US 2003018O352A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0180352 A1 Patel et al. (43) Pub. Date: Sep. 25, 2003 (54) SOLID CARRIERS FOR IMPROVED Publication Classification DELIVERY OF ACTIVE INGREDIENTS IN PHARMACEUTICAL COMPOSITIONS (51) Int. Cl." ........................ A61K 31/4439; A61K 9/20 (52) U.S. Cl. ............................................ 424/465; 514/338 (76) Inventors: Mahesh V. Patel, Salt Lake City, UT (US); Feng-Jing Chen, Salt Lake City, UT (US) (57) ABSTRACT Correspondence Address: The present invention provides Solid pharmaceutical com REED & ASSOCATES positions for improved delivery of a wide variety of active 800 MENLO AVENUE ingredients contained therein or Separately administered. In SUTE 210 one embodiment, the Solid pharmaceutical composition MENLO PARK, CA 94025 (US) includes a Solid carrier, the Solid carrier including a Substrate and an encapsulation coat on the Substrate. The encapsula (21) Appl. No.: 10/159,601 tion coat can include different combinations of active ingre (22) Filed: May 30, 2002 dients, hydrophilic Surfactant, lipophilic Surfactants and triglycerides, and Solubilizers. In another embodiment, the Related U.S. Application Data Solid pharmaceutical composition includes a Solid carrier, the solid carrier being formed of different combinations of (60) Continuation-in-part of application No. 09/800,593, active ingredients, hydrophilic Surfactants, lipophilic Surfac filed on Mar. 6, 2001, which is a division of appli tants and triglycerides, and Solubilizers. The compositions of cation No. 09/447,690, filed on Nov. 23, 1999, now the present invention can be used for improved delivery of Pat. No. 6,248,363. active ingredients. Patent Application Publication Sep. 25, 2003 Sheet 1 of 4 US 2003/0180352 A1 6 O 4 O --Present invention; Example 2 -O-Commercial Product; Micronase -e-Pure Bulk Drug O 60 120 180 Time (min) FIG. 1 Patent Application Publication Sep. 25, 2003 Sheet 2 of 4 US 2003/0180352 A1 1OO s :C 80 CD CDY U - EE 2 60 O D .2 ?h 5CD 40 98 -- Present invention; Example 6 O) 20 f -8-Present Invention; Example 3 -e-Pure Bulk Drug O O 60 120 18O Time (min) FIG. 2A Patent Application Publication Sep. 25, 2003 Sheet 3 of 4 US 2003/0180352 A1 30 -- Present invention; Example 6 -8-Present invention; Example 3 -O- Commercial Product; Prometrium O -e-Pure Bulk Drug 2 10 O 60 120 18O Time (min) FIG. 2B Patent Application Publication Sep. 25, 2003 Sheet 4 of 4 US 2003/0180352 A1 100 8 O 6 O -- Present invention; Example 8 --Present Invention; Example 7 -O- Commercial Product; Prilosec O 15 30 45 60 Time (min) FIG. 3 US 2003/018O352 A1 Sep. 25, 2003 SOLID CARRIERS FOR IMPROVED DELIVERY 0008. In addition, it is well known that active ingredients OF ACTIVE INGREDIENTS IN that are acid-labile, will degrade quickly when placed in PHARMACEUTICAL COMPOSITIONS contact with acids. An enteric coating therefore is typically applied to a core containing Such acid-labile drugs was 0001 CROSS REFERENCE To RELATED APPLICA applied to prevent the drug from contacting the acidic pH TIONS conditions of the Stomach upon oral administration. The 0002 This application is a continuation-in-part of U.S. acidic residue of the enteric coating, however, can degrade Ser. No. 09/800,593 filed on Mar. 6, 2001, which is a the acid-labile drug during Storage. To Solve this problem, a divisional of U.S. Ser. No. 09/447,690, filed on Nov. 23, Significant amount of inorganic alkaline materials were 1999, now issued as U.S. Pat. No. 6,248,363. introduced to the core by Specific processes, Such as granu lation So as to ensure the acid-labile drug being evenly in FIELD OF THE INVENTION contact with the basic inorganic Salt. 0003. The present invention relates to pharmaceutical 0009 Thus, there is a need for pharmaceutical composi delivery Systems for pharmaceutical active ingredients, Such tions and dosage forms, and methods therefor, that do not as drugs, nutritionals, cosmeceuticals, and diagnostic agents. Suffer from the foregoing disadvantages. Further, there In particular, the present invention provides compositions remains a need for Stable formulations of active ingredients and dosage forms including Solid carriers for improved Such as acid-labile compounds, that have minimal limita delivery of pharmaceutical active ingredients. tions with regards to processing techniqueS or material Selection. BACKGROUND OF THE INVENTION 0004 Hydrophobic active ingredients, such as progest SUMMARY OF THE INVENTION erone, cycloSporin, itraconazole and glyburide present deliv 0010. It is an object of the invention to provide solid ery challenges due to their poor aqueous Solubility and slow pharmaceutical compositions having active ingredients in a dissolution rate. Several commercial products of these hydrophobic drugs are available, the various products using rapid dissolvable and more solubilized state therein. different methods to try to enhance in Vivo performance. 0011. It is another object of the invention to provide solid One approach is size reduction by micronization, Such as in pharmaceutical compositions having more rapid dissolution Prometrium (micronized progesterone) and Micronase upon administration to a patient. (micronized glyburide). Other approaches include size reduction in emulsion formulations, Such as in Sandimmune 0012. It is another object of the invention to provide solid (cyclosporin emulsion) and NeOral (cyclosporin micro pharmaceutical compositions having more Sustained and emulsion). These approaches Suffer from Several disadvan complete Solubilization upon administration to a patient. tages. Micronization/nanonization presents processing and 0013. It is another object of the invention to provide solid Stability challenges, as well as dissolution limitations, Since pharmaceutical compositions capable of delivery a wide the micronized/nanosized drug Still possesses a high degree variety of pharmaceutical active ingredients. of crystallinity. Liquid formulations present drug precipita tion and packaging challenges, due to Solvent evaporation. 0014. It is another object of the invention to provide solid Moreover, non-Solid formulations are more prone to chemi pharmaceutical compositions of coated Substrate materials cal instability and capsule-Shell incompatibility, leading to without the need for binders. the possibility of leakage upon Storage. 0015. It is another object of the invention to provide solid 0005 Solid carriers for pharmaceutical active ingredients pharmaceutical compositions having increased chemical Sta offer potential advantages over micronized drugs, emulsions bility of the active ingredient or Solubilized formulations. Solid carriers, typically of size 0016. It is another object of the invention to provide solid less than about 2 mm, can easily pass through the Stomach, pharmaceutical compositions having increased chemical Sta thus making the performance leSS prone to gastric emptying bility of the active ingredient upon prolonged Storage. variability. Further, the problems of leakage and other dis advantages of liquid formulations are not present in Solid 0017. It is another object of the invention to provide solid carrier formulations. To date, however, Such Solid carrier pharmaceutical compositions having increased chemical Sta formulations generally have been limited to a few specific bility of the active ingredient in the gastrointestinal tract drugs, due to difficulties in formulating appropriate drug/ upon administration. excipient compositions to effectively coat the active ingre 0018. It is another object of the invention to provide solid dient onto a carrier particle. pharmaceutical compositions remaining Stable upon expo 0006 Conventional Solid dosage forms of hydrophobic Sure to moisture and/or acidic species, Such as protons. active ingredients, Such as tablets, or multiparticulates in capsules, often exhibit slow and incomplete dissolution and 0019. It is another object of the invention to provide solid Subsequent absorption. These formulations often show a pharmaceutical compositions having increased chemical Sta high propensity for biovariability and food interactions of bility of the active ingredient, without the need for the active the active ingredient, resulting in restrictive compliance/ ingredient to be evenly in contact with a basic inorganic Salt. labeling requirements. 0020. It is another object of the invention to provide solid 0007 Due to the slow dissolution and dependence on pharmaceutical compositions having Stable active ingredi gastric emptying, Solid dosage forms often delay the onset of ents, without the need for the inclusion of a basic inorganic Some hydrophobic active ingredients. Salt in the composition. US 2003/018O352 A1 Sep. 25, 2003 0021. It is another object of the invention to provide solid 0033. In another embodiment, the solid pharmaceutical pharmaceutical compositions having Stable active ingredi composition includes a Solid carrier, the Solid carrier includ ents, without the need for an enteric coating. ing a Substrate and an encapsulation coat on the Substrate. The encapsulation coat includes an active ingredient and an 0022. It is another object of the invention to provide solid ionic or non-ionic hydrophilic Surfactant, an active ingredi pharmaceutical compositions having minimal limitations ent and a lipophilic component Such as a lipophilic Surfac with regard to processing techniqueS or material Selection. tant or a triglyceride, or an active ingredient and both a 0023. It is another object