Implantable Pharmaceutical Composition Prepared From Components Consisting of Calcium Sulfate Alpha-Hemihydrate, Vancomycin and Tobramycin

Abstract

The present disclosure concerns a composition for an implantable pharmaceutical composition prepared from components consisting only of calcium sulfate α-hemihydrate in combination with two antibiotics, vancomycin and tobramycin, for the treatment of infection in bone and soft tissue.

Claims

1. A pharmaceutical composition prepared from components consisting of: a) 18.4 g pharmaceutical grade, phase pure calcium sulfate α-hemihydrate; b) 1000 mg of vancomycin hydrochloride; and c) 240 mg of tobramycin sulfate; wherein the calcium sulfate α-hemihydrate is prepared by first converting a source of pharmaceutical grade calcium sulfate dihydrate to soluble calcium sulfate anhydrite by hydrothermal treatment in suspension, and then converting the resulting soluble anhydrous calcium sulfate to calcium sulfate α-hemihydrate by: i) adding the calcium sulfate dihydrate to a quantity of water in a water:calcium sulfate dihydrate ratio of 0.3:1-0.5:1 to form a suspension and autoclaving the suspension at 235-265° C. for 1-2 hours to dehydrate to form soluble anhydrite; ii) allowing the soluble anhydrite to cool in the autoclave in suspension to rehydrate back to calcium sulfate dihydrate; iii) draining off excess water and autoclaving again at 110-150° C. for 1-2 hours to convert the rehydrated calcium sulfate dihydrate to calcium sulfate α-hemihydrate.

2. The composition according to claim 1, wherein the vancomycin hydrochloride and tobramycin sulfate are combined to form a suspension, and the suspension is combined with the calcium sulfate α-hemihydrate in powder form in a liquid:powder ratio of between 0.26 and 0.35 parts by weight.

3. The composition according to claim 2, wherein the liquid:powder ratio is between 0.28 and 0.32 parts by weight.

4. The composition according to claim 1, wherein the vancomycin hydrochloride is provided in a powder form and/or wherein the tobramycin sulfate is provided in a liquid form.

5. The composition according to claim 1, wherein the composition is in the form of beads or pellets, wherein the beads or pellets are optionally between about 2.8 and 3.2 mm in diameter at their widest point.

6. The composition according to claim 5, wherein the beads or pellets have a compressive strength of between 10 MPa and 20 MPa at 1 hour after setting.

7. The composition according to claim 5, wherein the beads or pellets have a BET specific surface area obtained using the Brunauer Emmett-Teller (BET) Method of between about 0.2 m.sup.2/g and 0.8 m.sup.2/g.

8. The composition according to according to claim 5, wherein the beads or pellets have a BJH adsorption average pore diameter (4v/A) area deduced according to the Barrett-Joyner-Halenda (BJH) pore size distribution method between about 10 nm and 25 nm.

9. A method of manufacturing a composition for delivery of an implantable drug comprising: a) mixing 1000 mg of vancomycin hydrochloride with 240 mg of tobramycin sulfate, the tobramycin sulfate being in the form of a liquid, to produce a suspension containing vancomycin and tobramycin; b) combining said suspension with a powder consisting of 18.4 g of pharmaceutical grade, phase pure calcium sulfate α-hemihydrate to form a mixture; c) forming said mixture into beads or pellets d) allowing the beads or pellets to set and solidify using a plurality of molds; and e) producing beads or pellets of the composition.

10. The method according to claim 9, wherein: a) the vancomycin hydrochloride is provided in the form of a powder; and b) the beads or pellets of the composition are individually shaped as a cylinder with a single hemispherical end.

11. The method according to claim 9, wherein in step (b), the suspension containing the vancomycin hydrochloride and tobramycin sulfate is combined with the calcium sulfate α-hemihydrate in powder form in a liquid:powder ratio of between 0.26 and 0.35 parts by weight.

12. The method according to claim 11, wherein the liquid:powder ratio is between 0.28 and 0.32 parts by weight.

13. The method according to claim 9, wherein the tobramycin is in the form of an aqueous solution.

14. The method according to claim 13 wherein the concentration of tobramycin in the aqueous solution is from about 25-50 mg/ml.

15. The method according to claim 13, wherein the volume of the aqueous solution to receive the vancomycin for a single dose of the composition is between about 5.5 ml and 7.5 ml.

16. The method according to any of claim 9, wherein the beads or pellets are prepared using a mold mat containing cavities wherein the size, spacing and geometric arrangement of cavities is such that any straight line drawn along the full length of the mold mat parallel to an edge of the mold mat in at least one direction and within the arrangement of cavities on the mat will always intersect at least one cavity.

17. The method according to claim 16, wherein the mold mat contains cavities on both sides of the mat.

18. The method according to any of claim 9, wherein the beads or pellets set in a time of between about 10 and 20 minutes as measured by the temperature rise method.

19. The method according to claim 18, wherein the setting time is determined by the insertion of a thermometer probe inside the prepared paste to track changes in temperature over time.

20. A method of treating infection in bone and soft tissue, the method comprising administering a composition according to claim 1 into a surgical void in a patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 illustrates the variation in dissolution between three commercially available calcium sulfates with different liquid/powder ratios as shown in Table 1 below, in accordance with the present disclosure:

TABLE-US-00001 TABLE 1 Commercially available calcium sulfates with different liquid/powder ratios Liquid/Powder Ratio Sample 1 (Synthecure) 0.240:1 Sample B (the calcium sulfate α- 0.320:1 hemihydrate of the disclosure) Sample C (InterSep ®) 0.395:1

[0033] FIG. 2 illustrates a plan view, sectional side view and perspective view of a 3 mm bead 2 having a diameter of 3 mm at its widest point, and made of the composition described in the present disclosure;

[0034] FIG. 3 illustrates a plan view of a mold used to make the beads in FIG. 2, having a plurality of cavities thereon, the diameter of which is 3 mm;

[0035] FIG. 4 illustrates two sectional side views of a bead mold, a first section sideview with a wider perspective two-sided mold with bead cavities on either side; and

[0036] FIG. 5 illustrates and additional another perspective view of the bead mold according to FIG. 3, further illustrating the plurality of cavities thereon; and

[0037] FIG. 6 illustrates standard elution profiles of vancomycin hydrochloride and tobramycin sulfate from the composition as analysed by liquid chromatography mass spectrometry with 1.5 g of beads in 4 ml of phosphate buffered saline (PBS), and partial solution exchange (1.5 ml) performed at 24 hour periods and replenished with fresh PBS.

DETAILED DESCRIPTION

[0038] The advantages, and other features of the method disclosed herein, will become more readily apparent to those having ordinary skill in the art from the following detailed description of certain preferred embodiments taken in conjunction with the drawings, which set forth representative embodiments of the present invention and wherein like reference numerals identify similar structural elements. It is understood that references to the figures such as up, down, upward, downward, left, and right are with respect to the figures and not meant in a limiting sense.

[0039] The present disclosure provides a composition prepared from components consisting of 18.4 g pharmaceutical grade, phase pure calcium sulfate α-hemihydrate, 1000 mg of vancomycin hydrochloride; and 240 mg of tobramycin sulfate; where the calcium sulfate α-hemihydrate is prepared using the steps (i)-(iii) discussed above. The composition is typically provided in the form of beads or pellets 2, which are formed by setting amounts of a paste of the composition within a mold mat 4 containing cavities 6 of a specific size and shape to produce cylindrical beads 2 with one hemispherical end for implantation into a surgical site.

[0040] The calcium sulfate used to prepare the composition is calcium sulfate α-hemihydrate. The composition of the disclosure is prepared using only calcium sulfate α-hemihydrate, vancomycin hydrochloride and tobramycin sulfate, and is free of processing and setting aids including calcium sulfate dihydrate, potassium phosphate, sodium chloride, sodium sulfate or calcium stearate. This simplifies the process, makes it less expensive, and reduces the variability in porosity and pore size of the composition.

[0041] The vancomycin is provided in the form of its hydrochloride salt. The vancomycin hydrochloride will typically be in powder form.

[0042] The tobramycin is provided in the form of its sulfate salt. The tobramycin sulfate will typically be in a solution and used for both solubilizing and suspending the vancomycin hydrochloride powder and hydrating the calcium sulfate hemihydrate to form set beads or pellets 2. The volume of solution typically used to hydrate the α-hemihydrate is 6 nil and represents a water powder ratio of 0.32.

[0043] If the composition is in the form of beads or pellets 2, they are formed by measuring the tobramycin sulfate solution at the appropriate dose and adding the solution to the specified weight of vancomycin hydrochloride powder. The vancomycin hydrochloride partly dissolves in the tobramycin sulfate solution to produce a suspension containing the two antibiotics. The suspension is then applied to the specified weight of calcium sulfate α-hemihydrate powder and mixed, typically for about 20 seconds. The resultant paste and then applied to a bead mold 4 and allowed to set.

[0044] Once set, the resultant beads 2 are then removed from the mold 4 and are ready for implantation into the surgical site. The beads 2 possess a specific surface area and pore size distribution allowing for a predictable and controlled rate of dissolution and drug elution when measured in vitro. In one specific embodiment, the beads 2 are cylindrical, having a diameter between 2.8 mm and 3.2 mm at their widest point. One end of the bead 2 is hemispherical. The bead mold 4 will typically contain a total of 837 cavities 6 to incorporate all the paste.

[0045] The bead mold 4 is typically a two-sided mold 4 with bead cavities 6 on both sides. This facilitates easier removal of the beads 2 by adding flexibility to the mold. The cavities 6 are typically identical on both sides. In one specific embodiment, the bead mold 4 is square in shape having sides of 152.5 mm and a depth of 7.5 mm.

[0046] The physical properties of the beads are a product of the antibiotic doses and the weight of the calcium sulfate hemihydrate powder used to make them. The ratio of drug concentration to hemihydrate powder (i.e. the liquid:powder ratio referenced above) is critical to the performance of the beads 2 once implanted. The liquid:powder ratio is linked to bead set time, compressive strength and elution profile of both pharmaceutical ingredients.

[0047] As discussed above, the porosity of the composition is determined in part by the volume of aqueous solution containing the active pharmaceutical ingredients. Adding too little of the aqueous solution to the powder results in only a partial conversion to calcium sulfate dihydrate, producing a weaker, more soluble biphasic material. Conversely, too much liquid results in surplus water for crystallization, which will not take part in the reaction and remains as free water in the material, contributing to the subsequent porosity and leaving a weaker material. The liquid to powder ratio is an important parameter to produce a finished material with the ideal surface area and pore size, critical factors in the dissolution of the beads 2 and consequently the elution of the added pharmaceutical ingredients.

[0048] The ideal liquid to powder ratio to fully convert the calcium sulfate α-hemihydrate is in the range of 0.26-0.35:1, more typically 0.28-0.32:1. The liquid to powder ratio of other commercially available calcium sulfate products use ratios, which are either lower or higher than this, as shown in Table 1 below, due to them being manufactured in different ways to the calcium sulfate α-hemihydrate used in the present disclosure.

[0049] In one specific embodiment, the dose of tobramycin sulfate in solution is 40 mg/ml, 6 ml of solution is used to partially dissolve the vancomycin hydrochloride at a dose of 1000 mg and the resultant aqueous suspension contains 166.66 mg/ml of vancomycin hydrochloride. This will fully hydrate 18.4 g of calcium sulfate α-hemihydrate powder. The addition of the extra weight of powders to the calcium sulfate α-hemihydrate does not require additional solution as the antibiotics do not take part in the setting reaction.

[0050] In the specific embodiment of 18.4 g calcium sulfate α-hemihydrate with 1000 g vancomycin and 240 mg tobramycin prepared as described, the set beads 2 have specific properties in terms of BET surface area of between about 0.2 m.sup.2/g and 0.8 m.sup.2/g; more typically between about 0.4 m.sup.2/g and 0.6 m.sup.2/g.

[0051] According to one embodiment of the disclosure, the beads or pellets 2 have a BJH adsorption average pore diameter (4v/A) area deduced according to the Barrett-Joyner-Halenda (BJH) pore size distribution method between about 10 nm and 25 nm.

[0052] The beads 2 when produced according to the aforementioned embodiments, have a setting time of under 20 minutes as defined as the time required from the combination of the aqueous suspension to the calcium sulfate alpha-hemihydrate until burdening is achieved. The disclosed embodiments produce antibiotic loaded calcium sulfate dihydrate beads 2 that maintain sufficient compressive strength that is not compromised by the addition of antibiotics. According to one embodiment, the compressive strength is between 10 and 20 MPa at 1 hour after mixing.

[0053] The beads 2 produced using the aforementioned method may be used in surgical procedures as part of an infection management strategy where they absorb and elution the full amount of vancomycin and tobramycin at the surgical site reducing the risk of systemic toxicity compared to systemic administration of the two antibiotics.

[0054] Also provided by the present disclosure is a method of administering two antibiotics to a patient, the method comprising inserting a composition as defined hereinabove into a surgical void in a patient.

[0055] Also provided by the present disclosure is a method of treating infection in bone and soft tissue, the method comprising administering a composition as defined hereinabove into a surgical void in a patient.

EXAMPLES

Example 1

[0056] Demonstrate Surface Area

[0057] 18.4 g of calcium sulfate α-hemihydrate was combined with 240 mg (6 ml) of tobramycin sulfate liquid with 1000 mg of vancomycin hydrochloride powder and formed into 3 mm beads 2 and allowed to set. A sample set of 3 beads 2 were selected at random for analysis. The beads 2 were vacuum degassed at room temperature and then isotherms were obtained using a nitrogen adsorption instrument (Tristar 11 Plus. Micromeritics Ltd.) Results are shown in Table 2.

TABLE-US-00002 TABLE 2 BET surface area of three lots of calcium sulfate combined with vancomycin and tobramycin BET Surface Sample Area (m.sup.2/g) Lot 1 Sample 1 0.356 Lot 1 Sample 2 0.364 Lot 1 Sample 3 0.372 Lot 2 Sample 1 0.272 Lot 2 Sample 2 0.256 Lot 2 Sample 3 0.280 Lot 3 Sample 1 0.254 Lot 3 Sample 2 0.267 Lot 3 Sample 3 0.275

Example 2

[0058] Demonstrate BJH Pore Size Distribution

[0059] 18.4 g of calcium sulfate α-hemihydrate was combined with 240 mg (6 ml) of tobramycin sulfate liquid with 1000 mg of vancomycin hydrochloride powder and formed into 3 mm beads 2 and allowed to set. A sample set of 3 beads 2 were selected at random for analysis. The beads 2 were vacuum degassed at room temperature and then isotherms were obtained using a nitrogen adsorption instrument (Tristar II Plus. Micromeritics Ltd.) Results are shown in Table 3.

TABLE-US-00003 TABLE 3 BJH Adsorption average pore diameter of three lots of calcium sulfate combined with vancomycin and tobramycin BJH Adsorption Average Pore Diameter (4V/A) Sample (nm) Lot 1 Sample 1 15.2249 Lot 1 Sample 2 14.9519 Lot 1 Sample 3 14.2940 Lot 2 Sample 1 21.5225 Lot 2 Sample 2 22.3880 Lot 2 Sample 3 20.2697 Lot 3 Sample 1 19.9426 Lot 3 Sample 2 18.9352 Lot 3 Sample 3 17.2245

Example 3

[0060] Elution Data for VT

[0061] 18.4 g of calcium sulfate α-hemihydrate was combined with 240 mg (6 ml) of tobramycin sulfate liquid with 1000 mg of vancomycin hydrochloride powder and formed into 3 mm beads 2 and allowed to set. Three grams of beads 2 were immersed in 4 mL of sterile phosphate-buffered saline (PBS) at 37° C. At each time point, 1.5 ml of the solution was sampled and replenished with fresh PBS. The samples were then syringe filtered using a 0.2 μm 13 mm PES syringe tilter into 2 mL amber glass vials.

[0062] Quantification of eluted antibiotics was measured using a single quadrupole mass spectrometer (MS) coupled to a 1260 infinity II series liquid chromatography stack (LCMS) (Agilent Technologies). Depending on the concentration, samples were analysed either neat or diluted to ensure values fell within the linear range of the standard curves. Concentrations were calculated from peak areas using standard curves developed from dilutions of antibiotic prepared to known concentrations. Separation was conducted with a Poroshell 120-SB-C18 column (21.X 100 mm, 2.17 μm).

[0063] LCMS conditions were Buffer A was 99.9% H2O, 0.1% Heptafluorobutyric Acid and B was 99.9% Acetonitrile (CAN), 0.1% % Heptafluorobutyric Acid. The gradient was held with 30.0% B for 2 min before increasing linearly to 95.0% over 5 min. The 100% B was maintained for a further 1 min before rapid equilibration in 100% A. The flow rate was constant at 0.3 mL/min.

[0064] The gas temperature in the source was 325° C. with a flow rate of 9 L/min. The nebulizer pressure was 35 pounds per square inch and the capillary voltage 3.5 kM. Fragmentor and collision energy voltages were optimized for each antibiotic. Eluted concentrations are shown in Table 4 and FIG. 6.

TABLE-US-00004 TABLE 4 Elution concentrations Tobramycin Vancomycin Day μg/ml μg/ml 1 7046.208 13420.69 3 4693.264 11787.92 4 3130.589 10336.16 7 1972.743 9807.795 8 1058.751 6936.349 9 574.1567 4778.238 10 354.742 3093.854 11 216.352 1932.859 14 135.2563 905.3717 15 109.8367 603.5953 17 15.486 135.9353 18 9.977667 147.697 21 7.125 91.762 22 5.193667 59.85067 23 3.865667 36.98767 24 3.277 23.549 25 2.913 16.01967 29 2.833 9.746 30 2.598 6.082333 31 2.453667 4.065667

[0065] The results demonstrate a controlled and reproducible elution profile with concentrations exceeding the minimally inhibitory concentrations (MIC) for most out to 31 days as demonstrated in this in-vitro experiment. Local concentrations are achieved higher than those which could safely be administered systemically.

[0066] While the subject technology has been described with respect to preferred embodiments, those skilled in the art will readily appreciate that various changes and/or modifications can be made to the subject technology without departing from the spirit or scope of the subject disclosure. The appended claims are exemplary and may be combined and arranged in any manner including with multiple dependencies and the like. It is of course to be understood that the present disclosure is not intended to be restricted to the foregoing examples, which are described by way of example only.