WO1993017711A1 - Nouvelles cyclodestrines et medicaments de formule nouvelle - Google Patents

Nouvelles cyclodestrines et medicaments de formule nouvelle Download PDF

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WO1993017711A1
WO1993017711A1 PCT/AU1993/000100 AU9300100W WO9317711A1 WO 1993017711 A1 WO1993017711 A1 WO 1993017711A1 AU 9300100 W AU9300100 W AU 9300100W WO 9317711 A1 WO9317711 A1 WO 9317711A1
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cyclodextrin
inclusion complex
group
substituted
complex according
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PCT/AU1993/000100
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English (en)
Inventor
Clive Frederick Palmer
Paul Chi Cui Ho
Susan Elisabeth Brown
Bruce Lindley May
Deborah Susanne Schiesser
Yin Luo
Nicholas Dennis
Stephen Frederick Lincoln
John Hewlett Coates
Christopher John Easton
Paul Duckworth
Peng Wang
Daniel R. Coghlan
Wit Janowski
Angelo Lepore
Michael Lloyd Williams
Steven John Van Eyk
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Australian Commercial Research & Development Limited
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Priority to EP93905115A priority Critical patent/EP0630261A4/fr
Priority to AU36241/93A priority patent/AU3624193A/en
Publication of WO1993017711A1 publication Critical patent/WO1993017711A1/fr

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    • 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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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

Definitions

  • drugs Many of today's commonly prescribed drugs have undesirable properties or delivery profiles which detract from their efficacy and/or beneficial nature. For example, some drugs may exhibit a poor or unpredictable bioavailability profile, which may be due, in part, to the drug's disadvantageous solubility characteristics.
  • Two examples of such drugs which have a disadvantageous solubility profile are Propofol, i.e., 2,6-bis(1-methylethyl) phenol, and Alfaxalone, i.e., 3-hydroxypregnane-11,20-dione, which are well-known anesthetics. Indeed, those drugs might find increased usage if their solubility profiles were improved.
  • embodiments of this invention provide inclusion complexes and pharmaceutical compositions comprising Propofol or Alfaxalone or a pharmacologically active derivative or metabolite thereof included in a substituted or unsubstituted cyclodextrin or salt thereof.
  • Another embodiment provides methods for increasing the solubility of Propofol or Alfaxalone or a derivative or metabolite thereof in a neutral or acidic aqueous solution, comprising the step of forming one of the above-described inclusion complexes.
  • Another embodiment of this invention provides a method for improving the bioavailability. of Propofol or Alfaxalone or a derivative or metabolite thereof in a host mammal comprising the step of forming one of the above-described inclusion complexes.
  • Another embodiment provides a method for treating a host mammal in need of such treatment, comprising orally or parenterally administering to said mammal a therapeutically effective amount of the aforementioned pharmaceutical compositions.
  • Cyclodextrin - refers to ⁇ - , ⁇ - , ⁇ -, or ⁇ - cyclodextrins, which are those that are generally available. It will be appreciated, however, that if other cyclodextrins are discovered or become available in sufficient commercial quantities, such cyclodextrins shall also be encompassed by this invention.
  • Cyclodextrin inclusion-Association Complex refers to an inclusion complex in which there are one or more associable groups or portions of a group located on a substituent that is substituted at a C2, C3 or C6 position of a cyclodextrin, which groups or portions form an association with one or more associable groups or portions of a guest atom or molecule.
  • the associable portions can include polar or charged groups or portions, or groups or portions capable of hydrogen bonding. This term also includes any salt or hydrate which can be formed from the inclusion-association complex.
  • Cyclodextrin Inclusion Salt - refers to an inclusion-association complex in which the associable group or portion of the cyclodextrin substituent carries a net positive or negative charge which causes it to associate with an oppositely charged group or portion of a guest atom or molecule. This term also includes any other salt or a hydrate which can be formed from the cyclodextrin inclusion salt.
  • Modified cyclodextrins in accordance with this invention can comprise an otherwise substituted or unsubstituted cyclodextrin in which at least one C2, C3 or C6 hydroxyl is substituted with a group selected from -XR 1 , YR 3 , siR 4 R 5 R 6 , and -R 7 ,
  • Y can represent , , ,
  • R 1 to R 11 can each represent the same or different groups selected from: the groups -XR 1 , YR 3 , siR 4 R 5 R 6 , and -R 7 are as defined above, hydrcgen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, and wherein any two or three groups bonded to the same substituent can be taken together to represent a single group multiply bonded to said same substituent, and wherein R l to R 11 may be further substituted by at least one -XR 1 , -YR 2 R 3 , -siR 4 R 5 R 6 , -R 7 , halogen, and OR 12 , wherein R 12 is as defined for R l to R 11 .
  • Cyclodextrins in which one or more C2, C3 or C6 hydroxyls are selectively substituted by ether substituents are also encompassed.
  • cyclodextrin derivatives thus substituted only on one or more secondary carbons, or uniformly substituted only on one, two or three, etc. primary carbons are encompassed.
  • the ether substituents may be further substituted with any of the foregoing groups.
  • preferred groups include the substituted amino cyclodextrins, i.e., cyclodextrins wherein at least one substitution for said C2, C3 or C6 hydroxyl is of the formula -YR 2 R 3 , wherein Y is N, and R 2 and R 3 are as previously defined.
  • R 2 is hydrogen and R 3 represents amino, hydroxyl, carboxyl, sulfonate (SO 3 ), phosphate (PO 4 -3 ), substituted alkyl, cylcoalkyl, or aryl, or wherein R 2 and R 3 are taken together to represent a hereto substituted multiply bonded alkyl group .
  • cyclodextrins in accordance with this invention will possess one or more pendant arms as described in the '359 and '071 Applications.
  • One general formula for preferred pendant arm cyclodextrin derivative are of the formula CD - w - R 13 - L, wherein
  • CD represents an otherwise substituted or unsubstituted cyclodextrin
  • W represents a functional linking group
  • R 13 represents a group defined the same as R 1 -R 12 above, and
  • L represents a group selected from reactive, charged, polar or associating groups.
  • W represents an optional, functional linking group such as amino, amide, ester, thioether, thioamide, thioester, etc.
  • R 13 represents an optional arm such as substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl, and
  • L represents an optional group selected from reactive, charged, polar or associating groups, e.g., amino, carboxyl, hydroxyl, sulfonate, phosphate, acyloxy, alkyloxy and thiyl.
  • each of the foregoing groups is optionally present.
  • the reactive, charged, polar or associating species can be bonded directly to the cyclodextrin or to the functional linking group.
  • a reactive, charged, polar or associating species may not always be desired.
  • such species can be anywhere on the arm, and there can be more than one such species on the arm, e.g, the arm could possess multiple groups that could associate with multiple groups on an included or associated molecule, such as biological molecules which may contain many .repeating groups such as amino, carboxyl, and hydroxyl.
  • the arm can also contain other functional or reactive groups which, in turn, may be used to link yet other arms and charged, polar or associating species.
  • Preferred modified cyclodextrins of CD-W-R-L group also include those in which a carboxyl-substituted alkyl group is linked to a C2, C3 or C6 position of the cyclodextrin through an amino, ester, amide, thioether, thioester, thioamide or other functional linking group.
  • Alkyl groups of from 1-3, 1-6, and 1-10 carbons comprise preferred groups. Those of from 10-20 comprise another preferred group, and those of greater than 20 carbons comprise yet another preferred group.
  • cyclodextrin derivatives in which at least one C2, C3 or C6 hydroxyl is substituted with a group having a net negative charge, or with a substituent that contains a group having a net negative charge.
  • groups that can carry a net negative charge include hydroxyl, carboxyl, phosphate (PO 4 -3 ) or sulfonate (SO 3 -1 ).
  • Other groups having net negative charges will be readily apparent to those skilled in the art.
  • Preferred modified cyclodextrins of this group include those in which a carboxyl-substituted alkyl group is linked to a C2, C3 or C6 position of the cyclodextrin through an amino, ester, amide, thioether, thioester, thioamide or other functional linking group.
  • Alkyl groups of from 1-3, 1-6, and 1-10 carbons comprise preferred groups. Those of from 10-20 comprise another preferred group, and those of greater than 20 carbons comprise yet another preferred group.
  • One example of such compounds is 6 A -amino-6 A -deoxy-6 A -N-(3-carboxypropanoyl)- ⁇ -cyclodextrin (hereinafter " ⁇ -CDNSc").
  • modified cyclodextrin, ⁇ -CDNSc is also an example of another preferred group of cyclodextrin derivatives having the formula CD - X - R 14 - Q, wherein:
  • X represents or
  • R 14 and R 15 represent groups as defined, by R 1 -R 13 above, and Q is a carboxylic acid group.
  • Q is a carboxylic acid group.
  • those where R 14 is alkyl comprise a preferred group of the alkyl groups, those of from 1-3, 1-6, and 1-10 carbons comprise preferred groups.
  • those of from 10-20 comprise another preferred group, and those of grearer than 20 carbons comprises y ⁇ t another preferred group. Preparation of such compounds is described in the '359 and '071 Applications.
  • ⁇ -cyclodextrin such as ⁇ -amino cyclodextrin and ⁇ -CDNSc.
  • ⁇ -cyclodextrin derivatives in addition to the ⁇ -cyclodextrin derivatives, in some instances it may be desirable to use ⁇ -cyclodextrin or derivatives thereof such as ⁇ -amino cyclodextrin and ⁇ -CDNSc.
  • a preferred group of the linked cyclodextrins are those in which only two cyclodextrins are linked together.
  • a first otherwise substituted or unsubstituted cyclodextrin can be linked through one of its primary (i.e., C6) carbons or one of its secondary (i.e., C2 or C3) carbons to a primary (i.e., C6) carbon or a secondary (i.e., C2 or C3) carbon of a second otherwise substituted or unsubstituted cyclodextrin.
  • otherwise substituted or unsubstituted cyclodextrins which are linked by C6-C6, C2-C2, C3- C3, C2-C3, C6-C3 or C6-C2 linkages comprise preferred embodiments of this invention.
  • the linked cyclodextrins are preferably linked by at least one linking group of the formula - X - R 16 - Y - or - R 17 - , wherein
  • X and Y can be the same or different, and represent functional linking groups
  • X and Y can be the same or different, and represent functional linking groups such as ether, thioether, ester, thioester, amide, thioamide, and amine, and
  • R 16 and R 17 represent groups as defined by R 1 -R 15 above, and are advantageously selected from substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl.
  • the otherwise substituted or unsubstituted cyclodextrins which are linked may also be the same or different.
  • an ⁇ -cyclodextrin can be linked to a ⁇ - , ⁇ - or ⁇ -cyclodextrin.
  • compositions may be in any pharmaceutically acceptable form for any type of administration, including topical, oral, rectal or parenteral administration.
  • Methods of treating a patient, including a human will comprise administering therapeutically effective amounts of such compositions. Preparation and administration of such compositions will be within the skill of persons in such arts.
  • compositions including protecting the pharmaceutical agents from enzymes and acids of the gastrointestinal tract, lytic agents in the body such as in the saliva, enzymes in the lungs and in the body, particularly at the surface and within cells such as polymorphic nuclear leukocytes, ma ⁇ rophages and other cells, and possible also from the destructive mechanisms found within the cytoplasm of most cells.
  • inclusion complexes formed with mambutone and cyclodextrins and methods for measuring inclusion complexes.
  • the invention described include the formation of Metalo-Cyclodextrins by 6 A -deoxy-B-Cyclodextrins by
  • B-CDOTs (5g, 3.75 m mole) was heated in 1,6 - diaminohexane (5g, 43 m mole) at 80 - 90°C for 5 hours. The hot mixture was poured into and stirred ethanol (100 ml) and allowed to stand overnight. The solid was filtered and the filter cake was washed with acetone (20 ml) and diethyl ether (20 ml) and then air dried. The solid was dissolved in 5 ml of hot water and then poured slowly into stirred ethanol (25 ml). The mixture was allowed to stand overnight and the solid was filtered off. The solid was crystalised from hot water (10 ml). On cooling, a white solid was produced which was filtered and dried in vacuo to yield 2 g of B-CDN6N. 6 A -Cyano-6 A -deoxy- ⁇ -cyclodextrin ( ⁇ -CDCN)
  • Impure ⁇ -CDOTs (5 g) and sodium cyanide (1 g) were dissolved in water (150 ml) with heating on a boiling water bath. Heating was continued and the reaction followed by t.l.c. (solvent A). After 3 hours no ⁇ -CDOTs remained.
  • the reaction mixture was concentrated in vacuo to 50 ml, filtered (0.22 urn) and loaded, via the pump, onto a C18 u -Bondapack column (19 ⁇ 150 mm). The column was eluted with 5% aqueous methanol in water at 15ml minute -1 and two peaks were observed both eluting very close to the void. Both contained the desired product with the first eluted peak also containing cyanide salts (3.2 g total). Peak 2 gave pure ⁇ -CDCN
  • Diaminobutne (10g) was dissolved in dichloromethane (50 ml). The solution was stirred vigorously whilst IbCl (1g) was added drop wise, and then allowed to stand for 4h. The mixture was added to dilute NaHCO 3 solution with ether (100ml). The mixture was shaken, then the organic layer was washed twice with water (40ml), dried
  • Impure ⁇ -CDN2,2N (5g) and NpNP (1.6 g) were heated together in dimethyl-formamide (10 ml) at 70°C overnight. The mixture was then poured into acetone (100 ml). The solid was collected by filtration, then dissolved in hot 50% aqueous ethanol (30 ml). The ethanol was evaporated in vacuo and the precipitate (6 g) was filtered off. TLC showed this to be a new compound, with minor amounts of ⁇ -CD and ⁇ -CDN2,2N. Recrystallisation from aqueous ethanol did not remove all the ⁇ -CD, but did remove ⁇ -CDN2,2N. T.l.c.
  • solvent B of the product showed: R c (relative to ⁇ -CD), ⁇ -CDN2,2N, 0.2; ⁇ -CD,1; ⁇ -CDN2, 2NNp, 1.1.
  • HPLC of the product using a 65% acetonitrile - water eluent showed: t R (relative to ⁇ -CD), ⁇ -CDN2,2NNp, 0.65; ⁇ -CD, 1; unknown, 1.6; ⁇ - CDN2,2N, 4.7.
  • FABMS 2276 2124 (152 Ts) and many others.
  • ⁇ -CDOTs 100 mg was dissolved in water (1 ml) with sodium sulfide (100 mg). after 3 h at 70°C, the mixture was poured into acetone (10 ml). The solid was centrifuged down, redissolved in hot water and precipitated with ethanol. This solid was removed and dried in vacuo.
  • the resultant dicyclohexylurea was removed by vacuum filtration through a sintered glass funnel, leaving the filtrate as a bright clear yellow solution.
  • the dimethylformamide was removed in vacuo to leave a pale yellow solid which was recrystallised from dry ethyl acetate (200 ml), during which dicyclohexylurea was removed by hot filtration. After standing for 90 minutes the remaining dicyclohexylurea crystallised out as fine off-white needles and collected by gravity filtration (Whatman N° 1 filter paper). The filtrate was placed in a fridge at 4°C overnight and the resulting product collected by vacuum filtration as a fine white powder (6.5g, 36%, m.p. 153-154°C).
  • ⁇ -CD (1.1 g) was dissolved in water (50 ml) and ScNP (0.15 g) in acetonitrile (10 ml) added in one portion. The reaction mixture turned yellow. After stirring for 5 min, dilute HCl was added to the reaction mixture until it reached pH-3. The solution was cooled and filtered to remove any unreacted ⁇ -CD. The filtrate was extracted twice with ether and the solvent removed in vacuo. T.l.c. analysis of the residue showed two components to be present, however chromatography isolated only ⁇ -CD. We were unable to prove that the dimer had been formed.
  • ⁇ -CD (relative to ⁇ -CD), ⁇ -CD, 1.0; ⁇ -CDNHCOCH 2 CH 2 -S- ⁇ -CD, 5.1
  • T.l.c. analysis revealed a streak from the baseline to an R f corresponding to that of the acrylamide.
  • the reaction mixture was diluted with water and upon addition of acetone a flocculant precipitate appeared. This material was collected by centrifuge to give a light brown powder. N.m.r. analysis showed vinyl signals still to be present.
  • Alphaxalone The solubility of alphaxalone is 0.0036 mg/ml. In a 1:1 complex with BCDNH 2 formulation it can easily be solubilised up to 12.44 mg/ml which is an increase of solubility of up to 3,455 times.
  • BCDNH 2 solubility constant of alphaxalone with ACRD's new CD is 59723M -1 .
  • the work carried out in respect of the BCDNH 2 formulations provides for a viable commercial product.
  • BCDNH is not toxic and causes no problems up to 2 grams/kilogram IV and up to 5 grams/kilogram oral and that it is non-mutagenic.
  • phase solubility diagram in Fig 7 & 8 indicated that the solubility of propofol increased linearly in increasing concentrations of ⁇ CDN4N and ⁇ CDN6N.
  • a solution of 25% of ⁇ -CDN6N gave a solubility of 10.24 mg/ml was achieved and a solution of 25% of ⁇ CDN6N gave a solubility of 12.88 mg/ml.
  • This solubilities are exceeding the strength of 10 mg/ml used in Diprivan, the therpeutic formulation.
  • a 5:1 dilution of the 25% solution i.e. the 5% solution of either of the cyclodextrins
  • Alphaxalone a steroidal anaesthetic, is extremely isoluble in water (3.5 ug/ml). It is formulated in a non-ionic detergent, Cremaphor (polyoxyethylenated castor oil), for clinical administration. However, the excipient, Cremaphor is associated with numerous allergic reactions. It would be desirable to solubilize alphaxalone without this detergent in the aqueous solution.
  • ⁇ CDN4N, ⁇ CDN6N two chemically modified cyclodextrins
  • Alphaxalone was supplied by Pharmatec, Inc. (Alachua, Florida, USA, Fl 32615). The chemically modified cyclodextrins were synthesized in our laboratory. Methanol used in the experiment was supplied by Waters (Division of Millipore). De-ionized water from Milli-Q water system (Millipore, Mass, USA) was used throughout the experiment. All chemicals were weighed on Mettler AJ 100 analytical balance. SOLUBILITY STUDIES
  • Saturated solutions of alphaxalone were made by adding 30 mg of the drug to 1 ml of water with respective 0, 1, 2, 5, 10, 15, 20, 25% of cyclodextrins.
  • the solutions were mixed on a Coulter Mixer for over 24 hours to ensure saturation.
  • the suspensions were then centrifuged (Dupont, Sorval, GLC-2B) at 3000 rpm for 15 min.
  • the upper layers of the solutions were collected with a 1 ml syringe and filtered through 0.45 urn filter, 4mm (Alltech, cat. no. 2091).
  • the concentrations of the drug in the filtrates were determined by HPLC analysis.
  • phase solubility diagrams in Fig 10 & 11 indicated that the solubility of alphaxalone increased linearly in increasing concentrations of ⁇ CDN4N and ⁇ CDN6N.
  • a solubility of 26.3 mg/ml was achieved in ⁇ CDN4N and 28.1 mg/ml in ⁇ CDN6N.
  • This solubilities are over 7300 and 7809 times the aqueous solubility of alphaxalone in water (3.6 ug/ml), exceeding the strength of 9 mg/ml used in Althesin, the therapeutic formulation.
  • This result showed that an unsaturated solution of the therapeutic strength can be prepared with over 10% of the cyclodextrins.
  • Previous preliminary studies also indicated that the ⁇ CDN4N and ⁇ CDN6N alphaxalone solutions did not give precipitation upon storage in refrigeration. This property is essential when these cyclodextrin are considered for intravenous applications.
  • Alphaxalone a steroidal anaesthetic, is extremely insoluble in water (3.6 microg/ml). It is formulated in a non-tonic detergent, cremaphor(polyoxyethylenated caster oil) for clinical administration. However, the excipient, cremaphor is associated with numerous allergic reactors. it would be desirable to solubilize alphaxalone without this detergent in the aqueous solution. In this report, we use two new ACRD cyclodextrins ⁇ - CDN4N and ⁇ -CDN6N. MATERIALS AND METHODS
  • Alphaxalone was supplied by Pharmatec, Inc. (Alachua, Florida USA, FL 32615). The two ACRD cyclodextrins ⁇ -CDN4N and ⁇ -CDN6N were synthesized in our laboratory. Methanol used in the experiment was supplied by Waters (Division of Millipore). De-ironized water from Milli-Q water system (Millipore, Mass, USA) was used throughout the experiment. All chemicals were weighed on Mettler AJ 100 analytical balance.
  • ⁇ -CDN4N and ⁇ -CDN6N alphaxalone solutions were injected i.p. in rats anaesthesic effect was observed in the rat receiving ⁇ -CDN4N alphaxalone solution, but not in the rat receiving CDN6 alphaxalone solution.
  • ⁇ -CDN4N cyclodextrin appears to be a suitable carrier for alphaxalone I.V. injection. This warrants further studies on its phase solubility and stability.
  • ⁇ -CDOTs (20g, 15.0 m mole) was heated in 1,6 - diaminohexane (20 g, 172 m mole) at 80 - 90°C for 5 hours. The hot mixture was poured into stirred ethanol (400 ml) and allowed to stand overnight. The solid was filtered and the filter cake was washed with acetone (80 ml) and diethyl ether (80 ml) and then air dried. The solid was dissolved in 20 ml of hot water and then poured slowly into stirred ethanol (100 ml). The mixture was allowed to stand overnight and the solid was filtered off. The solid was crystallised from hot water (40 ml). On cooling, a white solid was produced which was filtered and dried in vacuo to yield 12.5 g of ⁇ -CDN6N.
  • the rats were divided into two groups. Each group either received alphaxalone solubilised by the ACRD CD or the standard clinical formulation. The formulations were given intraperitoneally. The doses and dosing schedules are as follows:
  • the duration of anaesthesia after i.p. injection of saffan of alfaxalone - CD is shown in Table 1.
  • the mean duration of anaesthesia after injection of Saffan was 43.6 min and after injection of alphaxalone - CD, was 59 min.
  • a dose of alphaxalone - CD 48 mg/kg was given, the duration of anaesthesia in that animal was found to be 100 min.
  • the ACRD CD increased the solubility of alphaxalone by over 7000 times (refer to previous internal report).
  • the CD encapsulated alphaxalone formulation maintains the pharmacological effect of anaesthesia. Therefore, it is able to achieve an aqueous formulation of alphaxalone with the ACRD chemically modified cyclodextrin.
  • All ACRD cyclodextrins being chemically modified cyclodextrins used in this study were hydrochloride salts of such cyclodextrins and are prepared in standard manner as previously disclosed in earlier applications by Australian Commercial Research & Development Ltd.
  • the ⁇ -cyclodextrin tosylate (2a) was synthesized by the method of Melton and Slessor, 12 except that the crude product was purified by reverse-phase chromatography rather than by passage through a column of activated charcoal.
  • the corresponding derivative of ⁇ -cyclodextrin (2b) was prepared using a similar procedure.
  • the amines (4a) and (4b) were completely characterized.
  • the regiospecificity of incorporation of the amino group was confirmed by proton-coupled 13 C n.m.r. spectroscopy.
  • the ⁇ -cyclodextrin derivative (4a) displayed a triplet at ⁇ 42.8, characteristic for the C6 A carbon, while the corresponding signal for the ⁇ -cyclodextrin derivative (4b) was observed at ⁇ 42.1.
  • This value for the ⁇ -cyclodextrin derivative (4b) is well outside the range of 5.8-6.5 reported 16 during the current work and there is no obvious explanation for the discrepancy. Nevertheless it is clear that both the compounds (4a) and (4b) have unusually high pK b values for primary amines.
  • the amine hydrochloride salt (5b) was prepared by titration of an aqueous solution of the amine (4b) with hydrogen chloride.
  • the solubility of the salt (5b) in water at 25° was found to be 70.5 gm/100 ml [0.60 M], which is substantially higher than that of either the free base (4b) (3.75 gm/100ml [0.033 M]) or the parent cyclodextrin (1b) (1.85 gm/100 ml [0.016 M]).
  • the salt (5b) is particularly suitable for use in studies and applications of cyclodextrin inclusion complexes where a high concentration of the cyclodextrin derivative is required.
  • Thin layer chromatography (t.l.c.) was performed using Kieselgel 60 F 254 (Merck) on aluminium back plates, eluting with 14:3:3 butanone-methanol-water (Solvent A) or 8:1:1 acetic acid-chloroform-water (Solvent B), and visualized by wetting with a 1.5% solution of sulfuric acid and heating (the R,. value of a cyclodextrin derivative indicates the R f value relative to that of the parent cyclodextrin).
  • High performance liquid chromatography (h.p.l.c.) was carried out using an ICI LC1500 solvent delivery system coupled to a Knauer differential refractometer. Analytical h.p.l.c.
  • the tosylate (2a) was prepared using a modification of the procedure of Melton and Slessor. 12
  • the monotosylate (2a) (1.0g, 0.89 mmol) was dissolved in N,N-dimethylformamide (50 ml) in a 400 ml Parr pressure reaction vessel. Condensed ammonia (100 ml) was added carefully and the vessel was sealed. The mixture was then allowed to warm to room temperature, while the pressure inside the vessel increased to 10 6 Nm -2 . After stirring the mixture for 18 h at room temperature, the pressure was released, allowing the excess ammonia to evaporate, and the residual solution was concentrated under reduced pressure.
  • the pK b s of the amines (4a) and (4b) were determined from pH titrations carried out by hand using a Ross combination pH electrode (Orion Research Inc. Model No. 81-03) with a Radiometer PHM64a pH meter and a conventional semi-micro burette Alternatively, titrations were carried out automatically using a Ross combination liquid junction pH electrode (Orion Research Inc. Model No 81-72) with an Orion Research Inc. pH meter Model SA 720 and a 665 Dosimat autoburette (Metrohm) interfaced to a Laser XT/3 8085 personal computer.
  • Titrations were carried out in three-necked water-jacketted glass vessels which alowed room for a pH electrode, a titrant delivery tube and a high purity nitrogen delivery tube for blanketting the solution with CO 2 -free nitrogen.
  • a magnetic stirring bar was used to ensure complete mixing.
  • the pH meter was standardized with a phosphate buffer mixture (pH 6.865) and potassium hydrogen phthalate (pH 4.005) at 298.2 K. prior to the titration, a solution of the amine (4a) or (4b), of known volume and concentration was placed in the titration vessel and acidified with a known volume of standardized acid. Nitrogen was then bubbled through the solution for two hours to remove any contaminating CO 2 .
  • Titration of the protonated amine (4a) or (4b) was then carried out by the addition of standarized 0.100 mol dm -3 sodium hydroxide or potassium hydroxide.
  • the pK b s were computed from the titration data using the program SUPERQUAD, 18 optimizing both the value of pKw and the value of the purity of the amine (4a) or (4b).
  • CDs cyclodextrins
  • ⁇ -cyclodextrin, ⁇ CD, and 6 A -amino-6 A -deoxy- ⁇ -cyclodextrin, ⁇ CDNH 2 in which a primary hydroxyl group of ⁇ CD is replaced by an amino group which may be protonated to produce a positively charged species, ⁇ CDNH 3 +, 20,21 to examine the effect of substitution and charge on the complexation and chiral discrimination characteristics of ⁇ CD.
  • the guest species, benzoic acid, 4-methylbenzoic acid, RS-2-phenylpropanoic acid, and their conjugate bases provide convenient conjugate acid-base pairs to test the effect of changing the guest charge from neutral to negative on complexation by these three CD hosts.
  • ⁇ CD (Sigma) and ⁇ CDNH 2 , prepared as in the literature, 20'21 were dried to constant weight and stored over P 2 O 5 in a vacuum dessicator prior to use.
  • the carboxylic acids (Sigma) were used as received.
  • the enantiomeric purities of R- and S-2-phenylpropanoic acid were determined to be >95% and >97%, respectively, after HPLC analysis of their diastereomers formed with S-1-phenylethylamine. These purity limits were used in calculations of error limits of the stability constants characterising the complexation of these enantiomers by CDs.
  • Deionised water was purified with a MilliQ-Reagent system to produce water with a specific resistance of >15 Mohm cm, which was then boiled to remove CO 2 . All solutions were prepared from this water, and were 0.10 mol dm -3 in KCl which acted as the supporting electrolyte. Titrations were performed using a Metrohm - Dosimat E665 titrimator, an Orion SA 720 potentiometer, and an Orion 8103 Ross combination pH electrode which was filled with 0.10 mol dm -3 KCl and calibrated before use with appropriate buffer solutions.
  • a stream of fine nitrogen bubbles (previously passed through aqueous 0.10 mol dm -3 KCl) was passed. through the titration solution which was magnetically stirred and thermostatted at 298.2 ⁇ 0.1K in a water-jacketted titration vessel which was closed to the atmosphere with the exception of a vent which permitted egress of the nitrogen stream.
  • a pKw value was determined by titration of 1.0 ⁇ .10 -2 mol dm -3 HCl (8.0 or 2.0 cm 3 ) with standardised 5.0 ⁇ 10 -2 mol dm -3 NaOH.
  • the pKa values of the carboxylic acids and ⁇ CDNH 3 + were determined by titration of 2 ⁇ 10 -3 mol dm -3 aqueous solutions (8.0 or 2.0 cm 3 ) with standardised 5.0 ⁇ 10 -2 mol dm -3 NaOH.
  • the burette contained a solution of 1.5 ⁇ 10 -2 mol dm -3 ⁇ CD at pH 7.
  • the pH of each 2 ⁇ 10 -3 mol dm -3 carboxylic acid/carboxylate solution (2.0 cm 3 ) in the titration vessel was adjusted to a value near the pK a of the carboxylic acid.
  • the burette contained a solution of 1.6 ⁇ 10 -2 mol dm -3 ⁇ CDNH 3 + at pH 6.
  • the pH of each 2 ⁇ 10 -3 mol dm -3 carboxylic acid/carboxylate solution (2.0 cm 3 ) in the titration vessel was adjusted to a value near the pK a of the carboxylic acid.
  • Up to 3 cm 3 of ⁇ CDNH 3 + solution were titrated into the carboxylic acid/carboxylate solutions in increments not greater than 0.05cm and the pH increased by approximately 0.4 pH units in total.
  • At least three similar titrations were performed for each carboxylic acid system studied.
  • the burette contained a solution of 6.0 x 10 -3 mol dm -3 benzoic acid/benzoate at pH 4.
  • the pH of each 5 x 10 -3 mol dm -3 ⁇ CDNH 3 + solution (2.0 cm 3 ) in the titration vessel was adjusted to a value near pH 4.
  • each 2 ⁇ 10 -3 mol dm -3 ⁇ CDNH 2 solution (2.0 cm 3 ) in the titration vessel was adjusted to a value near the pK a of ⁇ CDNH 3 +.
  • Up to 3cm 3 of carboxylate solution were added to the ⁇ CDNH 3 +/ ⁇ CDNH 2 solutions in increments not greater than 0.05 cm 3 , and the pH increased by 0.1 - 0.3 pH units, depending on the carboxylate being studied.
  • At least three similar titrations, with starting pHs in the range 8.2-8.8 were performed for each carboxylate system studied.
  • the concentration of ⁇ CD or ⁇ CDNE 3 + was in the range 1.0 ⁇ 10 -2 - 9.0 ⁇ 1 0-2 mol dm -3
  • that of RS-2-phenylpropanoic acid or RS-2-phenylpropanoate was in the range 1.0 ⁇ 10 -3 - 1.0 ⁇ 10 -2 mol dm -3 so that ⁇ 90% of the guest species as complexed.
  • the resonances were assigned by adding resolved R-2-phenylpropanoic acid to the solution and observing which resonance increased in intensity.
  • the complexation of a carboxylic acid, HA, and its conjugate base, A-, by ⁇ CD may be expressed as in Figure 17 where the acidity constant, K a , characterises the carboxylic acid, K 1HA and K 1A are the stability constants for the complexation of HA and A-, respectively, by ⁇ CD, and K á characterises HA in the HA. ⁇ CD complex.
  • the complexation of a guest carboxylate (A-) by ⁇ CDNH 3 + and its conjugate base, ⁇ CDNH 2 may be expressed as in Scheme (2), where K a is the acidity constant of ⁇ CDNH 3 +, K 2A and K 3A are the stability constants for the complexation of A- by ⁇ CDNH 3 + and ⁇ CDNH 2 respectively, and pK á characterises ⁇ CDNH 3 + in the A-. ⁇ CDNH 3 + complex.
  • the complexation of HA and A- by ⁇ CDNH 3 + may be expressed as in Scheme (3), where K a , K á , K 2HA and K 2A are constants characterising the equilibria, and whose values appear in Figure 16.
  • K a , K á , K 2HA and K 2A are constants characterising the equilibria, and whose values appear in Figure 16.
  • the variations of the pH of R- and S-2-phenylpropanoic acid/phenylpropanoate solutions in the vicinity of the pK a of RS-2-phenylpropanoic acid as they were titrated with ⁇ CDNH 3 + solutions are shown in Figure 17C.
  • the magnitude of the CD inclusion complex stability constant reflects the competative abilities of the CD to complex the guest species and water to solvate it, and accordingly the data in Figure 16 indicate the changes in these abilities as both the natures of the host CD and the guest species are varied. Six distinct trends emerge from the data in Figure 16 and are now discussed. i) For all systems the carboxylic acid complex is of high stability than the analogues carboxylate complex.
  • the carboxylate will be more strongly solvated that the carboxylic acid, and evidently the decreased solvation resulting from inclusion in the CD annulus has a greater effect on the carboxylate with the consequence that it is destabilised by comparison to the included carboxylic acid.
  • This has the overall effect of descreasing the acidity of the carboxylic acid.
  • the decrease in acidity occuring on formation of the inclusion complex may be a consequence of disruption of the interactions between the -NH 3 + substituent and adjacent hydroxyl residues and the ether linkages which are thought to confer the rather low pK a value on ⁇ CDNH 3 +. 21
  • the cancellation of the ⁇ CDNH 3 + charge by that of the included carboxylate may decrease the acidity of ⁇ CDNH 3 +
  • the identification of the enantiomer resonances was made by adding R-2-phenylpropanoic acid to RS-2-phenylpropanoic acid in the presence of ⁇ CD and noting the relative increase in amplitude of the upfield doublet.
  • thermodynamic chiral discrimination occurs in the complexation of both RS-2-phenylpropanoic acid and RS-2-phenypropanoate by ⁇ CDNH 3 +, but no significant thermodynamic chiral discrimination occurs in the complexation of these guests by ⁇ CD.
  • the titrimetric method may detect a significant thermodynamic chiral discrimination. Such discrimination does not necessarily induce sufficient magnetic inequivalence in the diastereomeric complexes to be detectable by 1H NMR spectroscopy.
  • diastereomeric complexes may be identified by 1 H NMR spectroscopy, this does not necessarily imply the existence of a significant thermodynamic chiral discrimination as the energy differences involved in the spectroscopic distinction are small.
  • the pK a magnitudes characterising these acid dissociations were derived from data in the pH range 2.0 - 12.0. It should be noted that 6 A -amino-6 A -N-(3-(N-(2-N,2-N-(di-2-aminoethyl)-2-aminoethyl))- carbomylpropanoyl)-6A-deoxy- ⁇ -cyclodextrin decomposes in aqueous solution in the matter of several hours.
  • MilliQ-Reagent system to produce water with a specific resistance of >15 M cm, which was then boiled to remove CO 2 .
  • Titrations were performed using a Metrohm Dosimat E665 titrimator, an Orion SA 720 potentiometer, and an Orion 8103 Ross combination pH electrode which as filled with 0.10 mol dm -3 NaNO 3 .
  • Ni(ClO 4 ) 2 , Cu(ClO 4 ) 2 and Zn(ClO 4 ) 2 stock solutions (0.1004, 0.1007 and 0.1003 mol dm -3 , respectively) were prepared in water and standardised by edta titration in the presence of Murexide indicator in the first two cases and Eriochrome Black T in the case of Zn(ClO 4 ) 2 . 13 Ion exchange of Co 2+ on an Amberlite HRC-120 cation exchange column in the acid form followed by back titration of the liberated H + was used as the standardisation method for the 0.1005 mol dm -3 Co(ClO 4 ) 2 stock solution. E 0 and ply. values were determined by titration of 0.005 mol dm -3 HNO 3 (0.095 mol dm -3 in NaNO 3 ) against 0.100 mol dm -3 NaOH.
  • the pK a values of 6 A -amino-6 A -N-(2-N,2-N-(di-(2-aminoethyl))-2 -aminoethyl)-6 A -deoxy- ⁇ -cyclodextrin and 6 A -amino-6 A -N-(3-(N-(2-N,2 -N-(di-2-aminoethyl)-2-aminoethyl))-carbamoylpropanoyl)-6 A -deoxy- ⁇ -cyclodextrin were determined by titration of 10cm 3 aliquots of 0.001 mol dm -3 solutions.
  • the apparent stability constants for the formation of the metallo-6 A -amino-6 A -N-(3-(N-(2-N,2-N-(di-2 -aminoethyl)-2-aminoethyl))-carbamoylpropanoyl)-6 A -deoxy- ⁇ -cyclodextrins were determined by titration of 10cm 3 aliquots of 0.001 mol dm -3 6 A -amino-6 A -N-(3-(N-(2-N,2-N-(di-2-aminoethyl)-2- aminoethyl) ) -carbamoylpropanoyl) -6 A -deoxy- ⁇ -cyclodextrin with 95mm 3 or 45mm 3 of divalent metal perchlorate solution added.
  • the K a1 and K a2 magnitudes were derived from data in the pH range 6.0 - 11.5.
  • K CDRT and K CDST were derived from data in the pH range 8 - 10).
  • E 0 and pK w values were determined by titration of 0.010 mol dm -3 HClO 4 (0.09 mol dm -3 in NaClO 4 ) against 0.100 mol dm -3 NaOH.
  • the pK a values of 6 A -(3-aminopropylamino)-6 A -deoxy- ⁇ -cyclodextrin and tryptophan were determined by titration of 10cm 3 aliquots of 0.001 mol dm -3 solutions.
  • the apparent stability constants for the formation of the ⁇ -cyclodextrin-tryptophan and 6 A -(3-aminopropylamino)-6 A -deoxy- ⁇ -cyclodextrin-tryptophancomplexes were determined by titration of 5cm 3 each of 0.001 mol dm -3 solutions of either R- or S-tryptophan and the appropriate cyclodextrin.
  • the apparent stability constants for the formulation of the metal-tryptophan complexes and metallo-6 A -(3-aminopropylamino)-6 A -deoxy- ⁇ -cyclodextrins were determined by titration of 10cm 3 aliquots of 0.001 mol dm -3 either tryptophan or cyclodextrin with either 95mm 3 or 45mm 3 of divalent metal perchlorate solution added.
  • the apparent stability constants for the formation of the metallo-6 A -(3-aminopropylamino)-6 A -deoxy- ⁇ -cyclodextrin-tryptophan anion complexes were determined by titration of 5cm 3 each of 1.0 ⁇ 10 -3 mol dm -3 solutions of R- or S-tryptophan and 6 A -(3-aminopropylamino)-6 A -deoxy- ⁇ -cyclodextrin with 45mm 3 of divalent metal perchlorate solution added. Derivation of the stability constants was performed using the program SUPERQUAD. 13 At least three runs were performed for each system, and at least two of these runs were average; the criterion for selection for this averaging being that X for each run was ⁇ 12.6 at the 95% confidence level. 13
  • the curve through the data points represents the best fit of the data to the equilibria shown in (1) using SUPERQUAD.
  • the upper and lowed data sets refer to s- and R-2-phenylpropanoate, respectively.
  • the curves through the data points represent the best fits of the data to the equilibria shown in (2) using SUPERQUAD.
  • the upper and lower data sets refer to R- and S-2-phenylpropanoic acid/phenylpropanoate, respectively.
  • the curves through the data points represent the best fits of the data to the equilibria shown in (3) using SUPERQUAD.
  • FIGURE 22 Speciation plot for the ⁇ CDNH 2 / ⁇ CDNH 3 +/S-2-phenylpropanoic acid/S-2-phenylpropanoate system calculated from pK a , K 2SHA , K 2SA and K 3SA (Table 1).
  • the total concentration of S-2-phenylpropanoic acid/S-2-phenylpropanoate is 10 -3 mol dm -3 and the total concentration of ⁇ CDNH 2 / ⁇ CDNH 3 + is 1.5 ⁇ 10 -2 mol dm -3 .
  • the total concentration of S-2-phenylpropanoic acid/S-2-phenylpropanoate is defined as 100% and the free ⁇ CDNH 2 / ⁇ CDNH 3 + concentration is not shown.
  • the curves represent: a) S-2-phenylpropanoic acid. ⁇ CDNH 3 +, b) S-2-phenylpropanoic acid, c)S-2-phenylpropanoate. ⁇ CDNH 3 +, d)S-2-phenylpropanoate, and e)S-2-phenyl+propanoate. ⁇ CDNH 2 .
  • RS-2-phenylpropanoic acid (0.005 mol dm -3 ) in the presence of ⁇ CDNH 3 + (0.03mol dm -3 ) at pH 1.
  • RS-2-phenylpropanoic acid (0.002 mol dm -3 ) with added RS-2-phenylpropanoic acid (0.002 mol dm -3 ) in the presence of ⁇ CDNH 3 + (0.03mol dm -3 ) at pH 1.
  • RS-2-phenylpropanoate (0.01 mol dm -3 ) at pH 6.4.
  • Example 53 in Cyclodextrin compositions and methods for pharmaceutical and industrial applications.

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Abstract

On décrit un complexe d'inclusion comprenant (1) l'agent pharmaceutique Propofol (2,6-bis(méthyléthyle)phénol) de l'Alfaxalone, c'est-à-dire 3-hydroxyprégnane-11, 20-dione, et (2) un dérivé de cyclo dextrine comprenant une cyclodextrine substituée ou non où au moins un hydroxyle C2, C3 ou C6 est substitué par un groupe choisi parmi -XR?1, -YR2R3, -SiR4R5R6, et -R7¿, où X peut représenter (a), (b), (c) et où Y peut représenter (d), (e), (f), (g).
PCT/AU1993/000100 1992-03-11 1993-03-09 Nouvelles cyclodestrines et medicaments de formule nouvelle WO1993017711A1 (fr)

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AU36241/93A AU3624193A (en) 1992-03-11 1993-03-09 New cyclodextrins and new formulated drugs

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020222A1 (fr) * 1994-12-27 1996-07-04 Dimminaco Ag/Sa/Ltd. Nouveaux derives de cyclodextrines et leurs procedes de preparation
WO1996032135A1 (fr) * 1995-04-10 1996-10-17 Farmarc Nederland Bv Of Citco Trust International Management (T.I.M.) B.V. Composition pharmaceutique
WO2001070234A1 (fr) * 2000-03-20 2001-09-27 Jurox Pty. Ltd. Composition anesthesique
EP1383445A1 (fr) * 2001-03-20 2004-01-28 Cydex Inc. Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique
WO2011088503A1 (fr) * 2010-01-21 2011-07-28 Goodchild Investments Pty Ltd Formulation anesthésique
AU2013200895B2 (en) * 2010-01-21 2013-10-31 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
US10940128B2 (en) 2009-05-29 2021-03-09 Cydex Pharmaceuticals, Inc. Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399716A1 (fr) * 1989-05-24 1990-11-28 Innovet, Inc. Composition hypoallergénique stéroide à activité anesthésiante/hypnotique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0399716A1 (fr) * 1989-05-24 1990-11-28 Innovet, Inc. Composition hypoallergénique stéroide à activité anesthésiante/hypnotique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
International Journal of Pharmaceutics, 65(1990) 101-107, K.S. ESTES et al., "A Non-Surfactant Formulation for Alfaxalone Based on an Amorphous Cyclodextrin: Activity Studies in Rats and Dogs", pages 101-107, entire document. *
Journal of Parenteral Science & Technology, Vol. 43, No. 6, November-December 1989, MARCUS E. BREWSTER et al., "Development of a Non-Surfactant Formulation for Alfaxalone Through the Use of Chemically-Modified Cyclodextrins", pages 262-265, entire document. *
See also references of EP0630261A4 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020222A1 (fr) * 1994-12-27 1996-07-04 Dimminaco Ag/Sa/Ltd. Nouveaux derives de cyclodextrines et leurs procedes de preparation
AU713997B2 (en) * 1994-12-27 1999-12-16 Dimminaco Ag Novel cyclodextrin-derivatives and methods for the preparation thereof
WO1996032135A1 (fr) * 1995-04-10 1996-10-17 Farmarc Nederland Bv Of Citco Trust International Management (T.I.M.) B.V. Composition pharmaceutique
WO2001070234A1 (fr) * 2000-03-20 2001-09-27 Jurox Pty. Ltd. Composition anesthesique
US7897586B2 (en) 2000-03-20 2011-03-01 Jurox Pty. Ltd. Anaesthetic composition
US9427443B2 (en) 2000-03-20 2016-08-30 Jurox Pty. Ltd. Anaesthetic composition
EP1383445A1 (fr) * 2001-03-20 2004-01-28 Cydex Inc. Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique
EP1383445A4 (fr) * 2001-03-20 2005-04-13 Cydex Inc Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique
US11020363B2 (en) 2009-05-29 2021-06-01 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
US10940128B2 (en) 2009-05-29 2021-03-09 Cydex Pharmaceuticals, Inc. Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
AU2011207103B2 (en) * 2010-01-21 2013-03-21 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
US8975245B2 (en) 2010-01-21 2015-03-10 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
AU2013200895B2 (en) * 2010-01-21 2013-10-31 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
AU2013200895C1 (en) * 2010-01-21 2014-02-06 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
US8697678B2 (en) 2010-01-21 2014-04-15 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
CN102802635B (zh) * 2010-01-21 2014-07-30 吊桥药业有限公司 麻醉药制剂
GB2491491B (en) * 2010-01-21 2014-07-30 Drawbridge Pharmaceuticals Pty Ltd Anaesthetic formulation
GB2491491A (en) * 2010-01-21 2012-12-05 Goodchild Invest Pty Ltd Improved anaesthetic formulations comprising neuroactive steroids
RU2574022C2 (ru) * 2010-01-21 2016-01-27 Дробридж Фармасьютикалз Пти Лтд. Анестезирующий состав
CN102802635A (zh) * 2010-01-21 2012-11-28 古德柴尔德投资有限公司 麻醉药制剂
KR101747476B1 (ko) 2010-01-21 2017-06-14 드로브리지 파마슈티컬스 피티와이 엘티디 마취 제제
GB2484244B (en) * 2010-01-21 2012-10-31 Goodchild Invest Pty Ltd Anaesthetic formulation
GB2484244A (en) * 2010-01-21 2012-04-04 Goodchild Invest Pty Ltd Anaesthetic formulation
WO2011088503A1 (fr) * 2010-01-21 2011-07-28 Goodchild Investments Pty Ltd Formulation anesthésique

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