscope slide and covered with a cover slip.

[0193] The MG3 method was used to measure the maximum distance and / or total fiber length using the following instrument parameters:

[0194] One or more SOP optics: 10x

[0195] Light source: Transmissive (bottom light)

[0196] Threshold: 0-174

[0197] Scanning area: 15×25mm

[0198] Size bar: 81

[0199] Filter: Convexity ≤ 0.7

[0200] Intensity SD ≥ 25

[0201] The results of the analysis of three or more comparative samples of micronized crystalline opicapone and five or more inventive samples of micronized crystalline opicapone are shown in Table 4 below:

[0202] Table 4

[0203]

[0204] FTL = total fiber length (in μm) MD = maximum distance (in μm)

[0205] Experiment 3 – Grinding and / or Regrinding of Drug Products

[0206] Using MC Crystalline opicapone was ground using a 200 micronizer. Several trials were conducted to identify optimal grinding conditions. A feed rate of 150 g / 30 s and a grinding pressure of 6.0 bar were selected as the optimal grinding conditions. The results of regrinding non-compliant micronized crystalline opicapone (Comparative Examples 2 and 3 above) under these conditions are shown in Tables 5 and 6 below:

[0207] Table 5

[0208]

[0209] Table 6

[0210]

[0211] Experiment 4 – Bioavailability of different batches of drug product

[0212] 4.1 Bioavailability in rats

[0213] General Procedure

[0214] During the study, blood was collected from the tail vein at different time points, spun at 1500 x g for 15 minutes in a refrigerated centrifuge (4°C), and the resulting plasma was stored at -80°C until further analysis. Plasma samples collected from 30 animals (270 samples) were analyzed for opicapone exposure. Bioanalysis involved the use of LC-MS / MS after plasma precipitation.

[0215] Test materials

[0216] The studies were conducted using the following drug product: (i) no drug product according to the invention (Comparison 3), (ii) a drug product according to the invention (Invention 3 + Invention 1), and (iii) the same drug product as used in study (i), but regrinded to convert it into a product according to the invention (Regrind Comparison 3).

[0217] result

[0218] (i) Following a single oral administration of micronized crystalline opicapone (50 mg suspended in 100 ml of HPMC, 0.2%) to male Wistar rats, at a target dose level of 3 mg / kg, shortly after administration (T 最大 The mean concentration of opicapone detected in plasma ranged from 1 to 3 hours after administration, where C 最大 was 508.4 (62.5) ng / mL and AUC (0-最后) It is 1209.4 (55.4) ng*h / mL (n=10).

[0219] (ii) Following a single oral administration of micronized crystalline opicapone (50 mg suspended in 100 ml of HPMC, 0.2%) to male Wistar rats, at a target dose level of 3 mg / kg, the rats showed a significant decrease in morphology shortly after administration (T 最大 The mean concentration of opicapone detected in plasma ranged from 1 to 3 hours after administration, where C 最大 was 827.1 (55.9) ng / mL and AUC (0-最后) It is 2266.5 (36.0) ng*h / mL (n=10).

[0220] (iii) Following a single oral administration of micronized crystalline opicapone (50 mg suspended in 100 ml of HPMC, 0.2%) to male Wistar rats, at a target dose level of 3 mg / kg, the 最大 The mean concentration of opicapone detected in plasma ranged from 1 to 3 hours after administration, where C 最大 was 1009.6 (46.7) ng / mL and AUC (0-最后) It is 2193.7 (37.3) ng*h / mL (n=10).

[0221] in conclusion

[0222] Crystalline opicapone that has been micronized according to the claimed invention (ii) or that has been re-milled to make it conform to the claimed invention (iii) exhibits similar bioavailability that is much greater than the bioavailability exhibited by crystalline opicapone that has not been micronized according to the claimed invention (see Figure 9 ).

[0223] 4.2 Bioavailability in humans

[0224] General Procedure and Test Materials

[0225] An open-label, 3-period, 3-sequence, partially replicated, crossover clinical study was conducted in which a reference opicapone source (a drug product containing a drug product according to the present invention) was administered twice and a test opicapone source (a drug product containing a drug product not originally according to the present invention but which was reground to convert it into a product according to the present invention) was administered once. This allowed for the assessment of the variability of the reference source within subjects. The crossover design chosen for this study enabled the subjects to serve as their own controls. Randomization of the treatment sequence prevented any selection bias that might otherwise be caused by the treatment sequence. In addition, bioequivalence was assessed under fasting conditions after a single dose, as opicapone exposure is significantly reduced when administered in the fed state. These conditions were also considered to be the most sensitive to detect potential differences between the two opicapone sources.

[0226] result

[0227] In this clinical study, drug products manufactured using remilled crystalline opicapone (test) and compliant crystalline opicapone (reference) were found to be bioequivalent at the 50 mg strength with respect to AUC 0-t (105.32-117.13) and C 最大 The 90% CI for the GMR of (108.42-124.42) was within the acceptable range of bioavailability from 80.00% to 125.00% (see Table 7).

[0228] Table 7

[0229]

[0230] in conclusion

[0231] The drug product made from micronized crystalline opicapone that already complies with the claimed invention (reference) is bioequivalent to the drug product made from micronized crystalline opicapone that has been remilled to become compatible with the claimed invention (test).

[0232] Preparation Examples

[0233] The drug product of the present invention can be combined with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition suitable for oral administration. Preferably, the method comprises forming a granulate of the drug product and one or more excipients. More preferably, the method comprises forming a unit dose of the granulate. Even more preferably, the unit dose is a capsule or tablet.

[0234] In an exemplary embodiment, the pharmaceutical composition comprises 0.2% to 50% by weight of the drug product and 50% to 99.8% by weight of one or more pharmaceutically acceptable excipients, preferably 1% to 15% by weight of a binder and 33% to 85% by weight of a filler, and optionally 0.5% to 15% by weight of a lubricant and / or 1% to 15% by weight of a disintegrant, such as the following compositions and / or formulations:

[0235]

[0236]

[0237] Such pharmaceutical compositions may be in the form of dosage forms such as capsules or compressed forms such as tablets.

[0238] Fillers / diluents of the present disclosure include anhydrous calcium hydrogen phosphate (e.g., A-TAB TM 、Di-Cafos AN TM 、Anhydrous Emcompress TM and Fujicalin TM ); calcium hydrogen phosphate dihydrate (e.g., Cafos TM 、Calipharm TM 、Calstar TM 、Di-Cafos TM 、Emcompress TM ); and tricalcium phosphate (e.g., Tri-Cafos TM TRI-CAL TM WG, TRI-TAB TM In other embodiments, the filler may be selected from starch, lactose, and cellulose. In at least one embodiment, there may be a combination of at least two fillers, such as starch, lactose, and / or cellulose. The preferred filler is lactose.

[0239] Adhesives of the present disclosure include acacia, alginic acid, carbomer, sodium carboxymethylcellulose, ceratonia, cottonseed oil, dextrin, dextrose, gelatin, guar gum, type I hydrogenated vegetable oil, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, ethylcellulose, microcrystalline cellulose, polydextrose, polyethylene oxide, polymethacrylate, sodium alginate, starch, pregelatinized starch, stearic acid, sucrose and zein. A preferred adhesive is pregelatinized starch.

[0240] Lubricants / glidants of the present disclosure include calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, type I hydrogenated vegetable oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, sucrose stearate and zinc stearate, and mixtures thereof. A preferred lubricant is magnesium stearate.

[0241] Suitable disintegrants of the present disclosure include agar, calcium carbonate, alginic acid, calcium phosphate (tricalcium phosphate), carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, docusate sodium, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, polacrilin potassium, silicified microcrystalline cellulose, starch and pregelatinized starch, and mixtures thereof. The disintegrant may be a combination of disintegrants and / or there may be at least two disintegrants, for example sodium starch glycolate and sodium starch glycolate, such as those sold under the trade name Explotab. TM The preferred disintegrant is sodium starch glycolate, especially Explotab TM .

[0242] Additional examples of pharmaceutical compositions suitable for preparing 25 mg and 50 mg amounts of opicapone (BIA 9-1067) capsules and tablets are provided in Tables 8 and 9 below:

[0243] Table 8

[0244]

[0245] surface

[0246]

Claims

1. A micronized drug product comprising at least 95% by weight of micronized opicapone, said drug product being obtainable by micronizing opicapone and then determining the agglomerate distribution of the micronized opicapone batch, comprising the steps of: i) determining the percentage of bundle-like agglomerates and / or spherical agglomerates within a batch of micronized opicapone; ii) if the % bundle-like agglomerates of the micronized opicapone batch is greater than 30%, repeating the micronization; iii) Retention of micronized drug product with ≤ 30% bundle-like agglomerates.

2. The micronized drug product according to claim 1, wherein the bioavailability (AUC and / or C 最大 ) is within the range of 80% to 125% of the standard parameters established for the final pharmaceutical dose or drug product as approved by the regulatory agency.

3. The micronized pharmaceutical product according to claim 1 or claim 2, wherein the micronized opicapone has a % of bundle-like agglomerates of less than or equal to 25%, preferably less than or equal to 20%, more preferably less than or equal to 10%.

4. The micronized pharmaceutical product according to any one of claims 1 to 3, wherein the % of spherical agglomerates of the micronized opicapone is greater than or equal to 70%, preferably greater than or equal to 75%, more preferably greater than or equal to 80%, even more preferably greater than or equal to 90%.

5. The micronized drug product according to any one of claims 1 to 4, wherein the total area occupied by bundle-like agglomerates in 1 mg of a sample is less than 4.0×10 6 μm 2 / mg, preferably less than 3.0×10 6 μm 2 / mg, more preferably less than 2.0×10 6 μm 2 / mg, even more preferably less than 1.0×10 6 μm 2 / mg.

6. The micronized pharmaceutical product according to any one of claims 1 to 5, wherein the micronized opicapone has the following primary particle size distribution: i) a D50 (maximum distance) of 10 to 70 μm; and / or ii) D90 (maximum distance) less than or equal to 250 μm.

7. The micronized drug product of claim 6, wherein the micronized opicapone further has the following primary particle size distribution: iii) D10 (maximum distance) greater than or equal to 5 μm.

8. The micronized pharmaceutical product according to any one of claims 1 to 7, wherein the micronized opicapone has the following primary particle size distribution: i) a D50 (maximum distance) of 20 to 55 μm; and / or ii) D90 (maximum distance) less than or equal to 200 μm.

9. The micronized drug product of claim 8, wherein the micronized opicapone further has the following primary particle size distribution: iii) D10 (maximum distance) greater than or equal to 8 μm.

10. The micronized drug product according to any one of claims 1 to 9, wherein micronized opicapone constitutes at least 97 wt%, preferably at least 99 wt% of the total dry weight of the drug product.

11. The micronized drug product according to any one of claims 1 to 10, wherein the opicapone is crystalline prior to micronization.

12. The micronized drug product according to any one of claims 1 to 11, wherein the percentage of bundle-like agglomerates and / or spherical agglomerates within the micronized opicapone batch is determined by a technique selected from the group consisting of optical microscopy, scanning electron microscopy, atomic force microscopy, dynamic light scattering and static light scattering.

13. A pharmaceutical product comprising the micronized pharmaceutical product according to any one of claims 1 to 12 and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical product of claim 13, which is in the form of granules.

15. A pharmaceutical product comprising the pharmaceutical product of claim 14 and one or more pharmaceutically acceptable excipients.

16. A capsule for oral administration comprising the pharmaceutical product according to any one of claims 13 to 15.

17. A tablet for oral administration comprising the pharmaceutical product according to any one of claims 13 to 15.

18. Use of a micronized drug product as defined in any one of claims 1 to 12 in the manufacture of a medicament for the treatment of Parkinson's disease, wherein the medicament has an increased bioavailability of opicapone compared to the bioavailability of opicapone obtained from an equivalent medicament comprising a micronized drug product as defined in any one of claims 1 to 12 but with a % of bundle-like agglomerates greater than 30%.

19. Use according to claim 18, wherein the bioavailability of opicapone is increased by at least 10% and more preferably by at least 20%.

20. The use according to claim 18 or 19, wherein the agent is used in combination with levodopa.

21. The use according to claim 20, wherein the agent is used in combination with an AADC inhibitor such as benserazide or carbidopa.

22. Use of a micronized product of opicapone in the manufacture of a medicament for the treatment of Parkinson's disease, wherein the proportion of bundle-like aggregates in the micronized product is less than or equal to 30% of the total number of all types of aggregates present in the drug product, wherein biologically significant batch-to-batch variability of the drug product is eliminated, so that the bioavailability (AUC and / or C 最大 ) is within the range of 80% to 125% of the standard parameters established for the final pharmaceutical dose or drug product as approved by the regulatory agency.

23. Use of a micronized product of at least 95% by weight of opicapone, wherein the proportion of bundle-like aggregates in the micronized product is less than or equal to 30% of the total number of all types of aggregates present in the pharmaceutical product, for the manufacture of a bioequivalent pharmaceutical preparation for the treatment of Parkinson's disease.

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