WO2022129002A1

WO2022129002A1 - Coarse dispersion comprising statin and vitamin e oil

Info

Publication number: WO2022129002A1
Application number: PCT/EP2021/085623
Authority: WO
Inventors: Martin Thomas Kuentz; Zdravka MISIC; Andreas NIEDERQUELL; Jutta Scherzer
Original assignee: Dsm Ip Assets B.V.
Priority date: 2020-12-15
Filing date: 2021-12-14
Publication date: 2022-06-23

Abstract

The present invention relates to a coarse dispersion comprising statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former. Due to shear-thinning behavior, the dispersion can be easily filled into e.g. softgel capsules. The preferred softgel capsule of the invention comprises dl-alpha-tocopheryl acetate oil in an amount less than the applicable Tolerable Upper Intake Level and is preferably for use in the treatment of a diabetic patient who is likely to be haptoglobin 2-2 genotype and/or whose phenotype has been determined as haptoglobin 2-2.

Description

Coarse dispersion comprising statin and vitamin E oil

Technical field

The present invention relates to the tailoring of medical treatment to the characteristics of certain patient groups (precision medicine). It also relates to the use of HMG-CoA reductase inhibitors for the treatment of patients suffering from diabetes mellitus (DM).

Background of the invention

HMG-CoA reductase inhibitors, also known as statins, are a class of lipid-lowering medications. An example is atorvastatin calcium, commercially available under the tradename LIPITOR®. LIPITOR® is indicated as an adjunct therapy to reduce the risk of myocardial infarction (Ml) and stroke in adult patients with type 2 diabetes without coronary heart disease (CHD), but with multiple risk factors. Known risk factors for coronary heart disease are retinopathy, albuminuria, smoking and hypertension.

Levy et al. have found that the haptoglobin genotype is predictive of the risk of cardiovascular disease (CVD) in diabetic patients. EP 1 587 953 B1 discloses methods of predicting a benefit of antioxidant therapy for prevention of cardiovascular disease in hyperglycemic patients. Blum et al. determined the Hp genotype on diabetes mellitus (DM) participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death (Blum S, Vardi M, Brown JB, et al., “ Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype”. Pharmacogenomics. 2010;11 (5):675-684). In both trials, the participants received a placebo or each day 400 IU (international units) of vitamin E.

Whereas vitamin E supplementation reduces cardiovascular disease in diabetes patients with haptoglobin 2-2 genotype, vitamin E supplementation did not show any substantial benefit in genetically unselected populations (Levy et al. “The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes". Diabetes Care. 27(11 ):2767). ELISA® is an Enzyme-Linked Immunoassay for the Qualitative Determination of Haptoglobin Phenotypes in Diabetic. It is commercially available at Savyon® Diagnostics Ltd. (St. Ashdod, Israel) and allows for the qualitative determination of Hp phenotypes (Hp 1 -1 , Hp 2-1 or Hp 2-2) in human serum/plasma of diabetic patients.

All elements needed for reducing the risk of cardiovascular disease in diabetic patients are easily available:

- kits for testing the haptoglobin genotype of diabetes patients

- statin tablets as an adjunct therapy for diabetes patients

- effervescent tablets comprising vitamin E for vitamin E supplementation Nevertheless, most diabetes patients are still treated in the same manner as they were treated 10 or 20 years ago. This lacuna has its cost.

In 2017, the estimated total economic cost of diagnosed diabetes was $327 billion (Economic Costs of Diabetes in the U.S. in 2017, American Diabetes Association, Diabetes Care 2018;41 :917-928).

There is a need to reduce the burden that diabetes and its sequelae impose on society.

Summary of the invention

The problems underlying the present invention are solved by replacing current statin medication with a fixed-dose combination (FDC) of statin and vitamin E.

Patient compliance is notoriously low when two tablets instead of one only need to be taken on a regular basis. This is particularly true for diabetes patients as there is often further co-medication. Co-medication increases the so-called “pill count” (i.e. number of tablets to be administered) and hence, the risk of poor adherence to therapy. Patient compliance becomes even worse if one tablet comprises a prescription drug (Rx), whereas the second tablet may be bought in the supermarket. So far, patients are just not used to the combined intake of tablets that originate from very different supply channels. Non-responders to such kind of therapy are more likely to actually be non-adherers.

To manufacture a FDC of vitamin E and statin, commercially available vitamin E acetate powder could be used. Unfortunately, it is hardly possible to compress the required amount of vitamin E acetate powder together with statin into one single tablet. And even if it was possible by excess addition of compaction excipients, the tablet would be so large that patient compliances would not be increased, especially in the elderly population that experiences difficulties to swallow larger dosage forms. The present invention solves this problem by replacing vitamin E powder with vitamin E oil. Whereas the vitamin E content of spray-dried vitamin E powder is often not more than 50 weight-%, the vitamin E content is nearly 100 weight-% in vitamin E oil. This allows for a significant volume reduction of the dosage form.

The dosage form of the invention is a capsule that comprises a lipid-based dispersion of statin particles. Thereby, the lipid is vitamin E oil. Compliance to the therapy suggested by Levy et al. is increased by providing a FDC in the shape of a single capsule, i.e. by avoiding the need for a combined intake of tablets that originate from very different supply channels.

WO 2012/160559 discloses a self-emulsifying formulation of vitamin E oil. The formulation comprises no statin and thus, it is not a fixed-dose combination (FDC). In addition, the formulation comprises relatively high levels of surfactants. Surfactants can lead to local irritation of the gastro-intestinal mucosa and eventually to reflux with poor taste. This is detrimental to therapy adherence that is targeted by the present invention. Thus, partial or complete avoidance of surfactants would be a significant advantage over the prior art.

The present invention relates to a coarse dispersion that is preferably free of surfactants. It comprises statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former. The preferred coarse dispersion of the invention shows shear-thinning behaviour.

The present invention also relates to a method of manufacturing a fixed-dose combination of a statin and vitamin E, said method comprising the steps: a) providing the herein described coarse dispersion b) preferably stirring the coarse dispersion provided in step a) for reducing the viscosity of the coarse dispersion before and/or during filling the coarse dispersion into capsules

The present invention also relates to a capsule comprising the herein described coarse dispersion for use as a medicament, preferably for use in the treatment of a patient who is in need of an HMG-CoA reductase inhibitor and/or who is suffering from diabetes type 2.

Figures

In FIGURES 1 , 2 and 3, the flow curves of coarse dispersions #1 , #2 and #3 are shown. Dispersions #1 , #2 and #3 were prepared and measured in example 4. All three dispersions show shear-thinning behaviour.

FIGURE 4 shows mean instability indices of coarse dispersions #1 , #2 and #3. Instability indices were obtained from near-infrared analytical centrifugation as described for example in Kuentz, M. et al., ’’Rapid assessment of sedimentation stability in dispersions using near infrared transmission measurements during centrifugation and oscillatory rheology”, 2003, Eur. J. Pharm. Biopharm. 56(3), 355-361. Measurements are further described in example 5. Dispersion #1 (atorvastatin calcium, d50 = 36 pm; 2 wt.-% gel former) showed the lowest instability index and thus, the best stability. Second best stability was achieved by dispersion #3 (rosuvastatin calcium, d50 = 71 pm; 3 wt.-% gel former) and the lowest stability had dispersion #2 (rosuvastatin calcium, d50 = 71 pm; 2 wt.- % gel former).

FIGURE 5 shows an overview of the whole course of the Instability Index during the total centrifugation time (example 5; coarse dispersions #1 , #2 and #3; each measured in quadruplicates). A straight horizontal line would represent a perfectly stable (and thus theoretical) sample. In Figure 5, there is a change in the slope after approximately 2250 seconds of centrifugation at 4000 rpm. The sedimentation process of the biggest "particles" changes here to the separation of smaller formulation ingredients and compaction of the already separated phases.

FIGURE 6 is showing the position of the phase boundary of the dispersion along the cuvette (differentiation between the solid and liquid components in transmission mode) during the centrifugation time (example 5; coarse dispersions #1 , #2 and #3; each measured in quadruplicates). After a very long centrifugation time (» 32400 seconds = 9 hours), visually no clear discrimination between the samples can be done anymore. Here, the important separation processes are already finished and mostly a further compaction of the already separated phases occurs.

Detailed description of the invention

The present invention relates to a fixed-dose combination of statin and vitamin E. The fixed-dose combination is a single-dosed oral dosage form that can accommodate high amounts of vitamin E oil, together with the usual amounts of a statin. Generally, there is a certain risk that homogeneity of a suspension declines over time. For pharmaceutical suspensions filled in large bottles, this is a content uniformity issue. In case of single-dosed dosage forms, inhomogeneity does formally not reduce content uniformity as content is defined per unit dose. Nevertheless, any inhomogeneity is considered as a general quality issue because even in a single dosage form, any particle settling can be followed by a secondary process of particle caking with altered drug dissolution. Clearly, this is not acceptable.

Drug homogeneity may deteriorate due to unwanted sedimentation of statin particles in the oil. A preferred embodiment of the invention relates to a coarse dispersion that comprises a pharmaceutically acceptable gel former that prevents or reduces sedimentation of statin particles in vitamin E oil. The gel former of the invention is an excipient that increases viscosity of the vitamin E oil and thereby reduces or prevents the sedimentation of the statin particles. The preferred gel former is particulate (i.e. a powder consisting of particles). Definitions

Vitamin E exists in a number of different kinds that have different biological activities, a-tocopherol is an has eight stereoisomers (RRR-, RSR-, RRS-, RSS-, SRR-, SSR-, SRS-, SSS-), but only RRR-a-tocopherol occurs naturally in food. The synthetic form, all-rac-a-tocopherol, contains all eight stereoisomers in equal amounts and is only present in fortified foods and supplements. Tocopheryl acetate is the acetate ester of tocopherol. Vitamin E activity is limited to the 2R-stereoisomers that have a higher biological activity than the 2S-stereoisomers. The biological activity of the chosen vitamin E can be summarized as the number of “International Units (IU)” of vitamin E. In the context of the present invention, the amount of vitamin E is preferably indicated in International Units (IU). For a-tocopherol, the following conversion factors are used:

• 1 IU vitamin E is the biological equivalent of 0.67 mg d-a-tocopherol (also called RRR-a-tocopherol)

• 1 IU vitamin E is the biological equivalent of 1 mg dl-a-tocopherol (i.e. a racemic mixture also called all-rac-a-tocopherol)

• 1 IU vitamin E is the biological equivalent of 1 mg dl a tocopheryl acetate (i.e. a racemic mixture also called all-rac-a-tocopheryl acetate).

“Volume equivalent sphere diameter” is to be seen in the context of particle statistics and can be applied to particles of any shape. The notation “d50” refers to the median of measured particle sizes. The median is the diameter where half of the measured particle sizes are smaller than the indicated value and half are larger. In the context of the present invention, the terms “d50” and “d(v50)” are used synonymously.

Dispersions comprise at least two phases: the dispersed phase (the substance that is dispersed, also referred to as internal phase) and a continuous phase (also referred to as external phase). Based on the particle size of the dispersed phase, dispersions are generally classified as molecular dispersions, colloidal dispersions and coarse dispersions (Chandrasekar Manoharan et al., “Various Pharmaceutical Disperse Systems”, Chapter 1 of the monograph “Pharmaceutical Suspensions”, 2010, Springer New York). Molecular dispersions have dispersed particles lower than approx. 1 nm in size. Colloidal dispersions have particle sizes between approx. 1 nm and 1 pm.

In the context of the present invention, the term “coarse dispersion” refers to a lipid-based dispersion that comprises particles with a size (d50, preferably measured with a Morphology G3 instrument) greater than 1 pm, preferably greater than 10 pm and most preferably greater than 20 pm. A preferred embodiment of the invention relates to lipid-based dispersion that comprises particles with a size (d50, preferably measured with a Morphology G3 instrument) between 1 pm and 120 pm, preferably between 10 pm and 100 pm, and most preferably between 20 pm and 90 pm. Thereby, “lipid-based” means that the continuous phase is an oil (or a mixture of oils) that is liquid at 25°C. The coarse dispersion of the invention is a fluid whose viscosity can be determined.

Emulsions also comprise particles with a size greater than approx. 1 pm. However, the coarse dispersion of the invention is not an emulsion. The coarse dispersion of the present invention is preferably free of surfactants. The dispersed phase of the coarse dispersion of the invention are solid particles. Therefore, the coarse dispersion of the invention resembles a suspension. However, due to the presence of at least one gel former, solid particles of the coarse dispersion of the invention sediment slowly, very slowly or do not sediment at all.

In the context of the present invention, the term ”gel former” refers to a pharmaceutically acceptable excipient that can be used in pharmaceutical suspension formulations. The gel former of the invention stabilizes the coarse dispersion by slowing down sedimentation of solid, undissolved particles. Gel formers that turn coarse dispersions into rigid, non-pourable gels are excluded as such rigid gel would be unsuited for the filling into a capsule. The coarse dispersion of the invention is pourable or becomes pourable upon heating and/or stirring. The latter is known as shear-thinning.

The coarse dispersion of the invention may be filled into capsules. In the context of the present invention, the term “capsule” refers to a oral dosage form. Preferably, the coarse dispersion of the invention is enclosed in a hard or soft capsule, wherein soft gelatine capsules are preferred. In the context of the present invention, the terms “softgel capsule” and “soft gelatine capsule” are used synonymously.

The abbreviations “HP 2-2” and “hp 2-2” are used interchangeably and refer to haptoglobin 2-2.

In the context of the present invention, the term "prevalence of haptoglobin 2-2 genotype” refers to the number of individuals in a population who are haptoglobin 2-2 genotype, usually expressed as a percentage of the total population.

In the context of the present invention, the terms “haptoglobin 2-2 genotype” and “haptoglobin 2-2 phenotype” are used interchangeably. HP 2-2 genotype is also processed on the protein level. Therefore, testing will define the correct naming: when using the ELISA® test kit, it is phenotype; if DNA testing is done, it is genotype. Whereas genotyping is more accurate, detection on the protein level is less expensive. In the context of a non-toxic, well-established vitamin, both test approaches are acceptable. Due to this flexibility, the terms “haptoglobin 2-2 genotype” and “haptoglobin 2-2 phenotype” may be used interchangeably.

Haptoglobin genotype may be inherited. This explains prevalence of haptoglobin 2-2 genotype in the Chinese population and elsewhere. “Descent” (as used in the terms Chinese descent, Malay descent and Indian descent) is to be understood as biological derivation from an ancestor.

Type 2 diabetes is a disease that prevents the body from using insulin the way it should. People who are middle-aged or older are most likely to get this kind of diabetes. Therefore, it is sometimes called adult-onset diabetes. In the context of the present invention, “diabetes” refers preferably to diabetes mellitus type 2. Similarly, the term “diabetic patient” refers preferably to a patient suffering from type 2 diabetes. Coarse dispersion

The coarse dispersion of the invention comprises statin particles. Any kind of statin can be used, as long as it is poorly soluble in vitamin E oil or preferably insoluble in vitamin E oil.

In one embodiment of the invention, statin particles comprise or consist of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, pitavastatin, simvastatin or a mixture thereof. In a preferred embodiment of the invention, statin particles comprise or consist of a pharmaceutically acceptable salt of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, pitavastatin or simvastatin. In an also preferred embodiment of the invention, statin particles comprise or consist of a pharmaceutically acceptable salt of atorvastatin or a pharmaceutically acceptable salt of rosuvastatin. In an even more preferred embodiment of the invention, statin particles comprise or consist of atorvastatin calcium or of rosuvastatin calcium. In the most preferred embodiment of the invention, statin particles comprise or consist of rosuvastatin calcium. Currently available rosuvastatin tablets comprise 5 mg rosuvastatin calcium, 10 mg rosuvastatin calcium or 20 mg rosuvastatin calcium. These amounts can be accommodated within one capsule, together with the required amount of vitamin E oil.

The coarse dispersion of the present invention comprises preferably not more than 30 weight-%, more preferably not more than 25 weight-%, even more preferably not more than 20 weight-% and most preferably not more than 15 weight-% statin particles, based on the total weight of the coarse dispersion. In one embodiment of the invention, the coarse dispersion comprises preferably from 0.1 weight-% to 30 weight-%, more preferably from 1 weight-% to 25 weight-%, even more preferably from 1 weight-% to 20 weight-% and most preferably from 2 weight-% to 15 weight-% statin particles, based on the total weight of the coarse dispersion.

Most commercially available statins (i.e. bulk drug) comprise particles having a volume equivalent sphere diameter (d50) larger than 1 pm. When manufacturing the coarse dispersion of the invention, there is no need to reduce the size of such statin particles. Thus, the present invention makes milling of statin bulk in most cases obsolete, which is a substantial cost benefit.

One embodiment of the invention relates to a coarse dispersion comprising statin particles that have volume equivalent sphere diameter (d50) greater than 1 pm, preferably greater than 10 pm and most preferably greater than 20 pm when measured using a Morphology G3 instrument (Malvern Instruments Ltd.). A preferred embodiment of the invention relates to a coarse dispersion comprising statin particles that have volume equivalent sphere diameter (d50) from 30 pm to 80 pm, from 20 pm to 80 pm or from 30 pm to 90 pm when measured using a Morphology G3 instrument (Malvern Instruments Ltd.), wherein said statin particles preferably comprise or consist of rosuvastatin calcium.

The coarse dispersion of the invention also comprises vitamin E oil or a mixture of different kinds of vitamin E oils. To save cost and to reduce complexity, it is preferred that the coarse dispersion of the invention comprises one kind of vitamin E oil only. Whereas any kind of vitamin E oil could be used, it is preferred to use pharma grade vitamin E oils that are available at DSM® Nutrional Products (Switzerland). Not preferred is alpha tocopheryl polyethylene glycol succinate (TPGS). TPGS is a surfactant that is not a useful source of vitamin E in healthy humans with a normal fat absorption (Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on a request from the Commission related to d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) in use for food for particular nutritional purposes, The EFSA Journal (2007) 490, 1-20). One embodiment of the invention relates to a coarse dispersion comprising tocopherol, a tocopheryl ester or a mixture thereof. Preferred tocopheryl esters are tocopheryl acetate and tocopheryl palmitate. The most preferred tocopheryl ester is tocopheryl acetate.

A preferred embodiment of the invention relates to a coarse dispersion comprising tocopherol, tocopheryl acetate, tocopheryl palmitate or a mixture thereof. A more preferred embodiment of the invention relates to a coarse dispersion comprising dl-alpha-tocopherol, all rac-alpha-tocopherol, dl-alpha-tocopheryl acetate or a mixture thereof. However, due to stability reasons, the most preferred vitamin E oil is comprising dl-alpha-tocopheryl acetate. Thus, the most preferred embodiment of the invention relates to a coarse dispersion comprising dl-alpha-tocopheryl acetate.

The preferred coarse dispersion of the invention also comprises at least one pharmaceutically acceptable gel former. To save cost and to reduce complexity, it is preferred that the coarse dispersion of the invention comprises one kind of pharmaceutically acceptable gel former only. Thereby, particulate gel formers are preferred. One embodiment of the invention relates to a coarse dispersion comprising silicon dioxide powder. Thereby, colloidal silicon dioxide is the preferred silicon dioxide powder. A preferred embodiment of the invention relates to a coarse dispersion comprising amorphous anhydrous colloidal silicon dioxide. Pharmaceutically acceptable amorphous anhydrous colloidal silicon dioxide is commercially available under the tradename Aerosil® 200 Pharma (Evonik Industries, Germany).

Thus, the coarse dispersion of the invention comprises statin particles, at least one vitamin E oil and preferably at least one pharmaceutically acceptable gel former. In a preferred embodiment of the invention, the coarse dispersion consists of three ingredients only: (i) statin particles, (ii) a vitamin E oil and (iii) a gel former. It is surprising that a pharmaceutical formulation with three ingredients only can reduce the burden that diabetes and its sequelae impose on society. Such formulation has low complexity, is easy to manufacture at low cost and increases compliance as it is a FDC. The coarse dispersion of the invention preferably comprises or consists of (i) statin particles having a volume equivalent sphere diameter (d50) from 30 pm to 80 pm when measured using a Morphology G3 instrument, (ii) dl-alpha-tocopheryl acetate and (iii) colloidal silicon dioxide.

The addition of a gel former prevents deterioration of statin concentration homogeneity due to unwanted sedimentation of statin particles in the vitamin E oil. Very high concentrations of gel former are not preferred as this might possibly result in a rigid, non-pourable gel. One embodiment of the invention relates to a coarse dispersion as herein described comprising less than 15 wt.-%, preferably less than 10 wt.-% and most preferably less than 8 wt.-% of at least one pharmaceutically acceptable gel former, based on the weight of the vitamin E oil comprised in the coarse dispersion. A preferred embodiment of the invention relates to a coarse dispersion as herein described comprising 0.1 -15 wt.-%, preferably 0.1 -10 wt.-%, and most preferably 0.1 -5 wt.-% colloidal silicon dioxide, based on the weight of the vitamin E oil comprised in the coarse dispersion.

Typically, the statin dosage regimen of a patient remains unchanged if his current statin tablet is replaced by the herein described FDC. Therefore, the concentration of statin particles in the coarse dispersion of the invention is preferably chosen such that a capsule can be manufactured which is - in terms of statin - bioequivalent to an approved statin tablet. As an illustrative example, the concentration of rosuvastatin calcium particles in the coarse dispersion of the invention may be chosen such that a single-dosed oral dosage form comprising e.g. 5 mg rosuvastatin calcium can be manufactured by filling the coarse dispersion into a (normally sized) capsule. In terms of statin, such capsule is expected to be bioequivalent to the commercial 5 mg rosuvastatin calcium tablet.

The concentration of the at least one pharmaceutically acceptable gel former is preferably adapted to the concentration and to the size of the statin particles. Surprisingly, the coarse dispersion of the invention has a low instability index (and thus good stability) if the value

is less than 5 pm/(wt.-%)², preferably less than 4 pm/(wt.-%)² and most preferably less than 3 pm/(wt.-%)². The coarse dispersion of the invention has very good or even excellent stability if

— the concentrations of the at least one pharmaceutically acceptable gel former and

— the concentrations of the statin particles and

— the size of the statin particles are chosen such said value is preferably in the range from 0.8 to 4 pm/(wt.-%)², is more preferably in the range from 1 to 3 pm/(wt.-%)² and is most preferably from 1 .8 to 2.8 pm/(wt.-%)². Thereby, the following notation is used:

- ‘d50 of statin particles’ refers to the volume equivalent sphere diameter (d50) of the statin particles in the coarse dispersion in pm when measured using a Morphology G3 instrument (Malvern Instruments Ltd.)

- ‘wt.-% of statin particles’ refers to the concentration of the statin particles in the coarse dispersion, based on the weight of the at least one vitamin E oil of the coarse dispersion

- ‘wt.-% of gel former’ refers to the concentration of the pharmaceutically acceptable gel former in the coarse dispersion, and wherein ‘wt.-%’ refers to weight percentage, based on the weight of the at least one vitamin E oil of the coarse dispersion

Capsule

The present invention also relates to a capsule that comprises the herein described coarse dispersion. The capsule may be a liquid-filled hard capsule or a softgel capsule. Softgel capsules are preferred because more liquid can be filled in a softgel capsule than in liquid-filled hard capsule of the same volume.

A preferred embodiment of the invention relates to a soft gelatine capsule that comprises a coarse dispersion, wherein said coarse dispersion comprises statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former, with the proviso that said at least one vitamin E oil is not alpha tocopheryl polyethylene glycol succinate (TPGS), and/or with the proviso that said coarse dispersion comprises less than 0.1 weight-% of a surfactant, based on the total weight of the coarse dispersion.

In terms of Vitamin E oil, the capsule of the invention comprises preferably at least 0.1 ml, more preferably at least 0.3 ml, even more preferably at least 0.4 ml and most preferably at least 0.5 ml vitamin E oil, when measured at 25°C at a pressure of 1 bar. In another embodiment, the amount of vitamin E oil in one capsule of the invention corresponds to at least 100 III, preferably at least 200 III, more preferably at least 300 HI and most preferably at least 400 HI vitamin E. The maximum amount of Vitamin E oil is given by the size of the chosen capsule. Preferred capsules have size 3, 2, 1 , 0 or 00. The weight ratio statin : vitamin E oil is preferably from 1 :1 to 1 :50, is more preferably from 1 :1 to 1 :40, is even more preferably from 1 :1 to 1 :30 and is most preferably from 1 :2 to 1 :20.

A preferred embodiment of the invention relates to a soft gelatine capsule that comprises a coarse dispersion, wherein said coarse dispersion is free of surfactants, and wherein said coarse dispersion comprises or consists of statin particles, dl-alpha-tocopheryl acetate and more than 0.5 weight-% of colloidal silicon dioxide, based on the total weight of dl-alpha-tocopheryl acetate, and characterized in that said soft gel capsule comprises dl-alpha-tocopheryl acetate in an amount that corresponds to preferably at least 100 III, more preferably at least 200 IU, even more preferably at least 300 IU and most preferably at least 400 IU vitamin E. Thereby, said coarse dispersion is preferably prepared such that the value

is less than 5 pm/(wt.-%)², preferably less than 4 pm/(wt.-%)² and most preferably less than 3 pm/(wt.-%)², wherein all weight percentages are based on the weight of dl-alpha-tocopheryl acetate.

A not preferred embodiment of the invention relates to a capsule comprising the herein described coarse dispersion, characterized that said capsule is a gastro-resistant capsule such as a gastro-resistant softgel capsule.

Method of manufacturing

The present invention also relates to a method of manufacturing a fixed-dose combination of statin and vitamin E, said method comprising the provision of the herein described a coarse dispersion. In said method, the vitamin E oil is preferably a tocopheryl ester. Tocopherol is very sensitive and can hardly be processed at industrial scale. Tocopheryl esters, and in particular dl-alpha-tocopheryl acetate, are more stable and allow for the manufacturing of a product with a reasonably long shelf-life.

The fixed-dose combination of the invention is preferably a liquid-filled hard capsule or a softgel capsule. A preferred method of manufacturing a fixed-dose combination of a statin and vitamin E, comprises the steps: a) providing a coarse dispersion as herein described b) stirring the coarse dispersion provided in step a) for reducing the viscosity of the coarse dispersion before and/or during filling the coarse dispersion into capsules wherein said fixed-dose combination is a liquid-filled hard capsule or a softgel capsule, and wherein said fixed-dose combination is preferably a soft gelatine capsule.

An even more preferred method of manufacturing a fixed-dose combination of a statin and vitamin E comprises the steps: a) providing a coarse dispersion comprising statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former, wherein said statin particles have volume equivalent sphere diameter (d50) from 30 pm to 80 pm when measured using a Morphology G3 instrument (Malvern Instruments Ltd.), and wherein the value

is preferably in the range from 0.8 to 4 pm/(wt.-%)², is more preferably in the range from 1 to 3 pm/(wt.-%)² and is most preferably from 1 .8 to 2.8 pm/(wt.-%)², and wherein ‘d50 of statin particles’ refers to the volume equivalent sphere diameter (d50) of the statin particles in the coarse dispersion, and wherein ‘wt.-% of statin particles’ refers to the concentration of the statin particles in the coarse dispersion, and wherein ‘wt.-% of gel former’ refers to the concentration of the pharmaceutically acceptable gel former in the coarse dispersion, and wherein ‘wt.-%’ refers to weight percentage, based on the weight of at least one vitamin E oil of the coarse dispersion b) stirring the coarse dispersion provided in step a) for reducing the viscosity of the coarse dispersion before and/or during filling the coarse dispersion into capsules wherein said fixed-dose combination is a liquid-filled hard capsule or a softgel capsule, and wherein said fixed-dose combination is preferably a soft gelatine capsule.

Step b) of the method of the present invention takes advantage of the shear thinning properties of the herein described coarse dispersion. Due to shear thinning, the viscosity of the coarse dispersion is lowered such that the coarse dispersion can be filled into capsules at comparatively high speed, using a conventional capsule filling machine. Thus, an also preferred method of manufacturing a fixed-dose combination of a statin and vitamin E, comprises the steps: a) providing a coarse dispersion that shows shear-thinning behaviour b) stirring the coarse dispersion provided in step a) for reducing the viscosity of the coarse dispersion before and/or during filling the coarse dispersion into capsules wherein said fixed-dose combination is a liquid-filled hard capsule or a softgel capsule, and wherein said fixed-dose combination is preferably a soft gelatine capsule, and wherein said coarse dispersion comprises statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former, with the proviso that said at least one vitamin E oil is not alpha tocopheryl polyethylene glycol succinate (TPGS), and/or with the proviso that said coarse dispersion comprises less than 0.1 weight-% of a surfactant, based on the total weight of the coarse dispersion.

The present invention also relates to capsules obtainable by the herein described method of manufacturing a fixed-dose combination of a statin and vitamin E. Method of treatment

The present invention also relates to the use of the herein described coarse dispersion as a medicament, and to the use of the herein described capsule for use as a medicament.

The present invention further relates to a method of treating a patient who is in need of an HMG-CoA reductase inhibitor and/or who is suffering from diabetes, characterized in that the herein described fixed-dose combination of a statin and vitamin E is administered to the patient. Accordingly, the invention also relates to a fixed-dose combination as herein described for use in the treatment of a patient who is in need of a HMG-CoA reductase inhibitor and/or who is suffering from diabetes. Thereby, the fixed-dose combination is the herein described capsule.

The Tolerable Upper Intake Level (UL) for adults is set at about 1 ,000 mg/day alpha-tocopherol. A similarly high UL applies to other vitamin E oils such dl-alpha-tocopheryl acetate. Thereby, UL is the maximum daily intake that is unlikely to cause any adverse health effects.

Any reasonably sized capsule is likely to comprise less than 1 ,000 mg vitamin E oil, i.e. less than the applicable UL. Therefore, the capsule of the invention can be given to any patient who is in need of a HMG-CoA reductase inhibitor, regardless of the patient’s haptoglobin genotype. Accordingly, testing a patient’s genotype/phenotype before oral administration of the herein described fixed-dose combination is optional. This is a major advantage because testing someone’s genotype/phenotype requires significant resources.

Thus, the present invention also relates to a method of treating a diabetes type 2 patient whose haptoglobin genotype and/or phenotype has preferably not been determined, characterized in that a capsule which comprises at least one statin, at least one gel former and at least 0.1 ml, preferably at least 0.3 ml, more preferably at least 0.4 ml and most preferably at least 0.5 ml vitamin E oil, is administered to said diabetes patient, with the proviso that said capsule comprises less than 2 ml, preferably less than 1 ml vitamin E oil. Unless indicated differently, all volumes are to be measured at 25°C at a pressure of 1 bar. Whereas vitamin E supplementation is not harmful for any diabetes patient, Hp 2-1 diabetes patients are not expected to benefit from vitamin E supplementation in the same manner as diabetes patients with Hp 2-2. Therefore, the preferred method of the invention is a method, wherein the herein described fixed-dose combination of a statin and vitamin E is administered to a diabetes type 2 patient who has been determined as being haptoglobin 2-2 genotype and/or haptoglobin 2-2 phenotype.

In some populations, prevalence of haptoglobin 2-2 genotype is particularly high. The most pronounced example is India with about 72% of the population being Hp 2-2. Thus, any Indian descent is (statistically) more likely to be haptoglobin 2-2 genotype than not. Therefore, an also preferred method of the invention is a method, wherein the herein described fixed-dose combination of a statin and vitamin E is administered to a patient who is member of a population group whose prevalence of haptoglobin 2-2 genotype is at least 40%, preferably at least 45% and most preferably at least 55%. In the respective countries, the burden that diabetes and its sequelae impose on society can be reduced very effectively because there is even less need for testing the patients haptoglobin genotype and/or phenotype before oral administration of the herein described fixed-dose combination. In other words, the present invention also relates to the herein described capsule for use in the treatment of a patient who is in a need of an HMG-CoA reductase inhibitor and/or who is suffering from diabetes type 2, wherein said patient is member of a population group whose prevalence of haptoglobin 2-2 genotype is at least 40%, preferably at least 45% and/or wherein said patient is of Chinese descent or is of Malay descent or is of Indian descent.

Examples

Example 1 (solubility)

In example 1 , the solubility of the statins Rosuvastatin Ca (RC) and Atorvastatin Ca (ATC) in Vitamin E oil (dl-a-tocopheryl acetate) was assessed using high- performance liquid chromatography (HPLC) with photo spectrometric detection. Materials and Methods

For the experiments, HPLC-grade methanol was used. If not further specified, ultra-purified water was used (18 MW). Orthophosphoric acid was used to adjust the pH of the solvents.

Fifty mg of RC and ATC were respectively mixed with 2 g of the Vitamin E oil in 15-mL conical tubes. The tubes were continuously agitated by an orbital shaker at 25 °C for 24 and 72 hours (equilibration time). After this period, the samples were subsequently centrifuged at 13000 rpm for 60 min at 25 °C. After centrifugation, 1 g of the supernatant was collected and extracted with 2 mL of methanol/water buffer (70:30, %v/v; with the buffer consisting of orthophosphoric acid with pH adjusted to 3.0). Overall, for each sample, the extraction was repeated three times. Each of the three extracts were then combined and centrifuged at 7000 rpm for 15 min at 25 °C. Finally, the supernatant (upper phases) was collected. The supernatants were filtered with a 0.45 pm syringe prior to injection into the HPLC-UV system. Each statin sample was assessed in duplicate.

Analysis

The analysis of the statins was performed by a Thermo Scientific Ultimate 3000 UHPLC with UV detector. The separation of the statins was achieved by a Roc C18 LC column (150 mm x 4.6 mm i.d., 5 pm, Restek) equipped with a C18 security guard cartridge system (Restek). The mobile phase consisted of a combination of solvent A (water, adjusted to pH 3.0 with orthophosphoric acid) and B (methanol, adjusted to pH 3.0 with orthophosphoric acid). The chromatography was run at a flow rate of 1 mL min^-1. For the separation, a concentration gradient of the two solvents was set as follows: isocratic 70 % B (v/v) for 4 min, then from 70 % B to 85 % B at 5 min, hold until 8 min then to 100 % B at 9 min, hold until 14 min, finally back to 70 % B at 15 min followed by a re-equilibration step (70 % B) from 15 to 17 min. After a preliminary optimization of the UV detector by diode array, the wavelengths for the detection was set to 238, 252 and 280 nm. Quantification of the statin samples (RC and ATC) was obtained with a linear calibration curve built with standard statins concentrations in the range from 0.002 - 0.1 mg mL’¹.

The solubility of RC and ATC in a-tocopherol oil was expressed as mg g ’¹. The averaged results show that the solubility of RC, after 72 h of equilibration time at 25°C, was equal to 0.184 ± 0.021 mg/g of Vitamin E oil (CV = 11 %). Instead, the solubility of ATC after 72 h of equilibration time at 25°C, was equal to 0.332± 0.057 mg/g of Vitamin E oil (CV = 17%).

Example 1 shows that both, RC and ATC, are very poorly soluble in the Vitamin E oil and are therefore suitable for a formulation in the form of a coarse dispersion in Vitamin E oil, that has the potential to remain stable over time.

Example 2

In example 2, samples of atorvastatin calcium (C66H68CaF2N40io; abcr GmbH, Germany) and rosuvastatin calcium (C44H54CaF2N6Oi2S2; Biosynth Carbosynth Ltd, United Kingdom) were characterized. The results are indicated in below table:

¹ melting temperature; 2-3 melting points since the sample is most probably a polymorphous mixture; majority melts at 165.15°C

²glass transition temperature; the sample contains a lot of water and we see a big water belly in the DSC. There is only a tiny melting peak at 137.85°C

A Morphology G3 instrument (Malvern Instruments Ltd.) was used for particle size measurements: the process of measuring is a combination of optical microscopy and mathematical algorithms. In order to simplify the measurement process, it is often convenient to define the particle size using the concept of equivalent spheres. Image analysis captures a 2-dimensional image of the 3D particle and calculates various size and shape parameters from this 2D image. One of the principle diameters calculated is the CE diameter (Circle Equivalent diameter) which is the diameter of a sphere (or circle) being the same as the 2D image of the particle. In simpler words, a 3D-particle is captured as a 2D- particle, then converted to a sphere/circle of the same area, and finally the diameter of this circle can be measured with the software program.

The particle size is reported as a volume equivalent sphere diameter (CE diameter). The median is the diameter where half of the sizes are smaller than this value and half are larger. The median is called by various names including d50, dv50, d(v,0.5), d(v50%), d_v50% or x50. Using the same convention as the d50, the d90 describes the diameter, where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size. The d10 diameter has ten percent smaller and ninety percent larger. A three points specification featuring the d10, d50, and d90 will be considered complete and appropriate for most particulate materials.

The settings of the Morphology G3 device were set to a pressure of 0.8 bar for dry dispersion (clean dry air) of the sample on a glass plate and magnification factors of 25X with the light microscope for measurement of the particles were applied. As optical system, a camera Nikon® CFI 60 was used and the analysis software, version 3.0, measured selected characteristics of each particle.

Particle morphology was determined using a scanning electron tabletop microscope TM3030 (Hitachi) and the magnification factor of 2000X. A scanning electron microscope (SEM) is a type of electron microscope that produces images of a sample by scanning the surface with a focused beam of electrons. The electrons interact with atoms in the sample, producing various signals that contain information about the surface topography and composition of the sample. The product involves using vacuum and high voltages. TM3030 features built-in image processing to further enhance image quality, enhanced sharpness and contrast. XPD was done as follows: The statins were studied for their potential amorphous form by PXRD on a D2 Phaser diffractometer (Broker AXS GmbH, Karlsruhe, Germany) with a 1 -D Lynxeye detector. The instrument was equipped with a Ge-monochromator (Cu K radiation) providing X-ray radiation at a wavelength of 1 .541 A. During the measurements, a voltage of 30 kV and a current of 10 mA were used. The increment and time per step were set to 0.016° and 1 s, respectively. The measurements were scanning a range of 4° to 75° (29) and the samples were rotated during the measurement at 15 rpm.

DCS was done as follows: Samples were assessed by a differential scanning calorimeter on a DSC 3 (Mettler Toledo, Greifensee, Switzerland). The samples (7-8 mg) were placed in a 40 pL aluminum pan with a pierced lid. A heating rate of 10 °C/min from 0°C to 200°C was applied, while the surrounding sample cell was purged with nitrogen 200 mL/min. Moreover, the combination of heating, cooling and heating cycles was used to fully evaluate the samples. For the assessment of the initial form, the first heating was used. The thermograms and glass transition temperatures (Tg's) were analyzed with the STARe Evaluation- Software Version 16 (Mettler Toledo, Greifensee, Switzerland). All thermograms show exothermic events as upward peaks.

The conclusion of example 2 is the following: Particle size of rosuvastatin calcium (d50 = 71 pm) is larger than particle size of atorvastatin calcium (d50 = 36 pm). The particle morphology was different showing in case of atorvastatin calcium more needle-shaped particles and in the case of rosuvastatin Ca mostly plate-like shapes. DSC x-ray measurements revealed that both statins remained mostly amorphous after melting. The major part of completely crystalline atorvastatin calcium salt melts at 164.38°C. Additionally, two very small melting peaks, most probably different polymorphic forms, could be identified at 60.24°C and 119.66°C. Rosuvastatin calcium salt is mostly amorphous and has only partially a much smaller crystalline content. In the first heating cycle of the DSC thermogram two very small melting peaks at 72.65°C and 137.33 °C can be found, whereas the small melting peak at 72.65°C is part of (within) a broad water belly. Example 3 (sedimentation test)

In example 3, four coarse dispersions were prepared/tested as follows:

The individual components were weighed into the glass cuvettes, slightly hand mixed for 1 min and then observed for the sedimentation behaviour.

Qualitative assessment (visual observation) of the sedimentation behavior revealed that in case of both atorvastatin calcium dispersions, 1/3 of the drug sedimented after 30 min, but it took 16 h to completely sediment, while rosuvastatin calcium completely sedimented in both dispersions already after already 1 h.

At first, this result seems surprising as sedimentation of plates (i.e. rosuvastatin calcium) was expected to be slower than sedimentation of needles (i.e. atorvastatin calcium). However, it needs to be taken into account that rosuvastatin calcium particles as measured with Morphology G3 instrument are larger than atorvastatin calcium particles (71 pm vs. 36 pm; both d50; cf. preceding example).

Physical form and particle size both influence the stability of suspensions. In case of statin particles dispersed in vitamin E oil, the more important parameter seems to be the particle size: smaller particles (i.e. atorvastatin calcium) yield a lower rate of sedimentation. To reduce the faster settling of the larger rosuvastatin calcium particles, viscosity of the vitamin E oil can be increased by the addition of a gel former. Example 4 (viscosity measurements)

In example 4, a gel former (colloidal silicon dioxide, sold under the trade name Aerosil® 200 by Evonik Industries, Germany) was added to some of the dispersions of example 3 using an Ultraturax at 5000 ll/rnin in a stepwise approach (first mixing for 2 min and then additionally 5 min). In consideration of the qualitative observations of example 3, two rosuvastatin calcium dispersions were prepared (#2 and #3; cf. below table), wherein a higher amount of gel former was added to one of the two rosuvastatin calcium dispersions (3 wt.-% instead of 2 wt.-%; cf. dispersion #3 below).

Rheological analysis was done using the Gemini Advanced Rheometer from Bohlin Instruments Ltd. (Pforzheim, Germany; now acquired by Malvern Instruments Ltd.). A temperature-controlled cone-plate probing system (cone: 4° and 0 = 40 mm) with a gap size of 150 pm was used. All measurements were done in triplicate at 25°C. For each measurement, approximately 3 ml of the respective dispersion were placed on the measuring system. After an equilibration time of 5 minutes at 25°C (for temperature adjustment and relaxation), a flow curve was recorded in upward and downward direction (from 0.5 s’¹ to a shear rate of 120 s’¹ and after a holding phase for 30 seconds at 120 s’¹, the shear rate was again decreased back to 0.5 s’¹) with a total measuring time of 630 seconds and a total of 220 recorded data points. As a result, viscosity curves for the applied shear rate ranges were obtained. Using the Bohlin Instruments software v. 6.51.0.3, the analyzed viscosity was extracted at a shear rate at 100 s’¹ from the backward curve.

In Figures 1 , 2 and 3, the flow curves of dispersions #1 , #2 and #3 are shown. The viscosity versus shear rate curves show that viscosity decreases when the shear rate is increased. Such behavior is known as shear-thinning. Thus, the viscosity of the dispersion of the present invention can be decreased by stirring and alike. This facilitates the manufacturing of the fixed-dose combination of the invention.

The result of example 4 is summarized in the following table.

Example 4 shows that there is a positive correlation between the concentration of gel former and the resulting viscosity.

Example 4 also shows that at relatively high shear stress, the measured viscosity is independent of the size and shape of the statin particles. This is surprising as in other cases, the shape of the particles can affect the apparent viscosity of liquid-solid suspensions: external friction forces are usually smaller between particles of higher sphericity, resulting in a smaller resistance against shear deformation and a smaller apparent viscosity (Zhuoqing, Zhang et al., “Effect of particle shape on the apparent viscosity of liquid-solid suspensions”, in Powder Technology, 1 April 2018, 328:199-206).

Example 5 (sedimentation test under accelerated conditions)

In example 5, sedimentation of the dispersions of example 4 was tested under accelerated conditions. The results are indicated in below table:

A microprocessor controlled analytical centrifuge LU Mi Sizer® 612 from L.U.M. Ltd. (Berlin, Germany) was used to examine the suspension stability. The principle of this measurement is the detection of the transmitted NIR-profiles along the length of a cuvette as a function of time. Here, a CCD-line sensor records the NIR-light (wavelength of 870 nm), which passes through the rotating sample cells and allows the determination of space- and time resolved transmission profiles. In this study, 1 .60 g of each formulation was pipetted into disposable polyacrylate cells. All samples were conducted in quadruplicates at 4000 rpm for 1 day 17 hours 55 minutes and 2 seconds at 25°C. In each experimental run, 236 transmission profiles were recorded with a light factor of 1 , and the following interval setup was used: The first 25 profiles were recorded every 25 seconds, the next 25 profiles every 40, 60 and 80 seconds. Afterwards each 12 profiles after 150, 250 and 500 seconds. The final 30 and 70 profiles were measured after each 1000 and 1500 seconds. Using the LUMiSizer® software - SEPView V.6.1 from L.U.M. Ltd. (Berlin, Germany), the range of the cuvette length was individually selected according to the menisci of the samples. The baselines of the clarification profiles were normalized to zero to subtract static transmission noise and inhomogeneity. This allowed a comparison of samples with different initial turbidity. Results were expressed in terms of the instability index, which is here given by the ratio of the clarification profile at the end to the clarification profile at the beginning. The instability index is a dimensionless number between 0 and 1 , where 0 corresponds to very stable and 1 indicates very unstable samples.

The instability index is given by the ratio of transmission profile for a given separation time to the initial transmission profile at the beginning. It is a dimensionless number between 0 and 1 : zero: very stable, no changes under test conditions one: very instable

Another understanding of this parameter is: Change of space and time resolved transmission of a sample due to concentration changes of dispersed particles provoked by phase separation such as sedimentation (see Niederquell A. et al. “A diffusing wave spectroscopy study of pharmaceutical emulsions for physical stability assessment”, Int. J. Pharm. 530 (2017) 213-223).

The measurement principle of the STEP®-technology (Space and Time resolved Extinction Profiles) of the Lumisizer is explained in more detail in: Gross-Rohrer J. et al. “The application of STEP-technology® for particle and protein dispersion detection studies in biopharmaceutical research” Int. J. Pharm. 543 (2018) 257-268, https://doi.Org/10.1016/j.ijpharm.2018.03.050.

The results of example 5 are shown in Figures 4 to 6. The tests of example 5 show that sedimentation can be prevented or at least reduced by adding a gel former such as colloidal silicon dioxide. The more gel former is added to a coarse dispersion comprising statin particles, the higher the viscosity of the resulting dispersion and the slower is the sedimentation of the statin particles. Slow sedimentation means a more constant content uniformity and thus, longer shelf life. The person skilled in the art understands that this teaching applies within reasonable limits. If an unreasonable amount of gel former was added, the occurrence of adverse stability effects cannot totally be excluded.

Example 5 also confirms the influence of the particle size: To stabilize a dispersion comprising rosuvastatin calcium (d50 = 71 pm) to the same level as a dispersion comprising atorvastatin calcium (d50 = 36 pm), the amount of gel former (silicon dioxide) should be increased, for example from 2 weight-% to 3 weight-%, based on the weight of the oil phase.

In consideration of the herein disclosed data, the inventors have found that instability index of a coarse dispersions comprising statin particles and vitamin E oil is low if the value

is less than less than 5 pm/(wt.-%)², preferably less than 4 pm/(wt.-%)² and most preferably less than 3 pm/(wt.-%)². Without wishing to be bound by theory, it is believed that the following might be an explanation for this surprising technical teaching: i. If d50 of statin particles is larger, then wt.-% of gel former must be increased to maintain stability (cf. example 5). If both, the values of numerator (d50 of statin particles) and denominator (wt.-% of gel former) are increased in the same order of magnitude, the value of the respective fraction ) remains in the same order of

magnitude. ii. Viscosity increases as the total content of the dispersed phase increases. Viscosity directly affects instability index (cf. mean viscosity of dispersions #2 and #3). Thus, to maintain stability, the total content of the dispersed phase should be maintained. In other words: if wt.-% of statin particles is increased, then wt.-% of gel former should be decreased in order to keep the content of the dispersed phase constant. Mathematically: when multiplying two factors (wt. -% statin particles * wt. -% gel formers), the calculated product remains approx, the same if one factor is decreased while the other of two factors is increased in the same order of magnitude.

This new technical teaching is further illustrated in below table.

Example 6 (manufacturing of gastro-resistant capsules)

The herein described coarse dispersion may be filled into capsules. A less preferred embodiment of the invention relates to gastro-resistant capsules comprising the herein described coarse dispersion. When manufacturing gastro-resistant capsules, a two-step process is usually applied: a standard softgel encapsulation process followed by enteric coating of the capsules. The dispersion is filled into the machine’s hopper, from where it is pumped into an injection wedge. If needed, the dispersion is stirred in the hopper to descrase the viscosity. In most cases, this is not needed as the shear of pumping lowers the viscosity of the dispersion sufficiently. A suitable capsule machine is disclosed in US 6,935,090.

In an not preferred embodiment of the invention, the softgel capsule is gastro-resistant. To make the softgel capsule gastro-resistant, a functional coating can be applied upon encapsulation. In many cases where a drug product needs to be protected from acid in the stomach, enteric release coatings can provide such protection. Softgel capsules can be coated using a coating pan. Thereby, the bed temperature of the coating pan should be low due to the low melting point of the capsule’s gelatin. For successful enteric coating of softgels, the selection of the enteric polymer and the amount of plasticizer are crucial (Lan et all, Soft Gel Enteric Coating Using Methacrylic Acid - Ethyl Acrylate Copolymer 2017 AAPS Annual Meeting, At San Diego, CA, USA). An anti-tacking agent, such as talc is usually recommended to mix with the plasticized enteric polymer before spraying. Polymers that can be used for this coating process are Methacrylic Acid and Ethyl Acrylate Copolymer known under the brand name Kollicoat® MAE as sold by BASF, Germany.

There is also an option to produce enteric soft capsules using only one-step production process. The gelatin producer GELITA offers gelatine product (GELITA® EC) that is already formulated in such way that the capsule opens only once it reaches the intestine. Using GELITA® EC, capsule producers can manufacture enteric capsules using existing equipment in a one-step process, which brings to time and cost savings compared to two-step process.

Claims

32

Claims Coarse dispersion comprising statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former, with the proviso that said at least one vitamin E oil is not alpha tocopheryl polyethylene glycol succinate (TPGS), and/or with the proviso that said coarse dispersion comprises less than 0.1 weight-% of a surfactant, based on the total weight of the coarse dispersion. Coarse dispersion according to claim 1 , wherein said coarse dispersion is free of surfactants, and wherein said coarse dispersion preferably consists of statin particles, at least one vitamin E oil and at least one pharmaceutically acceptable gel former. Coarse dispersion according to claim 1 or 2, wherein said at least one pharmaceutically acceptable gel former is silicon dioxide powder, and wherein said silicon dioxide powder is preferably colloidal silicon dioxide and is more preferably amorphous anhydrous colloidal silicon dioxide. Coarse dispersion according to any one of claims 1 to 3, wherein said statin particles have a volume equivalent sphere diameter (d50) from 30 pm to 80 pm when measured using a Morphology G3 instrument (Malvern Instruments Ltd.), and wherein the value

is preferably in the range from 0.8 to 4 pm/(wt.-%)², is more preferably in the range from 1 to 3 pm/(wt.-%)² and is most preferably in the range from 1 .8 to 2.8 pm/(wt.-%)², and wherein ‘d50 of statin particles’ refers to the volume equivalent sphere diameter (d(v50)) of the statin particles in the coarse dispersion, and wherein ‘wt.-% of 33 statin particles’ refers to the concentration of the statin particles in the coarse dispersion, and wherein ‘wt.-% of gel former’ refers to the concentration of the pharmaceutically acceptable gel former in the coarse dispersion, and wherein ‘wt.-%’ refers to weight percentage, based on the weight of the at least one vitamin E oil of the coarse dispersion. Coarse dispersion according to any one of claims 1 to 4, wherein said statin particles comprise statin selected from atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, pitavastatin, simvastatin and pharmaceutically acceptable salts thereof, and wherein said statin particles preferably comprise statin selected from pharmaceutically acceptable salts of atorvastatin, pravastatin and rosuvastatin, and wherein said statin particles comprise even more preferably a pharmaceutically acceptable salt of atorvastatin or a pharmaceutically acceptable salt of rosuvastatin, and wherein said statin particles comprise most preferably atorvastatin calcium or rosuvastatin calcium. Capsule comprising the coarse dispersion according to any one of claims 1 to 5. Capsule according to claim 6, wherein said capsule comprises at least 0.1 ml, preferably at least 0.3 ml, more preferably at least 0.4 ml and most preferably at least 0.5 ml vitamin E oil, when measured at 25°C at a pressure of 1 bar, with the proviso that said capsule comprises preferably less than 2 ml, more preferably less than 1 ml vitamin E oil. Capsule according to claim 6 or 7, wherein said capsule comprises 5 mg rosuvastatin calcium, 10 mg rosuvastatin calcium or 20 mg rosuvastatin calcium, and/or wherein said capsule is a liquid-filled hard capsule or preferably a softgel capsule. Capsule according to any one of claims 6 to 8 for use in the treatment of a patient who is in need of a HMG-CoA reductase inhibitor and/or who is suffering from diabetes. Capsule for use according to claim 9, wherein said patient is haptoglobin 2-2 genotype and/or wherein said patient is member of a population group whose prevalence of haptoglobin 2-2 genotype is at least 40%, preferably at least 45%. Capsule for use according to claim 9 or 10, wherein said patient is of Chinese descent or is of Malay descent or is of Indian descent. Method of manufacturing a fixed-dose combination of a statin and vitamin E oil, said method comprising the step: a) providing a coarse dispersion according to any one of claims 1 to 5 Method according to claim 12, wherein said method further comprises the step: b) stirring the coarse dispersion provided in step a) for reducing the viscosity of the coarse dispersion before and/or during filling the coarse dispersion into capsules Method according to claim 12 or 13, wherein said fixed-dose combination is a liquid-filled hard capsule or a softgel capsule, and wherein said fixed-dose combination is preferably a soft gelatine capsule. Coarse dispersion, capsule or method according to any one of the preceding claims, wherein said vitamin E oil is tocopherol, a tocopheryl ester or a mixture thereof, and wherein said vitamin E oil is preferably selected from tocopherol, tocopheryl acetate and tocopheryl palmitate, and wherein said vitamin E oil is more preferably selected from dl-alpha-tocopherol, all rac-alpha- tocopherol, and dl-alpha-tocopheryl acetate, and wherein said vitamin E oil is most preferably dl-alpha-tocopheryl acetate.