Background

The purpose of this study is to advice the number of eyedrops available per party of a selection of generally prescribed glaucoma medications.

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Methods

Six party of every glaucoma medication were tested: three each in the vertical and also horizontal orientations. Bottles were housed in a customized force gauge device designed to mimic ballpoint fingertip call with a bottle. In ~ a conventional rate, every drops to be expressed from each bottle and also counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and also number were also estimated. The main outcome actions were: total number of drops, volume per bottle and also drops every milliliter (mL) that glaucoma medication.

Results

A total of 192 party from 32 party designs and also manufacturers to be tested. Twenty-two that the 32 party designs had a substantially different mean variety of drops in the vertical and also horizontal positions, v 10 designs have more drops dispensed in the horizontal orientation and also 12 in the vertical orientation. 6 of the 32 party designs had actually a significantly different mean complete bottle volume in the vertical and also horizontal positions, with all designs having better volume in the upright position. An readjusted ratio of mean variety of drops/mean bottle volume prove a range from 20.9 drops/mL to 40.8 drops/mL.

Conclusions

There is far-reaching variability in drops and also volume obtainable per party of glaucoma medication relying on both the bottle position and manufacturer. These data suggest to the require for circumspection in prescribing glaucoma medications and caution in assessing therapeutic outcomes.


Peer review reports


Background


Although data demonstrate improved outcomes with lowered intraocular pressure from ideal pharmacotherapy <1, 2>, countless patients v glaucoma struggle to adhere to your prescribed regimens. Numerous studies suggest patients comply through 70% or under of your glaucoma medicines <3,4,5>. Plenty of factors have been implicated <6>, but difficulty instilling drops has garnered current attention <7>. Suitable eyedrop management requires eye-hand coordination and dexterity, linking visual acuity through a secure hand and accurate proprioception <8>. No surprisingly, videotape proof demonstrated that glaucoma patient used an mean of 1.4–1.8 drops as soon as trying come instill a single eyedrop <9, 10>. A recent cross-sectional patient inspection revealed the 25% of patients reported problems with at an early stage eyedrop party exhaustion and also associated compliance through therapy. One-third of patients reported the factor for early bottle fatigue was due to bottle related difficulties such together “more than one drop come out” or “size of fall is as well large”. The latter complaint is supported by literature that demonstrates the volume of one eyedrop in an ophthalmic solution might vary from 25 come 70 μl <11>. Offered the regular tear film volume is 7 μl and only capable of comprise 30 μl there is no overflow, a significant portion of one eyedrop is wasted <12>. These data suggest that a significant number of glaucoma patients run out the eyedrops before a scheduled prescription refill and also that bottle associated mechanics play a duty <13>.

Despite the prominence of bottle architecture in ideal use of subject therapeutics, there exists no standardization of manufacture in regards to drop instillation dynamics <14>, and the only dosing necessity is come accurately label and package medication volume <15>. Being manufactured and sold on the basis of volume, eyedrops are distinctive from many other develops of pharmacotherapy, which space prescribed v a discrete number of doses to guide dispensing and refill rates. While the minimum volume of medicine consumers need to anticipate every container of medication is available, this does no necessarily interpret to number of applications, and without regulation, leads to the opportunity of inconsistency in the variety of drops of medicine obtainable per bottle. Numerous previous studies assessing a smaller number of medications in a non-standardized fashion have actually found far-ranging variability in the number of drops between both brand of medication and also position that the bottle <16,17,18>. Together such, the present study to be designed to further evaluate this possibility by objectively and systematically measuring the number of eyedrops in each bottle of many common glaucoma medications.


The number of eyedrops dispensed native various common glaucoma medications was measured. All drugs were purchase at expense from the university of Kentucky research Pharmacy and also represented available local brand and generic medications. A pressure gauge device consisting that a Mecmesin M500E Motorised Tension and Compression check Stand, Mecmesin 100 N progressed Force Gauge (Mecmesin Corporation, Sterling, VA, USA) and also custom grips and compressors were designed and also calibrated by JA King & firm (Whitsett, NC, USA) (Fig. 1). The compressors to be designed come mimic ballpoint fingertip contact with a bottle. For each medication, the party was housed in the apparatus and also clamps were adjusted until the ballpoint compressors were located at mid party length. Because that bottles with a rectangular instead of ring shape, the thinner dimensions were favored for compression, as this to represent the an approach most likely to be used by patients when instilling drops. Beginning at 0 kg-force (kgf) and also 0 mm (mm) displacement, the gauge was progressed in 0.1 mm increments until a fall of liquid fell from the bottle, together observed subjectively and also confirmed v an automatic VCD-BTD drop respond to (Vernier Software and also Technology, Beaverton, OR, USA) and LabQuest 2 display (Vernier Software and Technology, Beaverton, OR, USA). At a price of roughly one drop/s, 10 drops to be expressed, climate the apparatus was retracted come 0 kgf. This was repetitive until all drops were exhausted from the bottle.


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Force Gauge Apparatus. A force gauge apparatus consisting that a Mecmesin M500E motor Tension and Compression Stand, Mecmesin 100 N advanced Force Gauge and also custom grips and also compressors were designed and also calibrated through JA King & Company. a: The compressors were designed come mimic ballpoint fingertip contact with a party tip. b: because that each medication, the party was housed in the apparatus and clamps were changed until the ballpoint compressors were located at mid party length. The L-shaped compression clamp was then adjusted until the pressure gauge sensor was centered on the crosshairs that the clamp in ~ a 90-degree angle


Simultaneously, fall size and number was also estimated using the densitometric method for volume decision <19>. In twenty drop increments, the total volume of solution expressed was measured v a 0.0001 g analysis balance (Ohaus Corporation, Parsippany, NJ, USA). This was repetitive until all drops were tired from the bottle. A 200 uL pipette (Zhejiang Huawei clinical Instrument Co, LTD, Zhe Jiang, China) was supplied to remove 4 100-uL aliquots of each bottle. The average of the samples was split by 0.1 mL to estimate the volume of each drop and each bottle by dividing the massive of each by the calculation density. For any bottles with residual liquid in the container lid, this was eliminated with the pipette and volume was measured separately.

Six party of every medication were tested. 3 bottles to be tested in the vertical orientation v the bottle pointer at 180 degrees and also three bottles were tested in the close to horizontal orientation v the bottle tip at 30 degrees. The vertical and horizontal orientations were the beginning position for the bottle tip throughout each measurement, together compression of the party variably and slightly adjusted the tip position.

Statistical analysis

Mean an answer was contrasted by constructing an evaluation of variance because that a two way layout v factors: place (horizontal versus vertical) and bottle (all combine of medication name and formulation). A highly significant interaction in between position and also bottle was acquired (p 
Full dimension table
Full dimension table

The outcomes of this study imply there is significant variability in the variety of drops and volume per bottle of glaucoma medications, both in regards to which bottle design and manufacturer is utilized and the position the bottle is organized when squeezed. For example, if a representative patience from this an ar is prescribed a 5 mL party of timolol 0.5%, there room 5 different generic and brand bottle designs that might be dispensed. The patient could anticipate a range of 123–209 and 147–166 typical drops per party in the horizontal and also vertical positions, respectively. If instilled double daily, this would suggest a difference between 25.5 come 43 days of accessible medication depending upon the manufacturer and also bottle position.

This examine is the very first to our understanding to present an objective, automated and also reproducible method to measure up the variety of drops accessible per party of medication. Further, us measured countable drops instead of calculating the number of drops based on volume, which was displayed to it is in inaccurate. Number of previous studies have actually evaluated little samples of bottle formulations through similar, change results. A 1994 study of patients blinded come either use of a 5 mL bottle of timolol maleate versus levobunolol discovered a 21% higher length of usage of timolol (37 matches 29 days) <16>. An additional study evaluate 45 matches 90 degree administration of fabricated tear bottles and found a substantially greater variety of drops every bottle making use of densitometric analysis and smaller sized drop volume because that 4 the end of 5 formulations at 45 contrasted to 90 degrees. The writer suggest management at 45 degrees would result in as much as $1.93 savings every bottle compared to 90 degrees <17>. A study assessing 2.5 ml bottles of prostaglandin analogues hosted vertically, in ~ 45 degrees and horizontally found that upright instillation resulted in more drops per bottle for bimatoprost and also latanoprost, while 45 degrees was most efficient for travaprost. Presume 1 year that bilateral treatment at 2006 costs, the authors established use that the most effective instillation technique would an outcome in yearly to save of $109–192 <18>. Lastly, a recent study found significant variability in the variety of eyedrops per bottle of four regionally obtainable formulations the latanoprost as soon as measured through manually counting the variety of drops to express by hand, ranging from 77.6 come 88.7 drops every bottle. The authors approximated a similarly far-ranging difference in estimated annual cost, ranging from $184 to $1198 every formulation <20>.

Currently, over there exist no commonwealth guidelines to control bottle architecture or lot of drops available per volume of medicine <14, 15>. It has been said that pharmacists regularly use a rough guideline of 0.05 mL every eyedrop or 20 drops every mL (written personal communication, division of drug Information, FDA, in march 27, 2015). With that in mind, there room significantly much more eyedrops per bottle in this analysis than recommended, varying from 10.4% to 45.8% more mean autumn per party tested. This may show that manufacturers “overfill” the bottles to enable for a margin the error during dispensing. If true, this serves critical purpose, because it is known that countless patients require an ext than one eyedrop per application <9, 10>. However, this data suggests another problem has actually been produced by this practice: significant variability in the variety of doses per bottle.

Aside from party volume, secondary factor affect the variety of drops easily accessible per bottle is drop size. Us found far-reaching variability in the estimated drop size of studied formulations, ranging from 0.024 come 0.221 mL. The dimension of drop dispensed indigenous a bottle counts on three straightforward elements: the design of the dropper bottle and tip, properties of the included solution and also the position of the bottle. The surface ar area approximately the bottle tip and surface anxiety of the solution room both manufacturer regulated factors that affect drop size. Patient manipulations such together the angle and also rate autumn are created are less predictable <11>. Further, the outcomes of the current study and others suggest the most economical bottle place varies indigenous one style to the following <17–19>. A last potential determinant of drop size is the pressure required come squeeze the bottle, which regrettably is substantially variable in both the experimental and clinical setting <21, 22>. With every one of these influences, it may be complicated to design suitable bottle for instillation. One professional suggestion has actually been to use a dropper tip with a smaller outer orifice diameter the provides continual surface area because that a smaller-volume drop to loss <11>.

This study has actually several limitations. The experimental style was novel, and also although dimensions were automated, they have actually not been individually verified. Since the study was performed in one objective and also reproducible manner, it might not accurately reflect plenty of of the patient related factors in dosing; it is most likely that our patient experience also greater variability in the variety of drops obtainable per bottle. Just two bottle positions to be tested and also most ophthalmic containers are not intended come be ceded in a strict horizontal position. If 192 bottles from 32 bottle designs were tested, castle still represent a tiny sampling the all obtainable brand and also generic ophthalmic medications.

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In summary, this research demonstrates the far-reaching variability in drops and also volume obtainable per bottle of glaucoma medication depending on both the party position and manufacturer. This unregulated practice leaves prescribing physicians and pharmacists can not to accurately guess the quantity of medication to dispense. This may cause patients running out of medication beforehand or being left through excess and also associated costs. The variability from one refill come the next could be a contributor to restricted compliance. The experimental style in this study shows an objective, reproducible method to recognize drop number uniformly throughout different bottles and also designs. It must compel additional evaluation and also consideration the standardization in the industry.