A Brief Review on Stability testing of Eye Drop  

Sarang Chavan*, Dr. Gulam Javed Khan.

J.I.I.U’S Ali-Allana College of Pharmacy Akkalkuwa, Dist- Nandurbar (425415) Maharashtra, India.

*Correspondence: sarangchavan143@gmail.com; Tel.: (7721965683)

INTRODUCTION

Eye is the most unique organ of the body. [1] It is one of the challenging organs for drug delivery because its unique anatomy restricts drug absorption into the deep tissues. [2] A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, nonproductive absorption, transient residence time, impermeability of corneal epithelium, blinking, reflex lachrymation and drainage remove rapidly foreign substances, including drugs, from the surface of the eye.[3, 4] Due to these physiological and anatomical barriers, only a very small fraction of the drug, usually 1-5% or even less of the instilled dose, is effectively absorbed.[5] Moreover, the anatomy, physiology and barrier function of the cornea compromise the rapid absorption of drugs. Frequent instillations of eye drops are necessary to maintain a therapeutic drug level in the tear film or at the site of action. But the frequent use of highly concentrated solutions may induce toxic side effects and cellular damage at the ocular surface. Moreover, the anatomy, physiology and barrier function of the cornea compromise the rapid absorption of drugs. Frequent instillations of eye drops are necessary to maintain a therapeutic drug level in the tear film or at the site of action. But the frequent use of highly concentrated solutions may induce toxic side effects and cellular damage at the ocular surface. To enhance the amount of active substance reaching the target tissue or exerting a local effect in the cul-de-sac, the residence time of the drug in the tear film should be lengthened to improve patient compliance

Topical ophthalmic NSAIDs are used to treat ocular surface and anterior segment inflammation, post-operative management of pain and inflammation as well as treatment of seasonal allergic conjunctivitis. As a class, they have proven to be an effective, useful and a safe alternative to corticosteroids in the topical management of ocular inflammations, as corticosteroids cause serious side effects such as elevation of intraocular pressure and progression of cataracts [6].

Topical application of ocular anti-inflammatory drugs is the most advantageous route to treat eye

inflammation ion. It is affecting the anterior segment because it is easy to apply, can give a high drug concentration, and avoids systemic absorption. As a result of the physiological and anatomical constraints of the eye only few amounts of the drug is ocularly absorbed [7]. The continuous secretion of the tear fluid decreases the contact time with the eye surface. So, the viscosity increasing agents have been used to increase the contact time with ocular

surface [8].

Eye drops and ophthalmic products are the pharmaceutical products instilled in eye that are used to treat and prevent several ophthalmic disorders. Eyes are one of the main sensory organs of the living world. Even technologically so much advanced human too, depend on eyes for many of the chores. The modern world is so much depended on screens and the number of screens is increasing daily, but the effects of same can be seen as people with ophthalmic disorder is increasing and the effectiveness of ophthalmic product is promising in these cases. The alternative of using herbal products in eye drops is one of the best substitutes as herbs are easy to cultivate and contain several active pharmaceutically important constituents. The regulatory expectations for ophthalmic pharmaceutical products have always been among the most demanding (9). Products to be used in the eye are expected to be biocompatible with its sensitive tissues (including being at a suitable pH), isotonic with the relevant fluids (unless otherwise justified), and sterile until the container has been opened. If the product is intended to be used on more than one occasion, it should be preserved adequately. For some therapeutic uses, such as use while the eye is opened during surgical interventions, it is usually required that the product should be sterile, single use, and contain no antimicrobial preservatives and a minimum of other additives. General stability requirements for ophthalmic pharmaceuticals (e.g., eyedrops and eye ointments), other than humidity conditions and specific tests, are similar to other pharmaceuticals. Stability testing requirements for drug products are being harmonized via the International Conference on Harmonization (ICH) process among the United States, Europe, and Japan, involving input from the European Agency for the Evaluation of Medicinal Products (EMEA) (including the Committee for Proprietary Medicinal Products [CPMP] and the Quality Working Party [QWP]), the U.S. Food and Drug Administration (FDA), and the Japanese Ministry of Health. But, even after harmonization becomes complete and official, some countries will still have their own particular requirements for certain products; therefore, companies should continually maintain a dialogue with agencies to assess the regulatory climate for their products.

Sources of Regulatory Requirements For Stability Testing For Eye Drop:

ICH draft consensus guideline, Stability Testing of New Drug Substances and Products: Expands on current guidelines, for instance, for liquids in semipermeable containers, long-term stability at 25°C 6 2°C/40% 6 5% RH, accelerated condition of 40°C 6 2°C/not more than 25% RH, and intermediate condition (if 40°C fails) of 30°C 62°C/60% 6 5% RH, or the alternative of allowing studies at other humidity conditions and the application of stated ‘‘ratios’’ to derive water loss at the stated humidity conditions by calculation

[10] FDA draft (not for implementation) guidance document, Stability Testing of Drug Substances and Drug Products [11]: Expands on the ICH guideline, suggesting for liquids in semipermeable containers, long-term stability at 25°C 6 2°C/40% 65% RH, accelerated condition of 40°C 6 2°C/15%6 5% RH, and intermediate accelerated condition if 40°C fails) of 30°C 6 2°C/40% 6 5% RH CPMP Guideline, Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products [12]: Describes requirements for drug substance and finished products; for liquids in semipermeable containers, suggested storage conditions are 25°C 6 2°C/60% 6 5% RH long term and 40°C 6 2°C/15% 6 5% RH accelerated with an intermediate condition (if 40°C fails) of 30°C 6 2°C/40% 6 5% RH; also discusses changes in manufacturing process of active substance, composition, and immediate packaging of finished product

WHO, Guidelines on Stability Testing of Pharmaceutical Products Containing Well-Established Drug Substances in Conventional Dosage Forms [25]: Four climatic zones are defined for worldwide stability testing based on mean climate conditions: zone I, temperate, 21°C/45% RH; zone II, subtropical with possible high humidity, 25°C/60% RH; zone III, hot/dry, 30°C/35% RH; and zone IV, hot/ humid, 30°C/70% RH; also includes a WHO stability testing summary sheet and a WHO ‘‘essential’’ drug checklist United States Pharmacopeia (USP 23) guidelines on stability testing of new drug substances and products [13]: Based on the ICH guidelines, for instance, 25°C/60% RH long-term condition and 40°C/75% RH accelerated condition, but does not specifically address liquids in semipermeable containers or light exposure Japanese Pharmacopoeia [14]: Particular attention is paid to qualification of plastic containers used for drug products with regard to leachables, transparency, and the like and Japanese official stability testing guidelines (Japan is gradually adopting ICH guidelines) [15,16]

Stability Testing for Ophthalmic Pharmaceuticals:

Primary stability data for inclusion in a new product application should relate to the formulation and container/closure system that it is intended to market. Data for related formulations or a different container/closure system is not considered adequate for approval on their own.

The testing requirements for active ingredients used in ophthalmic products will not normally differ from those used in other types of product; therefore, they are not dealt with in detail here. Discussion is restricted to the products (dosage forms) themselves. However, because of the limited systemic exposure arising from the ocular route of administration, there may be some relaxation in the amount of data required for drugs administered by this route in some other sections of the application A number of aspects of the design of ophthalmic products are also addressed in the development pharmaceutics section of a marketing authorization application in Europe; many of these may have an impact on the design and conduct of stability trials.

These aspects include-

ü   Justification for the package type chosen and for the volume of product in the container (in terms of a reasonable period of use, considering the intended use for the product, and considering any relevant practice or regulatory guidelines)

ü   Product-container compatibility studies (adhesive, label, and container leaching, extraction, and adsorption)

ü   Biocompatibility with and non-irritancy of the formulation to the eye and the surrounding issue Uniformity of dosage for suspension products (including content uniformity and particle size distribution)

ü   The need for an overage of the active ingredient or a key excipient in the product and its justification The results from simulated in-use stability trials (with a focus on oxidation/degradation of components as well as preservative efficacy issues)

Stability Study :

Six bottles of the ataluren formulation were prepared and stored at 25 _ 3 _C. Physical and chemical examinations were performed in triplicate immediately after preparation (Day 0) and at Day 1, 3, 7, 14, 30, 60, and 90 to define drug stability throughout its period of storage for the eye drop. The chemical stability of the extemporaneous preparation was defined by the drug content that contained not less than 90% and not more than 110% of the labeled amount of ataluren [20].

The study was conducted following methodological guidelines issued by the International Conference on Harmonization (ICH) for stability studies [21]. The instability of ataluren solutions was considered by a variation of concentration outside the 90–110% range of initial concentration of drug and the presence of degradation products. The observed solutions must be limpid, of unchanged color, and clear of visible signs of precipitation.

Stability of eye drop

Ø  Physical Stability

There were no detectable visual changes in color and limpidity and no appearance of any visible particulate matter during the study period.

Ø  Chemical Stability

The ataluren 1% eye drop oily solution stored in LDPE ophthalmic bottles at 22–25 _C demonstrated chemical stability for up to 60 days. Ataluren retained at least 99% of its initial concentration at 60 days. Chromatograms showed no sign of degradation products throughout the study.

Ø Sterility Assay

The sterility applicability of the method was validated according to the European Pharmacopeia sterility assay [22]. The visual microbial growth in the control fertility experiments were clearly observed and comparable in the presence and absence of the product to be tested. No microbial growth was observed for any eye drop samples analyzed with this method over 14 days. Because the microbiological tests showed the absence of bacterial or fungal contamination of the preparation over time, the use of a preservative agent was not considered in the castor oil and DMSO eye drop formula.

Merit of Stability study on Eye drop:-

Ø  Stability study of Eye drop Give Very Important data which ultimately useful in estimating shelf life of drug

Ø  Useful Tool for eye Drop as Eye drop are Sensitive to Temperature & Humidity.

Ø  Stability study give idea about Microbial growth in Formulation

Ø  Stability study Help to get about Ideal Temperature & Humidity which help in Storage & Transportation of Formulation

Ø  Stability study gets importance in Eye drop as Formulation marketed in Different Countries & Continent which has different Climate Like Temperate, tropical. The countries Lies in middle East & that of Africa Which has High Temp. Throughout the year, if stability study not done Then Chances of Batch Fail Which Ultimately affect Company Name & Fame.

 Demerit of Stability Study:

Ø  Stability testing is Very Long Process in which Sample has to be put on different Temperature & Humidity

Ø  Required Lots of Sample for Testing Which Was Discarded.

CONCLUSION

The stability testing is Key Test for Eye drop As give Information About the stability  of eye drop in Different Temperature & Humidity, As Eye drop is sterile preparation it is important factor to maintain  its sterility through out its shelf life, additionally the eye drop marketed in different continent & countries which has Different Climate like Mediterranean, Tropical, Temperate & Equatorial which has totally different temperature & Humidity Throughout the year like Africa & Middle East which has high temperature On Other side Countries in Europe , North & South America which has Contrast temperature & Humidity So it is Important to make our preparation Such which can withstand the Climate.

ACKNOWLEDGMENT:

We are grateful to the President Jamia Islamia Ishatul Uloom Akkalkuwa Moulana Huzaifa Vastanvi Sahab for Providing Research Facility at Ali Allana College of Pharmacy, Akkalkuwa

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