Short Communication

A Review: Recent Strategies Involved in Brain Targeting Through Ocular Route - Patents and Application

Sunita Thakur*, Pramod Kumar Sharma and Rishabha Malviya
Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, India


*Corresponding author: Sunita Thakur, Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Yamuna Expressway, Greater Noida, India


Published: 24 Feb, 2017
Cite this article as: Thakur S, Sharma PK, Malviya R. A Review: Recent Strategies Involved in Brain Targeting Through Ocular Route - Patents and Application. Ann Pharmacol Pharm. 2017; 2(8): 1043.

Abstract

The eye is a highly sensitive organ. Its physiology and anatomy leads to considering it as a highly protected organ. Effective therapy depends on designing of delivery system. Brain targeting through the ocular delivering system, is a formidable task. But now a day’s ocular delivery plays a promising approach towards brain targeting. The Scientist has been found, some alternative models for brain targeting. These delivering systems have the ability to overcome limitations of current therapy. Treating brain tumors are kind of difficult task due to their uncontrollable growth & poor prognosis. Chemotherapy, aggressive surgical & radiotherapy is resulting in harmful side-effects to the human body. Toxicity and adverse effects can be minimized via the brain targeted delivery system. This will tend to enhance the accumulation of drug in tumor region. The ocular delivering system becomes a new strategy for brain therapy. This review deals with recent strategies, approaches, its vision, future aspects, patents & challenges in brain targeting. It also gives further insight for improved therapies in treating brain disorders via ocular route.
Keywords: Chemotherapy; Brain targeting; Prognosis; Therapy; Ocular delivery


Introduction

It has been studied that 1.5 billion of population was suffering from brain disorders. Upsetting part of the CNS delivering drug was blood brain barrier (BBB). Blood brain barrier act as big obstacle in distribution of CNS drugs. Hydrophilic drugs like neuropeptides creates problem while passing through the BBB. Innovative approaches have been utilized in CNS drug formulations. The approach mainly concerns about delivering drug to its pertinent sites [1]. The most challenging aspect is treating brain disorders. It considered as so because of many obstacles occurs during delivery of drug. Localizing the drug at its site is the main concern of treatment. Brain targeting facilitates localization of the drug to its target site (Table 1). So, toxicity and other side effects would be minimized. It will also lead to efficient treatment. New strategies include certain approaches through which targeting will be easy. The most effective approach is targeting via ocular route than conventional ones. Now days, it becomes a rational approach to treat brain disorders. To achieve successful targeting, a brief intracellular characterization of blood brain barrier should be concerned [2]. Various harmful effects come out after chemotherapy. Accumulation of drug in peripheral tissues can be minimized through ocular route in brain targeting. In recent decades, active drug targeting extensively employed for treating brain tumors. As tumors have idiosyncratic features from peripherally present tumors. That’s why, before targeting tumors, various factors should be kept in mind before targeting. Factors includes such as the microenvironment of tumors, the number of tumor cells (Table 2), extent of tumor cells, size, type of barriers present etc. [3]. Target specificity can be achieved through ocular route. This may reduces peripheral toxicity and direct targeting of drug towards site Brain targeted drug delivery deals with rate limiting step i.e. blood brain barrier. It is an major obstacle in delivery of drug for brain targeting [4]. This barrier has greater ability: To separate and restrict brain from circulatory network; allow molecules transportation which provides functional activity of brain; Prevents lipid and water soluble substance transportation to CNS; Improvement in BBB cell biology; restrain infiltration of the molecules [5]. For prevention of brain disorders, CNS related diseases; an effective amount of dose is needed for effective treatment. Optimum pharmaceutical composition, quantity of subject useful in ocular route of delivering drug system [2]. Ocular route preferred as an alternative route to deliver the drug to its target site. The effect of parameter such as physiochemical properties should be studied. Physiochemical properties include H-band capacity, shape, lipophilicity, size of molecules. Drug delivery vectors are also being utilized in crossing BBB. For example, mannitol modifies the BBB’s structure and osmotic balance. By doing so, it tends to facilitate penetration of drug across the BBB. However, possibility of complication may arise, such as ocular toxicity, seizures, etc. [6]. BBB considered as most challenging target site to exert therapeutic effects. For this it becomes important to maximize brain exposure towards drug instead of systemic exposure. Systemic exposure May leads to prevail systemic toxicity which would be undesirable. Due to incapability of providing sustained effect of the drug towards its specific site. Many formulations are rendered useless in the treatment of cerebral disorders. Current approaches are being employed for enhancing, delivering techniques through which drug can deliver into the brain. Now days, clinical failure is often not due to a potency deficiency in drug, but rather to method shortcomings through which drug can be delivered. That's why researchers have found some strategies through which delivering pattern have improved; there will be no need of invasive techniques requires treating cerebral disease [7].


Table 1

Another alt text

Table 1
The Various barriers affect CNS drug delivery.

Table 2

Another alt text

Table 2
Examples of Active Transporters.

Table 3

Another alt text

Table 3
Challenges of CNS concern during drug development in brain targeting.

Routes of ocular delivery system


Overview of the BBB

It acts as a dynamic interface which separates the brain from systemic circulation of the body. It can be morphologically characterized through tight junctions, complex in nature present in-between endothelial cells [8]. 98% of potential neuralpharmaceuticals have been rejected as they won't cross the blood brain barrier. It mainly performs neuronal functions by creating ionic homeostasis [9]. Some tasks such as providing nutrients to the CNS performed through BBB. But, through various transport systems, it protects CNS from toxic insults [10]. Many neuropharmaceuticals for example-protein drugs, biopharmacons, and nucleic acids do not reach towards its target i.e. in CNS [11]. Due to which CNS disorders treatment remains unsatisfactory. To get positive results, delivering system of drugs have been improved to achieve brain targeting [12].


Factors Involved in Brain Targeting

Physiological factor
Passive diffusion: Uncharged particles, (< 500 g/ml) small molecular size, lipophilicity, less hydrogen bonding potential are the main factors affecting drug diffusion across the BBB through this transport mechanism. This can be improved by reducing the size of molecules and enhancing lipophilicity which is dependent on ionization as well as the polarity of drug [7].
Transport through vesicular: It employs two types of transport mechanism, which are given below: i) Adsorptive endocytosis; ii) Fluid phase endocytosis. Possibility of binding phenomenon at the initial phase and the plasma membrane of cell also gets interacts in this process. Adsorptive endocytosis characterized via its steerable tendency & ligand selectivity properties. Transportation of various macromolecules from blood to brain occurs through endocytosis i.e receptor mediated endocytosis. This involves insulin & transferrin receptor mediated transport [13].
Active mediated transport: This transport mechanism is also termed as carrier mediated transport. Amino acids, nucleotides, glucose, LAT1, GLUT1 are some carrier mediated transporters. They have better and higher transport capability [14]. New strategies are being utilized in improving the passage of drugs across the blood brain barrier transcellularly. This strategy includes endogenous compounds linked with drugs that can be delivered across BBB [15- 23].
Other factors are: Concentration gradient of drug, Molecular weight of drug, Sequestration by cells, Metabolism of other tissues, Lipophilicity of drug, Affinity for efflux protein, Clearance rate of drug, Cellular enzymatic stability (Table 3), Pathological status, Systemic enzymatic stability.


Table 4

Another alt text

Table 4
Routes of ocular drug delivery.

The strategies involved in brain targeting & its applications: There are some strategies involved in brain targeting-[35]


Table 5

Another alt text

Table 5
Various strategies involved in brain targeting.

Recent patents involved-[36].


Table 6

Another alt text

Table 6
Recent patent applications.

Application of brain targeting through different.


Elements of Blood Brain Barrier

Transport pathways: It regulates supply of minerals, proteins, amino acids, vitamins, sugars, etc. It also allows metabolite regulation, provides protection against xenobiotics.
Metabolic barrier: It facilitates protection against the undesirable effects of bioactive molecules.
Anatomical barrier: In between CNS and blood free exchange of cells & solutes get restricted through this barrier [24].
Challenges of CNS in development of drug: Following table represents the two main challenges faced during drug development for brain targeting.


Table 7

Another alt text

Table 7
Applications -Brain targeting through various routes.

Approaches Employed for Increasing Brain Penetration

Brain penetration can be enhanced by using three approaches: invasive approach, non-invasive, miscellaneous approach [25,26].
Invasive approach
In this approach, a hole is made in the head through drilling afterwards infusion /IC (intracerebral) is given via ICV i.e. intracerebral- ventricular. Invasive approach is of following types: a) intracerebral implants. b) Intra-cerebro-ventricular infusion; c) Disruption of BBB; d) Convection-enhanced delivery.
Merits of invasive approach
Wide range of preparations can be employed in this approach either IC /ICV route. This approach can be applicable for delivering small as well as large molecules either in combination or alone itself. But, Invasive approach includes some limitations also given as below:
Demerits of invasive approach
High cost, hospitalization and anesthetic condition are required. Disruption of BBB results in spreading of cancerous cells. The entering of unwanted blood components may be possible. Neurons can be permanently damaged after employing this approach.
Noninvasive approach
Drug distribution in brain capillaries can be achieved through non-invasive technique. Noninvasive approach generally comprises of either manipulating drug or altering drug characteristics by using prodrug, colloidal/chemical techniques, liposomes, nanoparticles. It has some limitation also: a) Half life is short; b) stability is less; c) solubility is also low; d) Production cost is high; e) Leaking of encapsulated drug may be possible.
Miscellaneous approach
Transport mechanism; b) Intranasal drug delivery Intranasal/ ocular delivery: Drugs are delivered in cavity/mucosa of nasal/ ocular. Many drugs such as sedatives, CVS drugs, Corticoids, hormones, analgesic & vaccines. Mechanism of route: It includes both extracellular &intracellular mediated routes.
Ocular route: Drug delivery system
Ocular drug delivery is prompted through various barriers present in the eye. There are some factors which may affect the pharmacokinetics and future challenges of ocular delivery in brain targeting.


Pharmacokinetics of Ocular Route

Barriers of eye
Loss of drug through ocular surfaces: The lachrymal fluid tries to remove installed drug rapidly within a minute from ocular surface after instillation [27]. The elimination due to lachrymal flow decreases concentration of the drug in the blood. Therefore, ocular bioavailability of the drug in tear fluid becomes only 10% [28].
Lachrymal fluid barrier: Drug absorption of lachrymal fluid in the eye gets prohibited due to presence of corneal epithelium [29]. Hydrophobic drugs have great affinity across this barrier than hydrophilic drugs [30]. This will serve as an absorption route for peptides and proteins or larger bio-organic substances.
Blood ocular barriers: This barrier provides protection from xenobiotics to the blood. Blood ocular barrier constitutes two types of barriers: blood-retina barrier; and blood aqueous barrier. After crossing this barrier, drug can be easily reached to the choroid and retina. For this specific targeting is necessary.


Future Prospective in Brain Targeting

Various Integrated blood brain barrier centers have been recognized itself in present scenario. This will bring all the researchers, scientists & beginners together to develop new targeting strategies through which brain targeting can be achieved. These BBB centers lead generating technologies for both large as well as small molecules based pharmaceutical preparations. It mainly concerns those drugs which have less or no permeability across the blood brain barrier. These centers will be based on applied sciences, technology based (Table 4 and 5). This focuses on developing new technologies regarding delivering drug molecules. Utilization of such technologies leads to re-formulate the drugs which will provide its passage across the BBB. Advancement in certain areas will help to achieve specific brain targeting such as new BBB transporters would be identified for brain targeting; Validating targeting system through in-vivo models; optimizing pharmacokinetics of in-vivo models; developing such targeting processes through which recombinant proteins and neurotherapeutics can be delivered properly (Table 6 and 7). Acquiring various strategies and technologies will lead to achieving better brain targeting.


Conclusion

Brain targeting is quite challenging as delivered drugs get prohibited across the brain. It remains non-effective as it does not cross the BBB due to the presence of a variety of obstacles barriers. Barriers such as bio-chemical, physiological and metabolic barriers, including BCB, BTB, and BBB obstruct drug movements from blood to brain. Present scenario faces patients who were suffering from untreated CNS disorders and treatment failure. But advancement in delivering technologies looks forward to utilize certain strategies to overcome BBB. It may lead to facilitate brain targeting and effective CNS treatment. Effective mechanisms through which drugs can deliver to its site facilitates direct brain targeting devoid of toxicity. Based on improved approaches followed by some more pioneering transport platform will be required for treating a wide range of neurological disorders such as epilepsy, stroke, Parkinson diseases, etc. This paper aims to provide recent strategies involved in brain targeting through ocular route. It also discusses about various approaches, patents and application of brain targeted neuropharmaceuticals.


Acknowledgement

The Authors are immensely thankful to the faculty members and Department of pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida for providing support, library and computer facilities and inspiring me for research work.


References

  1. Mehmood Yasser, Tariq Ayesha, SiddiquiAhmad. Brain is targeting drug delivery system: A review. Int J Basic Med Sci Pharm. 2015;5(1):2049-4963.
  2. Misra A, Ganesh S, Shahiwala A, Shah SP. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci. 2003;6(2):252-73.
  3. Wei X, Chen X, Ying M, Lu W. Brain tumor-targeted drug delivery strategies. Acta Pharm Sin B. 2014;4(3):193-201.
  4. Kim S, Bell K, Mousa SA, Varner JA. Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol. 2000;156(4):1345-62.
  5. Olivier J, De Oliveira. Nanoparticulate systems for central nervous system drug delivery. Drugs Pharm Sci. 2007;166:281.
  6. Bodor Nicholas, Buchwald Peter. Brain targeted drug delivery. American J Drug Deliv. 2003;1(1):13-26.
  7. Roy Sandipan. Strategic Drug Delivery Targeted to the brain: A Review. Der Pharmacia Sinica. 2012;3 (1):76-92.
  8. Wolburg H, Lippoldt A. Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul Pharmacol. 2002;38(6):323-37.
  9. About N. Atrocity-endothelial interactions and blood-brain barrier permeability. J Anta. 2002;200(5):629-38.
  10. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41-53.
  11. Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov. 2002;1(2):131-9.
  12. Neuwelt E, Abbott NJ, Abrey L, Banks WA, Blakley B, Davis T, et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 2008;7(1):84-96.
  13. Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Staryk RM. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain-barrier. Proc Natl Acad Sci USA. 1991;88(11):4771-75.
  14. Audus K L, Chikhale P J, Miller DW, Thompson SE, Borchardt RT, Adv Drug Res. 1992;23:3-53.
  15. Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci. 2000;89(11):1371-88.
  16. Wade LA, Katzman R. Synthetic amino acids and the nature of L-DOPA transport at the blood-brain barrier. J Neurochem. 1975;25(6):837-42.
  17. Negri L, Lattanzi R, Tabacco F, Scolaro B, Rocchi R. Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood-brain barrier penetration. Br J Pharmacol. 1998;124(7):1516-22.
  18. Saheki A, Terasaki T, Tamai I, Tsuji A. In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Coal) reeducates inhibitors. Pharm Res. 1994;11(2):305-11.
  19. Mackey J, Mani R, Selmer M, Models D, Young J, Belt J, et al. Mechanisms of Uptake and Resistance to Troxacitabine, a Novel Deoxycytidine Nucleoside Analogue, in Human Leukemic and Solid Tumor Cell Lines. Cancer Res. 1998;58:4349-57.
  20. Yao S, Cass C, Young J, Cytokine-accessibility analysis of transmembrane domains 11–13 of human concentrative nucleoside transporter 3 Mol. Pharmacol.1996;50:388-93.
  21. Kannan R, Kuhlenkamp JF, Ookhtens M, Kaplowitz N. Transport of glutathione at blood-brain barrier of the rat: inhibition by glutathione analogs and age-dependence. J Pharmacol Exp Ther. 1992;263(3):964-70.
  22. Zlokovic B, Hyman S, Mccomb J, Lipovac M, Tang G, Davson H. Kinetics of argentine-vasopressin uptake at the blood-brain barrier. Brioche Biophys Acta. 1990;1025:191-98.
  23. Pan W, Kastin A. In vivo Techniques Quantifying Blood-Brain Barrier Permeability to Small Proteins in Mice Peptides. 1990;20:1091-98.
  24. Maria A D. Drug transport and the blood brain barrier. Solubility, Delivery and ADME Problems of drugs and drug candidates. 2011:144-65.
  25. Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci USA. 1996;93(24):14164-9.
  26. Tosi G, Costantino L, Ruozi B, Forni F, Vandelli MA. Polymeric nanoparticles for the drug delivery to the central nervous system. Expert Opin Drug Deliv. 2008;5(2):155-74.
  27. Urtti A, Salminen L. Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol. 1993;37(6):435-56.
  28. Pipkin J D, Rork G S. Controlled drug delivery devices for experimental ocular studies with timolol, Ocular and systemic absorption in rabbits. Int J Pharm. 1990;61:241-9.
  29. Maurice DM, Misaim S. Ocular pharmacokinetics, in: M. L. Spears, Handbook of Experimental Pharmacology. Springer Vela. 1984;69:16-119.
  30. Huang HS, Schoenwald RD, Lach JL. Corneal penetration behavior of beta-blocking agents II: Assessment of barrier contributions. J Pharm Sci. 1983;72(11):1272-9.
  31. Hornof M, Toropainen E, Urtti A. Cell culture models of the ocular barriers. Eur J Pharm Biopharm. 2005;60(2):207-25.
  32. Gomes dos Santos AL, Bochot A, Doyle A, Tsapis N, Siepmann J, Siepmann F, et al. Sustained release of nanosized complexes of polyethylenemine and anti-TGF-beta 2 oligonucleotide improves the outcome of glaucoma surgery. J Control Release. 2006;112:369-81.
  33. Pitkanen L, Ranta VP, Moilanen H. Permeability of retinal pigment epithelium: effect of permanent molecular weight and lipophilicity. Invest Ophthalmol Vis Sci. 2005;46:641-46.
  34. Ruponen M, Nieminen J. Vitreous is a barrier in non-viral gene transfer by cationic lipids and polymers. Pharm Res. 2003;20:576-83.
  35. Misra A, Ganesh S, Shahiwala A, Shah SP. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci. 2003;6(2):252-73.
  36. Pale Pallavi, Aggarwal Geeta, Kumar S L H. Brain targeted drug delivery system: a review. World J Pharm Pharmaceut sci. 2016;5(6):398-414.
  37. Minko T, Rodriguez R, Gorbuzesko OB. Composition and methods for delivering nucleic acid molecule and treating cancer US9289505B2. 2016.
  38. Tsang KY,Wang H,Bai H. Copolymer conjugates US9295728B2. 2016.
  39. Zhu, Young-Liang Q, Xiangping. Benzenesulfonamide derivatives of quinoxalines, pharmaceutical compositions and their use in methods for treating cancer US9295671. 2016.
  40. Smith DB. Substituted nucleotide analogs US9278990 B2. 2016.
  41. Murphy EA, Cherish DA, Arnold LD. Therapeutic methods and compositions involving allosteric kinase inhibition US9260417B2. 2016.
  42. Selders TJ, Wang B, Howard J. Lysophosphatidic acid receptor antagonists and their use in treatment of fibrosis US9272990B2. 2016.
  43. Nystrom S, Personnel L. Method, device and system for network -based remote control over contactless secure storages US9294917B2. 2016.
  44. Roppe JR, Parr TA, Hutchinson JH. Heterocyclic autotaxin inhibitors and uses WO2012166415A1. 2012.
  45. Quian X, Zhu Y. Substituted quinoxalines as B-RAF kinase inhibitors US9249111B2. 2016.
  46. Abdulrazik M, Method for central nervous system targeting through the ocular route of drug delivery. 2003.
  47. Method for central nervous system targeting through the ocular route of drug delivery. 2003.
  48. Capsoni S, Covaceuszach S, Ugolini G, Spirito F, Vignone D, Stefanini B, et al. Delivery of NGF to the brain: intranasal versus ocular administration in anti-NGF transgenic mice. J Alzheimers Dis. 2009;16(2):371-88.
  49. DI Fausto V, Fiore M, Tirassa P, Lambiase A, Aloe L. Eye drop NGF administration promotes the recovery of chemically injured cholinergic neurons of adult mouse for the brain. EUR J Neurosci. 2007;26 (9): 2473-80.
  50. Patel NK, Gill SS. GDNF delivery for Parkinson's disease. Acta Neurochir Suppl. 2007;97(Pt2):135-54.
  51. Hartrick CT, Hartrick KA. Extended-release epidural morphine (DepoDur): review and safety analysis. Expert Rev Neurother. 2008;8(11):1641-8.
  52. Rogawski MA. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics. 2009;6(2):344-51.
  53. Celtic Pharma. Celtic Pharma Terminates Trans MIDTM trial KSB311R/CIII/001. 2010.
  54. Dodge JC, Clarke J, Treleaven CM, Taksir TV, Griffiths DA, Yang W, et al. Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease. Exp Neurol. 2009;215(2):349-57.
  55. Cook AM, Mieure KD, Owen RD, Pesaturo AB, Hatton J. Intracerebroventricular administration of drugs. Pharmacother. 2009;29(7):832-45.
  56. De Rosa R, Garcia AA, Braschi C, Capsoni S, Maffei L, Berardi N, et al. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc Natl Acad Sci. 2005;102 (10):3811-16.