WO2014095628A1 - Formulation orale contenant une statine dans des acides gras polyinsaturés oméga-3 (n-3 pufa) - Google Patents

Formulation orale contenant une statine dans des acides gras polyinsaturés oméga-3 (n-3 pufa) Download PDF

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Publication number
WO2014095628A1
WO2014095628A1 PCT/EP2013/076533 EP2013076533W WO2014095628A1 WO 2014095628 A1 WO2014095628 A1 WO 2014095628A1 EP 2013076533 W EP2013076533 W EP 2013076533W WO 2014095628 A1 WO2014095628 A1 WO 2014095628A1
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pufa
fatty acids
composition according
omega
atorvastatin
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PCT/EP2013/076533
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English (en)
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Mosè Santaniello
Maria Grazia Cima
Giuseppe Giannini
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Sigma-Tau Industrie Farmaceutiche Riunite S.P.A.
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Publication of WO2014095628A1 publication Critical patent/WO2014095628A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/08—Solutions

Definitions

  • the present application relates to the medical field, and in particular to a composition
  • a composition comprising a statin totally solubilized in a solvent system consisting of omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters, and a ionic emulsifier.
  • a statin totally solubilized in a solvent system consisting of omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters, and a ionic emulsifier.
  • the pharmaceutical composition according to the present invention can be used in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and all the pathologies related.
  • Hypercholesterolemia has been recognized as a major risk factor for coronary heart disease (CHD).
  • CHD coronary heart disease
  • reducing serum LDL cholesterol has been demonstrated to decrease the incidence of CHD and to reverse atherosclerotic lesions.
  • Coronary heart disease and, more generally, cardiovascular disease (CVD) represents the primary cause of mortality for men and women in developed countries globally. These premature deaths come at great cost to both the individuals and their families, as well as representing a huge burden to the health care system of the countries.
  • the risk factors for coronary heart disease are well recognized and include: higher than average serum cholesterol, elevated levels of LDL; a low level of HDL in proportion to the LDL level; higher than average serum triglycerides; higher levels of lipid oxidation products creating plaques and streaks which cause blockages of coronary arteries. Reduction in these risk factors is effective to reduce the prevalence of coronary heart disease and its many costs.
  • the medical protocols for the treatment of these pathologies are well known in the art, and include the use of several drugs or combination of the same.
  • statins in the primary and secondary prevention of cardiovascular diseases have been demonstrated in a number of clinical studies.
  • systemic inflammatory markers Rosker P.M., et al.; N. Engl, J. Med. 344: 1959-65, 2001
  • statins Even though it has not been possible to prove that there is a direct relation of the antiinflammatory mechanism of statins in the reduction of cardiovascular events, some studies have shown that the treatment with statins improves plaque stability and reduces the arterial inflammatory reaction in patients subjected to endarterectomy (Crisby M., et. al.; Circulation 103:926-33, 2001 ).
  • therapy with statins in experimental models determines the reduction of expressors of the inflammatory lesion, such as for example of the macrophage infiltration content (Van der Wal A.C., et a); Circulation 89:36-44, 1994), of the release of VCAM-1 , of interleukin- 1 and of tissue factor in the arteriosclerotic lesion (Sukhova GK, et al.; Arterioscler Thromb Vaso Biol 22: 1452-8, 2002 ).
  • Atorvastatin is used as a medicine in cardiology against all forms of cholesterol, prevention of cardiovascular events in people with diabetes. Atorvastatin selectively inhibits the liver enzyme HMG-CoA reductase, responsible for the synthesis of cholesterol in the liver. In this way, as do all the other statins, it lowers levels of total cholesterol, LDL (bad) cholesterol, apolipoprotein B (carrying the bad cholesterol) and triglycerides in patients with primary hypercholesterolemia, including family, or mixed hyperlipidaemia, i.e. with both high levels of triglycerides. Atorvastatin also has other side effects, it reduces inflammation, inhibits platelet aggregation, improves the function of blood vessels, especially the coronary vessels.
  • Rosuvastatin has structural similarities with most other synthetic statins, but unlike other statins rosuvastatin contains sulfur. Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins. Its approximate elimination half life is 19 h and its time to peak plasma concentration is reached in 3-5 h following oral administration. Putative beneficial effects of rosuvastatin therapy on chronic heart failure may be negated by increases in collagen turnover markers as well as a reduction in plasma coenzyme Q10 levels in patients with chronic heart failure.
  • Pitavastatin like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis and is usually administrated for the treatment of hypercholesterolaemia and for the prevention of cardiovascular disease.
  • a 2009 study J Atheroscler Thromb. 2009 Oct; 16(5) :654-61) showes that pitavastatin increases HDL cholesterol (24.6%), especially in patients with HDL lower than 40 mg/dl, in addition to greatly reducing LDL cholesterol (-31.3%) .
  • Pitavastatin is most likely to be appropriate for patients with metabolic syndrome with high LDL, low HDL and diabetes mellitus.
  • Omega-3 polyunsaturated fatty acids have demonstrated a beneficial effect in the prevention of cardiovascular events (Bucher HC, et al.; Am. J.Med. 2002; 1 12:298-304 ), possibly by means of an antiinflammatory, antithrombotic and antiarrhythmic mechanism (Sethi S, et al.; Blood 2002: 100:-1340-6; Billman GE, et al.; Circulation 1999: 99:2452-7; My Svensson, et al. Clin J Am Soc Nephrol 2006, 1 : 780-786; Andy H Lee AH, Hiramatsu N. Nutrition and Dietary Supplements 201 1 :3 93-100).
  • GI SSI-Prevention trial (Lancet 1999 354: 447-55) was the first which demonstrated the efficacy and tolerability of n-3 PUFAs in post- myocardial infarction patients. According to the evidence in literature, today n-3 PUFAs are indicated for the primary and secondary prevention of ischemic cardiopathy and sudden cardiac death (SCD) (Mori TA, Beilin LJ.
  • SCD ischemic cardiopathy and sudden cardiac death
  • WO2006045865 describes the microencapsulation of simvastatin in an oil phase constituted by diethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
  • WO2011 150505 discloses a solid phase containing the statin suspended in an oil phase containing PUFA.
  • WO2006096806 is related to a composition in unit dosage comprising a statin and fish oil enriched in diethyl esters of PUFA, the experimental data reported, however, are quite all relative to formulations containing simvastatin and no experimental data are reported relative to atorvastatin, rosuvastatin and pitavastatin.
  • WO00/76482, WO00/57918 and WO00/57859 describe pharmaceutical compositions formed by lipid regulating agents in oils or in surfactants.
  • WO2013072767 describes to compositions comprising n-3 PUFA and at least one salicylate in a form of a self-nanoemulsifying drug delivery system (SNEDDS), a self- microemulsifying drug delivery system (SMEDDS), or a self-emulsifying drug delivery system (SEDDS), in order to avoid unwanted oxidation of the double bonds in EPA and /or DHA which results in fixed dose combinations.
  • SNEDDS self-nanoemulsifying drug delivery system
  • SMEDDS self- microemulsifying drug delivery system
  • SEDDS self-emulsifying drug delivery system
  • WO02/ 100394 and WO03/ 103640 describe pharmaceutical compositions formed by pure statin nanoparticles without any protective coating dispersed in pharmaceutically acceptable oils, however this type of formulations have stability problems for statins if the temperature of preparing the system exceeds 40 deg. C, as is the case for most oral preparations.
  • atorvastatin has been shown to possess activities additional to that strictly hypocholesterolemic, which contribute to the antiaterogenic action of the drug: 1) inhibition of proliferation and migration of vascular smooth muscle cells (Lea A.P., McTavish D., Drugs, 1997, 53 (5), 828); 2) reduction (67%) of the size of atherosclerotic lesions (lovastatin, pravastatin, simvastatin not show this property) (Bocan T.M.A. et el., Atherosclerosis, 1994, 11 1 , 127).
  • the plasmatic half- life of atorvastatin is comprised between 14 and 20 hours, in respect to 2-3 hours of simvastatin cells (Lea A.P., McTavish D., Drugs, 1997, 53 (5), 828); this fact means that the pharmacological activity of atorvastatin is prolonged with respect to the others and that the administration of the medicament containing it can be reduced.
  • Rosuvastatin has been shown to possess a number of advantageous pharmacological properties, including enhanced HMG-CoA reductase binding characteristics, relative hydrophilicity, and selective uptake into/ activity in hepatic cells.
  • Cytochrome p450 (CYP) metabolism of rosuvastatin appears to be minimal and is principally mediated by the 2C9 enzyme, with little involvement of 3A4; this finding is consistent with the absence of clinically significant pharmacokinetic drug- drug interactions between rosuvastatin and other drugs known to inhibit CYP enzymes.
  • Rosuvastatin has also been shown to be highly effective in reducing LDL- C, increasing high-density lipoprotein cholesterol (HDL-C), and producing favorable modifications of other elements of the atherogenic lipid profile in a wide range of dyslipidemic patients.
  • the substantial LDL-C reductions and improvements in other lipid measures with rosuvastatin treatment should facilitate achievement of lipid goals and reduce the requirement for combination therapy in patients with severe hypercholesterolemia.
  • Rosuvastatin is well tolerated alone, and in combination with fenofibrate, extended-release niacin, and cholestyramine, and has a safety profile similar to that of currently marketed statins (Olsson AG, McTaggart F, Raza A.; Cardiovasc Drug Rev. 2002 Winter;20(4) :303-28).
  • Pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Its characteristic structure provides improved pharmacokinetics and significant LDL-C-lowering efficacy at low doses.
  • the cyclopropyl group on the pitavastatin molecule appears to divert the drug away from metabolism by cytochrome P450 (CYP)3A4 and allows only a small degree of clinically insignificant metabolism by CYP2C9.
  • pitavastatin is minimally metabolized; most of the bioavailable fraction of an oral dose is excreted unchanged in the bile and is reabsorbed by the small intestine ready for enterohepatic recirculation. This process probably accounts for pitavastatin 's increased bioavailability relative to most other statins and contributes to its prolonged duration of action.
  • pleiotropic benefits that might lead to a reduction in residual risk have been suggested in vitro. These include beneficial effects on endothelial function, stabilisation of the coronary plaque, anti-inflammatory effects and anti-oxidation.
  • composition which comprises a solvent system consisting of omega-3 polyunsaturated fatty acid (n-3 PUFA), or their alkyl esters, and a ionic emulsifier selected between a deoiled phosphatidyl choline enriched lecithin and sodium docusate; and a statin, selected between of atorvastatin, rosuvastatin or pitavastatin, wherein the statin is completely dissolved in the solvent system in the solvent system.
  • n-3 PUFA omega-3 polyunsaturated fatty acid
  • a statin selected between of atorvastatin, rosuvastatin or pitavastatin, wherein the statin is completely dissolved in the solvent system in the solvent system.
  • a non limiting example of the lecithin according to the present invention is the one sold under the trade name "EpikuronTM 200".
  • composition according to the invention can also comprise other useful elements, without this substantially impairing the activity.
  • Another object of the present invention is a pharmaceutical composition containing the above-mentioned elements, optionally in a mixture with one or more pharmaceutically acceptable vehicles or excipients.
  • compositions of the invention together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use.
  • compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavours and the like.
  • composition according to the present invention can also be formulated as a food supplement or dietary supplement, which constitutes a further object of the invention.
  • compositions as a medicament, particular for the prevention and treatment of diseases related to hyperlipidemias, hypercholesterolemia and hypertriglyceridemia.
  • the medicament according to the invention can be used to treat the individual disease states or to exert a preventive or protective action against them, or to treat a complex pathological picture that includes one or more of the therapeutic aspects seen above.
  • composition according to the present invention comprises active ingredients which are known in the medical field and already used in clinical practice. Therefore, they are very easy to procure, inasmuch as they are products which have been on the market for some time and are of a grade suitable for human or animal administration .
  • the statins are a known class of drugs used for lowering cholesterol levels.
  • Statins are available on the market or can be prepared according to known methods described in the literature.
  • atorvastatin and rosuvastatin are particularly preferred.
  • the effective dose currently used for the statins is in an amount between 5 and 80 mg, the most common dose is 20 mg.
  • the term "omega-3 polyunsaturated fatty acids" (here abbreviated as "n-3 PUFA”) relates to a family of long-chain polyunsaturated fatty acids, generally C16-C24, in particular those having a C20-C22 chain, that have in common a carbon-carbon double bond in the n-3 position, i.e. the third bond from the methyl end of the fatty acid. Examples of the most common omega-3 polyunsaturated fatty acids found in nature are reported in the Table below together with the assigned names.
  • ALA a-Linolenic acid
  • ALA aZZ-cis-9, 12, 15-octadecatrienoic acid
  • ETE Eicosatrienoic acid
  • DPA Docosapentaenoic acid
  • 22:5 all-cis-7 10, 13, 16, 19-docosapentaenoic Clupanodonic acid (n-3) acid
  • DHA Docosahexaenoic acid
  • EPA cis-5, 8, 1 1 , 14, 17-eicosapentaenoic acid
  • DHA cis- 4,7, 10, 13, 16, 19-docosahexaenoic acid
  • the n-3 PUFA according to the invention is a mixture of fatty acids having a high content in EPA and DHA, for example with a content in EPA and DHA higher than 25% by weight, preferably from about 30% to about 100% by weight, in particular about between 75% and 95%, and more preferably at least 85% by weight on the total fatty acid weight.
  • the total content of n-3 PUFA according to the invention is a mixture of fatty acids having at least 90% of n-3 PUFA by weight on the total fatty acid weight.
  • PUFA and n-3 PUFA are intended to encompass their corresponding C 1-C3 alkyl esters, preferably ethyl esters, and/or from their salts with pharmaceutically acceptable bases such as sodium hydroxide, lysine, arginine or aminoalcohols such as choline.
  • pharmaceutically acceptable bases such as sodium hydroxide, lysine, arginine or aminoalcohols such as choline.
  • the ethyl esters are the most widely used and preferred according to the invention.
  • the composition of the invention is administered preferably orally, in particular in the form of soft gelatin capsules.
  • the unit dose generally comprises 100- 1000 mg of polyunsaturated fatty acids of the omega-3 series, preferably 500- 1000 mg or 300-500 mg, the total dose being usually around 0.1-3.0 g per day or per alternate day, according to the case concerned, and preferably 0.3-2.0 g per day and in particular 1.0 g per day.
  • This amount of product may be administered in the form of several daily divided doses or preferably as a single dose, in order to reach the desired blood level.
  • the clinician may vary the amount of product (or mixture with another therapeutic agent) to be administered, basing on the patient's conditions, age and weight.
  • formulation for oral administration are also suitable for the purposes of the invention; for example hard capsules or tablets, in which the polyunsaturated fatty acids are adsorbed on solid supports. It is also possible to use emulsions, granulates in dispersing excipients, syrups, droplets, etc., and other forms of administration able to ensure systemic absorption of the drug, such as sterile solutions or emulsions and the like, suitable for parenteral use and the like, as evaluated by the expert of the art, on the basis of the severity of the pathology.
  • compositions illustrated in the European Pharmacopea 2000 containing quantities greater than or equal to 80 wt% of mixtures of EPA and DHA ethyl esters and a total of omega-3 polyunsaturated fatty acid ethyl esters greater than or equal to 90 wt% are also suitable for the purposes of the present invention.
  • the pharmaceutical composition suitable for use according to the present invention generally comprise at least one pharmaceutically acceptable vehicle and/ or one diluent and/ or one surfactant and/ or one thickener and /or one binder and/ or one lubricant and /or one aromatizer and/ or one colorant and /or one stabilizer and the like, which can easily be selected by the expert of the art.
  • the most preferred ratio between EPA and DHA is about 0.6- 1.1 / 1.3- 1.8; in particular is comprised between 0.9 and 1.5.
  • the content of EPA is comprised between 40 and 51% by weight and the content of DHA (as ethyl ester) is comprises between 34 and 45% by weight on the total fatty acids weight.
  • PC Phosphatidyl cholines
  • ionic emulsifier is a deoiled and purified soy lecithin containing from at least 30% of phosphatidyl choline (EpikuronTM 130 ) to at least 92% phosphatidyl choline (EpikuronTM 200).
  • a deoiled and purified soy lecithin enriched with at least 92% of phosphatidyl choline is used.
  • suitable ionic emulsifiers are EpikuronTM 145 V and EpikuronTM 170.
  • soy lecithin is endowed with an anticholesterolemic activity. Therefore another advantage of the present invention is that said soy lecithin in combination with the omega-3 fatty acid and the statin will increase, in an additive manner, the anticholesterolemic activity of the composition of the invention.
  • Sodium docusate is often used as an emulsifying, wetting, and dispersing agent. It is an anionic surfactant, a substance that lowers the surface tension of water. It is used in symptomatic treatment of constipation, and in painful anorectal conditions such as hemorrhoids and anal fissures for people avoiding straining during bowel movements.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 g and 0.08 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • Rosuvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • ⁇ n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably 0.03 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • Sodium docusate in an amount comprised between 0.05 and 0.2 g, preferably 0.1 g;
  • Rosuvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • composition according to the present invention comprises: • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • Atorvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 and 0.04 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g;
  • composition in another embodiment of the present invention has a unitary form, in which the active ingredients are present in a single pharmaceutical form, particularly soft gelatin capsules.
  • the compositions according to the present invention optionally contain, along with the active ingredient, at least one pharmaceutically acceptable vehicle or excipient.
  • the pharmaceutical composition according to the present invention can be formulated in soft capsules for oral administration.
  • Said soft gelatin capsules preferably have an enteric coating.
  • the present invention is carried out according to following examples, but not limited to these examples.
  • omega-3 polyunsaturated fatty acids are a mixture of ethyl esters of polyunsaturated fatty acids with a content in EPA and DHA greater than 85%, in a ratio EPA/DHA comprised between 0.9 and 1 .5, and is a product provided by Pronova Biopharma Norge AS Norway
  • the atorvastatin used is atorvastatin calcium amorphous furnished by Biocon (India) ;
  • the pitvastatin used is pitavastatin calcium furnished by MSN Laboratories Pvt. Ltd (India);
  • the same method was applied to the preliminary solubility tests and to all the formulations in which the solution was clear at a first sight.
  • the solution to be analyzed is left under mechanical centrifugation and then the supernatant is separated trough filtration on PTFE (polytetrafluoroethylene) filter (size pore 0.22 ⁇ ) and analyzed by HPLC, using a COLUMN Intersil ODS-3 4.6x250mm, a solution of CH3CN/H2O 70/30 + 0.1% of CF3COOH as eluent, a flow of lml/min and a UV/VIS Detector.
  • PTFE polytetrafluoroethylene
  • n-3 PUFA omega-3 polyunsaturated fatty acids
  • the emulsifier was dissolved directly into the n-3 PUFA and left under mechanical stirring, then the atorvastatin was added and the appearance of the solution was evaluated.
  • the emulsifiers used were those already known in the medical field, available on the market and currently used for similar compositions .
  • a cosurfactant was added in a second step to further enhance the solubility of atorvastatin, the cosurfactant used was Transcutol P ® .
  • Tween 80 ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH (relative humidity); a clear solution was observed. After the addition of atorvastatin, the formation of a floating fluid was observed. Transcutol P ® in an amount of 0.02 g was added, but no change in the clearness of the solution was observed. The atorvastatin was not solubilized. Formulation 2
  • Cremophor EL ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a solution with opalescence was observed. After the addition of atorvastatin a precipitate was observed. The atorvastatin was not solubilized.
  • Solutol HS 15 ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was observed. After the addition of atorvastatin a clear solution was observed, but a waxy precipitate was observed after few minutes. The atorvastatin was not solubilized.
  • Labrasol ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH; a solution with opalescence was observed. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a white solid suspension was observed. The atorvastatin was not solubilized.
  • Labrasol ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 25°C and 75% RH; a solution with opalescence was observed. Transcutol P ® was added, no changing in the clearness of the solution was observed. After the addition of atorvastatin a large precipitate was observed. The atorvastatin was not solubilized.
  • the emulsifier was dissolved directly into the n-3 PUFA and left under mechanical stirring, then the atorvastatin was added and the appearance of the solution was evaluated.
  • the emulsifiers used were natural or synthetic lecithin derivatives already known in the medical field, available on the market and currently used for similar composition.
  • a cosurfactant was added in a second step to further enhance the solubility of atorvastatin, the cosurfactant used was Transcutol P ® .
  • EpikuronTM 200 SH was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a single phase solution was not obtained.
  • the EpikuronTM 200 SH was not solubilized in the oil.
  • Lipoid S PC-3 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a single phase solution was not obtained.
  • the Lipoid S PC-3 was not solubilized in the oil.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • At least 90% of the atorvastatin in the composition at an initial measurement time was maintained after 6 month at 5°C and 80% of RH.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C e 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C and 75% RH; a clear pale yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear pale yellow solution was observed.
  • atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of EpikuronTM 200 the solution was left again under mechanical stirring at 600 rpm for 18 hours at 25°C. After the addition of atorvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH and a clear solution was visible to the naked-eye. The complete solubilization of atorvastatin was confirmed analyzing the solution by HPLC with the method described.
  • Tween 80 ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH (relative humidity); an opalescent solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized. Formulation 16
  • Cremophor EL ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 2 hours at 25°C and 75% RH (relative humidity); a clear solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized.
  • Labrasol ® was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 2 hours at 25°C and 75% RH; a clear solution was observed. After the addition of rosuvastatin to 1 ml of the solution obtained, the solution was left under mechanical stirring at 600 rpm for 24 hours at 25°C a precipitate was observed. The rosuvastatin was not solubilized. Formulation 18
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear yellow solution was observed. After the addition of rosuvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye. The complete solubilization of rosuvastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C and 75% RH; a clear pale yellow solution was observed.
  • 20 mg of rosuvastatin the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH; a clear solution was visible to the naked-eye.
  • the complete solubilization of rosuvastatin was confirmed analyzing the solution by HPLC with the method described.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of the solution was left again under mechanical stirring at 600 rpm for 24 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of 20 mg of pitavastatin the solution was left under mechanical stirring at 600 rpm for 24 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.
  • the sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 25°C and 75% RH. After the addition of EpikuronTM 200 the solution was left again under mechanical stirring at 600 rpm for 18 hours 25°C; a clear solution was observed. After the addition of 20 mg of pitavastatin the solution was left under mechanical stirring at 600 rpm for 18 hours 25°C. A clear solution was visible to the naked-eye. The complete solubilization of pitavastatin was confirmed analyzing the solution by HPLC with the method described.
  • Formulation 23 (corresponding to formulation 7 of WO2006096806):
  • Transcutol P ® 80 mg were added to 20 mg of atorvastatin and stirred well manually until the solid was wet; after 20 min a clear solution was obtained. The n- 3 PUFA was added to the solution ad a white precipitate was observed.
  • Transcutol P ® 80 mg were added to 20 mg of rosuvastatin and stirred well manually until the solid was wet; after 20 min a clear solution was obtained. The n- 3 PUFA was added to the solution ad a precipitate was observed.
  • Formulation 15 (corresponding to formulation 15 of WO2006096806) : 50 mg of Lauroglycol 90TM was added to 20 mg of atorvastatin and stirred well manually until the solid was wetted then n-3 PUFA was added and the solution was left under mechanical stirring at 600 rpm for 10 min at 25°C and 75% RH; even after this stage the atorvastatin remained insoluble. Lastly the remaining 70 mg of Lauroglycol 90TM were added and a part of atorvastatin was solubilized while the other remained dispersed, giving an opalescent solution.
  • Lauroglycol 90TM 50 mg was added to 20 mg of rosuvastatin and stirred well manually until the solid was wetted then n-3 PUFA was added and the solution was left under mechanical stirring at 600 rpm for 24h at 25°C and 75% RH; even after this stage the rosuvastatin remained insoluble. Lastly the remaining 70 mg of Lauroglycol 90TM were added and a part of rosuvastatin was solubilized while the other remained insoluble, giving a precipitate.
  • the amount of degradation products after 1 , 3 and 6 month were calculated.
  • a suitable amount of the formulation to be analyzed was diluted wit methanol and left under mechanical centrifugation; supernatant is separated trough filtration on PTFE (polytetrafluoroethylene) filter (size pore 0.22 ⁇ ) and analyzed by HPLC, using a COLUMN Intersil ODS-3 4.6x250mm, a solution of CH3CN/H2O 70/30 + 0.1% of CF3COOH as eluent, a flow of lml/min and a UV/VIS Detector.
  • statin The main degradation product of the statin was the lattonic form. Stability tests on Formulation 8 and Formulation 12, were performed; the results obtained and summarized in Table 9 demonstrate that both the formulation have a good stability at 5°C
  • solubility of atorvastatin in n-3 PUFA alone thus increases by 600 times, reaching a maximum of 60 mg/ml in the formulations which use sodium docusate, and even to 90 mg/ml for formulations that use the EpikuronTM 200; that of pitavastatin is a bit higher than atorvastatin in n-3 PUFA alone (2.3 mg/ml) but it reaches a maximun amount of solubilization of more than 60 mg/ml.
  • the sodium docusate As for the sodium docusate , it assembles the characteristics of the emulsifier and the property of symptomatic treatment of constipation, which is a common adverse effect that occurs in patients treated with statins, and in particular with atorvastatin.
  • Medicaments can be prepared according to the formulations described in the present invention, using atorvastatin, rosuvastatin and pitavastatin, which, as is known in the art, have a pharmaceutical efficacy superior to that of simvastatin; such formulations therefore allow to use compounds with a lower minimum effective dose obtaining the same or better results. Consequently, assuming an equal estimated efficacy, side effects on the patient are reduced, thus demonstrating further effectiveness of the solution proposed by the present invention compared to the prior art.
  • compositions for oral administration for use in the treatment of pathologies related to hyperlipidemia and hypertriglyceridemia, hypercholesterolemia, pathologies for which the individual components are already used in standard treatment protocols known in the art.

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  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une composition contenant une statine totalement solubilisée dans un système solvant constitué d'acides gras polyinsaturés oméga-3 (n- 3 PUFA), ou de leurs esters d'alkyle, et d'un émulsifiant ionique sélectionné parmi le docusate de sodium et une lécithine enrichie en phosphatidylcholine. La composition pharmaceutique selon la présente invention peut être utilisée dans la prévention et le traitement de l'hyperlipémie, de l'hypercholestérolémie, de l'hypertriglycéridémie et toutes les pathologies associées.
PCT/EP2013/076533 2012-12-17 2013-12-13 Formulation orale contenant une statine dans des acides gras polyinsaturés oméga-3 (n-3 pufa) WO2014095628A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2952209A1 (fr) * 2014-06-04 2015-12-09 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Formulations homogènes comprenant des acides gras polyinsaturés omega-3 (n-3 PUFA) et de resvératrol pour administration orale
WO2016179137A1 (fr) * 2015-05-04 2016-11-10 Cytometix, Inc. Compositions et procédés pour l'administration de dérivés d'acides gras polyinsaturés et analogues
CN107405326A (zh) * 2015-01-21 2017-11-28 持田制药株式会社 ω3脂肪酸的自乳化组合物
WO2023126026A3 (fr) * 2021-12-29 2023-08-24 中国科学院上海药物研究所 Nanocomposite lipidique d'epa-ee, sa formulation, son procédé de préparation et son application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006096806A2 (fr) * 2005-03-08 2006-09-14 Reliant Pharmaceutiacals, Inc. Traitement avec une statine et des acides gras omega 3 et produit de combinaison correspondant
WO2011150505A1 (fr) * 2010-06-03 2011-12-08 Accucaps Industries Limited Formulations pharmaceutiques de statines et d'acides gras d'oméga-3 pour encapsulation
WO2012002464A1 (fr) * 2010-06-30 2012-01-05 持田製薬株式会社 PRÉPARATION À BASE DE COMPOSÉS D'ACIDE GRAS ω3

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006096806A2 (fr) * 2005-03-08 2006-09-14 Reliant Pharmaceutiacals, Inc. Traitement avec une statine et des acides gras omega 3 et produit de combinaison correspondant
WO2011150505A1 (fr) * 2010-06-03 2011-12-08 Accucaps Industries Limited Formulations pharmaceutiques de statines et d'acides gras d'oméga-3 pour encapsulation
WO2012002464A1 (fr) * 2010-06-30 2012-01-05 持田製薬株式会社 PRÉPARATION À BASE DE COMPOSÉS D'ACIDE GRAS ω3

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2952209A1 (fr) * 2014-06-04 2015-12-09 SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. Formulations homogènes comprenant des acides gras polyinsaturés omega-3 (n-3 PUFA) et de resvératrol pour administration orale
WO2015185238A1 (fr) * 2014-06-04 2015-12-10 Sigma-Tau Industrire Farmaceutiche Riunite S.P.A. Formulation homogène comprenant un acide gras polyinsaturé oméga-3 et du resvératrol pour administration orale
US10300035B2 (en) 2014-06-04 2019-05-28 Alfasigma S.P.A. Homogeneous formulation comprising omega-3 polyunsatured fatty acid and resveratrol for oral administration
EA032717B1 (ru) * 2014-06-04 2019-07-31 Альфасигма С.П.А. Гомогенная композиция для перорального введения, содержащая омега-3 полиненасыщенные жирные кислоты и ресвератрол
CN107405326A (zh) * 2015-01-21 2017-11-28 持田制药株式会社 ω3脂肪酸的自乳化组合物
CN107405326B (zh) * 2015-01-21 2021-06-15 持田制药株式会社 ω3脂肪酸的自乳化组合物
WO2016179137A1 (fr) * 2015-05-04 2016-11-10 Cytometix, Inc. Compositions et procédés pour l'administration de dérivés d'acides gras polyinsaturés et analogues
WO2023126026A3 (fr) * 2021-12-29 2023-08-24 中国科学院上海药物研究所 Nanocomposite lipidique d'epa-ee, sa formulation, son procédé de préparation et son application

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