Patent Application
20130071463
The present invention relates to implants for treatment of postoperative pain.
Postoperative pain following surgical procedures, particularly orthopedic procedures, can have a significant effect on patient recovery and quality of life, and can be difficult to treat. Oral and injectable opioids are commonly used to treat severe pain, but systemically administered opioids can be addictive, can cause adverse drug-drug interactions, and may have undesirable side effects such as respiratory depression, nausea and vomiting, somnolence, pruritis, constipation, and cognitive impairment. Additionally, patients develop tolerance to opioids, complicating treatment of pain over long periods. Local administration of pain drugs, either in solution or in delivery vectors such as liposomes, may be preferable to systemically administered drugs insofar as local administration can achieve effective drug concentrations at sites of administration while reducing systemic levels and associated side effects. However, when drugs are administered locally to surgical sites for sustained release, they may interfere with tissues or joints in a way that could cause discomfort or irritation for patients. Additionally, locally administered drugs for sustained release may migrate away from sites of post-operative pain over time. Accordingly, there is a need for drug delivery systems and methods for treating post-operative pain that are retained at surgical sites, that provide sustained release, and that minimize interference with tissues and joints and thereby minimize inflammation and patient discomfort.
The present invention addresses the need described above by providing, in one aspect, a medical implant that delivers one or more drugs for treatment of postoperative pain to a surgical site. In certain embodiments, the implant comprises one or more electrospun drug-loaded fibers having a diameter and length tailored to fit a surgical site and deliver a drug for the treatment of pain over a period of days or weeks. In certain embodiments, the implant delivers an opioid, an anesthetic, or a non-opioid analgesic. In contrast to injected drugs, liposomes or other sustained delivery vectors, implants of the present invention can be positioned within a surgical site and secured in place or otherwise resist migration, providing drug directly to a chosen area for an extended period.
In another aspect, the present invention provides methods of treating postoperative pain by placing an implant of the invention including a core-sheath fiber loaded with an analgesic within the tissue of a patient such as a joint, so that the concentration of the analgesic within the tissue increases to at least a first threshold sufficient to relieve or prevent pain over an extended period of time. In some embodiments, the concentration of the analgesic within the plasma of the patient is not increased above a second threshold at which side effects are observed. The implant can be held in place by flaps of tissue, sutures, screws, adhesive, or other fasteners. In certain embodiments, the implants are delivered to surgical sites using minimally invasive techniques.
Implants of the invention can release one or more drugs at relatively constant rates over extended periods of time. In some embodiments, a drug or drugs are released at a relatively rapid rate during an initial “burst phase” of release over approximately one day, and at a relatively slower “steady state” rate thereafter. The relative rates of release during burst and steady state phase are tuned, in certain embodiments, by applying a coating to an exterior surface of the implant or by adjusting a porosity of the implant, for example by providing a wound or coiled structure such as a yarn or a rope in which the degree of winding is selected to yield a desired porosity.
Implants of the present invention advantageously deliver analgesic drugs directly to surgical sites, achieving consistent, effective dosing locally while reducing the risk of systemic side effects. Implants of the present invention also advantageously deliver pain relieving drugs around the site of implantation over a period of days, weeks, or longer, thereby eliminating the need for repeated systemic dosing, multiple injections or implantation of transcutaneous catheters. The methods of the present invention facilitate patient ambulation and joint movement, and can contribute to improved patient outcomes, more rapid rehabilitation, shorter hospital stays and fewer readmissions due to pain.
The figures provided herein are not necessarily drawn to scale, with emphasis being placed on illustration of the principles of the invention.
With reference to the embodiments depicted in
Implants of the invention are characterized by flexibility and axial strength, and can be curved or bent, inserted through tissue flaps, grasped with forceps, and tied in one or more knots without being damaged. For example, in one embodiment of the present invention as shown in
In preferred embodiments, implants of the present invention are used to relieve pain following an orthopedic medical procedure. By way of example, an implant is placed at an interior surface of a joint capsule as shown in
In other embodiments, an implant is attached to a tissue such as a bone following an orthopedic procedure. The implant is secured using known fasteners including, but not limited to screws, staples, sutures or surgical adhesives. In certain embodiments, an implant is placed circumferentially around the bone and fastened at each end, for example with a suture. In other embodiments, an implant is placed within a cannulated screw after the screw has been set. In one embodiment, a mesh having dimensions of approximately 0.1 cm×2 cm×4 cm is placed along the top of the knee at the bottom of the femur following exposure of the knee joint.
In certain embodiments, implants of the present invention can be used to treat pain associated with tissue grafts. For example, in an anterior cruciate ligament (ACL) reconstruction, an implant is fastened to the graft using sutures or held in place using the securement mechanism used to hold the graft in place, for example an interference screw.
Implants of the present invention can also be placed outside of the joint capsule. In certain embodiments, as illustrated in
The cutaneous incision 180 and the incision into the joint capsule 170 closed with sutures 175 as depicted in
Implants of the present invention are well suited to control pain resulting from procedures involving osteotomies, or which result in bone damage. Certain preferred indications for the use of implants of the present invention afford access to the inside of a joint capsule and are associated with significant postoperative pain. Examples of such procedures are total knee replacements, total hip replacements, total shoulder replacements, partial replacement of the knee, hip or shoulder, arthroscopic or open ACL repairs, bunionectomies, hallux valgus surgery, hammertoe surgery, ankle fusion or replacement, spinal fusion, and iliac crest bone harvest.
Implants of the present invention can be sized to fit a particular implantation site. As shown in
The fiber or fibers 110 of implant 100 are loaded with a drug suitable for the treatment of pain. In preferred embodiments, the fiber or fibers 110 are loaded with an opioid such as morphine sulfate, morphine base, codeine, hydrocodone, hydromorphone, methadone, meperidine, butorphanol, buprenorphine, nalbuphine, alfentanil, sufentanil, fentanyl, tramadol, pentazocine, propoxyphene, oxycodone, thebaine, diacetylmorphine, oxymorphone, nicomorphine, remifentanyl, carfentanyl, ohmefentanyl, ketobemidone, dextropropoxyphene, etorphine, nalbufine, levorphanol, or tramdol. In preferred embodiments, the fiber or fibers release the opioid into the surrounding tissue and fluid for a period of 1 to 45 days. More preferably, drug release continues for between 3 and 14 days. In preferred embodiments, the fiber or fibers 110 comprise bioresorbable polymers that are resorbed on timescales longer than 1 to 45 days, permitting the rate of drug elution from fiber or fibers 110 to be controlled separately from the rate of fiber degradation. Longer resorption timescales also improve tolerability and biocompatibility by reducing inflammation associated with resorption. Alternatively, shorter resorption timescales can be used to partially control the rate of drug release—i.e. the rate of release will be a function of the rate of resorption.
The fiber or fibers preferably release drugs such as morphine at a rate of 0.005 to 10 mg/day, more preferably at a rate of 1 to 5 mg/day. In alternate embodiments, the fiber or fibers release buprenorphine. Buprenorphine is used as an analgesic for the treatment of moderate to severe post-operative pain, and may be superior to morphine for certain applications due to its higher potency, which may achieve effective pain control at lower drug volumes, permitting implant size to be decreased and thereby decreasing the amount of polymer that must be used and resorbed. Additionally, buprenorphine is a mixed agonist and antagonist of different opioid receptors, and may have a superior profile for side effects such as respiratory depression. Buprenorphine is preferably released from implants of the invention at a rate of 10-1200 micrograms/day, more preferably at a rate of 400-1000 micrograms/day. In other alternate embodiments, the fiber or fibers release hydromorphone or another morphine derivative. In still other embodiments, the fiber or fibers contain a potent lipophilic opioid, preferably fentanyl or sufentanil. If the implant contains sufentanil, the drug is preferably released at a rate of 5 to 10 micrograms/day.
In other embodiments, the fiber or fibers contain a local anesthetic, including as non-limiting examples, bupivacaine, lidocaine, chloroprocaine, cinchocaine, etidocaine, levobupivacaine, mepivacaine, ropivacaine or tetracaine. In still other embodiments, the fiber or fibers contain another class of drug that is useful in the treatment of pain, including, without limitation, a GABA receptor antagonist, barbiturate, alpha-2 adrenergic receptor agonist, COX-2 inhibitor, serotonin-noradrenaline reuptake inhibitor, amphetamine, vanilloid receptor antagonist, non-steroidal anti-inflammatory, acetylcholine receptor agonist, somatostatin analog, calcium channel blocker, sodium channel blocker, potassium channel blocker or chloride channel blocker. Specific drugs that can be used in certain embodiments of the present invention include, without limitation, baclofen, butalbitol, clonidine, rofecoxib, celecoxib, dexmedetomidine, gabapentin, ibuprofen, ketamine (S-, R-, or racemic mixture of enantiomers), ketorolac, midazolam, neostigmine, octreotide, somatostatin, saxitoxin, or ziconotide.
While the foregoing disclosure focuses on the use of core-sheath fibers, homogenous electrospun drug-loaded fibers as described in Palasis and Sharma can also be used in implants of the invention. Homogeneous electrospun fibers typically release drugs very rapidly (up to 90% release, by mass, within 24 hours) when exposed to a water-containing environment, a phenomenon termed “burst release” to distinguish it from the sustained “steady-state” kinetics also observed in implants of the invention. Burst release is also observed in core-sheath fibers, and in higher order structures such as yarns, ropes, tubes and meshes, whether those structures include homogeneous fibers or core-sheath fibers. The amount of burst release and/or steady-state release can be varied in implants of the invention according to the methods that follow.
Without wishing to be bound to any theory, it is thought that the amount of burst release (amount of drug released in 1 day) in higher order structures (such as ropes, yarns, and meshes) varies with the degree of accessibility of individual fiber surfaces to water, i.e. with the porosity of the structure: the higher the porosity of the structure, the more rapid the release of drug therefrom. The porosity (Φ) of a patch, yarn, rope or other structure is the fraction of the bulk volume (V) of the structure that is not occupied by fibers, (Vf), and can be estimated according to formula (I) below:
As the degree of coiling of a structure increases (i.e. as the structure is coiled more tightly) the bulk volume of the structure decreases to approach the volume of the fibers comprising it (i.e. the porosity of the structure decreases), decreasing the accessibility of water to fiber surfaces internal to the structure.
The inventors believe that, when homogeneous drug-loaded fibers are formed into yarns or ropes, the release of drug therefrom can be controlled by varying the porosity of such structures, which in turn may be controlled by varying parameters including, but not limited to, (1) the extent of twisting of individual fibers as they are formed into yarns (“yarn coiling”); (2) the extent of twisting of yarns as they are formed into ropes (“rope coiling”); (3) the number and thickness of the yarns used to form ropes; and (4) the homogeneity or heterogeneity of diameters among fibers used to form yarns, or among the yarns used in ropes. The degree of yarn coiling can be controlled by varying, among other things, the rate of twisting of individual fibers as they are collected and the duration of the collection period, both as described in Palasis. The release of drug can be further tuned by forming implants that include features affecting porosity with other features, such as coatings or enclosures, or by varying the hydrophobicity of the materials used to form fibers and implants of the invention.
Burst release of drugs such as morphine sulfate pentahydrate can be assayed by immersing drug-loaded fiber devices in PBS. At specified timepoints, the PBS bath is changed and morphine sulfate levels measured, for example by reversed-phase high-performance liquid chromatographic method (RP-HPLC) or by ultraviolet-visible (UV-Vis) spectroscopy.
Similar experiments exploring the relationship between implant porosity and drug elution were performed with structures made of fibers consisting of 70:30 85/15 L-PLGA:dexamethasone. In one experiment, drug elution was measured over 35 days for the ropes listed in Table 1, below:
As is shown in the figure, the release of dexamethasone from samples having undergone 3 rope revolutions was quite variable, though all 3-revolution ropes had released nearly all of their dexamethasone content by day 15. By contrast, the variability of release from 40-revolution ropes was relatively small over the first 20 days of measurement, and became more variable thereafter. Error bars represent standard deviation.
Apart from porosity, the number of yarns comprising a rope also has a strong effect on the rate of drug elution therefrom, as shown in
In general, as is evident in
The effects of yarn number and porosity on drug release are also illustrated in
The inventors have also discovered that the rate of burst release in higher-order structures can be tailored by varying the composition of the fibers within such structures.
In general, as
Burst release kinetics of yarns and ropes may be further modified by varying the degree of tension or compression applied to fibers or yarns during the twisting process: though not wishing to be bound to any theory, it is thought that as the tension applied to individual fibers or yarns increases during twisting, the fibers will tend to lie more closely together, reducing the porosity of the finished structure. Similarly, burst release kinetics may be modified by varying the direction of twisting of yarns and ropes: rope twisting may be in the direction opposite of yarn twisting (e.g. a rope with a left hand twist comprising yarns with a right hand twist), as is typical, or in the same direction (e.g. a rope with a right-hand twist comprising yarns with right-hand twist). Again, without wishing to be bound to any theory, it is believed that when yarn twisting and rope twisting directions are the same, fibers within the structure will line up more closely, leaving less room for water to access fiber surfaces and slowing burst release, while more space will exist between fibers in ropes in which the directions of yarn- and rope-twisting are opposite, resulting in better access and greater burst release.
Though the embodiments discussed above focus on ropes, the principles disclosed herein are broadly applicable to structures incorporating drug-loaded fibers. Drug release from patches, tubes and other structures comprising multiple drug-loaded fibers, as described in Palasis, may be tailored to specific applications by modulating the porosity of these structures, for example by forming them under compression or vacuum, to minimize spaces between fibers. Such structures may also be folded, crushed, crumpled, etc. to reduce porosity. Meshes and portions of meshes may also be stretched and twisted to tailor porosity and drug release. As discussed above, though not wishing to be bound to any theory, stretching results in closer alignment of fibers, permitting closer packing and decreasing porosity. In some embodiments, mesh strips may be twisted to form yarn-like structures and, optionally, woven or bound together to form superstructures having different porosity relative to the meshes used as starting materials. In some embodiments, a yarn or rope may be enclosed by a mesh.
In preferred embodiments, implants are coated with polymeric coatings such as hydrogels—as discussed in Palasis—or nonpolymeric coatings such as wax, which coatings may dissolve or erode away. Such coatings may advantageously alter the burst release characteristics of an implant, as well as improving the resistance of yarns and ropes to unraveling. The coatings may be applied as heat-shrink tubing, sprayed on, dipped, or applied in any other suitable way known in the art. This is illustrated in
In some embodiments, coatings are applied to implants, i.e. completed ropes, meshes or yarns, or to components, such as fibers or yarns that will subsequently be assembled into higher-order structures. Multiple coatings may be applied, for example first to implant components such as fibers or yarns, and again to the assembled implant. Alternatively, multiple coatings may be applied only to the exterior of the implant, or to different portions of the implant.
The coatings are preferably biocompatible, and may be bioabsorbable and/or mechanically or chemically erodible. Coatings may optionally contain drugs, such as antibiotics, antimycotics, anticoagulants, etc., and may be porous, or solid, and may be permeable, semipermeable or impermeable.
Implants of the invention may include multiple regions of different porosities or even porosity gradients. In some embodiments, yarns and ropes may be formed having regions of varying porosity by varying the extent of twisting among these regions. In some embodiments, these regions may be separated by pinch points, at which they are compressed and secured during the twisting process. These pinch points may optionally be delineated by any suitable means known in the art, including the inclusion of radiopaque, fluorescent, or pigmented marker bands as is described in Palasis.
Ropes and yarns having varying porosity may be fabricated by varying the degree of twisting among regions during rope or yarn formation, for example by pinching off regions of the rope at different stages of the twisting process. As shown in FIG. 14A,varying the degree of twisting along the length of a rope results in varying thicknesses as well and, when burst release among less tightly wound regions (“clipped end”) and more tightly wound regions is compared, the less tightly wound regions demonstrate a higher degree of burst release as shown in
In some embodiments, the ends of yarns, ropes and patches may be fixed by heat-setting, partial melting, chemical finishing, or any other suitable means known in the art, to prevent unraveling of the structures during their residence in a body. In addition, the surface of the fiber may be modified to reduce porosity. For example, this can be accomplished by brief exposure to heat. Thus, increasing the temperature on the surface sufficiently high to melt fibers together, but not allowing sufficient heat transfer to melt fibers on the interior. Alternately, brief exposure to a solvent for the polymer fiber (e.g. solvent vapor) can be used to similar effect.
Implants having porosity gradients as described above may be implanted individually to provide varying release rates from different portions of the implant. For example, one portion of the implant can be relatively more porous (or can lack a coating, etc.), and can release drug in a burst, while another portion of the implant that is relatively less porous (or which incorporates a coating, etc.) provides more steady-state drug release. Alternatively, such implants may be cut or otherwise separated into separate pieces, thereby forming smaller implants having relatively uniform drug release properties. One or more of these smaller implants may then be implanted into a patient in order to tailor administration of the drug. For example, an implant having a porosity gradient can be cut into a fairly porous implant and a relatively less porous implant, both of which can be implanted into a patient. In this system, the more porous implant provides relatively rapid, burst-like drug release, while the less porous implant provides sustained release. The manner in which the larger implant with the porosity gradient is cut into smaller pieces can be selected by a physician or an end user based upon the burst and/or steady-state release kinetics desired, as well as the amount of drug desired to be released into the patient. The amount of drug to be released into the patient can be determined, in turn, by the weight of the patient or other dosing guideline.
The principles of the invention are further illustrated by the following non-limiting examples:
Morphine eluting implants were fabricated through a coaxial electrospinning process as described in Palasis utilizing a core and sheath needle (20 and 10 gauge respectively). The core solution contained a 12% weight 75:25 PLGA polymer with respect to an acetonitrile solvent. Morphine sulfate was added to the core solution at 40% weight with respect to the polymer and mixed with a high-shear centrifugal mixer for 1 minute at 2000 rpm. For AC33, the core and sheath needles extruded solution at 2 and 3 mL/hr respectively. For AC34, the core and sheath needles extruded solution at 0.8 and 3.5 mL/hr respectively. The sheath solution for both devices was an 8% weight 75:25 PLGA polymer with respect to a 1:1 (by vol) tetrahydrofuran/dimethylformamide (THF/DMF) solvent. Extruded solutions were electrospun onto two ground collectors spaced approximately 10 centimeters apart for one minute to create one yarn. This process was repeated 15 times to create additional yarns. The yarns were dried for two days at 60° C. and then twisted around one another 8 times to create a rope with a calculated porosity of approximately 27%. The devices were dried for an additional hour at 60° C. to allow the polymer to set. Each rope was trimmed to approximately 4 cm in length and 1.2 mm and contained less than 250 ppm of residual DMF solvent. AC33 and AC34 contained approximately 11.4 mg (23 wt %) and 3.8 mg (13 wt %) of morphine, respectively.
Implants were fabricated through an electrospinning process in which drug loaded polymer fibers are collected and twisted around one another between a small gap in a 20% relative humidity atmosphere. The core solution contained a 12% weight 75:25 PLGA polymer with respect to an acetonitrile solvent. Morphine sulfate was added to the core solution at 40% weight with respect to the polymer and mixed with a high-shear centrifugal mixer for 1 minute at 2000 rpm. The sheath solution consisted of a 14.7 wt % blend of 50:50 DL-PLGA and 75:25 PLGA polymer (1:1 by mass) dissolved in a 1:1 (by vol) THF:DMF solvent system. Sheath and core solution were delivered from their respective nozzles at flow rates of 3 and 2 ml/h, respectively. Upon electric field activation, the solutions were electrospun onto two grounded collectors spaced approximately 10 centimeters apart for one minute to create one yarn. This process was repeated 15 times to create additional yarns. The fifteen yarns were dried for three days at 60° C. and then twisted around one another 8 times to create a rope with a porosity of approximately 24%. The devices were dried for an additional hour at 60° C. to allow the polymer to set. The final individual rope was approximately 4 cm in length and 1.2 mm in diameter and contained 17% weight morphine (approximately 7.5 mg) and less than 250 ppm of residual DMF solvent.
Morphine sulfate levels were measured during in vitro elution in PBS by using a reversed-phase high-performance liquid chromatographic method (RP-HPLC), and the cumulative release curves for AC33, AC34, and AC554 are shown in
The release of morphine sulfate from AC33 ropes is specific to the way in which it was fabricated. A comparison of the release of AC33 ropes vs AC33 yarns or meshes (
To characterize drug concentrations achieved in vivo by devices of the invention, intra-articular implantation of ropes of the invention was performed in sheep knees. The sheep model was selected specifically for these studies because the knee anatomy of the sheep is most similar in size and tissue physiology to humans than other species. (Martini L, Fini M, Giavaresi G, Giardino R. Sheep model in orthopedic research: a literature review, Comp Med. 2001 August; 51(4):292-9)
Devices were implanted for 3 and 7 days, then retrieved (“explanted”). Each animal received two implants: an AC33 device in one knee, and an AC34 device in another knee. [CORRECT?] All implantation and explantation procedures were performed by direct visualization of the intra-articular space. Implants were implanted beneath the synovial membrane on the lateral side of the femur. A stainless steel pushrod was inserted into the membrane to create space for the delivery system and device. The implant was then advanced into the joint, under direct visualization. To deploy the device, the pushrod (placed against the implant inside the catheter) was held in place while the catheter was withdrawn, as shown in
During the period of implantation, synovial fluid samples from each knee and plasma samples were collected at regular intervals and analyzed by a tandem mass spectrometry scope with a liquid chromatography method (Agilux, Worcester, Mass.). The samples collected were shipped with dry ice and stored at −80° C. prior to analysis. A solid phase extraction with an Oasis MCX plate (Waters, Milford, Mass., USA) was used to clean up the synovial and plasma samples. The analysis was carried out with an ACE C18-AR (2.1×50 mm id, 3 μm particle size). The mobile phase for morphine analysis consisted of acetonitrile and 2 mM ammonium acetate, acetonitrile and 0.1% pentafluoropropionic acid in 0.1% formic acid in water for vitamin B6 analysis. The analytes were detected on a triple quadrupole mass spectrometer (API 4000, Sciex, ON, Canada) equipped with an electrospray ionization source operating in the positive ion mode. Quantification was performed using the selective reaction monitoring (SRM) mode to study precursor→product ion transitions for morphine (m/z 286.19→152.2).
Morphine concentrations were determined for 29 of 30 successful taps. All synovial fluid taps for AC33 devices registered quantifiable levels of morphine across the seven day study, including devices that were determined to be outside the synovial membrane. One synovial fluid tap from the six AC34 devices registered a value below quantifiable limits. All remaining synovial fluid taps for AC34 devices registered quantifiable levels of morphine across the seven day study, including devices that were determined to be outside the synovial membrane. Morphine tap concentrations are shown in Table 5.
Residual morphine levels in devices explanted on days 3 and 7 are shown in Table 6. AC33 morphine sulfate values dropped from 12% to 8% between days 3 and 7 when compared to their predicted loading. AC34 morphine sulfate values dropped from 15% to 10% between days 3 and 7 when compared to their predicted loading. Four devices that were not located within the intra-articular space were not included in the averages.
Morphine concentrations in plasma were also measured at 1 and 4 hours in addition to days 1, 3, and 7. The morphine sulfate concentration for days 1, 3, and 7 were below quantifiable levels. The 1 and 4 hour concentration levels are shown in Table 7. Each animal had one AC33 and AC34 AxioCore device implant, 2 devices total.
To characterize drug release from devices of the invention, AC54 devices were implanted and explanted subcutaneously in a rabbit model. The rabbit SQ model was selected as a standard method for testing of in vivo drug elution. Each animal received two implants, one in each of the left and right flanks. The animals were sacrificed per schedule at day one, three, and seven post implantation (N=3 per timepoint). There were no device related deaths or adverse events. Animal health remained normal throughout the duration of the study as measured twice daily by MPI staff veterinarians. Animals were observed for clinical signs of test article effect and body weights were measured Morphine levels in plasma were low after the first day of implant. Device implant location and surgical procedure revealed no gross adverse inflammation or effects during the study as visually documented in the images.
Upon explant, the drug remaining in each device was measured and compared with the predicted implant loading. The six subcutaneous devices for each timepoint had an average of 57±6%, 49±4%, and 41±5% morphine sulfate remaining in the devices with respect to days 1, 3, and 7 when compared to its predicted loading. Morphine extraction values are outlined in Table 8 and
Comparisons of morphine release in in vitro and in vivo are set out in Tables 9 and 10. Results suggest the drug elution from the device in vivo is more rapid than expected from in vitro results during the first day of release. The cumulative release curves from days 2 through 7 for both profiles are comparable.
Sustained release of morphine sulfate was also achieved via encapsulation techniques in a mesh form factor.
In order to demonstrate control of release, different sheath and core flow rates were used: ACMMS30 had sheath and core flow rates of 10 and 2 ml/h, respectively; ACMMS36 had sheath and core flow rates of 20 and 2 ml/h, respectively; and ACMMS38 had sheath and core flow rates of 10 and 1 ml/h, respectively. Fibers were collected onto a grounded rotating mandrel located ˜20-30 cm away, resulting in a final device configuration shape of a non-woven tubular mesh. The different flow rates used resulted in different levels of burst release as shown in
Though not wishing to be bound to any theory, it is believed that meshes utilizing these formulations demonstrate improved drug encapsulation characteristics (e.g. relative to the AC33 meshes described above) because the relatively large diameter of the fibers (>2 microns) can accommodate morphine sulphate particles having a cross-sectional dimension of approximately 2 microns formed by high-shear mixing processes.
Release reates of morphine sulfate were influenced by the selection of sheath polymer. For example, instead of using 85/15 L-PLGA (as was used in ACMMS38), either 85/15 DL-PLGA or 50/50 DL-PLGA was used as the sheath polymer. All other fabrication conditions were kept the same. As can be seen in
The inventors have also observed that the daily release of morphine sulfate can be impacted by the elution medium in which the sample is submerged in. We compared the elution of ACMMS38 in PBS vs. fetal bovine serum (diluted to a protein concentration of 11 g/L). The results indicated that a protein environment led to significantly faster release than in PBS (
Formulation ACMMB1 is an electrospun mesh that contains morphine base instead of morphine sulfate. Fabrication of ACMMB1 occurs in a similar fashion as ACMMS38 except that the sheath solution is comprised of a 4.5% 85/15 PLGA in HFIP and the core solution is comprised of a 12 wt % PCL in HFIP containing 20% morphine base relative to the PCL.
It has been observed during electrospinning that the flowability of the core solution decreases substantially when the morphine sulfate content is increased. For example, at 20% morphine sulfate, the core solution has flowability, can be pushed through a syringe, and subsequently be electrospun. However, at 40% morphine sulfate content, the solution no longer possesses any flowability (the solution exhibits a cream-like texture) that leads to difficulty in the formation of consistent core-sheath Taylor cones. The inability to load high amounts of drug into the core solution severely limits the total loading that can be achieved in resulting meshes. We have discovered that the flowability of morphine sulfate suspensions can be modulated by solvent choice. Specifically, by substituting the methanol component of the core solution in ACMMS38 for acetonitrile, we were able to incorporate more morphine sulfate while still maintaining good flowability (Table 11). For example, 40% morphine sulfate added to 15 wt % PCL in 6:1 (by vol) CHCl3:MeOH results in a cream-like suspension that has poor flowability; conversely, 40% morphine sulfate added to 15 wt % PCL in 6:1 (by vol) CHCl3:Acetonitrile still possessed good flowability.
While not wishing to be bound to any theory, it is believed that acetonitrile has good wetting properties for morphine sulfate and therefore results in better dispersed morphine sulfate particles in solvent, leading to better flowability and/or hydrogen bonding with methanol leads to an increase in viscosity relative to acetonitrile. The ability to add 40% morphine sulfate into the core solution has a significant effect on the total drug loading. For example, the difference in the ability to incorporate 20% versus 40% drug into the core solution (and assuming everything else is equal) leads to an approximately two fold increase in total drug loading.
As used herein, the terms “drug” and “therapeutic agent” are used interchangeably to include small molecules, biologics, and other active ingredients used to produce a desired or expected biological effect. The term “threshold concentration” and the like is used herein to describe a concentration in tissue, serum, plasma, etc. at which such a certain biological effect is observed, such as a therapeutic effect or a side effect. Thus, a “therapeutic threshold concentration” or similar term may be used to refer to an ED50, a dosing recommendation, or other effective concentration in the tissue of the patient. Similarly, The term “fiber” is used primarily to refer to electrospun, drug-loaded fibers as described in Palasis, and may include homogeneous fibers and core-sheath fibers as described in Palasis, as well as other drug-loaded fibers currently known or conceivable which may be assembled into higher-order structures such as yarns, ropes, tubes and patches. The invention is compatible with any such drug-loaded fibers.
The phrase “and/or,” as used herein should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
The term “consists essentially of” means excluding other materials that contribute to function, unless otherwise defined herein. Nonetheless, such other materials may be present, collectively or individually, in trace amounts.
As used in this specification, the term “substantially” or “approximately” means plus or minus 10% (e.g., by weight or by volume), and in some embodiments, plus or minus 5%. Reference throughout this specification to “one example,” “an example,” “one embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the example is included in at least one example of the present technology. Thus, the occurrences of the phrases “in one example,” “in an example,” “one embodiment,” or “an embodiment” in various places throughout this specification are not necessarily all referring to the same example. Furthermore, the particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more examples of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology.
While various aspects and embodiments of the present invention have been described above, it should be understood that they have been presented by way of illustration rather than limitation. The breadth and scope of the present invention is intended to cover all modifications and variations that come within the scope of the following claims and their equivalents.
This application claims the benefit under 35 U.S.C. §119(e) of (i) U.S. Application Ser. No. 61/535,246 by Freyman, et al. entitled “Implants for Post-Operative Pain,” filed Sep. 15, 2011 and (ii) U.S. Application Ser. No. 61/598,484 by Sharma, et al. entitled “Acute Release of Drugs from Electrospun Implants,” filed Feb. 14, 2012 (hereinafter, “Sharma”). This application is a continuation in part of U.S. application Ser. No. 12/620,334, Publication No. 2010/0291182, by Palasis, et al. entitled “Drug-Loaded Fibers” (hereinafter, “Palasis”). The entire disclosure of each of the foregoing applications is hereby incorporated by reference for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 61535246 | Sep 2011 | US | |
| 61598484 | Feb 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12620334 | Nov 2009 | US |
| Child | 13616386 | US |
