WO1991004026A1 - Compositions de liberation de medicaments - Google Patents

Compositions de liberation de medicaments Download PDF

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Publication number
WO1991004026A1
WO1991004026A1 PCT/AU1990/000418 AU9000418W WO9104026A1 WO 1991004026 A1 WO1991004026 A1 WO 1991004026A1 AU 9000418 W AU9000418 W AU 9000418W WO 9104026 A1 WO9104026 A1 WO 9104026A1
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Prior art keywords
cyclodextrin
inclusion complex
amino
group
substituted
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PCT/AU1990/000418
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English (en)
Inventor
Clive Frederick Palmer
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Australian Commercial Research & Development Limited
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Publication of WO1991004026A1 publication Critical patent/WO1991004026A1/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
    • 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
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • This invention relates generally to inclusion complexes and pharmaceutical compositions comprising pharmaceutical compounds and substituted or unsubstituted cyclodextrins.
  • This invention also relates to methods for treating a host mammal with such pharmaceutical compositions. More specifically, this invention relates to inclusion complexes and pharmaceutical compositions comprising Amiodarone, nitrogen mustard agents, Naproxen or pharmacologically active derivatives or metabolites thereof in specific substituted or unsubstituted cyclodextrins.
  • melphalan contains a mustard group which can be hydrolyzed by stomach acid, thereby lessening the available amount of active drug.
  • Other drugs may be undesirable because they can cause harmful irritation to the gastrointestinal lining of some patients, thereby causing pain, discomfort or bleeding.
  • Naproxen is a nonsteroidal anti- inflammatory drug (NSAID) useful in treating arthritis and ether conditions involving inflammation.
  • embodiments of this invention provide inclusion complexes and pharmaceutical compositions comprising Amiodarone or a pharmacologically active derivative or metabolite thereof included in a substituted or unsubstituted cyclodextrin or salt thereof selected from the group consisting of ⁇ -, ⁇ -, ⁇ -, ⁇ - , dimethyl ⁇ -, and amino cyclodextrin.
  • Another embodiment provides methods for increasing the solubility of Amiodarone 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 Amiodarone 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.
  • Other groups of embodiments provide inclusion complexes, pharmaceutical compositions, methods for improving the solubility and bioavailability, for decreasing gastroirritation, and for treating host mammals similar to those described above for a compound containing a nitrogen mustard agent, Naproxen, or pharmacologically active derivatives and metabolites thereof.
  • Figure 1 is a graph illustrating the mean plasma concentrations of Amiodarone determined after oral administration of the drug alone or in combination with - , ⁇ - and dimethyl ⁇ - cyclodextrin;
  • Figure 2 is a graph illustrating the mean plasma concentrations of melphalan determined after oral administration of the drug alone or in combination with dimethyl ⁇ -cyclodextrin;
  • Figure 3 is a graph illustrating the mean plasma concentrations of Naproxen determined after oral administration of the drug alone or in combination with dimethyl ⁇ -cyclodextrin. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the first group of embodiments of this invention relates to Amiodarone compositions for oral or parenteral administration, and especially to compositions having improved water solubility and absorption in the gut.
  • Amiodarone which can be described chemically as (2- Butyl-3-benzofuranyl) [4-[2- (diethyl mino) ethoxyl] -3,5- diiodophenyl]methanone,* 2-butyl-3-benzofuranyl 4-[2- (diethylamino)ethoxyl-3,5-diiodophenyl etone; or2-butyl-3-[3,5- diiodo-4-(beta-diethylaminoethoxy)-benzoyl]benzofuran) is an iodinated benzofuran derivative which has potent class III antiarrhythmic activity, and is active on oral administration. It has the following formula:
  • Amiodarone prolongs action potential duration and hence the refractory period ventricular, atrial and nodal tissues.
  • the drug is effective in treating junctional, ventricular and supraventricular arrhythmias.
  • optimal therapy with Amiodarone is compromised by its unreliable absorption following oral administration.
  • the time for detectable concentrations of the drug to appear in plasma can be from less than about 30 minutes to about 3 hours, while the time to reach maximum plasma concentration can vary from 2 to 12 hours.
  • the average Amiodarone bioavailability reported in previously published studies is about 40%, with individual values ranging from 22% to 86% for an orally administered 400 mg dose.
  • cyclodextrins may be useful in the stabilization and solubilization of pharmaceutical agents.
  • the cyclodextrin having the most appropriately-sized annulus to form inclusion complexes with many drugs, namely beta cyclodextrin is the least soluble in water.
  • most cyclodextrin-drug inclusion complexes have low stability constants (which measure the drug's affinity to remain included) , which diminishes their potential for use as drug delivery systems.
  • one embodiment of this invention provides inclusion complexes comprising Amiodarone or a pharmacologically active derivative or metabolite thereof, together with a substituted or unsubstituted cyclodextrin or pharmacologically acceptable salt thereof.
  • the cyclodextrin is alpha-cyclodextrin, beta- cyclodextrin, gamma-cyclodextrin, or a derivative thereof selected from the group consisting of dimethyl beta-cyclodextrin (DMBCD) , or an amino cyclodextrin in which at least one C2, C3 or C6 cyclodextrin hydroxyl is substituted with -NH 2 , or a salt or hydrate thereof.
  • DMBCD dimethyl beta-cyclodextrin
  • Delta-cyclodextrins which are currently being developed, may also be useful.
  • the amino cyclodextrin one or both of the amino hydrogens may be replaced with suitable substituents. Where an amino cyclodextrin is used, the amino substitution is preferably at the C6 position, and beta cyclodextrins are preferred.
  • Suitable amino cyclodextrin derivatives and salts and hydrates thereof for use in the invention are disclosed in PCT application AU89/00359, published March 8, 1990 as WO 90/02141 and entitled "Compositions and Methods for Drug Delivery and Chromatography", the text of which is herein incorporated by reference.
  • the molar ratio of Amiodarone to cyclodextrin is from about 1:1 to about 10:1.
  • compositions comprising one of the aforementioned inclusion complexes together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers are well known to those skilled in this art, and are adequately discussed in published application WO 90/02141. Therapeutically effective amounts of such compositions can be determined by physicians having skill in this art.
  • Another embodiment of this invention provides a method for improving the solubility of Amiodarone or a pharmacologically active derivative or metabolite thereof in a neutral or acidic aqueous solution, comprising the step of forming an inclusion complex comprising said Amiodarone, derivative or metabolite thereof and one of the aforementioned cyclodextrins or derivatives thereof.
  • Another embodiment of this invention provides a method for improving the bioavailability of Amiodarone, derivative or metabolite thereof comprising the step of forming an inclusion complex comprising said Amiodarone, derivative or metabolite thereof and one of the aforementioned cyclodextrins or derivatives thereof.
  • Another embodiment of this invention provides a method for treating a mammal in need of such treatment (e.g., one that is suffering from a cardiac arrhythmia) , comprising the step of orally or parenterally administering to said mammal a therapeutically effective amount of one of the pharmaceutical compositions.
  • a mammal in need of such treatment e.g., one that is suffering from a cardiac arrhythmia
  • oral administration is preferred.
  • Example 1 illustrates the preparation and oral administration of inclusion complexes and pharmaceutical compositions within the scope of this invention. It will be seen that such complexes can effect a "sustained release" of Amiodarone. That is, effective serum concentration levels of Amiodarone can be maintained over a longer period of time when Amiodarone complexes in accordance with this invention are used. The beneficial effect is thus two-fold. First, the patient nee not take the dosages as often, and thus convenience is served. More importantly, however, the total amount of Amiodarone whic the patient must ingest can be decreased dramatically.
  • a second group of embodiments of this invention relate to compositions containing nitrogen mustard agents an cyclodextrins, and particularly to such compositions of improve solubility, stability, and improved bioavailability upon oral o parenteral administration.
  • Alkylating agents such as the nitrogen mustard compound melphalan, uracil mustard, cyclophosphamide, mechlorethamine, an chlora bucil have been widely used in the therapy of cancer sinc 1942. Their cytotoxic effect results from alkylation of DNA. Unlike the mustard gases used in chemical warfare, nitroge mustard compounds have no vesicant action.
  • Melphalan which can be described chemically as (4 [Bis(2-chloroethyl) amino]- hen.ylalanine; p-di ( 2 chloroethyl)amino-L-phenylalanine; L-phenylalanine mustard; alanine nitrogen mustard; L-PAM; melphalan; L-sarcolysine; NSC 8806; CB 3025; Alkeran; or Sarcoclorin, is an antineoplastic drug which is used chiefly for treating multiple myeloma and ovaria cancer.
  • the compound has the following formula:
  • melphalan presents a number of significant problems, including marked instability in solution. Furthermore, the absorption of melphalan from orally administered preparations is often low and variable, possibly due to its very - is about 90 minutes, and as much as 20-50% of the drug is recovered in the stools, while 10-15% is recovered unchanged in the urine.
  • compositions of a representative nitrogen mustard agent, melphalan, with dimethyl ⁇ -cyclodextrin show markedly improved absorption and bioavailability following oral administration. It is believed that amino substituted cyclodextrins and salts thereof also provide enhanced delivery.
  • an inclusion complex comprising a compound containing a nitrogen mustard group and a cyclodextrin derivative or salt thereof.
  • the cyclodextrin derivative is dimethyl beta-cyclodextrin (DMBCD) , or an amino cyclodextrin in which at least one C2 C3 or C6 cyclodextrin hydroxyl is substituted with - NH 2 , or a salt or hydrate thereof.
  • DMBCD dimethyl beta-cyclodextrin
  • amino cyclodextrins in which one or both of the amino hydrogens are replaced with suitable substituents may also be used.
  • amino cyclodextrin derivatives and salts and hydrates thereof for use in the invention are disclosed in the aforementioned PCT application WO 90/02141.
  • amino cyclodextrin preferably the amino substitution is at the C6 position, particularly for beta-cyclodextrins.
  • the nitrogen mustard agent is selected from the group consisting of melphalan, chlorambucil, cyclophosphamide, uracil mustard and mechlorethamine.
  • the molar ratio of nitrogen mustard agent to cyclodextrin derivative is from about 1:1 to about 10:1.
  • compositions comprising one of the aforementioned inclusion complexes and one or more pharmaceutically accepted carriers; a method for improving the solubility of a nitrogen mustard agent in a neutral or acidic aqueous solution by forming an inclusion complex with the agent and one of the recited cyclodextrin derivatives; a method for improving the bioavailability of a nitrogen mustard agent in a host mammal by forming said inclusion complexes; and a method for treating a mammal in need of such treatment (e.g., one suffering from a neoplastic disease) by orally or parenterally administering a therapeutically effective amount of an above described pharmaceutical composition. Determining suitable dosages is within the ordinary skill of physicians in this art. Where DMBCD is used, oral administration is preferred.
  • Example 2 infra, illustrates the preparation and oral administration of an inclusion complex and pharmaceutical composition within the scope of this invention. It will be seen that orally administering the inclusion complex of melphalan and DMBCD can rapidly achieve very high serum levels of melphalan. Such levels are almost twice as great as those achieved using melphalan alone. The obvious benefit is that either much higher serum levels can be achieved with the same amount of melphalan, or similar levels can be achieved with much smaller dosages.
  • Example 3 illustrates that some inclusion complexes which are outside the scope of the claims do not exhibit the same beneficial effects.
  • a third group of embodiments of this invention relates to compositions of Naproxen or its pharmacologically active derivatives or metabolites with cyclodextrin derivatives or salts thereof.
  • Naproxen (6-methoxy-alpha-methyl-2-naphthalene acetic acid) is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is a derivative of naphythlpropionic acid and has the following formula:
  • Naproxen is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma levels of Naproxen are attained in 2 to 4 hours, with steady- state conditions normally achieved after 4-5 doses. The mean hours, and at therapeutic levels it is greater than 99% bound. Approximately 95% of the dose is excreted in the urine, primarily as Naproxen, 6-0-desmethyl Naproxen or their conjugates.
  • Naproxen can cause gastrointestinal bleeding, though less frequently than some of the other drugs of its type. However, when bleeding occurs, it can be very severe.
  • an inclusion complex comprising Naproxen or a pharmacologically active derivative or metabolite thereof, together with a cyclodextrin derivative or salt thereof.
  • the cyclodextrin derivative is preferably dimethyl beta-cyclodextrin (DMBCD) or amino cyclodextrins. Where amino cyclodextrins are used, C6 substituted 3-cyclodextrins are preferred. The amino may be substituted with one or more substituents as described in WO 90/02141.
  • the molar ratio of Naproxen to water-soluble cyclodextrin is preferably from about 1:1 to about 10:1.
  • compositions comprising one of the aforementioned inclusion complexes and one or more pharmaceutically accepted carriers; a method for improving the solubility of Naproxen or a derivative or metabolite thereof in a neutral or acidic aqueous solution by forming an inclusion complex with the recited cyclodextrin derivatives; a method for decreasing the gastroirritation of Naproxen or a derivative or metabolite thereof in a host mammal by forming said inclusion complexes; and a method for treating a mammal in need of such treatment (e.g., one suffering from arthritic inflammation) by administering a therapeutically effective amount of an above described pharmaceutical composition.
  • a mammal in need of such treatment e.g., one suffering from arthritic inflammation
  • Example 4 illustrates the preparation and oral administration of an inclusion complex and pharmaceutical composition within the scope of this invention. It will be seen that administering the inclusion complex of Naproxen and DMBCD appears to delay and prolong the absorption of Naproxen with no compromise on the total bioavailability of the drug.
  • Amiodarone (Sigma Chemical Co., St. Louis, MO) was triturated with the appropriate cyclodextrin (Nihon Shokuhin Kako Co Ltd., Chiyoda-Ku, Tokyo, Japan) in a 2:1 molar ratio and filled without compaction into size 00 hard gelatin capsules (DFC Thompson, Sydney, Australia) .
  • the dose of Amiodarone administered to pigs in each of the final formulations was 1500 mg. No formulation problems were experienced.
  • indwelling cannula was implanted into an internal jugular vein using a surgical technique similar to that reported previously. (Niiyama et al., H. Jpn. J. Vet. Res... Vol. 33, pp. 109 (1985)). Cannulae were kept clear between samplings with a heparin lock, which, together with the sampling line, was kept protected inside a small zippered pouch fixed dorsally to the neck with a collar. The entry point of the cannula tubing was sprayed routinely with an iodine-based antiseptic solution to prevent infection.
  • Figure 1 shows the mean plasma concentrations of Amiodarone measured after oral administration of the drug alone or in combination with cyclodextrins. In most cases, measurable plasma concentrations of Amiodarone were present up to 12 hours, but never at 24 hours or later. The appearance of Amiodarone concentrations was delayed when the drug was administered in combination with the cyclodextrins. Surprisingly, drug released from the beta-cyclodextrin formulation peaked initially at 3 hours but gave a second, higher peak several hours later. Table 1 presents a summary of bioavailability parameters derived from the plotted data.
  • Amiodarone plus 5 342 (50) 7.22 (1.65) 2034 (585) alpha-cyclodextrin Amiodarone plus 5 250 (33) 4.80 (0.20) 1797 (360) beta-cyclodextrin Amiodarone plus 4 333 (36) 5.22 (1.03) 1951 (331)
  • AUC Amiodarone plasma concentration-time curve
  • Melphalan (Sigma Chemical Co., St. Louis, MO) was triturated with dimethyl beta-cyclodextrin, DMBCD (Nihon Shokuhin Kako Co. Ltd., Chiyoda-Ku, Tokyo, Japan) in a 2:1 molar ratio and filled without compaction into size 00 hard gelatin capsules (DFC Thompson, Sydney, Australia) .
  • the dose of melphalan administered was 40 mg. No formulation difficulties were experienced.
  • Example 1 Five healthy domestic pigs (Large White-Landrace hybrid) aged approximately 24 weeks and weighing 127-154 kg (mean 143; SE 7.9 kg) were selected for the study. An indwelling cannula was implanted into an internal jugular vein as described in Example 1.
  • each animal received melphalan without DMBCD, followed one week later by the melphalan-DMBCD formulation.
  • Animals were fasted for eighteen hours before drug administration, although free access to tap water was provided due to the propensity for pigs to suffer dehydration stress.
  • Capsules were deposited at the back of the throat using a hollow perspex tube with an internal plunger. Animals were observed closely for at least thirty minutes to ensure that the entire dose was ingested.
  • Plasma concentrations of melphalan were assayed within three weeks of blood collection using a modified HPLC procedure (Adair et al., 1985).
  • Figure 2 shows the mean plasma concentrations of melphalan determined after oral administration of the drug alone or in combination with DMBCD.
  • Melphalan. was more rapidly absorbed from the cyclodextrin formulation; the mean half life of absorption from Figure 2 was approximately 30 minutes compared with about 60 minutes when melphalan alone was administered.
  • the terminal half-life of melphalan in the pig was approximately 90 minutes, which compares favorably with that reported for the drug in man (Alberts et al., 1979).
  • the disappearance of melphalan from plasma appeared to be more rapid when the cyclodextrin formulation was given.
  • AUC Area under the melphalan plasma concentration-time curve
  • Cmax peak melphalan plasma concentration
  • Tmax time to reach peak concentration
  • Naproxen (Sigma Chemical Co., St Louis, Mo) was triturated with dimethyl beta-cyclodextrin, DMBCD (Nihon Shokuhin Kako Co. Ltd. Chihoda-Ku, Tokyo, Japan) in a 2:1 molar ratio and filled without compaction into size 00 hard gelatin capsules (DFC Thompson, Sydney, Australia) .
  • the dose of Naproxen administrated was 500 mg. No formulation difficulties were experienced.
  • Example 1 An indwelling cannula was implanted into an internal jugular vein using the surgical technique described in Example 1.
  • Plasma concentrations of Naproxen were assayed within three weeks of blood collection by gas chromatography.
  • Figure 3 shows the mean plasma concentrations of Naproxen determined after oral administration of the drug alone or in combination with DMBCD.
  • the Cmax, Tmax and the terminal half-life of Naproxen in the pigs receiving Naproxen alone were 38.9 mg/1, 2.21 hours and 12.7 hours, respectively, which compared favorably with that reported for the drug in man.
  • the parameters such as Cmax and Tmax were found to be significantly lower in pigs receiving Naproxen plus DMBCD.
  • AUC area under the Naproxen plasma concentrations time curve
  • Examples 5-10 illustrate the association constants between Naproxen and ⁇ -, ⁇ -, ⁇ -, dimethyl ⁇ -, and amino cyclodextrins.
  • a stock solution of 7.80xlO "4 M Naproxen and a stock solution of 4.23xlO "2 M 3-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.
  • Examples 11-13 illustrate the preparation of inclusion complexes with varying ratios of Naproxen and cyclodextrin derivative in solution. It has been found that, in some instances, greater concentrations of cyclodextrin derivative can more quickly include a given quantity of drug.
  • Example 14 illustrates the measurement of the solubility of Amiodarone HC1 in pure water.
  • the saturated solution of AmiodaroneHCl in pure water was prepared by adding an excess of AmiodaroneHCl (0.1 g) to 10 ml MILLI-Q water and shaking the sample bottle in a water bath thermostatted at 25.0°C for at least 3 days.
  • the clear solution (0.4 g) was mixed with 1.6 g ethanol.
  • the concentration of the solution was calculated from the measured absorbance at 242 nm and the known extinction coefficient, which led to he determination of the solubility of AmiodaroneHCl in pure water, 200 mg.l "1 . Same procedure was repeated 3 days after to assure the saturation of the solution.

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Abstract

L'invention se rapporte à des complexes d'inclusion contenant des agents pharmaceutiques, pesticides, herbicides, agricoles, cosmétiques ou de soins personnels ou des métabolites ou des dérivés pharmacologiquement actifs de ces agents, ainsi qu'à des procédés servant à améliorer la solubilité de ces agents dans une solution neutre ou acide, à améliorer la bio-disponibilité de ces agents et à diminuer l'effet d'irritation gastrique du naproxen, par formation de complexes d'inclusion contenant ces agents et des cyclodextrines substituées ou non substituées. Des procédés de traitement de mammifères par administration par voie buccale ou parentérale des compositions pharmaceutiques précitées sont également décrits.
PCT/AU1990/000418 1989-09-14 1990-09-14 Compositions de liberation de medicaments WO1991004026A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
AUPJ6356 1989-09-14
AUPJ6355 1989-09-14
AUPJ635689 1989-09-14
AUPJ635589 1989-09-14
AUPJ6913 1989-10-17
AUPJ691389 1989-10-17

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WO1991004026A1 true WO1991004026A1 (fr) 1991-04-04

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993006823A1 (fr) * 1991-10-04 1993-04-15 Golgi S.A. Utilisation de la verbenone et de ses proprietes anti-elastase dans le traitement de l'emphyseme pulmonaire
EP0579435A1 (fr) * 1992-07-14 1994-01-19 CYCLOPS h.f. Complexation à l'amide de cyclodextrines
EP0605753A1 (fr) * 1992-11-27 1994-07-13 Ensuiko Sugar Refining Company, Limited Complexe d'inclusion du taxol, procédé pour sa préparation et utilisation
EP0657176A2 (fr) * 1993-12-06 1995-06-14 Takeda Chemical Industries, Ltd. Composition à hydrosolubilité accrue contenant un composé insoluble ou légèrement soluble dans l'eau
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.
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
WO1995032737A1 (fr) * 1994-05-27 1995-12-07 Farmarc Nederland Bv Compostion pharmaceutique
US5635610A (en) * 1992-11-27 1997-06-03 Takeda Chemical Industries, Ltd. Production of saccharide carboxylic acids
US5684169A (en) * 1992-11-27 1997-11-04 Ensuiko Sugar Refining Co., Ltd. Cyclodextrin inclusion complex of taxol, and method for its production and its use
WO1998046214A1 (fr) * 1997-04-11 1998-10-22 Upsher-Smith Laboratories, Inc. Comprime pharmaceutique de sel d'amiodarone
US5840881A (en) * 1992-11-27 1998-11-24 Takeda Chemical Industries, Ltd. Composition containing a water-insoluble or slightly water-soluble compound with enhanced water-solubility
WO2003092590A2 (fr) * 2002-05-04 2003-11-13 Cydex, Inc. Preparations contenant de l'amiodarone et un sulfoalkylether de cyclodextrine
EP1396268A1 (fr) * 2002-09-05 2004-03-10 Bharat Serums & Vaccines Ltd. Formulations stables d'oxazaphosphorine-2-mercaptoethanesulfonate
CN100463678C (zh) * 2002-12-02 2009-02-25 印度血清及疫苗有限公司 用于肠胃外给药的异环磷酰胺组合物及其制备方法
WO2011156481A3 (fr) * 2010-06-11 2012-06-28 Baxter International Inc. Formulations comprenant de l'amiodarone et ses sels, et méthodes de production et d'utilisation de celles-ci
EP2434886A4 (fr) * 2009-05-29 2014-01-15 Cydex Pharmaceuticals Inc Compositions injectables à base de melphalan comprenant un dérivé de cyclodextrine et leurs procédés de fabrication et d'utilisation
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
CN112911934A (zh) * 2018-10-24 2021-06-04 阿达玛马克西姆有限公司 环糊精作为农用化学品递送系统的用途
US11279774B2 (en) 2019-01-03 2022-03-22 Underdog Pharmaceuticals, Inc. Cyclodextrin dimers, compositions thereof, and uses thereof

Citations (7)

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EP0657176A2 (fr) * 1993-12-06 1995-06-14 Takeda Chemical Industries, Ltd. Composition à hydrosolubilité accrue contenant un composé insoluble ou légèrement soluble dans l'eau
EP0657176A3 (fr) * 1993-12-06 1996-05-29 Takeda Chemical Industries Ltd Composition à hydrosolubilité accrue contenant un composé insoluble ou légèrement soluble dans l'eau.
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JP4764004B2 (ja) * 2002-05-04 2011-08-31 サイデックス・ファーマシューティカルズ・インコーポレイテッド アミオダロンおよびスルホアルキルエーテルシクロデキストリンを含む製剤
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KR100984197B1 (ko) * 2002-05-04 2010-09-28 사이덱스 파마슈티칼스, 인크. 아미오다론 및 설포알킬 에테르 사이클로덱스트린을함유하는 제제
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