Compositions and methods related to 3D printed devices

Abstract

The present disclosure provides compositions and methods of preparing compositions comprising a collection of polymers. In some aspects, 3D printing may be used to create a final pharmaceutical composition or device. In further aspects, the present disclosure comprises the development of the modular polymeric and composite structures using the portable 3D printing process for manufacturing of reversible intrauterine devices for therapeutic activity.

Description

DESCRIPTIONCOMPOSITIONS AND METHODS RELATED TO 3D PRINTED DEVICES

[0001] This application claims the benefit of priority to United States Provisional Application No. 63 / 583,797, filed September 19, 2023, the entire contents of which are hereby incorporated by reference.

[0002] This invention was made with government support under Grant no. 7200AA20CA00019 awarded by the US Agency for International Development. The government has certain rights in the invention.BACKGROUND OF THE INVENTION1. Field

[0003] The present disclosure relates generally to the field of pharmaceuticals and pharmaceutical manufacture. More particularly, it concerns compositions and methods of preparing functional molecules in a polymer matrix that maybe used in 3D printing of medical devices such as intrauterine devices.2. Description of Related Art

[0004] Intrauterine devices (IUDs) are one of the oldest forms of effective contraception. Some have been designed for controlled release of substances such as copper, silver or hormones. Regarding copper releasing IUDs, these devices have evolved from single strand copper wire folded into various shapes or forms to woven copper of circle, loops, crescent, T or Y shaped devices to the latest of 3D printed polymeric devices. The copper ions released from these conventional intrauterine devices proved to be effective in providing contraceptive action against sperms for birth control, which is the main application of intrauterine devices.

[0005] Intrauterine devices have a rich historical context tracing back to the 19th century when they were first introduced as intrauterine rings. Early designs were crude, often leading to complications such as infections and expulsions. Dr. Ernst Grafenberg revolutionized IUDs in the 1920s with the invention of the silver ring IUD, which had a better safety profile and was widely accepted. However, it was not until the mid- 20th century that plastic IUDs, introduced by Dr. lack Lippes, became popular due to their improved tolerance and effectiveness. In the 1960s, the T-shaped design was conceptualized and became auniversal model for most modem IUDs. Further evolution occurred with the advent of medicated IUDs. Progestasert, releasing progesterone, was introduced in the 1970s, and the Copper T380A, releasing copper ions, became available in the 1980s. These provided superior contraceptive effectiveness while reducing side effects. The 21st century saw the introduction of hormonal IUDs like Mirena and Skyla, which release levonorgestrel, a progestin hormone. These IUDs presented further improved safety and effectiveness, representing the current apex in IUD design evolution.

[0006] IUDs have revolutionized reproductive health over the past few decades. Traditionally used as long-term contraceptive devices, they are inserted into the uterus to prevent fertilization. However, the therapeutic scope of IUDs has expanded significantly beyond family planning. The first wave of IUDs was non-hormonal, usually copper-based, which prevented pregnancy by creating a hostile environment for sperm. With advancements in technology, a second wave of IUDs was developed, offering hormone-based therapies. These IUDs typically release progestin, significantly reducing menstrual bleeding and cramping, making them an effective treatment for conditions such as menorrhagia and endometriosis. Furthermore, recent studies have explored the potential of IUDs as a delivery system for targeted drug therapy. The inherent advantage of the intrauterine route allows for localized drug delivery, minimizing systemic side effects. The continuous evolution of IUDs has fostered improvements in women's health, particularly in terms of contraceptive choices and gynecological treatment options. The current trend in IUD innovation hints towards an exciting future, potentially involving personalized drug delivery systems for an array of medical conditions, further establishing IUDs as more than just contraceptive devices.

[0007] 3D printing of personalized medication and pharmaceutical dosage forms is a novel and promising field of research. In the last decade, this topic of research has attracted the attention of multiple research groups and its potential has been exploited by the pharmaceutical industry which has led to an exponential rise in the numbers of research publications and patents in this field. 3D printing or additive manufacturing can he defined as a process of making 3-dimensional objects from a digital file in a layer-by-layer fashion. Even though the process of 3D printing can be defined by its final product, multiple technologies work on different principles to manufacture the said 3-dimensional objects. Manufacturing 3D printed objects using a filament is such an approach. Fused deposition modeling (FDM) based 3D printing involves the additive deposition of melted feedstock (filament) extruded through acomputer-controlled deposition nozzle, giving the capability of creating complex geometries as well as 3D models with controlled composition and architecture. The printer consists most commonly of a hot end which is the extruder as well as a relatively cooler end which is generally the build platform. It works based on a filament entering the extruder where it is heated to its transition temperature and melted after which it is extruded out of a nozzle onto the build platform where rapid fusion and solidification takes place to form 3D printed structures while cooling to the surface temperature. This method is conducted in a layer-by- layer fashion ultimately allowing for the manufacture of complex three-dimensional constructs. The technique predominantly utilizes thermoplastic polymers as the feedstock which has paved the way for processing pharmaceutical compositions using FDM as they are also predominantly composed of thermoplastic polymers or their blends as excipients. Owing to the simplicity of the equipment coupled with the diverse choice of excipients as well as ease of producing dosage forms with complex geometries for personalized therapy, FDM has been the most evaluated 3D printing technique for the manufacturing of dosage forms.

[0008] FDM 3D printing requires filaments that have an excellent balance between flexibility and brittleness while ensuring the stability of the incorporated active pharmaceutical ingredients. This is essential to ensure smooth and accurate printing of the dosage form to ensure dose deposition accuracy. This optimization is done during the hot-melt extrusion process which is used to produce drug-loaded filaments. Since hot-melt extrusion is a well- established process, it is easy to limit the excipients used in the same to ensure drug stability over a period, and thus helps to reduce the additional excipients delivered to the patient, which increases the drug load. However, the current FDM-based processes used in pharmaceutical dosage form development involve a pre-print lag time to head the nozzles, followed by a postprint lag time for colling the nozzle before starting the next print. This lag time also involves, the manual intervention to remove the printed formulation and then starting a second print due to the small surface print bed area of these benchtop- sized printers, which limits the process to a personalized individual scaled application. Furthermore, the involvement of manual intervention followed by post-processing steps and collection, makes it unfavorable for regulating when scaling up and bringing to the market.

[0009] During the 1980s, stereolithography was developed as a solid freeform technique (SFT) and was the first commercially approved 3D SFT. SFT has significantly improved the ability to prepare structures with precise geometries, using computer-aideddesign, 3D scanning, and data from medical imaging. SLA is extremely versatile with respect to the freedom of designing structures and scales at submicron-sized structures.

[0010] The interest in biodegradable materials for biomedical applications has increased significantly. Both natural and synthetic biodegradable polymers have been broadly explored for various biomedical applications. These include scaffolds in tissue engineering, implants, carriers for targeted and / or sustained drug release, biomedical sensors, and artificial skin. On the other hand, additive manufacturing using these biodegradable polymers is limited and the design of polymers that may be used in these systems is of great interest. Because of this interest, the development of polymer compositions that may be used to create biodegradable materials is of great interest.SUMMARY OF THE INVENTION

[0011] In some aspects, the present disclosure provides a pharmaceutical composition comprising:(A) a functional composition; wherein the functional composition is a nanoparticle or microparticle, an active pharmaceutical ingredient, a polymer, a biologically active molecule, a conductive material, or a combination thereof; and(B) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester.

[0012] In some embodiments, the functional composition is embedded in the poyalkylene vinyl ester polymer. In some embodiments, the embedding of the functional composition in the polyalkylene vinyl ester polymer results in controlled release of the functional composition.

[0013] In some embodiments, the functional composition is a nanoparticle or microparticle, such as a metal nanoparticle or microparticle. In certain embodiments, the metal nanoparticle or microparticle is a transition metal nanoparticle or microparticle.

[0014] In some embodiments, the metal nanoparticle or microparticle is a copper nanoparticle or microparticle, a titanium nanoparticle or microparticle, a gold nanoparticle or microparticle, or a silver nanoparticle or microparticle. In some embodiments, the metal nanoparticle or microparticle is a copper nanoparticle or microparticle. In some embodiments, the nanoparticle or microparticle has a diameter from about 10 nm to about 25 pm. In some embodiments, the diameter is from about 25 nm to about 200 nm. In some embodiments, the diameter is from about 50 nm to about 100 nm. In other embodiments, the diameter is from about 100 nm to about 600 nm. In certain embodiments, the diameter is from about 200 nm to about 400 nm. In some embodiments, the diameter is from about 500 nm to about 10 pm. In further embodiments, the diameter is from about 750 nm to about 7.5 pm.

[0015] In some embodiments, the functional composition is an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is selected from anticancer agents, antiallergic agents, antifungal agents, psychiatric agents such as analgesics, consciousness level- altering agents such as anesthetic agents or hypnotics, nonsteroidal anti-inflammatory agents (NSAIDs), anthelmintics, antiacne agents, antianginal agents, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, a bleeding inhibiting agent, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, and sedatives.

[0016] In some embodiments, the active pharmaceutical ingredient is an antifungal agent, an antibiotic, a chemotherapeutical agent, an antiviral agent, a bleeding inhibiting agent, a contraceptive, or a non-steroidal anti-inflammatory agent. In certain embodiments, the active pharmaceutical ingredient is a non-steroidal anti-inflammatory agent, such as indomethacin.

[0017] In some embodiments, the pharmaceutical composition comprises 2 or more functional molecules. In certain embodiments, the pharmaceutical comprises from about 2 to about 6 functional molecules. In further embodiments, the pharmaceutical composition comprises 2 functional molecules. In some embodiments, the pharmaceutical composition comprises 3 functional molecules. In some embodiments, the pharmaceutical composition comprises two or more distinct functional molecules. In some embodiments, the first functional molecule is selected from a nanoparticle or microparticle or an active pharmaceutical ingredient. In some embodiments, the second functional molecule is a different nanoparticle or microparticle or a different active pharmaceutical ingredient.

[0018] In some embodiments, the functional molecule retains at least 50% of the activity after the pharmaceutical composition has been further processed relative to the unprocessed functional molecule. In further embodiments, the functional molecule retains at least 75% of the activity. In yet further embodiments, the functional molecule retains at least 80% of the activity. In still further embodiments, the functional molecule retains at least 90%of the activity. In yet further embodiments, the functional molecule retains at least 95% of the activity.

[0019] In some aspects, the polyalkylene vinyl ester comprises a C2-C4 alkylene. In some embodiments, the polyalkylene is polyethylene. In some aspects, the polyalkylene vinyl ester comprises a C2-C6 ester, such as an acetate. In some embodiments, the polyalkylene vinyl ester is polyethylene vinyl acetate.

[0020] In some embodiments, the polyalkylene vinyl ester comprises from about 10% to about 20% by weight of the vinyl ester. In further embodiments, the polyalkylene vinyl ester comprises from about 10% to about 15% by weight of the vinyl ester. In other embodiments, the polyalkylene vinyl ester comprises from about 15% to about 20% by weight of the vinyl ester. In some embodiments, the pharmaceutical composition comprises from about 5% to about 99% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 5% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In yet further embodiments, the pharmaceutical composition comprises from about 5% to about 15% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

[0021] In some embodiments, the pharmaceutical composition comprises from about 15% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 20% to about 30% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In other embodiments, the pharmaceutical composition comprises from about 60% to about 95% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 80% to about 90% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 25% to about 95% by weight of the functional molecule in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 50% to about 90% by weight of the functional molecule in the pharmaceutical composition. In yet further embodiments, the pharmaceutical composition comprises from about 65% to about 85% by weight of the functional molecule in the pharmaceutical composition.

[0022] In some aspects, the pharmaceutical composition comprises from about 1% to about 50% by weight of the functional molecule in the pharmaceutical composition. In further aspects, the pharmaceutical composition comprises from about 2% to about 30% by weight of the functional molecule in the pharmaceutical composition. In yet further aspects, the pharmaceutical composition comprises from about 3% to about 20% by weight of the functional molecule in the pharmaceutical composition.

[0023] In some embodiments, the pharmaceutical composition further comprises one or more excipients. In some embodiments, the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intrauterinally, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, or vaginally.

[0024] In some embodiuments, the pharmaceutical composition is formulated as a solid dosage form. In some embodiuments, the pharmaceutical composition is formulated for administered vaginally. In other embodiments, the pharmaceutical composition is formulated for administered intrauterine. In some embodiuments, the pharmaceutical composition is formulated as a unit dose. In some embodiuments, the pharmaceutical composition is formulated into a medical device. In some embodiuments, the medical device is an intrauterine device.

[0025] In some aspects, the present disclosure provides a method of preparing a pharmaceutical composition comprising:(A) obtaining a printing composition comprising:(z) a functional composition; wherein the functional composition is a nanoparticle or microparticle, an active pharmaceutical ingredient, a polymer, a biologically active molecule, or a combination thereof;(z'z) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester; and(B) subjecting the printing composition to an additive manufacturing technique.

[0026] In some embodiments, the functional composition is embedded in the poyalkylene vinyl ester polymer as a result of the additive manufacturing technique. In some embodiments, the embedding of the functional composition in the polyalkylene vinyl ester polymer results in controlled release of the functional composition.

[0027] In some aspects, the additive manufacturing technique is vat photopolymerization. In some aspects, the additive manufacturing technique is a stereolithography technique. In some aspects, the additive manufacturing technique applies sequential layers.

[0028] In some embodiments, the sequential layers have a thickness from about 5 nm to about 1 mm. In some embodiments, the thickness is from about 10 nm to about 750 nm. In further embodiments, the thickness is from about 20 nm to about 500 nm. In yet further embodiments, the thickness is from about 25 nm to about 400 nm.

[0029] In some embodiments, the method comprises repeating layers of similar size. In some embodiments, the method comprises repeating layers of distinct size. In some embodiments, the method comprises using an energy source with a specific power, such as a laser. In some embodiments, the specific power is from about 10 mW to about 10 W. In further embodiments, the specific power is 25 mW to about 1 W. In some embodiments, the specific power is from about 100 mW to about 500 mW. In some embodiments, the specific power is about 250 mW.

[0030] In some embodiments, the additive manufacturing technique comprises a printing speed from about 1 mm / s to about 25 mm / s. In further embodiments, the printing speed is from about 2.5 mm / s to about 10 mm / s. In yet further embodiments, the printing speed is 5 mm / s. In some embodiments, the additive manufacturing technique comprises a print temperature. In some embodiments, the print temperature is from about 100°C to about 400 °C. In further embodiments, the printing speed is from about 150°C to about 300 °C. In yet further embodiments, the print temperature is about 230 °C.

[0031] In some embodiments, the additive manufacturing technique comprises a bed temperature. In some embodiments, the bed temperature is from about 25 °C to about 250 °C. In further embodiments, the bed temperature is from about 75°C to about 125 °C. In someembodiments, the print temperature is about 100 °C. In some embodiments, the method further comprises extruding the printing composition before subjecting it to the additive manufacturing technique to create an extruded print composition.

[0032] In some embodiments, the extruded print composition results in one or more filaments. In some embodiments, the filaments comprise a filament size from about 0.5 mm to about 5 mm. In further embodiments, the filament size is from about 1 mm to about 3 mm. In some embodiments, the filament size is from about 1.25 mm to about 2.25 mm.

[0033] In some embodiments, the functional composition is a nanoparticle or microparticle, such as a metal nanoparticle or microparticle. In some aspects, the metal nanoparticle or microparticle is a transition metal nanoparticle or microparticle, such as a copper nanoparticle or microparticle. In some embodiments, the nanoparticle or microparticle has a diameter from about 10 nm to about 25 pm. In other embodiments, the diameter is from about 25 nm to about 200 nm. In further embodiments, the diameter is from about 50 nm to about 100 nm. In other embodiments, the diameter is from about 100 nm to about 600 nm. In further embodiments, the diameter is from about 200 nm to about 400 nm. In some embodiments, the diameter is from about 500 nm to about 10 pm. In some embodiments, the diameter is from about 750 nm to about 7.5 pm.

[0034] In some embodiments, the functional composition is an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is selected from anticancer agents, antiallergic agents, antifungal agents, psychiatric agents such as analgesics, consciousness level- altering agents such as anesthetic agents or hypnotics, nonsteroidal antiinflammatory agents (NSAIDs), anthelmintics, antiacne agents, antianginal agents, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, a bleeding inhibiting agent, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytics, lipid regulatingagents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, and sedatives.

[0035] In some embodiments, the active pharmaceutical ingredient is an antifungal agent, an antibiotic, a chemotherapeutical agent, an antiviral agent, a bleeding inhibiting agent, a contraceptive, or a non-steroidal anti-inflammatory agent. In some embodiments, the active pharmaceutical ingredient is a non-steroidal anti-inflammatory agent. In some embodiments, the non-steroidal anti-inflammatory agent is indomethacin.

[0036] In some embodiments, the pharmaceutical composition comprises 2 or more functional molecules. In some embodiments, the pharmaceutical comprises from about 2 to about 6 functional molecules. In some embodiments, the pharmaceutical composition comprises 2 functional molecules. In other embodiments, the pharmaceutical composition comprises 3 functional molecules. In some embodiments, the pharmaceutical composition comprises two or more distinct functional molecules.

[0037] In some embodiments, the first functional molecule is selected from a nanoparticle or microparticle or an active pharmaceutical ingredient. In some embodiments, the second functional molecule is a different nanoparticle or microparticle or a different active pharmaceutical ingredient. In some embodiments, the functional molecule retains at least 50% of the activity after the printing composition has been further processed relative to the unprocessed functional molecule. In further embodiments, the functional molecule retains at least 75% of the activity. In still further embodiments, the functional molecule retains at least 80% of the activity. In yet further embodiments, the functional molecule retains at least 90% of the activity. In yet further embodiments, the functional molecule retains at least 95% of the activity.

[0038] In some aspects, the polyalkylene vinyl ester comprises a C2-C4 alkylene. In some embodiments, the polyalkylene is polyethylene. In some embodiments, the polyalkylene vinyl ester comprises a C2-C6 ester, such as an acetate. In some embodiments, the polyalkylene vinyl ester is polyethylene vinyl acetate.

[0039] In some embodiments, the polyalkylene vinyl ester comprises from about 10% to about 20% by weight of the vinyl ester. In some embodiments, the polyalkylene vinyl ester comprises from about 10% to about 15% by weight of the vinyl ester. In other embodiments, the polyalkylene vinyl ester comprises from about 15% to about 20% by weight of the vinylester. In some embodiments, the pharmaceutical composition comprises from about 5% to about 99% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 5% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 5% to about 15% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In other embodiments, the pharmaceutical composition comprises from about 15% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 20% to about 30% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In other embodiments, the pharmaceutical composition comprises from about 60% to about 95% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 80% to about 90% by weight of the polyalkylene vinyl ester in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 25% to about 95% by weight of the functional molecule in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 50% to about 90% by weight of the functional molecule in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 65% to about 85% by weight of the functional molecule in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 1% to about 50% by weight of the functional molecule in the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises from about 2% to about 30% by weight of the functional molecule in the pharmaceutical composition. In further embodiments, the pharmaceutical composition comprises from about 3% to about 20% by weight of the functional molecule in the pharmaceutical composition.

[0040] In some embodiments, the printing composition further comprises one or more excipients. In some aspects, the present disclosure provides a pharmaceutical composition preparing using the methods described herein.

[0041] In some aspects, the present disclosure provides a pharmaceutical composition comprising:(A) an active pharmaceutical ingredient;(B) a metal nanoparticle or microparticle; and(C) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester.

[0042] In some aspects, the present disclosure provides a method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective dose of a pharmaceutical composition described herein. In some aspects, the functional molecule in the pharmaceutical composition is useful in treating the disease or disorder. In some aspects, the present disclosure provides a method of preventing a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective dose of a pharmaceutical composition described herein. In some aspects, the functional molecule in the pharmaceutical composition is useful in preventing the disease or disorder.

[0043] In some aspects, the present disclosure provides a medical device prepared using a pharmaceutical composition described herein. In some aspects, the present disclosure provides a medical device prepared using a pharmaceutical composition prepared using the methods described herein. In some embodiments, the medical device comprises one or more arms. In some embodiments, the medical device comprises two arms attached to a central cylindrical core. In some embodiments, the medical device comprises a tee shaped of cylinders. In some embodiments, the medical device comprises one or more pores. In some embodiments, the medical device comprises two to six pores. In some embodiments, the medical device comprises two pores.

[0044] In some embodiments, the medical device has a wall thickness from about 50 pm to about 10 mm. In further embodiments, the wall thickness is from about 100 pm to about 3000 pm. In some embodiments, the wall thickness is from about 500 pm to about 2000 pm. In some embodiments, the wall thickness is about 1200 pm. In some embodiments, the medical device has a diameter from about 25 pm to about 25 cm. In some embodiments, the diameter is from about 250 pm to about 10 cm. In some embodiments, the diameter is from about 500 pm to about 2.5 cm. In certain embodiments, the diameter is about 1 cm.

[0045] In some embodiments, the medical device has a height from about 100 pm to about 25 mm. In some embodiments, the height is from about 500 pm to about 10 mm. In certain embodiments, the height is from about 500 pm to about 6 mm. In some embodiments,the height is about 3 mm. In some embodiments, the medical device has a width from about 100 pm to about 25 mm. In some embodiments, the width is from about 500 |im to about 10 mm. In further embodiments, the width is from about 500 pm to about 6 mm. In some embodiments, the width is about 2.5 mm. In some embodiments, the medical device is an interuterine device.

[0046] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is ascribed to one particular generic formula doesn’t mean that it cannot also belong to another generic formula.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0048] FIG. 1 shows the hot-melt extrusion of EVA polymer. The white filament coming out of the nozzle is collected.

[0049] FIGS. 2A-E show the development of IUD segment [A] CAD design of the IUD segment to the specified dimensions (inset shows the EVA printed IUD segment), [B] Flattened top and bottom side, [C] A series of joined IUD segments, [D] A groups of joined IUD segments, and [E] the 3D printed series of joined IUD segments.

[0050] FIGS. 3A-E show the development and printing of full IUD using continuous printing process.

[0051] FIG. 4 shows the characterization of EVA- 18 formulations.

[0052] FIG. 5 shows the characterization of EVA- 12 formulations.

[0053] FIGS. 6A-F show the drug release of [A] release of indomethacin from EVA- 12 formulations, [B] Cumulative release of indomethacin from EVA- 12 formulations, [C] release of indomethacin from EVA- 18 formulations, [D] Cumulative release of indomethacin from EVA- 18 formulations, [E] Cumulative release of copper, and [F] copper release from the final formulations.

[0054] FIGS. 7A-F show the analysis of upgraded formulations from Trial-I [A] extruded filament, [B] 3D printed IUD segment, [C] cumulative release of indomethacin, [D] release of indomethacin, [E] cumulative copper release, and [F] copper release.

[0055] FIGS. 8A-F show the analysis of upgraded formulations from Trial-II [A] extruded filament, [B] 3D printed IUD segment, [C] cumulative release of indomethacin, [D] release of indomethacin, [E] cumulative copper release, and [F] copper release.

[0056] FIGS. 9A & B show (A) CAD design of the small animal porous intrauterine devices. (B) CAD design of the human animal porous intrauterine devices.

[0057] FIG. 10 shows the in vitro drug release data of formulation: loading: a hydrogel with 4 mg Indomethacin, and 35 mg Copper particles.

[0058] FIGS. 11A-E show [A] SLA printed scaffolds loaded with hydrogel+Copper+Indomethacin before and after crosslinking with UV for 30 min and then closed the opening with biocompatible UV curable resin (Bioflex described in International Patent Application No. PCT / US2023 / 072029) for 5 min, [B] Indomethacin release per day, [C] Cumulative release of indomethacin, [D] Copper release per day, and [E] Cumulative release of copper from the IUDs.DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0023] The present disclosure relates to a long-acting therapeutic drug delivery device fabricated with multi-material formulations using portable device fabrication method of three- dimensional (3D) printing. In some aspects, the present disclosure provides an IUD device with more standardized design that can deliver copper and indomethacin drugs simultaneously for long-term delivering the required doses per day to facilitate a better pain relief and contraception action.

[0024] The present disclosure IU3D (Intrauterine 3D printed devices) has pushed the IUD research into a new area of 3D printed controlled and systemic multidrug or multiple compound releasing devices. Three-dimensional printing is a portable and state-of-art technology for pharmaceutical manufacturing. The 3D printing of fused deposition modeling and stereolithography methods were employed to develop two unique modular IUD devices that are loaded with metal nanoparticles or microparticles (Copper) and NSAID drug (Indomethacin) for the application of contraception. The major side effect of the clinically employed commercial IUDs of hormonal or copper devices is pain and higher blood discharge during menstruation. The incorporation of drug into the IUDs is never done in a commercial IUD. The advantage is to deliver the activity contraception along with a pain relief medication for better quality of life for the IUD recipient.

[0025] To highlight the advantages that the proposed one-stop customized design device offers over current technologies in the field, these unique attributes set it apart and contribute to its potential impact in the realm of reproductive healthcare, (a) Comprehensive Customization: Unlike existing technologies that offer limited options, the device described herein provides a one-stop solution for customized design. This means that it can be tailored to meet individual needs and preferences, taking into account various anatomical considerations and personal requirements. By offering a wide range of customization options, it maximizes patient comfort and satisfaction, leading to improved outcomes and adherence, (b) Enhanced Patient-Centric Approach (c) Versatility and Adaptability (d) Simplified User Experience (e) Potential for Improved Effectiveness. These and other advantages are discussed in more detail below.I. Pharmaceutical Compositions

[0026] In some aspects, the present disclosure provides pharmaceutical compositions containing a functional composition; wherein the functional composition is a nanoparticle or microparticle, an active pharmaceutical ingredient, a polymer, a biologically active molecule, a conductive material, or a combination thereof. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other compound other than the functional component and the compounds in the polymer formulation.

[0027] The pharmaceutical compositions described herein comprise an active pharmaceutical ingredient. The pharmaceutical compositions described herein contain an active pharmaceutical ingredient in an amount between about 0.1 % to about 95% w / w, betweenabout 0.25% to about 90% w / w, between about 0.5% to about 50% w / w, or between about 1% to about 40% w / w of the total composition. In some embodiments, the amount of the active pharmaceutical ingredient is from about 0.1%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, 3.75%, 4%, 4.25%, 4.5%, 4.75%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33% 34%, 35%, 36%, 37%, 38%, 39%, 40%, 42%, 44%, 45%, 46%, 48%, 50%, 52%, 54%, 55%, 56%, 58%, 60%, 65%, 70%, 75%, 80%, to about 90% w / w or any range derivable therein. In some embodiments, the pharmaceutical composition is substantially, essentially, or entirely free of any other functional compositions.A. Functional Composition i. Active Pharmaceutical Ingredients

[0028] In some embodiments, the active pharmaceutical ingredient is classified using the Biopharmaceutical Classification System (BCS), originally developed by G. Amidon, which separates pharmaceuticals for oral administration into four classes depending on their aqueous solubility and their permeability through the intestinal cell layer. According to the BCS, drug substances are classified as follows: Class I — High Permeability, High Solubility; Class II — High Permeability, Low Solubility; Class III — Low Permeability, High Solubility; and Class IV — Low Permeability, Low Solubility.

[0029] While the pharmaceutical compositions and methods described herein can be applied to any BCS class of drugs, BCS class II and IV are of interest for the pharmaceutical compositions described herein. Additionally, other active pharmaceutical ingredients that are of specific consideration are those are those that are high melting point drugs such as a drug that has a melting point of greater than 60 °C. Alternatively, the active pharmaceutical ingredients used herein may have a melting point from about 35 °C to about 1,000 °C, from about 50 °C to about 750 °C, or from about 60 °C to about 200 °C. In particular, the melting point may be greater than 25 °C, 35 °C, 50 °C, 60 °C, 80 °C, 100 °C, 125 °C, 150 °C, 175 °C, 200 °C, or 250 °C. In particular, the composition may also comprise drugs that are laser sensitive. Such active pharmaceutical ingredients may be formulated with other compounds such as dyes that increase the stability of these active pharmaceutical ingredients.

[0030] Suitable active pharmaceutical ingredients may be any poorly water- soluble, biologically active pharmaceutical ingredients or a salt, isomer, ester, ether or other derivative thereof, which include, but are not limited to, anticancer agents, antifungal agents, psychiatric agents such as analgesics, consciousness level- altering agents such as anesthetic agents or hypnotics, nonsteroidal antiinflammatory agents (NSAIDS), anthelminthics, antiacne agents, antianginal agents, antiarrhythmic agents, anti- asthma agents, antibacterial agents, anti- benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, antiinflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, antiobesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, hormones, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, or sedatives.

[0031] In some aspects, the method may be mostly used with active pharmaceutical ingredients which undergo degradation at an elevated temperature or pressure / shear. The active pharmaceutical ingredients that may be used include those which decompose at a temperature above about 50 °C. In some embodiments, the active pharmaceutical ingredients decompose above a temperature of 80 °C. In some embodiments, the active pharmaceutical ingredients decompose above a temperature of 100 °C. In some embodiments, the active pharmaceutical ingredients decompose above a temperature of 150 °C. The active pharmaceutical ingredients that may be used include therein which decompose at a temperature of greater than about 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C, 120 °C, 125 °C, 130 °C, 135 °C, 140 °C, 145 °C, or 150 °C.

[0032] Alternatively, active pharmaceutical ingredients may be one that is sensitive to shear. These active pharmaceutical ingredients are compounds for which the chemical and / or physical properties may change due to friction resulting from the manufacturing process itself, including chemical degradation of a drug or the loss of molecular weight of a polymer as non-limiting examples. The degree of loss of the chemical or physical properties of acompound due to shear is often seen as a function of the degree of mixing (e.g. , blade RPM, rotation speed) and the properties of the polymer carrier (e.g. rheological properties). ii. Nanoparticles or Micorparticles

[0033] In some aspects, the functional molecule present in the composition may be a nanoparticle or microparticle. Nanoparticles are particles generally with a size from about 1 nm to about 100 nm, but could include particles up to 25,000 nm. Microparticles are generally from 1,000 nm to about 100,000 nm. In general, nanoparticles are less than 10 pm. The nanoparticles contained in the compositions described herein may be nanoparticles or microparticles with one or more of the functional molecules such as a nanoparticle or microparticles form of a conductive material such as graphene, a nanoparticle or microparticles form of a biologically active molecule such as a lipid nanoparticle or microparticles with one or more proteins, nucleic acids, sugars, or antibodies, or a nanoparticle or microparticles form of a polymer. Additionally, the present disclosure may further comprise one or more metallic nanoparticles or microparticles. These nanoparticles contain metals either as ions or in their ground state. The metal nanoparticles or microparticles may further comprise a mixture of two or metals. Some non-limiting examples of metals that may be used in the metal nanoparticles or microparticles contemplated herein include copper, silver, gold, zinc, manganese, nickel, platinum, or titanium. These metals may be as the ground state or in the form of a salt such as an oxide.

[0034] In particular, the present compositions may comprise one or more nanoparticles or microparticles, such as metal nanoparticles or microparticles that have a diameter from about 10 nm to about 25 pm. In particular, the range of diameters may be from about 25 nm to about 200 nm, from about 100 nm to about 600 nm, or from about 500 nm to about 10 pm. In some aspects, the present compositions may comprise a nanoparticle with a diameter that is from about 10 nm, 20 nm, 25 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 75 nm, 80 nm, 90 nm, 100 nm, 125 nm, 150 nm, 175 nm, 200 nm, 225 nm, 250 nm, 275 nm, 300 nm, 325 nm, 350 nm, 375 nm, 400 nm, 425 nm, 450 nm, 475 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1 pm, 2.5 pm, 5 pm, 7.5 pm, 10 pm, 15 pm, 20 pm, to about 25 pm, or any range derivable therein.

[0035] Also, the present compositions may further comprise one or more lipid nanoparticles or microparticles. These lipid nanoparticles or microparticles may comprise oneor more components in addition to a fatty acid containing component such as a steroid, phospholipid, surfactant, or a polymer conjugated lipid such as a PEGylated lipid.

[0036] Nanoparticles or microparticles used in the present embodiments include such nanoscale materials as a lipid-based nanoparticle or microparticles, a superparamagnetic nanoparticle or microparticles, a nanoshell, a semiconductor nanocrystal, a quantum dot, a polymer-based nanoparticle or microparticles, a silicon-based nanoparticle or microparticles, a silica-based nanoparticle or microparticles, a metal-based nanoparticle or microparticles, a fullerene and a nanotube (Ferrari, 2005). The conjugation of polypeptide or nucleic acids to nanoparticles or microparticles provides structures with potential application for targeted delivery, controlled release, enhanced cellular uptake and intracellular trafficking, and molecular imaging of therapeutic peptides in vitro and in vivo (West, 2004; Stayton et al. , 2000; Ballou et al. , 2004; Frangioni, 2003 ; Dubertret et al. , 2002; Michalet et al. , 2005 ; Dwarakanath et al. , 2004.B. Polymer Formulation

[0037] In some aspects, the present disclosure relates to compositions that may be used as resins to prepare devices and dosage forms. These compositions may contain a polymer formulation that contains a polyalkylene vinyl ester. In particular, the present compositiosn may further comprise one or more other polymers. In some aspects, the polyalkylene vinyl ester is a polymer that comprises both a polyalkylene component and a polyvinyl ester component. Each of the principle monomers may be present either as a block or randomly distributed in the polymer. In some embodiments, the alkylene and vinyl ester monomers are randomly distributed in the polymer.

[0038] The polyalkylene units may result from the polymerization of a C2-C4 alkylene monomer. In particular, the polymerization may be of an ethylene, propylene, or butylene monomer. In particular, the polymerization is of an ethylene monomer resulting in polyethylene.

[0039] The vinyl ester monomers, on the other hand, are ester with a C1-C6 alkyl group. The ester may result in a formyl ester, an acetate ester, or a propionate ester. In some embodiments, the vinyl ester monomers are vinyl acetate monomers. The polymers that may be used in the present applications may comprise from about 0.5% by weight to about 40% by weight of the vinyl ester in the polymer. The amount of the vinyl ester in the polymer may befrom about 0.5%, 1%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 7.5%, 8%, 9%, 10%, 11%, 12%, 12.5%, 13%, 14%, 15%, 16%, 17%, 17.5%, 18%, 19%, 20%, 21%, 22%, 22.5%, 23%, 24%, 25%, 26%, 27%, 27.5%, 28%, 29%, 30%, 32.5%, 35%, to about 40% by weight, or any range derivable therein.C. Other Excipients

[0040] In some aspects, the present disclosure provides pharmaceutical compositions that may further comprise one or more additional excipients. The excipients (also called adjuvants) that may be used in the presently disclosed compositions and composites, while potentially having some activity in their own right, for example, antioxidants, are generally defined for this application as compounds that enhance the efficiency and / or efficacy of the active pharmaceutical ingredient. It is also possible to have more than one active agent in a given solution so that the particles formed contain more than one active agent. In particular, the compositions may further comprise one or more flowability excipients such as a silicon compound. The silicon compound may include an oxide of silicon such as silicon dioxide.

[0041] Any pharmaceutically acceptable excipient known to those of skill in the art may be used to produce the pharmaceutical compositions disclosed herein. Examples of excipients for use with the present disclosure include, lignin, gelatin methacrylate, lactose, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quaternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol, sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, poloxamers (polyethylenepolypropylene glycol block copolymers), sucrose esters, sodium lauryl sulfate, oleic acid, lauric acid, vitamin E TPGS, polyoxyethylated glycolysed glycerides, dipalmitoyl phosphadityl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethylene glycols, polyglycolyzed glycerides, polyvinyl alcohols, polyacrylates, polymethacrylates, polyvinylpyrrolidones, phosphatidyl choline derivatives, cellulose derivatives, biocompatible polymers selected from poly (lactides), poly (glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co- glycolic acid)s and blends, combinations, and copolymers thereof.

[0042] As stated, excipients and adjuvants may be used in the pharmaceutical composition to enhance the efficacy and efficiency of the active agent in the pharmaceutical composition. Additional non-limiting examples of compounds that can be included are binders, carriers, cryoprotectants, lyoprotectants, surfactants, fillers, stabilizers, polymers, protease inhibitors, antioxidants, bioavailability enhancers, and absorption enhancers. The excipients may be chosen to modify the intended function of the active ingredient by improving flow, or bioavailability, or to control or delay the release of the API. Specific nonlimiting examples include: sucrose, trehalose, Span 80, Span 20, Tween 80, Brij 35, Brij 98, Pluronic, sucroester 7, sucroester 11, sucroester 15, sodium lauryl sulfate (SLS, sodium dodecyl sulfate. SDS), dioctyl sodium sulphosuccinate (DSS, DOSS, dioctyl docusate sodium), oleic acid, laureth-9, laureth-8, lauric acid, vitamin E TPGS, Cremophor® EL, Cremophor® RH, Gelucire® 50 / 13, Gelucire® 53 / 10, Gelucire® 44 / 14, Labrafil®, Solutol® HS, dipalmitoyl phosphatidyl choline, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrins, polyethylene glycols, Labrasol®, polyvinyl alcohols, polyvinyl pyrrolidones, and tyloxapol. In particular, the composition may further comprise one or more silicon compounds such as silicon dioxide that improves the flowability of the composition.

[0043] The stabilizing carrier may also contain various functional excipients, such as: hydrophilic polymer, antioxidant, super-disintegrant, surfactant including amphiphilic molecules, wetting agent, stabilizing agent, retardant, similar functional excipient, or a combination thereof, and plasticizers including citrate esters, polyethylene glycols, PG, triacetin, diethyl phthalate, castor oil, and others known to those of ordinary skill in the art. Extruded material may also include an acidifying agent, adsorbent, alkalizing agent, buffering agent, colorant, flavorant, sweetening agent, diluent, opaquing, complexing agent, fragrance, preservative or a combination thereof.

[0044] Compositions with enhanced solubility may comprise a mixture of the active pharmaceutical ingredient and an additive that enhances the solubility of the active pharmaceutical ingredient. Examples of such additives include but are not limited to surfactants, polymer-carriers, pharmaceutical carriers, thermal binders, or other excipients. A particular example may be a mixture of the active pharmaceutical ingredient with a surfactant or surfactant, the active pharmaceutical ingredient with a polymer or polymers, or the active pharmaceutical ingredient with a combination of a surfactant and polymer carrier or surfactantsand polymer-carriers. A further example is a composition where the active pharmaceutical ingredient is a derivative or analog thereof.

[0045] In some embodiments, the pharmaceutical compositions may further comprise one or more surfactants. Surfactants that can be used in the disclosed pharmaceutical compositions to enhance solubility include those known to a person of ordinary skill. Some particular non-limiting examples of such surfactants include but are not limited to sodium dodecyl sulfate, dioctyl docusate sodium, Tween 80, Span 20, Cremophor® EL or Vitamin E TPGS.

[0046] Solubility can be indicated by peak solubility, which is the highest concentration reached of a species of interest over time during a solubility experiment conducted in a specified medium at a given temperature. The enhanced solubility can be represented as the ratio of peak solubility of the agent in a pharmaceutical composition of the present disclosure compared to peak solubility of the reference standard agent under the same conditions. Preferably, an aqueous buffer with a pH in the range of from about pH 4 to pH 8, about pH 5 to pH 8, about pH 6 to pH 7, about pH 6 to pH 8, or about pH 7 to pH 8, such as, for example, pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.2, 6.4, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.4, 7.6, 7.8, or 8.0, may be used for determining peak solubility. This peak solubility ratio can be about 2:1, 3:1, 4:1, 5: 1, 6:1, 7:1, 8: 1, 9:1, 10:1, 12:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1 or higher.

[0047] Compositions of the active pharmaceutical ingredient that enhance bioavailability may comprise a mixture of the active pharmaceutical ingredient and one or more pharmaceutically acceptable adjuvants that enhance the bioavailability of the active pharmaceutical ingredient. Examples of such adjuvants include but are not limited to enzyme inhibitors. Particular examples are such enzyme inhibitors include but are not limited to inhibitors that inhibit cytochrome P-450 enzyme and inhibitors that inhibit monoamine oxidase enzyme. Bioavailability can be indicated by the Cmaxor the AUC of the active pharmaceutical ingredient as determined during in vivo testing, where Cmax is the highest reached blood level concentration of the active pharmaceutical ingredient over time of monitoring and AUC is the area under the plasma-time curve. Enhanced bioavailability can be represented as the ratio of Cmax or the AUC of the active pharmaceutical ingredient in a pharmaceutical composition of the present disclosure compared to Cmaxor the AUC of the reference standard the active pharmaceutical ingredient under the same conditions. This CmaXor AUC ratio reflectingenhanced bioavailability can be about 5:1, 6: 1, 7:1, 8:1, 9: 1, 10:1, 12:1, 15:1, 20:1, 25:1, 30: 1, 35:1, 40:1, 45: 1, 50: 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85:1, 90:1, 95: 1, 98: 1, 99: 1, 100: 1 or higher.

[0048] In other aspects, the present compositions may further comprise one or more opacifying agents. Opacifying agents include such compounds as titanium oxide and alter the clarity and ability of energy to be absorbed by the compositions. Alternatively, these compositions may alter the amount of energy needed to achieve appropriate processing of the compositions. Some non-limitnig examples of opacfying agents include those taught by U.S. Patent No. 4,009,139, U.S. Patent No. 5,571,334, and PCT Patent Application No. WO 2020 / 122950, the entire contents of which are hereby incorporated by reference. Some nonlimiting examples of opacifying agents including Aerosil®, Cab-0 Si®, or other silicon dioxides, aluminum hydroxide, alumina, aluminum silicate, arachidic acid, barium sulfate, bentonite, calamine, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium silicate, calcium sulfate, ceric oxide, cetyl alcohol, activated charcoal, charcoal, diatomaceous earth, erucamide, ethylene glycol monosterate, Fuller’s earth, guanine, hectorite, kaolin, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, magnesium phosphate tribasic, magnesium silicate, magnesium trisilicate, myristic acid, palmitic acid, silica, stannic oxide, stearic acid amide, stearoyl monoethanolamine sterate, stearyl palmitate, talc, titanium dioxide, Veegum® or other granular magnesium aluminum silicates , zinc carbonate basic, zirconium oxide, or zirconium silicate. In other aspects, these excipients may be a light absorbing excipient such as a dye or fluorophore. Some non-limiting examples of dyes include xanthene, BOPIDY, coumarin, cypate, or other well known conjugated systems of multiple bonds.

[0049] In some aspects, the amount of the excipient in the pharmaceutical composition is from about 0.1% to about 20% w / w, from about 0.25% to about 10% w / w, from about 0.5% to about 7.5% w / w, or from about 0.5% to about 5% w / w. The amount of the excipient in the pharmaceutical composition comprises from about 0.1 %, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.75%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.5%, 1.75%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9%, to about 10% w / w, or any range derivable therein, of the total pharmaceutical composition. In one embodiment, the amount of the excipient in the pharmaceutical composition is at 0.25% to 2.5% w / w of the total weight of the pharmaceutical composition.IL Therapeutic Devices

[0050] In some aspects, the present disclosure relates to a therapeutic device, unique optimized formulation and device fabrication method using a continuous 3D printer. Intrauterine devices (IUDs) are one of the oldest controlled and systematic release systems of copper or silver or hormones. These devices have evolved from single strand copper wire folded into various shapes or forms to woven copper wires as a circle, loops, crescent, T or Y shaped devices to the latest of 3D printed structures. The copper ions released from these devices proved to be more effective in providing the contraception action against sperms. The present invention IU3D (Intrauterine 3D printed devices) has pushed the IUD research into a new area of 3D printed controlled and systemic multianalyte releasing devices.

[0051] In some aspects, the present disclosure relates to the 3D printing of fused deposition modeling and stereolithography methods, which were employed to develop two unique IUD devices loaded with metal nanoparticles or microparticle (Copper) and NSAID drug (Indomethacin). The major side effect of the clinically employed commercial IUDs of hormonal or copper devices is pain and higher blood release during menstruation.

[0052] In some aspects, the process involves the solubilization of the drug in the polymeric matrix (no solubilization needed if interested in forming solid dispersion for drugs with good solubility) at a temperature below, at or above the melting temperature (Tm) of the API, depending on the exposed processing conditions. This is followed by the formation of intermolecular networks between the polymeric matrix and the drug, thus keeping the drug- loaded filaments stable for a time and preventing recrystallization in case of amorphous solid dispersions formed for poorly soluble drug delivery using filament-based printing approach. On temperature reduction, the API experiences a liquid-solid state conversion (wherein the solid can be crystalline or amorphous depending on the rate of cooling).

[0053] The filaments obtained in such a manner may be open to a wide variety of shapes and designs that can be produced using the 3D printing system, which is limited only by the operator's imagination. The system size and capacity can be modified to suit needs which could range from an individualized patient-centered point-of-care machinery, employed in a compounding pharmacy, to a large-scale process for mass manufacturing of medical devices and structures as well.

[0054] In some aspects, the polymer for loaded copper and indomethacin may be optimized to the 3D printing technique employed. This helps to deliver the appropriate dose per day to the end user. The parameters of printing and polymer properties facilitate a tailored release mechanism as needed.

[0055] In some aspects, the loading of NS AID drug provide pain relief to the user, averting any initial side effects reported during or after early insertion of the IU3D. In some embodiments, the design and dimensions can be adapted as a modular model to fit to the needs of the end user. The product development cycle is short and cost-effective. Any changes to the dosage and IUD characteristics may be modified before fabrication process.

[0056] In some aspects, the 3D printing facilitates on-demand fabrication process. This fabrication process provides more opportunities for the clinicians and end users to extract more uses from the invention. The current pharmaceutical manufacturing process involves multiple steps and the use of high-powered machinery in a designated space. The footprint and energy required for pharmaceutical manufacturing are very high and costly. In some aspects, the present technology describes a process of employing 3D printers and pharmaceutical dose filaments.III. Additive Manufacturing Methods

[0057] Various additive manufacturing including additive systems are contemplated in the present disclosure. These additive manufacturing or additive systems represent machines used for additive manufacturing. These machines operate under various process categories and are used to refer to a category of machines rather than a particular commercial vendor variation of process methodology. Several examples of additive manufacturing process categories include: binder jetting, directed energy deposition, material extrusion, material jetting, powder bed fusion, sheet lamination, and vat photopolymerization. Vat photopolymerization refers to an additive manufacturing process in which liquid photopolymer in a vat is selectively cured by light-activated polymerization. Similarly, stereolithography is a vat photopolymerization process used to produce parts from photopolymer materials in a liquid state using one or more lasers to selectively cure to a predetermined thickness and harden the material into shape layer upon layers. In particular, stereolithography apparatus is an SLA additive machine. As a non-limiting example, SLadditive machines are commercially available via various vendors, such as Envision Tec 3D, Formlabs, 3D systems corporation, etc.

[0058] The devices described herein are cured products of the resin composition for stereolithography. Specifically, the flexible AM devices of the present invention are cured by irradiating the polymer composition for stereolithography with laser / light. While the hardness, tensile strength at break, tensile elongation at break, and compression of the flexible shaped biomedical devices made using the pharmaceutical composition may be set appropriately according to the mechanical properties required for the product.

[0059] The flexible shaped biomedical devices made according to the methods described herein may be formed into any desired shapes by a stereolithography method. These flexible shaped biomedical devices may be produced by any known stereolithography methods, using the compositions described herein as raw material.

[0060] The method for producing the flexible biomedical devices can be suitably performed by using the composition described herein, in a conventionally known stereolithography method that uses a liquid resin as a raw material, such as being used in various stereolithography methods including LCD (stereolithography liquid display method: Liquid Crystal Display), DLP (stereolithography projector (surface exposure) method: Digital Light Processing), and SLA (stereolithography laser method: Stereolithography Apparatus).

[0061] In some aspects, the present disclosure provides composition that may be used to prepare biomedical devices described herein. These devices are prepared using a method including the steps of forming a first-layer cured product by supplying the compositions for stereolithography described herein onto a stereolithography platform, and irradiating the polymer composition for stereolithography with light / laser to cure the polymer composition for stereolithography; forming a second-layer cured product by supplying the composition described gereub for producing the second- layer cured product onto the first-layer cured product, and irradiating the compositions for stereolithography with laser / light to cure the polymer composition for stereolithography; and repeating the same step as the step of forming the second-layer cured product until a final layer is formed to devices (AM parts) with a three-dimensional shape. For a stereolithography method, any known 3D printer may be used and several types of 3D stereolithographic printer are commercially available.

[0062] In a stereolithography method, the thickness of a single layer upon curing the composition described herein is, for example, from about 1 micron to about 1 mm, from about 10 to about 750 microns, from about 20 to about 500 microns, or from about 25 to about 300 microns. The size of the layers may be from about 1 pm, 2.5 pm, 5 pm, 10 pm, 15 pm, 20 pm, 25 pm, 50 pm, 75 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, 350 pm, 400 pm, 450 pm, 500 pm, 600 pm, 700 pm, 800 pm, 900 pm, to about 1 mm, or any range derivable therein The irradiation light is typically ultraviolet light and preferably includes light with a wavelength of 405 nm. The wavelength of light may be from about 300 nm to about 800 nm, from about 350 nm to about 600 nm, or from about 400 nm to about 500 nm. Similarly, the laser used may have a power from about 10 mW to about 1 W, from about 50 nW to about 750 mW, or from about 100 mW to about 500 mW. The irradiation laser power is 250 mW. The irradiation time for curing a single layer of the composition depends on the stereolithography method and may be adjusted appropriately. For example, in the DLP method, the irradiation time is about 1 to 60 seconds, but again depends on the specific formulation and method of stereolithography. These devices may be produced in an environment at about room temperature (e.g., 15 to 35 °C.).

[0063] After the stereolithography, optionally, a general secondary treatment, such as high-pressure mercury lamp irradiation, metal halide lamp irradiation, UV-LED irradiation, or heating, may be additionally performed. The secondary treatment can modify the surface after stereolithography, improve the strength, or accelerate curing. The secondary treatment can be performed in combination with stereolithography, although the secondary treatment is not necessarily required, depending on the stereolithography conditions.

[0064] In particular, when UV-LED irradiation is employed as a secondary treatment in the method of preparing a device described herein, any unreacted monomer contained in the AM parts can be cured by radicals generated from the photopolymerization initiator, which can further increase the mechanical strength.

[0065] In other aspects, the pharmaceutical compositions described herein may also be used in an additive manufacturing platform. Some of the additive manufacturing platforms that may be used herein include 3D printing such as stereolithography may be used to obtain the final pharmaceutical composition.

[0066] In some aspects, the pharmaceutical compositions described herein are processed in a final dosage form instead of as a device. The granules that are produced by the process may be further processed into a capsule or a tablet. Before formulation into a capsule or tablet, the granule may be further milled before being compressed into the capsule or tablet.IV. Definitions

[0067] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” As used herein “another” may mean at least a second or more.

[0068] As used herein, the terms “drug”, “pharmaceutical”, “active pharmaceutical ingredient”, “active agent”, “therapeutic agent”, and “therapeutically active agent” are used interchangeably to represent a compound which invokes a therapeutic or pharmacological effect in a human or animal and is used to treat a disease, disorder, or other condition. In some embodiments, these compounds have undergone and received regulatory approval for administration to a living creature.

[0069] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive. As used herein “another” may mean at least a second or more.

[0070] The terms “compositions,” “pharmaceutical compositions,” “formulations,” “pharmaceutical formulations,” “preparations”, and “pharmaceutical preparations” are used synonymously and interchangeably herein.

[0071] “Treating” or treatment of a disease or condition refers to executing a protocol, which may include administering one or more drugs to a patient, in an effort to alleviate signs or symptoms of the disease. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. Alleviation can occur prior to signs or symptoms of the disease or condition appearing, as well as after their appearance. Thus, “treating” or “treatment” may include “preventing” or “prevention” of disease or undesirable condition. In addition, “treating” or “treatment” does not require complete alleviation of signs or symptoms, does notrequire a cure, and specifically includes protocols that have only a marginal effect on the patient.

[0072] The term “therapeutic benefit” or “therapeutically effective” as used throughout this application refers to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of this condition. This includes, but is not limited to, a reduction in the frequency or severity of the signs or symptoms of a disease. For example, treatment of cancer may involve, for example, a reduction in the size of a tumor, a reduction in the invasiveness of a tumor, a reduction in the growth rate of cancer, or prevention of metastasis. Treatment of cancer may also refer to prolonging the survival of a subject with cancer.

[0073] “Subject” and “patient” refer to either a human or non-human, such as primates, mammals, and vertebrates. In particular embodiments, the subject is a human.

[0074] As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0075] “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1 -carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid,salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylglucamine, and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0076] The term “derivative thereof’ refers to any chemically modified compound, wherein at least one of the compounds is modified by substitution of atoms or molecular groups or bonds. In one embodiment, a derivative thereof is a salt thereof. Salts are, for example, salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example, hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, salts with suitable carboxylic acids, such as optionally hydroxylated lower alkanoic acids, for example, acetic acid, glycolic acid, propionic acid, lactic acid or pivalic acid, optionally hydroxylated and / or oxo-substituted lower alkane dicarboxylic acids, for example, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, pyruvic acid, malic acid, ascorbic acid, and also with aromatic, heteroaromatic or araliphatic carboxylic acids, such as benzoic acid, nicotinic acid or mandelic acid, and salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example, methanesulfonates, benzenesulfonates, p-toluenesulfonates or / V-cyclohexylsulfamates (cyclamates).

[0077] The term “degradation” or “chemically sensitive” refers to a compound that is destroyed or rendered inactive and unacceptable for use. Degradation may include compounds which have one or more chemical bonds present in the compound has been broken.

[0078] The term “amorphous” refers to a noncrystalline solid wherein the molecules are not organized in a definite lattice pattern. Alternatively, the term “crystalline” refers to a solid wherein the molecules in the solid have a definite lattice pattern. The crystallinity of the active agent in the composition is measured by powder x-ray diffraction.

[0079] A “poorly soluble drug” refers to a drug which meets the requirements of the USP and BP solubility criteria of at least a sparingly soluble drug. The poorly soluble drug may be sparingly soluble, slightly soluble, very slightly soluble or practically insoluble. In a preferred embodiment, the drug is at least slightly soluble. In a more preferred embodiment, the drug is at least very slightly soluble. As defined by the USP and BP, a soluble drug is a drug which is dissolved from 10 to 30 part of solvent required per part of the solute, a sparingly soluble drug is a drug which is dissolved from 30 to 100 part of solvent required per part of the solute, a slightly soluble drug is a drug which is dissolved from 100 to 1,000 part of solvent required per part of the solute, a very slightly soluble drug is a drug which is dissolved from 1,000 to 10,000 part of solvent required per part of the solute, and a practically insoluble drug is a drug which is dissolved from 10,000 part of solvent required per art of solute. The solvent may be water that is at a pH from 1-7.5, preferably physiological pH.

[0080] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0081] As used in this specification, the term “significant” (and any form of significance such as “significantly”) is not meant to imply statistical differences between two values but only to imply importance or the scope of the difference of the parameter.

[0082] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value or the variation that exists among the study subjects or experimental studies. Unless another definition is applicable, the term “about” refers to ±10% of the indicated value.

[0083] The term “homogenous” is used to mean a composition in which the components are mixed in such a way that the components are uniformly distributed amongst the composition. In a preferred embodiment, the composition is uniformly distributed in such a manner that there are no regions of a single component that are greater than 1 pm or more preferably less than 0.1 pm. In one embodiment, the composition is so homogeneously mixed in such a manner that there are no atoms of the electromagnetic energy absorbing excipientsare adjacent to another atom of the electromagnetic energy absorbing excipients.

[0084] The terms “substantially” or “approximately” as used herein may be applied to modify any quantitative comparison, value, measurement, or other representation that could permissibly vary without resulting in a change in the basic function to which it is related.

[0085] A temperature, when used without any other modifier, refers to room temperature, preferably 23 °C unless otherwise noted. An elevated temperature is a temperature which is more than 5 °C greater than room temperature; preferably more than 10 °C greater than room temperature.

[0086] The term “unit dose” refers to a formulation of the pharmaceutical composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active agent to a patient in a single administration. Such unit dose formulations that may be used include but are not limited to a single tablet, capsule, or other oral formulations, or a single vial with a syringeable liquid or other injectable formulations. In some forms, the final pharmaceutical composition that is produced is no longer a powder and is further produced as a homogenous final product.

[0087] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements and parameters.

[0088] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.V. Examples

[0089] To facilitate a better understanding of the present disclosure, the following examples of specific embodiments are given. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered toconstitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. In no way should the following examples be read to limit or define the entire scope of the disclosure.Example 1 - Fused Deposition Modeling

[0090] Hot melt extrusion: The polymers EVA 12 and EVA 18 (vinyl acetate %) were tested for their extrudability in HME for making a filament. The polymers were fed at a constant rate into the Leistritz 12 mm twin screw corotation (50 rpm) extruder with 9 zones using a volumetric feeder. The processing conditions are provided in Table 1.Table 1: The processing conditions of pure polymer in hot- melt extrude

[0091] The extruded filament was checked for the diameter which was in the range of the expected 1.75+ / -0.5 mm (FIG. 1).

[0092] Three-dimensional (3D) printing: The extruded polymers were checked for the printability in a Creality printmill (Creality3D, China) printer with the parameters listed in Table 2.Table 2: Processing parameters for 3D printing of EVA polymer

[0093] Development of computer aided design ( CAD) of IUD segment: To evaluate the printability and optimization of the final IUD, a simple IUD segment was generated. The initial dimensions of the IUD segment is 10x2.2 mm (length x diameter) cylinder with rounded edges (FIG. 2A). To ensure better attachment of the model to the build surface, the top and bottom surfaces of the model were made flat. A hole was introduced to ensure for knotting a thread during the animal studies (FIG. 2B). For uniform and batch printing evaluation, the IUDs were joined together in a series to ensure a continuous print of the IUD segments (FIG. 2C).

[0094] For mass production of the IUDs the several of the above IUDs joined into a band of IUD segments for a sustainable batch printing (FIG. 2D). FIG. 2E shows the final printed IUD segments that has reached to the desired parameters of 9.13 x 4.72 mm (length x diameter) on average. The height value is double than the desired 2.2 mm which can be due to the swellability of the polymer during heat. This behaviour was contained with the addition of copper and indomethacin compounds as mentioned in further examples.

[0095] Development of the CAD model of full IUD: The dimensions for a full IUD of T- shaped structure were set to 30x30x3 mm (horizontal x vertical x diameter). The design evaluation was carried out with round shaped CAD model to the flat shaped CAD model to have better attachment to the build plate (FIGS. 3A-D). The final printed full IUD with the optimized CAD design employing the conditions mentioned previously was provided in FIG. 3E.Example 2 - Formulation Development of 3D Printed IUD Segment

[0096] Formulations with EVA 12 and 18 wt%: The following formulations (Table 3) were developed to test the release abilities of copper and indomethacin compounds.Table 3: Formulation of IUD segments

[0097] The formulations were extruded through hot-melt extruder and the filaments were printed into IUDs in the Creality3D mill printer. The filament cross sections were imaged under Scanning Electron Microscopy (SEM, Quant650, FEI, USA) and the copper presence across the formulations was confirmed by Energy Dispersive X-ray Spectrometer (EDS, Oxford Instruments, USA). The thermal profiles of the formulations were carried out using Differential Scanning Calorimeter (DSC, Q10, Perkin Elmer, USA) (FIGS. 4 & 5 for EVA- 18 and EVA-12 based formulations respectively).

[0098] The indomethacin drug and copper released from the printed IUD segments was conducted in the simulated intrauterine fluid at pH 7.0 (FIGS. 6A-D & E-F). The Indomethacin was quantified using HPLC (Vanquish, USA, with solvent system- Acetonitrile:0.1%Formic acid (45:55), flow rate-1.5 mL / min, C18 4.6 x 25 mm column, 5pm particle diameter, column temperature-30 °C, UV detection- 240 nm, and runtime- 10 min & elution time ~2 min). The copper was quantified using inductive coupled plasma mass spectrometer (ICP-MS).

[0099] Trial-I Formulation optimization: The formulation optimization was conducted to reach the targeted release of 5-30 pg of copper and indomethacin. The formulations in 2.1 showed that EVA- 12 are better at release of the copper and indomethacin than EVA- 18. The lower percentage of VinylAcetate percentage helps faster and better release. The copper nanoparticles or microparticles of 1-5 pm showed higher release of copper from both the EVA 12 and 18 % formulations. Hence the same copper particles are used for further formulation optimization here. To improve the release amounts further, the weight percentages of copper and indomethacin were increased (Table 4).Table 4; Formulation of IUD segments

[0100] The formulations were extruded through hot-melt extruder and the filaments were printed into IUDs in the Creality3D mill printer. The copper and indomethacin drug released from the printed IUD segments was conducted in the simulated intrauterine fluid atpH 7.0 (FIG. 7A-F). The Indomethacin was quantified using HPLC (Vanquish, USA, with solvent system- Acetonitrile:0.1%Formic acid (45:55), flow rate-1.5 mL / min, C18 4.6 x 25 mm column, 5pm particle diameter, column temperature-30 °C, UV detection- 240 nm, and runtime- 10 min & elution time ~2 min). The copper was quantified using inductive coupled plasma mass spectrometer (ICP-MS).

[0101] Trial-II Formulation optimization of IUD segments: The formulation optimization was conducted to reach the targeted release of 5-30 pg of copper and indomethacin. Also, the formulations were tweaked to reflect the loading of copper (35 mg / segment) and indomethacin (4 mg / segment) to the commercial IUDs. To improve even the release amounts further, the weight percentages of copper and indomethacin were increased (Table 5).Table 5: Formulation of IUD segments

[0102] The formulations were extruded through hot-melt extruder and the filaments were printed into IUDs in the Creality3D mill printer. The copper and indomethacin drug released from the printed IUD segments was conducted in the simulated intrauterine fluid at pH 7.0 (FIG. 8A-F). The Indomethacin was quantified using HPLC (Vanquish, USA, with solvent system- Acetonitrile: 0.1% Formic acid (45:55), flow rate-1.5 mL / min, C18 4.6 x 25 mm column, 5pm particle diameter, column temperature-30 °C, UV detection- 240 nm, and runtime- 10 min & elution time ~2 min). The copper was quantified using inductive coupled plasma mass spectrometer (ICP-MS).EXAMPLE 3 - CAD Design of IUD Devices

[0103] Small animal porous intrauterine devices: FIG. 9A illustrates the porous reservoir design. Table 5 provides detailed dimensions of the designed intrauterine system (IUS) segment. The reservoir was specifically designed to accommodate a pastry-like mixture composed of metal nanoparticles or microparticles (Copper), an NSAID drug (Indomethacin), and hydrogel (eg. GelMa). In the final IUD product, an additional UV posttreatment of 15 minutes was required for the photo-initiated polymerization of hydrogel (eg.GelMa). This step facilitated the formation of a semi-solid gel, enabling long-term controlled release of the incorporated drug.

[0104] The results indicated that by optimizing the biocompatible UV curable resin (described in International Patent Application No. PCT / US2023 / 072029) component, it was possible to customize the release characteristics for SLA printing of the designed devices, ultimately resulting in the production of prototypes.Table 5: Dimension of the IUD segments

[0105] Human porous-reservoir intrauterine device: In FIG. 9B, the design of the small animal intrauterine device (IUD) discussed previously, the reservoir of the human IUD was specifically engineered to accommodate a pastry-like mixture consisting of metal nanoparticles or microparticles (Copper), an NSAID drug (Indomethacin), and hydrogel (eg. GelMa). However, in the case of the human IUD, an extended UV post-treatment of 30 minutes was necessary for the photo-initiated polymerization of hydrogel (eg. GelMa). The increased treatment time can be attributed to the larger size of the human IUD compared to the small animal IUD. This step played a crucial role in the formation of a semi-solid gel, which facilitated the sustained and controlled release of the drug over an extended period.

[0106] FIG. 11 showcases the prototype of both IUD, along with the formulation of the printed samples, which consists of a biocompatible UV curable resin (such as that described in International Patent Application No. PCT / US2023 / 072029) 2:1:1 1 wt.% PI + Reactive Orange. The results indicated that by optimizing the biocompatible UV curable resin (such as described in International Patent Application No. PCT / US2023 / 072029) component, it was possible to customize the release characteristics for SLA printing of the designed devices, ultimately resulting in the production of prototypes. The design of the samples was customized based on the desired usage time of the IUD, such as 1 year, 3 years, 5 years, or even longer.

[0059] A pilot rabbit study was conducted at Eastern Virginia Medical School (Norfolk, VA) under IACUC approved protocol #22-015 with 3D printed IUD segments to assess proof-of-concept and safety. A single IUD segment was surgically implanted in one of the rabbit’s uterine horns and maintained for 2 months. The other uterine horn was used as a sham control. IUD segments tested contained either copper alone or combined with indomethacin with either SLA or EVA. Residual drug was measured from retrieved IUD segments confirming release. Median estimated daily release of copper was 0.32 mg / day and 0.16 mg / day for indomethacin. There were no adverse safety findings observed on study.* * *

[0107] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the disclosure as defined by the appended claims.

Claims

What Is Claimed Is:

1. A pharmaceutical composition comprising:(A) a functional composition; wherein the functional composition is a microparticle or nanoparticle, an active pharmaceutical ingredient, a polymer, a biologically active molecule, a conductive material, or a combination thereof; and(B) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester.

2. The pharmaceutical composition of claim 1, wherein the functional composition is embedded in the poyalkylene vinyl ester polymer.

3. The pharmaceutical composition of claim 2, wherein the embedding of the functional composition in the polyalkylene vinyl ester polymer results in controlled release of the functional composition.

4. The pharmaceutical composition of claim 1, wherein the functional composition is a microparticle or nanoparticle.

5. The pharmaceutical composition of either claim 1 or claim 4, wherein the microparticle or nanoparticle is a metal microparticle or nanoparticle.

6. The pharmaceutical composition of claim 5, wherein the metal microparticle or nanoparticle is a transition metal microparticle or nanoparticle.

7. The pharmaceutical composition of either claim 5 or claim 6, wherein the metal microparticle or nanoparticle is a copper microparticle or nanoparticle, a titanium microparticle or nanoparticle, a gold microparticle or nanoparticle, or a silver microparticle or nanoparticle.

8. The pharmaceutical composition of claim 7, wherein the metal microparticle or nanoparticle is a copper microparticle or nanoparticle.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the microparticle or nanoparticle has a diameter from about 10 nm to about 25 pm.

10. The pharmaceutical composition of claim 9, wherein the diameter is from about 25 nm to about 200 nm.

11. The pharmaceutical composition of either claim 9 or claim 10, wherein the diameter is from about 50 nm to about 100 nm.

12. The pharmaceutical composition of claim 9, wherein the diameter is from about 100 nm to about 600 nm.

13. The pharmaceutical composition of either claim 9 or claim 12, wherein the diameter is from about 200 nm to about 400 nm.

14. The pharmaceutical composition of claim 9, wherein the diameter is from about 500 nm to about 10 pm.

15. The pharmaceutical composition of either claim 9 or claim 14, wherein the diameter is from about 750 nm to about 7.5 pm.

16. The pharmaceutical composition of claim 1 , wherein the functional composition is an active pharmaceutical ingredient.

17. The pharmaceutical composition of either claim 1 or claim 16, wherein the active pharmaceutical ingredient is selected from anticancer agents, antiallergic agents, antifungal agents, psychiatric agents such as analgesics, consciousness level- altering agents such as anesthetic agents or hypnotics, nonsteroidal anti-inflammatory agents (NSAIDs), anthelmintics, antiacne agents, antianginal agents, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, a bleeding inhibiting agent, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunction improvement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, and sedatives.

18. The pharmaceutical composition according to any one of claims 1, 16, and 17, wherein the active pharmaceutical ingredient is an antifungal agent, an antibiotic, achemotherapeutical agent, an antiviral agent, a bleeding inhibiting agent, a contraceptive, or a non-steroidal anti-inflammatory agent.

19. The pharmaceutical composition according to any one of claims 1 and 16-18, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory agent.

20. The pharmaceutical composition of claim 19, wherein the non-steroidal antiinflammatory agent is indomethacin.

21. The pharmaceutical composition according to any one of claims 1-20, wherein the pharmaceutical composition comprises 2 or more functional molecules.

22. The pharmaceutical composition of claim 21, wherein the pharmaceutical comprises from about 2 to about 6 functional molecules.

23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition comprises 2 functional molecules.

24. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition comprises 3 functional molecules.

25. The pharmaceutical composition according to any one of claims 1-24, wherein the pharmaceutical composition comprises two or more distinct functional molecules.

26. The pharmaceutical composition of claim 25, wherein the first functional molecule is selected from a nanoparticle or an active pharmaceutical ingredient27. The pharmaceutical composition of either claim 25 or claim 26, wherein the second functional molecule is a different nanoparticle or a different active pharmaceutical ingredient.

28. The pharmaceutical composition according to any one of claims 1-27, wherein the polyalkylene vinyl ester comprises a C2-C4 alkylene.

29. The pharmaceutical composition of claim 28, wherein the polyalkylene is polyethylene.

30. The pharmaceutical composition according to any one of claims 1-29, wherein the polyalkylene vinyl ester comprises a C2-C6 ester.

31. The pharmaceutical composition of claim 30, wherein the ester is an acetate.

32. The pharmaceutical composition according to any one of claims 1-31, wherein the polyalkylene vinyl ester is polyethylene vinyl acetate.

33. The pharmaceutical composition according to any one of claims 1-32, wherein the poly alkylene vinyl ester comprises from about 10% to about 20% by weight of the vinyl ester.

34. The pharmaceutical composition of claim 33, wherein the polyalkylene vinyl ester comprises from about 10% to about 15% by weight of the vinyl ester.

35. The pharmaceutical composition of claim 33, wherein the polyalkylene vinyl ester comprises from about 15% to about 20% by weight of the vinyl ester.

36. The pharmaceutical composition according to any one of claims 1-35, wherein the pharmaceutical composition comprises from about 5% to about 99% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

37. The pharmaceutical composition according to any one of claims 1-36, wherein the pharmaceutical composition comprises from about 5% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

38. The pharmaceutical composition according to any one of claims 1-37, wherein the pharmaceutical composition comprises from about 5% to about 15% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

39. The pharmaceutical composition according to any one of claims 1 -36, wherein the pharmaceutical composition comprises from about 15% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

40. The pharmaceutical composition according to any one of claims 1-36 and 39, wherein the pharmaceutical composition comprises from about 20% to about 30% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

41. The pharmaceutical composition according to any one of claims 1-36, wherein the pharmaceutical composition comprises from about 60% to about 95% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

42. The pharmaceutical composition according to any one of claims 1 -36 and 41 , wherein the pharmaceutical composition comprises from about 80% to about 90% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

43. The pharmaceutical composition according to any one of claims 1-42, wherein the pharmaceutical composition comprises from about 25% to about 95% by weight of the functional molecule in the pharmaceutical composition.

44. The pharmaceutical composition according to any one of claims 1-43, wherein the pharmaceutical composition comprises from about 50% to about 90% by weight of the functional molecule in the pharmaceutical composition.

45. The pharmaceutical composition according to any one of claims 1-44, wherein the pharmaceutical composition comprises from about 65% to about 85% by weight of the functional molecule in the pharmaceutical composition.

46. The pharmaceutical composition according to any one of claims 1-42, wherein the pharmaceutical composition comprises from about 1% to about 50% by weight of the functional molecule in the pharmaceutical composition.

47. The pharmaceutical composition according to any one of claims 1-42 and 46, wherein the pharmaceutical composition comprises from about 2% to about 30% by weight of the functional molecule in the pharmaceutical composition.

48. The pharmaceutical composition according to any one of claims 1-42, 46, and 47, wherein the pharmaceutical composition comprises from about 3% to about 20% by weight of the functional molecule in the pharmaceutical composition.

49. The pharmaceutical composition according to any one of claims 1-48, wherein the pharmaceutical composition further comprises one or more excipients.

50. The pharmaceutical composition according to any one of claims 1-49, wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intrauterinally, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, or vaginally.

51. The pharmaceutical composition according to any one of claims 1-50, wherein the pharmaceutical composition is formulated as a solid dosage form.

52. The pharmaceutical composition according to any one of claims 1-51, wherein the pharmaceutical composition is formulated for administering vaginally.

53. The pharmaceutical composition according to any one of claims 1-51, wherein the pharmaceutical composition is formulated for administering intrauterine.

54. The pharmaceutical composition according to any one of claims 1-53, wherein the pharmaceutical composition is formulated as a unit dose.

55. The pharmaceutical composition according to any one of claims 1-54, wherein the pharmaceutical composition is formulated into a medical device.

56. The pharmaceutical composition of claim 55, wherein the medical device is an intrauterine device.

57. A method of preparing a pharmaceutical composition:(A) obtaining a printing composition comprising:(z) a functional composition; wherein the functional composition is a microparticle or nanoparticle, an active pharmaceutical ingredient, a polymer, a biologically active molecule, or a combination thereof;(z'z) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester; and(B) subjecting the printing composition to an additive manufacturing technique.

58. The method of claim 57, wherein the functional composition is embedded in the poyalkylene vinyl ester polymer as a result of the additive manufacturing technique.

59. The method of claim 58, wherein the embedding of the functional composition in the polyalkylene vinyl ester polymer results in controlled release of the functional composition.

60. The method according to any one of claims 57-59, wherein the additive manufacturing technique is vat photopolymerization.

61. The method of either claim 57 or claim 60, wherein the additive manufacturing technique is a stereolithography technique.

62. The method according to any one of claims 57-61, wherein the additive manufacturing technique applies sequential layers.

63. The method of claim 62, wherein the sequential layers have a thickness from about 5 nm to about 1 mm.

64. The method of either claim 62 or claim 63, wherein the thickness is from about 10 nm to about 750 nm.

65. The method according to any one of claims 62-64, wherein the thickness is from about 20 nm to about 500 nm.

66. The method according to any one of claims 62-65, wherein the thickness is from about 25 nm to about 400 nm.

67. The method according to any one of claims 57-66, wherein the method comprises repeating layers of similar size.

68. The method according to any one of claims 57-66, wherein the method comprises repeating layers of distinct size.

69. The method according to any one of claims 57-68, wherein the method comprises using an energy source with a specific power.

70. The method of claim 69, wherein the energy source is a laser.

71. The method of either claim 69 or claim 70, wherein the specific power is from about 10 mW to about 10 W.

72. The method according to any one of claims 69-71, wherein the specific power is 25 mW to about 1 W.

73. The method according to any one of claims 69-72, wherein the specific power is from about 100 mW to about 500 mW.

74. The method according to any one of claims 69-73, wherein the specific power is about 250 mW.

75. The method according to any one of claims 57-74, wherein the additive manufacturing technique comprises a printing speed from about 1 mm / s to about 25 mm / s.

76. The method of claim 75, wherein the printing speed is from about 2.5 mm / s to about 10 mm / s.

77. The method of either claim 75 or claim 76, wherein the printing speed is 5 mm / s.

78. The method according to any one of claims 57-77, wherein the additive manufacturing technique comprises a print temperature.

79. The method of claim 75, wherein the print temperature is from about 100°C to about 400 °C.

80. The method of either claim 78 or claim 79, wherein the printing speed is from about 150°C to about 300 °C.

81. The method according to any one of claims 78-80, wherein the print temperature is about 230 °C.

82. The method according to any one of claims 57-81, wherein the additive manufacturing technique comprises a bed temperature.

83. The method of claim 82, wherein the bed temperature is from about 25°C to about 250 °C.

84. The method of either claim 82 or claim 83, wherein the bed temperature is from about 75°C to about 125 °C.

85. The method according to any one of claims 82-84, wherein the print temperature is about 100 °C.

86. The method according to any one of claims 57-85, wherein the method further comprises extruding the printing composition before subjecting it to the additive manufacturing technique to create an extruded print composition.

87. The method of claim 86, wherein the extruded print composition results in one or more filaments.

88. The method of claim 87, wherein the filaments comprise a filament size from about 0.5 mm to about 5 mm.

89. The method of claim 88, wherein the filament size is from about 1 mm to about 3 mm.

90. The method of either claim 88 or claim 89, wherein the filament size is from about 1.25 mm to about 2.25 mm.

91. The method according to any one of claims 57-74, wherein the functional composition is a microparticle or nanoparticle.

92. The method according to any one of claims 57-91, wherein the microparticle or nanoparticle is a metal microparticle or nanoparticle.

93. The method of claim 92, wherein the metal microparticle or nanoparticle is a transition metal microparticle or nanoparticle.

94. The method of either claim 92 or claim 93, wherein the metal microparticle or nanoparticle is a copper microparticle or nanoparticle.

95. The method according to any one of claims 1-8, wherein the microparticle or nanoparticle has a diameter from about 10 nm to about 25 m.

96. The method of claim 95, wherein the diameter is from about 25 nm to about 200 nm.

97. The method of either claim 95 or claim 96, wherein the diameter is from about 50 nm to about 100 nm.

98. The method of claim 95, wherein the diameter is from about 100 nm to about 600 nm.

99. The method of either claim 95 or claim 98, wherein the diameter is from about 200 nm to about 400 nm.

100. The method of claim 95, wherein the diameter is from about 500 nm to about 10 pm.

101. The method of either claim 95 or claim 100, wherein the diameter is from about 750 nm to about 7.5 pm.

102. The method of claim 57, wherein the functional composition is an active pharmaceutical ingredient.

103. The method according to any one of claims 57-74 or 102, wherein the active pharmaceutical ingredient is selected from anticancer agents, antiallergic agents, antifungal agents, psychiatric agents such as analgesics, consciousness level- altering agents such as anesthetic agents or hypnotics, nonsteroidal anti-inflammatory agents (NSAIDs), anthelmintics, antiacne agents, antianginal agents, antiarrhythmic agents, anti-asthma agents, antibacterial agents, anti-benign prostate hypertrophy agents, anticoagulants, antidepressants, antidiabetics, antiemetics, antiepileptics, antigout agents, antihypertensive agents, anti-inflammatory agents, antimalarials, antimigraine agents, antimuscarinic agents, antineoplastic agents, anti-obesity agents, antiosteoporosis agents, antiparkinsonian agents, antiproliferative agents, antiprotozoal agents, antithyroid agents, antitussive agent, anti-urinary incontinence agents, antiviral agents, anxiolytic agents, appetite suppressants, beta-blockers, a bleeding inhibiting agent, cardiac inotropic agents, chemotherapeutic drugs, cognition enhancers, contraceptives, corticosteroids, Cox-2 inhibitors, diuretics, erectile dysfunctionimprovement agents, expectorants, gastrointestinal agents, histamine receptor antagonists, immunosuppressants, keratolytics, lipid regulating agents, leukotriene inhibitors, macrolides, muscle relaxants, neuroleptics, nutritional agents, opioid analgesics, protease inhibitors, and sedatives.

104. The method according to any one of claims 57-74, 102, and 103, wherein the active pharmaceutical ingredient is an antifungal agent, an antibiotic, a chemotherapeutic al agent, an antiviral agent, a bleeding inhibiting agent, a contraceptive, or a non-steroidal anti-inflammatory agent.

105. The method according to any one of claims 57-74 and 102-104, wherein the active pharmaceutical ingredient is a non-steroidal anti-inflammatory agent.

106. The method of claim 105, wherein the non-steroidal anti-inflammatory agent is indomethacin.

107. The method according to any one of claims 57-106, wherein the pharmaceutical composition comprises 2 or more functional molecules.

108. The method of claim 107, wherein the pharmaceutical comprises from about 2 to about 6 functional molecules.

109. The method of claim 108, wherein the pharmaceutical composition comprises 2 functional molecules.

110. The method of claim 108, wherein the pharmaceutical composition comprises 3 functional molecules.

111. The method according to any one of claims 57-110, wherein the pharmaceutical composition comprises two or more distinct functional molecules.

112. The method of claim 111, wherein the first functional molecule is selected from a nanoparticle or an active pharmaceutical ingredient113. The method of either claim 111 or claim 112, wherein the second functional molecule is a different nanoparticle or a different active pharmaceutical ingredient.

114. The method according to any one of claims 57-113, wherein the polyalkylene vinyl ester comprises a C2-C4 alkylene.

115. The method of claim 114, wherein the polyalkylene is polyethylene.

116. The method according to any one of claims 57-115, wherein the polyalkylene vinyl ester comprises a C2-C6 ester.

117. The method of claim 116, wherein the ester is an acetate.

118. The method according to any one of claims 57-117, wherein the polyalkylene vinyl ester is polyethylene vinyl acetate.

119. The method according to any one of claims 57-118, wherein the polyalkylene vinyl ester comprises from about 10% to about 20% by weight of the vinyl ester.

120. The method of claim 119, wherein the polyalkylene vinyl ester comprises from about 10% to about 15% by weight of the vinyl ester.

121. The method of claim 119, wherein the polyalkylene vinyl ester comprises from about 15% to about 20% by weight of the vinyl ester.

122. The method according to any one of claims 57-121, wherein the pharmaceutical composition comprises from about 5% to about 99% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

123. The method according to any one of claims 57-122, wherein the pharmaceutical composition comprises from about 5% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

124. The method according to any one of claims 57-123, wherein the pharmaceutical composition comprises from about 5% to about 15% by weight of the poly alkylene vinyl ester in the pharmaceutical composition.

125. The method according to any one of claims 57-122, wherein the pharmaceutical composition comprises from about 15% to about 40% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

126. The method according to any one of claims 57-122 and 125, wherein the pharmaceutical composition comprises from about 20% to about 30% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

127. The method according to any one of claims 57-122, wherein the pharmaceutical composition comprises from about 60% to about 95% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

128. The method according to any one of claims 57-122 and 127, wherein the pharmaceutical composition comprises from about 80% to about 90% by weight of the polyalkylene vinyl ester in the pharmaceutical composition.

129. The method according to any one of claims 57-128, wherein the pharmaceutical composition comprises from about 25% to about 95% by weight of the functional molecule in the pharmaceutical composition.

130. The method according to any one of claims 57-129, wherein the pharmaceutical composition comprises from about 50% to about 90% by weight of the functional molecule in the pharmaceutical composition.

131. The method according to any one of claims 57-130, wherein the pharmaceutical composition comprises from about 65% to about 85% by weight of the functional molecule in the pharmaceutical composition.

132. The method according to any one of claims 57-128, wherein the pharmaceutical composition comprises from about 1 % to about 50% by weight of the functional molecule in the pharmaceutical composition.

133. The method according to any one of claims 57-128 and 132, wherein the pharmaceutical composition comprises from about 2% to about 30% by weight of the functional molecule in the pharmaceutical composition.

134. The method according to any one of claims 57-128, 132, and 133, wherein the pharmaceutical composition comprises from about 3% to about 20% by weight of the functional molecule in the pharmaceutical composition.

135. The method according to any one of claims 57-134, wherein the printing composition further comprises one or more excipients.

136. A pharmaceutical composition preparing using the methods according to any one of claims 57-135.

137. A pharmaceutical composition comprising:(A) an active pharmaceutical ingredient;(B) a metal microparticle or nanoparticle; and(C) a polyalkylene vinyl ester polymer, wherein the polyalkylene vinyl ester comprises from about 5% to about 25% by weight of the vinyl ester.

138. The pharmaceutical composition of claim 137, wherein the functional composition is embedded in the poyalkylene vinyl ester polymer.

139. The pharmaceutical composition of claim 138, wherein the embedding of the functional composition in the polyalkylene vinyl ester polymer results in controlled release of the functional composition.

140. A method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective dose of a pharmaceutical composition according to any one of claims 1-55, 136, and 137, wherein the functional molecule in the pharmaceutical composition is useful in treating the disease or disorder.

141. A method of preventing a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective dose of a pharmaceutical composition according to any one of claims 1-55, 136, and 137, wherein the functional molecule in the pharmaceutical composition is useful in preventing the disease or disorder.

142. A medical device prepared using a pharmaceutical composition according to any one of claims 1-55, 136, and 137.

143. A medical device prepared using a pharmaceutical composition preparing using the methods of claims 57-135.

144. The medical device of either claim 142 or claim 143, wherein the medical device comprises one or more arms.

145. The medical device according to any one of claims 142-144, wherein the medical device comprises two arms attached to a central cylindrical core.

146. The medical device of either claim 144 or claim 145, wherein the medical device comprises a tee shaped of cylinders.

147. The medical device of either claim 144 or claim 145, wherein the medical device comprises one or more pores.

148. The medical device of claim 147, wherein the medical device comprises two to six pores.

149. The medical device of either claim 147 or claim 148, wherein the medical device comprises two pores.

150. The medical device according to any one of claims 142-149, wherein the medical device has a wall thickness from about 50 m to about 10 mm.

151. The medical device of claim 150, wherein the wall thickness is from about 100 pm to about 3000 pm.

152. The medical device of either claim 150 or claim 151, wherein the wall thickness is from about 500 pm to about 2000 pm.

153. The medical device according to any one of claims 150-152, wherein the wall thickness is about 1200 pm.

154. The medical device according to any one of claims 142-153, wherein the medical device has a diameter from about 25 pm to about 25 cm.

155. The medical device of claim 154, wherein the diameter is from about 250 pm to about 10 cm.

156. The medical device of either claim 154 or claim 155, wherein the diameter is from about 500 pm to about 2.5 cm.

157. The medical device according to any one of claims 154-156, wherein the diameter is about 1 cm.

158. The medical device according to any one of claims 142- 157, wherein the medical device has a height from about 100 pm to about 25 mm.

159. The medical device of claim 158, wherein the height is from about 500 pm to about 10 mm.

160. The medical device of either claim 158 or claim 159, wherein the height is from about 500 pm to about 6 mm.

161. The medical device according to any one of claims 158-160, wherein the height is about 3 mm.

162. The medical device according to any one of claims 144-161, wherein the medical device has a width from about 100 pm to about 25 mm.

163. The medical device of claim 162, wherein the width is from about 500 pm to about 10 mm.

164. The medical device of either claim 162 or claim 163, wherein the width is from about 500 m to about 6 mm.

165. The medical device according to any one of claims 162-164, wherein the width is about 2.5 mm.

166. The medical device according to any one of claims 142-165, wherein the medical device is an intrauterine device.

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