gota dos colírios lubrificantes : estudo farmacoeconômico Drop volume of artificial tear solutions : pharmacoeconomic study

Objective: To determine the mean drop volume produced by artificial tear solutions in different inclination angles and to determine the mean cost of the treatment. Methods: The drop volume of 3 original bottles of the artificial tear solutions Artelac®, Hylo Comod®, Lacrima® Plus, Systane® UL, Lacrifilm®, Hyabak®, Lacribell®, Ecofilm®, Mirugell®, Plenigell®, Fresh Tears®, Optive® and Endura® were determined at the inclination of 90o and 45o. The mean number of drops in each bottle was determined and a pharmacoeconomic evaluation of the drops was made. Results: The drop volume ranged from 32.2 to 64.0 μL at 45o and from 29.1 to 65.1 μL at 90o. The difference between drops in each inclination varied from 2 to 24%. The annual cost was from R$2,73 to R$130,73 according to the inclination of the bottle. The Maximum Duration of Treatment (MDT) was from 29.3 to 51.4 days at 45o and from 28.8 to 48.4 days at 90o, being the difference in MDT from 0.5 to 8 more or less days depending on each brand. Conclusion: None of the collyria studied presented ideal drops for human eyes, leading to a waste of the product and higher cost for the manufacturer and the consumer. We noted that there is a significant variation in the drop volume according to the inclination of the bottle, and that a variation of over 10% would bring financial impact for the patient.


I
n the ophthalmic practice, the main route of drug administration is made by eyedrops.The official medical eyedropper, according to the American Pharmacopoeia, presents an outter diameter of 3 mm and dispenses 20 drops of distilled water per mL at a temperature of 25 o C by positioning the eyedropper perpendicular to the person that will receive the drop (1) .
The maximum capacity of the conjunctival sac in humans is approximately 30 µL.Thus, a drop of larger volume applied to a human eye will have its excess overflowed through the face and drained by the lacrimal pathways (2) .
Whereas the basal tear secretion is approximately 7 µL, it was determined that the optimum concentration of a drug in the tear film is obtained with a droplet volume of around 20 µL, since smaller volumes might require increases in the concentration of the drug to ensure the same effectiveness.The optimal volume of a drop to be used in eyedrops would be of 20 to 23 µL to achieve the maximum use of the drug with the minimum waste possible (2) .
Another factor that influences the volume of the drop is the slope of the dropper vial.According to the shape of the tip of the stopper and the surface tension of the liquid, there is a tendency of each vial producing a bigger or smaller drop when tilted than when it is inverted at 90 o .
The present work aims at determining the average volume of the droplets produced by the vials of tear solution available in the Brazilian market when reversed at 90° and tilted at 45°, and determining the average cost of the treatment.

METHODS
The research consists of a study of laboratory experimentation conducted in LESIFAR -Semi-Industrial Lab School of Pharmacy of the Pharmacy Course at the University of Santo Amaro (UNISA), in São Paulo -SP.
The densitometry method for determining the volume was used to determine the volume of the drop (3)(4)(5)(6) .We used the analytical scale Ohaus® Adventurer Pro AV264P (precision of 0.0001 and capacity of 240 g) with certificate of calibration, Laborglas® volumetric pipette of 1.0 mL and Laborglas® watch glass to determine the mass of the liquids.
The eyedrops were open at the time of test, and the weighing of drops was held by the same researcher, being filed the batch of each vial.
The mass of 10 drops from each vial of the samples analised was determined at room temperature (20 ± 2°C), first with the vial at 90° and then at a tilt of 45°.Each vial of eyedrops was lightly pressed until a drop fell off from a height of 5.0 cm from the watch glass used on the scale, and the process was repeated until the cumulative total of 10 drops studied was reached.For proper tilt, a protractor was used as a guide in a reference plane, and in relation to the vial base (3,6) .
Later, the mass of 1.0 ml of each eyedrop was measured with a volumetric pipette.This way, the average volume of each droplet was determined by the ratio between the mass of 1.0 ml and the weight of 10 drops of each eyedrop (volume-to-weight ratio) (3,6) .
Te average number of droplets contained in each vial was also determined, taking into account the average volume of each drop and the total volume of the vial as advertised by the manufacturer on the product label (3)(4)(5)(6) .
Considering the dosage of 1 drop in each eye four times a day, for a total of 8 drops a day, the average cost of the drop, the monthly and the annual cost of the treatment were estimated according to the wholesale price, which is the highest price at which a laboratory or distributor of medicines can sell their product in the Brazilian market.This way, the wholesale price is the maximum allowable price for sales of medicines intended for pharmacies, drugstores, and Government entities.The prices of the medications analyzed are in Reais and with ICMS (Services and Merchandise Circulation Tax) of 18% (for the State of São Paulo), and were obtained by the Drug Market Regulation Chamber (CMED) of the Brazilian Sanitary Surveillance Agency (ANVISA), update on July 19, 2013 (7) .
It was decided not to use the Maximum Consumer Price (7) , since some of the eyedrops have the status of Free from Taxation.
According to the average number of droplets contained in each vial and the dosage defined, it was also determined the Maximum Treatment Duration for each eyedrop, as well as the number of vials consumed per year.

RESULTS
For the analysis of the results, the products were selected and randomly numbered for the definition of the sequence of data collection.
Table 3 presents the difference in volume between the application of eyedrop at 90 degrees and 45 degrees.The average number of drops per vial was determined by dividing the volume announced by the manufacturer (for the presentation of bigger content) by the average volume of each drop, also obtaining the difference of the number of droplets formed per vial according to the tilt.
The results show that there is a trickle pattern between the different vials studied, since the volume of the droplets ranged from 32.2 to 64.0 µL at 45° and from 29.1 to 65.1 µL at 90 o .The difference between the droplets in every tilt ranged between 2 and 24%.
The marks 1, 2 and 9 showed the droplet formed at 45°g reater than the droplet formed with the vial inverted at 90 o .In the other brands, the droplet formed at 90 o was bigger (Graph 1).Note that the percentage of the difference in the volume of the droplet is roughly the same as the difference in the number of droplets.However, with the sign reversed, the bigger the drop the smaller number of droplets contained in vials will be, increasing the final cost to the consumer.
Table 4 presents the average cost per droplet of each eyedrop and the difference in price between the two different tilts, as well as monthly and annual average cost for a treatment defined as 1 droplet in each eye four times a day, with a total of 8 droplets per day.
The Maximum Treatment Duration ranged from 29.3 to 51.4 days on a 45° tilt and from 28.8 to 48.4 days at 90°, and the difference in the Maximum Treatment Duration was from 0.5 day to 8 days more or less according to each brand (Table 5).
We also calculated the average number of vials consumed per year if droplets are applied at 45° or 90°, and the difference in the number of vials which should be acquired by the patient each year (Table 6).
It was observed that a variation greater than 10% in the number of droplets in a vial according to the tilt of application indicates an increase in the number of vials consumed in a year, since for eyedrops 3, 5, 7, 8 and 10 (which have a variation in the number of droplets of less than 10%) there was no increase in the number of vials used in the period of 1 year.

DISCUSSION
The 5th Edition of the Brazilian Pharmacopeia published in 2010 is the Official Pharmaceutical Code followed in Brazil, and sets the standards and specifications of pharmaceutical, medications and other products subject to sanitary surveillance.
In the previous edition, the Brazilian Pharmacopeia defined that any measurement tool to administer liquid medicines must meet specific volumetric standards: the droplets should be counted in a normal dropper, which must provide a flow tube with 3 mm of outer diameter and 0.6 mm of internal diameter, ending in a tubular section.Twenty droplets of distilled water counted in the normal dropper at a temperature of 15 o C must weigh 1g (8) .As 1g of distilled water corresponds to 1 mL, the volume of each droplet would have the volume of 50 µl, the measure mentioned by some authors as the maximum value allowed by the Ministry of Health for the volume of droplets of eyedrops (3,9) , being 'eyedrop' defined as the pharmaceutical liquid preparation intended for application on the ocular mucosa (10) .As the eyedrop is instilled in the form of droplets, it must follow the specifications defined by ANVISA to administer liquid medications.However, note that the current legislation does not bring the definition of determination of the droplet volume anymore, nor sets specific regulations for the droplet volume of eyedrops.The eyedrops are a class of medication that deserves special attention, as there is a maximum volume tolerated by the eye of approximately 30 µL (2) .
Besides that, in relation to the vial tilt, we found out that there is significant variation in the droplet volume, and there is a concern by manufacturers on this fact, since the directions of 12 out of the 13 brands tested fail to inform the consumer the correct way of instilling the eyedrop.
The American Pharmacopoeia (used as the main reference for Brazilian law) states that we must take into consideration that each substance has different characteristics, therefore the droplet size of each preparation will vary and, when the accuracy of each droplet is important (as in the case of eyedrops), the doser should be calibrated specifically for each preparation, assuming a variation of up to 15% in the volume of the droplet for each solution (1) .However, our analysis suggests that a variation above 10% in the volume of the droplet already bring financial impact to the consumer, since only for eyedrops 3, 5, 7, 8 and 10 (which have a variation in the number of droplets of less than 10%) there was no increase in the number of vials used in the period of 1 year.
The dosage used in this study for tear solutions was based on the way we usually prescribe these eyedrops in our service, also considering the fact that eyedrops with preservatives should not be used more frequently than 4 times a day, so that there is no damage to the eye surface.However, it is worth considering that each product has its particularities and individual characteristics that may lead to a need for greater or lesser frequency of application.
We are concerned that neither the Brazilian nor the American Pharmacopoeia considers the eye continent limit for the production of eyedrops, and we understand that more attention should be given to the production of droplets of smaller volume, so there is no waste or risk of increased systemic absorption of some drug.
The concept of pharmacoeconomics is growing nowadays, and concerns the application of the principles of economics to the study of medications and health practices, aiming at the optimization in the use of financial resources without prejudice to quality and treatment outcomes (11) .
Considering the therapeutic equivalence of tear solutions, the cost minimization analysis is a simple way of economic evaluation in which only the costs are subjected to comparisons because the efficacy or the effectiveness of the comparable alternatives are equal (11,12) .
Therefore, we realized that the droplet volume of eyedrop is still considerably high, and that this leads to a waste of the product and increased cost to the manufacturer and the consumer.Once the adjustment of the stopper to calibrate smaller droplets is a costly process, an immediate action to minimize the cost would be properly guide the consumers in a descriptive and illustrative way in the directions of which would be the best way of applying each eyedrop.

CONCLUSION
None of the eyedrop vials studied showed droplets ideal to the human eye, leading to product waste and increased cost to the manufacturer and the consumer.We noticed that there is a significant variation in droplet volume according to the vial tilt, and that a variation greater than 10% would bring financial impact for the patient.
Further studies should be conducted with other classes of eyedrops, and we must worry each time more about the droplet volume of eyedrop, so that an ideal is reached.

Table 6 Number of vials a year
(*) For the dosage of 1 droplet in each eye 4 times a day *For the dosage of 1 droplet in each eye 4 times a day *For the dosage of 1 droplet in each eye 4 times a day Drop volume of artificial tear solutions: pharmacoeconomic study Rev Bras Oftalmol.2015; 74 (6): 339-44