Source: http://patents.com/us-9750715.html
Timestamp: 2018-10-19 11:52:53
Document Index: 513518545

Matched Legal Cases: ['Application No. 200505259', 'Application No. 2', 'Application No. 2', 'Application No. 2', 'Application No. 2', 'Application No. 03157490', 'Application No. 03157490', 'Application No. 03157490', 'Application No. 97948333', 'Application No. 97948333', 'Application No. 97948333', 'Application No. 200501322', 'Application No. 130041', 'Application No. 170382', 'Application No. 170382', 'Application No. 10', 'Application No. 10', 'Application No. 10', 'Application No. 10', 'Application No. 10', 'Application No. 10', 'Application No. 541991', 'Application No. 336060', 'Application No. 541991', 'Application No. 19992936', 'Application No. 19992936', 'Application No. 19992936', 'Application No. 93103743', 'Application No. 93103743', 'Application No. 93103743', 'Application No. 0601003938', 'Application No. 1', 'Application No. 2', 'Application No. 200680032108', 'Application No. 04712312', 'Application No. 06813544', 'Application No. 10', 'Application No. 93103743', 'Application No. 2006279333', 'Application No. 200780003990', 'Application No. 200800593', 'Application No. 189583', 'Application No. 10', 'Application No. 2006279333', 'Application No. 2006279333', 'Application No. 200780003990', 'Application No. 200680032108', 'Application No. 200780003983', 'Application No. 200680032108', 'Application No. 200800593', 'Application No. 1414', 'Application No. 1413', 'Application No. 2006', 'Application No. 2008', 'Application No. 95130373', 'Application No. 2', 'Application No. 2', 'Application No. 200780003990', 'Application No. 200780003983', 'Application No. 06813544', 'Application No. 193099', 'Application No. 189583', 'Application No. 192545', 'Application No. 2008', 'Application No. 2008', 'Application No. 2008', 'Application No. 2008', 'Application No. 2008', 'Application No. 200780003983', 'Application No. 200780003983', 'Application No. 1414', 'Application No. 2008', 'Application No. 2013', 'Application No. 2013', 'Application No. 10', 'Application No. 14173782', 'Application No. 10', 'Application No. 11155958', 'Application No. 12192822', 'Application No. 2013', 'Application No. 2013', 'Application No. 2013', 'Application No. 2014', 'Application No. 2', 'Application No. 2', 'art 10']

US Patent # 9,750,715. Method of reversing, preventing, delaying or stabilizing soft tissue calcification - Patents.com
United States Patent 9,750,715
Chan , et al. September 5, 2017
Chan; Keith (Rockville, MD), Town; Winston (Hong Kong, HK), Chiang; Shou Shan (Linkou Shiang, TW)
Chan; Keith
Town; Winston
Chiang; Shou Shan
Panion & Biotech Inc. (TW)
Family ID: 1000002809615
12/162,558
PCT/US2007/002157
WO2007/089577
US 20090326060 A1 Dec 31, 2009
60763253 Jan 30, 2006
Aug 18, 2006 [WO] PCT/US2006/032585
Current CPC Class: A61K 31/295 (20130101); A61K 9/143 (20130101); A61K 31/555 (20130101); A61K 33/26 (20130101)
Current International Class: A61K 33/26 (20060101); A61K 31/555 (20060101); A61K 9/14 (20060101); A61K 31/295 (20060101)
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2272711 Feb 1999 CA
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336060 Jun 1999 NZ
541991 Feb 2004 NZ
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This application is the National Stage of International Application NO. PCT/US2007/002157, filed Jan. 26, 2007, which claims priority of Int'l App'l No. PCT/US2006/032385, filed Aug. 18, 2006, and claims benefit of U.S. Ser. No. 60/763,253, filed Jan. 30, 2006 the entire disclosure of which is incorporated by reference herein in its entirety.
1. A method of reversing soft tissue calcification in a subject, comprising administering to said subject an effective amount of ferric citrate having a dissolution rate of at least 2 mg/cm.sup.2/min, wherein soft tissue calcification is reversed.
2. The method of claim 1, wherein the ferric citrate has a dissolution rate from about 2 mg/cm.sup.2/min to about 4 mg/cm.sup.2/min.
3. The method of claim 1, wherein the soft tissue is selected from soft tissue in a joint, the skin, an eye, a heart valve, the myocardium, a coronary artery, a coronary arteriole, a kidney and a lung.
4. The method of claim 3, wherein the soft tissue is eye tissue.
5. The method of claim 1, wherein the ferric citrate is formulated for oral administration.
6. The method of claim 5, wherein the ferric citrate is formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit or a syrup.
7. The method of claim 1, wherein the effective amount of ferric citrate is 2 grams per day.
8. The method of claim 1, wherein the effective amount of ferric citrate is 4 grams per day.
9. The method of claim 1, wherein the effective amount of ferric citrate is 6 grams per day.
10. The method of claim 1, wherein calcification is reversed by up to 40%.
11. The method of claim 1, wherein calcification is reversed by up to 56%.
12. The method of claim 1, wherein calcification is reversed by up to 67%.
13. The method of claim 1, wherein calcification is reversed by up to 100%.
The present invention provides a method of treating soft tissue calcification in a subject, comprising administering to said subject an effective amount of a ferric organic compound. In one embodiment, the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm.sup.2/min.
The present invention also provides a therapeutic regimen for treating soft tissue calcification in a subject, the regiment comprises a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric organic compound, wherein the pharmaceutical composition is administered in single or multiple doses regimens. In one embodiment, the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm.sup.2/min. An example of ferric organic compound is ferric citrate.
The present invention also provides a pharmaceutical composition for treating soft tissue calcification in a subject, the composition comprising an effective amount of a ferric organic compound having a dissolution rate of at least approximately 2 mg/cm.sup.2/min. In general, the pharmaceutical composition can be formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
The present invention also provides uses of a pharmaceutical composition comprising an effective amount of ferric organic compound in preparation of a medicament for treating soft tissue calcification in a subject. In one embodiment, the ferric organic compound (e.g. ferric citrate) has a dissolution rate of at least approximately 2 mg/cm.sup.2/min.
In one embodiment, methods of the present invention comprise administering to a subject an effective amount of a ferric organic compound and a suitable carrier. As used herein, the term "suitable carrier" includes, but is not limited to, any suitable carrier for administering pharmaceutical compounds or compositions known to those of ordinary skill in the art. The type of carrier will vary depending on the mode of administration. An "acceptable or suitable carrier" may also include, but is not limited to, a liquid, an aerosol, a capsule, a tablet, a pill, a powder, a gel, an ointment, a cream, a granule, water, phosphate buffered saline, Ringer's solution, dextrose solution, serum-containing solutions, Hank's solution, other aqueous physiologically balanced solutions, oils, esters, glycols, biocompatible polymers, polymeric matrices, capsules, microcapsules, microparticles, bolus preparations, osmotic pumps, diffusion devices, liposomes, lipospheres, cells or cellular membranes. Biodegradable microspheres (e.g., polylactate polyglycolate) may also be employed as carriers.
The present invention also provides a method of treating soft tissue calcification in a subject, comprising administering to said subject an effective amount of a ferric organic compound. In general, the ferric organic compound has a dissolution rate of at least approximately 2 mg/cm.sup.2/min., e.g. from about 2 mg/cm.sup.2/min. to about 4 mg/cm.sup.2/min.
In one embodiment, the alkaline metal hydroxide is added at a rate of less than 20 ml/min, preferably between about 10 ml/min to about 20 ml/min., and the alkaline metal hydroxide is added to the ferric iron salt at a temperature of less than 40.degree. C., preferably between about 10.degree. C. to about 40.degree. C.
In one embodiment, the organic acid and the precipitate are heated to a temperature of between about 80.degree. C. to about 90.degree. C. Precipitating the ferric organic compound from the ferric organic acid solution by adding an organic solvent to the solution comprises cooling the ferric organic acid solution to less than 30.degree. C. before adding the organic solvent, preferably the ferric organic acid solution is cooled to a temperature between about 10.degree. C. to about 30.degree. C.
The present invention also provides a pharmaceutical composition for treating soft tissue calcification in a subject, the composition comprising an effective amount of a ferric organic compound having a dissolution rate of at least approximately 2 mg/cm.sup.2/min., e.g. from about 2 mg/cm.sup.2/min. to about 4 mg/cm.sup.2/min. The pharmaceutical composition can be formulated into various forms as described above, and it is useful for treating soft tissue calcification as described above.
The present invention also provides a use of a pharmaceutical composition comprising an effective amount of ferric organic compound in preparation of a medicament for treating soft tissue calcification in a subject. In one embodiment, the ferric organic compound (such as ferric citrate) has a dissolution rate of at least approximately 2 mg/cm.sup.2/min. The resulting medicament can be formulated into various forms as described above, and it is useful for treating soft tissue calcification as described above.
Referring to FIG. 1, the flowchart 10 is a general process for synthesizing a form of ferric organic compound or ferric citrate compound which can be used in the present invention. The starting materials, as indicated in box 20, comprise soluble ferric iron salts. The soluble ferric iron salts can comprise ferric chloride hexahydrate (FeCl.sub.36H.sub.2O), as indicated in box 21, or any other suitable soluble ferric iron salt. Next, an alkaline metal hydroxide (box 30) is added at a specific rate and temperature to the soluble ferric iron salt. The addition of the alkaline metal hydroxide at a specific rate, preferably between about 10 ml/min and about 20 ml/min, and temperature range, preferably below 40.degree. C., results in the formation of a uniform polyiron oxo colloidal suspension. The alkaline metal hydroxide can comprise sodium hydroxide, potassium hydroxide, or any other suitable alkaline metal hydroxide as indicated in box 31.
The colloidal suspension precipitate is collected and rinsed (box 40) with distilled water to remove any soluble impurities. After rinsing, the precipitate is re-suspended and, as indicated in box 50, crystalline organic acid is added to the precipitate and heated to a particular temperature range, preferably between about 80.degree. C. to about 90.degree. C. The organic acid can comprise any suitable organic acid. Box 51 lists some of the possible organic acids which can be used, including, but not limited to, citric acid, acetic acid, isocitric acid, succinic acid, fumaric acid, and tartaric acid. The addition of the organic acid allows the acid to form complexes with the precipitate in solution. At box 60, the ferric organic compound is precipitated out of solution with an organic solvent to form a novel form of ferric organic compound (box 70). Various organic solvents can be used, including, but not limited to, the solvents described in box 61, such as ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent.
in one embodiment of the invention, the ferric organic compound is ferric citrate. The starting materials for making a ferric citrate comprise a 1.85M solution of ferric chloride hexahydrate (FeCl.sub.36H.sub.2O). A volume of SM sodium hydroxide necessary to produce a 1:3 ratio of ferric iron to hydroxide ion is added to the ferric chloride hexahydrate solution at a rate of less than 20 ml per minute, preferably between about 10 ml per minute and about 20 ml per minute. The temperature of the mixture is maintained below 40.degree. C., preferably between about 10.degree. C. to about 40.degree. C., while the sodium hydroxide is added to form a polyiron oxide colloidal suspension of ferric hydroxide. The pH of the suspension is measured while the sodium hydroxide is added. Once the pH is above 7.0, the suspension is cooled until it is less than 30.degree. C., preferably between about 10.degree. C. to about 30.degree. C. The suspension is then filtered through a 1 mm pore filter to breakup aggregates and large particles of ferric hydroxide precipitate are then removed. The filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded, and the precipitated ferric hydroxide is centrifuged again to remove any remaining supernatant. The ferric hydroxide precipitate is then resuspended with distilled water. The centrifugation-resuspension steps are repeated two more times to wash the ferric hydroxide precipitate and remove water soluble impurities. The resulting ferric hydroxide precipitate is then homogenized.
An amount of citric acid necessary to produce a 1:1 ratio of ferric iron to citrate is added to the precipitate. The mixture is heated to between about 80.degree. C. to about 90.degree. C. in an oil bath until the color of the mixture changes from orange-brown to a clear black-brown, or until all of the ferric hydroxide precipitate is dissolved. The reaction is cooled until it is less than 30.degree. C., preferably between about 10.degree. C. to about 30.degree. C., and the pH is measured to determine that it is within 0.8 and 1.5. The reaction is centrifuged, and the supernatant is collected. Ferric citrate is precipitated from the supernatant by adding 5 volumes of organic solvent.
TABLE-US-00001 TABLE 1 Summary of Results Statistical Dose Response Significant Linear Regression Serum PO4 (mg/dL) Day 14 No No P = 0.0523 Day 28 Yes Yes (6 g/day) P = 0.0073 Serum Ca (mg/dL) Day 14 No No N.S. Day 28 No No N.S. Ca .times. PO4 (mg/dL).sup.2 Day 14 Yes No P = 0.0401 Day 28 Yes Yes (6 g/day) P = 0.0158 * N.S.: Not Significant
TABLE-US-00002 TABLE 2 Summary of Serum [PO4] (mg/dL) Placebo 2 g/day 4 g/day 6 g/day Dose (N = 16) (N = 31) (N = 32) (N = 32) Response Serum [PO4] (mg/dL) at 7.2 .+-. 1.43 7.2 .+-. 1.23 7.1 .+-. 1.27 7.3 .+-. 1.33 N/A Day 0 Serum [PO4] (mg/dL) at 6.7 .+-. 1.22 6.7 .+-. 1.50 6.4 .+-. 1.56 6.3 .+-. 1.72 No Day 14 (P = 0.0523) Serum [PO4] (mg/dL) at 7.2 .+-. 1.19 6.9 .+-. 2.22 6.0 .+-. 1.33 5.8 .+-. 1.76* Yes Day 28 *P < 0.05, Significant Difference Baseline Change as Compared to Placebo
TABLE-US-00003 TABLE 3 Summary of Serum [Ca] (mg/dL) Placebo 2 g/day 4 g/day 6 g/day Dose (N = 16) (N = 31) (N = 32) (N = 32) Response Serum [Ca] (mg/dL) at Day 0 8.71 .+-. 0.779 8.78 .+-. 0.981 9.02 .+-. 0.913 8.99 .+-. 0.812 No Serum [Ca] (mg/dL) at Day 14 8.91 .+-. 0.782 9.01 .+-. 1.232 9.47 .+-. 0.990 9.13 .+-. 0.909 No Serum [Ca] (mg/dL) at Day 28 8.74 .+-. 0.830 9.00 .+-. 0.953 9.29 .+-. 0.960 9.26 .+-. 0.865 No * P < 0.05, Significant Difference Baseline Change as Compared to Placebo
TABLE-US-00004 TABLE 4 Summary of Serum [Ca]*[PO4] (mg/dL).sup.2 Placebo 2 g/day 4 g/day 6 g/day Dose (N = 16) (N = 31) (N = 32) (N = 32) Response [Ca]*[PO4] 62.8 .+-. 13.91 62.9 .+-. 13.25 63.5 .+-. 10.69 65.8 .+-. 12.19 N/A (mg/dL).sup.2 at Day 0 [Ca]*[PO4] 59.9 .+-. 12.19 60.3 .+-. 16.50 59.9 .+-. 13.89 57.5 .+-. 16.27 Yes (mg/dL).sup.2 at Day 14 [Ca]*[PO4] 63.2 .+-. 12.55 61.7 .+-. 21.25 55.4 .+-. 13.36 54.1 .+-. 17.68* Yes (mg/dL).sup.2 at Day 28 *P < 0.05, Significant Difference Baseline Change as Compared to Placebo
TABLE-US-00005 TABLE 5 Treatment-Emergent Adverse Events Placebo 2 g/day 4 g/day 6 g/day (N = 16) (N = 33) (N = 34) (N = 33) # Event (%) # Event (%) # Event (%) # Event (%) Total number of subjects with at 7 (43.8) 16 (48.5) 12 (35.3) 17 (51.5) least one adverse event (T#at1AE) Sorted by Preferred Term (PT) Abdominal Pain 0 (0.0) 0 (0.0) 4 (11.8) 2 (6.1) Diarrhea 2 (12.5) 3 (9.1) 1 (2.9) 1 (3.0) Sorted by System Organ Class/PT GI Disorders (see above PT) 4 (25.0) 8 (24.2) 10 (29.4) 10 (30.3) General Disorders 2 (12.5) 4 (12.1) 2 (5.9) 4 (12.1) Infections and Infestations 2 (12.5) 0 (0.0) 3 (8.8) 1 (3.0) Skin and SC Tissue Disorders 0 (0.0) 3 (9.1) 0 (0.0) 4 (12.1) Sorted by SOC/PT/Severity T#at1AE, Mild 7 (43.8) 13 (39.4) 9 (26.5) 14 (42.4) T#at1AE, Moderate 0 (0.0) 6 (18.2) 3 (8.8) 2 (6.1) T#at1AE, Severe 1 (6.3) 0 (0.0) 2 (5.9) 1 (3.0) GI Disorders, Mild 4 (25.0) 6 (18.2) 8 (23.5) 9 (27.3) Sorted by SOC/PT/Relationship T#at1AE, Definitely 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) T#at1AE, Probably 1 (6.3) 2 (6.1) 2 (5.9) 5 (15.2) T#at1AE, Possibly 3 (18.8) 5 (15.2) 6 (17.6) 2 (6.1) GI Disorder, Definitely 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) GI Disorder, Probably 1 (6.3) 2 (6.1) 2 (5.9) 5 (15.2) GI Disorder, Possibly 3 (18.8) 3 (9.1) 6 (17.6) 1 (3.0)
In an open-label extension of a Phase II clinical study: "randomized, double-blind, placebo-controlled, dose-ranging study of the effects of ferric citrate on serum phosphate in patients with end stage renal disease (ESRD)", some of the patients were administered 2.about.6 g/day of ferric citrate and serum creatinine level was monitored to assess kidney function. Several patients who received 6 g/day of ferric citrate appear to have a trend of decreased serum creatinine level, which implies ferric citrate may modify, delay, arrest or prevent the progression chronic kidney disease. Results from 2 patients are shown in FIGS. 4-5.
An image analysis software called "Image J" was used for data analysis. The image analysis software is developed to display, edit, analyze, process, save and print 8-bit, 16-bit and 32-bit images. It can calculate area and pixel value statistics of user-defined selections, measure distances and angles, and create density histograms and line profile plots. It supports standard image processing functions such as contrast manipulation, sharpening, smoothing, edge detection and median filtering. The software is developed at the Research Services Branch of the National Institute of Mental Health, an institute of the National Institutes of Health (NIH). The software can be downloaded from the NIH website.
The image analysis software is able to measure calcified area and total cornea area that are subjectively defined by the user. To estimate calcified area, the observer first loads the patient's eye picture on to the image software, crops the specific calcified region, and the software will measure the defined section accordingly (defined as how many pixels in that area). It should be noted that because the pictures were taken by focusing on one side of cornea, the photos usually did not capture complete image of a cornea. To estimate the size of the full cornea, the observer used the image software to crop a 90 degrees fan-shape area on the available cornea region on the picture subjectively, and then let the software calculate the size of this fan-shape area to represent 1/4 of the full cornea. By multiply the number by four, the observer then got an estimate of total cornea area. An example photograph of cornea calcification is shown in FIG. 7.
The severity of cornea calcification was evaluated based on the percentage of the cornea surface occupied by calcification, i.e. % inner side calcification +% outer side calcification, wherein inner or outer side calcification is calculated as (calcified area on inner or outer cornea/total cornea area).times.100. See FIG. 8.
Within those 11 patients who received active treatment, their treatment period averaged 33 days and ranged from 28 to 57 days. The period between the 1st and 2nd examinations averaged 126 days and ranged from 50 to 217 days. Among these 11 patients, only 10 eye cornea calcification values exhibited worsened results (averaged +2.20%, range +0.08% to +6.989). In contrast, one eye cornea calcification value remained unchanged while 11 eye cornea calcification values exhibited improvement (averaged -2.07%, ranged -0.08% to -10.21%). Examples of worsened or improved cornea calcification are shown in FIGS. 9-10.
TABLE-US-00006 TABLE 6 Cornea Calcification In End Stage Renal Disease Patients Receiving Ferric Citrate Treatment Interval Difference between 1st Ferric citrate 1st eye test 2nd eye test between 1.sup.st Dose and 2nd eye treament period Calcified area Calcified area and 2.sup.nd tests Eye Subject ID (g/day) test (days) (days) on cornea (%) on cornea (%) (%) ID 2-01-001 Placebo 77 77 4.19% 5.47% 1.28% Right 4.32% 16.13% 11.81% Left 2-01-1-002 2 g/day 61 28 0.00% 0.00% 0.00% Right 3.90% 3.75% -0.15% Left 2-01-1-012 2 g/day 66 28 14.90% 4.69% -10.21% Right 3.50% 2.09% -1.41% Left 2-01-1-048 4 g/day 186 28 2.50% 2.09% -0.41% Right 1.85% 2.01% 0.16% Left 2-01-1-009 4 g/day 50 28 0.51% 1.00% 0.49% Right 1.16% 0.00% -1.16% Left 2-01-1-050 6 g/day 198 33 1.62% 1.54% -0.08% Right 0.86% 1.62% 0.76% Left 2-01-1-022 6 g/day 217 57 7.21% 7.29% 0.08% Right 1.39% 8.37% 6.98% Left 2-01-1-068 6 g/day 202 34 0.00% 2.24% 2.24% Right 1.05% 3.09% 2.04% Left 2-01-1-006 6 g/day 50 28 32.43% 29.27% -3.16% Right 50.95% 50.36% -0.59% Left 2-01-1-004 6 g/day 78 28 4.38% 2.20% -2.18% Right 2.50% 1.10% -1.40% Left 2-01-1-018 6 g/day 75 28 40.85% 38.86% -1.99% Right 5.93% 7.72% 1.79% Left 2-01-1-042 6 g/day 199 42 0.49% 3.73% 3.24% Right 0.67% 4.91% 4.24% Left
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