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United States Patent (19) 11 Patent Number: 5,858,410 Muller Et Al

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United States Patent (19) 11 Patent Number: 5,858,410 Muller Et Al USOO585841 OA United States Patent (19) 11 Patent Number: 5,858,410 Muller et al. (45) Date of Patent: Jan. 12, 1999 54 PHARMACEUTICAL NANOSUSPENSIONS OTHER PUBLICATIONS FOR MEDCAMENT ADMINISTRATIONAS SYSTEMS WITH INCREASED SATURATION Drug Facts and Compounds, p. 2103 (1994 ed.). SOLUBILITY AND RATE OF SOLUTION Mueller, “Nanosuspension for the iv administration of poorly Soluble drugs Stability during Sterilization and long 75 Inventors: Rainer H. Muller, Berlin; Robert term storage”, Proc. Int. Symp. Controlled Release Bioac Becker, Biberach; Bernd Kruss, tive Mater; Aug. 2, 1995, pp. 574-575. Hochdorf; Katrin Peters, Berlin, all of Bock, "High pressure homogenization of parenteral fat Germany emulsions-influence of process parameters on emulsion quality”, European J. Of Pharm. And Biopharm., Jun. 3, 73 Assignee: Medac Gesellschaft Fur Klinische 1994, pp. 157–160. Spezialpraparate, Hamburg, Germany Muller et al. “Nanosuspense For The I.V. Adminstration Of Poorly Soluble Drugs-Stability During Sterilization And 21 Appl. No.: 836,305 Long-Term Storage', Proceed. Intern. Symp. Control. ReL. Bioact. Mater, 22:274-575 (1995). 22 PCT Filed: Nov. 9, 1995 Brock et al. “High pressure Homogenisation of Parenteral Fat Emulsions-Influence of Process Parameters on Emul 86 PCT No.: PCT/EP95/04401 sion Quality”, Eur: Jnl. Pharm. & Biopharm., S371 Date: Jun. 19, 1997 40(3):157–160 (1994). Sucker et al. Pharmazeutische Technologie, 522, 535 S 102(e) Date: Jun. 19, 1997 (1978). 87 PCT Pub. No.: WO96/14830 Primary Examiner Thurman K. Page ASSistant Examiner Brian K. Seidleck PCT Pub. Date: May 23, 1996 Attorney, Agent, or Firm Jeffrey S. Melcher; Farkas & 30 Foreign Application Priority Data Manelli Nov. 11, 1994 DE Germany .......................... 44 40.337.2 57 ABSTRACT (51) Int. Cl. ................................................. A61K 9/14 Provided is a drug carrier comprising particles of at least one 52 U.S. Cl. .......................... 424/489: 424/491; 424/493; pure active compound which is insoluble, only sparingly 424/494; 424/495; 424/499 Soluble or moderately Soluble in water, aqueous media and/or organic Solvents, wherein Said active ingredient is 58 Field of Search ..................................... 424/489, 491, Solid at room temperature and has an average diameter, 424/493, 494, 495, 499 determined by photon correlation spectroscopy (PCS) of 10 nm to 1,000 nm, the proportion of particles larger than 5 um 56) References Cited in the total population being less than 0.1% (number distri bution determined with a Coulter counter), and, when intro U.S. PATENT DOCUMENTS duced into water, aqueous media and/or organic Solvents, the 4,879,308 11/1989 Alam et al.. active compound has an increased Saturation Solubility and 5,145,684 9/1992 Liversidge et al. ..................... 424/489 an increased rate of dissolution compared with powders of the active compound prepared using an ultraSonic probe, a FOREIGN PATENT DOCUMENTS ball mill or a pearl mill, the Solid particles having been O 361928 A3 4/1990 European Pat. Off. ....... A61K 9/107 comminuted, without prior conversion into a melt, by using O 600 528 A1 6/1994 European Pat. Off. ......... A61K 9/14 cavitation or shearing and impact forces with introduction of A 0600 528 6/1994 European Pat. Off.. a high amount of energy. (List continued on next page.) 57 Claims, 17 Drawing Sheets 14,000 12,000 10,000 8,000 6,000 4,000 2,000 O A 19 AUTOCLAVED 5,858,410 Page 2 FOREIGN PATENT DOCUMENTS 6-126143 (A) 5/1994 Japan - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - BO1F 5/06 WO 90/06746 6/1990 WIPO - - - - - - - - - - - - - - - - - - - - - - - - - - - - A61K 9/107 37 42473 A1 7/1988 Germany ......................... A61K 9/10 WOA 90 42 17842 A1 12/1993 Germany .. A61K 31/44 A 4217 842 12/1993 Germany. O6746 6/1990 WIPO. 41 40 195 C2 10/1994 Germany ......................... A61K 9/10 WO 93/18752 9/1993 WIPO - - - - - - - - - - - - - - - - - - - - - - - - - - - - A61K 9/127 60-258110 WOA 93 (A) 12/1985 Japan ............................... A61K 9/10 18752 11/1993 WIPO. 60-150221 WO 94/14426 7/1994 WIPO. (A) 6/1988 Japan ............................... A61K 9/10 WO 94/20072 9/1994 WIPO. U.S. Patent Jan. 12, 1999 Sheet 1 of 17 5,858,410 FIG. 1 90 80 70 60 DRUG GROUND 50 NAN AIR JET 40 30 20 10 O PARTICLE DIAMETER (um) U.S. Patent Jan. 12, 1999 Sheet 2 of 17 5,858,410 FIG.2 (Wri)(JELEWWIGETOILHwd DA+ SURFACTANT DA U.S. Patent Jan. 12, 1999 Sheet 3 of 17 5,858,410 FIG. 3 100 90 80 70 60 50 40 30 20 10 PARTICLEDIAMETER (um) U.S. Patent Jan. 12, 1999 Sheet 4 of 17 5,858,410 000|| 008 009 (uu WWIOS)WW U.S. Patent Jan. 12, 1999 Sheet 5 of 17 5,858,410 997 SETOÃOHOHE8||W[\N (uu) LWWIOSWAW U.S. Patent Jan. 12, 1999 Sheet 6 of 17 5,858,410 997 SETOWOHOHE8||W[\N (Wr)ZISTOLLWid U.S. Patent Jan. 12, 1999 Sheet 7 of 17 5,858,410 r/ung & STOILWO 99WN I U.S. Patent Jan. 12, 1999 Sheet 8 of 17 5,858,410 u/5u'ONOO Lo Lo Lo Lo v. C. c. CN CN v v O. O. I I s E. || U.S. Patent Jan. 12, 1999 Sheet 9 of 17 5,858,410 07 0?89#7Z (uuri)HELEWWIGETOLIHwd(ç01.09%)und10zz=Onuri/y/.OOT ç01,71 WN U.S. Patent Jan. 12, 1999 Sheet 11 Of 17 5,858,410 (un)ZISTOLLWed to r or on I U.S. Patent Jan. 12, 1999 Sheet 12 0f 17 5,858,410 (ur)ZISIOLLWed U.S. Patent Jan. 12, 1999 Sheet 13 0f 17 5,858,410 FIG. 13 Ya a -4 14,000 12,000 10,000 8,000 A 1+2 BEFORESTERILIZATION 6,000 7% A1+2AUTOCLAVED 4,000 A1+9 BEFORESTERILIZATION 2,000 A1+9 AUTOCLAVED U.S. Patent Jan. 12, 1999 Sheet 14 Of 17 5,858,410 | | | | || ? CD3. O I H D C cN R H CC i. U.S. Patent Jan. 12, 1999 Sheet 15 0f 17 5,858,410 In?urgC STOWOWN III U.S. Patent Jan. 12, 1999 Sheet 17 Of 17 5,858,410 (un)ZISIOIL&W T| 5,858,410 1 2 PHARMACEUTICAL NANOSUSPENSIONS solubility is low, the result is a relatively large volume to be FOR MEDCAMENT ADMINISTRATIONAS administered if an active compound is administered as a SYSTEMS WITH INCREASED SATURATION Solution. Alternatively, the active compound can be formu SOLUBILITY AND RATE OF SOLUTION lated as a nanoSuspension, the medicament particles being dispersed in a Saturated Solution of the active compound. This application claims benefit of international applica Infusion could thus be replaced by a bolus injection. tion PCT/EP95/04401, filed Nov. 9, 1995 published as 4. NanoSuspensions can be employed for controlled drug WO96/14830 May 23, 1996. delivery. After oral administration, oral immunization could 1. Field of the Invention take place via the M cells in the gastrointestinal tract, and The invention relates to a drug carrier of pure active Selective concentration in the absorption windows of the compound of high Saturation Solubility and high rate of gastrointestinal tract could be achieved via bioadhesives. dissolution, physical Stabilization-in particular also using 5. NanoSuspensions are delivery Systems for drug target very low Surfactant and Stabilizer concentrations-and pro ing. After intravenous injection, particles accumulate Spe ceSSes and process parameters for its preparation, which cifically in certain organs, e.g. liver, Spleen or bone marrow, produce drug carriers having an average diameter of 10-1, 15 as a function of their surface properties (R. H. Muller, 000 nm with simultaneously such a low content of micro Colloidal Carriers for Controlled Drug Delivery and particles in the particle population that, in addition to other Targeting, Wissenschaftliche Verlagsgesellschaft Stuttgart, ways of administration, intravenous injection is also poS 1991). After parenteral administration, accumulation in the sible. lymphatic System can be achieved. Targeted accumulation of 2. Definition and Advantages of NanoSuspensions the active compound at the Site of action reduces Side effects DEFINITION OF THE NANOSUSPENSION IN and increases the therapeutic efficiency and therefore the THE CONTEXT OF THE INVENTION therapeutic indeX. 3. State of knowledge of nanoSuspensions and preparation Disperse System of Solid-in-liquid or Solid-in-Semisolid, technology 25 the dispersed phase comprising pure active compound or an It has not yet been possible to utilise the advantages of active compound mixture. The average diameter of the nanoSuspensions, Since this particle Size range is accessible dispersed phase is between 10 nm and 1,000 nm (determined to only a very limited extent with conventional grinding by photon correlation spectroscopy), the distribution of the techniques (dry grinding in ball mills, air jet milling). population being quite narrow, that is to Say the proportion Although powders with 100% of the particles Smaller than of microparticles in the particle population is very low. The approx. 25-50 um are obtained by air jet milling, these nanoSuspension can be Surfactant-free, but can also com powders comprise only a proportion of a few per cent of prise Surfactants or Stabilizers or both. The nanoSuspension particles in the nanometer range. The particle size can also be lyophilized or spray dried, and the nanoparticles distribution, measured with a laser diffractometer (LD), of of a nanoSuspension can also be incorporated into a Solid the drug RMKP 22 (4-N-2-hydroxy-2-methylpropyl)- carrier matrix. 35 ethanolamine-2.7-bis(cis-2,6-dimethyl-morpholin-4-yl)-6- ADVANTAGES OF NANOSUSPENSIONS phenyl-pteridine) which has been ground in an air jet is shown in FIG. 1 by way of example. Although 100% of the The preparation of medicament particles having a size in particles are Smaller than 25 tim, only 8% of the particles are the nanometer range has many advantages from the phar 40 in the range below 1,000 nm, i.e.
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