WO2015185240A1 - Compositions contenant de la simvastatine dans des acides gras polyinsaturés oméga-3 - Google Patents

Compositions contenant de la simvastatine dans des acides gras polyinsaturés oméga-3 Download PDF

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WO2015185240A1
WO2015185240A1 PCT/EP2015/056533 EP2015056533W WO2015185240A1 WO 2015185240 A1 WO2015185240 A1 WO 2015185240A1 EP 2015056533 W EP2015056533 W EP 2015056533W WO 2015185240 A1 WO2015185240 A1 WO 2015185240A1
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composition according
pufa
simvastatin
fatty acids
homogeneous composition
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PCT/EP2015/056533
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English (en)
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Giuseppe Giannini
Mosè Santaniello
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Sigma-Tau Industrire Farmaceutiche Riunite S.P.A.
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Publication of WO2015185240A1 publication Critical patent/WO2015185240A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present application relates to the medical field, and in particular to a homogeneous unit dosage composition comprising simvastatin, omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters, and a ionic solvent.
  • the pharmaceutical composition according to the present invention is prepared with a method which enhances the stability of the final composition through dehydration.
  • composition according to the 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 diseases (CVD) represent 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.
  • 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 anti-inflammatory 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.
  • 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 all.; 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. Vase. Biol. 22:1452-8, 2002).
  • Simvastatin is a hypolipidemic drug used with exercise, diet, and weight-loss to control elevated cholesterol levels, or hypercholesterolemia. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
  • Omega-3 polyunsaturated fatty acids have demonstrated a beneficial effect in the prevention of cardiovascular events (Aarsetoey H. et al.;Cardiology Research and Practice, Volume 2012: 1-16) ), possibly by means of an antiinflammatory, antithrombotic and antiarrhythmic mechanism (Sethi S. et al.; Blood 2002:100:-1340-6; Billman GE, et al.; Circulation 3 1999: 99:2452-7).
  • the hypolipidic effect was the first detected, so at first these drugs had been used for the treatment of dislipidemic disorders, while the antiinflammatory, antithrombotic, antiatherosclerotic and antiarrhythmogenic effects have been found later.
  • n-3 PUFAs are indicated for the primary and secondary prevention of ischemic cardiopathy and sudden cardiac death (SCD) (Mori TA, Beilin L J. Long-chain omega-3 fatty acids, blood lipids and cardiovascular risk reduction. Curr. Opin. Lipidol. 2001;12:11-7). In Nutrition and Dietary Supplements, 2011 September 14;: 93-100 it is described the role of n-3 series polyunsaturated fatty acids in cardiovascular disease prevention.
  • SCD ischemic cardiopathy and sudden cardiac death
  • statins such as for example: US 5,180,589 or US 5,356,896 which describe pharmaceutical composition forms stabilized against pH-related degradation.
  • US 6,235,311 describes a pharmaceutical composition combining a statin and aspirin.
  • US 5,225,202 describes a pharmaceutical composition of statins in the form of pellets with an enteric coating so as to protect the product at low pH.
  • WO2006045865 describes the microencapsulation of simvastatin in an oil phase constituted by diethyl esters of eicosapentaenoic acid and docosahexaenoic acid.
  • WO2011150505 discloses a solid phase containing the statin suspended in an oil phase containing n-3 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, are quite all relative to formulations containing simvastatin.
  • WO00/76482, WO00/57918 and WO00/57859 describe pharmaceutical compositions formed by lipid regulating agents in oils or in surfactants.
  • WO02/100394 and WO03/103640 describe pharmaceutical compositions formed by pure statin nanoparticles without any protective coating dispersed in pharmaceutically acceptable oils.
  • simvastatin is very sensitive to both the oxidative degradation (Srinivasu MK., et al, J.Pharm. Biomed. Anal., 2002: 29, 715-721) and pH dependent hydrolytic degradation. For this reason, to avoid degradation, in the solid formulations (like the tablets) are often included small amounts of citric acid or ascorbic acid (which prevent hydrolytic degradation), or of butyl hydroxyanisole (which prevents oxidative degradation).
  • a homogeneous composition consisting of simvastatin, a ionic solvent (a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof) and omega-3 polyunsaturated fatty acid (n-3 PUFA) when dehydrated by means of activated molecular sieves (particularly zeolites), is maintained stable at least for 6 months.
  • a ionic solvent a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof
  • omega-3 polyunsaturated fatty acid n-3 PUFA
  • a homogeneous composition consisting essentially of simvastatin, a ionic solvent (a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof) and omega-3 polyunsaturated fatty acid (n-3 PUFA), wherein the composition is dehydrated and wherein the recovery of simvastatin after storage at 40°C for 6 months is at least 95% by weight.
  • a ionic solvent a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof
  • omega-3 polyunsaturated fatty acid n-3 PUFA
  • composition consisting essentially of simvastatin, a ionic solvent (a deoiled phosphatidylcholine enriched lecithin or sodium docusate, or mixtures thereof) and omega-3 polyunsaturated fatty acid (n-3 PUFA), wherein the composition is dehydrated and wherein the recovery of simvastatin after storage at 40°C for 3 months is at least 97% by weight.
  • a ionic solvent a deoiled phosphatidylcholine enriched lecithin or sodium docusate, or mixtures thereof
  • omega-3 polyunsaturated fatty acid n-3 PUFA
  • composition consisting essentially of simvastatin, a ionic solvent (a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof) and omega-3 polyunsaturated fatty acid (n-3 PUFA), wherein the composition is dehydrated and wherein the recovery of simvastatin after storage at 40°C fori month is at least 99% by weight.
  • a ionic solvent a deoiled phosphatidylcholine-enriched lecithin or sodium docusate, or mixtures thereof
  • omega-3 polyunsaturated fatty acid n-3 PUFA
  • step a) Mixing the solvent with the n-3 PUFA and leaving the solution under mechanical stirring at 600 rpm at 22°C at 60% relative humidity (RH); b) Adding the simvastatin to the solution of step a) and leaving the solution obtained under mechanical stirring at 600 rpm for 3 hours at 22°C; c) Adding molecular sieves, previously activated under vacuum at 150°C for 18 hours, to the solution of step b, and leaving the system overnight without mechanical stirring; and d) Collecting the oily solution of step c through decantation.
  • a non-limiting example of the activated molecular sieves are the zeolites.
  • a non-limiting example of the lecithin according to the present invention is the one sold under the trade name "EpikuronTM 200".
  • Homogeneous means that there is no separation of phase, there is no particle suspended, there is no solid precipitate, and the solute is completely dissolved in the solvent system.
  • composition according to the invention can also comprise other useful elements, without substantially impairing the activity.
  • Another object of the present invention is a homogeneous and dehydrated composition containing the above-mentioned elements, optionally in a mixture with one or more pharmaceutically acceptable vehicles or excipients.
  • composition of the invention together with a conventionally employed adjuvant, carrier, diluent or excipient may be manufactured into the form of pharmaceutical composition and unit dosages thereof, and 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 being suitable for oral use.
  • the composition is presented in unit dosage form to facilitate accurate dosing.
  • unit dosage form 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.
  • composition for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders.
  • the above described components for oral administration are merely representative. Further materials as well as processing techniques and the like are set out in Part 5 of Remington's Pharmaceutical Sciences, 20 th Edition, 2000, Merck Publishing Company, Easton, Pennsylvania, and is incorporated herein by reference.
  • the 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.
  • Other objects of the present invention are the uses of the above mentioned composition as a medicament, particularly for the prevention and treatment of diseases related to hyperlipidemia, 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 more complex pathological picture including 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.
  • 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.
  • the statin is simvastatin.
  • the effective dose currently used for the statins is a daily amount between 5 and 80 mg, the most common dose is 20 mg/day.
  • 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 their assigned names.
  • ETE Eicosatrienoic acid 20:3 (n-3) a//-c s-l l,14,17-eicosatrienoic acid
  • DPA Docosapentaenoic acid
  • DHA Docosahexaenoic acid 22:6 (n-3)
  • Tetracosahexaenoic acid (Nisinic a//-c s-6,9,12,15,18,21-
  • EPA a//-c s-5,8,ll,14,17-eicosapentaenoic acid
  • DHA all-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 based 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 based on the total fatty acid weight.
  • PUFA and n-3 PUFA are intended to encompass their corresponding C1-C3 alkyl esters, preferably ethyl esters, and/or 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 0.5-2.0 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, as evaluated by the expert of the art, on the basis of the severity of the pathology.
  • compositions illustrated in the European Pharmacopoiea 2000 containing quantities greater than or equal to 90wt% of omega-3 polyunsaturated fatty acid (n-3 PUFA) polyunsaturated fatty acid ethyl esters, of which an amount greater than or equal to 80wt% is represented by of mixtures of EPA and DHA ethyl esters and a are also suitable for the purposes of the present invention.
  • the pharmaceutical composition suitable for use according to the present invention generally can 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 comprised between 34 and 45% by weight on the total fatty acids weight.
  • PC Phosphatidylcholines
  • ionic solvent is a deoiled and purified soy lecithin enriched with at least 92% of phosphatidylcholine.
  • 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.
  • Zeolites are microporous aluminosilicate minerals commonly used as commercial adsorbents and catalysts. Zeolites are the aluminosilicate members of the family of microporous solids known as "molecular sieves.”
  • molecular sieves refers to a particular property of these materials, i.e., the ability to selectively sort molecules based primarily on a size exclusion process. This is due to a very regular pore structure of molecular dimensions. The maximum size of the molecular or ionic species that can enter the pores of a zeolite is controlled by the dimensions of the channels. Zeolites are widely used as ion-exchange beds in domestic and commercial water purification, softening, and other applications.
  • zeolites are used to separate molecules (only molecules of certain sizes and shapes can pass through), and as traps for molecules so they can be analyzed.
  • the term "dehydrated” according to the present invention is referred to a solution of homogeneous mixture which has been treated with a process of dehydration, by application on molecular sieves or by other processes known in the art, like those involving the elimination of water by high temperature in condition of low humidity or employing dehydrating agents i.e. calcium chloride or sodium sulphate.
  • composition according to the present invention means that the solid component, particularly the simvastatin, is completely dissolved in the oil phase.
  • the composition according to the present invention comprises:
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably from 0.8 to 0.9 g, more preferably 0.9 g;
  • Deoiled phosphatidylcholine enriched lecithin in an amount comprised between 0.01 and
  • Simvastatin in an amount comprised between 0.01 and 0.09 g, preferably between 0.02 g and 0.08, more preferably 0.02 g.
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably from 0.8 to 0.9 g, more preferably 0.9 g; 2.
  • Sodium docusate in an amount comprised between 0.01 and 0.8 g, preferably from 0.05 to 0.6 g, more preferably 0.1 g;
  • composition according to the present invention comprises:
  • n-3 PUFA in an amount comprised between 0.5 and 1.0 g, preferably from 0.8 to 0.9 g, more preferably 0.9 g;
  • Deoiled phosphatidyl choline enriched lecithin in an amount comprised between 0.01 and 0.8 g, preferably from 0.05 to 0.6 g, more preferably 0.09 g;
  • Sodium docusate in an amount comprised between 0.01 and 0.8 g, preferably from 0.05 to 0.6 g, more preferably 0.01 g;
  • the composition has a unitary form, in which the active ingredients are present in a single pharmaceutical form, particularly soft gelatin capsules.
  • the composition according to the present invention optionally contains, 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.
  • 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, Norway; ⁇ the simvastatin used is furnished by Biocon (India);
  • the adipic acid is furnished by FLUKA Milan, Italy
  • the citric acid is furnished by FLUKA Milan, Italy
  • the same method was applied to all the compositions in which the solution was clear at a first sight.
  • the formulations were left for 1, 3 and 6 months at 25°C at 60% RH and 1, 3 and 6 months at 40°C and 70% RH.
  • a 10ml sample was then taken and analyzed by HPLC, using a column Intersil ODS-3 4.6x250mm, a solution of CH3CN/H2O 60/40 as eluent, a flow of lml/min and a UV/VIS Detector.
  • the percent detected amount of EPA, DHA and simvastatin are expressed as % of weight.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C at 60% RH; a clear yellow solution was observed. After the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was visible to the naked eye.
  • compositions with small amounts of carboxy or hydroxy acids added to the solution were prepared.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C at 60% RH; a clear yellow solution was observed. After the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was visible to the naked eye.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C at 60% RH; a clear yellow solution was observed. After the addition of adipic acid the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was obtained. The amount of simvastatin was added and the solution was left again under mechanical stirring at 600 rpm for 3 hours at 22°C; the solution obtained was clear to the naked eye.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C at 60% RH; a clear yellow solution was observed. After the addition of palmitic acid the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was obtained. The amount of simvastatin was added and the solution was left again under mechanical stirring at 600 rpm for 3 hours at 22°C; the solution obtained was clear to the naked-eye.
  • EpikuronTM 200 was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C at 60% RH; a clear yellow solution was observed. After the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was visible to the naked eye.
  • the molecular sieves (0.4nm, beads about 2mm), previously activated under vacuum at 150°C for 18 hours, were then added to the solution and the system was left overnight without mechanical stirring. The oily solution was finally obtained by decantation.
  • Sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C at 60% RH; after the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was visible to the naked eye.
  • the molecular sieves (0.4nm, beads about 2mm), previously activated under vacuum at 150°C for 18 hours, were then added to the solution and the system was left overnight without mechanical stirring. The oily solution was finally obtained by decantation.
  • Formulation 10 (comparative example, similar to formulation 7 of WO2006096806)
  • Transcutol P was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C and 60% RH;. After the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was obtained.
  • the molecular sieves (0.4nm, beads about 2mm), previously activated under vacuum at 150°C for 18 hours, were then added to the solution and the system was left overnight without mechanical stirring. The oily solution was finally obtained by decantation.
  • Formulation 11 (comparative example, similar to formulation 15 of WO2006096806) PUFA 0.9 gr
  • Lauroglycol 90TM was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C at 60% RH. After the addition of simvastatin the solution was left under mechanical stirring at 600 rpm for 3 hours at 22°C; a clear solution was obtained.
  • composition with sodium docusate As for the composition with sodium docusate, it assembles the characteristics of the solvent and the property of symptomatic treatment of constipation, which is a common adverse effect that occurs in patients treated with statins.
  • 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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Abstract

La présente invention concerne des compositions comprenant de la simvastatine, des acides gras polyinsaturés oméga-3 (n-3 PUFA), ou leurs esters d'alkyle, et un solvant ionique choisi parmi le docusate de sodium et une lécithine enrichie en phosphatidylcholine, la récupération de simvastatine étant d'au moins 95 % au bout de 6 mois à 40 °C. La composition pharmaceutique selon la présente invention peut être utilisée dans la prévention et le traitement de l'hyperlipidémie, de l'hypercholestérolémie, de l'hypertriglycéridémie et de toutes les pathologies associées.
PCT/EP2015/056533 2014-06-04 2015-03-26 Compositions contenant de la simvastatine dans des acides gras polyinsaturés oméga-3 WO2015185240A1 (fr)

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* Cited by examiner, † Cited by third party
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US5180589A (en) 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5225202A (en) 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5356896A (en) 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
WO2000057918A2 (fr) 1999-03-31 2000-10-05 Abbott Laboratories Nouvelles formules comprenant des agents de regulation des lipides
WO2000057859A1 (fr) 1999-03-31 2000-10-05 Abbott Laboratories Preparations contenant des agents regulateurs de lipides
WO2000076482A1 (fr) 1999-06-11 2000-12-21 Abbott Laboratories Nouvelles formulations avec agents de regulation lipidique
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WO2002100394A1 (fr) 2001-06-12 2002-12-19 Galephar M/F Composition pharmaceutique orale comprenant un derive de statine
WO2003103640A1 (fr) 2002-06-10 2003-12-18 Elan Pharma International, Ltd Formulations nanoparticulaires comprenant des derives d'un inhibiteur de la hmg coa-reductase (≤statines≥), nouvelles combinaisons associees et production de ces compositions pharmaceutiques
WO2006045865A1 (fr) 2004-10-19 2006-05-04 Gp Pharm S.A. Formulation pharmaceutique comprenant des microcapsules de statines en suspension dans des esters alkyliques d'acides gras polyinsatures (pufa)
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
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* Cited by examiner, † Cited by third party
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US5180589A (en) 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5225202A (en) 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5356896A (en) 1991-12-12 1994-10-18 Sandoz Ltd. Stabilized pharmaceutical compositions comprising an HMG-CoA reductase inhibitor compound
US6235311B1 (en) 1998-03-18 2001-05-22 Bristol-Myers Squibb Company Pharmaceutical composition containing a combination of a statin and aspirin and method
WO2000057918A2 (fr) 1999-03-31 2000-10-05 Abbott Laboratories Nouvelles formules comprenant des agents de regulation des lipides
WO2000057859A1 (fr) 1999-03-31 2000-10-05 Abbott Laboratories Preparations contenant des agents regulateurs de lipides
WO2000076482A1 (fr) 1999-06-11 2000-12-21 Abbott Laboratories Nouvelles formulations avec agents de regulation lipidique
WO2002100394A1 (fr) 2001-06-12 2002-12-19 Galephar M/F Composition pharmaceutique orale comprenant un derive de statine
WO2003103640A1 (fr) 2002-06-10 2003-12-18 Elan Pharma International, Ltd Formulations nanoparticulaires comprenant des derives d'un inhibiteur de la hmg coa-reductase (≤statines≥), nouvelles combinaisons associees et production de ces compositions pharmaceutiques
WO2006045865A1 (fr) 2004-10-19 2006-05-04 Gp Pharm S.A. Formulation pharmaceutique comprenant des microcapsules de statines en suspension dans des esters alkyliques d'acides gras polyinsatures (pufa)
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
EP2517697A1 (fr) * 2009-12-23 2012-10-31 Defiante Farmacêutica, S.A. Composition de combinaison utile pour le traitement de maladies cardiovasculaires
WO2011150505A1 (fr) 2010-06-03 2011-12-08 Accucaps Industries Limited Formulations pharmaceutiques de statines et d'acides gras d'oméga-3 pour encapsulation
WO2012032414A2 (fr) * 2010-09-08 2012-03-15 Pronova Biopharma Norge As Compositions comprenant un mélange d'huile constituée d'acides gras, un tensioactif et une statine

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