WO2002026238A1 - Supplements a base de derive phosphate - Google Patents

Supplements a base de derive phosphate Download PDF

Info

Publication number
WO2002026238A1
WO2002026238A1 PCT/AU2001/001206 AU0101206W WO0226238A1 WO 2002026238 A1 WO2002026238 A1 WO 2002026238A1 AU 0101206 W AU0101206 W AU 0101206W WO 0226238 A1 WO0226238 A1 WO 0226238A1
Authority
WO
WIPO (PCT)
Prior art keywords
phosphate
electron transfer
transfer agents
tocopheryl
supplement
Prior art date
Application number
PCT/AU2001/001206
Other languages
English (en)
Inventor
Simon Michael West
David Kannar
Original Assignee
Vital Health Sciences Pty 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
Priority claimed from AUPR0393A external-priority patent/AUPR039300A0/en
Priority claimed from AUPR6847A external-priority patent/AUPR684701A0/en
Application filed by Vital Health Sciences Pty Ltd. filed Critical Vital Health Sciences Pty Ltd.
Priority to AU2001293488A priority Critical patent/AU2001293488A1/en
Publication of WO2002026238A1 publication Critical patent/WO2002026238A1/fr
Priority to US10/487,743 priority patent/US20040241225A1/en
Priority to PCT/AU2002/001321 priority patent/WO2003026673A1/fr
Priority to JP2003530308A priority patent/JP2005515969A/ja
Priority to MXPA04001779A priority patent/MXPA04001779A/es
Priority to AU2002333019A priority patent/AU2002333019B2/en
Priority to BR0212887-0A priority patent/BR0212887A/pt
Priority to CA002458279A priority patent/CA2458279A1/fr
Priority to EP02799356A priority patent/EP1429782A4/fr
Priority to ZA200401126A priority patent/ZA200401126B/en

Links

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
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin

Definitions

  • the invention relates to supplements containing phosphate derivatives of electron transfer agents. More particularly, the invention relates to supplements containing phosphate derivatives of electron transfer agents and having an enteric coating.
  • Hpophilic substances The absorption of poorly water soluble, Hpophilic substances following oral adrninistration is generally low and highly variable due to their low solubility within the gastrointestinal tract and the poor dissolution and dispersion properties of conventional formulations for compounds of this nature. This can impact on the pharmaceutical utility of such compounds. Variation in bioavailability demonstrated by Hpophilic substances may limit their use in medicine as the required dosage is unpredictable. If a dose could be predictably provided to humans and animals, the ut ⁇ ity of these HpophiHc substances would be greatiy increased.
  • Derivatisation has long been recognized as an important means of increasing efficacy and bioavailability.
  • derivatised pharmaceutical drugs and nutrients must then further exhibit capability to revert to the parent compound once absorbed into the systemic circulation in order to be useful.
  • a derivatised pharmaceutical drug or nutrient is the current use of vitamin E organic esters, typically acetate or succinate.
  • Hpase activity that releases free tocopherol from the esters of tocopherol, typically the acetate ester. This property permits a formulator using tocopheryl acetate as a nutritional source of Vitamin E, and avoids the instabiHty of free tocopherol.
  • tocopheryl phosphate The salts of tocopheryl phosphate have been known to be water-soluble for some time. These properties have led to research on the use of alpha tocopheryl phosphate as a very bioavailable form of Vitamin E activity for supplementation. Tocopheryl phosphate has been shown to have superior bioavailabiHty compared to ester derivatives, therefore the presence of the phosphate group on the tocopherol molecule may be important to bioavailabiHty.
  • Coenzyme Q 10 (also known as ubiquinone) is an essential HpophiHc 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 Hpid soluble antioxidant in its reduced form (ubiquinol). 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 Hpophilic (calculated log P ⁇ 20), poorly water soluble (aqueous solubiHty ⁇ 0.1 ⁇ g/ml) compound that is subject to poor and variable absorption properties foHowing oral ac____ ⁇ _istration. As stated above, this significantly limits its clinical utiHty.
  • die improved bioavailabiHty is thought to be due to fact that the enteric coating minimizes the formation of the insoluble forms of the phosphate derivatives.
  • the phosphate derivatives of electron agents must be solubiHsed in order to be absorbed by the body.
  • the enteric coating improves deHvery of the phosphate derivatives of electron transfer agents to the smaH intestine and thus improves bioavailabiHty of the compound.
  • electron transfer agent is used herein to refer to the class of chemicals which may be phosphorylated and which (in the non-phosphorylated form) can accept an electron to generate a relatively stable molecular radical or accept two electrons to aUow the compound to participate in a reversible redox system.
  • classes of electron transfer agent compounds that may be phosphorylated include hydroxy chromans including alpha, beta and gamma tocols and tocotrienols in enantiomeric and raecemic forms; quinols being the reduced forms of vitamin Kl and ubiquinone; hydroxy carotenoids including retinol; and ascorbic acid.
  • phosphate derivatives is used herein to refer to the acid forms of phosphorylated compounds, salts of the phosphates including metal salts such as sodium, magnesium, potassium and calcium and any other derivative where the phosphate proton is replaced by other substituents such as ethyl or methyl groups or phosphatidyl groups.
  • the word 'supplement' as used in this description refers to all forms of supplying pharmaceuticals or nutrients orally or enterally to humans or animals.
  • a supplement comprising one or more phosphate derivatives of electron transfer agents and having an enteric coating.
  • phosphate derivatives of electron transfer agents include ubiquinyl phosphate, retinyl phosphate, ascorbyl phosphate, menadiol disodium phosphate, tocopheryl phosphate, di-tocopheryl phosphate, tocopheryl pyrophosphate, di-tocopheryl pyrophosphate in their acid form or as acceptable salts or mixtures thereof.
  • the supplement comprises phosphate derivatives of tocols
  • the supplement also contains free tocopherol.
  • the tocol phosphate derivatives act as an emulsifier and assist the absorption of free tocopherol.
  • the enteric coating must be insoluble in the stomach (low pH) and survive the enzymes in saHva, but degrade in the absorption site which is just after the stomach at a pH greater than 6.
  • the coating is a water soluble polymer.
  • it may be a ceUulose ether, polyvinylpyrroHdone or polyethylene glycol.
  • the release of the phosphate derivatives of electron transfer agents is typicaUy delayed for at least 10 to 30 minutes to ensure maximum re-dissolution of the phosphorylated derivative of the electron transfer agent.
  • GeneraUy delays of more than 1 hour are not desirable as it is necessary for the supplement to be released in the proximal smaU intestine to maximise its usefulness.
  • Enteric coatings which cause a delay of more than 1 hour may result in release after the distal small intestine and are not likely to be suitable for use with this invention.
  • a person skilled in the art wiU realize that each person's digestive system functions differently and these timings are merely iUustrative.
  • the important feature is that the enteric coating ' must be insoluble in the stomach (low pH) and survive the enzymes in saliva, but degrade in the absorption site which is just after the stomach at a pH greater than 6.
  • the supplement wiU be in the form of a tablet, capsule, cross- linked soft or hard gelatin capsule.
  • the tablet or capsule wiU preferably be film coated with ceUulose or methylceUulose or a simUar substance designed to delay release of the active ingredients.
  • Enteric coating agents are used to protect the tablet core and phosphate derivatives of electron transfer agents from reacting with characteristic dissolution factors of the different regions of the gastrointestinal tract.
  • Polymers with pH dependant solubiHty properties (enteric coatings) have been found to be most useful for this appHcation.
  • Cross- linking of gelatin in the hard or soft gelatin capsule is understood to impart the same biological effect.
  • the phosphate derivatives of electron transfer agents may be spray dried to form micro-particles and then the micro-particles entericaUy coated. These enteric-coated micro-particles can then be used in a range of pharmaceutical and food dose forms including hard gelatin capsules, oral suspensions, children's formulations, enteral feeds and functional foods. Phosphate derivatives of electron transfer agents and their metaboHtes are absorbed through the Hning of the intestine into the portal vein and/ or lymph eventuaUy reaching the arteries, tissue and organs. Once in circulation the phosphate derivative of electron transfer agents and their metaboHtes can provide therapeutic benefits to the human recipient. It is anticipated that the use of an enteric coating wiU increase the amount of the phosphate derivatives electron transfer agents avaUable for absorption in the smaU intestine and increase beneficial effects.
  • a method for improving the bioavaUabiHty of one or more electron transfer agents comprising the step of applying an enteric coating to a supplement comprising one or more phosphate derivatives of one or more electron transfer agents.
  • a method for improving bioavaUabiHty of one or more electron transfer agents comprising the step of deHvering a supplement to the smaU intestine in a form such that one or more phosphate derivatives of one or more electron agents are released in the smaU intestine.
  • a dosage form of a phosphate derivative of one or more electron transfer agents comprising:
  • a method for rriinirnising the formation of insoluble forms of phosphate derivatives of electron transfer agents comprising:
  • This technology could not be used for ester derivatives or bioactive molecules that rely on acidic degradation in the upper stomach to remove an ester or other group releasing the free compound for absorption further down the gastrointestinal tract.
  • enteric coating strategy confer greater bioavaUabUity of the electron transfer agents. It would therefore be expected that release of phosphate derivatives of electron transfer agents by an enteric dose form strategy at the site of absorption in the smaU intestine, alone explains the observed increase in blood levels seen with oral adrriinistration of enteric coated forms compared to regular dose forms.
  • phosphate derivatives of electron transfer agents are put into a tablet or capsule form using any methods known to those skilled in the art. It wiU be readUy understood by those skilled in the art that phosphate derivatives of electron transfer agents can be put in tablet or capsule form in a number of different ways. It wiU be understood that a variety of different binders, fillers and a number of other excipients can be used.
  • the enteric coating is then appHed to the tablet or capsule by usual methods.
  • the enteric coating may include ceUulose, methylceUulose or a derivative of either of these or another simUar substance designed to delay the release of the active ingredients until they reach the region of the smaU intestine having a pH greater than 6. It is also possible to place the phosphate derivatives of electron transfer agents in a capsule which has been entericaUy coated or cross-linked. Each of these methods wiU delay the release of the phosphate derivatives of electron transfer agents until they reach the region of the smaU intestine having a pH greater than 6.
  • TypicaUy the maximum thickness of the enteric coating wiU be 0.5 mm or otherwise adequate to aUow the dose form to comply with estabkshed USP 2000 standards for delayed release dose forms.
  • the dose form moves down the digestive tract to the stomach.
  • the enteric coated tablet or capsule moves down the upper alimentary tract, the outer surface coating remains intact as a coating but changes chemical form creating insoluble acid complexes.
  • the majority of the coating adheres to the tablet, micro-particle or capsule core until reaching the more alkaline smaU intestine. At this point the enteric coating completely dissolves releasing content of the dose form.
  • the enteric coating ensures that the phosphate derivatives of electron transfer agents are not released until the smaU intestine, where it wiU be most effective.
  • Phosphate derivatives of electron transfer agents and/ or their metaboHtes are absorbed through the lining of the intestine into the lymphatic and/or portal vein eventuaUy reaching the arteries, tissue and organs. Once in circulation phosphate derivatives of electron transfer agents and/ or their metaboHtes can provide therapeutic benefits to the human recipient.
  • tocopheryl phosphate which was exposed to various environments to ascertain whether the phosphate group would be readUy cleaved.
  • ubiquinyl phosphate was exposed to acidic conditions simUar to that of the stomach to ascertain whether the phosphate group would be readUy cleaved.
  • Ubiquinyl phosphate was dispersed in a mixture of propionic acid and water having a pH of 1.0 at a temperature of 37°C. The mixture was then analyzed by 31 P NMR for free phosphate and ubiquinyl phosphate. The amount of free phosphate was negHgible. The mixture was analyzed again 3 hours later and there was still only a negHgible amount of free phosphate. Therefore, only a negHgible amount of ubiquinyl phosphate was cleaved in acidic conditions simUar to that of the stomach.
  • Example 1 Enteric coated tocopherol phosphate tablet
  • tocopherol phosphate which can be used in the supplement is -tocopherol phosphate powder although other forms may be possible. Although it is possible to use other tocopherol isomers in the supplement, it wiU be understood that the ⁇ -tocopherol isomer has been shown to have significantiy higher bioavaUabiHty than other tocopherol sources which may not provide the same health benefits due to inadequate plasma or tissue levels.
  • tocol phosphate derivative powder can be formulated a number of different ways. It wiU be understood that a variety of different binders, fillers and a number of other excipients can be used providing that the tablet core performs to the relative dissolution and disintegration standards pubHshed, for example, in the United States Pharmacopeia (USP 2000). Depending upon the dose required an uncoated tablet core may be formulated as foUowing:
  • enteric coatings It wiU be recognized by those skilled in appHcation of enteric coatings that several polymer and coating products can be used to form an effective enteric film coating.
  • protective polymers with free carboxyl groups are insoluble in acid solutions and dissolve by salt formation at a pH greater than 6.
  • coatings include but are not limited to ceUulose acetate pthalate, hydroxypropyl methylceUulose pthalate, carboxymethyl- ethylceUulose, sodium alginate and polyvinyl acetate phthalate (Opadry®, Pharmacoat®, Methocel®, Sepifilrn®, Eudragit® respectively) presented as both aqueous and organic coating formulations. Numerous formulation approaches are avaUable depending upon the film-forming polymer utilized and peculiarity of the tablet core.
  • Opadry®, Pharmacoat®, Methocel®, or SepifUm® is first suspended in hot water then cooled with stirring.
  • the pigment is mixed separately in suitable high-shear homogeniser and added just before use. If excessive foaming occurs during mixing, add an anti-foam emulsion (sorbitan sesqui oleate 0.0025%).
  • the tablet cores are loaded into a suitable conventional coating pan or fluidized bed coater (Hi-Coater, Rapid Coater, Kugelocoater etc) and pre-heated to 35 to 40°C with limited agitation to prevent attrition.
  • a first smaU portion of coating solution is then appHed very slowly to impart mechanical stabUity to the tablet core surface and reduce dust formation which may impair quality and performance of the finished film.
  • the heated air supply is then increased and the coating solution sprayed continuously onto the rapidly moving tablet core bed.
  • Inlet air temperatures are initially between 60 to 90°C, but may vary depending upon the spray rate, water content of the inlet air source and efficiency of the particular equipment utilized.
  • Each 10 ⁇ m of film coat usuaUy takes approximately one hour to apply using a pan coater and less than half this time in a fluidized bed coater.
  • the weight gain of a 400 gm tablet is approximately 1% and the tensUe strength of the finished film coat is typicaUy 20 to 45 N/mm 2 but may vary from 10 to 55 N/mm depending upon the ceUulose derivative used. Accordingly, if alternative polymers are utilized this variation may be even wider. If a higher gloss appearance is required a final coat of pure polymer may be appHed.
  • Example 2 Enteric coated tocopherol phosphate hard and soft gelatin capsules
  • Gelatin capsules can be coated to impart resistance to gastric fluid, improve stability to moisture and heat and utilized to deHver tocol phosphate derivatives. Cross linking of gelatin in the capsule has also been suggested as a means of delaying capsule degradation. Although appHcation of the film coating is basicaUy simUar to methods utilized for tablets, some additional problems are experienced due to the nature of capsule. Low porosity of the gelatin matrix reduces adhesion of the film to the capsule surface and can cause differences in elasticity of the coating polymer film and the capsule. This can cause the capsule to burst especiaUy when placed under mechanical stress experienced for example, when the capsule is squeezed out of bHster packaging.
  • a coating emulsion with water based solvent is utilized.
  • the water contained in the coating solution causes the gelatin to sweU sHghtly, aUowing the film to bond to the gelatin and adhere more effectively. This process prevents the capsule from embrittlement and with adaptation can be used for starch capsules.
  • Suitably sized hard gelatin capsules eg; Snap fit, Capsugel, Basel
  • suitable flow agents such as magnesium stearate etc.
  • the tocopherol powder mixture is then fed into the larger of the two capsule halves by hand or mechanicaUy in a capsule filler and band sealed again by hand or mechanical means.
  • the capsule can be coated with one of several film-forming polymers to delay absorption of the tocopherol until the alkaline smaU intestine.
  • the enteric coating may include the ceUulose derivatives previously mentioned, and formulation examples foUow: Formulation 4
  • the capsules are tipped into a suitable coating apparatus (Hi-Coater, Rapid Coater, Kugelocoater etc) and core temperature raised to and maintained at 30 to 32°C during appHcation of the film coat. FoUowing the same instructions for tablets, the enteric coating is then sprayed onto the capsule. After enteric coating appHcation the capsules are then conditioned at 50% relative humidity and cooled. After manufacture, the gelatin capsules can withstand up to 65N in a hardness tester and starch capsules up to 208N. Shelf Hfe at 37°C can extend to 2 years and disintegration in intestinal fluid ranges from 5 to 35 minutes.
  • Example 3 Enteric coated tocopherol phosphate micro-particle encapsulation and enteric delivery
  • Alginate micro-encapsulation and lecit-hin vesicular technology can also be used as enteric delivery strategies to delay particle release until the smaU intestine.
  • the alginate is typicaUy used in the sodium form and provides protection from gastric acid by converting to the insoluble alginic acid during transit in the stomach. After passage through this acidic environment the alginic acid converts back to the soluble sodium form as the pH is raised upon entry to the smaU intestine. Contents of the tablet or micro particle are therefore protected at acidic pH and only released at alkaline pH of the smaU intestine.
  • the alginate may be utilized as the primary film former, combinations with synthetic film formers such as polyvinyl acetate phthalate are also known.
  • Micro-encapsulation is used to entrap a wide variety of substances in the pharmaceutical, cosmetic and agricultural industries where delayed release is required in a micro-particle size.
  • Calcium alginate entrapment is particularly preferred because the process is expeditious, the manufactiiring conditions are mUd and non toxic reactants are employed.
  • Other micro- encapsulation materials can also be employed to control release of the active including geUan gum and gum arabic but not recommended due to the need for higher temperatures during manufacture.
  • Water soluble forms of tocol phosphate derivatives in the required dose are mixed in a 1-2% solution of sodium alginate using a suitably sterUe, pure water source. Effective preservation is achieved by addition of sodium benzoate at a concentration of 1000 ppm and clean manufacturing facUities.
  • the solution is then pumped through a small orifice (such as a needle) and aUowed to free faU for sufficient time to form a spherical bead. Size of this bead may be varied according to the size of the needle orifice, volume discharged and solution viscosity.
  • the spherical bead drops into a 1-2% calcium chloride solution or suitable di or tti- valent ion source, and gels upon contact remaining in the bath until hardened. Excess calcium ion solution is then rinsed from the bead and beads screened for size.
  • tocol phosphate derivative Release of the tocol phosphate derivative is generally rapid and corresponds to the high water solubihty of the tocol phosphate derivative. Accordingly release kinetics can be altered by using different tocol phosphate derivatives with higher dissolution possible with disodium salts and slower release with the monosodium salts.
  • ubiquinyl phosphate was prepared to be used in supplements having enteric coatings according to the invention.
  • lOOg ubiquinol was heated to 100 °C and 33g of P 4 O 10 was added. The mixture was stirred for 3 hours and 500 ml water was then introduced slowly into the mixture. The temperature of the reaction was maintained just below boiling point for a further 1 hour. Removal of water yielded ubiquinyl phosphate, and inorganic phosphates. The inorganic phosphates were removed by further washes with hot water. The remaining amorphous material was then mixed with 100 L of virgin grade canola oU containing at least 1 to 5% lecithin. The final mixture therefore provides lmg/ml and can be dispensed to give the required dose. The amorphous ubiquinyl phosphate can also be spray dried using conventional methods to for a buff coloured powder which can be sieved to the required mesh size.
  • Example 7 Equivalent to Example 3 substituting ubiquinyl phosphate powder for tocopheryl phosphate.
  • the aim of the study was to dose rats with deuterated tocopheryl phosphate or deuterated tocopheryl acetate by oral adrniiustrations, then determine the amounts of tocopheryl phosphate in Hvers foHowing treatment.
  • the procedure used is summarized as foUows:
  • rat wiU be anaesthetized with Nembutal (60 mg/kg i.p.).
  • a sample of blood wiU be taken from the taU vein, and the femoral vein exposed and injected with 500 units of heparin.
  • the abdominal cavity wiU be opened and the rat perfused with saline.
  • the Hver, heart and epidydimal fat pad removed and frozen in Hquid nitrogen.
  • Hind-leg muscle and brain wiU also be coUected and frozen.
  • the enteric coated doses were prepared as per Example 3 above in order to prepare tablets of an appropriate size for the rats.
  • Livers were be extracted according to the method below.
  • the extracts wiU be analyzed and quantitated for tocopheryl phosphate ( ⁇ g) content by ES MS. Any tissue samples left over at the end of the study was kept frozen at —80 °C. Liver extraction.
  • 1 g Hver was homogenized in 10 ml dichloromethane (analytical grade). Add 0.1 mg tocopheryl diphosphate (internal standard). Homogenize sample for 2 min, centrifuge and remove upper layer and evaporate under nitrogen. Add 9 ml KOH (2M) and stir for 1 hr at room temperature (or 20 min at 80 C). Add 10 ml hexane, shake and remove upper layer. Add 10 ml HCl (2M) and shake. Add 10 ml hexane to the solution and shake and remove upper layer. Evaporate top layer to dryness.
  • Tocopheryl phosphate was adr ⁇ iistered by IV to provide a value for absolute bioavaUabiHty. 10
  • the amounts in brackets are percentages when compared with the IV value.
  • absorption of a tocopherol analogue can improve tissue levels within a 24 hour period
  • entericaUy coated tocopheryl phosphate has higher bioavaUabiHty than both uncoated 15 tocopheryl phosphate and tocopheryl acetate.
  • the 30 mg/kg enteric coated tocopheryl phosphate supplement achieved simUar results to the 100 mg/kg tocopheryl acetate dose indicating that the tocopheryl phosphate enteric coated dose is approxirnately three times more bioavaUable than tocopheryl acetate to Hver tissue.
  • the word 'comprising' and forms of the word 'comprising' as used in this description and in the claims does not limit the invention claimed to exclude any variants or additions. Modifications and improvements to the invention wUl be readUy apparent to those skUled in the art. Such modifications and improvements are intended to be within the scope of this invention.
  • a supplement comprising one or more phosphate derivatives of one or more electron transfer agents and having an enteric coating.
  • the one or more phosphate derivatives of one or more electron transfer agents are selected from the group consisting of ubiquinyl phosphate, retinyl phosphate, ascorbyl phosphate, menadiol disodium phosphate, tocopheryl phosphate, di-tocopheryl phosphate, tocopheryl pyrophosphate, di-tocopheryl pyrophosphate in their acid form or as acceptable salts or mixtures thereof.
  • a supplement according to claim 2 wherein the electron transfer agents are selected from d e group consisting of tocopheryl phosphate, di-tocopheryl phosphate, tocopheryl pyrophosphate, di-tocopheryl pyrophosphate in their acid form or as acceptable salts or mixtures thereof.
  • enteric coating delays release of the phosphate derivatives of the electron transfer agents until they reach the region of the smaU intestine having a pH greater than 6.
  • a supplement according to claim 1 wherein the supplement is in the form of a tablet, capsule, cross-linked soft or hard gelatine capsule.
  • a supplement comprising one or more phosphate derivatives of one or more electron transfer agents selected from the group consisting of tocopheryl phosphate, di- tocopheryl phosphate, tocophetyl pyrophosphate, di-tocopheryl pyrophosphate in their acid form or as acceptable salts or mixtures thereof and having an enteric coating.
  • a supplement comprising one or more phosphate derivatives of ubiquinol and having an enteric coating.
  • a supplement in the form of a tablet, capsule, cross-linked soft or hard gelatine capsule comprising one or more phosphate derivatives of one or more electron transfer agents and having an enteric coating.
  • a method for minirnizing the formation of insoluble forms of phosphate derivatives of electron transfer agents comprising:
  • a method for improving bioavaUabiHty of one or more electron transfer agents comprising the step of deHvering a supplement to the smaU intestine in a form such that one or more phosphate derivatives of one or more electron agents are released in the smaU intestine.
  • a method of making a dosage form of a phosphate derivative of one or more electron transfer agents comprising: (c) preparing a supplement comprising one or more phosphate derivatives of one or more electron transfer agents; and
  • a method for minimising the formation of insoluble forms of phosphate derivatives of electron transfer agents comprising: (c) preparing a supplement comprising one or more phosphate derivatives of one or more electron transfer agents; and
  • a method for improving the bioavaUabiHty of one or more electron transfer agents comprising the step of applying an enteric coating to a supplement comprising one or more phosphate derivatives of one or more electron transfer agents.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un supplément comprenant un ou plusieurs dérivés phosphate d'agents de transfert d'électrons et possédant un revêtement entérique.
PCT/AU2001/001206 2000-09-26 2001-09-26 Supplements a base de derive phosphate WO2002026238A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU2001293488A AU2001293488A1 (en) 2000-09-26 2001-09-26 Phosphate derivative supplements
EP02799356A EP1429782A4 (fr) 2001-09-26 2002-09-26 Modulation du stockage de vitamines
CA002458279A CA2458279A1 (fr) 2001-09-26 2002-09-26 Modulation du stockage de vitamines
BR0212887-0A BR0212887A (pt) 2001-09-26 2002-09-26 Método para aumentar nìveis de uma forma de armazenagem de uma vitamina e uso de uma quantidade eficaz de um derivado de fosfato de uma vitamina
PCT/AU2002/001321 WO2003026673A1 (fr) 2001-09-26 2002-09-26 Modulation du stockage de vitamines
US10/487,743 US20040241225A1 (en) 2001-09-26 2002-09-26 Modulation of vitamin storage
JP2003530308A JP2005515969A (ja) 2001-09-26 2002-09-26 ビタミン貯蔵の調節
MXPA04001779A MXPA04001779A (es) 2001-09-26 2002-09-26 Modulacion de almacenamiento de vitamina.
AU2002333019A AU2002333019B2 (en) 2001-09-26 2002-09-26 Modulation of vitamin storage
ZA200401126A ZA200401126B (en) 2001-09-26 2004-02-12 Modulation of vitamin storage.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AUPR0393A AUPR039300A0 (en) 2000-09-26 2000-09-26 Tocol phosphate derivative supplements
AUPR0393 2000-09-26
AUPR6847 2001-08-06
AUPR6847A AUPR684701A0 (en) 2001-08-06 2001-08-06 Phosphate derivative supplements

Publications (1)

Publication Number Publication Date
WO2002026238A1 true WO2002026238A1 (fr) 2002-04-04

Family

ID=25646459

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2001/001206 WO2002026238A1 (fr) 2000-09-26 2001-09-26 Supplements a base de derive phosphate

Country Status (1)

Country Link
WO (1) WO2002026238A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003013550A1 (fr) * 2001-08-06 2003-02-20 Vital Health Sciences Pty Ltd. Phosphates micronutriants utilises comme supplements sanitaires et dietetiques
WO2003026673A1 (fr) * 2001-09-26 2003-04-03 Vital Health Sciences Pty Ltd. Modulation du stockage de vitamines
EP1589964A1 (fr) * 2003-01-17 2005-11-02 Vital Health Sciences Pty Ltd. Composes possedant des proprietes antiproliferatives
WO2006012692A1 (fr) 2004-08-03 2006-02-09 Vital Health Sciences Pty Ltd Vecteur pour administration enterale
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
CN105213348A (zh) * 2015-10-29 2016-01-06 合肥工业大学 一种还原响应性的载药纳米颗粒及其制备方法和用途
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0324387A2 (fr) * 1988-01-11 1989-07-19 Takeda Chemical Industries, Ltd. Composition pour le traitement des troubles ischémiques d'organes
US5114957A (en) * 1990-05-08 1992-05-19 Biodor U.S. Holding Tocopherol-based antiviral agents and method of using same
EP0661053A1 (fr) * 1993-12-29 1995-07-05 Senju Pharmaceutical Co., Ltd. Utilisation des toropherol acide ascorbique phosphates pour des maladies hemorrhoidales
EP0679399A1 (fr) * 1994-04-22 1995-11-02 Senju Pharmaceutical Co., Ltd. L'utilisation des diesters phosphatiques pour le traitement des maladies prolifératives de l'épiderme
EP0699440A1 (fr) * 1994-08-05 1996-03-06 Senju Pharmaceutical Co., Ltd. Utilisation d'un phosphate d'ascorbyle-tocophéryl pour la fabrication d'un médicament pour le traitement de la pancréatite

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0324387A2 (fr) * 1988-01-11 1989-07-19 Takeda Chemical Industries, Ltd. Composition pour le traitement des troubles ischémiques d'organes
US5114957A (en) * 1990-05-08 1992-05-19 Biodor U.S. Holding Tocopherol-based antiviral agents and method of using same
EP0661053A1 (fr) * 1993-12-29 1995-07-05 Senju Pharmaceutical Co., Ltd. Utilisation des toropherol acide ascorbique phosphates pour des maladies hemorrhoidales
EP0679399A1 (fr) * 1994-04-22 1995-11-02 Senju Pharmaceutical Co., Ltd. L'utilisation des diesters phosphatiques pour le traitement des maladies prolifératives de l'épiderme
EP0699440A1 (fr) * 1994-08-05 1996-03-06 Senju Pharmaceutical Co., Ltd. Utilisation d'un phosphate d'ascorbyle-tocophéryl pour la fabrication d'un médicament pour le traitement de la pancréatite

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003013550A1 (fr) * 2001-08-06 2003-02-20 Vital Health Sciences Pty Ltd. Phosphates micronutriants utilises comme supplements sanitaires et dietetiques
WO2003026673A1 (fr) * 2001-09-26 2003-04-03 Vital Health Sciences Pty Ltd. Modulation du stockage de vitamines
US8841342B2 (en) 2002-08-09 2014-09-23 Vital Health Sciences Pty. Ltd. Carrier
EP1589964A4 (fr) * 2003-01-17 2007-11-21 Vital Health Sciences Pty Ltd Composes possedant des proprietes antiproliferatives
EP1589964A1 (fr) * 2003-01-17 2005-11-02 Vital Health Sciences Pty Ltd. Composes possedant des proprietes antiproliferatives
EP2269650A3 (fr) * 2004-08-03 2012-05-16 Vital Health Sciences Pty Ltd. Support pour l'administration entérale
EP1778289A4 (fr) * 2004-08-03 2008-02-13 Vital Health Sciences Pty Ltd Vecteur pour administration enterale
US20090004166A1 (en) * 2004-08-03 2009-01-01 Simon Michael West Carrier For Enternal Administration
EP1778289A1 (fr) * 2004-08-03 2007-05-02 Vital Health Sciences Pty Ltd. Vecteur pour administration enterale
KR101238703B1 (ko) 2004-08-03 2013-03-04 바이탈 헬스 사이언시즈 피티와이 리미티드 경구 투여용 담체
WO2006012692A1 (fr) 2004-08-03 2006-02-09 Vital Health Sciences Pty Ltd Vecteur pour administration enterale
US9168216B2 (en) 2005-06-17 2015-10-27 Vital Health Sciences Pty. Ltd. Carrier comprising one or more di and/or mono-(electron transfer agent) phosphate derivatives or complexes thereof
US10071030B2 (en) 2010-02-05 2018-09-11 Phosphagenics Limited Carrier comprising non-neutralised tocopheryl phosphate
US9314527B2 (en) 2010-03-30 2016-04-19 Phosphagenics Limited Transdermal delivery patch
US9561243B2 (en) 2011-03-15 2017-02-07 Phosphagenics Limited Composition comprising non-neutralised tocol phosphate and a vitamin A compound
US10188670B2 (en) 2011-03-15 2019-01-29 Phosphagenics Limited Composition
CN105213348A (zh) * 2015-10-29 2016-01-06 合肥工业大学 一种还原响应性的载药纳米颗粒及其制备方法和用途
US10973761B2 (en) 2015-12-09 2021-04-13 Phosphagenics Limited Pharmaceutical formulation
US11753435B2 (en) 2016-12-21 2023-09-12 Avecho Biotechnology Limited Process

Similar Documents

Publication Publication Date Title
FI94094C (fi) Kantajakoostumus kestovaikutteiselle lääkeainevalmisteelle
EP0761212B1 (fr) Composition effervescente et sa préparation
KR100223131B1 (ko) 서방성 약제 용량 단위
KR100824104B1 (ko) 지효성 방출 비타민 조성물
EP1778289B1 (fr) Vecteur pour administration enterale
US20080300233A1 (en) Pharmaceutical Composition Comprising Simvastatin and Ezetimibe
WO2002026238A1 (fr) Supplements a base de derive phosphate
GB2204241A (en) Fat coated pharmaceutical compositions
RU2239435C2 (ru) Гранулы пролонгированного высвобождения, содержащие ставудин
JP2000007583A (ja) 光安定性の向上した脂溶性薬物含有組成物
JP2016210799A (ja) 三種混合製剤
RU2390332C2 (ru) Твердая фармацевтическая композиция
SA08290417B1 (ar) تركيبة دوائية ثابتة تشمل ملح فينفلونين القابل للذوبان فى الماء
JP5774308B2 (ja) 水溶性ビノレルビン塩の安定な医薬組成物
US20100178326A1 (en) Aminophosphonate carriers for liposome-based drug release systems
US20100055178A1 (en) Enteric-coated creatine compositions and methods of use thereof
AU2014237237A1 (en) Soft gel encapsulation
KR102262740B1 (ko) 밀크시슬을 함유한 정제 조성물 및 이의 제조 방법
WO2023220125A1 (fr) Compléments destinés à la santé cérébrale
EP1803447B1 (fr) Composition pharmaceutique à libération prolongée d'hydralazine et son utilisation comme soutien pour le traitement du cancer
JP2022069437A (ja) 医薬製剤およびその製造方法
AU2005220236B2 (en) Carrier for enteral administration
US20210069113A1 (en) Solid unit dosage form for dose individualized drug delivery
JP2020533369A (ja) チモキノン含有組成物の調製法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP