|||| US005665331A United States Patent 19 11 Patent Number: 5,665,331 Bagchi et al. (45) Date of Patent: *Sep. 9, 1997 54 CO-MICROPRECIPITATION OF OTHER PUBLICATIONS NANOPARTICULATE PHARMACEUTICAL J. Phys. Chem. 1994, 98,3215-3221. AGENTS WITH CRYSTAL GROWTH J. Am. Chem. Soc. 1985, 107, 311-3122. MOD FERS - Radiology, Jan. 1982, vol. 142, pp. 115-118. Lachman, et al., “The Theory and Practice of Industrial 75 Inventors: Pranab Bagchi, Webster; Raymond P. Pharmacy”, Chapter 2, Milling, p. 45, (1986). Scaringe, Rochester, both of N.Y.; H. Handbook of experimental Pharmacology, pp. 56-73, 1984. William Bosch, Bryn Mawr, Pa. International Journal of Pharmaceutics, 52(1989) 101-108. 73 Assignee: NanoSystems L.L.C., Collegeville, Pa. Primary Examiner Gary E. Hollinden Assistant Examiner-Michael G. Hartley * Notice: The portion of the term of this patent Attorney, Agent, or Firm-Rudman & Balosh subsequent to Oct. 1, 2013, has been disclaimed. 57 ABSTRACT This invention describes the coprecipitation of nanoparticu 21 Appl. No.: 370,998 late pharmaceutical agent dispersion via a process that comprises the dissolution of the said pharmaceutical agentin 22 Filed: Jan. 10, 1995 combination with a crystal growth modifier (CGM) in an (51] Int. Cl. ... A61K 49/04; A61K 9/14 alkaline solution and then neutralizing the said solution with an acid in the presence of suitable surface-modifying 52 U.S. Cl. ........................ 424/945; 424/9.4; 424/489; surface-active agent or agents to form a fine particle disper 424/490; 424/488; 424/1.29 sion of the said pharmaceutical agent, followed by steps of 58) Field of Search .................................... 424/94, 9.45, diafiltration clean-up of the dispersion and then concentra 424/450, 9.5, 488, 489, 490 tion of it to a desired level. This process of dispersion 56 References Cited preparation leads to microcrystalline particles of Z-average diameters smaller than 400 nm as measured by photon U.S. PATENT DOCUMENTS correlation spectroscopy. Various modification of precipita 4,107,288 8/1978. Oppenheim et al. .. ... 424/22 tion schemes are described, many of which are suitable for 4,250,113 2/1981 Nordai et al. ........................... 564/153 large-scale manufacture of these agent dispersions. It has 4,396,598 8/1983 Lin ............................................. 424/5 been discovered that coprecipitation with CGM leads to 4,540,602 9/1985 Motoyama et al. ... 427/213.31 smaller particle size compared to a case where precipitation 4,713,249 12/1987 Schroder ................................. 424/488 is carried out using the pharmaceutical agent alone. Thus, 4,725,442 2/1988 Haynes .................................... 424/490 this dispersion of instant invention is expected to have 4,826,689 5/1989 Violanto et al. ... 424/489 greater bioavailability. The CGM compound is a compound 5,118,528 6/1992 Fessi et al. ............. 427/23.36 that has at least about 75% of its chemical structure identical 5,145,684 9/1992 Liversidge et al...................... 424/489 to that of the pharmaceutical agent. 5,260,478 11/1993 Bacon et al. ............................ 560/110 5,264,610 11/1993 Bacon ....................................... 560/47 61 Claims, 9 Drawing Sheets U.S. Patent Sep. 9, 1997 Sheet 1 of 9 5,665,331 STEP f: PHARMACEUTICAL AGENT + AQUEOUS BASE STEP 2: AQUEOUS...ALKALINEAGENT SOLUTION AQUEOUS SURFACTANT SOLUTION (SLIGHTLY BASIC) STEP 3: AQUEOUS ALKALINE AGENT AND SURFACTANTSOLUTION + ACID SOLUTION NANOPARTICULATE AGENT DISPERSION STEP 4 : DIALYSIS OR DIAFILTRATION SALT-FREE NANOPARTICULATE AGENT DISPERSION STEP 5: CONCENTRATION SALT-FREE CONCENTRATED NANOPARTICULATE AGENT DISPERSION FIG. U.S. Patent Sep. 9, 1997 Sheet 2 of 9 5,665,331 F.G. 2 U.S. Patent Sep. 9, 1997 Sheet 3 of 9 5,665,331 FIG. 3 U.S. Patent Sep. 9, 1997 Sheet 4. Of 9 5,665,331 FIG. 4 U.S. Patent Sep. 9, 1997 Sheet 5 of 9 5,665,331 U.S. Patent Sep. 9, 1997 Sheet 6 of 9 5,665,331 s O o U.S. Patent Sep. 9, 1997 Sheet 7 of 9 5,665,331 U.S. Patent Sep. 9, 1997 Sheet 8 of 9 5,665,331 fgg is; - if YSia. y; CY83. {{y; if Rifi fi : Siyi - ; ; ; ; ; : ; Cof : ; ; ; FIG. 9A FIG. 9B U.S. Patent Sep. 9, 1997 Sheet 9 of 9 5,665,331 FiG iOA FG, OB 5,665,331 1. 2 COMCROPRECIPITATION OF divided particles ranging from 0.5 m (500 nm) or less to 5 NANOPARTICULATE PHARMACEUTICAL m (5,000 nm) in diameter. AGENTS WITH CRYSTAL GROWTH EPO 275,796 describes the production of colloidally MOD FERS dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solu FIELD OF THE INVENTION tion of the substance and a miscible non-solvent for the This invention deals with co-microprecipitation of phar substance and results in the formation of non-crystalline maceautical agents (diagnostic and therapeutic) with crystal nanoparticle. A somewhat more involved solvent shift 10 method is described in U.S. Pat. No. 4,826,689 (Violanto) growth modifiers (CGM) as stable, colloidal, nanoparticu which produces uniform particles of drugs with diameters late dispersions for pharmaceutical use. ranging between 0.5 to 1.0 um. Furthermore, precipitation BACKGROUND OF INVENTION techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic Bioavailability is the degree to which a drug becomes 15 and can be very difficult, if not impossible, to adequately available to the target tissue after administration. Many remove to pharmaceutically acceptable levels to be practi factors can affect bioavailability including the dosage form cal. and various properties, e.g., dissolution rate of the drug. Poor bioavailability is a significant problem encountered in U.S. Pat. No. 4,107,288 describes particles in the size the development of pharmaceutical compositions, particu range from 10 to 1,000 nm containing a biologically or 20 pharmaceutically active material. However, the particles larly those containing an active ingredient that is poorly comprise a crosslinked matrix of macromolecules having the soluble in water. Poorly water soluble drugs, i.e., those active material supported on or incorporated into the-matrix. having a solubility less than about 10 mg/mL, tend to be U.S. Pat. No. 4.725,442 (Haynes) describes water eliminated from the gastrointestinal tract before being insoluble drug materials solubilized in an organic liquid and absorbed into the circulation. Moreover, poorly water 25 incorporated in microencapsules of phospholipids. soluble drugs tend to be unsafe for intravenous administra However, the toxic effects of solubilizing organic liquids is tion techniques, which are used primarily in conjunction difficult to overcome. Other methods of formation of phar with fully soluble drug substances. maceutical drug microencapsule include: It is known that the rate of dissolution of a particulate drug a) Micronizing a slightly-soluble drug by subjecting a mix can increase with increasing surface area, i.e., decreasing 30 ture of the drug and a sugar or sugar alcohol to high-speed particle size. Consequently, methods of making finely stirring comminution or impact comminution (EP 411, divided drugs have been studied and efforts have been made 629A) together with suitable excipients or diluents. Such to control the size and size range of drug particles in a method of encapsule formation does not lead to particle pharmaceutical compositions. For example, dry milling size as Small as obtained by milling. techniques have been used to reduce particle size and hence 35 b) Polymerization of a monomer in the presence of the active influence drug absorption. However, in conventional dry drug material and a surfactant can lead to small-particle milling, as discussed by Lachman, et al., The Theory and microencapsule (International Journal of Pharmaceutics, Practice of Industrial Pharmacy, Chapter 2, "Milling." p. Vol. 52, pp. 101-108, 1989). This process, however, 45, (1986), the limit of fineness is reached in the region of contains difficult-to-remove contaminants such as toxic 100 microns (100,000 nm) when material cakes on the monomers. Complete removal of such monomers can be milling chamber. Lachman, et al. note that wet grinding is expensive in manufacturing scales. beneficial in further reducing particle size, but that floccu c) Co-dispersion of a drug or a pharmaceutical agent in lation restricts the lower particle size limit to approximately water with droplets of carbohydrate polymer has been 10 microns (10,000 nm). However, there tends to be a bias disclosed (U.S. Pat. No. 4.713.249 and WO-84/00294). in the pharmaceutical art against wet milling due to concerns 45 The major disadvantage of the procedure is that in many associated with contamination. Commercial airjet milling cases, a solubilizing organic co-solvent is needed for the techniques have provided particles ranging in average par encapsulation procedure. Removal of traces of such harm ticle size from as low as about 1 to 50 m (1,000-50,000 ful co-solvents can lead to expensive manufacturing pro mm). CCSSCS. Other techniques for preparing pharmaceutical composi 50 It is noted that filed concurrently herewith are a) EK tions include loading drugs into liposomes or polymers, e.g., Docket No. 71869 entitled, "Microprecipitation of Nano during emulsion polymerization. However, such techniques particulate Pharmaceutical Agents” by Pranab Bagchi et al; have problems and limitations. For example, a lipid soluble b) EK Docket No. 71871 entitled, “Microprecipitation of drug is often required in preparing suitable liposomes. Nanoparticulate Pharmaceutical Agents. Using Surface Further, unacceptable large amounts of the liposome or 55 Active Material Derived from Similar Pharmaceutical polymer are often required to prepare unit drug doses. Agents” by Pranab Bagchi et al; and c) EK Docket No.