WO2022129004A1 - Comprimé de statine enrobé comprenant de la poudre d'acétate de vitamine e - Google Patents

Comprimé de statine enrobé comprenant de la poudre d'acétate de vitamine e Download PDF

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Publication number
WO2022129004A1
WO2022129004A1 PCT/EP2021/085626 EP2021085626W WO2022129004A1 WO 2022129004 A1 WO2022129004 A1 WO 2022129004A1 EP 2021085626 W EP2021085626 W EP 2021085626W WO 2022129004 A1 WO2022129004 A1 WO 2022129004A1
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WIPO (PCT)
Prior art keywords
vitamin
statin
tablet
coated
acetate
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PCT/EP2021/085626
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English (en)
Inventor
Elger Funda
Denis Hug
Martin Thomas Kuentz
Zdravka MISIC
Jutta Scherzer
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Dsm Ip Assets B.V.
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Publication of WO2022129004A1 publication Critical patent/WO2022129004A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin

Definitions

  • Coated statin tablet comprising vitamin E acetate powder
  • the present invention relates to the use of HMG-CoA reductase inhibitors for the treatment of patients suffering from diabetes mellitus (DM). It also relates to the tailoring of medical treatment to the characteristics of certain patient groups (precision medicine).
  • DM diabetes mellitus
  • 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.
  • Ml myocardial infarction
  • CHD coronary heart disease
  • risk factors for coronary heart disease are retinopathy, albuminuria, smoking and hypertension.
  • 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.
  • 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.
  • the problems underlying the present invention are solved by replacing a patient’s current statin medication with a fixed-dose combination (FDC) of statin and vitamin E.
  • FDC fixed-dose combination
  • Such a fixed-dose combination reduces the number of individual dose units (so-called “pill count”) that the patient has to ingest, which greatly enhances patient compliance to pharmacological treatment.
  • Vitamin E as used in the HOPE and ICARE studies is an oil. Compressing relatively large amounts of oil into a tablet is technically not possible. Often, capsules (i.e. not tablets) are used for oral administration of oils: WO 2012/160559 discloses capsules comprising vitamin E oil.
  • the formulation suggested by the inventors of WO 2012/160559 is a self-emulsifying drug delivery system (SEDDS) and thus, contains significant amounts of surfactants - which is especially for chronic treatment problematic. 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.
  • SEDDS self-emulsifying drug delivery system
  • Capsules comprising oil are also disclosed in WO 2002/100394.
  • Vitamin E TPGS may optionally be added as surfactant.
  • TPGS 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).
  • vitamin E powder can be processed in a conventional tablet press, together with statin.
  • vitamin E powder can be produced. However, not all of them are suitable for manufacturing a fixed-dose combination (FDC) of statin in a tablet press.
  • FDC fixed-dose combination
  • Exceeding the threshold of 150 IU vitamin E is particularly smooth, if gelatine-based vitamin E beadlets are used. Among gelatine-based vitamin E beadlets, porcine gelatine beadlets perform best.
  • vitamin E acetate is the preferred source of vitamin E.
  • Vitamin E acetate is more stable than naturally occurring vitamin E oil.
  • the replacement of tocopherol by dl-a-tocopheryl acetate or any other vitamin E acetate does not negatively impact oral bioavailability; the acetate moiety of vitamin E acetate is hydrolyzed by bile salt-activated cholesterol esterase enzyme before absorption in the duodenum. 1 mg dl-a-tocopheryl acetate corresponds to 1 III vitamin E.
  • — 200 IU vitamin E is less than 25% of the Tolerable Upper Intake (TUI) of vitamin E. Therefore, a coated statin tablet comprising around 200 IU vitamin E can be safely given to any diabetic patient, regardless of the patient’s phenotype. Such approach reduces manufacturing cost due to the principle of economies of scale (the same kind of tablet for everybody). The need to determine someone’s haptoglobin phenotype is then also rendered moot.
  • TTI Tolerable Upper Intake
  • the present invention also relates to a coated statin tablet as herein described for use as a medicament.
  • the present invention further relates to a method for the treatment of a patient who is in need of an HMG-CoA reductase inhibitor and/or who is suffering from diabetes.
  • a coated statin tablet comprising not more than 150 IU vitamin E is administered to a diabetic patient whose haptoglobin phenotype and/or genotype has not been determined.
  • a coated statin tablet comprising more than 150 IU vitamin E is administered to a diabetic patient whose haptoglobin phenotype and/or genotype has been determined (typically by an in vitro test such as ELISA®).
  • the coated statin tablet of the invention comprises vitamin E acetate powder and at least one pharmaceutically acceptable excipient. Each tablet comprises preferably at least 50 mg vitamin E acetate powder.
  • vitamin E acetate beadlets are preferably used to manufacture coated statin tablets that comprise more than 150 IU vitamin E per tablet.
  • vitamin E acetate concentration can be a lot higher in beadlets.
  • Statin or a pharmaceutically acceptable salt thereof may be added separately to the mixture that is compressed into tablets. Alternatively, statin or a pharmaceutically acceptable salt thereof may be an integral part of the beadlets.
  • the present invention also relates to the use of gelatin for manufacturing beadlets which comprise dl-a-tocopheryl acetate and optionally at least one statin or a pharmaceutically acceptable salt thereof.
  • said gelatin is preferably fish gelatin or porcine gelatin.
  • beadlets comprising porcine gelatin and more than 50 weight-% dl-a-tocopheryl acetate, based on the total weight of the beadlets, are preferred.
  • Said preferred beadlets may or may not comprise statin or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows that for the tablet comprising the porcine gelatin beadlets as manufactured in example 3, hardness (Fcrush, measured in N) continuously increases as the compression force (Fpress, indicated in kN) is increased. This indicates that a tablet of sufficient hardness and thus, of good quality for patient handling has been produced.
  • figure 1 shows that hardness does not increase in the desired manner when the compression force is increased.
  • the results of example 2 indicate that this can be improved by reducing the vitamin E loading of the tablet to less than 200 IU, preferably less than 150 IU of vitamin E.
  • the present invention relates to a tablet that comprises both, statin and vitamin E.
  • a “tablet press” is a mechanical device that compresses powders into tablets of uniform size and weight.
  • a “compressed tablet” is a tablet obtained by compressing a powder in a tablet press.
  • the powder is mixture that comprises at least one pharmaceutically acceptable excipient.
  • statin tablet is a compressed tablet that comprises at least one statin or a pharmaceutically acceptable salt thereof.
  • a tablet that is free of any statin or a pharmaceutically acceptable salt thereof is not a statin tablet.
  • a “coated statin tablet” is a compressed tablet that comprises a coated tablet core, wherein said tablet core comprises at least one statin or a pharmaceutically acceptable salt thereof.
  • the coated statin tablet of the invention also comprises vitamin E.
  • the coated statin tablet of the invention is therefore a “fixed-dose combination” of statin and vitamin E. Any tablet that is free of any vitamin E and/or statin is not a tablet according to the present invention.
  • Vitamin E exists in a number of different kinds that have different biological activities, a-tocopherol has eight stereoisomers (RRR-, RSR-, RRS-, RSS-, SRR-, SSR-, SRS-, SSS-), but only RRR-a-tocopherol occurs naturally in food.
  • 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.
  • IU International Units
  • the amount of vitamin E is preferably indicated in International Units (IU).
  • IU International Units
  • 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).
  • the “Tolerable Upper Intake (TUI)” is the highest amount of an active that most people can take safely.
  • the Tolerable Upper Intake (TUI) of vitamin E is defined by national authorities and thus, varies from region to region and also depends on age, gender and health state of a patient. In most cases, however, the TUI of vitamin E is higher than 1 .000 IU per day.
  • vitamin E acetate powder comprises less than 100 weight-% vitamin E acetate, based on the total weight of the vitamin E acetate powder.
  • Powders comprise particles.
  • Beadlets are a specific kind of particles, prepared by a powder catch process.
  • the principle of the powder catch process is known from the prior art. It can be found for example in US 6,444,227 or WO 04/062382, the content of which hereby incorporated by reference.
  • Beadlets are well-known to the person skilled in the art. They are generally in the shape of spherical or spheroidal particles that are typically coated with a layer of a powder catch medium. Consequently, beadlets are larger than conventional spray-dried particles.
  • the terms “beadlet” and “beadlets” refer preferably to particles that are characterized in that:
  • Beadlets can also be determined by other well-known methods, such as (scanning) electron microscopy, laser diffraction following ISO 13320 or measuring MIE volume distribution by laser diffraction using Malvern Mastersizer® 2000. The latter is preferred.
  • Beadlets as used in the context of the present invention have preferably an average particle size D(v, 0.5) of at least 200 pm. More preferably, they have an average particle size D(v, 0.5) in the range from 200 pm to 800 pm or, even more preferably, in the range from 200 pm to 400 pm.
  • HP 2-2 and “hp 2-2” are used interchangeably and refer to haptoglobin 2-2.
  • Haptoglobin genotype may be inherited. This explains prevalence of haptoglobin 2-2 genotype in the Chinese population and elsewhere. “Descent” as used in the term “Chinese descent” etc. is to be understood as biological derivation from a respective ancestor.
  • 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.
  • HP 2-2 genotype is also processed on the protein level.
  • haptoglobin 2-2 phenotype is used.
  • Vitamin E supplementation shows benefit in the herein described population, regardless whether members of the population have been tested on protein level, on DNA level, on both levels or not all. Therefore, unless indicated differently, the terms “haptoglobin 2-2 genotype” and “haptoglobin 2-2 phenotype” may be used interchangeably.
  • 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.
  • diabetes refers preferably to diabetes mellitus type 2.
  • diabetes patient refers preferably to a patient suffering from type 2 diabetes.
  • the coated statin tablet of the present invention comprises at least one statin or a pharmaceutically acceptable salt thereof.
  • it comprises a pharmaceutically acceptable salt of a statin, more preferably a pharmaceutically acceptable salt of rosuvastatin or a pharmaceutically acceptable salt of atorvastatin.
  • the coated statin tablet of the invention comprises atorvastatin calcium. This is the active ingredient of LIPITOR®.
  • the coated statin tablet of the invention comprises rosuvastatin calcium. This is the active ingredient of CRESTOR®.
  • the amount of statin in the coated statin tablet of the invention is preferably identical with the amount of the same statin in a commercially available statin tablet.
  • the coated statin tablet of the present invention comprises rosuvastatin calcium in the same amount as a corresponding CRESTOR® tablet.
  • the coated statin tablet of the present invention comprises atorvastatin calcium in the same amount as a corresponding LIPITOR® tablet.
  • the coated statin tablet of the present invention also comprises vitamin E acetate powder.
  • Vitamin E acetate powder can be obtained by spray-drying, by a beadlet process or by any other method that is suitable for converting liquid oils into flowable powders, dl-a-tocopheryl acetate is the preferred vitamin E acetate, regardless of the chosen method.
  • the particles of the vitamin E acetate powder are beadlets.
  • said beadlets comprise in addition to vitamin E acetate also at least one statin or a pharmaceutically acceptable salt thereof.
  • the coated statin tablet of the invention is preferably obtained by compressing a mixture that comprises statin or a pharmaceutically acceptable salt thereof, vitamin E acetate powder and at least one pharmaceutically acceptable excipient.
  • the coated statin tablet of the invention is obtained by compressing a mixture that comprises vitamin E acetate powder and at least one pharmaceutically acceptable excipient, wherein the particles of said vitamin E acetate powder are beadlets, and wherein said beadlets comprise in addition to vitamin E acetate also statin or a pharmaceutically acceptable salt thereof.
  • the coated statin tablet of the present invention comprises preferably at least 50 III of vitamin E, more preferably at least 100 IU of vitamin E, even more preferably at least 120 IU of vitamin E.
  • the coated statin tablet of the present invention comprises preferably at least 50 mg vitamin E acetate powder, more preferably at least 100 mg vitamin E acetate powder, even more preferably at least 120 mg vitamin E acetate powder and most preferably at least 150 mg vitamin E acetate powder.
  • the vitamin E content of the coated statin tablet of the invention is preferably indicated in international units (IU) and depends on the concentration of vitamin E acetate in the vitamin E acetate powder. The more excipients are needed to convert vitamin E oil in a powder, the lower the concentration of vitamin E acetate in the obtained powder is.
  • Vitamin E acetate powder as herein described comprises preferably at least 45 weight-%, even more preferably at least 50 weight-% or 60 weight-%, and most preferably at least 65 weight-% dl- a-tocopheryl acetate, based on the total weight of the vitamin E acetate powder.
  • Excipients suitable for converting vitamin E oil into a powder include edible polymers.
  • Preferred edible polymers are hydrocolloids such as gelatin and modified starch. Both, fish gelatin and porcine gelatine can be used. However, porcine gelatin is preferred as it has a higher elasticity than fish gelatin. This might possibly be one of the reasons for higher mechanical resistance of porcine gelatin-based particles (e.g. beadlets) to destruction due to compression forces in a tablet press.
  • a preferred embodiment of the present invention relates to a coated statin tablet that comprises a pharmaceutically acceptable salt of a statin and vitamin E acetate powder, wherein said vitamin E acetate powder comprises at least 5 weight-%, preferably at least 10 weight-% and most preferably at least 15 weight-% gelatin, based on the total weight of the vitamin E acetate powder, and wherein said gelatin is preferably fish gelatin or porcine gelatine, and wherein said gelatin is most preferably porcine gelatine, and wherein the particles of said vitamin E acetate powder are preferably beadlets, said beadlets having preferably an average particle size D(v, 0.5) of at least 200 pm when measuring MIE volume distribution by laser diffraction using a Malvern Mastersizer® 2000 apparatus.
  • a preferred embodiment of the invention relates to a coated statin tablet comprising a pharmaceutically acceptable salt of a statin, vitamin E acetate powder and at least one pharmaceutically acceptable excipient, wherein the particles of said vitamin E acetate powder are beadlets, and wherein the coated statin tablet comprises preferably more than 150 IU vitamin E per tablet.
  • the particles of the vitamin E acetate powder are produced by spray-drying. Consequently, the concentration of vitamin E acetate in the vitamin E acetate powder is lower.
  • a coated statin tablet comprising a pharmaceutically acceptable salt of a statin, vitamin E acetate powder and at least one pharmaceutically acceptable excipient, wherein said coated statin tablet comprises from 50 IU to 149 IU vitamin E.
  • the pharmaceutically acceptable salt of a statin is preferably selected from atorvastatin calcium and rosuvastatin calcium.
  • the particles of the vitamin E acetate powder comprise preferably dl-a-tocopheryl acetate and at least one edible polymer, and wherein said at least one edible polymer is preferably a hydrocolloid.
  • a statin tablet that comprises a tablet core that has been coated, wherein said tablet core is obtainable by compressing a pulverulent mixture that comprises:
  • said vitamin E acetate powder comprises preferably at least 30 weight-%, more preferably at least 40 weight-% and most preferably at least 50 weight-% dl-a-tocopheryl acetate, based on the total weight of the vitamin E acetate powder, and wherein said vitamin E acetate powder comprises preferably at least 5 weight-%, more preferably at least 10 weight-% and most preferably at least 15 weight-% of at least one hydrocolloid, based on the total weight of the vitamin E acetate powder, and wherein said statin tablet comprises less than 150 III vitamin E in case said vitamin E acetate powder comprises less than 50 weight-% dl-a-tocopheryl acetate, based on the total weight of the vitamin E acetate powder.
  • the tablet’s loading of vitamin E can also be increased by choosing a co-processed excipient as pharmaceutically acceptable excipient.
  • Co-processed excipients are excipients which act at the same time as filler/binder, flow aid, disintegrant and/or lubricant.
  • An example of such co-processed excipient is PROSOLV®, commercially available at JRS Pharma.
  • the present invention also relates to a coated statin tablet comprising a pharmaceutically acceptable salt of a statin, vitamin E acetate powder and at least one pharmaceutically acceptable excipient, wherein said at least one pharmaceutically acceptable excipient is preferably a co-processed excipient.
  • the statin tablet of the invention is obtainable by compression of a pulverulent mixture that comprises:
  • statin at least one statin or preferably a pharmaceutically acceptable salt thereof
  • vitamin E acetate powder comprises:
  • vitamin E acetate at least 30 weight-%, preferably at least 40 weight-% and most preferably at least 50 weight-% vitamin E acetate, based on the total weight of the vitamin E acetate powder, wherein said vitamin E acetate is preferably dl-a-tocopheryl acetate, and
  • At least one edible polymer that is preferably a hydrocolloid, is more preferably gelatin, is even more preferably porcine gelatin or fish gelatine, and is most preferably porcine gelatin.
  • the statin tablet of the present invention is preferably a coated statin tablet. Any suitable kind of coating can be applied once the pulverulent mixture has been compressed into tablet cores.
  • the statin tablet of the invention is an enteric coated statin tablet.
  • the statin tablet of the invention is a film coated statin tablet.
  • a preferred film coating material is Opadry White YS-1 -7040 which comprises hypromellose, polyethylene glycol, talc and titanium dioxide.
  • a preferred embodiment of the invention relates to a statin tablet that comprises a tablet core that has been coated, wherein said tablet core is obtainable by compressing a pulverulent mixture that comprises:
  • At least one pharmaceutically acceptable excipient being preferably a co-processed excipient
  • said vitamin E acetate powder comprises preferably at least 30 weight-%, more preferably at least 40 weight-% and most preferably at least 50 weight-% dl-a-tocopheryl acetate, based on the total weight of the vitamin E acetate powder
  • said vitamin E acetate powder comprises preferably at least 5 weight-%, more preferably at least 10 weight-% and most preferably at least 15 weight-% of at least one edible polymer, based on the total weight of the vitamin E acetate powder
  • said at least one edible polymer is preferably gelatin such as fish gelatin or porcine gelatine, and wherein said gelatin is most preferably porcine gelatine.
  • One embodiment of the invention relates to a coated statin tablet comprising beadlets and at least one pharmaceutically acceptable excipient, wherein said beadlets comprise dl-a-tocopheryl acetate, at least one edible polymer and optionally a pharmaceutically acceptable salt of a statin, characterized in that said beadlets have an average particle size D(v, 0.5) in the range from 200 pm to 1000 pm and/or characterized in that said at least one edible polymer is a hydrocolloid, is preferably gelatin and is even more preferably porcine gelatin or fish gelatin and is most preferably porcine gelatin.
  • statin When manufacturing the tablet of the invention, statin may be added in different manners.
  • a pulverulent mixture comprising vitamin E acetate powder, statin particles (e.g. crystals of a pharmaceutically acceptable salt of a statin) and at least one pharmaceutically acceptable excipient is compressed into a pharmaceutical tablet.
  • statin particles e.g. crystals of a pharmaceutically acceptable salt of a statin
  • the present invention also relates to a method of producing coated statin tablets, wherein a mixture comprising at least one statin or a pharmaceutically acceptable salt thereof, vitamin E acetate powder and at least one pharmaceutically acceptable excipient is compressed into tablets, with the proviso that the particles of said vitamin E acetate powder are beadlets if tablets comprising more than 150 III vitamin E per tablet are produced.
  • the present invention also relates to a method of producing coated statin tablets, wherein a mixture comprising at least one statin or a pharmaceutically acceptable salt thereof, vitamin E acetate powder and at least one pharmaceutically acceptable excipient is compressed into tablets, wherein said at least one pharmaceutically acceptable excipient is preferably a co-processed excipient.
  • the vitamin E acetate powder comprises (in addition to vitamin E acetate) also statin or a pharmaceutically acceptable salt thereof.
  • the vitamin E acetate powder preferably comprises or consists of beadlets. Beadlets are larger than spray-dried particles and can therefore accommodate multiple components, e.g. also a pharmaceutically acceptable salt of a statin. In addition, beadlets are more resistant to compression force such that loading can be increased with less risk that the surface of the compressed tablet core is oily.
  • the present invention also relates to beadlets comprising dl-a-tocopheryl acetate, gelatin and pharmaceutically acceptable salt of a statin (such as atorvastatin calcium), wherein said gelatin is preferably fish gelatin or porcine gelatin, and wherein said gelatin is more preferably porcine gelatin.
  • a statin such as atorvastatin calcium
  • the present invention also relates to use of such beadlets for manufacturing a statin tablet that is preferably a film coated tablet.
  • the present invention also relates to the use of gelatin for manufacturing beadlets which comprise dl-a-tocopheryl acetate and at least one statin or a pharmaceutically acceptable salt thereof, wherein said gelatin is preferably fish gelatin or porcine gelatin, and wherein said gelatine is most preferably porcine gelatin.
  • the present invention also relates to a method of producing a coated statin tablet, characterized in that a mixture comprising beadlets and at least one pharmaceutically acceptable excipient is compressed into a tablet core which is subsequently coated, preferably film-coated.
  • said beadlets comprise preferably at least one pharmaceutically acceptable salt of a statin, dl-a-tocopheryl acetate and at least one edible polymer, wherein said at least one edible polymer is a hydrocolloid, is preferably gelatin and is even more preferably porcine gelatin or fish gelatin and is most preferably porcine gelatin.
  • coating is preferably done for functional and/or aesthetic reasons. More preferably, coating is done to improve patient compliance.
  • Conventional solvent-based film coating involves deposition of a thin polymer film on the surface of the tablet core.
  • the present invention relates to a method of treating a diabetic patient who is haptoglobin 2-2 phenotype and/or haptoglobin 2-2 genotype, said method comprising the oral administration of the herein described coated statin tablet. It also relates to the herein described coated statin tablet for use in the treatment of a diabetic patient who is haptoglobin 2-2 phenotype and/or haptoglobin 2-2 genotype.
  • a preferred embodiment of the invention relates to a coated statin tablet for use in the treatment of a diabetic patient who is preferably haptoglobin 2-2 genotype and/or haptoglobin 2-2 phenotype, wherein said coated statin tablet comprises a pharmaceutically acceptable salt of a statin, at least 150 III or at least 200 IU of vitamin E in the form of vitamin E acetate powder and at least one pharmaceutically acceptable excipient, and wherein said vitamin E acetate powder comprises at least 45 weight-%, preferably at least 50 weight-%, even more preferably at least 60 weight-% and most preferably at least 65 weight-% dl-a-tocopheryl acetate, based on the total weight of the vitamin E acetate powder.
  • the present invention also relates to a coated statin tablet for use as a medicament, said coated statin tablet comprising at least 50 mg vitamin E acetate powder and at least one pharmaceutically acceptable excipient, with the proviso that wherein coated statin tablets comprising more than 150 IU vitamin E per tablet are excluded unless the particles of said vitamin E acetate powder consists of beadlets.
  • the coated statin tablet comprises preferably more than 150 IU vitamin E per tablet and more preferably from 150 IU to 250 IU vitamin E per tablet.
  • the particles of the tablet’s vitamin E acetate powder are preferably beadlets.
  • the tablet’s at least one pharmaceutically acceptable excipient is preferably a co-processed excipient.
  • An also recommended method of treating a diabetic patient comprises the oral administration of 400 IU vitamin E per day, in addition to a daily oral administration of a pharmaceutically acceptable salt of statin. To reach such high dosage of vitamin E, it is preferred that the diabetic patient swallows each day two oral dosage forms:
  • the soft-gelatin capsule comprising vitamin E oil as the only active ingredient can be relatively small because the total amount of vitamin E is split between the tablet and the capsule. Reducing the size of a soft-gelatin capsule generally increases patient compliance, in particularly in an elderly population.
  • the present invention also relates to a kit comprising the herein described coated statin tablet and a solid oral dosage form whose only active ingredient is vitamin E for use in the treatment of a diabetic patient who is haptoglobin 2-2 phenotype and/or who is haptoglobin 2-2 genotype, wherein said coated statin tablet and said solid oral dosage form comprise together in total at least 300 III vitamin E, preferably at least 350 IU vitamin E and most preferably at least 400 IU vitamin E.
  • statin tablet that comprises less vitamin E than the tolerable upper intake level of vitamin E (i.e. less than about 1000 IU per day).
  • a statin tablet comprising 200 IU vitamin E or less can be safely given to any diabetic patient, regardless of his haptoglobin 2-2 phenotype and genotype.
  • One embodiment of the invention relates to a method of treating a diabetic patient who is in need of statin, wherein statin tablets that are currently taken by the diabetic patient are replaced by coated statin tablets of the present invention, characterized in that the coated statins tablet of the present invention comprise from 50 IU to 200 IU vitamin E, more preferably from 50 IU to 180 IU vitamin E and most preferably from 50 IU to 150 IU vitamin E per tablet.
  • coated statin tablet comprising vitamin E acetate powder and at least one pharmaceutically acceptable excipient for use in the treatment of a diabetic patient whose haptoglobin phenotype has not been tested, characterized in that coated statin tablet comprises preferably from 50 III to 200 IU vitamin E, more preferably from 50 IU to 180 IU vitamin E and most preferably from 50 IU to 150 IU vitamin E.
  • haptoglobin phenotype and/or genotype is also optional if the patient is member of a population group whose prevalence of haptoglobin 2-2 genotype is at least 40%.
  • Example 1 (statin tablets comprising fish gelatin bead lets)
  • Example 1 tablets comprising atorvastatin calcium and Vitamin E 75 HP were manufactured.
  • Dry Vitamin E 75 HP is a powder consisting of beadlets that comprise fish gelatin and vitamin E acetate. It has a vitamin E content of 75 weight-% and is commercially available at DSM® Nutritional Products (Switzerland).
  • Each tablet contained 293 mg of Dry Vitamin E 75 HP, which corresponds to 200 International Units (IU) of vitamin E /tablet (label claim) with 10 weight-% overage (total 220 lU/tablet). Total tablet weight was 1200 mg.
  • inactive ingredients were used: dicalcium phosphate anhydrous (DICAFOS A 150®, filler and binder), microcrystalline cellulose (Avicel PH 102, filler) and magnesium stearate (Magnesiumstearat-Parteck LUB MST, lubricant).
  • DICAFOS is a co-processed excipient that is commercially available at Chemische Fabrik Budenheim (Germany).
  • Tablet mixture for 850 tablets was prepared by weighing of Dry Vitamin E 75 HP and weighing and sieving through 1 mm sieve all excipients. Afterwards, Dry Vitamin E 75 HP, dicalcium phosphate anhydrous and microcrystalline cellulose were mixed in Turbula mixer (1 L) for 10 min at 23 rpm. To that mixture, magnesium stearate was added and mixed for another 5 min at 23 rpm.
  • Tablets were compressed with a Korsch XP 1 single punch tablet press (Korsch AG, Berlin, Germany) using an oblong punch of 21x8.8 mm. Compaction data were recorded with the Pharma Research® data recording system. During tableting, the tablet mixture was compressed with different compression forces (10 - 40 kN) and breaking force of tablets was measured. Tablet hardness vs. compression force was plotted to construct a compression profile.
  • Example 1 shows that statin tablets can be manufactured by compressing a mixture comprising fish gelatin beadlets, a co-processed excipient and other pharmaceutical acceptable excipients. It also shows that better tablets are obtained if the vitamin E acetate content is reduced to less than 200 IU per tablet.
  • Vitamin E 50% CWS/S is a powder consisting of spray-dried particles that comprise vitamin E acetate and an edible polymer. It has a vitamin E content of 50 weight-% and is commercially available at DSM® Nutritional Products (Switzerland).
  • Two tablet batches with different vitamin E potencies were produced.
  • One tablet batch contained 330 mg of this product, which corresponds to 150 lll/tablet with 10 weight-% overage (total 165 lll/tablet).
  • Second tablet batch contained 440 mg of Dry Vitamin E 50% CWS/S, which corresponds to 200 lll/tablet with 10 weight-% overage (total 220 lll/tablet).
  • Each tablet contained also 42 mg of atorvastatin calcium, which corresponds to 40 mg of atorvastatin.
  • the total tablet weight for all tablets was 1200 mg.
  • As inactive ingredients were used the same materials as in example 1 .
  • Tablet mixtures for 250 tablets for each batch were prepared by weighing, sieving and mixing in the same manner as in the example 1. Tablets were compressed using the same tableting press, punch and compression forces as in the example 1 . Tablet hardness was measured on the same equipment as in the example 1 , as described above.
  • Example 2 shows that statin tablets can be manufactured by compressing a mixture comprising a spray-dried vitamin E acetate, a co-processed excipient and other pharmaceutical acceptable excipients. It also shows that significantly better tablets are obtained if the vitamin E acetate content is reduced from 200 III per tablet to 150 IU per tablet. Considering the Tolerable Upper Intake (TUI) of vitamin E, such tablet can be safely given to any diabetic patient, regardless of his or her Hp genotype.
  • TTI Tolerable Upper Intake
  • Example 3 (statin tablets comprising porcine gelatin beadlets)
  • statin tablets comprising beadlets were manufactured, similar to example 1.
  • beadlets comprising porcine gelatin instead of fish gelatin were used.
  • Said beadlets also contained statin and were produced as follows:
  • Droplet diameter D[3,2] was 533 nm (measured with a Malvern Mastersizer 2000). 369 g of the emulsion was sprayed into a fluidized bed of 300 g corn starch and 300 g silica Sipernat 50. Excessive starch was removed by sieving with a 160 pm sieve. Beadlets were dried in fluid bed for 2 h at ambient temperature. 200 g beadlets were obtained. Content of vitamin E acetate was 57.8 weight-%.
  • Statin tablets were then manufactured. Each tablet contained 380.6 mg of the beadlets, which corresponds to 200 III of Vitamin E acetate /tablet (label claim) with 10 weight-% overage (total 220 lU/tablet). Total tablet weight was 1200 mg. As inactive ingredients, the same materials as in the example 1 were used.
  • Tablet mixtures for 250 tablets was prepared by weighing, sieving and mixing in the same manner as in the example 1. Tablets were compressed using the same tableting press, punch and compression forces as in the example 1. Tablet hardness was measured on the same equipment as in the example 1 , as described above.
  • Figure 1 shows a comparison of the compression profiles of the tablets of example 2 and example 3, both containing 200 IU of Vitamin E /tablet and atorvastatin calcium.
  • vitamin E acetate was added as Dry Vitamin E 50% CWS/S (spray dried form) and atorvastatin was added separately to the tablet mixture whereas in example 3, beadlets containing both, vitamin E acetate and atorvastatin were compressed in tablets.
  • the surface of the tablets of example 2 containing 200 IU of Vitamin E/tablet was slightly oily. This indicates that the portion of the Vitamin E acetate oil was squeezed out from the powder.
  • the surface of the tablets of example 3 also containing 200 III of Vitamin E/tablet was not oily, indicating that the beadlets containing porcine gelatin resisted the compression.
  • the surface of the tablets of example 1 (also containing 200 IU of Vitamin E/tablet) was slightly oily, indicating that the beadlets containing fish gelatin performed better than spray-dried powder, but did not resist the compression to the same degree as beadlets containing fish gelatin.
  • the haptoglobin phenotype of a Chinese diabetic patient is determined using the ELISA® test.
  • the result shows that he is haptoglobin 2-2 phenotype (and thus presumably also haptoglobin 2-2 genotype).
  • statin in combination with 400 III vitamin E. He therefore recieves the tablet of example 3 (with film coating).
  • Said tablet comprises the necessary amount of atorvastatin calcium, but only 200 IU vitamin E (lable claim) instead of the dosage of 400 IU vitamin E as used in the HOPE and ICARE study.
  • the patient swallows each day a soft-gel capsule comprising 200 IU vitamin E oil, giving in total a daily vitamin E dosage of 400 IU.
  • This is a very cost-effective solution as soft-gel capsules comprising vitamin E oil are manufactured at low cost in large quantities.
  • a soft-gel capsule comprising 200 III vitamin E oil is small and thus, easy to swallow. Therefore, the Chinese diabetic patient shows excellent compliance to his new treatment.
  • Example 4 shows the benefits of a kit comprising the coated statin tablet of the present invention and a solid oral dosage form whose only active ingredient is vitamin E.

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Abstract

La présente invention concerne une combinaison de dose fixe de statine et de vitamine E. La combinaison de dose fixe est un comprimé de préférence enrobé d'un film qui est administré par voie orale à un patient diabétique qui est un phénotype de l'haptoglobine 2-2. Le comprimé peut être obtenu par compression d'un mélange qui comprend de la poudre d'acétate de vitamine E. Dans un mode de réalisation préféré, la poudre d'acétate de vitamine E comprend de l'acétate de dl-α-tocophéryle et un polymère comestible qui est de préférence de la gélatine porcine.
PCT/EP2021/085626 2020-12-15 2021-12-14 Comprimé de statine enrobé comprenant de la poudre d'acétate de vitamine e WO2022129004A1 (fr)

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000044463A (ja) * 1998-07-30 2000-02-15 Sato Pharmaceutical Co Ltd 速溶解性錠剤
US6444227B1 (en) 1999-08-05 2002-09-03 Roche Vitamins Inc. Process for preparing fat soluble beadlets
WO2002100394A1 (fr) 2001-06-12 2002-12-19 Galephar M/F Composition pharmaceutique orale comprenant un derive de statine
WO2003059274A2 (fr) * 2002-01-14 2003-07-24 Bristol-Myers Squibb Company Composition vitaminique destinee a favoriser une bonne sante cardio-vasculaire
WO2004062382A1 (fr) 2003-01-10 2004-07-29 Dsm Ip Assets B.V. Procede de fabrication de preparations en poudre a partir de substances solubles dans la graisse
JP2008063322A (ja) * 2006-08-10 2008-03-21 Daiichi Sankyo Healthcare Co Ltd ＨＭＧ−ＣｏＡリダクターゼ阻害剤、トコフェロール類及びＣｏＱ１０を含有する医薬組成物
WO2008124120A1 (fr) * 2007-04-09 2008-10-16 Scidose, Llc Combinaisons de statines et d'agent anti-obésité
EP1587953B1 (fr) 2003-01-02 2012-02-22 Rappaport Family Institute for Research in the Medical Sciences Methodes de prediction de potentiel a tirer benefice d'un traitement antioxydant pour la prevention de maladies cardiovasculaires chez des patients hyperglycemiques
WO2012160559A1 (fr) 2011-05-22 2012-11-29 Rappaport Family Institute For Research In The Medical Sciences Compositions pharmaceutiques d'acétate de d-alpha tocophéryle
RU2491070C2 (ru) * 2011-10-11 2013-08-27 Общество с ограниченной ответственностью "Фармамед" Фармацевтическая композиция для профилактики и лечения сердечно-сосудистых заболеваний

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000044463A (ja) * 1998-07-30 2000-02-15 Sato Pharmaceutical Co Ltd 速溶解性錠剤
US6444227B1 (en) 1999-08-05 2002-09-03 Roche Vitamins Inc. Process for preparing fat soluble beadlets
WO2002100394A1 (fr) 2001-06-12 2002-12-19 Galephar M/F Composition pharmaceutique orale comprenant un derive de statine
WO2003059274A2 (fr) * 2002-01-14 2003-07-24 Bristol-Myers Squibb Company Composition vitaminique destinee a favoriser une bonne sante cardio-vasculaire
EP1587953B1 (fr) 2003-01-02 2012-02-22 Rappaport Family Institute for Research in the Medical Sciences Methodes de prediction de potentiel a tirer benefice d'un traitement antioxydant pour la prevention de maladies cardiovasculaires chez des patients hyperglycemiques
WO2004062382A1 (fr) 2003-01-10 2004-07-29 Dsm Ip Assets B.V. Procede de fabrication de preparations en poudre a partir de substances solubles dans la graisse
JP2008063322A (ja) * 2006-08-10 2008-03-21 Daiichi Sankyo Healthcare Co Ltd ＨＭＧ−ＣｏＡリダクターゼ阻害剤、トコフェロール類及びＣｏＱ１０を含有する医薬組成物
WO2008124120A1 (fr) * 2007-04-09 2008-10-16 Scidose, Llc Combinaisons de statines et d'agent anti-obésité
WO2012160559A1 (fr) 2011-05-22 2012-11-29 Rappaport Family Institute For Research In The Medical Sciences Compositions pharmaceutiques d'acétate de d-alpha tocophéryle
RU2491070C2 (ru) * 2011-10-11 2013-08-27 Общество с ограниченной ответственностью "Фармамед" Фармацевтическая композиция для профилактики и лечения сердечно-сосудистых заболеваний

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Title
"Diabetes Care", vol. 41, 2018, AMERICAN DIABETES ASSOCIATION, article "Economic Costs of Diabetes in the U.S. in 2017", pages: 917 - 928
BLUM SVARDI MBROWN JB ET AL.: "Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype", PHARMACOGENOMICS, vol. 11, no. 5, 2010, pages 675 - 684
LEVY ET AL.: "The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes", DIABETES CARE, vol. 27, no. 11, pages 2767, XP002995779
THE EFSA JOURNAL, vol. 490, 2007, pages 1 - 20

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