WO1996025181A1 - Procede de preparation d'agents de contraste utilisables en lymphographie - Google Patents

Procede de preparation d'agents de contraste utilisables en lymphographie Download PDF

Info

Publication number
WO1996025181A1
WO1996025181A1 PCT/US1996/001870 US9601870W WO9625181A1 WO 1996025181 A1 WO1996025181 A1 WO 1996025181A1 US 9601870 W US9601870 W US 9601870W WO 9625181 A1 WO9625181 A1 WO 9625181A1
Authority
WO
WIPO (PCT)
Prior art keywords
particle size
surface modifier
drug substance
preparing
less
Prior art date
Application number
PCT/US1996/001870
Other languages
English (en)
Inventor
H. William Bosch
Donna M. Marcera
Ronald L. Mueller
Jon R. Swanson
Original Assignee
Nanosystems L.L.C.
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 Nanosystems L.L.C. filed Critical Nanosystems L.L.C.
Priority to AU48672/96A priority Critical patent/AU4867296A/en
Publication of WO1996025181A1 publication Critical patent/WO1996025181A1/fr

Links

Classifications

    • 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
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0476—Particles, beads, capsules, spheres
    • A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
    • A61K49/049—Surface-modified nanoparticles, e.g. immune-nanoparticles

Definitions

  • This invention relates to a process for preparing nanoparticulate contrast agents used in connection with lymphography.
  • X-Ray contrast media containing an x-ray contrast agent are extensively used in radiographic diagnostic techniques to detect diseases of soft tissues of the body, such as cancer.
  • ymphographic technique involves the x-ray examination of lymphatic vessels and nodes using contrast media which is injected directly into a lymphatic trunk or lymph node to provide visualization of the regional lymph structures or the media is injected into the tissues containing lymph capillaries from which it is transported to the lymphatic trunks and nodes.
  • contrast agent for use in radiographic examination of the lymphatic system has been limited. It appears that in the U.S. the only commercially available contrast agent is ETHIODOL®, which consists of a mixture of ethyl esters of iodinated poppy seed oil. ETHIODOL® a thick oily consistency and its administration to the patient requires cannulation and massaging because it remains at the injection site in contact with local tissue for extended time periods which may cause toxicity problems. To minimize the problems the injection site must be massaged to promote lymphatic uptake. In addition, because of its oily consistency, administration of ETHIODOL®causes pain to the patient and it often causes inflammation. For these reasons lymphography with ETHIODOL®has been replaced to a great extent by computed tomography performed without contrast enhancing media.
  • compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization.
  • lipid soluble drug is often required in preparing suitable liposomes.
  • unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses.
  • techniques for preparing such pharmaceutical compositions tend to be complex.
  • a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process.
  • U.S. Patent No. 4,540,602 discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine.
  • Motoyama et al. teach that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 mm (500 nm) or less to 5 mm (5,000 nm) in diameter.
  • EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm.
  • the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance and results in the formation of non-crystalline nanoparticles.
  • U.S. Patent No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
  • U.S. Patent No. 5,145,684 discloses a process for preparing particles consisting of a crystalline drug substance having a surface modifier or surface active agent adsorbed on the surface of the particles in an amount sufficient to maintain an average particle size of less than about 400 nanometers.
  • the process of preparation comprises the steps of dispersing the drug substance in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug substance to an average particle size of less than 400 nm.
  • the particles can be reduced in the presence of a surface active agent or, alternatively, the particles can be contacted with a surface active agent after attrition.
  • the presence of the surface active agent prevents flocculation/agglomeration of the nanoparticles.
  • the mechanical means applied to reduce the particle size of the drug substance is a dispersion mill, the variety of which include a ball mill, an attrition mill, a vibratory mill and media mill, such as sand mill, and a bead mill.
  • the grinding media for the particle size reduction is spherical or particulate in form and includes: Zr ⁇ 2 stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina and Zr0 2 stabilized with yttrium. Processing time of the sample can be several days long. This patent is incorporated herein in its entirety by reference.
  • microfluidizers for preparing small particle- size materials in general.
  • Microfluidizers are relatively new devices operating on the submerged jet principle.
  • a premix flow is forced by a high pressure pump through a so-called interaction chamber consisting of a system of channels in a ceramic block which split the premix into two streams.
  • Precisely controlled sheer, turbulent and cavitational forces are generated within the interaction chamber during microfluidization.
  • the two streams are recombined at high velocity to produce droplet shear.
  • the so- obtained product can be recycled into the microfluidizer to obtain smaller and smaller particles.
  • the prior art has reported two distinct advantages of microfluidization over conventional milling processes (such as reported in U.S. Patent No. 5,145,684, supra) : substantial reduction of contamination of the final product, and the ease of production scaleup.
  • U.S. Patent No. 5,228,905 directed to producing an oil-in-water dispersion for coating a porous substrate, such as wood.
  • U.S. Patent No. 5,039,527 is drawn to a process of producing hexamethylmelamine containing parenteral emulsions.
  • the present invention is directed to a process incorporating the advantages of microfluidizer process over conventional milling processes along with utilizing formulation and/or process parameters necessary for successful particle size reduction of a pharmaceutical suspension prepared by microfluidization.
  • the primary forces attributed to microfluidization for producing either emulsions or dispersions, and for reducing the MPS of water insoluble materials include: shear, involving boundary layers, turbulent flow, acceleration and change in flow direction; impact, involving collision of solid elements and collision of particles in the chamber of microfluidizer; and cavitation, involving an increased change in velocity with a decreased change in pressure and turbulent flow.
  • An additional force can be attributed to conventional milling processes of attrition, i.e., grinding by friction. In reference to conventional milling process it is understood that the process involves the use of gravity, attrition and /or media mills, all containing a grinding media.
  • a process of preparing stable, dispersible drug nanoparticles consisting essentially of a crystalline drug substance having a surface modifier adsorbed on the surface thereon comprising the steps of: a) dispersing a drug substance in a liquid dispersion medium; and
  • a process for preparing a stable, nanoparticulate formulation for lymphographic imaging consisting essentially of ethyl ester of diatrizoic acid
  • EEDA polymeric surfactant adsorbed on the surface thereon.
  • a method for x-ray diagnostic imaging which comprises administering to a patient an effective contrast producing amount of a composition prepared by the process of the present invention.
  • the x-ray contrast composition of the present invention comprises particles of ethyl ester of diatrizoic acid ( IN8883) , i.e., ethyl-3 , 5-diacetamido- 2, 4, 6-triodobenzoate having the structure
  • compositions containing the particles exhibit excellent utility in lymphographic x-ray contrast imaging.
  • EEDA is poorly soluble in water, i.e., it has a solubility of less than 10 mg per ml of water.
  • the preferred dispersion/suspension medium for imaging formulations containing EEDA is water.
  • Other carriers include saline solutions and phosphate buffered saline solutions.
  • the particles useful in the practice of the present invention include a surface modifier.
  • Surface modifiers useful herein physically adhere to the surface of the x-ray contrast agent.
  • Surface modifiers can be selected from known organic and inorganic agents, such as various polymers, natural products and surfactants.
  • Particularly preferred surface modifiers include polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and poloxamines such as Tetronic 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, available from BASF, dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyanamid, Duponol P, which is a sodium lauryl sulfate, available from DuPont, Triton X-200, which is an alkyl aryl polyether sulfonate, availalbe from Rohm and Haas, Tween 80, which is
  • the Microfluidizer The Microfluidizer
  • Microfluidizers are available from Microfluidics International Corporation, Newton, MA. In the practice of the present invention Microfluidics International Corporation Model M-110Y was used, which is a laboratory scale microfluidizer equipped with a sanitary pressure transducer connected to a digital data acquisition system.
  • the primary forces attributed to microfluidization by the microfluidizer for producing either emulsions or dispersions, and for reducing mean particle size of water insoluble materials are:
  • shear involving boundary layers, turbulent flow, acceleration and change in flow direction
  • impact involving collision of the particles processed with solid elements of the microfluidizer, and collision between the particles being processed
  • cavitation involving an increased change in velocity with a decreased change in pressure, and turbulent flow.
  • the M-llOY laboratory scale microfluidizer consists of an air motor connected to a hydraulic pump which circulates the process fluid.
  • the formulation stream is propelled at high pressures (up to 23,000 psi) through a specially designed interaction chamber which has fixed microchannels that focus the formulation stream and accelerate it to a high velocity. Within the chamber the formulation is subjected to intense shear, impact and cavitation, all of which contribute to particle size reduction.
  • the formulation stream is passed through a heat exchanger coil and can be collected or recirculated through the machine.
  • the microfluidizer was typically used in a continuous processing mode for one hour of total processing time.
  • the heat exchanger and interaction chamber were externally cooled with a refrigerated circulating water bath.
  • microfluidization in pharmaceutical dosage form development has largely been limited to processing of emulsions or liposomes as previously discussed.
  • the x-ray contrast agent selected is obtained commercially and/or prepared by techniques known in the art as described above, in a conventional coarse form. It is preferred, but not essential, that the particle size of the coarse x-ray contrast agent selected be less than about 100 mm, as determined by sieve analysis. If the coarse particle size of the contrast agent is greater than about 100 mm then it is preferred that the coarse particles of the contrast agent be reduced in size to less than 100 mm using a conventional milling method such as airjet or fragmentation milling. The coarse imaging agent selected can then be added to a liquid medium in which it is essentially insoluble to form a premix.
  • the concentration of the agent in the liquid medium can vary from about 0.1 - 60% w/w, and preferably is from 5 - 30% (w/w) . It is preferred, but not essential, that the surface modifier be present in the premix.
  • the concentration of the surface modifier can vary from about 0.1 to 90%, and preferably is 1 - 75%, more preferably 20 - 60%, by weight based on the total combined weight of the drug substance and surface modifier.
  • the apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.
  • the premix then can be transferred to the microfluidizer and circulated continuously first at low pressures, then at maximum capacity having a fluid pressure of about 18,000 psi until the desired particle size reduction is achieved.
  • the particles must be reduced in size at a temperature which does not significantly degrade the imaging agent. Processing temperatures of less than about 30 - 40_are preferred.
  • particle size refers to a weight average particle size of less than about 400 nm as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation.
  • a weight average particle size of less than about 400 nm it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques.
  • the effective average particle size is less than about 250 nm. In some embodiments of the invention, an effective average particle size of less than about 200 nm has been achieved. With reference to the effective average particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In particularly preferred embodiments, essentially all of the particles have a size less than 400 nm.
  • Premixes of 15% w/w EEDA and 1.0 - 3.5% w/w of a preferred surfactant (Pluronic F68; F108 and Poloxamine 908) were prepared by manually mixing EEDA and the surfactant.
  • the premixes were processed through the microfluidizer. First, the samples were circulated continuously through the microfluidizer at low pressure for approximately 15 seconds, thus homogenizing the samples. After the initial mixing had taken place, a 12 ml aliquot was withdrawn for pre-processing analysis. The microfluidizer was then allowed to operate at maximum capacity at fluid pressures of about 18,000 psi. Every 15 minutes during processing a 1 ml aliquot of the formulation was removed for particle size analysis. After one hour had elapsed, additional samples were withdrawn for particle size and post- microfluidization analysis.
  • a preferred surfactant Pluronic F68; F108 and Poloxamine 908
  • Particle size distributions were determined by photon correlation spectroscopy using a Coulter N4MD particle size analyzer. Correct operation of the analyzer was confirmed by measurement of latex calibration standards (198 nm) prior to each set of determinations. The samples were prepared by vortexing for 30 seconds before analysis; 5 ml of formulation was then placed in a plastic 1 cm cuvette and diluted with filtered distilled water. All samples were measured using a run time of 200 sec.
  • the surfactant degradation analyses were determined by liquid chromatography using a Waters 712 WISP Autosampler equipped with a refractive index detector.
  • the column used was a Bio-Rad, Bio-Sil SEC 250 Gel Filtration HPLC column (catalog number 125- 0062) .
  • the mobile phase consisted of 10% methanol in a 25 mM NaCl solution.
  • the flow rate was 0.8 ml/min and the run time used was 22 min.
  • the column used was a Beckman Ultrasphere ODS (part number 235329) .
  • Trace metal contamination levels were measured by inductively coupled plasma mass spectrometry (ICP-MS) or atomic emission spectrometry (ICP-AES) for the following elements: Al, Cd, Cr, Cu, Fe, Mn, Ni, Pb, W, and Zr.
  • ICP-MS inductively coupled plasma mass spectrometry
  • ICP-AES atomic emission spectrometry
  • Formulations which contained polymeric surfactants were analyzed for surfactant degradation by gel permeation chromatography.
  • the Pluronic surfactants each displayed a small degree of decomposition which ranged from 1.4% (F68) to 6.3% (F108) .
  • no detectable quantities of degradation products were observed in the formulations which contained either B20-3800 or B20-5000.
  • the processed dispersions were analyzed for the presence of trace metal contamination which was found to be minimal. ICP-MS showed that for al formulations which contained polymeric surfactants, the concentrations of all trace metals assayed were very low. Levels of Al were less than 1 ppm, and the highest observed concentration of Fe was 1.1 ppm. The quantities of Cr and Ni did not exceed 0.32 and 0.13 ppm respectively. The formulation which contained DOSS had appreciably higher trace metal concentrations including 0.7 ppm Cr, 1.4 ppm Fe, and 0.36 ppm Ni. The process of the present invention represents a substantial improvement over media and ball milling in providing nanoparticulate drug formulations.
  • microfluidization can be used to reduce particle size distribution of lymphography contrast agent in a very short period of time, without causing unacceptable decomposition of the drug substance or excipients. Further, the process introduces little or no contamination in the form of trace metals and therefore may be especially well- suited for use in the preparation of nanoparticulate parenteral products in general.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biotechnology (AREA)
  • Medical Informatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Cette invention concerne un procédé de préparation d'agents de contraste nanoparticulaires pouvant être utilisés en lymphographie, lequel procédé consiste à préparer un mélange préalable contenant l'agent de contraste et un agent de modification de surface, puis à soumettre ce mélange préalable à un dispositif mécanique permettant de réduire la taille des particules de l'agent de contraste par effets de cisaillement, d'impacts, de cavitation et d'attrition.
PCT/US1996/001870 1995-02-14 1996-02-12 Procede de preparation d'agents de contraste utilisables en lymphographie WO1996025181A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48672/96A AU4867296A (en) 1995-02-14 1996-02-12 Process of preparing lymphography contrast agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US38809795A 1995-02-14 1995-02-14
US08/388,097 1995-02-14

Publications (1)

Publication Number Publication Date
WO1996025181A1 true WO1996025181A1 (fr) 1996-08-22

Family

ID=23532679

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/001870 WO1996025181A1 (fr) 1995-02-14 1996-02-12 Procede de preparation d'agents de contraste utilisables en lymphographie

Country Status (2)

Country Link
AU (1) AU4867296A (fr)
WO (1) WO1996025181A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0498482A2 (fr) * 1991-01-25 1992-08-12 NanoSystems L.L.C. Agents de contraste pour application en imagerie médicale
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5233995A (en) * 1991-11-21 1993-08-10 Sterling Winthrop Inc. Encapsulated particles useful as contrast agents in ultrasound and x-ray imaging compositions and methods
US5244925A (en) * 1987-12-18 1993-09-14 Kabi Pharmacia Aktiebolag Emulsion for parenteral administration
US5358702A (en) * 1990-04-10 1994-10-25 Unger Evan C Methoxylated gel particle contrast media for improved diagnostic imaging

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5244925A (en) * 1987-12-18 1993-09-14 Kabi Pharmacia Aktiebolag Emulsion for parenteral administration
US5358702A (en) * 1990-04-10 1994-10-25 Unger Evan C Methoxylated gel particle contrast media for improved diagnostic imaging
EP0498482A2 (fr) * 1991-01-25 1992-08-12 NanoSystems L.L.C. Agents de contraste pour application en imagerie médicale
US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5233995A (en) * 1991-11-21 1993-08-10 Sterling Winthrop Inc. Encapsulated particles useful as contrast agents in ultrasound and x-ray imaging compositions and methods

Also Published As

Publication number Publication date
AU4867296A (en) 1996-09-04

Similar Documents

Publication Publication Date Title
US5510118A (en) Process for preparing therapeutic compositions containing nanoparticles
US6555139B2 (en) Preparation of micron-size pharmaceutical particles by microfluidization
CA2190966C (fr) Procede de broyage de substances pharmaceutiques
US5534270A (en) Method of preparing stable drug nanoparticles
US5718919A (en) Nanoparticles containing the R(-)enantiomer of ibuprofen
US5622938A (en) Sugar base surfactant for nanocrystals
EP0810855B1 (fr) Copolymeres blocs de polyalkylene en tant que modificateurs de surface pour des nanoparticules
US5834025A (en) Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
US5543133A (en) Process of preparing x-ray contrast compositions containing nanoparticles
EP0577215B1 (fr) Procédé pour obtenir des nanoparticules d'un agent anticancereux avec une surface modifiée
KR100200061B1 (ko) 표면이 변형된 미립자 형태의 약제
US5571536A (en) Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
WO1996014830A1 (fr) Nanosuspensions pharmaceutiques pour application de medicaments constituant des systemes a solubilite de saturation et a vitesse de dissolution accrues
JPH06211646A (ja) ナノ粒子を含む組成物及びその製造方法
NZ248727A (en) Nanoparticles with x-ray contrast agent with high molecular weight surfactant adsorbed on the surface
WO1996024332A1 (fr) Formulations de composes se presentant sous forme de dispersions nanoparticulaires dans des huiles ou des acides gras digestibles
WO1997004756A2 (fr) Tensioactifs a squelette de methacrylate dans des formulations nanoparticulaires
WO1996025181A1 (fr) Procede de preparation d'agents de contraste utilisables en lymphographie

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN AZ BY KG KZ RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase