WO2009143947A1 - Process for the preparation of microspheres comprising semisynthetic polymers - Google Patents
Process for the preparation of microspheres comprising semisynthetic polymers Download PDFInfo
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- WO2009143947A1 WO2009143947A1 PCT/EP2009/003075 EP2009003075W WO2009143947A1 WO 2009143947 A1 WO2009143947 A1 WO 2009143947A1 EP 2009003075 W EP2009003075 W EP 2009003075W WO 2009143947 A1 WO2009143947 A1 WO 2009143947A1
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- microspheres
- hyaluronic acid
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- esterification
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
Definitions
- the present invention relates to a process for the preparation of microspheres comprising semisynthetic polymers using an electrically-controlled capillary flow method.
- EP 817620 discloses the preparation of microspheres of polysaccharide polymers, with dimensions of between 0.1 and 1 ⁇ m, for use as biomaterials, for example for drug release or the preparation of artificial tissues and orthopaedic prostheses.
- the polymers tested include hyaluronic acid esters, possibly cross-linked, chitin esters, alginic acid, pectin and gellan.
- the preparation method disclosed in EP 817620 is substantially a batch process which involves precipitation of microspheres from a solution of a polymer, dissolved in an aprotic solvent, through a coagulation medium which is a non-solvent for the polymer, consisting of a fluid, typically carbon dioxide or hydrofluorocarbons, in supercritical conditions.
- a coagulation medium which is a non-solvent for the polymer, consisting of a fluid, typically carbon dioxide or hydrofluorocarbons, in supercritical conditions.
- the greater limitations associated with this technique substantially involve the difficulty of eliminating all trace of solvent from the particles and disposing of industrial quantities of the solvents.
- Similar limitations are presented by the technique for manufacturing microspheres with dimensions of between 1 and 100 ⁇ m claimed in EP 517565; in this case, the microspheres are produced by extraction, through the use of a mineral oil and ethyl acetate.
- FIG. 1 shows the process of the invention.
- Figure 2 shows the scanning electron microscope images of microspheres obtained by varying the process parameters: A) 11 Kv, 26 gauge; B) 18 kV, 17 gauge.
- Figure 3 shows the effect of process parameters (applied voltage, diameter of capillary tube) on size of microspheres.
- Figure 4 shows the A) Water absorption tests; B) autofluorescence of microspheres indicated by confocal microscopy.
- Figure 5 shows the effect of coagulation bath rotation rate on shape of microspheres: A) 300 rpm; B) 600 rpm; c) 900 rpm.
- microspheres of biocompatible and biodegradable polymers in particular semisynthetic polymers such as hyaluronic acid esters, can be efficiently and advantageously obtained by an electrodynamic atomisation technique known as the electrically-controlled capillary flow technique, without using high-risk chemical solvents which are difficult to dispose of; the microspheres made with said technique have a substantially spherical shape, with a diameter of between 180 and 490 ⁇ m and a narrow size distribution.
- hyaluronic acid is a heteropolysaccharide consisting of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine, wherein the carboxyl functions of the glucuronic residue are partly or totally esterified with benzyl alcohol.
- Said derivatives maintain the biological properties of the starting molecule, but acquire different mechanical and rheological properties which, above all, can be modulated on the basis of the degree of esterification.
- the preparation of said esters is described in US 4851521 and EP 341745.
- the process described here can also be advantageously applied to hyaluronic acid benzyl esters with different degrees of esterification (75-100%) or to other polymers, such as chitin, alginic acid, pectin and gellan.
- the microspheres obtainable by electrodynamic atomisation present the advantage of being rapidly metabolised and rapidly eliminated by the body due to the high breakdown rate of the polymer which, as stated, can be regulated by the degree of esterification chosen. Said properties prevent the onset of any inflammatory response by the tissues which come into direct contact with the microspheres when the device of which they are made comes into contact with the body.
- the microspheres made according to the invention can therefore be advantageously used as a vehicle for the controlled release of small molecules or different types of drugs.
- the microsphere preparation process comprising semisynthetic polymers using the electrically-controlled capillary flow technique involves applying an electrical field generated by a potential difference of between
- the polymer solution is typically fed by a syringe pump, the volumetric flow rate of which ranges between 1 and 50 ml/h, preferably between 5 and 30 ml/h, and more preferably between 10 and 20 ml/h ( Figure 1).
- microspheres are collected in a water bath placed at a suitable distance from the output end of the capillary tube, depending on the size of the equipment used. Said distance generally ranges between 5 and 30 cm.
- the shape of the microspheres can be modified by suitably regulating the stirring rate of the collection bath; for example, an increase in the stirring rate causes an increase in the axial deformation of the spheres due to the growing action of the centrifugal force on the falling drops, which take on a discoid shape.
- the microspheres are substantially spherical at 300 rpm and discoid at 900 rpm.
- the mean size of the microspheres is mainly determined by the potential applied: the use of higher potential differences produces microspheres of larger average dimensions and vice versa.
- a crucial feature of the process is that the shape and size acquired during the electrically-controlled capillary flow process are maintained after extraction of the solvent, effected by the water with a reverse-phase mechanism.
- the Hyaff 1 1 ® microspheres obtained according to this invention present hydrogel behaviour, ie. a high water retention capacity, which can be modulated by varying the degree of esterification of the polymer.
- the presence of benzyl groups along the main chains of the polymer produces autofluorescent particles which can easily be monitored in acellular or cellular structures using in vitro culture or in vivo implant techniques.
- a hyaluronic acid ester wherein 75% of the carboxyl groups were esterif ⁇ ed with benzyl groups (Hyaff 11 ® ) was used.
- 1 gram of polymer was dissolved in 20 ml of dimethyl sulphoxide (DMSO) at the temperature of 40 0 C for 1 hour, under magnetic stirring. After cooling to ambient temperature, the solution was subjected to the electrically-controlled capillary flow technique using a syringe pump (Harvard Instruments) able to impose a volumetric flow rate of 15 ml/h through three different stainless steel capillary tubes with inner diameters of 1.1 mm, 0.8 mm and 0.4 mm, corresponding to 17, 20 and 26 gauge respectively.
- DMSO dimethyl sulphoxide
- a voltage of 11, 14 and 18 kV respectively was applied between each metal capillary tube and an aluminium plate 2 mm thick, and the device was earthed. This type of design allows a correlation to be established between the dimensions of the capillary tube, the voltage applied and the dimensions of the resulting microsphere.
- microspheres were collected in a water bath placed at a distance of 15 mm from the capillary electrode, and moved in the bath by means of magnetic stirring using a rotation rate of 300 rpm to reduce coalescence.
- the water + microspheres mixture was then subjected to preliminary filtration using filter paper with a retention dimension of 200 nm.
- the wet microspheres were then dried under vacuum at ambient temperature for 2 hours, after progressive dilutions in ethanol to ensure complete removal of the water.
- microspheres were morphologically characterised under a scanning electron microscope (Leica 420).
- Figure 2 shows the microspheres obtained, characterised by a substantially spherical shape and a narrow size distribution.
- Figure 3 A close correlation was observed between the size of the microspheres and the process parameters ( Figure 3).
- an ad hoc configuration of the voltage applied and the diameter of the capillary tube allowed the size of the microspheres to be predefined with certainty in a range of 180-490 ⁇ m, as verified by processing (with ImageJ 1.36 software) of the images obtained under the scanning electron microscope.
- the water retention capacity was also analysed by studying the absorption isotherm (Figure 4A) obtained by Dynamic Vapour Sorption (DVS).
- the measurement involves evaluating the weight variation in the material caused by the water retention capacity of the sample exposed under conditions of high humidity (up to 90%) at an assigned temperature. In this specific case, the measurement was conducted at the temperature of 37° to simulate the heat conditions physiologically present in the body.
- the blue curve shows the variation in the degree of humidity in the test chamber as a function of time
- the green curve shows the variation in weight of the sample induced by retention of the condensed water in the chamber, and also indicates the absorption kinetics over time.
- a 28% water uptake (% R) was calculated from the equation shown in Figure 4A.
- Figure 4B represents the autofluorescence properties of the microspheres determined by the intrinsic fluorescence of the benzyl groups present in the Hyaff 11 ® molecule, detected by confocal microscopy techniques.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
Disclosed is a process for the preparation of microspheres of semisynthetic polymers which comprises subjecting a polymer solution in an aprotic solvent to an electrospraying procedure through capillary tubes with a diameter of between 1 and 0.1 mm, applying a potential of between 10 and 20 kV.
Description
PROCESS FOR THE PREPARATION OF MICROSPHERES COMPRISING SEMISYNTHETIC POLYMERS
The present invention relates to a process for the preparation of microspheres comprising semisynthetic polymers using an electrically- controlled capillary flow method.
Prior art Microspheres of biocompatible polymers have been prepared by different methods. For example, EP 817620 discloses the preparation of microspheres of polysaccharide polymers, with dimensions of between 0.1 and 1 μm, for use as biomaterials, for example for drug release or the preparation of artificial tissues and orthopaedic prostheses. The polymers tested include hyaluronic acid esters, possibly cross-linked, chitin esters, alginic acid, pectin and gellan.
The preparation method disclosed in EP 817620 is substantially a batch process which involves precipitation of microspheres from a solution of a polymer, dissolved in an aprotic solvent, through a coagulation medium which is a non-solvent for the polymer, consisting of a fluid, typically carbon dioxide or hydrofluorocarbons, in supercritical conditions. The greater limitations associated with this technique substantially involve the difficulty of eliminating all trace of solvent from the particles and disposing of industrial quantities of the solvents. Similar limitations are presented by the technique for manufacturing microspheres with dimensions of between 1 and 100 μm claimed in EP 517565; in this case, the microspheres are produced by extraction, through the use of a mineral oil and ethyl acetate. Various studies in the literature illustrate the possibility of manufacturing microparticles with single or multiple emulsion processes from biodegradable polymers such as starches or polyesters (e.g. polycaprolactone), for use as controlled drug release systems. However, the emulsion techniques present a series of
application limitations associated with the difficulty of removing the organic solvents used during the process and the excessive friction stress on the interfaces between the dispersed and dispersing phase (oil/water), which reduces the possibility of fine-tuning the dimensions of the particles. There is also a difficulty inherent in the formation of oil/water emulsions using highly hydrophilic polymers due to the high miscibility of the dispersed and dispersing phases, which hinders the formation of interfaces. Techniques for manufacturing microspheres of biocompatible polymers with the spray-drying process are also known, which involve spraying a solution of the selected polymer and rapid evaporation of the solvent in order to obtain the required microspheres. However, this technique has proved ineffective due to the excessive dispersion of the sizes of the microspheres obtained; the process is consequently not advantageous either on a laboratory scale, as further microsphere grading stages are required, or on an industrial scale, as it is not very economical (Esposito et al., Int J Pharm, 2005, 288, 35-49).
Brief Description of the Figures
Figure 1 shows the process of the invention.
Figure 2 shows the scanning electron microscope images of microspheres obtained by varying the process parameters: A) 11 Kv, 26 gauge; B) 18 kV, 17 gauge.
Figure 3 shows the effect of process parameters (applied voltage, diameter of capillary tube) on size of microspheres.
Figure 4 shows the A) Water absorption tests; B) autofluorescence of microspheres indicated by confocal microscopy. Figure 5 shows the effect of coagulation bath rotation rate on shape of microspheres: A) 300 rpm; B) 600 rpm; c) 900 rpm.
Description of the invention
The Applicant has now surprisingly found that microspheres of
biocompatible and biodegradable polymers, in particular semisynthetic polymers such as hyaluronic acid esters, can be efficiently and advantageously obtained by an electrodynamic atomisation technique known as the electrically-controlled capillary flow technique, without using high-risk chemical solvents which are difficult to dispose of; the microspheres made with said technique have a substantially spherical shape, with a diameter of between 180 and 490 μm and a narrow size distribution.
The process disclosed in the invention is preferably applied to hyaluronic acid benzyl esters with a degree of esterification of 75%, marketed under the Hyaff 11 brand. Briefly, hyaluronic acid is a heteropolysaccharide consisting of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine, wherein the carboxyl functions of the glucuronic residue are partly or totally esterified with benzyl alcohol. Said derivatives maintain the biological properties of the starting molecule, but acquire different mechanical and rheological properties which, above all, can be modulated on the basis of the degree of esterification. The preparation of said esters is described in US 4851521 and EP 341745.
The process described here can also be advantageously applied to hyaluronic acid benzyl esters with different degrees of esterification (75-100%) or to other polymers, such as chitin, alginic acid, pectin and gellan. The microspheres obtainable by electrodynamic atomisation present the advantage of being rapidly metabolised and rapidly eliminated by the body due to the high breakdown rate of the polymer which, as stated, can be regulated by the degree of esterification chosen. Said properties prevent the onset of any inflammatory response by the tissues which come into direct contact with the microspheres when the device of which they are made comes into contact with the body. The microspheres made according to the invention can therefore be advantageously used as a vehicle for the controlled release of small molecules or different types of drugs.
The microsphere preparation process comprising semisynthetic polymers using the electrically-controlled capillary flow technique involves applying an electrical field generated by a potential difference of between
10 and 20 kV to a polymer solution flowing through a metal capillary tube with a diameter of between 1 and 0.1 mm.
The polymer solution is typically fed by a syringe pump, the volumetric flow rate of which ranges between 1 and 50 ml/h, preferably between 5 and 30 ml/h, and more preferably between 10 and 20 ml/h (Figure 1).
The microspheres are collected in a water bath placed at a suitable distance from the output end of the capillary tube, depending on the size of the equipment used. Said distance generally ranges between 5 and 30 cm.
The shape of the microspheres can be modified by suitably regulating the stirring rate of the collection bath; for example, an increase in the stirring rate causes an increase in the axial deformation of the spheres due to the growing action of the centrifugal force on the falling drops, which take on a discoid shape. As clearly shown in Figure 5, the microspheres are substantially spherical at 300 rpm and discoid at 900 rpm. However, the mean size of the microspheres is mainly determined by the potential applied: the use of higher potential differences produces microspheres of larger average dimensions and vice versa. A crucial feature of the process is that the shape and size acquired during the electrically-controlled capillary flow process are maintained after extraction of the solvent, effected by the water with a reverse-phase mechanism. This means that the shape and size of the microspheres most suitable for the required type of application can be established simply and safely in advance. The Hyaff 1 1® microspheres obtained according to this invention present hydrogel behaviour, ie. a high water retention capacity, which can be modulated by varying the degree of esterification of the polymer. Moreover, the presence of benzyl groups along the main chains of the polymer produces
autofluorescent particles which can easily be monitored in acellular or cellular structures using in vitro culture or in vivo implant techniques.
The invention will now be illustrated in greater detail in the following example. EXAMPLE
A hyaluronic acid ester wherein 75% of the carboxyl groups were esterifϊed with benzyl groups (Hyaff 11®) was used. In particular, 1 gram of polymer was dissolved in 20 ml of dimethyl sulphoxide (DMSO) at the temperature of 400C for 1 hour, under magnetic stirring. After cooling to ambient temperature, the solution was subjected to the electrically-controlled capillary flow technique using a syringe pump (Harvard Instruments) able to impose a volumetric flow rate of 15 ml/h through three different stainless steel capillary tubes with inner diameters of 1.1 mm, 0.8 mm and 0.4 mm, corresponding to 17, 20 and 26 gauge respectively. A voltage of 11, 14 and 18 kV respectively was applied between each metal capillary tube and an aluminium plate 2 mm thick, and the device was earthed. This type of design allows a correlation to be established between the dimensions of the capillary tube, the voltage applied and the dimensions of the resulting microsphere.
The microspheres were collected in a water bath placed at a distance of 15 mm from the capillary electrode, and moved in the bath by means of magnetic stirring using a rotation rate of 300 rpm to reduce coalescence. The water + microspheres mixture was then subjected to preliminary filtration using filter paper with a retention dimension of 200 nm. The wet microspheres were then dried under vacuum at ambient temperature for 2 hours, after progressive dilutions in ethanol to ensure complete removal of the water.
The microspheres were morphologically characterised under a scanning electron microscope (Leica 420). Figure 2 shows the microspheres obtained, characterised by a substantially spherical shape and a narrow size distribution.
A close correlation was observed between the size of the microspheres and the process parameters (Figure 3). In particular, an ad hoc configuration of the voltage applied and the diameter of the capillary tube allowed the size of the microspheres to be predefined with certainty in a range of 180-490 μm, as verified by processing (with ImageJ 1.36 software) of the images obtained under the scanning electron microscope.
The water retention capacity was also analysed by studying the absorption isotherm (Figure 4A) obtained by Dynamic Vapour Sorption (DVS). The measurement involves evaluating the weight variation in the material caused by the water retention capacity of the sample exposed under conditions of high humidity (up to 90%) at an assigned temperature. In this specific case, the measurement was conducted at the temperature of 37° to simulate the heat conditions physiologically present in the body. In detail, the blue curve shows the variation in the degree of humidity in the test chamber as a function of time, while the green curve shows the variation in weight of the sample induced by retention of the condensed water in the chamber, and also indicates the absorption kinetics over time. A 28% water uptake (% R) was calculated from the equation shown in Figure 4A.
Figure 4B represents the autofluorescence properties of the microspheres determined by the intrinsic fluorescence of the benzyl groups present in the Hyaff 11® molecule, detected by confocal microscopy techniques.
Analysis of the data presented here demonstrates that the process claimed, when applied to hyaluronic acid ester derivatives, goes far beyond the state of the art, because it allows microspheres of a biocompatible, biodegradable polymer to be obtained simply, without the use of solvents which are difficult to dispose of, ensuring a very narrow size distribution of the microspheres which can be predetermined with certainty upstream of the process, thus making it industrially economical.
Claims
1. Process for preparing microspheres comprising semisynthetic polymers by means of electrodynamic atomisation through the application of an electrical field generated by a potential difference of 10-20 kV to a polymer solution flowing along a metal capillary tube with an inner diameter of between 1.1 and 0.1 mm.
2. Process as claimed in claim 1, wherein the microspheres have a spherical shape with a diameter of between 180 and 490 μm and a narrow size distribution.
3. Process as claimed in claim 1 or 2, wherein the polymers are selected from hyaluronic acid esters, chitin, alginic acid, pectin and gellan.
4. Process as claimed in claim 3, wherein the polymer is a benzyl ester of hyaluronic acid with a degree of esterification of 75-100%.
5. Process as claimed in claim 4, wherein the hyaluronic acid benzyl ester has a degree of esterification of 75%.
6. Microspheres comprising semisynthetic polymers obtainable from the process claimed in claims 1-5.
7. Microspheres as claimed in claim 6, wherein the polymer is selected from hyaluronic acid esters, chitin, alginic acid, pectin and gellan.
8. Microspheres as claimed in claim 7, wherein the polymer is a hyaluronic acid benzyl ester with a degree of esterification of 75-100%.
9. Microspheres as claimed in claim 7, wherein the hyaluronic acid benzyl ester has a degree of esterification of 75%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2008A000981 | 2008-05-27 | ||
| ITMI20080981 ITMI20080981A1 (en) | 2008-05-27 | 2008-05-27 | PROCESS FOR THE PREPARATION OF MICROSFERE OF SEMI-SYNTHETIC POLYMERS |
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| WO2009143947A1 true WO2009143947A1 (en) | 2009-12-03 |
| WO2009143947A8 WO2009143947A8 (en) | 2010-02-04 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103933908A (en) * | 2014-04-25 | 2014-07-23 | 江苏大学 | Equipment and method for preparing microcapsules by liquid-liquid electrostatic micro-jet atomization |
| CN104383860A (en) * | 2014-11-20 | 2015-03-04 | 中国科学技术大学 | Microcapsule droplet generator and preparation method thereof |
| CN106552284A (en) * | 2016-12-06 | 2017-04-05 | 华中科技大学 | A kind of development embolism materials and preparation method thereof |
| CN114316162A (en) * | 2022-01-18 | 2022-04-12 | 四川大学 | Photo-crosslinking injectable nanofiber-hydrogel compound and preparation method and application thereof |
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| WO1995024429A1 (en) * | 1994-03-11 | 1995-09-14 | Fidia Advanced Biopolymers S.R.L. | Highly reactive esters of carboxy polysaccharides and novel carboxy polysaccharides derived therefrom |
| EP0979648A2 (en) * | 1991-05-31 | 2000-02-16 | FIDIA S.p.A. | Microspheres of esters of hyaluronic acid for controlled release of an active |
| WO2006086654A2 (en) * | 2005-02-11 | 2006-08-17 | Battelle Memorial Institute | Nanoformulations |
-
2008
- 2008-05-27 IT ITMI20080981 patent/ITMI20080981A1/en unknown
-
2009
- 2009-04-28 WO PCT/EP2009/003075 patent/WO2009143947A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0979648A2 (en) * | 1991-05-31 | 2000-02-16 | FIDIA S.p.A. | Microspheres of esters of hyaluronic acid for controlled release of an active |
| WO1995024429A1 (en) * | 1994-03-11 | 1995-09-14 | Fidia Advanced Biopolymers S.R.L. | Highly reactive esters of carboxy polysaccharides and novel carboxy polysaccharides derived therefrom |
| WO2006086654A2 (en) * | 2005-02-11 | 2006-08-17 | Battelle Memorial Institute | Nanoformulations |
Non-Patent Citations (3)
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|---|
| DEZHI WU ET AL: "Pattern deposition of electrosprayed polymer nanoparticles", 7TH IEEE CONFERENCE ON NANOTECHNOLOGY, 2007 : IEEE-NANO 2007 ; HONG KONG, CHINA, 2 - 5 AUG. 2007, PISCATAWAY, NJ : IEEE SERVICE CENTER, 2 August 2007 (2007-08-02), pages 271 - 274, XP031307771, ISBN: 978-1-4244-0607-4 * |
| XIE ET AL: "Electrospray in the dripping mode for cell microencapsulation", JOURNAL OF COLLOID AND INTERFACE SCIENCE, ACADEMIC PRESS, NEW YORK, NY, US, vol. 312, no. 2, 21 June 2007 (2007-06-21), pages 247 - 255, XP022126021, ISSN: 0021-9797 * |
| ZHOU Y ET AL: "Scalable encapsulation of hepatocytes by electrostatic spraying", JOURNAL OF BIOTECHNOLOGY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 117, no. 1, 20 April 2005 (2005-04-20), pages 99 - 109, XP004836790, ISSN: 0168-1656 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103933908A (en) * | 2014-04-25 | 2014-07-23 | 江苏大学 | Equipment and method for preparing microcapsules by liquid-liquid electrostatic micro-jet atomization |
| CN103933908B (en) * | 2014-04-25 | 2016-04-06 | 江苏大学 | The Apparatus for () and method therefor of microcapsules is prepared in a kind of liquid liquid electrostatic microjet atomization |
| CN104383860A (en) * | 2014-11-20 | 2015-03-04 | 中国科学技术大学 | Microcapsule droplet generator and preparation method thereof |
| CN106552284A (en) * | 2016-12-06 | 2017-04-05 | 华中科技大学 | A kind of development embolism materials and preparation method thereof |
| CN106552284B (en) * | 2016-12-06 | 2020-07-03 | 华中科技大学 | Developing embolism material and preparation method thereof |
| CN114316162A (en) * | 2022-01-18 | 2022-04-12 | 四川大学 | Photo-crosslinking injectable nanofiber-hydrogel compound and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| ITMI20080981A1 (en) | 2009-11-28 |
| WO2009143947A8 (en) | 2010-02-04 |
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