industrial perspective in ocular drug delivery

ws 58 (2006) 1258–1268www.elsevier.com/locate/addr

Advanced Drug Delivery Revie

Industrial perspective in ocular drug delivery☆

Yusuf Ali a,⁎, Kari Lehmussaari b

a Santen Inc., 555 Gateway Drive, Napa, CA 94559, USAb Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland

Received 12 June 2006; accepted 31 July 2006Available online 15 September 2006

Abstract

In the development of a commercial drug product, the formulator must consider various perspectives. The bioavailability ofthe active drug substance is often the major hurdle to overcome. In the past it has been common to add viscosity-enhancingagents or mucoadhesive polymers into formulations to improve ocular bioavailability. In addition to these conventionalapproaches, non-conventional technologies such as nanotechnology, microspheres and prodrugs could be considered tooptimize the product.

Along with bioavailability, the formulator must also consider the tolerability and stability of the final drug product. Quiteoften, the final formulation is the ideal compromise between the three.

Authorities in different parts of the world have set strict requirements and guidelines for development and approval of drugproducts. In order to secure an expeditious development process and the shortest possible review and approval time, theformulator should be familiar with the current requirements and regulations.© 2006 Elsevier B.V. All rights reserved.

Keywords: Ocular drug delivery; Eye drops; Suspensions; Ointments; Gels; Dosage forms; Mucoadhesives; Regulatory requirements; New drugapplication; Marketing authorization application; Clinical trial application; Investigational new drugs

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12592. Conventional ophthalmic dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1259

2.1. Aqueous solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12592.2. Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12602.3. Ointments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12622.4. Gels and mucoadhesive polymer systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1262

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Ocular Drug Delivery”, Vol. 11, 2006.⁎ Corresponding author. Tel.: +1 707 256 1420; fax: +1 707 254 1760.E-mail address: [email protected] (Y. Ali).

0169-409X/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.addr.2006.07.022

mailto:[email protected]

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1259Y. Ali, K. Lehmussaari / Advanced Drug Delivery Reviews 58 (2006) 1258–1268

3. Non-conventional ophthalmic delivery systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12633.1. Non-erodible ocular inserts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12633.2. Prodrugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12633.3. Microspheres and nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1263

4. Regulatory considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12645. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267

1. Introduction

Sustained and controlled delivery of drugs to theocular tissues continue to remain a major objective forformulation scientists and engineers in light of theemergence of more potent drugs and biologicalresponse modifications with limited biological half-lives. In ophthalmic drug delivery, in the front of theeye, the major hurdles of optimum drug bioavailabilityinclude rapid turn over, lacrimal drainage, reflexblinking and drug dilution by tears [1].

Another physiological constraint is the limitedpermeability of cornea resulting into low absorptionof ophthalmic drugs. A major portion of the adminis-tered dose drains into the nasolacrimal duct and thuscan cause unwanted systemic side effects. Addition-ally, the rapid elimination of the drug through thepunctum results in a short duration of the therapeuticeffect resulting in a frequent dosing regime. Asignificant challenge for the formulation is to circum-vent these protective barriers of the eye withoutcausing permanent damage to the tissue.

Currently, typical ophthalmic dosage forms arepreferred way to achieve therapeutic levels ofpharmacological agents used to treat ophthalmicdiseases. The conventional formulations for this thetypical route fell into several categories: solutions,suspensions, gels and ointments. In spite of significantcriticisms over the efficacy of these conventionalsystems, such as limited bioavailability, these prepara-tions are extensively used in a majority of commercialproducts. A number of articles have covered severalaspects of these dosage forms such as formulation,manufacturing process, packaging etc. It is not theobjective of this paper to report this informationextensively here, but rather to provide a summary ofconventional dosage forms and examine opportunitiesto improve the efficacy of these dosage forms.

The second part of the paper will address the non-conventional ophthalmic dosage forms either currentlymarketed or are under investigation and regulatoryconsideration in order to obtain government approvalto market these products.

2. Conventional ophthalmic dosage forms

2.1. Aqueous solutions

Majority of topical ophthalmic preparations avail-able today are in the form of aqueous solutions. Ahomogeneous solution dosage form offers manyadvantages including the simplicity of large scalemanufacture. The factors that must be taken intoaccount while formulating aqueous solution includeselection of appropriate salt of the drug substance,solubility, therapeutic concentration required, oculartoxicity, pKa, the effect of pH on stability andsolubility, tonicity, buffer capacity, viscosity, compat-ibility with other formulation ingredients as well aspackaging components, choice of preservative, ocularcomfort and ease of manufacturing. Several bioavail-ability experiments must be conducted in order toarrive at the optimum formulation. Corneal penetrationenhancement can be achieved best by increasingsolution concentration, increasing contact time in theprecorneal packet, selection of the drug with appro-priate pKa and offering optimal lipid solubility.Commonly used viscosity agents to improve drugbioavailability include hydroxyl methylcellulose,polyvinyl alcohol, hydroxypropyl methylcellulose,carboxy methylcellulose and carbomers. Recentlynatural polymers have also been used to affect theviscosity of the formulation and thereby improvebioavailability of drugs. Examples of these polymersare hyaluronic acid (HA), guar gum, gellan gum etc.

1260 Y. Ali, K. Lehmussaari / Advanced Drug Delivery Reviews 58 (2006) 1258–1268

The rheological characteristics of a polymer areimplicated in the ocular retention of dosage form.

The choice of pH for the formulations is a keyattribute for the formulator. The solubility and stability,and corneal permeability of the drugs are quitedependent on pH. Quite often pH of the preparationis a best possible compromise between stability andbioavailability. Additionally, ocular comfort must bekept in mind before finalising the pH of the dosageform. In general ophthalmic solutions are formulatedin the range of pH 4 to 8.0. If the pH of the dosageform is outside the physiological range, eye irritationor ocular discomfort may become the issue. Eyeirritation is normally accompanied by an increase influid secretion to aid in the restoration of normalphysiological conditions. The excessive tearing alsoresults into flushing of the drug rapidly to thenasolacrimal gland with a probable influence on theocular efficacy. Additionally, proper choices of bufferand buffer capacity are essential to optimize drugbioavailability as well as ocular comfort.

Another important ingredient in a typical multidoseophthalmic product is antimicrobial preservative. Itsprimary purpose is to prevent the patient fromadministering microbiologically contaminated productin the eye. The main criteria for selecting a preservativeare (a) should be effective at a low concentrationagainst a broad spectrum of organisms (b) soluble in theformulation (c) compatible with the drug packagingcomponents (d) effective over the shelf life. Preserva-tives that meet most of these criteria are the quaternaryammonium compounds e.g., benzalkonium chloride,parabens, chlorobutanol and 2-poly(ethyl alcohol).Newer preservatives are peroxide-generating com-pounds such as Purite®.

The stability of ophthalmic solutions and otherdosage forms determine the shelf life and expirationdating of the product. The drug product is analyzedfor physical, chemical and microbiological para-meters throughout the shelf life. Typical physicalparameters include pH, osmolality, viscosity, colorand appearance of the product. Chemical parametersinclude assays for the active and degradation productand preservative content. Microbiological parametersinclude sterility and antimicrobial preservative effi-cacy of the product and bioburden of all components.

In general, aqueous ophthalmic solutions aremanufactured by a process which calls for the

dissolution of the active ingredient and other inactiveingredients and the sterilization of this solution by heator by sterile filtration. This sterile solution may furtherbe then mixed with additional components such aspreviously sterilized solutions of viscosity – includingagents and then the batch is brought to final volumewith additional sterile water.

Besides drug efficacy, safety, and stability, manu-facture of ophthalmic dosage forms including solu-tions must meet certain safety criteria of freedom fromextraneous foreign particulate matter. For example,current United States standards of good manufacturingpractices (GMPs) provide for the use of speciallydesigned, environmentally controlled areas for themanufacture of sterile ophthalmic products. Theseareas must meet the requirements of class 100,000space in all areas where open containers and closuresare not exposed, or where product filling and cappingare not taking place. In areas where open containersand closures are exposed, they must meet therequirements of Class 100. Often these design criteriaare coupled with laminar airflow concepts. Addition-ally, the materials used for construction of the facility,as well as personnel attire, training, and conduct in thespace, and the entrance and egress of personnel,equipment, packaging and product all bear heavily onthe assurance or product sterility and minimization offoreign particulate matter.

2.2. Suspensions

Suspensions form an important part of the oph-thalmic dosage forms and offer distinct advantages.Many of the recently developed drugs are hydro-phobic and have limited solubility in water. For-mulation of a sterile, preserved, effective, stable andpharmaceutically elegant suspension is more com-plex and challenging compared to conventional oph-thalmic solutions. Some of the difficulties that aformulator should overcome during the developmentof a suspension are non-homogeneity of the dosageform, settling, cake formation, aggregation of thesuspended particles, resuspendability, effective preser-vation, and ease of manufacture. The understanding ofinterfacial properties, wetting, particle interaction zetapotential, aggregation, sedimentation and rheologicalconcepts are required for formulating an effective andelegant suspension [2].

Table 1Relative property of flocculated and deflocculated particles insuspension [2]

Deflocculated Flocculated

1. Particles exist in suspension asseparate entities.

Particles form loose aggregates

2. Rate of sedimentation is slowbecause each particle settlesseparately and particle size isminimal.

Rate of sedimentation is highbecause particles settle as afloc, which is a collection ofparticles.

3. A sediment is formed slowly. A sediment is formed rapidly.4. The sediment eventually

becomes very closely packedas a result of weight of theupper layers of sedimentingmaterial. Repulsive forcesbetween particles are overcomeand a hard cake is formed thatis difficult, if not impossible, toredisperse.

The sediment is loosely packedand possesses a scaffold-likestructure. Particles do not bondtightly to each other and a harddense cake does not form. Thesediment is easy to redisperse,so as to reform the originalsuspension.

5. The suspension has a pleasingappearance, because thesuspended material remainssuspended for a relatively longtime. The supernatant alsoremains cloudy, even whensettling is apparent.

The suspension is somewhatunsightly because of rapidsedimentation and the presenceof an obvious, clear supernatanregion. This can be minimizedif the volume of sedimentis large. Ideally, volumeof sediment should encompassthe volume of suspension


.

,

t

Table 2Wetting and solubilizing agents [2]

Benzalkonium chlorideBenzethonium chlorideCetylpyridinium chlorideDocusate sodiumNonoxynol 10Octoxynol 9PoloxamerPolyoxyl 50 stearatePolyoxyl 10 oleyl etherPolyoxyl 20 cetostearyl etherPolyoxyl 40 stearatePolysorbate 20Polysorbate 40Polysorbate 60Polysorbate 80Sodium lauryl sulfateSorbitan monolaurateSorbitan mono-oleateSorbitan monopalmitateSorbitan monostearate

Suspensions are kinetically stable but thermodynami-cally unstable systems, and when left undisturbed for along period of time, lead to aggregation of particles,sedimentation and eventually caking. When theparticles are held together in a loose open structure,the system is said to be in the state of flocculation. Theflocculated particles settle rapidly and for sediment butthey are readily dispersible. Relative properties offlocculated and deflocculated particles in suspensionare provided in Table 1.

Particle size of the active agent plays a key rolein physical stability and bioavailability of the drugproduct. The rate of sedimentation, agglomeration andresuspendability are affected by particle size. In mostophthalmic suspension, the average particle size is lessthan 10 μm. The most efficient method of producingsuch particle size is by dry milling. However, wetmilling may be desirable for potentially explosiveingredients. Other methods of particle size reductioninclude micro-pulverization, grinding, and controlledprecipitation.

An ophthalmic suspension contains many inactiveingredients such as dispersing and wetting agents,suspending agents, buffers and preservatives. Wettingagents are surfactants that lower the contact anglebetween the solid surface and the wetting liquid.Generally used wetting and solubilizing agents areprovided in Table 2. Suspending agents are used toprevent sedimentation by affecting the rheologicalbehavior of a suspension. An ideal suspending agentshould have certain attributes. It should produce astructured vehicle. It should be compatible with otherformulation ingredients. It should be non-toxic.Generally used suspending agents in ophthalmicsuspension include cellulosic derivatives such asmethyl cellulose, caboxy methyl cellulose, and hydro-xyl propyl methyl cellulose, synthetic polymers suchas carbomers, poloxamers, and polyvinyl alcohol. Theselection of buffers and preservatives for suspensionare similar to that of ophthalmic solutions in almost allaspects except that they must also be compatible withthe flocculating systems.

The manufacture of the ophthalmic suspensioninclude sterilization of the micronized active drugeither by dry heat, exposure to gamma irradiation orethylene oxide or in some cases steam sterilization ofthe concentrated slurry followed by ball-milling [3].In general, key steps of manufacturing ophthalmic

Table 3Mucoadhesive performance of several polymers [5]

Substance Adhesiveperformance

Carboxymethylcellulose ExcellentCarbopol ExcellentCarbopol and hydroxypropyl cellulose GoodCarbopol base with white petrolatum/

hydrophilic petrolatumFair

Carbopol 934 and EX 55 GoodPoly (methyl methacrylate) ExcellentPoly acrylamide GoodPoly (acrylic acid) ExcellentPolycarbophil ExcellentHomopolymers and copolymers of acrylic

acid and butyl acrylateGood

Gelatin FairSodium alginate ExcellentDextran GoodPectin PoorAcacia PoorPovidone PoorPoly (acrylic acid) crosslinked with sucrose Fair


suspensions are (a) preparation of a dispersion of thedrug (b) preparation of the structured vehicle, followedby addition of the drug dispersion (c) addition of theother adjuncts and (d) homogenization. Continuousmixing is required during the filling process to assurehomogeneity of the dosage form. Some of these stepsmay include aseptic handling of sterile materials.Manufacturing of ophthalmic suspension is morecomplicated than conventional solutions.

2.3. Ointments

While ophthalmic solutions are by far the mostpreferred dosage forms, ophthalmic ointments are stillbeing marketed for night time applications and whereprolonged therapeutic actions are required. Majordisadvantage of the ophthalmic ointments is that theycause blurred vision due to refractive index differencebetween the tears and the non-aqueous nature of theointment and inaccurate dosing [4]. Nevertheless,desirable attributes for ointment development shouldinclude factors such as (a) they should not be irritatingto the eye (b) they should be uniform (c) they shouldnot cause excessive blurred vision and (d) they shouldbe easily manufacturable. Typical manufacturingprocess for an ophthalmic ointment includes micro-nization and sterilization of the active agent by dryheat, ethylene oxide irradiation or gamma irradiation.Antimicrobial preservatives (if required) such aschlorobutanol or parabens are dissolved in a mixtureof molten petrolatum and mineral oil and cooled toabout 40 °C with continuous mixing to assurehomogeneity. Sterilized and micronized active is thenadded aseptically to the warm sterilized petrolatum/mineral oil mixture with continuous mixing until theointment is homogeneous. The ointment is then filledinto presterilized ophthalmic tubes.

2.4. Gels and mucoadhesive polymer systems

Mucoadhesive polymers can provide a localizeddelivery of an active agent to a specific site in the bodysuch as the eye. Such polymers have a property knownas bioadhesion meaning attachment of a drug carrier toa specific biological tissue such as the epithelium andpossibly to the mucosal surface of such tissues. Thesepolymers are able to extend the contact time of thedrug with the biological tissues and thereby improve

ocular bioavailability. The choice of the polymer playsa critical role in the release kinetics of the drugs fromthe dosage form. There are several bioadhesivepolymers now available with varying degree ofmucoadhesive performance [5] as shown in Table 3.

A few examples of ophthalmic products utilizingmucoadhesive properties are described below. Anophthalmic gel utilizing carbomer 940 and pilocarpinehas been available in the Unites States for several years.This product is manufactured using conventionalsolution/gel manufacturing technology. The key stepsinclude preparation of the polymeric gel at higherconcentration followed by autoclaving. Pilocarpine andother ingredients are dissolved in water and then sterilefiltered into the gel. The pH of the batch is then adjustedaseptically and the product is filled in sterile tubes.

Another example of an ophthalmic productutilizing bioadhesive polymer is timolol gel formingsolution. The polymer used in this preparation is apolysaccharide, namely gellan that gels in the eyepresumably by the interaction with lysozymes presentin the tears. This product provide efficacy of timololfor 24 h as compared to earlier ophthalmic solutionsthat required a twice a day regimen. Additionalexample include introduction of Timosan (0.1%)approved in Europe that uses carbomer 974P as a


mucoadhesive agent. This product is equivalent toTimoptic, 0.5% administered BID. A tear substituterecently introduced in the United States employshydroxy propyl guar gum as a mucoadhesive polymerto increase ocular comfort and tear break up time.

Particulate systems that incorporate bioadhesivepolymers have also been utilized as drug deliverysystems. An ophthalmic product, namely Betoptic S hasbeen approved in various countries utilizing thisconcept. Betoptic S, 0.25% is considered equivalent toBetoptic, 0.5% solution. By binding betaxolol to an ionexchange resin particles in a mucoadhesive suspendingmedium, it was shown that the drug release was retardedin the tear and the bioavailability was increased [6–8].Additionally, the ocular comfort of betaxolol was alsogreatly enhanced by reducing the availability of the freedrug molecules in the precorneal tear film. Thus,microparticulate technology with mucoadhesive poly-mers introduces the advantage of superior patientacceptability thus improving compliance.

Fig. 1. Chemical structures of epinephrine and DPE.

3. Non-conventional ophthalmic delivery systems

3.1. Non-erodible ocular inserts

In 1975, the first controlled-release ophthalmicdosage form was marketed in United States by AlzaCorporation. TheOcusert pilocarpine ocular systems arenoted for several reasons. The strength of the drug isspecified in the labeling by the rates at which theydeliver pilocarpine in vivo. The Ocusert is an ellipticalshaped membrane which is soft and flexible anddesigned to be placed in the cul de sac between thesclera and the eyelid and continuously release pilocar-pine at a steady rate (20 μg/h and 40 μg/h) for 1 week.The design of the dosage form is described by Urquhart[9] in terms of an open looped therapeutic system havingthree major components (a) the drug (b) a drug deliverymodule and (c) a platform. The drug in Ocusert ispilocarpine base. The drug delivery module consists of:(a) a drug reservoir, and a carriermaterial namely, alginicacid; (b) a rate controller namely, ethylene/vinyl acetate(EVA) copolymer membrane; (c) an energy source,namely the concentration of pilocarpine in the reservoirand (d) a delivery portal, the copolymer membrane.

This product was and still is considered as a technicalbreakthrough. However, the market success of the pro-

duct has been quite limited due to a variety or reasons.Since, most of the glaucoma patients are geriatric, inser-tion and removal of Ocusert in the eye on a weekly basishas been quite difficult for users. Additionally, manymore efficacious drugs such as beta blockers and pros-taglandins have been introduced in the market as an eyedrop making pilocarpine a less desirable drug due to itslower potency and higher side effect profile. Further-more, the issue of tachphylaxis [10] with pilocarpinewhen administered continuously also diminished fullpotential of a rather innovative drug delivery system.

3.2. Prodrugs

Prodrugs are chemical modifications of knownpharmacological agents. These drugs, when adminis-tered to biological systems, are biotransformed to theparent compound. In the past, epinephrine has beenroutinely used to control ocular hypertension. However,due to its chemical structure as shown in Fig. 1, it doesnot have optimal ocular bioavailability characteristics.

A prodrug of epinephrine namely, dipivefrin (DPE)has been developed successfully for several years.Some key advantages of such prodrugs are (a) enhancedbioavailability (b) increased potency (c) lower dose (d)prolonged duration of action (e) reduce side effects and(f) enhanced chemical stability. The lipophilic nature ofDPE as shown in Fig. 1 is responsible for its greaterbioavailability in ocular tissues. As discussed byKrause[11], DPE at 0.1% concentration produces intraocularpressure lowering response which is clinically compar-able to 2% epinephrine while showing greatly reducedocular tolerance and no cardiovascular effects.

3.3. Microspheres and nanoparticles

Particulate polymeric delivery systems includemicrospheres and nanoparticles. The differencebetween these systems is based on their size. Particlesin the micrometer size (>1 um) are called microspheres

Table 4IND – format and content outline⁎

Part 1 Form FDA 1571Part 2 Table of contentsPart 3 Introductory statement – brief introductory statemen

to include:a. Name(s) of the drugDrug's pharmacological classDrug's structural formulaDosage form and formulationRoute of administrationBroad objectives and planned duration of theproposed clinical investigationsb. Brief summary of previous human experience withthe drug:Reference to other IND/NDAs, if pertinentInvestigational or marketing experience in thecountries that may be relevant to the safety of theproposed clinical investigation(s)c. Identification of countries where drug has beenwithdrawn from investigation or marketing for anyreasons related to safety or effectiveness and reasonsfor withdrawal

Part 4 General investigational plan – brief description othe overall plan for investigating the drug product fothe following year to include:a. Rationale for drug studyb. Indication(s) to be studiesc. General approach to be followed in evaluating thedrugd. Kinds of clinical trials to be conducted in the firsyear (indicate if plans not developed for full year)e. Estimate number of patients to be given the drugf. Safety risks anticipated – any risks of particulaseverity or seriousness anticipated based ontoxicology data or prior human experience with thedrug or related drugs

Part 5 Investigator's brochure – to contain the followinginformation:a. Brief description of the drug (include structuraformula) and the formulationb. Summary of the pharmacological toxicological effectsof the drug in animals and to the extent known, in manc. Summary of pharmacokinetics and biologicadisposition of the drug in animals and if known, in mand. Summary of information relating to safety and


whereas those in the range of <1 μm are known asnanoparticles. This discrimination is useful because oftheir different biological and physicochemical beha-viors. Although, there are no marketable sterile ophthal-mic products based on these systems, their potential inthe ocular field, particularly in delivering the drug to theback of the eye in the retinal space is quite exciting.

These particles are either biodegradable such aspolylactic acid (PLA) and polyglycolic acids (PLGA) ornonbiodegradable such as poly(alkyl cyanoacrylate),poly (butyl cyanoacrylate), isobutyl cyanoacrylate,cellulose acetate phthalate, poly (ethyl cyanoacrylate)and poly (hexadecyl cyanoacrylate). A summary ofocular application for these systems are reported byAmrite and Kompella [12].

For retinal drug delivery biodegradable polymersare preferable and in most cases required. Both lacticacid and glycolic acids are biodegradable and theyproduced and eliminated by the body. These polymersdecompose into carbon dioxide and water. Commer-cially, these polymers are available either from syn-thetic origin or natural origin. Both polylactic acid andpolyglycolic acid can be polymerized with good con-trol for molecular weight and molecular weightdistribution. Additionally, they can be polymerized re-sulting into poly (lactide co-glycolide or PLGA system.The chemical structure of PLGA is shown in Fig. 2.

The manufacture of sterile microspheres andnanoparticles is more complicated as compared toconventional dosage forms such as aqueous solutionsand suspensions. Several manufacturing processessuch as milling and homogenization techniques [13],supercritical fluid technology [14] and emulsiontechnology [15] have been developed over the years.

4. Regulatory considerations

Knowledge of the regulations governing animaland clinical testing and filing appropriate applications

effectiveness in humans from prior clinical studies(can append reprints when pertinent and useful)e. Description of possible risks and side effects to beanticipated based on experience with the drug or withrelated drugs. Precautions or special monitoring to bedone as part of the investigations.

Part 6 Clinical investigationa. Protocol for each planned studyb. Investigators

Fig. 2. Chemical structure of PLGA.

t

fr

t

r

l

l

Name and address and CVof each investigatorName of each subinvestigatorName and address of research facilitiesName and address of IRc. Monitor – name, title and CV (The personresponsible for monitoring the conduct and progressof the clinical investigations)Safety monitor(s) – name, title and CV (The personor persons responsible for review and evaluation oinformation relevant to safety of the drug)d. Contract Research Organizations (CRO)i. Name and address of CRO used for any part of theclinical studiesii. Identify the studies and CRO monitoriii. List sponsor obligations transferred to CRO, if anye. Labeling for clinical supplies

Part 7 Chemistry, manufacturing, and controls informationa. Drug substance1. Description of physical and chemical characteristics2. Name and address of manufacturer3. Method of preparation4. Reference standard5. Specifications6. Methods of analysis7. Stabilityb. Drug product1. Components (reasonable alternatives)i. Inactive components – tests and specifications2. Composition (reasonable variations)3. Name and address of manufacturer4. Manufacturing and packaging procedure5. Specifications6. Methods of analysis7. Packaging8. Stability9. Labeling for clinical supplies10. Placebo – composition, manufacture and contro11.Environmentalanalysis–claimforcategoricalexclusion

Part 8 Pharmacology and toxicologya. Pharmacology and drug disposition1. Section describing the pharmacologic andmechanism(s) of action of the drug in animals2. Section describing theADMEof the drug, if knownb. Toxicology1. ID and qualifications of persons conducting andevaluating results of studies concluding reasonablysafe to begin proposed investigations2. Statement where studies conducted and whererecord available for inspection3. Integrated summary of the toxicological effects othe drug in animals and in vitro4. Detailed tox study reports with full tabulations odata for each study primarily intended to support thesafety of the proposed clinical investigation

(continued on next page

5. GLP compliance statement(s)Part 9 Previous human experience

Summary of known prior human experience with theinvestigational drug to include:a. If previously investigated or marketed (anywhere):i. Detailed information about such experience relevantto safety of proposed investigation or rationaleii. If drug has been subject of controlled clinical trialdetailed information on such trials relevant to anassessment of the drug's effectiveness for the proposedinvestigational useiii. Published material directly relevant to safety oreffectiveness for the proposed investigational use –provide full copies.Publishedmaterial less directly relevant– bibliographyb. For combination of drugs – Part 9a information foreach drug.c. Foreign marketingi. List of countries where marketed.ii. List of countries where drug has been withdrawnfrom marketing for reasons potentially related tosafety or effectiveness.

⁎Adapted from 21 CFR 31223.

Table 4 (continued ) Table 4 (continued )

Part 6 Clinical Investigationsb. Investigators

Part 8 Pharmacology and Toxicologyb. Toxicology


f

l

f

f

)

to market ophthalmic drug delivery product is essentialfor an expedited product launch in various marketsaround the world. While, regulatory requirements differconsiderably around the world, there are harmonizationefforts underway in major markets such as the EuropeanUnion, Japan and the Unites States. Ultimately, it ishoped that in the future it would be possible to filecommon regulatory documents for these countriesleading to mutually recognized approvals. New drugsor delivery systems require Investigational New DrugApplication (IND) in the United States or Clinical TrialNotification (CTN) in Europe to conduct human clinicaltrials. New Drug Application or NDA in the UnitedStates and Marketing Authorization Application orMAA in the European Union are required for marketingapplication. It is important to recognize that a new drugis not just a new chemical or biological entity but it couldhave several extensions for regulatory purposes asshown below by relevant ophthalmic examples [16]

a. The drug, Dipivefrin, is a new derivative of aknown molecule such as a prodrug of epinephrine.

b. A previously approved drug, with a new clinicalindication or use such as a NSAID to inhibit miosisduring cataract surgery.

Table 5NDA – format and content outline⁎

1. Index to entire application2. Summarya. Labeling text annotated to both summary and technical sectionsb. Pharmacological class, scientific rationale, intended use(s) andpotential clinical benefitsc. Foreign marketing history – applicant and others if known

i. Countries in which marketedii. Countries where withdrawn from market for safety or efficacyiii. Counties where marketing applications pending

d. Summary of chemistry, manufacturing and controls sectione. Summary of nonclinical pharmacology and toxicology sectionf. Summary of human P-kinetics and bioavailability sectiong. Summary of microbiology sectionh. Summary of clinical section including statistical analysisi. Concluding discussion – benefit/risk consideration

3. Chemistry, manufacturing, and controls sectiona. Drug substance

i. Description of chemical and physical characteristicsii. Stabilityiii. Source and location of manufacturer(s)iv. Synthesis, purification and controlsv. Specifications and analytical methodsvi. Reference standard

b. Drug producti. Componentsii. Specs and test methods for inactivesiii. Compositioniv. Name and location of each manufacturerv. Manufacturing andpackaging procedures and in-process controlsvi. Acceptance specifications for each batchvii. Analytical and microbiological test methodsviii. Packaging container/closure systemsix. Stability data and protocolsx. Proposed expiry dating and storage conditions

c. Environmental assessment of manufacturing process andultimate use

4. Samples, methods validation, labelinga. Description and assay results of samples for FDA validationb. Methods validation package (regulatory specs and methods)c. Container labels and package insert labeling

5. Nonclinical pharmacology and toxicologya. Pharmacology studiesb. Toxicology studiesc. Animal ADME studiesd. GLP compliance statements

6. Human pharmacokinetics and bioavailablitya. Waiver for topical or injectable product bioavailability studiesb. For each human bio or pharmacokinetic study:

i. Study report including analytical and statistical methodsii. IRB/informed consent compliance statements

c. For specs or methods to assure bioavailability of drug or product:i. Rationale for establishing spec or methodii. Data and information supporting rationale

d. Summary discussion and analysis ofi. Pharmacokinetics and metabolism or active ingredientii. Bioavailability and/or bioequivalence of drug product

7. Microbiology (for anti-infectives only)8. Clinical data

a. Clinical pharmacology studiesb. Controlled clinical studiesc. Uncontrolled clinical studiesd. All other data and information relevant to evaluation of safetyand effectiveness of the drug producte. Integrated summary of effectivenessf. Integrated summary of safetyg. Studies related to abuse potential or overdosagesh. Integrated summary of benefits and risksi. Compliance statements (IRB and IC) for each clinical studyj. Contract research organizations and obligations transferredk. List of studies where original subject records were audited oreviewed to verify accuracy of case reports

9. Reserved for safety update reportsa. Required after NDA filed ati. 4 monthsii. Approvable letter and whenever FDA request update

b. New safety information from any source that may reasonablyaffect the labelingc. Case report forms for patients who died or were adverse evendropouts

10. Statistical sectiona. Copy of the following clinical data sectionsi. Controlled studiesii. Integrated summary of effectivenessiii. Integrated summary of safety

b. Documentation and supporting statistical analysis used toevaluate each of the above clinical data section

11. Case report tabulationsData on each patient from

a. Each adequate and well-controlled study (Phase 2 and 3)b. Each Phase 1 clinical pharmacology studyc. Safety data from other clinical studies

12. Case report formsa. Original application only for patients who:Died during a clinical study orDid not complete study due to adverse event whether or no

thought to be drug related including patients on reference drug oplacebob. Additional CRFs may be requested after submission and musbe submitted within 30 days of FDA request

13. Patent information – listing of all U.S. patents which claima. Drugb. Drug product compositionc. Intended use

⁎Adapted from 21 CFR 314.50.

Table 5 (continued )

6. Human pharmacokinetics and bioavailablity


r

t

tr

t


c. A part of a drug delivery device in Ocusert such asan EVA polymer to control the release of pilo-carpine in the eye or a gel-forming polymer such asgelan to extend the duration of timolol.

d. Two or more approved drugs are combined for usein a fixed combination such as timolol andpilocarpine or combination of tobramycin anddexamethasone.

e. A change in the route of administration is madesuch as ophthalmic dosage form of acetazolamidefor glaucoma.

f. A change is made in the dosage or the strength ofapproved drug such as betaxolol and timolol forglaucoma.

The regulatory authorities such as the Food andDrug Administration (FDA) specify the format andcontent requirements for human clinical trials as shownin Table 4. These applications inform the authorities asto what drug is to be tested, the objectives of the clinicalexperiments and scientific data and existing knowl-edge. The regulatory authorities use this information todetermine the adequacy of the data to support initiationof human trials. Clinical testing generally occurs invarious phases and an IND can be filed for one or moreof these phases. Typically, an IND would be filed withspecific protocol for Phase I and a general outline of theclinical plan for Phase II. Phase I for ophthalmic drugusually is focused on the potential for toxicity inhealthy volunteers. In Phase II trials, the drug is usuallyfirst introduced into patients with the disease and a doseresponse is investigated. Frequency of dosing or dosingregimen may also be established during Phase II trials.Typically, there are several Phase II trials that areconducted to arrive at the right concentration andfrequency of dosing. The final Phase III trials areessential for providing substantial evidence from well-controlled studies for proof of safety and efficacy. It isquite important that the endpoints used to measure theefficacy of the delivery system are clinically relevantand that the size of the patient population is adequate todetect a significant difference.

After obtaining sufficient information from clinicaltrials in humans, safety testing in animals and chemistryand manufacturing experience to assure that the newdrug is safe and effective, a drug company submits aNew Drug Application or an NDA to the FDA to obtainapproval to market and distribute the product commer-

cially within the United states or to export the product toother countries where it is approved. A marketingauthorization Application or an MAA is required toobtain approval to market and distribute the productcommercially within Europe.

There are six major technical sections comprisingthe data and information generated to support the NDAapproval

(1) Chemistry, manufacturing and control for thedrug substance and the drug product

(2) Microbiology-applicable only if an anti-infec-tive drug

(3) Human Pharmacokinetics–ADME data fromhuman studies

(4) Pharmacology–preclinical animal data for phar-macology, toxicology, and pharmacokinetics

(5) Clinical–human data for safety and efficacy(6) Statistics–mathematical analysis of the human

clinical data

The format and content requirements for the NDA isshown in Table 5.

5. Conclusion

Ocular drug delivery is difficult because of multiplebarriers imposed by the eye against the entry of xeno-biotics. Over last several years, attempts have beenmadeto improve ocular bioavailability through manipulationof product formulation such as viscosity and applicationof mucoadhesive polymers. Thus far, these approachesto prolong corneal contact time have led to modestimprovement in ocular bioavailability. Consequently, itseems logical to consider non-conventional approachessuch as nanotechnology, microspheres, appropriate pro-drugs and effective delivery of gene therapy to furtherenhance ocular absorption and reduce side effects.

References

[1] O. Olejnik, Conventional systems in ophthalmic drug delivery,in: A.S. Mitra (Ed.), Ophthalmic drug delivery systems, MarcelDekker, Inc., 1993, pp. 177–198.

[2] H.N. Bhargava, D.W. Nicolai, B.J. Oza, Topical suspensions,in: H.A. Lieberman, R.M. Rieger, G.S. Banker (Eds.),Pharmaceutical dosage forms: Disperse systems, vol. 2, MarcelDekker, Inc., 1996, pp. 183–241.


[3] Y. Ali, R. Beck, R. Sport Process for manufacturing ophthalmicsuspension, U.S. Patent 6,071,904, 2000.

[4] K.M. Bapatla, G. Hecht, Ophthalmic ointments and suspen-sions, in: H.A. Lieberman, R.M. Rieger, G.S. Banker (Eds.),Pharmaceutical dosage forms: Disperse systems, vol. 2, MarcelDekker, Inc., 1996, pp. 357–397.

[5] R. Krishnamoorthy, A.K. Mitra, Mucoadhesive polymers inocular drug delivery, in: A.S. Mitra (Ed.), Ophthalmic drugdelivery systems, Marcel Dekker, Inc, 1993, pp. 199–221.

[6] O. Jani, Y. Gan, Y. Ali, R. Rodstrom, S. Hancock, Ion-exchange resins for ophthalmic delivery, J. Ocul. Pharmacol.10 (1) (1994) 57–67.

[7] R. Jani, R. Harris, Sustained release, comfort formulation forglaucoma therapy, U. S. Patent 4,911,920, 1990.

[8] Y. Ali, R. Jani, G. McCarty. Compositions for treatment ofglaucoma, U.S. Patent 5,554,367, 1996.

[9] J. Urquhart, Development of the OCUSERT pilocarpine oculartherapeutic systems — a case history, in: J. Robinson (Ed.),Ophthalmic delivery systems, APhA Publishers, Washington,D.C, 1980, pp. 105–118.

[10] E.H. Barany, Pilocarpine-induced subsensitivity to carbacholand pilocarpine of ciliary muscle in vervet and cynomolgusmonkeys, Acta Ophthalmol. 55 (1977) 141–163.

[11] P.D. Krause, Dipivefrin (DPE): preclinical and clinical aspectsof its development for use in the eye, in: J. Robinson (Ed.),Ophthalmic delivery systems, APhA Publishers, Washington,D.C, 1980, pp. 91–103.

[12] A. Amrite, U. Kompella, Nanoparticles for ocular drugdelivery, in: R. Gupta, U. Kompella (Eds.), Nanoparticletechnology for drug delivery, Taylor and Francis, New York,2006, pp. 319–360.

[13] R. Muller, J. Moschwitzer, F. Bushrab, Manufacturing ofnanoparticles by milling and homogenization techniques, in: R.Gupta, U. Kompella (Eds.), Nanoparticle technology for drugdelivery, Taylor and Francis, New York, 2006, pp. 21–52.

[14] R. Gupta, Supercritical fluid technology for particle engineer-ing, in: R. Gupta, U. Kompella (Eds.), Nanoparticle technol-ogy for drug delivery, Taylor and Francis, New York, 2006,pp. 53–84.

[15] R. Gupta, Polymer or protein stabilized nanoparticles fromemulsions, in: R. Gupta, U. Kompella (Eds.), Nanoparticletechnology for drug delivery, Taylor and Francis, New York,2006, pp. 319–360.

[16] R.E. Roehrs, S.D. Krueger, Regulatory considerations, in: A.S.Mitra (Ed.), Ophthalmic drug delivery systems, Marcel Dekker,2003, pp. 663–694.

industrial perspective in ocular drug delivery

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