Patent Application
20230149603
The present invention relates to a drug-releasing polymer composition that releases a first drug and a second drug over a time period of at least 30 days when introduced into an aqueous environment consistent with being introduced into the body and being surrounded by tissue. The present invention also relates to a medical device designed to be implanted into body tissue, wherein the medical device includes a surface layer comprising a drug-releasing polymer composition that releases a first drug and a second drug over a time period of at least 30 days.
Various medical devices are required to penetrate a patient's skin and reside inside the body for extended periods of time. Such devices are prone to introducing or causing infection at the penetration site, and to allowing the growth of biofilm on the device or inside the site, which is very difficult to treat with systemic antibodies. For example, in the use of external bone fixators, such infections are a recognized hazard referred to as pin track infections. Entire protocols are devoted to the prevention or treatment of such infections, and even to the re-siting of pins as is sometimes required. The introduction of infection is believed to be associated with the growth of biofilm on the fixator pins, and onto surrounding tissue. Another example is that certain catheters, such as central venous, dialysis, or indwelling catheters, must be replaced at routine intervals simply because of the potential growth of biofilm on them. Devices that are entirely implanted in the body, as opposed to passing through the skin, are also subject to similar problems. Therefore, improvements in efforts to counteract bacterial introduction and biofilm formation and growth are still needed.
A composition is provided according to the present disclosure. The composition can be provided on an implantable medical device designed to be located or implanted in body tissue for an extended period of time, such as, at least about 20 days, at least about 30 days, or at least about 40 days and provide a concentration of drug each day that is greater than the minimum inhibitory concentration of a selected bacteria, and preferably provide a concentration each day that is at least 10 times the minimum inhibitory concentration of a selected bacteria.
The composition includes: a host polymeric material making up a major portion of said composition; a first release-modifying material, said first release-modifying material being mixed together with said host polymeric material, said first release-modifying material making up a minor portion of said composition; a second release-modifying material, said second release-modifying material being different from said first release-modifying material, said second release-modifying material being mixed together with said host polymeric material, said second release-modifying material making up a minor portion of said composition; a first drug; and a second drug, wherein at least some of said first drug is present in the form of discrete first particles within said composition, and at least some of said second drug is present in the form of discrete second particles within said composition, and wherein each of said drugs has a respective cumulative release of said drug from said composition to an aqueous environment that is greater than would occur with an identical composition absent said second release-modifying material.
An alternative composition includes: a host polymeric material making up a major portion of said composition; at least one release-modifying material, said first release-modifying material being mixed, together with said host polymeric material, said first release-modifying material making up a minor portion of said composition; a first drug; and a second drug, wherein at least some of said first drug is present in the form of discrete first particles within said composition, and at least some of said second drug is present in the form of discrete second particles within said composition, wherein said first drug has a respective cumulative release of said first drug from said composition to an aqueous environment that is greater than would occur with an identical composition absent said second drug, and wherein said second drug has a respective cumulative release of said second drug from said composition to an aqueous environment that is greater than would occur with an identical composition absent said first drug.
Another alternative composition includes: a host polymeric material making up a major portion of said composition, said host polymeric material being a silicone; and a first drug, wherein at least some of said first drug is present in the form of discrete first particles within said composition.
A device for implanting in body tissue comprising: and implantable device having an exterior surface and being configured for implanting in body tissue, wherein at least a portion of the exterior surface comprises a composition according to any composition described herein. An exemplary composition includes: a host polymeric material making up a major portion of said composition; a first release-modifying material, said first release-modifying material being mixed together with said host polymeric material, said first release-modifying material making up a minor portion of said composition; a second release-modifying material, said second release-modifying material being different from said first release-modifying material, said second release-modifying material being mixed together with said host polymeric material, said second release-modifying material making up a minor portion of said composition; a first drug; and a second drug, wherein at least some of said first drug is present in the form of discrete first particles within said composition, and at least some of said second drug is present in the form of discrete second particles within said composition, wherein each of said drugs has a respective cumulative release of said drug from said composition to an aqueous environment that is greater than would occur with an identical composition absent said second release-modifying material. Exemplary implantable devices include: External fixator pin cover, molded sleeve around K-wire, fixators that are transdermal, devices designed for fixation such as mandibular fixators and elbow fixators, transcutaneous catheter, orthopedic surgical equipment, sleeves for orthopedic surgical equipment, pods or other shapes to be incorporated into prosthesis, orthopedic implants, sleeve/pouch for breast implants and other implants, urinary catheter, intra-Uterine devices (IUDs) and Ancillary equipment for IUDs, catheter lock/plug, ancillary catheter equipment such as molded fittings and connectors, implants, wound cover, dermal applications such as patches where controlled release of anti-inflammatory compounds and antibiotics would be beneficial, covers of implantable screws, rods, discs plates for traumatic fracture repair, ancillary equipment for cardioverter defibrillators, drug impregnated coronary stents, covers and guards for medical equipment, incorporation in tracheal tubes for anesthesia and breathing pathways, vascular graft prosthesis, antibacterial tubing and guards for cardiopulmonary bypass, dialysis, and ECMO (extracorporeal membrane oxygenation) machines (long procedures that could use antibacterial protection; ECMO in particular has long term use), drug releasing polymer mesh bag for pacemaker, tack cover release for sacculotomy, endolymphatic shunts and ear tubes, tympanostomy tubes, ear mold/ear plugs for swimmers to prevent swimmers ear infections, endovascular shunt adaptors, suture covers/the sutures themselves, implantable clips, burr hole cover for neurosurgery, fallopian tube prosthesis, long term intravascular catheter, incorporation in breast implants, and incorporation into prosthetics.
Embodiments of the invention are further illustrated but are in no way limited by the illustrations herein.
FIG. 5A1 shows a DualCap® device with isopropyl alcohol sponge.
FIG. 5A2 shows a ClearGuard HD device, with coating of chlorhexidine acetate.
In an embodiment, there may be provided a composition that is capable of releasing a drug when in contact with an aqueous or interstitial tissue fluid environment.
A composition according to an embodiment of the invention may comprise a host polymeric material, which may make up a major portion of the composition. It should be appreciated that a “major portion” refers to the largest component, by amount, of a composition. An example of such a material is ethylene vinyl acetate copolymer. It should be understood that other polymers including, for example, polyurethanes and silicones can be used. This polymeric material is commercially available under the name Elvax, from Dow (formerly DuPont) (Midland, Mich.). Within the Elvax family of materials, various proportions of ethylene and of vinyl acetate are available. In the examples described herein, two compositions of Ethylene Vinyl Acetate copolymer were used in different experiments. One composition used was Elvax150, which contains 32% vinyl acetate, and the balance (68%) ethylene. A second composition used was Elvax40W, which contains 40% vinyl acetate, and the balance (60%) ethylene. As the content of ethylene increases, the material becomes more hydrophobic and the melting temperature becomes higher. Elvax150 is more hydrophobic than Elvax40W and in general releases drug less rapidly than Elvax40W. Therefore, Elvax40W was used in most of the current experiments as the host polymeric material, rather than Elvax150. For other embodiments of the invention, silicone also was examined as a possible host polymer. Silicone was sourced from NuSil Technology, Avantor Sciences (Carpinteria, Calif.). Two different silicone polymers were tested, referred to as PRO-3389 and MED-6215. PRO-3389 is a 1:1 mixture ratio silicone, and MED-6215 is a 10:1 mixture. In regard to quantities of drug released, the two versions of silicone polymers did not release as much drug as Elvax40W, but can be tailored and designed to provide equivalent drug release. However, because of the extensive use and safety of silicone in various medical devices, for some embodiments of the invention, it may be desirable to use silicone polymers. In still other embodiments of the invention, the host polymeric material may be polyurethane or other biocompatible polymers.
In an embodiment, the composition may further comprise a first release-modifying material in addition to the host polymeric material, in order to modify the drug releasing properties of the host polymeric material. The first release-modifying material may make up a minor portion of the composition. It should be appreciated that a “minor portion” refers to a component that is not present as a major portion. It is believed that for at least some of the examples discussed herein, the host polymeric material and the first release-modifying material form a predominantly uniform heterogeneous material. In such a scenario, the first release-modifying material may be thought of as a pore-forming or diffusion-promoting agent which may create pathways by which drug may be conducted from the interior of the implant to its surface. The first release-modifying material may be a material that is more hydrophilic than the host polymeric material. An example of a first release-modifying material is polyethylene glycol (PEG). Other equivalent drug-releasing agents may be used including but not limited to polyvinyl alcohol and resorbable polymers without limitation.
In an embodiment, the composition may further comprise a second release-modifying material in addition to the host polymeric material and the first release-modifying material, in order to further modify the drug releasing properties of the composition. The second release-modifying material may make up a minor portion of the composition. An example of a second release-modifying material is polycaprolactone (PCL). PCL is known to be biodegradable although the time scale for its biodegradation is thought to be longer than the typical time scale of desired drug release. PEG and PCL are at least partially miscible with Elvax.
In an embodiment, the composition may further comprise a drug whose release from the composition is desired. More specifically, in an embodiment, the composition may comprise two drugs, namely, a first drug and a second drug that is different from the first drug. The two drugs may have different purposes or different target microorganisms that they are effective against. For example, one of the drugs may be effective against gram-positive bacteria while the other drug may be effective against gram-negative bacteria. As another example, one drug could be useful for inhibiting bacteria and another drug could be useful as an anti-inflammatory or for some other purpose. For example, minocycline has anti-inflammatory properties in addition to its bactericidal effects. The two drugs may have different solubilities in water or aqueous environments. The two drugs may have different degrees of hydrophilicity or hydrophobicity, or log p (octanol/water partition coefficient), as it is known in pharmaceutics or in the drug delivery field. Either drug or both of the drugs may have some degree of solubility or ability to form a mixed phase with the host polymeric material or the first release-modifying material or the second release-modifying material. Either or both of the drugs may be partially soluble in the polymer or may form a solid-solid dispersion with the host polymeric material or the first release-modifying material or the second release-modifying material.
In an embodiment of the invention, one of the drugs may be minocycline. Minocycline is a tetracycline antibiotic that is used to treat many different bacterial infections. Minocycline is effective against a wide range of bacteria, but notably does not affect Staphylococcus infections. It seems to have good effectiveness against a wide range of gram negative infections, and some gram positive infections. Minocycline is highly water-soluble. In current experiments, minocycline was present in the form of relatively small particles, with the particles being too small to discern a change of shape associated with dissolution of the drug into solid solution in the matrix (at least using optical microscopy).
Minocycline is available in both a hydrochloride form and a free base form. Either or both of these forms can be used in embodiments of the invention. The two forms have different release characteristics and different stabilities. We have found that the minocycline in the free base form seems to be less stable, seeming to oxidize and darken when in the polymer, and seeming to oxidize when dissolved in water as well. We are currently preferring the use of the hydrochloride form because it is more commonly available and seems to be more stable, even if the free base may provide a slight benefit in the form of possibly increased release rate in the early part of the release transient.
In an embodiment, the minocycline (or that portion of the minocycline that is not dissolved in other components of the composition) may be present in the form of particles.
In an embodiment of the invention, another of the drugs may be rifampin. Rifampin (also known by the names rifampicin, rifamycin, and rifadin) is a broad-spectrum antibiotic that is in a class called antimycobacterials. Rifampin is effective against gram-positive bacteria and is particularly effective against staphylococcus infections. Rifampin has low solubility in water. Rifampin has a relatively high octanol-water partition coefficient, meaning that it preferably dissolves into the oily liquid rather than into water.
In current experiments, rifampin was present in the form of relatively larger particles (larger than the particles of minocycline) that have the shape of rectangular or polygonal plates. Images of particles of Rifampin are shown herein in Example 13, illustrating a crystalline structure of Rifampin.
In an embodiment of the invention, the composition may be such that it is capable of providing release of one or both drugs, to an aqueous environment, at clinically effective concentrations, for a time duration of at least 30 days and preferably at least 40 days. It should be appreciated that a clinically effective therapeutic concentration refers to the amount needed for the drug to provide efficacy.
In embodiments of the invention, we are working with compositions that are melt processable or are able to be formed using hot melt extrusion and injection molding. This enables the production of desirable shapes that are manufacturable by those processes. Another benefit of melt processing is the higher drug loading that is achievable as a result of the presence of solid particles of drug. The common competing method is solvent impregnation, but that method is limited to lower drug contents.
In an embodiment of the invention, the various ingredients may be chosen such that the described composition is melt-processable and can be made in different shapes or sizes. For example, the host polymeric material may have a melting temperature or a temperature at which it is soft enough to be extruded, molded, formed, or otherwise processed. The first release-modifying material and the second release-modifying material do not have to be able to melt at that temperature, but they may be chosen such that they at least are able to be mixed and processed at that temperature. The drugs may be such that they do not significantly degrade or decompose at that processing temperature. For example, the drugs may be such that they have less than ˜3% degradation when exposed to 140° C. for 10 minutes, which is about the amount of time, or slightly more than the amount of time, for which the drugs are exposed to that temperature during melt mix extrusion. Either the first drug or the second drug or both may be such that they do not fully melt at that processing temperature. The lack of melting may contribute to at least some of the drug being present as discrete particles of the drug. It is believed that the presence of the drugs as discrete particles may contribute to the ability to store enough of the drug in the composition to provide long-duration release, and may contribute to the achieving of the release profiles described herein.
In an embodiment of the invention, the more-soluble drug may be more soluble in water than the less-soluble drug by a factor of at least 10 and yet the two drugs may have respective release rates from the composition to an aqueous environment that differ from each other by a factor of less than that solubility ratio.
In embodiments of the invention, it is unexpectedly found, as described elsewhere herein, that the behavior of the release rates and cumulative releases for the minocycline and for the rifampin are similar to each other. Based on this observation, in these experiments the concentration of the minocycline and the concentration of the rifampin are formulated as being equal to each other. This similarity of release rates is observed despite the fact that the minocycline is a high-water-solubility drug and was present in the form of micronized powder particles having a relatively large specific surface area, while the rifampin is a low-water-solubility drug and was present in the form of large plate-like particles having a relatively small specific surface area. This observation is both unexpected and significant, given the differing solubility, log p, and hydrophilicity characteristics of the two drugs.
It is believed possible that there is a plurality of phases in which the PEG/PCL exists in the copolymer matrix. PEG and PCL are miscible or partially miscible with Elvax. It is not wished to be limited to any particular explanation about the structure of the composition.
It should be appreciated that in a composition according to the present disclosure, the composition can contain the polymer component in an amount of about 40 wt % to 98 wt %, optionally 45 wt % to 85 wt %, optionally 50 wt % to 80 wt %, and optionally 55 wt % to 75 wt %. In addition, the composition can include the first release modifying component in an amount of 1 wt % to 20 wt %, optionally 3 wt % to 17 wt %, optionally 5 wt % to 15 wt %, and optionally 7.5 wt % to 12.5 wt %, the composition can contain the second release modifying component which is different from the first release modifying component, and which is an optional component, in an amount of 1 wt % to 20 wt %, optionally 3 wt % to 17 wt %, optionally 5 wt % to 15 wt %, and optionally 7.5 wt % to 12.5 wt %. The composition can contain the first drug in an amount of 1 wt % to 20 wt %, optionally 3 wt % to 17 wt %, optionally 5 wt % to 15 wt %, and optionally 7.5 wt % to 12.5 wt %, the composition can contain the second drug which is different from the first drug, and which is an optional component, in an amount of 1 wt % to 20 wt %, optionally 3 wt % to 17 wt %, optionally 5 wt % to 15 wt %, and optionally 7.5 wt % to 12.5 wt %. While the composition is described in the context of the polymer component, two release modifying components, and two drugs, it should be appreciated that the composition can be provided with only one release modifying agent and/or only one drug. In addition, it should be appreciated that the composition can include more that one or two different release modifying components and/or more than two different drugs.
In an embodiment of the invention, the described composition may be used to form a sleeve, a coating, an enclosure, or similar device that is suitable to be placed at or near where a medical device penetrates the skin of a patient. The sleeve or similar device will be located at the interface between the device and the tissue. Examples of such skin-penetrating devices are fixator pins and wires for external bone fixators. An embodiment of the invention may have a shape that fits around or is geometrically complementary to the shape or features of the device that is placed in the patient's body or that penetrates the skin of the patient. An example of a fixator pin is illustrated in
The device shown in
In usages other than bone fixator pins, it is possible to use a similar sleeve geometry around other devices that penetrate the skin. For example, such a sleeve could be used around a catheter or other implants including prosthesis or other devices used in orthopedic or bone treatment. This could be applicable, for example, to peritoneal dialysis, hemodialysis or extracorporeal treatments, without limitation.
Yet another example is a tympanostomy tube such as is commonly used to treat otitis media. A tympanostomy tube 50 may be made out of or may comprise the described composition. Such a tympanostomy tube is shown in
Referring now to
Alternatively, it would also be possible that the pin could have a recess, and material of an embodiment of the invention could be molded into the recess.
It can be noted that devices of embodiments of the invention could also be used with a K-wire (Kirschner wire). A K-wire typically has an outside diameter of about 1 mm. The mold as illustrated also contains, in its lower region, a mold cavity that is a simple small-diameter cylinder that can be used to mold the composition of the invention around a cylinder, such as a K-wire (Kirschner wire) whose diameter is smaller than the diameter of what is in the upper portion of the mold. It is likely that, in view of the already small diameter of a K-wire, the embodiment device would simply surround the exterior of the K-wire without the presence of a recess in the K-wire.
Catheters are known sources of local and systemic infection, clotting, occlusion, patency issues, growth of biofilm, and other problems. A catheter lock solution is a liquid that is used to occupy a lumen of a catheter when the catheter does not have a flowing fluid inside it. Such catheter lock solution can be used with generally any type of catheter, including central venous catheters, urinary catheters, peritoneal dialysis catheters, hemodialysis catheters, tubes for intravenous delivery, enteral or parenteral feeding tubes, and other kinds of catheters. In some situations, it is possible that the region of interest for prevention of problems is near the end of the catheter that is suitable to connect to another component, such as in the region of a luer lock fitting. In other situations, it is possible that the region of interest extends along a substantial length of the catheter. The catheter lock solution is typically used to prevent the development of infection or clotting or biofilm growth inside or on a surface of the catheter. Examples of ingredients that may be present in catheter lock solutions include antibiotics, citrate and heparin. For such purposes, the catheter lock solution is manufactured specifically for that purpose and is supplied as a separate product and is introduced into the catheter lumen at the appropriate time by medical personnel.
As an alternative to providing a catheter lock solution, it is possible to leave the liquid that is already inside the catheter inside the catheter, while providing a cap or similar device to close off the end of the catheter, and such cap may be effective to disinfect the end of the connector. DualCap® device, made by Merit Medical (South Jordan, Utah), is a commercially available cap for a luer connection for purposes of disinfection. The disinfecting agent is a sponge that contains 70% isopropyl alcohol. The molded plastic cap simply mechanically holds another component, the sponge, which in turn contains a disinfecting liquid within its pores. Such a device only is effective for the duration of the presence of the isopropyl alcohol. Such a device is only effective for the duration of the presence of the isopropyl alcohol and is not sufficient to prevent infections over a longer period of time, such as, for example, after the isopropyl alcohol is exhausted. FIG. 5A1 illustrates a DualCap® device 80, made by Merit Medical (South Jordan, Utah), with an isopropyl alcohol sponge 82.
Another known device is ClearGuard HD device (ICU Medical, Inc., San Clemente, Calif.), in which the antimicrobial agent is provided in the form of a coating, of chlorhexidine acetate, on the threads and also on the rod (stylet). FIG. 5A2 illustrates a ClearGuard HD device 86 with a coating of chlorhexidine acetate 88 where the rod and threads are coated with chlorhexidine, a broad spectrum antimicrobial agent.
As alternative to providing a specific separate catheter lock solution, it is possible to deliver a desired amount of a desired drug (e.g., antimicrobial or antibiotic) to the liquid inside the catheter, directly from the material of which the cap is made. In an embodiment, as illustrated in
Furthermore, as illustrated in
As a result, the stylet or element can deliver drug to the region of liquid that surrounds it, which can extend some distance into the lumen of the catheter. The entire stylet 92 (or a portion of it) may comprise a drug-delivering material, which may be the same as the material of which the cap is made or may be different. In addition, the rod and the thread 94 (or a portion of it) may comprise a drug-delivering material, which may be the same as the material of which the cap is made or may be different.
In still other embodiments of the invention, a catheter, or tubing, may be made of material described herein, such as, for example, EVA, silicone, polyurethane or other polymer including blends thereof, which further may contain particles or other physical form of one or more drug, such as rifampin or minocycline or both. Such a catheter or tubing would have the ability to deliver its drug all along its length, thereby discouraging biofilm growth at all such places. Still other devices that can be made of the inventive drug-loaded silicone or polyurethane are discussed elsewhere herein. Embodiments of the invention are not limited to the polymer or blends described above.
Embodiments of the invention are further described but are in no way limited by the Examples presented herein. Experiments were conducted using protocols and equipment as described herein. It is noted that other equipment and process can be adapted to make the compositions of the invention by persons skilled in the art.
Measurements of drug release typically are performed by producing (through extrusion or molding other methods) a sample of the composition of interest, and immersing the sample in water or an aqueous salt solution for a known immersion interval of time under mixing as it is known in the art of drug release or drug delivery. At the beginning of the immersion interval, the sink solution into which the drug is to be released (water or aqueous salt solution) does not contain any drug. At the end of the immersion interval, the concentration of the drug in the water or aqueous salt solution is measured as a function of time, which indicates how much drug release has occurred during that interval. In experiments performed herein, usually, the measurement interval was 1 day. For intervals longer than one day that were unmeasured, such as weekends, we took the total measured amount released and divided it by the measurement interval, using a spectrophotometer, as was done for all data presented here. Concentration of drug released into the sink solution is measured using a Shimadzu spectrophotometer UV-2101/3101PC. The liquid volume of bath is 10 ml, and the coupon has dimensions of 6.35 mm diameter and 1.27 mm thickness. Serial dilutions are made when required as known in the art of drug release.
Some of the graphs presented herein are graphs of incremental drug release (taken during discrete intervals that are usually one day in duration), which is essentially a drug release rate averaged over a one-day time period, or a release rate per day. These incremental drug releases are plotted as a function of time. In some of these graphs, the quantity that is plotted on the vertical axis is the concentration of the drug in the bath/sink fluid after the coupon of the embodiment composition has been immersed in the bath for a period of (typically one day). The concentration data is measured using the spectrophotometer. This quantity is proportional to the amount of drug released during the interval (typically one day), and so it can be viewed as representing a rate of release (quantity of drug released per day). In other graphs of incremental release, the quantity plotted on the vertical axis is the actual amount of drug released, in units of micrograms.
Other graphs are graphs of cumulative drug release amounts, plotted as a function of time. Information about cumulative release of a drug was obtained by mathematically summing the measured incremental releases of all previous increments for that experiment. More specifically, herein, for the plots of cumulative drug release, the horizontal axis, against which the data are plotted, is the square root of time, which is a common way of presenting such data for situations in which diffusion-release mechanism dominates transport from a polymer matrix. In general, for diffusion-dominated systems, it is theoretically expected that the cumulative release should have an approximately linear relationship with the square root of time.
It can be understood that a graph of cumulative release is essentially an integral of a graph of incremental (daily) release. Indeed, both types of graphs are obtained from the same set experimental data. The cumulative release graph is a summation adding together all of the incremental releases prior to a time point. Both types of plots are slightly stepwise, in view of the time increment (usually one day) at which measurements are taken.
For some experiments, the polymeric material and drug were processed using a single-screw extruder. For the single-screw extruder results reported here, we passed the material through that single-screw extruder four times to ensure good and uniform mixing. For most experiments, we used a Brabender extruder, which is a twin-screw extruder that is believed to mix material thoroughly with one pass of the material through the extruder. It is available from Brabender Instruments, Inc., South Hackensack, N.J. (MetaTorque Plasti-Corder, with the blades being roller blades). The only data included herein that was obtained using the single screw extruder are data from Example 4 (comparison of Elvax150 vs. Elvax40W, in which all data taken for Elvax 150 is from single screw extrusion) and Example 5 (use of two release-modifying materials in combination). All other data reported herein was obtained using the Brabender extruder.
The extrusion temperature was 140° C. and the time during which the composition was at the extrusion temperature was less than 10 minutes. Extrusion was carried out with a Brabender twin screw extruder. Compounded by weight percent, the blends are listed in the table below. The process was carried out by first weighing and mixing the polymers and drug compounds, then loading it into the Brabender and carrying out mixing until there was a uniform torque applied through the mixture. The torque first spiked when the mixture was introduced, then as the blend homogenized torque lowered. This took place at 140° C. for 8 minutes for each blend, with the exception of Compositions 10 and 14, which took 10 minutes to homogenize. The mixture was then scraped from the screws and allowed to cool on aluminum foil before storage. Material yield was 80% (˜40 g yield from 50 g raw material). The excess was lost stuck to the blades/inside of the extruder. The mixture for each blend appeared a bright red color after extrusion due to inclusion of rifampin which is red and after cooling and resting settled into a somewhat darker color. Compression molding was carried out with a carver heated lab press at 130° C. (266° F.). 10.2 grams of polymer were weighed and placed into a flat circular stainless steel die. Coupons pressed are 4″ diameter circle×1.27 mm thickness. The die and polymer are placed between two aluminum plates with a teflon sheet on each. They were then put into the lab press at around 3000 psi. Coupons were allowed to cool between the aluminum with air blasted over the surface of the metal, then, removing the aluminum, over the surface of the polymer. Coupons were pressed for each blend. Coupons appeared uniform. From these coupons, samples were cut for each release study. This pressing demonstrates ease of moldability of the polymer. This was reconfirmed by injection molding through a manual PIM-Shooter model 150 A, though all examples utilize samples used for release studies which were cut from the original pressed coupons.
Various experiments were performed herein using a series of experimental compositions, in which the compositions are referred to as Blends 1-20. The compositions are given in Table 1 as percent composition (by weight) of each ingredient. These compositions are used in both the Release study and the Zone of Inhibition study. Silicone compositions are not included in the table and can be found in example 1.
From In Vitro release testing both in phosphate buffered saline and in distilled water, a summary of results can be seen tabulated below. Results shown include linearized release rate in micrograms per square root day and the total release from sample at day 30 in micrograms for each drug and each medium. (The linearized release rate is the slope of a graph of cumulative release as a function of the square root of time, which is the format of certain plots herein.)
Tables 2A-2D contain descriptive statistics used for comparing blends to each other. Linearized release rate is descriptive of the overall rate of release. It is measured by the slope of the cumulative release graph after linearization and can give a good indication of how quickly the drug content is depleted over the time of implantation. The other descriptive statistic is the total release of drug at day 30. This gives an indication of the effectiveness out to 30 days and gives some idea of the order of magnitude of drug expected when the polymer is in use. These statistics are provided for each drug in the composition and for each different set of environmental conditions.
S. Aureus S. Epidermidis, A. Baumannii,
and E. Coli
As described elsewhere herein, ethylene vinyl acetate copolymer is commercially available under the name Elvax, and two specific commercially available compositions are Elvax150 (32% vinyl acetate comonomer, balance ethylene) and Elvax40W (40% vinyl acetate comonomer, balance ethylene). In this Example, the release properties of two compositions of Elvax were investigated and compared by preparing each composition of Elvax also including two release-modifying materials as described elsewhere herein and also including a chosen concentration of one drug. The composition tested here was: drug content 1% Rifampicin; first release modifying material PEG at a concentration of 7.5%; second release modifying material PCL at a concentration of 7.5%; balance Elvax, which was either Elvax 40W or Elvax 150. These additives and concentrations are reported also in various other examples herein and are constituents and concentrations used for this experiment were typical of the constituents and concentrations that are of interest for present purposes.
In some experiments, silicone was also used as a host polymer incorporating minocycline and rifampicin. Two different silicone hosts were tested and are referred to as PRO-3389 and MED-6215. Both are two part silicones. PRO-3389 is a 1:1 mixture ratio and MED-6215 is a 10:1 mixture ratio. PRO-3389 is a 1:1 mixture ratio silicone, and MED-6215 is a 10:1 mixture. The mixture ratio refers to part A (as designated by the manufacturer) to part B (which is described by the manufacturer as siloxanes and silicones, dimethyl, methyl hydrogen, and octamethylcyclotetrasiloxane). Samples were prepared by mixing the first part of the silicone elastomer with the drug compound in a petri dish and then stirring in the second part, before leaving to cure. Samples with 1% drug were cured at 80° C. on a hot plate for 15-25 minutes. 5% drug composition was cured at 68° C. for 20 minutes. Silicone samples exhibited notable release and are usable as a host polymer, especially in the 5% polymer. Release graphs for the blends in the table below are carried out in distilled water.
It can be seen from the
It is known in the art that, in combination with a polymeric host material that is Elvax, polyethylene glycol (PEG) functions as a release-modifying material. The PEG increases the drug release rate, compared to what the release rate would be for Elvax alone. In the current work, we wanted even a larger release than was available from Elvax+PEG. So, we tried the combination with an additional additive, Elvax+PEG+polycaprolactone (PCL). Adding PCL, i.e., using a composition comprising Elvax+PEG+PCL, seems to increase release rate compared to Elvax+PEG alone. In the comparison reported in this Example, the total concentration of release-modifying polymer is the same for both tested compositions. In one composition there was a 15% concentration of PEG. In the other composition, there was a 7.5% concentration of PEG and a 7.5% concentration of PCL. This is reported in
In the work reported here, when our compositions contain both PEG and PCL ingredients, we use equal proportions of each. We consider it to be a surprising and fruitful result that having PCL+PEG causes a substantial increase in drug release, compared to the release rate from the presence of PEG alone in a concentration that is equal to the total of PEG+PCL in comparable case.
It appears that the total concentration of release-modifying polymer is not determinative of release performance, but rather the combination of two release-modifying polymers produces larger release than all-PEG in a concentration equal to the total concentration of the two release-modifying polymers.
It can be speculated that the PCL biodegrades or biosors and forms release channels resulting from its biodegradation. However, the time frame of these experiments is 20 to 40 days, and the general knowledge about PCL is that although PCL is biodegradable, the rate at which it degrades is too slow for it to change or biodegrade very much during a 20 or 40 day period of experimentation or use. This suggests that the PCL is not functioning by hydrolysis forming channels, but rather is functioning by some other unidentified mechanism.
Inclusion of PCL seems to increase drug release, but it is not wished to be limited to attributing the increase to any particular physical mechanism.
As a separate but related investigation specifically about PCL, an experiment was conducted using pure PCL as a polymer host (with no Elvax present) but with one drug present. It was found that using pure PCL as a polymer host does not result in good release characteristics. Incremental release of drug (rifampicin) from pure PCL as a polymer host is shown in
The data reported in
First, release experiments were conducted using Blend 1 through Blend 5 in distilled water. These experiments were conducted to identify general trends and select compositional ranges of certain ingredients, as a starting point for still later experiments.
Each of the two drugs used in present experiments (Rifampin and Minocycline) addresses a different category or class of bacteria according to Gram classification, either Gram positive or Gram negative. When the two drugs are delivered together, the combination provides a broad spectrum of treatment against a variety of bacteria which is significant to the purpose of the devices described herein.
Minocycline is water-soluble, while rifampin has quite low solubility in water. The difference between the two drugs in water solubility is slightly more than one order of magnitude. This by itself might suggest some difference in release between the two drugs. However, in our experiments so far, the particle sizes of the two drugs were inconsistent with each other, so that making a direct comparison is perhaps not available yet. In fact, the direction in which the particle sizes of the two drugs differ from each other makes it even more surprising that the release rates of the two drugs were observed to be as similar as they were.
In our experiments so far, the minocycline (which is a high-water-solubility drug) was present in the form of micronized powder particles having particle sizes around 10 microns, which means that the minocycline has a relatively large specific surface area. Both of these factors seem like they should promote a relatively large release rate for minocycline. On the other hand, the rifampin (which is a low-water-solubility drug) was present in the form of larger plate-like particles having particle size around 100 microns and therefore having a relatively smaller specific surface area. Both of these factors seem to suggest an expectation of a relatively small release rate for rifampin.
Nevertheless, the releases of minocycline and rifampin (present together in the same samples) were measured to be fairly similar to each other. It is not understand why, and it appears to be unexpected, possibly indicating a synergy between the release of the two drugs. Of course, this explanation or theory is not binding herein.
The data presented in this Example were mixed in the Brabender mixer/extruder. These results are not normalized by coupon mass or surface area. These results are for samples that contain:
One finding from our various experiments reported herein is that the release rates of minocycline and rifampin have the same general shape or release profile as each other, with respect to time. The cumulative release of minocycline is about double the cumulative release of rifampin. It is possible that there is some synergy between the two drugs (Rifampin and Minocycline) in regard to the release characteristics. It is not known what the mechanism is or whether the synergy can be generalized to other drug combinations.
In present circumstances, compared to rifampicin, the minocycline is intrinsically more water-soluble by slightly more than an order of magnitude and it also is present in smaller particles, so intuitively it might be expected that the release of minocycline would be much faster than the release of rifampicin. However, experimentally it is found that the minocycline release is only slightly faster than the rifampicin release and in fact is almost comparable. So, when there is comparable release between a drug with a very small particle size and a higher solubility in water, it is a significant and unexpected result since we would expect a greatly higher release of the minocycline from our polymer matrix.
Following are incremental daily releases for Rifampicin and minocycline from a sample that contains both minocycline and rifampicin.
First, presented is incremental daily release, which is essentially a release rate with a resolution of one day, plotted as a function of time.
Referring now to
Referring now to
Referring now to
Based on the data reported in Table 6, we concluded that, in regard to the release-modifying additives, a preferred combination and concentration is 10% concentration of PEG and 10% concentration of PCL (as represented by Blend 1, Blend 2, Blend 5) is preferable, rather than a 7.5% concentration of PEG and a 7.5% concentration of PCL (as represented by Blend 3, Blend 4).
From this, we concluded that, in regard to concentration of API (with the concentrations of minocycline and of rifampin being equal to each other), a drug concentration of 5% for each drug is preferable to a 2.5% concentration of each drug, because it gives a larger release which is desirable. Actually, based on these results, Blend 6-Blend 15 were formulated to contain still larger concentrations of drug, in some cases.
From this, we also made a comparison about minocycline free base vs minocycline hydrochloride. Blend 5 and Blend 2 were the same (each having a 5% concentration of minocycline), except that in Blend 2 the minocycline is the hydrochloride form, while in Blend 5 the minocycline is the free base form. In these cumulative release results, it can be seen that in the early part of the release experiment (up to day 36 approximately), the freebase form (Blend 5) gives larger release of minocycline, while in later days the cumulative release of Blend 5 drops below that of Blend 2. We are not sure if this is due to degradation (we should not have already dumped all of our drug to the point of reaching depletion). So, it is possible that if a priority is large release early in the transient, then freebase would be good; nevertheless, for present purposes we are more concerned about longer-term release, so in later experiments we designate Blend 9 (which contains minocycline hydrochloride) as a preferred composition which is used extensively in later experiments. The minocycline hydrochloride also has an advantage in terms of stability.
We performed another series of experiments also using Blend 1 through Blend 5. In this new set of experiments, in contrast to the just-presented results, the bath into which the drug is released is Phosphate Buffered Saline, having a pH of 6.7, at 37° C., stirred, and the data extends to a longer period of time. Stirring and buffering at the higher temperature better mimics conditions in the human body, which makes the release study a better analogue to its possible applications. Referring now to
Release data includes data from five blends having varying concentrations of API and varying concentrations of PEG/PCL. This demonstrates effects of polymer additives (composition having 10% concentration each of PEG and PCL has more release than composition having 7.5% concentration each of PEG and PCL). This also demonstrates the effects of increasing Minocycline content from 2.5% to 5% (Release from a composition containing 5% minocycline is greater than release from a composition containing 2.5% minocycline). The data is reported in Table 7.
From the cumulative release graphs, it can be seen that the change of environmental conditions increased the overall release from polymer samples roughly fivefold. This indicates that conditions of the human body will increase release from the polymer over time. This study also reconfirms the trends from the first release study, namely: the benefit of increasing API concentration, the benefit of 10% polymer additive over 7.5% polymer additive, and the indication of degradation of free base minocycline (while still indicating passable release).
A further series of experiments was performed using Blend 6 through Blend 15. The choice of compositions for Blend 6 through Blend 15 used some of the optimization conclusions just described that were learned from experiments using Blend 1 through Blend 5. Table 8 includes the compositions of Blend 6 through Blend 15.
It can be seen that Blend 9 was again the blend with the most consistent release as desired for present purposes, having a relatively high release and a substantially straight profile in this form of plot. Also, it has a larger release (which is desirable for present purposes) than most of the other compositions.
Blends (Blends 10 and 14), which contain a 20% concentration of drug, are observed to have a cumulative release profile that does not so much exhibit a linear relationship in the above form of plot. Instead, the cumulative release profile is fairly high in the early portion of this graph and then somewhat flattens out in the later part of the graph. It is believed that those two compositions somewhat run out of drug in the later part of the experiment, which results in the flattening of the curve that is visible after around day 26.
These graphs also clearly illustrate the benefit of having an additional release-modifying additive in the form of PCL. The release from Blend 8 is well above the release from Blend 11. An important difference in composition is that Blend 8 contains PCL while Blend 11 does not contain PCL. This demonstrates that there is a benefit of including PCL in the blend of polymers.
In
As was the case in the experiments presented herein for which both drugs were present in the composition, the concentration of minocycline and the concentration of rifampin were equal in the formulation. For the composition of Blend 9, the graph shows both minocycline release and rifampin release (cumulative release) graphed on the same plot. Minocycline release is plotted in blue, and rifampicin release is plotted in orange. This illustrates that the two drugs show similar trends trend although there is some difference in the magnitudes of the releases. For example, at most time points, the cumulative release of minocycline is approximately double the cumulative release of rifampin. See
We might expect rifampin to release at a slower rate than minocycline because rifampin is significantly more hydrophobic than minocycline, as well as having an aqueous solubility that is smaller by more than an order of magnitude. This experimental result shows that while rifampin release is somewhat slower than minocycline release, it is not as much slower as might have been expected, and there is still a useful amount of release of both drugs.
An experiment was conducted to investigate release properties of Elvax alone and of Elvax with either or both of two additives, PEG and PCL. For this experiment, the concentration of each drug in the formulation was 5%. The concentration of Elvax was adjusted to accommodate the concentrations of the various other substances. Release of each drug is measured individually. The graph below shows the measurements for minocycline, and the graph after that shows similar measurements for rifampicin.
The results of this experiment seem to indicate that the release from Elvax alone is small, and the release with a 10% concentration of PCL added to the Elvax is almost unchanged from the Elvax-only release. If 10% PEG is added to the Elvax, the release slightly more than doubles compared to the Elvax-only release. If the additives to Elvax include both PEG at 10% concentration and PCL at 10% concentration, the release is still further increased. For the PEG+PCL combination, the cumulative release approximately doubles again and is about four times the Elvax-only release. This suggests that including both PEG and PCL as additives is further helpful in achieving release and achieves the best result. The data is summarized in Table 9. See
An experiment was conducted measuring the release of rifampicin in two different circumstances that otherwise were identical. In one instance, rifampin and minocycline were present in equal concentrations. In the other instance, rifampin was present alone without any minocycline. Both formulations included a 10% concentration of PEG and a 10% concentration of PCL, with the Elvax concentration being adjusted in accordance with the presence or absence of minocycline. It can be seen that in the presence of minocycline, the cumulative release of rifampin is greater, an increase by a factor of about 2.5. This suggests some sort of synergy involved in the release of rifampin, when minocycline is present compared to when minocycline is absent. Release of Rifampicin in the presence or absence of minocycline in the composition. The data is summarized in Table 10. See
A similar experiment was conducted measuring the release of minocycline in two different circumstances that otherwise were identical. In one instance, minocycline and rifampin were present in equal concentrations. In the other instance, minocycline was present alone without any rifampin. Both formulations included a 10% concentration of PEG and a 10% concentration of PCL, with the Elvax concentration being adjusted in accordance with the presence or absence of rifampin. It can be seen that in the presence of rifampin, the cumulative release of minocycline is greater, an increase by a factor of about 8. This suggests some sort of synergy involved in the release of minocycline when rifampin is present, compared to when minocycline is absent. The data is summarized in Table 11.
It also is possible to investigate how the release of drug depends on the absolute magnitude of the concentration of drug in the composition. In this experiment, at the time of manufacture, the concentration of minocycline in the composition and the concentration of rifampin in the composition were always equal to each other. The compositions tested here had an individual drug concentration of either 5% or 10% or 20%. (With the individual drug concentrations being 5% or 10% or 20%, the total drug concentration was 10% or 20% or 40%.) In these various formulations, the concentration of PEG was held constant at 10% and the concentration of PCL was held constant at 10%. The concentration of Elvax 40 was what was varied to compensate for the varying amounts of drug.
This phenomenon can also be seen in
Rifampicin is obtained commercially in the form of flat crystalline particles of typical dimension 70-100 microns. For some formulations, the rifampin is mixed into the blend in that as-purchased crystalline form. For other formulations, the rifampin is ground into a smaller particle size before being mixed into the blend. Grinding was performed using a planetary mill, Pulverisette 7, made by Fritsch International (Pittsboro, N.C.). This is done to see if there is an effect of particle size on drug release characteristics. The ground particles were smaller than the unground particles, and there seemed to be little effect. The comparison is shown in
In
In
From this data. It appears that there is not much effect on the release profile according to whether the rifampin particles are ground or not. The data is reported in Table 14.
Cumulative release graphs, as have been shown in some previous Examples, are well suited for showing trends when composition was varied, and this was useful in various Examples. On the other hand, if we are concerned with demonstrating effectiveness against bacteria, we want to show that every single day sufficient drug is released to achieve effectiveness against bacteria. This favors display of data essentially as release rate, which is plotted herein as incremental (daily) release rate, with the measurement interval usually being one day.
In connection with displaying drug release data, it is helpful to realize that in a clinical situation, there is some characteristic volume of tissue, near the fixator pin or other medical device, into which the drug is released. This is in recognition of the fact that drug released into tissue or interstitial fluid will have some tendency to disperse or travel within that tissue or interstitial fluid. In regard to the latter, it can be appreciated that there is not likely to be a sharp boundary between where drug is present and where drug is absent. Nevertheless, in order to obtain a rough approximate idea of effectiveness, it is useful is to assign the released drug to an assumed space. Herein, such space is referred to as a Pin Volume Estimate. The purpose of the pin volume estimate is to contextualize the results of In vitro release testing (IVRT). What the estimate does is normalize for the size of the coupon and the volume of the experimental bath, which are both different from the environment in the human tissue, but can be related to the environment in the human tissue. In applications of interest such as the region around a fixator pin or catheter, a typical geometry is likely to be cylindrical or annular.
Pin volume parameters used in further calculations herein are shown in Table 15.
The mass of the pin is calculated using the assumed dimensions of a concentric cylinder as shown in
Even when distribution of the released drug in an assumed pin volume is taken into consideration, there remains yet another factor in assessing how effective that drug release is in particular situations. One such factor is how much drug is required in order to be effective against a particular species of bacteria. This varies for different combinations of drug and species of bacteria. This is usually expressed as Minimum Inhibitory Concentration, which is the minimum concentration of a particular drug that is needed to be effective against a particular species of bacteria.
For present calculations, the values of MIC used for various bacteria are given in Table 16 in units of micrograms per ml. This is averaged between the high and low of the MIC shown on
S. Aureus
S. Epidermidis
A. Baumanii
E. Coli
It can further be appreciated that while achieving a concentration of exactly the MIC in human tissue would have some merit, in a practical sense it would be desirable to exceed the MIC by some factor. For present purposes, it is considered that a desirable factor compared to the MIC is a factor of approximately 10.
In
These are basically graphs of incremental daily release, similar to certain earlier graphs, which make it easier to see if MIC is achieved and by what margin, and at what times during the duration of the experiment. For presentation and analysis, the data in the graphs are normalized in certain ways. For the vertical axis on the left side of the graph, the incremental daily release of the drug is considered to be distributed within the pin volume, which results in a concentration of the drug per unit of tissue volume. Corresponding to this is a right-hand vertical axis which is that drug concentration divided by the MIC for a particular bacteria species. This ratio, which is ideally greater than 1 and perhaps greater than 1 by a large factor, indicates the degree of certainty of killing that particular species of bacteria. Each have a right-hand scale that is unique to a particular bacteria species. These graphs show that Blend 9 is expected to be well above the minimum inhibitory concentration for the entirety of the release study.
It can be noted that Blend 9 contains both minocycline and rifampin. If the composition contains only one antibiotic alone, we noticed there were some colonies within the zone of inhibition that became resistant. Accordingly, it is believed that the combination of both drugs prevents development of resistance.
From the graphs it should be noted that the magnitude of the right hand axis is significant for the device's capability of killing each targeted bacteria. For each graph, none fall below the MIC for the entirety of the release and are many times the minimum inhibitory concentration. This set of graphs shows the expected coverage of a fixator pin with a sleeve made blend 9 using its release data.
Experimental results are presented here for zone of inhibition. In a petri dish, a culture of a specified bacterium, which is sometimes referred to as a “lawn” is grown on agar.
Then, a specimen or coupon containing drug-releasing material is placed on the lawn. In the petri dishes presented here, either two or three specimens are placed in a petri dish. The coupon is disc-shaped having a diameter of 0.25 inch (6.35 mm). The release of drug from the coupon is influenced by the release characteristics of the drug+carrier coupon itself, and also by the amount of drug present in the coupon, which in turn may be influenced by how much drug (if any) has already been released from the coupon. In various experiments, some coupons (referred to as time zero) are from as-manufactured material that has never spent any time immersed in a bath. Other coupons are from the same initial material composition after it has been immersed in phosphate buffered saline for a specified period of time such as 18 days. After the coupon is placed on the lawn, the coupon and the lawn are incubated at 37 C and allowed to interact for a period of 24 hours. As a result of that period of interaction, the release of drug from the coupon kills bacteria within an approximately circular region of the lawn, centered around the coupon. This region, which is visibly different from the rest of the lawn in terms of color and other appearance, is called the Zone of Inhibition. It can be measured photographically. The photographs are taken after 24 hours of incubation.
In the photographs, the coupon appears black or some similarly dark color. The coupon, as mentioned, is disc-shaped having a diameter of 0.25 inch (6.35 mm). The petri dish itself, for reference, has a diameter of 100 mm and it has a depth of 15 mm. Incubation is performed for a period of 24 hours at a temperature of 37 C. The Zone of Inhibition is indicated by color change or similar visual indication. The indicated numerical result is the diameter of the Zone of Inhibition. The coupon on the left is an as-manufactured coupon that has been exposed to the drug release bath. The coupon on the right is a coupon that has spent a total of 18 days in the drug release bath prior to being placed in the petri dish. In the petri dishes containing three specimens, the coupon at the top is an as-manufactured coupon that has not been exposed to the drug release bath. The coupon at the lower right is a coupon that has spent a total of 14 days in the drug release bath prior to being placed in the petri dish. The coupon at the lower left is a coupon that has spent a total of 48 days in the drug release bath prior to being placed in the petri dish.
In the photographs presented herein, the “lawn” of culture medium and bacteria is a generally light background color. Each very dark circle is a coupon of the drug-releasing polymeric composition. Surrounding the coupon is an intermediate-colored generally circular region, which is the region in which bacteria are killed, called the Zone of Inhibition. In general, a larger zone of inhibition is more desirable than a smaller zone of inhibition. Culturing to produce the zone of inhibition was done inside an incubator maintaining the temperature at 37 C, and was done for a period of one day after the coupon had been exposed to a bath for the specified number of days.
The photographs are also labeled as to what bacterium is grown on the lawn, and what is the composition of the coupon material.
In some experiments, the bacteria used are E. coli ATCC 25922, and P. aeruginosa ATCC 27853. These are gram negative bacteria and so are especially relevant for applications such as use in catheters and renal applications. The compositions used in these experiments were Blends 9 and 10. The time points are: Day 0; and Day 18.
In other experiments, the bacteria used are: S. aureus ATCC 6538; S. epidermidis ATCC 35984; A. baumannii ATCC 19606.
Petri dishes that contain three specimens show experimental results that are for gram positive bacteria. For a fixator pin, gram positive bacteria are more important. Petri dishes that contain two specimens show experimental results that are for gram negative bacteria.
For petri dishes containing two samples, the photographs show left side is day 0 (coupon as manufactured never having been exposed to the bath); right side is after 18 days releasing. Dimensional measurements of the diameter of the zone of inhibition are taken for two coupons for each condition, and results reported in this table are for two individual specimens and also the average of the two specimens.
This set of experiments shows Blend 9 and Blend 10, interacting with either E. coli or P. aeruginosa, in each possible combination. The data is reported in Table 17.
E. coli ATCC 25922
P.aeruginosa ATCC 27853
Another set of Zone of Inhibition experiments was performed using different bacteria. In this set of experiments, the bacteria used were S. aureus ATCC 6538; S. epidermidis ATCC 35984; and A. baumannii ATCC 19606. These bacteria are especially relevant for applications such as the external fixator. The results are displayed with three samples per petri dish, representing three different time points. In these experiments, the time points for which Zone of Inhibition data are shown are: 0 days in bath; 14 days in bath; and 48 days in bath. In the photos, the plates are organized in a grid by blend number and bacteria. The top coupon is day 0, the bottom right coupon is day 14, and the bottom left coupon is day 48. The compositions used in these experiments were Blends 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15.
This set of experiments shows, with the three different bacteria, the effect of polymer additives. Blend 13 contains only Elvax 40W, with neither PEG nor PCL. Blend 11 contains Elvax 40W with PEG but no PCL. Blend 12 contains Elvax 40W with PCL but no PEG. Bend 8 contains Elvax 40W with both PEG and PCL. The data is reported in Table 18.
This set of experiments, for Elvax 40W with the same concentrations of PEG (10%) and PCL (10%), shows the effect of increasing concentration of both minocycline and rifampin (with equal concentrations of each drug). The data is reported in Table 19.
In regard to concentration of drug in the compositions, an intuitive expectation might be that larger drug loading should give larger release. This appears true from a comparison of the data of 5% concentration of each drug (Blend 8) and 10% concentration of each drug (Blend 9). However, from these results (looking at Blend 10, which contains a 20% concentration of each drug), it also seems that too large a drug concentration can be undesirable, in that a drug concentration can be undesirably large such that by the 48-day point, the Zone of Inhibition is vanishingly small, even though the samples started out containing the largest concentration of the drugs. In this situation it perhaps appears that the drug has already depleted from the coupons. This is consistent with the observations in the release studies using these same compositions.
The data is reported in Table 20.
In these experiments, the compositions containing unground rifampicin were Blend 8 (at 5% concentration of unground rifampicin) and Blend 10 (at 20% concentration of unground rifampicin). The compositions containing ground rifampicin were Bend 15 (at 5% concentration of ground rifampicin) and Blend 14 (at 20% concentration of ground rifampicin). In all compositions, minocycline was present at a concentration equal to the rifampicin concentration. These experiments seem to show that at 5% rifampin concentration, the unground and the ground rifampin produce very similar results. At 20% rifampin concentration, the results are similar to the results for the lower concentrations of rifampin, except that at the longest-duration data point there is some difference in the appearance of the zone of inhibition.
The data is reported in Table 21.
In this set of experiments, the drugs present in the composition were either rifampin only (at a 5% concentration) (Blend 6); minocycline only (at a 5% concentration) (Blend 7); or both rifampin and minocycline (each at a 5% concentration) (Blend 8).
Table 22 is a summary of the measured diameters of the zones of inhibition for various coupon compositions, time points and bacteria.
S. aureus
S. epidermidis
A. baumannii
The minocycline particles are generally smaller particles than the rifampicin particles. It appears that the minocycline particles are, at most, about half the size of the rifampicin particles.
As a qualitative observation, it is possible to make photographic comparisons that lead to the conclusion that there is some dissolution of drug particles into the polymeric carrier. In this observation, the drug that is photographed is rifampicin. The particles of rifampicin are irregular and plate-like or crystal-like in shape, and, specifically, have sharp corners.
It is believed that, if mass is leaving the drug particles and is going into solution in the polymeric carrier, that is favorable for mass transport. This is due to an increase in the surface area available for transport as well as the drug being more readily available to desorp from the polymer than from a crystalline form. If this is happening, it would result in initially sharp-cornered particles becoming more rounded at their corners. It is believed that this is observed, as shown in the following photographs.
We know that at the processing temperature (140° C.), both minocycline and rifampin are stable and the processing temperature is well below the melting point of both drugs, so the corner-rounding is not likely to be due to degradation. The corner-rounding is believed to happen during the mixing while the rifampin is exposed to 140° C.
Photographic results about the stability of the two forms of minocycline are shown in
Thermogravimetric analysis was performed on the APIs used in compositions. Each drug was ramp heated to 140° C. and held at that temperature for 10 minutes. For all compositions, time spent melt-mixing is 8-10 minutes. The decomposition of the API in that time was less than 0.5% for each drug, meaning that the API are stable during processing. For Rifampin, the change in mass was 0.292%; for Minocycline HCl the change in mass was 0.421%; and for minocycline Free Base the change in mass was 0.137%.
Curves for each drug are presented in
In embodiments of the invention, in addition to the already-described host material comprising ethylene vinyl acetate copolymer, other host materials are also possible. Another example of such a possible host polymeric material is polyurethane (PU) and composites that include polyurethane. The polyurethane family includes (but is not limited to) Aliphatic and Aromatic chemistries, as well as carbonate based chemistries and Polyether based chemistries. These various chemistries can provide various different biocompatible options with beneficial physical properties relating to degradation and rigidity.
Still other examples of possible polymeric host material may include silicones, poly(acrylates), and other copolymers. This group of polymer host materials may be combined with the other components described herein, such as release modifying polymer additives and various drug combinations. Any embodiment could include host polymers and additives that are either resorbable or non-resorbable.
A still further list of possible polymers for use in the composition or in the device according to the present disclosure, and which may be the major component, includes:
In embodiments of the invention, in addition to the already-described drugs, other possible drugs that could be used include:
In embodiments of the invention, here are some possible types of implants and applications of the inventive Controlled Release Polymer:
Compositions of embodiments of the invention could be used with or to make any kind of catheter, such as: central venous catheter; triple lumen catheter; a catheter for neurosurgery; external ventricular drains; ventricular peritoneal shunt.
Compositions of embodiments of the invention could be used with transcutaneous driveline devices for myocardial assist devices, either as a sleeve where the driveline penetrates the skin or as a material of which the driveline itself is made of or comprises.
Also, compositions of embodiments of the invention could be used with devices that are fully implanted rather than transcutaneous. For example, breast implants may comprise an enclosure made of silicone, which encloses a liquid. The enclosure may be made of a drug-loaded silicone composition of embodiments of the invention. The embodiment may be used not just to deliver drug but to prevent capsular contraction, i.e., the formation of scar tissue, because bacteria on the surface of the implant may cause chronic capsular contraction. Also, it is possible that anaplastic large cell lymphoma may be caused by bacteria on the surface of the implant, so the inventive composition may serve a role as an antineoplastic, in addition to combatting infection.
Other examples of fully implanted devices that could use compositions of embodiments of the invention, as a coating or as any portion of the device, include: cardiac pacemakers; intraventricular pumps; implantable pumps for delivering anesthetic, insulin, chemotherapy drugs or other drugs; and glucose monitors that are implanted under the skin.
Orthopedic implants may contain pods of the composition of embodiments of the invention, such as small pieces that may be press-fitted into a cavity in the implant, even if much of the overall surface of the implant is left bare for purposes of interacting with bone. The pods may be placed at implant locations that are not highly stressed, so that their placement would not significantly weaken the component in which they are placed. Some orthopedic joint replacement implants comprise a metal part, and another metal part, and a polymeric part between the two metal parts, with the polymeric part serving as a surface that is involved in articulation. The pods may be located near the polymeric part. In yet another embodiment, the polymeric part may itself be made of a composition of an embodiment of the invention, such as a drug-loaded polyurethane or a drug-loaded ultra high molecular weight polyethylene. A part of some knee implants may be an artificial patella, which is believed to experience mechanical loads that are not severe. The articulating (posterior-facing) surface of an artificial patella could be made of a composition of an embodiment of the invention.
Embodiments of the invention could be used to make an endotracheal tube. (The antibiotics used could be other than minocycline and rifampin.)
Embodiments of the invention could be used to make antimicrobial sutures.
In general, although minocycline and rifampin have been used in the experiments described herein, other antibiotics could also be used.
In embodiments of the invention, the composition of the invention can be dispersed and incorporated in another polymer to function as drug releasing entities. The composition of the invention can be made in the form of small particles to be implanted or placed around an implanted prosthesis/device. The composition of the invention can be made in the form of a sleeve to wrap around an implanted prosthesis or device or can be formed to wrap around or partially surround an organ or nerve or blood vessel or other anatomic element.
In general, any combination of disclosed features, components and methods described herein, that is physically possible, is intended to be within the scope of the claims.
All cited references are incorporated by reference herein.
Although embodiments have been disclosed, it is not desired to be limited thereby. Rather, the scope should be determined only by the appended claims.
This application claims the benefit of provisional patent Application Ser. No. 63/278,595 filed with the United States Patent and Trademark Office on Nov. 12, 2021. The entire disclosure of U.S. Application Ser. No. 63/278,595 is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63278595 | Nov 2021 | US |
