WO2023244207A1 - Production of microneedles for transdermal drug delivery by dynamic light processing - Google Patents
Production of microneedles for transdermal drug delivery by dynamic light processing Download PDFInfo
- Publication number
- WO2023244207A1 WO2023244207A1 PCT/TR2023/050579 TR2023050579W WO2023244207A1 WO 2023244207 A1 WO2023244207 A1 WO 2023244207A1 TR 2023050579 W TR2023050579 W TR 2023050579W WO 2023244207 A1 WO2023244207 A1 WO 2023244207A1
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- WIPO (PCT)
- Prior art keywords
- gelma
- microneedles
- solution
- drug delivery
- methacrylate
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 17
- 238000013271 transdermal drug delivery Methods 0.000 title abstract description 15
- 238000012545 processing Methods 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 36
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims abstract description 18
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- 229960003165 vancomycin Drugs 0.000 claims description 2
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- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 description 5
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y10/00—Processes of additive manufacturing
-
- 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
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Definitions
- the invention relates to a method of producing microneedle patches for transdermal drug delivery using dynamic light processing (DLP) technique using Gelatin Methacrylate (GelMA) or a mixture of Gelatin Methacrylate (GelMA) + Keratin Methacrylate (KerMA) or a blend with different methacrylated natural or synthetic polymers.
- DLP dynamic light processing
- the skin is the largest organ of the human body, accounting for about 15% of the total body weight. It consists of three layers, including the epidermis, dermis and hypodermis.
- the stratum corneum the outermost layer of the epidermis, acts as a skin barrier as it only allows certain molecules to pass through it, such as lipophilic and low molecular weight drugs.
- Hypodermic needles and topical creams are commonly used to deliver medication through the skin. However, needles are less accepted by patients due to the pain they cause and topical creams are less bioavailable. At this point, transdermal drug delivery is an important alternative to the aforementioned treatments for drug delivery.
- Microneedles are being used to overcome the limitations of conventional approaches for transdermal drug delivery.
- Microneedle arrays consist of micronsized needles that allow the transfer of a compound or signal through the outer layer of a tissue. Due to their microscale size, MNs can seamlessly penetrate the skin and deliver a range of therapeutic molecules, including small molecules, biomacromolecules and even nanoparticles. The penetration of MNs can be arranged to penetrate only the epidermis without damaging neurons in the dermis, hence it is a painless and minimally invasive method. It is also easy to selfadminister and exhibits a high drug bioavailability.
- MNs are classified as solid, coated, porous, dissolving, hollow and hydrogel and are usually made of metal, silicon, polymer, glass or ceramic.
- polymeric (hydrogel) microneedles have attracted more attention due to their unique properties such as biocompatibility, biodegradability, high drug loading rate and cost-effectiveness.
- Drugs can be easily encapsulated in the polymeric matrix or conjugated on the surface of the substrate materials forming the microneedles and, after penetration into the skin, are released spontaneously through polymer degradation, dissolution or swelling under physiological conditions.
- Manufacturing strategies for MNs include micro-milling, wet and dry etching, photolithography, molding-based techniques, injection molding, laser patterning and drawing lithography.
- Micro-molding techniques laser drilling, injection and casting
- these techniques can produce microneedles with limited geometries where only one of the microneedle parameters such as height, spacing and shape is varied.
- these techniques require manual steps and labor-intensive work, with problems related to complexity and high cost.
- the United States patent document US20210386985A1 which is in the known state of the art, mentions a microneedle patch that can be used to deliver therapeutic agents to living tissue (e.g., skin). Transmission rates can be adjusted according to the degree of cross-linking of the polymer (gelatin methacryloyl (GelMA)) patch.
- the United States patent document US2022118416A1 which is in the known state of the art, discloses new composite materials and methods of preparation thereof comprising cross-linked biodegradable polymers and non-cross-linked biodegradable polymers.
- the inventive subject matter required the realization of a fast, easy, accessible and low-cost microneedle patch production method capable of producing hydrogel microneedles in the desired size and geometry for transdermal drug delivery applications.
- the object of the present invention is to provide a method of manufacturing microneedle patches for transdermal drug delivery using vat photopolymerization 3D printing techniques (stereolithography - SLA, Digital Light Processing - DLP, liquid crystal display - LCD, etc.), comprising Gelatin Methacrylate (GelMA) or a mixture of Gelatin Methacrylate (GelMA) + Keratin Methacrylate (KerMA) or a mixture with different methacrylated natural or synthetic polymers.
- vat photopolymerization 3D printing techniques stereolithography - SLA, Digital Light Processing - DLP, liquid crystal display - LCD, etc.
- Another object of the present invention is to provide a fast, easy, accessible and low-cost microneedle patch production method capable of producing hydrogel microneedles of desired size and geometry for transdermal drug delivery applications.
- Figure la is a graph of the temperature ramp test in the rheological analysis of the GelMA hydrogel used in the inventive method.
- Figure lb is a graph of the frequency sweep test for the rheological analysis of the GelMA hydrogel used in the inventive method.
- Figure 1c is the graph of the rotational shear rate-viscosity measurement in the rheological analysis of the GelMA hydrogel used in the inventive method.
- Figure l is a view of Fourier transform infrared (FTIR) spectra of pure gelatin and GelMA hydrogel.
- Figure 3 is a scanning electron microscope (SEM) image of microneedles produced by the inventive method.
- the invention relates to a method of producing a microneedle patch and comprises the steps;
- the main biomaterial for the microneedle patch to be produced is GelMA.
- GelMA is synthesized at a concentration suitable for 3D printing.
- GelMA is a biocompatible, biodegradable and low-cost material.
- the presence of methacryloyl side groups allows the GelMA molecule to undergo rapid polymerization in the presence of UV light and a photoinitiator, resulting in covalent crosslinking through the formation of a methacryloyl backbone. This makes it a suitable material for printing in vat photopolymerization techniques.
- the GelMA solution used as the main material for the microneedle patch is prepared at the appropriate concentration.
- Antibiotics gentamicin, amoxicillin, vancomycin, etc.
- the antibiotic or therapeutics to be used can be changed according to the disease being treated. Gentamicin was chosen as the antibiotic to be used in the experiments.
- photoinitiator LAP
- KerMA is a biocompatible material, has high mechanical strength due to the presence of disulfide bond and does not dissolve easily.
- a CAD model of the microneedles in the prescribed dimensions is designed and transferred to the 3D printer software.
- the microneedle patch is produced using vat photopolymerization techniques (SLA, DLP, LCD, etc.) with the specified material (and materials/drugs to be added).
- Vat photopolymerization uses a vat of liquid photopolymer resin, out of which the model is constructed layer by layer. An ultraviolet (UV) or laser light is used to cure resin, whilst a platform moves the object being made downwards after each new layer is cured according to the CAD model.
- GelMA hydrogel microneedles can be printed in the desired geometry, with high resolution, in a short time and at low cost.
- concentration for microneedles, the amount of photoinitiator and the parameters of the 3D printer can be optimized.
- Gelatin type- A was stirred in 0.1 M carbonate-bicarbonate buffer solution with a concentration of 10% (w/v), adjusted to pH 9 and stirred at 60° C with a magnetic stirrer until a homogeneous solution was obtained.
- MAA methacrylic anhydride
- the pH of the solution taken at the end of the reaction is adjusted to 7.4.
- the solution is passed through ordinary filter paper. Then it is transferred to a dialysis membrane and dialyzed against pure water at 40° C for 3 days. The dialysis water is refreshed every day.
- the solution is taken into the lyophilization device and lyophilized until complete drying.
- GelMA in solid form is stored in the dark at 4° C.
- 2% methacrylic anhydride (MAA) is added to the solution at a rate of 0.5 mL/min, adjusted to pH 9 and allowed to react at 50 °C for 3 hours.
- the pH of the solution is adjusted to 7.4. It is then transferred to a dialysis membrane and dialyzed against pure water at 40° C for 1 week. Dialysis water is refreshed every day. The solution is taken into the lyophilization device and lyophilized until complete drying. KerMA in solid form is stored in the dark at 4° C.
- the microneedles are designed in SolidWorks, attached to a solid 10mm x 10mm x 1 mm substrate with a 6x6 array.
- the microneedle model is saved in ".stl” format and then the model is converted by the "Chitubox" program into a G-Code that a vat photopolymerization device, i.e., Phrozen Shuffle DLP Printer with a layer thickness of up to 10 microns can understand.
- the layer thickness for microneedles was set to 20 microns and the UV exposure time to 50 s.
- the synthesized GelMA was weighed in appropriate amounts and dissolved in phosphate buffered saline (PBS) (pH 7.4) solution at a concentration of 10% (w/v) at 40°C. Then, 0.5% (w/v) lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) was added to the solution as photoinitiator and the mixture was stirred at 40°C for 15 minutes and then syringed and transferred to 3D printer. The printing process was performed with pre-optimized parameters for the device.
- PBS phosphate buffered saline
- the microneedle height is approximately 670 pm and is suitable for transdermal applications.
- Microneedle sharpness is determined by tip radius and is approximately 32 pm. Tip radii of 20-40 pm are sharp enough to penetrate the skin. The resulting tip radii are therefore among the sharpest needles printed using a low-cost printing system.
- the inventive method enables the production of hydrogel microneedles of the desired size and shape using vat photopolymerization 3D printing techniques, which is a high-resolution, fast and low-cost method different from the methods used so far for transdermal drug delivery applications.
- computationally designed hydrogel microneedles can be produced directly in a single step without molds, with minimal time and without the geometric limitations imposed by conventional producing methods.
- the hydrogel microneedles produced have a high mechanical strength that allows penetration through the skin when dry and swell when inserted into the skin due to the presence of interstitial fluid. This leads to the formation of channels between the capillary circulation and the medicated microneedle patch. During swelling they act as a rate-controlling membrane. They have a higher drug loading capacity and an adjustable drug release rate. These factors are often directly linked to the polymer cross-linking rate, which is not easily controlled in conventional microneedle forms. They are flexible in size and shape. They are also easily sterilized and removed from the skin intact.
- microneedle-mediated transdermal drug release requires that the material has sufficient mechanical strength to penetrate the skin barrier, is biocompatible and does not cause immune reactions after application, the material does not dissolve or biodegrade, and the release profile of the drug is slow and uniform to ensure a sustained release over a long period of time. Therefore, the use of combined hydrogels in production will improve microneedle properties (e.g. mechanical properties) and increase the efficiency of transdermal drug delivery.
- vat photopolymerization 3D printing technique Another advantage of using the vat photopolymerization 3D printing technique is the high resolution and fast printability of the microneedles, allowing for personalized design.
- microneedle patch production with this technique provides cost savings in terms of dose savings, production and logistics. The fact that the applicability of the microneedle patches produced is also effortless will provide convenience for both the patient and the doctor.
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- Health & Medical Sciences (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Manufacturing & Machinery (AREA)
- Materials Engineering (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a method of manufacturing microneedle patches for transdermal drug delivery using dynamic light processing (DLP) technique using Gelatin Methacrylate (GelMA) or a mixture of Gelatin Methacrylate (GelMA) + Keratin Methacrylate (KerMA) or a blend with different methacrylated natural or synthetic polymers.
Description
PRODUCTION OF MICRONEEDLES FOR TRANSDERMAL DRUG DELIVERY BY DYNAMIC LIGHT PROCESSING
Technical Field
The invention relates to a method of producing microneedle patches for transdermal drug delivery using dynamic light processing (DLP) technique using Gelatin Methacrylate (GelMA) or a mixture of Gelatin Methacrylate (GelMA) + Keratin Methacrylate (KerMA) or a blend with different methacrylated natural or synthetic polymers.
Prior Art
The skin is the largest organ of the human body, accounting for about 15% of the total body weight. It consists of three layers, including the epidermis, dermis and hypodermis. The stratum corneum, the outermost layer of the epidermis, acts as a skin barrier as it only allows certain molecules to pass through it, such as lipophilic and low molecular weight drugs. Hypodermic needles and topical creams are commonly used to deliver medication through the skin. However, needles are less accepted by patients due to the pain they cause and topical creams are less bioavailable. At this point, transdermal drug delivery is an important alternative to the aforementioned treatments for drug delivery.
Microneedles (MNs) are being used to overcome the limitations of conventional approaches for transdermal drug delivery. Microneedle arrays consist of micronsized needles that allow the transfer of a compound or signal through the outer layer of a tissue. Due to their microscale size, MNs can seamlessly penetrate the skin and deliver a range of therapeutic molecules, including small molecules, biomacromolecules and even nanoparticles. The penetration of MNs can be arranged to penetrate only the epidermis without damaging neurons in the dermis,
hence it is a painless and minimally invasive method. It is also easy to selfadminister and exhibits a high drug bioavailability.
MNs are classified as solid, coated, porous, dissolving, hollow and hydrogel and are usually made of metal, silicon, polymer, glass or ceramic. Among these materials, polymeric (hydrogel) microneedles have attracted more attention due to their unique properties such as biocompatibility, biodegradability, high drug loading rate and cost-effectiveness. Drugs can be easily encapsulated in the polymeric matrix or conjugated on the surface of the substrate materials forming the microneedles and, after penetration into the skin, are released spontaneously through polymer degradation, dissolution or swelling under physiological conditions.
Manufacturing strategies for MNs include micro-milling, wet and dry etching, photolithography, molding-based techniques, injection molding, laser patterning and drawing lithography. Micro-molding techniques (laser drilling, injection and casting) are widely used in the production of hydrogel microneedles, especially for transdermal drug delivery applications. However, these techniques can produce microneedles with limited geometries where only one of the microneedle parameters such as height, spacing and shape is varied. In addition, these techniques require manual steps and labor-intensive work, with problems related to complexity and high cost.
In the document titled Biodegradable gelatin methacryloyl microneedles for transdermal drug delivery, the development of GelMA microneedle patch for transdermal drug delivery is described. The microneedle patch was produced by micro-molding method.
The United States patent document US20210386985A1, which is in the known state of the art, mentions a microneedle patch that can be used to deliver therapeutic agents to living tissue (e.g., skin). Transmission rates can be adjusted according to the degree of cross-linking of the polymer (gelatin methacryloyl (GelMA)) patch.
The United States patent document US2022118416A1, which is in the known state of the art, discloses new composite materials and methods of preparation thereof comprising cross-linked biodegradable polymers and non-cross-linked biodegradable polymers.
In the document titled Silk fibroin microneedles fabricated by digital light processing 3D printing, the single-stage 3D fabrication of protein-based microneedles using the digital light processing (DLP) technique is described.
When the works in the art were examined, the inventive subject matter required the realization of a fast, easy, accessible and low-cost microneedle patch production method capable of producing hydrogel microneedles in the desired size and geometry for transdermal drug delivery applications.
Objects of the Invention
The object of the present invention is to provide a method of manufacturing microneedle patches for transdermal drug delivery using vat photopolymerization 3D printing techniques (stereolithography - SLA, Digital Light Processing - DLP, liquid crystal display - LCD, etc.), comprising Gelatin Methacrylate (GelMA) or a mixture of Gelatin Methacrylate (GelMA) + Keratin Methacrylate (KerMA) or a mixture with different methacrylated natural or synthetic polymers.
Another object of the present invention is to provide a fast, easy, accessible and low-cost microneedle patch production method capable of producing hydrogel microneedles of desired size and geometry for transdermal drug delivery applications.
Detailed Description of the Invention
The results of the evaluation of the microneedle production method for achieving the objects of the present invention are shown in the accompanying figures.
These figures;
Figure la is a graph of the temperature ramp test in the rheological analysis of the GelMA hydrogel used in the inventive method.
Figure lb is a graph of the frequency sweep test for the rheological analysis of the GelMA hydrogel used in the inventive method.
Figure 1c is the graph of the rotational shear rate-viscosity measurement in the rheological analysis of the GelMA hydrogel used in the inventive method.
Figure l is a view of Fourier transform infrared (FTIR) spectra of pure gelatin and GelMA hydrogel.
Figure 3 is a scanning electron microscope (SEM) image of microneedles produced by the inventive method.
The invention relates to a method of producing a microneedle patch and comprises the steps;
- Preparation of gelatin methacrylate (GelMA) solution to be used as the base material,
Adding certain proportions of keratin methacrylate (KerMA) hydrogel (or other methacrylated natural or synthetic polymers) to the resulting GelMA solution
Adding antibiotics or other therapeutic biomolecules (plant extracts, proteins, peptides nanoparticles, etc.) to the prepared gelatin methacrylate (GelMA) solution or GelMA+KerMA mixture (or its mixture with different methacrylated natural or synthetic polymers) for antibacterial properties, Then adding photoinitiator (LAP) to the prepared solution to ensure crosslinkability in a vat photopolymerization 3D printing (SLA, DLP, LCD, etc.) device,
- Design of computer-aided design (CAD) model of microneedles for transdermal applications in prescribed dimensions,
- Production of microneedle patch using vat photopolymerization techniques on the material obtained with the designed model.
In the inventive method, the main biomaterial for the microneedle patch to be produced is GelMA. GelMA is synthesized at a concentration suitable for 3D printing. GelMA is a biocompatible, biodegradable and low-cost material. The presence of methacryloyl side groups allows the GelMA molecule to undergo rapid polymerization in the presence of UV light and a photoinitiator, resulting in covalent crosslinking through the formation of a methacryloyl backbone. This makes it a suitable material for printing in vat photopolymerization techniques.
First, the GelMA solution used as the main material for the microneedle patch is prepared at the appropriate concentration.
Antibiotics (gentamicin, amoxicillin, vancomycin, etc.) or different therapeutic biomolecules are then added to the solution for antibacterial properties. The antibiotic or therapeutics to be used can be changed according to the disease being treated. Gentamicin was chosen as the antibiotic to be used in the experiments. Then photoinitiator (LAP) is added to the prepared solution to ensure crosslinkability in vat photopolymerization 3D printing. It can be combined with different hydrogels to increase the mechanical stability of the microneedle. KerMA is a biocompatible material, has high mechanical strength due to the presence of disulfide bond and does not dissolve easily.
For transdermal applications, a CAD model of the microneedles in the prescribed dimensions is designed and transferred to the 3D printer software.
Ultimately, the microneedle patch is produced using vat photopolymerization techniques (SLA, DLP, LCD, etc.) with the specified material (and materials/drugs to be added). Vat photopolymerization uses a vat of liquid photopolymer resin, out
of which the model is constructed layer by layer. An ultraviolet (UV) or laser light is used to cure resin, whilst a platform moves the object being made downwards after each new layer is cured according to the CAD model. GelMA hydrogel microneedles can be printed in the desired geometry, with high resolution, in a short time and at low cost. The concentration for microneedles, the amount of photoinitiator and the parameters of the 3D printer (such as layer thickness, curing time) can be optimized.
Details of the inventive microneedle production method are described below.
Synthesizing Gelatin Methacrylate (GelMA)
Gelatin (type- A) was stirred in 0.1 M carbonate-bicarbonate buffer solution with a concentration of 10% (w/v), adjusted to pH 9 and stirred at 60° C with a magnetic stirrer until a homogeneous solution was obtained. Add MAA into the solution at the rate of 0.1 mL of methacrylic anhydride (MAA) per gram of gelatin, adjust the pH to 9 and react at 60 °C for 1 hour. The pH of the solution taken at the end of the reaction is adjusted to 7.4. The solution is passed through ordinary filter paper. Then it is transferred to a dialysis membrane and dialyzed against pure water at 40° C for 3 days. The dialysis water is refreshed every day. The solution is taken into the lyophilization device and lyophilized until complete drying. GelMA in solid form is stored in the dark at 4° C.
Synthesizing Keratin Methacrylate (KerMA)
Keratin concentration of 2% (w/v) in 0.25 M carbonate-bicarbonate buffer solution adjusted to pH 9 and stirred at 50 °C with a magnetic stirrer until a homogeneous solution is obtained. 2% methacrylic anhydride (MAA) is added to the solution at a rate of 0.5 mL/min, adjusted to pH 9 and allowed to react at 50 °C for 3 hours. At the end of the reaction, the pH of the solution is adjusted to 7.4. It is then transferred to a dialysis membrane and dialyzed against pure water at 40° C for 1 week. Dialysis water is refreshed every day. The solution is taken into the lyophilization device
and lyophilized until complete drying. KerMA in solid form is stored in the dark at 4° C.
Once the hydrogels are synthesized, the microneedles are designed in SolidWorks, attached to a solid 10mm x 10mm x 1 mm substrate with a 6x6 array. The microneedle model is saved in ".stl" format and then the model is converted by the "Chitubox" program into a G-Code that a vat photopolymerization device, i.e., Phrozen Shuffle DLP Printer with a layer thickness of up to 10 microns can understand. In the "Chitubox" program, the layer thickness for microneedles was set to 20 microns and the UV exposure time to 50 s.
The synthesized GelMA was weighed in appropriate amounts and dissolved in phosphate buffered saline (PBS) (pH 7.4) solution at a concentration of 10% (w/v) at 40°C. Then, 0.5% (w/v) lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) was added to the solution as photoinitiator and the mixture was stirred at 40°C for 15 minutes and then syringed and transferred to 3D printer. The printing process was performed with pre-optimized parameters for the device.
Test information regarding the inventive method is described below.
Rheological characterization
To determine the viscoelastic properties of 10% (w/v) GelMA hydrogel, shear modulus and viscosity were evaluated by rheological testing. The hydrogel showed a temperature dependent gelation behavior (Figure la).
The intersection of the storage modulus (G1) and loss modulus (G") curves is the gelation temperature of the hydrogel. Below about 22 °C, the GelMA hydrogel exhibited solid properties (G1 > G"). When the temperature was increased, a sol-gel transition occurred around 22 °C (G1 = G") and at higher temperatures the hydrogel showed liquid-like behavior (G" > G"). Oscillation frequency sweep of GelMA hydrogel tested in the range of 0.1 rad/s to 100 rad/s angular frequency showed an increase in both G' and G" with increasing frequency (Figure lb).
In Figure 1c, the viscosity decreased with increasing shear rate, supporting the shear thinning property of GelMA hydrogel.
FTIR analysis
The FTIR spectra of pure gelatin and GelMA hydrogel are shown in Figure 2. The shifts and changes detected in the GelMA (b) peaks compared to pure gelatin (a) indicate that the lysine groups of gelatin are successfully substituted by methacrylate groups.
Morphological characterization (SEM)
SEM images of 10% (w/v) GelMA microneedles are shown in Figure 3. Microneedles formed as a result of 50 s curing of each layer by vat photopolymerization 3D printing technique were well printed and exhibited a uniform structure. The microneedle height is approximately 670 pm and is suitable for transdermal applications. Microneedle sharpness is determined by tip radius and is approximately 32 pm. Tip radii of 20-40 pm are sharp enough to penetrate the skin. The resulting tip radii are therefore among the sharpest needles printed using a low-cost printing system.
The inventive method enables the production of hydrogel microneedles of the desired size and shape using vat photopolymerization 3D printing techniques, which is a high-resolution, fast and low-cost method different from the methods used so far for transdermal drug delivery applications. Thus, computationally designed hydrogel microneedles can be produced directly in a single step without molds, with minimal time and without the geometric limitations imposed by conventional producing methods.
The hydrogel microneedles produced have a high mechanical strength that allows penetration through the skin when dry and swell when inserted into the skin due to the presence of interstitial fluid. This leads to the formation of channels between the capillary circulation and the medicated microneedle patch. During swelling they
act as a rate-controlling membrane. They have a higher drug loading capacity and an adjustable drug release rate. These factors are often directly linked to the polymer cross-linking rate, which is not easily controlled in conventional microneedle forms. They are flexible in size and shape. They are also easily sterilized and removed from the skin intact.
It is also unique in that it is the first polymeric microneedle in which two different photo-crosslinkable hydrogels have been combined for the first time using vat photopolymerization 3D printing technique for transdermal drug delivery applications. Microneedle-mediated transdermal drug release requires that the material has sufficient mechanical strength to penetrate the skin barrier, is biocompatible and does not cause immune reactions after application, the material does not dissolve or biodegrade, and the release profile of the drug is slow and uniform to ensure a sustained release over a long period of time. Therefore, the use of combined hydrogels in production will improve microneedle properties (e.g. mechanical properties) and increase the efficiency of transdermal drug delivery.
Another advantage of using the vat photopolymerization 3D printing technique is the high resolution and fast printability of the microneedles, allowing for personalized design. In addition, microneedle patch production with this technique provides cost savings in terms of dose savings, production and logistics. The fact that the applicability of the microneedle patches produced is also effortless will provide convenience for both the patient and the doctor.
Claims
1. The invention relates to a method of producing a microneedle patch characterized in that it comprises the steps;
- Preparation of gelatin methacrylate (GelMA) solution to be used as the base material,
Adding keratin methacrylate (KerMA) hydrogel in certain proportions to the obtained GelMA solution
Adding antibiotics to the prepared gelatin methacrylate (GelMA) solution or GelMA+KerMA mixture for antibacterial properties,
Then adding photoinitiator (LAP) to the prepared solution to ensure crosslinkability in a vat photopolymerization 3D printing device,
- Design of computer-aided design (CAD) model of microneedles for transdermal applications in prescribed dimensions,
- Production of the microneedle patch using vat photopolymerization 3D printing technique on the material obtained with the designed model.
2. The invention relates to a method of producing a microneedle patch according to claim 1, characterized in that drugs such as gentamicin, amoxicillin, vancomycin are used as antibiotics.
3. The invention relates to a method of producing a microneedle patch according to claim 1, characterized in that lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) is used as photoinitiator.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2022/010005 | 2022-06-16 | ||
| TR2022/010005A TR2022010005A2 (en) | 2022-06-16 | 2022-06-16 | MICRONEEDLE PRODUCTION WITH DYNAMIC LIGHT PROCESSING FOR TRANSDERMAL DRUG RELEASE |
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| WO2023244207A1 true WO2023244207A1 (en) | 2023-12-21 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3492074A1 (en) * | 2016-08-01 | 2019-06-05 | Pusan National University Industry - University Cooperation Foundation | Microneedle patch and manufacturing method therefor |
| WO2019176146A1 (en) * | 2018-03-16 | 2019-09-19 | 国立大学法人東京大学 | Microneedle patch and method for manufacturing microneedle patch |
| KR20220013765A (en) * | 2020-07-27 | 2022-02-04 | 한국과학기술연구원 | Interdigitated electrode type microneedle patches |
| US20220118416A1 (en) * | 2020-10-18 | 2022-04-21 | Pathak Holdings Llc | Crosslinked multilayered material compositions, methods for their preparation and applications thereof |
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2022
- 2022-06-16 TR TR2022/010005A patent/TR2022010005A2/en unknown
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3492074A1 (en) * | 2016-08-01 | 2019-06-05 | Pusan National University Industry - University Cooperation Foundation | Microneedle patch and manufacturing method therefor |
| WO2019176146A1 (en) * | 2018-03-16 | 2019-09-19 | 国立大学法人東京大学 | Microneedle patch and method for manufacturing microneedle patch |
| KR20220013765A (en) * | 2020-07-27 | 2022-02-04 | 한국과학기술연구원 | Interdigitated electrode type microneedle patches |
| US20220118416A1 (en) * | 2020-10-18 | 2022-04-21 | Pathak Holdings Llc | Crosslinked multilayered material compositions, methods for their preparation and applications thereof |
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