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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5441_Библиотеки_им_академика_М_И_Перельмана.pdf
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The various bioprinting technologies are available by which we can produce high-
resolution medical devices with any type of stem cells. The laser-assisted bioprint-
ing (LaBP) technology is one of the most precise, exible and powerful techniques
for generating corneal tissues from stem cells. First and foremost, bioprints do not
affect their biological and functional properties. The most interesting thing is that
the articial corneas are able to maintain the ideal systemic curved shape and dis-
tinctive arrangement of collagen lamellae. Isaacson et al. used a pneumatic 3D
extrusion bioprinter in 2018 to develop 3D bioprinted corneas (Fig.12.6) (Isaacson
etal. 2018).
3D model of human cornea is constructed by collecting topographical data from
matured human cornea. Different types of bio-ink combination with a low viscosity
like collagen and alginate were tested while doing these experiments. In result they
found the enhancement in mechanical stability of models which are printed with
collagen-1 bio-ink combined with alginate. The corneal keratocytes’ remarkable
vitality persisted for 7 days following printing and cell insertion. Therefore, the
preservation of high viability keratocytes implies that composite bio-ink made up of
Table 12.1 Types of bio-inks made up of various types of biomaterials
Bioinks
Biomaterials
References
1. Bioink consist of
hydrogels and particles
• PLGA-PEG (poly(lactic-co-glycolic
acid-polyethylene glycol) with cell-laden
CMC
• PLGA/gelatin combines with
methacryloyl (GelMa)
Ashammakhi
etal. (2019)
2. Bioink made up of
synthetic and natural
biomaterials
• GelMa
3. Bioink made up of
synthetic biomaterials
• PEG-diacrylate (PEGDA)
• PEGDA with alginate
4. Bioink made up of natural
biomaterials
• Chitosan with gelatin
• Cellulose with alginate
Fig. 12.6 The image showing the 3DP process of printing corneal structure and its outcome
before the incubation (Isaacson etal. 2018)
12 Advances inOphthalmic Formulation Development
302
collagen and alginate is able to use for 3DP corneas. Despite innovative ways for
replicating corneal structures, like magnetism or electrospinning, the ndings dem-
onstrate poor transparency. Shear-induced bres may be produced with the use of
3DP technology. As collagen bres differ from collagen brils and can even impact
corneal keratocytes, thin collagen brils generated from decellularized corneal tis-
sues can be employed (Muthusubramaniam etal. 2012; Kim etal. 2019).
12.4.2 Contact Lens
The introduction of hydrogel soft lenses was a key advancement in contact lens
development. Contact lens manufacturing is still a complex procedure as it involved
many steps and has limited exibility for design. The utilization of newer tech-
niques like 3DP is used to develop different types of contact lenses such as smart
contact lenses which helps to diagnose and control eye diseases. The light-curing-
based polymerization is mainly done by digital light printing (DLP) as compared to
fused deposition modelling (FDM) because DLP printing has a much higher resolu-
tion (Bandari etal. 2021). DLP printing can generate corrective contact lenses by
using Asiga Dental Clear resin which is mostly used in the dental industry (Alam
etal. 2021). Fahad Alam etal. prepared and customized contact lenses for the man-
agement of colour blindness with the help of 3D printing. They used wavelength-
selective ltering dyes and a resin made up of in situ synthesized poly(2-hydroxyethyl
methacrylate, or pHEMA). To lter out unwanted wavelengths, two dyes (Atto 565
and 488) were functionalized in contact lenses. These dyes have absorption bands
in the range of 550–580 and 480–500nm wavelengths. The coloured contact lenses
efciently blocked 80–90% of the unwanted wavelengths, where colour vision-
decient patients have difculty discriminating between shades of specic colours.
Using the Ishihara test, contact lenses were evaluated on colourblind patients, and
the results showed a clear improvement in the participants’ sense of colour (Alam
etal. 2022).
12.4.3 Drug Delivery
Hydrogel-based formulations for 3D printed patches can also enable the drug
release effectively in the eye, such as the conjunctiva, without impairing vision or
making the user uncomfortable blinking (Table 12.1). Tagami et al. developed
lyophilized ophthalmic patches capable of manufacturing unique doses that may be
tailored to hospital patients (Tagami etal. 2022). The antibiotic levooxacin was
incorporated in the drug release patches. The patch is printed by using different
hydrogel-based bioink containing mannitol, HPMC, xylitol and drug. Most cru-
cially, the patches can contain numerous active medicinal components and be
designed to release varied amounts based on the needs of the patients. These eye
patches may be made to administer various medication formulations, such as eye
drops for those having cataract surgery (Gonzalez-Gonzalez etal. 2014) and mini
R. Bhawale et al.
303
tablets to treat inferior conjunctival fornix (Moosa etal. 2014). A tailored ophthal-
mic patch for each patient may be built using the chemical and physical properties
of the materials used in the drug-release patch. For individuals who have had cata-
racts and glaucoma surgery, the biocompatible drug-releasing patch can assist
reduce the need for frequent eye drop administration.
12.4.4 Regulatory Considerations of3DP inOphthalmology
Despite the promising future of 3DP applications in the medical industry, the legal
framework for 3DP technology in pharmaceutical goods is not yet complete.
Although the FDA authorized the 3DP medication Spritam in 2015, the application
guidelines for 3DP were not available until 2017 (Tsui etal. 2022). Furthermore, the
FDA has not published any restrictions regarding 3DP technology (Mohammed
etal. 2021). It is a hindrance to the application of 3DP medical devices and restricts
the clinical translation of 3DP goods to patients. As a result, it is hard to specify who
will bear legal liability for disputes over the safety of 3DP items. However, the regu-
latory bodies have just recently designated teams and started programs to begin
developing the 3DP standard requirements (Mohammed etal. 2021). Following the
FDA’s early attempts in 2019, the Medicines and Healthcare Products Regulatory
Agency (MHRA), Therapeutic Goods Administration (TGA, Australia), European
Medicines Agency (EMA) and other national regulatory bodies have begun to
explore laws enabling innovative 3DP uses in medicine (Tsui etal. 2022).
12.5 Challenges intheDevelopment
ofOphthalmic Formulation
Although eye drops or ointments can be used to treat some viral or inammatory
eye conditions. The various anatomical and physiological obstacles that the eye has
mean that achieving the required therapeutic effectiveness as well as ocular bio-
availability remains challenging. Despite enormous effort in developing an effective
ocular delivery method, several innovations have yet to be successfully turned into
a marketable product. The majority of technologies that have undergone clinical
trials have proven to be suitable effective and safe in animal models. Promising nd-
ings in animal models, however, may not always transfer into the same results in
human trials. Any animal model showing illnesses and conditions cannot be the
same as the physiological reactions in humans, particularly for ocular disorders.
Although rodent models are well known, inexpensive and simple to use, rodent eyes
are smaller and have a proportionately bigger lens and corneal surface than human
eyes; rodent eyes also contain nictitating membranes (Mann etal. 2018; Rodrigues
etal. 2018).
Rabbits are widely utilized to investigate ophthalmic formulations because their
eyes are more similar in size to human eyes than rodent eyes. However, as compared
to human eyes, rabbit eyes create more mucus, have fewer tears and blink less
12 Advances inOphthalmic Formulation Development
304
(Mann etal. 2018; Ahn etal. 2016). These variations in anatomy and physiology
have an impact on PK, highlighting how challenging it is to extrapolate from prom-
ising preclinical ndings to clinical success (Rodrigues et al. 2018). There are
genetically modied animal models available for testing medicinal effectiveness.
Although naturally occurring disease models are more likely to describe correct
pathophysiology, the practicalities of having animal models available on demand
are hard (Mann etal. 2018). As previously stated, good preclinical results do not
correctly predict comparable outcomes in humans, particularly in research related
to nanoformulations. The effective clinical translation of nanomedicines is pre-
dicted to enhance medication therapy for human illnesses; yet nanomedicines have
had limited success in reaching the clinic and have remained as “possible” remedies
for the previous few decades (Satalkar etal. 2016; Park 2017).
Because of several anatomical and physiological obstacles, drug delivery experts
and ophthalmologists have long had difculty delivering medications into the eye
(Fig.12.7). Invincible static and dynamic ocular barriers prevent xenobiotics from
entering the eye and inhibit therapeutic drugs from being actively absorbed. The
intention behind developing ideal drug delivery is to improve the bioavailability and
controlled release of the drug at the site of action which helps to cross different
ocular barriers. Current advancements for anterior ocular segment disorders, such
as punctum plugs, drug-eluting contact lenses and ocular implants, represent state-
of-the-art drug release technologies. Parallel attempts for ocular delivery technol-
ogy for back of the eye ailments have led in the approval of different intravitreal
implants. Nanoparticles, nanowafers, dendrimers, nano micelles, liposomes and
microneedles are among the novel drug-delivery methods being investigated for
Fig. 12.7 The anatomical diagram of the eye shows various ocular barriers and drug delivery sites
and challenges/problems/side effects, respectively
R. Bhawale et al.
305
anterior and posterior disorders. To improve patient compliance for back of the eye
problems, innovative techniques for the non-invasive administration of effective
treatment drugs are being developed (Cabrera etal. 2019). As a result, the primary
issue in the eld of ocular drug delivery is to overcome these obstacles to obtain
therapeutically appropriate drug molecule concentrations with increased sustained
bioavailability in the target ocular location.
12.6 Evaluations Parameters/Test
oftheOphthalmic Formulations
The eye is a delicate organ, and thus ophthalmic drug delivery systems need to
evaluate on different parameters to conrm its safety and compatibility to ocular
tissues. Unlike other delivery systems, ophthalmic delivery systems used to evaluate
in terms of its stability, compatibility with ocular tissue, along with physiochemical
properties such as viscosity, osmolarity, pH, etc.
There are two kinds of testing protocols and acceptability standards for ophthal-
mic products: (1) those that evaluate general quality features, such as identity, impu-
rities, potency, particulate matter and sterility and (2) those that evaluate invitro
product performance, such as dissolution or release of the drug ingredient from the
drug product. This section addresses the quality tests for ophthalmic products. The
performance tests (dissolution/drug release) are addressed by Ophthalmic Products-
Performance Tests <1771>. All the tests described below are according to the United
States Pharmacopoeia (USP) 43 NF 38.
12.6.1 Physical Appearance
A qualitative description of the drug product should be provided. The nal qualify-
ing criteria should include a clear appeared formulation, packaging, colour, etc. A
quantitative technique can be necessary if the hue varies while being stored. This is
not a standard test, but it is part of the drug’s manufacturer’s specication.
12.6.2 Identification
In order to distinguish between compounds with potentially present closely related
structural similarities, identication tests must rst identify the drug or drugs’ pres-
ent moiety. Identity testing should be drug-specic [e.g., infrared (IR) spectros-
copy]. If the test is nonspecic, at least two orthogonal nonspecic tests should be
used. Near-infrared (NIR) or Raman spectrophotometric methods could be accept-
able for the identication of the drug product. The chromatographic identication of
the products is considered under the <621> and<201> in USP 43 NF 38.
12 Advances inOphthalmic Formulation Development
306
12.6.3 Assay
The strength (content) of the medicinal product should be determined using a par-
ticular and stability-indicating test. When using a nonspecic assay test, it is impor-
tant to apply additional supporting analytical techniques to obtain overall specicity.
When there is indication that an excipient is interfering with a nonspecic assay
test, a specic approach should be utilized. Antibiotics-Microbial experiments
<81>, Ion Chromatography <1065> and<621> all have further details on individual
experiments.
12.6.4 Impurities
The drug ingredient and excipients utilized in the production of the drug product
may contain process impurities, synthetic byproducts and additional inorganic and
organic contaminants. We can avoid respective impurities with the help of mono-
graphs of drug ingredients and excipients mentioned in the pharmacopeia. It’s
important to keep an eye on organic impurities that develop during the production
process of a drug product as well as those that result from the degradation of the
active ingredient in the drug. All articles fulll the standards of Elemental Impurities-
Limits <232>and Residual Solvents <467>.
12.6.5 Particulate andForeign Matter
All ophthalmic items should be scrutinized for package integrity and the presence
of visible foreign and particulate materials, to the greatest degree practicable.
Extrinsic, or external matter, and intrinsic, or stuff associated to the product, are the
two origins of these undesirable particles. Extrinsic material cannot be connected to
the product or process. Intrinsic particles are introduced during product manufactur-
ing or as a result of a change over time. One hundred percent inspection of inject-
able products in clear packages is required to remove nal packages with visible
particles. When 100% inspection of the injectable product in the nal package is
difcult, such as in opaque containers, alternative methods may be used to deter-
mine acceptability. Visible Particulates in Injections <790> provides further guid-
ance for general inspection methods and a denition of “essentially free of visible
particles” for batch compliance. Products intended for intraocular use must abide by
Particulate Matter in Ophthalmic Solutions <789>. Products intended for external
use must adhere to Particulate Matter in Injections <788>. Considerations for prod-
uct evaluation and the background for both subvisible methods are found in Methods
for the Determination of Particulate Matter in Injections and Ophthalmic
Solutions <1788>.
R. Bhawale et al.
307
12.6.6 Antimicrobial Preservatives
Products that are stored in containers that permit the extraction or administration of
numerous doses require the addition of antimicrobial agents unless one of the fol-
lowing situations occurs:
1. Each monograph contains a separate set of instructions.
2. A radionuclide in the material has a physical half-life of <24h.
3. The product satises the criteria of the Antimicrobial Effectiveness Testing
<51>, even without the use of additional agents.
Antimicrobial Agents-Content <341> and<51> specications must be followed
by substances. It is important to set acceptance standards for antimicrobial preserva-
tives used in multi-unit products.
12.6.7 Bacterial Endotoxins
All injectable ophthalmic medication products must be manufactured in a way that
minimizes bacterial endotoxins, as specied in the Bacterial Endotoxins Test <85>.
For ocular irrigation products, the limit is NMT 0.5 EU/mL, and for injectable or
implanted medication products, the limit is NMT 2.0 EU/dose/eye. It is not appli-
cable to topical ophthalmic products.
12.6.8 Uniformity ofDosage Units
Dosage forms supplied in single-unit containers are suitable for this test. It takes
into account both the dosage form’s bulk and the amount of drug substance(s) con-
tained within. The test can be carried out using either content uniformity or weight
variation (see Uniformity of Dosage Units <905>).
12.6.9 Sterility Test
Ophthalmic dosage formulations must fulll the Sterility Tests <71> criteria. If the
formulation’s individual constituents do not lend themselves to conventional steril-
izing processes, substances that fulll the sterility standards mentioned in <71>, as
well as aseptic production, may be employed. At the moment of lling and sealing,
the immediate container for ophthalmic products must be sterile. The sterility test
according to various ofcial pharmacopeias is shown below in the diagram
(Fig.12.8a, b) (Paradkar and Parmar 2017).
12 Advances inOphthalmic Formulation Development
308
12.6.10 Osmolarity
Ophthalmic products may be tolerated over a wide range of tonicity (0.5–5% sodium
chloride, equivalent to about 171–1711mOsm/kg). Hypotonic solutions are better
tolerated than hypertonic solutions. Precautions should be taken to ensure that the
product maintains its osmolarity during shelf life. Any possible contributions or
interferences from the packaging system should be considered <771>.
Human tears have an osmolarity of around 310mOsm/kg and a tonicity compa-
rable to 0.9% w/v NaCl solution. The presence of sodium, chorine and bicarbonate
Fig. 12.8 Schematic presentation of ophthalmic formulation sterility test according to (a) US
Pharmacopeia (USP) (2020) and British Pharmacopoeia (BP) (2022), (b) Indian Pharmacopoeia
(IP) (2022)
R. Bhawale et al.
309
transport helps to keep osmotic pressure in check. The physical characteristics of
drug also have a role in the permeability of the blood-aqueous barrier. The pH of the
formulation must be the same as the tear which is around 7.4. Various hydrophilic
ointments are easy to wash, but their use is restricted by consideration of the osmotic
effect (Dubald etal. 2018). The osmolarity of the prepared formulation is calculated
by the following equation:
m
OsmL
ConcentrationgL
Molecular weight
/
/
=
()
×
100
If the prepared formulation is found to be hypotonic, we must add some specic
amount of substance which will adjust the tonicity of the prepared formulation.
Sodium chloride (NaCl) is mainly added as an adjustable substance. To calculate the
required amount of sodium chloride (NaCl), the following equation is useful:
Weight
of NaCl required
Freezing point of unadjustablesolut
=
−
052. iion
Freezing point depression of solutionofdrug1%
12.6.11 Ocular Irritation
Ocular irritation is one of the most important parameters to evaluate and check the
irritation caused by the prepared formulation. It promises safety and valuable
assessment for local compatibility. The Draize rabbit eye test developed by John
H.Draize in 1944 is accepted worldwide and accepted by FDA which is used to
check eye irritation after applying the formulation to the eyes (Luechtefeld 2016).
Three separate eye tissues—the iris, conjunctiva and cornea—are examined as part
of the examination. The albino rabbit was chosen as the test species. To evaluate the
irritancy of the prepared formulation, either 0.1 mL or 0.1 g of the formulation
which may be an ointment, liquid, solid or paste is installed in different tissue like
the cul-de-sac of the conjunctiva and cornea of the one eye. Another eye should be
untreated or treated by only the excipient or vehicle. The evaluation is done at 1, 4,
24, 48 and 71h on exposure to the material. If needed time may extend up to 4, 7
and 21days. Record the irritation behaviour based on observation (Kolle etal. 2015).
12.6.12 Isotonicity Evaluation
Eye irritation and damage of eye tissues are the main reasons of ophthalmic prepa-
ration whose isotonicity is not maintained according to standard. The prepared for-
mulation was mixed with a small quantity of blood to evaluate and observe the
changes in blood cell shapes under 40× magnication. This change in the shape of
blood cells is compared with the shape of blood cells kept in an isotonic solution
12 Advances inOphthalmic Formulation Development
310
(0.9% NaCl). If the formulation is hypertonic, cells will shrink, and if the formula-
tion is hypotonic, cells will get swell or might burst (Maiti etal. 2011).
12.6.13 Stability Study
As per ICH guidelines, keep the formulation at different conditions mentioned
below in Table12.2. Later, evaluate the formulation for its particle size, viscosity,
drug content and % entrapment efciency (Paradkar and Parmar 2017).
12.6.14 pH
The pH of normal tears is around 7.4. The eye can withstand items with pH levels
ranging from 3.0 to 8.6, depending on the formulation’s buffering ability. The pH
value of the formulation should be the one where the drug product is the most stable.
Patients will tolerate formulations that aim for the extremes of the permissible pH
range more readily if they have a limited buffering capacity <791> (Lim etal. 2014).
12.6.15 Viscosity
The residence time of ophthalmic formulation in the eye is an important consider-
ation which totally depends on the viscosity of prepared formulation. Rheometer is
used to determine the viscosity of prepared formulation with the 101–1800 rpm
shear rate (Lievens etal. 2019).
12.7 Regulatory andFuture Consideration
Due to a lack of stringent laws and appropriate regulatory requirements for ocular
delivery, developing fresh administration routes and innovative formulations faces
unsurmountable difculties when it comes to constructing nonclinical programs,
which are essential to accurately assessing risk for people. Regulations pertaining to
nonclinical testing of ocular formulations are also not well dened due to concur-
rent regional variances. Therefore, these complexities offer new prospects to NDA
and ANDA applicants in ophthalmic drug development and commercialization.
This section includes a brief summary of the regulatory perspective which is helpful
in the development of a safe, effective and quality nal product. A further require-
ment of 21 CFR 211.167, which regulates foreign, harsh or abrasive particles in
Table 12.2 Stability test
conditions for ophthalmic
formulations
Temperature Stored for
30–35°C 30days
2–8 °C 30days
R. Bhawale et al.