Source: https://patents.justia.com/patent/8986737
Timestamp: 2020-02-26 23:33:33
Document Index: 128440317

Matched Legal Cases: ['§119', 'Application No. 60', 'Application No. 1353', 'Application No. 1353', 'Application No. 03824634', 'Application No. 03824634', 'Application No. 2497973', 'Application No. 2003272284']

US Patent for Antibiotic microspheres for treatment and prevention of osteomyelitis and enhancement of bone regrowth Patent (Patent # 8,986,737 issued March 24, 2015) - Justia Patents Search
Justia Patents Particulate Form (e.g., Powders, Granules, Beads, Microcapsules, And Pellets)US Patent for Antibiotic microspheres for treatment and prevention of osteomyelitis and enhancement of bone regrowth Patent (Patent # 8,986,737)
Dec 10, 2008 - Wm. Marsh Rice University
This application is a continuation-in-part of U.S. patent application Ser. No. 10/655,639, filed Sep. 5, 2003, which claims priority under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/408,496, filed Sep. 5, 2002 and U.S. Provisional Application Ser. No. 60/408,502, filed Sep. 5, 2002, the disclosures of said applications are hereby incorporated herein by reference.
FIG. 8 is a microphotograph of a section taken from a bony defect/metal implant site in a rabbit treated in accordance with the embodiment of the invention. The section was stained with methylene blue and was negative for infection. The antibiotic microspheres appear as clear bubbles (indicated by solid white arrows) and take up 10.12% of the image, the tantalum implant appears as black (indicated by dashed white arrows) and takes up 30.11% of the image, the bone is blue (indicated by crosshatched white arrows) and takes up 17.568% of the image. Thus in this section, the bone is occupying 29.4% of the available space.
FIG. 9 is a higher magnification microphotograph of another section taken from a bony defect/metal implant site of a rabbit treated in accordance with an embodiment of the invention. This section was stained with methylene blue and basic fuchsin (similar to an H&E stain), and was negative for bacterial growth. The bony ingrowth and the presence of microspheres (clear bubbles indicated by white arrows) inside the tantalum implant (black), are shown. In this image, bone is occupying 100% of the available space, the implant takes up 7.771% of this image, and the microspheres take up 32.924% of this image.
Example 1 PLGA/Tobramycin Drug Delivery System
Each formulation had a large initial release of tobramycin in the first 24 hours, followed by a few days of lowered release and then a few weeks of nearly steady release. Linear fits of the elution curves during the 7-28 day time period demonstrated correlations ranging from r2=0.7748 to 0.9770, indicating that the release of antibiotic is very linear over this time period. Table 1 shows the calculated average linear release of tobramycin for each formulation for days 7 through 28 in absolute amounts and percentage of total amount of drug.
99 1 0 42.8% 0.3852 0.48 95 5 0 2.3586 0.37 90 10 0 45.8% 4.4510 0.41 94 1 5 61.8% 0.5131 0.33 90 5 5 40.2% 1.3415 0.27 85 10 5 52.4% 8.7916 0.67
Timepoint 10% tobramycin 10% tobramycin Days 0% PEG 5% PEG
1 1 4 3 7 3 14 21 1 1 30-40 1
Example 2 PLGA/Tobramycin/PMMA Parenteral Antibiotics
Categories Scores Size of Defect (length in mm at longest point) 0-10 New Bone Formation Full (2 cortices + matrix) 0 Moderate (2 cortices, no matrix) 1 Mild (1 cortex) 2 None 3 Maximum (worst) Score 13
Presence of Bacteria Marked 3 Moderate 2 Mild 1 None 0 Intraosseous Inflammation Severe, abscess with fibrosis 3 Moderate, with fibrosis 2 Mild, with fibrosis 1 None, fibrosis only 0 New Bone Formation Minimal - <25% 3 Mild - 25-50% 2 Moderate - 50-75% 1 Full - 75-100% 0 Maximum (worst) Score 9
Cefazolin 2 32 Tobramycin 4-8 16
0 ++ ++ ND ND 2 + − ND ND 4 + − ND 125 8 − − 120 ND 16 − − 0 86 32 − − 0 0 64 − − 0 0 T = Tobramycin C = Cefazolin
Example 3 PLGA/Vancomycin/PMMA Microspheres
( bone ⁢ ⁢ % ) ( 100 - implant ⁢ ⁢ % )
Statistical analysis was performed using SPSS™ version 15 (SPSS Inc, Chicago, Ill.). The proportion of each group testing positive for bacteria at sacrifice was compared using a chi square analysis. For this analysis, the proportion of the untreated side was taken as the expected frequency. Further comparisons to investigate the effect of infection and microspheres in bony ingrowth were performed using T-tests. FIG. 9 is a higher magnification microphotograph of a section taken from a bony defect/metal implant site of a rabbit treated as described above. This section was stained with methylene blue and basic fuchsin (similar to an H&E stain), and was negative for bacterial growth. Within the area of bony ingrowth four microspheres can be seen (indicated by white arrows) inside the tantalum implant (black).
% Bony Ingrowth: Limb Mean (std deviation) Implants with Micro spheres (n = 11) Contralateral Limb Infected (n = 7) 28.90 (8.732) Contralateral Limb Not Infected (n = 4) 46.18 (7.946) Implants without Microspheres (n = 11) Limb Infected (n = 7) 19.46 (14.486) Limb Not Infected (n = 4) 49.01 (9.777)
1. A method for controlled release antibiotic treatment of an infection at a site of an existing or potential infection in the body of a patient, comprising:
formulating a biodegradable microsphere of 6 microns to 25 microns in diameter wherein said microspheres comprise: 85% to 99% by weight of polylactic-co-glycolic acid (PLGA); 0.1 to 5% by weight of polyethylene glycol (PEG); and 1% to 15% by weight of a first antibiotic;
placing said biodegradable microspheres at said site; and
inhibiting growth of the infective organism, and enhancing tissue ingrowth at said site by delivering a near-linear dosage of said antibiotic to said site for at least 4 weeks, wherein said dosage exceeds minimum inhibitory concentrations (MIC) for an infective organism.
6. The method according to claim 1, wherein said step of placing the biodegradable microspheres at said site comprises placing said microspheres at an existing or potential site of osteomyelitis in the body of the patient.
7. The method of claim 1, wherein said microspheres are formulated to deliver a near-linear dosage of said antibiotic agent for at least the first week of said 4 week period at levels exceeding the minimum inhibitory concentration (MIC) for organisms commonly found to be the cause of infections at such sites.
8. The method according to claim 1, wherein said antibiotic agent is selected from the group consisting of Ancef, Tobramycin, Cefadroxil, Cefazolin, Cephalexin, Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef, Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, and Vancomycin.
9. The method according to claim 1, wherein said microspheres are about 20 μm in diameter.
10. The method according to claim 1, wherein said microspheres are from 15 μm to 25 μm in diameter.
11. The method according to claim 1, wherein said controlled release comprises near linear release of the antibiotic agent over a 7-28 day period within said 4-week period, with a greater release during the first 24 hours of elution.
12. The method of claim 1, wherein said placing is totally or partially within the body at a site of existing or potential infection.
13. The method of claim 1, wherein said PLGA polymer comprises 50:50: ratio of lactic acid to glycolic acid.
14. The method of claim 1, wherein said microspheres comprise 1% to 10% of said first antibiotic.
15. A method of enhancing tissue ingrowth at a site of infection or potential infection in a patient, comprising:
inhibiting an infective organism and enhancing tissue ingrowth by: 1) formulating a biodegradable microsphere of 6 microns to 25 microns in diameter wherein said microspheres comprise: 85% to 99% by weight of polylactic-co-glycolic acid (PLGA); 0.1 to 5% by weight of polyethylene glycol (PEG); and 1% to 15% by weight of a first antibiotic; 2) placing a microsphere at said site; and 3) delivering a near-linear dosage of said antibiotic to said site for at least 4 weeks, wherein said dosage exceeds minimum inhibitory concentrations (MIC) for said organism and wherein said microspheres do not undergo phagocytosis.
16. The method of claim 15, wherein said tissue growth is bone ingrowth.
17. The method of claim 16, wherein said microspheres remain at said site for at least thirty days.
18. The method of claim 1, wherein said microspheres remain at said site for at least thirty days.
19. A microsphere configured to enhance tissue ingrowth at a site of infection or potential infection in a patient, wherein said microsphere comprises:
85% to 99% by weight of polylactic-co-glycolic acid (PLGA); 0.1 to 5% by weight of polyethylene glycol (PEG); and
1% to 15% by weight of a first antibiotic; wherein said microsphere delivers a near-linear dosage of the antibiotic to the site for at least 4 weeks, and wherein the microsphere enhance tissue ingrowth by at least 10% compared to bony ingrowth in the absence of the microspheres.
20. The method according to claim 12, wherein said step of placing biodegradable microspheres totally or partially within the body at a site of existing or potential infection comprises implanting or injecting said microspheres at said site.
21. The method according to claim 15, wherein said site comprises existing or potential osteomyelitis.
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Patent number: 8986737
Patent Publication Number: 20090148497
Assignees: Wm. Marsh Rice University (Houston, TX), Board of Regents of the Univeristy of Texas System (Austin, TX)
Inventors: Catherine G. Ambrose (Houston, TX), Terry A. Clyburn (Bellaire, TX), Antonio G. Mikos (Houston, TX)
Application Number: 12/332,026
Current U.S. Class: Particulate Form (e.g., Powders, Granules, Beads, Microcapsules, And Pellets) (424/489); Implant Or Insert (424/422); Surgical Implant Or Material (424/423); Contains Solid Synthetic Resin (424/501); Contains Waxes, Higher Fatty Acids, Higher Fatty Alcohols (424/502)
International Classification: A61K 9/14 (20060101); A61K 9/58 (20060101); A61K 9/00 (20060101); A61K 9/16 (20060101);