WO2024250016A2 - Encapsulation d'ingrédients pharmaceutiques actifs - Google Patents

Encapsulation d'ingrédients pharmaceutiques actifs Download PDF

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Publication number
WO2024250016A2
WO2024250016A2 PCT/US2024/032279 US2024032279W WO2024250016A2 WO 2024250016 A2 WO2024250016 A2 WO 2024250016A2 US 2024032279 W US2024032279 W US 2024032279W WO 2024250016 A2 WO2024250016 A2 WO 2024250016A2
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
uhmwpe
particles
implant
active pharmaceutical
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PCT/US2024/032279
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WO2024250016A3 (fr
Inventor
Orhun Muratoglu
Ebru ORAL BHATIA
Mehmet D. ASIK
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General Hospital Corp
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General Hospital Corp
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Priority to AU2024283092A priority Critical patent/AU2024283092A1/en
Priority to EP24816672.0A priority patent/EP4719358A2/fr
Publication of WO2024250016A2 publication Critical patent/WO2024250016A2/fr
Publication of WO2024250016A3 publication Critical patent/WO2024250016A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)

Definitions

  • the present disclosure relates to encapsulating compounds in an encapsulating medium, e. g., encapsulating active pharmaceutical ingredients (API) such as antibiotics, non-steroid antiinflammatory drugs (NSAIDs), analgesics, and other drugs in polyethylene (PE) for the treatment/prevention of infection and/or pain management or encapsulating inactive ingredients such as salts, rubbers, or ceramics in polyethylene to alter its physical and/or chemical characteristics for the fabrication of medical devices.
  • active pharmaceutical ingredients such as antibiotics, non-steroid antiinflammatory drugs (NSAIDs), analgesics, and other drugs in polyethylene (PE) for the treatment/prevention of infection and/or pain management or encapsulating inactive ingredients such as salts, rubbers, or ceramics in polyethylene to alter its physical and/or chemical characteristics for the fabrication of medical devices.
  • Total joint replacements are essential in alleviating pain and improving the quality’ of life for individuals suffering from end-stage joint disease.
  • One of the primary failure modes associated with total joint replacements is prosthetic joint infection (PJI), which can occur through surgical site infection, hematogenous spread, or contiguous infection. While the risk of total joint infection is relatively low — with infection rates typically ranging from 0.6% to 2.4% — the consequences can be severe, leading to significant morbidity and mortality 7 . Infection in a total joint replacement can result in prolonged hospitalization, the need for additional surgeries (such as implant removal or revision), increased pain, functional impairment, and reduced quality of life for the affected individual.
  • PJI prosthetic joint infection
  • PJIs are commonly treated with intravenous or oral antibiotic therapy, surgical debridement, and irrigation with retention of components or revision of the joint components (one- or two-stage).
  • a two-stage revision which is considered the gold standard for treatment, involves replacing the infected components with an antibiotic spacer and administering a prolonged course of systemic antibiotics before performing a second surgery' to implant new 7 components.
  • Antibiotic spacers are typically made of bone cement, which is mixed w ith high doses of antibiotics, commonly vancomycin and gentamicin/tobramycin.
  • the primary 7 role of spacers is to presen e the joint space and prevent joint contracture. Also, local antibiotic elution from spacers supports the effect of systemic antibiotics by minimizing the risk of bacteria growth and recolonization on the spacer implants and the local tissues.
  • Antibiotic spacers while moderately valuable in managing PJI, have limitations that can affect their overall success. These include the risk of spacer fracture, dislocation, synovitis caused by spacer implant wear and limited long-term antibiotic release.
  • Ultrahigh molecular weight polyethylene UHMWPE was proposed as an alternative material for antibiotic spacers for its therapeutic potential as well as load-bearing properties.
  • Antibiotic-releasing polyethylene offers several advantages that can potentially address limitations associated with traditional bone cement spacers with better mechanical properties, reduced risk of particulate generation (low er wear), and improved long-term antibiotic release.
  • the present disclosure provides pharmaceutical compositions and methods that overcome the aforementioned drawbacks by providing a blending process that offers enhanced mechanical properties.
  • Incorporation of UHMWPE with sub-micron API particles provides enhanced mechanical properties and drug release profiles relative to traditional blending techniques.
  • the pharmaceutical composition can 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.
  • UTS ultimate tensile strength
  • EAB elongation at break
  • the pharmaceutical composition can comprise at least 6% by weight the active pharmaceutical ingredient, and the active pharmaceutical ingredient can have a release rate of at least 0.1 mg/day per 100 cm 2 for 28 days and/or a cumulative release of at least 3% in 5 days, as measured in water at 37°C.
  • a method of preparing a pharmaceutical composition can comprise generating a dispersion of an active pharmaceutical ingredient in a liquid phase comprising a solvent.
  • the method can further comprise contacting the dispersion of the active pharmaceutical ingredient with a porous encapsulating medium, thereby producing the pharmaceutical composition, wherein particles of the active pharmaceutical ingredient are encapsulated in the pores of the porous encapsulating medium.
  • the active pharmaceutical ingredient can include an antibiotic, such as gentamicin sulfate.
  • the method comprises generating a dispersion of gentamicin sulfate in a liquid phase comprising about 30% (v/v) water and about 70% (v/v) ethanol.
  • the method can further comprise dry ing and/or dehydrating the pharmaceutical composition to produce a dried pharmaceutical composition.
  • the method can further comprise molding the dried pharmaceutical composition by a heat molding process.
  • the present disclosure provides a pharmaceutical composition produced by the preparation method as described herein.
  • the present disclosure provides a medical device comprising a pharmaceutical composition as described herein or a pharmaceutical composition produced by the preparation method as described herein.
  • the medical device can be, for example, an implant such as a joint replacement implant.
  • a joint replacement implant comprises a heat molded polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate, wherein particles of gentamicin sulfate are encapsulated in pores of the heat molded polymeric material.
  • UHMWPE ultra-high molecular weight polyethylene
  • a method of preparing an implant comprises: generating a dispersion of a gentamicin sulfate in a liquid phase comprising a solvent and a non-solvent; contacting the dispersion of gentamicin sulfate with a porous polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE), thereby producing an implant composition, wherein particles of gentamicin sulfate are encapsulated in the pores of the porous polymeric material; and heat molding the implant composition to produce the implant.
  • UHMWPE ultra-high molecular weight polyethylene
  • FIG. 1 A is a flow chart of a method for preparing a pharmaceutical composition, according to aspects of the present disclosure.
  • FIG. IB is a flow- chart of a method of preparing an implant, according to aspects of the present disclosure.
  • FIG. 2 is a set of elemental analysis images of polyethylene blocks prepared w ith API particles UHMWPE blends and cold molding cycle.
  • Top Left Electron image.
  • Top Right Overlapped C, O, and S Kai image.
  • Bottom Middle O Kai image.
  • FIG. 3 is a set of elemental analysis images of polyethylene blocks prepared w ith API particles UHMWPE blends and hot molding cycle. Top Left: Electron image. Top Right: EDS layered image. Bottom Left: S Kai image. Botom Middle: O Kai image. Botom Right: C Kai image.
  • FIG. 4A is a light microscopy image of polyethylene blocks prepared with API particles UHMWPE blends and hot molding cycle.
  • FIG. 4B is a light microscopy image of polyethylene blocks prepared with conventional blending and cold molding cycle.
  • FIG. 5A is a plot of the gentamicin release rate from UHMWPE prepared with GSWE-140 pow der and tablets.
  • FIG. 5B is a plot of the gentamicin percent cumulative release from UHMWPE prepared w ith GSWE-140 powder and tablets.
  • FIG. 6A is a plot of gentamicin release rate from UHMWPE prepared with WGSE -140 powder and tablets.
  • FIG. 6B is a plot of gentamicin percent cumulative release from UHMWPE prepared with WGSE -140 powder and tablets.
  • FIG. 7A is a plot of the tensile test results of GSWE -140 Powder.
  • FIG. 7B is a plot of the tensile test result of GSWE-140 Tablet.
  • FIG. 8A is a plot of the ultimate tensile strength of WGSE -140 with different gentamicin loading ratios.
  • FIG. 8B is a plot of the elongation at break of WGSE -140 with different gentamicin loading ratios.
  • FIG. 9 is a plot of IZOD test results of WGSE -140 with different gentamicin loading ratios.
  • FIG. 1 OH is a SEM EDX combined elemental map of FIGS. 9E-9G.
  • FIG. 101 is a FIB-SEM micrograph.
  • FIG. 10J is a FIB-SEM EDX nitrogen elemental map (N in green).
  • FIG. 1 OK is a FIB-SEM EDX nitrogen sulfur elemental map (S in orange).
  • FIG. 10L is a FIB-SEM image with combined map of FIGS. 9I-9K.
  • FIG. 10M is a schematic of boundaries of the UHMWPE flakes in resolidified (left), as- received (middle), and sub-micron GS UHMWPE blends (right).
  • FIG. 11 A is a plot of the ultimate tensile strength (UTS) for 10% GS UHMWPE blend show ed vary 7 ing mechanical properties among resolidified, as-received, and sub-micron GS UHMWPE blends. Sub-micron GS UHMWPE blend showed the highest UTS (A).
  • UTS ultimate tensile strength
  • FIG. 1 IB is a plot of the elongation at break (EAB) for 10% GS UHMWPE blend showed varying mechanical properties among resolidified, as-received, and sub-micron GS UHMWPE blends. EAB measurements w ere lower only for the resolidified particles among the three blends studied.
  • FIG. 11C is a plot of the yield strength (YS) for 10% GS UHMWPE blend showed vary ing mechanical properties among resolidified, as-received, and sub-micron GS UHMWPE blends. YS of the sub-micron blend was higher than those of as-received and resolidified blends (C).
  • FIG. 1 ID is a plot of the EAB for vary ing GS UHMWPE blend percentages. Increased GS content led to reductions in EAB.
  • FIG. 1 IE is a plot of the UTS for varying GS UHMWPE blend percentages. Increased GS content led to reductions in UTS.
  • FIG. 1 IF is a plot of IZOD impact strength for varying GS UHMWPE blend percentages. Increased GS content led to reductions in IZOD impact strength.
  • FIG. 12A is a plot comparing the normalized release rate of resolidified GS UHMWPE, as- received GS UHMWPE, and sub-micron GS UHMWPE blend of GS eluted from varying size GS UHMWPE blends as a function of time.
  • the release rate did not vary between resolidified and as- received GS UHMWPE blends after the 6-hour burst, while that of sub-micron GS UHMWPE blend w as significantly higher than those of the other two blends. After the 6-hour and I -day burst releases, the release rate stayed constant for 6% and 8% GS loading in sub-micron GS UHMWPE blends.
  • FIG. 12B is a plot comparing the fractional cumulative release of resolidified GS UHMWPE, as-received GS UHMWPE, and sub-micron GS UHMWPE blend of GS eluted from varying size GS UHMWPE blends as a function of time.
  • FIG. 12C is a plot comparing the normalized cumulative release of resolidified GS UHMWPE, as-received GS UHMWPE, and sub-micron GS UHMWPE blend of GS eluted from varying size GS UHMWPE blends as a function of time.
  • FIG. 12D is a plot comparing the normalized release rate of GS eluted from sub-micron GS UHMWPE blends w ith different loadings (10%, 8%, and 6%) as a function of time. Release rate of 10% sub-micron GS UHMWPE was significantly higher than those of the other tw o blends for 28 days.
  • FIG. 12E is a plot comparing the fractional cumulative release of GS eluted from sub-micron GS UHMWPE blends with different loadings (10%, 8%, and 6%) as a function of time.
  • FIG. 12F is a plot comparing the normalized cumulative release of GS eluted from sub-micron GS UHMWPE blends with different loadings (10%, 8%, and 6%) as a function of time.
  • FIG. 12G is a plot of the predicted in-vivo concentrations resulting from gentamicin release from the 6%, 8%, and 10% sub-micron GS UHMWPE blends. Sub-micron GS UHMWPE blends with both 8% and 10% loading could maintain intra-articular concentrations for lOOxMIC levels at 28 days.
  • FIG. 12H is a plot of the predicted in-vivo concentrations resulting from gentamicin release from sub-micron GS UHMWPE blends, solidified GS UHMWPE blends, and as-received GS UHMWPE blends.
  • FIG. 13 A is a plot of the predicted intraarticular GS concentration resulting from gentamicin release from 6%, 8%, and 10% sub-micron GS UHMWPE blends (3-hour half-life scenario).
  • FIG. 13B is a plot of the predicted intraarticular GS concentration resulting from gentamicin release from 6%, 8%, and 10% sub-micron GS UHMWPE blends (6-hour half-life scenario).
  • the predictive models indicated a discernible difference in intraarticular GS concentration between the 3- hour (FIG. 12A) and 6-hour half-life scenarios.
  • the GS concentration for an 8% loading fell below the 100x MIC threshold but remained significantly above the I0x MIC limit.
  • the 6-hour half-life model exhibited sustained concentrations above both MIC thresholds for a longer duration.
  • FIG. 14A is a plot of the predicted GS concentration in joint spaces resulting from gentamicin release from different sizes of GS UHMWPE blends, including resolidified, as-received, and submicron GS (3-hour half-life scenario).
  • FIG. 14B is a plot of the predicted GS concentration in joint spaces resulting from gentamicin release from different sizes of GS UHMWPE blends, including resolidified, as-received, and submicron GS (6-hour half-life scenario).
  • FIG. 15 is a 'H NMR spectra of GS (panel A) and GS eluted from the sub-micron GS UHMWPE blend (panel B).
  • the spectra exhibited a high degree of structural similarity. Both spectra displayed characteristic peaks at specific chemical shift values, suggesting the preservation of key functional groups in GS after its integration with the UHMWPE matrix. The consistency in the intensity and multiplicity of these peaks further supported the notion that the chemical environment of the hydrogen atoms in GS remained largely unchanged after blending and high temperature (170 °C molding). This was particularly evident in the overlapping regions of the spectra, where the alignment of peaks indicated a similar distribution of chemical environments. Additionally, the absence of new or shifted peaks in the spectrum of eluted GS (B) suggested that the blending and molding processes did not significantly alter the molecular structure of GS.
  • FIG. 17 is a comparison of J H NMR spectra ranges of GS (black line) and GS eluted from submicron GS UHMWPE blend (red line).
  • the specific chemical shift ranges examined were: 4.18-4.04 (top left panel), 3.61-3.38 (top right panel), 2.52 -1.9 (bottom left panel), and 1.32-1.22 ppm (bottom right panel).
  • a key observation was the variation in peak heights, attributable to concentration differences between the control GS and the eluted GS. Despite these differences, the overall peak patterns appeared comparable across all ranges. This similarity suggests that the elution process does not significantly alter the fundamental molecular structure of GS.
  • API particles are dry blended with an encapsulation media, dehydrated, and molded.
  • gentamicin sulfate particles are dry blended with UHMWPE powder flakes, dehydrated, and molded.
  • the molded articles ty pically have domains of clustered API articles within the encapsulation media, for example, gentamicin sulfate particles clustered within the UHMWPE matrix. These clusters adversely affect the mechanical properties of UHMWPE.
  • implant performance depends on many factors, especially on the mechanical properties of the implant, some of w hich could be fabricated with UHMWPE/ API blends.
  • aspects of the present disclosure allow 7 for control of the particle size of the API within the encapsulation media by precipitating the API from a solution by using precipitation agents, such as solvents, in which the API has low solubility' to control the particle size of the API domains.
  • precipitation agents such as solvents
  • the present methods and compositions result in a much smaller API particle size in the encapsulation media and hence results in better mechanical properties and better w ear resistance of the consolidated blend.
  • the present method and compositions also allow' for better control of the burst release and long-term elution rate of the API from the encapsulating media.
  • API(s) encapsulated within encapsulation media with tailored mechanical properties and/or API elution characteristics can be administered to achieve desired therapeutic outcomes.
  • a medical device fabricated from UHMWPE encapsulated with antibiotics with high strength, high wear resistance, antibiotic elution at therapeutic levels can be used to treat periprosthetic joint infection in total joint patients or can be used to prevent infection or can be used to provide an implant that decreases the extent of bacterial colonization on implant surfaces.
  • Another example is a medical device fabricated from UHMWPE encapsulated with analgesics with desirable mechanical properties and/or wear resistance that can be used as an implant to help in pain management.
  • in-situ formed active pharmaceutical ingredient (API) particles can be encapsulated in an encapsulation media for instance UHMWPE, PLGA, bone cement by: (i) Adding the API into a solvent or a mixture of solvents whereby creating a solution, (ii) precipitating particles of API in said solution by a variety' of methods, for instance by adding a nonsolvent, (iii) mixing said API particles yvith an encapsulation media forming a blend, (iv) drying said blend, (v) optionally dehydrating the dried blend, and (vi) molding the blend.
  • an encapsulation media for instance UHMWPE, PLGA, bone cement by: (i) Adding the API into a solvent or a mixture of solvents whereby creating a solution, (ii) precipitating particles of API in said solution by a variety' of methods, for instance by adding a nonsolvent, (iii) mixing said API particles yvith an encapsulation media forming a blend, (
  • API-doped encapsulation media blocks and encapsulating active and/or inactive ingredients are described.
  • This novel method can be used to encapsulate any compound in an encapsulating medium to create a composite material and tailor its properties for a variety- of applications, such as delivery of a therapeutic agent, a medical implant, a fixation method to fix implants to bone, or a load bearing component.
  • the present disclosure describes decreasing antibiotic particle size encapsulated in UHMWPE to improve mechanical strength.
  • GS is typically a loose poyvder in its as-received form, and particle sizes are usually under 100 pm. Resolidification from solution is one method to fabricate larger GS particles, yvhich are commonly used in GS-containing bone cement. Smaller particles can be obtained by solvent/non-solvent precipitation.
  • UHMWPE samples are blended yvith gentamicin sulfate of different particle sizes and the effect of particle size and content on mechanical properties, elution characteristics, and morphological attributes are assessed.
  • a GS UHMWPE spacer that offers enhanced mechanical properties can be critical for patients yvith PJI.
  • a GS UHMWPE implant that combines high strength, superior wear resistance, and effective antibiotic elution at therapeutic levels could be a pivotal advancement: It has the potential to prevent periprosthetic j oint infections not just in high-risk revision cases but also in primary’ total joint arthroplasty- procedures.
  • the compositions and methods could significantly reduce the high morbidity and mortality- associated yvith PJIs and potentially save the US healthcare system over a billion dollars every- year.
  • the invention comprises, consists of, or consists essentially of the follo ving features, in any combination.
  • the present disclosure provides a pharmaceutical composition comprising a porous encapsulating medium and particles of an active pharmaceutical ingredient encapsulated in the pores of the porous encapsulating medium.
  • the encapsulating medium can be polymeric, metallic, ceramic, wood, fabric, composite material, or mixtures thereof.
  • the encapsulating medium comprises a polymeric material.
  • the encapsulating medium can be high density polyethylene, low density polyethylene, linear low density' polyethylene, ultra-high molecular weight polyethylene (for example GUR 1020, GUR 1050), or radiation or chemical crosslinked polyethylene.
  • the polymeric material can comprise ultra-high molecular weight polyethylene (UHMWPE).
  • the encapsulating medium has a porous surface.
  • a polymeric encapsulating medium may be UHMWPE in the form of powder flakes. These flakes can have surface porosity and bulk porosity to facilitate encapsulation of API particles.
  • the encapsulating medium contains antioxidants, for example vitamin- E, Irganox 1010 or other similar compounds as listed in US Patents Methods for Making Oxidation Resistant Material.
  • antioxidants for example vitamin- E, Irganox 1010 or other similar compounds as listed in US Patents Methods for Making Oxidation Resistant Material.
  • US Patent 12/904,481 Highly Crystalline Cross-linked Oxidation Resistant Polyethylene, US Patent 9,168,683, Oxidation Resistant Homogenized Polymeric Material.
  • US Patent 8,461,225 are examples of antioxidants, for example vitamin- E, Irganox 1010 or other similar compounds as listed in US Patents Methods for Making Oxidation Resistant Material.
  • US Patent 12/904,481 Highly Crystalline Cross-linked Oxidation Resistant Polyethylene, US Patent 9,168,683, Oxidation Resistant Homogenized Polymeric Material.
  • US Patent 8,461,225 US Patent 8,461,225.
  • pore,’' “porous,” or “porosity” as used herein in connection with the encapsulating medium can include any opening, void space, or hollow structure on the surface or inside of the material, such as surface pores, holes, and channels.
  • the encapsulating medium can have a porous surface and/or a porous bulk structure. In some embodiments, the encapsulating medium has a porous surface.
  • the pores of the porous encapsulating medium can have an average size of at least 0.010 pm, at least 0. 1 pm, at least 0.5 pm, at least 1 pm, at least 5 pm, at least 10 pm, at least 50 pm, at least 100 pm, at least 500 pm, or at least 1000 pm.
  • the active pharmaceutical ingredient as used herein can include an antibiotic, a non-steroid anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.
  • the active pharmaceutical ingredient comprises an antibiotic.
  • API vancomycin, tobramycin, gentamicin, cefadroxil, cefazolin, cephalexin, cefaclor, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef, cefdinir, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftozoxime, ceftriaxone, cefepime, amikacin, streptomycin, doxycycline, ery thromycin, gentamicin, isoniazid, rifampin, and ethambutol.
  • Sulfonamides including penicillin, cephalosporin, and carbepenems, aminoglycosides, quinolones, and oxazolidinones, and metals such as copper, iron, aluminum, zinc, gold, compound, and ions thereof, and various combinations thereof.
  • Nonsteroid anti-inflammatory drugs including but not limited to salicylate, indomethacin, flubiprofen, diclofenac, ketorolac, naproxen, piroxicam, tabferon, ibuprofen, etodolac, nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone, phenyl Butazone, Clofezone, Oxyphenbutazone, Plexazone, Apazone, Benzidoamine, Bucolome, Cinchopen, Clonixin, Ditrazol, Epilizol, Fenoprofen, Floctafenil, Flufenamic acid, Graphenin, Indoprofen, Ketoprofen, Meclofenamic acid, Mephenamine Acid, niflumic acid, phenacetin, salidifamide, sulindac, suprofen, tolmetin and their salts.
  • Salicylates include acetylsalicylic acid, sodium acetylsalicylate, calcium acetylsalicylate, salicylic acid and sodium salicylate.
  • the active pharmaceutical ingredient comprises an antibiotic, which comprises gentamicin sulfate.
  • the antibiotic is gentamicin sulfate.
  • Analgesics include opioid agonist and antagonists.
  • the opioid agonists include but are not limited to alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitmmide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levo
  • the opioid antagonists include but are not limited to naloxone (U.S. 3,254,088, which is incorporated herein by reference in its entirety), naltrexone (U.S. 3,332,950, which is incorporated herein by reference in its entirety) and mixtures thereof; or a pharmaceutically acceptable salt thereof.
  • the opioid analgesic or the analgesic is a combination of an opioid agonist and opioid antagonist (examples include, but are not limited to, suboxone which is a combination of buprenorphine and naloxone).
  • LPS lipopolysaccharides
  • CPG polyguanidines
  • bacterial lysates defensins and their salts such as hydrochloride sodium, sulfate, acetate, phosphate or diphosphate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, tartrate, aluminum, and/or gluconate.
  • APIs are local anesthetic agents, for example bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, xylocaine, and mixtures thereof.
  • the local anesthetic can be in the form of a salt, for example, hydrochloride, bromide, acetate, citrate, carbonate or sulfate.
  • APIs also comprise therapeutic biomolecules, for example polypeptides, proteins, amino acids, polysaccharides, disaccharides, lipids, natural and synthetic nucleic acids, including but not limited to modified ribonucleic acids (RNA), mRNAs, microRNAs, siRNAs, shRNAs, and other RNAi types, double strand linear deoxyribonucleic acids (DNA), double strand circular DNA, single strand linear DNA and mixtures thereof.
  • RNA modified ribonucleic acids
  • mRNAs mRNAs
  • microRNAs microRNAs
  • siRNAs siRNAs
  • shRNAs shRNAs
  • DNA double strand linear deoxyribonucleic acids
  • the API particles include or are replaced vx ith a compound (or particles of the compound) comprising of chemicals such as salts, metals, ceramics, composites, rubbers and any reinforcing agents such as calcium chloride, and/or nano-sized rubber particles.
  • the particles of the active pharmaceutical ingredient have an average size of less than 1 pm.
  • the encapsulated particles of the API can have an average size of less than 0.9 pm, less than 0.8 pm, less than 0.6 pm, less than 0.4 pm, less than 0.2 pm, less than 0.1 pm, less than 0.05 pm, less than 0.01 pm, less than 0.005 pm, or less than 0.001 pm.
  • the pharmaceutical composition can have about 1% to about 50% by weight the API.
  • the pharmaceutical composition can have 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 the API.
  • the amount of the API in the present pharmaceutical composition can 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.
  • the pharmaceutical composition comprises about 2% to about 20% by weight the API, such as about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, or about 18% by weight.
  • the present disclosure provides a pharmaceutical composition, in which the encapsulating medium includes the polymeric material UHMWPE, the API comprises gentamicin sulfate (GS), and the particles of the API have an average size of less than 1 pm, and which comprises about 1% to about 20% (such as about 2% to about 20% or about 2% to about 10%) by weight the API.
  • the encapsulating medium includes the polymeric material UHMWPE
  • the API comprises gentamicin sulfate (GS)
  • the particles of the API have an average size of less than 1 pm, and which comprises about 1% to about 20% (such as about 2% to about 20% or about 2% to about 10%) by weight the API.
  • 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.
  • the pharmaceutical composition may be a molded solid.
  • the present pharmaceutical composition may have improved mechanical properties as compared to conventional compositions.
  • the present pharmaceutical composition may have an ultimate tensile strength (UTS) of at least 30 MPa, and elongation break (EAB) of at least 300%, and/or a yield strength of at least 15 MPa.
  • UTS ultimate tensile strength
  • EAB elongation break
  • the present pharamaceutical composition may have improved release profile of the encapsulated API as compared to conventional compositions.
  • the release rate can be adjusted, for example, by controlling the API load, the porosity of the encapsulating medium, and the inclusion of other components in the formulation.
  • the release rate can be measured at a predetermined API load (wt %) over a period of time under relevant conditions (such as release in water at 37°C).
  • the pharmaceutical composition comprises at least 6% by w eight the active pharmaceutical ingredient, and the active pharmaceutical ingredient has a release rate of at least 0.1 mg/day per 100 cm 2 for 28 days and/or a cumulative release of at least 3% in 5 days, as measured in water at 37°C.
  • Release rate is synonymous with elution rate and they both refer to rate at which the API is released from the encapsulating medium.
  • the unit for the release rate is defined as the mass of API per day per surface area of the encapsulating medium.
  • the encapsulating medium is a tibial implant used in total knee arthroplasty' surgery' - ty pically the articular surface area together yvith the surface area of the side w all of the implant is approximately 100 cm 2 . Therefore, the release rate can be measured as mass of API released per day per 100cm 2 , for example, to represent the release rate from a tibial implant fabricated from an encapsulating medium comprising API.
  • the release rate can be, for example, 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, per 100 cm 2 for 28 days.
  • the cumulative release can be, for example, at least 5%, at least 10%, at least 15%, or at least 20% in 5 days.
  • the pharmaceutical composition comprises at least 6% by weight gentamicin sulfate and has a release rate of at least 0. 1 mg/day per 100 cm 2 for 28 days and/or a cumulative release of at least 3% in 5 days, as measured in water at 37°C.
  • the present disclosure provides a method of preparing a pharmaceutical composition.
  • the method comprises: generating a dispersion of an active pharmaceutical ingredient in a liquid phase comprising a solvent; and contacting the dispersion of the active pharmaceutical ingredient with a porous encapsulating medium, thereby producing the pharmaceutical composition, wherein particles of the active pharmaceutical ingredient are encapsulated in the pores of the porous encapsulating medium.
  • the method may be used to prepare a pharmaceutical composition as described herein.
  • the particles of the active pharmaceutical ingredient have an average size of less than 1 pm.
  • the encapsulating medium comprises a polymeric material.
  • the polymeric material can comprise ultra-high molecular weight polyethylene (UHMWPE).
  • the active pharmaceutical ingredient comprises an antibiotic, a non-steroid antiinflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.
  • the active pharmaceutical ingredient comprises an antibiotic.
  • the antibiotic can comprise gentamicin sulfate.
  • the antibiotic is gentamicin sulfate.
  • the pharmaceutical composition produced by the present method comprises about 1% to about 50% (such as about 2% to about 20% or about 2% to about 10%) by weight the active pharmaceutical ingredient.
  • the solvent used herein can include any medium in which the active pharmaceutical ingredient can be dissolved.
  • Suitable solvents include polar, nonpolar, aqueous, and organic solvents, and mixtures thereof.
  • Example solvents include, for example, water, ethanol, isopropanol, acetone, or a combination thereof.
  • the solvent comprise water.
  • the active pharmaceutical ingredient can form a solution in the solvent, from which a dispersion of the active pharmaceutical ingredient in a liquid phase can be generated.
  • the dispersion can include particles of the active pharmaceutical ingredient and can be formed, for example, by adding other agents to a solution of the active pharmaceutical ingredient.
  • inactive ingredients are added to solvents or mixtures of solvents.
  • the inactive ingredients increase the dispersion of API particles or alter solubility of APIs to create said API particles.
  • Inactive ingredients are substances that have no known therapeutic effects but augment the API by providing better control over the loading capacity of the active ingredient and/or the release kinetics of the ingredients. These include but not limited to viscosity' modifiers, salts, pH modifiers, surfactants, solvents, and/or gases or mixtures thereof.
  • the liquid phase further comprises an inactive ingredient, a precipitating agent, a viscosity modifier, a surfactant, a pH modifier, an emulsifying agent, or a combination thereof.
  • the liquid phase further comprises a precipitating agent.
  • a precipitating agent as used herein can include any chemical agent that facilitates precipitation or separation of the active pharmaceutical ingredient from a solution of the active pharmaceutical ingredient in a solvent.
  • Precipitation agent can include any solvents, gases, solutions, and/or pH modifiers that change the solubility of a compound in a solvent and result in the precipitation of that compound.
  • Compounds, such as an API have different solubility in different solvents. The solubility in that solvent can be a function of temperature, pH, and/or other attributes of that solvent.
  • solvents yvith high solubility' for a compound are also called good solvents for that compound, and ones yvith loyv solubility are called bad solvents (or non-solvents) for that compound.
  • a bad solvent or anon-solvent for a compound also can be a precipitating agent for that compound yvhen that compound is in solution in a solvent. With the addition of the precipitating agent, the active pharmaceutical ingredient may form particles, thereby a dispersion of the active pharmaceutical ingredient may be produced.
  • Suitable precipitating agent may include, for example, non-solvents, salts, or mixtures thereof.
  • a non-solvent can include any substance (e.g., aqueous or organic liquids) in yvhich the API is not soluble or has loyv solubility, as compared to the solvents as used herein.
  • the liquid phase of the dispersion further comprises a precipitating agent, yvhich comprises a nonsolvent.
  • the present method includes encapsulating API particles in an encapsulating medium.
  • the API particles are particles yvhich may or may not be spherical in morphology . Particle size range may vary” for instance, about a 0.001 to 100 micrometer or 0.001 to 10 micrometer. In some embodiments, the API particles have an average size of less than 1 pm. Particles are produced either in liquids or using other techniques, including but not limited to microfluidic fabrication, freeze drying, spray drying, and/or nanoprecipitation.
  • the API particles comprise an API, yvater, and/or other solvents. For example, yy hen GS is precipitated out of a yvater solution by adding ethanol to that solution the particles formed comprise GS and yvater and/or some trace amount of ethanol.
  • the API particles are preferably in a size range that enables the said particles to penetrate the porosity (comprising pores, holes, and/or channels) in the encapsulating media. Regardless of the polarity (hydrophilic or hydrophobic) or surface charges of the encapsulating media any API particle is able to penetrate the porosity' in a liquid carrier phase (for example yvater/alcohol mixture).
  • a liquid carrier phase for example yvater/alcohol mixture.
  • This liquid carrier keeps the API in particle form while creating a favorable environment between the surface/porosity of encapsulating media and API particles.
  • liquid carrier is the mixture that is used for API particle formation.
  • the encapsulating media is subjected to compression (channel-die compression, uniaxial compression, or hydrostatic compression) after the API particles are placed in the porosity of the said encapsulating media.
  • the API comprises gentamicin sulfate
  • the solvent is an aqueous solvent (such as water)
  • the liquid phase comprises a non-solvent to facilitate formation of a dispersion of the API.
  • the non-solvent can be, for example, ethanol.
  • gentamicin sulfate particles are formed with nanoprecipitation by dissolving GS in water and adding ethanol to GS/water solution to cause GS to precipitate and form particles that comprise GS.
  • the method may comprise generating a dispersion of GS in a liquid phase comprising about 30% (v/v) water and about 70% (v/v) ethanol.
  • the API particles are fabricated by dissolving API in water and adding an alcohol to precipitate API particles in the solution. For instance, adding 140 proof ethanol to an aqueous solution of gentamicin sulfate would precipitate gentamicin sulfate particles: these particles will settle under gravity or by centrifugation. These particles can also be forced into suspension by violent shaking, such as by vortexing. These particles primarily comprise GS and some water and/or some ethanol.
  • the suspended particles of gentamicin sulfate can be mixed with UHMWPE powder. This powder mixture is then dried and dehydrated, and then compression molded to encapsulate the gentamicin sulfate in UHMWPE.
  • vancomycin hydrochloride particles are formed by adding ethanol to vancomycin hydrochloride aqueous solution.
  • gentamicin sulfate and vancomycin hydrochloride particles are formed by adding ethanol to an aqueous solution of both of these APIs.
  • the API particles formed in an aqueous solution are mixed with encapsulating media either as a suspension or as individual particles.
  • the individual particles are isolated from the aqueous solution in which they are formed.
  • the particles can be isolated through centrifugation or settling the particles by gravity and removing the supernatant.
  • the API particles are mixed with the encapsulating media while they are in suspension in the aqueous solution.
  • the API is hydrophobic; therefore organic solvents are used to dissolve the API and a non-solvent is added to precipitate the particles.
  • a dispersion agent is added to the solution containing API particles to form a suspension of the API particles in the said solution.
  • Dispersion agent comprises viscosity modifier(s), surfactant(s), buffer(s), salt(s), pH modifier(s), precipitation agent(s), gases, and/or solvent(s) or mixtures thereof.
  • the dispersion agent is added to the solution comprising particles of one or more APIs.
  • the API particles are formed in situ in the solution comprising dispersion agent, preferably by precipitating API particles from an API solution with the addition of a precipitation agent.
  • the API particles are added to encapsulating medium.
  • Viscosity modifiers are added to the solution containing API particles.
  • Viscosity modifiers comprise polyvinylpyrrolidones (PVP) (preferably having a molecular weight of about 10,000 or less to about 360,000 or more, as well as mixtures containing one or more grades of PVP with different molecular weight), cellulose derivatives (including, but not limited to, hydroxyethyl cellulose, carboxymethyl cellulose or its salts, hydroxypropyl methylcellulose or hypromellose, and the like), glycosaminoglycans including but not limited to heparin, chondroitin sulfate, keratan sulfate, heparan sulfate or their salts, carrageenan, guar gum, chitosan, alginates, carbomers, polyethylene glycols, lipids, oils, sugars, polyvinyl alcohol, xanthan gum, and/or their derivates or mixtures thereof.
  • PVP polyviny
  • surfactants are added to the solution containing API particles, either after forming the particles or before forming the particles.
  • Surfactants comprise nonionic, anionic, cationic, zw-itter ionic, and/or amphoteric compound.
  • surfactants are used to reduce interfacial tension.
  • surfactant is used the reduce the interfacial tension between the API particles and the surrounding solution.
  • nonionic surfactants are poly(vinyl alcohol) (PVA), poloxamer 188, polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), polyoxyethylene 15 hydroxy stearate (Macrogol 15 hydroxy stearate, Solutol HS15®), polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40), polyoxyethylene stearates (Myrj®), sorbitan fatty acid esters (Span®), polyoxyethylene alky l ethers (Brij®), and/or polyoxyethylene nonylphenol ether (Nonoxynol®) and lecithin) or mixtures thereof.
  • PVA poly(vinyl alcohol)
  • poloxamer 188 polyoxyethylene sorbitan fatty acid esters
  • Polysorbate, Tween® polyoxyethylene 15 hydroxy stearate
  • Microgol 15 hydroxy stearate Macrogol 15 hydroxy stearate, Sol
  • anionic surfactants are ammonium lauryl sulfate, sodium laureth sulfate, sodium lauryl sarcosinate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium lauryl sulfate, a olefin sulfonate, and/or ammonium laureth sulfate or mixtures thereof.
  • cationic surfactants are benzalkonium chloride, and/or cetylpyridinium chloride or mixtures thereof.
  • amphoteric surfactants are betaines or sulfobetaine and natural substances such as amino acids and/or phospholipids or mixtures thereof.
  • One of the preferred surfactants used herein is poly (vinyl alcohol). Another preferred surfactant is vitamin E.
  • the encapsulating medium comprises an antioxidant.
  • vitamin-E is blended with UHMWPE flake then API particles are encapsulated in the flakes followed by molding.
  • antioxidants are alpha- and delta-tocopherol; propy l, octy l, or dedocyl gallates; lactic, citric, and tartaric acids and their salts; orthophosphates, tocopherol acetate, and Irgonox 1010 (see, for example, WO 01/80778, U.S. Pat. No. 6,448,315).
  • Vitamin E a common antioxidant, comprise a group of eight fat-soluble compounds that include four (alpha, beta, gamma, delta) tocopherols and four (alpha, beta, gamma, delta) tocotrienols.
  • Tocopheryl acetate is also known as vitamin E.
  • the encapsulating medium comprises a crosslinking agent.
  • crosslinking agents are peroxides such as inorganic peroxides, organic peroxides, diacyl peroxides, peroxyesters, peoxydicarbonates, dialkyl peroxides, ketone peroxides, peroxyketals cyclic peroxides, peroxymonocarbonates and hydroperoxides benzoyl peroxide, dicumyl peroxide, methyl ethyl peroxide ketone peroxide, acetone peroxide, 2,5 - Di ( tert - butylperoxy ) -2,5 - dimethyl - 3 - hexyne ( Luperox® 130 ), 3, 3, 5, 7, 7 pentamethyl - 1,2,4 trioxepane ( Trigonox®311 ), etc.
  • peroxides are dilauryl peroxide, methyl ether ketone peroxide, t - amyl peroxy acetate, t - butyl hydroperoxide, t - amyl peroxybenzoate, D - 1 amyl peroxide, 2,5 - Dimethyl 2,5 - Di(t - butylperoxy) hexane, t - butylperoxy isopropyl carbonate, succinic acid 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 - butyl cumyl peroxide, Di - sec - butyl - peroxy
  • peroxides are members of the Luperox® family supplied by Arkema.
  • Other examples of peroxides are 1,1 Di(tert - butylperoxy )-3,3,5 - trimethylcyclohexane, 2,5 - Dimethyl - 2,5 - di (tert - buty lperoxylhexane , 3, 3, 5, 7, 7 - Pentam ethyl - 1,2,4 - trioxepane, Butyl 4,4 - di ( tert - butylperoxy ) valerate , Di ( 2,4 - dichlorobenzoyl )peroxide, Di ( 4 methylbenzoyl )peroxide , Di(tert - butylperoxyisopropyl benzene, tert - Butyl cumyl peroxide, tert - Butyl peroxy - 3,5, 5 - trimethylhexanoate , tert - Butyl peroxy 2
  • salts are added to API solution (from which the API dispersion is formed) to cause pH buffering, this pH buffering/alterations can be used to form the API particles or change the particle size or change the interaction between API and encapsulating media.
  • Salts include but are not limited to sodium chloride, calcium chloride, citrates, acetates, potassium dihydrogen phosphates, disodium hydrogen phosphates, or mixtures thereof.
  • pH modifiers are added to the API solution to initiate or complete the API particle formation.
  • the pH modifiers either increase or decrease the pH of the solution they are added to. Examples include but are not limited to soda ash, sodium hydroxide, sodium silicate, sodium phosphates, lime, sulfuric acid, hydrofluoric acid, tri-potassium citrate monohydrate, sodium hydrogen carbonate, tartaric acid, and/or adipic acid or mixtures thereof.
  • solvents are used to dissolve APIs and/or other additives such as salts, pH modifiers, and other solid substance(s).
  • non-solvents are added to these solutions to precipitate particles, such as nanoparticles, for encapsulation.
  • Solvents can be either an organic or aqueous solvent. Examples are aqueous solvents such as sterile water, phosphate buffer, saline solution, and organic solvents such as DMSO ethyl acetate, chloroform, dichloromethane. Solvents also include alcohols, such as ethanol, iso-propanol, and ketones, such as acetone. Preferably the API is dissolved in a solvent and then a precipitation agent, such as a non-solvent, is used to precipitate API particles.
  • a precipitation agent such as a non-solvent
  • dispersion or emulsifying agents are used to facilitate and control the formation of particles.
  • the dispersion or emulsifying agents act like a surfactant and help in particle formation, for instance in the form of emulsion droplets or dispersions, and stabilize the emulsion or dispersion.
  • Dispersion agent(s) aid in inhibiting the aggregation of particles formed in the dispersion fluid.
  • Dispersion agent(s) comprise at least one chemically hydrophobic group and at least one hydrophilic group. These chemical groups can be amines, carboxylic acid, hydroxyls, and any potential side group that can interact with API(s) and encapsulating media.
  • Dispersion agents may include but not limited to vitamins such as vitamin E, 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-Camitine, L-Serine, L-Glutamine, Aspartic Acid, L-Proline, L- Glycine, Taurine, L-Cysteine, Gamma-aminobutyric acid (GABA), L-Alanine, and L-Glulamic acid and their other conformations thereof.
  • vitamins such as vitamin E, vitamin K
  • amino acids such as L-Lysine, L- Valine, L-Tryptophan, L-Phenylalanine, L-Methionine, L-Leucine, L-Threonine, L-Isoleucine, L-
  • aqueous solutions are used in many embodiments to form API particles.
  • An aqueous solution is a solution in which solutes such as dispersion agent(s), for example PVA, emulsifying agent(s), compound(s), and/or API(s) are solubilized in water, ionized w ater or PBS or other aqueous solvents.
  • the aqueous solution also comprises salts such as sodium chloride.
  • APIs or compounds used in the current disclosure are hygroscopic.
  • gentamicin sulfate or vancomycin hydrochloride are hygroscopic APIs.
  • the APIs are encapsulated in a polymeric material and subsequently heated and pressurized to consolidate shapes that w ould allow fabrication of medical devices.
  • Direct compression molding into a finished or semi-finished medical device shape are used.
  • Extrusion or compression molding are also used, typically followed by machining to fabricate a medical device that contains API and can elute API. Thermal degradation rate of hygroscopic APIs is higher when the said APIs are hydrated.
  • the blend of API and encapsulation agent are dehydrated to reduce the water content to minimize the degradation during the subsequent molding stage.
  • dehydration can be performed in air, in vacuum, or in inert gasses such as argon gas.
  • Particles of API and/or compounds are formed in a solvent or a mixture of solvents. For instance, gentamicin sulfate is dissolved in water; ethanol is added to this aqueous solution of gentamicin sulfate. The addition of ethanol causes gentamicin sulfate to form particles in the water/ethanol mixture. These particles are easily encapsulated in the pores found in UHMWPE flakes.
  • the mixture of gentamicin sulfate/ ater/ethanol/UHMPWE is dried to partially or fully evaporate the solvents, for example by heating in air, in inert gas, or in vacuum.
  • the pharmaceutical composition may be dried and/or dehydrated to produce a dried pharmaceutical composition.
  • the drying step can follow dehydration to minimize the bound water in the hygroscopic API.
  • the dried and/or dehydrated mixture of gentamicin sulfate particles in UHMWPE flake is compression molded and, optionally machined, to form a medical device.
  • the method comprises molding the dried pharmaceutical composition by a heat molding process.
  • Suitable heat molding processes may include, for example, ram extrusion, extrusion, direct compression molding, compression molding, calendaring, thermoforming, welding, lamination, pultrusion, forging, and other techniques.
  • the appropriate conditions for the heat molding process can depend on the chemical nature of the active pharmaceutical ingredient, the components of the encapsulating medium, and intended application of the pharmaceutical composition.
  • FIGS. 1A and IB A representative process of preparing a pharmaceutical composition (e.g., containing GS particles encapsulated in UHMWPE) according to the present preparation method is illustrated in FIGS. 1A and IB.
  • the composition produced by the method can be incorporated in a medical device (such as an implant) by know n technique (such as heating molding) and shaped (e.g., by machining) into desired size and shape.
  • an API solution is prepared by dissolving the API in a solvent; then, the said API solution is mixed with another solvent that is not a good solvent (or a non-solvent) for the said API, resulting in the formation of API particles.
  • the API particles form a dispersion in the two solvent mixture, where one solvent is a good solvent, and the other is a bad solvent or a nonsolvent for the said API.
  • the API dispersion in the solvent mixture is then mixed with an encapsulation agent and the mixture is dried to substantially evaporate the solvents. It is beneficial to reduce the solvent content in the mixture as much as possible before molding.
  • the API is dissolved in one or solvents.
  • the API is dissolved in a mixture of solvents. In some solvents and mixtures of solvents the API is dissolved at elevated temperatures.
  • the encapsulating media in powder form to achieve better mixing with the API particles or the dispersion particles.
  • encapsulating media has flakes, such as UHMWPE; the flakes consist of antioxidants, such as vitamin E, and crosslinking agents, such as peroxides.
  • an aqueous solution of gentamicin sulfate is prepared by dissolving GS in water; then the said aqueous solution of GS is mixed with ethanol. Mixing w ith ethanol results in GS particle formation; if left undisturbed the GS in water/ethanol mixture phase separates into an amber-colored viscous solution (also called a plug) that settles to the bottom of the container and a clear supernatant liquid lying above the said plug. The same phase separation is obtained if the GS in water/ethanol mixture is centrifuged.
  • GS gentamicin sulfate
  • the GS in w ater/ethanol mixture is then shaken to mix the two phases, that is the viscous, amber-colored plug and the clear supernatant, to form a liquid dispersion, where the GS particles are dispersed in the water/ethanol mixture.
  • the liquid dispersion is then mixed with UHMWPE powder and the mixture is dried to substantially evaporate water and ethanol.
  • the dried mixture is then 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.
  • the present disclosure provides a pharmaceutical composition produced by the preparation method as descried herein.
  • the produced pharmaceutical composition may have improved mechanical properties and/or improved API elution profile.
  • elution profile is meant the profile of the curve of elution as a function of time.
  • the pharmaceutical composition produced by the present method has 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.
  • the pharmaceutical composition comprises at least 6% by weight the active pharmaceutical ingredient, and the active pharmaceutical ingredient has a release rate of at least 0.
  • the API in the pharmaceutical composition produced by the present method comprises gentamicin sulfate.
  • the present disclosure provides a medical device comprising a pharmaceutical composition as described herein or a pharmaceutical composition produced by the preparation method as described herein.
  • the medical device may be an implant.
  • medical devices that comprise API encapsulated in an encapsulating media are tibial inserts, acetabular liners, joint spacers, total knee femoral component, femoral head, acetabular shell, tibial trat, glenoid, trauma plate, fracture fixation devices, cochlear devices, visual prostheses, brain computer interfaces contact lenses, intraocular lenses, urinary and peripheral vascular catheters, endotracheal tubes, cardiac valves, embolic coils, vascular grafts, pacemakers, coronary stents, hernia meshes, total heart replacements and their cables, left ventricular assist devices and their cables, dental implants, penal implants, mammary implants and plastic surgery augmentation devices.
  • the implant is ajoint replacement implant.
  • the present disclosure provides a joint replacement implant, which comprises a heat molded polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate (GS), wherein particles of GS are encapsulated in pores of the heat molded polymeric material.
  • UHMWPE ultra-high molecular weight polyethylene
  • GS gentamicin sulfate
  • the particles of gentamicin sulfate have an average size of less than 1 pm.
  • the joint replacement implant comprises about 2% to about 20% (including, for example, about 2% to about 10% and about 5% to about 10%) by weight gentamicin sulfate.
  • the present disclosure provides a method of preparing an implant, which comprises generating a dispersion of a gentamicin sulfate (GS) in a liquid phase comprising a solvent and a non-solvent.
  • the method further comprises contacting the dispersion of GS with a porous polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE), thereby producing an implant composition, w herein particles of GS are encapsulated in the pores of the porous polymeric material.
  • the method further comprises heat molding the implant composition to produce the implant.
  • the solvent and non-solvent may be any of the previously described solvents and nonsolvents.
  • the heat molding process can be carried out by the techniques as described herein.
  • the method further comprises removing the solvent and the non-solvent from the implant to produce a dried implant composition and heat molding the dried implant composition to produce the implant.
  • the method further comprises machining the implant produced by heat molding to form a shaped implant.
  • the particles of gentamicin sulfate in the implant preparation method have an average size of less than 1 pm.
  • the implant comprises about 2% to about 20% (including, for example, about 2% to about 10% and about 5% to about 10%) by w eight gentamicin sulfate.
  • the implant preparation method further comprises machining the implant produced by heat molding to form a shaped implant.
  • the present disclosure provides ab implant produced by the implant preparation method as described herein.
  • the produced implant can be shaped to be used as a joint replacement implant or a joint replacement spacer implant to treat and/or prevent infection .
  • the examples provided below illustrate the method, compositions, and device detailed herein, and are not intended to be limiting.
  • Example 1 Gentamicin sulfate particle formation with 140 proof ethanol and mixing with UHMWPE.
  • GS (1,770 mg) was added to 17.70 ml of 140-proof ethanol (70% v/v ethanol in water mixture). GS rapidly formed an agglomeration with a gummy appearance. The mixture was then vortexed to break down the agglomeration. After several minutes of vortexing, the mixture turned into a liquid dispersion. Under gravity or following centrifugation, the dispersion phase separated: (i) 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. A sample of the amber-colored fluid on a glass slide revealed the presence of particles, likely GS particles, under optical microscopy.
  • the phase- separated mixture w as reversibly converted to the liquid dispersion form by shaking, for instance by vortexing.
  • the mixture in its liquid dispersion form was mixed with 13,500 mg of GUR 1020 UHMWPE powder using a plastic spatula to generate a wet powder mixture.
  • the wet powder was either used as-is (wet powder) or after it was dried in a fume hood at room temperature for about 16 hours through evaporation of the liquid w ater/ethanol phase (dry pow der).
  • Example 2 Wet tablet molding using blend from Example 1.
  • the w et powder mixture of Example 1 was used to make tablets.
  • the powder was placed inside cavity of a 13-mm diameter die and a plunger was used to apply 5 metric tons of force.
  • the pressed tablets w ere left in a fume hood at room temperature for about 16 hours to dry through evaporation of the liquid phase (w ater/ethanol mixture).
  • the tablets w ere subsequently dehydrated by heating in an oven at 110°C for 2 hours.
  • the dehydrated tablets were then consolidated at 170°C and 20MPa in an aluminum/bronze mold.
  • the mold and the plunger were heated first and then the tablets were placed in the mold cavity.
  • the tablets were molded by applying a 20MPa pressure with the plunger.
  • Example 3 Dry powder molding using blend from Example 1.
  • the dry powder mixture of Example 1 was dehydrated in an oven at 110°C for 2 hours.
  • the dehydrated powder mixture was then consolidated at 170°C and 20MPa in an aluminum/bronze mold in a manner similar to the one described in Example 2.
  • the molded sample was cut w ith a razor blade and imaged using an optical microscope, revealing a "cobblestone” morphology' w ith embedded domains comprising GS.
  • the domains w ere located on either side of the typical resin flake boundaries of molded UHMWPE (FIG. 2).
  • Example 4 Dry tablet molding using blend from Example 1.
  • Example 1 The dry- powder mixture of Example 1 was used to make tablets. The pow der was placed inside cavity' of a 13-mm diameter die and a plunger was used to apply 5 metric tons of force. Tablets were dehydrated in an oven at 110°C for 2 hours. The dehydrated tablets were then consolidated at 170°C and 20MPa in an aluminum/bronze mold in a manner similar to the one described in Example 2.
  • Example 5 Gentamicin sulfate particle formation with ethanol or acetone addition to aqueous GS solution and mixing with UHMWPE.
  • aqueous GS solutions w ere prepared, each by adding 1,770 mg of GS to 5.31 ml of water.
  • Non-solvents were added to these solutions as shown in Table 1 to obtain formulations F5.1, F5.2, F5.3, F5.4, and F5.5.
  • the addition of non-solvents to aqGS solutions caused GS to precipitate.
  • the liquid dispersion comprised API particles and earner media.
  • the liquid dispersions of F5.1, F5.2, and F5.3 phase separated: (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. Samples of the amber-colored fluid on a glass slide revealed the presence of particles, likely GS particles, under optical microscopy.
  • the liquid dispersion of F5.4 separated into 4 phases: (i) a clear supernatant, (ii) a white supernatant, (iii) a dark amber color layer, and (iv) a translucent, amber-colored, highly viscous fluid that settled at the bottom of the container.
  • Optical microscopy revealed the presence of particles, likely GS particles, in fluid layers (ii), (iii), and (iv) on a glass slide.
  • phase-separated forms of all four of these mixtures were reversibly converted to their liquid dispersion forms by shaking, for instance, by vortexing.
  • the mixtures, in their liquid dispersion form were individually mixed (manual mixing) with 13,500 mg of GUR 1020 UHMWPE powder using a plastic spatula.
  • the manual mixing can be replaced or augmented by using a hand cranked or motorized mixer, such as a bone cement mixer.
  • the resulting w et pow der blends w ere either used as-is (wet powder) or after they were dried in a fume hood at room temperature for about 16 hours through evaporation of the liquid water/ethanol phase (dry powder).
  • Example 6 Dry powder molding using blends from Example 5.
  • Example 5 The dry' powders of Example 5 (F5.1, F5.2, F5.3, and F5.4) were individually dehydrated in an oven at 110°C for 2 hours. The dehydrated powder mixtures were then individually consolidated at 170°C and 20MPa in an aluminum/bronze mold in a manner similar to the one described in Example 2.
  • the wet powder of F5.4 from Example 5 was dried in an oven at 45°C for about 16 hours.
  • the dried powder was dehydrated in an oven at 110°C for 2 hours.
  • the dehydrated powder mixture was then consolidated at 170°C and 20MPa in an aluminum/bronze mold in a manner similar to the one described in Example 2.
  • Example 7 Dry tablet molding using blend from Example 5.
  • Example 5 The dry powder of Example 5 (F5. 1) w as used to make tablets. The powder was placed inside cavity 7 of a 13-mm diameter die and a plunger was used to apply 5 metric tons of force. Tablets were dehydrated in an oven at 110°C for 2 hours. The dehydrated tablets were then consolidated at 170°C and 20MPa in an aluminum/bronze mold in a manner similar to the one described in Example 2.
  • Example 8 Dry powder molding with different drying/dehydration conditions using blend from Example 1 .
  • Example 2 The w et pow der of Example 1 w as dried in an oven at different temperatures and durations followed by consolidation in a mold.
  • the dried and then dehydrated powder blends were consolidated at 170°C and 20MPa in an aluminum/bronze mold as described in Example 2.
  • Most of the dry ing and dehydration was carried out in air as indicated in Table 2, indicating that the oven was filled with air at ambient pressure. Partial vacuum drying/dehydration conditions were achieved by partially evacuating the air from the oven chamber using a vacuum pump. When the oven is under partial vacuum the pressure in the oven chamber is below ambient pressure. In some embodiments the oven chamber is filled wi th an inert gas before evacuating to achieve partial vacuum.
  • Table 2 are the various sequences used in dry ing and dehydrating the wet powder blend (GS and UHMWPE) of Example 1.
  • Example 9 Vancomycin Hydrochloride (VH) particle formation ith ethanol or acetone addition to aqueous VH solution and mixing with UHMWPE.
  • aqueous VH solutions w ere prepared, each by adding 708 mg of GS to 5.31 ml of water.
  • Non-solvents were added to these solutions, as shown in Table 3 to obtain the formulations F9.1, F9.2, F9.3, and F9.4.
  • the addition of non-solvents to aqVH solutions caused VH to precipitate.
  • the dispersion was milky and slightly pink-colored.
  • the VH particles were suspended in the liquid phase.
  • Example 10 Vancomycin Hydrochloride (VH) particle formation with ethanol or acetone addition to aqueous VH solution and mixing with UHMWPE.
  • VH Vancomycin Hydrochloride
  • VH solutions were prepared, each by adding 354 mg of VH to 17.70 ml of ethanol -water mixtures, including 80, 90,100,120, and 140 proof ethanol.
  • the solutions were individually mixed with 14,700 mg of GUR 1020 UHMWPE powder to prepare wet blends.
  • VH particle formation occurred in situ in and/or around the PE flakes after blending as a result of changes that occurred in the ethanol to water ratio in the mixture during drying as described in Example 12 below.
  • Example 11 VH and GS particle formation with ethanol addition to aqueous VH/GS solution and mixing with UHMWPE.
  • VH and GS solutions were prepared by dissolving 354 mg VH and 1,062 mg GS in 5.31 ml water. Following the recipe for F5.1 of Table 1, ethanol was added to the VH/GS aqueous solution to form VH and GS particles. There was a phase separation in the aqueous VH/GS dispersion similar to what was observed in Example 5. Following shaking and/or mixing, 13,800 mg of GUR 1020 UHMWPE powder w as added to the liquid dispersion to form a w et blend. This w et blend w as used as dry a pow der blend after evaporating the liquid phase as described in Example 12 below 7 .
  • Example 12 Dry powder molding with different drying/dehydration conditions using blends from Examples 9, 10 and 11.
  • Example 13 Blending, drying, and dehydration with Dual Asymmetric Centrifuge and powder molding.
  • aqueous GS solution was prepared by adding 18.80 g of GS to 70.8 ml of water. 165.2 ml ethanol was added to this solution, which caused a phase separation, resulting in a liquid dispersion.
  • 184 g of GUR 1020 UHMWPE was added to the liquid dispersion to make a mixture, w hich w as placed into a Dual Asymmetric Centrifuge device (Speedmixer, Flacktek). The SpeedMixer w as operated at 800rpm for 1 minute to blend the mixture. This is also known as homogenization of the mixture to increase the uniformity of the GS particles blended in w ith the UHMWPE flakes.
  • the rotational speed of the SpeedMixer w as then increased to 1400 RPM under vacuum to evaporate the solvents, that is ethanol and water.
  • the rotational mixing achieved in the mixture caused an increased in temperature, which together w ith vacuum helped dry and dehydrate the mixture in about 20 minutes.
  • Several such blends were made and stored either in sealed jars with minimal headspace or in vacuumed and heat-sealed pouches until they were consolidated. Dehydrated powder blends were consolidated at 170 °C and 20MPa in an aluminum/bronze mold, as described in Example 2.
  • Example 14 Blending, drying, and dehydration with industrial scale blender and pow der molding.
  • An aqueous GS solution was prepared by adding 18.80 g of GS to 70.8 ml of w ater and placed in Littleford M-5 industrial mixer. 1 5.2 ml ethanol w as then added to the mixer and the mixer w as operated at 3Hz for 10 minutes to make a liquid dispersion of GS particles in water/ethanol mixture. The mixer was brought to a stop and 184 g of GUR 1020 UHMWPE w as added to the dispersion in the mixer. The mixer was operated at 3Hz under vacuum and heated to 45 °C to dry the blend. Drying removes both ethanol and water. The blending was continued for 16 hrs.
  • the dehydration temperature can be 110°C.
  • the temperature of the mixer was reduced to 60°C.
  • Dehydrated blends were stored in sealed jars with minimal headspace or vacuumed pouches until consolidated. Dehydrated powder blends were consolidated at 170 °C and 20MPa in an aluminum/bronze mold, as described in Example 2.
  • Example 15 Gentamicin sulfate particle mixtures and mixing with UHMWPE under high pressure.
  • the ethanol/aqGS /UHMWPE mixture from sample 5 is poured into a high-pressure chamber.
  • the pressure is set at a minimum of 1 bar, and the mixture is left under pressure for at least 1 minute.
  • the pressurized wet powder mixture is left at room temperature for at least 16 hrs. to evaporate the liquid (water/ethanol mixture) or placed in an oven at a temperature above room temperature, for instance at any of the oven drying conditions listed in Table 2.
  • the powder mixture is then further heated in an oven at 110 °C for 2 hrs. to further remove the bound water in GS or any dehydration conditions listed in Table 2.
  • the dehydrated powder mixture is then consolidated at 170 °C and 20MPa in an aluminum/bronze mold.
  • API particles and the carrier media (water and ethanol) from Example 5 were added to UHMWPE GUR 1050 blended with di-cumyl peroxide and vitamin E (see US17/222,398 High Temperature Melting, US 14/389,852 Peroxide Cross-Linking of Polymeric Materials in the Presence of Antioxidants (Abandoned), US16/29L283 Peroxide cross-linking and high temperature melting. US17/703,288 Di-Cumyl Peroxide Crosslinking of UHMWPE, US 2004/0156879; U.S. application Ser. No. 11/465,544, filed Aug. 18, 2006; PCT/US2006/032329 Published as WO 2007/024689).
  • Example 17 GS Particle Encapsulation in UV Crosslinked UHMWPE
  • the API particles and the liquid carrier media (water and ethanol) from Example 5 are added to UHMWPE blended with a UV initiator, for instance 4h-benzophenone or other initiators mentioned in US16/635,105 UV -Initiated Reactions In Polymeric Materials.
  • the wet powder mixture is dried and heated to further remove the bound water in the GS. Then, the dehydrated powder mixture is consolidated.
  • the consolidated blocks are machined into implant shape and crosslinked by shining UV light on surfaces, preferably on articular surfaces.
  • Example 18 GS Particle Encapsulation in Radiation Crosslinked UHMWPE
  • the molded blocks from Examples 6, 7, and 8 are radiation crosslinked either before or after the molded blocks are machined into the shape of an article such as an implant.
  • Crosslinking is achieved by ionizing radiation, such as electron beam, gamma radiation, x-ray radiation, or radiation methods described in US8,933,145 High Temperature Melting, US7,205,339 Selective controlled manipulation of polymers, US14/400375 Antioxidant-stabilized joint implants the details of which incorporated in full.
  • Example 19 GS particle formation with ethanol addition to aqueous GS solution and mixing wi th Polymethylmethacrylate
  • An aqueous GS solution with ethanol was prepared by dissolving 1000 mg of GS in 14.16 ml of water and by adding 33.04 ml of ethanol.
  • Another aqueous GS solution with ethanol was prepared by dissolving 1000 mg of GS in 4.248 ml of water and by adding 9.912 ml of ethanol.
  • the liquid dispersions formed contained particles of GS.
  • the liquid dispersions were individually mixed with Simplex-P bone cement by blending the liquid dispersions with 40 g of premix PMMA powder, including 6 g PMMA, 30 g of methyl methacrylate-styrene- copolymer (containing 1.7% Benzoyl peroxide), and 4 g of Barium sulfate.
  • the mixtures w ere further mixed with a bone cement mixer (MixeVac III, Stryker).
  • the dried blends were individually sieved with a 300- micrometer sieve.
  • a solution of 19.5 ml methyl methacrylate 0.5ml N,N dimethyl- para-toluidine and 75 ppm hydroquinone was added to the dry blend and mixed to cure the materials.
  • the curing boFne cement is used as a bone void filler, as a fixation device to fix implants in place, and/or as a spacer to treat periprosthetic joint infection patients.
  • Example 20 Enhanced Antibiotic Release and Mechanical Strength in UHMWPE Antibiotic Blends: The Role of Sub-Micron Getnamicin Sulfate Particles
  • Ethanol and isopropyl alcohol were sourced from Sigma Aldrich (St. Louis, MO), GUR 1020 UHMWPE flakes from Ticona (Florence, KY), and gentamicin sulfate (GS) from Fujian Fukang Pharmaceutical Co. (China). [00179] Methods
  • GS Particles and Blending with UHMWPE The sub-micron particles were produced by adding ethanol into a water-based GS solution, resulting in GS particle dispersions in the ethanol-water mixture. These dispersions with GS precipitates were then blended with UHMWPE flakes using a dual asymmetric centrifugal (DAC) mixer, specifically the SpeedMixer DAC 1200-1000 Twin Vacuum model (Flacktek, South Carolina) operated at 1200 RPM under 25 mbar vacuum to help remove ethanol and water from the mixture.
  • the sub-micron GS particles were blended with UHMWPE flakes at concentrations of 6%, 8%, and 10% by weight and molded to produce the sub-micron GS UHMWPE blends.
  • Resolidified particles w ere produced by freezing a GS aqueous solution for 16 hours at -20°C and subsequently lyophilizing it for 48 hours. A mortar and pestle were used to break down the lyophilized residue, which was sieved first through a 150-pm and then a 75-pm sieve. Particles between 75 and 150 pm in size were blended with UHMWPE flakes at a concentration of 10% by weight using the DAC, operated at 1200 RPM under 25 mbar vacuum and molded to produce the resolidified GS UHMWPE blends.
  • GS UHMWPE blends were compression molded in an aluminum-bronze rectangular mold (50x85 mm 2 ) at 170°C for 20 minutes under 5MPa for 5 minutes, lOMPa for 5 minutes, and 20 MPa for 10 minutes and allowed to cool under 20MPa of pressure for 50 minutes.
  • the thickness of the molded test samples w as 1cm.
  • Imaging Digital light microscopy, SEM, and FIB-SEM were performed to investigate the morphology' of the consolidated GS UHMWPE blends.
  • Type V tensile specimens were prepared by machining 3.2-mm thick sections (Shopbot Tools, Inc., Durham, NC) and templating the sections with a die sample cutter using Dewes-Gumbs Manual Expulsion Press, Model 1.5T DGD (Dewes-Gumbs Die Company, Long Island City, NY), and Expulsion die for press Model ASTM D638-V (Dewes-Gumbs Die Company, Long Island City, NY).
  • Specimens were tested on an MTS Insight 2 electromechanical load frame (Eden Prairie, MN) at a crosshead speed of 10 mm/min.
  • An MTS LX300 laser extensometer was used to measure true strain.
  • ASTM D638 standards were follow ed to calculate the % elongation-at-break (EAB), yield strength (YS) in MPa, and the ultimate tensile strength (UTS) in MPa.
  • EAB % elongation-at-break
  • YS yield strength
  • UTS ultimate
  • IZOD specimens were made by machining the molded blocks to the desired dimensions (63.5x12.7x3.2 mm). The resulting bars were notched using a Panpress 502 with posi-stop (PanaVise, Reno, NV) and validated geometry using an STM6 Measuring Microscope (Olympus, Waltham, MA). The toughness was determined using a CEAST 9050 pendulum impact testing machine (Instron, Norwood, MA) following ASTM F648.
  • Pin on disk (POD) wear testing A multidirectional Ortho-PODTM w ear tester (AMTI, Watertown, MA) was used to determine the w ear rate of the GS UHMWPE blends as outlined in ASTM F732-17 Annex A2 (ASTM. Vol. 13.01 ASTM Standard F732-17 (2017)).
  • a Paul-type variable load curve with a peak contact stress of 5.1 MPa was applied axially during articulation.
  • CLSI Clinical and Laboratory' Standards
  • ATCC American Type Culture Collection
  • TSA tryptic soy agar
  • MIC was defined as the lowest concentration of antibiotic that completely inhibited the growth of the microorganism as detected by the unaided eye. For a test to be considered valid, a>2mm button or definite turbidity needed to be observed in grow th-control wells and no wells were skipped.
  • MBC w as determined by drop plating three 5 l volumes of MIC, 2xMIC, and 4xMIC, withdrawn from their corresponding w ells. These plates were incubated at 35°C overnight. The MBC was defined as the concentration that exhibited no growth across all three replicates.
  • NMR Nuclear Magnetic Resonance
  • the UTS of the sub-micron blend w as significantly higher than that of the resolidified blend (p ⁇ 0.01) and was not different from that of the as-received blend.
  • the EAB of sub-micron blends w as similar to those of resolidified and as-received GS UHMWPE blends.
  • increased GS content led to reductions in EAB, UTS, and IZOD impact strength (FIGS. 1 ID-1 IF).
  • the IZOD impact strength of 6% GS UHMWPE blend w as similar to that of virgin UHMWPE, whereas the impact strengths of 8% and 10% blends ere lower (FIG. 1 IF).
  • Antimicrobial Testing against Staphylococcus aureus confirmed the activity and the stability' of eluted GS: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) ranges of GS eluted from the GS UHMWPE blends regardless of GS particle size on the blends (0.5-2 pg/ml and >4 pg/ml. respectively) and control GS solutions were not different.
  • Elution The release rate, percent cumulative release, and cumulative release as a function of elution time were highest for the 10% sub-micron GS UHMWPE blend in comparison with the resolidified and as-received GS UHMWPE blends with the same GS loading.
  • the release rates of 6% and 8% sub-micron GS particles were 0.12 and 1.30 mg/day, respectively.
  • the release rate of 6% was not statistically different between elution days 1-28.
  • the 10% sub-micron GS UHMWPE blend had more cumulative release over the 28 days compared to all other groups (p ⁇ 0.01).
  • the release rate of the 10% sub-micron GS UHMWPE blend was similar between days 1-21, and on day 28, it was approximately 10 and 100 times more compared to those of the 8% and 6% sub-micron GS UHMWPE blends, respectively.
  • Pharmacokinetic model a pharmacokinetic (PK) model was employed to predict the in vivo release of gentamicin sulfate (GS) from GS UHMWPE blends. This model computes clearance of GS using the half-life of GS and a first-order kinetics. Due to the absence of data on intra-articular half-life of GS, amikacin sulfate (AS) was utilized as a surrogate, given its similar serum half-life to GS (2-3 hours as per aminoglycoside guidelines). Hence, GS's intra-articular half-life was inferred from the known intra-articular half-life of AS (3.8-4.6 hr). The following equations describe the pharmacokinetics of GS:
  • Predicted GS concentration profiles in joint spaces for different sizes of GS UHMWPE blends including resolidified, as-received, and sub-micron GS and calculated drug concentrations over time for both 3-hour and 6-hour half-life scenarios, assessing the ability' of each blend size to maintain therapeutic levels above I00x MIC.
  • the findings indicate no significant differences in the GS concentration profiles between the 3-hour and 6-hour half-life scenarios across all blend sizes.
  • a critical distinction w as observed in the ability to maintain the 100* MIC threshold. While resolidified and as-received blends failed to sustain this threshold, sub-micron GS UHMWPE blends consistently maintained concentrations significantly above the 100* MIC limit.
  • UHMWPE is not melt-processable due to its high molecular weight (around 2-5 million g/mol), very' highly entangled molecular structure, and high melt viscosity. Instead, UHMWPE flakes are sintered together by applying heat and pressure without substantial flow, commonly referred as consolidation 1. Finished articles, such as implants, are machined after the sintering/consolidation step. Mechanical properties depend on the quality of the fusion of the resin flakes where any fusion defects adversely affect material strength. Diffusion of the UHMWPE chains across the flake boundaries is necessary for the efficient fusion of the material and improved mechanical properties.
  • This distinct cobblestone structure yvas only apparent yvith sub-micron GS particles, yvhich yvere small enough to penetrate into the porosity of UHMWPE flakes during blending, thus not interrupting the fusion of flakes during consolidation.
  • the voids in the polymer resulting from the elution of GS may induce better lubrication by acting as reservoirs of bovine serum used as lubricant during yvear testing.
  • the maintenance of wear rates at a similar lex el to virgin UHMWPE is particularly significant, as it suggests that sub-micron GS UHMWPE blends could have short- and mid-term performance similar to conventional primary implants fabricated w ith virgin UHMWPE.
  • NMR analysis of the GS released in deuterated water from the 10% sub-micron GS UHMWPE blend demonstrated the heat stability of GS after exposure to 170°C for 20 minutes during consolidation, as evidenced by the absence of significant shifts in the observed peaks (FIGS. 16 and 17).
  • MIC/MBC studies confirmed the stability and functionality of eluted GS from consolidated samples.
  • UHMWPE ultra-high molecular weight polyethylene
  • the tortuosity of UHMWPE flakes enables the penetration of sub-micronsized particles into the UHMWPE, and due to very low melt flow rate, particles stay- inside the pores, creating a confined structure during molding.
  • a pharmaceutical composition comprising: a porous encapsulating medium; and particles of an active pharmaceutical ingredient encapsulated in the pores of the porous encapsulating medium.
  • Clause 5 The pharmaceutical composition of any one of clauses 1-4, wherein the active pharmaceutical ingredient comprises an antibiotic, a non-steroid anti-inflammatory drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.
  • Clause 6 The pharmaceutical composition of clause 5, wherein the active pharmaceutical ingredient comprises an antibiotic.
  • Clause 7 The pharmaceutical composition of clause 6, wherein the antibiotic comprises gentamicin sulfate.
  • Clause 8 The pharmaceutical composition of any one of clauses 1-7, comprising about 1% to about 50% by w eight the active pharmaceutical ingredient.
  • Clause 9 The pharmaceutical composition of clause 1, wherein the encapsulating medium comprises ultra-high molecular weight polyethylene (UHMWPE), wherein the active pharmaceutical ingredient comprises gentamicin sulfate, wherein the particles of the active pharmaceutical ingredient have an average size of less than 1 pm, and w herein the pharmaceutical composition comprises about 1% to about 20% by w eight the active pharmaceutical ingredient.
  • UHMWPE ultra-high molecular weight polyethylene
  • Clause 10 The pharmaceutical composition of any one of clauses 1-9, which is a molded solid.
  • Clause 11 The pharmaceutical composition of any one of clauses 1-10, 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.
  • UTS ultimate tensile strength
  • EAB elongation at break
  • Clause 12 The pharmaceutical composition of any one of clauses 1-11, wherein the pharmaceutical composition comprises at least 6% by w eight the active pharmaceutical ingredient, and wherein the active pharmaceutical ingredient has a release rate of at least 0.1 mg/day per 100 cm 2 for 28 days and/or a cumulative release of at least 3% in 5 days, as measured in water at 37°C.
  • Clause 13 The pharmaceutical composition of clause 12, wherein the active pharmaceutical ingredient comprises gentamicin sulfate.
  • a method of preparing a pharmaceutical composition comprising: generating a dispersion of an active pharmaceutical ingredient in a liquid phase comprising a solvent; and contacting the dispersion of the active pharmaceutical ingredient with a porous encapsulating medium, thereby producing the pharmaceutical composition, wherein particles of the active pharmaceutical ingredient are encapsulated in the pores of the porous encapsulating medium.
  • Clause 15 The method of clause 14, wherein the particles of the active pharmaceutical ingredient have an average size of less than 1 pm.
  • Clause 16 The method of any one of clauses 14-15, wherein the encapsulating medium comprises a polymeric material.
  • Clause 18 The method of any one of clauses 14-17, wherein the active pharmaceutical ingredient comprises an antibiotic, anon-steroid anti-inflammatory 7 drug, an analgesic, a local anesthetic, a therapeutic biomolecule, or a combination thereof.
  • Clause 21 The method of any one of clauses 14-20, where the produced pharmaceutical composition comprises about 1% to about 50% by weight the active pharmaceutical ingredient.
  • the liquid phase further comprises an inactive ingredient, a precipitating agent, a viscosity modifier, a surfactant, a pH modifier, an emulsifying agent, or a combination thereof.
  • Clause 24 The method of any one of clauses 14-23, comprising generating a dispersion of gentamicin sulfate in a liquid phase comprising about 30% (v/v) w ater and about 70% (v/v) ethanol.
  • Clause 26 The method of any one of clauses 14-25, wherein the porous encapsulating medium comprises a crosslinking agent.
  • Clause 27 The method of any one of clauses 14-26, further comprising drying and/or dehydrating the pharmaceutical composition to produce a dried pharmaceutical composition.
  • Clause 28 The method of clause 27, further comprising molding the dried pharmaceutical composition by a heat molding process.
  • Clause 29 A pharmaceutical composition produced by the method of any one of clauses 14-28.
  • Clause 30 The pharmaceutical composition of clause 29, 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.
  • UTS ultimate tensile strength
  • EAB elongation at break
  • Clause 31 The pharmaceutical composition of any one of clauses 29-30, wherein the pharmaceutical composition comprises at least 6% by w eight the active pharmaceutical ingredient, and wherein the active pharmaceutical ingredient has a release rate of at least 0. 1 mg/day per 100 cm 2 for 28 days and/or a cumulative release of at least 3% in 5 days, as measured in w ater at 37°C.
  • Clause 32 The pharmaceutical composition of any one of clauses 29-31, wherein the active pharmaceutical ingredient comprises gentamicin sulfate.
  • Clause 33 A medical device comprising the pharmaceutical composition of any one of clauses 1-13 and 29-32.
  • Clause 34 The medical device of clause 33, which is an implant.
  • Clause 35 The medical device of clause 34, which is a joint replacement implant.
  • Clause 36 The medical device of clause 34, which is a joint replacement spacer implant to treat and/or prevent infection.
  • a joint replacement implant comprising a heat molded polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE) and gentamicin sulfate, wherein particles of gentamicin sulfate are encapsulated in pores of the heat molded polymeric material.
  • UHMWPE ultra-high molecular weight polyethylene
  • Clause 38 The joint replacement implant of clause 37, wherein the particles of gentamicin sulfate have an average size of less than 1 pm.
  • Clause 39 The joint replacement implant of any one of clauses 37-38, comprising about 2% to about 20% by w eight gentamicin sulfate.
  • a method of preparing an implant comprising: generating a dispersion of a gentamicin sulfate in a liquid phase comprising a solvent and a non-solvent; contacting the dispersion of gentamicin sulfate w ith a porous polymeric material comprising ultra-high molecular weight polyethylene (UHMWPE), thereby producing an implant composition, w herein particles of gentamicin sulfate are encapsulated in the pores of the porous polymeric material; and heat molding the implant composition to produce the implant.
  • UHMWPE ultra-high molecular weight polyethylene
  • Clause 41 The method of clause 40, comprising: removing the solvent and the non-solvent from the implant composition to produce a dried implant composition; and heat molding the dried implant composition to produce the implant.
  • Clause 42 The method of any one of clauses 40-41, wherein the particles of gentamicin sulfate have an average size of less than 1 pm.
  • Clause 45 An implant produced by the method of any one of clauses 40-44.

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Abstract

La présente divulgation concerne des compositions pharmaceutiques présentant une résistance mécanique améliorée et des propriétés d'élution d'ingrédients pharmaceutiques actifs (API) utiles pour des dispositifs médicaux tels que des implants. La divulgation concerne également des procédés de fabrication de ces compositions, qui peuvent comprendre la formation de particules submicroniques d'API et le mélange avec un matériau d'encapsulation poreux. Dans un mode de réalisation, les procédés peuvent consister à former une solution de l'API et à précipiter des particules de celle-ci, par exemple par ajout d'un non-solvant à la solution. L'API précipitée peut être mélangée avec le milieu d'encapsulation pour former un mélange, qui peut ensuite être séché, déshydraté et moulé pour former un matériau souhaité, un dispositif médical ou un implant.
PCT/US2024/032279 2023-06-02 2024-06-03 Encapsulation d'ingrédients pharmaceutiques actifs Ceased WO2024250016A2 (fr)

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