Claims:1. A method for designing and testing a polymer hydrogel based formulation for controlled release of an active molecule, the method comprising:
providing a set of monomer and polymer properties as a first input to a design module using a user interface, wherein the monomer corresponds to main constituent of the polymeric hydrogel;
providing a set of synthesis parameters as a second input to the design module;
providing cross-linker concentration and charge on the cross-linker molecule as a third input to the design module;
providing a set of design parameters as a fourth input to the design module using the user interface;
providing a set of system parameters as a fifth input to the design module using the user interface, wherein the system parameters are provided to perform in-silico testing of the hydrogel;
employing, by a processor, Nernst-Planck equation on the design module to describe the fluxes of ionic and other active molecules in terms of gradients of concentration and electric potential;
employing, by the processor, Poisson’s equations on the design module to describe the spatial distribution of electric potential;
employing, by the processor, equation of motion on the design module to describe deformation of the polymeric hydrogel;
employing, by the processor, equation of reaction kinetics on the design module to take into account the presence and effect of functional groups; and
measuring, by the processor, an output of the design module over a period of time interval, wherein the output represents release kinetics of the active molecule in vitro or in the body of a human being and swelling kinetics of the hydrogel;
comparing, by the processor, the release kinetics of active molecule with the desired release kinetics of the active molecule; and
modifying, by the processor, based on the comparison, at least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel, using an optimization module in a hierarchical manner to design the hydrogel polymer to achieve the desired release kinetics of the active molecule.
2. The method of claim 1, wherein the formulation is a mixture comprising at least one of an active molecule, the polymer, a solvent, a cross-linker, and one or more or no functional groups.

3. The method of claim 1, wherein the set of monomer and polymer properties include at least one of charge on the monomer, dissociation constant of the ionizable group present on the monomer, concentration of the monomer, polymer molecular weight or distribution, cross-linking density and modulus of elasticity of the gel.

4. The method of claim 1, wherein the set of synthesis parameters include concentration of fixed charged groups in the monomer and concentration and type of functional groups loaded or present on the surface of the polymeric hydrogel

5. The method of claim 1, wherein the design parameters include size and shape of the polymeric hydrogel.

6. The method of claim 1, wherein the active molecule is a drug or a perfume.

7. The method of claim 1, wherein the system parameters comprise ionic strength, chemical composition of the solvent or body fluids, its temperature and pH.

8. The method of claim 6, wherein the charge on the monomer is non-zero for an ionic monomer and zero for a neutral monomer.

9. The method of claim 1, wherein the polymeric hydrogel could be swelling and non-swelling hydrogel.

10. A system for designing and testing a polymer hydrogel based formulation for controlled release of an active molecule, the system comprising:
an input device, wherein the input device is configured to provide a set of monomer and polymer properties as a first input, a set of synthesis parameters as a second input, a cross-linker concentration and charge of the cross-linking molecule as a third input, a set of design parameters as a fourth input and a set of synthesis parameters as a fifth input; and,
a processor, wherein the processor comprising,
a design module receiving inputs from the input device, the design module configured to model the release kinetics of the active molecule, wherein the design module configured to perform the steps of:
employing Nernst-Planck equation to describe the ionic fluxes in terms of gradients of concentration and electric potential,
employing Poisson’s equations to describe the spatial distribution of electric potential,
employing equation of motion to describe deformation of the polymeric hydrogel, and
employing equation of reaction kinetics to account for chemical reactions due to the presence of functional groups;
a measurement module measuring an output of the design module over a period of time interval defined by the user, wherein the output represents release kinetics of active molecules in the body of a human being or in any solvent of choice and swelling kinetics of the gel in the selected solvent medium;
a comparison module comparing the release kinetics of active molecule and desired release kinetics of the molecule, and
an optimization module modifying, based on the comparison, at least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel, using the optimization module in a hierarchical manner to arrive at a hydrogel based formulation that can achieve the desired release kinetics of the active molecule.

11. The system of claim 10, wherein the system is configured to perform one of a one or two or three dimensional simulations based on the requirements to study the polymer hydrogel swelling and active molecule release kinetics.
, Description:
FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(See Section 10 and Rule 13)

Title of invention:
METHOD AND SYSTEM FOR DESIGNING A POLYMERIC HYDROGEL FOR CONTROLLED RELEASE OF ACTIVE MOLECULES

Applicant:
Tata Consultancy Services Limited
A company Incorporated in India under the Companies Act, 1956
Having address:
Nirmal Building, 9th floor,
Nariman point, Mumbai 400021,
Maharashtra, India

The following specification particularly describes the embodiments and the manner in which it is to be performed.

FIELD OF THE INVENTION

[001] The present application generally relates to model driven design of polymer hydrogels. More particularly, but not specifically, the invention provides a system and method for designing and testing a polymeric hydrogel for controlled release of an active molecules such as drugs.

BACKGROUND OF THE INVENTION

[002] The use of polymer particles and hydrogels for controlled drug delivery has the potential to revolutionize biotechnology and medical applications. These hydrogels responds to different stimuli such as pH, temperature, glucose concentration, electric and magnetic field, etc. These hydrogels swell/de-swell based on the strength of the external stimuli. pH and glucose sensitive hydrogels are of particular interest as they can respond to conditions generally observed in a human body such as different pH in GI tract (pH varies from 3 to 7) and also glucose concentration.

[003] One of the major challenges in health care is the design of controlled drug delivery systems for achieving an appropriate drug dosage rate and to minimize harmful side effects. Polymer-based systems due to their biocompatibility are being developed to address this challenge. The swelling behavior of a hydrogel can be tuned using different formulation conditions to influence drug/active molecule release. Polymer hydrogels are being developed at the laboratory scale as vehicles or carriers for controlled drug delivery. The use of polymeric hydrogel is not limited to drug delivery. They are also being used for delivery of other active molecules such as fragrances.

[004] Normally, the drug or an active molecule is delivered in a formulation whenever its controlled release is desired. A polymer hydrogel based formulation generally consists of the drug or an active molecule, a polymer, a solvent, cross-linker, and functional groups. The swelling behavior of hydrogel is greatly influenced by the above formulation parameters. Since, controlled delivery of a given drug or active molecule is influenced by swelling behavior of hydrogel, it is necessary to undertake a large number of experiments in order to arrive at a correct design of the hydrogels to achieve the desired release kinetics. This is because the release kinetics depends on chemical make of the hydrogel, its size and shape, properties of the solvent, environment surrounding the hydrogel, and the interactions between the active molecule, polymer, solvent and the environment.

[005] Fig. 1 shows the physics involved in swelling of pH sensitive hydrogels. Fig. 2 shows the physics involved in the swelling of glucose sensitive hydrogels. The polymeric hydrogels are being developed to provide controlled drug delivery to patients by releasing drug either at desirable pH in case of oral drug delivery or at high glucose concentration as observed in a diabetic patient. There are many factors involved in the synthesis of hydrogel, such as: (i) Selection of a monomer with appropriate dissociation constant of the charged group. (ii) Concentration of ionic monomer (iii) Cross-linking ratio to be used (iv) Concentration and type of functional groups immobilized on hydrogel (v) Size and shape of the hydrogel. Generally it requires factorial design of experiments to arrive at an optimized design of hydrogel which is time consuming and usually leads to waste of resources. Therefore a model based design of hydrogels can not only help in finding the synthesis parameters needed to arrive at an optimized design but can also be used to test the hydrogel under different environments. Accurate modeling of polymer hydrogel swelling kinetics and release kinetics of an active molecule plays a vital role in the design of polymeric hydrogels.

[006] Usually, a researcher utilizes one or more monomers in different concentrations along with a desired cross-linking agent and its concentration to arrive at a viable composition of the hydrogel. A mixture consisting of monomer, cross-linkers and functional groups are then used to synthesize a hydrogel. An active molecule, controlled release for which is desired, can be loaded in the hydrogel during or after synthesis. The active molecule loaded hydrogel is then immersed in a suitable solvent that mimics the physiological conditions encountered in the body. The solvent can be a simulated intestinal fluid or a simulated gastric fluid. The concentration of the active molecule is measured at regular intervals from the collected sample of the solvent. This completes the forward cycle of design of a hydrogel. Depending on the observed release kinetics, one has to change the chemical make-up of the hydrogel and even its shape and size.

[007] Since it takes considerable amount of time, effort and money to undertake experimental studies, mathematical models are being developed to aid in the design of polymeric systems such as particles and gels for controlled release of active molecules. The important physicochemical phenomena involved in molecular release through polymer hydrogels include diffusion of the active molecule, solvent and ionic species present in the body fluids through hydrogels and swelling of hydrogels due to absorption of the solvent and due to the effect of environment parameters such as temperature, nature and concentration of ionic species, pH, glucose concentration, mechanical stresses and any applied magnetic or electric field. Models have been developed to predict the swelling kinetics of stimuli sensitive hydrogels or release kinetics of an active molecule. However, the models proposed so far do not couple the kinetics of gel swelling with the release kinetics of active molecule. Secondly, model-based optimization was not carried out to arrive at appropriate design parameters of the carrier to achieve a desired release profile.

[008] Researchers have focused on factorial design of experiments to arrive at an optimal design of polymer hydrogel. Most of the modeling work till now has opted to account only for few of the phenomena involved during release of an active molecule such as diffusion of water and encapsulated active molecule, thus neglecting the effect of ionic species, electric potential and structural properties of hydrogel. Prior modeling work has not focused on quantifying the release of an encapsulated active molecule in response to stimuli change such as pH or glucose concentration. In addition to that, the models till now have not been subjected to physiological conditions that will be encountered during oral delivery using a hydrogel. Prior work also did not apply design of carriers through model-based optimization.

[009] Various other methods and systems have also been designed to provide accurate modelling release of active molecules. None of the methods and devices provides an efficient and effective way to model the delivery of active molecules. Therefore, there still exists a need to provide an economical and effective control method for design and testing of a polymeric hydrogel while taking multiple parameters into consideration.

OBJECTIVE OF THE INVENTION

[0010] In accordance with the present invention, the primary objective is to provide a system and method for designing and testing a polymer hydrogel based formulation for controlled release of an active molecule.

[0011] An objective of the present invention is to provide a system and method for designing the polymeric hydrogel by coupling the kinetics of swelling of the polymeric hydrogel and the kinetics of the release of the active molecule.

[0012] Another objective of the invention is to provide a simulation tool for in-silico design of polymeric hydrogels.

[0013] Yet another objective of the invention is to provide a system and method for predicting the effect of type of monomer and its concentration on swelling of polymeric hydrogel and release of an active molecule.

[0014] Still another objective of the invention is to provide a system and method for predicting the effect of cross-linking ratio on the polymeric hydrogel’s swelling and release of an active molecule.

[0015] Still another objective of the invention is to provide a system and method for predicting the effect of functional group concentration.

[0016] Other objectives and advantages of the present invention will be more apparent from the following description when read in conjunction with the accompanying figures, which are not intended to limit the scope of the present disclosure.

SUMMARY OF THE INVENTION

[0017] Before the present methods, systems, and hardware enablement are described, it is to be understood that this invention is not limited to the particular systems, and methodologies described, as there can be multiple possible embodiments of the present invention which are not expressly illustrated in the present disclosure. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0018] The present application provides a system for designing and testing a polymer hydrogel for controlled release of an active molecule. The system comprises an input device and a processor. The input device provides a set of monomer and polymer properties as a first input, a set of synthesis parameters as a second input, a cross-linker concentration as a third input, a set of design parameters as a fourth input and a set of system parameters as a fifth input. The processor further comprises a design module, a measuring module, a comparison module and an optimization module. The design module receives inputs from the input device. The task of the design module is to simulate release kinetics of the active molecule. The design module performs the steps of: employing Nernst-Planck equation to describe the fluxes of ionic and other active molecules in terms of gradients of concentration and electric potential, diffusion equation to describe release of an active molecule from the ever changing gel mesh size, employing Poisson’s equation to describe the spatial distribution of electric potential, employing equation of motion to describe deformation of the polymeric hydrogel, and employing reaction kinetics due to the presence of functional groups. The measuring module measures an output of the design module over a period of time interval. The output may represent release kinetics of active molecule or swelling kinetics of the gel in the medium of choice. The comparison module compares the simulated release kinetics of an active molecule for the given input parameters and the desired release kinetics. The optimization module modifies, based on the comparison, at least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel, using an optimization module in a hierarchical manner to design the hydrogel polymer to achieve the desired release kinetics of the active molecule.

[0019] According to another embodiment the present application also provides a method for designing and testing a polymeric hydrogel for controlled release of an active molecule. Initially,
a set of monomer and polymer properties, a set of synthesis parameters, a cross-linker concentration, a set of design parameters and a set of system parameters are provided as a plurality of inputs to a design module. The plurality of inputs are provided using a user interface. In the next step, Nernst-Planck equation is employed in the design module to describe the fluxes of ionic species and active molecules in terms of gradients of concentration and electric potential. Followed by employing Poisson’s equation in the design module to describe the spatial distribution of electric potential. Followed by employing equation of motion on the design module to describe deformation of the polymeric hydrogel. Followed by employing reaction kinetics on the design module to implement the presence of functional groups. In the next step an output of the design module is measured by the processor over a period of time interval. The output represents release kinetics of the active molecule in vitro or in the body of a human being. The release kinetics of the active molecule is then compared by the processor with the desired release kinetics. Finally, the processor modifies based on the comparison, at least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel using an optimization module. The modification is performed in a hierarchical manner to design the hydrogel polymer to achieve the desired release kinetics of the active molecule.

BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The foregoing summary, as well as the following detailed description of preferred embodiments, are better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there is shown in the drawings exemplary constructions of the invention; however, the invention is not limited to the specific methods and devices disclosed. In the drawings:

[0021] Fig. 1 shows a flowchart representation of the phenomena involved in swelling of pH sensitive hydrogels;

[0022] Fig. 2 shows a flowchart representation of the phenomena involved in swelling of glucose responsive hydrogels;

[0023] Fig. 3 shows an illustrative block diagram showing a system for designing and testing a polymeric hydrogel for controlled release of an active molecule, in accordance with an embodiment of the invention;

[0024] Fig. 4 shows a schematic representation of the design module along with input and output in accordance with an embodiment of the invention;

[0025] Fig. 5 shows a flow chart illustrating the steps involved in designing and testing a polymeric hydrogel for controlled release of an active molecule in accordance with an embodiment of the invention;

[0026] Fig. 6 shows a graphical representation of the comparison of simulation results for steady state swelling of poly (Hydroxyethyl methacrylate-co-methacrylic acid) hydrogel with the experimental observations in accordance with an embodiment of the invention;

[0027] Fig. 7A shows the graphical representation of the swelling kinetics of 300 micron sized poly (Hydroxyethyl methacrylate-co-methacrylic acid) hydrogel, in accordance with an embodiment of the invention;

[0028] Fig. 7B shows the graphical representation of the swelling kinetics of 150 micron sized hydrogel, in accordance with an embodiment of the invention;

[0029] Fig. 8A shows the graphical representation of the release kinetics of phenylpropanolamine from poly (Hydroxyethyl methacrylate-co-methacrylic acid) hydrogel at pH=1 in accordance with an embodiment of the invention;

[0030] Fig. 8B shows the graphical representation of the release kinetics of phenylpropanolamine from poly (Hydroxyethyl methacrylate-co-methacrylic acid) hydrogel at pH=7 in accordance with an embodiment of the invention;

[0031] Fig. 9 shows the graphical representation of the pH profile observed in the GI tract in accordance with an embodiment of the invention;

[0032] Fig. 10 shows the graphical representation of the swelling kinetics of poly(Hydroxyethyl methacrylate-co-methacrylic acid) hydrogel through transit in the GI tract in accordance with an embodiment of the invention;

[0033] Fig. 11 shows the graphical representation of the release kinetics of the drug phenylpropanolamine from the hydrogel during passage through GI tract in accordance with an embodiment of the invention;

[0034] Fig 12 shows the graphical representation of the swelling behavior of sulfonamide group based hydrogel in response to glucose concentration in accordance with an embodiment of the invention;

[0035] Fig. 13 shows the graphical representation of the swelling kinetics of a poly (HEMA-co-DMAEMA) hydrogel as it is immersed in a bathing solution of glucose concentration 27 mmol/L in accordance with an embodiment of the invention.

[0036] Fig. 14 shows the graphical representation of the effect of using a monomer for hydrogel synthesis with a charged group having different dissociation constant in accordance with an embodiment of the invention;

[0037] Fig. 15 shows the graphical representation of the swelling behavior of hydrogel by increasing/decreasing the concentration of ionic monomer in the hydrogel in accordance with an embodiment of the invention; and

[0038] Fig. 16 shows the graphical representation of the change of the swelling behavior of glucose responsive hydrogel by increasing/decreasing the concentration of glucose oxidase (enzyme concentration, Cenz) in accordance with an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION
[0039] Some embodiments of this invention, illustrating all its features, will now be discussed in detail.

[0040] The words "comprising," "having," "containing," and "including," and other forms thereof, are intended to be equivalent in meaning and be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items.

[0041] It must also be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Although any systems and methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred, systems and methods are now described. In the following description for the purpose of explanation and understanding reference has been made to numerous embodiments for which the intent is not to limit the scope of the invention.

[0042] One or more components of the invention are described as module for the understanding of the specification. For example, a module may include self-contained component in a hardware circuit comprising of logical gate, semiconductor device, integrated circuits or any other discrete component. The module may also be a part of any software program executed by any hardware entity for example processor. The implementation of module as a software program may include a set of logical instructions to be executed by a processor or any other hardware entity.

[0043] The disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms.

[0044] Method steps of the invention may be performed by one or more computer processors executing a program tangibly embodied on a computer-readable medium to perform functions of the invention by operating on input and generating output. Suitable processors include, by way of example, both general and special purpose microprocessors. Generally, the processor receives (reads) instructions and data from a memory (such as a read-only memory and/or a random access memory) and writes (stores) instructions and data to the memory. Storage devices suitable for tangibly embodying computer program instructions and data include, for example, all forms of non-volatile memory, such as semiconductor memory devices, including EPROM, EEPROM, and flash memory devices; magnetic disks such as internal hard disks and removable disks; magneto-optical disks; and CD-ROMs. Any of the foregoing may be supplemented by, or incorporated in, specially-designed ASICs (application-specific integrated circuits) or FPGAs (Field-Programmable Gate Arrays). A computer can generally also receive (read) programs and data from, and write (store) programs and data to, a non-transitory computer-readable storage medium such as an internal disk (not shown) or a removable disk.

[0045] The present application provides a system for designing and testing a polymer hydrogel based formulation for controlled release of an active molecule. The system comprises an input device and a processor. The input device provides a set of monomer and polymer properties as a first input, a set of synthesis parameters as a second input, a cross-linker concentration as a third input, a set of design parameters as a fourth input and a set of system parameters as a fifth input. The processor further comprises a design module, a measuring module, a comparison module and an optimization module. The design module receives inputs from the input device. The task of design module is to simulate the release kinetics of the active molecule. The design module further performs the steps of: employing Nernst-Planck equation to describe the fluxes of ionic species and other active molecules in terms of gradients of concentration and electric potential, diffusion equations describe drug/active molecule release from the changing mesh size of the gel, employing Poisson’s equation to describe the spatial distribution of electric potential, employing equation of motion to describe deformation of the polymeric hydrogel, and employing equation of reaction kinetics due to the presence of functional groups. The measuring module measures an output of the design module over a period of time interval. The output represents a drug/active molecule release kinetics and or swelling kinetics of the gel in the testing medium. The comparison module compares the drug/active molecule release kinetics and a desired release kinetics. The optimization module modifies, based on the comparison, at least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel, using an optimization module in a hierarchical manner to design the polymer hydrogel to achieve the desired release kinetics of the active molecule.

[0046] A system 100 for designing and testing a polymeric hydrogel for controlled release of an active molecule is shown in Fig. 3 according to an illustrative embodiment. It should be appreciated that the system 100 estimates both the kinetics of both the swelling of the polymeric hydrogel and the release of the active molecule. The system 100 can be used majorly for the controlled release of the active molecule through optimization of carrier design parameters. The system 100 can also be used for various active molecules such as drug, perfume etc., though in the present disclosure, the invention has been explained with the help of drug molecules. The system consists of a mathematical model to estimate drug release kinetics through the polymer hydrogel and an optimization methodology for optimizing the carrier design parameters. The model is applicable for non-swelling as well as swelling polymer particles or hydrogels.

[0047] The system 100 includes a user interface 102, a processor 104 and a memory 106 in communication with the processor 104. The processor 104 further comprises a plurality of modules such as a design module 108, a measurement module 110, a comparison module 112 and an optimization module 114. The processor 104 may also include other modules for performing various other functions. The system 100 is configured to provide a simulation model of pH sensitive polymeric hydrogel that can be used for oral delivery of proteins or other agents susceptible to acidic pH in gut. According to another embodiment, the system 100 is also configured to provide a simulation model of glucose sensitive polymeric hydrogel that can be used for self-regulating insulin delivery. In general, the system 100 can consist of a model of polymer hydrogel to predict drug release kinetics.

[0048] Fig. 4 shows the inputs needed by mathematical model to predict drug/active molecule release kinetics. These inputs range from the synthesis parameters that can be easily changed during fabrication of hydrogels to system parameters that are fixed for a given system such as oral drug delivery. According to an embodiment of the invention, the user interface 102 is configured to provide a plurality of inputs to the design module 108 as shown in Fig. 4. The charge on the monomers and their concentrations (if more than one monomer used), polymer molecular weight and its density are the parameters that correspond to a polymer used to synthesize a hydrogel and this forms the first set of input to the design module, 108. Monomer is used to synthesize the polymer that forms the main constituent of the hydrogel. A set of synthesis parameters are provided as the second input. The synthesis parameters include concentration of fixed charged groups in the monomer and concentration and type of functional groups loaded or present on the surface of the polymeric hydrogel. The charge of the cross-linker molecule used and its concentration is provided as the third input to the design module 108. The cross-linking molecule joins different polymer chains thus forming a polymer network of the hydrogel. The cross-linking molecules can also act as an ionizable group and thus be responsible for the swelling of the hydrogels. A set of design parameters are provided as the fourth input to the design module 108. The design parameters include size and shape of the polymeric hydrogel. A set of system parameters are provided as the fifth input to the design module 108. The set of system parameters are provided to perform in-silico testing of the hydrogel. The set of system parameters may include body temperature, pH and concentration of ionic species present in body fluid.

[0049] According to an embodiment of the invention, the design module 108 is further configured to generate an output. The output can be release kinetics of the active molecules and/or swelling kinetics of the hydrogel. A model is employed on parameters given as an input to the design module 108 to simulate the release of the active molecule or swelling behaviour of the hydrogel in the human body. This model employs Nernst-Planck and Poisson’s equations to describe the mechanism of transport of ionic species. These equations are coupled with equation of motion to describe deformation of hydrogel under the stresses generated. The reaction kinetics due to presence of functional groups is also included the model, for e.g. oxidation of glucose to gluconic acid in presence of glucose oxidase. Additionally, the model also includes equations for drug release kinetics that can be a simplified to diffusion equation in case of a neutral molecule or can be another Nernst-Planck equation in case of ionic molecules. The optimization algorithm consists of an objective function that compares the difference between the desired release kinetics and the one estimated by the model. It consists of an algorithm that modifies the formulation parameters such as charge on the monomer, its concentration, polymer molecular weight, cross-linking ratio and its charge in a hierarchical manner so as to minimize the objective function. The algorithm does so while taking into account constraints on system variables such as body temperature, pH, ionic strength and parameters of the hydrogel based carrier. Therefore, the invention can be used for in-silico design of hydrogel based formulation for controlled delivery of active molecules.

[0050] According to an embodiment of the invention, the model of drug release from polymer hydrogel mainly involves the following steps: (1) Migration of ionic species and other active molecules under gradients of concentration and electric potential (2) Reaction of the species with functional/immobilized groups (3) Movement of hydrogel boundary under osmotic pressure (4) Diffusion of the drug to the outside solution.

[0051] The invention presents a framework to design polymer hydrogel based formulation with reactive functional groups. Nernst-Planck equation is used to describe the fluxes of ionic species and active molecules in terms of gradients of concentration, electric potential and chemical reactions. The example presented here is for a glucose responsive hydrogel. For these hydrogels, chemical reaction kinetics in presence of glucose oxidase that accounts of conversion of glucose to gluconic acid is considered. Hydrogen peroxide is one of the byproducts of the chemical reaction, another enzyme, catalase, is generally added in glucose responsive hydrogels to form water and recover the consumed oxygen. We have also included the hydrogen peroxide decomposition in our model. The spatial distribution of electric potential is found by solving the Poisson’s equation. The deformation of hydrogel is further calculated using linear elastic theory. The model has been parameterized such that the end user has the option to select charge of the ionic monomer, concentration of monomer, modulus of elasticity of hydrogel that is correlated with cross-linker concentration (thus cross-linker concentration can be provided where elastic modulus is not available), its Poisson’s ratio, ionic strength of the bathing solution, reaction rate constants in presence of reacting immobilized enzymes or functional groups, size of dry gel and diffusion coefficients of species in the solvent. Thereby allowing the user to have control over the fabrication parameters that can be easily changed during synthesis of hydrogel.

[0052] According to an embodiment of the invention, the governing equations for polymer hydrogel can be explained as follows:
Diffusion of ionic species

Where Vmax, KGlu and KOx are reaction constant for michaelis menten kinetic type reactions. COx is the concentration of oxygen and CGlu is concentration of glucose.

Diffusion of drug (Same equation is applied for an active molecule if it is neutral)

Poisson’s Equation for estimating spatial variation of electric potential

Where cf, the concentration of fixed charge ionizable groups available in the hydrogel is given as:

For anionic hydrogels
For cationic hydrogels

Equation of mechanical deformation

Where ? and µ are two lame’ elastic constants associated with Shear Modulus, G, Elastic Modulus, E and Poisson’s ratio ? as follows:

ci = molar concentration of diffusive ions (Na+, Cl-, H+); cDr = molar concentration of drug; Di = Diffusion coefficient of mobile ionic species; DDr = Diffusion coefficient of drug, µk is ionic mobility and F is Faraday’s constant. Also, cSmo here represents the initial concentration of fixed charged groups. The ratio of interstitial fluid volume to solid gel volume is depicted as H and K is the dissociation constant of fixed charged groups. Furthermore, E is elastic modulus and ? is the Poisson’s ratio.

[0053] According to another embodiment of the invention, the system 100 is also configured to perform at one of a one dimensional, a two dimensional or a three dimensional simulations based on the requirements to study the polymeric hydrogel swelling and release kinetics of active molecules.

[0054] A flowchart 200 to design and test the hydrogels is shown in Fig. 5 according to an illustrative embodiment of the invention. Initially at step 202, a set of monomer and polymer properties is provided as a first input to the design module 108 using the user interface 102. The monomer is corresponding to the polymer which is used to synthesize the polymeric hydrogel. At step 204, the set of synthesis or formulation parameters is provided as a second input to the design module 108. The synthesis parameters include concentration of fixed charged groups in the monomer and concentration and type of functional groups loaded or present on the surface of the polymeric hydrogel. At step 206, a cross-linker concentration and charge on the cross-linker molecule is provided as a third input to the design module. The cross-linker molecule can also act as ionizable group along with the ionic monomer used for synthesizing the hydrogel. At step 208, a set of design parameters is provided as fourth input to the design module 108 using the user interface 102. The design parameters include size and shape of the polymeric hydrogel. And at step 210, a set of system parameters is provided as a fifth input to the design module 108 using the user interface 102. The set of system parameters is provided to perform in-silico testing of the polymeric hydrogel. The set of system parameters include body temperature, pH and concentration of ionic species present in body fluid. The first input, the second input, the third input, the fourth input and the fifth input are considered as the input to the design module 108 and can be provided in any order.

[0055] In the next step 212, Nernst Planck equation is employed on the design module 108. The Nernst Planck equation describes the ionic fluxes in terms of gradients of concentration and electric potential. The Nernst-Planck equation is simplified to a diffusion equation in case of a neutral molecule and thus can be used to predict diffusive flux of neutral molecules in the gel. Furthermore, a modified form of the Nernst-Planck equation is used to describe the reaction kinetics in presence of functional groups. At step 214, Poisson’s equation is employed on the design module 108. The Poisson’s equation describe the spatial distribution of electric potential. At step 216, the equation of motion is employed on the design module 108. The equation of motion predicts the displacement vector and thus helps in finding the deformation of the polymeric hydrogel due to osmotic pressure and elastic stress of polymer network. At step 218, user defined functions that include expressions for reaction kinetics are included which is used as an input by Nernst-Planck equation.

[0056] At step 220, the output of the design module 108 is measured by the measuring module 110. The output of the design module 108 is measured over a period of time interval. The output represents the release of the active molecule in vitro conditions or in the body of a human being. In the next step 222, it is compared by the comparison module 112, to check whether the simulated release kinetics of the active molecule is same as the desired release kinetics. If the simulated release kinetics is same then it can be concluded that the desired polymeric hydrogel design is achieved. If the simulated release kinetics is not same as the desired release kinetics then at step 224, the plurality of inputs are modified using the optimization module. At least one of the monomer and its concentration, the cross-linker and its concentration, the functional group and its concentration or the design parameters of the polymeric hydrogel are modified using the optimization module 114. The modification is done in a hierarchical manner to design the hydrogel polymer by minimizing the objective function.

[0057] According to an embodiment of the invention the model can be used to predict steady state swelling behavior or deformation of polymer hydrogel in response to pH and glucose, the transient analysis of deformation of polymer hydrogel, release kinetics of encapsulated drug/active molecule, effect of different fabrication parameters on swelling and release kinetics of an active molecule and effect of composition of bathing solution on swelling behavior and release kinetics of active molecules.

[0058] According to another embodiment of the invention, the model has been validated with experimental results. Fig. 6 shows the comparison of simulation results for steady state swelling of the polymeric hydrogel with the experimental observations, when pH of the outside buffer solution is changed. The hydrogel was made by using HEMA (Hydroxy-ethyl-methacrylic acid) and methacrylic acid via free radical polymerization. The line shows the simulation result and symbols represent experimental data taken from the literature (Aluru N R et al., J Microelectromech Syst, (2002), 11(4), 544-555).

[0059] According to an embodiment of the invention, the transient swelling behavior of pH sensitive hydrogel has also been validated as pH in bathing solution changes from 3 to 6 as shown in Fig. 7A and 7B. Fig. 7A demonstrates the swelling kinetics of 300 micron sized hydrogel whereas Fig. 7B shows swelling behavior of 150 micron sized hydrogel. The continuous lines shows the simulation result and circles represent experimental data taken from the literature (Aluru N R et al., J Microelectromech Syst, (2002), 11(4), 544-555).

[0060] The simulation tool could correctly predict the release kinetics of phenylpropanolamine (drug) under different pH conditions as shown in Fig. 8A and Fig. 8B. Fig. 8A shows drug release from hydrogel at pH=1 whereas Fig. 8B depicts release kinetics of the same drug at pH=7. The continuous line shows the simulation results while circles experimental data taken from the literature (Kou Jim H. et al., Pharm Res (1988), 5(9), 592-597). The continuous line shows the simulation results while circles experimental data taken from the literature (Kou Jim H. et al., Pharm Res (1988), 5(9), 592-597). Fig. 9 shows the pH profile generally observed in GI tract. The stomach is highly acidic whereas pH becomes neutral in small intestine. The swelling of hydrogel and drug release under pH condition encountered inside gastrointestinal tract of a human body is shown in Fig. 10 and Fig. 11 respectively. This case demonstrates the use of our simulation tool to test the release kinetics of an active molecule through the hydrogel for oral drug delivery. This is just one of the many examples that can be used to demonstrate the use of the tool as prediction or testing tool.

[0061] According to another embodiment of the invention, the tool has also been able to predict the swelling behavior of glucose sensitive hydrogels. These type of gels can potentially be used for self-regulating insulin delivery. Fig. 12 shows the steady state swelling behavior of sulfonamide group based hydrogel in response to glucose. The continuous line shows the simulation results while symbols represent experimental data taken from the literature (Kang S Il et al., Journal of Controlled Release (2003), 86(1), 115-121). Fig. 13 shows the swelling kinetics of a poly (HEMA-co-DMAEMA) hydrogel as it is immersed in a bathing solution of glucose concentration 27 mmol/L. Continuous line shows the simulation result while symbols represent the experimental data taken from the literature (Traitel T et al., Biomaterials (2000) 21(16), 1679-1687).

[0062] According to another embodiment of the invention, the simulation tool can also be used to predict the effect of synthesis/formulation conditions on hydrogel swelling and release of active molecules. Fig. 14 shows the effect of using a monomer for hydrogel synthesis with a charged group having different dissociation constant. The swelling behavior of hydrogel can also be drastically changed by increasing/decreasing the concentration of ionic monomer in the hydrogel as shown in Fig. 15. The concentration of immobilized functional groups such as glucose oxidase will also change the swelling behavior of polymer hydrogel as shown in fig. 16.

[0063] In view of the foregoing, it will be appreciated that the present invention provides a method and system for design and testing of a polymer hydrogel based formulation for controlled release of an active molecule. Still, it should be understood that the foregoing relates only to the exemplary embodiments of the present invention, and that numerous changes may be made thereto without departing from the spirit and scope of the invention as defined by the following claims.