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\def\citeauthor{~Venkata~Lokesh~G,
              ~Madhuvani~M,
              ~Chatla~Chandana,
              ~Sarad~Pawar~Naik~B,
              ~Bhargavi~S,
              ~Manasa~A}
\def\citetitle{Conventional Opthalamic Drug Delivery System: An Outlook}
\def\copyrightstmt{This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.}
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\begin{document}


\def\RunningAuthor{Sarad Pawar Naik B et al.}
\firstPage{85}
\articleType{Review Article}
\receivedDate{03 Apr 2021}
\acceptedDate{16 Apr 2021}
\revisedDate{15 Apr 2021}
\journalVolume{1}
\journalIssue{3}
\journalDoi{fjphs.v1i3.207}
\copyrightYear{2021}
\eISSN{2583-116X}
\journalDoi{fjphs.v1i3.207}
\def\authorCount{6}
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\def\journalTitle{Future Journal of Pharmaceuticals and Health Sciences}

\title{Conventional Opthalamic Drug Delivery System: An Outlook}
\author{Venkata~Lokesh~G\textsuperscript{1},  
            Madhuvani~M\textsuperscript{2},  
            Chatla~Chandana\textsuperscript{2},  
            Sarad~Pawar~Naik~B\textsuperscript{*}\textsuperscript{3},  
            Bhargavi~S\textsuperscript{3}, 
            Manasa~A\textsuperscript{4}~\\[5pt]{\textsuperscript{1}Department of Pharmacy Practice, Rao's College of Pharmacy, Chemudugunta (V\&P), Venkatachalam (M), S.P.S.R.Nellore-524 320, Andhra Pradesh, India}~\\{\textsuperscript{2}Rao's College of Pharmacy, Chemudugunta (V\&P), Venkatachalam (M), S.P.S.R.Nellore-524 320, Andhra Pradesh, India}~\\{\textsuperscript{3}Department of Pharmaceutics, Rao's College of Pharmacy, Chemudugunta (V\&P), Venkatachalam (M), S.P.S.R.Nellore-524 320, Andhra Pradesh, India}~\\{\textsuperscript{4}Department of Pharmacology, Rao's College of Pharmacy, Chemudugunta (V\&P), Venkatachalam (M), S.P.S.R.Nellore-524 320, Andhra Pradesh, India}}

\begin{abstract}
The most sensitive and complex organ in the human body is the eye, so special attention should be needed for the administration of pharmaceutical substances into the eye. It is one of the most difficult for researchers in the preparation of drug delivery to the eye. The anatomical characteristics and physiological properties of the eye should be considered in drug delivery. The properties of pharmaceutical dosage forms depend upon the anatomy and physiology of the eye. Drug delivery on to the outer part as well as in the inner part of the ocular structure for the therapy is a unique and challenging one. Physiochemical, microbiological, and pharmaceutical properties lead to absorption and elimination of active therapeutic agents into and out of the eye. Loss of precorneal more and fastly occurs due to drainage in the region of extraocular are some of the drawbacks in ocular drug delivery of conventional dosage forms. To overcome these problems, advancements in conventional dosage forms take place. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Ocular Drug Delivery System,\newline Conventional Approaches,\newline Ocular Inserts,\newline Bioerosion
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright{\Large$^\ast$}Corresponding Author\par Name:\ Sarad~Pawar~Naik~B~\\ Phone:\ +91 9966555743~\\  Email:\ drsaradpawar@gmail.com
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\section{Introduction}
Issues such as absorption, distribution, metabolism, and elimination (ADME) must be considered for developing a strategy of drug delivery \unskip~\cite{1072500:21976194}.\ensuremath{^{}} When it comes to the delivery of pharmaceuticals, the eye presents unique challenges and opportunities. Pharmaceutical scientists face interesting and challenging attempts in ocular drug delivery development \unskip~\cite{1072500:21976195}.\ensuremath{^{}} The eye is intensely impermeable to outer substances due to anatomical, physiological and biochemical properties of the eye. Various barriers protect the eyeball from foreign particles and external stress. There are several routes of administration such as eye drops, sub-conjunctival, sub-tendon's, and intravitreal injection and/or implant. Most of the drugs used in the eye should be moved into the eye through several protective barriers despite drug administration \unskip~\cite{1072500:21976192}.\ensuremath{^{}} Clinically, Drugs are normally applied for the eye through systemic, periocular, or intraocular injections to treat eye disorders because drugs that are applied topically, do not move to the inner regions of the eye (retina, vitreous, and choroid) \unskip~\cite{1072500:21976189,1072500:21976200}.\ensuremath{^{}} Normally, local therapy is mostly preferable for the eye as against systemic therapy to prevent the risk of injury or harm to the eye from more concentrations of drug in the blood, which is not considered for the eye \unskip~\cite{1072500:21976196}.

\textbf{Physiology of the Eye}

The eye comprises the lens, transparent cornea, and vitreous body without blood vessels. The aqueous humour that is having the same osmotic pressure and having more oxygen so that the transport of oxygen and nutrients to this non-vascular tissue through the blood. The aqueous humour in humans has a volume of 300 \ensuremath{\mu}l which is present in front of the lens. This volume fills the front portion of the eye. At the cornea sclerotic junction, a thin epithelial layer covers the cornea along with the conjunctiva continuously. Crises - crossing layers of collagen forms the main bulk of cornea and is surrounded by elastic lamina on both anterior and posterior portion. Endothelium layer covers the back portion. Free nerve endings are richly supplied incorrectly. The transparent cornea comprises tough fibrous tissue and is continued posteriorly into the opaque white sclera. Intraocular tension is continuously maintained in the eye. Intraocular tension is resisted by both sclera and cornea. Generally, lacrimal apparatus are used for cleaning and lubrication purposes of the eye. 

\textbf{Eye}\textbf{ co}\textbf{emprises}\textbf{ of }\textbf{4} \textbf{ Structures}


  
  \begin{enumerate}
  \item \relax Naso-lacrimal duct 
  \item \relax lacrimal sac 
  \item \relax Lacrimal canals 
  \item \relax Lacrimal glands.
  \end{enumerate}
  Lacrimal glands secrete the lacrimal fluid is emptied on the conjunctiva surface of the anterior portion of the eyelid at a turnover rate of 16\% per min. By the blinking action of eyelids, it cleans over the eyeball and is washed off \unskip~\cite{1072500:21976199}. Enlargement of the sac, due to relaxation of muscle; the lacrimal fluid is pulled from the edges of the eyelids into the lacrimal sacs through the lacrimal canals occurs due to the muscles associated with the blinking reflux compress the lacrimal sac. The lacrimal fluid volume in humans is 7 \ensuremath{\mu}l and is an isotonic aqueous solution of sodium chloride and bicarbonate with a pH of 7.4. It provides dilution of irritant substances or removes the foreign particles out of the conjunctival sac \unskip~\cite{1072500:21976190}. It contains lysozyme, which decreases the bacterial count in the conjunctiva sac which is having bactericidal activity. The physiological barriers to productive absorption and diffusion of a drug that is applied typically present in the precorneal and corneal spaces. Solution drainage, lacrimation, tear dilution, tear turnovers are the ocular conventional dosage forms, and conjunctival absorption undergoes poor bioavailability due to precorneal constraints \unskip~\cite{1072500:21976197}.

\textbf{Classification of Ocular Drug Delivery System}

Based on their physical forms, they are categorized as follows


  
  \begin{enumerate}
  \item \relax Solids: Corneal protector, Artificial tear inserts, Ocular inserts, Contact lenses.
  \item \relax Powders: Lotions and drops.
  \item \relax Liquids: Suspensions, Solutions, Sprays, Sol to gel systems.\ensuremath{^{}}
  \item \relax Semi-solids: Gels and Ointments.\ensuremath{^{}}
  \item \relax Parenteral Preparations: Intravitreous or retrobulbar injections, Intracorneal.\ensuremath{^{}}
  \item \relax Miscellaneous: Ocular penetration, Ocular iontophoresis, Vesicular dosage forms, Mucoadhesive systems \unskip~\cite{1072500:21976184}.
  \end{enumerate}
  \textbf{Merits of Ocular Drug Delivery System }


  
  \begin{enumerate}
  \item \relax Absorption is very rapid due to the large surface area for absorption.
  \item \relax More vascularisation may lead to the rapid onset of action. 
  \item \relax As an alternative to other administration routes, ocular administration of the suitable drug would therefore be effective in emergency therapy. 
  \item \relax The First-pass metabolism can be eluded that occurs in the liver and thus in contrast to oral delivery, the dose can be lowered. 
  \item \relax Easy convenience and no needle for application of the drug and no need for trained persons.
  \item \relax As compared to parenteral routes, administration of self-medication, thus patient compliance improvement. 
  \item \relax Good penetration of drugs such as polar and low molecular weight can be transported very easily to the eye. 
  \end{enumerate}
  \textbf{Demerits of Ocular Drug Delivery System}


  
  \begin{enumerate}
  \item \relax Unwanted systemic side effects occur if a large quantity of the dose that is administered moves into the lacrimal duct \unskip~\cite{1072500:21976186}. 
  \item \relax Frequent dosing regimen occurs due to the forced expulsion of the delivered drug. It may lead to a short duration of therapeutic effect because of tear flow from the eye and blinking of the eye.
  \item \relax Low absorption of ophthalmic drugs occurs due to physiological limitations of the eye and there is the low penetrability of the cornea. 
  \end{enumerate}
  \textbf{Conventional Approaches in Ocular Delivery}

Solutions, suspensions, and ointments are the Conventional dosage forms that stand for almost 90\% of the presently available ophthalmic formulations on the market. Ease of formulation, ease of drug delivery, and low costs of preparation are the advantages offered by conventional dosage forms. Although, using conventional solutions, such as very low contact time with the ocular surface and the rapid nasolacrimal drainage, both leading to low drug bioavailability but there are also remarkable demerits. Still, eye drops that are in conventional form remain the widely used dosage forms for ophthalmic delivery \unskip~\cite{1072500:21976185,1072500:21976187}.

\textbf{Solutions}

Normal price, ease of development of preparation and development, and more patient allowable drugs are the reasons for selecting solutions over other dosage forms. More and rapid loss of precorneal, the rapid absorption via the conjunctiva of the eye and duct of nasolacrimal that causes side effects to the systemic circulation, as well as rapid installation of drug that results in patient non-compliance are the major drawbacks exhibited by conventional dosage forms. By the adding of viscosity improving agents such as derivate of cellulose, that are believed to enhance the thickness of the drug formulation and consequently decrease the drainage rate that can reduce some of the problems.

\textbf{Suspensions}

If the active compound is water-insoluble, due to the formulation of the micronized drug ({\textless}5\ensuremath{\mu }m) suspension with a suitable aqueous vehicle. Sustained release effect is promoted, if the particles of the drug deposit in the sac of the conjunctiva. Several limitations are present in the suspensions. They have to be properly shaken well before use to make sure proper dosing and the amount of drug required to achieve benefits of their therapeutic activity, only a moderate enhance in bioavailability, providing suspensions with more cost in terms of their price of production. Furthermore, the size of the drug particle works a key role in the method of formulation, particles with more than a size of 10 \ensuremath{\mu }m cause discomfort to the patient and therefore reflexes tearing.

\textbf{Ointments}

Generally, ointments comprise a dispersed and a dissolved form of the drug in a proper vehicle base. They are fairly safe, well-tolerated and enhance the bioavailability of ocular drug that makes the semisolid preparations used commonly. Ointment breaks up into tiny oily droplets that are present in the drug after the application of the drug. Due to the shearing action of the eyelids, the drug generally moves into the ointment-tear interface.

\textbf{Advantages of Topical Ointment }

Decreased dilution of the medication through the lacrimal layer, nasolacrimal pathway resistance, and an increased contact time of precorneal. Blurry vision, loosening of the eyelids thus, lead to discomfort for the patient as well as general irritation of ocular mucosa caused by ocular oily viscous preparations like ointments. Therefore, generally, ointments are co-administered with eye drops during the daytime whereas the ointment is provided during the night when proper vision is not required.

\textbf{Advancements in Conventional Dosage Forms}

There are major advancements in conventional dosage forms such as the Viscosity increasing system, In-situ gelling system, and ocular inserts.

\textbf{Viscosity Increasing Systems}

Several polymers are added to enhance the thickness of the eye drops of conventional dosage forms. This will decrease the lachrymal clearance of ocular solutions. Polyvinyl pyrrolidone (PVP), Polyvinyl alcohol (PVA), and derivatives of cellulose like methylcellulose and polyacrylic acids are the polymers that are hydrophilic analyzed in the area of ocular drug delivery. They are used to assess the solution of pilocarpine methylcellulose in albino rabbits and found a reduced drainage rate with enhancing thickness. The relationship between contact time and viscosity, exhibited a viscosity of 12- 15 cps at an optimum range for a methylcellulose solution in rabbits as investigated by the same group. During the inter-blinking periods, the ocular shear rate ranges from 0.03 s-1 to 4,250- 28,500 s-1. The flow properties of ocular dosage forms such as viscosity and the consequent bioavailability of the drug that is incorporated have been influenced by blinking. If the viscosity is too high, Systems of Newtonian do not show any original development in bioavailability below a definite thickness and becomes eye blinking very painful, followed by tearing of reflex. While the viscosity of Newtonian systems is not depending on the shear rate, with increasing shear rates non-Newtonian pseudoplastic or shear-thinning systems provide a reduction in viscosity of drug. It offers less resistance to blinking and therefore, shows widely accepted by patients as compared to Newtonian systems of the same viscosity, this pseudoplastic behavior is favorable for ocular delivery dosage forms.

\textbf{In-Situ Gelling Systems}

These are based on polymers, viscous fluids that provide phase transition from sol to gallon on the surface of the eye due to change in a unique physicochemical property such as ionic strength, pH, and temperature. They can be simply administered in the form of liquid and are highly advantageous over preformed gels. Due to gelling, they can increase the duration of the drug formulating agents on the surface of the eye. Simple, exact, and reproducible administrations of a dose are the main advantages of in situ gelling systems in contrast to the administration of preformed gels. In the year, early 1980 the idea of forming gels in situ was recommended primarily, and ever since then, various triggers have been further analyzed in situ gelling. Under the effect of enhanced ionic strength, Gollan gum is a type of polysaccharide in an anionic form that goes through a phase transition. The amount of cations such as monovalent and divalent forms present in the tear fluid proportionally increases the gel strength. As a result, due to the increased amount of lacrimal fluid and thus more cations concentration, the usual reflex tearing, which causes dilation of common viscous liquids then increases the sticky of gallon gum formulations \unskip~\cite{1072500:21976201}.

\textbf{Ocular Inserts}

These are solid (or) semisolid uniform preparations. Volume and state of the inserts are mainly prepared for ocular administration (i.e., rods or shields). These inserts are set down in the fornix of the lower side mostly whereas they are placed in the fornix of the upper side or on the cornea in a less common. They are specially used for topical therapy and are usually comprised of a polymeric vehicle consists of drugs \unskip~\cite{1072500:21976193,1072500:21976198}.

\textbf{Merits of Ocular Inserts}

There are many advantages exhibited by ocular inserts such as: 


  
  \begin{enumerate}
  \item \relax Increased residence of the eye, have an extended activity of the drug, and a more bioavailability about standard vehicles. 
  \item \relax Chances of releasing drugs at a constant and controlled rate. 
  \item \relax Exact dosing opposing to eye drops that cannot be properly administered to the patient and lost after administration incompletely, every insert can be prepared to contain an accurate dose that is fully present at the administered site.
  \item \relax Absorption through systemic circulation can be reduced (that happens easily with eye drops through the nasal mucosa and nasolacrimal duct). 
  \item \relax Due to a reduction in the frequency of administration, there is better patient compliance.
  \item \relax Mean life of the drug will be enhanced concerning aqueous solutions.
  \item \relax Reduction in the chances of antigen and antibody reactions by the exclusion of preservatives.
  \item \relax Administering different new chemical/technological applications can be possible.
  \end{enumerate}
  \textbf{Demerits of Ocular Inserts }


  
  \begin{enumerate}
  \item \relax Ocular inserts are perceived by the patient as an outer material in the eye is the main disadvantage.
  \item \relax For the user acceptance and compliance, this may comprise a forbidding barrier of psychological and physical.
  \item \relax It is harder by the unnecessary movement of the insert to the upper fornix of the eye, their movement around the eye, in rare occurrences. 
  \item \relax In situations like sleeping or rubbing of eyes, there is occasional inadvertent loss 
  \item \relax They mostly interfere with vision.
  \item \relax Placing of ocular inserts are very difficult and expelling of insoluble types \unskip~\cite{1072500:21976188}.
  \end{enumerate}
  \textbf{Methods of Drug Release \ensuremath{^{}}}

The methods of drug release into the eye are at a controlled rate as follows: 


  
  \begin{enumerate}
  \item \relax Diffusion
  \item \relax Osmosis 
  \item \relax Bioerosion \unskip~\cite{1072500:21976191}.
  \end{enumerate}
  \textbf{Diffusion}

In the process of diffusion, the drug releases constantly at a rate of a controlled form via the membrane into the lacrimal fluid, if the solid non- erodible body insert is formed with pores and dispersed drug. The release of the drug takes place via pores by the process of diffusion. Regulation of drug release at a controlled rate. This occurs in solid dispersed drugs present in the matrix by the process of dissolution progressively. This is due to aqueous solutions of inward diffusion.

\textbf{Osmosis}

In this osmosis process, a transverse elastic membrane present in the insert. This membrane-impermeable in nature. Insert divides the inner part of the insert into 2-compartments;(1) 1\ensuremath{^{st }}compartment and (2) 2\ensuremath{^{nd }}compartment

The 1\ensuremath{^{st}} compartment is surrounded by an impermeable elastic membrane and the semipermeable membrane whereas the second compartment is surrounded by an elastic membrane and the impermeable material. In the impermeable wall of the insert, there is an aperture for the release of the drug.

\textbf{Bioerosion}

In the process of bioerosion, the drug is dispersed in the arrangement of the body of the insert. This material is taking up from a matrix of bio-erodible material. Sustained release of the drug at a controlled rate from the matrix by the process of bioerosion results from contact of the insert with tear fluid. If the drug is superficially concentrated, the drug may be dispersed all over the matrix equally. The release of drugs at a controlled rate is acquired if it occurs by a chemical or enzymatic hydrolytic reaction that causes solubilization of polymers or breakdown into tiny forms and hydrophilic molecules for a truly erodible device.
    
\section{Conclusion}
It is a great demand to all researchers for ocular drug delivery has been developed due to its distinctive anatomical structure and physiological characteristics that contain various types of barriers like different layers of cornea, sclera, and retina for the drug delivery. It is mainly used to treat eye infections such as glaucoma and conjunctivitis. Conventional dosage of ocular drug delivery like solutions, ointments, and suspensions are the most commonly used conventional dosage forms. However, rapid and more loss of precorneum caused by drainage in the area of extraocular region and turnover of more tear fluid is the major drawback of conventional dosage forms to delivery. To overcome this problem, several new approaches have been developed in conventional dosage forms. Now a day's nanotechnology is also used for ocular drug delivery.
\section*{Acknowledgement}I would like to thank Chairman (Dr Y. Koteswara Rao Garu) \& Principal (V. Gunasekaran Garu) Rao's College of Pharmacy, Chemudugunta (V\&P), Venkatachalam (M), S.P.S.R.Nellore-524 320, Andhra Pradesh, India.

\textbf{Conflict of interest}

The authors declare that they have no conflict of interest in this study.

\textbf{Funding support}

The authors declare that they have no funding support for this study.
    

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