WO2018030956A1 - Article imprimé en 3d, procédé d'utilisation et procédé de fabrication - Google Patents

Article imprimé en 3d, procédé d'utilisation et procédé de fabrication Download PDF

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Publication number
WO2018030956A1
WO2018030956A1 PCT/SG2017/050397 SG2017050397W WO2018030956A1 WO 2018030956 A1 WO2018030956 A1 WO 2018030956A1 SG 2017050397 W SG2017050397 W SG 2017050397W WO 2018030956 A1 WO2018030956 A1 WO 2018030956A1
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WO
WIPO (PCT)
Prior art keywords
capsule
therapeutic
delivery
chamber
release
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Application number
PCT/SG2017/050397
Other languages
English (en)
Inventor
Reno Antony Louis LEON
Original Assignee
Structo Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Structo Pte Ltd filed Critical Structo Pte Ltd
Publication of WO2018030956A1 publication Critical patent/WO2018030956A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

Definitions

  • the invention relates to the delivery of therapeutics, and in particular, the capsules used for delivery. Specifically, the invention relates to the 3D printing of said capsules.
  • the invention provides a capsule for the delivery of a therapeutic, the capsule comprising: a casing arranged to be dissolved on ingestion by a patient; a plurality of chambers defined by chamber walls, each chamber arranged to contain a therapeutic; at least one of said chamber walls includes at least a portion of said casing; wherein the capsule is arranged to deliver the therapeutic on dissolving on said chamber walls.
  • the invention may allow the ability to accommodate various physical forms of formulations such as solids, liquids and gas in one a modular design to suit specific patient needs.
  • the personalization of medication and delivery rates adjusted to individual patient levels is a significant feature of the present invention.
  • other advantages of the present invention may include, a reduction in the number of intakes/drug/time/person from a factor of 100 to a mere Once', initiation of sequential and sustained release of desired therapeutics at any desired time interval and on-the-fly printable therapeutics.
  • Figure 1 is an isometric view of a capsule according to one embodiment of the present invention.
  • Figures 2A and 2B are isometric views of capsules according to further embodiments of the present invention.
  • Figure 3 is a characteristic of a Release in Parallel capsule according to a further embodiment of the present invention.
  • Figure 4 is a characteristic of a Release in Series capsule according to a further embodiment of the present invention.
  • Figure 5 is a characteristic of a Release in Tandem capsule according to a further embodiment of the present invention.
  • Figure 6A and 6B are isometric views of a therapeutic loading process according to a further embodiment of the present invention.
  • Figure 7 is a flow chart of the patient-healthcare-capsule production process
  • Figures 8A to 8C are various cross-sectional views of a capsule according to a further embodiment of the present invention.
  • Figures 9A to 9C are a pictogram and SEM images of 3D printed hydrogels according to further embodiments of the present invention.
  • Figures 10A and 10B graphs for the change in release mechanisms for embodiments having varying geometry, according to the present invention, and;
  • Figure 1 1 is an isometric view of an integrated capsule according to a further embodiment
  • Structomer bio was formulated in-house. Glycine, Polyethylene (glycol) diacrylate (PEGDA 700) , brilliant blue G, caffeine, poly lactic acid (PLA), poly(vinyl) alcohol (PVA), poly (lactic-co-glycolic) acid, sodium chloride (NaCl), potassium chloride (KCl), sodium hydrogen phosphate (Na 2 HP0 4 ), potassium hydrogen phosphate (KH 2 P0 4 ), heptane, calcium chloride, ammonium lauryl sulfate (ALS), span 20, span 80, pluronic surfactant F127, sodium dodecylsulfate (SDS), silicone oil and vegetable oil (light) were purchased from Sigma-Aldrich (Singapore) and used as received. Sodium Alginate, ethyl acetate and ethyl cellulose (99.9%) was purchased from Fischer scientific (Singapore). Ultrapure water was used to prepare aqueous solutions.
  • Two phase W/O (water-in-oil) emulsion system was prepared using vegetable oil as continuous phase and water as the dispersed phase.
  • the outer oil phase (O) constitutes 1% wt/wt acetaminophen (model active pharmaceutical ingredient 'API' 1) along with 0.5% (w/w) surfactant for emulsion stabilization.
  • the aqueous phase (W) was prepared by dissolving 8 mg aniline (model API 2) in 100 ml ultrapure water and stirred for 30 minutes. The solution was then loaded into a spraying system whose pressure was adjusted to control nozzle output velocity and droplet size. The mist released through the spray nozzle was collected in a beaker containing the outer oil phase. Stable and monodisperse W/O emulsion was thus prepared and stored for further use.
  • Alginate microgels loaded with caffeine were prepared as follows. About 100 mg of caffeine was dissolved in 50 ml ultrapure water. 2% (w/w) alginate (ALG) and 5% (w/w) pluronic surfactant F68 was then added to the premixed solution and stirred for 2 hours. The un-crosslinked mixture was then dripped using a needle into a water bath containing 8% (w/w) CaC12 and was stirred with a magnetic stirrer at 100 rpm. The microgels formed were then washed by exchanging the calcium chloride cross-linking solution three times with deionized water. They were then filtered, dried in a vacuum oven at 60 °C for over 2 days and stored in an airtight canister for further use. Polymeric microparticle preparation
  • Prepolymer solution was prepared by mixing lOOg PEGDA and 0.5% w/w orange food dye (model API 4) together with 5% (w/w) Irgacure 819.
  • the continuous phase was prepared by mixing ultrapure water with 2% w/w pluronic F127.
  • the un-crosslinked prepolymer mixture was then dripped using a needle into the pluronic solution being irradiated with 420 nm blue light (Intensity 300 mW/cm 2 ) and was stirred with a magnetic stirrer at 1000 rpm.
  • the resulting polymeric microparticles were washed with deionized water and filtered using a 50 ⁇ mesh filter paper. They were then placed in an ultrasonicator for 10 minutes and subsequently dried using a vacuum oven at 40°C for over 5 hours. The clean and dry microparticles were then stored in an airtight container for further use.
  • Structomer bio a biocompatible and biodegradable material was used for 3D printing of the capsules.
  • the material possesses superior mechanical properties in terms of young's modulus, tensile and flexural strengths.
  • the capsule was designed using CAD software.
  • the CAD design was sliced using Materialize Magics software and loaded for 3D printing.
  • a Structo omniform 3D printer was used for the study. The printing time for 20 different design iterations was 30 minutes in total.
  • the capsules were collected and ultrasonicated in an isopropanol bath for 10 minutes to make sure the unpolymerised resin was thoroughly washed off. The capsules were then washed with warm water at 40°C and vacuum dried for 30 mins.
  • Capsules were loaded using a needle-syringe in a range of combinations as listed in Table 1. The composition of ingredients per compartment was carefully measured and ensured for minimal contamination across the array of samples. In contain embodiments, the ability to accommodate physical forms of solid, liquid or gas in each compartments is a significant advantage of capsules according to the present invention.
  • Solid formulations ranging from powders, micro/nanoparticles, crystals, pellets, beads, rods, cones, core-shells etc., liquids such as emulsions, gels, syrups, pastes, oil, creams, ointments, wax etc., and gaseous forms such as bubbles, foams, aerosols, sprays etc. may be loaded in amounts into one or many of the available compartments of capsule.
  • Table 1 List of variation of content loaded into the capsules for demonstration purposes. The choice of ingredient is not restricted to the list of content mentioned in the above table.
  • the size distribution, morphology and print accuracy data were obtained using microscopic image analysis.
  • the size distribution studies used was an inverted microscope and operated in bright field mode.
  • the average diameter of microparticles and standard deviations were based on measurements of at least 100 samples.
  • the number of samples was restricted to 10.
  • the choice of material for the capsule production is a function of the durability, shelf life, integrity, degradation and release characteristics of the capsule.
  • the degradation process is determined by the relative rates of solvent penetration into the polymer.
  • the choice of material is aimed for surface degradation accommodating for the progressive evolution of release profiles aimed to be established with the study.
  • a bulk degradation polymer may be used with a different modular design where cumulative release would be the dominant factor as compared to a synergistic and sequential release pattern.
  • Choice of materials may include PLA, PGA, PLGA, GelMA, HPMA, PEG, PEGDA, PEI, dextran, dextrin, chitosan, HPMC and alginate.
  • Environmentally responsive polymer compositions also known as smart polymers may be used for active physical or chemical change upon an external trigger such as pH, temperature, ultrasound, light, magnetic or electrical fields, ionic strength, redox potential, chemical or biochemical agents etc.
  • CAD software was used to design an array of capsules with varying morphologies for a range of release profiles.
  • Active ingredients loaded into capsules may take the physical form of
  • a solid pill, tablet, capsule (hard and soft), powder, polymorphic crystals, granulation, flakes, troches (lozenges and pastilles), suppositories, semi solid ointments, micro/nano particles, patches, micro-chips, stents, nanobots
  • liquid solution, emulsion, spirit, elixir, syrup, fluid extract, gels, cells, proteins, vaccines, antibody, hormones, pastes, creams
  • Capsules can also be used for delivery of pharmaceuticals, biologies, nutraceuticals, vitamins, dietary supplements, minerals, food extracts individually or in combination. These may include (a) monodisperse o/w emulsions, (b) co-formulated PLGA microparticles for ocular drug delivery, (c) insulin crystals, (d) spherical agglomerates of glycine, (e) polymorphic controlled spherical crystals of ROY, (f) multiple emulsions for multi-drug payload, (g) magnetic responsive nano shells for antibody delivery, (h) homogeneous gold nano spheres, (i) homogeneous gold nano rods, (j) microneedle patch for transdermal delivery, (k-m) biologies (schematic illustrations of animal cell, antibody, enzyme), (n) homogeneous gas bubbles generates on a chip and (o) nano robot for
  • a key feature of the technology is to use loaded capsules for orchestrated release.
  • the idea is to control release based on deliberate choice of the capsule materials, design iterations and choice of loading.
  • the delivery can be structured in a way that
  • chambers of the casing dissolve or degrade from all sides of the capsule to follow a homogeneous trend resulting in all the encapsulated content releasing simultaneously.
  • the rate of release may be controlled by the nature of the content (e.g. solid vs liquid), relative concentration of carrier, medium of release, hydrophobic/hydrophilic properties, size of particulates, wall thickness of capsule etc.
  • a typical parallel release characteristic for RIP-capsule based on the choice of contents in the chamber in is shown in Figure 3.
  • the chamber design for RIS-capsule may involve compartments encapsulated in one another resulting in box-in-a-box effect or by varying the wall thickness. There are primary, secondary and tertiary compartments diligently placed to control the sequential release of the contents one after another. The number of compartments or the variation in wall thickness in this scenario is a matter of the resolution achievable for printing the smallest chamber or wall and being able to load the ingredients within. A conscious choice of content to aid in the controlled RIS is totally achievable as described in the characteristic shown in Figure 4.
  • the third variation of release focuses on combining the advantages offered by RIP and RIS by bridging them together as a RIT-capsule.
  • the chambers in the RIT design include sub-compartments within and chambers with fixed/varied wall thickness structurally arranged in the vicinity of one another. This allows for a diverse release orchestration of controlled, concomitant, simultaneous, sequential and sustained release in tandem. A typical characteristic of the complexity of release profile trials possible can be envisioned as shown in Figure 5.
  • the design iteration can be extended to a range of modular variations and combinations offering a wide choice of designer on-the-fly capsule designs for personalized and customized delivery.
  • Each one of the capsules 120, 125, 130 according to the present invention may be a unique design printed specifically based on a single patient's requirement.
  • FIG. 6A and 6B A conceptual design on a scaled-up production 115 of a capsule is as shown in Figures 6A and 6B.
  • the loading may be completely digitalized and monitored to regulate dosage levels according to prescription tying up neatly with the present therapeutic scheme of practice.
  • the ingredients 150, 160 for the capsule can be stored in cartridges and dispensed 145 in precision quantities in to each of the capsule chambers 155 using nozzles 140 of auto-feeders 135 making the entire process efficient with minimum human error.
  • Figure 7 shows a schematic flow diagram of a customized medication approach using the present invention.
  • a patient 170 applies to the hospital/clinic/pharmacy 180 for analysis.
  • a formulated solution 175 is found and the appropriate capsule printed 190, covering the delivery regime, as a function of delivery period, therapeutic involved and rate of delivery.
  • the patient then receives the customised capsule 185.
  • Figure 1 shows one example of the capsule 5 according to the present invention.
  • the capsule 5 comes in two pieces in the main body 10 and a cap 15 which in this case is a snap fit onto the body through ring clip 35.
  • the capsule 5 includes a casing 12, having portions 20A, 20B which are of different thickness.
  • the different thickness allows for a variation in the time to dissolve once the capsule has been ingested by a patient.
  • the casing 12 encloses individual chambers 30A, 30B into which may be placed a therapeutic (not shown).
  • the chambers 3 OA, 30B are defined by chamber walls, with portions 20A, 20B of the casing 12 separating the chambers from the outside and an internal division 25 internally separating the chambers 30A, 30B.
  • the capsules 40, 65 shown in Figures 2A and 2B include three chambers.
  • the number of chambers in a capsule may vary accordingly to user/patient requirements.
  • the figures provided here are purely for illustration purposes only.
  • Figure 2 A shows an alternative attachment system to attach the cap 60 to the body 43.
  • the cap 60 includes a shaft 50 which maybe 3D printed with a thread on the shaft 50. This threaded shaft corresponds to the aperture 45 within the body, which has been printed with a corresponding thread to allow the cap 60 to screw into place, completing the capsule 40.
  • the flange 55 then seals off the chambers within the body 43, completing the capsule 40.
  • Figure 2B shows a similar arrangement to Figure 1 wherein the capsule 65 includes a cap 70 arranged to be snapped fit onto the body in order to enclose the chambers.
  • the cap may be a screw in, snap fit or stopper cork based on ease of design and usage.
  • the cap may also be functional as a flexible sheath or a rigid solid for permeability and control of burst release if necessary.
  • a capsule may therefore have a single delivery regime or several depending upon the intended use.
  • Figure 3 shows an example characteristic of a "release in parallel" capsule which may include a "burst" delivery 90 whereby a chamber has a conventional wall in the outer casing, and once dissolved, releases all the therapeutic in that chamber in an concentrated burst.
  • the erosion delivery 75 may have a permeable wall in the outer casing and thus the therapeutic slowly permeates through the wall as the wall is dissolved. Once dissolved, the therapeutic is then delivered in a burst.
  • the wall may be of a higher permeability, but also a lower solubility.
  • the chamber wall for a sustained delivery allows for a higher rate of delivery through the wall than the erosion delivery, but as the solubility is lower, the wall does not dissolve until all the therapeutic has been delivered.
  • a thin impermeable layer may be included over, or as part of, the casing to prevent premature leaking of the therapeutic, aiding in storage life.
  • Figure 4 shows a characteristic for a different capsule design.
  • the capsule includes a burst 90 together with a sustained pulse 105.
  • the sustained pulse has a delay 102 indicating that the chamber wall in the outer casing was of substantial thickness and therefore delaying commencement of delivery.
  • the capsule in question further includes an erosion delivery 75 corresponding to a further delay in exponentially increased pulse once the corresponding chamber wall has been dissolved.
  • the capsule having a characteristic of Figure 4 includes a step 100. As the step includes a delay and then a rapid increase in therapeutic delivery suggests that again the wall of the chamber corresponding to the therapeutic of step function 100 is subject to a considerable delay.
  • the radial thickness of the chamber is relatively thin and so the entire contents of the chamber is delivered more rapidly than a chamber such as that shown in Figure 1.
  • the chambers 30A, 30B of Figure 1 are relatively deep, extending from the centre of the capsule to the outer casing 12.
  • the distance between the wall 20A and the thickness of the chamber 30A suggests that it will be a rapid delivery but not instantaneous. It will be noted that once a thin chamber wall has dissolved, the contents of the chamber may very rapidly be delivered and having a characteristic similar to the step delivery 100 of figure 4.
  • a wall protecting a very thin chamber may be of non-uniformed thickness such as an undulation (not shown) so that portions of the wall dissolve quickly around the circumference of a chamber. This may further aid in the (instantaneous) delivery of a step delivery 100 shown in Figure 4.
  • Figure 5 shows a further characteristic of a capsule according to the present invention.
  • the capsule includes a burst delivery 90, erosion delivery 75, a pulse delivery 85 and a sustained delivery 80.
  • the capsule having a characteristic of Figure 5 further includes a sequential delivery 1 10 and a step delivery 100.
  • Figures 8 A to 8C show a further capsule 195 according to the present invention.
  • the capsule 195 includes multiple delivery compartments with the thickness of the casing 200 being variable and the inclusion of an internal chamber 240.
  • cap of the capsule 195 has been omitted for clarity.
  • the chamber walls are designed so as to deliver the therapeutic, either through permeability or through dissolution, at a pre-determined time corresponding to the therapeutic benefit sought. It will be appreciated that different materials will have different dissolution rates, but that these times can be determined readily through experimentation. It is therefore part of the present invention that the chamber walls can be designed to achieve a therapeutic release within a given time.
  • the sequence of delivery for the capsule 195 will have the chamber wall 210 dissolving so as to expose the annular chamber 235. This will be in a relatively rapid burst arrangement.
  • the timing of the next delivery will be chambers 224, 226 shown in Figure 8B resembling a sustained delivery.
  • Next will be the dissolving of chamber wall 220 exposing internal chamber 240 in the form of an erosion delivery whereby the wall 220 is partially protected by the delivery of the therapeutic in the annular chamber 235. Once dissolved the therapeutic in the internal chamber 240 will rapidly be delivered
  • chambers 225 and 230 will undergo a delayed, sustained delivery once the thickened wall 206 protecting the chambers 225,230 is dissolved. It will be appreciated that aspects of the capsules described may be combined and omitted in order to create capsules having a higher degree of variability of delivery.
  • the invention therefore relates to personalized and customized medication with 3D printing of patient-oriented capsules.
  • the multi compartmentalization serves to add to the feature of multi-modal therapy at one shot greatly influencing patient compliance, cost and therapeutic time.
  • the design aspects of the capsule allows for triggered and digitalized release of the contents of choice to specific targets.
  • Multi- combinatory therapy at a customized level is hence very much achievable.
  • Geometry and wall thickness may have a significant effect on the release mechanism of 3D printed hydrogel capsules.
  • 3D printed hydrogels using MSLA technology were studied for micro architecture using SEM and swelling studies were performed, such as those shown in Figures 9A to 9C, which shows a pictogram and SEM images of 3D printed hydrogels, to a scale of 100 ⁇ .
  • the gels were printed at 50 and 100 ⁇ layer thickness with an exposure time of 25 seconds and 30 seconds respectively.
  • the gels were printed as cube and cylinders. Subsequent swelling studies were perfomied as follows. The prints were soaked in water for 5 days. Equilibrium swelling weight was recorded. The gel prints were then freeze-dried and their dry weight was recorded. Gel prints with two different exposure times showed different swelling patterns. 25 second and 30 second exposure times showed anisotropic and isotropic swelling respectively.
  • the wall thickness had an effect on the release kinetics.
  • the 50 ⁇ thickness offered a higher cumulative release as compared to the ⁇ ⁇ thickness which was slow and sustained as seen in Figure 10B, which shows the change in release mechanisms with varying micro-geometry (wall thickness) of 3D printed capsule.
  • varying the wall thickness could have a substantial influence in directing release kinetics of drugs using customized capsules.
  • 3D printed customized capsules may enable personalized therapeutics and delivery kinetics as per patient requirements and schedules.
  • a method for oral application delivery as a dental device combined with therapeutic delivery can be seen in the Figure 11 , which shows an illustrative example of a dental device 250 with customized delivery capsule 245, placed so as to degrade over time to deliver the required therapeutic.
  • the capsule according to the present invention may also be integrated with a device, rather than simple ingestion. Therefore, the delivery of the therapeutic may be incorporated with a more complex regime incorporating such medical devices.

Abstract

L'invention porte sur une capsule pour l'administration d'un agent thérapeutique, la capsule comprenant : une enveloppe agencé pour être dissous lors de l'ingestion par un patient; une pluralité de chambres définies par des parois de chambre, chaque chambre étant conçue pour contenir un agent thérapeutique; au moins une desdites parois de chambre comprend au moins une partie dudit enveloppe; la capsule étant agencée pour délivrer l'agent thérapeutique lors de la dissolution sur lesdites parois de chambre.
PCT/SG2017/050397 2016-08-08 2017-08-08 Article imprimé en 3d, procédé d'utilisation et procédé de fabrication WO2018030956A1 (fr)

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SG10201606579X 2016-08-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110651877A (zh) * 2019-11-08 2020-01-07 刘澍聪 生命最低营养糖丸
CN111249257A (zh) * 2020-03-27 2020-06-09 武汉大学 3d打印药物缓释胶囊及其制备方法与应用

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GB2148841A (en) * 1983-11-04 1985-06-05 Warner Lambert Co Capsulated medicaments
US4738817A (en) * 1983-11-17 1988-04-19 Warner-Lambert Company Method for forming pharmaceutical capsules from hydrophilic polymers
US20050008690A1 (en) * 2002-04-10 2005-01-13 Miller Fred H. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20050191346A1 (en) * 1999-07-09 2005-09-01 Edward Nowak Delivery capsules
US20060057201A1 (en) * 2002-07-25 2006-03-16 Bonney Stanley G Multicomponent pharmaceutical dosage form
US20090155354A1 (en) * 2007-12-14 2009-06-18 Mclean Barbara Wanamaker Dispensing encapsulated liquids into body cavities
US20100119597A1 (en) * 1999-07-30 2010-05-13 Clarke Allan J Multi-component pharmaceutical dosage form
US20100203130A1 (en) * 2009-02-06 2010-08-12 Egalet A/S Pharmaceutical compositions resistant to abuse
US20110250241A1 (en) * 1999-11-17 2011-10-13 Aquasol Ltd. Injection-moulded water-soluble container
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GB2148841A (en) * 1983-11-04 1985-06-05 Warner Lambert Co Capsulated medicaments
US4738817A (en) * 1983-11-17 1988-04-19 Warner-Lambert Company Method for forming pharmaceutical capsules from hydrophilic polymers
US20050191346A1 (en) * 1999-07-09 2005-09-01 Edward Nowak Delivery capsules
US20100119597A1 (en) * 1999-07-30 2010-05-13 Clarke Allan J Multi-component pharmaceutical dosage form
US20110250241A1 (en) * 1999-11-17 2011-10-13 Aquasol Ltd. Injection-moulded water-soluble container
US20050008690A1 (en) * 2002-04-10 2005-01-13 Miller Fred H. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20060057201A1 (en) * 2002-07-25 2006-03-16 Bonney Stanley G Multicomponent pharmaceutical dosage form
US20150132376A1 (en) * 2007-10-19 2015-05-14 Capsugel Belgium Nv Multi-compartmented container
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110651877A (zh) * 2019-11-08 2020-01-07 刘澍聪 生命最低营养糖丸
CN111249257A (zh) * 2020-03-27 2020-06-09 武汉大学 3d打印药物缓释胶囊及其制备方法与应用
CN111249257B (zh) * 2020-03-27 2021-07-06 武汉大学 3d打印药物缓释胶囊及其制备方法与应用

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