WO2021040646A1 - Systèmes d'administration de médicament auto-microémulsifiants (smedds) comprenant de l'olmésartan médoxomil - Google Patents

Systèmes d'administration de médicament auto-microémulsifiants (smedds) comprenant de l'olmésartan médoxomil Download PDF

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WO2021040646A1
WO2021040646A1 PCT/TR2020/050722 TR2020050722W WO2021040646A1 WO 2021040646 A1 WO2021040646 A1 WO 2021040646A1 TR 2020050722 W TR2020050722 W TR 2020050722W WO 2021040646 A1 WO2021040646 A1 WO 2021040646A1
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smedds
olmesartan
formulation
surface active
active agent
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PCT/TR2020/050722
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English (en)
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Yelda KOMESLİ
Ercüment Karasulu
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Komesli Yelda
Karasulu Ercuement
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Publication of WO2021040646A1 publication Critical patent/WO2021040646A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention is related to therapeutic compositions comprising SMEDDS formulation (OM-SMEDDS) and SMEDDS pre-formulation comprising Olmesartan medoximil. Moreover the invention is related to usage of the formulation for a test model and applications in determining oral bioavailability and biodistribution by marking the pre-formulation with NIR dyes.
  • Olmesartan Medoximil is an active agent developed by Daiichi Sankyo. Initially it has been marketed as a mono product with the brand name Olmetec® in the year 2002. It is being marketed in USA with the names Benicar®, Benicar® HCT, Azor®, Tribenzor®. In Japan it is available in the market as Olmetec®, Rezaltas®. In Europe there are several drugs that comprise olmesartan from single therapy to ternary combination forms. Since then dual combinations with Hydrochlorothiazide and Amlodipin and ternary combinations with Hydrochlorothiazide + Amlodipin have been developed.
  • olmesartan is found in 10, 20, 40 mg tablets in the market and while its usage in children with the ages of 6-16 is 2.5-20mg for children weighing between 20-35kg, the dose in children weighing 35kg and more is 5-40 mg.
  • the base suspension is obtained by mixing two standard carriers (Ora Sweet®, Ora Plus®) and it is recommended that twenty tablets within the box are powdered and suspended by the pharmacist and given to the elderly and children in a measured amounts. This process is a dosing process that can only be carried out by the pharmacist.
  • the tablet containing Olmesartan Medoxomil is powdered with a difficult process as it is hydrophobic and is diluted and given to children and elderly patients. Due to this reason a new formulation is required for the drug to be given with low and correct doses, suitable per kilogram.
  • OM-SMEDDS shall increase bioavailability 10 times (according to (IVIS) test the optical imaging of oral biodistribution was increased 24 times, antihypertensive effects was increased at least 3.1 times with pharmacodynamic (NIBP) test and it is 100 times more permeable according to the PAMPA test results) and which was 26% for the olmesartan tablet that is the only preparation available in the market and it shall provide better efficiency with lower amounts of active agent thereby providing pharmaeconomic advantage, it shall increase patient tolerability and it shall make dosing feasible.
  • IVIS pharmacodynamic
  • Our invention is a SMEDDS formulation that has been developed according to the physical-chemical properties of Olmesartan medoxomil which is an antihypertensive active agent that is widely used in treating hypertension which is a diseases that has been defined as the most frequent cause of death by WHO.
  • the present invention comprises the following features:
  • the Olmesartan SMEDDS formulation subject of our invention is a pharmaceutical pre-mixture that comprises oleic acid as a fat, at least two surface active agents, an inactive surface active agent, an active agent and water. It comprises approximately 10-20% (14.72%) oleic acid as a fat, approximately 10-20% (16.218%) Tween 80 and approximately %10-20% (16.218%) Span 80 as surface active agents, approximately 25-35% (32.435%) Transcutol as inactive surface active agent, and approximately 15-25% (20.41%) water, and approximately 10, 20, 40 mg Olmesartan medoximil as an active agent.
  • the surface active agent/inactive surface active agent ratio is approximately 1:1.
  • OM-SMEDDS can be sweetened and flavorized and can be placed in the market in liquid form, tablet loaded with liquid and or in hard or soft gelatin capsules.
  • the side effects of drug molecules that have other bioavailability problems, that cause celiac alike side effects or gastrointestinal side effects can be reduced by being formulated with SMEDDS.
  • the real time biodistribution of these drugs in the body can be monitored, the bioavailability rate can be measured, the organ location of the drug can be monitored, organ targeting can be performed with the drug, it could be checked if the blood brain barrier has been crossed and all of these parameters can be illustrated mathematically.
  • Our invention includes a method in which different SMEDDS and other lipid-based micro/nanoparticle formulations prepared specifically for the physicochemical properties of the active substances to be monitored in the body, can be marked with different NIRs and monitored in the body.
  • celiac disease can be formed in rats by means of the suspension we have been using in the Celiac rat model that has been established during the experiment, and this model can be used for the diagnosis and treatment of the disease.
  • the ARB’s that cause celiac side effects or the gastrointestinal side effects of other problematic drug molecules can be compared with the prepared SMEDDS and suspension.
  • the Olmesartan SMEDDS formulation subject of our invention is a pharmaceutical pre-mixture that comprises oleic acid as a fat, at least two surface active agents, an inactive surface active agent, an active agent and water. It comprises approximately 10-20% (14.72%) oleic acid as a fat, approximately 10-20% (16.218%) Tween 80 and approximately %10-20% (16.218%) Span 80 as surface active agents, approximately 25-35% (32.435%) Transcutol as inactive surface active agent, and approximately 15-25% (20.41%) water by weight to the total weight of the composition, and approximately 10, 20, 40 mg Olmesartan medoximil as an active agent.
  • the surface active agent/inactive surface active agent ratio is approximately 1:1.
  • Olmesartan SMEDDS is prepared after mixing homogenously oleic acid, surface active agents (Tween 80, Span 80) and the inactive surface active agent (Transcutol) at the determined amounts for 5-20 minutes at approximately 300 rpm (25 ⁇ 0.5°C) and water is added titration is continued until a turbid mixture is obtained.
  • OM addition to the Formula is carried out with the prior dissolving of the active agent in transcutol.
  • It is possible to treat hypertension with OM-SMEDDS as it provides an economic advantage as a result of increased patient tolerability, eliminated celiac side effects and increased bioavailability.
  • Olmesartan SMEDDS can be sweetened and flavorized and can be placed in the market in liquid form, tablet loaded with liquid and or in hard or soft gelatin capsules.
  • e)By means of the method of our invention after the oral administration of SMEDDS other lipid based micro/nano particle drug carriers that have been marked with Vivotag 680 XL, Xenolight DiR or other fluorophores, the real time biodistribution of these drugs in the body can be monitored, the bioavailability rate can be measured, the organ location of the drug can be monitored, organ targeting can be performed with the drug, it could be checked if the blood brain barrier has been crossed and all of these parameters can be illustrated mathematically.
  • our invention includes a method in which different SMEDDS and other lipid-based micro/nanoparticle formulations prepared specifically for the physicochemical properties of the active substances to be monitored in the body, can be marked with different NIRs and monitored in the body.
  • the control dye solution marked with Vivotag® 680 XL comprises 0.45 mg VivoTag® 680 XL per 150 m ⁇ per mouse (such that it comprises 3 mg/ml Vivotag 680 XL per one mouse).
  • the solution is prepared with 270 m ⁇ stock dye, 480 m ⁇ water and 150 m ⁇ buffer (50 mM NaHCOs) as 900 m ⁇ by volume for 6 mice.
  • the OM-SMEDDS solution marked Vivotag 680 XL is prepared with 270 m ⁇ stock dye, 480 m ⁇ OM-SMEDDS and 150 m ⁇ buffer (50 mM NaHCOs) as 900 m ⁇ by volume for 6 mice. During the washing process carried out in order to remove excess dye, 900 m ⁇ PBS (pH 7) is added to this mixture, it is vortexed and is centrifuged for 10 minutes at 15300 rpm. The washing stage is repeated twice. Every time, 900 m ⁇ supernatant is removed. The OM-SMEDDS that is precipitated is transferred into another eppendorf with care with a micropipette.
  • the remaining washed section is given with a 150m1 oral gavage to mice.
  • the control dye solution marked Xenolight DiR comprises 0.3 mg Xenolight® DiR in 150m1 liquid to be given per mouse.
  • the solution is prepared as 900m1 with 720m1 PBS, 180m1 stock dye for 6 mice (such that it comprises 2 mg/ml 1 Xenolight® DiR per 2 mice).
  • the OM-SMEDDS solution marked with Xenolight® DiR is prepared as 900m1 with 720m1 OM-SMEDDS and 180m1 stock dye according to the same calculation. The excess dye is removed with the same method mentioned above.
  • a rat test model can be developed in order to carry out assays for the treatment of celiac disease.
  • Our invention comprises a rat animal model for establishing enteropathy similar to celiac with histological imaging following the oral application of the suspension to rats at a dose of 1.3 mg/kg for 1 month comprising 1 mg/ml OM and 0.25% w/v CMC (carboxymethylcellulose).
  • the OM suspension has been prepared by topping up 0.25 g CMC and 100 mg OM with 100 ml distilled water and suspending the mixture. The amount of dispersant in the suspension and/or type of dispersant and the carrier body solvent can change.
  • a model study can be carried out with other experimental animals instead of the rat animal model or cell cultures.
  • Our invention can comprise OM or other drug molecules that have other bioavailability problems that cause celiac alike side effects or gastrointestinal side effects as the active agent.
  • the animal model our invention comprises can be used at a number or amount that can be repeated or that is sustainable in the diagnosis and treatment of celiac disease. It can be beneficial in scientific studies by allowing endless numbers of simulation of the disease. It can also explain the mechanisms of action of other drugs that lead to gastrointestinal side effects. This data, can be supported, confirmed by immuno histochemical studies, gene expression and ELISA based antibody analysis, and thereby the severity and progress of the disease can be measured. These models can serve humanity in the pharmaceutical sector and the celiac diagnosis and treatment field, by being widening the scope and by variations using different animal species and cell cultures.
  • the premix of the invention is a premix that comprises, a fat, at least two surface active agents, an inactive surface active agent, an active agent and water and it is prepared by titrating in order to create microemulsion (SMEDDS).
  • the premix comprises by weight 10-20% (14.72%) fat, approximately 10-20% (%16,218) two surface active agents, approximately 25-35% (32,435%) an inactive surface active agent and approximately 15-25% (20.41%) water and 10-40 mg olmesartan medoxomil.
  • the premix comprises at least two surface active agents selected from nonionic, anionic, cationic and zwitterionic surface active agents.
  • non-ionic surfactans such as Sorbitan esters (Span), Polysorbates (Tween), Ethylene glycol distearate Glyceril monostearate Propylene glycol monostearate Glyceryl monostearate Diethylene glycol monolaurate, poloxamer 188, anionic surfactants such as acacia, sodium lauryl sulfate, cationic surfactants such as cetrimonium bromide, cetylpridine chloride can be used.
  • Products sold under the commercial name Span® in the market are non-ionic surface active agents containing Sorbitan Monolaurate, Monopalmitate, Monostearate, Tristearate, Monooleate or Trioleate esters.
  • the product sold in the market with the commercial name Tween® are nonionic surface active agents that comprise polyoxyethylene sorbitan esters.
  • the pre-mix comprises approximately 10-20% oleic acid as fat, 10-20% Tween and approximately 10-20% Span mixture as surface active agent, and approximately 25-35% Transcutol as the inactive surface active agent and distilled water.
  • the premix comprises 10, 11, 12, 13, 14,
  • Tween 80 as surface active agent, approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% Span 80 inactive surface active agent, approximately 25-35% or approximately 30% Transcutol as the active agent and distilled water.
  • the formulation of the invention comprises Tween 80/Span 80 surface active agent mixture, approximately at a rate of 25-35% (32.435%) Tween or Span 80.
  • the ratio of the Tween 80 or Span 80 in the mixture is approximately 10-20% (16,218%).
  • compositions of the present invention comprise at least one inactive surface active agent.
  • the inactive surface active agent is added into the premix in order to form an emulsion, stability and/or emulsification together with at least a surface active agent.
  • Transcutol with 6 carbons (2-(2-ethoxyethoxy) ethanol), short chain alcohols with 1 to 6 carbons (for example ethanol), benzyl alcohol, alkane diols and triols (for example Propylene Glycol, glycerol, polyethylene glycols such as PEG and PEG 400), glycol ethers such as tetraglycol and glycorol (for example tetrahydrofurfuryl PEG ether), pyrrolidone derivatives such as N-methyl pyrrolidone (for example Pharmasolve®)and 2-pyrrolidone (for example Soluphor® P) and bile salts, for example sodium deoxycholate, ethyl oleate can be used.
  • Transcutol has been selected in the formulation of the invention. Transcutol can be used in the formulation at the ratio of 20-40%, 25-35%, 30-35%, approximately 30, 31, 32, 33, 34, 35% approximately 32,435%.
  • the oleic acid that forms the fat portion is located in the formula as 10-20% (14,72%) by weight relative to the total weight of the pre-mix.
  • the ratio of the surface active agent mixture (Tween 80 - Span 80) to the inactive surface active agent (transcutol) is between 0.8: 1.2 and 1.2:0.8, approximately 1/1.
  • the preferred surface active agent - inactive surface active agent ratio (Tween 80 /Span 80 mixture transcutol ratio) is approximately 50% (1:1).
  • the mixture ratio of the surface active agents Tween80/Span80 in the present invention among themselves is 1/1 and the ratio by weight of these surface active agents within the total surface active agent in the formulation according to the weight of the premix is 25-35% (32,435%).
  • the mixture ratio of the surface active agent/ inactive surface active agent in the formulation of the present invention (Ratio of Transcutol to 1/1 Tween80-Span80 mixture) is approximately 1:1 and the inactive surface active agent according to the weight of the premix is approximately 25-35% (32,435%) by weight.
  • the formulation of the present invention is an oil/water type formulation and this type of formation is provided by HLB calculations carried out.
  • the water part is approximately 15-25% (20.41%) by weight relative to the total weight of the pre-mix.
  • the formulation that provides the highest microemulsion area has been determined with a triangular phase diagram method ( Figure 1).
  • the formulation comprises approximately 10 mg, 20mg or 40mg Olmesartan medoximil as active agent.
  • the pre-mix of the present invention can be in the form of self nano emulsifying drug release systems (SNEDDS), self micro emulsifying drug release systems (SMEDDS) or self emulsifying drug delivery systems (SEDDS).
  • the pre-mix forms an emulsion in the body comprising micelle particles inside the aqueous solution when it comes into contact with the gastric and/or intestinal medium.
  • SNEDDS / SMEDDS / SEDDS can contain a particle size (particle diameter) that varies between approximately 20 nm to approximately 200 nm. For example in some formulation arrangements particle size varies between approximately 5nm to 50 nm or approximately 100 nm to approximately 150 nm.
  • the pre-mix fat, oleic acid, surface active agents (Tween 80, Span 80) and the inactive surface active agent (Transcutol) at determined amounts is mixed at a suitable rate for example 300 rpm at a suitable temperature for example (25 ⁇ 0.5°C) for a suitable period of time, for example 5-20 minutes and the mixture is titrated with a measured amount of water until a turbid product is obtained.
  • the active agent addition to the Formula is carried out with the prior dissolving of the active agent in transcutol.
  • the pre-mix comprising olmesartan medoximil has been prepared with the mentioned method.
  • the pre-mix and/or SNEDDS/SMEDDS/SEDDS may also contain at least an antioxidant.
  • Suitable antioxidants can be a-tocopherol (vitamin E), calcium disodium EDTA, a-tocopherol acetates, butylhyroxytoluenes (BHT) and butyl hydroxyanisoles (BHA).
  • the refraction index of the SMEDDS formulas has been measured with a refractometer by adding a drop of diluted liquid SMEDDS.
  • the self emulsion time of SMEDDS on its own, has been evaluated in a pH 1.2 gastric fluid medium with a USP Type II dissolution apparatus at 50 rpm.
  • the 10 dispersion time of SMEDDS has been recorded as the microemulsification time.
  • SMEDDS pH measurements have been conducted using pH meter.
  • SMEDDS electrical conductivity has been evaluated using a conductivity meter in order to determine the oil/water microemulsion type.
  • the in vitro Diffusion Studies of SMEDDS has been carried out by monitoring the diffusion of 10 mg/ml OM-SMEDDS from a diffusion floating tube (Sigma Aldrich) of 1 kDa MWCO (cut in molecular weight) in order to determine the release profile of SMEDDS from the low porous membrane in gastric fluid.
  • Olmesartan SMEDDS can be sweetened and flavorized and can be placed in the market in liquid form, tablet loaded with liquid and or in hard or soft gelatin capsules.
  • an excipient is added into the formulation in order to stabilize the form efficiently, such that is suitable and/or acceptable for usage, and to conserve, colour, add flavor to said formulation.
  • Colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide and xanthan gum can be selected as at least one inactive agent.
  • the tablet formulation that can be loaded with liquid can contain magnesium aluminometasilicate, crospovidone XL 10 and magnesium stearate talk.
  • SGcaps® Capsugel, Posilok®, Qualicaps, Licaps Qualicaps can be used in the hard gelatin capsule SMEDDS formulation.
  • the flavored and aromatized SMEDDS liquid formulation can comprise Kollidon® 25, Kollidon® 30, glycerol, sodium cyclamate, orange or raspberry aroma.
  • the pharmaceutical compositions can also comprise at least a superdisintegrant.
  • the pharmaceutical composition can comprise approximately 1% to approximately 25% of at least a super disintegrant by weight of the composition, it can contain, for example approximately 1% to approximately 20% or approximately 1% to approximately 15% super disintegrant by weight of the invention.
  • the compositions that comprise at least a super disintegrant can be in the form of a tablet.
  • croscarmellose a cross-linked cellulose
  • crospovidone a cross-linked polymer
  • sodium starch glycolate cross-linked starch
  • soy polysaccharides are available as super disintegrants.
  • Commercial examples are Kollidon® (BASF), Polyplasdone® XL (ISP) and Ac-Di-Sol (FMC BioPolimer).
  • the pharmaceutical composition can be in the form of syrup, tablet, a liquid loaded tablet or any other drug delivery form.
  • the pre-mix can be encapsulated within a hard or soft gelatin capsule.
  • the capsule filling content can be approximately between 0.400 g to 1.600 g.
  • compositions can be used for any kind of therapeutic treatment and/or program related to at least a health issue such as treatment of hypertension or cardiovascular diseases that result in heart attacks, heart or kidney failure, strokes and blindness. It is possible to treat hypertension with Olmesartan SMEDDS that provides economical advantage as it has increased patient tolerability, the celiac side effects are eliminated and it has increased bioavailability.
  • dose adjusted base SMEDDS can be prepared for children, geriatric patients and adults.
  • SMEDDS syrup formulations for children and geriatric patients by selecting suitable sweeteners and flavors and SMEDDS hard or soft gelatin capsules and liquid loaded tablets for adults can be developed.
  • OM-SMEDDS has been able to be fluorescently marked with Vivotag 680 XL and Xenolight DiR and the real time oral bioavailability of the drug has been determined.
  • OM-SMEDDS subject to our invention, that has been fluorescently marked with Vivotag and Xenolight has included the hydrophobic active agent into an oil phase and it has improved solubility and adsorption of the drug and increased its bioavailability and thereby a different distribution pattern has been observed in comparison to the control dye and it has been enabled for the drug to be monitored real-time in the body.
  • the optical imaging method enables to see the real-time biodistribution of the drug, the metabolism, elimination, and efficiency against the disease and the tumor in real time.
  • Imaging studies are generally techniques involving radiation, and this condition poses a health problem for both those exposed and those around them.
  • the optical imaging system with fluorescent marking allows imaging without radiation.
  • SMEDDS subject to our invention that is marked with Vivotag 680 XL and Xenolight DiR has ground breaking properties in determining oral bioavailability.
  • Our invention provides a solution as it can be prepared according to the physical-chemical properties of these types of problematic active agents.
  • the present invention may comprise any kind of active agent that allows drug targeting with bioavailability and biodistribution assay.
  • the real-time biological distribution of the self microemulsifying drug release system (SMEDDS) comprising an active agent that is marked (tagged) with fluorescent dyes can be determined by the real-time optical imaging method.
  • SMEDDS containing the fluorescently marked active ingredient will enable to determine increased bioavailability as it will exhibit stronger fluorescent emission in predetermined minutes, in vivo, in comparison to the control dye solution.
  • VivoTag® 680 N-hydroxysuccinimide(NHS)- ester
  • DMC18 (7) or l,l’-dioctadecyltetramethyl indotricarbocyanine iodine fluorescent dyes have been used.
  • the real time biodistribution of these drugs in the body can be monitored, the bioavailability rate can be measured, the organ location of the drug can be monitored, organ targeting can be performed with the drug, it could be checked if the blood brain barrier has been crossed and all of these parameters can be illustrated mathematically.
  • Our invention includes a method in which different SMEDDS and other lipid-based micro/nanoparticle formulations prepared specifically for the physicochemical properties of the active substances to be monitored in the body, can be marked with different NIRs and monitored in the body following oral application.
  • control dye solution marked with Vivotag 680 XL has been prepared and 150plcontrol dye solution has been applied per mouse.
  • This amount of solution comprises 0.45 mg VivoTag® 680 XL (3 mg/ml Vivitag 680 XL).
  • the solution is prepared with 270 m ⁇ stock dye, (dissolved in 5 mg VivoTag® 680 XL, 500 mg dimethylsulfoxide), 480 m ⁇ water and 150 m ⁇ buffer (50 mM NaHC03) as 900 m ⁇ by volume for 6 mice.
  • OM-SMEDDS solution marked Vivotag 680 XL is prepared with 270 m ⁇ stock dye, 480 m ⁇ OM-SMEDDS and 150 m ⁇ buffer (50 mM NaHCOs) as 900 m ⁇ by volume according to the same calculation.
  • 900 m ⁇ PBS (pH 7) is added to this mixture, it is vortexed and is centrifuged for 10 minutes at 15300 rpm. The washing stage is repeated twice. Every time, 900 m ⁇ supernatant is removed.
  • the OM-SMEDDS that is precipitated is transferred into another eppendorf with care with a micropipette. The remaining washed section is given with a 150m1 oral gavage to mice.
  • the control dye solution marked Xenolight DiR however comprises 0.3 mg Xenolight® DiR in 150m1 liquid to be given per mouse.
  • the solution is prepared as 900m1 for 6 mice (such that it comprises Xenolight® DiR 2 mg/ml per mouse) with 180m1 stock dye, (25 mg dye is dissolved in 2.5 ml ethanol) 720m1 PBS.
  • the OM-SMEDDS solution marked with Xenolight® DiR is prepared as 900m1 with 720m1 OM-SMEDDS and 180m1 stock dye according to the same calculation.
  • Vivotag 680 XL which is strongly bound to small molecules and proteins, and Xenolight® DiR fluorescent dyes with lipophilic properties were used to display the lipid characteristic of OM-SMEDDS (Table 2). The detailed labeling procedures of each dye have been described below.
  • OM-SMEDDS containing nano-sized droplets, is a novel technique developed for the first time to display low resolution class drug biodistribution, and it has given promising results.
  • Vivotag 680 XL marked OM-SMEDDS emits 4.2 times stronger in the body than the control dye group at the end of the 5th hour and this rate increased 24 times at the end of the 6th hour.
  • the real-time biodistribution of Xenolight DiR marked OM-SMEDDS has shown 2 times stronger emission in the body.
  • Ex vivo organ findings (heart, liver, lung, kidney, spleen, colon) were evaluated 7 hours after the application of VivoTag® 680 XL and Xenolight DiR-labeled OM-SMEDDS to confirm the in vivo imaging results of real-time biodistribution.
  • mice group that were administered OM-SMEDDS labeled with Vivotag® 680 XL and Xenolight® DiR have emitted 3.96 and 1.7 times stronger fluorescence respectively in comparison to mice that were administered with the control dye.
  • OM-SMEDDS showed strong localization in the stomach and intestines while the control dye was leaving the body at the same time points ( Figure 3, 4), (Table 3, 4).
  • Table 3 Comparison of the Ex vivo IVIS® emission findings in organs (liver, lung, stomach, colon and ileum) following the application of the control dye for 6 hours and the Vivotag 680 XL fluorescent marked SMEDDS.
  • the ROI signal intensity has been expressed as (photons / s / cm 2 / sr).
  • the SMEDDS formulation provided 3.96 times more emission in comparison to the control group and the findings have shown that the absorption in tissue and organs of the group that had taken SMEDDS was higher.
  • the developed OM-SMEDDS formulation has the advantage that it does not cause celiac side effects in comparison to OM suspension.
  • An aspect of the invention is that it provides an animal model for celiac disease to be established following the oral application of the olmesartan suspension in a test subject.
  • the model comprises the below mentioned steps:
  • the experimental model obtained with the present invention can be used for the diagnosis, treatment and follow-up of celiac disease, and the modeling process can be repeated and olmesartan in treatment doses, can be given for prolonged periods of time.
  • celiac disease other than the gluten diet today and it is important to try alternative treatment methods by creating an artificial animal model. Due to this reason, animal models that can be easily created are needed; therefore the usage of our model during drug analysis, to monitor the side effects of such drugs that cause these types of intestinal inflammation shall make it easier to compare the advantages of the formulations.
  • the OM suspension obtained by the addition of 1 mg / ml active agent and suspension thereof, to the 0.25% w/v CMC suspension (0.25g CMC per 100 ml) has been given to the rats by oral route at a dose of 1.3 mg/kg for 1 month.
  • OM-Suspension and OM-SMEDDS has been given to two different groups of rats 1 time a day by means of oral gavage, for 1 month, and in comparison to the control group that was not given any medication and the group given OM-SMEDDS, the rat intestinal images of the group that was given OM suspension showed intensive leucocyte infiltration, histologically.
  • the present invention comprises a rat animal model for establishing enteropathy similar to celiac with histological imaging following the oral application of the suspension to rats at a dose of 1.3 mg/kg for 1 month comprising 1 mg/ml OM and 0.25% w/v CMC (carboxymethylcellulose) to prove that the SMEDDS formulation comprising Olmesartan medoximil does not lead to celiac side effects.
  • a celiac disease model can be created in test animals by giving the suspension loaded with the pure drug that creates enteropathy similar to celiac for 1 month at the treatment dose.
  • This model simulates celiac disease and it can be beneficial to scientific studies as it can be used any number of times or scale, that can be repeated or that is sustainable in the diagnosis and treatment of celiac disease. It can also explain the mechanisms of action of other drugs that lead to gastrointestinal side effects. These models can serve civilization in the pharmaceutical sector and the celiac diagnosis and treatment field, by being widening the scope and by variations using different animal species and cell cultures.
  • the present invention provides an economic and practical model in the related experiments with the diagnosis and treatment of celiac disease by means of the “celiac rat model induced with olmesartan”.
  • the mechanisms of action of other drugs that cause intestinal inflammation can be investigated in detail by immunohistochemical, genetic, histological and ELISA-based antibody analysis.
  • the present invention is related to being used in both bioavailability and efficacy studies in the pharmaceutical sector and in Celiac research in clinic.
  • OM-SMEDDS shall prevent the side effects of olmesartan that has been approved by the FDA and included in the prospectus of the drug. It has been reported by FDA that Olmesartan had celiac alike side effects in the intestines following usage for 3-6 months in humans and that it caused diarrhea and weight loss and this information has been added into the prospectus of the drug. (FDA Safety Announcement 7-3-2013). In patients with this phenomenon, complaints of chronic diarrhea, vomiting, severe abdominal pain, bloating and weight loss intestinal enteropathy are observed and this phenomenon has been the subject of many lawsuits. The originating company (Daichii Sankyo) has spared a very high budget in order to pay the compensations of the lawsuits related to these side effects.
  • OM-SMEDDS can be presented for use as dosage forms that can be easily given in measured doses to children and elderly hypertensive patients by sweetening and aromatizing them, or as hard gelatin capsules or in tablet forms that can be loaded with liquid to adults as dosage forms that reduce the side effects of the drug. This is a solution to the problems caused by the tablet form available in the market.
  • OM-SMEDDS has increased its bioavailability by including hydrophobic OM active ingredient in the oil phase and improving the solubility and absorption of the drug as a solution to the solubility and bioavailability problem of olmesartan.
  • mice given OM-SMEDDS with fluorescent Xenolight® DiR dye label gave a stronger signal.
  • I, J Ex vivo IVIS® findings of the organs (liver, lung, stomach, colon and ileum) following the 7 hour application of Xenolight DiR.
  • K The OM-SMEDDS group organs (top) emitted higher emission in comparison to the control group (bottom).
  • FIG. 5 Images of histopathologic examinations carried out in rat duodenum following a 1 month treatment with Olmesartan SMEDDS or suspension. Enteropathic findings similar to celiac have not been observed in the instestinal images of the control group (Al, A2, A3) that have been given olmesartan SMEDDS (Cl, C2, C3) contrary to the rats that were given the suspension.
  • the biopsy of the duodenum did show enteropathic findings similar to celiac related to olmesartan in rats that were given the suspension (Bl, B2, B3).
  • the arrows show increased mononuclear cell infiltration. Scaling has been carried out as 20 pm in A2, 50 pm in A3, B3, C3, 100 pm in Al, B2, C2 and 500 pm in Bl, Cl.

Abstract

L'invention concerne des compositions thérapeutiques comprenant une formulation de SMEDDS (OM-SMEDDS) et une pré-formulation de SMEDDS comprenant de l'olmésartan médoximil. La pré-formulation de SMEDDS contient de l'acide oléique en tant que matière grasse, au moins un agent tensioactif et au moins un agent actif de surface inactive et de l'eau. De plus, l'invention concerne des applications de détermination de la biodisponibilité orale et de la biodistribution par marquage de la pré-formulation avec des colorants NIR. De plus, l'invention concerne l'établissement d'un modèle de test afin de mesurer l'effet secondaire de la maladie cœliaque suite à l'application orale de la suspension avec une dose de 1,3 mg/kg comprenant OM-SMEDDS comprenant 1 mg/ml de OM, la même dose de OM et de OM comprenant 25 % en p/v de CMC (carboxyméthylcellulose) pendant 1 mois à des rats hypertendus qui ont été artificiellement créés avec L-Name afin de mesurer l'effet pharmacodynamique du médicament. Les résultats ont montré que la formulation de SMEDDS s'est dissoute tout en empêchant les effets secondaires de la maladie cœliaque de OM sur l'exposition intestinale par réduction de ladite exposition et qu'elle présente une biodisponibilité améliorée. De plus, la biodistribution du SMEDDS marqué par fluorophore comprenant de l'olmésartan a été suivie dans le corps en étant surveillée optiquement en temps réel et un modèle animal cœliaque induit par olmésartan et une suspension d'olmésartan pur a pu être établi.
PCT/TR2020/050722 2019-08-27 2020-08-18 Systèmes d'administration de médicament auto-microémulsifiants (smedds) comprenant de l'olmésartan médoxomil WO2021040646A1 (fr)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ASHISH GAJERA: "Formulation development of olmesartan medoxomil solid self micro emulsifying drug delivery system", IJAR- INDIAN JOURNAL OF APPLIED RESEARCH, vol. 8, no. 10, October 2018 (2018-10-01), pages 1 - 5, XP055796493 *
KOMESLI YELDA, BURAK OZKAYA ALI, UGUR ERGUR BEKIR, KIRILMAZ LEVENT, KARASULU ERCUMENT: "Design and development of a self-microemulsifying drug delivery system of olmesartan medoxomil for enhanced bioavailability", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 45, no. 8, 3 August 2019 (2019-08-03), pages 1292 - 1305, XP055796482 *
PATHARKAR PALLAVI, TARKASE K N: "Development and evaluation of solid self-emulsifying drug delivery system of olmesartan medoxomil by using adsorption to solid carrier techniques", INT. J. DRUG RES. TECH. INTERNATIONAL JOURNAL OF DRUG RESEARCH AND TECHNOLOGY, vol. 6, no. 3, 2016, pages 209 - 227, XP055796489 *
PATNI, POOJA ET AL.: "Development and evaluation of self micro emulsifying drug delivery system of olmesartan medoxomil", INVENTI RAPID: PHARM TECH, 2014 *

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