WO1991013100A1 - Compositions a base de cyclodextrines - Google Patents

Compositions a base de cyclodextrines Download PDF

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Publication number
WO1991013100A1
WO1991013100A1 PCT/AU1991/000071 AU9100071W WO9113100A1 WO 1991013100 A1 WO1991013100 A1 WO 1991013100A1 AU 9100071 W AU9100071 W AU 9100071W WO 9113100 A1 WO9113100 A1 WO 9113100A1
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WIPO (PCT)
Prior art keywords
cyclodextrin
substituted
group
cyclodextrin derivative
cyclodextrins
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PCT/AU1991/000071
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English (en)
Inventor
John Hewlett Coates
Christopher John Easton
Stephen Frederick Lincoln
Stephen John Van Eyk
Bruce Lindley May
Michael Lloyd Williams
Susan Elizabeth Brown
Angelo Lepore
Ming-Long Liao
Yin Luo
Vilma Macolino
Deborah Susanne Schiesser
Craig Bernard Whalland
Ian S. C. Mckenzie
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Australian Commercial Research & Development Limited
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Publication of WO1991013100A1 publication Critical patent/WO1991013100A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • 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

Definitions

  • cyclodextrin derivatives including covalently linked cyclodextrins, which are capable of achieving inclusion complexes of greater stability.
  • the '359 Application provided, inter alia., many new cyclodextrin derivatives and processes, as well as synthetic pathways and intermediates for preparing such derivatives.
  • many pharmaceutical agents can incite an immune response in a patient.
  • penicillin in some individuals is antigenic, giving rise to anti-penicillin antibodies. This can pose two adverse consequences. First, if penicillin is given to an allergic individual, a severe reaction may occur which can vary from a skin rash or asthma to anaphylaxis and death. Second, the drug does not react at its site of activity because it is sequestered by antibody.
  • Other pharmaceutical agents which may be potentially immunogenic are antibodies themselves, peptides or other synthetic or natural materials.
  • this specification provides, inter alia, cyclodextrin derivatives, inclusion complexes, processes, syntheses and intermediates which are useful in the application of cyclodextrins to, inter alia, pharmaceutical (diagnostic and therapeutic) and industrial applications.
  • a first embodiment provides a method for designing cyclodextrin inclusion complexes comprising a useful agent and an otherwise substituted or unsubstituted cyclodextrin or two or more otherwise substituted or unsubstituted cyclodextrins linked by at least one linking group.
  • the process comprises first determining whether the useful agent possesses at least one group capable of non-covalent association. Next, the orientation of the agent in the cyclodextrin annulus and the relative position of the associable group is determined by considering the dipole moment of the agent and the position of hydrophobic or apolar groups on the agent.
  • cyclodextrin derivatives and inclusion complexes including cyclodextrin derivatives comprising groups which are charged, polar or are capable of forming a non-covalent association with another group.
  • the inclusion complexes can comprise an active agent such as a pharmaceutical, herbicidal, pesticidal, agricultural, cosmetic or personal care agent. Synthetic procedures for preparing such derivatives are also provided.
  • substitutions to the cyclodextrin can be tailored to achieve maximum effect.
  • This method of design can be particularly important in instances where the guest theoretically is capable of more than one orientation within the cyclodextrin annulus.
  • substitutions for the primary hydroxyls can be made so that they will exert a desired effect on the portion of the included molecule expected to be present in that vicinity.
  • substitutions for the secondary hydroxyls can also be made.
  • This method of inclusion complex design is generally illustrated in Figure 4. Whether to substitute for primary or secondary hydroxyls thus becomes a function of the molecule to
  • the cyclodextrin is negatively polarized in the vicinity of the secondary hydroxyls
  • This can thus enhance the attraction with the guest, and thereby enhance one or more properties of the inclusion complex such as stability.
  • Figures 7A to C illustrate inclusion complexes comprising two cyclodextrins wherein each cyclodextrin has one or more substituents which can associate.
  • linked cyclodextrins contain associable groups X and Y, which represent charged or polar atoms or groups of atoms, or some other group capable of interaction (e.g., hydrogen bonding) .
  • the groups can be selected to provide desired release profiles.
  • the selected groups can be oppositely charged in the acidic environment of the stomach, but one or both could lose its charge (or take on opposite charges) in the relatively neutral environment of the intestines.
  • Cyclodextrins in which one or more C2, C3 or C6 hydroxyls are selectively substituted by ether substituents are also encompassed.
  • ether substituents may be further substituted with any of the foregoing groups.
  • inclusion complexes in which at least one pharmaceutical, pesticidal, herbicidal, agricultural, cosmetic, personal care or other useful agent is included in a modified cyclodextrin as described above.
  • cyclodextrins in accordance with this invention will possess one or more pendant arms as described in the '359 Application.
  • 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
  • R 13 represents a group defined the same as R ! -R 12 above, and
  • L represents a group selected from reactive, charged, polar or associating groups.
  • SUBSTITUTESHEET 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
  • 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.
  • SUBSTITUTESHEET can carry a net negative charge include hydroxyl, carboxyl, phosphate (P0 4 *3 ) or sulfonate (SOj" 1 ) .
  • Other groups having net negative charges will be readily apparent to those skilled in the art.
  • 6 A -amino-6 A -deoxy-6 A -N-(3-carboxypropanoyl) - ⁇ -cyclodextrin hereinafter "j8-CDNSc"
  • j8-CDNSc 6 A -amino-6 A -deoxy-6 A -N-(3-carboxypropanoyl) - ⁇ -cyclodextrin
  • j8-CDNSc 6 A -amino-6 A -deoxy-6 A -N-(3-carboxypropanoyl) - ⁇ -cyclodextrin
  • modified cyclodextrin, /8-CDNSc is also an example of another preferred group of cyclodextrin derivatives having the formula CD - X - R 14 - Q, wherein:
  • the compound can be used either for delivery of drugs such as amiodarone, or as an intermediate in the preparation of other cyclodextrin derivatives, including especially asymmetric linked cyclodextrins and prodrugs.
  • the carboxylic acid advantageously can be derivatized to undergo substitution, for example, by forming an acid chloride, acid anhydride or ester.
  • another preferred embodiment of this invention comprises at least two otherwise substituted or unsubstituted cyclodextrins covalently bonded to each other by at least one linking group.
  • the at least one linking group links a first cyclodextrin at a C2, C3 or C6 position to a second cyclodextrin at a C2, C3 or C6 position.
  • the cylodextrins can be substituted as described above.
  • that linking group is other than a disulfide that links the two cyclodextrins at the C6 position.
  • a preferred group of the linked cyclodextrins are those in which only two cyclodextrins are linked together. Further, from the discussion in Section II above, one can also see the importance of linked cyclodextrins in which a first otherwise substituted or unsubstituted cyclodextrin is linked through one of its primary (C6) carbons to a secondary (C2 or C3) carbon of a second otherwise substituted or unsubstituted cyclodextrin. Thus, otherwise substituted or unsubstituted cyclodextrins which are linked by C6-C3 or C6-C2 linkages comprise yet another preferred embodiment of this invention. As discussed below, preparation of such asymmetrical linked cyclodextrins is greatly facilitated by the above-described intermediates of the formula CD-X-R-Q.
  • 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 such as ether, thioether, ester, thioester, amide, thioamide, and amine, and
  • the otherwise substituted or unsubstituted cyclodextrins which are linked may also be the same or different.
  • an ⁇ -cyclodextrin can be linked to a ⁇ - , y- or tf-cyclodextrin.
  • Such an asymmetrical configuration may be advantageous when the guest contains multiple hydrophobic groups of different size.
  • the length of the linking group may be varied to accommodate guest molecules of different sizes.
  • a first group of carriers comprises those atoms or molecules which can be used to target cells of interest within a patient.
  • examples of such can include antibodies or fragments thereof which are specific to tumors for the therapy of cancer, hormones or interleukins for the therapy of infectious disease, cancer and for the treatment of immune deficiency.
  • the cyclodextrin derivative generally first would be conjugated to the carrier by a chemical reaction. Thereafter, the carrier- cyclodextrin conjugate would be exposed to the pharmaceutical agent which would form an inclusion complex with the cyclodextrin.
  • cyclodextrin prodrugs could be covalently attached to the targeting carrier.
  • using such carriers may provide other advantages such as: (a) the amount of drug which can be conjugated to the carrier
  • a carboxylic acid group could be derivatized to undergo substitution by forming an acid chloride, acid anhydride or ester, which could then be reacted with an amino group on an antibody to form an amide bond.
  • the form of the pharmaceutical agent is not altered and can be targeted to the cells of interest in the protected form of the inclusion complex.
  • compositions may be in any pharmaceutically acceptable form for any type of administration, including topical, oral, rectal or parenteral administration. And because cyclodextrins and derivatives thereof can mask taste, different types of oral administrations may be possible, including chewable or effervescent tablets (e.g., for antacids), gargles, topical solutions and suspensions, pastes, ointments, etc. All forms of such compositions, including those which have been freeze-dried and spray dried are within the scope of this invention. 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.
  • SUBSTITUTE SHEET (c) the pleural or pericardial spaces for the treatment of infection or cancer;
  • cyclodextrins cyclodextrin derivatives and pharmaceutical 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, macrophages and other cells, and possibly also from the destructive mechanisms found within the cytoplasm of most cells.
  • another embodiment of this invention comprises an inclusion complex comprising cimetidine included in a cyclodextrin derivative, or a cyclodextrin prodrug comprising the residue of cimetidine covalently bonded to a cyclodextrin derivative as described herein or in the '359 Application, or a
  • SUBSTITUTESHEET pharmaceutical composition containing such inclusion complex or prodrug.
  • Any of the aforementioned forms of pharmaceutical compositions is envisioned, including those comprising carriers for targeted or prolonged delivery.
  • R is as described above, and preferably represents alkyl groups of from 1-3, 1-6, 1-10, 10-20 or greater than 20 carbons;
  • Amino acids are organic compounds that have at least one amino (-NH 2 ) group and at least one carboxyl (-COOH) group.
  • Oligopeptides are amino acid oligomers which are formed by reacting amino and carboxyl groups from different amino acids to release a water molecule and form a peptide linkage.
  • Polypeptides are amino acid polymers which are formed in the same way. Generally, oligopeptides have between 2 and 20 peptide linkages whereas polypeptides have more. Proteins are very large polypeptides.
  • polypeptides may possess unique conformations (combinations of
  • SUBSTITUTESHEET Also useful are factor II, factor VII, factor VIII, factor IX, factor X and Xa, antithrombin III, transferrin, haptoglobin, fibronectin, gamma globulins, protein C, protein S and thrombin; toxoids, such as diphtheria and tetanus; vaccines, including attenuated vaccines (such as those for cholera, influenza, meningitis, Yersinia pestis or plague, pneumonia, poliomyelitis, rabies, typhoid and staphylococcus) and live vaccines (such as those for poliomyelitis, measles, rubella and mumps) ; growth factors, hormones and like bioactive peptides, as illustrated by ⁇ -1-antitrypsin, atrial natriuretic factor (diuretic) , calcitonin, calmodulin, choriogonadotropin (or and ⁇ )
  • polypeptides contemplated by this invention have use in immunology. These include monoclonal antibodies, polyclonal antibodies (unconjugated) , second antibodies (alkaline phosphatase conjugated) , immunoglobulin screening and isotyping kits, protein A products and immunoassay reagents.
  • monoclonal antibodies include monoclonal antibodies for human cell surface antigens, monoclonal antibodies for murine cell surface antigens, monoclonal antibodies to complement and blood proteins, monoclonal antibodies to immunoglobulins (human) , monoclonal antibodies to neurological antigens, monoclonal antibodies to tumor markers, monoclonal antibodies to cell components, Epstein Barr virus antigens, human lymphocyte antigen (HLA) typing, hematology antibodies, leucocyte antibodies,
  • SUBSTITUTESHEET bacterial antigens include parasitic antigens, T-cell lymphotropic virus (HIV-III) and cytoskeletal antibodies.
  • Useful polyclonal antibodies include affinity purified antibodies to immunoglobulins, antibodies to plant viruses, antisera to human isoenzymes and chromatographically purified antibodies.
  • polypeptides contemplated for use herein are polypetides of particular interest in the field of molecular biology, including various enzymes and reagents.
  • the enzymes can include labelling enzymes, modifying enzymes, nucleases,
  • EXAMPLE 17 / 8-CDOTs (340 mg) was dissolved in 0.880 ammonia solution (10 ml) and left standing at room temperature for 2 weeks. After removing the ammonia in vacuo the residue was poured into acetone (50 ml) . The precipitate was collected by gravity filtration and dried in vacuo to give j8-CDNH 2 (301 mg). T.l.c. and HPLC showed a spot corresponding to ]8-CDNH 2 .
  • SUBSTITUTESHEET showed: Re (relative to ⁇ -CD), ⁇ -CDNH 2 , 0.7; ⁇ -CDNAc, 1.1.
  • HPLC of the crude product using a 75% CH 3 CN-H 2 0 eluant showed: t R (relative to ⁇ -CD), unknown, 0.6; ⁇ -CDNAc, 0.9; ⁇ -CDNH 2 , 1.2.
  • Examples 33 to 42 illustrate preparation of prodrugs in which Ibuprofen ( ⁇ -methyl-4--- (2-methylpropyl) -benzeneacetic acid) or Naproxen (6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid) are covalently bonded directly to a cyclodextrin through ester linkages .
  • Step 1 3-Nitrophenyl (S)-6-methoxy- ⁇ -methyl-2- naphthaleneacetate (NpNP) can be prepared as follows. A mixture of (S)-6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid (1.0 g) and 3-nitrophenol (0.6 g) were dissolved in dry ethyl acetate (100 ml). The solution was cooled to 0°C, DCC (1.0 g) was added and the reaction for one hour. The reaction mixture was allowed to warm to room temperature and stirred overnight. DCU was removed by filtration and the filtrate evaporated in vacuo to yield the crude ester as a solid.
  • Step 2 To a solution of /3-CD (1.13 g) in aqueous DMF (10 ml, 1:3) was added NpNP (0.351 g) and the reaction mixture was stirred at 100 - 110°C for 24 hours. After this time analysis of a portion of this mixture by HPLC showed: t R (relative to ⁇ - CD) , jS-2CDONp, 0.36; 3-CD, 1.0. The reaction was heated for a further 24 hours, the reaction mixture cooled and acetone was added until precipitation was complete. The precipitate was collected by gravity filtration (Whatman N 5 1 qualitative filter paper) and recrystallized from water to give a solid which was poorly soluble in water. HPLC using a 70% CH 3 CN-H 2 0 eluant showed: t R (relative to /3-CD), 0.36, 1.00.
  • SUBSTITUTESHEET H8 and H9 split into 2 quartets and 2 doublets respectively.
  • Horse liver acetone powder (0.89 g) was added to a suspension of IbOMe (0.89 g, 4.04 mmol) in 0.2 M phosphate buffer (36 ml). The reaction was followed by t.l.c. (5% acetic acid, 10% ethyl acetate, 85% hexane) . Conversion of the 50% of the IbOMe (R f 0.37) to Ibuprofen (R f 0.15) appeared complete after 11 hours. The reaction was quenched by adding 1 M hydrochloric acid until the solution reached pH 2. Ether (20 ml) was added to the reaction mixture and the two layers centrifuged (3000 r.p.m., 15 minutes) .
  • Step 1 To a solution of (R)- ⁇ -methyl-4-(2-methylpropyl)- benzeneacetic acid (Example 39, 80 mg, 0.4 mmol) in dry methanol (2 ml) was added cesium carbonate (70 mg, 0.22 mmol) in portions over a 5 minute period with stirring. The mixture was allowed to stir at room temperature for a further 55 minutes and then
  • Examples 43- 50 illustrate preparation of prodrugs in which Ibuprofen ( ⁇ -methyl-4- (2-methylpropyl) -benzeneacetic acid) or Naproxen (6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid) is covalently bonded directly to a cyclodextrin through amide linkages .
  • Step 1 ⁇ -Methyl-4-(2-methylpropyl)-benzeneacetic acid anhydride (Ib ) was prepared as follows. ⁇ -Methyl-4-(2- methylpropyl)-benzeneacetic acid (1500 mg) was dissolved in dry ether (60 ml) and DCC (750 mg) was added. Insoluble DCU forms
  • Step 2 ⁇ -CDNH 2 (600 mg) was dissolved in dry methanol (13 ml) and IbjO (1.3 g) added. The reaction was stirred at room temperature for 6 hours and water (20 ml) added. The mixture was stirred for a further 10 minutes and then filtered (Whatman * 1 filter paper) directly into acetone (200 ml) . The resulting precipitate was collected by gravity filtration and washed with acetone (2 x 20 ml) . The resultant solid was dried in vacuo to give both ⁇ -CDNIb and ⁇ -CDNH 2 (370 mg) .
  • X H n.m.r. and 13 C n.m.r. indicate an isomeric mixture of the ⁇ -CDNIb X H n.m.r. ⁇ H 0.87, J 7 Hz, Me ⁇ , Me ⁇ ; 1.34, J 7 Hz, 1.39, J 7 Hz, ⁇ Me (2 isomers); 1.84, m, J 7 Hz, CH ⁇ ; 2.48, J 7Hz, (CH j Ji B ,,; 3.2 -5.1, 60H; 7.23, q, ArH. 13 C n.m.r.
  • Step 1 (S)-6-Methoxy- ⁇ -methyl-2-naphthaleneacetic acid anhydride (Np 2 0) was prepared as follows. (S)-6-Methoxy- ⁇ - methyl-2-naphthaleneacetic acid (250 mg) was dissolved in dry ether (10 ml) and DCC (130 mg) was added. Insoluble DCU formed immediately. After 1 hour the ether was removed in vacuo and ethyl acetate (100 ml) added to the residue. The product only
  • EXAMPLE 52 ⁇ -CDOTs (30 g) was dissolved in DMF (50 ml) with diaminobutane (5 g) and heated at 100°C for 3 hours. The mixture was poured into acetone (200 ml) and the solid was filtered off. Then the solid was dissolved in hot water (50 ml) and left to recrystallize. After standing for 2 days the solid was filtered off. Soxhlet extraction with ethanol overnight removed trapped diaminobutane. Recrystallization from hot water afforded pure ⁇ -CDN4N after prolonged standing.
  • Step 1 Bis-(3-nitrophenyl) succinate can be prepared as follows. Succinic acid (11.8 g) and 3-nitrophenol (27.8 g) were dissolved in dry ethyl acetate (1 1, 4A sieve) and the solution
  • H 2 0 eluant showed: t R (relative to / 3-CD), 0.54, 0.77, 1.0, 2.90,
  • Step 2 To a stirred solution of dry
  • Step 2 Bis-(3-nitrophenyl) succinate (160 mg) was added in portions to a solution of ⁇ -CDNH 2 (1 g) in dry pyridine with stirring over one hour. The reaction was followed by t.l.c. and appeared to be complete after 5 days. The pyridine was removed in vacuo and the solid dissolved in water. The water was removed in vacuo to remove traces of pyridine. The solid was dissolved in a minimum of water (8 ml) and added dropwise to ice-cold acetone (80 ml) and stirred rapidly for 10 minutes. The white powdery solid was collected by vacuum filtration and washed with
  • Examples 60 and 61 illustrate alternative methods for the preparation of N,N' -Bis- (6 A -deoxy-6 A - ⁇ -cyclodextrin) succinamide .
  • BioRex 70 The acid form of BioRex 70 was prepared by taking BioRex 70 (Na + form, as supplied, 100 ml) and batch rinsing in a scintered glass funnel as follows:-
  • the resin from above (- 50 ml) was suspended in Milli-Q® water (200 ml) with stirring. A solution of /8-CD 2 NSc (8 g) in Milli-Q® water (100 ml) was added and the mixture left to stir overnight at room temperature. The resin was collected by filtration in a scintered glass funnel and rinsed with water (5 x 100 ml) at 50°C. The combined filtrates were dried in vacuo to give 4.7 g of /S-CDjNSc. This was dissolved in water (20 ml) and filtered (0.22 ⁇ filter). Ethanol (- 20 ml) was added until a faint haze persisted.
  • EXAMPLE 64 6 A -Amino-6 A -deoxy-6 A -N- (4-0-(3-nitrophenyl)- carboxypropanoy1)- ⁇ -cyclodextrin ( ⁇ -CDNScNP)
  • EXAMPLE 65 6 A -Amino-6 A -deoxy-6 A -N-(4-0-(3-nitro ⁇ henyl)- carboxypropanoyl)-/3-cyclodextrin (/3-CDNScNP)
  • SUBSTITUTE SHEET product showed: Re (relative to /8-CD) , /3-CDNScNP, 1.3.
  • Examples 67 and 68 illustrate alternative methods for the preparation of 6 A -Amino-6 A -deoxy-6 A -N- (3-carboxypropanoyl) - ⁇ - cyclodextrin.
  • EXAMPLE 72 6 A -Amino-6 A -N-(2-N,2-N-(di-2-aminoethyl)-2-aminoethyl)-6 A - deoxy- ⁇ -cyclodextrin ( ⁇ -CDTren)
  • FAB MS M+H + requires 1102 found 1000, 1101, 1129, 1157. 13 C n.m.r (D 2 0) 31.0 5 , 36.9 3 , 38.8 0 , 46.3 8 , 47.5 4 , 50.8 4 , 53.6 9 , 54.7 3 , 55.0 5 , 61.6 6 , 67.7 9 , 72.0 7 , 72.9 X , 73.0 9 , 74.4 1# 82.4 7 , 85.0 i r 102.6 6 , 165.4 4 .
  • SUBSTITUTESHEET Step 2 The product from above (447 mg) was dissolved in anhydrous trifluoroacetic acid (10 mL) and the solution was left to stand at room temperature for 18 hours. The solution was evaporated to dryness and acetone (30 mL) was added to the oily residue. A solution formed and this was evaporated to dryness. Water (10 mL) was added to the residue but none of the residue dissolved. On evaporation of the water, ethanol was added to obtain a white solid. The ethanol was evaporated and the residue was dissolved in water (10 mL) . This solution was filtered (0.22 ⁇ m) and dropped into acetone (150 mL) . The precipitate was collected by vacuum filtration, rinsed with acetone (10 mL) and ether (10 mL) and dried to give 448.7 mg of white powder (81% yield based on starting glutamic acid) .
  • Reagents used were of reagent grade unless otherwise stated.
  • Buffer systems (0.2 M carbonate buffers , pH 9.5, 10.0, 10.5, 11.0 and 11.5) were prepared by mixing calculated amounts of NaHC0 3 and Na 2 C0 3 in H 2 0. NaOH or HC1 (0.1 M) was used in pH adjustments of buffers with the aid of a Ross pH electrode (Model 81-03, Orion Research) and a pH meter (pHM64a, Radiometer A/S, Copenhagen) . The ionic strength of all buffer solutions was adjusted to 0.6 with potassium chloride.
  • the thermoregulator used consisted of a model 1419 Thermomix (B. Braun, W. Germany) and a Tecam incubator. Where a UV detector is mentioned a Waters
  • a diastereomeric mixture of /8-CDOIb (1.4 g) was dissolved with heating in water (200 ml) and equilibrated to 37°C.
  • the hydrolysis was followed by HPLC using a 73:27 v/v acetonitrile - water mobile phase and a Waters model 441 UV absorbance detector.
  • the retention times for diastereomers A and B were 8.6 and 9.9 minutes respectively.
  • / 8-CDOIb" was selectively hydrolysed to release enriched (R)-Ibuprofen.
  • SUBSTITUTESHEET was used as the mobile phase and that a Waters Model 441 UV Absorbance Detector at 254 nm was used for detection of the ester.
  • the retention time of the ester was 5.5 minutes.
  • the ester showed very rapid hydrolysis at pH 7.8 and 37°C as indicated by the yellow colour of the released 3-nitrophenol.
  • the rate constant (k lft ) was calculated to be 5.9542 hr" 1 which corresponds to a half-life of 7.0 minutes.
  • All cyclodextrins were stored in an evacuated dessicator over P 2 0 5 .
  • All drugs were stored in a dessicator over P 2 0 5 .
  • All dyes were stored in sealed containers to maintain a known water content determined by microanalysis. All weights were measured on a Mettler AE 160 balance. All spectra were recorded on a Zeiss DMR10 doublebea spectrophotometer with a thermostatted cell block ( ⁇ 0.1 K) at 298 K. Cells used for difference spectra experiments were two compartment QS 80 cells, with a pathlength of either 2 x 1.000 cm or 2 x 0.4375 cm. Cells used for straight spectra experiments were single compartment Ql cells of pathlength 0.201 cm.
  • the resultant spectrum must be due to the absorbance of the drug- cyclodextrin complex from the mixed drug-cyclodextrin solution.
  • This spectrum may have a magnitude large enough to measure accurately, and if so, a series of spectra could be obtained
  • Abs(reference cell) 0 for straight spectra method
  • K/E(AB) are estimated and iterated until convergence is SUBSTITUTESHEET found .
  • association constant should be constant within errors over all wavelengths.
  • the actual values for the association constant were found to vary with wavelength, and thus needed to be averaged to give a final association constant value. From the difference spectrum, regions were chosen which had a reasonable change in absorbance across the cyclodextrin concentration range.
  • the association constant values at these wavelengths were accepted as reasonable to include in the average, and were weighted according to the reciprocal of their error, and a mean value calculated. The root-mean-square deviation of the accepted values could then be calculated to give a final value, with error, for the association constant.
  • a stock solution of 8.27X1C 4 M Naproxen and a stock solution of 1.34X10 '1 M ⁇ -CD were made up in phosphate buffer at pH 6.9. A total of 17 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 8.92x10 ⁇ M Naproxen and a stock solution of 1.58xl0" 2 M /3-CD were made up in phosphate buffer at pH 6.9.
  • a total of 16 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 7.99x10"* M Naproxen and a stock solution of 1.2xl0" 2 M 7-CD were made up in phosphate buffer at pH 6.9. A total of 23 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 7.80 x 10 -4 M Naproxen and a stock solution of 4.23 x 10" 2 M /8-CDN4N were made up in tris buffer at pH 8.6. A total of 15 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 7.00xl0 "3 M Ibuprofen and three stock solutions of 4.37 x 10' 2 M, 8.91xl0" 3 M and 4.47xl0" 3 M DIMEB were made up in phosphate buffer at pH 6.9.
  • a total of 16 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 1.96x10"* M Piroxicam and a stock solution of 1.49X10" 1 M DIMEB were made up in phosphate buffer. A total of 20 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 3.96x10"* M Panadol and a stock solution of 1.17X10" 2 M / 8-CD were made up in phosphate buffer at pH 6.9. A total of 18 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • SUBSTITUTESHEET recorded in 0.8750 cm pathlength cells over 300-220 nm, sampling at 1.0 nm intervals, using an integration time of 3.2 seconds per wavelength and a band width of 1.0 nm. Fitted values in the region 267-250 nm were averaged to give an association constant of 130 ⁇ 10.
  • a stock solution of 3.94x10"* M Panadol and a stock solution of 1.005xl0" 3 M DIMEB were made up in phosphate buffer at pH 6.9. A total of 19 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • each sample/reference solution pair was recorded in 0.8750 cm pathlength cells over 300-220 nm, sampling at 1.0 nm intervals, using an integration time of 3.2 seconds per wavelength and a band width of 1.0 nm. Fitted values in the region 259-255 nm were averaged to give an association constant of 83 ⁇ 3. When values in the region 261-260 nm, 254 nm and 232- 224 nm were included in the average the association constant was averaged to be 110 ⁇ 50.
  • a stock solution of 1.56X10 "4 M Crystal Violet and a stock solution of 1.60X10 "2 M /3-CD were made up in phosphate buffer at pH 6.9. A total of 16 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • a stock solution of 1.56x10 * * M Crystal Violet and a stock solution of 3.00xl0" 2 M /3-CDNH 2 were made up in phosphate buffer at pH 6.9. A total of 15 spectra were run, both sample and reference solutions being made up by weight dilutions of the stocks.
  • the peak of the fluorescence was found to be at 442 nm. The fluorescence intensities at this wavelength, increasing with the increase of [CD], were measured for all the sample solutions.
  • SUBSTITUTE SHEET chemicals used to measure association constants of drugs by liquid chromatography in Example 119 is as follows .
  • the negative peak which occurs at about 6 minutes corresponds to a depletion of drug in the eluant due to both dilution (calculated from the injection of pure buffer) and inclusion of the drug by the cyclodextrin.
  • the included drug elutes with the cyclodextrin at about 2 minutes and gives rise to a positive peak.
  • the concentrations of indomethacin used to elute the column were 1.003 x 10"* M, 2.006 x 10"* M, 4.012 X 10"* M and 1.003 x 10' 3 M and were prepared by dilution of a stock solution of indomethacin (359.0 g, 1.003xl0 "3 mole) in buffer (1L) . All solutions were passed through a 0.22 ⁇ m filter before use.
  • the solution was diluted to 1 1 with Milli-Q® water and dry methanol (432 ml) added.
  • Substrate solution. BTEE (14.8 mg) was dissolved with sonication in the buffer solution (100 ml) .
  • UV measurements volumes were measured with a 1000 ⁇ l or a 200 ⁇ l variable pippetor. Where 3 ml volumes were required 3 x 1000 ⁇ l samples were used. Where 150 ⁇ l was required a single 150 ⁇ l sample was used. All solutions were placed in the spectrophotometer room for three hours before measurements were taken to allow equilibration of the solutions to room temperature. Measurements were made in a matched pair of 1 cm quartz cells the absorption was measured over time at 256 nm.
  • Figure 1 shows a typical plot of the experiments. Note the rate of hydrolysis of BTEE in the presence of /8-CD is slower than without /8-CD.
  • the rate of the enzyme catalysed hydrolysis is proportional to the effective (or available) [BTEE] at concentrations below K,,,.
  • the effective [BTEE] equals the total [BTEE], therefore:
  • [/8-CD] [/8-CD] 0 - [/8-CD.BTEE]
  • [BTEE] [BTEE] ⁇ .,.,,,
  • EXAMPLE 132 Naproxen with 6 A -amino-6 A -deoxy-/8-cyclodextrin 1:1 complex
  • a solution of /8-CDNH 2 250 mg, 0.22 mmol
  • Milli-Q® water 10 ml
  • solid Naproxen 50 mg, 0.22 mmol
  • the resulting suspension was stirred at room temperature for 4 hours during which time a clear colorless solution was obtained.
  • Filtration and evaporation to dryness in vacuo resulted in the isolation of a glassy material. Drying to constant weight in vacuo over phosphorus pentoxide gave a yellow powder (268 mg) which was the Naproxen modified cyclodextrin formulation.
  • Amiodarone.HCl (Sigma, 0.0200 g, 0.0293 mmol) and /8-CDNSc (0.0763 g, 0.0618 mmol) were mixed in 40 ml Milli-Q® water and stirred with a magnetic stirrer for 24 hours. The resulting solution contained only a slight haze of undissolved material. The solution was filtered (0.2 ⁇ m filter) and dried in vacuo. The collected crystals, which were almost transparent, readily dissolved in pure water but not in phosphate buffer of pH 7.
  • Amiodarone.HCl has a maximum absorbance at 242 nm in ethanol, pure water and ethanol/water mixture (4:1 ratio by weight) .
  • the extinction coefficient of amiodarone.HCl in ethanol/water mixture solution (4:1 ratio by weight) was measured using a series of solutions of amiodarone.HCl in this solvent. These were prepared by diluting an amiodarone.HCl solution of known concentration in pure ethanol with the appropriate amount of ethanol and water.
  • the extinction coeffecient of amiodarone.HCl at 242 nm in such a mixed solvent is 46,000 (g amiodarone.HCl / g solvent)" 1 .cm" 1 .
  • EXAMPLE 136 Composition and solubility of the amiodarone//3-CDNSc solid Anhydrous amiodarone//S-CDNSc complex (0.0364 g) was dissolved in 1.0089 g Milli-Q® water. The resulted solution was very viscous and seemed to be close to its saturation. The solution was diluted 100 fold with water for taking UV spectra.
  • the extinction coefficient of /3-CDNSc is 77 M ⁇ .cm" 1 and its contribution to the absorbance at 242 nm of the 100 fold diluted amiodarone.HCl//3-CDNSc solution above would be only 0.003, negligibly small compared to the total of -0.6 absorbance unit.
  • plasma amiodarone levels fell substantially in the first 10 to 15 minutes and then declined slowly with a long elimination half-life.
  • SUBSTITUTE SHEET improvement in the pharmacokinetic profile of the drug may allow a more accurate prediction of drug levels from the doses administered and amiodarone therapy for patients can be individually tailored.
  • EXAMPLE 138 Stability Constants for the inclusion of Cimetidine by ⁇ - Cyclodextrin and 6 A -amino-6 A -deoxy-6 A -N-(3-carboxypropanoyl)- ⁇ - cyclodextrin
  • a 50 ⁇ l sample of pure buffer was run as a blank, followed by 50 ⁇ l samples of each of the cyclodextrin solutions, injected via an autosampler.
  • the negative peak which occurs at about 6 minutes corresponds to a depletion of Cimetidine in the eluent due to both dilution (calculated from the injection of pure buffer) and the inclusion of cimetidine by the cyclodextrin.
  • the included cimetidine elutes with the cyclodextrin at about 2 minutes and gives rise to a positive peak.
  • Cimetidine (0.08 g) and 6 A -amino-6 A -deoxy-6 A -N-(3- carboxypropanoyl)- ⁇ -cyclodextrin (0.43g) were dissolved in water (10ml) .
  • the solution was evaporated to dryness under reduced pressure and the resulting solid was dried in a dessicator over P 2 0 5 .
  • the 1:1 formulation of cimetidine with 6 A -amino-6 A -deoxy- 6 A -N-(3-carboxypropanoyl)- ⁇ -cyclodextrin prepared in this way dissolved completely in water (0.5ml) to give a clear solution.
  • cyclodextrin derivatives and inclusion complexes in accordance with this invention.
  • uses can include therapeutic and diagnostic drug delivery, such as multiple routes of administration (i.v. , p.o. , ophthalmic, transdermal, etc.) , improved bioavailability, reduction of irritating drug effects, quantitative reliability, reduced dosing volume, elimination of organic solvents, stable, convenient storage and handling, and previously insoluble or unstable drugs may now be considered for development which enhances removal of lipophilic substances from blood.
  • diagnostic kits include improved low end sensitivity, reduced reaction times, more stable liquid components, greater recovered bioactivity in lyophilized components, reduced effect of interfering substances in serum, plasma and urine specimens and enhanced spectrophotometric response.

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Abstract

On décrit des dérivés de cyclodextrines et des composés les renfermant, ainsi que des intermédiaires et des synthèses pour leur production. On décrit également des procédés permettant de concevoir des composés afin d'obtenir des propriétés améliorées. L'invention concerne aussi des compositions pharmaceutiques, entre autres la cimétidine, l'amiodarone, les polypeptides et le piroxicame, ainsi que de nombreux procédés dans lesquels on peut utiliser les dérivés de cyclodextrines.
PCT/AU1991/000071 1990-03-02 1991-03-01 Compositions a base de cyclodextrines WO1991013100A1 (fr)

Applications Claiming Priority (26)

Application Number Priority Date Filing Date Title
AUPJ889990 1990-03-02
AUPJ8899 1990-03-02
AUPJ8993 1990-03-08
AUPJ899390 1990-03-08
AUPJ9344 1990-03-28
AUPJ934490 1990-03-28
AUPJ937390 1990-03-29
AUPJ9373 1990-03-29
AUPJ9756 1990-04-23
AUPJ975690 1990-04-23
AUPK153890 1990-08-03
AUPK1538 1990-08-03
AUPK1755 1990-08-16
AUPK175590 1990-08-16
AUPK2269 1990-09-12
AUPK226990 1990-09-12
AUPK3596 1990-11-29
AUPK359690 1990-11-29
AUPK3624 1990-11-30
AUPK362490 1990-11-30
AUPK428491 1991-01-21
AUPK4284 1991-01-21
AUPK4603 1991-02-14
AUPK460391 1991-02-14
AUPK485691 1991-02-27
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WO1994020091A1 (fr) * 1993-03-05 1994-09-15 Hexal Pharma Gmbh Complexes cristallins d'insertion de cyclodextrine de l'hydrochlorure de ranitidine, et leur procede de preparation
EP0624599A2 (fr) * 1993-05-13 1994-11-17 L'oreal Dérivés de mono (6-amino 6-désoxy)cyclodextrine substituée en position 6 par un reste d'alpha-aminoacide, leur procédé de préparation et leurs utilisations
EP0630261A1 (fr) * 1992-03-11 1994-12-28 AUSTRALIAN COMMERCIAL RESEARCH & DEVELOPMENT LIMITED Nouvelles cyclodestrines et medicaments de formule nouvelle
DE4338508A1 (de) * 1993-11-11 1995-05-18 Asta Medica Ag Arzneimittelzubereitungen enthaltend Thioctsäure oder Dihydroliponsäure in Form von Einschlußverbindungen mit Cyclodextrinen oder Cyclodextrinderivaten und in Form von Granulaten, Kau- oder Brausetabletten
FR2714067A1 (fr) * 1993-12-22 1995-06-23 Commissariat Energie Atomique Nouveaux dérivés de cyclodextrines, utilisables en particulier pour solubiliser des composés chimiques hydrophobes tels que des médicaments, et leur procédé de préparation.
FR2713934A1 (fr) * 1993-12-22 1995-06-23 Commissariat Energie Atomique Utilisation de cyclodextrines aminées pour la solubilisation aqueuse de composés hydrophobes, en particulier de molécules pharmaceutiquement actives.
AU672814B2 (en) * 1992-07-27 1996-10-17 University Of Kansas, The Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO1998042382A1 (fr) * 1997-03-24 1998-10-01 Therabel Industries S.A. Compositions pharmaceutiques contenant des derives de propanamine et de la cyclodextrine
WO1999024474A1 (fr) * 1997-11-11 1999-05-20 Ceramoptec Inc. Detoxication de substances pharmaceutiques actives a l'aide d'oligomeres de cyclodextrines
EP0917872A1 (fr) * 1997-11-24 1999-05-26 Korea Research Institute Of Chemical Technology Médicament pour la délivrance de poduits acifs par iontophorèse
EP1035135A1 (fr) * 1999-03-05 2000-09-13 Wolff Walsrode AG Esters d'oligosaccharides et de polysaccharides substitués de façon régiosélective et procédé de préparation
US6165995A (en) * 1994-12-27 2000-12-26 American Cyanamid Company Cyclodextrin-derivatives and methods for the preparation thereof
WO2001051524A1 (fr) * 2000-01-13 2001-07-19 Ceramoptec Industries, Inc. Dimeres de cyclodextrine pourvus de sequences d'espacement presentant des structures peptidiques pour l'encapsulation de principes pharmaceutiquement actifs susceptibles de provoquer des effets secondaires importants
WO2003105906A1 (fr) * 2002-06-17 2003-12-24 Chiesi Farmaceutica S.P.A. Procede pour preparer des composes d'inclusion de piroxicam:b-cyclodextrin
WO2004022099A2 (fr) * 2002-09-06 2004-03-18 Insert Therapeutics, Inc. Polymeres a base de cyclodextrine pour administration de medicaments
US6869939B2 (en) 2002-05-04 2005-03-22 Cydex, Inc. Formulations containing amiodarone and sulfoalkyl ether cyclodextrin
JP2007126494A (ja) * 2005-11-01 2007-05-24 Mie Univ シクロデキストリン誘導体の単離精製方法
JP2011190341A (ja) * 2010-03-15 2011-09-29 Nano Dex Kk シクロデキストリン化合物
US8492538B1 (en) 2009-06-04 2013-07-23 Jose R. Matos Cyclodextrin derivative salts
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US9827324B2 (en) 2003-12-31 2017-11-28 Cydex Pharmaceuticals, Inc. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
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
US11027022B2 (en) 2016-05-20 2021-06-08 Polytherics Limited Conjugates and conjugating reagents
WO2021255291A1 (fr) 2020-06-18 2021-12-23 The University Of Bristol Complexes d'acides gras de protéine de spicule de coronavirus et leur utilisation
WO2022029334A1 (fr) 2020-08-07 2022-02-10 Gbiotech S.À.R.L. Polythérapies pour le traitement d'une infection à coronavirus
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof
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Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0630261A1 (fr) * 1992-03-11 1994-12-28 AUSTRALIAN COMMERCIAL RESEARCH & DEVELOPMENT LIMITED Nouvelles cyclodestrines et medicaments de formule nouvelle
EP0630261A4 (fr) * 1992-03-11 1996-11-06 Australian Commercial Research Nouvelles cyclodestrines et medicaments de formule nouvelle.
EP0566142A1 (fr) * 1992-04-16 1993-10-20 LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. Complexes d'inclusion de dérivés optiquement actifs et racémiques de la 1,4-dihydropyridine et de cyclodextrines
AU672814B2 (en) * 1992-07-27 1996-10-17 University Of Kansas, The Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
WO1994020091A1 (fr) * 1993-03-05 1994-09-15 Hexal Pharma Gmbh Complexes cristallins d'insertion de cyclodextrine de l'hydrochlorure de ranitidine, et leur procede de preparation
US5665767A (en) * 1993-03-05 1997-09-09 Hexal Pharma Gmbh Crystalline cyclodextrin complexes of ranitidine hydrochloride, process for their preparation and pharmaceutical compositions containing the same
EP0624599A2 (fr) * 1993-05-13 1994-11-17 L'oreal Dérivés de mono (6-amino 6-désoxy)cyclodextrine substituée en position 6 par un reste d'alpha-aminoacide, leur procédé de préparation et leurs utilisations
EP0624599A3 (fr) * 1993-05-13 1994-12-21 L'oreal Dérivés de mono (6-amino 6-désoxy)cyclodextrine substituée en position 6 par un reste d'alpha-aminoacide, leur procédé de préparation et leurs utilisations
DE4338508A1 (de) * 1993-11-11 1995-05-18 Asta Medica Ag Arzneimittelzubereitungen enthaltend Thioctsäure oder Dihydroliponsäure in Form von Einschlußverbindungen mit Cyclodextrinen oder Cyclodextrinderivaten und in Form von Granulaten, Kau- oder Brausetabletten
WO1995017432A1 (fr) 1993-12-22 1995-06-29 Commissariat A L'energie Atomique Derives de cyclodextrine, utilisables pour solubiliser des composes chimiques hydrophobes tels que des medicaments, et leurs procedes de preparation
WO1995017191A1 (fr) * 1993-12-22 1995-06-29 Commissariat A L'energie Atomique Utilisation de cyclodextrines aminees pour la solubilisation aqueuse des dibenzazepines utilisables comme agent anti-epileptique
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