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WO2000047187A1 - Formes parenterales a base d'albumine serique de macrolides de polyene - Google Patents

Formes parenterales a base d'albumine serique de macrolides de polyene Download PDF

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Publication number
WO2000047187A1
WO2000047187A1 PCT/CA2000/000146 CA0000146W WO0047187A1 WO 2000047187 A1 WO2000047187 A1 WO 2000047187A1 CA 0000146 W CA0000146 W CA 0000146W WO 0047187 A1 WO0047187 A1 WO 0047187A1
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WO
WIPO (PCT)
Prior art keywords
polyene macrolide
serum albumin
polyene
solid dispersion
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2000/000146
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English (en)
Inventor
Glen S. Kwon
Bong K. Yoo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kinetana Inc
Original Assignee
Kinetana Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kinetana Inc filed Critical Kinetana Inc
Priority to AU25307/00A priority Critical patent/AU2530700A/en
Publication of WO2000047187A1 publication Critical patent/WO2000047187A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention is directed to the field of polyene macrolides and. in particular, to polyene macrolides having antifungal activity.
  • amphotericin B and nystatin are key drugs for treating systemic fungal diseases. Such diseases are common with immunocompromised patients. These drugs act at a membrane level binding sterols and forming pores that lead to cell death.
  • the selectivity of amphotericin B and nystatin for fungal cells over mammalian cells is due to preferred binding of ergosterol, the primary fungal sterol, over the mammalian sterol cholesterol.
  • the selectivity of the drugs is poor and therefore the drugs are highly toxic.
  • the second major drawback of the drugs is poor water solubility. As a result of these drawbacks, amphotericin B administered to patients results in side effects such as nephrotoxicity and cardiotoxicity.
  • Liposomal formulations such as through phospholipid vesicles. Liposomes have a number of disadvantages. They are normally difficult to prepare reproducibly in bulk and can be unstable. Their size instability when stored in an aqueous medium is a major drawback to using such formulations. Typically, amphotericin B-liposome formulations which have an initial size distribution between 200-300 nm will spontaneously
  • Liposomes with sizes greater than about 1-2 microns are generally more toxic than smaller liposomes when administered parenterally.
  • amphotericin B emulsion system While it is possible to produce an amphotericin B emulsion system by the admixture of commercial fat emulsion products with the commercial solubilized system of amphotericin B, this system is unstable. It produces a precipitate of the drug after this admixture and has poor stability if stored for more than a few hours. As well, the amphotericin B is not intercalated at the oil-water interface in the additive formulation.
  • Amphotericin B and nystatin easily form aggregates in water and aggregated species of the drugs have been shown to be responsible for their toxicity toward mammalian cells in vitro and in vivo.
  • substantially or fully deaggregated or monomeric species of the drugs have been shown to be less toxic or even nontoxic for mammalian cells but still retain activity toward fungal cells. Ways of deaggregating these drugs are needed as a means of dissociating their toxicity.
  • Detergents have been used to deaggregate amphotericin B. However, extremely high levels of detergents are required. At these high levels, they are too toxic for parenteral administration. The parenteral route of administration is used for polyene macrolides to treat systemic fungal disease since the drugs lack absorption through the oral
  • the present invention provides a composition containing polyene macrolides which retains the antifungal activity of the polyene macrolides but reduces its toxicity and improves its solubility while retaining the same or greater efficacy.
  • the present invention provides for a composition comprising polyene macrolide and serum albumin.
  • the composition of the present invention is prepared in such a manner as to provide for an improved polyene macrolide composition which is a solid dispersion.
  • the present invention also provides for a method of preparing the polyene macrolide- serum albumin solid dispersion comprising the steps of combining the polyene macrolide with serum albumin and freeze-drying the polyene macrolide-serum albumin composition.
  • the solid dispersion is reconstituted with a sterile aqueous vehicle prior to administration.
  • Figure 1 shows the results of X-ray diffraction of nystatin, human albumin serum (HSA), and solid dispersions of nystatin and HSA;
  • Figure 2 is a graph showing the hemolysis of pure nystatin and a solid dispersion of
  • nystatin and HSA The present applicant has found that serum albumin can be used in combination with polyene macrolides to improve their solubility including amphotericin B and nystatin. It has also been found that human serum albumin can be used to obtain similar results as with bovine serum albumin. The resulting solid dispersion of human serum albumin and a polyene macrolide shows a lower toxicity, improved solubility, and deaggregation in vitro without any loss or a significant loss of antibiotic activity towards fungal cells.
  • the resulting polyene macrolide-serum albumin solid dispersions have improved solubility and decreased toxicity with no (significant) loss in antifungal activity when compared with the polyene macrolide alone or with the polyene macrolide simply mixed with serum albumin. Further, the compositions of the present invention are less aggregated as compared to polyene macrolides alone or with polyene macrolides simply mixed with serum albumin.
  • the method of the present invention comprises the steps of dissolving the polyene macrolide in a cosolvent and mixing it with serum albumin; freeze-drying the resulting composition; and reconstituting the composition under suitable conditions.
  • the polyene macrolide is dissolved in a cosolvent and then mixed with human serum albumin (HSA).
  • HSA human serum albumin
  • the polyene macrolide is preferably pre-solubilized and can therefore bind the HSA more readily. It may be dissolved in any suitable cosolvent and examples of suitable cosolvents are dimethylacetamide and dimethylsulfoxide.
  • suitable cosolvents are dimethylacetamide and dimethylsulfoxide.
  • the predissolution of the polyene macrolide also increased the ability of the polyene macrolide and the serum albumin to interact.
  • the dissolved polyene macrolide is added to an aqueous solution of HSA.
  • the resulting composition is freeze-dried in accordance with well known industry
  • the composition may be freeze-dried at a low temperature with or without excipients such as a cryoprotectant. Preferably the temperature is below -40 °C.
  • the water freezes first and may be pulled off with a high vacuum resulting in the concentration of the product.
  • Other known methods of evaporation may be used including spray drying the composition at elevated temperatures.
  • the solid dispersion After freeze drying, the solid dispersion is present in the amorphous state.
  • the polyene macrolide in its natural state is present in both amorphous and crystalline form.
  • no significant amount of a crystalline product appears to be present.
  • the amorphous state provides one rationale for the increased solubility due to the lack of crystal energy in amorphous forms of drugs.
  • the amorphous form of nystatin for example, readily undergoes dissolution as compared with the crystalline form which undergoes slow dissolution.
  • the freeze-dried composition can be easily reconstituted with a sterile aqueous vehicle. After reconstitution, the composition reaches levels required for use in therapy. By using this method, the resulting composition is less toxic with no (significant) loss of antifungal activity and may result in an increase in antifungal activity.
  • the method also provides for little or no loss of composition during the process of manufacture. The present method therefore provides an increase in the therapeutic index of polyene macrolides.
  • the method of the present invention may also include the additional step of incubating the polyene macrolide-serum albumin composition prior to the step of freeze-
  • This incubation allows for the ready deaggregation of the polyene macrolide and binding to the serum albumin.
  • the polyene macrolide and serum albumin composition is incubated at elevated temperatures at neutral or alkaline pH for '/_ - 1 hour. Preferably, the incubation temperature is above 25 °C.
  • This incubation step also increases the ability of the polyene macrolide and the serum albumin to interact and to ensure that the full amount of each component in the aqueous solution is used thereby reducing or eliminating loss of composition.
  • composition of the present invention includes a polyene macrolide such as amphotericin B and nystatin. It also includes serum albumin, and preferably human serum albumin. It may optionally include a cryoprotectant such as mannitol and an antioxidant such as butylated hydroxyanisole.
  • Polyene macrolides includes those antibiotics having large lactone rings connected to sugar moieties and having a number of double bonds. Variations in both the lactone rings and the sugar moieties are known and result in a large number of polyene macrolides. They include such polyene antibiotics as the tetraenes such as nystatin, pentaenes such as aliomycin, methylpentaenes such as filipin, carbonylpentaenes such as mycoticin, hexaenes such as cryptocidine, carbonylhexaenes such as dermostatin, and heptaenes such as amphotericin B. More preferably, the polyene macrolides used in the present invention are nystatin or amphotericin B. Most preferably, the polyene macrolide is nystatin.
  • the polyene macrolides may be purchased in commercially available clinical formulations. However, it has been found that the results of experiments using clinical formulations of amphotericin B with serum albumin are poor. Such formulations were used by Brezis. It is believed that the poor results are due to the presence of sodium deoxycholate in the clinical formulation. When sodium deoxycholate is present in solution, it inhibits Solubilization by serum albumin thus reducing the amount of polyene macrolide present in solution from the polyene macrolide-serum albumin solid dispersion. While some results are achieved with the present invention when small amounts of sodium deoxycholate are present, it is preferred that no or chemically insignificantly amounts are present in solution for best results.
  • the polyene macrolide-HSA composition made in accordance with the present invention has increased solubility, reduced toxicity, and is deaggregated when compared with the drug alone or when the drug is simply mixed with HSA. It is also stable at refrigerated conditions for an extended period of time.
  • the antifungal activity of the resulting compositions is the same as or improved over the drug alone or the drug simply mixed with HSA.
  • the polyene macrolide-human serum albumin formulation may be administered in number of well known manners but is preferably administered parenterally for example by continuous intravenous infusion or by injection which may be intravenous, subcutaneous, or intramuscular. Sustained release preparations may be used. The daily dose will be determined by a skilled person with reference to the patient, drug and the disease.
  • the formulations taught by the present invention may be used to treat a variety of fungal infections in animals and in humans.
  • amphotericin B dissolved in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Various concentrations of amphotericin B were prepared by dilution with 1% or 4% bovine serum albumin (BSA) in isotonic phosphate buffer solution (PBS) at pH 7.4.
  • BSA bovine serum albumin
  • PBS isotonic phosphate buffer solution
  • Fatty acid content of BSA was varied by adding ethanolic solution of lauric acid into BSA solution.
  • Final solutions were incubated at 37°C or 50°C and followed by UN/VIS spectroscopy.
  • the absorbance ratio of Peak I (348 nm) to Peak IV (409 nm) which is an index of aggregation was measured as a function of time.
  • the effect of DOC on the deaggregation of amphotericin B was also monitored in isotonic PBS at pH 7.4.
  • This solution had a mole ratio of ⁇ ys to HSA of 1 :2.
  • the solution of ⁇ ys and HSA was
  • Nys prepared as a solid dispersion with serum albumin was about 1,800 ⁇ g/ml.
  • Nys added as a solid to an aqueous solution of 5% HSA and equilibrated at 37°C for 30 minutes has a solubility of 240 ⁇ g/ml.
  • the increase in solubility is due to the method used to prepare the solid dispersion.
  • Nys is present in an amorphous state, which readily undergoes dissolution.
  • Nys as a solid in an aqueous solution undergoes slow dissolution due to its crystalline state.
  • Red blood cells were diluted with isotonic PBS, pH 7.4. An appropriate amount of RBC was added to each tube.
  • RBC Red blood cells
  • Nys 20 mg was dissolved in 0.50 ml of DMAC, and varied amounts were added to RBC.
  • Each tube was incubated in a water bath at 37° C for 30 minutes. Unlyzed RBC was removed by centrifugation for 30 seconds. Supernatant was collected and analyzed for hemoglobin by measurement of absorbance at 576 nm by UVNIS spectroscopy. The percentage of lyzed RBC was determined by the following equation:
  • % Hemolysis 100 x (A-Ao)/(A 10 o-Ao) where A, A Q and A 100 (0.80) were the absorbances for the sample, control with no Nys and control in the presence of 20 ⁇ g/ml of AmB as Fungizone, respectively.
  • Nys alone causes 50% hemolysis. Nys prepared as a
  • solid dispersion with HSA causes 50% hemolysis at about 270 ⁇ g/ml.
  • the minimal inhibitory concentration (MIC) was defined as the minimum concentration of Nys that showed a full inhibition of Saccharomyces cerevisiae in the microcentrifuge tube, examined by naked eyes and confirmed by the measurement of absorbance by UV/VIS spectrophotometry at 600 nm.
  • the MIC of Nys alone for Saccharomyces cerevisiae was 3 ⁇ g/ml.
  • the MIC of Nys of the solid dispersion with HSA was 3 ⁇ g/ml. Therefore, the solid dispersion of nystatin with human serum albumin showed no decrease in antifungal activity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production d'une dispersion solide d'albumine sérique humaine de macrolides de polyène, présentant une solubilité accrue par rapport au macrolide de polyène seul ou au macrolide de polyène mélangé à l'albumine sérique humaine. Par ailleurs, ladite dispersion solide ne présente aucune perte d'activité antifongique. Le procédé de production de ladite dispersion consiste à dissoudre le macrolide de polyène dans un co-solvant; à le mélanger à la solution d'albumine sérique humaine; et à lyophiliser ladite solution de sorte qu'une dispersion solide soit formée. La dispersion solide est reconstituée avant l'administration. Avant la lyophilisation, la composition peut être incubée à des températures élevées.
PCT/CA2000/000146 1999-02-11 2000-02-10 Formes parenterales a base d'albumine serique de macrolides de polyene Ceased WO2000047187A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU25307/00A AU2530700A (en) 1999-02-11 2000-02-10 Serum albumin-based parenteral formulations of polyene macrolides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24825499A 1999-02-11 1999-02-11
US09/248,254 1999-02-11

Publications (1)

Publication Number Publication Date
WO2000047187A1 true WO2000047187A1 (fr) 2000-08-17

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AU (1) AU2530700A (fr)
WO (1) WO2000047187A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068102A3 (fr) * 2000-03-10 2002-04-04 Wisconsin Alumni Res Found Formulation de nystatine a toxicite reduite
KR20020062494A (ko) * 2001-01-22 2002-07-26 유봉규 단량체 폴리엔마크로리드계열 항생제를 함유한 고체분산체조성물
WO2003094894A1 (fr) * 2002-05-06 2003-11-20 Elan Pharma International Ltd. Formulations de nystatine nanoparticulaires
WO2004062645A1 (fr) * 2003-01-15 2004-07-29 Universidad Complutense De Madrid Microspheres d'amphotericine b
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
WO2025172860A1 (fr) * 2024-02-14 2025-08-21 Biosergen As Compositions de macrolides polyéniques et leurs utilisations

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58216126A (ja) * 1982-06-11 1983-12-15 Ono Pharmaceut Co Ltd 可容化製剤
US4842856A (en) * 1987-01-24 1989-06-27 Bayer Aktiengesellschaft Parenteral solution
EP0326618A1 (fr) * 1987-03-04 1989-08-09 Nippon Hypox Laboratories Incorporated Composition medicinale contenant de l'albumine en tant que support et procede de preparation
US5100591A (en) * 1989-09-14 1992-03-31 Medgenix Group S.A. Process for preparing lipid microparticles
US5534502A (en) * 1990-11-06 1996-07-09 Nippon Shinyaku Co. Ltd. Process for producing fat emulsion
WO1999013914A1 (fr) * 1997-09-18 1999-03-25 Human Rt. Compositions pharmaceutiques contenant une proteine du plasma

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58216126A (ja) * 1982-06-11 1983-12-15 Ono Pharmaceut Co Ltd 可容化製剤
US4842856A (en) * 1987-01-24 1989-06-27 Bayer Aktiengesellschaft Parenteral solution
EP0326618A1 (fr) * 1987-03-04 1989-08-09 Nippon Hypox Laboratories Incorporated Composition medicinale contenant de l'albumine en tant que support et procede de preparation
US5100591A (en) * 1989-09-14 1992-03-31 Medgenix Group S.A. Process for preparing lipid microparticles
US5534502A (en) * 1990-11-06 1996-07-09 Nippon Shinyaku Co. Ltd. Process for producing fat emulsion
WO1999013914A1 (fr) * 1997-09-18 1999-03-25 Human Rt. Compositions pharmaceutiques contenant une proteine du plasma

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BREZIS M ET AL.: "REDUCED AMPHOTERICIN TOXICITY IN AN ALBUMIN VEHICLE", JOURNAL OF DRUG TARGETING, vol. 1, 1993, U.S.A., pages 185 - 189, XP000886695 *
PATENT ABSTRACTS OF JAPAN vol. 008, no. 062 (C - 215) 23 March 1984 (1984-03-23) *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068102A3 (fr) * 2000-03-10 2002-04-04 Wisconsin Alumni Res Found Formulation de nystatine a toxicite reduite
US6413537B1 (en) 2000-03-10 2002-07-02 Wisconsin Alumni Research Foundation Nystatin formulation having reduced toxicity
KR20020062494A (ko) * 2001-01-22 2002-07-26 유봉규 단량체 폴리엔마크로리드계열 항생제를 함유한 고체분산체조성물
WO2003094894A1 (fr) * 2002-05-06 2003-11-20 Elan Pharma International Ltd. Formulations de nystatine nanoparticulaires
WO2004062645A1 (fr) * 2003-01-15 2004-07-29 Universidad Complutense De Madrid Microspheres d'amphotericine b
ES2212904A1 (es) * 2003-01-15 2004-08-01 Universidad Complutense De Madrid Microesferas de anfotericina b.
US11634257B2 (en) 2017-10-09 2023-04-25 Terumo Bct Biotechnologies, Llc Lyophilization container and method of using same
US11609042B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11609043B2 (en) 2019-03-14 2023-03-21 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11604026B2 (en) 2019-03-14 2023-03-14 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11740019B2 (en) 2019-03-14 2023-08-29 Terumo Bct Biotechnologies, Llc Lyophilization loading tray assembly and system
US11747082B2 (en) 2019-03-14 2023-09-05 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
US11815311B2 (en) 2019-03-14 2023-11-14 Terumo Bct Biotechnologies, Llc Lyophilization container fill fixture, system and method of use
US11994343B2 (en) 2019-03-14 2024-05-28 Terumo Bct Biotechnologies, Llc Multi-part lyophilization container and method of use
WO2025172860A1 (fr) * 2024-02-14 2025-08-21 Biosergen As Compositions de macrolides polyéniques et leurs utilisations

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