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WO2001087355A1 - Medicament lipophile - Google Patents

Medicament lipophile Download PDF

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Publication number
WO2001087355A1
WO2001087355A1 PCT/AU2001/000571 AU0100571W WO0187355A1 WO 2001087355 A1 WO2001087355 A1 WO 2001087355A1 AU 0100571 W AU0100571 W AU 0100571W WO 0187355 A1 WO0187355 A1 WO 0187355A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
lipophilic compound
coq
release
minutes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2001/000571
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English (en)
Inventor
William Neil Charman
Susan Ann Charman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AUSTRALIAN RURAL GROUP Ltd
Original Assignee
AUSTRALIAN RURAL GROUP Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AUSTRALIAN RURAL GROUP Ltd filed Critical AUSTRALIAN RURAL GROUP Ltd
Priority to AU2001258044A priority Critical patent/AU2001258044A1/en
Publication of WO2001087355A1 publication Critical patent/WO2001087355A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • FIELD OF THE INVENTION relates to lipophilic compounds and their bioavailability upon oral administration to humans and other animals.
  • the invention relates to novel formulations of lipophilic compounds such as Coenzyme Q 10 that have improved bioavailability upon administration.
  • This invention also relates to methods of preparation and administration of lipophilic compounds such as Coenzyme Q 10 .
  • Lipid-based formulations in particular, self-emulsifying drug delivery systems (SEEDS) and self micro-emulsifying drug delivery systems (SMEDDS) which utilise isotropic mixtures of triglyceride oils, non-ionic surfactants and drugs, have been shown to overcome some of these barriers resulting in improved absorption characteristics and more reproducible plasma profiles (Constantinids, P.P., 1995. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res. 12: 1561-1572).
  • SEEDS self-emulsifying drug delivery systems
  • SMEDDS self micro-emulsifying drug delivery systems
  • SEDDS and SMEDDS can be filled into either soft or hard gelatine capsules, allowing rapid emulsification following release of the capsule contents and exposure to gentle agitation in an aqueous media.
  • the fine oil droplets ( ⁇ 5 ⁇ in diameter) empty rapidly from the stomach and promote wide distribution of the lipophilic drug throughout the gastrointestinal tract. This fine droplet distribution presents a high surface area for the drug to partition into the intestine and thereby be available for absorption.
  • SEDDS and SMEDDS formulations are most advantageous when used with drugs which are sufficiently lipid soluble to obtain the necessary drug load within the lipid-based formulation. It is critical that the total drug load in the capsule formulation be in solution prior to release of the formulation. It is critical that the total drug load in the capsule formulation be in solution prior to release of the formulation contents from the capsule in order for the compound to be incorporated in the oil phase of the resulting emulsion.
  • Coenzyme Q 10 (also known as ubiquinone) is an essential lipophilic compound required for many bodily functions by both humans and animals. In particular, it is a component of the mitochondrial respiratory chain, where it acts as an electron carrier. CoQ 10 also functions as a lipid soluble antioxidant in its reduced form. It has been suggested that supplementary CoQ 10 may also protect against LDL oxidation and reduce free radical damage in certain patients.
  • CoQ 10 is a highly lipophilic (calculated log P ⁇ 20), poorly water soluble (aqueous solubility ⁇ 0.1 ⁇ g/ml) compound that is subject to poor and variable absorption properties following oral administration. As stated above, this significantly limits its clinical utility (Weis, M., Mortensen, S.A., Rassing, M.R., Moller-Sonnergaard, J., Poulsen, G. and Rasmussen, S.N., 1994. Bioavability of four oral Coenzyme Q 10 formulations in healthy volunteers. Molec. Aspects Med. 15 (supplement): 273-280; 1994; Chopra, R.K., Goldman, R., Sinatra, ST.
  • Congestive heart failure is a condition characterised by exertional fatigue, increasing breathlessness and oedema, as a result of poor left venticular function.
  • Current therapeutic treatment options aim to improve left venticular function, quality of life, survival and correct any underlying neuroendocrine abnormality. These treatment aims are commonly met with angiotensin-converting enzyme (ACE) inhibitors, diuretics, vasodilators and in some cases inotropic agents, however even with early diagnosis, prognosis remains poor.
  • ACE angiotensin-converting enzyme
  • After oral treatment with CoQ 10 heart failure patients demonstrate improved stroke volume, pulmonary capillary wedge pressure, and pulmonary artery pressure indicating an improvement in left ventricular performance, thereby demonstrating the potential value of CoQ 10 in congestive heart failure.
  • the treatment of patients with CoQ 10 has been limited by the poor and variable bioavailability with currently available CoQ 10 formulations.
  • vitamin A Rosarz, K.B., Cox, J.M., Sharma, S., Clement, L., Humphrey, J., Gleason, C, Abbey, H., Sehnert, S.S., Risby, T.H. Possible antioxidant effect of vitamin A supplementation in premature infants. Journal of Pediatric Gastroenterology & Nutrition. 1997; 25(4):408-14
  • vitamin E Dimitrov, N.V., Meyer-Leece, C, McMillan, J., Gilliland, D., Perloff, M., Malone, W. Plasma ⁇ -tocopherol concentrations after supplementation with water-soluble and fat-soluble vitamin . Am. J. Clin. Nutr. 1996;64:329-35).
  • lipophilic compounds including CoQ 10 have a very high temperature dependent solubility in various lipid-based formulations limiting the quantity of material which can be solubilised in such formulations.
  • By delaying the release of a formulation containing such lipophilic compounds after ingestion of the medicament by humans and other animals will enable re-dissolution of any precipitated drug and increased and/or less variable bioavailability.
  • the invention provides a pharmaceutical formulation comprising a lipophilic compound and a pharmaceutically- acceptable carrier or excipient encased so as to delay release of said lipophilic compound for at least about 10 minutes after administration to an animal.
  • release of the lipophilic compound is delayed for no longer than about 1 hour.
  • release of the lipophilic compound is delayed for approximately 30 minutes.
  • the lipophilic compound is selected from the group consisting of Coenzyme Q 10 (CoQ 10 ), vitamin A, vitamin E, vitamin K and derivatives of these.
  • the lipophilic compound is CoQ 10 .
  • the pharmaceutical formulation comprises between about 10 mg and 100 mg of CoQ 10 .
  • the lipophilic compound is encased in a capsule.
  • the lipophilic compound is encased in a coating.
  • the lipophilic compound is encased in a capsule which has an additional coating.
  • the coating is a water soluble polymer.
  • the coating may be a cellulose ether, polyvinylpyrrolidone or polyethylene glycol.
  • the coating is a pH sensitive polymer.
  • the thickness of the coating is preferably less than 2mm.
  • the thickness of the coating and the material selected for the coating will vary depending upon the delay desired. Such delay will vary depending on a number of factors including the characteristics of the lipophilic compound.
  • the pharmaceutically-acceptable carrier or excipient is Soybean: Maisine 35-1 (1 :1 ), ethanol 65%, Cremopher El (Cr) at 30% or 35%.
  • the invention provides a method of preparing a pharmaceutical formulation, said method including the step of encasing a lipophilic compound and a pharmaceutically-acceptable carrier or excipient so as to delay release of said lipophilic compound for between about 10 minutes and 1 hour after administration to an animal.
  • the invention provides a method of administering a pharmaceutical formulation comprising a lipophilic compound to an animal, said method including the step of preventing release of said lipophilic compound for between about 10 minutes and 1 hour after administration to said animal.
  • the pharmaceutical formulation is orally administered.
  • the animal is a human.
  • An example of a disease condition that may be treated or prevented by the present invention is congestive heart failure, wherein the lipophilic compound is preferably CoQ 10 .
  • FIG. 1 Representative structure of Coenzyme Q 10 .
  • FIG. 2 Results of experiments where CoQ 10 solubility (mg/g lipid) is plotted versus the mole fraction of Captex 355 (CPX) in Capmul MCM (CPM). The solubilities were determined at 15°C, 25°C, 30°C and 37°C. DETAILED DESCRIPTION OF THE INVENTION
  • CoQ 10 has been shown to be highly soluble in various lipid- based formulations, some of which are suitable for preparation of SEDDS and SMEDDS, however the solubility in these formulations exhibits a very steep temperature dependence over the temperature range typically encountered in capsule shipping and storage. This extreme temperature dependence of solubility is related to the flexible structure of CoQ 10 which results in a high entropy of solution. Importantly, this characteristic limits the potential advantages of lipid based formulations for CoQ 10 as marked crystallisation of the drug occurs with decreasing storage temperature (i.e. temperatures in the range of 15°C to 25°C). The same would be true for other lipophilic drugs that shown similar high temperature-dependent solubility.
  • CoQ 10 formulations containing different excipients afford no advantage in overcoming the temperature dependence of their solubility.
  • the crystals that precipitate during storage have been shown to re- dissolve within the lipid formulations rapidly once the temperature increases to approximately 30°C-37°C.
  • lipophilic compound refers to lipophilic compounds exhibiting high temperature dependant solubility over the temperature range of approximately 4°C to 37°C.
  • lipophilic compounds include CoQ 10 , vitamin A and its derivatives, vitamin E and its derivatives and vitamin K and its derivatives.
  • lipophilic compounds that exhibit a high entropy of solution in lipid-based formulations.
  • lipid-based formulation for the formulation of a lipophilic compound into a suitable lipid-based system, the filling of the formulation into either a hard or a soft gelatine capsule and the coating of the capsule with a polymer to retard the release of the capsule contents for between about 10 minutes and 1 hour has been found to overcome the problems associated with the temperature dependent solubility of such lipophilic compounds.
  • Preparation of a lipid-based formulation in this manner will ensure a delay between capsule ingestion and rupture thereby exposing the capsule contents to physiological temperature (37°C) for a predetermined time period prior to actual release of the capsule contents. This delay in capsule rupture ensure that any precipitated or crystallised drug present in the capsule as a result of storage has sufficient time to re- dissolve in the formulation in order to provide the maximum benefit (i.e. bioavailability) of the lipid-based formulation after administration.
  • the release of the formulation containing the lipophilic compound and therefore capsule rupture should be delayed for at least about 10 minutes.
  • the delay required will depend on a number of factors including the lipophilic substance, the lipid-based solvent, the temperature at which the medicament has been stored, and the recipient of the medicament including what that person has eaten recently.
  • a delay of 30 minutes will generally ensure maximum re-dissolution of the lipophilic compounds.
  • a delay of even about 10 minutes will be sufficient to increase bioavailability and decrease variability in bioavailability.
  • the capsule can generally be coated with any substance which ensures delayed capsule rupture by at least about 10 minutes from the time the capsule is ingested.
  • delays of more than 1 hour are not desirable as it is necessary for the capsule to rupture in the stomach or the proximal small intestine to maximise the efficacy of the pharmaceutical formulation of the invention.
  • many types of enteric coatings can be used with this invention. Enteric coatings ensure that the capsule does not rupture until it reaches the upper small intestine where the conditions are more alkaline tan in the stomach. This will generally ensure a delay of at least about 10 minutes. Enteric coatings which cause a delay of more than 1 hour or result in capsule rupture after the distal small intestine are less preferred for use with this invention.
  • Suitable coatings for the capsule include: (i) water soluble polymers such as the cellulose ethers (e.g. methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose), polyvinylpyrrolidone and polyethylene glycols applied at an appropriate thickness to delay capsule rupture for between 10 and 60 minutes following exposure to an aqueous media at 37°C with gentle agitation (testing using a standard dissolution apparatus); and
  • water soluble polymers such as the cellulose ethers (e.g. methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose), polyvinylpyrrolidone and polyethylene glycols applied at an appropriate thickness to delay capsule rupture for between 10 and 60 minutes following exposure to an aqueous media at 37°C with gentle agitation (testing using a standard dissolution apparatus); and
  • lipid-based pharmaceutically-acceptable carriers or excipients are known by those skilled in the art. Examples are Soybean: Maisine 35-1 (1 :1), ethanol 5%, Cremophor El (Cr) at either
  • the desired delay before capsule rupture will vary depending on the particular lipophilic compound being administered, and the delay required to ensure re-dissolution, the carrier or excipient, storage temperature, the nature of the disease or condition and the individual being treated. Factors such as the time since last eating can also be important.
  • the glycerides Captex 355 and Capmul MCM (Abitec Corporation, Janesville, Wl), soybean oil BP (Croda Chemicals, UK), Maisine 35-1 (Gattefosse s.a., Saint-Priest, France), peanut oil and linoleic acid (Sigma), and oleic acid (Ajax Chemicals, Australia) were used as supplied.
  • a gradient HPLC assay was utilised to analyse CoQ 10 .
  • the 0 assays were performed using a Waters Alliance 3690 Separation Module
  • the flow rate was kept constant at 1.2 mL/min and the injection volume was 20 ⁇ L.
  • DSC Differential Scanning calorimetry
  • DSC Differential scanning calorimetry
  • the lipidic formulations were prepared as detailed above, with CoQ 10 loading doses ranging from 30-60mg/g lipid. Volumes of 1.0 mL were aliquoted into 2mL glass ampoules and sealed. The ampoules were stored at 4°C, 15°C and 25°C for a minimum of 48 hours to allow equilibration. Separate samples were also held at 4°C for prolonged period of time (up to 9 days). The ampoules were removed from the temperature stations and placed in a water bath held at 37°C. The time for any precipitated crystals to re-dissolve was recorded.
  • the percentage of CoQ 10 precipitated after equilibration at the target temperature for 48 hours was determined.
  • the samples were centrifuged to remove any undissolved CoQ 10 , a droplet of supernatant was removed and weighed, and assayed as described for the solubility measurements.
  • Table 2 displays that CoQ 10 solubility in mg/g liquid in standard medium (Captex, Capmul) and long chain glycerides (Soyabean, Maisine) used as formulation components for lipophilic self emulsifying systems at temperatures of 25°C and 37°C. A significant decrease in solubility was observed with a reduction in temperature over this narrow temperature range.
  • lipid systems were unsaturated long-chain glycerides (linoleic, oleic), mixtures of medium chain glycerides, with long- chain glycerides (CPX Maisine 35-1 1 :1 , Soybean: CPM 1 :1 , Peanut: CPM 1 :1 , CPX: Soybean 1 :1 and CPM Maisine 35-1 1 :1), and the addition of the dispersing agent PVP (CPX: CPM: 3:1 , 370 PVP).
  • co-solvents and surfactants in formulations can enhance the solubility for some compounds by producing a non-ideal thermodynamic situation. Conversely, the inclusion of such excipients can also serve to reduce a compound's solubility.
  • a variety of co-solvents and surfactants were studies to identify any with beneficial properties regarding CoQ 10 solubility. A marginal advantage was witnessed with the use of 10% ethanol, but no benefit was observed with any of the surfactants tested (Table 5). Table 5 shows the solubility of CoQ 10 (mg/g lipid) in Captex:Capmul (CPX:CPM) 3:1 mixtures including co-solvents and surfactants at 15°C and 30°C.
  • the co-solvents are Ethanol and RH 40.
  • the surfactants are Tween 80 and Span 80.
  • Table 6 shows the solubility of CoQ 10 (mg/g lipid) in representative medium chain (MCT) and long chain (LCT) triglyceride formulations as a function of temperature.
  • MCT medium chain
  • LCT long chain
  • the MCT formulations contain Captex 355 and Capmul at the ratio 2:1 , Cremophor El (Cr) and 5% absolute ethanol (EtOH).
  • the LCT formulations differ only in that they contain Maisine 35-1 and Soyabean oil at a ration of 1:1 in place of the Captex and Capmul.
  • Tables 2 to 5 show that the sharp temperature dependent solubility of lipophilic compounds, in particular CoQ 10 is not alleviated by using standard variations in SEDDS or SMEDDS formulations.
  • An important feature of the present invention is the ability of crystallised or precipitated lipophilic compound, present in a capsule formulation, to rapidly re-dissolve following exposure to physiological temperature (37°C) for at least about 10 minutes.
  • Table 7 illustrates the percentage of the loading dose that had precipitated from MCT formulations following storage of the ampoules for 48 hours at either 4°C, 15°C, or 25°C.
  • the formulations contained Captex:Capmul (2:1), ethanol 5%, Cremophor El (Cr) at either 30% or 35% and different loading doses of CoQ 10 . As the temperature was reduced, the proportion of the loading dose remaining in solution decreased consistent with the results of the previous solubility studies TABLE 7
  • Table 8A shows the time required for >95% of precipitated CoQ 10 to re-dissolve in MCT formulations at 37°C after storage at 4°C, 15°C and 25°C for 48 hours.
  • the formulations contained Captex:Capmul (2:1), ethanol 5%, Cremophor El (Cr) at either 30% or 35% and different loading doses of CoQ 10 .
  • Table 8B shows the time required for precipitated CoQ 10 to re-dissolve in MCT formulations at 37°C after storage at 4°C for up to 216 hours.
  • the formulations contained Captex:Capmul (2:1), ethanol 5%, Cremophor El (Cr) at either 30% or 35% and different loading doses of CoQ 10 .
  • Table 9 illustrates the percentage of the loading dose of CoQ 10 that had precipitated form LCT formulations following storage of the ampoules for 48 hours at either 4°C, 15°C, or 25°C.
  • the LCT formulations contained Soyabean: Maisine 35-1 (1 :1), ethanol 5%, Cremophor EL (Cr) at either 30% or 35% and different loading doses of CoQ 10 . Again, as the temperature was reduced, the proportion of the loading dose remaining in solution decreased consistent with the results for the MCT formulations.
  • Tables 8-10 show that significant amounts of lipophilic compound, in this case CoQ 10 , precipitate out of solution at relatively low temperatures. Further, the lipophilic compound, CoQ 10 will re-dissolve within about 10 to 30 minutes at 37°C, (physiological temperature).
  • the bioavailability of lipophilic compounds, including CoQ 10 when provided orally to humans or other animals is dependent on the percentage of lipophilic compound in solution. Inconsistent and often minimal bioavailability will be obtained when the CoQ 10 has precipitated or is not in solution.
  • CoQ 10 solubility is highly temperature dependent, and further that if CoQ 10 which has precipitated is exposed to 37°C for at least about 10 minutes it will re- dissolve. This re-dissolution will result in increased and more consistent bioavailability compared to a CoQ 10 formulation in which a large percentage of the CoQ 10 has precipitated during room temperature storage.
  • the invention exposes the capsule and therefore also its contents to physiological temperature (37°C) for at least 10 minutes.
  • physiological temperature 37°C

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Abstract

L'invention concerne une formulation pharmaceutique administrable par voie orale renfermant un composé lipophile et un support ou excipient pharmaceutiquement acceptable enrobé de façon à empêcher la libération du composé lipophile pendant environ 10 minutes à 1 heure après administration. Le composé lipophile peut être la coenzyme Q10, les vitamines A, E, K ou leurs dérivés. De préférence, le composé lipophile est la CoQ10 enrobée dans une capsule de gélatine et une couche qui peut être un polymère soluble dans l'eau, par exemple de l'éther de cellulose, de la polyvinylpyrrolidone ou du polyéthylèneglycol ou un polymère sensible au pH tel que phtalate d'hydroxypropylméthylcellulose ou phtalate d'acétate de polyvinyle. L'invention concerne également un procédé de préparation de la formulation pharmaceutique et un procédé d'administration de ladite formulation conçu pour empêcher la libération du composé lipophile pendant environ 10 minutes à 1 heure après administration. Selon l'invention, l'administration de la formulation pharmaceutique peut être particulièrement utile pour traiter ou prévenir une insuffisance cardiaque globale.
PCT/AU2001/000571 2000-05-18 2001-05-18 Medicament lipophile Ceased WO2001087355A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258044A AU2001258044A1 (en) 2000-05-18 2001-05-18 Lipophilic medicament

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPQ7611A AUPQ761100A0 (en) 2000-05-18 2000-05-18 Lipophilic medicament
AUPQ7611 2000-05-18

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1464341A1 (fr) 2003-04-03 2004-10-06 Visufarma S.R.L. Formulation hydrosoluble comprénant de l'ubiquinone pour utilisation oculaire
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
WO2007029847A1 (fr) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Dérivé de pyridone substitué aromatique bicylique
WO2007049798A1 (fr) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Nouveau derive de benzoxathiine
WO2007055418A1 (fr) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Derive spiro aza-substitue
WO2008038692A1 (fr) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. dÉrivÉ de diarylcÉtimine
WO2009119726A1 (fr) 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine
WO2009154132A1 (fr) 2008-06-19 2009-12-23 萬有製薬株式会社 Dérivé de spirodiamine-diarylcétoxime
WO2010013595A1 (fr) 2008-07-30 2010-02-04 萬有製薬株式会社 Dérivé de cycloalkylamine à noyaux fusionnés à (5 chaînons)-(5 chaînons) ou (5 chaînons)–(6 chaînons)
EP4193989A1 (fr) * 2021-12-09 2023-06-14 Atlas Molecular Pharma, S.L. Formulation pour une administration orale efficace de ciclopirox sans toxicité gastro-intestinale adverse

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4983403A (en) * 1987-12-15 1991-01-08 Rhone-Poulenc Sante Granules for feeding ruminants with an enzymatically degradable coating
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
WO2001037808A1 (fr) * 1999-11-23 2001-05-31 Lipocine, Inc. Excipients solides pour administration amelioree d'ingredients actifs contenus dans des compositions pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4983403A (en) * 1987-12-15 1991-01-08 Rhone-Poulenc Sante Granules for feeding ruminants with an enzymatically degradable coating
US5593694A (en) * 1991-10-04 1997-01-14 Yoshitomi Pharmaceutical Industries, Ltd. Sustained release tablet
WO2001037808A1 (fr) * 1999-11-23 2001-05-31 Lipocine, Inc. Excipients solides pour administration amelioree d'ingredients actifs contenus dans des compositions pharmaceutiques

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1464341A1 (fr) 2003-04-03 2004-10-06 Visufarma S.R.L. Formulation hydrosoluble comprénant de l'ubiquinone pour utilisation oculaire
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
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