WO1999042111A1 - Complexes de cyclodextrine extremement energetiques - Google Patents

Complexes de cyclodextrine extremement energetiques Download PDF

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Publication number
WO1999042111A1
WO1999042111A1 PCT/IS1999/000003 IS9900003W WO9942111A1 WO 1999042111 A1 WO1999042111 A1 WO 1999042111A1 IS 9900003 W IS9900003 W IS 9900003W WO 9942111 A1 WO9942111 A1 WO 9942111A1
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drug
cyclodextrin
complexation
ring
weight
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PCT/IS1999/000003
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English (en)
Inventor
Thorsteinn Loftsson
Mar Masson
Einar Stefansson
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Cyclops, Ehf.
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Priority to EP99906440A priority Critical patent/EP1067942A1/fr
Priority to AU26385/99A priority patent/AU759280C/en
Priority to NZ505951A priority patent/NZ505951A/xx
Priority to CA002320772A priority patent/CA2320772A1/fr
Priority to JP2000532126A priority patent/JP2003522207A/ja
Publication of WO1999042111A1 publication Critical patent/WO1999042111A1/fr
Priority to IS5572A priority patent/IS5572A/is

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    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • the invention relates to methods for enhancing the complexation of a heterocyclic drug with cyclodextrin and to methods for enhancing the availability of a heterocyclic drug following administration of a cyclodextrin-drug complex.
  • Cyclodextrins are a group of structurally related saccharides which are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltransferases. Cyclodextrins are cyclic oligosaccharides, consisting of ( ⁇ - l,4)-linked ⁇ -D-glucopyranose units, with a somewhat lipophilic central cavity and a hydrophilic outer surface. The most common naturally occurring cyclodextrins are ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively. Of these three derivatives, ⁇ -cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability, low cost and other properties.
  • ⁇ -cyclodextrin The natural cyclodextrins, in particular ⁇ -cyclodextrin, have limited aqueous solubility and their complex formation with lipophilic drugs often results in precipitation of solid drag-cyclodextrin complexes.
  • solubility of ⁇ - cyclodextrin in water is only about 18.5 mg/ml at room temperature.
  • This low aqueous solubility is, at least partly, associated with strong intramolecular hydrogen bonding in the cyclodextrin crystal lattice. Substitution of any of the hydrogen bond-forming hydroxyl groups, even by hydrophobic moieties such as methoxy groups, will increase the aqueous solubility of ⁇ -cyclodextrin.
  • these manipulations since these manipulations frequently produce large numbers of isomeric -2-
  • chemical modification can transform the crystalline cyclodextrins into amorphous mixtures increasing their aqueous solubility.
  • Cyclodextrin derivatives of current pharmaceutical interest include the hydroxypropyl derivatives of ⁇ -, ⁇ - and ⁇ -cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether ⁇ -cyclodextrin, alkylated cyclodextrins such as the randomly methylated ⁇ -cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl- ⁇ -cyclodextrin (T. Loftsson and M.E. Brewster, "Cyclodextrins as pharmaceutical excipients", Pharm. Technol. Eur.
  • cyclodextrins form complexes with many drugs through a process in which the water molecules located in the central cavity are replaced by either the whole drug molecule, or more frequently, by some lipophilic portion of the drug structure.
  • the drug molecules may be dissociated through complex dilution, by replacement of the included drug by some other suitable molecule (such as dietary lipids or bile salts in the GI tract) or, if the complex is located in close approximation to a lipophilic biological membrane (such as the mucosal membrane of the GI tract), the drug may be transferred to the matrix for which it has the highest affinity.
  • the suspension formed is equilibrated (for periods of up to one week at the desired temperature) and then filtered or centrifuged to form a clear drug-cyclodextrin complex solution. Since the rate determining step in complex formation is often the phase to phase transition of the drug molecule, it is sometimes possible to shorten this process by formation of supersaturated solutions through sonication followed by precipitation.
  • the water is removed from the aqueous drug-cyclodextrin solutions by evaporation or sublimation, e.g. spray-drying or freeze-drying.
  • kneading methods can also be applied to prepare solid drug- cyclodextrin complexes including kneading methods, co-precipitation, neutralization and grinding techniques.
  • kneading method the drug is added to an aqueous slurry of a poorly water-soluble cyclodextrin such as ⁇ -cyclodextrin.
  • the mixture is thoroughly mixed, often at elevated temperatures, to yield a paste which is then dried.
  • This technique can frequently be modified so that it can be accomplished in a single step with the aid of commercially available mixers which can be operated at temperatures over 100 °C and under vacuum.
  • the kneading method is a cost-effective means for preparing solid cyclodextrin complexes of poorly water-soluble drugs. Co-precipitation of a cyclodextrin complex through addition of organic solvent is also possible. Unfortunately, the organic solvents used as precipitants can interfere with complexation which makes this approach less attractive than the kneading method. However, we have discovered that some organic solvents under some specific conditions, e.g. 10% (v/v) aqueous acetic acid solution, can enhance the complexation.
  • Solid complexes of ionizable drugs can sometimes be prepared by the neutralization method wherein the drug is dissolved in an acidic (for basic drugs) or basic (for acidic drugs) aqueous cyclodextrin solution. The solubility of the drug is then lowered through appropriate pH adjustments (i.e. formation of the unionized drug) to force the complex out of solution. Finally, solid drug-cyclodextrin complexes can be formed by the grinding of a physical mixture of the drug and cyclodextrin and then heating the mixture in a sealed container to 60 to 90 °C.
  • Drug ionization can increase the complexation efficiency through increase in S 0 .
  • Addition of certain low molecular weight acids, such as acetic, citric, malic, or tartaric acid, to aqueous complexation media can enhance cyclodextrin solubilization of basic drugs through increase in S 0 (i.e. salt formation, pH changes and lowering melting point) and/or increase in the apparent K c .
  • Water-soluble polymers can increase the complexation efficiency through increase in the apparent K Q .
  • cyclodextrin molecules are relatively large (molecular weight ranging from almost 1000 to over 1500), with a hydrated outer surface, and under normal conditions, cyclodextrin molecules will only permeate biological membranes with considerable difficulty (R.A. Rajewski and V.J. Stella, "Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery", J. Pharm. Sci. 85(11), 1142-1168 (1996); T. Irie and K. Uekama, "Pharmaceutical applications of cyclodextrins. 3. Toxicological issues and safety evaluation", J. Pharm. Sci. -6-
  • cyclodextrins act as true carriers by keeping the hydrophobic drug molecules in solution and deliver them to the surface of the biological membrane, e.g. skin, mucosa or the eye cornea, where they partition into the membrane.
  • the relatively lipophilic membrane has low affinity for the hydrophilic cyclodextrin molecules and therefore they remain in the aqueous membrane exterior, e.g. the aqueous vehicle system, salvia or the tear fluid.
  • Conventional penetration enhancers such as alcohols and fatty acids, disrupt the lipid layers of the biological barrier.
  • Cyclodextrins act as penetration enhancers by increasing drug availability at the surface of the biological barrier.
  • CD cyclodextrin
  • K c apparent stability constant of the drug-cyclodextrin complex
  • S 0 apparent intrinsic solubility of the drug.
  • K c can be increased by addition of water-soluble polymers to the aqueous complexation media and S 0 can be increased by ionization of the drug molecule, as described previously.
  • increased complexation efficiency by itself does not necessarily result in increased drug availability in the aqueous complexation media or increased drug availability from solid drug-cyclodextrin complexes.
  • the drug-cyclodextrin complexes are prepared under conditions which ensure enhanced complexation and if the complexation efficiency decreases upon administration, then enhanced drug availability will be observed.
  • the present invention involves: i) enhancement of the complexation efficiency and ii) reduction of the complexation efficiency after administration.
  • ionizable drugs For example, it is possible to enhance the complexation efficiency of many ionizable drugs by preparing the complexes at a pH where the drug is ionized but obtain decreased efficiency upon administration due to pH changes and consequent decreased ionization.
  • phenytoin pKa 8.1
  • Its solubility in water at room temperature (25 °C) is only 18 ⁇ g/ml at pH 5 and 32 ⁇ g/ml at pH 8 (P. A. Schwartz, C.T. Rhodes and J.W. Cooper, "Solubility and ionisation characters of phenytoin" , J. Pharm.
  • K Q can, for example, be increased by addition of certain low molecular weight acids, by addition of water-soluble polymers to the aqueous complexation media or by using mixed solvent systems such as aqueous 10% (v/v) acetic acid.
  • a method for enhancing the complexation efficacy, i.e. efficiency, of a drug with cyclodextrin said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said drug to chemically reversible ring-opening so that at least a portion (at least 0.1 % by weight) thereof is in ring-opened form, and complexing said drug with cyclodextrin.
  • a method for enhancing the complexation efficiency of a drug with cyclodextrin said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal -10-
  • said method comprising complexing said drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring- opening of at least a portion (at least 0.1 % by weight) of said drug.
  • a method for enhancing the availability of a drug following administration of a cyclodextrin- drug complex to a warm-blooded animal in need of same said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imine, hemiacetal or hemiketal, said method comprising complexing said drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring-opening of at least a portion (at least 0.1 % by weight) of said drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.
  • the present invention provides a method for enhancing the availability of a basic drug (i.e. a proton acceptor) following administration of a cyclodextrin-drug complex to a warm-blooded animal in need of same, said basic drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said basic drug to complexation in an aqueous medium at a pH level below the pKa+2 value of said basic drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.
  • a basic drug i.
  • the present invention provides a method for enhancing the availability of an acidic drug following administration of a cyclodextrin-drug complex to a warm-blooded animal in need of same, said acidic drug having a structure comprising at least one heterocyclic ring having a total of 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said acidic drug to complexation in an aqueous medium at a pH level above the pKa-2 value of said acidic drug to enhance the complexation efficiency, followed by administering the cyclodextrin- drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.
  • Fig. 1 is a graph illustrating the effect of pH on the phase-solubility of phenytoin (pKa 8.1) in aqueous hydroxypropyl- ⁇ -cyclodextrin (HP ⁇ CD) solutions at 25°C at pH 10.19 ( ⁇ ); pH 7.55 ( ⁇ ) and pH 2.74 (•);
  • Fig. 2 is a graph illustrating the effect of pH on the solubility of alprazolam (pKa 2.4) in aqueous 10% (w/v) HP ⁇ CD solutions at room temperature;
  • Fig. 3 is a graph illustrating the effect of pH (i.e. the diazepine ring- opening) on the solubility of midazolam (pKa 6.2) in pure aqueous buffer solutions (•), aqueous buffer solutions containing 10% (w/v) HP ⁇ CD ( ⁇ ) and aqueous buffer solutions containing both 10% (w/v) HP ⁇ CD and 0.10% (w/v) hydroxypropyl methylcellulose (HPMC) ( ⁇ ) at room temperature;
  • pH i.e. the diazepine ring- opening
  • Fig. 4 is a graph illustrating the effects of cyclodextrins, pH and 10% (v/v) acetic acid on the solubility of midazolam in aqueous solutions: pure aqueous buffer solution (A); aqueous 10% (v/v) acetic acid solution (•); 10% w/v HP ⁇ CD solution containing 0.10% (w/v) HPMC in aqueous 10% (v/v) acetic acid solution -12-
  • Fig. 5 is a graph plotting the concentration in ng/ml of midazolam in serum after intravenous administration of 2 mg of a commercial intravenous formulation of midazolam (O) and nasal administration of 4.8 mg of a nasal formulation of midazolam prepared in accord with the present invention ( ⁇ ), against time in minutes, where each point represents the mean value and error bars represent standard deviation.
  • Table 2 lists some of the currently available cyclodextrins contemplated for use in the present invention.
  • cyclodextrins for use herein are hydroxypropyl- ⁇ - cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, the branched ⁇ -cyclodextrins (especially glucosyl- ⁇ -cyclodextrin and maltosyl- ⁇ -cyclodextrin), ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and ⁇ -cyclodextrin.
  • the drug for use herein is one having a structure comprising at least one heterocyclic ring.
  • the heterocyclic ring generally has a total of 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms. While each hetero ring atom can be nitrogen, oxygen or sulfur, heterocycles having at least one nitrogen or oxygen ring atom are preferred.
  • the drug has at least one heterocyclic ring which is a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal.
  • Especially desirable drugs for use in accord with the present invention are benzodiazepines.
  • Benzodiazepines contain a benzene ring fused with a diazepine ring which is a 7-membered ring with nitrogen atoms in positions 1 and 4.
  • alprazolam is 8-chloro-l-methyl-6-phenyl- 4H-s-triazolo[4,3-a][l,4]benzodiazepine
  • midazolam is 8- chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,5-a][l,4]benzodiazepine
  • that of triazolam is 8-chloro-6-(o-chlorophenyl)-l-methyl-4H-s-triazolo[4,3- a][l,4]benzodiazepine.
  • the 1,4-benzodiazepine strucmre with a double bond between nitrogen atom number 4 and carbon atom number 5 (which gives the molecule a cyclic imine strucmre).
  • the benzodiazepines are cyclic imines. They are all basic, i.e. they are proton acceptors.
  • Preferred benzodiazepines for use herein are alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam and lorazolam.
  • midazolam alprazolam, clonazepam, lorazepam and triazolam.
  • barbituric acid derivatives Another group of preferred drugs for use herein consists of the barbituric acid derivatives.
  • the barbimric acids contain a 2,4,6-trihydroxypyrimidine (also called 2,4,6-trioxohexahydropyrimidine) ring in their strucmre, a 6-member ring with nitrogen in positions 1 and 3.
  • the chemical name of barbital is 5,5- diethyl-2,4,6(lH,3H,5H)-pyrimidinetrione and that of phenobarbital is 5-ethyl-5- phenyl-2,4,6(lH,3H,5H)-pyrimidinetrione.
  • the barbimric acids can be characterized as cyclic amides or lactams (cyclic amides are called lactams) or imides (which are nitrogen analogues of cyclic anhydrides).
  • Barbimric acids are weak acids.
  • Preferred barbimric acid derivatives are barbital, butobarbital, amobarbital, phenobarbital, aprobarbital, secobarbital, crotylbarbital, cyclobarbital, phenobarbital, hexobarbital, methylphenobarbital, thiopental, isopropylbromallylbarbituric acid, cyclohexenylallylthiobarbimric acid and their salts.
  • Hydantoins are, like barbimric acids, cyclic urea derivatives.
  • the ring-opened acyl derivatives of hydantoins and barbimric acids are sometimes called ureides. Both hydantoins and barbimric acids can form urea upon hydrolysis.
  • Hydantoins contain a 2,4-imidazolidinedione ring in their strucmre, a 5-membered ring with nitrogen in positions 1 and 3.
  • the chemical name of, for example, phenytoin is 5,5-diphenyl-2,4-imidazolidinedione.
  • Hydantoins are closely related to barbimric acids and are acids like them.
  • Still another group of preferred drugs for use in the present invention consists of pyrazole derivatives.
  • pyrazole derivatives as used ⁇ herein includes drugs containing a pyrazole ring, 3-pyrazoline ring or pyrazolidine ring in their strucmre, all of which are 5-membered rings with nitrogens in positions 1 and 2. These compounds are either basic or acidic.
  • derivatives for use herein include phenazone, phenylphenazone, metamidazole, phenylbutazone, oxyphenbutazone and sulfinpyrazone.
  • imidazole derivatives include drugs containing an imidazole, imidazoline or imidazolidine ring in their strucmre. These are 5-membered rings with nitrogen atoms in positions 1 and 3. These compounds are either basic or acidic. Preferred compounds of this type include histamine, miconazole, pilocarpine, naphazoline and clonidine.
  • pyrimidine derivatives Another group of preferred drugs for use in this invention are pyrimidine derivatives. These drugs contain a 6-membered ring with nitrogen atoms in positions 1 and 3. These derivatives are usually basic. Preferred pyrimidine derivatives include thiamine, trimethoprim, orotic acid, methylthiouracyl and prothiouracyl.
  • purine derivatives which contain purine, that is, imidazo(4,5-d)pyrimidine, in their strucmres. These drugs are frequently basic but some of them are acidic.
  • Preferred purine derivatives include caffeine, theophylline, etophylline, proxyphylline and theobromine.
  • Cyclic drugs having heterocyclic rings characterized as enamines, lactones, lactams, thiolactams, anhydrides, imides, imines, hemiacetals and hemiketals are thus appropriate for use in preferred embodiments of the invention, in which ring opening of the heterocyclic ring takes place.
  • the drug is subjected to chemically reversible ring-opening so that at least a portion thereof is in ring-opened form.
  • the portion in ring-opened form is at least 0.1 % by weight, preferably at least 1 or 2% by weight, more preferably at least 5 % by weight of said drug.
  • the amount of drug in ring-opened form is frequently from about 5 to about 10% by weight and usually no more than about -17-
  • the portion of drug in ring-opened form can generally be much higher, frequently about 50% or more, and sometimes even about 90 to 95% .
  • the method of the invention comprises complexing the drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring-opening of at least a portion (at least 0.1 % by weight) of the drug
  • the complexation is advantageously conducted at a pH level which affords ring- opening of at least 5% by weight of said drug.
  • the complexation is conducted at a pH level of below about 5.
  • the drug is a basic drug, especially a benzodiazepine, and the complexation is conducted at a pH level of below about 5.
  • the cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, ⁇ - cyclodextrin sulfobutyl ether, a branched ⁇ -cyclodextrin (especially glucosyl ⁇ - cyclodextrin or maltosyl- ⁇ -cyciodextrin), ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin or ⁇ -cyclodextrin.
  • the benzodiazepine is alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam or loprazolam; and that the cyclodextrin-drug complex thus obtained be formulated as a nasal spray, sublingual tablet or parenteral solution, especially when formulated suitable for use in producing a sedative, anti-anxiety, anticonvulsant or muscle relaxant effect, most especially as a pre-anaesthetic medication, or to supplement anaesthesia, to induce and/or maintain anaesthesia
  • the benzodiazepine is midazolam, alprazolam, clonazepam, lorazepam or triazolam;
  • the cyclodextrin is hydroxypropyl- ⁇ -cyclodextrin, ⁇ - cyclodextrin sulfobutyl ether, a branched ⁇ -cyclodextrin (especially glucosyl ⁇ - cyclodextrin or maltosyl ⁇ -cyclodextrin), ⁇ -cyclodextrin, hydroxypropyl- ⁇ - ⁇ 18-
  • the drug is an acidic drug.
  • the drug is a barbimric acid derivative, a hydantoin, a pyrazole derivative, an imidazole derivative, a pyrimidine derivative or a purine derivative.
  • the drug is a barbimric acid derivative
  • it is preferably barbital, butobarbital, amobarbital, phenobarbital, aprobarbital, secobarbital, crotylbarbital, cyclobarbital, phenobarbital, hexobarbital, methylphenobarbital, thiopental, isopropylbromallylbarbituric acid, or cyclohexenylallylthiobarituric acid, or a salt thereof.
  • the drug is a hydantoin, it is preferably phenytoin.
  • the drug is a pyrazole derivative
  • it is preferably phenazone, propylphenazone, metamidazole, phenylbutazone, oxyphenbutazone or sulfinpyrazone.
  • the drug is an imidazole derivative, it is preferably histamine, miconazole, pilocarpine, naphazoline or clonidine.
  • the drug is a pyrimidine derivative, it is preferably thiamine, trimethoprim, orotic acid, methylthiouracyl or prothiouracyl.
  • the drug is a purine derivative, it is preferably caffeine, theophylline, etophylline, proxyphylline or theobromine.
  • the present invention comprises complexing the drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring-opening of at least a portion (at least 0.1 % by weight) of the drug to enhance the complexation efficacy, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficacy
  • the complexation is generally conducted at a pH level which affords ring-opening of at least 5% by weight of the drug.
  • the complexation is conducted at a pH level of below about 5, especially between about 3 and about 5.
  • the cyclodextrin is preferably hydroxypropyl- ⁇ - -19-
  • cyclodextrin ⁇ -cyclodextrin sulfobutyl ether, a branched ⁇ -cyclodextrin (especially glucosyl- ⁇ -cyclodextrin or maltosyl- ⁇ -cyclodextrin), ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the drug is preferably a benzodiazepine, especially midazolam, alprazolam, clonazepam, lorazepam or triazolam.
  • the cyclodextrin-drug complex is preferably administered in the form of an aqueous solution or a hydrogel, particularly as a nasal spray or nasal drops, or as a parenteral solution.
  • the aqueous solution is advantageously brought to a pH level of below about 6, preferably below about 4.7, most especially to a pH between about 3 and about 4.7.
  • the cyclodextrin-drug complex is preferably formulated as a tablet for oral, buccal or sublingual administration. The water may be removed from the aqueous complexation medium after formation of the cyclodextrin-drug complex.
  • the present invention comprises subjecting a basic drug to complexation in an aqueous medium at a pH level below the pKa+2 value of said basic drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to an animal under conditions which reduce the complexation efficiency
  • the basic drug is preferably a benzodiazepine.
  • Benzodiazepines of particular interest are alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam and loprazolam.
  • benzodiazepines are alprazolam, midazolam, clonazepam, lorazepam and triazolam.
  • the cyclodextrin-benzodiazepine complex obtained in the complexation step is preferably formulated as a nasal spray, sublingual tablet or parenteral solution, which is preferably administered in an effective sedative, anti-anxiety, anticonvulsant or muscle relaxant amount, particularly as a pre-anaesthetic -20-
  • the pH level of the aqueous complexation medium is advantageously selected so that it also affords ring-opening of at least 5 % by weight of the drug.
  • the complexation is preferably conducted at a pH level of below about 5, most preferably between about 3 and about 5.
  • the complexation is carried out in the presence of from about 0.001 to about 5 % (weight/volume) of a pharmacologically inactive,, pharmaceutically acceptable water-soluble polymer at a temperature of from about 30°C to about 150°C.
  • the polymer is a cellulose derivative or a polyvinyl polymer; more preferably, the polymer is methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl ethylcellulose, hydroxyethyl ethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone.
  • An especially preferred cellulose derivative is hydroxypropyl methylcellulose.
  • the complexation is also carried out in the presence of acetic acid and/or one or more pharmaceutically acceptable salts of acetic acid, the acetate-water ratio of the aqueous complexation medium being from about 1: 1000 to about 2: 1, preferably from about 1:100 to about 1: 1, more preferably from about 1:20 to about 1:4.
  • the drug is midazolam and the cyclodextrin is hydroxypropyl- ⁇ - cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether, a branched ⁇ -cyclodextrin
  • the present invention comprises subjecting an acidic drug to complexation in an aqueous medium at a pH level above the pKa-2 value of said acidic drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to an animal under conditions which reduce the complexation efficiency, preferably the pH level of the aqueous complexation medium is selected such that it also affords ring-opening of at least 5% by weight of said drug.
  • Phenytoin (5,5-diphenylhydantoin) is a water-insoluble weak acid (pKa 8.1) which forms a somewhat water-soluble anion in alkaline solution.
  • FIG. 1 illustrates the effect of pH on the phase-solubility of phenytoin (pKa 8.1) in aqueous HP ⁇ CD solutions at 25°C.
  • the results set forth in FIG. 1 show significant enhancement in the HP ⁇ CD solubilization (i.e. the efficiency of the complexation) of the drug at pH 10.19 ( ⁇ ) where the drug is mainly in the ionized form. Formation of phenytoin-HP ⁇ CD complexes at pH 10.19 can result in enhanced bioavailability of phenytoin.
  • phenytoin-HP ⁇ CD complexes at pH of about 10 (e.g. in aqueous ammonia solutions) and lyophilization of the complex will result in phenytoin- HP ⁇ CD complex powder which can, for example, be formulated into tablets.
  • the bioavailability of phenytoin from such tablets will be enhanced compared to the phenytoin availability from tablets containing phenytoin-HP ⁇ CD complex prepared at lower pH, e.g. at pH 2.7 (•) or 7.6 ( ⁇ ).
  • FIG. 2 illustrates the effect of pH on the solubility of alprazolam (pKa 2.4) in aqueous 10% (w/v) HP ⁇ CD solutions at room temperature.
  • the results set forth in FIG. 2 show significant enhancement in the HP ⁇ CD solubilization (i.e. the efficiency of the complexation) of the drug at a pH at which the drug is mainly in the ionized form.
  • the sharp increase in the solubility can, however, only partly be explained by the ionization of the alprazolam molecule.
  • strucmre is the lH-l,4-diazepine ring which, for example, is an essential strucmre of the benzodiazepine derivatives.
  • These strucmral changes are p ⁇ -dependent and reversible, and it is known that the open form frequently coexists with the closed one in several commercial products.
  • One example is the iv solution of midazolam (DormicumTM from F. ⁇ offmann-LaRoche & Ltd, -24-
  • sulfobutylether ⁇ -cyclodextrin SBE ⁇ CD
  • degree of substitution DS
  • CD ⁇ -cyclodextrin
  • ⁇ CD ⁇ -cyclodextrin
  • .4 benzodiazepine concentration was 1x10 M.
  • the concentration of the closed form was determined immediately after dissolving the benzodiazepine in the aqueous cyclodextrin solution and again 24 hours later (i.e. after equilibration at 23 °C). Preliminary experiments had shown that equilibrium between the closed and the open form was attained within 3 hours at 23 °C.
  • Midazolam is a water-insoluble weak base (pKa 6.2) which forms a somewhat water-soluble cation in acidic solution. Solubility (S) of midazolam at several different pH levels was determined in: a) pure aqueous buffer solutions (i.e.
  • FIG. 3 illustrates the effect of pH (i.e. the ring-opening) on the solubility of midazolam (pKa 6.2) in pure aqueous buffer solutions (•), aqueous buffer solutions containing 10% (w/v) HP ⁇ CD ( ⁇ ), and aqueous buffer solutions containing both 10% (w/v) HP ⁇ CD and 0.10% (w/v) HPMC ( ⁇ ) at room temperamre.
  • the results set forth in FIG. 3 show significant enhancement in the HP ⁇ CD solubilization (i.e. the efficiency of the complexation) of the drug at pH levels where the drug exists partly in the open form. Addition of HPMC significantly improves the efficiency.
  • Solubility (S) of midazolam at several different pH levels was determined in: a) pure aqueous buffer solutions (i.e. without cyclodextrin, polymer or acetic acid); b) aqueous buffer solutions containing 10% (v/v) acetic acid as a co-solvent; c) aqueous buffer solutions containing 10% (w/v) sulfobutylether ⁇ -cyclodextrin -28-
  • Addition of the acetic acid increases the value of S Q without having any significant effect on the value of K c which significantly improves the complexation efficiency and, consequently, enhances the cyclodextrin solubilization of the drug.
  • Midazolam carries a positive charge at acidic pH and, thus, the negatively charged SBE ⁇ CD forms a more stable complex than the uncharged HP ⁇ CD with midazolam at these conditions.
  • Addition of 10% (v/v) acetic acid as a co-solvent resulted in a small decrease in the fraction of the open ring form of the drug.
  • Example 6 Female hairless mice were sacrificed by cervical dislocation and their full- thickness skins removed. The outer surface of the skin was rinsed with 35 % (v/v) methanol in water and subsequently with distilled water to remove any -29-
  • the skin was placed in Franz diffusion cells.
  • the receptor phase consisted of phosphate buffer saline pH 7.4.
  • the skin diffusion cells were stirred with a magnetic bar and kept at 37 °C by circulating water through an external jacket.
  • the donor phase (2.0 ml) consisted of a solution of the drug in aqueous 7% (w/v) SBE ⁇ CD solution pH 3.3, or aqueous cyclodextrin solution where the pH had been raised from 3.3 to 4.1 (by addition of NaOH) before it was applied to the skin.
  • the alprazolam concentration in the donor phase was 1.85 mg/ml at pH 3.3.
  • Samples (200 ⁇ l) of receptor phase were removed from the cells at various time intervals up to 48 hours and replaced with a fresh buffer solution.
  • the flux of alprazolam through hairless mouse skin consisted of aqueous pH 3.3 buffer solution containing 7% (w/v) SBE ⁇ CD saturated with the drug.
  • the pH of the donor phase was kept constant at pH 3.3, but in the other case the pH was raised to 4.1 (by addition of NaOH) before it was applied to the skin.
  • the alprazolam concentration in the donor phase was 1.85 mg/ml at pH 3.3.
  • the dielectric constant of the reaction medium will, however, decrease upon addition of the organic solvents. It is possible that this decrease in the dielectric constant will reduce the ability of the reaction media to stabilize the transition state which could explain the decrease in the observed rate constant. Addition of cyclodextrin decreased significantly, in all cases, the rate of ring -31-
  • the cyclodextrins formed stable complexes with the ring-open form of the drug and, thus, the rate decreased upon addition of cyclodextrin.
  • Addition of EtOH or DMSO to the cyclodextrin-containing reaction media resulted in increase in the rate, compared to reaction media containing only cyclodextrin, which could be due to decreased complexation of the diazepine ring-open form.
  • EtOH and DMSO will compete with the diazepine ring-open form for a space in the cyclodextrin cavity resulting in decreased complexation.
  • Example 8 The bioavailability of midazolam in a nasal spray according to the invention was evaluated.
  • the composition of the midazolam nasal spray was as follows: midazolam 1.70% (w/v), sulfobutylether ⁇ -cyclodextrin sodium salt (Captisol ® ) 14.00% (w/v), benzalkonium chloride 0.02% (w/v), sodium edetate (EDTA tetrasodium) 0.10% (w/v), hydroxypropyl methylcellulose 0.10% (w/v), phosphoric acid 0.50% (v/v), sodium hydroxide quantum satis ad pH 4.35 in purified water.

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Abstract

Procédés servant à augmenter l'efficacité de complexation d'un médicament avec cyclodextrine, ainsi que la disponibilité d'un médicament à la suite de l'administration d'un complexe de cyclodextrine et de médicament.
PCT/IS1999/000003 1998-02-23 1999-02-16 Complexes de cyclodextrine extremement energetiques WO1999042111A1 (fr)

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EP99906440A EP1067942A1 (fr) 1998-02-23 1999-02-16 Complexes de cyclodextrine extremement energetiques
AU26385/99A AU759280C (en) 1998-02-23 1999-02-16 High-energy cyclodextrin complexes
NZ505951A NZ505951A (en) 1998-02-23 1999-02-16 A method for enhancing the complexation efficiency of a heterocyclic drug with cyclodextrin, by subjecting the heterocycloc drug to chemically reversible ring-opening
CA002320772A CA2320772A1 (fr) 1998-02-23 1999-02-16 Complexes de cyclodextrine extremement energetiques
JP2000532126A JP2003522207A (ja) 1998-02-23 1999-02-16 高エネルギーシクロデキストリン複合体
IS5572A IS5572A (is) 1998-02-23 2000-07-25 Orkuríkar sýklódextrínfléttur

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Cited By (24)

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Publication number Priority date Publication date Assignee Title
WO2001030391A2 (fr) * 1999-10-27 2001-05-03 Farmarc Nederland Bv Composition pharmaceutique contenant du midazolam
WO2001072338A1 (fr) * 2000-03-28 2001-10-04 Farmarc Nederland Bv Complexes d'inclusion d'alprazolame et compositions pharmaceutiques les contenant
WO2003022270A1 (fr) * 2001-09-13 2003-03-20 Noven Pharmaceuticals, Inc. Administration transcutanee d'un ester d'enalapril
US6805878B2 (en) 2001-09-13 2004-10-19 Noven Pharmaceuticals, Inc. Transdermal administration of ACE inhibitors
WO2005067893A2 (fr) * 2004-01-14 2005-07-28 Merkus Franciscus Wilhelmus He Compositions pharmaceutiques contenant du midazolam dans une concentration elevee
WO2010076112A2 (fr) 2008-12-29 2010-07-08 Unilever Plc Produits alimentaires enrichis en méthylxanthines
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US8025898B2 (en) 2001-06-18 2011-09-27 Noven Pharmaceuticals, Inc. Enhanced drug delivery in transdermal systems
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US9200088B2 (en) 2008-04-28 2015-12-01 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions
WO2016029179A1 (fr) 2014-08-22 2016-02-25 Cydex Pharmaceuticals, Inc. Compositions de cyclodextrine alkylée fractionnées et leurs procédés de préparation et d'utilisation
US9493582B2 (en) 2012-02-28 2016-11-15 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
US9585893B2 (en) 2011-02-23 2017-03-07 Coeruleus Ltd. Flumazenil complexes, compositions comprising same and uses thereof
US9751957B2 (en) 2012-02-15 2017-09-05 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
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US9827324B2 (en) 2003-12-31 2017-11-28 Cydex Pharmaceuticals, Inc. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
US10040872B2 (en) 2012-10-22 2018-08-07 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
US10463677B2 (en) 2008-11-07 2019-11-05 Cydex Pharmaceuticals, Inc. Composition containing sulfoalkyl ether cyclodextrin and latanoprost
US11806352B2 (en) 2010-05-19 2023-11-07 Upfield Europe B.V. Theobromine for increasing HDL-cholesterol

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528215B (zh) * 2006-10-20 2011-10-19 艾科斯有限公司 Chk1抑制剂和环糊精的组合物
CA2669705A1 (fr) * 2006-11-21 2008-05-29 Novartis Ag Formulation parenterale stable contenant un inhibiteur de vsr d'une structure de benzodiazepine
EP2106786A1 (fr) 2008-04-04 2009-10-07 Roewer, Norbert, Univ.-Prof. Dr. med. Préparation pharmaceutique comprenant du cyclodextrine permethylé
US9925274B2 (en) 2012-11-15 2018-03-27 Sapiotec Gmbh Delphinidin complex as an antiphlogistic or immunosuppressive active ingredient
KR20150107742A (ko) 2012-12-11 2015-09-23 자피오텍 게엠베하 흑색종 세포를 퇴치하기 위한 델피니딘

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002518A1 (fr) * 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR0166088B1 (ko) * 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
WO1994002518A1 (fr) * 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
INJOON OH ET AL: "Stability and solubilization of oxathiin carboxanilide, a novel anti-HIV agent", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 73, 1991, pages 23 - 31 *

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US9585893B2 (en) 2011-02-23 2017-03-07 Coeruleus Ltd. Flumazenil complexes, compositions comprising same and uses thereof
EP3702374A1 (fr) 2012-02-15 2020-09-02 CyDex Pharmaceuticals, Inc. Procédé de production de dérivés de cyclodextrine
US10633462B2 (en) 2012-02-15 2020-04-28 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
US11208500B2 (en) 2012-02-15 2021-12-28 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
EP4083075A1 (fr) 2012-02-15 2022-11-02 CyDex Pharmaceuticals, Inc. Procédé de production de dérivés de cyclodextrine
US9751957B2 (en) 2012-02-15 2017-09-05 Cydex Pharmaceuticals, Inc. Manufacturing process for cyclodextrin derivatives
US9493582B2 (en) 2012-02-28 2016-11-15 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
US10323103B2 (en) 2012-02-28 2019-06-18 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
US10800861B2 (en) 2012-10-22 2020-10-13 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
US10040872B2 (en) 2012-10-22 2018-08-07 Cydex Pharmaceuticals, Inc. Alkylated cyclodextrin compositions and processes for preparing and using the same
WO2016029179A1 (fr) 2014-08-22 2016-02-25 Cydex Pharmaceuticals, Inc. Compositions de cyclodextrine alkylée fractionnées et leurs procédés de préparation et d'utilisation
US10851184B2 (en) 2014-08-22 2020-12-01 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

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CA2320772A1 (fr) 1999-08-26
JP2003522207A (ja) 2003-07-22
AU759280B2 (en) 2003-04-10
AU759280C (en) 2004-01-22
AU2638599A (en) 1999-09-06
EP1067942A1 (fr) 2001-01-17
NZ505951A (en) 2003-02-28
IS5572A (is) 2000-08-16

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