Description:TECHNICAL FIELD
[0001] The present disclosure relates to drug delivery systems, in particular, the present disclosure relates to a microneedle patch and a method for preparing the microneedle patch for emergency drug delivery.
BACKGROUND
[0002] In the field of drug delivery systems, intravenous drug administration is used because it allows medicines to enter the bloodstream directly. The intravenous drug administration enables the drug to circulate rapidly throughout the body and reach the target site. As a result, the intravenous drug administration is useful in emergencies where immediate therapeutic effect is required, such as treating allergic reactions, seizures, or severe pain. However, the intravenous drug administration requires trained personnel, sterile environments, and clinical infrastructure that make the intravenous drug administration impractical in out-of-hospital or resource-limited settings.
[0003] To address the limitations posed by the intravenous drug administration, microneedle-based drug delivery system has emerged as an alternative. The microneedle-based drug delivery system uses microneedles for delivering drugs into the body. The microneedles are micron-scale projections that can painlessly penetrate the outermost layer of the skin. The microneedles are engineered to dissolve after penetration, releasing the drug without leaving behind any sharp waste. The microneedle-based drug delivery system provides reduced patient discomfort, self-administration capability, improved compliance, avoidance of first-pass metabolism, and readily available to use and without any need for particular skills for administration.
[0004] The existing microneedle-based drug delivery system has a dissolution time exceeding one to two minutes. The existing microneedles lack the mechanical integrity required for complete and efficient tissue penetration, leading to breakage or incomplete drug delivery. The tissue includes skin or mucosal membrane. To improve the structural stability of the microneedles, chemical crosslinkers such as glutaraldehyde and formaldehyde-based crosslinkers are used. Such chemical crosslinkers often introduce toxicity and regulatory concerns and require extensive safety testing and regulatory approval. Furthermore, the existing microneedle-based drug delivery system fails to achieve the balance between rapid disintegration, sufficient mechanical strength, and high essential for emergency drug delivery applications. Thus, there exists a technical problem of how to develop a drug delivery system that combines rapid drug release, sufficient mechanical strength, and patient-friendly administration.
[0005] Therefore, in light of the foregoing discussion, there exists a need to overcome the aforementioned drawbacks.
SUMMARY
[0006] The present disclosure provides a microneedle patch and a method for preparing a microneedle patch for emergency drug delivery. The present disclosure addresses the technical problem of how to develop a drug delivery system that combines rapid drug release, sufficient mechanical strength, and patient-friendly administration. The present disclosure aims to provide a solution that overcomes at least partially the problems encountered in the prior art and provides an improved microneedle patch and an improved method for preparing a microneedle patch for emergency drug delivery featuring a physically cross-linked network for enabling enhanced dissolution of each microneedle of the microneedle patch.
[0007] One or more objectives of the present disclosure are achieved by the solutions provided in the enclosed independent claims. Advantageous implementations of the present disclosure are further defined in the dependent claims.
[0008] In one aspect, the present disclosure provides a microneedle patch for emergency drug delivery, comprising:
a plurality of microneedles, each microneedle of the plurality of microneedles comprising a physically cross-linked network formed by hydrogen bonding between polyacrylic acid and a carbohydrate,
wherein the polyacrylic acid in each microneedle is neutralized by a neutralizing agent to convert at least a portion of polyacrylic acid to carboxylate anions to generate electrostatic repulsion forces within the physically cross-linked network; and
wherein upon contact with aqueous medium, water molecules of the aqueous medium displace the carbohydrate from bonding sites on the polyacrylic acid and the electrostatic repulsion forces accelerate disintegration of the physically cross-linked network, which causes dissolution of each microneedle within a predetermined time period.
[0009] The present disclosure provides the microneedle patch comprising the plurality of microneedles. Each microneedle of the plurality of microneedles comprises a physically cross-linked network formed through hydrogen bonding between polyacrylic acid and the carbohydrate. The physically cross-linked network provides structural integrity to the plurality of microneedles to enable insertion into biological surfaces such as skin or mucosal tissue without mechanical failure. The structure of the physically cross-linked network eliminates the need for chemical crosslinkers, enhancing biocompatibility and simplifying the formulation of the microneedle patch. The polyacrylic acid in each microneedle is partially neutralized by a neutralizing agent, such that a portion of the carboxylic acid groups is converted to carboxylate anions. The conversion of carboxylic acid groups to carboxylate anions increases the hydrophilicity of the physically cross-linked network and establishes internal electrostatic repulsion forces within the physically cross-linked network. The electrostatic repulsion forces remain latent in the dry state but act as destabilizing forces when activated by moisture, facilitating rapid microneedle breakdown. Upon exposure to an aqueous medium, water molecules from the aqueous medium interact with the hydrogen bonding sites of the polyacrylic acid and displace the carbohydrate. The displacement of the carbohydrate weakens the physically cross-linked network, initiating the disassembly of the network of the microneedle. The combination of hydrogen bond disruption due to water absorption and internal electrostatic repulsion among carboxylate groups results in rapid disintegration of the physically cross-linked network. As a result, each microneedle dissolves within the predetermined time period, enabling timely and efficient release of the drug content loaded within the microneedle patch.
[0010] In another aspect, the present disclosure provides a method for preparing microneedle patch for emergency drug delivery, the method comprising:
mixing a polyacrylic acid solution with a carbohydrate solution to form a mixture with a physically cross-linked network;
adding a neutralizing agent to the mixture to form a pH-neutralized mixture, wherein the neutralizing agent converts polyacrylic acid from the polyacrylic acid solution to carboxylate anions and the carboxylate anions generate electrostatic repulsion forces within the pH-neutralized mixture;
applying a pressure reduction to the pH-neutralised mixture to form a microneedle of a plurality of microneedles; and
forming a microneedle patch by integrating the plurality of microneedles with a patch base configured to retain the microneedles and enable placement on a target site,
wherein each microneedle configured to dissolve upon contact with an aqueous medium through displacement of carbohydrate from the carbohydrate solution from bonding sites on the polyacrylic acid by water molecules and the electrostatic repulsion forces accelerate disintegration of the physically cross-linked network.
[0011] The method for preparing microneedle patch for emergency drug delivery achieves all the advantages and technical effects of the microneedle patch for emergency drug delivery formed in the present disclosure.
[0012] Additional aspects of the present disclosure would be made apparent from the drawings and the detailed description of the illustrative implementations construed in conjunction with the appended claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the present disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those in the art will understand that the drawings are not to scale. Wherever possible, like elements have been indicated by identical numbers.
[0014] Embodiments of the present disclosure will now be described, by way of example only, with reference to the following diagrams wherein:
FIG.1 is a flowchart illustrating a method for preparing a microneedle patch for emergency drug delivery, in accordance with an embodiment of the present disclosure;
FIG. 2A is a graphical representation illustrating swelling behaviour of polymer film specimens over time, in accordance with an embodiment of the present disclosure;
FIG. 2B is a graphical representation illustrating swelling behaviour of another polymer film specimen over time, in accordance with an embodiment of the present disclosure;
FIG. 2C is a graphical representation illustrating swelling behaviour of another polymer film specimens over time, in accordance with an embodiment of the present disclosure;
FIG. 2D is a graphical representation illustrating swelling behaviour of yet another polymer film specimens over time, in accordance with an embodiment of the present disclosure;
FIG. 3 is a graphical representation illustrating cumulative drug release profiles, in accordance with an embodiment of the present disclosure;
FIG. 4 is a graphical representation illustrating Fourier transform infrared (FTIR) spectroscopy analysis of different components of the formulation of the microneedle patch, in accordance with an embodiment of the present disclosure;
FIG. 5 is a graphical representation illustrating cell viability of various microneedle formulation components at different concentrations, in accordance with an embodiment of the present disclosure;
FIG. 6 is a graphical representation illustrating a force-distance relationship during microneedle insertion, in accordance with an embodiment of the present disclosure;
FIG. 7 is a graphical representation illustrating insertion depth with various formulations, in accordance with an embodiment of the present disclosure; and
FIG. 8 is a graphical representation illustrating insertion efficiency of microneedle formulations at various penetration depths, in accordance with an embodiment of the present disclosure.
[0015] In the accompanying drawings, an underlined number is employed to represent an item over which the underlined number is positioned or an item to which the underlined number is adjacent. A non-underlined number relates to an item identified by a line linking the non-underlined number to the item. When a number is non-underlined and accompanied by an associated arrow, the non-underlined number is used to identify a general item at which the arrow is pointing.
DETAILED DESCRIPTION OF EMBODIMENTS
[0016] The following detailed description illustrates embodiments of the present disclosure and ways in which they can be implemented. Although some modes of carrying out the present disclosure have been disclosed, those skilled in the art would recognise that other embodiments for carrying out or practicing the present disclosure are also possible.
[0017] FIG.1 is a flowchart illustrating a method for preparing a microneedle patch for emergency drug delivery, in accordance with an embodiment of the present disclosure. With reference to FIG. 1, a method 100 includes steps 102 to 108.
[0018] At step 102, the method 100 includes mixing a polyacrylic acid solution with a carbohydrate solution to form a mixture with a physically cross-linked network. The polyacrylic acid solution comprises polyacrylic acid having pendant carboxyl groups (-COOH) dissolved in an aqueous medium. In an implementation, the polyacrylic acid has a molecular weight ranging from 90 kilodalton (kDa) to 1250 kDa. In another implementation, the polyacrylic acid solution has a concentration of 2% to 50% weight by weight. The concentration of the polyacrylic acid solution varies based on the molecular weight of the polyacrylic acid used in the solution. The carbohydrate solution comprises a carbohydrate having multiple hydroxyl groups (-OH) dissolved in the aqueous medium. In an implementation, the carbohydrate is selected from the group consisting of dextrose, trehalose, sucrose, glucose, maltose, fructose, galactose, and combinations thereof. In another implementation, the carbohydrate solution has a concentration ranging from 10% to 50% weight by weight. The polyacrylic acid solution is mixed with the carbohydrate solution under controlled conditions to promote the formation of the mixture comprising a physically cross-linked network. The controlled conditions include maintaining temperature between 25 degrees Celsius and 35 degrees Celsius and preventing exposure to excessive humidity or contamination during mixing to ensure consistency and reproducibility of the hydrogen bonding interaction. In an implementation, the polyacrylic acid solution is added dropwise to the carbohydrate solution while maintaining continuous stirring to ensure proper molecular interaction and to prevent agglomeration. In another implementation, the mixing is performed using magnetic stirring at 300 RPM for a duration of 30 minutes to 2 hours to achieve complete homogenization and hydrogen bond formation between the polyacrylic acid and carbohydrate molecules in the carbohydrate solution. In yet another embodiment, the polyacrylic acid solution is mixed with the carbohydrate solution using overhead mechanical stirring, vortex mixing, or ultrasonic agitation, under mild heating conditions. For example, the temperature ranges between 30 degrees Celsius to 40 degrees Celsius. The temperature depends on the viscosity and scale of the mixture to ensure uniform dispersion and interaction between the polyacrylic acid solution and the carbohydrate solution. The physically cross-linked network is formed through intermolecular hydrogen bonding between the carboxyl groups of the polyacrylic acid and the hydroxyl groups of the carbohydrate. The physically cross-linked network creates a three-dimensional structure.
[0019] In an implementation, the carbohydrate acts as a plasticizer that reduces intermolecular forces between polyacrylic acid chains and as a pore-forming agent that creates hydrophilic channels within the physically cross-linked network.
[0020] The carbohydrate acts as the plasticizer by positioning itself between adjacent polymer chains of the polyacrylic acid. The spatial interference between the polymer chains reduces intermolecular Van der Waals forces. The reduction in Van der Waals forces increases the mobility of the polymer chains. Also, the carbohydrate serves as the pore-forming agent. Upon contact with water, the hydrophilic nature of the carbohydrate causes it to dissolve preferentially, resulting in the formation of interconnected water channels within the microneedle matrix. In an implementation, the interconnected water channels have an average diameter ranging from 50 to 200 nanometers and accelerate water penetration. The working of the carbohydrate as the plasticizer and the pore forming agent enhances the flexibility of the polymer chains. In addition, the internal aqueous channel formation in the polymer chains improves that contributes directly to the fast and complete disintegration of the microneedle structure upon application to a biological surface.
[0021] At step 104, the method 100 includes adding a neutralizing agent to the mixture to form a pH-neutralized mixture. The neutralizing agent refers to a substance capable of partially or fully neutralizing acidic functional groups. The neutralizing agent comprises a basic compound capable of neutralizing the acidic carboxyl groups of the polyacrylic acid. In an implementation, the neutralizing agent is sodium hydroxide (NaOH). The sodium hydroxide has a capability of controlled neutralization and has biocompatibility with pharmaceutical formulations. In other words, the sodium hydroxide adjusts the pH of the mixture gradually and without overshooting a predefined range. In an implementation, the predefined range may be between 6.5 and 7.5. In another implementation, alternative neutralizing agents such as potassium hydroxide (KOH), sodium carbonate may be employed. Other examples of neutralizing agents are but not limited to potassium hydroxide, sodium bicarbonate
[0022] The neutralizing agent is added to the mixture under controlled conditions to achieve optimal pH adjustment while preserving the integrity of the physically cross-linked network. In an implementation, the neutralizing agent is prepared as a 5 molar (5M) solution in aqueous medium to ensure suitable neutralization. In another implementation, the neutralizing agent is added dropwise to the mixture while maintaining continuous stirring at 300 RPM to ensure uniform distribution. The continuous stirring prevents over-neutralization that could disrupt the hydrogen bonding in the physically cross-linked network and also prevent precipitation of the polymeric chain. The neutralizing agent is added to the mixture at ambient temperature between 20 degrees Celsius to 30 degrees Celsius to maintain stability of the hydrogen bonding interactions. In yet another implementation, the neutralizing agent is added using precision pipettes to achieve reproducible neutralization across different batches of the mixture.
[0023] The neutralizing agent converts polyacrylic acid from the polyacrylic acid solution to carboxylate anions, and the carboxylate anions generate electrostatic repulsion forces within the pH-neutralized mixture. The carboxylate anions (-COO⁻Na⁺) are formed through the chemical conversion of carboxyl groups (-COOH) upon neutralization with the neutralizing agent. The chemical conversion creates negatively charged sites along the polyacrylic acid chains that generate electrostatic repulsion forces within the pH-neutralized mixture.
[0024] The method 100 further includes incorporating additional components into the pH-neutralized mixture to enhance fabrication and performance characteristics. In an implementation, a mold release agent such as polysorbate is incorporated at a range from 0.03% to 0.5% weight by weight into the pH-neutralized mixture to facilitate easy removal of the plurality of microneedles from the molds. The polysorbate acts as a surfactant that reduces surface tension between the pH-neutralized mixture and a surface of the mold. The polysorbate maintains the sharp tips and precise geometry of the plurality of microneedles for effective skin penetration. In another implementation, active pharmaceutical ingredients are incorporated into the pH-neutralized mixture while maintaining the structural integrity of the physically cross-linked network. In another implementation, a non-ionic surfactant such as Tween 20 or Tween 80 is incorporated into the pH-neutralized mixture as a multifunctional excipient. The Tween molecules include a hydrophilic polyoxyethylene head group and a hydrophobic fatty acid tail group. The amphiphilic structure of the tween molecule allows to localize at aqueous interfaces and form micelles in the pH-neutralized mixture. The micelles reduce interfacial tension and further interact through hydrogen bonding and Van der Waals forces with the polyacrylic acid chains and the carbohydrate chains, thereby modulating the internal hydrogen-bonded network. In an implementation, the non-ionic surfactant is incorporated at a concentration ranging between 0.1% and 0.5% weight by weight. At this concentration, the non-ionic surfactant enhances homogeneity of the pH-neutralized mixture and reduces internal stress during drying without disrupting the physically cross-linked network. In an implementation, the micelles formed by the Tween molecules encapsulate amphiphilic or poorly water-soluble active pharmaceutical ingredients in the pH-neutralized mixture. The encapsulation prevents aggregation or crystallization of the active pharmaceutical ingredients during drying and ensures uniform distribution throughout the microneedle matrix. Therefore, the incorporation of the non-ionic surfactant improves hydration, modulates mechanical integrity of the plurality of microneedles, and enhances drug formulation performance in the microneedle patch.
[0025] The method 100 includes casting the pH-neutralized mixture into molds. The molds comprise a plurality of cavities to shape the mixture into thin protrusions that define the geometry of each microneedle, including height, base width, and taper angle of each microneedle. In an implementation, the molds are fabricated from polydimethylsiloxane (PDMS). The PDMS provides flexibility, biocompatibility, and easy drug release properties.
[0026] In an implementation, the pH-neutralized mixture is first dispensed into the plurality of cavities of the mold to initiate filling of the microneedle geometry. After the preliminary filling, a controlled pressure reduction is applied to the mold to remove entrapped air and to drive the pH-neutralized mixture completely into the microneedle cavities.
[0027] The microneedles can have different height and geometry based on the application. For example, a plurality of microneedles on the microneedle patch has a height ranging from 500 micrometers to 700 micrometers, a tip diameter of approximately 50 micrometers, and a base diameter of approximately 300 micrometers to ensure suitable skin penetration while maintaining the mechanical integrity of the microneedle patch. Each microneedle in the patch is fabricated with defined geometric parameters to ensure mechanical stability during insertion and efficient dissolution post-insertion. The height and tip diameter of the plurality of microneedles are selected based on experimental validations that show optimal penetration through the stratum corneum without reaching the dermis, minimizing pain while ensuring adequate drug delivery. The tip sharpness aids in clean entry, and the height provides the volume needed for drug loading. For instance, cone-shaped microneedles formed through mold casting using a vacuum-assisted drying process consistently achieved the specified dimensions with minimal deformation.
[0028] At step 106, the method 100 includes applying a pressure reduction to the pH-neutralized mixture to form microneedle of the plurality of microneedles. The pressure reduction refers to the controlled decrease in atmospheric pressure applied to the filled molds to eliminate air bubbles and ensure complete filling of the plurality of cavities with the pH-neutralized mixture. In an implementation, after applying vacuum pressure up to 760 mmHg, the pressure is reduced to 0 gradually over a period of 1 to 2.5 hours. The pressure reduction is performed by initially applying vacuum pressure up to 760 mmHg using vacuum chambers or vacuum ovens to create a controlled low-pressure environment. The vacuum pressure is then gradually reduced to 0 mmHg over a period ranging from 1 to 2.5 hours. For example, the vacuum pressure may be reduced from 760 mmHg to 380 mmHg over the first hour, then further reduced to 0 mmHg over the remaining 0.5 to 1.5 hours. The gradual pressure reduction prevents sudden deformation or collapse of the microneedle cavities during evacuation and ensures complete filling of all needle cavities with uniform density distribution throughout the physically cross-linked network. In another implementation, the pressure reduction is combined with gentle heating at temperatures between 30 degrees Celsius to 40 degrees Celsius to enhance the flow characteristics of the pH-neutralized mixture and improve cavity filling efficiency.
[0029] The method 100 includes drying the plurality of microneedles to achieve final solidification and structural stability for storage and application. The drying of the plurality of microneedles involves controlled removal of moisture from the plurality of microneedles formed. The plurality of microneedles formed maintains the structural integrity and preserves the hydrogen bonding in the physically cross-linked network. In an implementation, the drying is performed at a temperature of 30 degrees Celsius to 40 degrees Celsius for 20 to 28 hours at 25% to 35% relative humidity to prevent thermal degradation of heat-sensitive components such as therapeutic proteins, peptides, or small-molecule drugs loaded within the plurality of microneedles.
[0030] At step 108, the method 100 includes forming the microneedle patch by integrating the plurality of microneedles with a patch base configured to retain the plurality of microneedles and enable placement on a target site. The patch base provides structural support for the plurality of microneedles and facilitates application to the target site for emergency drug delivery. In an implementation, the patch base is fabricated from biocompatible materials such as medical-grade adhesive backing or flexible polymeric substrates that conform to skin contours. In another implementation, the patch base includes an adhesive layer for secure attachment to skin or other biological surfaces during drug delivery, ensuring consistent contact and effective drug release. In an implementation, the patch comprises an adhesive backing configured to maintain skin contact during the predetermined time period. The microneedle patch includes the adhesive backing layer configured to maintain close contact between the microneedles and the biological surface during the required dissolution period. The adhesive backing is fabricated using medical-grade pressure-sensitive adhesives that are biocompatible and skin-safe. For instance, acrylate-based adhesives with moisture tolerance can be laminated onto the rear surface of the patch base. The adhesive of the adhesive backing ensures consistent contact between the plurality of microneedles and the target site such as skin or mucosal surface. The adhesive of the adhesive backing prevents premature detachment and ensuring uniform microneedle penetration and dissolution. The microneedle patch is useful when applied in high-mobility areas such as forearms or shoulders, where accidental dislodgement is a concern.
[0031] The plurality of microneedles formed are removed from the molds and attached to the patch base. In an implementation, the plurality of microneedles is bonded to the patch base using biocompatible adhesives. In another implementation, the plurality of microneedles is bonded to the patch base through mechanical interlocking mechanisms that maintain the structural integrity of each microneedle during handling and application. In another implementation, the patch base is engineered with alignment features to ensure proper orientation and spacing of each microneedle for drug delivery.
[0032] The microneedle patch is configured for emergency drug delivery applications with rapid dissolution of the microneedles and drug release. Each microneedle of the plurality of microneedles is configured to dissolve upon contact with aqueous medium through displacement of the carbohydrate from bonding sites on the polyacrylic acid by water molecules of the aqueous medium. The electrostatic repulsion forces generated by the carboxylate anions accelerate disintegration of the physically cross-linked network, enabling complete dissolution of each microneedle within a predetermined time period. In an implementation, the predetermined time period is between 20 to 40 seconds. The dissolution occurs when water molecules from skin interstitial fluid or applied aqueous medium displace carbohydrate molecules from hydrogen bonding sites on the chains of the polyacrylic acid. For example, complete dissolution may occur in 25 seconds, 30 seconds, or 35 seconds depending on the carbohydrate concentration and pH neutralization level. The complete dissolution enables immediate drug release for emergency medical applications while ensuring complete absorption of the microneedle without leaving residual polymer fragments in the skin. In a first example, a pH-neutralized mixture was prepared comprising 35% weight by weight polyacrylic acid (250 kDa), 25% weight by weight dextrose, neutralized with 5M NaOH to pH 7.0. The plurality of microneedles formed from such pH-neutralized mixture has a complete dissolution in 28 ± 3 seconds when contacted with phosphate buffered saline at 37 degrees Celsius. The drug release was 95% complete within 30 seconds.
[0033] In a second example, the polymer, without any excipient as in the first example, requires 145 ± 12 seconds for complete dissolution. The dissolution rate of the microneedles indicates the vital role of electrostatic repulsion forces.
[0034] The steps 102 to 108 are only illustrative, and other alternatives can also be provided where one or more steps are added, one or more steps are removed, or one or more steps are provided in a different sequence without departing from the scope of the claims herein.
[0035] The synthesis of the microneedle patch for emergency drug delivery includes the formation of the physically cross-linked network with suitable dissolution characteristics. The synthesis of the microneedle patch begins with the preparation of the polyacrylic acid solution. The polyacrylic acid solution is prepared by dissolving polyacrylic acid in a pharmaceutical-grade aqueous medium such as deionized water at a concentration of 2% to 50% weight by weight. In an implementation, the polyacrylic acid is dissolved using gentle heating at 40 degrees Celsius to 50 degrees Celsius combined with magnetic stirring at 200 RPM to 400 RPM for 2 hours to 4 hours to ensure complete dissolution and prevent degradation of the polymer chains. The dissolution process is monitored to achieve a homogeneous, clear solution free from undissolved particles or aggregates that could compromise the quality of the microneedles to be formed.
[0036] Further, the carbohydrate solution is prepared by dissolving the carbohydrate in the aqueous medium under controlled stirring conditions. In an implementation, the dextrose is dissolved in deionized water at a concentration of 10% to 50% weight by weight using magnetic stirring at 300 RPM for 30 minutes to ensure complete dissolution and molecular dispersion. In another implementation, alternative carbohydrates such as trehalose, sucrose, glucose, maltose, fructose, or galactose may be used individually or in combination. In another implementation, different gums such as xanthan gum and tragacanth, gum acacia may be used individually or in combination. The preparation of the carbohydrate solution further includes filtration through sterile filters to remove any particulate matter and ensure pharmaceutical-grade purity suitable for emergency drug delivery applications.
[0037] In an implementation, the carbohydrate is present at 10-50% weight by weight. The carbohydrate reduces intermolecular forces between the polymer chains of the polyacrylic acid by inserting between the polymer chains and disrupting polymer-polymer interactions. For example, at 20% weight by weight, the dextrose molecules position themselves between polyacrylic acid chains, increasing chain mobility and flexibility. The carbohydrate further creates hydrophilic channels within the physically cross-linked network by forming water-soluble domains that dissolve preferentially upon contact with the aqueous medium. The hydrophilic channels facilitate rapid water penetration throughout the microneedle structure, accelerating the dissolution process and enabling immediate drug release upon skin or mucosal surface contact.
[0038] The synthesis of the microneedle patch continues with the controlled combination of the polyacrylic acid solution and carbohydrate solution to initiate hydrogen bonding interactions. The polyacrylic acid solution is added dropwise to the carbohydrate solution while maintaining continuous stirring at 300 RPM under a temperature between 25 degrees Celsius to 35 degrees Celsius. In an implementation, the dropwise addition is performed at a controlled rate of 1 milliliter per minute to 5 milliliters per minute, depending on the batch size, to ensure gradual integration and optimal hydrogen bond formation between the carboxyl groups of the polyacrylic acid and the hydroxyl groups of the carbohydrate. The mixing process is continued for 30 minutes to 2 hours to achieve complete homogenization and formation of the physically cross-linked network throughout the mixture.
[0039] The neutralizing agent solution is prepared and added dropwise to the mixture while monitoring the pH continuously. In an implementation, the pH is adjusted to a target range of 6.5 to 7.5 through controlled addition of the neutralizing agent at a rate of 0.1 milliliters per minute to 0.5 milliliters per minute while maintaining constant stirring to ensure uniform distribution and prevent localized over-neutralization. The neutralization process converts carboxyl groups (-COOH) of the polyacrylic acid to the carboxylate anions (-COO⁻Na⁺). The conversion of the carboxyl groups (-COOH) to the carboxylate anions (-COO⁻Na⁺) creates the electrostatic repulsion forces within the pH-neutralized mixture while preserving the hydrogen bonding interactions with the carbohydrate.
[0040] In an implementation, the pH neutralization is monitored using calibrated pH meters with real-time data logging to maintain precise control over the conversion of the carboxyl groups (-COOH) to the carboxylate anions (-COO⁻Na⁺).
[0041] The microneedle patch formed is used for drug delivery. A method of using the microneedle patch involves applying the patch to a biological surface for emergency drug delivery. In an implementation, a person experiencing a severe allergic reaction requires immediate epinephrine injection. The microneedle patch containing epinephrine is removed from its packaging. The patch is positioned on the arm or thigh area of the person. Firm pressure is applied to the patch for 5 to 10 seconds. The microneedles penetrate through the outer skin layer called the stratum corneum. The tips of the microneedle patch are configured such that the microneedles do not reach the deeper skin layers and therefore do not damage regions where blood vessels and nerve endings are present.
[0042] In an implementation, the microneedles contact skin moisture and interstitial fluid immediately after penetration. Water molecules from the skin start interacting with the microneedles of the microneedle patch. The water molecules interact with dextrose molecules for bonding sites on the polyacrylic acid chains. The interaction of the water molecules with the dextrose molecules breaks the hydrogen bonds holding the structure of the microneedle patch together. The carboxylate anions created during pH neutralization generate repulsion forces. The repulsion forces push the polymer chains apart and speed up the breakdown process.
[0043] In an implementation, the dissolution of the microneedles occurs through a dual mechanism comprising hydrogen bond disruption by water molecules and electrostatic repulsion forces generated by the carboxylate anions. The dissolution initiates when the plurality of microneedles of the microneedle patch comes into contact with the aqueous medium such as interstitial fluid. The water molecules of the aqueous medium begin to disrupt hydrogen bonds formed between the polyacrylic acid and the carbohydrate, as a result, loosening the physically cross-linked network. Concurrently, the carboxylic acid groups that were converted into carboxylate anions during the pH-neutralization generate internal electrostatic repulsion forces. The repulsion forces increase the spacing between polymer chains, further destabilizing the physically cross-linked network. For example, a microneedle containing 10% polyacrylic acid partially neutralized with sodium hydroxide shows complete disintegration within 20-40 seconds after skin application while, the polyacrylic acid alone can dissolve within 120-150 seconds. The dual mechanism ensures rapid and complete microneedle dissolution, which is suitable for rapid drug delivery in emergency medical scenarios.
[0044] In an implementation, the microneedle structure dissolves completely within 20 to 40 seconds after skin contact. For example, a microneedle containing 25% dextrose dissolves in approximately 30 seconds. The epinephrine drug trapped inside the dissolving polymer is released directly into the skin tissue. The drug enters the bloodstream through small blood vessels in the skin. The person receives the emergency medication without needing a traditional needle injection. The dissolved polymer materials are harmless and naturally processed by the body.
[0045] In an implementation, the patch base can be removed after drug delivery is complete. The microneedles have completely dissolved, leaving only the backing material. No sharp objects remain in the skin. The person experiences immediate relief as the epinephrine takes effect. The entire process from application to drug delivery takes less than one minute.
[0046] FIG. 2A is a graphical representation illustrating swelling behaviour of polymer film specimens over time, in accordance with an embodiment of the present disclosure. FIG. 2A is described in conjunction with elements of FIG. 1. With reference to FIG. 2A, there is shown a graphical representation 200A including a first swelling pattern 202A of a carboxymethyl cellulose (CMC) film at 10% concentration. Further, the graphical representation 200A includes a second swelling pattern 204A of a carboxymethyl cellulose (CMC) film at 15% concentration.
[0047] The polymer film specimens are utilized as preliminary evaluation models to assess dissolution characteristics and water uptake behaviour prior to microneedle fabrication. The polymer film specimens serve as screening tools to optimize polymer concentrations and predict the dissolution kinetics of the formulations of the plurality of microneedles. The polymer film specimens are prepared using the polymer solutions employed in the synthesis of the plurality of microneedles. The swelling behaviour of the polymer film specimens is utilized to evaluate the water absorption capacity and dissolution characteristics of polymer film specimens. The water absorption capacity and dissolution characteristics of polymer film specimens directly correlate to the dissolution kinetics of the formulation of the plurality of microneedles. The swelling percentage indicates the extent of water uptake by the polymer, with higher swelling percentage indicating increased hydrophilicity and faster dissolution rates. The time is measured in seconds on an abscissa axis, while the swelling percentage is expressed on an ordinate axis.
[0048] The first swelling pattern 202A, indicates an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 600 seconds. The first swelling pattern 202A achieves a maximum swelling percentage of approximately 520%. The first swelling pattern 202A, exhibits a broader peak formation in a region 206A, approximately ranging between 400 seconds to 800 seconds. The first swelling pattern 202, exhibits a gradual decline after the region 208A. The gradual decline is approximately ranging between 800 seconds to 1400 seconds. The region 206A indicates the starting of the dissolution of the CMC film at 10% concentration.
[0049] The second swelling pattern 204A exhibits an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 400 seconds, reaching a maximum swelling of approximately 350%. The second swelling pattern 204A includes a peak formation in a region 208A, approximately ranging between 400 to 600 seconds. The second swelling pattern 204A exhibits a gradual decline after the region 208A. The gradual decline is approximately ranging between 600 to 1400 seconds and indicates the beginning of the breakdown of the polymer film specimen and the weakening of the structure of the microneedle. The region 208A indicates the starting of the dissolution of the CMC film at 15% concentration.
[0050] The first swelling pattern 202A and the second swelling pattern 204A indicate that polymer concentration significantly influences the swelling and dissolution characteristics of the polymer film specimens. The second swelling pattern 204A exhibits approximately 50% higher value of maximum swelling compared to the first swelling pattern 202A. The comparison between the swelling percentage of the first swelling pattern 202A and the second swelling pattern 204A indicates that a lower polymer concentration allows greater water absorption. The swelling percentage increases initially and then gradually decreases in the first swelling pattern 202A and the second swelling pattern 204A, confirming that the polymer begins to dissolve after absorbing a maximum amount of water.
[0051] FIG. 2B is a graphical representation illustrating swelling behaviour of another polymer film specimen over time, in accordance with an embodiment of the present disclosure. FIG. 2B is described in conjunction with elements from FIGs. 1 to 2A. With reference to FIG. 2B, there is shown a graphical representation 200B including a first swelling pattern 202B of a polyvinylpyrrolidone K30 (K30) film at 60% concentration. Further, the graphical representation 200B includes a second swelling pattern 204B of a polyvinylpyrrolidone (PVP) film at 65% concentration. The time is measured in seconds on an abscissa axis, while the swelling percentage is expressed on an ordinate axis.
[0052] The first swelling pattern 202B shows an initial increase in swelling percentage, with a peak 206B with value of approximately 20% reached within the first 150-200 seconds. After the peak 206B, the swelling percentage gradually decreases. The decline progresses steadily until around 1200 seconds, where the swelling percentage reaches approximately “−90%”, indicating almost complete dissolution of the K30 film.
[0053] The second swelling pattern 204B indicates an initial increase in swelling percentage, with a peak 208B with value of approximately 25% within 150-200 seconds. Following the peak 208B, the swelling percentage decreases gradually, maintaining higher values than the first swelling pattern 202B over the same time range. At approximately 1200 seconds, the swelling percentage of the second swelling pattern 204B is approximately “−70%”. The swelling percentage of “-70%” indicates partial material loss compared to the more complete dissolution observed in the first swelling pattern 202B.
[0054] A comparison between the first swelling pattern 202B and the second swelling pattern 204B exhibits that the type of polymer and concentration influence the swelling behaviour and the dissolution kinetics. The first swelling pattern 202B representing K30 film at 60% concentration exhibits a steeper decline in swelling, indicating faster dissolution, whereas the second swelling pattern 204B representing PVP film at 65% concentration shows slower reduction, indicating relatively higher structural stability before breakdown. The graphical representation 200B confirm that slight changes in polymer type and concentration alter water uptake, swelling behaviour, and dissolution rate of the film specimens.
[0055] FIG. 2C is a graphical representation illustrating swelling behaviour of another polymer film specimens over time, in accordance with an embodiment of the present disclosure. FIG. 2C is described in conjunction with elements from FIGs. 1 to 2B. With reference to FIG. 2C, there is shown a graphical representation 200C including a first swelling pattern 202C of a sodium alginate (SA) film at 1% concentration. Further, the graphical representation 200C includes a second swelling pattern 204C of a sodium alginate (SA) film at 10% concentration. The time is measured in seconds on an abscissa axis, while the swelling percentage is expressed on an ordinate axis.
[0056] The first swelling pattern 202C indicates an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 200 seconds. The first swelling pattern 202C achieves a maximum swelling percentage of approximately 930%. The first swelling pattern 202C exhibits a peak formation in a region 206C, approximately ranging between 150 seconds to 250 seconds. The first swelling pattern 202C exhibits a gradual decline after the region 206C. The gradual decline is approximately ranging between 250 seconds to 1400 seconds, reaching negative swelling values of approximately -150%.
[0057] The second swelling pattern 204C exhibits an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 150 seconds, reaching a maximum swelling of approximately 600%. The second swelling pattern 204C includes a peak formation in a region 208C, approximately ranging between 100 seconds to 200 seconds. The second swelling pattern 204C exhibits a continuous decline after the region 208C. The continuous decline is approximately ranging between 200 seconds to 1400 seconds, reaching negative swelling values of approximately “-100%”. The continuous decline in swelling values indicates the beginning of the breakdown of the polymer film specimen and the complete dissolution of the structure of the plurality of microneedles.
[0058] The first swelling pattern 202C and the second swelling pattern 204C indicate that sodium alginate-based polymer concentrations exhibit high initial swelling followed by dissolution characteristics. The first swelling pattern 202C exhibits approximately 70% higher maximum swelling compared to the second swelling pattern 204C. The comparison between the swelling percentage of the first swelling pattern 202C and the second swelling pattern 204C indicates that lower polymer concentration allows significantly greater water absorption. The swelling percentage increases dramatically and then gradually decreases to negative values in the first swelling pattern 202C and the second swelling pattern 204C, confirming that the sodium alginate polymers undergo extensive swelling before complete dissolution.
[0059] FIG. 2D is a graphical representation illustrating swelling behaviour of yet another polymer film specimens over time, in accordance with an embodiment of the present disclosure. FIG. 2D is described in conjunction with elements from FIGs. 1 to 2C. With reference to FIG. 2D, there is shown a graphical representation 200D including a first swelling pattern 202D of a polyvinyl alcohol (PVA) 31kDa film at 25% concentration. Further, the graphical representation 200D includes a second swelling pattern 204D of a polyvinyl alcohol (PVA) 9kDa film at 25% concentration. The time is measured in seconds on an abscissa axis, while the swelling percentage is expressed on an ordinate axis.
[0060] The first swelling pattern 202D indicates an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 300 seconds. The first swelling pattern 202D achieves a maximum swelling percentage of approximately 95%. The first swelling pattern 202D exhibits a peak formation in a region 206D approximately ranging between 250 seconds to 350 seconds. The first swelling pattern 202D exhibits a gradual decline after reaching maximum swelling. The gradual decline is approximately ranging between 350 seconds to 1400 seconds, reaching values of approximately 30%.
[0061] The second swelling pattern 204D exhibits an initial rapid increase in swelling percentage, approximately ranging between 0 seconds to 200 seconds, reaching a maximum swelling of approximately 60%. The second swelling pattern 204D includes a peak formation approximately ranging between 150 seconds to 250 seconds. The second swelling pattern 204D exhibits a continuous decline after the peak formation. The continuous decline is approximately ranging between 250 seconds to 1400 seconds, reaching negative swelling values of approximately -80%, and indicates the beginning of breakdown of the polymer film specimen and the dissolution of the structure.
[0062] The first swelling pattern 202D and the second swelling pattern 204D indicates that polyvinyl alcohol molecular weight significantly influences the swelling and dissolution characteristics of the polymer film specimens. The first swelling pattern 202D exhibits approximately 60% higher maximum swelling compared to the second swelling pattern 204D. The comparison between swelling percentage of the first swelling pattern 202D and the second swelling pattern 204D indicates that higher molecular weight polyvinyl alcohol demonstrates greater water retention capacity and slower dissolution kinetics. The swelling percentage increases and then exhibits different decline behaviours in the first swelling pattern 202D and the second swelling pattern 204D, confirming that molecular weight variations in polyvinyl alcohol affect both swelling capacity and dissolution rates.
[0063] The negative swelling values shows a measurable reduction in the mass or volume of the polymer film specimens due to dissolution. The negative swelling occurs after the polymer reaches a maximum water absorption capacity and begins to lose structural integrity. In particular, the second swelling pattern 204D shows a sharp decline in swelling percentage reaching up to “-80%”. The sharp decline in swelling percentage indicates dissolution of the polyvinyl alcohol (PVA) 9kDa film at 25% concentration polymer film. The sharp decline is consistent with rapid breakdown and loss of material from the surface, and do not align with the targeted dissolution timeframe of 20-40 seconds required for emergency drug delivery systems. The first swelling pattern 202D and the second swelling pattern 204D indicates that the polymer film specimens first swells and then start dissolving. The dissolution of the polymer film specimen after swelling takes approximately more than 150 seconds. Therefore, negative swelling values serve as a quantitative indicator of complete polymer dissolution and are useful in validating the performance of the microneedle formulations intended for fast and controlled drug release.
[0064] FIG. 3 is a graphical representation illustrating cumulative drug release profiles, in accordance with an embodiment of the present disclosure. FIG. 3 is described in conjunction with elements from FIGs. 1 to 2D. With reference to FIG. 3, there is shown a graphical representation 300 in which time measured in seconds is represented on the abscissa axis while cumulative drug release measured in percentage is represented on the ordinate axis. The graphical representation 300 includes a curve 302 depicting drug release from the first formulation. The graphical representation 300 includes a curve 304 depicting drug release from the second formulation. The graphical representation 300 includes a curve 306 depicting drug release from the third formulation.
[0065] The curve 302 starts at 0% drug release at time zero seconds. The curve 302 shows rapid drug release. The curve 302 reaches 70% drug release at a point 902A at approximately 30 seconds. The curve 302 continues to rise and reaches 95% release at 90 seconds. The curve 302 maintains a steady release of around 95% from 90 to 180 seconds. The rapid drug release initially during 0 to 30 seconds indicates fast dissolution of the first formulation.
[0066] The curve 304 begins at 0% drug release and shows initial drug release reaching 80% at approximately 30 seconds at a point 304A. The curve 304 continues rising to 90% release at 60 seconds. The curve 304 reaches maximum release of 95% at approximately ranging between 90 and 120 seconds.
[0067] The curve 306 starts at 0% drug release and exhibits initial drug release reaching 90% at approximately 30 seconds at a point 306A. The curve 306 continues a gradual rise to 95% release at 60 seconds. The curve 306 shows a decline in cumulative drug release reaching 85% at 90 seconds and maintains around 80% release from 120 to 180 seconds.
[0068] The cumulative drug release profiles demonstrate that all formulations achieve more than 90% drug release within the predetermined time period of 20-40 seconds, with the second formulation (25% dextrose) providing optimal balance of 95% release at 30 seconds. The rapid drug release profile is useful for emergency applications such as epinephrine delivery for anaphylaxis, where therapeutic levels must be achieved within 60 seconds of application.
[0069] FIG. 4 is a graphical representation illustrating Fourier transform infrared (FTIR) spectroscopy analysis of different components of the formulation of the microneedle patch, in accordance with an embodiment of the present disclosure. FIG. 4 is described in conjunction with elements from FIGs. 1 to 3. With reference to FIG. 4, there is shown a graphical representation 400 depicting the absorption of infrared light by different components at different wavelengths. The transmittance percentage is represented on the ordinate axis. The wavenumber is measured in centimeters inverse (cm⁻¹) on the abscissa axis. Transmittance percentage quantifies the amount of light that passes through a sample or material, expressed as a percentage of the original light intensity. The wavenumber is defined as the number of wavelengths per unit distance. The graphical representation 400 includes a curve 402 depicting the spectral behaviour of the pH-neutralized mixture. Further, the graphical representation 400 includes a curve 404 representing the spectral behaviour of sodium hydroxide. The graphical representation 400 includes a curve 406 representing the spectral behaviour of a mixture of polyacrylic acid with dextrose. The graphical representation 400 includes a curve 408 representing the spectral behaviour of dextrose. Further, the graphical representation 400 includes a curve 410 representing the spectral behaviour of polyacrylic acid.
[0070] The curve 402 exhibits a broad absorption dip in a region 402A, approximately ranging between 3200 cm⁻¹ to 3600 cm⁻¹, which corresponds to O-H stretching vibrations from hydroxyl groups. The broad absorption dip signifies the presence of hydrogen bonding interactions between polyacrylic acid and dextrose molecules in the pH-neutralized mixture. The curve 402 further includes a region 402B approximately ranging between 1500 cm⁻¹ to 1610 cm⁻¹, corresponding to sodium carboxylate stretching vibrations. The region 402B indicates the conversion of carboxyl groups to carboxylate anions during pH neutralization with sodium hydroxide. The sodium hydroxide (NaOH) increases pH by releasing hydroxide ions (OH-) into water, which then react with hydrogen ions (H+) to create water and raise the pH.
[0071] The curve 404 exhibits absorption characteristics in a region 404A, approximately ranging between 1400 cm⁻¹ to 1600 cm⁻¹, corresponding to the presence of sodium hydroxide. The absorption characteristics in the region 404A confirm the role of the neutralizing agent in converting carboxyl groups of the polyacrylic acid to carboxylate anions. The conversion of the carboxyl groups of the polyacrylic acid to carboxylate anions generates electrostatic repulsion forces for the rapid dissolution of the microneedles.
[0072] The curve 406 includes a region 406A having a first dip approximately ranging between 1630 cm⁻¹ to 1640 cm⁻¹. The first dip corresponds to aldehyde or C=O stretching vibrations in the carboxylic acid group. The region 406A includes a second dip approximately ranging between 1715 cm⁻¹ to 1730 cm⁻¹. The second dip corresponds to carboxylic acid stretching vibrations. The height of the second peak is less than the first peak, indicating the confirmation of hydrogen bond formation between aldehyde and carboxylic acid, establishing the physically cross-linked network structure.
[0073] The curve 408 exhibits absorption characteristics in a region 408A. The region 408A includes a dip approximately ranging between 1000 cm⁻¹ to 1400 cm⁻¹. The dip corresponds to aldehyde skeletal band vibrations and C-O stretching vibrations from the multiple hydroxyl groups present in the dextrose. The curve 408 shows prominent O-H stretching vibrations approximately ranging between 3200 cm⁻¹ to 3600 cm⁻¹. The O-H stretching vibrations confirm the presence of hydroxyl groups available for hydrogen bonding interactions with the polyacrylic acid.
[0074] The curve 410 exhibits characteristic absorption features in a region 410A. The region 410A includes a first dip approximately ranging between 1630 cm⁻¹ to 1640 cm⁻¹. The first dip corresponds to aldehyde or C=O stretching vibrations in carboxylic acid groups. The region 410A exhibits a second dip, approximately ranging between 1715 cm⁻¹ to 1730 cm⁻¹. The second dip corresponds to carboxylic acid stretching vibrations, indicating the presence of pendant carboxyl groups available for hydrogen bonding and neutralization reactions.
[0075] FIG. 5 is a graphical representation illustrating cell viability of various microneedle formulation components at different concentrations, in accordance with an embodiment of the present disclosure. FIG. 5 is described in conjunction with elements from FIGs. 1 to 4. With reference to FIG. 5, there is shown a graphical representation 500 in which the cell viability measured in percentage (%) is represented on the ordinate axis. The concentration measured in percentage (%) is labelled along the abscissa axis. The graphical representation 500 includes a bar 502A, a bar 502B, a bar 502C, and a bar 502D illustrating cell viability of polyacrylic acid at concentrations including 10%, 20%, and 50% concentrations. Further, the graphical representation 500 includes a bar 504A, a bar 504B, a bar 504C, and a bar 504D illustrating cell viability of formulation for synthesis of the microneedle patch at concentrations including 10%, 20%, and 50% concentrations. Further, the graphical representation 500 includes a bar 506A, a bar 506B, a bar 506C, and a bar 506D illustrating cell viability of pH-neutralized formulation for synthesis of microneedle patch at concentrations of 10%, 20%, and 50%, alongside a control.
[0076] At the control concentration (0%), the cell viability for the bar 502A, the bar 504A, and the bar 506A is close to 100%. The cell viability close to 100% indicates that cells were exposed only to the culture medium without any added formulation.
[0077] At 10% concentration, the bar 502B has a cell viability of approximately 8 to 10%. The bar 502B indicates a decline in biocompatibility with the introduction of polyacrylic acid. The bar 504B has a cell viability of approximately 18 to 20%. The cell viability of the bar 504B indicates that the carbohydrate component in the formulation provides a limited protective effect. In contrast, the bar 506B has a cell viability of approximately 75%. The cell viability of bar 506B indicates that pH neutralization improves cell compatibility at 10% concentration.
[0078] At 20% concentration, the bar 502C has a cell viability of approximately 8 to 10%. The bar 502C indicates a further reduction in biocompatibility with increasing concentration of polyacrylic acid. The bar 504C has a slightly lower cell viability as compared to the bar 504B of approximately 15 to 18%. The cell viability of the bar 504C indicates that the presence of carbohydrate in the formulation provides a minor protective effect. In contrast, the bar 506C has a cell viability of approximately 75%. The cell viability of the bar 506C indicates that pH neutralization continues to maintain improved cell compatibility at 20% concentration.
[0079] At 50% concentration, the bar 502D has a cell viability of approximately 10%. The bar 502D indicates significant cytotoxicity at 50% concentration. The bar 504D shows a similar trend with cell viability of approximately 12 to 15% as compared to the bar 504C. The cell viability of the bar 504D indicates that the addition of carbohydrate does not offer sufficient protection at 50% concentration. In contrast, the bar 506D has a cell viability of approximately 78 to 80%. The cell viability of the bar 506D indicates that pH neutralization provides enhancement in cell compatibility even at 50% concentration.
[0080] FIG. 6 is a graphical representation illustrating a force-distance relationship during microneedle insertion, in accordance with an embodiment of the present disclosure. FIG. 6 is described in conjunction with elements from FIGs. 1 to 5. With reference to FIG. 6, there is shown a graphical representation 600 in which the force (in Newton) is represented on the ordinate axis, and the distance (in millimeters) is represented on the abscissa axis. The graphical representation 600 includes a curve 602.
[0081] The curve 602 has a region 604 with almost zero force for a distance approximately ranging between 0 to 1.5 mm. The region 604 indicates initial contact between the microneedles and the biological surface, followed by slight compression of the tip of the microneedle before penetrating the biological surface. In an implementation, the biological surface is an in vitro skin simulating parafilm stack and acts as a surrogate for biological skin. A distinct change in slope is observed in a region 606 approximately ranging between 1.5-2.5 mm. The region 606 indicates the onset of deformation or puncture of the biological surface by the microneedles. Beyond 2 mm, the curve 602 steeply rises, indicating increased resistance during deeper insertion. The rise in the curve 602 reflects the elastic or structural resistance of the in vitro skin simulating parafilm stack.
[0082] FIG. 7 is a graphical representation illustrating insertion depth with various formulations, in accordance with an embodiment of the present disclosure. FIG. 7 is described in conjunction with elements from FIGs. 1 to 6. With reference to FIG. 7, there is shown a graphical representation 700 in which various formulations are represented on the abscissa axis while the insertion depth, measured in micrometers, is represented on the ordinate axis. The graphical representation 700 includes a bar 702 depicting insertion depth for a first formulation. Further, the graphical representation 700 includes a bar 704 depicting insertion depth for a second formulation. The graphical representation 700 includes a bar 706 depicting insertion depth for a third formulation. The first formulation is a combination of polyacrylic acid and 10% dextrose. The second formulation is a combination of polyacrylic acid and 25% dextrose. Further, the third formulation is a combination of polyacrylic acid and 50% dextrose.
[0083] The bar 702 exhibits an insertion depth of approximately 350 micrometers. The insertion depth of the bar 702 indicates the penetration capability of the first formulation. The insertion depth of the bar 702 has skin penetration characteristics that enable delivery of therapeutic agents into the epidermis and upper dermis layers of the biological surface, such as skin. The insertion depth of the bar 702 is attributed to the reduced mechanical strength of microneedles formed with lower carbohydrate concentrations, resulting in increased flexibility and decreased resistance to compression forces during insertion in the skin.
[0084] The bar 704 exhibits the insertion depth of approximately 600 micrometers. The bar 704 indicates the penetration capability of the second formulation. The bar 704 has mechanical properties that enable deeper penetration into the skin while maintaining structural integrity during insertion of the microneedles. The insertion depth of the bar 704 is greater than the insertion depth of the bar 702. The difference in insertion depth indicates that the 25% dextrose concentration provides a balance between mechanical strength and dissolution characteristics. The balance allows the microneedles to penetrate through the stratum corneum and reach the viable epidermis layers where rapid drug absorption can occur.
[0085] The bar 706 exhibits an insertion depth of approximately 480 micrometers. The insertion depth of the bar 706 indicates a reduction in insertion penetration compared to the second formulation, illustrated by the bar 704. The decrease in insertion depth for the third formulation is attributed to the increased brittleness of microneedles due to 50% concentration of the dextrose. The dextrose concentration results in excessive cross-linking within the physically cross-linked network, leading to reduced flexibility and increased susceptibility to fracture during skin insertion.
[0086] The insertion depth data indicate that carbohydrate concentration significantly influences the mechanical properties and penetration performance of the microneedle formulations. The bar 704 exhibits approximately 70% higher insertion depth compared to the bar 702, while the bar 706 shows approximately 20% lower insertion depth compared to the bar 704. The comparison between insertion depths demonstrates that the 25% dextrose formulation achieves suitable mechanical strength for skin penetration while maintaining the rapid dissolution characteristics essential for emergency drug delivery applications. The insertion depth variations confirm that the physically cross-linked network formed by hydrogen bonding between the polyacrylic acid and the dextrose can be tuned to achieve desired penetration depths by controlling carbohydrate concentration within the pH-neutralized mixture.
[0087] FIG. 8 is a graphical representation illustrating insertion efficiency of microneedle formulations at various penetration depths, in accordance with an embodiment of the present disclosure. FIG. 8 is described in conjunction with elements from FIGs. 1 to 7. With reference to FIG. 8, there is shown a graphical representation 800 in which depth, measured in micrometers, is represented on the abscissa axis while insertion efficiency, measured in percentage, is represented on the ordinate axis. The graphical representation 800 includes a curve 802 depicting the insertion efficiency of the first formulation. The graphical representation 800 includes a curve 804 depicting the insertion efficiency of the second formulation. The graphical representation 800 includes a curve 806 depicting the insertion efficiency of the third formulation.
[0088] The curve 802 begins at 100% insertion efficiency at 100 micrometers depth and maintains the insertion efficiency until approximately 200 micrometers. The curve 802 shows a sharp decline starting at a point 802A at 200 micrometers. The curve 802 drops to 70% efficiency at 250 micrometers at a point 802B. The curve 802 continues declining to reach 10% efficiency at 400 micrometers depth. The decline indicates that the 10% dextrose in the first formulation loses structural integrity of the microneedles rapidly with increasing penetration depth.
[0089] The curve 804 maintains 100% insertion efficiency from 100 to 200 micrometers depth. The curve 804 shows a gradual decline starting at 300 micrometers depth at a point 804A. The curve 804 reaches 40% efficiency at 350 micrometers. The curve 804 drops to 20% efficiency at 400 micrometers depth.
[0090] The curve 806 maintains 100% insertion efficiency until 200 micrometers. The curve 806 shows a moderate decline starting at 250 micrometers. The curve 806 shows a steep decline starting from a point 806A, approximately at 300 micrometers depth. The curve 806 drops to 50% efficiency at approximately 400 micrometers and continues to approximately 10% efficiency at point 806B at 500 micrometers.
[0091] The curve 806 maintains the highest efficiency at deeper penetration levels, whereas the curve 804, representing the second formulation, provides suitable efficiency up to 350 micrometers. The curve 802 shows rapid efficiency loss beyond 200 micrometers depth. The curve 804 provides a balance between rapid disintegration, sufficient mechanical strength, and high drug-loading capacity essential for emergency drug delivery applications.
[0092] Modifications to embodiments of the present disclosure described in the foregoing are possible without departing from the scope of the present disclosure as defined by the accompanying claims. Expressions such as "including", "comprising", "incorporating", "have", "is" used to describe and claim the present disclosure are intended to be construed in a non-exclusive manner, namely allowing for items, components or elements not explicitly described also to be present. Reference to the singular is also to be construed to relate to the plural. The word "exemplary" is used herein to mean "serving as an example, instance or illustration". Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments. The word "optionally" is used herein to mean "is provided in some embodiments and not provided in other embodiments". It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable combination or as suitable in any other described embodiment of the disclosure.
, Claims:CLAIMS
We claim:
1. A microneedle patch for emergency drug delivery comprising:
a plurality of microneedles, each microneedle of the plurality of microneedles comprising a physically cross-linked network formed by hydrogen bonding between polyacrylic acid and a carbohydrate,
wherein the polyacrylic acid in each microneedle is neutralized by a neutralizing agent to convert at least a portion of polyacrylic acid to carboxylate anions to generate electrostatic repulsion forces within the physically cross-linked network; and
wherein upon contact with aqueous medium, water molecules of the aqueous medium displace the carbohydrate from bonding sites on the polyacrylic acid and the electrostatic repulsion forces accelerate disintegration of the physically cross-linked network, which causes dissolution of each microneedle within a predetermined time period.
2. The microneedle patch as claimed in claim 1, wherein the predetermined time period is between 20 to 40 seconds.
3. The microneedle patch as claimed in claim 1, wherein the carbohydrate is selected from the group consisting of dextrose, trehalose, sucrose, glucose, maltose, fructose, galactose, different gums and combinations thereof.
4. The microneedle patch as claimed in claim 1, wherein the neutralizing agent is sodium hydroxide and the polyacrylic acid is neutralized to a pH of 6.5 to 7.5.
5. The microneedle patch as claimed in claim 1, wherein the carbohydrate is present at 10-50% weight by weight and acts as a plasticizer that reduces intermolecular forces between polyacrylic acid chains and as a pore-forming agent that creates hydrophilic channels within the physically cross-linked network.
6. The microneedle patch as claimed in claim 1, wherein the dissolution occurs through a dual mechanism comprising hydrogen bond disruption by water molecules and electrostatic repulsion forces generated by carboxylate anions.
7. The microneedle patch as claimed in claim 1, wherein the patch comprises an adhesive backing configured to maintain skin contact during the predetermined time period.
8. A method (100) of preparing microneedle patch for emergency drug delivery comprising:
mixing a polyacrylic acid solution with a carbohydrate solution to form a mixture with a physically cross-linked network;
adding a neutralizing agent to the mixture to form a pH-neutralized mixture, wherein the neutralizing agent converts polyacrylic acid from the polyacrylic acid solution to carboxylate anions and the carboxylate anions generate electrostatic repulsion forces within the pH-neutralized mixture;
applying a pressure reduction to the pH neutralised mixture to form a microneedle of a plurality of microneedles; and
forming a microneedle patch by integrating the plurality of microneedles with a patch base configured to retain the microneedles and enable placement on a target site,
wherein each microneedle configured to dissolve upon contact with an aqueous medium through displacement of carbohydrate from the carbohydrate solution from bonding sites on the polyacrylic acid by water molecules and the electrostatic repulsion forces accelerate disintegration of the physically cross-linked network.
9. The method (100) as claimed in claim 8, wherein the neutralizing agent is sodium hydroxide, and the pH-neutralized mixture has a pH of 6.5-7.5.
10. The method (100) as claimed in claim 8, further comprising casting the pH-neutralized mixture into molds prior to the pressure reduction.
11. The method (100) as claimed in claim 8, further comprising incorporating 0.03-0.1% weight by weight polysorbate as an agent to release the plurality of microneedles from the molds into the pH-neutralized mixture prior to the pressure reduction.
12. The method (100) as claimed in claim 8, after applying vacuum pressure up to 760 mmHg, the pressure is reduced to 0 gradually over a period of 1-2.5 hours.
13. The method (100) as claimed in claim 8, further comprising drying the plurality of microneedles at temperature ranging from 30 to 40 degree Celsius for 20-28 hours after applying the pressure reduction.
14. A method of using the microneedle patch as claimed in claim 1, comprising:
applying the microneedle patch to a biological surface of a subject in need of drug administration.