Classifications

• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

• the subject of invention is about self-micro / nano emulsifying system as a pharmaceutical carrier of rosuvastatin for oral administration.
• This formulation can be used in the pharmaceutical industry and intended to the treatment of dyslipidemia.
• Rosuvastatin is the newest of the statin group in 2003, has received approval for the treatment of hyperlipidemia. Rosuvastatin shows the effect by inhibiting the HMG-CoA( hydroxymethylglutaryl coenzyme A ) reductase enzyme. In addition rosuvastatin decreases total and LDL cholesterol, plasma triglycerides and apolipoprotein B levels. However, the studies showed that rosuvastatin had around 20 % of the bioavailability. Therefore, although achieve more LDL-C reduction with rosuvastatin; compared to atorvastatin, pravastatin and simvastatin 8, 26, 18 % of LDL-C reduction; oral bioavailability of rosuvastatin is not at the desired level.
• WO 2012032414 describes the micro and nano emulsifying drug delivery system, but this formulation is in the form of tablets or capsules.
• different statin groups were used. Simvastatin, iovastatin, pravastatin, fluvastatin and l atorvastatin considered between the statin groups.
• SMEDD formulation has been developed. Eicosapentaenoik acid (EPA) and docozahegzaenoik acid (DHA) ethy! ester or triglyceride form as an oil phase; poiysorbate 20, polysorbate 80 and the mixture of these two materials with different proportions as surfactant are used.
• EPA Eicosapentaenoik acid
• DHA docozahegzaenoik acid
• oleic acid is used as an oil phase. Different surfactants and cosurfactants with different ratios are used. Rosuvastatin is used as active ingredient in our patent application.
• K 20020042218 A describes micro emulsion drug delivery systems for the treatment of hypercholesterolemia.
• lovastatin or simvastatin is used as active ingredient.
• Twin, Span, Brij as surfactants; propylene glycol monocaprylate containing fatty acid esters polyglycolate oleic acid and linoieic acid, propylene glycol monolaurate and polyglyceryl dioleate as enhancing dissolution agent, coconut oil, olive oil, corn oil, castor oil, hazelnut oil, apricot oil as vegetable oil is used.
• Polyethylene glycol, dimetylsosorbid, diethyleneglycolmonoethylether is used as cosurfactant.
• statin group is different.
• surfactants cosurfactants and the oil phase are different ratios and types.
• KR 20050011323 A discloses a nano emulsion drug delivery systems for the treatment of hyperlipidemia.
• nanoemu!sions systems contained simvastatin,, polyoxyiated castor oil 35, the diethyleneglycolmonoethylether, transcuto!, dimethyl isosorbide, polyethylene glycol, and tocopherol acetate.
• statin group is different.
• surfactants cosurfactants and the oil phase are different ratios and types.
• Rosuvastatin is widely used for dyslipidemia treatment but it has bioavailability problem.
• the invention aims to develop self-micro / na no-emulsifying drug delivery systems containing Rosuvastatin for the treatment of dyslipidemia and demonstrate its treatment efficacy.
• the formulations were selected at desired component ratios.
• the rosuvastatin-incorporating SMEDDS were prepared by dissolving the drug powder into the SMEDD system.
• % Amount of substance ranges are as follows:
• Macrogoigiyceroli oleas (Labrafii M 1944) % 6-11
• the surfactant, cosurfactant, oil and water ratios were given in Table 2 during test period.
• the SMEDDS were freeze (5 °C ⁇ 3 °C, 24 hour) and thawed (40°C ⁇ 2°C, 75% ⁇ 5%, 24 hour) three times. After that, they were centrifuged at 3000 rpm/min during 5 minutes. Phase separation and turbidity of SMEDDS were controlled. The results are shown in Table 3.
• SMEDDS formuiations were diluted with certain amount of distilled water that provided from pseudo ternary phase diagram results.
• SMEDDS were stored at 25°C ⁇ 2°C, 60% ⁇ 5% RH and 40°C ⁇ 2°C, 75% ⁇ 5% RH conditions during 30 days and particle size of SMEDD was measured. The particle size measurement results are shown in Table 4.
• PDI 0,61 0,766667 0,726667 0,416667 0,235 Fl, F2 and F3 showed both in terms of droplet size and more stable physicochemical perspective when compared to other formulations for 30 days.
• droplet size is between 250-270 nm.
• the droplet size of SMEDDS is 40-70 nm in anhydrous.
• Coronary heart disease in the Vietnamese population (CHD) is increasing in frequency and takes first place among the causes of mortality, Hyperiipidemia is the most important risk factor for CHD and statins are the most commonly used for treatment.
• rosuvastatin to increase oral bioavailability and effectiveness of rosuvastatin and to decrease dose the drug for treating hyperiipidemia will aim with to develop new SMEDDS.
• new form of rosuvastatin is improved patient compliance and intended to be an alternative to other oral formulations.
• SEDD systems are creating opaque emulsion with a droplet size between 100 and 300 nm; SMEDD systems generally comprise a transparent emulsion with a droplet size less than 50 nm. Oil phase composition is 40-80% at SEDD systems whereas oil phase ratio in SMEDD system is less than 20%. SEDD systems are irritating the gastrointestinal tract and low chemical stability. However SMEDD system is physically stable and produced easily. SMEDD system is biocompatible and has oil, surfactant and one or more co surfactants. These systems are more sensitive and metastable dispersible dosage forms. In gastrointestinal channel lumen, SMEDD systems are transformed to the emulsion systems (micro / nano) with helping of liquid phase at this channel. Because of these advantages of SMEDD system, it was found appropriate to eliminate solubility and low bioavailability problems of rosuvastatin.
• This invention aims to increase the bioavailability and of course pharmacodynamics activity of the drug by changing in the pharmacokinetic profile with SMEDD.
• SMEDD self-micro / nano -emulsifying drug delivery systems can be solved an important health problem in our country and the world.
• the wide range of health expenditure in this area is reduced by drug dose reducing.
• the target audiences of the invention are the pharmaceutical industry and patients with dyslipidemia treated.
• the present invention as an alternative is to self-micro / nano -emulsifying drug delivery systems in an inert pharmaceutical co-agent adsorbed lipid tablet can be prepared.
• S EDDS have been identified to be a pharmaceutical dosage forms for the rosuvastatin in the literature.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Health & Medical Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Dispersion Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2014
  • 2014-03-21 TR TR2014/03323A patent/TR201403323A2/tr unknown
• 2015
  • 2015-03-23 EP EP15720228.4A patent/EP3119381A1/en active Pending
  • 2015-03-23 WO PCT/TR2015/000120 patent/WO2015142307A1/en active Application Filing

Non-Patent Citations (2)

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