BRAIN TARGETING NANOPARTICLE FORMULATION VIA NASAL ROUTE FOR THE TREATMENT OF ALZHEIMER'S DISEASE

Abstract

The present invention relates to pharmaceutical 5 formulations, particularly to polymeric nanoparticles designed for the delivery of Memantine (MEM), a therapeutic agent indicated for the treatment of Alzheimer’s disease (AD). This invention encompasses methods of preparing Memantine-bound polymeric nanoparticles, their characterization, and their application in enhancing the 10 bioavailability and therapeutic efficacy of MEM. Specifically, the invention focuses on the use of nanoparticles as a drug delivery system to improve the pharmacokinetic profile of Memantine through various administration routes, including nasal and oral delivery.

Specification

Description:FIELD OF THE INVENTION
The present invention relates to pharmaceutical 5 formulations, particularly to
polymeric nanoparticles designed for the delivery of Memantine (MEM), a
therapeutic agent indicated for the treatment of Alzheimer's disease (AD). This
invention encompasses methods of preparing Memantine-bound polymeric
nanoparticles, their characterization, and their application in enhancing the
10 bioavailability and therapeutic efficacy of MEM.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a progressive neurodegenerative disorder
characterized by cognitive decline and memory loss, affecting millions
15 worldwide. Current therapeutic approaches primarily focus on symptomatic relief
rather than halting disease progression. Memantine, a low-affinity, voltagedependent
uncompetitive antagonist of N-methyl-D-aspartate (NMDA)
receptors, is approved for moderate to severe cases of AD. It has been
demonstrated to improve cognitive function when used in conjunction with
20 acetylcholinesterase inhibitors such as galantamine, donepezil, and rivastigmine.
However, while Memantine is effective in managing symptoms, it does not
prevent the underlying neurodegenerative processes associated with Alzheimer's
disease.
Despite the clinical utility of Memantine, its bioavailability is limited due to first25
pass metabolism and poor solubility, necessitating the exploration of innovative
delivery methods to enhance its therapeutic potential. Recent studies have
highlighted the potential of nanoparticle-based delivery systems to improve the
bioavailability of poorly soluble drugs by enabling controlled release, reducing
3
systemic side effects, and facilitating targeted delivery to the central nervous
system (CNS).
Polymeric nanoparticles have garnered attention for their biocompatibility,
biodegradability, and ability to encapsulate therapeutic agents. These
nanoparticles can protect Memantine from degradation, 5 and facilitate its transport
across biological barriers, including the blood-brain barrier (BBB). Moreover, the
use of a nasal route for administration can bypass first-pass metabolism, offering
a promising alternative to traditional oral delivery methods.
However, existing analytical techniques for quantifying Memantine in biological
10 matrices, such as plasma, cerebrospinal fluid (CSF), and brain homogenate, have
significant limitations, including low sensitivity and the requirement for large
sample sizes. Therefore, the development of a validated, sensitive, and costeffective
analytical method for Memantine quantification is essential to evaluate
the pharmacokinetics and brain uptake of Memantine delivered via nanoparticle
15 formulations.
This invention aims to address these unmet needs by providing a novel
formulation of Memantine encapsulated within nanoparticles, along with a
validated analytical method for accurate quantification in biological matrices. By
improving the delivery and efficacy of Memantine, this invention seeks to
20 enhance the treatment options available for Alzheimer's disease and potentially
improve patient outcomes.
SUMMARY OF THE INVENTION
The present invention relates to a novel formulation of Memantine (MEM)
25 encapsulated within polymeric nanoparticles, specifically designed for the effective
treatment of Alzheimer's disease (AD). Memantine, an uncompetitive antagonist
4
of the N-methyl-D-aspartate (NMDA) receptor, is currently used to manage
moderate to severe cases of AD but is limited by its poor bioavailability, rapid firstpass
metabolism, and low solubility. This invention addresses these limitations
through the development of Memantine-loaded polymeric nanoparticles, enhancing
its pharmacokinetic pr 5 ofile and therapeutic efficacy.
The formulation utilizes biocompatible and biodegradable polymeric materials,
such as poly(lactic-co-glycolic acid) (PLGA), which provide structural integrity,
targeted delivery, and controlled release of Memantine. These nanoparticles are
10 engineered to facilitate the crossing of biological barriers, particularly the bloodbrain
barrier (BBB), thereby ensuring that Memantine effectively reaches the
central nervous system. The innovative delivery system aims to minimize systemic
side effects while maximizing therapeutic effects.
15 The efficacy of the Memantine-loaded polymeric nanoparticles is further supported
by comprehensive in vitro and in vivo studies, demonstrating improved cell
viability, enhanced brain distribution, and favorable therapeutic outcomes
compared to free Memantine solutions. Behavioral tests and histological analyses
confirm the superiority of the nanoparticle formulation in promoting cognitive
20 function and neuronal protection in models of Alzheimer's disease.
In summary, this invention offers a transformative approach to Alzheimer's disease
treatment by providing a novel Memantine delivery system that enhances
bioavailability, and targeted action, along with a validated analytical method for
25 accurate drug quantification. By addressing the existing challenges associated with
Memantine therapy, this invention holds the potential to significantly improve
patient outcomes and broaden the therapeutic options available for managing
Alzheimer's disease.
5
DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the present disclosure.
The embodiments are in such detail as to clearly communicate the disclosure.
However, the amount of detail offered 5 is not intended to limit the anticipated
variations of embodiments; on the contrary, the intention is to cover all
modifications, equivalents, and alternatives falling within the spirit and scope of the
present disclosure.
Unless the context requires otherwise, throughout the specification which follow,
10 the word "comprise" and variations thereof, such as, "comprises" and "comprising"
are to be construed in an open, inclusive sense that is as "including, but not limited
to."
Orientation throughout this specification to "one embodiment" or "an embodiment"
means that a particular feature, structure or characteristic described in connection
15 with the embodiment is included in at least one embodiment. Thus, the appearances
of the phrases "in one embodiment" or "in an embodiment" in various places
throughout this specification are not necessarily all referring to the same
embodiment. Furthermore, the particular features, structures, or characteristics may
be combined in any suitable manner in one or more embodiments.
20 The headings and abstract of the invention provided herein are for convenience only
and do not interpret the scope or meaning of the embodiments.
The present invention relates to pharmaceutical formulations, particularly to
polymeric nanoparticles designed for the delivery of Memantine (MEM), a
therapeutic agent indicated for the treatment of Alzheimer's disease (AD). This
25 invention encompasses methods of preparing Memantine-bound polymeric
nanoparticles, their characterization, and their application in enhancing the
6
bioavailability and therapeutic efficacy of MEM. Specifically, the invention focuses
on the use of nanoparticles as a drug delivery system to improve the
pharmacokinetic profile of Memantine through various administration routes,
including nasal and oral delivery
All formulations' particle sizes were examined 5 using the zeta-sizer equipment. For
Run-16 (Figure a), the PNs of Memantine had an optimised size range of 148.9 nm.
The created formulation of memantine-loaded PLGA-NPs displayed spherical
surface shape and a consistent 200 nm particle size distribution. The increased
PLGA content may have influenced the particle size, causing them to seem hazy
10 (i.e., due to greater aggregation). For Run-16, the ZP findings for the relevant
formulation were 23.8 mV (as seen in the following figure).
In-vitro diffusion studies
Following figure depicts the behaviour pattern of medication release for the pure
15 medication and optimised PNs of medication. The optimised drug loaded PNs R2
values were determined to be 0.835, 0.868, and 0.944, respectively, compared to
the obtained R2 values of 0.921 for pure drug, 0.934 for first-order, 0.940 for the
Higuchi model, and 0.921 for zero-order. The Higuchi model for pure-drug
Memantine and optimised PNs of Memantine appeared to be the best fit, according
20 to the R2 values obtained for several kinetic models. For the pure drug Memantine
and the optimised PNs of Memantine formulation, the release exponent (n) values
were 0.689 and 0.478, respectively. As a result, whereas Memantine-optimized PNs
exhibit non-Fickian diffusion kinetics, the drug release from pure drug exhibits
Fickian diffusion kinetics.
25
Cytotoxicity studies
Brain endothelial cells and rat astrocyte primary cultures were used to gauge the
cell viability of MEM-PLGA NPs. Together, these cells are thought to be an
7
appropriate model to investigate the cytotoxicity of nanoparticles because they
collectively make up the BBB. The accompanying figure shows that MEM-PLGA
NPs did not exhibit any detectable harmful effects after being incubated for 24
hours. These findings demonstrate that both endothelial glial brain cells and the
5 produced particles are biocompatible.
In-vitro and in-vivo transport across the BBB
The in-vitro model's cell membrane preserved 40% of the initial MEM-PLGA NPs
after 1 hour of incubation, while only 30% of the initial MEM was discovered inside
10 the barrier, according to the results.
Morris water maze test
The MWM test, which is depicted in the following picture, was used to evaluate
how the MEM therapy affected the conduct of the animals.
15
Immunohistochemistry
Tiofavin-S staining allowed researchers to see the development of A plaques, a
pathologic hallmark of AD.
20 Accelerated stability outcomes
The accelerated stability studies' p values for the design are presented. For each
CQA, the p value was more than 0.05, indicating that there had been no significant
change. The optimised freeze-dried PNs of memantine were therefore determined
to satisfy the stability criteria since little to no significant changes in CQAs were
25 observed across the stability period. , Claims:1) A polymeric nanoparticle formulation for the delivery of Memantine (MEM).
2) The polymeric nanoparticle formulation as claimed in claim 1, wherein brain
targeting nanoparticle formulation via nasal route for alzheimer's disease.
3) The polymeric 5 nanoparticle formulation as claimed in claim 1, comprising;
- Memantine encapsulated within a biocompatible and biodegradable
polymer matrix selected from the group consisting of poly(lactic-coglycolic
acid) (PLGA), and combinations thereof;
- A stabilizer selected from Poloxamer-188 or other suitable surfactants; and
10 - A particle size ranging from 100 nm to 300 nm..
4) The polymeric nanoparticle formulation as claimed in claim 1 wherein, the
polymeric nanoparticles are prepared via a method comprising
nanoprecipitation followed by ultrasonication.

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