http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–8 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2014.999786

REVIEW ARTICLE

Gelatin-based particulate systems in ocular drug delivery

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Rania M. Hathout and Mohamed K. Omran Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

Abstract

Keywords

Despite all scientists efforts exerted over the past years, the ocular delivery of drugs remains a great challenge due to several barriers and hurdles faced by this kind of administration. The exploitation of gelatin that has a long history of safe use in pharmaceuticals and which is considered as a GRAS (Generally Regarded As Safe) material by the FDA was not fully achieved in this field. This review summarizes the recent studies and findings where gelatin-based microand nanoparticles were used for successful ocular delivery aiming at drawing the attention of researchers and scientists to this valuable biomaterial that has not been fully explored.

Biomaterial, drug delivery, gelatin, ocular, particles

Introduction Gelatin is a denatured protein that is usually obtained from a natural source: collagen by acid or alkaline hydrolysis. This naturally abundant protein can offer huge benefit as a biomaterial1. It is considered as a poly-ampholyte having both cationic and anionic groups together with hydrophobic ones in the approximate ratio of 1:1:1. Physically, the gelatin molecule is 13% positively charged due to the presence of lysine and arginine amino acids, 12% negatively charged due to glutamic and aspartic acid presence and 11% of the chain is hydrophobic in nature due to the presence of the following amino acids: leucine, isoleucine, methionine and valine2. Other amino acids; glycine, proline and hydroxyproline form the rest of the chain. This unique structure and nature suggests its successful use as a drug carrier system that can be suitable for a wide variety of drug molecules. The triple helical structure of gelatin is attributed to the repeating sequence of specific amino acids depicted by the representation (Gly-X-Pro)n, where X represents the amino acid, mostly lysine, arginine, methionine and valine 6%3. One-third of the chain is composed of glycine and another one-third is either proline or hydroxyproline. The rest of the chain is composed of other residues. Commercially, gelatin is available as both cationic (gelatin type A, isoelectric point (pI) 7–9, prepared by an acid hydrolysis of pig skin type I collagen) or anionic (gelatin type B, pI 4.8–5, prepared by an alkaline hydrolysis of bovine collagen) protein without any need for further functionalization2. Figure 1 introduces the aforementioned basic composition of gelatin. Gelatin particulate systems have been developed over the past three decades and have been reported for the successful drug and gene delivery. Amongst the successful gelatin-delivered drug

Address for correspondence: Rania M. Hathout, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, African Union St., 11566 Cairo, Egypt. Tel: +2 0 100 5252919; + 2 02 22912685. Fax: +2 02 24011507. E-mail: [email protected]

History Received 30 September 2014 Revised 7 December 2014 Accepted 9 December 2014 Published online 8 January 2015

classes were the anticancer drugs4–10, antimalarials11, antimicrobials12–14, intra-articular drugs15–17, growth factors18, immunemodulators and potential vaccines19–21, topical ophthalmic drugs22 as well as several genetic materials and other macromolecules23–36. Moreover, gelatin nanoparticles were additionally utilized as immune-adjuvants37,38. Furthermore, composites of gelatin microspheres were also used as bone regeneration fillers39,40. Gelatin microspheres also proved successful for brain delivery41. Gelatin has many properties that encourage its use in ocular delivery; first, it has a long history of safe use in pharmaceuticals, cosmetics, as well as food products and it is considered as a Generally Regarded As Safe (GRAS) material by the FDA. Second, it has very low antigenicity because of being denatured, third, its functional groups are accessible and can be easily chemically modified, a property which may be incalculably useful in developing targeted drug delivery vehicles1,19,42–47. Yet, exploiting this valuable biomaterial in the ocular field has not been fully accomplished. Researches adopting gelatin pop-up like fashion from time to time and then disappear! Table 1 shows this pattern where the first ocular application of gelatin-based particulate systems appeared on 1989 followed by complete disappearance for this application till 2004. Another six years passed before an article appeared on 2010 followed by few researches between 2011 and 2013. The reasons for the paucity in gelatin-based studies intended for ocular delivery are not explained. This scarcity may be attributed to the relatively tedious common methods of preparation or due to its hydrophilic nature (although advantageous in some cases). This hydrophilicity may impose an obstacle during corneal penetration due to this layer dual nature as will be discussed in the following section. This encourages the use of nano- versus micro- and cationized versus neutral particles to facilitate the penetration in presence of this obstacle. Nevertheless, in this review, we summarize the few researches that were adopted on utilizing gelatin-based particulate systems in ophthalmic drugs delivery and highlight the importance and advantages of this biomaterial usage.

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Figure 1. The basic chemical structure of gelatin. Table 1. Gelatin-based particulate systems for ocular delivery. Year

Encapulant

Type of particles

Method of preparation

1989 2004 2004 2010

Pilocarpine Pilocarpine HCl Hydrocortisone Adrenaline

Gelatin microspheres Gelatin nanoparticles Gelatin nanoparticles Chitosan/gelatin particulate systems

2011–2013

Plasmid encoding the human mucin (MUC5AC) – Bovine serum albumin

Cationized nanoparticles with or without polyanions Gelatin nanoparticles Gelatin nanoparticles

Emulsification method Single desolvation method Single desolvation method Double cross-linking in an emulsion-phase separation medium Ionic gelation

2013 2013

Eye and ocular drug delivery Ocular drug delivery is one of the most challenging endeavors faced by pharmaceutical drug formulators and scientists working in the multidisciplinary areas pertaining to the eye due to the special anatomy and pharmacokinetics of the eye that restricts the entry of drug molecules at the required site of action48–50. The topical administration of opthalmic drugs usually has two different purposes: to treat superficial eye diseases, such as the common eye infections like conjunctivitis and blepharitis and to provide intraocular therapy through the cornea for serious diseases such as glaucoma or uveitis. However, the eye is characterized by its complex structure (Figure 2) and low impermeability to foreign substances including drugs. After encountering the tear film, comes the main barrier for ocular delivery: the cornea which is distinguished by three membranes – epithelium, endothelium and inner stroma (Figure 3). The outermost layer is the corneal epithelium, which is lipophilic in nature, acts as a selective barrier for small molecules and prevents the diffusion of macromolecules via the paracellular route. The stroma, the middle layer, is a highly hydrophilic layer making up of 90% of the cornea. Beneath lies the corneal endothelium that consists of a single layer of flattened epithelium-like cells and is responsible for maintaining normal corneal hydration. Because the cornea is characterized by lipophilic and hydrophilic structures, it represents an effective hurdle to eye penetration of both hydrophilic and lipophilic molecules51. And since the conventional topical formulations are amenable to application of the anterior portion, most of the applied dose is lost due to the defensive mechanism of the eye. As a result, less than 5% of the administered drug has the ability to penetrate the cornea and reach the intraocular tissues52. Although, more than 90% of the marketed ophthalmic formulations exist in the form of eye drops containing soluble drugs; yet these conventional systems cannot be considered

Double desolvation method w/o microemulsion method

References 83 22 22 109 97,110,111 60 112

optimal in the treatment of vision-threatening ocular diseases, in that most of the drugs are washed from the eye by its various defense mechanisms such as: lacrimation, tear dilution and tear turnover resulting in short residence time53 that make it difficult to achieve effective drug concentrations at the effective area54. After instillation of an ophthalmic drug solution, the drug is first mixed with the lacrimal fluid and remains in contact with the ocular mucosa for a very short period of time, typically 1–2 min, because of the continuous production of lacrimal fluid (0.5– 2.2 mL/min). Drainage through the upper and lower canaliculus into the lacrimal sac, which opens in the nasolacrimal duct, suggests a rapid elimination of conventional dosage forms during blinking. The conjunctiva and sclera are more permeable than the cornea for drugs topically applied into the eye, but the circulation removes the drugs before it can be absorbed by inner ocular tissues. Both trans-conjunctival penetration and trans-nasal absorption after drainage are generally undesirable, not only because of the loss of active ingredient but also because of possible severe systemic side effects. Penetration of drugs across the corneal epithelium occurs via the transcellular pathway (mainly for lipophilic drugs) or paracellular pathway (hydrophilic drugs). Nevertheless, the trans-corneal penetration seems to be hindered by the binding of the drug to the corneal tissues. However, these tissues can act as drug reservoirs55. Moreover, it is commonly understood that the lipid membranes are more permeable to the nonionized form of the drug than the ionized form. Accordingly, in the case of ionizable drugs (weak acids and weak bases), the permeation depends on the chemical equilibrium between the ionized and nonionized forms in the formulation and eventually in the lacrimal fluid. Therefore, the overall charge of the compound plays another role in drug permeation. Hence, hydrophilic charged cationic compounds permeate more easily through the cornea than anionic forms, because the corneal epithelium is negatively charged above its iso-electric point56–58. Additionally, the pH and buffering capacity of the instilled preparation can have a significant effect

DOI: 10.3109/10837450.2014.999786

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Figure 2. Schematic diagram showing the eye anatomy. Adapted from references 50 and 75.

Figure 3. Schematic diagram of the tear film and corneal barriers. Adapted from reference 78.

on ophthalmic drug absorption59. Thus, the main objectives of most ocular therapeutics is to maintain an adequate concentration of the drug at the site of action and to provide enhanced corneal penetration60.

Significance of the use of particulate systems in ocular drug delivery In order to overcome the aforementioned hurdles for ocular delivery, several approaches have been proposed such as the use of viscosity enhancers like the addition of chitosan to drug solutions61, in situ forming gels using poloxamers62,63 or ionactivated gelling polymers like gellan gum and carrageenan64,65, penetration enhancers66,67 and drug delivery using ophthalmic surgeries. In the case of viscosity enhancers, studies indicate that these substances have a limited value, because the formulations are still liquid and will be easily removed from the eye by its defensive mechanisms. Concerning the penetration enhancers, although several are being applied, the higher sensitivity of the eye tissues imposes great caution in their selection. Besides, there is an evidence that penetration enhancers themselves have the capability to penetrate the eye and hence have serious toxicological effects66. For drug delivery systems such as the in situ forming gels, because they must remain in the point of application for several hours, irritation of local tissue and blurred vision can be more problematic than for eye drops, which are usually

eliminated within few seconds. As for the fourth approach, the inflammatory response of the ocular tissues is a common side effect associated with ophthalmic surgery68. In light of the above, an alternative approach is to develop a drug delivery system that would solve the problems associated with the conventional systems and provide the advantages of targeted delivery of drugs for extended periods of time and be patient-friendly at the same time. In this context, an optimal ocular drug delivery system should be developed so that it could be administered in the form of eye drops, causing no blurred vision or irritability, and would require no more than one or two instillations a day. Much of the published data suggest that in the case of ophthalmic drug delivery systems, an appropriate particle size and a narrow size range ensuring low irritation, adequate bioavailability and compatibility with ocular tissues, should be sought for every administered drug. Accordingly, several micro- and nano-carriers have been adopted for ocular delivery such as the microemulsions69,70, the vesicular systems such as liposomes71, discomes and niosomes72–74, lipid-based particles and polymeric particles. The use of microemulsions usually leads to high corneal penetration values but the risk of irritation due to high surfactants and co-surfactants percentages remains problematic. On the other hand, while the vesicular systems possess the highest compatibility with the cornea75, yet, they always suffer from poor chemical stability that hinders their scale-up development76. Similar to liposomes, the lipid-based particles such as: the solid

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lipid nanoparticles and the nano-structured lipid carriers were successfully utilized for opthalmic delivery77. In addition, they solved various solubility-related problems of many drugs such as: dexamethasone and ganciclovir78. However, they suffer formulation problems like the possibility of drug expulsion from their lipid matrix especially for loading percentages above 50%. In addition, sterilization of these carriers is considered a difficult task due to high probability of chemical changes in case of using g-radiation generating free radicals. Sterilization could also lead to physical changes such as aggregation in case of heat sterilization79. In this context, the polymeric particles pose several advantages regarding the ocular delivery as they are usually more stable, have high loading capacities and can be tailored to encapsulate or conjugate wide range of drugs. Synthetic polymers, namely PLGA and poly("-caprolactone) were used for the ocular delivery of flurbiprofen and indomethacin, respectively, and demonstrated successful results80,81. However, foreign-body and localized multi-nuclear giant cell reactions were reported to associate with PLGA particulate systems82. Accordingly, particles derived from polymers of natural origin such as: chitosan, albumin and gelatin are particularly important due to their compatibility with the ocular tissues. Specifically, the delivery of drugs via this particulate-based product (micro- or nanoparticles) fulfills four main objectives: enhancement of drug permeation, controlled release, decreasing sensitivity and/or irritation and possible targeting. While nanoparticles may be more capable in corneal penetration, microparticles still possess small particle size that is undetectable as particles by the eye but big enough to resist drainage from the eye83. Nanotechnology-based drug delivery is specifically very efficient in overcoming hard-to-cross specific membrane barriers, such as the blood retinal barrier in the eye84. The drug delivery carriers prepared on nanotechnology basis may prove to be the best drug delivery tools for some chronic ocular diseases, in which frequent drug administration is necessary, for example in ophthalmic diseases like chronic cytomegalovirus retinitis (CMV). Furthermore, nanotechnology based drug delivery systems are extremely suitable in the case of retinal and choroidal neovascularization (CNV) as these diseases are associated with similar environments to that of solid tumors, in which the enhanced permeation and retention effect (EPR) may be available for drug targeting by nanoparticles85.

Rationale of using gelatin particulate systems in ocular drug delivery The choice of gelatin as a very promising biomaterial for ocular delivery is mainly based on its high biocompatibility and biodegradability. Precisely, collagen, the native protein from which gelatin is derived, is innately present in the eye, more specifically in the stroma, the middle cell layer of the cornea, and has been extensively employed in ocular applications86. Moreover, gelatin, like chitosan, possess good mucoadhesive properties that are usually beneficial in ocular delivery as both of them contain positively charged amine groups in their chemical structure that could interact with the negatively charged mucus layer87,88. Recently, proteins are posed as the natural alternatives to synthetic polymers for the development of particulate systems. They offer several advantages over synthetic polymers being GRAS drug delivery devices with high nutritional value and abundant renewable sources. Regarding the safety issues, they are metabolizable in vivo by digestive enzymes into un-harmful peptides whereas synthetic polymers may give toxic degradation products. Additionally, protein nanoparticles exhibit high loading capacity of various drugs due to multiple binding sites present in their molecules. They exhibit several possible drug loading

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mechanisms including electrostatic attractions, hydrophobic interactions and covalent bonding89. Concerning the cost, proteins are much less expensive compared to synthetic polymers, an issue that should not be ignored when thinking of the large-scale production in the pharmaceutical industry.

Fabrication of gelatin particulate systems The synthesis process of gelatin nanoparticles has been reviewed earlier by Elzoghby, where he published a comprehensive review on the synthesis, surface modification, targeted delivery and applications of this biodegradable nanoparticles2. The commonly reported methods of preparation were the single and double desolvation90–92, coacervation-phase separation93, emulsificationsolvent evaporation26, reverse phase microemulsion94, nanoprecipitation95,96 and self assembly of gelatin molecules. The normal ionic-gelation method was also successful for the preparation of cationized gelatin nanoparticles97. Usually, the mechanical properties, swelling behavior and thermal properties depend significantly on the cross-linking degree of gelatin98. Regarding microspheres, the methods that were adopted for their preparation included: the emulsification29, cross-linking with glyceraldhyde99 and polymerization. Although all the aforementioned methods have several advantages, there are some limitations for their use, especially for the ocular route delivery. In case of emulsification and microemulsification techniques, large amount of surfactants are required to produce the small-sized gelatin nanoparticles, which needs a complicated post-process100,101. The coacervation method is a process of phase separation followed by cross-linking step. This method usually leads to non-homogeneous cross-linking with unsatisfied loading efficiency102. Moreover, gelatin nanoparticles prepared by many of these methods were found to be large in size and have a high polydispersity index (PDI) due to heterogeneity in molecular weight of the gelatin polymer. To this end, the two-step desolvation was developed that enabled the production of the nanoparticles with a reduced tendency for aggregation103. This method is now recommended for the preparation of gelatin nanoparticles because it solves many problems of the conventional methods and improves the former single desolvation method where after the first desolvation step, the low molecular gelatin fractions (not expected to produce nanoparticles) presented in the supernatant are removed by decanting, and subsequently the high molecular fractions presented in the sediment are redissolved. Table 1 shows several studies that use one- and two-step desolvation to produce gelatin nanoparticles for ocular use22,60,83. Recently, the nanoprecipitation technique was introduced. It is considered rapid, easy, straightforward compared to other methods and leads to the formation of stable and small-sized particles104. It only requires two miscible solvents: the polymer is soluble in one (the solvent, e.g. water), but not in the other (the nonsolvent, e.g. ethanol). The polymer in the solvent phase is then added to the nonsolvent containing a stabilizer (usually poloxamers). Macromolecules were successfully formulated in gelatin nanoparticles prepared by this method105. Regarding microspheres, we hypothesize that the emulsification method would impose no problems for the preparation of microspheres intended for ocular delivery where non-toxic materials can be utilized such as: vegetable oils (e.g. olive oil) in the presence of safe emulsifiers such as the phospholipids or non-ionic surfactants such as: Tweens or spans106. It is worth noting that microspheres can also be formed by emulsification in the absence of emulsifiers as gelatin itself being a protein can serve as an ampholytic surface active agent where microspheres can be obtained at high stirring or homogenization speeds107,108.

DOI: 10.3109/10837450.2014.999786

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Ocular drug and gene delivery using gelatin-based particulate systems The first reported trial on the use of gelatin microspheres returns back to 1989, where the traditional miotic drug, pilocarpine, was encapsulated in gelatin microspheres prepared by emulsification using sunflower oil. The recovered gelatin microspheres showed discrete free flowing and spherical-shaped particles in the size range of 30 mm. The in vitro release of pilocarpine was bi-phasic with initial burst of the drug, then a sustained release behavior. After carrying miosis studies on rabbits, a prolonged and more intense therapeutic effect was achieved compared to the solution of the free drug83. In 2004, Vandervoot and Ludwig prepared drugloaded gelatin A and B nanoparticles for topical ophthalmic use containing two model drugs: pilocarpine HCl and hydrocortisone. The particles were prepared using the single desolvation method using ethanol. Specifically, hydrocortisone, a water-insoluble drug, was first complexed with cyclodextrins before loading in the gelatin nanoparticles. The obtained hydrocortisone-loaded nanoparticles were smaller in size than the pilocarpine counterparts due to less aggregation. The type of gelatin used did not significantly alter the produced particle size in contrast to the pH, which had a profound effect on the size of the particles. A sustained release profile was obtained for both drugs compared to the aqueous drug solutions despite the differences in zetapotentials recorded22. In another study, double cross-linked chitosan–gelatin particulate systems prepared in two cross-linking steps in an emulsion-phase separation system were obtained in the size range of 0.202–4.956 mm. They were assessed on animals and human volunteers for the effective delivery of adrenaline, and the particles demonstrated good adherent properties without irritations and were successful in controlling the release of the investigated hormone109. Cationized gelatin nanoparticles were also investigated as an important candidate for gene delivery. Gene therapy may shortly become a powerful therapeutic modality in the treatment of several ocular diseases by introducing, into the ocular cells, genes that encode down-regulated proteins. The ability of hybrid cationized gelatin nanoparticles, containing a plasmid specially designed to encode the human mucin (MUC5AC), to transfect ocular epithelial cells was evaluated. With small particle size (5200 nm), positive zeta-potentials (+20 to +30 mV) and high plasmid association efficiency (495%), the results provided an evidence of success of these nanoparticles as vehicles for gene therapy and for restoring the MUC5AC concentration in the ocular surface97. The formulations showed good performance on experimental dry eye murine model110. In the same context, the same group developed hybrid nanoparticles comprising cationized gelatin nanoparticles together with the polyanions dextran sulphate and chondroitin sulphate for ocular gene therapy. The prepared systems were able to associate plasmid DNA and to protect it from DNase I degradation. The introduction of the polyanions was ascribed to the in vitro toxicity reduction without compromising the transfecion efficiency111. Recently, Tseng et al. assessed the effective ocular delivery of two differently charged gelatin nanoparticles formulations in vitro on human corneal epithelium (HCE cells) and in vivo using New Zealand rabbits. No significant difference in cell viability was observed between the control group and the gelatin nanoparticle-treated groups (positively charged) even after treating with 500 mg/ml of nanoparticles for 2 h. It was proven that gelatin nanoparticles as cationic colloidal carriers were efficiently adsorbed on the negatively charged cornea without irritating the eyes of the rabbits and can be retained in the cornea for a longer time. The corneal thickness and the intraocular pressure did not change significantly after treatment with positively charged gelatin nanoparticles. It was hence concluded that cationic gelatin nanoparticles have a great potential as

Gelatin-based particulate systems in ocular drug delivery

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vehicles for ocular drug delivery60. A new biocompatible nanocomposite contact lens, made of copolymer of 2-hydroxyethyl methacrylate and 2-aminoethyl methacrylate p(HEMA-coAEMA), containing a hydrophilic protein (bovine serum albumin) loaded in gelatin nanoparticles was further developed and demonstrated a prolonged release for seven days112. This new approach would introduce these types of composites as an alternative tool for continuous topical ocular drug delivery over a prolonged period of time. Additionally, this approach, introducing potential for new treatment strategies besides serving as a method for studying disease mechanisms, holds great promise in the treatment of diseases but requires proof of – concept of – its efficacy in animal models and humans. Table 1 summarizes the published studies that utilized gelatin-based particulate systems for ocular delivery.

Conclusion and future trends Although not fully explored, gelatin micro- and nanoparticles hold all the needed properties that pose successful topical ophthalmic delivery that can enrich the different delivery formats. The formulation of this biodegradable polymer as carrier systems holds significant promise for ocular drug delivery since it is suitable for several drugs and would allow drop-wise administration while maintaining the drug activity at the site of action. Moreover, by interaction with the glycoproteins of the cornea and conjunctiva, they can form a precorneal depot resulting in a prolonged release of the bound drug. It can also help to develop an effective and robust gene therapy for the treatment of genetically based blinding diseases. In this context, more studies are necessary to provide further information and insight on exploiting this carrier and mining it as a treasure in ophthalmic drug delivery.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Gelatin-based particulate systems in ocular drug delivery.

Despite all scientists efforts exerted over the past years, the ocular delivery of drugs remains a great challenge due to several barriers and hurdles...
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