NOVEL APPROACHES IN POLYMERIC CAPSULE ENGINEERING

Abstract

The present invention refers to a core comprising the active pharmaceutical ingredient, coated with a variety of multiple layers of polymers (103, 104, 105) that has been designed to release at variable rates in the time-release polymeric capsule system (101) used for controlled drug release. Major features of the encapsulated core include pH-sensitive layers (106), enzyme-sensitive layers (107), and thermosensitive layers (108), while nanostructured materials (111) enhance the solubility of the drug and improve its release. Surface modifications (112) enhance mucoadhesive and targeted properties. A manufacturing process (109) and quality control methods (110) ensure consistent production. This multi versatile system offers real control over drug release kinetics, reduced dosing frequency, and improved therapeutic outcomes across a number of clinical contexts.

Specification

Description:The polymeric capsule system according to the invention is a highly complex drug delivery system engineered to achieve release control of APIs over signi fit time spans. This section lists all the different components, their functions, and the working principles behind the invention.

1. Core Component (102): The drug core is the central part of the capsule and contain the API. It formulated as:
a) Solid core: The API is compressed into the form of a tablet or a pellet containing, if desired, an excipient to improve stability or dissolution.
b) Semi-solid core: The API is dispersed in a gel-like matrix. Such a system very useful for delivering drugs like hydrophilic drugs in a controlled manner.
c) Liquid core: API is dissolved or suspended in a suitable liquid medium, which then is encapsulated within an innermost polymer layer.

The core further comprises nanostructured materials (111), such as mesoporous silica or cyclodextrins, which enhance the solubility and dissolution rate of poorly water-soluble drugs.

2. Multiple polymer layers (103, 104, 105) Drug release from the core be regulated by multiple layers of polymers wherein all contribute in their own way to the profile of drug release:
a) Outermost layer (103) Rapidly degrading polymers, such as PVP or low molecular weight PEG. This layer contributes to an initial burst release of the drug that rapidly achieves therapeutic concentrations.
b) Intermediate layers (104): These include polymers that dissolve at an intermediate rate, such as HPMC or ethylcellulose. These layers control the release of drugs at the intermediate phase of treatment.
c) Innermost layer (105): This is made from slowly dissolving or swellable polymers such as high molecular weight polyethylene oxide (PEO) or cross-linked polyacrylic acid. In this layer, drug is released over long periods of time.

3. Specific polymer types: The following specific types of polymers are incorporated into the capsule for maximization of its functionality:
a) pH-sensitive polymer (106): They are placed in the layer structure at positions that make it react to changes in pH environments within the GI tract. These are polymers like Eudragit L100-55 or cellulose acetate phthalate, which are more stable in the acidic environment of the stomach than they are to be in the higher pH environment of the intestine, thus making these drugs selectively release.
b) Enzyme-sensitive polymers (107): Azon-cross-linked hydrogels or derivatives of pectin are added that break down by the action of certain enzymes present in the colon. This property is useful for drug delivery through the colon in the treatment of inflammatory bowel disease.
c) Thermosensitive polymers (108): In this category, materials such as poly(N-isopropylacrylamide) (PNIPAM) or pluronics have been added to the formulations in order to modulate release of the drug based on temperature changes. These could be used in externally triggered release or to respond to fever conditions.

4. Surface Modifications (112): Alterations be made to the outermost surface of the capsule in order to enhance the delivery system's performance:

a) Mucoadhesive coatings: Polymers such as chitosan or carbomers be coated onto the systems to extend residence time in the gastrointestinal tract.
b) Targeting ligands Specific molecules (e.g., antibodies, aptamers) be conjugated to the surface for targeted delivery to specific tissues or cell types.
c) Stealth coatings PEGylation or other hydrophilic coatings be applied to reduce immunogenicity and prolong circulation time for parenteral formulations.

5. Manufacturing Process (109): The production of these multi-layered capsules involves a sophisticated manufacturing process:
a) Cores Preparation. Using suitable techniques such as compression, extrusion, or spray drying, the API will be formulated into the desired core structure.
b) Layer-by-layer Assembly. Applicating polymer layers one after another using techniques like spray coating or dipping, or electrostatic deposition.
c) 3D Printing. Advanced 3D printing techniques could also be adopted to ensure simultaneous control of layer thickness and composition.
d) Crosslinking: The polymer layers are crosslinked, when necessary, with UV irradiation or chemical crosslinking agents to ensure stability.
e) Surface modification: The last steps involve the addition of any surface coatings or conjugation of targeting ligands.

6. Quality Control Methods (110): A very strict quality control procedure is followed at every step of manufacturing:
a) In-process controls. Size, layer thickness and uniformity of particles are controlled during production.
b) Dissolution testing: Dissolution behaviour of the drug is studied under various simulated physiological conditions.
c) Stability studies: Integrity and stability of the capsule, as well as the drug are studied under different storage conditions.
d) Imaging techniques: Sning electron microscopy (SEM) and confocal microscopy are applied to elucidate the microscopic structure and uniformity of the layers.

7. Release Mechanism and Kinetics The overall pattern of drug release is affected by several factors together:
a) Dissolution of individual polymer layers
b) Diffusion of the drug through the polymer matrix
c) Erosion or swelling of certain polymer components
d) Response to certain stimuli (pH, enzymes, temperature)
With proper design of composition, thickness, and sequencing of polymer layers, a plethora of release profiles be obtained including zero order release for constant drug delivery, pulsatile release for chrono-therapeutic applications, and biphase release combining immediate and extended-release components.

8. Flexibility and Adaptation. The capsule system due to its modular character is very adaptable to offer a range of variety for different therapeutic purposes:
a) Compatibility with API. This core and innermost could be adjusted to serve for stability and compatibility towards most forms of APIs.
b) Dosing duration. Changing the number and even the composition of layers, then it last from hours until days.
c) Trigger-based release: Multiple stimuli-responsive polymers allow designing capsule systems that respond to particular physiological conditions or external triggers.

9. Potential Applications: Overall, it has wide potential applications for the following:
a) Chronic diseases, such as hypertension and diabetes management
b) Reduced frequency dosing of pain management
c) Targeted delivery of chemotherapeutic agents in cer treatment
d) Optimized delivery of antibiotics for reduction of antimicrobial resistance
e) Neurological disorders' management with improved efficacy

10. Advantages of the present invention:
a) Higher control over release kinetics be obtained by the multi-layered design
b) Reduced dosing frequency result in better compliance in patients
c) The ability to have multiple release mechanisms in one dosage form
d) Possible protection of sensitive APIs against the harsh conditions of the gastrointestinal tract;
e) Versatility in adapting to various drug types and therapeutic requirements
f) Less side effects due to optimized drug release profiles

The polymeric capsule-based controlled drug delivery of the present technology is at a great advancement level. This multi-layered system with integrated special polymers and production technologies guarantees unparalleled control over the kinetics of release of drugs. This way, treatment regimens for a broad range of medical conditions could be revolutionized, hence improving therapeutic outcomes and enhancing quality of life of patients.

Method of Performing the Invention
The optimal implementation of the time-release polymeric capsule system involves a carefully designed combination of materials, manufacturing processes, and quality control measures. The following description outlines the best mode of performing the invention, integrating all embodiments to produce the most effective and versatile drug delivery system.

1. Core Formulation (102): For optimal performance, the core is prepared as a multi-component system:
a) API micronization: The active ingredient is first micronized to enhance dissolution rate and bioavailability.
b) Nanostructured carriers (111): Mesoporous silica nanoparticles are used to encapsulate the micronized API, further improving solubility and release characteristics.
c) Matrix formation: The nanoparticle-encapsulated API is dispersed in a hydrophilic polymer matrix (e.g., low molecular weight polyethylene glycol) to form a semi-solid core.

2. Layer Composition and Sequence: The optimal layer structure from innermost to outermost is as follows:
a) Innermost layer (105): A blend of high molecular weight polyethylene oxide (PEO) and ethylcellulose, providing long-term sustained release.
b) pH-sensitive layer (106): Eudragit® L100-55, protecting the drug from gastric acid and enabling intestinal release.
c) Enzyme-responsive layer (107): Azo-crosslinked chitosan, allowing for colon-specific drug release.
d) Thermosensitive layer (108): Poly(N-isopropylacrylamide) (PNIPAM) copolymerized with acrylic acid, enabling temperature-modulated release.
e) Intermediate layers (104): Multiple thin layers of hydroxypropyl methylcellulose (HPMC) with varying molecular weights, creating a gradient for controlled release.
f) Outermost layer (103): A rapidly dissolving layer of polyvinylpyrrolidone (PVP) mixed with a small amount of the API for immediate release.

3. Manufacturing Process (109): The optimal manufacturing process combines several advanced techniques:
a) Core preparation:
- API micronization using jet milling
- Loading of API into mesoporous silica nanoparticles using supercritical CO2 impregnation
- Dispersion of loaded nanoparticles in PEG matrix using hot-melt extrusion
b) Layer application:
- Innermost and pH-sensitive layers: Precision spray coating using a fluidized bed system
- Enzyme-responsive and thermosensitive layers: Layer-by-layer electrostatic deposition
- Intermediate HPMC layers: Alternating spray coating and brief curing steps
- Outermost layer: Final spray coating with immediate-release formulation
c) Surface modification (112):
- Application of a thin mucoadhesive chitosan layer using dip-coating
- Conjugation of targeting ligands (e.g., folic acid for cer targeting) using carbodiimide chemistry
d) Curing and stabilization:
- Controlled humidity curing to optimize polymer chain interactions
- Brief exposure to gamma irradiation for sterilization and polymer crosslinking

4. Quality Control Methods (110): Comprehensive quality control is implemented throughout the manufacturing process:
a) In-process controls:
- Real-time monitoring of particle size and layer thickness using laser diffraction and ultrasonic sensors
- Spectroscopic techniques (NIR, Raman) for continuous composition analysis
b) Final product testing:
- High-resolution imaging (SEM, TEM, confocal microscopy) for layer structure visualization
- Dynamic mechanical analysis for assessing layer integrity and interactions
- Dissolution testing under biorelevant conditions using USP apparatus 3 (reciprocating cylinder)
- Stability studies under various temperature and humidity conditions (ICH guidelines)

5. Release Mechanism Integration: The invention integrates multiple release mechanisms:
a) Initial burst release from the PVP outermost layer (103)
b) pH-sensitive polymer layer release in the intestine via Eudragit® layer dissolution (106)
c) Gradual diffusion through HPMC layers with erosion-mediated release (104)
d) Enzyme-triggered release in the colon through azo-bond cleavage (107)
e) Temperature-modulated release via PNIPAM layer for fever-responsive delivery (108)
f) Long-term sustained release from the PEO/ethylcellulose innermost layer (105)

6. Customization for Specific Applications: The system's versatility allows for application-specific optimizations:
a) Cardiovascular diseases: Incorporation of chronotherapy principles by adjusting the thickness of intermediate layers for early morning peak drug release.
b) cer treatment: Enhanced targeting through surface-conjugated folate ligands and incorporation of penetration enhancers in the core formulation.
c) Neurological disorders: Integration of omega-3 fatty acids in the core to enhance BBB penetration, combined with sustained release for symptom management.

7. Advantages of the Best Mode: This optimal implementation offers several key advantages:
a) unprecedented control over release kinetics through the integration of multiple responsive polymers and layering techniques.
b) Enhanced bioavailability of poorly soluble drugs via nanostructured core formulation.
c) Reduced dosing frequency (potentially once-daily or once-weekly) due to the multi-mechanism sustained release profile.
d) Ability to respond to physiological changes (pH, enzymes, temperature) for adaptive drug release.
e) Improved patient compliance through reduced dosing frequency and potentially reduced side effects.
f) Versatility in adapting to various drug types and therapeutic requirements without signifit changes to the manufacturing process.

By combining these advanced features and production methods, this best mode of performing the invention represents the cutting edge of controlled drug delivery technology, offering signifit improvements over existing systems in terms of release control, therapeutic efficacy, and patient outcomes.
, Claims:1. A time-release polymeric capsule system for controlled drug delivery, comprising:
a) a core (102) containing an active pharmaceutical ingredient (API);
b) multiple polymer layers (103, 104, 105) surrounding the core, each layer designed to dissolve at a different rate;
c) at least one pH-sensitive polymer layer (106);
d) at least one enzyme-triggered polymer layer (107);
e) at least one thermosensitive polymer layer (108);
f) nanostructured materials (111) incorporated within the core or polymer layers to enhance drug solubility and release characteristics; and
g) surface modifications (112) for improved mucoadhesion or targeted delivery;
wherein, the combination and arrangement of said layers provide a predetermined drug release profile over an extended period.

2. A method for manufacturing the time-release polymeric capsule system as claimed in claim 1, comprising:
a) preparing the core (102) by micronizing the API, loading it into nanostructured carriers (111), and dispersing in a polymer matrix;
b) sequentially applying multiple polymer layers (103, 104, 105, 106, 107, 108) using a combination of spray coating, layer-by-layer assembly, and 3D printing techniques;
c) applying surface modifications (112) through dip-coating or chemical conjugation;
d) curing and stabilizing the capsule system under controlled conditions;
e) implementing quality control methods (110) throughout the manufacturing process to ensure consistency and efficacy of the final product.

3. The time-release polymeric capsule system as claimed in claim 1, wherein the core (102) comprises mesoporous silica nanoparticles (111) loaded with the API and dispersed in a hydrophilic polymer matrix.

4. The time-release polymeric capsule system as claimed in claim 1, wherein the multiple polymer layers comprise:
a) an innermost layer (105) composed of a blend of high molecular weight polyethylene oxide (PEO) and ethylcellulose;
b) intermediate layers (104) composed of hydroxypropyl methylcellulose (HPMC) with varying molecular weights;
c) an outermost layer (103) composed of rapidly dissolving polyvinylpyrrolidone (PVP).

5. The time-release polymeric capsule system as claimed in claim 1, wherein the pH-sensitive polymer layer (106) is composed of L100-55 polymer or S100 polymer.

6. The time-release polymeric capsule system as claimed in claim 1, wherein the enzyme-triggered polymer layer (107) is composed of azo-crosslinked chitosan or pectin derivatives.

7. The time-release polymeric capsule system as claimed in claim 1, wherein the thermosensitive polymer layer (108) is composed of poly(N-isopropylacrylamide) (PNIPAM) copolymerized with acrylic acid.

8. The time-release polymeric capsule system as claimed in claim 1, wherein the surface modifications (112) comprise a mucoadhesive coating of chitosan and conjugated targeting ligands.

9. The time-release polymeric capsule system as claimed in claim 1, wherein the predetermined drug release profile comprises:
a) an initial burst release from the outermost layer (103);
b) a pH-triggered release in the intestine;
c) a gradual diffusion through intermediate layers (104);
d) an enzyme-triggered release in the colon;
e) a temperature-modulated release; and
f) a long-term sustained release from the innermost layer (105).

10. A method of treating a medical condition using the time-release polymeric capsule system as claimed in claim 1, comprising administering said capsule system to a patient in need thereof, wherein the capsule system provides controlled release of the API over an extended period, resulting in reduced dosing frequency and improved therapeutic efficacy.

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