WO2015185240A1 - Compositions containing simvastatin in omega-3 polyunsaturated fatty acids - Google Patents

Compositions containing simvastatin in omega-3 polyunsaturated fatty acids Download PDF

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Publication number
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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French (fr)
Inventor
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/en

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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.

Abstract

The present application relates to compositions comprising simvastatin, omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters, and a ionic solvent selected between sodium docusate and a phosphatidylcholine-enriched lechitin, wherein the recovery of simvastatin is at least 95% after 6 months at 40°C. 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.

Description

Field of the invention
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.
The composition according to the invention can be used in the prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and all the pathologies related.
Background of the invention Hypercholesterolemia has been recognized as a major risk factor for coronary heart disease (CHD). In clinical trials, 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.
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.
The efficacy of the statins in the primary and secondary prevention of cardiovascular diseases has been demonstrated in a number of clinical studies. Several evidence suggests that the clinical benefit obtained with therapy with statins could be related to a reduction of systemic inflammatory markers (Ridker P.M., et al.; N. Engl, J. Med. 344:1959-65, 2001) more than to the reduction of cholesterol level. 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. al.; Circulation 103:926-33, 2001 ). In addition, 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 (n-3 PUFA) 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. GISSI-Prevention trial (Lancet 1999 354: 447-55) was the first trial demonstrating 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 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.
Different patents have been published which describe pharmaceutical formulations of 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.
Even if many studies have been focused on finding a suitable method for enhancing the stability of the system when delivering simvastatin and n-3 PUFA in a single dose, none of them provides any stable composition wherein simvastatin is in contact with n-3 PUFA. Most of the known methods of preparing a composition containing simvastatin and n-3 PUFA include the physical separation of the two components by microencapsulation or coating, processes which are long and expensive. The main degradation product is the acid form of simvastatin; it is produced by hydrolysis of the lactone function of the statin.
It is known that 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).
Considering the advantages in providing simvastatin and n-3 PUFA in an homogenous and stable single dosage, for the prevention and treatment of pathologies related to hyperlipidemia, hypercholesterolemia and hypertriglyceridemia, it becomes more and more noticeable the need to find a method for preparing a stable composition with a simple, fast and economically advantageous method.
Summary of the invention
It has now surprisingly been found that 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.
It is therefore the object of the present invention 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.
It is a further object of the present invention 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 3 months is at least 97% by weight.
It is a further object of the present invention 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 fori month is at least 99% by weight.
It is a further object of the present invention a method of preparing a dehydrated 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), comprising the following steps:
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 "Epikuron™ 200".
Homogeneous, according to the present invention 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.
The 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.
The 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. Commonly, the composition is presented in unit dosage form to facilitate accurate dosing. The term "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.
The 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, 20th 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.
Detailed description of the invention
The 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. For the purposes of the present invention 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.
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 their assigned names. Common name Lipid name Chemical name
- 16:3 (n-3) a//-c s-7,10,13-hexadecatrienoic acid a-Linolenic acid (ALA) 18:3 (n-3) a//-c s-9,12,15-octadecatrienoic acid a//-c s-6,9,12,15-octadecatetraenoic
Stearidonic acid (STD) 18:4 (n-3)
acid
Eicosatrienoic acid (ETE) 20:3 (n-3) a//-c s-l l,14,17-eicosatrienoic acid
Eicosatetraenoic acid (ETA) 20:4 (n-3) a//-c s-8,l l,14,17-eicosatetraenoic acid a//-c s-5,8,ll,14,17-eicosapentaenoic
Eicosapentaenoic acid (EPA) 20:5 (n-3)
acid
Docosapentaenoic acid (DPA), a//-c s-7,10,13,16,19-docosapentaenoic
22:5 (n-3)
Clupanodonic acid acid a//-c s-4,7,10,13,16,19-docosahexaenoic
Docosahexaenoic acid (DHA) 22:6 (n-3)
acid a//-c s-9,12,15,18,21-
Tetracosapentaenoic acid 24:5 (n-3)
Tetracosapentaenoic acid
Tetracosahexaenoic acid (Nisinic a//-c s-6,9,12,15,18,21-
24:6 (n-3)
acid) Tetracosahexaenoic acid
The ones most preferred are a//-c s-5,8,ll,14,17-eicosapentaenoic acid (EPA) and all-cis- 4,7,10,13, 16,19--docosahexaenoic acid (DHA).
Preferably 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. Preferably 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.
The terms "PUFA" and "n-3 PUFA", as used here, 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. 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. For oral use, 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. Of course, 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.
Other types of 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.
Those compositions illustrated in the European Pharmacopoiea 2000 (EuPh. 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.
Preferably the content of EPA (as ethyl ester) 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.
Specific drugs containing n-3 PUFA that meet the above specifications, as active ingredient and that can be used according to the present invention, are already available on the market.
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a head group. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically extracted using hexane. It is known in the art that soy lecithin is endowed with an anticholesterolemic activity. Therefore another advantage of the present invention is that said soy lecithin in combination with the n-3 PUFA and the statin will increase, in an additive manner, the anticholesterolemic activity of the composition of the invention. In the present invention the 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." The term 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. In chemistry, 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.
The term "homogeneous" according to the present invention means that the solid component, particularly the simvastatin, is completely dissolved in the oil phase. In one embodiment the composition according to the present invention comprises:
1. 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. Deoiled phosphatidylcholine enriched lecithin in an amount comprised between 0.01 and
0.8 g, preferably from 0.05 to 0.6 g, more preferably 0.1 g; 3. 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.
In another embodiment the composition according to the present invention comprises:
1. 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;
3. 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. In another embodiment the composition according to the present invention comprises:
1. 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. 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;
3. 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;
4. 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. In another embodiment of the present invention 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.
In order to demonstrate the substantial advantage and unexpected effect of the present invention, the present invention is carried out according to following examples, but not limited to these examples.
EXAMPLES
Materials and Methods:
For the purpose of the present invention the following materials have been used:
• the omega-3 polyunsaturated fatty acids (n-3 PUFA) 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 deoiled phosphatidylcholine-enriched lecithin, also known under the trade name Epikuron™ 200 used is furnished by Cargill; • the sodium docusate used is furnished by Sigma-Aldrich s.r.l., Milan, Italy;
• the 2-[2-ethoxyethoxy)ethanol used, also known under the trade name Transcutol P®, is furnished by GATTEFOSSE' ITALIA, S.r.l [Milan, Italy);
• the propylene glycol monolaurate used, also known under the trade name Lauroglycol 90™, is furnished by GATTEFOSSE' ITALIA, S.r.l [Milan, Italy).
• the ascorbil palmitate is furnished by Sigma-Aldrich s.r.l., Milan, Italy;
• The adipic acid is furnished by FLUKA Milan, Italy The citric acid is furnished by FLUKA Milan, Italy
• The activated molecular sieves are provided by Merck KGaA, Darmstadt, Germany Stability Analysis :
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.
Preliminary solubility tests
As first step it was looked for the best solvent which could allow preparing the highest number of formulations with the broadest spectrum of concentration of simvastatin: different solvents were added to the combination of simvastatin and omega-3 and the maximum solubility of the simvastatin in each solvent is reported in Table 1. Table 1
Figure imgf000014_0001
The results showed that the maximum solubility reached with the different solvent was quite similar, although in the formulations comprising Epikuron and docusate the solubility directly increased with the amount of solvent added: with 20% of Epikuron and the solubility reached 70 mg/ml; for the non-ionic solvents Transcutol P® and Lauroglycol 90™ the solubility was not increased using a higher amount of solvent.
Examples
Formulation 1
PUFA 0.9 gr
Epikuron™ 200 O.lgr Simvastatin 0.02 gr
Epikuron™ 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 stability test was carried out with the method described; the results are hereunder reported. Time (Month) Temperature (°C) Recovery of simvastatin (%)
1 25°C 98.1
1 40°C 90.0
In order to increase the stability, other compositions with small amounts of carboxy or hydroxy acids added to the solution were prepared.
Formulation 2
PUFA 0.9 gr
Epikuron™ 200 0.09gr Citric acid 0.0 lgr
Simvastatin 0.02 gr
Epikuron™ 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.
An aqueous solution of 10% v/v of citric acid was prepared, then ΙΟμΙ of this solution were added to the oily solution under stirring and the excess water was quickly removed with a stream of argon. The complete removal of the water was visible to the naked-eye, highlighted by the changing of the solution from turbid to clear.
Formulation 3
PUFA 0.9 gr
Epikuron™ 200 0.09gr
Adipic acid O.Olgr Simvastatin 0.02 gr
Epikuron™ 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.
Formulation 4
PUFA 0.9 gr Epikuron™ 200 0.09gr Palmitic acid 0.015gr Simvastatin 0.02 gr
Epikuron™ 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.
The stability tests were carried out and the results are reported in Table 2 Table 2
Figure imgf000016_0001
The presence of a carboxylic or hydroxy acid doesn't enhance the stability, contrary to what it was expected. The hydroxy acids, in fact, are used as stabilizing agents in the solid composition containing simvastatin already known and available on the market. Formulation 5
PUFA 9 gr
Epikuron™ 200 0.9gr Sodium docusate 0.15gr Simvastatin 0.2 gr
Sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm at 22°C at 60% RH up to complete solubilization. After the addition of Epikuron™ 200 the solution was left under mechanical stirring at 600 rpm for 18 hours at 22°C. A clear pale yellow 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.
Formulation 6
PUFA 0.9 gr
Epikuron™ 200 0.09gr Sodium docusate 0.015g] Simvastatin 0.02 gr
Activated molecular sieves 2 gr
Sodium docusate was added to n-3 PUFA and the solution was left under mechanical stirring at 600 rpm at 22°C at 60% RH up to complete solubilization. After the addition of Epikuron™ 200 the solution was left under mechanical stirring for 18 hours at 600 rpm at 22°C; a clear pale yellow 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. 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.
The stability tests gave surprising results, which are reported in Table 3. Table 3
Figure imgf000018_0001
With the same procedure other compositions were prepared.
Formulation 7 PUFA 0.9 gr
Epikuron™ 200 O.lgr Simvastatin 0.02 gr
Activated molecular sieves 2gr
Epikuron™ 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.
This composition represents the dehydrated analogous of Formulation 1. Formulation 8
PUFA 0.9 gr
Sodium docusate O.lgr Simvastatin 0.02 gr 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.
Formulation 9
PUFA 0.9 gr
Sodium docusate O.lgr Simvastatin 0.02 gr
Activated molecular sieves 2gr
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.
The stability was tested and the results are reported in table 4
Table 4
Figure imgf000020_0001
Further Solubility Tests - Comparative Examples
Two compositions disclosed in WO2006096806 were further treated with activated molecular sieves. The results demonstrate that solvents different from Epikuron™ 200 are not useful to provide the stability required:
Formulation 10 (comparative example, similar to formulation 7 of WO2006096806)
PUFA 0.9 gr
Transcutol P O.lg
Simvastatin 0.015g
Activated molecular sieves 2gr
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 90™ 0.1 g
Simvastatin 0.015g
Activated molecular sieves 2gr
Lauroglycol 90™ 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.
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 retrieving the sieves through decantation. The stability tests were carried out and the data compared with those of Formulations 6, 7 and 9; the results are summarized in Table 5.
Table 5
Recovery of
Time Temperature
Form. Solvent simvastatin
(month) C°c)
(%)
6 Epikuron™ 200+ Sodium 1 40 99.4
7 Epikuron™ 200 1 40 98.3
9 Sodium docusate 1 40 99.3
10 Transcutol 1 40 75
11 Lauroglycol 1 40 82 Discussion of the results:
The experimental data reported in this application show that the dehydration procedure applied to the compositions allows to achieve the target to have a unit dosage composition stable for long time and completely solubilized. This result, as shown in Table 5 cannot be achieved with the most common solvents present in the state of the art. The great advantage of the compositions prepared with the process described is to drastically reduce time and expenses for the physical isolation of simvastatin and omega-3 in order to avoid the degradation. As shown by the present invention this can be obtained with a very simple, fast and cheap procedure, these characteristics rendering the process particularly suitable for industrial applicability.
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.
The stability demonstrated by the solutions prepared makes them useful in the of preparation of pharmaceutical 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.

Claims

1. An homogeneous composition in unit dose form, comprising:
a) omega-3 polyunsaturated fatty acids (n-3 PUFA), or their alkyl esters;
b) a ionic solvent selected between a deoiled phosphatidylcholine-enriched lecithin and sodium docusate or mixture thereof; and
c) simvastatin; 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.
2. The homogeneous composition according to claim 1, characterized in that the recovery of simvastatin after storage at 40°C for 3 months is at least 97% by weight.
3. The homogeneous composition according to claim 1, characterized in that the recovery of simvastatin after storage at 40°C for 1 month is at least 99% by weight.
4. The homogeneous composition according to claim 1, characterized in that the omega-3 polyunsaturated fatty acids (n-3 PUFA) are selected from the group consisting of eicosapentaenoic acid, the docosahexaenoic acid or mixtures thereof.
5. The homogeneous composition according claim 4, characterized in that the ratio between eicosapentaenoic acid and docosahexaenoic acid is comprised between 0.9 and 1.5
6. The homogeneous composition according to claim 1, characterized in that the omega-3 polyunsaturated fatty acids (n-3 PUFA) are a mixture of fatty acids having a content in EPA and DHA comprised between 75% and 95% by weight, preferably at least 85%, on the total fatty acids weight, and wherein the total content of n-3 PUFA is at least 90% by weight on the total fatty acids weight.
7. The homogeneous composition according to claim 1, wherein the omega-3 polyunsaturated fatty acids (n-3 PUFA) are a mixture of ethyl esters of EPA and DHA in a ratio comprised between 0.9 and 1.5 and the content of EPA ethyl ester is comprised between 40 and 51 % and the content of DHA ethyl ester is comprised between 34 and 45% by weight on the total fatty acids weight.
8. The homogeneous composition according to claim 1, characterized in that the alkyl ester of omega-3 polyunsaturated fatty acids (n-3 PUFA) are selected from the group consisting of ethyl, methyl, propyl esters or mixtures thereof.
9. The homogeneous composition according to claim 1, in which the omega-3 polyunsaturated fatty acids (n-3 PUFA) are in an amount comprised between 0.5 and 1.0 g, preferably between 0.8 and 0.9 g, more preferably 0.9 g.
10. The homogeneous composition according to claim 1, in which the simvastatin is in an amount comprised between 0.02 and 0.09 g.
11. The homogeneous composition according to claim 1 characterized in that the ionic solvent is a deoiled phosphatidylcholine-enriched lecithin in which the content of phosphatidyl choline is greater than 92%.
12. The homogeneous composition according to claim 1, in which the deoiled phosphatidylcholine-enriched lecithin is in an amount comprised between 0.01 and 0.8 g, preferably between 0.05 and 0.6 g, more preferably 0.1 g.
13. The composition according to claim 1, in which the sodium docusate is in an amount comprised between 0.05 and 0.2 g, preferably 0.1 g.
14. The homogeneous homogeneous composition according to claims 1-13, in the form of dietary or nutritional supplement
15. A pharmaceutical composition comprising the homogeneous composition according to claims 1-13, further comprising at least one pharmaceutically acceptable vehicle or excipient.
16. The pharmaceutical composition according to claim 15 for use in the prevention and treatment of pathologies related to hyperlipidemia, hypercholesterolemia and hypertriglyceridemia.
17. The pharmaceutical composition according to claims 15 or 16 characterized in that is encapsulated by soft gelatin capsules, optionally having an enteric coating, for oral administration.
18. A process for the preparation of the homogeneous composition according to claim 1, comprising the following steps:
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.
19. The process according to claim 1, in which the activated molecular sieves are zeolites.
PCT/EP2015/056533 2014-06-04 2015-03-26 Compositions containing simvastatin in omega-3 polyunsaturated fatty acids WO2015185240A1 (en)

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