Timolol Maleate 0.5% Eye Drop Preparation

Formulation of eye drops
(TIMOLOL MALEATE 0.5% m/V EYE DROPS)
By:
Introduction
The Timolol Maleate 0.5% M/V Eye Drops is indicated for the reduction the intraocular pressure in the (IOP) persons suffering from ocular hypertension or glaucoma they are insufficiently responsive to the topical Beta Blockers. It is shown to reduce IOP in patients that have chronic open-angle glaucoma, ocular hypertension, and in Aphakic patients with signs of glaucoma and in those patients who wear contact classes (Siegal, 2007). It also shows a reduction of IOP in patients having narrow angles and those with iatrogenically-induced narrow angle closures.

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The inactive ingredients or excipients in Timolol sodium hydroxide used for pH adjustment, monobasic and dibasic sodium phosphates, and purified water. Purified water is used for injection purposes. 0.01% Benzalkonium chloride is used as a preservative. The preservative is a quaternary ammonium. Its mechanism of action involves the intrinsic detergent processes that result in the dissolution of the bacterial membranes and cell walls, thus preserving the medicine (Wang et al., 2012). It is particularly focused on the preservation against gram-positive bacteria.
The aim of this project is to prepare a Timolol maleate 0.5% eye drop using the sterilization method. The autoclave sterilization method is based on the WHO standard.
Methods
Alcohol wipes were used to initially clean the top panel of the laminar flow cabinet. The direction of cleaning was from back to front (from one corner towards the airflow direction). It was wiped twice while ensuring that the wiping stripes overlapped. It was disinfected until the top panel. Then, starting from one side of the panels, it was disinfected until the bottom of the panel. The processes were repeated until all the side panels and bottom panels were adequately disinfected.
The production sheet record was filled and completed before the start of the experiment. 50 ml of Timolol maleate was weighed; Disodium Hydrogen Orthophosphate and Dihydrogen Sodium Phosphate were also weighed and put in separate test tubes. Centrimide 0.5% Stock Solution was added to half of distilled water in a beaker. The mixture was stirred gently. Disodium Hydrogen Orthophosphate and Dihydrogen Sodium Phosphate were added to the mixture and stirred to dissolve. Timolol maleate was added to the mixture and stirred to dissolve. Freshly distilled water was added to the solution to make up to the final volume. Sintered glass filter method was used. The filtrate was put into the beaker. It was then poured into pre-sterilized bottles. The filtrate was filled up to the bottle shoulder. The dropper was inserted into the bottles, and caps screwed tightly by hand (WHO, 2002).
Autoclave sterilization was carried out on the solution at 121-124 oC. The process was carried out for 15 minutes at approximately 200 kPa or 1 atmosphere above the atmospheric pressure. The solution was viewed and labelled after sterilization and cooling of the solution.
Results
Table 1: Microbiological methods

Purpose

Medium

Control Organism

Theoretical Results

Actual Results

Aerobic tests (Ar)

Nutrient Broth (NB)

 

–

+

Anaerobic test (An)

Robertson’s cooked meat medium (RCMM)

 

–

–

Fungal test (Fr)

Yeast dextrose broth (YDB)

 

–

+

Aerobic Control (Ac)

NB 0.1%

 

+

–

Anaerobic control (Nc)

RCMM 0.1%

Clostridium sporogenes

+

+

Fungal Control (Fc)

YDB 0.1%

Candida albicans

+

+

Table: 2. Environmental monitoring

Settle Plates should be accurately positioned in the Laminar Flow Cabinet by placing one settle plate for each corner. That is, one should be placed to the back left, one to the back right, one to the front left and one to the front right. A minimum of 10 cm gap should be left between the settle plates and the walls of the cabinet.

Figure: 1. Autoclave controls before sterilization

Figure: 2. Results after sterilization
Discussion
As shown in figure 2, the autoclave turned black after the sterilization process. This shows that it was sterilized. The Sterikon® Plus indicators have nutrient broth made up of sugar, spores of a pathogenic bacillus stearothermophilus and a pH indicator. When the sterilization process is carried out, the ampules in the indicator retain the red-violet color. On the other hand, if sterilization does not take place, then bacterial growth occurs. This leads to ampules becoming turbid and changing color to yellow (Block, 2001). The manufacturing processes are valid and the cleanliness levels achieved throughout the sterilization process.
From table 1, there was growth in aerobic tests in a nutrient broth medium and fungal tests in a Yeast dextrose broth medium. This indicates that the conditions were favorable for growth. The anaerobic control and fungal control also indicated growth under Robertson’s cooked meat medium and Yeast dextrose broth media respectively. From table 2, there was no growth all the settle plates placed in different positions.
The sterilization process is a reliable approach because high temperatures are achieved through steam under pressure mechanisms. The moist heat reaches temperatures above the boiling point, thus achieving effective sterilization. This approach is the best because pressurized steam destroys all forms of life and bacterial spores (Mazhar, 2009).
References
Block, SS 2001, Disinfection, Sterilization, and Preservation. London: Lippincott Williams & Wilkins.
Mazhar, H 2009, Autoclaving: Real Sterilization. Viewed 23 January, 2014 fromhttp://microbiologyon-line.blogspot.com/2009/08/autoclaving-real-sterilization.html
Siegal, PA 2007. Glaucoma Medical Therapy: Principles and Management: Principles and Management. Oxford: Oxford University Press.
Wang, H, Switlick, K, Ortiz, C, Zurita, B & Connor, C 2012. Health Insurance Handbook: How to Make It Work. World Bank Publications.
WHO 2002, The Local Small-Scale Preparation of Eye Drops: Eye Drop Update 2002.WHO/PBL/01.83
Standard Operating Procedure A
Cleaning and Disinfecting Laminar Flow Cabinets
Step 1: Wear suitable Size Gloves.
Step 2: Using alcohol wipes initially wipe the top panel of the laminar flow cabinet starting from one corner and in the direction of the airflow (i.e. from back to front). Repeat this process for another strike. But ensure that the wiping strips overlap. Continue disinfecting until reaching the other side of the top panel. Every now and then turn around the alcohol wipe to use a clean side.
Step 3: Starting from one of the side panels, place an unused alcohol wipe on the top and the back corner of the panel, and wipe in the direction of the airflow (i.e. from back to front.) Repeat this process for another strike, but ensure that wiping strips overlap. Continue disinfecting until reaching the bottom panel. Every now and then turn over the alcohol wipe to use a clean side.
Step 4: Apply the step 2 process for the other side panel.
Step 5: Apply step 1 process for the bottom panel.
Standard Operating Procedure B
Positioning Settle Plates inside a Laminar Flow Cabinet
Step 1: Place one settle plate in each corner, i.e. one to the back left, one to the back right, one to the front left and one to the front right.
Step 2: Give a minimum of 10 cm gap between the settle plates and walls of the cabinet.
QC SHEET
Manufacturer’s Label
Name: Timolol Maleate 0.5% Eye Drops (TIMOPTIC-XE)
Type of Medicine: Beta-blocker eye drop preparation
Use: Chronic open angle glaucoma
Available as: Eye drops, eye gel, single-use eye drops
Manufacturer Code: TM5483-67
Manufacture License: TM3421-564-6
Expiry Date: 12:01:2015
Manufacturer Address:
MJU Advertising LLC
PO BOX: 22874
OUT METHA, DUBAI
UNITED ARAB EMIRATES
Raw Material Identification and Quantification
Active: Brimonidine Tartrate 0.2% w/v
Timolol Maleate IP equivalent to Timolol 0.5% w/v
Inactive Ingredients: Sodium chloride, Disodium EDTA, Sodium dihydrogen Phosphate dihydrate, Disodium hydrogen phosphate, Sodium hydroxide, Water for Injections.