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WO1995000126A1 - Microspheres d'albumine a surface modifiee et compositions pharmaceutiques les contenant - Google Patents

Microspheres d'albumine a surface modifiee et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1995000126A1
WO1995000126A1 PCT/EP1994/002025 EP9402025W WO9500126A1 WO 1995000126 A1 WO1995000126 A1 WO 1995000126A1 EP 9402025 W EP9402025 W EP 9402025W WO 9500126 A1 WO9500126 A1 WO 9500126A1
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WO
WIPO (PCT)
Prior art keywords
albumin
microspheres
microspheres according
modified
particles
Prior art date
Application number
PCT/EP1994/002025
Other languages
English (en)
Inventor
Thomas Kissel
Bernhard Mueller
Original Assignee
Sandoz Ltd.
Sandoz-Patent-Gmbh
Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H.
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
Priority claimed from GB939312872A external-priority patent/GB9312872D0/en
Priority claimed from GB939312873A external-priority patent/GB9312873D0/en
Priority claimed from GB9409439A external-priority patent/GB9409439D0/en
Priority claimed from GB9410853A external-priority patent/GB9410853D0/en
Application filed by Sandoz Ltd., Sandoz-Patent-Gmbh, Sandoz-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Sandoz Ltd.
Priority to EP94922858A priority Critical patent/EP0705096A1/fr
Priority to JP7502439A priority patent/JPH08511553A/ja
Publication of WO1995000126A1 publication Critical patent/WO1995000126A1/fr

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to microspheres, especially to nanospheres and to pharmaceutical compositions containing such particles , loaded with drug compounds.
  • An important objective in current drug therapy is the selective delivery of drugs to a specific target site in the body. Adverse reactions and unwanted side effects could be avoided and highly bioactive drugs like analogs of hormones (LH-RH) or cytokines(interleukines, interferons, tumour necrosis factors) entrapped in colloidal carriers could be delivered to their site of action.
  • LH-RH hormones
  • cytokines(interleukines, interferons, tumour necrosis factors) entrapped in colloidal carriers could be delivered to their site of action.
  • the mononuclear phagocyte system (MPS) however is one of the major obstacles to prolonged circulation of colloidal carriers in blood. This disadvantage is a common feature of all particulate carriers unless they are modified appropriately to circumvent the host's defence system.
  • Proteins covalently modified with PEG derivatives have shown decreased immunogenicity and clearance in vivo. J. Control. Rel. 11 , p. 139-140, (1990). These interesting properties of PEG may be combined with a chemically and physically stable carrier system, albumin microspheres, which are known to be biodegradable. Albumin micropsheres are acceptable for human application. The surface of chemically crosslinked albumin nanospheres provides suitable functionalities for chemical modification, as shown in Fig.1.
  • the invention provides intemally cross-linked albumin microspheres, especially nanospheres, their surface being modified by attachment of polyoxy(C 1 . 4 )alkylene chains having a terminal ether group.
  • polyoxy(C 1 . 4 )alkylene chains having a terminal ether group For example their surface has been modified by covalent attachment of poly(ethylene)glycol or polyoxyethylene amine having one terminal ether group (see Figure 1).
  • the polyoxyalkylene moieties have preferably a molecular weight of from 120 to 40.000 daltons, e.g. 500 to 10.000 daltons, especially 5000 daltons.
  • the albumin substance is preferably human serum albumin, bovine serum albumin or egg albumin cross-linked by an aliphatic dialdehyde, e.g. glutaraldehyde, glyoxyl, dimethylglyoxal or ketones, e.g. 2,3-butane dione, esters, e.g. ethylene glycol bis- succin-imidyi-succinate, acid chlorides, e.g. terephthalic acid dichloride and diisocyanates, e.g. toluene diisocyanate, or by di-, tri- and tetravalent metallic cations or by heat (90-170"C, 10-60 min). [Tomlinson. E and Burger. J. (1987) in Ilium L. Davis S.S. (ed), Wright, pp 25-48]. These methods may be effected in conventional manner.
  • an aliphatic dialdehyde e.g. glutaraldehyde, g
  • the polyoxyalkylene moiety may be reacted with the surface carboxylic acid and amino groups e.g. by condensation with an appropriate functional group, e.g. amino or alcohol group in the presence of a condensation agent e.g. 1 , 1 - c a r b o n y l d i i m i d a z o l a n d N - ( 3 - d i - m e t h y l - aminopropyl)-N'-ethylcarbodiimidehydrochloride (EDC).
  • a condensation agent e.g. 1 , 1 - c a r b o n y l d i i m i d a z o l a n d N - ( 3 - d i - m e t h y l - aminopropyl)-N'-
  • the protecting terminal ether group is preferably an (C, alkyl ether, e.g. a methylether group.
  • the presence of the terminal ether group is a preferred measure for the preparation of the modified microspheres. Without its presence unprotected poly(ethylene)glycol or poiyoxyethyleneamine used for the preparation of the modified microspheres would be bifunctional and thus cross-link the nanospheres externally to a compact water insoluble useless mass.
  • Phagocytic uptake of colloidal carriers can be quantified by several methods, [Jungi T W, (1988) In: Pal SB (ed.) Macmillan Press, pp. 31-55].
  • the oxidative burst of polymorphonuclear neutrophils (PMNs) following phagocytosis is a convenient model to study factors influencing this defence mechanism against particulate foreign material.
  • the oxidative burst leads to the production of peroxide radicals which are quantified by chemiiuminescence, [Allen R C, Loose L D (1976) Biochem. Biophys. Res. Com. 69: 245-252].
  • albumin microspheres were changed by covalently coupling mPEG to their surface in order to reduce phagocytic uptake.
  • intemally cross-linked albumin microspheres are described, bound via a spacer, e.g. a shorter or longer bifunctional polyoxyethylene chain, to a galactose group, used for liver specific drug targeting.
  • a spacer e.g. a shorter or longer bifunctional polyoxyethylene chain
  • a galactose group used for liver specific drug targeting.
  • a pharmacologically active substance e.g. the antitumor compound 5-fluorouracil is incorporated for the treatment of liver cancer.
  • the polyoxyethylene spacer is not used for an improved resistance against phagocytes and thus a prolonged residence in the blood circulation, but mainly for providing a better flexibility between the albumin and the galactose group and thus less steric hindrance and thus for improving the binding capacity of the galactose part to the asialoglycoprotein receptors of hepatocytes.
  • a central nucleus preferably an intemally cross-linked albumin, is described, bound to antibodies, e.g. antifibrin antibodies, and to drug substances, e.g. thrombolytic agents e.g. streptokinase, each via bifunctional dextran or polyoxyethylene groups e.g. for the treatment of fibrin clots.
  • antibodies e.g. antifibrin antibodies
  • drug substances e.g. thrombolytic agents e.g. streptokinase
  • the drug substance is thus externally bound to cross-linked albumin.
  • the macromolecular complex is provided with a detectable marker, e.g. a radioactive isotope, preferably introduced into the albumin part.
  • a detectable marker e.g. a radioactive isotope
  • the complex is contacted and binded via the antibody part with the target and the bound complex is detected, thereby measuring the residence time of the complex at the target site, not primarily the residence time of free, unbounded complex in the blood circulation (see claim 39, page 35, lines 28-34 and page 36, lines 1-5).
  • a direct measure just as according to the invention to enlargen the resistance to phagocytes and to prolong the residence time in the blood with a monofunctional polyoxyethylene group on the surface of the albumin part of the macro-molecular complex, is not taken.
  • Crosslinking was then inititated by adding 0.2 ml of glutaraldehyde- saturated methylene chloride and accomplished by stirring the emulsion during 60 min. After washing with methanol, acetone and finally with n-hexan, the particles were isolated as free flowing brownish powder wich was dried under high vacuum for 24 h. The diameters of the nanospheres were measured by photon correlation spectrometry (Zetasizer III, Malvem Instr. Ltd.Malvern, FRG).
  • Albumin microspheres containing octreotide were prepared according to the procedure outlined in Example 1 with the additional measure that 0.05 g octreotide/g albumin was dissoved in the aqueous albumin phase.
  • Albumin microsphrere ⁇ containing IL-6 were prepared in the manner according to Example 2 using 0.05 g IL-6 /g albumin.
  • particles with diameters larger than 200 nm can be produced by reducing the emulsifying intensity e.g. by replacing the high energy ultrasonic processor by a 4-bladed impeller and using higher concentrations of albumin (e.g. 10 - 25 % mV).
  • the electrophoretic mobility of the particles was determined by Laser Doppler Anemometry (Zetasizer III, Malvern Instr. Ltd.Malvern, FRG) and transformed to a zeta potential using the Smoluchowski equation . These measurements were performed (in quadruplicate) in a diluted phosphate buffer saline solution with anionic strength of 0.002 M and a pH of 7.4 at 25 * C.Results are the mean and standard deviation of five measurements. The morphology of the spheres was observed by scanning electron microscopy (Stereoscan 180, Cambridge.UK).
  • m-PEG Coupling of mPEG to amino residues, [Beauchamp CO, Gomas SL, Menapace DP, Pizzo SV (1983) Anal. Biochem. 131 : 25-33], m-PEG was activated by 1 ,1'-carbonyldiimidazol in THF under argon at 40 ° C for 12 hr. To this solution a suspension of nanoparticles in THF and triethylamine were added. The reaction was carried out at 60°C under argon and while stirring.
  • the PEG-modified nanoparticles were isolated by centrifugation (47800g, 10 min) (Sorvall RC>-5B, Sorvall, Wilmington, U.S.A) and several washing steps in methanol. Finally the nanospheres were collected on a 0.1 m filter and dried under high-vacuum for 24 hours.
  • Phagocytosis in vitro Fresh human PMNs from healthy donors were prepared by separation on a percoll gradient [Hansel T T, De Vries I J M, Iff T, Rihs S, Wandzilak M, Betz S, Blaser K, Walker C (1991), J. Immunol. Methods 145: 105-110] and diluted with hanks' buffered salt solution (HBSS). The cell number was adjusted to 7x10 6 cells /ml. Cell preparations were counted on an automated cell counter (Microcell Counter CC-18,Sysmex,Japan).
  • Cytospins were prepared on a Shandon Cytospin 2 (Shandon.U.K.) and stained with the May-Gr ⁇ nwald-Giemsa method prior to light microscopic cell differentiation.
  • the preparation of PMNs was of 96%-98% purity.
  • HBSS and phosphate buffered saline (PBS) was enriched with 2% foetal calf serum (FCS).
  • the stock solution of Lucigenin was made by dissolving in HBSS to a final concentration of 2.5x10-4 M.
  • To measure the chemiluminescence 100 microliter of lucigeninsolution, 100 microliter of particles and 50 microliter of cellsuspension were added to one well of a 96-weil plate (Dynatech, FRG) and the measurement in a MTP-Reader (Hamamatsu Photonics Deutschland GMBH) at 37°C was immediatly started. In general the chemiluminescence (CL) was measured during 40 min with a sampling time of 10 sec. Each experiment was performed quadruplicate (4 wells).
  • the relative standard deviation of the mean was about 5%.
  • the cellresponse was taken as background and subtracted for each experiment from the CL time profile of the particle assays.
  • the intensity/time profiles were analysed using the MTP-Reader software and the AUC (arbitrary units) was calculated as the time integral of CL emission accumulated over 40 min.
  • Unmodified albumin nanoparticles showed an average diameter of 220 nm, whereas particles with mPEG attached to amino- and carboxylic groups showed an increase of 44nm in mean diameter with no change in polydispersity (Fig. 2). No difference in morphology of the spheres was detected by scanning electron microscopy.
  • This gradual decrease of zeta potential relates to increased polymer layer thickness based on increasing chain length of PEG.
  • the polymer layer shifts the plane of shear of the diffuse layer to a larger distance from the particle surface which results in a decrease of the measured zeta potential [Napper D H, Netschey A J (1971) Colloid and Interface Science 37: 528-535].
  • a higher steric barrier activity is observed with increasing chain lenght of PEG.
  • mPEGamine was linked with free carboxylic acid residues on the surface of previously with mPEG-5000 modified particles. This procedure resulted in a 94% (35 mV) reduction of the zeta potential (Fig. 3).
  • This additional treatment of the carboxylic acid residues with mPEG led to a nearly complete screening of the surface charge.
  • Direct modification of the carboxylic groups of the particles with EDC without previous attachment of mPEG to the amino groups was followed by interparticulate crosslinking and agglomeration. Hence quenching the amino groups with mPEG causes steric stabilization and prevents interactions between particles during further chemical modifications.
  • Measuring the phagocytic activity of PMNs by a chemiluminescence assay does not require labelling of the particles with fluorescent dyes or radioactive compounds and therefore possible particle surface alterations can be avoided.
  • CL was used to monitor time-dependent phagocytic uptake. With regard to reducing the volumes of human blood required for the assay and getting a sufficient sensible response 350O00 cells per well were chosen.
  • the CL response expressed as AUC showed for mPEG-750 modified particles a reduction of 13% compared to unmodified particles. Particles grafted with mPEG-2000 showed a 76%, those with mPEG-5000 a 85% decrease respectively. Additional treatment of the mPEG-5000 particles with mPEGamine led to a striking reduction of 92% of the CL response (Fig. 5).
  • Other studies of liposomal formulations with different molecular weights of PEG [Mori A, Klibanov A L, Torchilin V P, Huang L (1991) FEBS Letters 284: 263-266] confirm the observations that the shielding effect of lower molecular weights of PEG was not as effective as higher ones.
  • Blood level curves of albumin nanoparticles marked with 125 iodine, having a mean diameter of 180 nanometer, modified with PEG-5000 and with mPEG -5000 -amine were during at least 1 hour significantly different from corresponding curves of unmodified nanoparticles (see Fig. 6).
  • Albumin nanoparticles generally show a light accumulation in special body organs, liver, spleen, and also the bone marrow which last phenomenon is of interest for cytokines, and other immune modulating substances, if incorporated in the nanoparticles.
  • the modified microspheres according to the invention preferably contain pharmacologically active agents. They are used for sustained release and selective delivery of the agents to a specific target site in the body, e.g. the bone marrow.
  • the formulations according to the invention may be used to administer a wide variety of classes of active agents, e.g. pharmacologically active agents such as contraceptives, sedatives, steroids, sulphonamides, vaccines, vitamines, anti-migraine drugs, enzymes, bronchodilators, cardiovascular drugs, analgesics, anti-tumor compounds, antibiotics, antigens, anti-convulsive drugs, anti-inflammatory drugs, anti-parkinson drugs, prolaction secretion inhibitors, anti-asthmatic drugs, geriatics and anti-malarial drugs.
  • the active agent may be chosen from a wide variety of chemical compounds, e.g. lipophilic and/or hydrophilic active agents, including peptides, such as octreotide (described in the UK Patent GB 2 234 896A).
  • the active agent may be incorporated in the albumin particles in conventional manner, e.g. by adding to the pre cross-linking mixture of albumin. Typical final concentrations are from 0.01% to 30% of the resultant microspheres.
  • the invention therefor provides also pharmaceutical compositions containing pharmacologically active agents in intemally cross-linked albumin microspheres, their surface being modified by attachment of polyoxy(C 1 . 4 )alkylene chains having a terminal ether group.
  • the formulations may be used for the known indications of the particular drug compound incorporated therein and may have a depot function.
  • the active proteins or peptides are preferably cytokines, e.g. interleukins, G-CSF, M-CSF or GM-CSF, and cyclosporins or analogs of hormones e.g. octreotide.
  • compositions may be used for centuries.
  • the pharmaceutical compositions may be used for centuries.
  • cytokines e.g. interleukins (IL-3, IL-6), hematopoietic colony stimulating factors (G-CSF, GM-CSF, M-CSF),
  • cytostatic treatment e.g. cytokines esp. interleukins (IL-3, IL-6) or a lipid derivative e.g. the compound described in EP 0309411 , especially in Example 1 ,
  • cancer treatment e.g. with octreotide, cytokines esp. interleukins, and anti- tumor compounds,
  • the exact amounts of drug compound and of the depot formulation to be administered depends on a number of factors, e.g. the condition to be treated, the desired duration of treatment, the rate of release of drug compound and the degradability of the albumin matrix.
  • the desired formulations may be produced in known manner.
  • the amount of the pharmacologically active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, e.g. how long a particular active agent concentration in the blood plasma remains at an acceptable level.
  • the degradability of the matrix may also be obtained by in vitro or especially in vivo techniques, for example wherein the amount of matrix materials is determined by measuring the amount of radio-active label in the organs.
  • the formulations of the invention may be administered, e.g. subcutaneously or intramuscularly, preferably as intravenous suspensions, particularly as a suspension in a suitable liquid carrier.
  • Repeated admiministration of the formulations of the invention may be effected when the albumin matrix has sufficiently been degraded, e.g. from several hours to several days or weeks.
  • albumin matrices of the invention are that during and after the release of the drug compound they may be quickly degraded to a molecular size, which may be transported by the body fluids from the site of administration.
  • Examples of doses for octreotide are e.g. 1 mg per day for human beings of 70 kg of body weight for acromegaly breast cancer or gastroenteropancreatic tumors in a depot formulation having microspheres which contains the peptide in an amount from at least 0.05, preferably 0.05 to 30 percent by weight relative to the albumin matrix, especially 0,1 to 0,5% of weight.
  • the release time of the peptide from the microspheres may be from several hours to about 2 weeks or longer.
  • the sustained release formulation comprises the octreotide in the albumin carrier which, when administered to a rat subcutaneously at a dosage of 10 mg octreotide per kg of animal body weight, exhibits a concentration of octreotide in the blood plasma of at least 0.3 ng/ml and preferably less than 20 ng/ml during a longer period.
  • Examples of doses for the preferred compound IL-6 are 0.05 - 0.5 mg per day for human beings for e.g. immune stimulation in chemotherapy and bone marrow transplantation in e.g. a parenteral formulation having microspheres which contain the peptide in an amount of at least 0.05, preferably 0.05 to 30 percent by weight relative to the albumin matrix, especially 0.3 to 5% of weight.
  • the invention also provides a method of administering a pharmaceutical composition according to the invention to a subject, which comprises a parenteral, oral or ocular administration to a subject in need of such treatment.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Microsphères d'albumine à réticulation interne, dont la surface est modifiée par la liaison de chaînes de polyoxy(C1-4)alkylène possédant un groupe éther terminal, en particulier du type contenant des agents ayant une activité pharmacologique, et pouvant être utilisées pour des compositions pharmaceutiques.
PCT/EP1994/002025 1993-06-22 1994-06-21 Microspheres d'albumine a surface modifiee et compositions pharmaceutiques les contenant WO1995000126A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP94922858A EP0705096A1 (fr) 1993-06-22 1994-06-21 Microspheres d'albumine a surface modifiee et compositions pharmaceutiques les contenant
JP7502439A JPH08511553A (ja) 1993-06-22 1994-06-21 表面修飾アルブミンマイクロスフェアおよびそれらを含む医薬組成物

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GB939312872A GB9312872D0 (en) 1993-06-22 1993-06-22 Organic compounds
GB939312873A GB9312873D0 (en) 1993-06-22 1993-06-22 Organic compounds
GB9312873.4 1993-06-22
GB9312872.6 1993-06-22
GB9409439.8 1994-05-12
GB9409439A GB9409439D0 (en) 1994-05-12 1994-05-12 Organic compounds
GB9410853A GB9410853D0 (en) 1994-05-31 1994-05-31 Organic compounds
GB9410853.7 1994-05-31

Publications (1)

Publication Number Publication Date
WO1995000126A1 true WO1995000126A1 (fr) 1995-01-05

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PCT/EP1994/002025 WO1995000126A1 (fr) 1993-06-22 1994-06-21 Microspheres d'albumine a surface modifiee et compositions pharmaceutiques les contenant

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EP (1) EP0705096A1 (fr)
JP (1) JPH08511553A (fr)
CA (1) CA2161781A1 (fr)
WO (1) WO1995000126A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020256A3 (fr) * 1997-10-17 1999-08-19 Dds Drug Delivery Service Ges Particules d'excipient de medicament convenant a l'application d'un medicament propre aux tissus
WO2000041679A1 (fr) * 1999-01-13 2000-07-20 Johns Hopkins University School Of Medicine Immunisation genetique avec administration conjointe d'acide nucleique et de cytokines
EP1787658A1 (fr) 2005-11-10 2007-05-23 South Shore Properties Inc. Formulations à libération prolongée contenant des inhibiteurs de l'hormone de croissance analogues de la somatostatine
US7329402B2 (en) 1995-06-07 2008-02-12 Imarx Pharmaceutical Corp. Methods of imaging and treatment

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MUELLER, B., ET AL.: "Camouflage nanospheres: A new approach to bypassing phagocytic blood clearance by surface modified particulate carriers", PHARMACEUTICAL AND PHARMACOLOGICAL LETTERS, vol. 3, no. 2, July 1993 (1993-07-01), pages 67 - 70 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7329402B2 (en) 1995-06-07 2008-02-12 Imarx Pharmaceutical Corp. Methods of imaging and treatment
WO1999020256A3 (fr) * 1997-10-17 1999-08-19 Dds Drug Delivery Service Ges Particules d'excipient de medicament convenant a l'application d'un medicament propre aux tissus
EP1300139A3 (fr) * 1997-10-17 2004-01-28 Dds Drug Delivery Service Gesellschaft Zur Förderung Der Forschung In Pharmazeutischer Technologie Und Biopharmazie Mbh Particules d'excipient de médicament convenant à l'application d'un médicament propre aux tissus
WO2000041679A1 (fr) * 1999-01-13 2000-07-20 Johns Hopkins University School Of Medicine Immunisation genetique avec administration conjointe d'acide nucleique et de cytokines
EP1787658A1 (fr) 2005-11-10 2007-05-23 South Shore Properties Inc. Formulations à libération prolongée contenant des inhibiteurs de l'hormone de croissance analogues de la somatostatine

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Publication number Publication date
JPH08511553A (ja) 1996-12-03
EP0705096A1 (fr) 1996-04-10
CA2161781A1 (fr) 1995-01-05

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