WO1998008490A1 - Coprecipites solides augmentant la biodisponibilite de substances lipophiles - Google Patents

Coprecipites solides augmentant la biodisponibilite de substances lipophiles Download PDF

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Publication number
WO1998008490A1
WO1998008490A1 PCT/US1997/015072 US9715072W WO9808490A1 WO 1998008490 A1 WO1998008490 A1 WO 1998008490A1 US 9715072 W US9715072 W US 9715072W WO 9808490 A1 WO9808490 A1 WO 9808490A1
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composition
tpgs
coprecipitate
solid
lipophilic substance
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PCT/US1997/015072
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English (en)
Inventor
Shimon Amselem
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Pharmos Corporation
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Priority claimed from IL11917696A external-priority patent/IL119176A/en
Priority claimed from US08/833,076 external-priority patent/US5891469A/en
Application filed by Pharmos Corporation filed Critical Pharmos Corporation
Priority to JP51187998A priority Critical patent/JP2001523221A/ja
Priority to AU42373/97A priority patent/AU730216B2/en
Priority to CA002264718A priority patent/CA2264718C/fr
Priority to EP97940639A priority patent/EP1017366A4/fr
Publication of WO1998008490A1 publication Critical patent/WO1998008490A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • compositions comprising solid coprecipitates for improved oral delivery and enhanced bioavailability of lipophilic substances, and to methods for the preparation and use of these compositions. More particularly, these compositions include tocopherol polyethyleneglycol succinate powdered coprecipitates of lipophilic substances.
  • Lipophilic substances possessing low water solubility often have poor oral bioavailability. These substances, being hydrophobic by nature, show wetting difficulties and poor dissolution. These properties obviously represent a rate-limiting step in their absorption from solid oral dosage forms and, in turn, cause a subsequent reduction in their bioavailability.
  • these lipophilic substances are usually administered in the form of liquid preparations dissolved in edible oils or formulated in oil-in-water emulsions or microemulsions. Even in these formulations, however, the oral bioavailability of many of them is still very low. Thus, even today, there remains an unresolved need for safe and useful formulations that provide enhanced oral bioavailability for such substances.
  • Cannabinoids are one example of a family of lipophilic substances with very poor water solubility.
  • Cannabinoids such as ⁇ '-tetrahydrocannabinol ( ⁇ '-THC) ,
  • ⁇ 6 -tetrahydrocannabinol ⁇ 6 -THC
  • ⁇ 9 -tetrahydrocannabinol ⁇ 9 -THC
  • cannabinol cannabidiol
  • cannabidiol cannabidiol
  • THC tetrahydrocannabinol
  • Dexanabinol (also denoted HU-211) , is disclosed in US Patents 4,876,276 and 5,521,215, as a synthetic non- psychoactive cannabinoid with novel neuroprotective activity in the multiple-action treatment of brain damage associated with stroke, head trauma, and cardiac arrest.
  • Dexanabinol is a very lipophilic compound which is practically insoluble in water (less than 50 ⁇ g/ml) and, like other lipophilic drugs, exhibits poor oral bioavailability.
  • Coenzyme Q10 chemically named 2,3-dimethoxy-5-methyl-6- decaprenyl-l,4-benzoquinone and also known by the names Ubiquinone or Vitamin K, is classified as a fat-soluble quinone, a naturally occurring enzyme. It has been identified as an essential component of the mitochondrial respiratory chain, and, thus, a necessary part of a cell's energy production. More particularly, it constitutes a redox-link between flavoproteins and cytochromes and acts as an electron shuttle controlling the efficiency of oxidative phosphorylation. It is a very lipophilic compound and practically insoluble in water due to its long side chain of 10 isoprenoid units.
  • CoQIO has been previously identified as a natural antioxidant with potential use as a dietary supplement to protect against age-related degeneration and as an adjuvant vitamin to prevent or treat many disease states.
  • Supplementary Coenzyme Q10 has reportedly shown beneficial influences in a variety of conditions or diseases, including: periodontal disease, certain blood circulation diseases, impaired memory, fatigue, irregular heartbeat, high blood pressure, immune system impairment, and the aging process.
  • the recommended daily allowance for coenzyme Q10 has not been determined. Most experts agree, however, that the daily requirement lies somewhere between 30 and 60 milligrams. When treating illnesses, dosages of 100 to 300 milligrams are commonly used.
  • the oral bioavailability of CoQIO is related to the dissolution rate of the formulation (Kishi et al . , Metabolism of exogenous coenzyme Q10 in vivo and the bioavailability of coenzyme Q10 preparations in Japan, in: K. Folkers, and Y. Yamamura, eds., Biomedical and Clinical Aspects of Coenzyme Q10, Vol. 4, Elsevier, Amsterdam, 1984,pp. 131-142). Given CoQIO 1 s poor solubility in water, the ability to formulate this substance in a suitable form affording convenient and efficient oral bioavailability is a desired goal.
  • lipids in the form of emulsions, liposomes, icroparticles and nanoparticles
  • These known lipid formulations have comprised particles dispersed in an aqueous medium, and are suitable for various routes of administration, including primarily intravenous administration, as disclosed in: WO 95/05164, which discloses microparticles and nanoparticles in aqueous suspension; US Patent 4,824669, which discloses fatty emulsions; US Patent 4,636,381, which discloses liposomes; and US Patent 4,483,873, which discloses aqueous dispersions or solutions.
  • the neurohormone elatonin is synthesized in the pineal gland with a nocturnal circadian rhythm. Sleep disorders, seasonal depression, mood disorders, migraine, and jet lag are some of the disorders that have been correlated to a disruption of normal, physiological melatonin secretion. There are reports on the beneficial effect of exogenous melatonin administration to reestablish the synchronization of circadian rhythm. However, these studies have shown large variations in oral melatonin absorption, as well as highlighted the inconvenience of employing a continuous intravenous delivery system. Therefore, an oral formulation of melatonin with good bioavailability is needed.
  • a melatonin buccal mucoadhesive sustained release delivery patch mimicking endogenous secretion, has already been shown as one alternative means for delivering melatonin (Benes et al . , Proceed. Intl. Symp. Control. Rel. Bioact. Mater., 21:551-552, 1994).
  • Additional examples of lipophilic drugs with very poor water solubility and low oral bioavailability which could benefit from oral dosage forms are the peptide drug cyclosporin A, the antifungal agent araphotericin B, the anticancer drug etoposide, as well as tamoxifen and its analogs.
  • TPGS vitamin E derivative tocopherol polyethyleneglycol succinate
  • Oily compositions of anti-tumor drugs utilizing TPGS as a solubilizing adjuvant have also been disclosed for instance in US 4578391. Further uses of TPGS as a surface active substance (US 4,668,513), as a cryoprotectant (US 5,198,432) or to improve the bioavailability of vitamin E (US patents 5,179,122 and 5,223,268) have also been disclosed.
  • a powder formulation of water dispersible vitamin E compositions for use as a vitamin E supplement has also been disclosed in US
  • TPGS The structure of TPGS is shown in scheme 2.
  • compositions comprising tocopherol polyethyleneglycol succinate (TPGS) solid coprecipitates useful for the oral delivery of lipophilic substances with low oral bioavailability, and to methods for preparing and using such compositions.
  • TPGS tocopherol polyethyleneglycol succinate
  • the solid coprecipitate compositions of the present invention include a lipophilic substance in an amount sufficient to provide a therapeutic effect when administered to a mammal; tocopherol polyethyleneglycol succinate (TPGS) in an amount sufficient to increase the oral availability of the lipophilic substance; and a dispersion adjuvant in an amount sufficient to assist in dispersing the lipophilic substance in the succinate.
  • TPGS tocopherol polyethyleneglycol succinate
  • the solid TPGS coprecipitates of the present invention comprise a dispersion adjuvant selected from the group consisting of polyvinylpyrrolidone, a medium chain triglyceride, a long chain triglyceride, tocopherol acetate, and polyethyleneglycol.
  • the solid TPGS coprecipitates of the present invention comprise polyvinylpyrrolidone ("PVP") as the dispersion adjuvant.
  • the solid TPGS coprecipitates of the present invention may advantageously further comprise a known freeflow imparting agent, such as fumed silica or the like.
  • a known freeflow imparting agent such as fumed silica or the like.
  • Lipophilic substances incorporated in the powdered TPGS coprecipitates of the present invention have shown unexpectedly improved drug release in simulated gastric fluid in vitro and enhanced oral bioavailability in vivo.
  • the present invention further relates to methods for producing the powdered TPGS coprecipitate compositions, comprising: co-melting TPGS and the lipophilic substance at 40-60°C; adding a dispersion adjuvant to the melted mixture with agitation; adding a fumed silica to the mixture with agitation; and drying the resultant mixture at 100°C to get a dry coprecipitate.
  • the dispersion adjuvant used in accordance with this method may be added as an aqueous solution, an organic cosolvent solution, or an oil.
  • the solid TPGS coprecipitate compositions according to the present invention may be prepared by freeze-drying the TPGS/lipophilic substance/dispersing adjuvant mixture.
  • the solid TPGS coprecipitates compositions according to the present invention may be prepared by spray-drying the TPGS/ lipophilic substance/dispersing adjuvant mixture.
  • the TPGS/ lipophilic substance/dispersing adjuvant coprecipitate formulations can be spray dried or freeze-dried to obtain dry powdered compositions, suitable for the preparation of solid-dosage forms such as hard gelatin capsules or tablets.
  • these solid dosage TPGS coprecipitate compositions are advantageous for the oral delivery of Coenzyme Q10 as a dietary nutrient supplement, melatonin, dexanabinol, amphotericin B, cyclosporin A, etoposide, tamoxifen quaternary amine analogs, or for any appropriate lipophilic substance.
  • FIG. 1 shows the in vitro release patterns of Dexanabinol in simulated gastric fluid from powdered TPGS/PVP solid lipid coprecipitate compositions containing about 2.5 mg drug prepared as described in Example 1 (Table 1) and packed in hard gelatin capsules.
  • FIG. 2 shows the in vitro release patterns of Dexanabinol in simulated gastric fluid from powdered TPGS/PVP/Miglyol solid lipid coprecipitate compositions containing about 2.5 mg drug prepared as described in Example 1 (Table 2) and packed in hard gelatin capsules.
  • FIG. 4 shows the oral pharmacokinetics in rats of Dexanabinol formulated in a solid TPGS lipid coprecipitate (Formulation AY-91-155, Example 1, Table 2) at three different dosages.
  • FIG. 6 shows the in vitro release of CoQIO in simulated gastric fluid from commercial CoQIO gelatin capsules and from a powdered solid TPGS/PVP lipid coprecipitate formulation (ED-107-157, Example 5, Table 5) packed in gelatin capsule.
  • TPGS/PVP lipid coprecipitate formulation ED-107-157, Example 5, Table 5
  • This invention is directed to compositions comprising dry tocopherol polyethyleneglycol succinate solid coprecipitates useful for the oral delivery of lipophilic substances, and to methods for preparing and using such compositions.
  • More specific compounds include cannabinoids, as exemplified by dexanabinol, and vitamins, enzymes or coenzymes, as exemplified by CoQIO.
  • Preferred lipophilic substances are those which have a water solubility of ⁇ 200 ⁇ g/ml in water at room temperature (25°C) , and more preferably ⁇ 50 ⁇ g/ml. Depending on the inherent activity of the active ingredient its quantity has to be adjusted for each specific drug. One of ordinary skill in the art can determine the appropriate concentration by routine testing.
  • compositions according to the invention can contain, for example, as the active lipophilic ingredient: steroids or non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antihistamines, antineoplastics or im unosuppressives.
  • steroids or non-steroidal anti-inflammatory drugs, antibiotics, antifungals, antivirals, antihistamines, antineoplastics or im unosuppressives.
  • Specific examples would include substances such as clotrimazole, bifonazole, tetracycline, miconazole, triamcinolone, amphotericin, erythromycin hydrocortisone, iodoxuridine, diphenhydramine, minoxidil, lidocaine, tetracaine.
  • drugs are suitable: hypnotics, sedatives, anxiolytices, antidepressants, anticonvulsants, anti-inflammatory drugs, anti-fungals, prostanoids, prostanoid agonists, prostanoid antagonists, analgesics, hormones and vitamins.
  • the active ingredient may be for example Vitamin A, Vitamin E, a polyunsaturated fatty acid such as eicosapentanoic acid, retinoids, carotenes.
  • a wide variety of active ingredients including steroids such as estradiol, progestins, androgens and their antagonists are suitable for formulation according to the present invention.
  • compositions of the present invention are also useful for the enhanced oral availability of certain peptides or proteins such as the hydrophobic or lipophilic peptides exemplified by the immunosuppressive agent cyclosporin.
  • the present invention discloses a novel way to increase the oral bioavailability of any of these lipophilic substances. More particularly, the invention relates to solid coprecipitates comprising the lipophilic substance, a surfactant vehicle having a melting point close to human body temperature, and at least one dispersion agent/adjuvant.
  • TPGS alpha-tocopherol polyethylene glycol succinate
  • TPGS is a water soluble compound (to 20% w/v) and forms micellar solutions with a critical micelle concentration (CMC) of 0.4-0.6 mM/L (about 0.075%).
  • CMC critical micelle concentration
  • HLB hydrophilic-lipophilic balance
  • TPGS is safe for ingestion by humans as a dietary or nutritional supplement.
  • TPGS can be safely used as a surfactant and a bioenhancer for lipophilic substances of limited absorption in gastrointestinal region.
  • the antioxidative properties of TPGS improve the stability of TPGS containing formulations.
  • solid TPGS coprecipitate formulations self-emulsify when dispersed in a aqueous medium, like gastric fluid, forming very small drug mixed-micelles. Lipophilic substances loaded in TPGS solid coprecipitate formulations will be absorbed more easily by the gastrointestinal tract enhancing its oral bioavailability.
  • the solid TPGS coprecipitates of the present invention are composed of three essential ingredients: a lipophilic substance with low water solubility, tocopherol polyethyleneglycol succinate, and at least one dispersion adjuvant.
  • the solid TPGS coprecipitates of the present invention may advantageously further comprise a free-flowing imparting agent, such as fumed silica (Cab-O-Sil, Cabot Corp. , USA) .
  • a free-flowing imparting agent such as fumed silica (Cab-O-Sil, Cabot Corp. , USA) .
  • Lipophilic substances incorporated in the solid TPGS coprecipitates of the present invention have shown unexpectedly improved in vitro drug release in simulated gastric fluid and enhanced oral bioavailability.
  • the lipophilic substance content in the solid TPGS coprecipitates of the present invention may range from about 0.01-50% of the total solid weight of the composition, more preferably in the range of about 5-30% of the total solid weight of the composition, and still more preferably about 10-20% of the total solid weight of the composition.
  • the content of TPGS in the final coprecipitate formulations of the present invention is in the range of about 5-65% of the total solid weight of the composition, more preferably in the range of about 10-60% of the total solid weight of the composition, and still more preferably in the range of about 10-50% of the total solid weight of the composition.
  • the content of dispersion adjuvant in the final coprecipitate formulations of the present invention is in the range of about 5-75% of the total solid weight of the composition, more preferably in the range of about 10-40% of the total solid weight of the composition, and still more preferably in the range of about 10-30% of the total solid weight of the composition.
  • This dispersion adjuvant is included to facilitate the homogeneous dispersion of the lipophilic substance in the mixture.
  • the solid TPGS coprecipitates of the present invention comprise a dispersion adjuvant selected from the group consisting of polyvinylpyrrolidone (PVP) ; a medium chain triglyceride or MCT oil; a long chain triglyceride or LCT oil; tocopherol acetate; polyethyleneglycol; or other adjuvant substance that can improve the dissolution of the lipophilic substance into the mixture or to help the lipophilic substance disperse homogeneously in the TPGS.
  • PVP polyvinylpyrrolidone
  • dispersion adjuvants include: Povidone (ISP Technologies, USA) ; Kollidon 12 PF (BASF, Germany) ; Miglyol 812 (Hulls, Germany) ; LCT oil (Croda) ; and Carbowax 1450 (Union Carbide, USA) .
  • the solid TPGS coprecipitates of the present invention may further comprise any suitable nontoxic carrier or diluent powder known in the art to serve as a free-flow imparting agent.
  • suitable nontoxic carrier or diluent powder known in the art to serve as a free-flow imparting agent.
  • suitable nontoxic carrier or diluent powder known in the art to serve as a free-flow imparting agent.
  • Such additives are silicon dioxide, starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, and dicalcium phosphate.
  • the tablet or pill can be coated or otherwise compounded with pharmaceutically acceptable materials known in the art to provide a dosage form affording prolonged action or sustained release.
  • the solid TPGS coprecipitates may also be prepared in gelatin capsules.
  • solid TPGS coprecipitates are further mixed with fumed silica, such as CAB-O-SIL® (Cabot Corp., IL. , US), which is a powdery material with extremely small particle size and enormous surface area.
  • fumed silica such as CAB-O-SIL® (Cabot Corp., IL. , US), which is a powdery material with extremely small particle size and enormous surface area.
  • Fumed silica can act as a dry lubricant, promoting the free flow of the powdery mixture and preventing the mixture from caking or lumping.
  • the free-flow, anti-caking and anti-clogging characteristics which are imparted to powders, granules and pellets by the addition of small amounts of fumed silica are the result of several actions.
  • the submicroscopic size of the silica aggregates permits them to move easily between the larger particles of the other dry ingredients, and in most cases fumed silica probably forms a coating on the powder particles.
  • the fumed silica layer also decreases bulk tensile strength and shear strength, while neutralizing the electrostatic charge on the particles.
  • fumed silica After blending with the other powders, fumed silica adsorbs some or all the moisture which may be present in or on the product particles.
  • the fumed silica aggregates prevent other particles from contacting each other to form the nuclei that would otherwise lead to the formation of larger lumps and cakes.
  • This spacing and lubricating action helps to keep materials moving through the apertures of process equipment valves, spray heads, storage bin openings, bag and drum spouts, and aerosol nozzle orifices.
  • Most powdered materials can be kept free flowing by adding a concentration of fumed silica in the final product range of about 0.5-25% (total solid weight). The optimum concentration can be determined by working up or down in small steps.
  • the more preferred weight percent of fumed silica in the final product will be in the range of about 1-20% (total solid weight) . Even powders which have already become caked can usually be rendered free flowing by blending them with fumed silica (about 2% of the total solid weight, or less) .
  • Products which cannot be processed beyond a sticky or tacky powder can be made free flowing by adding the proper level of fumed silica as a final finishing step. Fumed silica can also be used to promote free flow in spray-dried or freeze-dried products.
  • the preparation of solid TPGS powdered coprecipitates of lipophilic substances of the present invention may be prepared by different methods as described in the following non-limiting examples.
  • xample l Preparation of tocopherol polyethyleneglycol succinate/polyvinylpyrrolidone powdered coprecipitates of Dexanabinol by freeze-drying.
  • This example illustrates the preparation of tocopherol polyethyleneglycol succinate/polyvinylpyrrolidone (TPGS/PVP) powdered coprecipitates of Dexanabinol by freeze-drying.
  • the final weight/weight % composition of the different formulations prepared were as described in Table 1.
  • TPGS Eastman-Kodak Co., USA
  • PVP Kerdon PF 12, BASF, Germany
  • Dexanabinol was added to the melted materials and the mixtures were gently agitated for several minutes.
  • Cab-O-Sil Cab-O-Sil (Cabot CORP., USA, added from a 5% solution in water) was added and the mixtures were agitated again for several minutes.
  • TPGS/PVP/dexanabinol coprecipitates were formed. The coprecipitates were freeze-dried overnight using a Christ beta lyophilize (Germany) .
  • Powdered free-flowing coprecipitates quickly dispersible in water were obtained.
  • TPGS/PVP/dexanabinol coprecipitates containing additionally tocopherol acetate and Miglyol 812 as described in Table 2 were also prepared by freeze-drying using the same method, which resulted in the formation of powdered free-flowing coprecipitates quickly dispersible in water.
  • the obtained powdered coprecipitates were filled in hard gelatin capsules (No. 1) for in vitro release experiments in simulated gastric fluids and for oral bioavailability studies in rats (minicapsules, Torpac, NJ, USA) .
  • Example 2 Preparation of TPGS/PVP powdered coprecipitates of Dexanabinol by spray-drying
  • This example illustrates the preparation of a TPGS/PVP powdered coprecipitate of Dexanabinol by spray-drying.
  • the final weight/weight % composition of the formulation prepared is described in Table 3:
  • TPGS (249 mg) was melted in a water bath at 50° C.
  • Dexanabinol (249 mg) were then added to the melted TPGS and the mixture was shaken for several minutes at 50° C.
  • PVP (2.2 ml of a 10% solution in water) was added to the comelted mixture of TPGS/Dexanabinol TPGS and the mixture was shaken again for several minutes.
  • Cab-O-Sil 2.3 ml of a 5% solution in water was added and the formulation was shaken again for 1 hr at 50° C.
  • the resultant formulation was spray-dried using a Yamato Pulvis GA32 Mini spray-dryer.
  • the drying conditions were: flow rate 7 ml/min, inlet temperature 130 C°, outlet temperature 80° C, and drying air flow 0.45 m 3 /min.
  • a homogeneous and quickly water-dispersible dry powder of the TPGS/PVP/Dexanabinol coprecipitate was obtained.
  • Example 3 In vitro release of Dexanabinol from solid lipid TPGS coprecipitates in simulated gastric fluid.
  • Dexanabinol was determined by HPLC using a Kontron instrument equipped with pump, UV detector, and autosampler. A summary of the typical chromatographic conditions of the method is provided below:
  • Example 4 Enhanced oral bioavailability of Dexanabinol in solid TPGS coprecipitate formulations.
  • the solid TPGS powdered coprecipitates were filled in hard gelatin minicapsules (Torpac, NJ, USA) and tested for their oral bioavailability in rats.
  • Blood samples were collected at 0,0.5, 1.0, 2.0, 3.0, 5.0, 8.0, and 24 hour time intervals.
  • Plasma samples were centrifuged at 10,000 rpm for 5 min and the plasma was separated and stored frozen at -20° C until plasma Dexanabinol levels were analyzed. Determination of Dexanabinol in the plasma was performed by HPLC. The chromatographic conditions were as described in Example 3. Plasma samples stored at -20° C were defrosted and diluted 1:4 as follows: 150 ⁇ l plasma sample was transferred into a 1.8 ml Eppendorf tube and 150 ⁇ l of acetonitrile were added. The sample was vortexed and centrifuged in a microfuge for 10 minutes at 10,000 rpm. The upper clear liquid was then transferred into an HPLC glass conical vial. A calibration curve was used for calculating Dexanabinol plasma levels. Corrections of sample peak areas were done by subtracting the of average value of the peak area obtained for samples at zero time (blank plasma) .
  • a two fold increase in Dexanabinol plasma levels was obtained with the coprecipitate formulation compared to the oil solution, demonstrating enhanced oral absorption of Dexanabinol from the solid TPGS coprecipitate formulation.
  • This data indicates the good water dispersibility of the formulation, which, in turn, probably facilitates the uptake of the drug from the gastrointestinal tract.
  • Figure 3 shows the rat oral pharmacokinetics of Dexanabinol from TPGS solid lipid coprecipitate formulation (Formulation AY-91-155 prepared as described in Example 1, Table 2) at three different doses. A maximal drug concentration (C ⁇ x ) was obtained after 5 hours (t ⁇ ) for all three doses tested, 10, 25, and 50 mg/kg.
  • Figure 4 illustrates the oral pharmacokinetics of
  • the figure shows increased plasma levels of the drug and demonstrating the improved delivery and oral bioavailability of Dexanabinol.
  • Example 5 Preparation of solid TPGS lipid coprecipitates of Ubiquinone (coenzyme Q10) .
  • Ubiquinone (Coenzyme Q10) was obtained from Global Marketing Associates, Inc. (San Francisco, CA) .
  • the polyethyleneglycol used was Carbowax PEG 1450 from Union Carbide (CT, USA) .
  • the MCT oil (medium chain triglycerides) used was Miglyol 812 (Hulls, Germany) .
  • LCT oil (long chain triglycerides) was from Croda.
  • TPGS/CoQIO coprecipitates were prepared by heating together all the components at 50°-60° C with consequent cooling to room temperature.
  • Compositions containing polyvinylpyrrolidone (PVP K-12) were prepared using 50% PVP solutions in absolute ethanol and drying the obtained mixture at 40°-45° C for 4-6 hours. The obtained TPGS/CoQIO coprecipitates showed quick water dispersibility with rapid release of the CoQIO.
  • Example 6 Preparation of TPGS/PVP powdered coprecipitates of Ubiquinone (coenzyme Q10) by freeze-drying.
  • TPGS Eastman-Kodak Co. , USA
  • Coenzyme Q10 was added to the melted TPGS and the mixtures were gently agitated for several minutes.
  • PVP Kerdon PF 12, BASF, Germany
  • Cab-O-Sil Cab-O-Sil (Cabot CORP., USA, added from a 5% solution in water) was added and the mixtures were agitated again for several minutes. After cooling to room temperature TPGS/PVP/CoQIO coprecipitates were formed.
  • coprecipitates were freeze-dried overnight using a Christ beta lyophilizer (Germany) . Powdered free-flowing coprecipitates quickly dispersible in water were obtained. They were packed in hard gelatin capsules for in vitro release studies.
  • Example 7 In vitro Release of Coenzyme Q10 from powdered TPGS/PVP coprecipitates in simulated gastric fluid.
  • Figure 5 shows the in vitro release patterns of CoQIO from a powdered TPGS/PVP coprecipitate formulation compared to a commercial product ENERGYCO® CoQIO (Herbamed-Assutech Ltd., Rehovot, Israel) in simulated gastric fluid.
  • CoQIO was determined in the commercial product, the powdered TPGS/PVP coprecipitate formulation, and in the release medium in vitro by extraction with Dole reagent (isopropanol:heptane:water, 45:36:17) by measuring the absorbance at 270 nm using a calibration curve.
  • Dole reagent isopropanol:heptane:water, 45:36:17
  • CoQIO was extracted selectively in Dole heptane upper phase, which was transferred to a quartz cuvette for absorbance measurement.
  • the % release of CoQIO from the marketed product was very low compared to a very quick and significant release from the powdered TPGS/PVP coprecipitate formulation.
  • Each ENERGYCO® CoQIO hard gelatin capsule contains 50 mg of CoQIO mixed with rice powder. After capsule disruption in the simulated gastric fluid, big aggregates or clusters of CoQIO and swelled rice powder were observed. These observations may explain the low CoQIO dissolution into the release medium.
  • Example 8 Preparation of TPGS/PVP powdered coprecipitate of Melatonin.
  • TPGS 500 mg was melted at 40°-60° C in a water bath.
  • Melatonin 100 mg, from Jansenn Chimica, Belgium
  • PVP Kinollidon PF 12, 2.6 ml of a 10% solution in water
  • Cab-O-Sil 2.8 ml of a 5% solution in water
  • TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) .
  • a powdered free-flowing TPGS/PVP/melatonin coprecipitate quickly dispersible in water was obtained.
  • Example 9 Preparation of TPGS/PVP powdered coprecipitate of Amphotericin B.
  • TPGS 500 mg was melted at 40°-60° C in a water bath.
  • Amphotericin B 100 mg, from Dumex, Denmark was added to the melted material and the mixture was agitated for several minutes.
  • a small amount of absolute ethanol up to 5%, v/v was added in order to get an homogeneous mixture.
  • TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) .
  • a powdered free-flowing TPGS/PVP/Amphotericin B coprecipitate quickly dispersible in water was obtained.
  • Example 10 Preparation of TPGS/PVP powdered coprecipitate of Tamoxifen methyliodide.
  • TPGS 500 mg was melted at 40°-60° C in a water bath.
  • Tamoxifen methiodide 100 mg, from Phar os Corp., FL, USA
  • PVP Kinollidon PF 12, 2.6 ml of a 10% solution in water
  • Cab-O-Sil 2.8 ml of a 5% solution in water
  • TPGS/PVP/Tamoxifen methiodide mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) .
  • a powdered free-flowing TPGS/PVP/melatonin coprecipitate quickly dispersible in water was obtained.
  • Example 11 Preparation of TPGS/PVP powdered coprecipitate of Etoposide.
  • TPGS 500 mg was melted at 40°-60° C in a water bath.
  • Etoposide 100 mg, from Sigma, St. Louis, USA was added to the melted material and the mixture was agitated for several minutes.
  • a small amount of absolute ethanol up to 5%, v/v was added in order to get an homogeneous mixture.
  • TPGS/PVP/melatonin mixture was then freeze-dried overnight using a Christ beta lyophilizer (Germany) . A powdered free-flowing TPGS/PVP/Etoposide coprecipitate quickly dispersible in water was obtained.
  • Example 12 Preparation of TPGS/PVP powdered coprecipitate of Clycosporin A by freeze-drying.
  • This example illustrates the preparation of tocopheryl polyethylenegylcol succinate powered coprecipitate of the peptide drug cyclosporin A, a very lipophilic undecapeptide with very low water solubility and poor oral bioavailability, by freeze-drying.
  • the final weight/weight % composition of the formulations prepared was as described in Table 6:
  • Table 6 Weight/weight % composition of TPGS/PVP/Cyclosporin A coprecipitate formulation prepared by freeze-drying.
  • lipid components and cyclosporin were dissolved in ethanol.
  • Cab-O-sil was added from a 5% water dispersion to the ethanolic solution (at a final ethanol:water v/v ratio of 1:1) and the mixture was shaken at 40°C for several minutes. The mixture was then frozen at -30°C for several hours and lyophilized overnight using a Christ lyophilizer (Germany) . Homogeneous dry quick-dispersible power containing the cyclosporin-lipid mixture was obtained.

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Abstract

On fait fondre des principes actifs lipophiles avec du succinate de tocophérol polyéthylèneglycol (TPGS) et un adjuvant de dispersion, de façon à obtenir des compositions de coprécipités secs solides convenant comme forme galénique orale. Les coprécipités de TPGS solides de principes actifs lipophiles permettent une meilleure libération des médicaments in vitro et présentent une meilleure biodisponibilité orale in vivo.
PCT/US1997/015072 1996-09-01 1997-08-27 Coprecipites solides augmentant la biodisponibilite de substances lipophiles WO1998008490A1 (fr)

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JP51187998A JP2001523221A (ja) 1996-09-01 1997-08-27 親油性物質の促進された生物学的利用能のための固形共沈物
AU42373/97A AU730216B2 (en) 1996-09-01 1997-08-27 Solid coprecipitates for enhanced bioavailability of lipophilic substances
CA002264718A CA2264718C (fr) 1996-09-01 1997-08-27 Coprecipites solides augmentant la biodisponibilite de substances lipophiles
EP97940639A EP1017366A4 (fr) 1996-09-01 1997-08-27 Coprecipites solides augmentant la biodisponibilite de substances lipophiles

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IL11917696A IL119176A (en) 1996-09-01 1996-09-01 Soluble coprecipitates for enhanced oral bioavailability of lipophilic substances
IL119176 1996-09-01
US08/833,076 US5891469A (en) 1997-04-02 1997-04-02 Solid Coprecipitates for enhanced bioavailability of lipophilic substances
US08/833,076 1997-04-02

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WO1999047175A1 (fr) * 1998-03-13 1999-09-23 Recordati S.A. Chemical And Pharmaceutical Company Compositions pharmaceutiques contenant des complexes d'inclusion de melatonine
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US8012494B2 (en) 1999-09-13 2011-09-06 Hoffmann-La Roche Inc. Pharmaceutical compositions containing lipase inhibitors
WO2001039836A1 (fr) * 1999-12-01 2001-06-07 Natco Pharma Limited Composition pharmaceutique lyophilisee a action rapide s'administrant par voie orale utilisee pour traiter la migraine
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WO2002062392A2 (fr) * 2001-02-02 2002-08-15 National Research Council Of Canada Compositions solubles dans l'eau de composes lipophiles bioactifs
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WO2006047067A1 (fr) * 2004-10-22 2006-05-04 Eastman Chemical Company Comprimes comprenant un agent actif faiblement compressible et succinate de tocopherol polyethyleneglycol (tpgs)
WO2008007728A1 (fr) * 2006-07-13 2008-01-17 Kaneka Corporation Préparation orale contenue dans une structure à membrane lipidique, et agent contre la fatigue comprenant une coenzyme comme ingrédient actif
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WO2014009926A1 (fr) 2012-07-12 2014-01-16 Laboratori Guidotti S.P.A. Compositions liquides orales pédiatriques contenant du nepadutant
US9351517B2 (en) 2013-03-15 2016-05-31 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and compositions containing same
US9693574B2 (en) 2013-08-08 2017-07-04 Virun, Inc. Compositions containing water-soluble derivatives of vitamin E mixtures and modified food starch
WO2015071837A1 (fr) * 2013-11-12 2015-05-21 Druggability Technologies Holdings Limited Complexes de cyclosporine a et ses dérivés, leur procédé de préparation et compositions pharmaceutiques contenant ceux-ci
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WO2015193673A1 (fr) * 2014-06-18 2015-12-23 Perioc Limited Nouvelles formulations pharmaceutiques et leur utilisation dans le traitement d'une maladie parodontale
US10285971B2 (en) 2014-09-18 2019-05-14 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
US10016363B2 (en) 2014-09-18 2018-07-10 Virun, Inc. Pre-spray emulsions and powders containing non-polar compounds
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US11246852B2 (en) 2016-12-02 2022-02-15 Receptor Holdings, Inc. Fast-acting plant-based medicinal compounds and nutritional supplements
CN108245683A (zh) * 2018-01-26 2018-07-06 华中科技大学 一种具有p-糖蛋白抑制功能的抗肿瘤前药及制备方法
CN108245683B (zh) * 2018-01-26 2020-02-14 华中科技大学 一种具有p-糖蛋白抑制功能的抗肿瘤前药及制备方法
CN114845702A (zh) * 2019-12-20 2022-08-02 英特维特国际股份有限公司 一种吡唑药物组合物
WO2021123949A1 (fr) * 2019-12-20 2021-06-24 Idorsia Pharmaceuticals Ltd Compositions pharmaceutiques comprenant du n-[1-(5-cyano-pyridin-2-ylméthyl)-1h-pyrazol-3-yl]-2-[4-(1-trifluorométhyl-cyclopropyl)-phényl]-acétamide
CN115103668A (zh) * 2019-12-20 2022-09-23 爱杜西亚药品有限公司 包含n-[1-(5-氰基-吡啶-2-基甲基)-1h-吡唑-3-基]-2-[4-(1-三氟甲基-环丙基)-苯基]-乙酰胺的药物组合物
WO2021123108A1 (fr) * 2019-12-20 2021-06-24 Intervet International B.V. Composition pharmaceutique de pyrazole
EP4282475A3 (fr) * 2019-12-20 2024-02-28 Intervet International B.V. Composition pharmaceutique à base de pyrazole
CN114845702B (zh) * 2019-12-20 2024-03-15 英特维特国际股份有限公司 一种吡唑药物组合物
IT202200002528A1 (it) * 2022-02-11 2023-08-11 Pierpaoli Exelyas S R L Composizione comprendente melatonina ad alta biodisponibilità
WO2023152672A1 (fr) * 2022-02-11 2023-08-17 Pierpaoli Exelyas S.R.L. Composition comprenant de la mélatonine à biodisponibilité élevée

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AU730216B2 (en) 2001-03-01
AU4237397A (en) 1998-03-19
EP1017366A1 (fr) 2000-07-12
CA2264718A1 (fr) 1998-03-05
EP1017366A4 (fr) 2006-03-22
CA2264718C (fr) 2006-05-30
JP2001523221A (ja) 2001-11-20

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