Ophthalmic drug delivery systems- types and challenges.pptx

Ophthalmic drug delivery systems- types and challenges

1. 1 Ophthalmic Formulations (Part - 2) Presented By Suryawanshi Kranti Ashok First Semester, M. Pharmacy Department of Pharmaceutics Guided By Dr. A. B. Gangurde Head of Department Department of Pharmaceutics KBHSS Trust Institute Of Pharmacy, Bhaygaon Road, Malegaon

2. Types of Ocular drug Delivery System Topical Administration Intracameral Injections Intracameral injections involve administering antibiotics directly into the vitreous cavity or the anterior part of the eyeball. It is typically performed after cataract surgery in order to prevent endophthalmitis brought on by an eye infection that may arise during cataract surgery. Intravitreal Injections/Implants A medication called an intravitreal injection is injected into the vitreous, which is located near the retina at the back of the eye. A single intravitreal injection of vitamin E/poly-lactic-co-glycolic acid microspheres containing neurotrophic factor produced from glial cell lines is one innovative method for treating glaucoma. For six months, this method offered an extended release . 2

3. For the treatment of diabetic macular edema and neovascular age-related macular degeneration, intravitreal injections of the biodegradable Rho kinase and protein kinase C inhibitor demonstrated extended release for approximately 6 months. Juxtascleral Injections Certain posterior part disorders which respond poorly to topical treatment are treated with juxtascleral injections. It is used to treat conditions associated to diabetes, trauma, and cystoid macula edema. A novel method of treating AMD includes intra-transscleral injections of anecortave cortisone, which demonstrated prolonged release in the retina and choroid for 6 months. For the purpose of treating retinal genes, sophisticated trans-scleral microneedles have been developed to deliver adeno-associated viruses. Retrobulbar Injection The retrobulbar technique involves injecting the drug into the retrobulbar space behind the globe by means of the orbital fascia and eyelid. 3

4. Amphotericin B administration via retrobulbar injection shown superior antifungal activity compared to intravenous injection. Chlorpromazine injections retrobulbarly are used to treat painful, blind eyes. Triamcinolone injections intrabulbarly are used to treat macular edema resulting from retinal vein blockage. Subconjunctival Injection When topical treatment results in minimal drugs penetration into the anterior region of the eye, subconjunctival injection is commonly employed. When used as PEGylated liposomes, subconjunctival injections of steroids were shown to exhibit long-lasting anti-inflammatory effects and to target the required ocular tissue for at least 1 month. IOP was well managed for 10 days after subconjunctival injection of brinzolamide PLGA nanoparticles. Sub-Tenon Injections Using a blunt cannula, sub-tenon injections are given into a cavity between the sclera and the tenon's capsule. This treatment does not  require serious anesthesia prior to procedure. Since the sub-tenon route avoids the need for sharp needles, it seems to be a safer and more effective way to administer anesthetic than the retrobulbar and peribulbar routes 4

5. Fig no 1 : Topical ophthalmic Preparation 5

6. Iontophoresis A kind of technique for delivering drugs to the posterior portion of the eye is iontophoresis. It makes use of a voltage gradient. Instruments based on microneedles are used in novel systems. The length of drug uptake into choroidal capillaries is 550–1300 times shorter when iontophoretic administration and contact lenses are combined. Higher penetration and bioavailability were obtained by short-duration iontophoresis of the acyclovir product. Dexamethasone phosphate ocular iontophoresis shown improved effectiveness in treating non-infectious anterior uveitis. Microneedles The device known as microneedles was invented to treat glaucoma using microvascular injection. It is made up of a flexible, tapered tubing with a blunted needle attached to the end for inserting a microneedle or micropipette into tiny blood capillaries. This is a minimally invasive method used to administer hydrophilic and hydrophobic medications into the eyes. To treat disorders in the posterior segment, microneedles may be used to deliver medication into the sclera without the risks and difficulties of intraocular injection or systemic delivery. 6

7. Sonophoresis Sonophoresis, often known as ultrasound, is the use of ultrasonic frequencies greater than 20 kHz to improve ocular and transdermal penetration. Through a coupling medium, such as an emulsion or suspension of any formulation that permits the propagation of an acoustic field, an ultrasound is administered to the epithelium. Fig no 2: Topical ophthalmic drug delivery 7

8. Liquid Dosage Forms Eye Drops Eye drops are sterile suspensions of drops or aqueous or oily solutions that are inserted into the eye using a dropper. Typically, they contain drugs with meiotic, mydriatic, antiseptic, anesthetic, and anti-inflammatory activities. The ideal pH for eye drops should be 7.4%, which is identical to the pH of tear fluid. On the other hand, extending the duration of the medication's residency at the surface of the eye drop and boosting drug penetration through the cornea may enhance ocular bioavailability. Excipients such cyclodextrins, viscosity modifying agents, and permeation enhancers are utilized for this purpose in order to improve the formulation's efficiency. For example, due of its surfactant characteristics benzalkonium chloride may be used as both a penetration enhancer and a preservative. Eye Suspensions Ocular suspensions are aqueous solvent-based dispersions of hydrophobic drugs. Because of the drug's retention in the conjunctival cul-de-sac, their contact time is increased. 8

9. During the preparation process, the tear fluid's particle size, solubility, and dissolution rate are crucial factors. Particles smaller than 10 μm often have higher solubility, faster rates of dissolution, and less retention on the surface of the eye. Particles larger than 10 μm , however, may cause eye discomfort and induce tears. One drawback of ocular suspension is its lack of stability. Eye Emulsions Emulsion-based formulations aim to improve the solubility and bioavailability of the drugs they encapsulate. Water-in-oil (W/O) and oil-in-water (O/W) emulsions serve as the main formulative mechanisms for this design. O/W emulsions are preferred over W/O emulsions for the application of drug delivery to ocular tissues because of their advantageous properties, which include reduced ocular irritation and enhanced eye tolerance. Currently drugs on the market utilizing emulsion technology include AzaSite ®, Refresh Endura®, and RestasisTM . Prodrug The permeability of a drug through the cornea is also increased by modifying its characteristics through the development of a prodrug. 9

10. Several pharmacological compounds, such as epinephrine, phenylephrine, timolol, and pilocarpine, have been produced as prodrugs. Because of its 600-fold higher lipophilicity at pH 7.2, dipivefrin, a diester of pivalic acid and epinephrine, has a 17-fold greater corneal permeability than epinephrine. As a result, a small quantity of dipivefrine given to the eyeball has the same medicinal benefits as epinephrine. By altering the chemical structure, this technique confers new properties specifically, selectivity and site specificity to the active ingredient. Semisolid Dosage Forms Eye Gels Eye gels are a semisolid dose form with a large amount of water. Their viscosity gives them improved absorption and retention time. Even with gels high water content, visual impairment is still possible. Ocular gels could be made from a variety of polymers, including carboxymethyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid, and acrylic acids. 10

11. Eye Ointments Mineral oil and white petroleum are the ingredients of eye ointments, which are semisolid dosage forms. Because they obstruct eyesight, they are only applied to the lower eyelid at night. They are frequently utilized by younger patients. Due to their anhydrous nature, they are an excellent fit for medications that are moisture-sensitive and lipophilic. When compared to solutions, they have a longer retention period and greater bioavailability. Solid Dosage Forms Eye Powders These are water-sensitive medication dose forms in sterile, solid form. Cefuroxime, moxifloxacin, and voriconazole are administered as injectables through intracameral injection. Voriconazole is reconstituted in water, whereas cefuroxime and moxifloxacin are reconstituted in saline. After reconstitution, cefuroxime and voriconazole solutions remain stable for a period of seven days. On the other hand, the moxifloxacin solution lasts for 24 weeks. 11

12. Ocular Inserts Ocular inserts are biodegradable polymer dose forms that are solid. The zero-order drug release model is displayed. High residence time, sustained drug delivery, consistent release, and decreased adverse effects are some of the benefits of inserts. Fig no 3 : Ocular insert 12

13. Therapeutic Contact Lens According to recent research, a therapeutic contact lens's prolonged residence duration and close contact with the cornea can increase bioavailability by more than 50% . Their residence period is 10 times longer than that of traditional eye drops. They also lessen systemic absorption, dosage requirements, and intervals between doses. Numerous methods, including molecular imprinting, ion ligation, soaking, and the utilization of nanoparticles, can used to confine the medicine inside a contact lens. Compared to standard eye drops, it demonstrated a 200-fold increase in drug retention in the retina. 13

14. Mixed Dosage Forms In Situ Gel One of the most innovative drugs delivery systems has emerged: the "in situ gel" technology. With its unique feature of shifting from "sol to gel," the in-situ gel drug delivery system promotes patient compliance, comfort, and a sustained and regulated release of the drug. An in-situ gelling system is a formulation that, prior to entering the body, is in solution form but, under certain physiological conditions, transforms into gel form. A variety of factors including pH changes, temperature changes, and solvent exchanges, combine to transform solutions into gels. Fig no 4 : In Situ Gel Formulation 14

15. Nanostructured Platforms Liposomes Liposomes are lipid vesicles that include one or more phospholipid bilayers that trap water within. Liposomes typically have a size between 0.08 and 10 μm . Liposomes are the best delivery vehicles for ocular applications because of their superior biocompatibility, structure resembling a cell membrane, and capacity to encapsulate both hydrophilic and hydrophobic medications. In numerous investigations, liposomes proved to be a good medication delivery method for the anterior and posterior segments of the eyes. Niosomes Niosomes are bi-layered drug carrier systems that can hold both hydrophilic and lipophilic drugs. They are created by the self-association of cholesterol and non-ionic surfactant in the aqueous phase. Because of their unique structural features, low toxicity due to their nonionic nature, chemical stability, and lack of need for extra care when handling surfactants, niosomes are the ideal vesicular delivery mechanism for topical ocular applications. 15

16. Nanomicelles The most popular carrier systems for dissolving medicinal substances in transparent aqueous solutions are nanomicelles . Amphiphilic molecules make up these nanomicelles . These compounds are either polymeric or surfactant in nature. The development of nanomicellar formulation-based technology for ocular medication delivery is currently receiving a great deal of attention. The medicinal drugs' bioavailability in ocular tissues is increased by the micellar formulation. Long-term systemic circulation of nanomicelles causes them to accumulate in exhausted tissue. Nanoparticle The colloidal carriers with particle sizes ranging from 10 to 1000 nm are called nanoparticles. Lipids, proteins, and natural or synthetic polymers such albumin, sodium alginate, chitosan, poly (lactide-co- glycolide ) (PLGA), polylactic acid (PLA), and polycaprolactone are the usual components of nanoparticles. Because of their small particle size, they increase patient compliance, especially in cases of chronic symptoms. They have better penetration, a slower rate of elimination, and a longer duration of drug release. 16

17. Nanocrystals The drug being used is primarily composed of nanocrystals, which are stabilized and encased by other excipients. Their characteristics include low particle size, easy production methods, strong mucoadhesion , and enhanced bioavailability. Dendrimers A dendrimer is a type of macromolecule with a highly branching three-dimensional structure, high compatibility, and multivalency. As a result, they play a significant role in the rapidly developing field of nanomedicine. Dendrimers' highly branching structure makes it possible to incorporate a variety of medications, both hydrophobic and hydrophilic. According to various reports, dendrimer offers promising results for ocular drugs delivery. Cubosomes The bicontinuous cubic liquid crystalline nanocarriers are produced by the stabilizing process when lipids are emulsified in water. Their large surface area allows them to trap a significant number of drugs, making them stable, biodegradable, and somewhat safe. They are also easy to produce. It improved corneal permeability and anti-inflammatory action. 17

18. Olaminosomes The primary components of olaminosomes are surfactant, oleylamine , and oleic acid. Natural unsaturated free fatty acids include oleic acid. Oleic acid is biocompatible, safe, and biodegradable. Thus, the creation of ocular nanocarriers frequently involves the usage of oleic acid. Olaminosomes exhibit enhanced corneal penetration, safety, activity, and a high degree of drug entrapment capability due to their small particle size. Fig no 5 : Illustration of numerous nanostructured platform 18

19. Key Ingredients Used In Ophthalmic Formulations Preservatives Viscosity Modifiers pH Adjusters Buffers Stabilizers Lubricants Active Pharmaceutical Ingredients (APIs) Preservatives Preservatives are crucial components in ophthalmic formulations to prevent microbial contamination and maintain product sterility over the shelf-life. Commonly used preservatives include benzalkonium chloride (BAK), chlorhexidine, and polyquaternium-1. Viscosity Modifiers Viscosity modifiers are added to ophthalmic formulations to control their rheological properties, ensuring proper administration and retention on the ocular surface. 19

20. These modifiers influence the formulation's viscosity, spreadability , and residence time. Examples of viscosity modifiers include hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose ( NaCMC ), and hyaluronic acid. pH Adjusters pH adjusters are used to maintain the desired pH range of ophthalmic formulations, ensuring compatibility with ocular tissues and optimizing drug stability and bioavailability. Common pH adjusters include sodium hydroxide, hydrochloric acid, and phosphates. Buffers Buffers are added to ophthalmic formulations to maintain pH stability and prevent drastic changes in acidity or alkalinity, which can compromise ocular comfort and drug efficacy. Buffers help maintain the formulation within the physiological pH range of tears, minimizing irritation and enhancing patient compliance. Commonly used buffers include phosphate buffers, borate buffers, and citrate buffers. Stabilizers Stabilizers are additives that enhance the stability of ophthalmic formulations by preventing degradation or aggregation of active pharmaceutical ingredients (APIs) and other components. 20

21. Stabilizers play a crucial role in preserving the formulation's efficacy and shelf-life under various storage conditions. Examples of stabilizers include antioxidants (e.g., sodium metabisulfite), chelating agents (e.g., EDTA), and surfactants. Lubricants Lubricants are included in ophthalmic formulations to improve patient comfort during administration and minimize friction between the formulation and ocular tissues. Lubricants enhance the spreadability of formulations, reduce irritation, and facilitate blinking without compromising drug delivery. Common lubricants used in ophthalmic formulations include glycerin, propylene glycol, and mineral oil. Active Pharmaceutical Ingredients (APIs) APIs are the primary therapeutic agents in ophthalmic formulations, responsible for exerting pharmacological effects to treat ocular diseases or conditions. These active ingredients may include antibiotics, anti-inflammatory agents, antiglaucoma medications, antiviral drugs, and artificial tears. The selection of APIs is based on their efficacy, safety profile, and targeted therapeutic indication. 21

22. Evaluation Test For Ophthalmic Formulation There are two types of examinations that must be done to ascertain the properties: in vitro and in vivo. Sterility, pH, clarity of solutions, visual evaluation, particle size, tonicity/osmolarity, viscosity, amount of material, amount of preservative, stability, and in vitro release are all determined by the former. These latter consist of the in vivo release and the Draize eye test. Other important evaluations, carried out for specific drug forms, include the measurement of encapsulation efficiency for multicompartment drug delivery systems and emulsions or the analysis of ions and oxygen permeability for contact lenses. In Vitro Examinations Sterility Examination Sterile forms have to satisfy the basic requirements before they are applied to the eyeball. The process of testing for sterility involves inoculating the sample under aseptic conditions onto two microbiological media: thioglycolate medium, which is utilized for the growth of both aerobic and anaerobic bacteria, and soya-bean casein digest media, which is used for the growth of both aerobic and fungal bacteria. 22

23. Determining pH The most common method for determining the pH of solutions, drops, suspensions, and in situ gels is the potentiometric method. By detecting the potential difference between electrodes placed in studied and reference solutions with known pH values, or between measurement electrodes (glass) and reference electrodes (calomel or silver chloride), both placed in analyzed preparations, the pH value is found using this method. Clarity Examination Evaluating formulation visually on a black and white background in appropriate lighting is known as a clarity examination. With the exception of suspensions, it is done for liquid forms. Eye drops and in situ gels both before and after gelling are included by this evaluation. Utilizing a UV-Vis spectrophotometer, transmittance testing is another technique for examining clarity. Examination of Size and Morphology of Particles Optical microscopy (microscopic particle count test), Light obscuration particle count test, Dynamic imaging analysis, 23

24. Laser diffraction particle analyzers, Electron microscopy (SEM, TEM, AFM), DLS (dynamic light scattering), Coulter Counter test, and nanoparticle tracking analysis (NTA) Examination of Content of Substance or Preservative The analysis of the drug or preservative content in a specific formulation is labeled using the appropriate analytical technology, such as HPLC or spectrophotometric method.   Examination of Drug and Carrier Interaction/Compatibility Using FTIR, DSC, and XRD Methods. In order to find potential interactions between the active ingredient and other ingredients of the preparation, tests using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD) are carried out for a variety of substances, including pure substances, physical mixtures of drug and polymers used to obtain formulation, and the ingredients of the formulation. 24

25. Stability Examination The goal of a stability examination is to identify changes in the quality of an active ingredient or medicinal product over time that result from the effects of temperature, humidity, and light on the substance or product under examination. Drug Release Studies A number of techniques used to assess the availability of drugs in ophthalmic forms were explained. These include The diffusion method using a Franz cell, the modified rotating paddle apparatus, The bottle method, The modified rotating basket method, and The flow-through device method. 25

26. Other examinations performed for ophthalmic drug forms include Viscosity examinations using viscometer, Osmolarity examinations using osmometers and The light refractive index measurement using ellipsometers/refractometers Other Examinations Performed for Chosen Drug Forms Examinations for In Situ Gels Analyzing Gel-Forming Capability. The purpose of this investigation is to evaluate the formulation's capacity to produce gels on the surface of the eyeball. A vial containing a solution whose components simulate a tear fluid is filled with a sample of the formulation under examination, and the sol-gel phase transition is evaluated visually. Examinations for Inserts Swelling Index Depending on the relative resistance of the matrix network structure to the passage of water particles, hydrophilic polymers with varying structures show varying degrees of swelling.       26

27. The swelling index, which measures how much of the liquid is absorbed, is determined using the formula: where 𝑊 0 is the initial sample weight and 𝑊𝑡 is the sample weight at 𝑡 time. Examinations of Moisture Absorption and Loss These tests are carried out to evaluate the physical stability and integrity of the polymer matrix of the inserts in dry and humid environments. formula is used to determine the percentage of moisture absorption : and the formula is used to determine the percentage moisture loss. 27

28. In Vivo Examinations Eye Irritancy Test (Draize Eye Test) A known amount of test material is placed in one eye of each of 6 albino rabbits the other eye remains untreated, serving as a control. The eyes are not washed after instillation and are examined at 24,48 and 72 hours for ocular reaction. The test is considered positive if ulceration, opacity of the cornea, inflammation of the iris, swelling of the conjunctiva occurs. A substance is an eye irritant if, 4 of six rabbits score positive it is considered a non irritant if none or only one of the 6 animals exhibit irritation. 28

29. Trans-corneal Permeation Study Similar to the Draize eye test, a sufficient number of healthy albino rabbits are selected for the transcorneal permeation investigation in order to ensure accurate results. After that the introduction of the formulation to the conjunctival sac, the amount of the active substance in the aqueous humor is noted at predetermined intervals. Using a syringe and needle, an aqueous humor sample (about 150–200 𝜇 L) is taken after an intramuscular or intravenous anesthetic injection (which may contain, depending on application, ketamine hydrochloride, xylazine hydrochloride, or pentobarbital sodium). This sample is then stored at a negative temperature (such as −20 ∘ C) until HPLC analysis. Sometimes, just before or during paracentesis, additional inhalation anesthesia is administered, for example, in the form of 4% isoflurane oxygen mixture. For example, xylocaine solution, a type of regional anesthesia, may be used. 29

30. Challenges and future perspectives for ocular drug-delivery technologies The present ocular drug-delivery system has limitations, including poorer bioavailability for topically delivered medications and the intrusive nature of posterior implants. However, novel technologies are emerging to provide more effective treatment for ocular illnesses. Ocular problems, including cataracts, dry eye disease, wet and dry AMD, glaucoma, DR, and DME, are expected to increase in the next two decades. Eye drops are the safest and most convenient option for treating most anterior segment problems. Eye drops have minimal absorption at the target tissue. Nano formulations, including nano micelles, nanoparticles, liposomes, dendrimers, nanowafers , and micro-needles, can enhance medication bioavailability in anterior tissues like the conjunctiva and cornea. Currently, all therapies for back of the eye problems include invasive procedures. Frequent intravitreal injections can cause retinal detachment, bleeding, and irritation to patients. Scientists in the field of ocular medication administration face a challenge in designing a noninvasive sustained drug delivery system for the posterior segment. New noninvasive drug delivery techniques are needed to overcome ocular barriers, sustain drug release, and maintain effective levels in the back of the eye. 30

31. Thank You 31