WO1989010739A1 - Complexe antibiotique de polyene fongicide-hydroxyalkyl cyclodextrine - Google Patents

Complexe antibiotique de polyene fongicide-hydroxyalkyl cyclodextrine Download PDF

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WO1989010739A1
WO1989010739A1 PCT/US1989/001912 US8901912W WO8910739A1 WO 1989010739 A1 WO1989010739 A1 WO 1989010739A1 US 8901912 W US8901912 W US 8901912W WO 8910739 A1 WO8910739 A1 WO 8910739A1
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cyclodextrin
matter
composition
hydroxypropyl
hydroxyalkyl
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PCT/US1989/001912
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English (en)
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Elias J. Anaissie
Joseph Pitha
Gerald P. Bodey
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Board Of Regents, The University Of Texas System
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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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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

  • the present invention relates to a composition of matter comprising hydroxyalkyl cyclodextrin and amphotericin B. This composition is particularly useful for treatment of disseminated fungal infection.
  • Infection is the cause of death in 51% of patients with lymphoma and 75% of patients with leukemia.
  • bacteria are the causative organisms of many such infections, fungi account for 13% of the fatal infections in patients with lymphoma and for more than 20% of patients with leukemia.
  • the fungus Candida albicans causes more than 80% of these infections, and Aspergillus spp. is also a frequent cause of such infections.
  • fungal infection is a major cause of morbidity and mortality in patients with congenital and acquired deficiencies of the immune system.
  • amphotericin B remains the drug of choice for treatment of most systemic mycoses in cancer and other immuno-compromised patients.
  • Amphotericin B a polyene antib-otic, is a lipophilic compound which interacts with ergosterol in fungal membranes, thus creating transmembrane channels which permit the escape of may ions and metabolites that are essential to the cell's continued vitality.
  • the drug also interacts appreciably with the cholesterol found in mammalian cell membranes. This interaction with the cell membrane of mammalian cells is probably the basis of the toxic effects which it exerts on the mammalian kidney, he atopoietic system and central nervous system.
  • Amphotericin B is insoluble in aqueous solution, consequently it is supplied commercially as a combination of amphotericin B, desoxycholate and buffers, suspended in a glucose solution to form a colloidal suspension for administration to the patient. It is usually given intravenously over a period of from two to six hours. Faster infusions may result in cardiotoxicity. Other toxic effects of amphotericin B may manifest themselves as real disfunction, anemia, fever and hypotension. Amphotericin B is supplied commercially under the brandname FUNGIZONE ® by E. R. Squibb & Sons, Inc. The side effects and contraindications of FUNGIZONE ® are discussed at page 1929 et seq. of the Physicians' Desk Reference, 37th Ed. (Oradell, N.J., Medical Economics Co., 1983). (The references cited in this application are incorporated by reference herein for the reasons cited.)
  • amphotericin B limits the total amount of the drug which may be used in the treatment of a fungal infection. Furthermore, it is often ineffective in neutropenic and immunodeficient patients, patients who are highly susceptible to fungal infections. Consequently, there is a need for a system which decreases the toxicity of amphotericin B to the mammalian system while simultaneously enhancing its effectiveness against the fungal infection.
  • Amphotericin B is the most potent antifungal drug available for some purposes. Its use, however, is limited by its serious toxicity. Cyclodextrin represents a novel drug carrier system that has the ability to improve drug properties such as solubility, stability, and bioavailability and to reduce their side effects.
  • the bioavailability of drugs from their solid-state form depends primarily on their dissolution properties: fast dissolution and the ability to form a concentrated solution usually result in good absorption of a drug.
  • the dissolution characteristic of a compound is mainly a function of its structure, but to a lesser degree can be changed by manipulation of the solid state of the drug.
  • Various polymorphs and solvates of drugs differ in rates of dissolution and in solubility; the proper choice of the crystalline state thus may aid its dissolution.
  • a drug may also be converted from a crystalline state into an amorphous state which dissolves better, unfortunately, the amorphous state is metastable. The amorphous state may be obtained and stabilized by various means.
  • the present invention concerns the complexation of a drug with water- soluble polymers (compounds which are intrinsically amorphous themselves).
  • inclusion complexes of a drug with nontoxic agents is a type of manipulation used to improve the dissolution properties of drugs.
  • Cyclodextrins have been used extensively as such complexation agents.
  • molecules of the drug are enclosed in the hydrophobic cavity of a cyclodextrin molecule or in a channel formed by several molecules of cyclodextrin.
  • These cyclodextrin complexes are crystalline, and the structure of many of them are known.
  • Alpha-, beta- and gamma-cyclodextrins are cyclic oligomers of glucose respectively containing 6, 7 or 8 glucose residues. These glucose residues are arranged in a circle with a toroidal shape in which all the primary hydroxy groups are on the narrower base and secondary hydroxy groups are on the wider base of the toroid. There are no hydroxy groups on the inside of the circle of glucose residues and consequently the cavity of the toroid has a non-polar character. In a hydrated state the cavity of alpha-, beta- or gamma-cyclodextrin is filled with 6, 11 or 17 water molecules, respectively, and these molecules of water may be replaced with a gain of energy by molecules of a non-polar compound.
  • the crystalline complexes of drugs with cyclodextrins represent an encapsulation of drugs on the molecular level; molecules of drug are individually encapsulated in and separated from each other by cyclodextrin molecules; these complexes have established importance in pharmaceutics (see, e.g. , Frank (1975) J.
  • Amphotericin B has previously been solubilized and stabilized by inclusion in gamma-cyclodextrin (see, e.g., Rajagopolan et al. (1986) Int. J. Pharm., .29:161-168; and Vikmon et al. (1985) J. Antibiotics, 31:1822-1824).
  • the present invention involves the creation and use of a new antifungal agent, namely amphotericin B included in hydroxypropyl-gamma-cyclodextrin.
  • the present invention concerns a composition of matter comprising antifungal polyene macrolide and hydroxyalkylated cyclodextrin.
  • the hydroxyalkyl is preferably hydroxypropyl, more preferably, 2- hydroxypropyl.
  • Hydroxyalkyl functions usable in the practice of the present invention may also include hydroxyethyl, hydroxyisobutyl, and 2, 11, 12-trihydroxy-4, 9-dioxadodecyl.
  • the hydroxyalkyl cyclodextrin of the present invention may have six to eight glucose units, most preferably seven (beta cyclodextrin) or eight (gamma cyclodextrin), bound in 1-4 glucosidic linkages, each glucose unit having a hydroxyalkyl radical in ether linkage.
  • the more preferably hydroxyalkyl cyclodextrins have seven cyclized glucosic units (beta cyclodextrin) or eight cyclized glucosic units (gamma cyclodextrin) .
  • the usual hydroxyalkyl cyclodextrin derivatives have glucose units each having a hydroxyalkyl radical in ether linkage.
  • the hydroxyalkyl radical is most preferably bound in ether linkage to carbon 2, 3 or 6 of the glucose unit or to the carbon-2 of another hydroxypropyl radical.
  • the hydroxyalkyl cyclodextrins involved in the present invention have glucose units bound in 1-4 glucosidic linkages, each glucose unit having a hydroxyalkyl radical in ether linkage.
  • the ether linkage connecting the hydroxyalkyl substituent is to a carbon 2,3 or 6 of the glucose unit.
  • the antifungal polyene macrolide preferably used in the composition of matter and method of the present invention is most preferably amphotericin B, nystatin, natamycin, mepartricin, candicidin or lagosin.
  • the present invention further involves a method for treating a mammal with a disseminated fungal infection such as a yeast infection.
  • a disseminated fungal infection such as a yeast infection.
  • Particularly infective yeasts which may be treated include Candida albicans, Candida tropicalis, Candida parapsilosis and Torulopsis glabrata infection.
  • This method of treatment most preferably comprises parenteral and/or oral administration of the composition of matter described above comprising a cyclodextrin and an antifungal polyene macrolide to a mammal with a fungal infection.
  • the present invention involves administering to the mammal a fungicidally effective amount of a composition of matter comprising antifungal polyene macrolide and hydroxyalkyl cyclodextrin.
  • the preferred fungicidally effective amount useful for therapy according to the present invention contains between about 0.4 mg antifungal polyene macrolide per kg body weight and about 4.0 mg antifungal poly
  • the present invention further involves a composition of matter comprising amphotericin B and hydroxyalkyl- gamma-cyclodextrin.
  • the hydroxyalkyl-gamma-cyclodextrin is preferably hydroxypropyl-gamma-cyclodextrin, most preferably 2-hydroxypropyl-gamma-cyclodextrin.
  • the cyclodextrin utilized in the practice of the present invention comprises rings of eight glucose units bound in 1-4 glucosidic linkages, each glucose unit having a hydroxyalkyl radical in ether linkage.
  • the composition of matter of the present invention preferably comprises a cyclodextrin ring of eight glucose units bound in 1-4 glucosidic linkages, substantially each glucose unit having a 2-hydroxypropyl radical in ether linkage.
  • the present invention also involves methods for the treatment of an animal with fungal infection or the prophylaxis of fungal infection.
  • This method may comprise administering to the animal a fungicidally effective amount of a composition of matter as described above comprising amphotericin B and hydroxyalkyl-gamma- cyclodextrin.
  • the administration is preferably parenteral, particularly for disseminated fungal infection, but could be internal or topical, depending upon the particular site of fungal infection and desires of the treating physician.
  • Topical treatment may include administration of an aerosolized amphotericin B- cyclodextrin complex.
  • the disseminated fungal infection most preferably treated is a yeast infection such as a Candida albicans, Candida tropicalis, Candida parapsiloses or Torulopsis qlabrata infection.
  • the fungicidally effective amount useful for treatment of disseminated fungal infection contains between about 0.4 mg amphotericin B per kg body weight and about 4.0 mg amphotericin B per kg body weight.
  • Figure 1 schematically shows the chemical structure of gamma-cyclodextrin (where R is H) and hydroxypropyl- gamma-cyclodextrin (where R is -CH 2 -CH0H-CH_,) .
  • Figure 2 graphically shows the relationship of amphotericin B solubility to the addition of gamma - cyclodextrin and hydroxypropyl-gamma-cyclodextrin.
  • Figure 3 shows the relationship of nata ycin aqueous solubility to the presence of 200 mg cyclodextrin complex.
  • Hydroxyalkyl cyclodextrin may synthesized according to the methodologies outlined in the following manuscripts
  • amphotericin B When amphotericin B is included in hydroxyalkyl- gamma-cyclodextrin or gamma-cyclodextrin (g-CD) the solubility of amphotericin B in an aqueous solution is drastically increased. Likewise, the solubility in an aqueous solution of amphotericin B is increased more greatly by hydroxyalkyl-gamma-cyclodextrin than by g-CD. This phenomenon was demonstrated by including amphotericin B with g-CD or the prototypical hydroxyal yl-gam a- cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin (HP-g-CD) in the following manner.
  • amphotericin B was added to each of a series of 1 ml aliquots of an aqueous solution containing increasing concentrations of HP-CD.
  • gamma-CD was substituted for HP- gamma-CD.
  • Each suspension was stirred at 37'C for three hours and filtered.
  • the filtrate was diluted with 50% ethanol/dimethylsulfoxide and the concentration of amphotericin B analyzed using a Beckman 25 UV spectrophotometer.
  • the absorption wavelength used to quantitate amphotericin B was 408 nm.
  • the yeasts to be tested were suspended in sterile saline to a "MacFarland #1" standard (approximately 85% light transmission at 540 nm) .
  • Drug solutions were prepared in buffered yeast nitrogen base broth at an initial concentration of 100 ug/ml. Twofold serial dilutions were made from the first well in the microtiter plate used through well 11. No drug was added to well 12 (negative control) and all wells of the microtiter plate were inoculated. The plate was incubated at 30"C for 24 hours. The minimal inhibitory concentration (MIC) was defined as the lowest drug concentration that prevented visible growth.
  • MIC minimal inhibitory concentration
  • MICs were identical (0.78 ug/ml) demonstrating that there was no loss of antifungal activity when amphotericin B is complexed with g-CD or HP-g-CD.
  • the in vivo antifungal activity of free amphotericin B, amphotericin B complexed with g-CD and amphotericin B complexed with HP-g-CD was determined with animals having disseminated infections by fungi such as various yeasts.
  • the experimental scheme for this testing was as follows: A strain of Candida albicans (C.A. 366) isolated from a patient with disseminated candidiasis was chosen to infect Halstoner mice 6-8 weeks years old, 18-20 gms. weight. The inoculum was cultivated for 18 hours on Sabouraud dextar agar, and diluted in .9% sodium chloride.
  • Drugs utilized were as follows: amphotericin B (fungizone)-0.8 mg/kg (maximum dose); Hydroxypropyl gamma cyclodextrin - amphotericin B complex as used at the same dose for comparison. Only one dose of either fungizone or hydroxypropyl gamma cyclodextrin - amphotericin B was used.
  • follow up data reveals that while control animals all died within 11 days, treated mice survived for a median of 32 days. There was no significant difference in the survival time between fungizone treated mice and those treated with the cyclodextrin complex of amphotericin B.
  • hydroxypropyl gamma cyclodextrin - amphotericin B complex remained in solution in a stable state for more than 9 months after preparation, while the gamma cyclodextrin-amphotericin B became cloudy around 24-48 hours after preparation. Therefore, not only was the water solubility of amphotericin B improved by using hydroxypropyl gamma-cyclodextrin instead of gamma- cyclodextrin, but also the stability of the complex was significantly improved.
  • natamycin also known as pimaracin
  • natamycin has a significantly superior activity on molds, in particular aspergillus, as compared to amphotericin B. Therefore, it was of interest to formulate a new drug that has potent antiaspergillus activity.
  • natamycin When natamycin was included in a hydroxypropyl gamma cyclodextrin, gamma cyclodextrin or hydroxypropyl beta cyclodextrin complex, the solubility in a water solution of natamycin was increased more greatly by hydroxy alkyl gamma cyclodextrin or hydroxy alkyl beta cyclodextrin then by beta or gamma cyclodextrin. This phenomenon was demonstrated by including natamycin with gamma cyclodextrin, hydroxypropyl gamma cyclodextrin, and hydroxypropyl beta cyclodextrin in the following manner.
  • natamycin was added to each of a series of 1 ml aliquots of water solution containing increasing concentrations of the beta cyclodextrins at 37 held for 3 hours and filtered. The filtrate was diluted with 50% ethanol-dimethyl sulfoxide and the concentration of natamycin was analyzed using a Beckman 25UB spectrophotometer. The absorption wave-length used to quantitate natamycin was 330 nanometer. The results are shown in Fig. 3. The complexes formed by hydroxypropyl beta or gamma cyclodextrin and natamycin remained in solution for more than 9 months after preparation.
  • the in vitro antifungal activity of free natamycin, natamycin complexed with hydroxypropyl gamma or hydroxypropyl beta-cyclodextrin was determined with various yeasts.
  • the yeasts to be tested was suspended in sterile saline to a McFarland #1 standard (approximately 5% light transmittance at 540 mm) .
  • Drug solutions were prepared in buffered yeast nitrogen broth at initial concentrations of 100 ug/ml. Two-fold serial dilutions were made from the first well in the microtiter plate through well 11. No drug was added to well 12 (negative control) and all wells of the microtiter plate were inoculated with 100 microliters of the yeast solution.
  • MIC minimal inhibitory concentration
  • natamycin hydroxypropyl cyclodextrin complex over natamycin cyclodextrin complex was illustrated by a 200- 300% improvement in water solubility.
  • hydroxypropyl cyclodextrin maintained natamycin in solution with water up to a period of 9 months while cyclodextrin without the hydroxypropyl component resulted in a turbid solution with precipitation of natamycin within 24 hours.
  • the simplicity of the preparation and the abolition of the in vitro toxicity of natamycin will make of this complex a suitable alternative to amphotericin B for the use of antifungal treatment and prophylaxis.
  • this will allow the development of tablets, sprays, suppositories, and cream forms of the drug.
  • Candida albicans 3.1 3.1 1.56 Candida tropicalis 3.1 1.56 3.1
  • natamycin encapsulated in hydroxypropyl beta or gamma cyclodextrin was tested in Halstoner mice (6-8 weeks old, 18-20 gm. weight). Mice were injected with increasing doses of natamycin. Doses of up to 450 ug/mouse of natamycin in 20% methanol were injected into animals without death. However, because of solubility problems of natamycin with methanol, higher doses could not be injected. Injection of a 20% methanol control solution resulted in no deaths.
  • the blood urea nitrogen for animals injected with 200 ug/mouse hydroxypropyl beta CD-natamycin, 800 ug/mouse hydroxypropyl beta CD-natamycin, or 2500 ug/mouse hydroxypropyl gamma-natamycin were 23.3, 26 and 26.75 respectively, not very different from the control mice having a hemoglobin value of 2.5.
  • liver enzymes particularly SGPT in animals treated with 200 ug/mouse of hydroxypropyl beta CD-natamycin, 800 ug/mouse of hydroxypropyl beta Cd-natamycin, or 2500 ug/mouse of hydroxypropyl gamma Cd-natamycin again were very close and were respectively as follows: 50, 44, and 41 for a value of 40 for the control mice.
  • all pathology material which consisted of both kidneys, liver, spleen, lungs, and brain (4 animals in each group, i.e.
  • hydroxypropyl beta Cd-natamycin 200 mg/mouse, hydroxypropyl beta Cd-natamycin 800 ug/mouse, and hydroxypropyl gamma Cd-natamycin 2500 mg/mouse and control) were all reviewed by a single pathologist. After careful review, it was felt that there was no evidence whatsoever of any organ damage that could be seen by the light microscope. In conclusion, there was no apparent toxicity even after intravenous administration of very high doses of hydroxypropyl beta or hydroxypropyl gamma cyclodextrin natamycin complexes to Halstoner mice for up to 3 months after injection.
  • the minimum inhibitory concentrations (MIC gn ), i.e., the MIC inhibiting 90% of n vitro growth were as follows: One ug/ml for Cryptococcus neoformans, 2 ug/ml for Candida tropicalis, glabrata, and parapsilosis: 1 ug/ml for Trichosporon, 2 ug/ml for Fusarium spp., and 1 ug/ml for Aspergillus spp. Based on in . vivo data, these MIC values were well below the non-lethal blood levels that could be achieved in dogs with natamycin encapsulated in cyclodextrin.
  • MIC minimal inhibitory concentration
  • Acute n vivo toxicity of natamycin encapsulated in G-beta-CD or 2G-beta-CD was tested in CF1 outbred mice (6-2 weeks old, 24 gm weight) Mice were injected with increasing dose of natamycin. Doses of up to 450 ug/mouse of natamycin in 20% methanol were injected into animals without death. However, injection of G-beta-CD or 2G- beta-CD natamycin. complexes at increasing doses from 500 to 2,000 ug/ml resulted in no death, even at the dose of 2,000 ug/mouse.
  • Dogs The in vivo toxicity and pharmacology in higher animals (dogs) were also determined. Dogs weighing 20 kg were injected with natamycin solubilized in HP-beta-CD. These injections were given as an intraveous bolus over a 10 seconds period. In the first set of experiments, four dogs were injected with a 2.5 mg/kg dose of natamycin encapsulated in HP-beta-CD. Serial determinations of natamycin plasma levels were obtained after 5, 15, 30, 60, 120, and 360 minutes. The peak level obtained after 15 minutes, was 10 ug/ml. This was not associated with any toxicity, particularly no acute toxicity.
  • amphotericin B the polyene antifungal drug of choice currently used in humans, may result in sudden death from arrythmias if dogs are injected over a 20 second bolus injection. Two dogs which were injected with a 0.6 mg/kg dose of amphotericin B as a 20 second bolus died instantly.
  • substitution of natamycin for amphotericin B may permit rapid administration of the antifungal compound, a significant advantage over the slow administration of amphotericin B which is supposed to be over a 4 to 6 hour period, by standard medical practice (Bodey, GP: Topical and systemic antifungal agents. Med. Clin. North Amer. 1988. 1988, 72(3) :637-659) . This new data also clearly shows that natamycin has significantly less acute toxicity than amphotericin B.
  • the serum levels achieved with HP-beta-CD-natamycin are at least 10 fold higher than those obtained with amphotericin B, a finding suggesting a great potential for improvement in the response rate of fungal infections over amphotericin beta-CD.
  • this discovery may represent a major breakthrough for the treatment of these two conditions (Bode ) .
  • amphotericin beta in the treatment of fungal infection in humans is its lack of availability as an oral formulation. This is because of the very low absorption (bioavailability) from the gastrointestinal tract. The reason for this poor absorption appears to be a poor dissolution rate. Efficient dissolution is known to be essential for absorption of drug through the gastrointestinal tract (Frijlink, H.W. , Schooner, A.J.M., Lerk, C.F.: The effects of cyclodextrins on drug absorption. I. In vitro observations. Int. J. Pharm. 1989, 49:91-102).
  • the bioavailability of drugs from their solid state form depends primarily on their dissolution properties; fast dissolution and the ability to form a concentrated solution usually result in good absorption of the drug.
  • the dissolution characteristic of a compound is mainly a function of structure, but to a lesser degree can be changed by manipulation of the solid state of the drug.
  • Solvents of drugs differ in rates of dissolution and insolubility; the proper choice of the crystalline state does make it dissolution.
  • a drug may also be converted from the crystalline state into an amorphic state which dissolves better. Unfortunately, the amorphic state is metastable.
  • the present invention concerns the complexation of polyene antibiotics with cyclodextrin.
  • Cyclodextrin has been used extensively as a complexation agent, and has been associated with a significant improvement in the bioavailability of drugs.
  • amphotericin B and other polyenes were always considered not bioavailable.
  • these drugs can now be give orally. This can result in simplification of antifungal chemotherapy and major savings in health costs. In times of spiralling medical costs and budget restraints, it becomes essential to lower the cost of treating such deadly diseases as AIDS and cancer. It should be pointed out that this economical aspect of this invention is indeed very important as patients with AIDS and fungal infections may remain on antifungal therapy for extended periods. With amphotericin B, this would be very costly as patients need to receive the drug intravenously, usually in the hospital setting.
  • the antifungal complexes of the present invention should be an additional weapon in the armamentarium against raising medical costs, and should constitute a solid basis for the patentability of our invention.
  • the results of this experiment showed a total inhibition of growth of Fusarium solani on the potatoes that were treated twice daily with natamycin (zero CFU) as compared to the excessive growth all over the potatoes surface in the group that was for control (too many CFU's to count).
  • vitro antifungal activity as previously tested with these polyenes were encapsulated with hydroxypropyl gamma cyclodextrin as compared to the three polyenes.
  • in. vivo activity of candicidin encapsulated in hydroxypropyl gamma cyclodextrin revealed that encapsulation with hydroxypropyl gamma cyclodextrin results in similar in vivo activity than candicidin solubilized in dimethylsulfoxide 20% solution against a model of C_j_ albicans 336 disseminated fungal infection in CF1 Swiss mice.
  • the cyclodextrin-antifungal polyene macrolide combinations of the present invention also may prove useful in the prophylaxis and/or treatment of disease caused by human immunodeficiency virus (HIV) , formerly T lymphotropic retrovirus, (HTLV-III/LAV) .
  • HIV human immunodeficiency virus
  • HTLV-III/LAV formerly T lymphotropic retrovirus
  • HIV may be carried in vivo by monocytes and macrophages (see, e.g. , p 51, Scientific American, January, 1987, pp 47-56). These cells types may thus serve as potentially infections and deadly HIV reservoirs.
  • the phagocytes of the blood characteristically bind and ingest foreign substances, even prior to an immune response. These phagocytes also are among the first cells to take up circulating foreign complexes. It appears likely that parenteral administration to an animal of cyclodextrin complexes comprising a polyene macrolide should be useful to inhibit intracellular HIV proliferation. Although studies confirming this usefulness of the cyclodextrin-antifungal polyene macrolides complexes have not yet been confirmed, it may be predicted that the complexes of the present invention should have a role in therapy and by prophylaxis of AIDS,

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Abstract

La présente invention concerne une composition comprenant l'amphtotéricine B et l'hydroxyalkyl-gamma-cyclodextrine. L'hydroxyalkyl-gamma-cyclodextrine est de préférence l'hydroxypropyl-gamma-cyclodextrine, plus préférablement 2-hydroxypropyl-gamma-cyclodextrine. La cyclodextrine utilisée dans l'application de la présente invention comprend des anneaux de huit unités glucose liés dans une à quatre liaisons glucosidiques, chaque unité de glucose ayant un radical hydroxyalkyle en liaison éther. Le radical hydroxyalkyle est lié dans la liaison éther au carbone 5 de l'unité de glucose. La composition de la présente invention comprend de préférene un anneau cyclodextrine de huit unités glucose liées dans une à quatre liaisons glucosidiques, chaque unité glucose ayant un radical 2-hydroxypropyl en liaison éther. La présente invention concerne également un procédé de traitement d'un animal atteint d'une infection fongueuse. Ce procédé consiste à administrer à l'animal une quantité efficace d'une composition décrite ci-dessus, comprennant l'amphotéricine B et l'hydroxyalkyl-gamma-cyclodextrine. L'administration se fait de préférence par voie parentérale, en particulier pour une infection fongueuse disséminée, mais pourrait se faire par voie interne ou par application locale, en fonction du site particulier de l'infection fongueuse et de ce que désire le docteur traitant. L'infection fongeuse disséminée qui se traite le mieux est une infection par des saccharomyces tels que Candida albicans, Candida tropicalis, Candida parapsiloses ou Torulopsis glabrata. La dose d'efficacité fongicide utile pour le traitement d'une infection fongueuse disséminée contient entre 0,4 mg environ d'amphotéricine B par kilogramme de poids du corps et 4,0 mg environ d'amphotéricine B par kilogramme de poids du corps.
PCT/US1989/001912 1988-05-11 1989-05-05 Complexe antibiotique de polyene fongicide-hydroxyalkyl cyclodextrine WO1989010739A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501267A1 (fr) * 1991-02-25 1992-09-02 F. Hoffmann-La Roche Ag Composés d'inclusion d'apocarotinal ou de lycopin dans une cyclodextrine
US5254541A (en) * 1991-11-15 1993-10-19 Merck Frosst Canada, Inc. (Quinolin-2-ylmethoxy)indole/cyclodextrin complex
EP1710244A1 (fr) * 2004-01-29 2006-10-11 Eisai R&D Management Co., Ltd. Methode de stabilisation d un compose de macrolide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0147851A2 (fr) * 1983-12-29 1985-07-10 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Formes hydrosolubles d'antibiotiques du type polyène et procédé de leur préparation
EP0197571A2 (fr) * 1985-03-15 1986-10-15 Janssen Pharmaceutica N.V. Dérivés de gamma-cyclodextrine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0147851A2 (fr) * 1983-12-29 1985-07-10 CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. Formes hydrosolubles d'antibiotiques du type polyène et procédé de leur préparation
EP0197571A2 (fr) * 1985-03-15 1986-10-15 Janssen Pharmaceutica N.V. Dérivés de gamma-cyclodextrine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501267A1 (fr) * 1991-02-25 1992-09-02 F. Hoffmann-La Roche Ag Composés d'inclusion d'apocarotinal ou de lycopin dans une cyclodextrine
US5221735A (en) * 1991-02-25 1993-06-22 Hoffmann-La Roche Inc. Cyclodextrin-polyene inclusion complexes
US5254541A (en) * 1991-11-15 1993-10-19 Merck Frosst Canada, Inc. (Quinolin-2-ylmethoxy)indole/cyclodextrin complex
EP1710244A1 (fr) * 2004-01-29 2006-10-11 Eisai R&D Management Co., Ltd. Methode de stabilisation d un compose de macrolide
EP1710244A4 (fr) * 2004-01-29 2009-06-17 Eisai R&D Man Co Ltd Methode de stabilisation d un compose de macrolide
US7655442B2 (en) 2004-01-29 2010-02-02 Eisai R&D Management Co., Ltd. Method for stabilizing macrolide compounds

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