WO2001001955A1 - Formulation comprenant un antifongique, a administrer par voie nasale - Google Patents

Formulation comprenant un antifongique, a administrer par voie nasale Download PDF

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Publication number
WO2001001955A1
WO2001001955A1 PCT/EP2000/005679 EP0005679W WO0101955A1 WO 2001001955 A1 WO2001001955 A1 WO 2001001955A1 EP 0005679 W EP0005679 W EP 0005679W WO 0101955 A1 WO0101955 A1 WO 0101955A1
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WO
WIPO (PCT)
Prior art keywords
formulation
cyclodextrin
antifungal
formulation according
sch
Prior art date
Application number
PCT/EP2000/005679
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English (en)
Inventor
Marc Karel Jozef FRANÇOIS
Urbain Alfons Lieven Delaet
Original Assignee
Janssen Pharmaceutica N.V.
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 Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to AU59757/00A priority Critical patent/AU5975700A/en
Publication of WO2001001955A1 publication Critical patent/WO2001001955A1/fr

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Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention concerns novel formulations comprising an antifungal agent having a low solubility in aqueous media, a process for preparing said formulations and pharmaceutical dosage forms comprising said novel formulations for nasal administration.
  • Formulations containing antifungals can be administered intranasally to treat patients suffering from fungal inflammations or fungal infections, more in particular fungus- associated mucosal conditions and fungal asthma.
  • the development of efficacious aqueous pharmaceutical compositions of antifungals is often hampered considerably by the fact that they are often only very sparingly soluble in water.
  • the solubility of the antifungals can be increased by formulating them in an extremely acidic medium, e.g. a medium of pH 1.5.
  • solubility may also be increased by adding a significant amount of a co- solvent, such as PEG 400, propylene glycol, glycerol, to the aqueous formulation.
  • a co- solvent such as PEG 400, propylene glycol, glycerol
  • US-4,916,134 describes an oral formulation of a triazole antifungal comprising 60 % (v/v) glycerol and 0.05 % (w/v) 2,3-dihydroxybutanedioic acid.
  • solubility of the azole antifungals can also be increased by complexation with cyclodextrins or derivatives thereof, as described in WO 85/02767 and US-4,764,604 .
  • the aqueous formulations comprising cyclodextrins have an acidic pH and contain a considerable amount of co-solvents. Hostetler et al. (Antimicrobial Agents and Chemotherapy, 1992, 36, pp.
  • a strong acidic pH or a high concentration of co-solvents causes irritation of the nasal mucosa and affects mucociliary function. Especially in the case of nasal washes where large volumes of irrigation solutions have to be applied, these side-effects have to be avoided.
  • the present invention concerns a formulation for nasal administration comprising an antifungal and a sufficient amount of a cyclodextrin or a derivative thereof characterized in that the bulk liquid carrier of said formulation is an aqueous buffered solution having a pH ranging from 6.0 to 8.0.
  • the bulk liquid carrier of said formulation is an aqueous buffered solution having a pH ranging from 6.0 to 8.0.
  • the formulation according to the present invention is suitable for treating patients suffering from fungal inflammations or fungal infections, particularly for treating patients with fungus-associated mucosal conditions, such as fungal sinusitis, fungal rhinosinusitis, allergic fungal sinusitis, fungus balls in the sinuses, fungal asthma, fungus-induced bronchial pulmonary allergy.
  • the formulations of the present invention are preferably topically, more in particular intranasally, administered to treat the above mentioned conditions.
  • Suitable antifungals in the present invention are itraconazole, saperconazole, ketoconazole, fluconazole, miconazole, clotrimazole, voriconazole, econazole, isoconazole, bifonazole, lanoconazole, sertaconazole, orconazole, doconazole, parconazole, elubiol, terconazole, butoconazole, oxiconazole, sulconazole, flucytosine, amphotericine B, SCH-39304, SCH- 42427, SCH-42538, SCH-45012, SCH-51048, UR-9746, UR-9751, UK-109496, (2S-cis)- l-[4-[4-[4-[4-[[4-[[4-[[4-[4-[[4-[4-[[4-(4-(2,4-difluorophenyl)-4
  • the concentration of the antifungal in the formulation depends on the actual antifungal being used and the fungus that has to be tackled.
  • the concentration of the antifungal typically ranges from about 0.001% to about 0.1% (w/v), and preferably is 0.01% (w/v).
  • cyclodextrin derivatives are ⁇ -, ⁇ , ⁇ -cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with Ci .galkyl, particularly methyl, ethyl or isopropyl; hydroxyCi _6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxy-butyl; carboxyCi .galkyl, particularly carboxymethyl or carboxyethyl; C ⁇ _6alkyl-carbonyl, particularly acetyl; C ⁇ .galkyloxycarbonylCi.galkyl or carboxyCi- ⁇ alkyl-oxyCi .galkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C ⁇ _6alkylcarbonyloxyCi-6alkyl, particularly 2-acetyloxypropyl.
  • complexants and/or solubilizers are ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD.
  • substituted cyclodextrins include sulfobutylcyclodextrins
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
  • the average molar substitution is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose.
  • the M.S. is in the range of 0.125 to 10, in particular of 0.3 to 3, or from 0.3 to 1.5.
  • the M.S. ranges from about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and most particularly is about 0.4.
  • M.S. values determined by NMR of IR preferably range from 0.3 to 1, in particular from 0.55 to 0.75.
  • the average substitution degree refers to the average number of substituted hydroxyls per anhydroglucose unit.
  • the D.S. is in the range of 0.125 to 3, in particular of 0.2 to 2 or from 0.2 to 1.5.
  • the D.S. ranges from about 0.2 to about
  • D.S. values determined by NMR of IR preferably range from 0.3 to 1, in particular from 0.55 to
  • ⁇ - and ⁇ -cyclodextrin hydroxyalkyl derivatives for use in the compositions according to the present invention are partially substituted cyclodextrin derivatives wherein the average degree of alkylation at hydroxyl groups of different positions of the anhydroglucose units is about 0% to 20% for the 3 position, 2% to 70% for the 2 position and about 5% to 90% for the 6 position.
  • the amount of unsubstituted ⁇ - or ⁇ - cyclodextrin is less than 5% of the total cyclodextrin content and in particular is less than 1.5%.
  • Another particularly interesting cyclodextrin derivative is randomly methylated ⁇ - cyclodextrin.
  • cyclodextrin derivatives for use in the present invention are those partially substituted ⁇ -cyclodextrin ethers or mixed ethers having hydroxypropyl, hydroxyethyl and in particular 2-hydroxypropyl and/or 2-(l -hydroxypropyl) substituents.
  • the most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl- ⁇ -cyclodextrin having a M.S. in the range of 0.35 to 0.50 and containing less than 1.5% unsubstituted ⁇ -cyclodextrin.
  • M.S. values determined by NMR or IR preferably range from 0.55 to 0.75.
  • cyclodextrin may be directed by the ability of the selected drug compound to be complexed by a particular cyclodextrin - thus the cyclodextrins with greater affinity for the particular drug compound may be preferred.
  • cyclodextrins can be prepared according to procedures described in US-3,459,731, EP-A-0,149,197, EP-A-0,197,571, US-4,535,152, WO-90/12035 and GB-2, 189,245.
  • Other references describing cyclodextrins for use in the compositions according to the present invention, and which provide a guide for the preparation, purification and analysis of cyclodextrins include the following : "Cyclodextrin Technology” by J ⁇ zsef Szejtli, Kluwer Academic Publishers (1988) in the chapter Cyclodextrins in Pharmaceuticals; "Cyclodextrin Chemistry” by M.L.
  • the formulations according to the present invention typically comprise from about 0.1% to about 20% (w/v) of cyclodextrins or a derivative thereof, preferably from about 2.5% to about 15% (w/v), and more preferably about 10% (w/v).
  • the weight ratio of cyclodextrin to antifungal preferably ranges from about 250 to about
  • an alcoholic co-solvent may optionally be employed in the formulations according to the present invention.
  • First dissolving the antifungal in a suitable co-solvent followed by mixing this solution with an aqueous cyclodextrin medium considerably shortens and simplifies the production process.
  • Particular suitable alcoholic co-solvents are ethanol, propylene glycol, glycerol, polyethylene glycol, tetraglycol, glycofurol, with propylene glycol being preferred.
  • the concentration of the alcoholic co-solvent preferably ranges from about 0.01% to about 1% (v/v), more preferably from about 0.1% to about 0.5% (v/v), and most preferred is about 0.25% (v/v).
  • an aqueous buffered medium having a pH ranging from 6.0 to 8.0, preferably having a pH of 7.0. Buffering close to a neutral pH renders the nasal formulation more tolerable, it reduces irritation of the nasal mucosa and hence, it increases patient compliance.
  • the bulk liquid carrier of the present invention can be buffered by using a pharmaceutically acceptable buffer system, such as, for example, an acetate, citrate, carbonate, borate, phosphate, TRIS buffer, with a phosphate buffer being preferred.
  • a pharmaceutically acceptable buffer system such as, for example, an acetate, citrate, carbonate, borate, phosphate, TRIS buffer, with a phosphate buffer being preferred.
  • the water making up the bulk liquid carrier is preferably water for injections, purified water, or demineralized water, water for injections being preferred.
  • Typical pharmaceutically acceptable tonicity adjusting agents include sodium chloride, potassium nitrate, dextrose, mannitol, sorbitol, lactose, boric acid, sodium tartrate, propylene glycol, glycerol, and other organic and anorganic solutes.
  • Sodium chloride is preferred, especially when combined with a sodium containing buffer system.
  • the amount of the tonicity adjusting agents is dependent upon the concentration and the degree of dissociation of the other excipients.
  • the formulations can also optionally contain other additives such as one or more preservatives in order to increase the shelf life of the formulation.
  • Pharmaceutically acceptable preservatives include quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride, benzododecinium chloride, cetyl pyridium chloride, cetrimide, domiphen bromide; alcohols such as benzyl alcohol, chlorobutanol, o-cresol, chlorocresol, phenol, phenyl ethyl alcohol, glycerol, propylene glycol; organic acids or salts and derivatives thereof such as benzoic acid, sodium benzoate, potassium sorbate, parabens, thiomersal, phenylmercuri nitrate,-borate,-acetate, chloorhexidine diacetate,- digluconate; or complex forming agents such as EDTA.
  • the concentration of the preservative will range from 0% to 2% (w/w), depending on the actual preservative being used.
  • preservatives are preferably omitted from the formulation as to avoid irritation, toxicity and impairment of mucociliary function associated with the application of a large volume.
  • An interesting formulation according to the present invention comprises by weight or volume based on the total volume of the formulation : (a) 0.01% (w/v) itraconazole; (b) 10% (w/v) hydroxypropyl- ⁇ -cyclodextrin;
  • the present invention also relates to a process of preparing a formulation for nasal administration comprising the steps of (a) dissolving the antifungal in an acid, optionally in combination with an alcoholic co- solvent;
  • the above general route of preparation of the formulation of the present invention may be modified by a person skilled in the art by for instance adding certain ingredients at other stages than indicated above.
  • the antifungal can also be dissolved in a solution of cyclodextrin, acid and water.
  • the formulation of the present invention can be provided in any pharmaceutically acceptable form suitable for being introduced into the nostrils and sinus cavities, such as nasal spray bottles, droppers, nasal irrigations, lavages or washes, nasal injections, inhalers or atomizer-type squeeze or pump bottles, all being suitable among other delivery means and being provided with suitable devices for nasal administration, such as inhalers, nebulizers, masks, syringes, sprayers, canisters, tubes.
  • the formulation of the present invention is preferably provided in a pharmaceutically acceptable form suitable for nasal irrigation or lavage.
  • the volume administered into the nostrils and sinus cavities preferably ranges from 0.01 ml to 100 ml per nostril, more preferably ranges from 10 to 30 ml per nostril, and most preferably is about 20 ml per nostril.
  • the frequency of the nasal administration will typically range from about 3 to 4 times daily to only once every month, depending on the severity of the condition being treated.
  • the formulations of the present invention are preferably sterilized by using conventional sterilization methods, such as by heating in an autoclave, using moist heat, dry heat, filtration, ultra-violet light, radiation, gaseous sterilization.
  • conventional sterilization methods such as by heating in an autoclave, using moist heat, dry heat, filtration, ultra-violet light, radiation, gaseous sterilization.
  • a further aspect of the present invention provides the use of the above formulation as a medicine, especially the use for the manufacture of a medicament for treating patients suffering from fungal sinusitis, fungal rhinosinusitis, allergic fungal sinusitis, fungus balls in the sinuses, fungal asthma, fungus-induced bronchial pulmonary allergy.
  • a method of treating a patient suffering from these conditions by administering the nasal formulation of the present invention is provided.
  • composition of the nasal antifungal formulation 0.01% (w/v) itraconazole; 10% (w/v) hydroxypropyl- ⁇ -cyclodextrin; 0.25% (v/v) propylene glycol; 0.376 ⁇ l 12 N HCl;
  • O.Olg of itraconazole was dissolved in 250 ⁇ l propylene glycol and 37.6 ⁇ l 12 N HCl. lOg of hydroxypropyl- ⁇ -cyclodextrin was dissolved in water and the itraconazole solution was added while stirring until a homogeneous solution was obtained. NaOH was added to adjust the pH of the solution to 7.0. Sodium chloride was added to make the formulation isotonic compared to blood. Aqueous NaH 2 PO 4 .H 2 O/Na 2 HPO 4 buffer of pH 7.0 was added to bring the total volume of the formulation up to 100ml.

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  • 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)
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Abstract

L'invention concerne des nouvelles formulations comprenant un agent antifongique possédant une faible solubilité dans un milieu aqueux, un procédé de préparation desdites formulations et des formes posologiques comprenant lesdites nouvelles formulations à administrer par voie nasale.
PCT/EP2000/005679 1999-07-02 2000-06-20 Formulation comprenant un antifongique, a administrer par voie nasale WO2001001955A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59757/00A AU5975700A (en) 1999-07-02 2000-06-20 Nasal formulation of an antifungal

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP99202170 1999-07-02
EP99202170.9 1999-07-02

Publications (1)

Publication Number Publication Date
WO2001001955A1 true WO2001001955A1 (fr) 2001-01-11

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6824763B2 (en) 2002-05-30 2004-11-30 Kimberly-Clark Worldwide, Inc. Anti-fungal powder having enhanced excipient properties
WO2005082416A2 (fr) * 2004-01-30 2005-09-09 Pfizer Products Inc. Conservateurs antimicrobiens permettant l'obtention d'une formulation multi-dose au moyen de beta-cyclodextrines pour des formes posologiques liquides
WO2007140614A1 (fr) * 2006-06-09 2007-12-13 Camille Toutounghi Formulation nasale
WO2009102814A2 (fr) * 2008-02-11 2009-08-20 Accentia Biopharmaceuticals, Inc. Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon
CN103251565A (zh) * 2013-04-09 2013-08-21 珠海亿邦制药股份有限公司 一种注射用伏立康唑冻干粉针剂及其制备方法
US20170275388A1 (en) * 2014-08-22 2017-09-28 Cydex Pharmaceuticals, Inc. Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same
US10633462B2 (en) 2012-02-15 2020-04-28 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
US10780177B2 (en) 2008-04-28 2020-09-22 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions
US10800861B2 (en) 2012-10-22 2020-10-13 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985002767A1 (fr) * 1983-12-21 1985-07-04 Janssen Pharmaceutica N.V. Compositions pharmaceutiques contenant des medicaments instables ou peu solubles dans l'eau et leurs procedes de preparation
EP0468392A1 (fr) * 1990-07-27 1992-01-29 Jagotec Ag Procédé pour la préparation de compositions pharmaceutiques à vitesse de dissolution des substances actives élevée, et les compositions obtenues
EP0579435A1 (fr) * 1992-07-14 1994-01-19 CYCLOPS h.f. Complexation à l'amide de cyclodextrines
WO1995008993A1 (fr) * 1993-09-30 1995-04-06 Janssen Pharmaceutica N.V. Formulations orales pour un antifongique
WO1998055148A1 (fr) * 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO1999020261A2 (fr) * 1997-10-22 1999-04-29 Jens Ponikau Procedes et substances destines au traitement et a la prevention de l'inflammation de tissus muqueux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985002767A1 (fr) * 1983-12-21 1985-07-04 Janssen Pharmaceutica N.V. Compositions pharmaceutiques contenant des medicaments instables ou peu solubles dans l'eau et leurs procedes de preparation
EP0468392A1 (fr) * 1990-07-27 1992-01-29 Jagotec Ag Procédé pour la préparation de compositions pharmaceutiques à vitesse de dissolution des substances actives élevée, et les compositions obtenues
EP0579435A1 (fr) * 1992-07-14 1994-01-19 CYCLOPS h.f. Complexation à l'amide de cyclodextrines
WO1995008993A1 (fr) * 1993-09-30 1995-04-06 Janssen Pharmaceutica N.V. Formulations orales pour un antifongique
WO1998055148A1 (fr) * 1997-06-05 1998-12-10 Janssen Pharmaceutica N.V. Compositions pharmaceutiques comprenant des cyclodextrines
WO1999020261A2 (fr) * 1997-10-22 1999-04-29 Jens Ponikau Procedes et substances destines au traitement et a la prevention de l'inflammation de tissus muqueux

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6824763B2 (en) 2002-05-30 2004-11-30 Kimberly-Clark Worldwide, Inc. Anti-fungal powder having enhanced excipient properties
US8183230B2 (en) 2004-01-30 2012-05-22 Pfizer Inc. Antimicrobial preservatives to achieve multi-dose formulation using beta-cyclodextrins for liquid dosage forms
WO2005082416A2 (fr) * 2004-01-30 2005-09-09 Pfizer Products Inc. Conservateurs antimicrobiens permettant l'obtention d'une formulation multi-dose au moyen de beta-cyclodextrines pour des formes posologiques liquides
WO2005082416A3 (fr) * 2004-01-30 2006-07-27 Pfizer Prod Inc Conservateurs antimicrobiens permettant l'obtention d'une formulation multi-dose au moyen de beta-cyclodextrines pour des formes posologiques liquides
WO2007140614A1 (fr) * 2006-06-09 2007-12-13 Camille Toutounghi Formulation nasale
WO2009102814A3 (fr) * 2008-02-11 2009-12-03 Accentia Biopharmaceuticals, Inc. Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon
WO2009102814A2 (fr) * 2008-02-11 2009-08-20 Accentia Biopharmaceuticals, Inc. Formulation d'amphotéricine b liquide n'irritant pas les muqueuses, et procédé pour traiter une mucosite non invasive induite par champignon
US10780177B2 (en) 2008-04-28 2020-09-22 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions
US11806402B2 (en) 2008-04-28 2023-11-07 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions
US11208500B2 (en) 2012-02-15 2021-12-28 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
US10633462B2 (en) 2012-02-15 2020-04-28 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
US10800861B2 (en) 2012-10-22 2020-10-13 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
CN103251565A (zh) * 2013-04-09 2013-08-21 珠海亿邦制药股份有限公司 一种注射用伏立康唑冻干粉针剂及其制备方法
US20170275388A1 (en) * 2014-08-22 2017-09-28 Cydex Pharmaceuticals, Inc. Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same
US11795241B2 (en) 2014-08-22 2023-10-24 Cydex Pharmaceuticals, Inc. Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same
US10851184B2 (en) * 2014-08-22 2020-12-01 Cydex Pharmaceuticals, Inc. Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same

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