Encapsulation of active pharmaceutical ingredients

Abstract

This disclosure provides pharmaceutical compositions having improved mechanical strength and active pharmaceutical ingredient (API) dissolution properties useful for medical devices such as implants. Simultaneously, methods for creating these compositions are also provided, which may include forming submicron particles of the API and mixing them with a porous encapsulation material. In one embodiment, these methods may include generating a solution of the API and precipitating the particles by adding a non-solvent to the solution. The precipitated API can be mixed with an encapsulation medium to form a blend, which can then be dried, dehydrated, and molded to form desired materials, medical devices, and implants.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Application No. 63 / 506,024, filed on 2 June 2023, which is incorporated herein by reference in its entirety.

[0002] (Description of research funded by the federal government) Not applicable.

[0003] This disclosure relates to encapsulating compounds in an encapsulation medium, for example, encapsulating active pharmaceutical ingredients (APIs) such as antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and other drugs in polyethylene (PE) for the treatment / prevention of infections and / or pain management, or encapsulating inert components such as salts, rubber, or ceramics in polyethylene to alter the physical and / or chemical properties of polyethylene for the manufacture of medical devices. [Background technology]

[0004] Total joint replacement surgery (over 2 million surgeries performed annually) is essential for people suffering from end-stage joint disease to alleviate pain and improve their quality of life. One of the main modes of complications associated with total joint replacement is prosthetic joint infection (PJI), which can occur through surgical site infection, hematogenous spread, or adjacent infection. While the risk of prosthetic joint infection is relatively low, typically ranging from 0.6% to 2.4%, the consequences can be severe and lead to significant morbidity and mortality. Infections in total joint replacement can lead to prolonged hospital stays, the need for additional surgeries (such as implant removal or modification), increased pain, functional impairment, and a reduced quality of life for the patient. PJI is usually treated with intravenous or oral antibiotic therapy, surgical debridement, and lavage, in addition to preservation or revision (one-stage or two-stage) of joint components. The gold standard of treatment, two-stage revision surgery, involves replacing the infected component with an antibiotic spacer and administering long-term systemic antibiotics before the second stage surgery to implant a new component. Antibiotic spacers are typically made of bone cement mixed with high doses of antibiotics, such as vancomycin and gentamicin / tobramycin. The primary role of the spacer is to maintain joint space and prevent joint contracture. Additionally, local antibiotic leaching from the spacer supports the effectiveness of systemic antibiotics by minimizing the risk of bacterial proliferation and re-establishment in the spacer implant and local tissue.

[0005] While antibiotic spacers have some usefulness in managing PJI, they are limited in their potential impact on overall success. This includes risks such as spacer failure, dislocation, synovitis due to spacer implant wear, and limitations in long-term antibiotic release. Ultrahigh molecular weight polyethylene (UHMWPE) has been proposed as an alternative material to antibiotic spacers due to its therapeutic potential and load-bearing capacity. Antibiotic-releasing polyethylene offers several advantages that could overcome the limitations associated with conventional bone cement spacers, including better mechanical properties, reduced risk of particle generation (reduced wear), and improved long-term antibiotic release.

[0006] Conventional mixing methods involve mixing solid particles of API with solid particles of ultra-high molecular weight polyethylene (UHMWPE) and then compression molding the resulting material. The mechanical properties of such blends depend on the particle size distribution and the uniformity of the blend. However, conventional mixing methods have problems such as the clustering of API particles and the difficulty in achieving a uniform particle distribution, both of which negatively affect the mechanical properties. The phase separation regions of API may have reduced strength and toughness compared to untreated (unused) UHMWPE, limiting its long-term use. Furthermore, controlling the particle size distribution is not practical with conventional mixing methods.

[0007] Therefore, there is still a need for alternative API compositions that are suitable for long-term use as implant components, possessing improved mechanical strength and toughness while also exhibiting API release properties. [Overview of the project]

[0008] This disclosure provides pharmaceutical compositions and methods that overcome the aforementioned drawbacks by providing a mixing process that offers enhanced mechanical properties. Incorporating submicron API particles into UHMWPE provides enhanced mechanical properties and drug release profiles compared to conventional mixing techniques.

[0009] In one aspect of this disclosure, a pharmaceutical composition is described. The pharmaceutical composition comprises a porous encapsulation medium and particles of an active pharmaceutical ingredient encapsulated within the pores of the porous encapsulation medium. In some embodiments, the particles of the active pharmaceutical ingredient have an average size of less than 1 μm. The encapsulation medium may include a polymer material such as ultra-high molecular weight polyethylene (UHMWPE). The active pharmaceutical ingredient may include an antibiotic such as gentamicin sulfate. The pharmaceutical composition may have a solid shape, such as a molded solid. The pharmaceutical composition may have improved mechanical properties and / or an API elution profile. As a non-limiting example, the pharmaceutical composition may have an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break (EAB) of at least 300%, and / or a yield strength of at least 15 MPa. As a non-limiting example, the pharmaceutical composition comprises at least 6% by weight of the active pharmaceutical ingredient, and the active pharmaceutical ingredient, when measured in water at 37°C, is 100 cm³ over 28 days. 2 It is possible to have a release rate of at least 0.1 mg / day and / or a cumulative release of at least 3% over 5 days.

[0010] In other embodiments of this disclosure, a method for preparing a pharmaceutical composition is described. The method may include generating a dispersion of an active pharmaceutical ingredient in a liquid phase containing a solvent. The method may further include producing the pharmaceutical composition by contacting a porous encapsulation medium with the dispersion of the active pharmaceutical ingredient, wherein particles of the active pharmaceutical ingredient are encapsulated within the pores of the porous encapsulation medium. For example, the active pharmaceutical ingredient may include an antibiotic such as gentamicin sulfate. In some embodiments, the method may include generating a dispersion of gentamicin sulfate in a liquid phase containing about 30 (v / v)% water and about 70 (v / v)% ethanol. The method may further include producing a dry pharmaceutical composition by drying and / or dehydrating the pharmaceutical composition. The method may further include molding the dry pharmaceutical composition by a thermoforming process.

[0011] In another embodiment, the present disclosure provides pharmaceutical compositions prepared by the preparation method described above.

[0012] In other embodiments, the Disclosure provides medical devices comprising a pharmaceutical composition described herein, or a pharmaceutical composition prepared by a preparation method described herein. Such medical devices may be, for example, implants such as joint replacement implants.

[0013] In another aspect of the present disclosure, a joint replacement implant is described. The joint replacement implant comprises a thermoformed polymer material comprising ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate, wherein particles of gentamicin sulfate are encapsulated within the pores of the porous encapsulation medium.

[0014] In another aspect of the present disclosure, a method for preparing an implant is described. The method includes generating a dispersion of gentamicin sulfate in a liquid phase containing a solvent and a non-solvent, producing an implant composition by contacting a porous encapsulation medium containing ultra-high molecular weight polyethylene (UHMWPE) with the dispersion of gentamicin sulfate, thereby encapsulating gentamicin sulfate particles in the pores of the porous encapsulation medium, and producing the implant by thermoforming the implant composition.

[0015] Herein, some embodiments of the present disclosure will be described with reference to the accompanying drawings. This description, together with the drawings, will make it clear to those skilled in the art how some embodiments of the present disclosure may be carried out. These drawings are for illustrative purposes only and are not intended to show structural details of the embodiments beyond what is necessary for a basic understanding of the teachings of the present disclosure. None of the drawings in this specification are shown to actual size. Where dimensions are given in the text or drawings, these dimensions are illustrative only and do not limit the scope or spirit of the disclosed invention. [Brief explanation of the drawing]

[0016] [Figure 1A] This is a flowchart of a method for preparing a pharmaceutical composition according to each aspect of the present disclosure. [Figure 1B] This is a flowchart of a method for preparing implants according to each aspect of this disclosure. [Figure 2] This diagram shows the elemental analysis of polyethylene blocks prepared in a cold molding cycle using API particle UHMWPE blend. The upper left is the electronic image. The upper right is the superimposed Kα1 images of C, O, and S. The lower left is the Kα1 image of S. The lower center is the Kα1 image of O. The lower right is the Kα1 image of C. [Figure 3]Figure of elemental analysis of a polyethylene block prepared by a thermoforming cycle using an API particle UHMWPE blend. The upper left is an electron image. The upper right is an EDS stratification diagram. The lower left is an image of the Kα1 of S. The central part of the lower side is an image of the Kα1 of O. The lower right is an image of the Kα1 of C. [Figure 4A-4B] Figure 4A is an optical microscope image of a polyethylene block prepared by a thermoforming cycle using an API particle UHMWPE blend. Figure 4B is an optical microscope image of a polyethylene block prepared by a cold forming cycle using a conventional blend. [Figure 5A] Plot of the gentamicin release rate from UHMWPE prepared using GSWE-140 powder and tablets. [Figure 5B] Plot of the cumulative gentamicin release rate from UHMWPE prepared using GSWE-140 powder and tablets. [Figure 6A] Plot of the gentamicin release rate from UHMWPE prepared using WGSE-140 powder and tablets. [Figure 6B] Plot of the cumulative gentamicin release rate from UHMWPE prepared using WGSE-140 powder and tablets. [Figure 7A] Plot regarding the results of the tensile test of GSWE-140 powder. [Figure 7B] Plot regarding the results of the tensile test of GSWE-140 tablets. [Figure 8A] Plot regarding the ultimate tensile strength of WGSE-140 with different gentamicin loadings. [Figure 8B] Plot regarding the elongation at break of WGSE-140 with different gentamicin loadings. [Figure 9] Plot regarding the IZOD test results of WGSE-140 with different gentamicin loadings. [Figure 10A-10D]Figure 10A is a micrograph of the resolidified UHMWPE blend. The scale bar is 100 μm. Figure 10B is a micrograph of the received UHMWPE blend. The scale bar is 100 μm. Figure 10C is a micrograph of the submicron GS UHMWPE blend. The scale bar is 100 μm. Figure 10D is a micrograph showing submicron GS particles appearing as clusters in either of the fusion lines within the UHMWPE matrix (scale bar is 50 μm). [Figure 10E-10H] Figure 10E is an SEM micrograph of a submicron GS particle cluster in one of the fusion lines (scale bar is 100 μm). Figure 10F is an SEM EDX nitrogen element map of a submicron GS particle cluster in one of the fusion lines (N is green) (scale bar is 100 μm). Figure 10G is an SEM EDX sulfur element map of a submicron GS particle cluster in one of the fusion lines (S is orange) (scale bar is 100 μm). Figure 10H is an SEM EDX composite element map of Figures 9E-9G. [Figure 10I-10L] Figure 10I is a FIB-SEM micrograph. The FIB-SEM shows the size of subsurface pores from 0.060 to 0.350 μm (scale bar is 5 μm). Figure 10J is a FIB-SEM EDX nitrogen element map (N is green). Figure 10K is a FIB-SEM EDX nitrogen sulfur element map (S is orange). Figure 10L is a FIB-SEM image with a composite map of Figures 9I to 9K. [Figure 10M] This is a schematic diagram of the boundaries between re-solidified UHMWPE flakes (left), UHMWPE flakes upon receipt (center), and submicron GS UHMWPE blend (right). [Figure 11A-11C]Figure 11A plots the ultimate tensile strength (UTS) for 10% GS UHMWPE blends, showing various mechanical properties across re-solidification, acceptance, and submicron GS UHMWPE blends. The submicron GS UHMWPE blend showed the best UTS (A). Figure 11B plots the elongation at break (EAB) for 10% GS UHMWPE blends, showing various mechanical properties across re-solidification, acceptance, and submicron GS UHMWPE blends. Of the three blends examined, only the particles after re-solidification had low EAB measurements. Figure 11C plots the yield strength (YS) for 10% GS UHMWPE blends, showing various mechanical properties across re-solidification, acceptance, and submicron GS UHMWPE blends. The YS of the submicron blend was higher than the YS of the acceptance and re-solidification blend (C). [Figure 11D-11F] Figure 11D plots EAB for various GS UHMWPE blend ratios. Increasing the amount of GS resulted in a reduction in EAB. Figure 11E plots UTS for various GS UHMWPE blend ratios. Increasing the amount of GS resulted in a reduction in UTS. Figure 11F plots IZOD impact strength for various GS UHMWPE blend ratios. Increasing the amount of GS resulted in a reduction in IZOD impact strength. [Figure 12A-12C]Figure 12A is a graph comparing the normalized release rates of GS eluted from various sizes of GS UHMWPE blends as a function of time for resolidified GS UHMWPE, received GS UHMWPE, and submicron GS UHMWPE blends. After a 6-hour burst, the release rates did not change between the resolidified GS UHMWPE blend and the received GS UHMWPE blend, but the release rate of the submicron GS UHMWPE blend was significantly higher than the other two blends. After 6-hour and 1-day bursts, the release rates remained constant for GS loadings of 6% and 8% in the submicron GS UHMWPE blends. Figure 12B is a plot comparing the cumulative release rates as a function of time for resolidified GS UHMWPE, received GS UHMWPE, and submicron GS UHMWPE blends of GS eluted from various sizes of GS UHMWPE blends. Figure 12C is a plot comparing normalized cumulative emissions as a function of time for re-solidified GS UHMWPE, GS UHMWPE at receipt, and submicron GS UHMWPE blends eluted from GS UHMWPE blends of various sizes. [Figures 12D-12F] Figure 12D is a plot comparing the normalized release rates as a function of time for GS eluted from submicron GS UHMWPE blends with various loading concentrations (10%, 8%, and 6%). After 28 days, the release rate of the 10% submicron GS UHMWPE was significantly higher than that of the other two blends. Figure 12E is a plot comparing the cumulative release rates as a function of time for GS eluted from submicron GS UHMWPE blends with various loading concentrations (10%, 8%, and 6%). Figure 12F is a plot comparing the normalized cumulative releases as a function of time for GS eluted from submicron GS UHMWPE blends with various loading concentrations (10%, 8%, and 6%). [Figure 12G-12H]Figure 12G plots predicted in vivo concentrations attributable to gentamicin released from submicron GS UHMWPE blends with varying loading rates (10%, 8%, and 6%). Submicron GS UHMWPE blends with 8% and 10% loading rates can maintain intra-articular concentrations at 100×MIC levels for 28 days. Figure 12H plots predicted in vivo concentrations attributable to gentamicin released from submicron GS UHMWPE blends, re-solidified GS UHMWPE blends, and GS UHMWPE blends at reception. For predicted in vivo concentrations, the 6% submicron GS UHMWPE blend and the 10% re-solidified GS UHMWPE can maintain a 10×MIC for similar durations, while GS UHMWPE at reception can only maintain a level above 1×MIC. [Figures 13A-13B] Figure 13A plots the predicted in vivo GS concentrations obtained from gentamicin released from 6%, 8%, and 10% submicron GS UHMWPE blends (3-hour half-life scenario). Figure 13B plots the predicted in vivo GS concentrations obtained from gentamicin released from 6%, 8%, and 10% submicron GS UHMWPE blends (6-hour half-life scenario). This predictive model showed a discernible difference in intra-articular GS concentrations between the 3-hour half-life (see Figure 12A) and 6-hour half-life scenarios. Notably, in the 3-hour half-life model, the GS concentration at 8% load was below the 100×MIC threshold but significantly above the 10×MIC threshold. In contrast, in the 6-hour half-life model, concentrations exceeding both MIC thresholds persisted for a longer period. [Figure 14A-14B] Figure 14A plots the predicted intra-articular GS concentrations due to gentamicin release from GS UHMWPE blends of different sizes, including resolidified GS, received GS, and submicron GS (3-hour half-life scenario). Figure 14B plots the predicted intra-articular GS concentrations due to gentamicin release from GS UHMWPE blends of different sizes, including resolidified GS, received GS, and submicron GS (6-hour half-life scenario). [Figure 15]These are the 1H NMR spectra of GS (Panel A) and GS eluted from a submicron GS UHMWPE blend (Panel B). These spectra showed a high degree of structural similarity. Both spectra exhibited characteristic peaks at specific chemical shift values, suggesting that the key functional groups of GS were retained even after integration with the UHMWPE matrix. The consistency of the intensity and multiplicity of these peaks further supports the idea that the chemical environment of hydrogen atoms in GS remained largely unchanged after mixing and high-temperature molding (170°C). This is particularly evident in the overlapping regions of the spectra, where the arrangement of peaks suggests a similar distribution of chemical environments. Furthermore, the absence of new or shifted peaks in the spectrum of eluted GS (Panel B) suggests that the blending and molding processes did not cause significant changes to the molecular structure of GS. [Figure 16] The images show the 1H NMR spectrum of GS (upper spectrum) and the GS eluted from the submicron GS UHMWPE blend (lower spectrum). The assigned multiples for GS are 1H NMR (D2O, 500MHz)δ 5.91-5.81 (1H,m), 5.09 (1H,d,J=3.7Hz), 4.21-4.09 (2H,m), 4.07-3.95 (2H,m), 3.80 (3H,qd,J=8.9,5.2Hz), 3.61-3.49 (1H,m), 3.49-3.39 (3H,m), 2.88 (4H,s), 2.71 (1H,s), 2.49 (1H,s), 2.56-2.46 (1H,m), 2.10-1.97 (2H,m), 1.88 (1H,s), 1.59-1.49 (1H,m), and 1.32-1.22 (7H,m). [Figure 17]This is a comparison of the 1H NMR spectral ranges of GS (black line) and GS eluted from a submicron GS UHMWPE blend (red line). The specific chemical shift ranges examined were 4.18–4.04 ppm (upper left panel), 3.61–3.38 ppm (upper right panel), 2.52–1.9 ppm (lower left panel), and 1.32–1.22 ppm (lower right panel). The key observation was the variation in peak height due to the difference in concentration between the control GS and the eluted GS. Despite these differences, the overall peak pattern appeared similar across all ranges. This similarity suggests that the elution process does not significantly alter the fundamental molecular structure of GS. [Modes for carrying out the invention]

[0017] Conventionally, commercially available API particles are dry-blended with an encapsulation medium, dehydrated, and molded. For example, gentamicin sulfate particles are dry-blended with UHMWPE powder flakes, dehydrated, and molded. Using this method, the particle size of the API does not change throughout the mixing and molding process. The molded article typically has cluster regions of API particles within the encapsulation medium. For example, gentamicin sulfate particles form clusters within the UHMWPE matrix. These clusters adversely affect the mechanical properties of the UHMWPE. In medical device applications, the performance of implants depends on many factors, particularly the mechanical properties of the implant, some of which can be manufactured with UHMWPE / API blends. Each aspect of this disclosure makes it possible to control the particle size of APIs within the encapsulation medium by precipitating the APIs from the solution using a precipitating agent, such as a solvent in which the APIs have low solubility, thereby controlling the particle size of the API regions. In this case, the smaller the API particles in the encapsulation medium, such as polyethylene, the better the mechanical properties and the more appropriately the API elution properties can be controlled. This method and composition improve the mechanical properties and abrasion resistance of the solidified blend by significantly reducing the size of API particles in the encapsulation medium. Furthermore, this method and composition enable better control over the burst release and long-term elution rates of API from the encapsulation medium.

[0018] APIs encapsulated in a medium having desired mechanical properties and / or API elution properties can be administered to achieve desired therapeutic outcomes. For example, a medical device manufactured from UHMWPE containing an antibiotic with high strength, high wear resistance, and therapeutic-level antibiotic elution can be used to treat or prevent periarthritis in prosthesis patients, or to provide an implant that reduces the degree of bacterial colonization on the implant surface. Another example is a medical device manufactured from UHMWPE containing an analgesic with desirable mechanical properties and / or wear resistance, which can be used as an implant to aid in pain management.

[0019] According to non-limiting examples described herein, active pharmaceutical ingredient (API) particles formed in situ can be encapsulated in encapsulation media such as UHMWPE, PLGA, and bone cement by (i) adding API to a solvent or solvent mixture to prepare a solution, (ii) precipitating the API particles in the solution by various methods, such as adding a non-solvent, (iii) mixing the API particles with an encapsulation medium to form a blend, (iv) drying the blend, (v) optionally dehydrating the dried blend, and (vi) molding the blend. Several techniques for manufacturing API-added encapsulation medium blocks and encapsulating active and / or inactive components are described in this disclosure. This novel method can be used to create composite materials by encapsulating any compound in an encapsulation medium and to tailor their properties to various applications, such as therapeutic drug delivery, medical implants, fixation methods for fixing implants to bone, or support components.

[0020] This disclosure describes improving the mechanical strength of antibiotics encapsulated in UHMWPE by reducing their particle size. GS is typically a loose powder in its raw state, with particle sizes usually less than 100 μm. Re-solidification from solution is one method for producing larger GS particles commonly used in GS-containing bone cement. Smaller particles can be obtained by solvent / non-solvent precipitation. As described herein, UHMWPE samples are mixed with gentamicin sulfate of different particle sizes, and the effects of particle size and content on mechanical, elution, and morphological properties are evaluated.

[0021] GS UHMWPE spacers with enhanced mechanical properties are crucial for PJI patients. Furthermore, GS UHMWPE implants, combining high strength, excellent wear resistance, and effective antibiotic elution at therapeutic levels, represent a significant advancement, potentially preventing periarthritis not only in high-risk revision cases but also in initial total joint replacement surgeries. These compositions and methods could significantly reduce the high morbidity and mortality rates associated with PJI, potentially resulting in annual savings of over $1 billion for the U.S. healthcare system.

[0022] The present invention includes, consists of, or is essentially composed of, any combination of the following features:

[0023] (composition) In one embodiment, the disclosure provides a pharmaceutical composition comprising a porous encapsulation medium and particles of an active pharmaceutical ingredient encapsulated within the pores of the porous encapsulation medium.

[0024] As used herein, the encapsulation medium may be a polymer, metal, ceramic, wood, fabric, composite material, or a mixture thereof. In some embodiments, the encapsulation medium includes a polymer material. In some embodiments, the encapsulation medium may be high-density polyethylene, low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene (e.g., GUR® 1020, GUR® 1050), or radiation-crosslinked or chemically crosslinked polyethylene. For example, the polymer material may include ultra-high molecular weight polyethylene (UHMWPE). Preferably, the encapsulation medium has a porous surface. For example, the polymer encapsulation medium may be UHMWPE in the form of powder flakes. These flakes may have surface porosity and bulk porosity to facilitate the encapsulation of API particles.

[0025] In some embodiments, the encapsulation medium contains antioxidants, such as vitamin E, Irganox 1010, and other similar compounds listed in U.S. Patent Application No. 12 / 904,481 for "Methods for Making Oxidation Resistant Material," U.S. Patent No. 9,168,683 for "Highly Crystalline Cross-linked Oxidation Resistant Polyethylene," and U.S. Patent No. 8,461,225 for "Oxidation Resistant Homogenized Polymeric Material."

[0026] Here, the terms “pore,” “porous,” or “porosity” as used in relation to the encapsulating medium may include any openings, void spaces, or hollow structures on or within the surface of the material, such as surface pores, holes, and channels. The encapsulating medium may have a porous surface and / or a porous bulk structure. In some embodiments, the encapsulating medium has a porous surface.

[0027] The pores of the porous encapsulation medium can have an average size of at least 0.010 μm, at least 0.1 μm, at least 0.5 μm, at least 1 μm, at least 5 μm, at least 10 μm, at least 50 μm, at least 100 μm, at least 500 μm, or at least 1000 μm.

[0028] The active pharmaceutical ingredients used herein may include antibiotics, nonsteroidal anti-inflammatory drugs, analgesics, local anesthetics, therapeutic biomolecules, or combinations thereof. In some embodiments, the active pharmaceutical ingredients include antibiotics. Examples of APIs include vancomycin, tobramycin, gentamicin, cefadroxil, cefazolin, cephalexin, cefaclor, cefotetan, cefoxitin, cefprodil, cefuroxime, loracalbef, cefdinir, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftozoxime, ceftriaxone, cefepime, amikacin, streptomycin, doxycycline, erythromycin, gentamicin, isoniazid, rifampicin, ethambutol, and others. These include sulfonamides, penicillins, cephalosporins, beta-lactams including carbepenems, aminoglycosides, quinolones, oxazolidinones, metals such as copper, iron, aluminum, zinc, and gold, their compounds and ions, and various combinations thereof. Nonsteroidal anti-inflammatory drugs include, but are not limited to, salicylates, indomethacin, fluviprofen, diclofenac, ketrolac, naproxen, piroxicam, tabferon, ibuprofen, etodolac, nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone, clofezon, oxyfenbutazone, prexazone, apazon, benzydoamine, bucolom, cincopene, clonixin, ditrazole, epirizole, fenoprofen, phloxtaphenyl, flufenamic acid, graphenin, indoprofen, ketoprofen, meclofenamic acid, mefenamic acid, niflumic acid, phenacetin, salidifamide, sulindac, suprofen, tolmetin, and their salts. Salicylates include acetylsalicylic acid, sodium acetylsalicylate, calcium acetylsalicylate, salicylic acid, and sodium salicylate. In some embodiments, the active pharmaceutical ingredient includes an antibiotic comprising gentamicin sulfate. In some embodiments, the antibiotic is gentamicin sulfate.

[0029] Analgesics include opioid agonists and opioid antagonists. Opioid agonists include alfentanil, allylprozine, alphaprozine, anilelizine, benzylmorphine, vegitrimide, buprenorphine, butorphanol, clonitazen, codeine, desomorphine, dextromoramide, dezosine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazosine, etoheptadine, ethylmethylthiambutene, ethylmorphine, etonitazenfentanil, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levofenol, levofenol This includes, but is not limited to, nasylmorphan, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, mirofin, nalbufine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazosin, phenoperidine, piminodin, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, remifentanil, sufentanil, tyridine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0030] Opioid antagonists include, but are not limited to, naloxone (see U.S. Patent No. 3,254,088, which is incorporated herein by whole reference), naltrexone (see U.S. Patent No. 3,332,950, which is incorporated herein by whole reference), and mixtures thereof, or pharmaceutically acceptable salts thereof. In yet another embodiment, the opioid analgesic or analgesic is a mixture of an opioid agonist and an opioid antagonist (for example, suboxone, which is a mixture of buprenorphine and naloxone).

[0031] For a more detailed explanation of analgesics, see Chapter 23, "Opioid Analgesics" by Gutstein et al. (pages 569-619) and Chapter 27, "Analgesic - Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout" by Roberts et al. (pages 687-731), in "in Remington: The Science and Practice of Pharmacy" by ARGennaro (1995, 19th edition, Vol. 2, pages 1196-1221). See "Analgesic, Antipyretic, and Anti-Inflammatory Drugs" by R. Hanson.

[0032] Other APIs include lipopolysaccharides (LPS), polyguanidines (CPG), bacterial lysates, defensins, and salts thereof such as sodium chloride, sulfate, acetate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, tartrate, aluminum, and / or gluconate. Examples include vancomycin hydrochloride, gentamicin sulfate, tobramycin sulfate, and / or polyhexamethylene guanidine phosphate, or mixtures thereof.

[0033] Other APIs are local anesthetics, such as bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and mixtures thereof. These local anesthetics can take the form of salts, such as hydrochloride, bromide, acetate, citrate, carbonate, or sulfate.

[0034] APIs include, but are not limited to, natural and synthetic nucleic acids, including therapeutic biomolecules such as polypeptides, proteins, amino acids, polysaccharides, disaccharides, lipids, and modified ribonucleic acid (RNA), mRNA, microRNA, siRNA, shRNA, and other RNAi types, double-stranded linear deoxyribonucleic acid (DNA), double-stranded circular DNA, single-stranded linear DNA, and mixtures thereof.

[0035] In some embodiments, the API particles include, or are replaced by, compounds (or particles of such compounds) containing chemical substances such as salts, metals, ceramics, composite materials, rubber, and calcium chloride and / or any reinforcing materials such as nano-sized rubber particles.

[0036] In some embodiments, the particles of the active pharmaceutical ingredient have an average particle size of less than 1 μm. The encapsulated particles of the API can have an average particle size of less than 0.9 μm, less than 0.8 μm, less than 0.6 μm, less than 0.4 μm, less than 0.2 μm, less than 0.1 μm, less than 0.05 μm, less than 0.01 μm, less than 0.005 μm, or less than 0.001 μm.

[0037] In non-limiting examples, the pharmaceutical composition may contain about 1% to about 50% by weight of API. The pharmaceutical composition may contain at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 8%, at least 10%, at least 20%, at least 30%, or at least 40% by weight of API. The amount of API in the pharmaceutical composition may be, for example, about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 2% to about 40%, about 2% to about 30%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, or about 5% to about 10% by weight. In some embodiments, the pharmaceutical composition contains, by weight, about 2% to about 20% of APIs, for example, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, or about 18% of APIs by weight.

[0038] As a non-limiting example, the present disclosure provides a pharmaceutical composition comprising a polymer material UHMWPE as the encapsulation medium, a gentamicin sulfate (GS) as the API, and the API particles having an average size of less than 1 μm, and comprising about 1% to about 20% (about 2% to about 20% or about 2% to about 10%) of the API by weight.

[0039] As a non-limiting example, the pharmaceutical composition may be a solid composition. The solid composition may be formed by known techniques such as compression, molding, extrusion, or other suitable methods. For example, the pharmaceutical composition may be a molded solid.

[0040] As will be described in more detail in the following examples, the pharmaceutical composition may have improved mechanical properties compared to conventional compositions. In non-limiting examples, the pharmaceutical composition may have an ultimate tensile strength (UTS) of at least 30 MPa, an elongation break (EAB) of at least 300%, and / or a yield strength of at least 15 MPa.

[0041] The pharmaceutical composition may have an improved release profile of the encapsulated API compared to conventional compositions. The release rate can be adjusted, for example, by controlling the amount of API loaded, the porosity of the encapsulation medium, and the content of other components in the formulation. For example, the release rate can be measured at a predetermined amount of API (wt%) over a period of time under appropriate conditions (e.g., release in water at 37°C). In some embodiments, the pharmaceutical composition contains at least 6 wt% of an active pharmaceutical ingredient, and the active pharmaceutical ingredient releases 100 cm³ in 28 days when measured in water at 37°C. 2 It has a release rate of 0.1 mg / day or more and / or a cumulative release rate of 3% or more over 5 days. Release rate is synonymous with elution rate, and both refer to the rate at which the API is released from the encapsulation medium. In some embodiments, the unit of release rate is defined as the daily mass of API per unit surface area of ​​the encapsulation medium. In some embodiments, the encapsulation medium is a tibial implant used in total knee arthroplasty, and typically the combined surface area of ​​the joint surface area and the side wall surface area of ​​the implant is approximately 100 cm². 2 Therefore, the release rate, for example, when representing the release rate from a tibial implant manufactured using an encapsulation medium containing API, is 100 cm per day. 2 It can be measured as the mass of API released per unit area. Other implant shapes have different API release rates, but these can be calculated by appropriately normalizing the surface area of ​​the implant with the API-containing encapsulating medium. The release rate is, for example, 100 cm³ over 28 days. 2 The amount can be at least 0.2 mg / day, at least 0.5 mg / day, at least 1 mg / day, at least 2 mg / day, at least 5 mg / day, or at least 10 mg / day. The cumulative release can be, for example, at least 5%, at least 10%, at least 15%, or at least 20% over 5 days. In a non-limiting example, the pharmaceutical composition contains at least 6% by weight of gentamicin sulfate and, when measured in water at 37°C, releases 100 cm³ over 28 days.2 It has a release rate of at least 0.1 mg / day and / or a cumulative release of at least 3% over 5 days.

[0042] (Preparation method) In another embodiment, the Disclosure provides a method for preparing a pharmaceutical composition. This method includes generating a dispersion of an active pharmaceutical ingredient in a liquid phase containing a solvent, and bringing the dispersion of the active pharmaceutical ingredient into contact with a porous encapsulation medium to produce the pharmaceutical composition in which particles of the active pharmaceutical ingredient are encapsulated within the pores of the porous encapsulation medium.

[0043] The method described herein can be used to prepare the pharmaceutical compositions described herein. In some embodiments, the particles of the active pharmaceutical component have an average size of less than 1 μm. In some embodiments, the encapsulation medium comprises a polymer material. For example, the polymer material comprises ultra-high molecular weight polyethylene (UHMWPE). In some embodiments, the active pharmaceutical component comprises an antibiotic, a nonsteroidal anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof. In some embodiments, the active pharmaceutical component comprises an antibiotic. For example, the antibiotic may comprise gentamicin sulfate. In some embodiments, the antibiotic is gentamicin sulfate. In some embodiments, the pharmaceutical composition produced by the method comprises about 1% to about 50% by weight of the active pharmaceutical component (such as about 2% to about 20%, or about 2% to about 10%).

[0044] The solvent used herein may include any medium capable of dissolving the active pharmaceutical ingredient. Suitable solvents include polar solvents, nonpolar solvents, aqueous solvents, organic solvents, and mixtures thereof. Examples of solvents include, for example, water, ethanol, isopropanol, acetone, or combinations thereof. In some embodiments, the solvent includes water.

[0045] The active pharmaceutical component can form a solution in the solvent, from which a dispersion of the active pharmaceutical component in the liquid phase can be generated. This dispersion may contain particles of the active pharmaceutical component and can be formed, for example, by adding other drugs to the solution of the active pharmaceutical component.

[0046] This disclosure describes the use of inert components in several embodiments. Inert components are added to a solvent or a mixture of solvents. In some embodiments, inert components produce API particles by improving the dispersibility of the API particles or by altering the solubility of the API. Inert components are substances that do not have a known therapeutic effect but enhance the API by providing more favorable control over the loading of the active ingredient and / or the release kinetics of the ingredient. These include, but are not limited to, viscosity modifiers, salts, pH modifiers, surfactants, solvents, and / or gases, or mixtures thereof. In some embodiments, the liquid phase further includes inert components, precipitants, viscosity modifiers, surfactants, pH modifiers, emulsifiers, or combinations thereof.

[0047] In non-limiting examples, the liquid phase further comprises a precipitating agent. The precipitating agent as used herein may include any chemical agent that facilitates the precipitation or separation of the active pharmaceutical component from a solution of the active pharmaceutical component in a solvent. The precipitating agent may include any solvent, gas, solution, and / or pH adjuster that alters the solubility of a compound in the solvent, resulting in the precipitation of the compound. Compounds such as APIs have different solubility in different solutions. Their solubility in a solvent may be a function of temperature, pH value, and / or other properties of the solvent. Generally, a solvent with high solubility for a compound is also called a good solvent for that compound, and a solvent with low solubility is called a poor solvent (or non-solvent) for that compound. A poor solvent or non-solvent for a compound can also act as a precipitating agent for that compound if the compound is dissolved in the solvent. The addition of a precipitating agent allows the active pharmaceutical component to form particles, thereby enabling the production of a dispersion of the active pharmaceutical component. Suitable precipitating agents may include, for example, non-solvents, salts, or mixtures thereof. The non-solvent may be any substance (e.g., an aqueous liquid or an organic liquid) in which the API does not dissolve or has low solubility compared to the solvent used herein. In some embodiments, the liquid phase of the dispersion further comprises a precipitant containing the non-solvent.

[0048] This method involves encapsulating API particles in an encapsulation medium. The API particles are morphologically spherical or non-spherical particles. The particle size ranges from approximately 0.001 micrometers to 100 micrometers, or from 0.001 micrometers to 10 micrometers. In some embodiments, the API particles have an average particle size of less than 1 μm. The particles are produced in a liquid or by other techniques including, but not limited to, microfluidic manufacturing, freeze-drying, spray-drying, and / or nanoprecipitation. The API particles contain API, water, and / or other solvents. For example, when GS precipitates from an aqueous solution by adding ethanol to the solution, the resulting particles contain GS, water, and / or trace amounts of ethanol.

[0049] The API particles are preferably within a size range that allows them to penetrate the porosity (including pores, holes, and / or channels) of the encapsulation medium. Regardless of the polarity (hydrophilic or hydrophobic) or surface charge of the encapsulation medium, any API particles can penetrate the porosity in a liquid carrier phase (e.g., a water / alcohol mixture). This liquid carrier keeps the API in particulate form while creating a favorable environment between the surface / porosity of the encapsulation medium and the API particles. In one embodiment, the liquid carrier is a mixture used to form the API particles. In one embodiment, after the API particles are positioned in the porosity of the encapsulation medium, the encapsulation medium is subjected to compression (channel-die compression, uniaxial compression, or hydrostatic compression).

[0050] In some embodiments, the API comprises gentamicin sulfate, the solvent is an aqueous solvent (such as water), and the liquid phase comprises a non-solvent that facilitates the formation of a dispersion of the API. The non-solvent is, for example, ethanol. For example, gentamicin sulfate particles are formed by nanoprecipitation by dissolving GS in water and adding ethanol to the GS / aqueous solution to precipitate the GS, thereby forming particles containing GS. For example, the method may involve generating a dispersion of gentamicin sulfate in a liquid phase containing about 30 (v / v)% water and about 70 (v / v)% ethanol. In one embodiment, the API particles are produced by dissolving the API in water and adding alcohol to precipitate the API particles in the solution. For example, adding 140 proof ethanol to an aqueous solution of gentamicin sulfate causes gentamicin sulfate particles to precipitate, and these particles settle by gravity or centrifugation. These particles can also be suspended by vigorous shaking, such as vortexing. These particles mainly consist of GS, some water, and / or some ethanol. Then, the suspended particles of gentamicin sulfate can be mixed with UHMWPE powder. This powder mixture is then dried and dehydrated, and then compressed and molded to encapsulate the gentamicin sulfate in the UHMWPE. By processing the UHMWPE into an implant shape, an implant capable of eluting gentamicin sulfate can be obtained. In another embodiment, vancomycin hydrochloride particles are formed by adding ethanol to an aqueous solution of vancomycin hydrochloride. In yet another embodiment, particles of gentamicin sulfate and vancomycin hydrochloride are formed by adding ethanol to aqueous solutions of both of these APIs.

[0051] API particles formed in an aqueous solution are mixed with a encapsulation medium as a suspension or as individual particles. Individual particles are isolated from the aqueous solution in which they were formed. The particles can be isolated by centrifugation or by gravity sedimentation and removal of the supernatant. In most embodiments, API particles are mixed with the encapsulation medium while suspended in an aqueous solution. In some embodiments, since APIs are hydrophobic, an organic solvent is used to dissolve the APIs, and a non-solvent is added to precipitate the particles.

[0052] In some embodiments, a dispersant is added to a solution containing API particles to form a suspension of API particles in the solution. The dispersant comprises one or more viscosity modifiers, one or more surfactants, one or more buffers, one or more salts, one or more pH modifiers, one or more precipitants, gases, and / or one or more solvents, or mixtures thereof. The dispersant is added to a solution containing one or more API particles. Preferably, the API particles are formed in situ in the solution containing the dispersant, and preferably, they are formed by precipitating the API particles by adding a precipitant to the API solution. The API particles are added to a encapsulation medium.

[0053] In some embodiments, a viscosity modifier is added to the solution containing API particles. The viscosity modifier includes glycosaminoglycans, including but not limited to polyvinylpyrrolidone (PVP) (preferably a mixture containing one or more PVP grades with different molecular weights ranging from about 10,000 to about 360,000 or more), cellulose derivatives (including but not limited to hydroxyethylcellulose, carboxymethylcellulose or its salts, hydroxypropylmethylcellulose, hypromellose, etc.), heparin, chondroitin sulfate, keratan sulfate, heparan sulfate or their salts, carrageenan, guar gum, chitosan, alginates, carbomer, polyethylene glycol, lipids, oils, sugars, polyvinyl alcohol, xanthan gum, and / or derivatives or mixtures thereof.

[0054] In some embodiments, surfactants are added to a solution containing API particles either after or before particle formation. Surfactants include nonionic, anionic, cationic, zwitterionic, and / or amphoteric compounds. Typically, surfactants are used to reduce interfacial tension. For example, surfactants are used to reduce the interfacial tension between API particles and the surrounding solution. Examples of nonionic surfactants include polyvinyl alcohol (PVA), poloxamer 188, polyoxyethylene sorbitan fatty acid ester (polysorbate, Tween®), polyoxyethylene 15-hydroxystearate (macrogol 15-hydroxystearate, Solutol HS15®), polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH40), polyoxyethylene stearate (Myrj®), sorbitan fatty acid ester (Span®), polyoxyethylene alkyl ether (Brij®), and / or polyoxyethylene nonylphenol ether (Nonoxynol® and lecithin), or mixtures thereof. Examples of anionic surfactants include ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium lauryl sulfate, sodium α-olefin sulfonate, and / or ammonium laureth sulfate, or mixtures thereof. Examples of cationic surfactants include benzalkonium chloride, cetylpyridinium chloride, or mixtures thereof. Examples of amphoteric surfactants include betaine or sulfobetaine, natural substances such as amino acids and / or phospholipids, or mixtures thereof. One preferred surfactant used here is polyvinyl alcohol. Another preferred surfactant is vitamin E.

[0055] In some embodiments, the encapsulation medium includes an antioxidant. In one embodiment, vitamin E is mixed with UHMWPE flakes, and then API particles are encapsulated in the flakes and molded. Examples of antioxidants include alpha-tocopherol and delta-tocopherol, propyl gallic acid, octyl gallic acid, or dedosyl gallic acid, lactic acid, citric acid, tartaric acid and their salts, orthophosphates, tocopherol acetate, and Irgonox® 1010 (see, for example, International Publication No. 01 / 80778, U.S. Patent No. 6,448,315). Vitamin E, a common antioxidant, is composed of eight lipid-soluble compounds, including four (alpha, beta, gamma, delta) tocopherols and four (alpha, beta, gamma, delta) tocotrienols. Tocopherol acetate is also known as vitamin E.

[0056] In some embodiments, the encapsulation medium includes a crosslinking agent. Examples of crosslinking agents include inorganic peroxides, organic peroxides, diacyl peroxides, peroxyesters, peroxydicarbonates, dialkyl peroxides, ketone peroxides, peroxyketal cyclic peroxides, peroxymonocarbonates, and hydroperoxide benzoyl peroxides, dicumyl peroxides, methyl ethyl peroxide ketone peroxides, acetone peroxides, 2,5-di(tert-butylperoxy)-2,5-dimethyl-3-hexine (Luperox® 130), 3,3,5,7,7-pentamethyl-1,2,4-trioxepane (Trigonox® 311), or mixtures thereof. Other examples of peroxides include dilauryl peroxide, methyl ether ketone peroxide, t-amyl peroxyacetate, t-butyl hydroperoxide, t-amyl peroxybenzoate, Dt-amyl peroxide, 2,5-dimethyl-2,5-di(t-butyl peroxy)hexane, t-butyl peroxyisopropyl carbonate, succinyl peroxide, cumene hydroperoxide, 2,4-pentanedione peroxide, t-butyl perbenzoate, diethyl ether peroxide, acetone peroxide, arachidonic acid 5-hydroperoxide, carbamide peroxide, tert-butyl hydroperoxide, t-butyl peroctoate, t-butylcumyl peroxide, di-sec-butyl peroxydicarbonate, D-2-ethylhexyl peroxydicarbonate, and 1,1-di(t-butyl peroxy)cyclohexane. Other examples of peroxides include products in the Luperox® family supplied by Arkema.Other examples of peroxides include 1,1-di(tert-butylperoxy)-3,3,5-trimethylcyclohexane, 2,5-dimethyl-2,5-di(tert-butylperoxyhexane), 3,3,5,7,7-pentamethyl-1,2,4-trioxepane, butyl-4,4-di(tert-butylperoxy)valerate, di(2,4-dichlorobenzoyl)peroxide, di(4-methylbenzoyl)peroxide, di(tert-butylperoxyisopropylbenzene), tert-butylcumylperoxide, tert-butylperoxy-3,5,5-trimethylhexanoate, and tert-butylperoxy-2-ethylhexylcarbonate. Other examples of peroxides include products from the Trigonox® or Perkadox® families supplied by Akzo Nobel.

[0057] In some embodiments, a salt is added to the API solution (to form an API dispersion) to produce a pH buffering effect. This pH buffering / change effect can be used to form API particles, change particle size, or change the interaction between the API and the encapsulation medium. The salt may be, but is not limited to, sodium chloride, calcium chloride, citrate, acetate, potassium dihydrogen phosphate, disodium hydrogen phosphate, or mixtures thereof.

[0058] In certain embodiments, a pH adjuster is added to the API solution to initiate or complete the formation of API particles. The pH adjuster raises or lowers the pH of the solution to which it is added. Examples include, but are not limited to, soda ash, sodium hydroxide, sodium silicate, sodium phosphate, lime, sulfuric acid, hydrofluoric acid, tripotassium citrate monohydrate, sodium bicarbonate, tartaric acid, and / or adipic acid, or mixtures thereof.

[0059] In some embodiments, the solvent is used to dissolve additives such as APIs and / or salts, pH adjusters, and other solid substances. In some embodiments, a non-solvent is added to these solutions to precipitate and encapsulate particles such as nanoparticles. The solvent may be either an organic solvent or an aqueous solvent. Examples include aqueous solvents such as sterile water, phosphate buffer, and physiological saline, and organic solvents such as ethyl DMSO, chloroform, and dichloromethane. The solvent also includes alcohols such as ethanol and isopropanol, and ketones such as acetone. Preferably, the API is dissolved in the solvent, and then a precipitating agent such as a non-solvent is used to precipitate the API particles.

[0060] In some embodiments, dispersants or emulsifiers are used to promote and control particle formation. Dispersants or emulsifiers act like surfactants, assisting particle formation, for example, in the form of emulsion droplets or dispersions, and stabilizing the emulsion or dispersion. Dispersants help to suppress the aggregation of particles formed in the dispersion. Dispersants comprise at least one chemically hydrophobic group and at least one hydrophilic group. These chemical groups may be amines, carboxylic acids, hydroxyl groups, and any side-chain groups that may interact with the API and the encapsulating medium. The dispersants include, but are not limited to, vitamins such as vitamin E and vitamin K, amino acids such as L-lysine, L-valine, L-tryptophan, L-phenylalanine, L-methionine, L-leucine, L-threonine, L-isoleucine, L-arginine, L-histidine, L-tyrosine, L-carnitine, L-serine, L-glutamine, aspartic acid, L-proline, L-glycine, taurine, L-cysteine, gamma-aminobutyric acid (GABA), L-alanine, L-glutamic acid, and other conformations thereof.

[0061] In some, and in many, embodiments, an aqueous solution is used to form API particles. An aqueous solution is a solution in which a dispersant, emulsifier, compound, and / or solute such as API is dissolved in water, ionized water, PBS, or other aqueous solvent. The aqueous solution also contains salts such as sodium chloride.

[0062] Some of the APIs or compounds used in this disclosure are hygroscopic. For example, gentamicin sulfate or vancomycin hydrochloride are hygroscopic APIs. In some embodiments, the API is encapsulated in a polymer material and then heated and pressurized to solidify into a shape that allows for the manufacture of a medical device. Direct compression molding into the shape of a finished or semi-finished medical device is used. Extrusion or compression molding is also used, and the resulting product is usually subsequently machined to produce a medical device containing and capable of eluting the API. The thermal decomposition rate of hygroscopic APIs is higher when the API is hydrated. In some embodiments, the mixture of the API and the encapsulant is dehydrated to reduce the moisture content and minimize degradation in subsequent molding steps. In some embodiments, dehydration can be carried out in air, vacuum, or in an inert gas such as argon.

[0063] The API and / or compound particles are formed in a solvent or solvent mixture. For example, gentamicin sulfate is dissolved in water, and ethanol is added to this aqueous gentamicin sulfate solution. The addition of ethanol causes the gentamicin sulfate to form particles in the water / ethanol mixture. These particles are readily encapsulated in the pores of the UHMWPE flakes. Subsequently, the gentamicin sulfate / water / ethanol / UHMWPE mixture is dried by partially or completely evaporating the solvent, for example, by heating in air, an inert gas, or a vacuum. In some, but not limited to, the pharmaceutical composition may be dried and / or dehydrated to produce a dried pharmaceutical composition. For example, the drying step can be performed after dehydration to minimize bound water in the hygroscopic API. In some embodiments, the dried and / or dehydrated mixture of gentamicin sulfate particles in UHMWPE flakes is compression molded and optionally machined to form a medical device.

[0064] In non-limiting examples, the method includes forming a dry pharmaceutical composition by a thermoforming process. Suitable thermoforming processes may include, for example, ram extrusion, extrusion, direct compression molding, compression molding, calendering, thermoforming, welding, lamination, pultrusion, forging, and other techniques. Appropriate conditions for the thermoforming process may depend on the chemical properties of the active pharmaceutical ingredient, the composition of the encapsulation medium, and the intended use of the pharmaceutical composition.

[0065] A typical process for producing a pharmaceutical composition (e.g., GS particles encapsulated in UHMWPE) according to the manufacturing method of the present invention is shown in Figures 1A and 1B. In some, but not limited to, compositions produced by this method can be incorporated into medical devices (e.g., implants) by known techniques (e.g., thermoforming) and can be molded (e.g., machined) to desired sizes and shapes.

[0066] In one embodiment, the API is dissolved in a solvent to prepare an API solution, which is then mixed with another solvent (or non-solvent) that is not a good solvent for the API, thereby forming API particles. The API particles then form a dispersion in a mixture of two solvents, where one solvent is a good solvent for the API and the other is a poor solvent or non-solvent. The API dispersion in the solvent mixture is then mixed with a mounting agent, and the mixture is dried to substantially evaporate the solvent. It is beneficial to reduce the solvent content in the mixture as much as possible before molding. In some embodiments, the API is dissolved in one or more solvents. Some of these individual solvents do not dissolve the API on their own, but their solubility increases when mixed with other solvents. Solubility can also be increased by increasing the temperature.

[0067] In other embodiments, the API is dissolved in a solvent mixture. In some solvents and solvent mixtures, the API is dissolved at an elevated temperature.

[0068] In some embodiments, it is preferable to have the encapsulation medium in powder form to improve miscibility with API particles or dispersed particles. In some cases, it is beneficial to make the encapsulation agent porous to better encapsulate the API particles.

[0069] In some embodiments, the encapsulation medium has flakes such as UHMWPE, the flakes comprising an antioxidant such as vitamin E and a crosslinking agent such as a peroxide.

[0070] In one embodiment, an aqueous solution of gentamicin sulfate (GS) is prepared by dissolving GS in water, and then the GS aqueous solution is mixed with ethanol. The result of mixing with ethanol is the formation of GS particles, and upon standing, the GS in the water / ethanol mixture undergoes phase separation into an amber-colored viscous solution (also called a plug) that settles at the bottom of the container and a clear supernatant liquid above the plug. Similar phase separation can also be obtained by centrifuging the GS in the water / ethanol mixture. The GS in the water / ethanol mixture is then shaken to mix the two phases, the viscous amber-colored plug and the clear supernatant liquid, thereby forming a dispersion in which the GS particles are dispersed in the water / ethanol mixture. The dispersion is then mixed with UHMWPE powder, and the mixture is dried to substantially evaporate the water and ethanol. The dried mixture is dehydrated to further remove residual water and ethanol and then molded. It is beneficial to reduce the water and ethanol content in the mixture as much as possible before molding.

[0071] In another embodiment, this disclosure provides pharmaceutical compositions prepared by the preparation methods described herein. The pharmaceutical compositions prepared may have improved mechanical properties and / or improved API dissolution profiles. Dissolution profile means the profile of the dissolution curve as a function of time. In some embodiments, the pharmaceutical compositions prepared by this method have an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break (EAB) of at least 300%, and / or a yield strength of at least 15 MPa. In some embodiments, the pharmaceutical composition contains at least 6% by weight of an active pharmaceutical ingredient, the active pharmaceutical ingredient having a release rate of at least 0.1 mg / day per 100 cm² over 28 days and / or a cumulative release of at least 3% over 5 days, when measured in water at 37°C. In some embodiments, the API in the pharmaceutical composition prepared by this method contains gentamicin sulfate.

[0072] (Medical devices) In another embodiment, the Disclosure provides medical devices comprising pharmaceutical compositions described herein or pharmaceutical compositions manufactured by the preparation methods described herein. For example, the medical device can be an implant. Examples of medical devices comprising APIs encapsulated in an encapsulation medium include tibial inserts, acetabular liners, joint spacers, complete knee-femoral components, femoral heads, acetabular shells, tibial trusses, glenoid fossae, trauma plates, fracture fixation devices, cochlear implants, visual prostheses, contact lenses for brain-computer interfaces, intraocular lenses, urethral and peripheral vascular catheters, endotracheal tubes, heart valves, embolization coils, vascular grafts, pacemakers, coronary stents, hernia meshes, total cardiac replacements and their cables, left ventricular assist devices and their cables, dental implants, penile implants, breast implants, and plastic surgery augmentation devices. In some embodiments, the implant is a joint replacement implant. In some embodiments, the implant is a joint replacement spacer implant for the treatment and / or prevention of infection.

[0073] In another embodiment, the disclosure provides a joint replacement implant comprising a thermoformed polymer material comprising ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate (GS), wherein GS particles are encapsulated within the pores of the thermoformed polymer material. In some embodiments, the average particle size of the gentamicin sulfate particles is less than 1 μm. In some embodiments, the joint replacement implant comprises about 2% to about 20% by weight of gentamicin sulfate (e.g., including about 2% to about 10% by weight and about 5% to about 10% by weight).

[0074] In another embodiment, the Disclosure provides a method for manufacturing an implant, comprising generating a dispersion of gentamicin sulfate (GS) in a liquid phase comprising a solvent and a non-solvent. The method further comprises manufacturing an implant composition by contacting a porous encapsulation medium comprising ultra-high molecular weight polyethylene (UHMWPE) with the dispersion of gentamicin sulfate, thereby encapsulating particles of gentamicin sulfate within the pores of the porous encapsulation medium. The method further comprises manufacturing the implant by thermoforming the implant composition. The solvent and the non-solvent can be either the aforementioned solvent and non-solvent. The thermoforming process can be carried out by the technique described herein.

[0075] In a non-limiting example, the method further includes removing the solvent and the non-solvent from the implant composition to produce a dry implant composition, and thermoforming the dry implant composition to produce the implant.

[0076] In a non-limiting example, the method further includes processing the implant manufactured by thermoforming to form a shaped implant.

[0077] In some embodiments, the gentamicin sulfate particles have an average size of less than 1 μm.

[0078] In some embodiments, the implant contains about 2% to about 20% by weight of gentamicin sulfate (for example, including about 2% to about 10% and about 5% to about 10%).

[0079] In some embodiments, the implant preparation method further includes processing the implant manufactured by thermoforming to form a shaped implant.

[0080] In another aspect, the present disclosure provides an artificial joint implant manufactured by an implant preparation method described herein. For example, the manufactured implant can be shaped to be used as a joint replacement implant or joint replacement spacer implant for the treatment and / or prevention of infection.

[0081] The following examples illustrate, but are not limited to, the methods, compositions, and devices detailed herein.

[0082] (Examples) Example 1 describes the formation of gentamicin sulfate particles by mixing 140-proof ethanol and UHMWPE. GS (1,770 mg) was added to 17.70 ml of 140-proof ethanol (70 (v / v)% ethanol aqueous solution). The GS rapidly formed gummy aggregates. Next, the mixture was vortexed to break down the aggregates. After vortexing for several minutes, the mixture changed into a liquid dispersion. The dispersed phases were separated by gravity or centrifugation. (i) The first phase was a clear supernatant, and (ii) the second phase was a translucent, amber-colored, highly viscous liquid that settled at the bottom of the container. The amber-colored liquid was collected on a glass slide and observed under an optical microscope, confirming the presence of particles believed to be GS particles. The phase-separated mixture reversibly changed into a liquid dispersion by shaking, such as vortexing. A wet powder mixture was prepared by mixing 13,500 mg of GUR 1020 UHMWPE powder with a plastic spatula. This wet powder was used either as is (wet powder) or after drying in a fume hood at room temperature for approximately 16 hours to evaporate the water / ethanol liquid phase (dry powder).

[0083] Example 2 describes wet tablet molding using the mixture from Example 1. Tablets were manufactured using the wet powder mixture from Example 1. The powder was placed in the cavity of a 13 mm diameter die, and a force of 5 tons was applied using a plunger. The compressed tablets were left in a fume hood at room temperature for approximately 16 hours to evaporate the liquid phase (water / ethanol mixture) and dry them. Subsequently, the tablets were dehydrated by heating them in an oven at 110°C for 2 hours. The dehydrated tablets were solidified in an aluminum / bronze mold at 170°C and a pressure of 20 MPa. First, the mold and plunger were heated, and then the tablets were placed in the mold cavity. A pressure of 20 MPa was applied with the plunger to mold the tablets.

[0084] Example 3 involves dry powder molding using the blend from Example 1. The dry powder mixture from Example 1 was dehydrated in an oven at 110°C for 2 hours. The dehydrated powder mixture was then solidified in an aluminum / bronze mold at 170°C and 20 MPa, as in Example 2. When the molded sample was cut with a razor and observed under an optical microscope, a "cobblestone" morphology with embedded GS-containing regions was revealed. These regions were located on both sides of the typical resin flake boundary of the molded UHMWPE (see Figure 2).

[0085] Example 4 describes dry tablet molding using the mixture from Example 1. Tablets were manufactured using the dry powder mixture from Example 1. The powder was filled into the cavity of a 13 mm diameter die, and a force of 5 tons was applied using a plunger. The tablets were dehydrated in an oven at 110°C for 2 hours. The dehydrated tablets were then solidified at 170°C and 20 MPa using an aluminum / bronze mold, as in Example 2.

[0086] Example 5 describes the formation of gentamicin sulfate particles by adding ethanol or acetone to an aqueous GS solution and mixing with UHMWPE. Several aqueous GS solutions (aqGS) were prepared by adding 1,770 mg of GS to 5.31 ml of water. As shown in Table 1, a non-solvent was added to these solutions to obtain formulations F5.1, F5.2, F5.3, F5.4, and F5.5. Upon addition of the non-solvent to the aqGS solution, the GS precipitated. Subsequently, a liquid dispersion was formed by shaking, for example, in a vortex mixer. This liquid dispersion contained API particles and a carrier medium. After gravity or centrifugation, the dispersions of F5.1, F5.2, and F5.3 underwent phase separation. (i) The first phase was a clear supernatant, and (ii) the second phase was a translucent, amber-colored, highly viscous fluid that settled at the bottom of the container. The amber-colored fluid was collected on a glass slide and observed under an optical microscope, confirming the presence of particles believed to be GS particles.

[0087] After gravity or centrifugation, the F5.4 dispersion separated into four phases: (i) a clear supernatant, (ii) a white supernatant, (iii) a dark amber layer, and (iv) a translucent amber, highly viscous fluid that settled at the bottom of the container. Observation with an optical microscope confirmed the presence of particles, presumably GS particles, in fluid layers (ii), (iii), and (iv) on the glass slide.

[0088] The phase-separated forms of these four mixtures were reversibly converted to liquid dispersion forms by shaking, e.g., vortex stirring. The liquid dispersions were individually mixed with 13,500 mg of GUR1020 UHMWPE powder using a plastic spatula (manual mixing). Manual mixing can be substituted or assisted by using a manual or electric mixer, such as a bone cement mixer. The resulting wet powder mixture was used as is (wet powder) or after drying in a fume hood at room temperature for approximately 16 hours to evaporate the liquid water / ethanol phase (dry powder). [Table 1]

[0089] Example 6 is a dry powder molding process using the mixture from Example 5. The dry powders from Example 5 (F5.1, F5.2, F5.3, and F5.4) were each dehydrated in an oven at 110°C for 2 hours. The dehydrated powder mixtures were then molded using aluminum / bronze molds at 170°C and 20 MPa, as in Example 2.

[0090] The wet powder of F5.4 obtained in Example 5 was dried in an oven at 45°C for approximately 16 hours. The dried powder was dehydrated in an oven at 110°C for 2 hours. Subsequently, the dehydrated powder mixture was solidified at 170°C and 20 MPa using an aluminum / bronze mold, as in Example 2.

[0091] Example 7 describes dry tablet molding using the mixture from Example 5. Tablets were prepared using the dried powder from Example 5 (F5.1). The powder was filled into the cavity of a 13 mm diameter die, and a force of 5 tons was applied using a plunger. The tablets were dehydrated in an oven at 110°C for 2 hours. The dehydrated tablets were then solidified at 170°C and 20 MPa using an aluminum / bronze mold, as in Example 2.

[0092] Example 8 is a dry powder molding using the blend from Example 1 under different drying / dehydration conditions. The wet powder from Example 1 was dried in an oven at different temperatures and times, and then solidified in a mold. The dried and dehydrated powder blend was solidified in an aluminum / bronze mold at 170°C and 20 MPa, as described in Example 2. Most of the drying and dehydration was carried out in air, as shown in Table 2, and it can be seen that the oven was filled with air at atmospheric pressure. Partial vacuum drying / dehydration conditions were achieved by partially removing air from the oven chamber using a vacuum pump. When the oven is in a partial vacuum state, the pressure inside the oven chamber is below atmospheric pressure. In some embodiments, the oven chamber is filled with an inert gas before evacuation to achieve partial vacuum. Table 2 below shows the various procedures used for drying and dehydrating the wet powder blends (GS and UHMWPE) from Example 1. [Table 2]

[0093] Example 9 describes the formation of VH particles by adding ethanol or acetone to an aqueous solution of vancomycin hydrochloride (VH) and mixing it with UHMWPE. Several aqueous VH solutions (aqVH) were prepared by adding 708 mg of GS to 5.31 ml of water. As shown in Table 3, a non-solvent was added to these solutions to obtain formulations F9.1, F9.2, F9.3, and F9.4. Upon addition of the non-solvent to the aqVH solution, VH precipitated. The dispersion was milky white with a slight pink tint. The VH particles were suspended in the liquid phase.

[0094] Wet mixtures were prepared by mixing each of the liquid dispersions in Table 1 with 14,400 mg of GUR1020UHMWPE powder. The wet mixtures were used as a dry powder mixture after the liquid phase was evaporated as described in Example 12 below. [Table 3]

[0095] Example 10 describes the formation of VH particles by adding ethanol or acetone to an aqueous solution of vancomycin hydrochloride (VH) and mixing it with UHMWPE. Several VH solutions were prepared by adding 354 mg of VH to 17.70 ml of ethanol-water mixtures containing 80, 90, 100, 120, and 140 proof ethanol. Each of these solutions was mixed with 14,700 mg of GUR1020UHMWPE powder to prepare a wet mixture. As described in Example 12 below, VH particles formed in situ within and / or around the PE flakes after mixing as a result of changes in the ethanol-to-water ratio in the mixture during drying.

[0096] Example 11 describes the formation of VH and GS particles by adding ethanol to a VH / GS aqueous solution and mixing it with UHMWPE. The VH and GS solution was prepared by dissolving 354 mg of VH and 1,062 mg of GS in 5.31 ml of water. Ethanol was added to the VH / GS aqueous solution according to the formulation in F5.1 of Table 1 to form VH and GS particles. Phase separation similar to that observed in Example 5 was observed in the VH / GS aqueous solution. After shaking and / or mixing, 13,800 mg of GUR1020UHMWPE powder was added to the liquid dispersion to form a wet mixture. This wet mixture was used as a dry powder mixture after the liquid phase was evaporated as described in Example 12 below.

[0097] Example 12 is a dry powder molding process using the blends from Examples 9, 10, and 11 under different drying / dehydration conditions. The wet blends from Examples 9, 10, and 11 were dried in an oven at different temperatures and times (T12.1, T12.2, T12.3, T12.4, T12.6, T12.7) and solidified in a mold. The dried and dehydrated powder blends were solidified in an aluminum / bronze mold at 170°C and 20 MPa, as described in Example 2. As shown in Table 4, most of the drying and dehydration was carried out in air. In some embodiments, a drying condition of T12.5 can be used. [Table 4]

[0098] Example 13 describes mixing, drying, dehydration, and powder molding using a dual asymmetric centrifuge. 18.80 g of GS was added to 70.8 ml of water to prepare an aqueous GS solution. When 165.2 ml of ethanol was added to this solution, phase separation occurred, and a liquid dispersion was obtained. 184 g of GUR1020UHMWPE was added to this liquid dispersion to prepare a mixture, which was then placed in a dual asymmetric centrifuge (Speedmixer®, manufactured by Flacktek). The SpeedMixer® was operated at 800 rpm for 1 minute to mix the mixture. This is also called homogenization of the mixture to improve the uniformity of the GS particles mixed with the UHMWPE flakes. Next, the rotation speed of the SpeedMixer® was increased to 1400 RPM under vacuum, and the solvents, ethanol and water, were evaporated. The rotational mixing of the mixture increased the temperature, and combined with the vacuum, drying and dehydration were accelerated in about 20 minutes. Multiple such mixtures were prepared and stored in airtight bottles with minimal headspace, or in vacuum-sealed and heat-sealed pouches, until solidified. The dehydrated powder mixtures were solidified at 170°C and 20 MPa using aluminum / bronze molds, as described in Example 2.

[0099] Example 14 involves mixing, drying, and dehydration using an industrial blender and powder molding. An aqueous GS solution was prepared by adding 18.80 g of GS to 70.8 ml of water and placing it in a Littleford M-5 industrial mixer. Next, 165.2 ml of ethanol was added to the mixer, and the mixer was operated at 3 Hz for 10 minutes to prepare a liquid dispersion of GS particles in a water / ethanol mixture. The mixer was stopped, and 184 g of GUR1020UHMWPE was added to the dispersion in the mixer. The mixer was operated under vacuum at 3 Hz and heated to 45°C to dry the mixture. Drying removed both ethanol and water. Mixing continued under vacuum at 45°C for 16 hours, at which point the mixer temperature rose to 90°C, and mixing continued under vacuum for a further 3 hours to dehydrate the sample. In some embodiments, the dehydration temperature can be 110°C. In some embodiments, after dehydration, the mixer temperature was reduced to 60°C. The dehydrated mixture was stored in a sealed bottle or vacuum pouch with minimal headspace and allowed to solidify. The dehydrated powder mixture was solidified at 170°C and 20 MPa using an aluminum / bronze mold, as described in Example 2.

[0100] Example 15 is a mixture of gentamicin sulfate particle mixture and UHMWPE under high pressure. The ethanol / aqGS / UHMWPE mixture from Example 5 is poured into a high-pressure chamber. The pressure is set to a minimum of 1 bar, and the mixture is left under pressure for at least 1 minute. After releasing the pressure, the pressurized wet powder mixture is left at room temperature for at least 16 hours to evaporate the liquid (water / ethanol mixture), or placed in an oven at a temperature above room temperature (e.g., any of the oven drying conditions listed in Table 2). The powder mixture is then further heated in the oven at 110°C for 2 hours to further remove bound water in the GS, or dried under any of the dehydration conditions listed in Table 2. The dehydrated powder mixture is then solidified in an aluminum / bronze mold at 170°C and 20 MPa.

[0101] Example 16 involves the encapsulation of GS particles in peroxide-crosslinked UHMWPE. The API particles and carrier medium (water and ethanol) from Example 5 were added to UHMWPEGUR1050 blended with dicumyl peroxide and vitamin E (US Patent Application No. 17 / 222,398, subject to "High Temperature Melting"; abandoned US Patent Application No. 14 / 389,852, subject to "Peroxide Cross-Linking of Polymeric Materials in the Presence of Antioxidants"; US Patent Application No. 16 / 291,283, subject to "Peroxide cross-linking and high temperature melting"; "Di-Cumyl Peroxide Crosslinking of See U.S. Patent Application No. 17 / 703,288, U.S. Patent Publication No. 2004 / 0156879, U.S. Patent Application No. 11 / 465,544, filed on 18 August 2006, and International Application PCT / US2006 / 032329, published as International Publication No. 2007 / 024689, both relating to "UHMWPE". Methods for producing UHMWPE with dicumyl peroxide and vitamin E are described in the various patents referenced above, all of which are incorporated herein by reference. The wet powder mixture was left in an oven at 45°C for at least 16 hours to evaporate the carrier liquid. The powder mixture was then heated in an oven at 110°C for 2 hours to further remove bound water in the GS. The dehydrated powder mixture was then solidified under aeration using an aluminum / bronze mold at 170°C and 20 MPa.

[0102] Example 17 involves the encapsulation of GS particles in UV-crosslinked UHMWPE. The API particles from Example 5 and a liquid carrier medium (water and ethanol) are added to UHMWPE blended with a UV initiator (e.g., 4h-benzophenone, or other initiators described in U.S. Patent Application No. 16 / 635,105, subject to "UV-Initiated Reactions In Polymeric Materials"). The wet powder mixture is dried and heated to further remove bound water in the GS. The dehydrated powder mixture is then solidified. The solidified block is machined into an implant shape and crosslinked by irradiating the surface, preferably the articular surface, with UV light.

[0103] Example 18 involves the encapsulation of GS particles into radiation-crosslinked UHMWPE. The molded blocks of Examples 6, 7, and 8 are radiation-crosslinked before or after machining them into the shape of an article such as an implant. Crosslinking is achieved by ionizing radiation such as electron beams, gamma rays, or X-rays, or by radiation methods described in U.S. Patent No. 8,933,145, subject to "High Temperature Melting", U.S. Patent No. 7,205,339, subject to "Selective controlled manipulation of polymers", and U.S. Patent Application No. 14 / 400375, subject to "Antioxidant-stabilized joint implants", details of which are fully incorporated herein by reference.

[0104] Example 19 describes the formation of GS particles by adding ethanol to an aqueous GS solution and mixing with polymethyl methacrylate. An aqueous GS solution with ethanol was prepared by dissolving 1000 mg of GS in 14.16 ml of water and adding 33.04 ml of ethanol. An aqueous GS solution with ethanol was also prepared by dissolving 1000 mg of GS in 4.248 ml of water and adding 9.912 ml of ethanol. The resulting liquid dispersion contained GS particles. After shaking and / or mixing, the liquid dispersion was mixed separately with Simplex-P bone cement by mixing it with 40 g of a premix PMMA powder containing 6 g of PMMA, 30 g of methyl methacrylate-styrene copolymer (containing 1.7% benzoyl peroxide), and 4 g of barium sulfate. The mixture was further mixed in a bone cement mixer (MixeVac® III, Stryker). The resulting mixture was wet and therefore needed to be dried by evaporating the water and ethanol. The dried mixture was individually sieved through a 300 micrometer sieve. After sieving, a solution of 19.5 ml of methyl methacrylate, 0.5 ml of N,N-dimethylparatoluidine, and 75 ppm of hydroquinone was added to the dried mixture and mixed to harden the material. The hardened bone cement is used as a bone space filler, a fixation device for securing implants, and / or as a spacer in the treatment of periprosthetic joint infections.

[0105] Example 20 describes the role of submicron gentamicin sulfate particles in improving antibiotic release and mechanical strength in UHMWPE antibiotic blends. (material) Ethanol and isopropyl alcohol were obtained from Sigma Aldrich (St. Louis, Missouri), GUR1020UHMWPE flakes from Ticona (Florence, Kentucky), and gentamicin sulfate (GS) from Fujian Fukang Pharmaceutical Co. (China).

[0106] (method) For the preparation of GS particles and their mixing with UHMWPE, submicron particles were produced by adding ethanol to an aqueous GS solution, and the GS particles were dispersed in the ethanol-water mixture. These dispersions, containing the GS precipitate, were mixed with UHMWPE flakes using a dual asymmetric centrifugal separation (DAC) mixer, specifically a SpeedMixer® DAC1200-1000 TwinVacuum model (manufactured by Flacktek, South Carolina). The mixer was operated at 1200 RPM under a vacuum of 25 mbar to remove ethanol and water from the mixture. The submicron GS particles were mixed with UHMWPE flakes at concentrations of 6%, 8%, and 10% by weight and molded to produce submicron GS UHMWPE blends.

[0107] The received particles were sieved through a 75 μm sieve. Particles smaller than 75 μm were mixed with UHMWPE flakes at a concentration of 10 wt% using a DAC, operated at 1200 rpm under a vacuum of 25 mbar, and then molded to produce the received GS UHMWPE blend.

[0108] Re-solidified particles were prepared by freezing an aqueous GS solution at -20°C for 16 hours and then freeze-drying it for 48 hours. The freeze-dried residue was crushed using a mortar and pestle, and then sieved first with a 150 μm sieve and then with a 75 μm sieve. The 75-150 μm particles were mixed with UHMWPE flakes at a concentration of 10% by weight using a DAC operating at 1200 rpm under a vacuum of 25 mbar, and then molded to prepare a re-solidified GS UHMWPE blend.

[0109] For the GS UHMWPE blend consolidation, the GS UHMWPE blend is processed in a rectangular aluminum bronze mold (50 x 85 mm). 2 Using [a specific tool / method], pressure molding was performed at 170°C for 20 minutes, at 5 MPa for 5 minutes, at 10 MPa for 5 minutes, and at 20 MPa for 10 minutes. After that, it was cooled under a pressure of 20 MPa for 50 minutes. The thickness of the molded test sample was 1 cm.

[0110] For imaging, the morphology of the solidified GS UHMWPE blend was investigated using a digital optical microscope, SEM, and FIB-SEM.

[0111] The morphology of submicron, received, and re-solidified GS UHMWPE blends was visualized using a digital optical microscope. Samples were prepared by cutting thin films from molded products using a microtome. Subsequently, the thin films were imaged using ring light imaging with an optical microscope (SZX12 optical microscope / DP11 digital camera, Olympus Life Science Corporation, USA) and a digital optical microscope (Keyence VHX-6000) and VH-ZST (ZS-200) lens to visualize the GS region within the UHMWPE.

[0112] The morphology of the 10% submicron GS UHMWPE blend was visualized using a freeze-fractured SEM sample coated with a 5nm thick 80:20 ratio Pt:Pd using a Q150T sputter coater (Quorum Technologies, East Sussex, UK). Imaging was performed at 5kV using a JEOL JSM-7900F field emission scanning electron microscope (Peabody, Massachusetts). Elemental analysis was performed at 10kV using an Ultim Max EDS detector (Oxford Instruments, Concord, Massachusetts).

[0113] The morphology of a 10% submicron GS UHMWPE blend was visualized using a FIB-SEM (Zeiss Crossbeam 550 Focused Ion Beam with Gemini2, Germany). Samples were prepared by coating them with a 1 μm Pt precursor in a chamber. To visualize the particles below the surface, a window was created using FIB (3-15 nA).

[0114] For mechanical testing, Type V tensile test specimens were prepared by machining a 3.2 mm thick cross section (Shopbot Tools, Inc., Durham, North Carolina) and then molding the cross section with a die sample cutter using a Dewes-Gumbs Manual Expulsion Press, Model 1.5T DGD (Dewes-Gumbs Die Company, Long Island City, New York) and an extrusion die for press model ASTM D638-V (Dewes-Gumbs Die Company, Long Island City, New York). The specimens were tested on an MTS Insight 2 electromechanical load frame (Eden Prairie, Minnesota) at a crosshead speed of 10 mm / min. An MTS LX300 laser extensometer was used to measure true strain. Elongation at break (EAB) as a percentage, yield strength (YS) in MPa, and ultimate tensile strength (UTS) in MPa were calculated according to the ASTM D638 standard.

[0115] Izod test specimens were prepared by machining a molded block to the specified dimensions (63.5 × 12.7 × 3.2 mm). The resulting bars were notched using a Panpress 502 with positive stop function (PanaVise, Reno, Nevada), and their shape was verified using an STM6 measuring microscope (Olympus, Waltham, Massachusetts). Toughness was measured in accordance with ASTM F648 using a CEAST 9050 pendulum impact tester (Instron, Norwood, Massachusetts).

[0116] For the Pin-on-Disk (POD) abrasion test, the abrasion rate of the GS UHMWPE blend outlined in ASTM F732-17 Annex A2 (ASTM.Vol.13.01 ASTMStandard F732-17(2017)) was measured using a multi-directional Ortho-POD® abrasion tester (AMTI, Watertown, Massachusetts). A cylindrical pin with a diameter of 9 mm and a height of 13 mm and a flat end was brought into contact with a flat polished CoCr disk with Ra < 0.06 μm at 2 Hz along a 10 mm × 5 mm rectangular path. During contact, a pole-type variable load curve with a peak contact stress of 5.1 MPa was applied axially. The tests were conducted using ethylenediaminetetraacetic acid (EDTA, Acros Organics, Waltham, Massachusetts) and room-temperature bovine calf serum (Sigma-Aldrich, St. Louis, Missouri) stored in penicillin-streptomycin solution (Sigma-Aldrich). The tests were interrupted after the first 0.5 million cycles (MC), and then evaluated every 0.157 MC thereafter, continuing until the 1-week test was completed with a total of 1.128 MC.

[0117] At each evaluation interval, the pins were cleaned, dried, and weighed. The wear rate was calculated by linear regression, excluding the first 0.5 MC test, and expressed in milligrams per million cycles.

[0118] The POD pins were pre-treated to ensure accurate results in the POD abrasion test and to eliminate the influence of weight changes due to the elution of GS (gentamicin sulfate) from the UHMWPE blend. The UHMWPE pins, injected with submicron GS, underwent a thorough immersion step. This involved immersing the pins in a specially prepared 50 ml solution containing bovine serum, EDTA, and a penicillin-streptomycin mixture. The purpose of this pre-immersion was to stabilize the weight by allowing the pins to absorb the liquid into the pores remaining after GS elution and reach equilibrium.

[0119] During this pretreatment stage, the pins were periodically removed from the solution, dried, and weighed. This process was repeated until important stability criteria were met. That is, the weight of the pins had to be kept constant, and the variation in the measured values taken twice consecutively had to be less than 0.1%. Achieving this stability was extremely important. This indicated that the release of GS from the pins had stopped, and the weight changes during the subsequent POD wear test were considered to be due to wear rather than the elution of GS.

[0120] For elution, prismatic elution strips (3×5×20 mm 3 ) were processed and cleaned according to an ultrasonic cleaning method for orthopedic implants (manufactured by Orchid, Detroit, Massachusetts). Specifically, two ultrasonic cleaning tanks (manufactured by Fisher, Waltham, Massachusetts) were prepared, one filled with a 10 g / l solution of a high-concentration anionic detergent (manufactured by Alconox, White Plains, New York) and the other with pure water. Each bath was heated to 49 °C. Next, the strips were immersed in each bath for 15 minutes and ultrasonicated. After cleaning, the strips were shaken into a beaker filled with 100% isopropyl alcohol and dried overnight in a draft.

[0121] Six prismatic strips (n = 6) of each GS UHMWPE blend were eluted in a shaking incubator at 37 °C with a 2 ml or 20 ml syringe filled with DI water. The entire eluate was collected at predetermined time points (0.25, 1, 2, 3, 4, 7, 10, 14, 21, and 28 days) and replenished with DI water. The collected samples were derivatized using a fluorescence o-phthalaldehyde assay and measured with a spectrofluorometer plate reader (manufactured by Biotek, Agilent, Santa Clara, California). The cumulative release amount and cumulative percent release amount with respect to the normalized surface area of 100 cm 2 and the daily release rate were calculated. MATLAB (registered trademark) was used to analyze the release data by a single-compartment pharmacokinetic model and predict the in-vivo concentration of the GS UHMWPE blend.

[0122] (Antibacterial testing) The GS function after elution from the molded 10% submicron GS UHMWPE blend was validated by antimicrobial susceptibility testing according to Clinical and Laboratory Standards (CLSI) protocol M07-A10. Staphylococcus aureus American Type Culture Collection (ATCC) strain 12600 was cultured overnight at 35°C on trypsin-soybean agar (TSA) plates. After elution at 37°C for 6 hours, the gentamicin concentration of eluates obtained from six elution strips was measured. In a sterile 96-well plate, 50 μl of eluate was serially diluted with 50 μl of cation-adjusted Mueller-Hinton broth (CA-MHB) to achieve a concentration range including the predicted MIC of gentamicin. Additionally, 50 μl of CA-MHB was added to all wells. Next, well-isolated colonies from 4-5 wells of each plate were suspended in 3 ml of physiological saline, and the initial turbidity was adjusted to 1 × 10 CFU / ml. The bacterial suspension was then diluted 100-fold with CA-SMHB. 100 μl of the diluted bacterial stock was added to all wells except the media control, and 10 4 ~10 5 The concentration was set to CFU / ml. Assay plates were incubated at 35°C for 16–20 hours (overnight) according to the CLSI guidelines for each strain.

[0123] The MIC (Inhibitory Control Intake) was defined as the lowest antibiotic concentration that completely inhibits microbial growth visible to the naked eye. For a test to be considered effective, a button of 2 mm or more or clear turbidity should be observed in the growth control well, and no wells should be skipped.

[0124] MBC was determined by dispensing 5 μl of MIC, 2×MIC, and 4×MIC concentrations into the corresponding wells and performing drop-in culture in three separate steps. These plates were incubated overnight at 35°C. MBC was defined as the concentration at which no growth was observed in all three replicate tests.

[0125] For nuclear magnetic resonance (NMR), three prismatic elution strips prepared from a 10% submicron GS UHMWPE blend were placed in 5 ml of deuterium water and eluted at 37°C for 24 hours. The GS eluted from these samples in deuterium water was compared to a 2 mg / ml GS solution (control) in deuterium water. 1 Analysis was performed using 1H NMR (500 MHz Varian spectrometer, Palo Alto, California) and MNova software (MestreLabs, Santiago de Compostela, Spain). The NMR results of the eluted GS were compared with those of the control GS solution.

[0126] Regarding statistics, the tensile test results of the GS UHMWPE blend were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's HSD (Honestly Significant Difference) test to evaluate the effect of loading. This method was also separately applied to investigate the type of GS particles and the loading rate of submicron particles. Furthermore, the effect of submicron particle loading on the abrasion rate was examined using the same statistical method. In the dissolution experiments, the effect of time and loading on the results was investigated by performing two-way analysis of variance (ANOVA) followed by Tukey's HSD test, which minimized the significance of the difference. All statistical analyses were performed using IBM SPSS Statistics version 28.0.0.0(190).

[0127] (result) Morphologically, morphological examination of UHMWPE loaded with resolidified GS particles, received GS particles, and submicron GS particles showed significant variability. Resolidified and received GS particles formed distinct GS regions within the UHMWPE matrix (see Figures 10A-10B). In contrast, submicron particles were distributed along the contours within the fusion lines of the UHMWPE flakes (see arrows in Figures 10C-10D), forming a characteristic "cobblestone" pattern. Scanning electron microscopy (SEM) confirmed the presence of submicron GS particles and the formation of this cobblestone structure, and elemental analysis showed high concentrations of oxygen and sulfur along the fusion lines of the flakes, confirming the presence of small GS particles forming the cobblestone structure (see Figures 10E-10H). Furthermore, in focused ion beam (FIB) SEM images, submicron-sized pores are revealed, which were likely the original locations of the GS particles, but are thought to have been moved during FIB-SEM surface cutting, leaving only the visible pores (see Figures 10I-10L). As shown in the schematic diagram of Figure 10M, in the resolidified and received states, the presence of GS particles inhibits the effective fusion of UHMWPE flakes, blocking the fusion lines and partially replacing them with interfaces with low interfacial strength between the UHMWPE flakes and GS inclusions. These particles form barriers between the flakes, preventing them from forming complete fusion. On the other hand, in the GS UHMWPE blend, the distribution of submicron particles within the UHMWPE pores allows for complete fusion of the UHMWPE flakes.

[0128] Regarding mechanical properties, as the GS particle size increased from submicron to the time of receipt and then to after resolidification, there was a significant decrease in ultimate tensile strength (UTS), elongation at break (EAB), and yield strength (YS) (Figures 11A-11C). Specifically, the YS of submicron particles was significantly higher than that of GS UHMWPE blends at the time of receipt and after resolidification (p<0.01). On the other hand, the YS of submicron GS UHMWPE blends were almost the same (p>0.05) (submicron GS 2%-10% blends: 20.4±0.3, 20.4±0.2, 20.2±0.4, 20.3±0.2, and 21.1±1.2 MPa). The UTS of the submicron blend was significantly higher than that of the resolidified blend (p<0.01), and there was no difference compared to the UTS of the blend at the time of receipt. The EAB of the submicron blend was comparable to that of the GS UHMWPE blend after resolidification and at the time of receipt. In the submicron GS UHMWPE blend, increasing GS content resulted in decreases in EAB, UTS, and IZOD impact strength (see Figures 11D-11F). The IZOD impact strength of the 6% GS UHMWPE blend was comparable to that of virgin UHMWPE, but the impact strengths of the 8% and 10% blends were lower (see Figure 11F).

[0129] In the pin-on-disk abrasion test, the abrasion rate of the submicron GS UHMWPE blend when in contact with polished Co-Cr discs was no different compared to virgin UHMWPE. The measured values ​​for the 10%, 8%, and 6% submicron GS UHMWPE blends and virgin UHMWPE were -12.98±1.56, -11.43±1.39, -13.24±1.31, and -12.14±0.98 mg / million cycles, respectively (p>0.05 in all comparisons).

[0130] Regarding antimicrobial testing, the activity and stability of eluted GS were confirmed by antimicrobial testing against Staphylococcus aureus. The ranges of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of GS eluted from the GS UHMWPE blend did not differ among control GS solutions, regardless of the GS particle size on the blend (0.5–2 μg / ml and greater than 4 μg / ml, respectively).

[0131] Regarding elution, the 10% submicron GS UHMWPE blend showed the highest elution rate, percentage of cumulative release rate, and cumulative release rate as a function of elution time compared to the re-solidified and received GS UHMWPE blends with the same GS content. In terms of release rate, the order was 10% submicron GS UHMWPE blend, 10% re-solidified GS UHMWPE blend, and 10% received GS UHMWPE blend (see Figures 12A-12C). The elution rate of the 10% submicron GS UHMWPE blend at day 28 was significantly higher than that of the re-solidified GS blend and the received GS UHMWPE blend (11.28 mg / day vs. 0.11 mg / day and 0.26 mg / day, respectively). In the submicron GS UHMWPE blend, the release rate decreased with decreasing GS content (see Figures 12D-12F). On day 28, the release rates for 6% and 8% submicron GS particles were 0.12 mg / day and 1.30 mg / day, respectively. There was no statistically significant difference in the 6% release rate between elution days 1 and 28. The 10% submicron GS UHMWPE blend had a higher cumulative release over 28 days compared to all other groups (p<0.01). The release rates for the 10% submicron GS UHMWPE blend were similar from days 1 to 21, but by day 28, they were approximately 10-fold and 100-fold higher, respectively, compared to the 8% and 6% submicron GS UHMWPE blends. Predicted in vivo concentrations based on gentamicin release from the 8% and 10% submicron GS UHMWPE blends were higher than 100×MIC over 28 days, whereas predicted concentrations for the GS UHMWPE blend after resolidification and at receipt rapidly fell below this level (see Figures 12G-12H).

[0132] Regarding the pharmacokinetic model, a pharmacokinetic (PK) model was used to predict the in vivo release of gentamicin sulfate (GS) from a GS UHMWPE blend. This model calculates the clearance of GS using its half-life and first-order kinetics. Since there is no data on the intra-articular half-life of GS, amikacin sulfate (AS), which has a similar serum half-life (2-3 hours according to aminoglycoside guidelines), was used as a substitute. Therefore, the intra-articular half-life of GS was estimated from the known intra-articular half-life of AS (3.8-4.6 hours). The following equation represents the pharmacokinetics of GS. [Mathematics 1] t 1 / 2 =0.693 / λ (Equation 1) Here, t 1 / 2 λ is the half-life of GS (in hours), λ is the decay constant (1 / hour), and the following equation is given. [Math 2] dC=C t -C t ×e -λdt +k×dt n / V (Formula 2) Here, C tλ is the GS concentration in the synovial fluid (mg / ml) at a given time t, dC is the concentration change over time (dt, in units of time), and λ is the decay constant of GS in the synovial fluid. The coefficients k and n were derived by applying the Korsmeyer-Peppas model to the cumulative elution profile of the GS blend (mg). In the concentration calculation process, the values ​​(k and n) obtained from the Korsmeyer-Peppas equation were normalized by the corresponding effect volume, denoted as V. The typical synovial fluid volume in a healthy adult is 0.5–4 mL, but an increase in volume has been observed in cases of swelling due to knee infection. A fixed volume of 4 mL was used in the calculations. The time derivative of the cumulative release curve was calculated using the Korsmeyer-Peppas equation, and a nonlinear regression model was applied in MATLAB (registered trademark, R2022b Update 1, MathWorks, USA). The resulting model was used as input to Equation 2, enabling the estimation of the instantaneous concentration within a specified volume. Simulations were performed for intra-articular GS under three different scenarios: short-term, nominal, and long-term (3 hours, 4.5 hours, and 6 hours, respectively) (see Figures 13A-13B). In all scenarios, the predicted GS concentration in the knee joint was below the bolus injection level (80 mg), indicating that the GS UHMWPE blend can be safely used in clinical practice. Incidentally, simulations were also performed under two different scenarios with intra-articular GS half-lives of 3 hours and 6 hours, respectively (see Figures 14A-14B). The ability of each blend size to maintain a therapeutic level above 100×MIC was evaluated against the predicted GS concentration profiles in the articular cavity and the calculated drug concentrations over time under the 3-hour and 6-hour half-life scenarios for different sizes of GS UHMWPE blends, including re-solidified GS, received GS, and submicron GS. The results show no significant difference in GS concentration profiles between the 3-hour and 6-hour half-life scenarios across all blend sizes. However, significant differences were found in the ability to maintain the 100×MIC threshold. While re-solidification and blending upon receipt failed to maintain this threshold, the submicron GS UHMWPE blend consistently maintained concentrations well above the 100×MIC limit.

[0133] Regarding NMR, elution GS 1 ¹H NMR analysis showed no significant shift in the observed peaks compared to the control GS (see Figure 15). A comprehensive list of chemical peaks can be found in Table 5. [Table 5]

[0134] For the analysis of the NMR spectra of GS eluted from the submicron GS UHMWPE blend, MestReNova software (version 14.2.0-26256) was used. The spectra of both samples were compared using superposition mode, and peak identification was assisted by an automated assignment tool (see Figure 16). In this comparison, it was found that the original GS showed 16 multiplets corresponding to 32 hydrogen atoms, while the GS eluted from the blend showed 15 multiplets corresponding to 31 hydrogen atoms (see Table 5 for details).

[0135] As shown in Figure 17, the main differences in the multiplet assignment were observed in the chemical shift ranges of 4.18–4.04, 3.61–3.38, 2.52–1.9, and 1.32–1.22 ppm. Further investigation revealed that these differences were mainly due to variations in peak height and slight peak shifts. Such changes are consistent with the concentration differences between the control GS sample and the eluted sample.

[0136] Importantly, these changes observed in the NMR spectrum do not suggest any alteration of the molecular structure or functional integrity of GS. Since the differences in the NMR spectrum are thought to be due to concentration effects rather than structural changes, the core molecular framework and pharmacological functionality of GS remain intact. Therefore, even when eluted from the submicron GS UHMWPE blend, the essential properties of GS are preserved.

[0137] (Consideration) Our hypothesis regarding the effect of particle size on the encapsulation of gentamicin sulfate particles in UHMWPE was validated. Morphological analysis of re-solidification, acceptance, and submicron GS particles, as well as their integration into the UHMWPE matrix, revealed distinct morphological characteristics that significantly influenced the resulting material properties.

[0138] Due to its molecular weight (approximately 2 to 5 million g / mol), highly entangled molecular structure, and high melt viscosity, UHMWPE cannot be melt-processed. Instead, UHMWPE flakes are sintered by applying heat and pressure without virtually flowing, a process commonly referred to as solidification. Finished products, such as implants, are machined after the sintering / solidification process. Mechanical properties depend on the quality of the fusion of the resin flakes, and certain fusion defects negatively affect material strength. Diffusion of UHMWPE chains beyond the flake boundaries is essential for efficient material fusion and improved mechanical properties. In gentamicin-supported UHMWPE, the flakes solidify around the GS particles, creating discontinuities and fusion defects in the case of receiving and re-solidifying particles, negatively impacting mechanical properties. In contrast, submicron GS particles, positioned on both sides of the fusion line, do not inhibit fusion and do not result in fusion discontinuities (see Figure 10M). These effects are reflected in the improved mechanical properties of the submicron GS UHMWPE blend compared to other blends (see Figures 11A-11C).

[0139] UHMWPE incorporated into submicron GS particles exhibited a distinctive "cobblestone or honeycomb" morphology (see Figures 10C–10D). After compaction, clearly defined fusion lines were observed, with submicron particles concentrated on both sides of these lines. Observed by SEM, FIB-SEM, and digital microscopy (see Figures 10C–10M), this particular arrangement suggests better fusion of polymer chains across grain boundaries, resulting in greater cohesiveness and potentially stronger fusion. In other words, the diffusion of polymer across grain boundaries during compaction is minimally inhibited by the submicron GS particles. This distinctive cobblestone structure was only pronounced in submicron GS particles small enough to penetrate the porosity of the UHMWPE flakes during blending, and therefore did not hinder flake fusion during compaction.

[0140] The POD wear rate of UHMWPE is not affected by the addition of submicron GS particles, which is consistent with results reported for untreated particles. The wear rate of UHMWPE is primarily linked to the plastic deformation of the network, with orientation towards the main direction of motion weakening the lateral material. Since the EAB of the GS UHMWPE blend is not significantly affected, the large-scale deformation capacity of the network is not significantly affected by the therapeutic area, and as a result, a similar wear rate is likely to be obtained. Incidentally, the voids in the polymer created by the elution of GS may result in better lubrication by acting as a reservoir for bovine serum used as a lubricant during wear testing. Maintaining a wear rate comparable to that of virgin UHMWPE is particularly important, suggesting that the submicron GS UHMWPE blend may have similar short- and medium-term performance to conventional primary implants fabricated with virgin UHMWPE.

[0141] The incorporation of submicron particles improved the dissolution rate (higher dissolution rates at each time point and higher overall dissolution, as evident from the release rate curve), in addition to improving mechanical properties. This is thought to be due to the unique distribution of submicron particles along fusion lines within the UHMWPE matrix. The submicron GS particles created a uniform spatial arrangement that can be explained by a two-dimensional Archimedes honeycomb percolation model. Increased percolation of this structure allows for more efficient penetration and release of antibiotics, leading to a significant increase in the observed dissolution rate. This is a crucial factor in infection prevention in combination with orthopedic implants. For example, Whiteside et al. (see "Intra-articular infusion," The Bone & Joint Journal 98-B, 31-36 (2016)) reported that injecting antibiotics directly into the joint to maintain high local concentrations (3956-32150 μg / ml) resulted in infection-free outcomes in 95% of patients, but was ineffective at intra-articular concentrations close to the antibiotic's MIC (2-3 × MIC).

[0142] NMR analysis of GS eluted from a 10% submicron GS UHMWPE blend into deuterated water demonstrated the thermal stability of GS even after exposure to 170°C for 20 minutes during solidification, with no significant shift in the observed peaks (see Figures 16 and 17). Furthermore, MIC / MBC studies confirmed the stability and functionality of GS eluted from the solidified samples. Taken together, these findings support the conclusion that the ng process used to produce the submicron GS UHMWPE blend block did not impair the stability or functionality of GS, suggesting that this method is promising for preparing these materials for medical applications.

[0143] As described herein, a novel method for incorporating drug particles into ultra-high molecular weight polyethylene (UHMWPE) flakes has the potential to enable sustained and consistent delivery of a variety of drugs. The flexibility of UHMWPE flakes allows submicron-sized particles to penetrate the UHMWPE, and the extremely low melt flow rate allows the particles to remain within the pores, forming a confined structure during molding. This study confirmed that the new morphology created by incorporating reduced-particle-size drugs significantly improves the material's mechanical properties, and more importantly, enhances the persistence and intensity of drug release. The mechanical properties of GS UHMWPE blends prepared using submicron GS particles are comparable to those of clinically available implant materials, suggesting the potential use of GS-infused UHMWPE in other arthroplasty applications. This potential paradigm shift makes it possible to incorporate therapeutic agents into UHMWPE while minimizing strength reduction and controlling the sustained release of therapeutic agents. This technology is suitable not only as an antibiotic spacer in the treatment of infected whole-joint patients, but also for a variety of surgical scenarios, including high-risk revision cases, other revision surgeries, and even infection prevention measures in initial surgery. This development has the potential to have a significant clinical impact and could result in annual savings of approximately $1 billion for the US healthcare system. Furthermore, by applying this honeycomb percolation model to the encapsulation of other drugs, UHMWPE has the potential to become a novel drug delivery material that can address a wide range of diseases.

[0144] Each reference identified herein is incorporated herein by reference in its entirety.

[0145] While the concept of the present invention has been described with reference to specific embodiments, those skilled in the art will understand that various substitutions and / or other modifications can be made to the embodiments without departing from the spirit of the concept of the invention. Accordingly, the description herein is illustrative and does not limit the scope of the concept of the invention.

[0146] Many examples are provided here. It should be understood that various modifications are possible. For example, if the described techniques are performed in a different order, and / or if the components within the described systems, architectures, devices, or circuits are combined in different ways, and / or replaced or supplemented with other components or their equivalents, suitable results may be obtained. Therefore, other embodiments are also within the scope of the concept of the present invention.

[0147] While the disclosed subject matter is described above in relation to specific embodiments and examples, it will be understood by those skilled in the art that the present invention is not necessarily limited thereto. Furthermore, numerous other embodiments, examples, uses, modifications, and departures from embodiments, examples, and uses are intended to be encompassed within the claims appended herein. Each reference cited herein is incorporated herein by reference in its entirety.

[0148] Various features and benefits are described in the numbered footnotes below.

[0149] For completeness, various aspects of the present invention are specified in the following numbered appendices.

[0150] (Additional note 1) A pharmaceutical composition comprising a porous encapsulation medium and particles of an active pharmaceutical ingredient encapsulated within the pores of the porous encapsulation medium.

[0151] (Additional note 2) The pharmaceutical composition according to Appendix 1, wherein the particles of the active pharmaceutical ingredient have an average size of less than 1 μm.

[0152] (Additional note 3) The encapsulating medium is a pharmaceutical composition according to any one of the appendices 1 to 2, comprising a polymer material.

[0153] (Additional note 4) The aforementioned polymer material is the pharmaceutical composition according to Appendix 3, comprising ultra-high molecular weight polyethylene (UHMWPE).

[0154] (Additional note 5) The pharmaceutical composition according to any one of the appendices 1 to 4, wherein the active pharmaceutical ingredient includes an antibiotic, a nonsteroidal anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.

[0155] (Additional note 6) The active pharmaceutical ingredient is an antibiotic, as described in Appendix 5 of the pharmaceutical composition.

[0156] (Additional note 7) The aforementioned antibiotic is the pharmaceutical composition described in Appendix 6, comprising gentamicin sulfate.

[0157] (Additional note 8) A pharmaceutical composition according to any one of the appendices 1 to 7, comprising approximately 1% to approximately 50% by weight of the active pharmaceutical ingredient.

[0158] (Additional note 9) The aforementioned encapsulation medium includes ultra-high molecular weight polyethylene (UHMWPE), The active pharmaceutical ingredient includes gentamicin sulfate, The particles of the active pharmaceutical ingredient have an average size of less than 1 μm. The pharmaceutical composition contains approximately 1% to approximately 20% by weight of the active pharmaceutical ingredient. The pharmaceutical composition described in Appendix 1.

[0159] (Additional note 10) A molded solid pharmaceutical composition as described in any one of the appendices 1 to 9.

[0160] (Additional note 11) A pharmaceutical composition according to any one of the appendices 1 to 10, having an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break (EAB) of at least 300%, and / or a yield strength of at least 15 MPa.

[0161] (Additional note 12) The pharmaceutical composition comprises at least 6% by weight of the active pharmaceutical ingredient. The active pharmaceutical ingredient, when measured in water at 37°C, has a release rate of at least 0.1 mg / day per 100 cm² over 28 days, and / or a cumulative release of at least 3% over 5 days. A pharmaceutical composition as described in any one of the appendices 1 to 11.

[0162] (Additional note 13) The active pharmaceutical ingredient is the pharmaceutical composition described in Appendix 12, comprising gentamicin sulfate.

[0163] (Additional note 14) A method for preparing a pharmaceutical composition, A dispersion of the active pharmaceutical ingredient is generated in a liquid phase containing a solvent. The process includes manufacturing the pharmaceutical composition by bringing a porous encapsulation medium into contact with the dispersion of the active pharmaceutical component, The particles of the active pharmaceutical ingredient are enclosed within the pores of the porous encapsulation medium. A method for preparing a pharmaceutical composition.

[0164] (Additional note 15) The method according to Appendix 14, wherein the particles of the active pharmaceutical ingredient have an average size of less than 1 μm.

[0165] (Additional note 16) The encapsulation medium is a polymer material, as described in any one of appendices 14 to 15.

[0166] (Additional note 17) The polymer material is the method described in Appendix 16, comprising ultra-high molecular weight polyethylene (UHMWPE).

[0167] (Additional note 18) The method according to any one of Appendix 14 to 17, wherein the active pharmaceutical ingredient includes an antibiotic, a nonsteroidal anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.

[0168] (Additional note 19) The method described in Appendix 18, wherein the active pharmaceutical ingredient includes an antibiotic.

[0169] (Additional note 20) The antibiotic is the method described in Appendix 19, comprising gentamicin sulfate.

[0170] (Additional note 21) The method according to any one of the appendices 14 to 20, wherein the manufactured pharmaceutical composition contains about 1% to about 50% by weight of the active pharmaceutical ingredient.

[0171] (Additional note 22) The method according to any one of the appendices 14 to 21, wherein the liquid phase further comprises an inert component, a precipitant, a viscosity modifier, a surfactant, a pH adjuster, an emulsifier, or a combination thereof.

[0172] (Additional note 23) The method according to Appendix 22, wherein the liquid phase further comprises a precipitant containing a non-solvent.

[0173] (Additional note 24) The method according to any one of the appendices 14 to 23, comprising generating a dispersion of gentamicin sulfate in a liquid phase containing approximately 30 (v / v)% water and approximately 70 (v / v)% ethanol.

[0174] (Additional note 25) The porous encapsulation medium is an antibiotic, as described in any one of the appendices 14 to 24.

[0175] (Additional note 26) The porous encapsulation medium is a method according to any one of appendices 14 to 25, comprising a crosslinking agent.

[0176] (Additional note 27) The method according to any one of the appendices 14 to 26, further comprising drying and / or dehydrating the pharmaceutical composition to produce a dried pharmaceutical composition.

[0177] (Additional note 28) The method according to Appendix 27, further comprising molding the dry pharmaceutical composition by a thermoforming process.

[0178] (Additional note 29) A pharmaceutical composition manufactured by the method described in any one of the appendices 14 to 28.

[0179] (Additional note 30) The pharmaceutical composition according to Appendix 29, having an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break of at least 300%, and / or a yield strength of at least 15 MPa.

[0180] (Additional note 31) The pharmaceutical composition comprises at least 6% by weight of the active pharmaceutical ingredient. The aforementioned active pharmaceutical ingredient, when measured in water at 37°C, was found to have a concentration of 100 cm³ over 28 days. 2 Having a release rate of at least 0.1 mg / day and / or a cumulative release of at least 3% over 5 days, A pharmaceutical composition as described in any one of the appendices 29 to 30.

[0181] (Additional note 32) The active pharmaceutical ingredient is a pharmaceutical composition according to any one of the appendices 29 to 31, comprising gentamicin sulfate.

[0182] (Additional note 33) A medical device comprising the pharmaceutical composition described in any one of the appendices 1 to 13 and 29 to 32.

[0183] (Additional note 34) An implant, a medical device as described in Appendix 33.

[0184] (Additional note 35) A joint replacement implant, a medical device as described in Appendix 34.

[0185] (Additional note 36) A medical device as described in Appendix 34, which is a joint replacement spacer for the treatment and / or prevention of infection.

[0186] (Additional note 37) A joint replacement implant comprising a thermoformed polymer material containing ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate, wherein gentamicin sulfate particles are encapsulated within the pores of the thermoformed polymer material.

[0187] (Additional note 38) The gentamicin sulfate particles have an average size of less than 1 μm, as described in Appendix 37, for the joint replacement implant.

[0188] (Additional note 39) A joint replacement implant as described in any one of the appendices 37-38, containing approximately 2% to 20% by weight of gentamicin sulfate.

[0189] (Additional note 40) A method for preparing implants, A dispersion of gentamicin sulfate is prepared in a liquid phase containing a solvent and a non-solvent. An implant composition is manufactured by contacting a porous encapsulation medium containing ultra-high molecular weight polyethylene (UHMWPE) with the dispersion of gentamicin sulfate, thereby encapsulating the gentamicin sulfate particles within the pores of the porous encapsulation medium. A method comprising manufacturing the implant by thermoforming the implant composition.

[0190] (Additional note 41) A dry implant composition is produced by removing the solvent and the non-solvent from the implant composition. The process includes manufacturing the implant by thermoforming the dried implant composition. The method described in Appendix 40.

[0191] (Additional note 42) The gentamicin sulfate particles have an average size of less than 1 μm, as described in any one of appendices 40 to 41.

[0192] (Additional note 43) The implant is provided according to any one of the appendices 40 to 42, comprising approximately 2% to 20% by weight of gentamicin sulfate.

[0193] (Additional note 44) The method according to any one of the appendices 40 to 43, further comprising processing the implant manufactured by thermoforming to form a shaped implant.

[0194] (Additional note 45) An implant manufactured by the method described in any one of the appendices 40 to 44.

Claims

1. Porous encapsulation medium and The porous encapsulating medium contains particles of an active pharmaceutical ingredient encapsulated within its pores, Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the particles of the active pharmaceutical component have an average size of less than 1 μm.

3. The pharmaceutical composition according to claim 1, wherein the encapsulating medium comprises a polymer material.

4. The pharmaceutical composition according to claim 3, wherein the polymer material comprises ultra-high molecular weight polyethylene (UHMWPE).

5. The pharmaceutical composition according to claim 1, wherein the active pharmaceutical component includes an antibiotic, a nonsteroidal anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.

6. The pharmaceutical composition according to claim 5, wherein the active pharmaceutical ingredient includes an antibiotic.

7. The pharmaceutical composition according to claim 6, wherein the antibiotic comprises gentamicin sulfate.

8. The pharmaceutical composition according to claim 1, comprising approximately 1% to approximately 50% by weight of the active pharmaceutical ingredient.

9. The aforementioned encapsulation medium includes ultra-high molecular weight polyethylene (UHMWPE), The active pharmaceutical ingredient includes gentamicin sulfate, The particles of the active pharmaceutical ingredient have an average size of less than 1 μm. The pharmaceutical composition contains approximately 1% to approximately 20% by weight of the active pharmaceutical ingredient. The pharmaceutical composition according to claim 1.

10. The pharmaceutical composition according to claim 1, which is a molded solid.

11. The pharmaceutical composition according to claim 1, having an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break (EAB) of at least 300%, and / or a yield strength of at least 15 MPa.

12. The pharmaceutical composition comprises at least 6% by weight of the active pharmaceutical ingredient. The aforementioned active pharmaceutical ingredient, when measured in water at 37°C, was found to have a concentration of 100 cm over 28 days. ２ Having a release rate of at least 0.1 mg / day and / or a cumulative release of at least 3% over 5 days, The pharmaceutical composition according to claim 1.

13. The pharmaceutical composition according to claim 12, wherein the active pharmaceutical ingredient comprises gentamicin sulfate.

14. A method for preparing a pharmaceutical composition, A dispersion of the active pharmaceutical ingredient is generated in a liquid phase containing a solvent. The process includes manufacturing the pharmaceutical composition by bringing a porous encapsulation medium into contact with the dispersion of the active pharmaceutical component, The particles of the active pharmaceutical ingredient are enclosed within the pores of the porous encapsulation medium. A method for preparing a pharmaceutical composition.

15. The method according to claim 14, wherein the particles of the active pharmaceutical ingredient have an average size of less than 1 μm.

16. The method according to claim 14, wherein the encapsulation medium comprises a polymer material.

17. The method according to claim 16, wherein the polymer material comprises ultra-high molecular weight polyethylene (UHMWPE).

18. The method according to claim 14, wherein the active pharmaceutical ingredient includes an antibiotic, a nonsteroidal anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.

19. The method according to claim 18, wherein the active pharmaceutical ingredient includes an antibiotic.

20. The method according to claim 19, wherein the antibiotic comprises gentamicin sulfate.

21. The method according to claim 14, wherein the manufactured pharmaceutical composition contains about 1% to about 50% by weight of the active pharmaceutical ingredient.

22. The method according to claim 14, wherein the liquid phase further comprises an inert component, a precipitant, a viscosity modifier, a surfactant, a pH adjuster, an emulsifier, or a combination thereof.

23. The method according to claim 22, wherein the liquid phase further comprises a precipitant containing a non-solvent.

24. The method according to claim 14, comprising generating a dispersion of gentamicin sulfate in a liquid phase containing about 30 (v / v)% water and about 70 (v / v)% ethanol.

25. The method according to claim 14, wherein the porous encapsulation medium contains an antibiotic.

26. The method according to claim 14, wherein the porous encapsulation medium includes a crosslinking agent.

27. The method according to claim 14, further comprising drying and / or dehydrating the pharmaceutical composition to produce a dried pharmaceutical composition.

28. The method according to claim 27, further comprising molding the dried pharmaceutical composition by a thermoforming process.

29. A pharmaceutical composition produced by the method described in claim 14.

30. The pharmaceutical composition according to claim 29, having an ultimate tensile strength (UTS) of at least 30 MPa, an elongation at break of at least 300%, and / or a yield strength of at least 15 MPa.

31. The pharmaceutical composition comprises at least 6% by weight of the active pharmaceutical ingredient. The aforementioned active pharmaceutical ingredient, when measured in water at 37°C, was found to have a concentration of 100 cm over 28 days. ２ Having a release rate of at least 0.1 mg / day and / or a cumulative release of at least 3% over 5 days, The pharmaceutical composition according to claim 29.

32. The pharmaceutical composition according to claim 29, wherein the active pharmaceutical ingredient comprises gentamicin sulfate.

33. A medical device comprising the pharmaceutical composition described in claim 1.

34. The medical device according to claim 33, which is an implant.

35. A medical device according to claim 34, which is a joint replacement implant.

36. A medical device according to claim 34, which is a joint replacement spacer for the treatment and / or prevention of infectious diseases.

37. A joint replacement implant comprising a thermoformed polymer material containing ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate, wherein gentamicin sulfate particles are encapsulated within the pores of the thermoformed polymer material.

38. The joint replacement implant according to claim 37, wherein the gentamicin sulfate particles have an average size of less than 1 μm.

39. The joint replacement implant according to claim 37, comprising approximately 2% to approximately 20% by weight of gentamicin sulfate.

40. A method for preparing implants, A dispersion of gentamicin sulfate is prepared in a liquid phase containing a solvent and a non-solvent. An implant composition is manufactured by contacting a porous encapsulation medium containing ultra-high molecular weight polyethylene (UHMWPE) with the dispersion of gentamicin sulfate, thereby encapsulating the gentamicin sulfate particles within the pores of the porous encapsulation medium. A method comprising manufacturing the implant by thermoforming the implant composition.

41. A dry implant composition is produced by removing the solvent and the non-solvent from the implant composition. The process includes manufacturing the implant by thermoforming the dried implant composition. The method according to claim 40.

42. The method according to claim 40, wherein the gentamicin sulfate particles have an average size of less than 1 μm.

43. The method according to claim 40, wherein the implant contains about 2% to about 20% by weight of gentamicin sulfate.

44. The method according to claim 40, further comprising processing the implant manufactured by thermoforming to form a shaped implant.

45. An implant manufactured by the method described in claim 40.

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