Patent Grant
9138410
The present invention relates to pharmaceutical compositions that are administered via the nasal mucosa in granule form. Specifically, the present invention relates to granular compositions for nasal administration of physiologically active peptides such as insulin, or peptide-related compounds.
At present, insulin is clinically used as a treatment for diabetes in the form of an injectable formulation, and in most cases, it is self-administered by a comparatively simple subcutaneous injection. However, due to the characteristics of this type of injection formulation, the patient is required to self-administer one to four times a day before meals, for life. This troublesome procedure is one of the many problems associated with the treatment of diabetes. Besides insulin, many pharmaceutical peptides are also administered by injections, and there is an ongoing development of dosage forms for convenient administration.
Formulations for nasal administration, in particular, have been proposed to overcome the difficulties associated with administration. For example, a dosage form of insulin formulation, which uses crystalline cellulose as a base and has 90 wt % of particles in the diameter range of 20 to 150 μm, is described in Examined Published Japanese Patent Application No. (JP-B) Sho 62-42888. Considering that for this formulation, “physiologically active polypeptides are preferably water-soluble for nasal mucosal absorption,” the Example of this publication discloses that compositions having 90 wt % or more of particles with a diameter of 75 to 149 μm are obtained by: dissolving insulin in aqueous 0.1 N HCl and freeze-drying; mixing the thus-obtained soluble insulin powder with crystalline cellulose; and sifting.
In comparison with compositions in the above-mentioned JP-B Sho 62-42888, Unexamined Published Japanese Patent Application No. (JP-A) Hei 10-59841 (corresponding to EP-A1-943326) discloses compositions which demonstrate excellent nasal absorption and increased maximum blood concentration with highly hydrophilic pharmaceuticals, highly lipophilic pharmaceuticals, and high molecular weight peptides. According to this publication, the above-described effect can be achieved by actively using a water-absorbing and gel-forming base, such as hydroxypropylcellulose, in combination with a crystalline cellulose aggregate comprising particles with a diameter greater than 150 μm, which is contrary to what JP-B Sho 62-42888 suggests.
However, the present inventors are not aware of any information on the practical application of formulations for nasal administration, in particular, those for nasal administration of polypeptide hormones including insulin as described in these prior arts.
In contrast to what is suggested in the above-described JP-B Sho 62-42888 and JP-A Hei 10-59841, the present inventors discovered that compositions for nasal administration of polypeptide hormones or peptide-related compounds, which are prepared by using a partially pregelatinized starch powder having a specific particle diameter, alone or in combination, with a crystalline cellulose powder having a specific sieving particle diameter distribution of less than 150 μm, unexpectedly increase the absorbability and efficacy of pharmaceuticals significantly, compared to compositions in the prior art.
The present invention is based on this finding.
Accordingly, the present invention provides granular compositions for nasal administration comprising a powdered pharmaceutical and a substantially water-insoluble polysaccharide powder as a carrier thereof, wherein the pharmaceutical is selected from physiologically active peptides with a molecular weight of 30,000 or less, in particular, polypeptide hormones and peptide-related compounds, and more specifically, FK-506; and wherein the water-insoluble polysaccharide is at least one selected from: a crystalline cellulose powder with 85 wt % or more of the particles distributed over a partial or the entire sieving particle diameter range of 20 to 60 μm, and a partially pregelatinized starch powder with a mean particle diameter of 20 to 100 μm. Among such compositions, compositions comprising insulin as a pharmaceutical and only the above-described crystalline cellulose as a water-insoluble polysaccharide are also disclosed by the Applicant in JP-A 2001-204784.
Pharmaceuticals of the present invention include physiologically active peptides with a molecular weight of 30,000 or less and peptide-related compounds; in particular, polypeptide hormone compounds and FK-506, that have higher in vivo absorption efficiency than nasal administration and are capable of exerting the efficacy in an effective manner, which are in accordance with the objectives of the present invention.
The physiologically active peptides with a molecular weight of 30,000 or less include linear and cyclic peptides, such as insulin, growth hormone, calcitonin, glucagon, glucagon-like peptide-1 (GLP-1), interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-releasing hormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP), C-peptide, and cyclosporine. The term “peptide-related compounds” refers to physiologically active substances which comprise at least one peptide bond (amide or imide bond) in the molecular structure, and which are predominantly produced by microorganisms or organisms. A representative example of the peptide-related compounds is FK-506. These pharmaceuticals should not be limited by their origins, preparation methods, or the like. In addition, modified or altered pharmaceuticals can also be used so long as they have the desired efficacy. For example, the term “insulin” includes: human insulin, purified bovine insulin, purified porcine insulin, semi-synthesized human insulin, human iso-insulin, and such, that are currently in clinical use; and all genetically engineered human insulin and insulin modified therefrom, which have an activity equivalent to that of human insulin. Insulin of the present invention is preferably used in powder form. Preferably, the modified insulin powder is only slightly soluble in water or almost insoluble in water (specifically, 1 g of the corresponding insulin powder requires a solvent of 1,000 mL or more and less than 10,000 mL, or 10,000 mL or more to be solved; see, Japanese Pharmacopoeia 13th Edition (Dai 13 Kaisei Nippon Yakkyoku Hou Kaisetu Sho), General Rule A-51). The above-mentioned insulins are slightly soluble or almost insoluble in water, and can be used as an insulin powder of the present invention. Similarly to insulin, other physiologically active peptides and peptide-related compounds that can be used are also not limited; however, the commercially available ones are preferred.
Powdered pharmaceuticals such as the above-described insulin must be a crystalline or non-crystalline fine powder, and must be finer than cellulose particles that constitute a crystalline cellulose powder, or partially pregelatinized starch particles described below. Generally, the surface or the surface microstructure (e.g., pores) of the above-described particles are required to have a particle size that allows the adhesion or inclusion of multiple pharmaceutical powders. Various commercially available pharmaceuticals in bulk powder can be employed directly or after being finely pulverized.
Generally, crystalline cellulose powders (or particles) used in the present invention can be obtained by: obtaining cc-cellulose as pulp from a fibrous plant, partially depolymerizing with an acid, and purifying the water-insoluble fraction. It is possible to use crystalline cellulose powders obtained from rayon filaments or such, as long as they meet the objectives of the present invention. Specifically, crystalline cellulose powders employed in the present invention can be obtained using, for example, the Avicel® series and its modified versions as described in JP-B Sho 39-12469, JP-13 Sho 56-38128, JP-B Sho 61-21201, and JP-B Hei 5-38732, by reducing the particle size using a high-speed impact pulverizer or an air flow-type pulverizer, as necessary; and/or finely pulverizing while increasing the bulk density; and size classifying or sifting to obtain an assembly of particles with the desired particle size.
The crystalline cellulose powder can usually be produced by depolymerization as described above, and its average degree of polymerization is not limited, as long as it meets the objectives of the present invention. A crystalline cellulose powder of the present invention can generally be selected from crystalline cellulose having an average polymerization degree of 15 to 400, preferably 20 to 250, and more preferably 30 to 50. The crystalline cellulose powders of the present invention are not limited, and crystalline cellulose powders that have a bulk density of 0.20 to 0.65 g/cm3, and preferably 0.22 to 0.40 g/cm3 can be utilized. These bulk density values are determined using the Scott Volumeter.
The critical criteria for selecting crystalline cellulose powders of the present invention are the size and distribution pattern of particles which constitute a crystalline cellulose powder. Specifically, it is necessary that approximately 85 wt % or more of the particles are in a partial or the entire sieving particle diameter range of 20 to 60 μm.
Hereinafter, the term “particle diameter” means sieving particle diameter, unless defined otherwise.
The partially pregelatinized starch powder (or particles) used as a second carrier in the present invention can be obtained from any starch using any method of partial pregelatinization, so long as it meets the objectives of the present invention. Without being limited thereto, physically denatured (i.e., heat-denatured) cornstarch is preferred. Such partially pregelatinized starch should be substantially water-insoluble. The term “substantially water-insoluble” means that 5% or less, and preferably 2.5% or less of the content is a water-soluble component at room temperature. The degree of swelling of the “partially pregelatinized” starch measured in pure water at about 20° C. is preferably adjusted to approximately 8 to 9 cm3/g.
Starch which has been size classified into a mean particle diameter of 20 to 100 μm, and preferably about 32 μm or less is used. A representative example of the partially pregelatinized starch, PCS® (degree of swelling: 8 to 9 cm3/g) supplied by Asahi Kasei Corporation, can be employed after the particle size classification, as necessary.
The term “partial or entire range” used to express a particle size distribution of the above-described powders means that in the example of crystalline cellulose, about 85 wt % or more of the crystalline cellulose particles have a particle diameter distribution within the entire range of 20 to 60 μm, or in a partial range thereof, for example, 20 to about 40 μm, 20 to about 55 μm, about 25 to 38 μm, about 25 to 53 μm, or about 38 to 53 μm. Specifically, commercially available Avicel® PH-F20 or PH-M15 can be used after size classification or as it is. Without being limited thereto, the crystalline cellulose powders preferably have a particle diameter distribution of:
10 wt % or fewer particles with a diameter smaller than 25 μm;
20 to 60 wt % particles with a diameter of 25 to 38 μm;
20 to 60 wt % particles with a diameter greater than 38 μm and smaller than or equal to 53 μm; and
the remaining particles having a diameter greater than 53 μm (total particles=100 wt %).
According to the present invention, the mixing ratio of powdered insulin, powdered glucagon, powdered calcitonin, parathyroid hormone, gastric inhibitory polypeptide (GIP), C-peptide, cyclosporine, or powdered FK-506, and a crystalline cellulose powder or partially pregelatinized starch, can be adjusted to 1:1 to 1:500 by weight, and more preferably 1:2 to 1:100 by weight.
To prepare compositions of the present invention by homogeneously mixing the above-mentioned powdered insulin with a crystalline cellulose aggregate, a commonly used device (for example, a blender or mixer) for homogeneously mixing a powdered pharmaceutical with a solid carrier can be used. Particles with a diameter smaller than 10 μm or greater than 100 μm may be subsequently removed; however, according to the present inventors' experience, such removal procedures are not needed.
Compositions of the present invention can comprise, in addition to the above-described components, other carriers or base materials, excipients, preservatives, antiseptics, absorption enhancers, or such, as long as they do not contradict the objectives of the present invention. For example, other carriers may include cellulose derivatives described in JP-A Hei 10-59841, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose. The absorption enhancers include the angelica described in U.S. Pat. No. 5,731,303, which is an essential oil, and its component, cyclopentadecanolide. When other carriers or absorption enhancers like these are used, the resulting compositions are preferably sifted so that more than 80% of the composition particles may have a particle diameter of 70 to 100 μm, preferably 20 to 60 μm.
Hereinbelow, the present invention will be specifically described with reference to examples of compositions for nasal absorption of physiologically active peptides according to the present invention, but it is not to be construed as being limited thereto. In the Examples, the compositions for nasal absorption were nasally administered in a single dose to cynomolgus monkeys (3 to 7 kg weight). Administration was conducted according to a method to administer each capsulated composition into the nasal cavity using an intranasal administration device (Jetlizer, Unisia Jecs Corporation).
Compositions for nasal absorption were prepared by thoroughly mixing in a mortar, 35 mg (insulin as originally provided) of a water-insoluble insulin powder (Intergen Company, 28.7 IU/mg) and 965 mg of crystalline cellulose (Avicel® PH-101 or Avicel® PH-F20, Asahi Kasei Corporation). Water-soluble insulin was prepared by dissolving 100 mg of a water-insoluble insulin powder in 1 mL of 0.1 N HCl, adding 40 mL of purified water thereto, and freeze-drying the resulting insulin solution. 36 mg of the water-soluble insulin powder (27.7 IU/mg) thus obtained was then mixed with 964 mg of the above-mentioned crystalline cellulose in a mortar to prepare compositions for nasal absorption. Each of the compositions for nasal absorption was administered nasally to cynomolgus monkeys (n=6), and then serum insulin and glucose concentrations were measured.
The serum insulin and glucose concentrations were measured using the EIA method (enzyme immunoassay) and the Glck·G-6-PDH method, respectively.
Pharmacokinetic parameters (mean±standard deviation) obtained using the serum insulin concentrations are shown in Table 1.
For each of the above-described compositions for nasal absorption, the time-course changes in serum insulin and glucose concentrations are shown in
Table 1 shows that when 16 IU/body of insulin was intranasally administered, water-insoluble insulin revealed the greatest insulin absorbability with Avicel® PH-F20, followed by water-soluble insulin with Avicel® PH-F20, water-insoluble insulin with Avicel® PH-101, and water-soluble insulin with Avicel® PH-101. In other words, compositions of water-insoluble insulin plus Avicel® PH-F20, water-insoluble insulin plus Avicel® PH-101, and water-soluble insulin plus Avicel® PH-F20, were found to achieve higher insulin absorbability than the water-soluble insulin plus Avicel® PH-101 composition.
Compositions for nasal administration were prepared by thoroughly mixing in a mortar, 17.5 mg of powdered human growth hormone (comprising 14.3% human growth hormone; Wako Pure Chemical Industries, Ltd.) and 62.5 mg of crystalline cellulose (Avicel® PH-F20; Asahi Kasei Corporation). The control composition for nasal administration, which comprises crystalline cellulose (Avicel® PH-101; Asahi Kasei Corporation) as a carrier, was also prepared in the same manner. Either of the compositions was nasally administered in a single dose to cynomolgus monkeys (n=3), and then the serum concentrations of human growth hormone were measured.
The human growth hormone concentrations were measured using the EIA method (enzyme immunoassay).
Pharmacokinetic parameters (mean±standard deviation) obtained using the human growth hormone concentrations (the initial value is subtracted) are shown in Table 6.
Time-course changes in the human growth hormone concentrations (the initial value is subtracted) are shown in
In Table 6, the human growth hormone compositions for nasal administration comprising Avicel® PH-F20 as a carrier showed an absorbability clearly higher than using Avicel® PH-101 as a carrier (see also
The composition (hereinafter F20) comprising Avicel® PH-F20 as a carrier was compared to the following compositions, using a water-insoluble insulin powder (Intergen Company; 28.7 IU/mg).
An insulin composition (hereinafter in-PCS) was prepared by thoroughly mixing in a mortar, 35 mg of water-insoluble insulin powder (Intergen Company; 28.7 IU/mg) (insulin as originally provided) and 965 mg of partially pregelatinized starch (PCS®, Asahi Kasei Corporation) as a carrier, which has been size classified into 32 μm or less (hereinafter s-PCS).
A second composition (hereinafter in-PCS+F20 (1:1)) was prepared by: thoroughly mixing in a mortar, 35 mg of water-insoluble insulin powder (Intergen Company; 28.7 IU/mg) (insulin as originally provided) and 965 mg of crystalline cellulose (Avicel® PH-F20, Asahi Kasei Corporation), to prepare an insulin composition (hereinafter F20); and then mixing in-PCS with F20 at a ratio of 1:1.
Additional compositions were prepared by adding 1% or 10% s-PCS to F20 (hereinafter, F20+1% s-PCS and F20+10% s-PCS).
Each of these compositions was nasally administered to cynomolgus monkeys (n=3 to 6) at 16 IU insulin per body. Serum insulin and glucose concentrations were measured following the administration of each composition.
Insulin and glucose concentrations were measured using the EIA method (enzyme immunoassay) and the Glck·G-6-PDH method, respectively.
Table 9 shows pharmacokinetic parameters (mean±standard deviation) obtained using the serum insulin concentrations, and pharmacological parameters obtained using the serum glucose concentrations.
As shown in Table 9, in-PCS, in-PCS+F20 (1:1), and F20+10% s-PCS have AAC0.4/AUC0.4 values between 0.9 and 1.6, which are significantly higher than that of F20 (0.5), suggesting that compositions using PCS as a carrier or an additive can reduce blood glucose more efficiently, but have lower insulin absorbability than compositions using F20 as a carrier (see also
Compositions for nasal administration were prepared by thoroughly mixing in a mortar, crystalline cellulose (Asahi Kasei, Corporation; Avicel® PH-F20) and as a physiologically active peptide, 0.6 mg of glucagon (derived from swine; Bachem), 100 IU of salmon calcitonin (Bachem), or 30 μg of parathyroid hormone (1-34, Penisula Laboratories Inc.), for every 16 mg of the composition. The control composition for nasal administration was prepared using crystalline cellulose (Asahi Kasei Corporation; Avicel® PH-101) as a carrier in the same manner. Each of the above-described compositions was nasally administered in a single dose to a cynomolgus monkey (n=1), and then the concentrations of glucagon, salmon calcitonin, and parathyroid hormone in blood were measured.
The blood concentrations of glucagon, salmon calcitonin, and parathyroid hormone were measured using the RIA double antibody method.
Time-course changes in the blood concentrations of glucagon, salmon calcitonin, and parathyroid hormone are shown in
The glucagon-, salmon calcitonin-, and parathyroid hormone-comprising compositions for nasal administration, respectively shown in
The present invention provides compositions for nasal administration which are capable of efficiently increasing the blood concentration of pharmaceuticals. Thus, compositions of the present invention can be utilized in the medical field including the pharmaceutical industry.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3906950 | Cocozza | Sep 1975 | A |
| 4013075 | Cocozza | Mar 1977 | A |
| 4159345 | Takeo et al. | Jun 1979 | A |
| 4226233 | Kritzer | Oct 1980 | A |
| 4300545 | Goodnow et al. | Nov 1981 | A |
| 4613500 | Suzuki et al. | Sep 1986 | A |
| 4889114 | Kladders | Dec 1989 | A |
| 5098907 | Kondo et al. | Mar 1992 | A |
| 5320094 | Laube et al. | Jun 1994 | A |
| 5419315 | Rubsamen | May 1995 | A |
| 5647349 | Ohki et al. | Jul 1997 | A |
| 5672581 | Rubsamen et al. | Sep 1997 | A |
| 5674507 | Banker et al. | Oct 1997 | A |
| 5683361 | Elk et al. | Nov 1997 | A |
| 5731303 | Hsieh | Mar 1998 | A |
| 5756483 | Merkus | May 1998 | A |
| 5804209 | De Ponti et al. | Sep 1998 | A |
| 5810004 | Ohki et al. | Sep 1998 | A |
| 5939100 | Albrechtsen et al. | Aug 1999 | A |
| 5942242 | Mizushima et al. | Aug 1999 | A |
| 5948749 | Igarashi et al. | Sep 1999 | A |
| 5958458 | Norling et al. | Sep 1999 | A |
| 5989217 | Ohki et al. | Nov 1999 | A |
| 6136295 | Edwards et al. | Oct 2000 | A |
| 6197328 | Yanagawa | Mar 2001 | B1 |
| 6248363 | Patel et al. | Jun 2001 | B1 |
| 6273086 | Ohki et al. | Aug 2001 | B1 |
| 6298846 | Ohki et al. | Oct 2001 | B1 |
| 6516795 | Bougamont et al. | Feb 2003 | B1 |
| 6815424 | Vickery et al. | Nov 2004 | B2 |
| 6824080 | Matsugi et al. | Nov 2004 | B2 |
| 6835389 | Dohi et al. | Dec 2004 | B1 |
| 6855913 | Nikodym | Feb 2005 | B2 |
| 6906027 | Oki et al. | Jun 2005 | B2 |
| 7022311 | Ohkuma et al. | Apr 2006 | B1 |
| 7115281 | Singh et al. | Oct 2006 | B2 |
| 7278982 | Tsutsui | Oct 2007 | B2 |
| 7306787 | Tarara et al. | Dec 2007 | B2 |
| 7353823 | Tsutsui | Apr 2008 | B2 |
| 7638138 | Oki et al. | Dec 2009 | B2 |
| 7806117 | Tsutsui | Oct 2010 | B2 |
| 8062670 | Baran, Jr. et al. | Nov 2011 | B2 |
| 8337817 | Nagata et al. | Dec 2012 | B2 |
| 8435554 | Oki et al. | May 2013 | B2 |
| 20010027301 | Lau et al. | Oct 2001 | A1 |
| 20010038824 | Horii et al. | Nov 2001 | A1 |
| 20020002172 | Bell-huff et al. | Jan 2002 | A1 |
| 20020012688 | Dohi et al. | Jan 2002 | A1 |
| 20020040139 | Billotte et al. | Apr 2002 | A1 |
| 20020062829 | Ohki et al. | May 2002 | A1 |
| 20030199424 | Smith et al. | Oct 2003 | A1 |
| 20040063615 | Oki et al. | Apr 2004 | A1 |
| 20040076588 | Batycky et al. | Apr 2004 | A1 |
| 20040092428 | Chen et al. | May 2004 | A1 |
| 20040173211 | Kladders et al. | Sep 2004 | A1 |
| 20040241232 | Brown et al. | Dec 2004 | A1 |
| 20050022812 | Hrkach | Feb 2005 | A1 |
| 20050042177 | Ryde et al. | Feb 2005 | A1 |
| 20050118272 | Besse et al. | Jun 2005 | A1 |
| 20050142073 | Watts et al. | Jun 2005 | A1 |
| 20050158250 | Oki et al. | Jul 2005 | A1 |
| 20050177095 | Tsutsui | Aug 2005 | A1 |
| 20050232988 | Venkatesh et al. | Oct 2005 | A1 |
| 20060057213 | Larhrib et al. | Mar 2006 | A1 |
| 20060106057 | Daniel et al. | May 2006 | A1 |
| 20060116657 | Schmid | Jun 2006 | A1 |
| 20060216352 | Nystrom et al. | Sep 2006 | A1 |
| 20060217658 | Tsutsui | Sep 2006 | A1 |
| 20060233715 | Oki et al. | Oct 2006 | A1 |
| 20070055200 | Gilbert | Mar 2007 | A1 |
| 20070060868 | Tsutsui et al. | Mar 2007 | A1 |
| 20070065509 | Kanikanti et al. | Mar 2007 | A1 |
| 20070098804 | Aronhime et al. | May 2007 | A1 |
| 20070178164 | Blau | Aug 2007 | A1 |
| 20070184109 | Floyd et al. | Aug 2007 | A1 |
| 20070249674 | Bolton et al. | Oct 2007 | A1 |
| 20070272763 | Dunne et al. | Nov 2007 | A1 |
| 20080029084 | Costantino et al. | Feb 2008 | A1 |
| 20080031959 | Blondino et al. | Feb 2008 | A1 |
| 20080090841 | Johnson et al. | Apr 2008 | A1 |
| 20080127972 | Morton | Jun 2008 | A1 |
| 20080260848 | Nagata et al. | Oct 2008 | A1 |
| 20080286362 | Baran, Jr. et al. | Nov 2008 | A1 |
| 20090157037 | Iyer et al. | Jun 2009 | A1 |
| 20110033544 | Nagata et al. | Feb 2011 | A1 |
| 20110045088 | Tsutsui et al. | Feb 2011 | A1 |
| 20130095145 | Nagata et al. | Apr 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 0122036 | Oct 1984 | EP |
| 0147755 | Jul 1985 | EP |
| 0761248 | Mar 1997 | EP |
| 0943326 | Sep 1999 | EP |
| 1025859 | Aug 2000 | EP |
| 1108423 | Jun 2001 | EP |
| 1454648 | Sep 2004 | EP |
| 1504780 | Feb 2005 | EP |
| 1785145 | May 2007 | EP |
| 2395900 | Jun 2004 | GB |
| 2448183 | Oct 2008 | GB |
| 3912469 | Jul 1964 | JP |
| 53127553 | Nov 1978 | JP |
| S 54-20126 | Feb 1979 | JP |
| 54062328 | May 1979 | JP |
| 59-34267 | Feb 1984 | JP |
| S 59-163313 | Sep 1984 | JP |
| 60-185564 | Sep 1985 | JP |
| 60-224616 | Nov 1985 | JP |
| 62-42888 | Sep 1987 | JP |
| 63267731 | Nov 1988 | JP |
| 3-29146 | Mar 1991 | JP |
| 5032560 | Feb 1993 | JP |
| 7-165613 | Jun 1995 | JP |
| 8-098888 | Apr 1996 | JP |
| H 08-206208 | Aug 1996 | JP |
| 08243164 | Sep 1996 | JP |
| 9-276405 | Oct 1997 | JP |
| 9-291026 | Nov 1997 | JP |
| 10059841 | Mar 1998 | JP |
| 11216357 | Aug 1999 | JP |
| 11-322582 | Nov 1999 | JP |
| 2000-229859 | Aug 2000 | JP |
| 2000-239187 | Sep 2000 | JP |
| 2001-55323 | Feb 2001 | JP |
| 2002-255795 | Sep 2002 | JP |
| 2003-154006 | May 2003 | JP |
| 2003-175103 | Jun 2003 | JP |
| 2003-206227 | Jul 2003 | JP |
| WO 9404133 | Mar 1994 | WO |
| WO 9512399 | May 1995 | WO |
| WO 9534582 | Dec 1995 | WO |
| WO 9731626 | Sep 1997 | WO |
| WO 9830207 | Jul 1998 | WO |
| WO 9916422 | Apr 1999 | WO |
| WO 9916470 | Apr 1999 | WO |
| WO 9951205 | Oct 1999 | WO |
| WO 0012063 | Mar 2000 | WO |
| WO 0012136 | Mar 2000 | WO |
| WO 0023023 | Apr 2000 | WO |
| WO 0038811 | Jul 2000 | WO |
| WO 0126630 | Apr 2001 | WO |
| WO 0132125 | May 2001 | WO |
| WO 0232406 | Apr 2002 | WO |
| WO 02094233 | Nov 2002 | WO |
| WO 03004048 | Jan 2003 | WO |
| WO 03030872 | Apr 2003 | WO |
| WO 03077825 | Sep 2003 | WO |
| WO 03095008 | Nov 2003 | WO |
| WO 2004004922 | Jan 2004 | WO |
| WO 2005013937 | Feb 2005 | WO |
| WO 2005056008 | Jun 2005 | WO |
| WO 2005104712 | Nov 2005 | WO |
| WO 2006016530 | Feb 2006 | WO |
| WO 2006040680 | Apr 2006 | WO |
| WO 2008031028 | Mar 2008 | WO |
| WO 2008075102 | Jun 2008 | WO |
| WO 2008078730 | Jul 2008 | WO |
| WO 2008031028 | Nov 2008 | WO |
| WO 2009095684 | Aug 2009 | WO |
| Entry |
|---|
| U.S. Appl. No. 12/576,219, filed Oct. 8, 2009, Tsutsui et al. |
| “Fluorouracil” definition viewed on the National Cancer Institute website at www.cancergov/drugdictionary?cdrid=43130 on May 31, 2012. |
| European search report and opinion dated Dec. 19, 2011 for Application No. 07860016.0. |
| European search report dated Jul. 15, 2008 for Application No. 05768543.0. |
| Hens, et al., “BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction,” Development 2007, 134, pp. 1221-1230. |
| Hibberd, et al. Immunization strategies for the immunocompromised host: the need for immunoadjuvants. Ann Intern Med. Jun. 15, 1989;110(12):955-6. |
| International search report (partial) dated Dec. 21, 2010 for PCT Application No. IB2010/02168. |
| International search report Jun. 8, 2010 for PCT Application No. JP2010/003285. |
| International search report and written opinion dated Jun. 28, 2011 for PCT Application No. IB2010/02168. |
| International search report dated Nov. 1, 2005 for PCT Application No. JP2005/014389. |
| International search report dated Feb. 5, 2008 for PCT Application No. JP2007/074787. |
| International search report dated May 7, 2003 for PCT Application No. JP2003/001948. |
| Ishikawa, et al. Improved nasal bioavailability of elcatonin by insoluble powder formulation. Int J Pharm. Aug. 14, 2001;224(1-2):105-14. |
| Kleinebudde, et al. Influence of degree of polymerization on behavior of cellulose during homogenization and extrusion/spheronization. AAPS Pharmasci 2000, 2(2) Article 21, 1-10. |
| Merriam-Webster's Collegiate Dictionary, 10th edition, Merriam-Webster Incorporated: Springfield, Massachusetts, 1993, pp. 41. |
| Office action dated Jan. 13, 2011 for U.S. Appl. No. 12/346,537. |
| Office action dated Jan. 20, 2011 for U.S. Appl. No. 12/576,219. |
| Office action dated Jan. 29, 2008 for U.S. Appl. No. 10/545,764. |
| Office action dated Mar. 4, 2013 for U.S. Appl. No. 12/848,850. |
| Office action dated Apr. 12, 2012 for U.S. Appl. No. 12/576,219. |
| Office action dated Apr. 20, 2012 for U.S. Appl. No. 12/780,433. |
| Office action dated May 7, 2013 for U.S. Appl. No. 11/660,131. |
| Office action dated Jun. 4, 2012 for U.S. Appl. No. 12/521,116. |
| Office action dated Jun. 10, 2013 for U.S. Appl. No. 12/576,219. |
| Office action dated Jun. 25, 2012 for U.S. Appl. No. 12/346,537. |
| Office action dated Sep. 6, 2011 for U.S. Appl. No. 12/346,537. |
| Office action dated Sep. 6, 2011 for U.S. Appl. No. 12/576,219. |
| Office action dated Sep. 24, 2008 for U.S. Appl. No. 10/545,764. |
| Office action dated Sep. 27, 2010 for U.S. Appl. No. 11/660,131. |
| Office action dated Sep. 28, 2011 for JP Application No. 2006-531575 (in Japanese with English translation). |
| Office action dated Oct. 10, 2012 for U.S. Appl. No. 12/780,433. |
| Office action dated Oct. 15, 2012 for U.S. Appl. No. 12/848,850. |
| Office action dated Oct. 29, 2009 for U.S. Appl. No. 11/660,131. |
| Office action dated Nov. 1, 2012 for U.S. Appl. No. 11/660,131. |
| Office action dated Dec. 5, 2011 for U.S. Appl. No. 12/346,537. |
| Rowe, et al (Eds). Handbook of Pharmaceutical Excipients. Pharmaceutical Press. 2003. p. 108-109. |
| UK combined office action and search report dated Nov. 10, 2010 for Application No. GB1012959.1. |
| UK search report dated Sep. 9, 2011 for Application No. GB1012959.1. |
| Advisory action dated Sep. 13, 2013 for U.S. Appl. No. 12/848,850. |
| European search report and opinion mailed Dec. 20, 2013 for Application No. 10774745.3. |
| Office action dated Jan. 6, 2014 for U.S. Appl. No. 12/576,219. |
| Component definition, Dictionary.com, accessed Apr. 1, 2014, pp. 1-4. |
| Labiris, et al. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. Dec. 2003;56(6):588-99. |
| Office action dated Apr. 9, 2014 for U.S. Appl. No. 12/780,433. |
| Partition Coefficient, Wikipedia, accessed Mar. 31, 2014, pp. 1-8. |
| Topliss, John. Quantitative Structure-Activity Relationships of Drugs, 1983, pp. 2. |
| Notice of allowance dated Sep. 24, 2014 for U.S. Appl. No. 12/576,219. |
| Office action dated Oct. 15, 2014 for U.S. Appl. No. 12/780,433. |
| Office action dated Nov. 24, 2014 for U.S. Appl. No. 13/649,515. |
| Notice of allowance dated Apr. 22, 2015 for U.S. Appl. No. 12/780,433. |
| Office action dated Apr. 2, 2015 for U.S. Appl. No. 13/649,515. |
| Number | Date | Country | |
|---|---|---|---|
| 20130287852 A1 | Oct 2013 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12346537 | Dec 2008 | US |
| Child | 13827859 | US | |
| Parent | 10545764 | US | |
| Child | 12346537 | US |
