A Recent Advances in Drug Delivery to Brain- A Review
Shailaja Jimidi Bhaskar
Department of Pharmaceutics, Bharat Institute of Technology,
Mangalpally, Ibrahimpatnam, Hyderabad, Telangana – 501510.
*Corresponding Author E-mail: bhaskarbehappy@gmail.com
ABSTRACT:
The most distressing fact about delivery of drugs to the CNS is the presence of blood brain barrier that have a tendency to impair the drug distribution and denotes the major impediment for the development of CNS drugs. Neuropeptides and many drugs which are hydrophilic in nature, possibly will encompass the intricacy while passing the blood brain barrier. The net amount of delivered drug and its capability to gain access to the pertinent target sites are the main considering points for CNS drug development. In order to distribute the drugs into the CNS via passing the blood brain barrier. Finally, one particular area that is often neglected in brain drug barrier delivery is the influence of aging on the BBB, which is captured in this review based on the limited studies in the literature.
KEYWORDS: Blood brain barrier, CNS, Neopeptides.
INTRODUCTION:
In the central nervous system, targeted action can be achieved by direct administration of the drugs in to the CNS. Blood brain barrier can considerably impair the effect of the large number of drugs (e.g. antibiotics, antineoplastic agents and Neuropeptides-CNS stimulant drug) because of its obstinate hindrance affect. From some recent studies, it has been represented that the blood brain barrier is usually does not cross by almost 100% of large molecule drugs and 98% of small molecule drugs. Presently, numerous approaches with enhanced pharmacodynamics effects, have been developed for the treatment of brain disorders. Drug discovery and drug delivery technologies are the two main fields where advancement is required for drug delivery to the brain. Nanoparticles drug delivery system (NDDS) is one of the advanced technology that can be utilized to deliver drug molecules directly into the brain and proved to be very effective against several CNS disorders1.
This review discusses recent development in the understanding of the BBB and its disruption in disease conditions. It focuses on new strategies that have been investigated to deliver therapeutic and diagnostic agents to the brain in the past five years.
Blood brain barrier
Cerebro spinal fluid
Physiochemical factors
Approaches:
Invasive, pharmacological and Physiological.
Invasive:
Intra cerebro ventricular, convention enhanced Polymer/microchip Implants.
Pharmacological:
Some molecules freely enter the rainy e.g. Alcohol, Nicotine, Benzodiazepine mol size C 500 D. Penetrates the BBB.
Physiological:
Used for increasing brain delivery, transcytosis capacity. E.g. Receptor mediated transcytosis, lypophilic. A drug must exhibit high potency and selectivity towards the biological target, as well as reach a concentration above an experimentally determined threshold within brain tissue.
There are multiple functions of BBB:
As an active pump
As a metabolic barrier
Regulation of BBB function
Protecting the brain from foreign substances in blood that may injure the brain
Protects the brain from hormones and neurotransfers in the rest of the body2.
It emphasizes on drug delivery to brain and also to study the BBB. The process of passing therapeutically active mol. across the BBB; for targeting brain cells. These systems have potential to target the desired tissues and attain sustained drug release for a longer period (Days/weeks). There are various routes of administration, as well as conjugation of drugs. With liposomes, nanoparticles are considered. Examples of drugs that can be formulation in NDDS are: Polysorbate 80-coated nanoparticles. Tubocurarine, Doxorubicin. The specific targeting along with sustained and controlled release delivery. The challenge is to deliver therapeutic agents to specific regions of brain in most brain disorder. It controls the entry of compounds into the brain barrios thereby regulates homeostasis. The capillaries lined with a layer of special endothelial cells, sealed with tight junctions. It regulates passage of molecules in and out of brain to maintain neural environment. Junctional adhesion molecules are important for trafficking of T-lymphocytes, neutrophils, and dendrite cells from the vascular compartment to the brain during immune surveillance and inflammatory responses. Adherens junctions provide strong mechanical attachments between adjacent cells and are built from cadherins and catenins. The compact network of interconnections is conferring to the endothelial layer of the BBB a transelectrical resistance >1500 cm2, which is the highest among all other endothelial districts. Basically, should also possess properties of hydrophilicity and lipophilicity3.
· Drug delivery is even for challenging when the target is a CNS tumor.
· Drug delivery to neoplastic cell in a solid tumor is compromised by heterogeneous distribution of microvasculature throughout the tumor interstitial, which leads to spatially inconsistent drug delivery.
· Further more, as a tumor grows large, the vascular surface area decreases, leading to reduction in trans-vascular exchange of blood- borne molecules.
· At the same time, intra-capillary distance increases, leading to a greater diffusional requirement for drug delivery ton neoplastic cells.
· As a result, the cerebral microvasculature in these tumor adjacent regions of normal brain may be even less permeable to drugs than normal brain endothelium, leading to exceptionally low extra-tumoral interstitial drug concentrations.
· Brain tumors may be also disrupt BBB, but these are also local and nonhomogeneous disruptions.
Crossing the BBB remains a key obstacle in the development of drug for brain diseases despite decades of research.
The parameters considered optimum for a compound to transport across BBB are:
a) Non-ionization.
b) Log P value near to 2.
c) Molecular weight less than 400 Da.
d) Cumulative number of hydrogen bonds between 8 to 10.
Intranasal Delivery of Drugs:
There are so many drugs that reach the CNS after nasal administration in different animal models as well as in humans. However, to deliver sizable amount of drug into the brain intranasal administration of neuroprotective agents is found to be more useful for the treatment of ischemic brain injury. It is a preferable method used to deliver local ailments of cold cough, rhinitis, and so forth. Further, to accelerate the action of drug colloidal nanoparticles mucosal or tumor barrier intranasal delivery method is applied to send them to various parts of brain. But delivery of peptides and proteins seems to be very hard to send them for systemic use through nasal route4.
Intraventricular Drug Delivery:
Intraventricular drug delivery is used for pain medication and drug is delivered within the cerebrospinal fluid of the cistern (C1-2 vertebra) and intracranial ventricles. This method is primarily used for delivery of analgesic drugs for patients having, tumors of head, face, and neck. More often it is used in cerebral drug targeting by administering medication directly. It needs less amount of drug and imposes fewer side effects than orally administered drugs. In this methods a plastic reservoir is used, which is implanted subcutaneously in the scalp and connected to the ventricles within the brain by an outlet catheter5.
Several drugs do not have adequate physiochemical characteristics such as high lipid solubility, low molecular size and positive charge which are essential to succeed in traversing BBB.
The thought behind this approach was to break down the barrier momentarily by injecting mannitol solution into arteries in the neck. The resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells, shrinking them, thus opening tight junction. The effect lasts for 20-30 minute, during which time drugs diffuse freely, that would not normally cross the BBB. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma, malignant glioma and disseminated CNS germ cell tumors. Physiological stress, transient increase in intracranial pressure, and unwanted delivery of anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans.
Possible systems for drug delivery-colloidal drug carriers Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles show great promise as drug delivery systems. The goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties6.
Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. The fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles. Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control.
Liposomes were first produced in England in 1961 by Alec D. Bangham. One end of each molecule is water soluble, while the opposite end is water insoluble. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends; fat-soluble medications were incorporated into the phospholipid layer7.
There is a need to target therapeutics to specific brain region / cell types.
Also a need to understand BBB; transport system. Also colloidal drug carrier system vesicle, liquid crystal dispersion and size ranging from 10 to 400nm. Need to in-vivo evaluation of brain drug pharmacokinetics. Also, a need to identify new brain drug targeting systems. Speed development and application of molecular imaging robes ad targeted contrast agents8.
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Received on 03.10.2023 Modified on 28.12.2023
Accepted on 31.01.2024 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2024; 14(1):83-86.
DOI: 10.52711/2231-5691.2024.00013