Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5441_Библиотеки_им_академика_М_И_Перельмана.pdf
291
To preserve the visual accuracy and vision ability of the eye, several ocular tis-
sues, membranes and mechanisms are working, but these defence mechanisms are
creating hurdles for effective ocular drug delivery, thus commonly known as ocular
barriers (Srivastava etal. 2023; Zulliger etal. 2015). The ocular barriers are mainly
classied into two types, i.e. static and dynamic. The cornea, retina, sclera and
blood-retinal barriers come under static barriers, whereas tear dilution, lymphatic
clearance and conjunctival blood ow are considered as dynamic barriers. Delivering
a drug across the cornea is a major restriction for drug delivery systems; thus the
ocular bioavailability of drugs depends on how easily the drug will cross the above-
mentioned barriers. The existence of cellular cornea and tear lm acts as amphiphi-
lic barriers for drug molecules (Agarwal etal. 2016). The different types of ocular
barriers are enlisted in Fig.12.3.
Fig. 12.2 Physiological classication of the human eye
Fig. 12.3 Various ophthalmic barriers in the human eye
12 Advances inOphthalmic Formulation Development
292
The conventional method of drug administration, i.e. simple eye drops and solu-
tion, is used as a preferred and easier ophthalmic dosage form; however poor ocular
bioavailability is associated with them (Wu et al. 2019). High tear uid turnover
washing off 90–95% of the total drug administered produces the most challenging
event of ocular drug delivery. Advancement in ocular delivery is very important to
improve or prolong the ocular residence time of drug. Undesirable loss of drug
molecules mostly occurs through nasolacrimal drainage, systemic absorption,
blood-retinal barrier, enzymatic degradation and protein binding (Zhu etal. 2018;
Bisht etal. 2018). Recent development in ophthalmic preparations has made it pos-
sible for prescribers to choose the best dosage forms for certain eye diseases
(Bhosale etal. 2022; Maulvi etal. 2021; Rakhmetova 2020).
Even having some disadvantages and limitations like the administration of for-
mulation and high drug loss due to precorneal space, the topical route is the most
accepted route for ophthalmic drug administration. Systemic administration con-
sists high amount of drugs which can cause various side effects. Drug delivery to the
posterior structure of the eye by injection is the effective way but has lots of danger-
ous disadvantages like retinal detachment and haemorrhage. Considering these
points the development of ophthalmic preparations focuses on the topical route of
administration with prolonged residence time, site-specic delivery, sustained
release prole and better corneal permeability (Baranowski etal. 2014). In the past
few years, various drug delivery systems came into research with the help of using
permeation enhancers, in situ gel, implants, stimuli-responsive and prodrugs, and
also some nanotechnologies like nanoparticles, liposomes, dendrimers, niosomes
and microneedles are taken into consideration which helped to increase ocular resi-
dence time and drug permeability across different ocular barriers and helped to
improve drug bioavailability. Various natural polymers are used to formulate sus-
tained-release ophthalmic formulations like xanthan gum, hyaluronic acid, cellu-
lose derivative, gellan gum, alginate, chitosan, etc. (Dubashynskaya et al. 2019;
Pathak et al. 2023). This chapter included the recent advancement in ophthalmic
formulation till now and also discussed about different technologies that contribute
to the ophthalmic eld to deliver drugs.
12.2 Ideal Properties andTypes ofOphthalmic Preparation
12.2.1 Ideal Properties forOphthalmic Preparation
12.2.1.1 Sterility (Absence ofPyrogen)
Sterility is one of the essential properties of ophthalmic preparations as the eye
contains favourable conditions for growth of microorganisms. Nutrient-rich tear
uid, humidity, mucin and optimum temperature are perfect environment for micro-
organism ourishment. Presence of microorganisms in ophthalmic preparations
may cause several severe corneal infections. To avoid such horrifying conditions
and protect the eye, ophthalmic products should be sterile and free from pyrogens
or its byproducts. For multi-dose containers, preservatives are very essentials in
R. Bhawale et al.
293
order to maintain sterility. The preservative should not be poisonous, irritating or
incompatible with medications (Hasegawa etal. 2021).
12.2.1.2 Absence ofForeign Particle
As explained earlier the eye is a very sensitive and delicate organ; thus it needs to
be taken extra care during administration of the dosage form. Even a small foreign
particle may cause severe irritation, redness or allergic conditions to the eye. To
avoid entrance of foreign particles inside the eye, several barriers are present such
as eye lid, eye lashes, tear uid turnover, blinking and a submucosal secretory
immunoglobulin system. In the same order, ophthalmic products should be clear,
non-hazy and devoid of impurities or particles. To achieve the foreign body-free
product, ophthalmic preparations should pass through an appropriate membrane
and sintered glass lters, and check for clarity test (Paradkar and Parmar 2017).
12.2.1.3 Corneal Tissue Compatibility
To penetrate the cornea and ocular tissues, the ophthalmic preparation should have
the vehicle, which shows good wettability and penetrability. Advanced ocular prod-
ucts were developed to achieve prolonged residence time and enhanced contact time
with corneal tissue; thus the product should be compatible with ocular tissues. The
excipients and vehicles of formulation should be tested for biocompatibility study
with corneal tissues to avoid irritation and toxicity (Patel 2013).
12.2.1.4 Isotonicity
Isotonicity is again an important characteristic of ocular drug delivery systems. To
avoid the irritation and discomfort of the eye, the formulation should be isotonic
with lachrymal secretions. Osmolarity of tear uid ranges from 290 to 310 mOsmol/
kg that will be isotonic to 0.9% NaCl solution, i.e. normal saline. Various isotonic
vehicles are used to prepare ophthalmic formulations such as sodium acid phos-
phate buffer and 1.9% w/v boric acid (Patel 2013; Pramar 2009). Formulation
should be isotonic to physiological; uid is necessary to avoid irritation and discom-
fort to the eyes.
12.2.1.5 Optimum pH oftheSolution
The stability, therapeutic activity, solubility and patient convenience of ophthalmic
formulations mostly depend on pH which should be almost near to 7.4, i.e. pH of
physiological uid. The eye can handle solutions with a wide pH range as long as
they are not heavily buffered since the tear will quickly return the eye’s pH to nor-
mal (Lim etal. 2014).
12.2.1.6 Viscosity (Appropriate Rheological Properties)
Conventional ocular products are of liquid physical state, possessing very less vis-
cosity, but the advanced ocular products have variable rheological properties in
order to improve residence time. Sol-gel transitions are the most fascinating
approach for advancing ophthalmic products, but they need to maintain optimum
viscosity as highly viscous product may cause irritation and discomfort to the eye.
12 Advances inOphthalmic Formulation Development
294
Optimum viscosity for ophthalmic products ranges from 25 to 50 cps. Thickening
agents are added in ophthalmic preparation to improve and prolong the contact time
of drug in the eye (Lievens etal. 2019). The preparations should be viscous enough
to stick to the corneal surface but liquid enough to pass through lters at the time of
sterilization.
12.2.2 Types ofOphthalmic Preparations
The various ophthalmic formulations are classied based on the state of the nal
formulations, viz. liquid, solid and semi-solid (Baranowski etal. 2014). The clas-
sication of the various ophthalmic formulations is shown in Fig.12.4.
12.3 Novel Drug Delivery Systems (NDDS)
forOphthalmic Formulations
12.3.1 In Situ Gelling System
Drug-laden polymeric solutions are intended to have low viscosity for simple instil-
lation; nevertheless, when administered in cul-de-sac, it alters into pseudo-plastic
gels that prolong the drug contact duration with the ocular tissues (Sokolowski
2018). In situ gelling can be achieved by various stimulations such as ionic altera-
tion, thermo-stimulation, pH responsive or change in microenvironment (Ranch
etal. 2021).
The antibacterial activity against methicillin-resistant Staphylococcus aureus
(MRSA) in rabbits was increased by another pH-sensitive in situ gel containing
vancomycin that provided a sustained release, releasing 39.2% after 24h. The lipid
lm hydration process was utilized to formulate vancomycin-loaded niosomes with
Fig. 12.4 Classication of ophthalmic dosage forms
R. Bhawale et al.
295
an average diameter of 53.7nm (Allam etal. 2019). When compared to a regular
eye drop solution, a pH-sensitive in situ gel containing bimatoprost (BIM) solid-
lipid nanoparticles (SLN) was safe and increased the precorneal drug residence
time. Rita etal. prepared, characterized and evaluated the BIM-SLN for the treat-
ment of glaucoma. The high shear homogenization prepares SLN by following the
probe sonication and later on incorporates into the pH-sensitive gel to form in situ
gel containing BIM. The prepared formulation results in prolonged release, and
HET-CAM test results show there is no evidence of eye irritation by formulation.
On the same side, histopathological study proves there is no tissue damage due to
application of the prepared formulation (Wadetwar etal. 2020).
12.3.2 Mucoadhesives
To improve contact time and reduce the clearance of drug through tear turnover,
advancement in drug delivery system is introduced by utilizing the mucous layer of
the eye. The contact of a substance, often a polymer, whether natural or synthetic,
with the mucosa or any accompanying mucus is known as mucoadhesion (Bayer
2022). The interaction of the dosage form with mucus-coated mucosal epithelial
membranes is the key to the administration of mucoadhesive drugs. Because of this
interaction, residence duration rises, giving the drug more opportunity to enter its
designated site of action (Grassiri etal. 2021). The various theories are intended to
explain the mucoadhesion of dosage form to the ocular surface (Shaikh etal. 2011).
• Electronic theory: Electron transport between the dosage form and the mucosal
surface causes the interaction.
• Wetting theory: It generally applies to liquid mucoadhesive where the polymer
and mucin have structural similarities. As a result, the mucoadhesive polymer
may spread over the mucosal surface, and surface tension is reduced.
• Adsorption theory: Electrostatic effects, hydrogen bonds and van der Waals
forces are used as the attraction processes at this place. Additionally, hydropho-
bic effects are involved, especially when amphiphilic mucoadhesive polymers
are used and mucins and other particular polymers may form covalent bonds.
• Diffusion theory: It takes into account how soluble mucins diffuse into the
mucoadhesive and how polymers interact with mucus.
Abovementioned theories do not take place as they explain straightforward. But
the mechanism of adhesion appears according to the abovementioned theories. We
can’t say any theory via adhesion takes place, but the part of theory might involve at
the time of adhesion (Smart 2005; Khutoryanskiy 2011). If we consider the series
of events in how this theory participates in the mucoadhesive mechanism, initially
wetting is followed by electronic, adsorption and diffusion. Again, electronic like
this cycle repeats (Khutoryanskiy 2011; Ravindran etal. 2012).
Li etal. prepared drug-loaded chitosan lm for ocular drug delivery to treat glau-
coma. In order to prepare a chitosan-brimonidine tartrate (BT) lm, the
12 Advances inOphthalmic Formulation Development
296
anti-glaucoma drug BT was dissolved in a solution based on ordinary water. The
resultant lm is transparent, structurally sound and mucoadhesive. Crystals of the
anti-glaucoma BT medication are in micron-sized form and are evenly scattered in
the chitosan lm. High corneal permeability and quick drug release kinetics are
made possible by the chitosan-BT lm, which may one day be used to deliver drugs
to the eyes (Li etal. 2020).
12.3.3 Ophthalmic Micro- andNano-Emulsions
In this biphasic system, a non-ionic surfactant or stabilizer is used to disperse a non-
aqueous liquid into aqueous vehicles (Koli etal. 2021). We can deliver the hydro-
phobic drug incorporated in oil droplets as an emulsion that will improve aqueous
solubility of cargo and thus nally available in the form of eye drops. Comparing
the aqueous external phase-containing emulsion to the non-aqueous external phase,
it was discovered to be less irritating and more tolerated by the eye (Maulvi etal.
2020a; Pandey etal. 2020). The erythromycin-loaded microemulsion was prepared
by using ethanol, oleic acid and Tween
®
80 to improve permeation in the goat
model. Microemulsion also appeared as a transparent, and globule size was found
to be a minimum of ~12.1nm (Mukhopadhyay and Butola 2020). When the drug
was delivered to the posterior region of the eye using a microemulsion loaded with
uocinolone acetonide and cow ghee (CG) as a permeation enhancer, there were
increased penetration and improved invivo drug kinetic characteristics. Water titra-
tion methods were used to prepare microemulsion, and CG, Labrasol (surfactant)
and Transcutol (co-surfactant) act as corneal penetration enhancer. The transcorneal
drug permeability got improved because of micellar formation. Drugs’ ocular per-
meability is improved by the fatty acids in CG, which serve as an effective carrier
(Gupta etal. 2019).
Another study involves cannabidiol-loaded nano-emulsion for effective ocular
delivery. The nano-emulsion was prepared by using glycerin (tonicity adjuster) and
Carbopol
®
940 NF (mucoadhesive agent) in the rabbit model. The investigation’s
primary goal was to fully assess CBD’s effects on the IOP (intraocular pressure) in
the model. Utilizing hot homogenization and probe sonication, the nano-emulsion
was formulated. At various temperatures, the formulation was tested for its stability
study, and then the effect of formulation on IOP of the rabbit model was observed.
IOP was decreased in the animal model under study when CBD was applied topi-
cally and prepared as a mucoadhesive nano-emulsion (Senapati etal. 2022).
12.3.4 Ophthalmic Nano-Suspensions
The water-insoluble drug dispersed in aqueous vehicles to form ophthalmic suspen-
sions. Ophthalmic suspensions sometimes have longer residence time because drug
particles have a propensity to accumulate in the conjunctival cul-de-sac (Peters etal.
2020). Particle size, dissolution rate of drug in tear uids and intrinsic solubility are
R. Bhawale et al.
297
considered as a critical factor during the production of ophthalmic suspensions
(Schoenwald and Stewart 1980). The particle size of <10 μm shows poor drug reten-
tion time on the ocular surface but also shows high solubility and dissolution rate.
On the other hand, a particle size of >10μm shows ocular irritation and rapid drain-
age from the ocular surface because of excessive tearing (Li etal. 2014). The stabil-
ity of ophthalmic suspension is one of the major issues faced by the ophthalmologist.
If a suspension is stored in a frozen condition will provide the problem of re-
dispersion since in cold condition particles will clog together to produce a cack
(Joshi 1994). To avoid the side effects associated with frequent dosage, a high-
pressure homogenizer was used to manufacture a stable long retentive posaconazole
ocular solution utilizing a polymer system (Carbopol 974P and xanthan gum). The
zeta potential of −47.3mV indicates an electrically stable suspension that is resis-
tant to occulation. Posaconazole suspension proved effective against Candida
albicans fungal infection (10
−8
CFU/mL). In accelerated stability studies, the prod-
uct (which has a shelf life of 24months) was stable for 6months (Simta etal. 2020).
During storage, changes in the crystal structure may occur, causing particle size to
grow or decrease, inuencing medication solubility and bioavailability. The result
of olopatadine-loaded Kollidon
®
SR nanosuspension via spray once a day shows
sustained release and relatively narrow particle size. The spray drying method was
employed to prepare nanosuspension along with particle size ranging from 75 to
145nm. The nding of invivo experiment performed on Anatolian Merino sheep
shows improved drug retention time (Güven and Yenilmez 2019).
12.3.5 Nanotechnologies Enabled Drug Delivery System
inOphthalmic Formulation Development
In the past few years, various drug delivery systems came into research with the
help of using permeation enhancers, in situ gel, implants, stimuli-responsive and
prodrugs, and also some nanotechnologies like nanoparticles, liposomes, den-
drimers, niosomes and microneedles are taken into consideration which helped to
increase ocular residence time and drug permeability across different ocular barriers
and also helped to improve drug bioavailability. Qiao etal. developed a liposomal
formulation with high stability, good patient compliance and a sustained release to
treat dry eye disease. Rats were used to assess the retention, tolerance and therapeu-
tic efcacy of rebamipide (RBM) liposomes. In vivo evaluation of RBM’s ocular
distribution was done on rabbit eyes. In comparison to suspensions, RBM lipo-
somes exhibit greater corneal retention. RBM liposomes maintain the same effec-
tiveness and enhance the concentration in the cornea and aqueous humour while
lowering the dose of the drug and causing ocular surface irritation. RBM liposomes
offered an additional use in ophthalmic medicine, particularly for the treatment of
dry eye disease (DED) (Qiao etal. 2022). Mitra etal. formulated a 0.1% cyclospo-
rine A (CsA) nanomicelle system using a 0.05:1.0% mixture of octoxynol-40 and
hydrogenated castor oil-40, which has extremely low critical micelle concentrations
(0.00707%). The rabbit’s cornea, conjunctiva and sclera received therapeutically
12 Advances inOphthalmic Formulation Development
298
substantial doses of CsA from the 0.1% CsA nanomicelle preparation (Cholkar
etal. 2015). The CsA concentration after a single installation in each ocular tissue
of rabbits is shown in Fig.12.5.
Additionally, CsA concentrations in all ocular tissues—aside from the tear and
upper eyelid—were markedly increased compared to Restasis
®
when repeatedly
administered with a 0.05% CsA nanomicelle formulation (OTX-101) (Weiss and
Kramer 2019). These results could be the consequence of better interaction between
the tear’s outer oil layer and the oil-based vehicle. In adult patient for treatment of
DED, the US FDA approved OTX-101in 2018 as Cequa
®
(OTX-101, 0.09%) oph-
thalmic solution (Mandal etal. 2019). Therefore, effective medication therapy for
DED may be made possible by surfactant-based nanomicellar systems. Allam etal.
sought to extend the pharmacological effect of vancomycin by inserting drug-loaded
niosomes into a pH-sensitive in situ forming gel. Unexpectedly, the formulation
showed physicochemical stability. Additionally, greater antibacterial activity was
seen invitro and invivo as compared to vancomycin hydrochloride-free medication
solution, and EE% of niosomes was greater than 46%. Additionally, niosomes had
shown sustained release for longer than 24h (Allam etal. 2019).
12.3.6 Therapeutic Contact Lenses
The contact lenses loaded with drug which are able to show therapeutic effect are
known as therapeutic contact lenses. Therapeutic contact lenses may increase the
Fig. 12.5 The CsA concentration after single installation in each ocular tissue of rabbit (Nagai
and Otake 2022)
R. Bhawale et al.
299
bioavailability of drug by at least 50% by causing the high residence time and come
into close contact with the cornea (Desai etal. 2020). Drugs released through con-
tact lenses have a residence time of more than 30min in the pre- and post-tear lm,
compared to eye drops which are only 1–2min (Tieppo etal. 2012; Hui and Willcox
2016). The use of therapeutic contact lenses can lower the total drug dose required,
the frequency of dosing and the quantity of drug lost through systemic absorption
(Hiratani et al. 2005; Hsu et al. 2015). In general, the lenses are well tolerated
(Maulvi etal. 2020b). Soaking, ion ligation, molecular imprinting and the use of
colloidal polymeric nanoparticles or supercritical uids are some of the methods
developed to laden contact lenses (Maulvi etal. 2014, 2016, 2019, 2020c). When
compared to routinely inserted eye drops, dexamethasone kept in lenses using a lm
resulted in 200× larger quantities of the medication in the retina (Ross etal. 2019).
Coating the surface of the ACUVUE
®
TrueEye™ contact lenses with phomopsidi-
one nanoparticles (average size=77.45 nm) produced a sustained release of the
drug for 48h. Keratitis might be treated using this lens. The test microorganisms
employed in this investigation were methicillin-resistant Staphylococcus aureus
(MRSA), Candida albicans, Proteus mirabilis, Pseudomonas aeruginosa, Serratia
marcescens, and Candida utilis (Bin Sahadan etal. 2019). Dexamethasone-laden
contact lenses are able to prevent anterior uveitis caused by lipopolysaccharide for
5days and suture-induced corneal neo-vascularization for 7days. The PLGA encap-
sulation process was used to prepare lm and merged it into a hydrogel contact lens
(Bengani etal. 2020).
12.3.7 Ocular Inserts
These are intended to deliver the drug based on diffusion at zero order rate constant
(Rathore and Nema 2009). Ocular insert can prolong drug delivery, increase drug
residence durations, improve bioavailability, and prevent peak and valley release
patterns to get around the side effects that go along with those features (Wolters
Kluwer 2023). Ketorolac-laden polymethyl methacrylate (PMMA) microspheres
can be used as ocular coils in the lower conjunctival fornix to administer drugs over
several months. By using the o/w emulsication method, the microspheres were
prepared. With the aid of technology based on funnel volume, the ocular coils were
lled with PMMA microspheres in their lumen. Voriconazole was successfully used
in antibacterial investigations by porous rod-shaped hydrogel polymer that provided
a regulated release of the medication for 12h in Aspergillus and Fusarium. The
rods, however, induced more tear production and were removed from the eye
(Rakhmetova 2020).
12 Advances inOphthalmic Formulation Development
300
12.4 Implementations of3DP (Three-Dimensional Printing)
inOphthalmology andIts Regulatory Consideration
Three-dimensional printing (3DP) is not a new invention, but its use in the health-
care sector is a new approach which is helpful to solve the recent problems and
clinical challenges in ophthalmic drug delivery as well as in other drug delivery too.
This technique is cost-efcient and requires a biocompatible material for printing
that should match to human physiology and thus helpful in organ transplantation,
surgery as well as in the development of new drug delivery systems. Additionally,
3D printed medical implants and gadgets may be personalized for every patient to
offer a more customized treatment strategy. Patients with various eye problems can
benet from the advantages and uses of 3DP, and recent developments in 3D bio-
printing have opened up new therapeutic possibilities in ophthalmology. 3DP has
the ability to offer more exibility for patient-specic customization is a key aspect
(Bhawale etal. 2023; Fan etal. 2020).
The future and present outlook for treating patients with a variety of eye prob-
lems may be greatly altered by the prospective applications of 3DP.A solution to
the serious corneal donor scarcity may have been found with the development of
3DP cornea (Zhang etal. 2019). The 3DP technology also has the potential to cus-
tomize a design to the demands of each patient, which can lead to a better anatomi-
cal t. Traditional manufacturing techniques have been used to create a large number
of ocular implants likely laser beam machining (LBM) and computer numerical
control (CNC) machining which are subtractive manufacturing technique types via
casting and forging (Davis etal. 2022). By using an effective 3DP medication deliv-
ery system in place of the current medical therapy, 3DP can be helpful in ophthal-
mology. Utilizing properly chosen biomaterials, the 3DP technology’s adaptability
and personalization may potentially be utilized to design glaucoma and cataract
implants that are unique to each patient. The future of 3DP can help many individu-
als who have problems after eye surgery and from the side effects of medical treat-
ments, even if there are still many challenges in choosing biocompatible materials
and their printability under various 3DP techniques.
12.4.1 Corneal Tissue Bioprinting
To design 3D bioprints, the corneal tissue is viable to combine biomaterials with
human proteins (Table12.1). Corneal tissues can be rebuilt by using biocompatible
materials, but at the time of selection, the criteria should be followed carefully for
its invitro settings. A stromal structure made of human adipose tissue-derived stem
cells (hASCs) was able to mimic the characteristics of native corneal stroma with
high cell survival rates using 3D bioprinting (Sorkio etal. 2018). The form and
biological activities of limbal epithelium produced from human embryonic stem
cells that were employed in different bioprinting were likewise those of the corneal
epithelium. The interaction of the 3DP stroma integrating hASCs with a porcine
cornea revealed its preliminary biocompatibility to integrate with the host tissue.
R. Bhawale et al.