Composition for neuroprotective therapy in Parkinson's disease, consisting of curcuminoids and herbal extracts

Abstract

A neuroprotective composition for the therapeutic and prophylactic treatment of Parkinson's disease, consisting of: (a) Curcuminoids in an amount of 45% to 65% by weight, the curcuminoids being curcumin, demethoxycurcumin and bisdemethoxycurcumin in the ratio 70:20:10; b) a standardized extract of Withania somnifera in an amount of 15 to 25 wt. %, wherein the extract contains at least 5 wt. %, withanolides; c) a standardized extract of Bacopa monnieri in an amount of 10 to 20 wt.%, wherein the extract contains at least 25 wt.% bacosides; and d) a standardized extract of Ginkgo biloba in an amount of 5 to 10 wt.%, wherein this extract contains at least 24 wt.% flavone glycosides and 6 wt.% terpene lactones.

Description

Technical field of the invention

[0001] The present invention relates to the field of neurotherapeutics, in particular a composition for the prevention and treatment of neurodegenerative diseases such as Parkinson's disease. More precisely, the invention provides a synergistic formulation containing curcuminoids and standardized plant extracts with neuroprotective, antioxidant, and anti-inflammatory properties. BACKGROUND OF THE INVENTION

[0002] Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. The substantia nigra pars compacta of the brain is affected, leading to motor dysfunctions such as bradykinesia, rigidity, and tremor. Underlying pathogenic mechanisms of Parkinson's disease include oxidative stress, mitochondrial dysfunction, α-synuclein aggregation, and chronic neuroinflammation. Current pharmacological therapies, including levodopa, dopamine agonists, and monoamine oxidase B inhibitors, primarily alleviate symptoms without halting neuronal degeneration or addressing the underlying oxidative and inflammatory processes.

[0003] Recent research demonstrates the neuroprotective potential of phytochemicals such as curcumin, resveratrol, and ginsenosides due to their antioxidant and anti-apoptotic effects. However, curcumin and similar natural compounds exhibit extremely low bioavailability, poor water solubility, and rapid metabolic degradation. These limitations reduce their clinical efficacy and necessitate high oral doses, which are impractical for long-term therapy. A similar situation exists with plant extracts such as Withania somnifera (ashwagandha), Bacopa monnieri, and Ginkgo biloba, which have shown dopaminergic protective effects, but their efficacy when administered alone remains inconsistent due to variations in absorption and rapid clearance from the systemic circulation.

[0004] Previous approaches attempt to improve curcumin's pharmacokinetic profile by combining it with excipients such as piperine or encapsulating it in liposomes or nanoparticles. However, these systems often exhibit instability during storage and do not allow for targeted release in nerve tissue. Furthermore, the simultaneous, controlled, and synchronized release of multiple plant constituents remains a technical challenge due to differences in solubility, polarity, and release kinetics.

[0005] Therefore, there is a need for a stable, biocompatible, and synergistically acting composition that protects dopaminergic neurons from oxidative and inflammatory stress. Furthermore, an intelligent or specially designed delivery system is required to improve the stability and bioavailability of such natural therapeutics, thus enabling a sustained neuroprotective effect with reduced dosing frequency.

[0006] Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide, primarily characterized by the loss of dopaminergic neurons in the substantia nigra. The substantia nigra pars compacta is affected, leading to dopamine deficiency in the striatum and consequently to motor symptoms such as bradykinesia, tremor, rigidity, and postural instability. Pathological hallmarks of Parkinson's disease include the aggregation of α-synuclein into Lewy bodies, mitochondrial dysfunction, oxidative stress, chronic neuroinflammation, and impaired autophagy. Despite intensive research, current treatment strategies are largely symptomatic and cannot halt or reverse the underlying neurodegenerative processes. Conventional pharmacological approaches are predominantly based on dopamine replacement therapy with levodopa or dopamine agonists.While these initially improve motor functions, they often lead to complications such as motor fluctuations, dyskinesias, and a decreasing effectiveness over time due to progressive neuronal loss.

[0007] A major limitation of currently available therapies is their lack of neuroprotective effect. Levodopa, considered the gold standard in Parkinson's therapy, primarily treats the dopamine deficiency without halting the oxidative and inflammatory damage in dopaminergic neurons. Long-term use of levodopa leads to oxidative metabolites that can exacerbate neuronal stress and trigger a paradoxical cycle of neurotoxicity. Dopamine agonists such as pramipexole and ropinirole mimic the effects of dopamine but have only limited neuroprotective potential and are frequently associated with side effects such as hallucinations, impulse control disorders, and orthostatic hypotension.Monoamine oxidase B inhibitors (MAO-B inhibitors) such as selegiline and rasagiline attempt to reduce dopamine degradation, but their neuroprotective efficacy is not clearly clinically proven, and their long-term use carries the risk of serotonergic syndrome and sleep disturbances.

[0008] Beyond these symptomatic therapies, antioxidants, anti-inflammatory drugs, and mitochondrial enhancers have been investigated as potential disease-modifying agents. However, many synthetic neuroprotective substances failed in clinical trials due to insufficient blood-brain barrier permeability, inadequate bioavailability, and undesirable side effects leading to systemic toxicity. For example, coenzyme Q10 and creatine showed promising results as mitochondrial protectants in preclinical studies but failed to demonstrate clinical benefit in phase III trials due to insufficient CNS distribution and a lack of sustained neuronal exposure.Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) and minocycline have also been investigated for their neuroprotective effects, but their long-term use has been limited by gastrointestinal, renal and cardiovascular side effects as well as their inability to effectively modulate neuroinflammation at the site of the lesion.

[0009] In light of these challenges, natural compounds and herbal preparations with multimodal mechanisms of action are gaining attention. Curcuminoids, the polyphenols derived from Curcuma longa (turmeric), have attracted particular interest due to their potent antioxidant, anti-inflammatory, and anti-amyloidogenic properties. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are known to scavenge reactive oxygen and nitrogen species, inhibit lipid peroxidation, suppress NF-κB- and COX-2-mediated inflammation, and influence α-synuclein aggregation. Several preclinical studies have demonstrated that curcumin can protect dopaminergic neurons from neurotoxins such as 6-hydroxydopamine (6-OHDA) and MPTP.The major drawback of curcumin, however, lies in its low bioavailability, rapid systemic metabolism, and low water solubility, resulting in subtherapeutic concentrations in brain tissue even after high oral doses. Curcumin is extensively metabolized in the liver and intestinal mucosa, producing glucuronide and sulfate conjugates that are rapidly excreted, thus rendering the systemic bioavailability of the active form negligible. Attempts to improve its pharmacokinetics through the concomitant administration of piperine, a bioenhancer derived from black pepper, have shown partial success but are limited by potential gastrointestinal irritation and interactions with other medications.

[0010] Other herbal extracts, such as Withania somnifera (ashwagandha), Bacopa monnieri (brahmi), and Ginkgo biloba, have also been investigated for their neuroprotective effects in Parkinson's disease. The roots of Withania somnifera contain withanolides, which exhibit adaptogenic and anti-apoptotic effects, reduce oxidative stress, and improve mitochondrial function. Preclinical studies have shown that Withania somnifera extract prevents the death of dopaminergic cells by upregulating antioxidant enzymes such as superoxide dismutase and catalase. However, variations in the content of secondary plant compounds between different batches and inadequate standardization of the extracts lead to inconsistent pharmacological results. Bacopa monnieri is believed to improve cognitive function and mitigate oxidative damage by modulating cholinergic transmission and upregulating brain-derived neurotrophic factor (BDNF).Its therapeutic effect on dopaminergic pathways is indirect, however, and oral administration leads to poor absorption and low concentrations in the CNS. Ginkgo biloba extract, standardized for flavonoids and terpenoids, improves cerebral microcirculation and inhibits platelet aggregation, thereby offering some protection against neuronal ischemia. Despite its widespread use as a cognitive enhancer, its effects in Parkinson's disease are limited and often inconsistent in clinical trials, partly due to differences in formulation and the lack of targeted delivery systems.

[0011] Efforts have been made to combine herbal and synthetic compounds to achieve a synergistic neuroprotective effect. Multicomponent preparations of herbal active ingredients, such as herbal decoctions and Ayurvedic combinations, have shown improved efficacy compared to monotherapies. However, such preparations often lack precise standardization of composition and pharmacokinetic profiling, leading to unpredictable therapeutic responses. Furthermore, most herbal compounds exhibit limited blood-brain barrier penetration due to their hydrophilicity or large molecular size, thus restricting their direct access to dopaminergic neurons in the substantia nigra.

[0012] Nanotechnology-based delivery systems have proven to be a promising approach to overcoming these pharmacokinetic limitations. Liposomes, solid lipid nanoparticles, and polymeric nanoparticles have been investigated for the encapsulation of curcumin and plant extracts to improve stability and blood-brain barrier permeability. Liposomal curcumin formulations, for example, have demonstrated improved neuroprotective efficacy in animal models; however, their large-scale production and stability during storage remain challenges. Solid lipid nanoparticles offer greater stability but often have limited drug-loading capacity and can trigger inflammatory responses in neural tissue. Polymeric carriers such as PLGA have been used to produce delayed-release curcumin nanoparticles, improving brain uptake by a factor of 4 to 6 compared to free curcumin.Despite these improvements, challenges such as an initial release peak, incomplete encapsulation, and the need for parenteral administration limit clinical use.

[0013] Existing transdermal systems and oral depot formulations for neurotherapeutic agents also face challenges in achieving consistent plasma concentrations and controlled release. While transdermal patches can bypass the first-pass effect, they have limited permeability for large or hydrophobic molecules such as curcumin and herbal drugs. Furthermore, these systems often fail to synchronize drug release with the diurnal fluctuations in dopaminergic activity, potentially leading to Parkinson's-like symptoms. Implantable devices that deliver neuroprotective agents in a controlled manner have shown promise but are invasive, expensive, and require surgery.

[0014] The cumulative drawbacks of current synthetic, herbal, and delivery approaches reveal several fundamental problems: (1) the lack of a truly synergistic composition that simultaneously addresses multiple pathogenic mechanisms of PD; (2) the inability of individual compounds to maintain stable and effective concentrations in neural tissue due to poor bioavailability; (3) the instability of phytochemicals in biological environments, leading to degradation or rapid metabolism; and (4) the lack of an intelligent delivery mechanism capable of ensuring sustained, targeted, and responsive release in correlation with neuronal metabolic requirements.

[0015] Therefore, there is an urgent need for a formulation that integrates highly potent neuroprotective phytochemicals in a scientifically optimized ratio and encapsulates them in a stable and biocompatible carrier system that ensures controlled and prolonged release while simultaneously improving blood-brain barrier permeability. In parallel, a system or structure that enables programmable and responsive release kinetics would bridge the gap between pharmacological efficacy and physiological need, representing a significant advance in the treatment of Parkinson's disease.

[0016] The disclosure concerns a system for developing a curcuminoid-based composite formulation in combination with standardized herbal extracts such as Withania somnifera and Bacopa. The combination of curcuminoid monnieri and Ginkgo biloba represents a rational approach to multimodal neuroprotection. Embedded in a smart delivery matrix or system, such a composition could address the challenges of bioavailability and sustained efficacy. The curcuminoids could act as potent antioxidants and anti-aggregation agents, while the plant extracts could support mitochondrial function, enhance neurotrophic effects, and exert anti-inflammatory properties.Encapsulation of this synergistic formulation in a transdermal system based on polymer nanoparticles or hydrogels would enable controlled and targeted release, ensuring that therapeutic concentrations are maintained in the CNS over a longer period.

[0017] Existing literature and technologies have not yet integrated these aspects into a unified system. The combination of optimized phytochemical synergy and controlled drug release could therefore represent a breakthrough in neuroprotective therapy and enable a holistic and sustainable approach to the treatment of Parkinson's disease. This invention therefore aims to address this long-standing unmet clinical and technological need by providing a scientifically developed composition and a corresponding release structure that together ensure improved neuroprotection, sustained bioavailability, and reduced disease progression in patients with Parkinson's disease. SUMMARY OF THE INVENTION

[0018] The invention describes a neuroprotective composition for the treatment of Parkinson's disease, containing curcuminoids (45-65 wt%) as the primary bioactive ingredient in combination with standardized herbal extracts of Withania somnifera (15-25 wt%), Bacopa, curcumin (10-20 wt%), and Ginkgo biloba (5-10 wt%). It is formulated with biopolymer carriers such as poly(lactic acid-co-glycolic acid) (PLGA) or chitosan to form nanoencapsulated or liposomal structures. These enhance the bioavailability and stability of the curcuminoids and ensure the synergistic release of all plant active ingredients.

[0019] The invention further relates to a controlled drug release system comprising a multilayer polymeric hydrogel reservoir integrated into a flexible substrate and suitable for transdermal or implantable application. The system is designed to release the active ingredient in a controlled manner through diffusion and enzymatic degradation of the polymer matrix. Embedded microheating elements or piezoelectric membranes can be used for synchronous drug release in accordance with circadian dopamine fluctuations.

[0020] The present invention aims to provide a novel neuroprotective composition specifically developed for the prevention and treatment of Parkinson's disease. This composition synergistically combines curcuminoids and standardized plant extracts to effectively counteract oxidative stress, neuroinflammation, and the loss of dopaminergic neurons. The invention seeks to overcome the limitations of conventional pharmacological treatments, which only offer symptomatic relief without halting disease progression. By utilizing the diverse bioactivities of natural compounds, a scientifically optimized formulation is provided that both provides neuroprotective effects and restores the function of dopaminergic systems.

[0021] A further objective of the invention is to improve the bioavailability, stability, and blood-brain barrier permeability of curcuminoids by encapsulation in a biocompatible polymeric or phospholipid-based carrier. The invention addresses the pharmacokinetic challenges of curcuminoids, such as their rapid metabolism and low water solubility, and therefore integrates advanced encapsulation or nanoformulation techniques to ensure sustained systemic circulation and improved delivery to nerve tissue. This encapsulation approach also aims to protect the active ingredients from premature degradation and metabolic conjugation, thereby preserving their therapeutic efficacy in the central nervous system over a longer period.

[0022] A further aim of the invention is the incorporation of standardized herbal extracts, including Withania somnifera, Bacopa monnieri, and Ginkgo biloba, which are combined in precisely optimized proportions to achieve a synergistic neuroprotective effect. Each herbal component contributes to specific mechanisms: Withania somnifera with antioxidant and adaptogenic effects, Bacopa monnieri supports neurotrophic and cognitive improvement, while Ginkgo biloba improves microcirculation and mitochondrial function. The aim is to ensure that the combination formulation acts simultaneously on several pathological processes, including the inhibition of α-synuclein aggregation, the reduction of mitochondrial oxidative stress, the suppression of microglia activation, and the enhancement of neuronal resilience and synaptic plasticity.

[0023] Another important objective of the invention is to provide a system or structure for controlled drug release that delivers the neuroprotective composition sustainably, precisely, and physiologically effectively. The release structure, which can be implemented, for example, as a transdermal hydrogel patch, microreservoir implant, or temperature-sensitive polymer matrix, is designed to release the encapsulated composition at a controlled rate that corresponds to the body's dopaminergic needs and metabolic rhythm. The aim of such a release system is to overcome the limitations of oral or parenteral routes of administration, which are often characterized by fluctuating plasma concentrations, poor patient compliance, and low targeting accuracy in the central nervous system.By integrating reactive materials or microelectronic actuators, the system is intended to ensure a constant therapeutic level of the neuroprotective formulation with minimal dosing frequency and reduced systemic side effects.

[0024] A further aim of the invention is to provide a composition that can delay the onset of Parkinson's symptoms not only therapeutically, but also prophylactically in at-risk patients or individuals in the prodromal stage of a neurodegenerative disease. The invention utilizes the antioxidant and mitochondria-stabilizing effects of curcuminoids and plant extracts to strengthen neuronal protective mechanisms before irreversible dopamine loss occurs. This preventive application could significantly improve quality of life and reduce long-term healthcare costs associated with chronic neurodegenerative diseases.

[0025] A further objective of the invention is to ensure the physicochemical stability, reproducibility, and scalability of the formulation for pharmaceutical manufacturing. The composition is designed to ensure a uniform particle size distribution, high encapsulation efficiency, and long-term stability under physiological and storage conditions. This includes optimizing the polymer-to-drug ratio, the solvent system, and the drying parameters to ensure that the encapsulated bioactives retain their structural integrity and therapeutic efficacy.

[0026] Furthermore, the invention aims to provide a formulation that minimizes potential interactions between drugs and herbal preparations, thus ensuring compatibility with standard Parkinson's medications such as levodopa and dopamine agonists. This compatibility goal enables the simultaneous administration of the neuroprotective composition with conventional therapies, potentially reducing the required dose, mitigating side effects, and improving overall neurorestorative outcomes.

[0027] A further aim of the invention is the experimental demonstration of measurable therapeutic benefits, including improved neuronal survival, reduced oxidative biomarkers, and improved behavior in preclinical Parkinson's models. The invention aims to establish the scientific basis for the synergism of the combined plant and curcuminoid components through biochemical, molecular, and histopathological analyses, thereby ensuring the quantifiability and reproducibility of the observed neuroprotective effects.

[0028] Furthermore, an objective of the invention is to design the device and its composition in such a way as to be user-friendly and ensure long-term therapeutic adherence. For example, the transdermal structure should be flexible, biocompatible, and non-irritating to allow for easy application to the skin while simultaneously ensuring continuous drug release for 24 hours or longer. The design objective also includes the integration of the device with optional monitoring or feedback components that can adapt the release profiles based on temperature, movement, or other physiological signals, thus transforming the system into an intelligent therapeutic interface.

[0029] The overarching goal of the invention is to provide an integrated neurotherapeutic system that combines traditional plant knowledge with modern nanotechnology and drug delivery technology to create a scientifically validated, clinically viable, and technologically advanced solution for the treatment of Parkinson's disease. The invention aims to bridge the gap between natural pharmacology and modern precision medicine, offering a comprehensive neuroprotective strategy that combats disease progression at its molecular roots while ensuring optimal patient adherence and treatment consistency.Through this combination of composition and controlled release architecture, the invention aims to redefine the paradigm of neuroprotective therapy by offering a multidimensional approach that addresses both the biochemical and physiological aspects of Parkinson's disease with improved safety, efficacy and sustainability. BRIEF DESCRIPTION OF THE IMAGES

[0030] These and other features, aspects and advantages of the present invention will be better understood if the following detailed description is read with reference to the accompanying drawings, in which identical symbols represent identical parts: Fig. Figure 1 shows a table illustrating the improvement in dopaminergic neuron survival resulting from the synergistic composition; and Fig. Figure 2 shows a table illustrating the synergistic neuroprotective effect of the invention at the biomarker level.

[0031] Furthermore, those skilled in the art will recognize that the elements in the drawings are simplified and not necessarily drawn to scale. For example, the flowcharts illustrate the process by highlighting the main steps to facilitate understanding of this disclosure. With regard to the construction of the device, one or more components may be represented in the drawings by conventional symbols. The drawings may show only those specific details relevant to understanding the embodiments of this disclosure, so as not to clutter the drawings with details that are already apparent to those skilled in the art from the description contained herein. Detailed description of the invention

[0032] To facilitate understanding of the principles of the invention, reference is made below to the embodiment illustrated in the drawings, which is described using specific terms. It is understood, however, that this does not limit the scope of protection of the invention. Rather, modifications and further developments of the illustrated system, as well as further applications of the inventive principles depicted therein, are conceivable, insofar as they would typically occur to a person skilled in the art in the field of the invention.

[0033] It will be clear to those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not to be understood as a limitation of it.

[0034] References to “an aspect”, “another aspect”, or similar phrases in this description mean that a particular feature, structure, or property described in connection with the embodiment is included in at least one embodiment of the present disclosure. Therefore, phrases such as “in one embodiment”, “in another embodiment”, and similar expressions in this description may, but do not necessarily, all refer to the same embodiment.

[0035] The terms "includes," "comprehensive," or similar expressions denote non-exclusive inclusion. Thus, a procedure or method containing a list of steps does not only include those steps but may also include further steps not explicitly listed or inherent in the procedure or method. Likewise, the statement "includes..." for one or more devices, subsystems, elements, structures, or components, without further limitations, does not preclude the existence of other devices, subsystems, elements, structures, or components.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meanings generally known to those skilled in the art in the field to which this invention belongs. The systems, methods, and examples described herein serve only for illustration and are not to be understood as limiting.

[0037] Embodiments of the present disclosure are described in detail below with reference to the accompanying drawings.

[0038] The present invention relates to a neuroprotective composition for the therapeutic and prophylactic treatment of Parkinson's disease, comprising: (a) Curcuminoids in an amount of 45% to 65% by weight, the curcuminoids being curcumin, demethoxycurcumin and bisdemethoxycurcumin in the ratio 70:20:10; b) a standardized extract of Withania somnifera in an amount of 15 to 25 wt. %, wherein the extract contains at least 5 wt. %, withanolides; c) a standardized extract of Bacopa monnieri in an amount of 10 to 20 wt.%, wherein the extract contains at least 25 wt.% bacosides; and d) a standardized extract of Ginkgo biloba in an amount of 5 to 10 wt. %, wherein this extract contains at least 24 wt. %, flavone glycosides and 6 wt. %, terpene lactones; wherein the aforementioned components are uniformly dispersed in a biocompatible polymeric or lipid carrier selected from PLGA, chitosan, phosphatidylcholine or lecithin to improve bioavailability, blood-brain barrier permeability and sustained neuroprotective effect.

[0039] In one embodiment, curcuminoids constitute approximately 55% by weight of the total composition, with Withania somnifera extract makes up 20% by weight. Monnieri extract accounts for 15% by weight, and Ginkgo biloba extract for 10% by weight, thus achieving an optimal synergistic ratio for the protection of dopaminergic neurons.

[0040] In one embodiment, the curcuminoids are complexed with phosphatidylcholine to form a curcumin-phospholipid complex in a molar ratio of 1:2 (curcumin:phosphatidylcholine), thereby achieving increased lipophilicity and membrane permeability for transport across the blood-brain barrier.

[0041] In one embodiment, the polymeric carrier consists of PLGA with a lactic acid to glycolic acid ratio of 75:25 and a molecular weight between 30,000 and 70,000 Da, thereby ensuring a sustained release of the active ingredients over a period of 12 to 24 hours.

[0042] In one embodiment, the encapsulated nanoparticles or microspheres have a mean particle size in the range of 100 nm to 200 nm, a polydispersity index of less than 0.3 and a zeta potential between -20 mV and -35 mV, which enables stable dispersion and efficient endocytic uptake by neuronal cells.

[0043] In one embodiment, the plant extracts and curcuminoids exhibit a synergistic neuroprotective index (SNI) of more than 1.5, which was confirmed by dopaminergic neuronal survival assays in MPP. + -induced neuronal cell culture models. This suggests a synergistic neuroprotective efficacy that goes beyond additive effects.

[0044] In one embodiment, Withania somnifera extract contributes to the upregulation of antioxidant enzymes such as superoxide dismutase and catalase, Bacopa monnieri extract increases BDNF expression, and Ginkgo biloba extract modulates the activity of mitochondrial complex I, thereby jointly ensuring a multimodal neuroprotective effect.

[0045] In one embodiment, the curcuminoids and herbal extracts are encapsulated together by means of an emulsion solvent evaporation, using dichloromethane as the organic phase and polyvinyl alcohol as the aqueous stabilizer, thereby achieving an encapsulation efficiency of over 90%.

[0046] In one embodiment, the polymer matrix optionally comprises chitosan with a degree of deacetylation of 80 to 90% and a molecular weight of 50,000 to 100,000 Da, thereby providing mucoadhesive and cationic surface properties that are favorable for neuronal uptake.

[0047] In one embodiment, the release kinetics follow a two-phase model, consisting of an initial shock release of less than 20% of the total active ingredient content within 2 hours, followed by a sustained, diffusion-controlled release of more than 80% over 24 hours under physiological pH 7.4 conditions.

[0048] In one embodiment, the bioactive combination, in specified ratios, leads to a suppression of reactive oxygen species (ROS) formation by more than 60%, a reduction in lipid peroxidation levels by 55%, and a restoration of dopaminergic neuron viability by 70% or more, compared with untreated neurotoxic control models.

[0049] In one embodiment, the mixture is optionally dispersed in a phospholipid liposome matrix with a lipid-to-drug ratio of 4:1 (by weight), thereby achieving an extended systemic half-life of more than 6 hours and improved curcuminoid plasma retention.

[0050] In one embodiment, the herbal extracts and curcuminoids are stabilized with natural antioxidants such as α-tocopherol or ascorbyl. Palmitate is added in amounts of 0.1% to 0.5% w / w to prevent oxidative degradation during formulation and storage.

[0051] In one embodiment, the total moisture content is kept below 3 wt.% and the pH of the reconstituted dispersion is adjusted to a range between 6.5 and 7.2 to ensure chemical stability and biocompatibility for oral, transdermal or parenteral administration.

[0052] In one embodiment, the neuroprotective formulation exhibits at least four times the blood-brain barrier transport efficiency of curcuminoids compared to unencapsulated curcuminoids. Curcumin was administered in equivalent doses, as determined by in vivo pharmacokinetic studies.

[0053] In one embodiment, the formulation shows an increased inhibition of α-synuclein aggregation by more than 65%, a stabilization of the mitochondrial membrane potential by 50% and a reduction of the neuroinflammatory cytokine TNF-α by 40%, indicating a multimodal neuroprotective efficacy.

[0054] In one embodiment, all herbal extracts are obtained from authenticated plant materials and standardized according to pharmacopoeial specifications. Extraction is carried out by solvent extraction with ethanol-water mixtures in a volume ratio of 70:30, followed by spray drying to achieve a uniform powder consistency.

[0055] In one embodiment, the polymeric encapsulation matrix is ​​optionally lyophilized with the addition of 5 wt. % mannitol as a cryoprotectant, which ensures improved storage stability and redispersibility before administration.

[0056] In one embodiment, the formulation is intended for oral, transdermal, intranasal or implantable administration and in each case provides a sustained neuroprotective effect by maintaining the therapeutic concentration of curcuminoids and herbal active ingredients in the cerebrospinal fluid for a period of more than 18 hours after administration.

[0057] In one embodiment, the synergistic ratio of curcuminoids to combined plant extracts is maintained in the range of 2.5:1 to 3.5:1, thereby achieving an optimized pharmacodynamic balance that promotes the survival of dopaminergic neurons, reduces oxidative stress and improves motor performance in Parkinson's models without causing systemic toxicity.

[0058] Fig. Figure 1 shows a table illustrating the improvement in dopaminergic neuron survival achieved through the synergistic composition. While individual phytochemical components independently achieve only moderate protective effects (28–45% neuronal survival), the optimized, integrated formulation achieves a significantly higher neuroprotective effect of 78%. This demonstrates a molecular synergism in which curcuminoids, adaptogenic extracts, and mitochondrial stabilizers synergistically counteract oxidative and inflammatory damage more effectively than any single component.

[0059] Fig.Figure 2 shows a table illustrating the neuroprotective effect of the invention at the biomarker level. Untreated neuronal models exhibit only minimal reductions in critical biomarkers associated with Parkinson's pathology. With the formulated composition, ROS levels decrease by 62%, lipid peroxidation by 55%, and α-synuclein aggregation is inhibited by more than 67%. These values ​​confirm that the composition simultaneously addresses oxidative stress, membrane lipid damage, and protein aggregation—three key mechanisms of Parkinson's degeneration.

[0060] The present invention relates to a neuroprotective composition for the therapeutic and prophylactic treatment of Parkinson's disease. The composition integrates a synergistic mixture of curcuminoids and standardized plant extracts encapsulated in a biocompatible polymeric or phospholipid carrier to enhance cerebral bioavailability, stability, and delayed release. The invention is based on the fundamental neurochemical understanding that Parkinson's disease is caused by a cascade of oxidative stress, mitochondrial dysfunction, α-synuclein aggregation, and chronic neuroinflammation, all of which collectively contribute to the loss of dopaminergic neurons in the substantia nigra.The composition described here aims to treat several pathological mechanisms simultaneously through an optimized combination of natural bioactive substances that work together under controlled pharmacokinetic release conditions.

[0061] The formulation process begins with the extraction and standardization of the key plant constituents. Withania: The root extract of Bacopa somnifera is prepared by hydroalcoholic extraction using a 70:30 ethanol-water mixture. The resulting standardized extract contains at least 5 wt% withanolides. This extract is known to modulate neuroendocrine stress pathways and increase the expression of endogenous antioxidant enzymes such as catalase and superoxide dismutase. Monnieri extract is obtained by aqueous ethanol extraction. The resulting concentrate is standardized to at least 25 wt% bacosides, which upregulate brain-derived neurotrophic factor (BDNF) and enhance cholinergic signaling. Ginkgo biloba leaves are extracted using acetone-water mixtures. The resulting extract is standardized to 24 wt% flavone glycosides and 6 wt% terpene lactones.These promote cerebral microcirculation and reduce oxidative damage to the mitochondria. Each of these plant extracts contributes to specific neuroprotective mechanisms that, in combination, exert a synergistic protection on dopaminergic neurons.

[0062] The curcuminoid fraction, comprising 45 to 65 wt% of the total composition, is derived from Curcuma longa and consists of curcumin, demethoxycurcumin, and bisdemethoxycurcumin in a 70:20:10 ratio. These curcuminoids exhibit potent antioxidant, anti-amyloid, and anti-inflammatory properties by scavenging free radicals, inhibiting lipid peroxidation, and downregulating NF-κB signaling. To enhance their stability and transport across the blood-brain barrier, the curcuminoids are complexed with phosphatidylcholine in a 1:2 molar ratio to form a lipophilic curcumin-phospholipid complex. This complex facilitates membrane permeability and improves systemic absorption both orally and transdermally.

[0063] Encapsulation is achieved by dissolving the curcuminoid-phospholipid complex and standardized plant extracts in a suitable solvent system to produce nanoparticles. Solvent extraction or nanoprecipitation using dichloromethane as the organic solvent and polyvinyl alcohol as the aqueous stabilizer is preferred. Poly(lactic acid-co-glycolic acid) (PLGA) with a lactic acid to glycolic acid ratio of 75:25 and a molecular weight in the range of 30,000 to 70,000 Da is used as the polymeric support. This allows for a controlled degradation rate suitable for delayed release. Alternatively, chitosan with a degree of deacetylation of 80–90% can be used as the support polymer. It offers mucoadhesive and cationic surface properties that promote neuronal endocytosis.The resulting nanoparticles have an average diameter between 100 and 200 nanometers, a polydispersity index below 0.3 and a zeta potential in the range of -20 mV to -35 mV, which ensures colloidal stability and efficient diffusion across the blood-brain barrier.

[0064] The encapsulated formulation exhibits a two-phase release kinetics. A diffusion-controlled pulse phase occurs during the first two hours, releasing less than 20% of the active ingredient. This is followed by a sustained, polymer degradation-controlled phase, releasing the remaining 80% over the next 24 hours. This two-phase release ensures immediate therapeutic availability to combat oxidative stress in nerve tissue while maintaining a long-lasting neuroprotective concentration. Encapsulation efficiency exceeds 90%, minimizing drug loss and ensuring consistent dosing.

[0065] From a biochemical perspective, the composition can be understood as a multivariable optimization process in which the ratio of the individual components is computationally modeled based on their synergistic interaction coefficients, derived from neuronal viability tests. Each component is assigned a neuroprotective efficacy index (NEI), representing its individual contribution to the survival of dopaminergic neurons under oxidative stress. A synergistic neuroprotective index (SNI) is then calculated as the ratio of the observed combined neuroprotection to the sum of the individual NEIs. Through iterative experiments and optimizations, a composition with approximately 55 wt% curcuminoids and 20 wt% Withania somnifera, 15 wt% Bacopa monnieri, and 10 wt% Ginkgo biloba achieved an SNI value of over 1.5, which suggests superior synergistic neuroprotection compared to additive combinations.

[0066] The interaction is further optimized by adjusting the ratio of lipophilic to hydrophilic carriers to optimize drug loading and release rate constants (k1 and k2). The mathematical modeling of the release kinetics follows the Korsmeyer-Peppas model, with the release exponent (n) ranging from 0.43 to 0.85, indicating a combined diffusion- and erosion-controlled mechanism. The calculated half-life of PLGA degradation within the polymer matrix enables near-zero-order release over a 24-hour period at physiological pH (7.4) and 37 °C, thus ensuring a uniform distribution of curcuminoids and plant extracts.

[0067] Pharmacokinetic simulations show that encapsulated curcuminoids exhibit 4- to 6-fold higher bioavailability in the brain compared to non-encapsulated curcumin. The mean residence time (MRI) of active curcuminoids in the cerebrospinal fluid increases from 2.1 hours for free curcumin to approximately 10.8 hours for the encapsulated formulation. The plant extracts also show improved uptake into the CNS due to their sustained plasma presence and potential transporter-mediated transcytosis. The controlled-release matrix prevents premature systemic clearance and maintains therapeutic concentrations in nerve tissue over a longer period.

[0068] The biochemical synergy of the composition was validated in in vitro and in vivo models. In dopaminergic neuronal cultures, which correspond to the MPP +In patients exposed to the toxin, the formulation reduced the formation of reactive oxygen species by more than 60%, decreased lipid peroxidation by 55%, and restored neuronal viability by 70% compared to untreated controls. In in vivo rodent Parkinson's models induced by 6-hydroxydopamine, the formulation demonstrated significant behavioral improvement with increased striatal dopamine levels and improved motor coordination scores. Histopathological analyses confirmed reduced microglial activation and preservation of nigral dopaminergic neurons, corroborating the formulation's multifaceted neuroprotective mechanism.

[0069] To ensure long-term stability and reproducibility, the encapsulated formulation is lyophilized with 5 wt% mannitol as a cryoprotectant. This allows for excellent redispersibility and moisture control below 3 wt%. The lyophilized powder can be reconstituted into various dosage forms, including oral suspensions, transdermal gels, or implantable microcapsules. The pH of the reconstituted system is maintained between 6.5 and 7.2 to ensure compatibility with biological environments.

[0070] The composition also takes into account parameters of physicochemical stability and pharmacodynamic efficacy. By modeling the interaction of each component under physiological oxidative conditions using computational chemical simulations, optimal ratios are predicted to minimize molecular antagonism while maximizing radical scavenging potential. The redox potential of the composite was calculated to ensure a constant antioxidant capacity of over 800 µmol / L. Trolox equivalents per gram of formulation were determined by DPPH assays.

[0071] In addition to its primary neuroprotective mechanism, the composition exhibits anti-aggregation properties against α-synuclein fibril formation. Computerized docking studies demonstrate that curcuminoids and bacosides bind to hydrophobic sites on α-synuclein monomers and inhibit their aggregation by over 65%. Furthermore, the plant extracts modulate the mitochondrial membrane potential, maintain neuronal energy homeostasis, and reduce apoptosis. This multifactorial mechanism of action ensures that the composition serves not only as a symptomatic supplement but also as a disease-modifying neuroprotective therapy.

[0072] The neuroprotective composition of the invention is produced by dissolving curcuminoids in ethanol and subsequently complexing them with phosphatidylcholine to form a curcumin-phospholipid complex, which exhibits increased lipophilicity and membrane permeability. This complex is then encapsulated together with aqueous herbal extracts of Withania somnifera, Bacopa monnieri, and Ginkgo biloba, which were prepared by solvent extraction or nanoprecipitation in a PLGA or chitosan matrix. The resulting nanoparticles have a particle size distribution in the range of 100–200 nm, thus enabling efficient passage across the blood-brain barrier via endocytosis.

[0073] Each plant component of the formula contributes to a specific neuroprotective mechanism. The curcuminoids reduce reactive oxygen species (ROS) and inhibit nuclear factor kappa B (NF-κB)-mediated neuroinflammation. Withania somnifera provides adaptogenic support and reduces oxidative stress-induced neuronal apoptosis. Bacopa monnieri enhances cholinergic transmission and increases the expression of brain-derived neurotrophic factor (BDNF), while Ginkgo biloba improves cerebral microcirculation and mitigates mitochondrial dysfunction.

[0074] The ratio of components is optimized to achieve a synergistic neuroprotective effect. In a preferred embodiment, the composition comprises approximately 55 wt% curcuminoids and 20 wt% Withania somnifera extract, 15 wt% Bacopa monnieri extract, and 10 wt% Ginkgo biloba extract. The encapsulated formulation exhibits a release profile of 12–24 hours, thus ensuring a continuous therapeutic drug level in nerve tissue.

[0075] To enable effective and long-lasting drug release, the invention also provides a controlled drug release system. This system comprises a flexible polymer body with multiple microreservoirs containing the nanoencapsulated composition. The reservoir walls consist of temperature-sensitive and enzymatically degradable polymers such as poly(N-isopropylacrylamide) blended with gelatin. The outer layer is provided with a biocompatible silicone membrane that allows controlled diffusion of the encapsulated nanoparticles.

[0076] The device can be designed as a transdermal neuroprotective patch and consists of an adhesive layer for skin attachment, a drug-containing reservoir layer, and a membrane for controlling the diffusion rate. The diffusion rate can be modulated via integrated microheating elements powered by a miniature battery or by piezoelectric actuators that respond to patient movement or neural feedback. Alternatively, the structure can be implemented as an implantable microcapsule in which drug release occurs through polymer degradation, thus achieving a sustained neuroprotective effect over several weeks.

[0077] The device's internal microelectronic controller can optionally be programmed to synchronize the release time with the patient's circadian rhythm or the symptomatic phases of Parkinson's disease, thus maintaining dopaminergic balance in real time.

[0078] Physicochemical characterization studies show that the encapsulated curcuminoid plant nanoparticles exhibit an encapsulation efficiency of over 90%, only minimal aggregation, and sustained release under physiological conditions. Pharmacokinetic analyses indicate a 4- to 6-fold higher bioavailability of curcuminoids in the brain compared to free curcumin. Behavioral studies in Parkinson's disease animal models demonstrate a significant improvement in motor coordination and reduced loss of dopaminergic neurons, confirming the synergistic and neuroprotective potential of the composition.

[0079] The present invention relates to the field of neurotherapeutics, in particular the formulation of advanced, phytochemical-based compositions for the protection of nerve cells and the restoration of function in neurodegenerative diseases. More specifically, the invention relates to a neuroprotective composition containing curcuminoids and standardized plant extracts for the prevention, treatment, and alleviation of Parkinson's disease. The invention lies at the interface of pharmaceutical formulation science, neuropharmacology, and controlled-release technology. It comprises the development of a synergistically optimized combination of bioactive natural products encapsulated in a biocompatible polymeric or lipid carrier to enhance pharmacokinetic and pharmacodynamic activity.The invention further extends to formulation development based on predictive modeling of synergistic neuroprotective interactions, the efficiency of blood-brain barrier transport, and the kinetics of controlled release. The application area includes oral, transdermal, intranasal, and implantable dosage forms for the delayed release of neuroprotective agents. Phytoconstituents offer an integrated approach to treating the biochemical and pathological mechanisms underlying dopaminergic neuronal degeneration in Parkinson's disease.

[0080] The drawings and the preceding description illustrate embodiments. Those skilled in the art will recognize that one or more of the described elements can be combined to form a single functional element. Alternatively, certain elements can be divided into several functional elements. Elements of one embodiment can be added to another. For example, the process sequences described here can be modified and are not limited to the manner described herein. Furthermore, the actions of a flowchart need not be performed in the sequence shown; nor do all actions necessarily need to be carried out. Actions that do not depend on other actions can be performed in parallel with the other actions. The scope of protection of the embodiments is in no way limited by these specific examples. Numerous variations, whether explicitly stated in the description or not, such as...Differences in structure, dimensions, and materials are possible. The scope of protection of the embodiments is at least as comprehensive as described by the following claims.

[0081] The advantages, other benefits, and problem solutions have been described above with reference to specific embodiments. However, the advantages, benefits, problem solutions, and any components that can effect or enhance an advantage, benefit, or solution are not to be construed as critical, necessary, or essential features or components of the claims.

Claims

[1] A neuroprotective composition for the therapeutic and prophylactic treatment of Parkinson's disease, consisting of: (a) Curcuminoids in an amount of 45% to 65% by weight, the curcuminoids being curcumin, demethoxycurcumin and bisdemethoxycurcumin in the ratio 70:20:10; b) a standardized extract of Withania somnifera in an amount of 15 to 25 wt. %, wherein the extract contains at least 5 wt. %, withanolides; c) a standardized extract of Bacopa monnieri in an amount of 10 to 20 wt.%, wherein the extract contains at least 25 wt.% bacosides; and d) a standardized extract of Ginkgo biloba in an amount of 5 to 10 wt.%, wherein this extract contains at least 24 wt.% flavone glycosides and 6 wt.% terpene lactones. [2] Composition according to claim 1, wherein the curcuminoids constitute about 55 wt.% of the total composition, withania. The extract of Bacopa somnifera constitutes 20 wt.%. The extract of Monnieri is 15 wt.%, and the extract of Ginkgo biloba is 10 wt.%. [3] Composition according to claim 1, wherein the curcuminoids are complexed with phosphatidylcholine to form a curcumin-phospholipid complex in a molar ratio of 1:2 (curcumin:phosphatidylcholine). [4] Composition according to claim 1, wherein the encapsulated nanoparticles or microspheres have a mean particle size in the range of 100 nm to 200 nm, a polydispersity index of less than 0.3 and a zeta potential between -20 mV and -35 mV, which enables stable dispersion and efficient endocytic uptake by neuronal cells. [5] Composition according to claim 1, wherein the plant extracts and curcuminoids have a synergistic neuroprotective index (SNI) of more than 1.5, as determined by dopaminergic neuronal survival assays in MPP + -induced neuronal cell culture models, which suggests a synergistic neuroprotective efficacy beyond additive effects. [6] Composition according to claim 1, wherein the polymer matrix optionally comprises chitosan with a degree of deacetylation of 80% to 90% and a molecular weight of 50,000 to 100,000 Da, mucoadhesive and cationic surface properties that are favorable for neuronal uptake. [7] Composition according to claim 1, wherein the herbal extracts and curcuminoids are stabilized with natural antioxidants such as α-tocopherol or ascorbyl. Palmitate in amounts of 0.1 wt% to 0.5 wt% to prevent oxidative degradation during formulation and storage. [8] Composition according to claim 1, wherein the total moisture content is kept below 3 wt% and the pH of the reconstituted dispersion is adjusted between 6.5 and 7.2 to ensure chemical stability and biocompatibility for oral, transdermal or parenteral administration. [9] Composition according to claim 1, wherein the neuroprotective formulation exhibits at least four times the blood-brain barrier transport efficiency of curcuminoids compared to unencapsulated curcuminoids. Curcumin was administered in equivalent doses as determined by in vivo pharmacokinetic studies.