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WO1998056368A1 - Superiorite des preparations comprenant la coenzyme q10 de l'huile de coco - Google Patents

Superiorite des preparations comprenant la coenzyme q10 de l'huile de coco Download PDF

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Publication number
WO1998056368A1
WO1998056368A1 PCT/US1998/011827 US9811827W WO9856368A1 WO 1998056368 A1 WO1998056368 A1 WO 1998056368A1 US 9811827 W US9811827 W US 9811827W WO 9856368 A1 WO9856368 A1 WO 9856368A1
Authority
WO
WIPO (PCT)
Prior art keywords
oil
formulation
coenzyme
coq
hydrogenated
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/US1998/011827
Other languages
English (en)
Inventor
Richard Willis
Mark Anthony
Karl A. Folkers
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.)
University of Texas System
University of Texas at Austin
Original Assignee
University of Texas System
University of Texas at Austin
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 University of Texas System, University of Texas at Austin filed Critical University of Texas System
Priority to AU78267/98A priority Critical patent/AU7826798A/en
Publication of WO1998056368A1 publication Critical patent/WO1998056368A1/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
    • A61K31/12—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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

Definitions

  • This invention relates to new formulations comprising coenzyme Q 10 (CoQ 10 ) in saturated vegetable oils for use in clinical medicine.
  • the saturated vegetable oils are those commonly used in the food and pharmaceutical industries.
  • CoQ 10 (2,3-dimethoxy-5-methyl-6- decaprenyl benzoquinone) dissolved in unsaturated vegetable oils
  • oral supplementation with currently available formulations of CoQ 10 in unsaturated vegetable oils is slow to produce clinically beneficial blood levels of CoQ 10 , taking a minimum of 5-7 days in rats and 7-14 days in humans.
  • This slow absorption may relate to the insolubility of CoQ 10 in aqueous media and relatively low solubility of CoQ 10 in unsaturated vegetable oils.
  • Coenzyme Q 10 being highly hydrophobic, is essentially insoluble in aqueous solutions.
  • CoQ 10 to be absorbed in the digestive tract, it must be contained in a stable formulation in which it will remain dispersed under conditions of normal storage and use.
  • oral supplements include CoQ 10 in a tablet or capsule form mixed with one or more dry inert ingredients or CoQ 10 partially dispersed in unsaturated vegetable oil in a gelcap.
  • Some formulations of each type also include other biologically active substances, e.g., vitamin E. Since oral supplements are administered with water or some other aqueous solution, the formulations which are tablets or dry powder capsules are associated with very slow abso ⁇ tion.
  • Unsaturated vegetable oils can be warmed to levels at or above 50°C to allow dispersal of about 33 mg of CoQ 10 per 350 ⁇ L of oil (the oil content of a standard gelcap), but cooling of the mixture to room temperature results in a significant amount of the CoQ 10 falling to the bottom of the container. Gently warming the unsaturated oil/CoQ 10 to body temperature does not fully re-disperse the separated CoQ 10 . It is likely that the undispersed CoQ 10 , like that in the tablets and dry capsules, is poorly absorbed. Another approach has been to use formulations of unsaturated vegetable oils containing CoQ 10 and a dispersant.
  • the present invention comprises a stable and non-toxic CoQ 10 formulation with superior bioavailability suitable for oral administration to an animal or a human to rapidly produce clinically effective blood levels of CoQ 10 .
  • Clinically effective blood levels of CoQ 10 are generally agreed to be between about 2 //g/mL and about 4 g/mL.
  • the formulation consists of saturated vegetable oil as a vehicle in which CoQ 10 is dissolved.
  • the formulation preferably contains CoQ 10 at a level of about 100 mg to about 150 mg dissolved in about 350 ⁇ L to about 500 ⁇ L of saturated vegetable oil enclosed in a gelatin capsule.
  • the clinically effective vegetable oil is saturated, preferably coconut oil.
  • the present invention also comprises a method for preparing a stable and non-toxic CoQ 10 formulation with superior bioavailability suitable for oral administration to an animal or a human to produce clinically effective blood levels of CoQ 10 .
  • This method involves the mixing of CoQ 10 with a saturated vegetable oil which has been warmed to 50°C to achieve a formulation having a CoQ 10 concentration of about 100 mg per 350 ⁇ of oil.
  • the CoQ 10 is most preferably added to coconut oil and mixed by any of the many well-known means, such as the use of a magnetic stirrer on an electric warming plate.
  • the present method also includes a method for raising blood levels of CoQ 10 to a clinically effective level in an animal or a human.
  • the method comprises first obtaining a stable and non-toxic CoQ 10 formulation with superior bioavailability, preferably comprising a mixture of CoQ 10 in a saturated vegetable oil such as coconut oil, such that the concentration of
  • CoQ 10 in the mixture is about 100 mg per 350 ⁇ L of oil.
  • the next step is to encapsulate the mixture such that the resultant capsule will contain about 100 mg of CoQ 10 .
  • the capsule can then be administered orally to an animal or a human to achieve a blood level of CoQ 10 of between about 2 ⁇ g/mL and about 4 //g/mL.
  • FIG. 1 shows the results of a bioavailability study comparing a formulation of coenzyme Qio in soybean oil to one in coconut oil.
  • Coenzyme Q 10 is essentially insoluble in aqueous media. This insolubility is related to the 50-carbon atom isoprenoid side chain, of hydrocarbon nature, as shown in the following structure of CoQ ]0 .
  • CoQ 10 formulations are either dry tablets or capsules containing CoQ 10 in solid form mixed with a dry inert substance; are low concentrations of CoQ 10 mixed in unsaturated vegetable oil requiring many capsules to be taken; or are higher concentrations of CoQ 10 in unsaturated vegetable oil in which much of the CoQ 10 has separated from the oil.
  • formulations provide all or significant amounts of the CoQ 10 to the intestinal tract in solid form, which will not dissolve in the aqueous milieu of the intestinal tract.
  • a formulation has been devised of CoQ 10 thoroughly dispersed in saturated vegetable oil (coconut oil) in which oral administration may provide increased bioavailability as evidenced by a rapid attainment of a clinically effective blood concentration of CoQ 10 .
  • the more bioavailable oral CoQ 10 formulations of the present invention allow for rapid delivery of clinically effective amounts of CoQ 10 into blood for transport to organs such as liver and heart and other tissues for therapeutic benefit.
  • the slowly absorbed formulations in current use may be ineffective for acute and life-threatening clinical situations due to their poor bioavailability.
  • a rapid and efficient abso ⁇ tion into blood is essential for patients who need maximum benefit of the potentially life-saving and/or life-extending activities of CoQ 10 .
  • a clinically effective and usable oral formulation of CoQ 10 should be stable at common ambient temperatures and remain essentially unchanged in dispersion characteristics for a period of at least a year, because this period would be about that required for preparation; analysis; shipment to distribution centers; shipment to and storage in hospitals, offices and homes until use, etc.
  • the object of the present invention is the achievement of a formulation of CoQ 10 in saturated vegetable oil which has excellent dispersion, stability and bioavailability characteristics. As disclosed herein, such a formulation has been produced and is safe and effective for medical use.
  • One embodiment of the present invention is a formulation consisting essentially of a dispersion of CoQ 10 in coconut oil which has excellent dispersion, stability and bioavailability characteristics.
  • the present inventors prepared and tested a variety of formulations against the commonly available formulation of about 33 mg of CoQ 10 in about 350 ⁇ L of soybean oil, which is the best of the currently available formulations.
  • patients are typically given 100 mg to 600 mg of such a CoQ 10 formulation per day, thus requiring that from about three to about 18 capsules be taken.
  • concentration level of 33 mg of CoQ ]0 in 350 ⁇ L of soybean oil a significant portion of the CoQ 10 typically separates as solid CoQ 10 during storage at room temperature.
  • gentle warming to 37°C, body temperature as would occur when a capsule is swallowed, does not result in a complete redispersal of the CoQ 10 . Therefore, less than the full dose of such preparations is dispersed in the absorbable oil milieu.
  • CoQ 10 in soybean oil at identical concentration by administering each formulation to animals via gavage. Again, no important differences in blood or liver concentrations of CoQ 10 were seen.
  • both soybean oil and coconut oil formulations were significantly (p ⁇ 0.005) better than a placebo but were not significantly different from each other.
  • the results of this study are shown in FIG. 1.
  • FIG. 1 shows, (i) both formulations produced a significant increase in blood levels of subjects supplemented at the level of 100 mg/day as compared to a placebo; (ii) in this experiment the two formulations were not significantly different from each other at any point in the project; and (iii) both formulations achieved a blood level plateau within 7 days of supplementation.
  • the primary advantage of the new formulation is simply that one capsule of 100 mg of coenzyme Q 10 in a coconut oil formulation is equivalent to three capsules of 33.3 mg of coenzyme Q 10 in a soybean oil formulation.
  • one capsule of the coconut oil formulation can be made to contain as much as 150 mg of CoQ 10 , giving a clear advantage over existing oil formulations.
  • Coenzyme Q 10 dispersed at the level of 100 mg in 350 ⁇ L of coconut oil has a melting point of about 33°C, which is below human body temperature (37°C). Coenzyme Q 10 is completely dispersed in coconut oil at this concentration at room temperature and remains so at lower temperatures to which the formulation might expect to be exposed, e.g., during refrigeration. Pure triglycerides were tested as possible dispersants. Concentrations of 100 mg of CoQ 10 in 350 ⁇ L of trilaurin and of tristearin were found to have melting points well above body temperature (45°C and 71°C, respectively), making them unsuitable for formulations contemplated for human use. Here, the coconut oil formulation proved superior to formulations comprising pure triglycerides.
  • the saturated vegetable oil present in our exemplary formulation is coconut oil.
  • saturated vegetable oils such as hydrogenated unsaturated oils (e.g., corn, soy, peanut, olive, canola, cottonseed, safflower, rice, wheat, etc.) or such as palm or other tropical oils, or such as saturated fats from animal sources, are within the scope of this invention.
  • hydrogenated unsaturated oils e.g., corn, soy, peanut, olive, canola, cottonseed, safflower, rice, wheat, etc.
  • palm or other tropical oils e.g., palm or other tropical oils
  • the saturated fat formulations of the present invention may be used, for example, to provide 100 mg to 150 mg of CoQ 10 in 350 ⁇ L of coconut oil per capsule.
  • this increased level of CoQ 10 per capsule above the currently available 33 mg of CoQ 10 in 350 ⁇ L of soybean oil allows the use of fewer capsules to achieve a comparable or higher blood level in a patient.
  • one capsule of 100 mg of CoQ 10 in coconut oil may be superior to three capsules of 33 mg of CoQ 10 in soybean oil.
  • Coenzyme Q I0 -coconut oil formulations have been prepared for oral administration to patients. These formulations will allow for the development of a clinically effective blood level of between about 2.0 //g/mL and about 4.0 //g/mL within a relatively short time period. It is common in clinical medicine to administer up to 600 mg CoQ 10 per day (i.e. eighteen 33 mg capsules) in an attempt to achieve a blood level of between about 2.0 //g/mL and about 4.0 //g/mL and this may require several weeks. The current formulation not only achieves a clinically effective blood level quickly, but may do so at lower daily dosages than with current formulations.
  • the preferred technique for preparing a formulation of the present invention involved the addition of CoQ 10 to warm (50°C) coconut oil at a level of 100 mg of CoQ 10 in 350 ⁇ L of coconut oil. After the CoQ 10 was completely dispersed in the oil, the mixture was then cooled to room temperature to form an orange (due to the color of CoQ 10 ) solid having the consistency of vegetable shortening. This was sufficient for the pu ⁇ oses of the laboratory preparation as appropriate (e.g. 350 //L) doses could be measured out and used. In commercial preparations, the mixture is preferably encapsulated into soft gel capsules.
  • CoQio did not separate at room temperature, under refrigeration, nor upon chilling to 0°C.
  • soy oil preparation at a concentration of 33 mg in 350 ⁇ L of soybean oil noticeably separated at room temperature, and especially under refrigeration, and even more so at 0°C.
  • a small aliquot of the solid mixture of CoQ 10 and coconut oil was applied to the skin of the back of the hand it very quickly melted into a uniform orange colored liquid which quickly spread over and into the skin.
  • a small drop of the liquid mixture of the soybean oil formulation containing separated CoQ 10 was placed on the skin of the back of the hand, the oil quickly spread across the skin but, even after several minutes, small pieces of CoQ 10 remained intact as separate bits of solid. This suggests that any improved uptake into the blood may be due to the complete and stable dispersal of CoQ 10 in the coconut oil and the ease with which the CoQ 10 remains in lipid solution at body temperature.
  • CoQ 10 is stable in the currently available soft gelatin capsules in which it is dispersed with soybean oil for up to six years. Since saturated oils are more chemically stable than unsaturated oils (e.g., soybean oil), it is anticipated that the formulation of CoQ 10 in coconut oil will be as stable or more stable than the soybean oil formulations. The stability of the formulations described in this invention will be sufficient to meet all commercial and medical needs for stability.
  • CoQ 10 has a clinical record of safety over two decades and a record of stability of over 6 years in soybean oil capsules, and since coconut oil is widely and safely used within the food and pharmaceutical industries, the CoQ I0 -coconut oil formulation of the present invention provides assurance of safety and stability and efficacy of therapeutic benefit, particularly, for example, in cardiology.
  • CoQj 0 -coconut oil formulation for commercial use.
  • the appropriate changes in procedure between the laboratory and factory scale production are readily determined and are within the scope of this invention.
  • the exemplary formulations of the present invention will allow the use of a minimal number of capsules to achieve a medically important blood level of CoQ 10 of about 2.0 ⁇ g to about 4.0 //g/mL.
  • this blood level may be achieved more quickly than with current formulations, and this may prove critically important for end-stage cardiomyopa hy patients.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une préparation stable et non toxique à base de coenzyme Q10 possédant une biodisponibilité supérieure et conçue pour l'administration par voie orale à un humain ou à un animal pour produire rapidement des taux cliniquement efficaces de coenzyme Q10 dans le sang. Il est convenu que les taux cliniquement efficaces de coenzyme Q10 dans le sang sont compris entre environ 2 νg/ml et 4 νg/ml. La préparation est constituée d'huile végétale saturée, de graisse animale ou d'huile végétale hydrogénée, qui servent d'excipient dans lequel on dissout la coenzyme Q10. De préférence, la proportion de la coenzyme Q10 dans la préparation est comprise entre environ 100 mg et 150 mg, dissous dans environ 350 νL à 500 νL d'huile végétale saturée, de graisse animale ou d'huile végétale hydrogénée conditionnée dans une capsule de gélatine. L'huile végétale cliniquement acceptable est une huile saturée, de préférence, l'huile de coco.
PCT/US1998/011827 1997-06-09 1998-06-09 Superiorite des preparations comprenant la coenzyme q10 de l'huile de coco Ceased WO1998056368A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU78267/98A AU7826798A (en) 1997-06-09 1998-06-09 Superiority of formulations containing coenzyme q10 in coconut oil

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4916897P 1997-06-09 1997-06-09
US60/049,168 1997-06-09

Publications (1)

Publication Number Publication Date
WO1998056368A1 true WO1998056368A1 (fr) 1998-12-17

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PCT/US1998/011827 Ceased WO1998056368A1 (fr) 1997-06-09 1998-06-09 Superiorite des preparations comprenant la coenzyme q10 de l'huile de coco

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AU (1) AU7826798A (fr)
WO (1) WO1998056368A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1474992A4 (fr) * 2002-01-18 2005-04-13 Kaneka Corp Aliments enrichis en ubiquinone
US8158162B2 (en) 2001-11-14 2012-04-17 Jarrow Formulas, Inc. Eutectic-based self-nanoemulsified drug delivery system
US8865032B2 (en) 2003-09-29 2014-10-21 Soft Gel Technologies, Inc. Method of making a soft gel capsule comprising CoQ-10 solubilized in a monoterpene
US8932585B2 (en) 2003-09-29 2015-01-13 Soft Gel Technologies, Inc. Solubilized CoQ-10
US9345672B2 (en) 2007-03-15 2016-05-24 Soft Gel Technologies, Inc. Ubiquinol and alpha lipoic acid compositions
CN109394725A (zh) * 2018-12-05 2019-03-01 天津铸源健康科技集团有限公司 一种辅酶q10软胶囊及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4869900A (en) * 1985-02-01 1989-09-26 Zambon S.P.A. Pharamaceutical composition containing ubidecarenone
US5011858A (en) * 1987-03-30 1991-04-30 The Board Of Regents, The University Of Texas System Therapy with coenzyme Q10 of patients having AIDS or other retroviral diseases
US5180747A (en) * 1989-02-28 1993-01-19 Nisshin Flour Milling Co., Ltd. Stabilized fat-soluble vitamin compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4869900A (en) * 1985-02-01 1989-09-26 Zambon S.P.A. Pharamaceutical composition containing ubidecarenone
US5011858A (en) * 1987-03-30 1991-04-30 The Board Of Regents, The University Of Texas System Therapy with coenzyme Q10 of patients having AIDS or other retroviral diseases
US5180747A (en) * 1989-02-28 1993-01-19 Nisshin Flour Milling Co., Ltd. Stabilized fat-soluble vitamin compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE STN HCAPLUS 1 January 1900 (1900-01-01), XP002910240, Database accession no. 83-723373 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8158162B2 (en) 2001-11-14 2012-04-17 Jarrow Formulas, Inc. Eutectic-based self-nanoemulsified drug delivery system
US8790723B2 (en) 2001-11-14 2014-07-29 Jarrow Formulas, Inc. Eutectic-based self-nanoemulsified drug delivery system
EP1474992A4 (fr) * 2002-01-18 2005-04-13 Kaneka Corp Aliments enrichis en ubiquinone
AU2003203261B2 (en) * 2002-01-18 2007-11-29 Kaneka Corporation Ubiquinone-enriched foods
US7678404B2 (en) 2002-01-18 2010-03-16 Kaneka Corporation Ubiquinone-enriched foods
US8932584B2 (en) 2003-09-29 2015-01-13 Soft Gel Technologies, Inc. Solubilized CoQ-10
US8865032B2 (en) 2003-09-29 2014-10-21 Soft Gel Technologies, Inc. Method of making a soft gel capsule comprising CoQ-10 solubilized in a monoterpene
US8932585B2 (en) 2003-09-29 2015-01-13 Soft Gel Technologies, Inc. Solubilized CoQ-10
US10166192B2 (en) 2003-09-29 2019-01-01 Soft Gel Technologies, Inc. Solubilized CoQ-10
US10166193B2 (en) 2003-09-29 2019-01-01 Soft Gel Technologies, Inc. Method of making a soft gel capsule comprising CoQ-10 solubilized in a monoterpene
US10314793B2 (en) 2003-09-29 2019-06-11 Soft Gel Technologies, Inc. Solubilized CoQ-10
US9345672B2 (en) 2007-03-15 2016-05-24 Soft Gel Technologies, Inc. Ubiquinol and alpha lipoic acid compositions
CN109394725A (zh) * 2018-12-05 2019-03-01 天津铸源健康科技集团有限公司 一种辅酶q10软胶囊及其制备方法

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Publication number Publication date
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