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WO2002067992A2 - Compositions medicamenteuses a meilleure solubilite - Google Patents

Compositions medicamenteuses a meilleure solubilite Download PDF

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Publication number
WO2002067992A2
WO2002067992A2 PCT/US2002/004368 US0204368W WO02067992A2 WO 2002067992 A2 WO2002067992 A2 WO 2002067992A2 US 0204368 W US0204368 W US 0204368W WO 02067992 A2 WO02067992 A2 WO 02067992A2
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WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
tpgs
drug
monoester
mono
Prior art date
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Ceased
Application number
PCT/US2002/004368
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English (en)
Inventor
Stephen Hong-Wei Wu
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Eastman Chemical Co
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Eastman Chemical Co
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Filing date
Publication date
Application filed by Eastman Chemical Co filed Critical Eastman Chemical Co
Publication of WO2002067992A2 publication Critical patent/WO2002067992A2/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • This invention relates to drug compositions having enhanced water- solubility.
  • the water solubility of hydrophobic drugs is improved by blending the drug(s) with a mono-ester tocopheryl polyethylene glycol succinate (mono-TPGS), and optionally, an organic adjuvant.
  • mono-TPGS mono-ester tocopheryl polyethylene glycol succinate
  • TPGS Tocopheryl polyethylene glycol succinate
  • U.S. Patent No. 5,364,631 describes the use of TPGS as a stabilizer to allow formation of, or maintenance of, the bilayer based liposomes in an acidic environment.
  • U.S. Patent No. 5,447,729 describes a pharmaceutical preparation wherein a pharmaceutical agent is incorporated into particles comprising a core formed from a hydrophilic material, a hydrophobic material or a hydrophobic emulsion or dispersion, and an alternating sequence of hydrophilic/hydrophobic layers, wherein TPGS is used as a component.
  • U.S. Patent No. 5,583,105 describes an emulsion preconcentrate composition containing cyclosporin, ethanol, a lipophilic and/or amphiphilic solvent, wherein TPGS is disclosed as an emulsifier and adjuvant, and an oxidative inhibitor for fatty oils in the composition.
  • 5,558,876 describes a topical ophthalmic formulation comprising an acidic drug, TPGS, benzalkonium chloride, and caffeine, wherein TPGS is used to solubilize the acidic drug and reduce ocular discomfort.
  • U.S. Patent No. 5,545,407 describes a dermatological composition for treating skin lesions comprising benzoyl peroxide, a topical carrier, and a compound for reducing skin irritation such as TPGS.
  • U.S. Patent No. 5,891 ,845 describes a pharmaceutical composition comprising a solid solution of active drug components and TPGS that provides controlled release of the drugs into the gastrointestinal tract.
  • U.S. Patent No. 5,179,122 describes a solid composition comprising vitamin E acetate, TPGS and an inert carrier.
  • a composition comprising a monoester tocopheryl polyethylene glycol succinate (mono-TPGS) and an organic adjuvant that is particularly suitable for enhancing the water-solubility of a hydrophobic drug.
  • compositions comprising a hydrophobic drug and mono-TPGS, and optionally an organic adjuvant, wherein the compositions are preferably characterized by enhanced water solubility of the hydrophobic drug.
  • a process for enhancing the water solubility characteristic of a hydrophobic drug comprising mixing the hydrophobic drug with mono-TPGS, or with a composition comprising mono-TPGS and an organic adjuvant.
  • a composition comprising a monoester tocopheryl polyethylene glycol succinate (mono-TPGS) and an organic adjuvant that is particularly suitable for enhancing the water-solubility of a hydrophobic drug.
  • compositions comprising a hydrophobic drug and mono-TPGS, and optionally an organic adjuvant, wherein the compositions are preferably characterized by enhanced water solubility of the hydrophobic drug.
  • a process for enhancing the water solubility characteristic of a hydrophobic drug comprising mixing the hydrophobic drug with mono-TPGS, or with a composition comprising mono-TPGS and an organic adjuvant.
  • the compositions comprising mono-TPGS and an organic adjuvant are described in more detail.
  • the mono-TPGS used herein may be produced by any method known in the art. For example, a method that can be employed involves initially producing tocopheryl polyethylene glycol succinate (herein TPGS) by esterifying tocopheryl acid succinate (herein TAS) with polyethylene glycol (herein PEG), in accordance with the process described in U.S. Patent No.2,680,749, incorporated herein by reference. As mentioned in the U.S.
  • esterification of tocopheryl acid esters with polyethylene glycol is a well known procedure.
  • the esterification procedure is said to be desirably effected in a solvent media; promoted by any well known esterification catalyst; desirably effected at elevated temperatures, with water formed during the esterification being removed by azeotropic distillation.
  • the polyethylene glycol (PEG) used in the esterification of the tocopheryl acid succinate (TAS) preferably has a number average molecular weight ranging from 300 to 6000, with a preferred range of from 400 to . 1500.
  • the resulting polyethylene glycol ester of tocopheryl acid succinate is then contacted by any method known in the art to provide the mono-ester tocopheryl polyethylene glycol succinate (mono-TPGS).
  • TPGS polyethylene glycol ester of tocopheryl acid succinate
  • the TPGS was contacted to yield the mono-TPGS by using a conventional preparation high pressure liquid chromatograph (HPLC) method.
  • HPLC high pressure liquid chromatograph
  • a TPGS sample was dissolved in isopropyl alcohol at 30 weight percent.
  • a 2-inch diameter reversed phase column Utilized herein was Dynamax high performance analytical and preparative column (Varian Inc., California).
  • the column was loaded with a solvent system for the separation.
  • a step gradient program was used throughout the experiment.
  • the solvent system consisted of a combination of acetonitrile (ACN) and isopropyl alcohol (IPA) ranging from 80% ACN/20% IPA to 100% IPA, by weight.
  • the pumps of the HPLC were started and the ultraviolet detector of the HPLC system was turned on. The system was then allowed to run for a few minutes to become stabilized.
  • the injector loop of the HPLC system was loaded with 5 ml of sample solution, and then the sample was injected into the HPLC column.
  • the resultant mono-TPGS is miscible with water.
  • the mono-TPGS is then combined with an organic adjuvant to provide a composition that is particularly suitable for enhancing the water solubility of a hydrophobic drug.
  • Any non-volatile or volatile organic adjuvant is suitable for use herein provided that the organic adjuvant is miscible with the mono-TPGS.
  • the amounts of mono-TPGS and organic non-volatile adjuvant present in the composition are such that the weight ratio of mono-TPGS to non-volatile (boiling point above 260°C) organic adjuvant is greater than 80:20, preferably greater than 85:15, up to a maximum of 99:1.
  • the weight ratio of mono- TPGS to volatile organic adjuvant is at least 30:70, preferably at least 50:50, up to a maximum of 99:1.
  • the compositions of mono-TPGS and organic adjuvant may be prepared by any method known in the art, such as by admixing or blending the components, or the like. In preparing the compositions of the mono-TPGS and the organic adjuvant, if desired, more than one organic adjuvant may be used.
  • the compositions of mono-TPGS and organic adjuvant must be soluble, dispersible, or miscible with water.
  • any organic adjuvant that is miscible with the mono- TPGS is suitable for use in the present invention.
  • exemplary organic adjuvants suitable for use herein include diester tocopheryl polyethylene glycol succinate, polyethylene glycol, ethanol, propylene glycol, glycofurol, a lipid material such as vegetable oils, medium chain glycerides, vitamin E oils, an emulsifier having an HLB value of 4-12, triacetin, diethyl phthalate, triethyl citrate, sucrose acetate isobutyrate, glycerin, monoglycerides, acetylated monoglycerides, ethoxylated castor oil, fatty acid based emulsifiers suitable for pharmaceutical applications, and the like.
  • compositions of the present invention comprising mono-TPGS and at least one organic adjuvant.
  • compositions comprising any hydrophobic drug and mono-TPGS or a composition comprising mono-TPGS and at least one, or more, organic adjuvant, as described herein.
  • the drug compositions of the present invention comprising mono-TPGS, or a composition comprising mono- TPGS and at least one organic adjuvant, are prepared by any method known in the art.
  • the components of the composition may be admixed or blended, or the like.
  • the components were prepared as follows:
  • Mono-TPGS was liquefied at a temperature above its melting temperature, and the drug was then dissolved in the liquefied mono-TPGS. Heat may be used to ensure that the drug was completely dissolved in the liquefied mono-TPGS. The mixture was cooled to solidify. If desired, other excipients can be mixed with the mixture. Further an organic adjuvant can be added to the mixture of drug and mono-TPGS. The resulting mixture was then admixed with water.
  • An alternative procedure that may be used involves dissolving mono- TPGS, optionally with an organic adjuvant, in water, and then admixing the drug in the mono-TPGS solution.
  • compositions there may be used varied amounts of hydrophobic drug and mono-TPGS, or composition of mono-TPGS and at least one organic adjuvant as follows.
  • the weight ratio of drug to mono-TPGS, or to composition mono-TPGS and organic adjuvant varies from 1 :100 to 3:1.
  • any organic adjuvant is usable in preparing the compositions.
  • Any hydrophobic drug may be used as the drug component of the drug-containing composition of the present invention.
  • a hydrophobic drug is a drug, which in its non-ionized form is more soluble in lipid or fat than in water.
  • the water solubility of a hydrophobic drug is usually, but not limited to, less than 0.1 mg/ml.
  • exemplary hydrophobic drugs suitable for use herein include oil-soluble nutrients such as natural and synthetic tocopheryl and their derivatives including vitamin E acetate, vitamin E succinate, diester tocopheryl polyethylene glycol succinate, beta- carotene, coenzyme Q10, and other oil-soluble nutrients.
  • oil-soluble nutrients such as natural and synthetic tocopheryl and their derivatives including vitamin E acetate, vitamin E succinate, diester tocopheryl polyethylene glycol succinate, beta- carotene, coenzyme Q10, and other oil-soluble nutrients.
  • drugs subjected to p-glycoprotein efflux such as cyclosporin, nifedipine, paclitaxes, digoxin and HIV protease inhibitors such as amprenavir.
  • hydrophobic drugs useful herein include griseofulvin, estradiol and its derivatives, fluocinolone acetonide and its derivatives, and triamcinolone acetonide, carbamazapine, hydrocortisone, and ibuprofen.
  • griseofulvin estradiol and its derivatives
  • fluocinolone acetonide and its derivatives fluocinolone acetonide and its derivatives
  • triamcinolone acetonide carbamazapine
  • hydrocortisone hydrocortisone
  • ibuprofen ibuprofen
  • the drug compositions comprising the mono-TPGS, or the composition comprising mono-TPGS and at least one organic adjuvant will have a solubility in water improved or enhanced as compared to the solubility in water of the hydrophobic drug in the absence of the mono- TPGS component of the composition.
  • MWn Molecular Weight (MWn) - Number average molecular weight was determined by calculation based on the number average MW of polyethylene glycol (PEG) and the MW of tocopherol succinate which are added, and then subtracting from the sum, the MW of water.
  • PEG polyethylene glycol
  • °C. Melting Point (MP), °C. was determined by DSC. Differential scanning calorimetry (DSC) was used for determining m. p of PTGS. The instrument used was a Mettler differential scanning calorimeter (Model 821 , Mettler Toledo Inc., Columbus, Ohio). A TPGS sample of about 4.8 mg was placed on the sample holder. The heating and cooling cycles were set between 0°C and 85°C with a 10°C/min heating rate. Cooling was done by liquid nitrogen purge. The melting temperature of TPGS was then determined by the temperature at which abrupt changes of heat absorption curve occurred.
  • M H is the formula weight of the hydrophilic portion of the molecule
  • M is the formula weight of the lipophilic (hydrophobic) portion of the molecule.
  • CMC - critical micelle concentration was determined by measuring the change of surface tension of aqueous solutions of TPGS. The surface tension values were determined by using a tensiometer (model K-10, Kruss USA, Charlotte, NC). The concentration of TPGS in water ranges from 0.0001 to 0.25 wt %. A distinct change of surface tension values at about 0.02 wt % concentration can be determined.
  • vitamin E TPGS NF d-alpha-tocopheryl polyethylene glycol succinate commercially available from Eastman Chemical Company.
  • the vitamin E TPGS NF is described by Eastman as being a water soluble derivative of natural-source vitamin E, and as being prepared by the esterification of the acid group of crystalline d-alpha- tocopheryl acid succinate by polyethylene glycol.
  • the number average molecular weight (MWn) of the polyethylene glycol was 1030.
  • the vitamin E TPGS NF d-alpha-tocopheryl polyethylene glycol succinate was subjected to the preparative HPLC method, described herein, to isolate the mono-TPGS.
  • the HPLC instrument used in this example was Sep Tech 800C, modified with 0.03 inch ID (inside diameter) tubing, Valco unions, and Valco injection valve.
  • Eastman's commercial Vitamin E TPGS NF sample 100 grams was dissolved in isopropyl alcohol at 30 weight percent.
  • the preparative HPLC system for separation utilized a 2-inch reversed phase column.
  • the column used was a Dynamax C18 preparative HPLC column (Varian Inc., CA).
  • the column was loaded with a solvent system.
  • a step gradient program consisting of a combination of acetonitrile (ACN) and isopropyl alcohol (IPA) ranging from 80% ACN/20% IPA, to 0% ACN/100% IPA was used throughout the example.
  • ACN acetonitrile
  • IPA isopropyl alcohol
  • the HPLC pumps were started and the ultraviolet detector was turned on. The system was run for a few minutes to become stabilized.
  • the injector loop was loaded with 5 ml of sample solution, and then the sample was injected into the HPLC column. The components of the sample separated on the column, and the purified mono-TPGS was collected upon exiting the column, using a UV detector at 290 nm. The solvent was evaporated from the collected sample to obtain the purified mono-TPGS.
  • the mono-TPGS was characterized by having a MW n of 1543, a MP of 40°C - 43°C, an HLB value of 13.4, a CMC value of 0.02%, and was miscible with water.
  • Example 2 In this example, there is described the effect on the water solubility of a hydrophobic drug, resulting from mixing with the drug varying amounts of the mono-TPGS prepared in Example 1.
  • the hydrophobic drug used in Example 2 was diester tocopheryl polyethylene glycol succinate (herein di- TPGS).
  • the Example describes the effect on water solubility of solely drug, with no mono-TPGS component, to solely mono-TPGS, in the absence of drug component.
  • the binary mixtures of hydrophobic drug and the mono-TPGS were prepared by admixing mono-TPGS and di-TPGS in liquid form at the ratios of 85/15, 80/20, and 75/25 by weight, respectively, at a temperature of about 60°C.
  • composition comprising the mono-TPGS, the organic adjuvant, and the hydrophobic drug, is expected to have enhanced or improved water solubility.
  • Paclitaxel is a hydrophobic drug that is insoluble in water.
  • the solubility of paclitaxel with, and without, 0.1% of mono-TPGS plus adjuvant in an assay buffer was compared.
  • the assay buffer was Hanks' Balanced Salt Solution which contains 0.14 g/L CaCI 2 , 0.40 g/L KCI, 0.10 g/L MgCI 2 » 6H 2 0, 0.10 g/L MgSO -7H 2 O, 8.00 g/L NaCI, 0.35 g/L NaHCO 3 , and 1.0 g/L D-glucose.
  • HEPES buffer N-2- Hydroxyethylpiperazine-N'-2-Ethane Sulfonic Acid
  • D-glucose D-glucose

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L"invention concerne une nouvelle composition comprenant un succinate monoester de tocophéryl polyéthylène glycol et un adjuvant organique, particulièrement indiqué pour améliorer l"hydrosolubilité d"un médicament hydrophobe. L"invention concerne également de nouvelles compositions médicamenteuses hydrophobes renfermant un médicament hydrophobe et un succinate monoester de tocophéryl polyéthylène glycol, éventuellement avec un adjuvant organique, les compositions médicamenteuses étant de préférence caractérisées par une meilleure hydrosolubilité. L"invention concerne en outre un procédé permettant d"améliorer la solubilité dans l"eau d"un médicament hydrophobe.
PCT/US2002/004368 2001-02-22 2002-02-14 Compositions medicamenteuses a meilleure solubilite Ceased WO2002067992A2 (fr)

Applications Claiming Priority (2)

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US79105801A 2001-02-22 2001-02-22
US09/791,058 2001-02-22

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WO2002067992A2 true WO2002067992A2 (fr) 2002-09-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105228470A (zh) * 2013-03-15 2016-01-06 维尔恩公司 维生素e水溶性衍生物制剂及包含其的组合物
US10285971B2 (en) 2014-09-18 2019-05-14 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
US10668029B2 (en) 2008-03-20 2020-06-02 Virun, Inc. Compositions containing non-polar compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10668029B2 (en) 2008-03-20 2020-06-02 Virun, Inc. Compositions containing non-polar compounds
CN105228470A (zh) * 2013-03-15 2016-01-06 维尔恩公司 维生素e水溶性衍生物制剂及包含其的组合物
JP2016518817A (ja) * 2013-03-15 2016-06-30 バイラン・インコーポレイテッドＶｉｒｕｎ，Ｉｎｃ． ビタミンｅの水溶性誘導体の製品およびそれを含む組成物
US10285971B2 (en) 2014-09-18 2019-05-14 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same

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