CONTROLLED RELEASE DRUG DELIVERY SYSTEM

Abstract

A controlled-release nano-suspension drug delivery system (101) with an adaptive release profile. The system comprises nano-sized drug particles (102) suspended in a polymer matrix (103), a stimuli-responsive polymer layer (104), and surface-modified nanocarriers (105). A microprocessor-controlled release mechanism (106) modulates drug release based on physiological feedback. The invention incorporates pH-sensitive polymers (107), enzymatically degradable linkers (108), and a multilayered nanostructure (109) for targeted, sustained drug release. A hydrogel-based diffusion barrier (110) and thermosensitive polymers (111) further enhance control over the release kinetics, providing a versatile platform for optimized therapeutic outcomes.

Specification

Description:The following is a step-by-step description of the invention, detailing the components, and their functionalities mentioned below:

The present invention, a controlled-release nano-suspension drug delivery system (101) with an adaptive profile, comprises several innovative components working in synergy to achieve unprecedented control over drug release kinetics. The following detailed description outlines the structure, function, and interrelationships of these components.

Nano-sized Drug Particles (102): Nano-sized Drug Particles of the system consists of drug molecules reduced to nanoscale dimensions, typically ranging from 10 to 500 nanometers in diameter. This size reduction is achieved through various methods such as high-pressure homogenization, wet milling, or controlled precipitation. The nano-sizing process significantly increases the surface area-to-volume ratio of the drug particles, leading to enhanced dissolution rates and improved bioavailability.

Polymer Matrix (103): The nano-sized drug particles are embedded within a specially formulated polymer matrix that serves several essential functions. First, it stabilizes the drug nanoparticles by preventing their aggregation, ensuring the suspension remains uniform and effective. Second, the matrix acts as a barrier, enabling controlled drug release by regulating diffusion rates over time. Third, it provides protection, shielding the drug molecules from environmental degradation, such as oxidation or hydrolysis. The matrix is composed of biodegradable and biocompatible polymers like poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and chitosan, with the specific blend tailored to the drug and desired release profile.

Stimuli-Responsive Polymer Layer (104): The stimuli-responsive polymer layer surrounding the polymer matrix is a crucial innovation in the system, designed to modulate drug release in response to specific physiological triggers. This smart layer adjusts its properties based on external stimuli, ensuring targeted and controlled drug delivery. For instance, pH-sensitive polymers change their conformation or solubility depending on pH levels, allowing site-specific drug release in different areas of the gastrointestinal tract or within cellular compartments. Thermosensitive polymers, on the other hand, undergo phase transitions at defined temperatures, enabling temperature-controlled release. Additionally, enzyme-responsive polymers are engineered to degrade upon encountering specific enzymes at the target site, facilitating localized drug release and minimizing side effects.

Surface-Modified Nanocarriers (105): The outermost layer of the nanostructure comprises surface-modified nanocarriers, which are crucial for improving the targeting and cellular uptake of the drug delivery system. These nanocarriers are engineered with various surface modifications to enhance their functionality. Ligand attachment is one such modification, where specific ligands like antibodies, peptides, or aptamers are conjugated to the surface, enabling precise targeting of receptors that are overexpressed on particular cell types. PEGylation, the addition of polyethylene glycol (PEG), is another common modification that improves the nanocarrier's circulation time in the bloodstream and reduces recognition and clearance by the immune system (opsonization). Additionally, charge modification is employed to optimize the nanocarrier's surface charge, enhancing its interaction with target cell membranes and promoting better cellular uptake of the drug payload.

Microprocessor-Controlled Release Mechanism (106): The microprocessor-controlled release mechanism is a standout feature of the system, enabling dynamic and responsive drug release. It integrates miniaturized sensors that continuously monitor physiological parameters such as pH, temperature, or specific biomarkers relevant to the treatment. The microprocessor processes this data, applying pre-programmed algorithms to determine the optimal drug release rate based on real-time conditions. Actuators then adjust the drug release mechanism according to the microprocessor's instructions, physically modulating the release based on the sensed environment. For instance, the system can increase drug release when high levels of inflammatory markers are detected or slow it down when the drug concentration in the bloodstream reaches a predetermined threshold, ensuring precise control over the therapeutic process.

pH-Sensitive Polymers (107): The system incorporates pH-sensitive polymers within the nanostructure to provide targeted drug release based on the surrounding pH levels. These polymers include poly(methacrylic acid-co-ethyl acrylate), which dissolves at pH levels greater than 5.5, making it ideal for enteric delivery, where the drug bypasses the stomach and is released in the intestines. Another example is poly(2-vinylpyridine), which becomes soluble in acidic conditions, allowing for efficient drug release in the gastric environment. These pH-sensitive polymers ensure that the drug is released precisely at the desired location in the gastrointestinal tract or cellular environment, enhancing therapeutic efficacy and minimizing side effects.

Enzymatically Degradable Linkers (108): Enzymatically degradable linkers play a crucial role in ensuring the nanostructure components release their payloads at the right time and place within the body. These linkers are specifically designed to be cleaved by enzymes found at target sites, triggering the release of the drug. For instance, matrix metalloproteinase (MMP)-cleavable peptides are used to target the tumor microenvironment, where MMPs are often overexpressed, allowing for localized drug release in cancer therapy. Similarly, phospholipase-sensitive linkers are cleaved inside cells after endocytosis, enabling the drug to be released intracellularly. These linkers provide an additional layer of precision in drug delivery, enhancing efficacy and minimizing off-target effects.

Multilayered Nanostructure (109): The multilayered nanostructure is designed to optimize drug delivery through a series of strategically organized layers. At the core, nano-sized drug particles are encapsulated, providing the therapeutic payload. Surrounding the core, the inner layer consists of a polymer matrix that stabilizes the nanoparticles and enables initial controlled release. The middle layer is composed of stimuli-responsive polymers, which adjust the release rate based on specific physiological triggers like pH or temperature. Finally, the outer layer features surface-modified nanocarriers, tailored for enhanced targeting and cellular uptake. This multilayered design enables sequential release and provides multiple mechanisms to finely control drug release kinetics, ensuring precise and effective treatment.

Hydrogel-Based Diffusion Barrier (110): The hydrogel-based diffusion barrier adds an extra layer of control within the nanostructure by using a hydrogel composed of cross-linked hydrophilic polymers. When exposed to aqueous environments, the hydrogel swells, creating a mesh-like structure that controls the rate at which drug molecules diffuse out of the nanocarrier. By adjusting the swelling behavior and mesh size of the hydrogel, the diffusion rates can be finely tuned to match the desired release profile, allowing for sustained and regulated drug delivery over time. This barrier adds an additional mechanism for ensuring precise control of drug release kinetics.

Thermosensitive Polymers (111): Thermosensitive polymers are incorporated into the nanostructure to enable temperature-dependent control of drug release. These polymers respond to specific temperature thresholds by changing their solubility or structure, allowing for precise release modulation. For instance, Poly(N-isopropylacrylamide) (PNIPAM) transitions from hydrophilic to hydrophobic above 32°C, while Poly(vinyl caprolactam) (PVCL) exhibits similar behavior around 31°C. This temperature-sensitive response can be leveraged to trigger drug release in response to minor changes in body temperature, such as those caused by inflammation or infection. These polymers add another customizable layer to control the release profile, enhancing therapeutic precision.

The preparation of this advanced nano-suspension drug delivery system involves several steps:

• Preparation of nano-sized drug particles through high-pressure homogenization or controlled precipitation.
• Formation of the polymer matrix through emulsion-solvent evaporation technique.
• Layer-by-layer assembly of the stimuli-responsive polymers and pH-sensitive polymers.
• Integration of enzymatically degradable linkers through click chemistry reactions.
• Surface modification of the nanostructure with targeting ligands and PEGylation.
• Incorporation of the hydrogel-based diffusion barrier through in situ polymerization.
• Assembly of the microprocessor-controlled release mechanism and integration with the nanostructure.
• Final formulation of the nano-suspension in an appropriate vehicle for administration.

The microprocessor-controlled release mechanism operates as follows:

• Sensors continuously monitor relevant physiological parameters (e.g., pH, temperature, specific biomarkers).
• Sensor data is transmitted to the microprocessor.
• The microprocessor analyzes the data using pre-programmed algorithms.
• Based on the analysis, the microprocessor sends signals to the actuators.
• Actuators modulate the drug release by:
o Altering the permeability of certain layers in the nanostructure.
o Triggering the degradation of specific enzymatically degradable linkers.
o Inducing conformational changes in stimuli-responsive polymers.
• The process continues in a feedback loop, constantly adjusting the release profile based on real-time physiological data.

This innovative system provides unprecedented control over drug release kinetics, adapting to the patient's physiological state to optimize therapeutic outcomes.




Method of Performing an Invention:

The optimal method for preparing and utilizing this controlled-release nano-suspension drug delivery system involves the following steps:

1. Drug Selection and Nano-sizing:
- Choose a drug with poor water solubility and a narrow therapeutic index.
- Employ high-pressure homogenization to reduce the drug particle size to 100-200 nm.
- Verify particle size distribution using dynamic light scattering (DLS).

2. Polymer Matrix Formation:
- Prepare a blend of PLGA (50:50 lactide:glycolide ratio) and PEG (MW 5000) in a 70:30 ratio.
- Dissolve the polymer blend in dichloromethane.
- Emulsify the nano-sized drug particles in the polymer solution using ultrasonication.
- Remove the solvent through controlled evaporation to form the polymer matrix.

3. Stimuli-Responsive Layer Application:
- Prepare a solution of poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-co-AA)) in ethanol.
- Apply the P(NIPAM-co-AA) solution to the polymer matrix using a layer-by-layer deposition technique.
- Cross-link the P(NIPAM-co-AA) layer using N,N'-methylenebisacrylamide as a cross-linking agent.

4. pH-Sensitive Polymer Integration:
- Dissolve poly(methacrylic acid-co-ethyl acrylate) in a mixture of ethanol and water (1:1 v/v).
- Apply this solution as an additional layer using the layer-by-layer technique.

5. Enzymatically Degradable Linker Incorporation:
- Synthesize a peptide sequence (GPLGIAGQ) sensitive to matrix metalloproteinase-2 (MMP-2).
- Conjugate the peptide to the surface of the nanostructure using carbodiimide chemistry.

6. Surface Modification:
- Prepare a solution of maleimide-functionalized PEG (mal-PEG) in phosphate buffer (pH 7.4).
- React mal-PEG with thiolated targeting ligands (e.g., folic acid-SH for cancer targeting).
- Apply the PEG-ligand conjugate to the nanostructure surface.

7. Hydrogel Diffusion Barrier Formation:
- Prepare a pre-gel solution of low molecular weight hyaluronic acid and thiolated pluronic F-127.
- Encapsulate the nanostructure in this solution and induce gelation through oxidative cross-linking.

8. Microprocessor-Controlled Release Mechanism Integration:
- Fabricate a miniaturized circuit board with integrated pH and temperature sensors.
- Program the microprocessor with the desired release profile algorithms.
- Encapsulate the circuit in a biocompatible, hermetically sealed casing.
- Attach the casing to the nanostructure using biocompatible adhesives.

9. Final Formulation:
- Suspend the complete nanostructures in a isotonic, buffered solution (e.g., phosphate-buffered saline, pH 7.4).
- Adjust the final concentration to achieve the desired drug dosage.

10. Quality Control and Characterization:
- Perform particle size analysis, zeta potential measurements, and polydispersity index determination.
- Conduct in vitro release studies under various pH and temperature conditions.
- Verify the functionality of the microprocessor-controlled release mechanism.
- Assess the stability of the formulation at different storage conditions.

11. In Vivo Evaluation:
- Conduct pharmacokinetic studies in appropriate animal models.
- Evaluate biodistribution using fluorescently labeled nanostructures.
- Assess therapeutic efficacy in disease-specific animal models.
- Perform toxicity and biocompatibility studies.

This method provides a comprehensive approach to preparing and characterizing the controlled-release nano-suspension drug delivery system, ensuring optimal performance and reproducibility.
, Claims:1. A controlled-release nano-suspension drug delivery system comprising:
(a) nano-sized drug particles (102);
(b) a polymer matrix (103) encapsulating said nano-sized drug particles;
(c) a stimuli-responsive polymer layer (104) surrounding said polymer matrix;
(d) surface-modified nanocarriers (105) on the outer surface of said stimuli-responsive polymer layer;
(e) a microprocessor-controlled release mechanism (106) integrated with said nanocarriers;
(f) pH-sensitive polymers (107) incorporated within the nanostructure;
(g) enzymatically degradable linkers (108) connecting components of the nanostructure;
(h) a multilayered nanostructure (109) comprising said components;
(i) a hydrogel-based diffusion barrier (110) encapsulating said multilayered nanostructure; and
(j) thermosensitive polymers (111) integrated within said nanostructure;
wherein, said system provides adaptive and controlled release of a drug in response to physiological conditions.

2. A method for preparing a controlled-release nano-suspension drug delivery system, comprising the steps of:
(a) preparing nano-sized drug particles (201);
(b) forming a polymer matrix encapsulating said nano-sized drug particles (202);
(c) applying a stimuli-responsive polymer layer around said polymer matrix (203);
(d) modifying the surface with nanocarriers (204);
(e) integrating a microprocessor-controlled release mechanism (205);
(f) incorporating pH-sensitive polymers within the nanostructure (206);
(g) connecting components using enzymatically degradable linkers (207);
(h) assembling a multilayered nanostructure (208);
(i) encapsulating said nanostructure in a hydrogel-based diffusion barrier (209); and
(j) integrating thermosensitive polymers within said nanostructure (210).

3. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said nano-sized drug particles have a size range of 10-500 nanometers.

4. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said polymer matrix comprises a blend of biodegradable and biocompatible polymers selected from the group consisting of poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and chitosan.

5. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said stimuli-responsive polymer layer responds to stimuli selected from the group consisting of pH, temperature, and enzymatic activity.

6. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said surface-modified nanocarriers comprise ligands selected from the group consisting of antibodies, peptides, and aptamers.

7. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said microprocessor-controlled release mechanism comprises sensors for detecting physiological parameters, a microprocessor for data processing, and actuators for modulating drug release.

8. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said pH-sensitive polymers are selected from the group consisting of poly(methacrylic acid-co-ethyl acrylate) and poly(2-vinylpyridine).

9. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said enzymatically degradable linkers are sensitive to enzymes selected from the group consisting of matrix metalloproteinases and phospholipases.

10. The controlled-release nano-suspension drug delivery system as claimed in claim 1, wherein said hydrogel-based diffusion barrier comprises cross-linked hydrophilic polymers, and thermosensitive polymers are selected from the group consisting of poly(N-isopropylacrylamide) (PNIPAM) and poly(vinyl caprolactam) (PVCL).

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