Wetting agent formulation

Abstract

A first alternative to a composition for preventing or retarding degradation of a functional coating on a medical device includes an antioxidant selected from gallic acid or a derivative thereof. A second alternative to a composition for preventing or retarding degradation of a functional coating on a medical device includes carboxymethyl cellulose or a derivative or salt thereof. The use of the compositions for preventing or retarding degradation of a functional coating on a medical device from reactive species generated during exposure of radiation, and a wetting agent comprising the compositions, are also provided. The wetting agent prevents or retards the hydrolytic degradation of the coating during the intended shelf-life of the wetted coated product.

Claims

1. A wetting liquid formulation, comprising: a liquid comprising an aqueous or oil-based base solution, a lipid media, or a combination of both; an antioxidant dissolved in the liquid, the antioxidant being an oxadiazole derivative of gallic acid, and further comprising a solution enhancer to increase dissolvability of the antioxidant; and wherein wetting a medical device with the wetting liquid formulation reduces degradation of a functional coating on the medical device.

2. The wetting liquid formulation of claim 1, wherein the oxadiazole derivative of gallic acid is present in an amount of 0.001% to 5% by weight based on a total weight of the composition.

3. The wetting liquid formulation of claim 1, wherein the aqueous base solution is selected from a group consisting of distilled water, deionized water, reverse osmosis water, filtered water and a saline solution.

4. The wetting liquid formulation of claim 1, wherein the aqueous base solution is present in an amount of from 50% to 99.99% by weight, based on a total weight of the composition.

5. The wetting liquid formulation of claim 1, wherein the oxadiazole derivative of gallic acid is present as a suspension within and/or around the functional coating.

6. The wetting liquid formulation of claim 1, further comprising a stabilizer and/or a buffer solution.

7. The wetting liquid formulation of claim 3, wherein the solution enhancer is selected from ethylene glycol, diethylene glycol, propylene glycol, or glycerol, and is present in an amount of 0.1% to 49.8% by weight, based on the total weight of the composition.

8. The wetting liquid formulation of claim 6, wherein the buffer solution has a pH of from 2.0 to 7.4 and wherein the buffer solution prevents the gallic acid derivatives from recrystallization.

9. The wetting liquid formulation of claim 1, wherein the composition is free of polyvinyl alcohol.

10. The wetting liquid formulation of claim 1, further comprising polyvinylpyrrolidone (PVP) in an amount of 0.1 to 40% by weight.

Description

EXAMPLES

(1) General Procedure for the Preparation of the Propyl Gallate Solutions:

(2) Propyl Gallate is only slightly soluble in water, but with the addition of propylene glycol the solubility of propyl gallate increases. Propylene glycol has a great affinity to water and also is a viable alternative additive to glycerol from a costing perspective.

(3) 1. Using a standard disposable pipette, 5 g of propylene glycol or glycerol was placed in a 200 ml glass beaker.

(4) 2. 10 g of 0.9 wt % saline (9 g/L sodium chloride solution) was then added to the propylene glycol or glycerol.

(5) 3. 0.01 to 0.5 g of propyl gallate is added to the beaker and distilled water or 0.9 wt % saline (9 g/L sodium chloride solution) was added to amount to 100 ml of solution.

(6) 4. Taking the beaker by hand, the contents was gently swirled for about 2 minutes to promote mixing, resulting with the propyl gallate being visibly dissolved. This pre-mixing ratio of saline or water with propylene glycol or glycerol delivers a method whereby heating of the beaker is not required to achieve complete dissolution of the propyl gallate. However, in the case where glycerol is employed, it may be necessary to add some heat to the solution in order to achieve full dissolution of the propyl gallate. While the addition of glycerol to distilled water/water/saline increases the degree of dissolution and dissolution rate of propyl gallate, it is significantly less effective than propylene glycol. For that reason, it may be necessary to add heat when using glycerol, especially where relatively high concentration of propyl gallate is being considered (i.e. 0.15 to 0.5 wt % propyl gallate).

(7) 5. Other additives such as polyvinylpyrrolidone (PVP; Sigma Aldrich; K60, 45% in H.sub.2O), surfactants such as Tween 20 and 80 (non-ionic agent supplied by Sigma Aldrich), buffer solutions (pH 4.00 (20° C.); citric acid/sodium hydroxide/hydrogen chloride supplied by Merck Chemicals KGaA), may optionally be added after mixing of the propyl gallate has been accomplished.

(8) 6. A magnetic stirrer bar was placed in the beaker and the beaker placed on a magnetic stirrer (IKA RT5 Magnetic Stirrer). The heat settings are set at zero and the rotation speed set between the 3 and 4 mark on the stirrer equipment. The contents are stirred slowly for an hour to ensure a homogenous solution.

(9) The amounts of the components are shown in Tables 1 to 5 below.

(10) General Procedure for the Preparation of the CMC Solutions:

(11) Preparation of Sodium Carboxylmethyl Cellulose (Na-CMC) Pre-Mix:

(12) 1. 100 g of deionized water was weighed and poured into a glass beaker.

(13) 2. The required amount of Na-CMC as specified by Tables 6 and 7 was weighed.

(14) 3. The water was placed on a magnetic stirrer and the stirrer set to 80° C. to promote the dispersion and dissolution of the Na-CMC powder.

(15) 4. The Na-CMC was slowly added over 2-3 hour period until dissolved into the water (the mixing time may greatly reduce depending on the amount of CMC required).

(16) 5. The mixture was allowed to cool to room temperature while stirring of the solution was maintained.

(17) 6. When the mixture has cooled, 5 g of buffer (pH 4) was added and stirring was continued for 15-30 minutes.

(18) Preparation of Wetting Agent Pre-Mix:

(19) 1. The correct amount of propyl gallate in accordance with Tables 6 and 7 was weighed and placed into a 100 mL glass beaker.

(20) 2. 5 g of polypropylene glycol was added to the glass beaker containing the propyl gallate.

(21) 3. In short succession, 9.5 mL of saline solution was added to the glass beaker containing the mixture of propyl gallate and polypropylene glycol.

(22) 4. The glass beaker and its contents was stirred by hand for 2 minutes until all the propyl gallate has visually dissolved in the liquid mixture.

(23) 5. Where specified in Table 6 for ultrasonic agitation of the mixture, immediately after adding the 9.5 mL of saline fluid to the propyl gallate and polypropylene glycol mixture, this 100 mL glass beaker (containing all ingredients) was placed into an ultrasonic bath for 30 seconds.

(24) Combining Pre-Mixes:

(25) 1. Wetting Agent Premix was added into the CMC Premix

(26) 2. The contents were stirred employing a magnetic stirrer with no heat

(27) 3. Stirring was permitted for 2 hours.

(28) Other additives such as Tween 20 and 80 (non-ionic agent supplied by Sigma Aldrich), buffer solutions (pH 4.00 (20° C.); citric acid/sodium hydroxide/hydrogen chloride supplied by Merck Chemicals KGaA), may optionally be added after mixing of the Na-CMC and/or propyl gallate has been accomplished.

(29) General Procedure for the Preparation of the Test Specimen:

(30) Extruded polymer shafts reflecting a diameter of 4.5 mm with an ID of 3.0 mm were selected for the testing. These shafts had been dipped and cured resulting with a uniform hydrophilic coating along the polymeric tube substrate. It is important to ensure that the same processing parameters of dipping and UV curing of the coating was maintained so as to eliminate any variability in coating integrity. The shaft material used for these series of trials was polyurethane block copolymers and plasticized polyvinyl chloride. The shafts were placed on a cutting matt and with a sharp blade; the polymeric coated tubes were cut to a length of approximately 200 mm. The distal end of the shaft was cut at an angle to distinguish the distal end form the proximal end (at the distal end, the coating tends to be slightly thicker and the angle cut provides information for the friction test operator). For all specimens prepared for friction testing, latex gloves were worn during all handling and cutting steps to prevent contamination of the surfaces of specimen substrates.

(31) Friction Testing (Coefficient of Friction—COF):

(32) 1. The protocol test program option was selected to access the test parameters

(33) 2. The following information was inputted into the program: a. Clamp force=300 g b. Test Speed=180 mm/minute c. Test distance=60 mm. d. Repeated Friction Test Cycles=25 e. Speed=3 cm/s

(34) 3. A stainless steel mandrel of appropriate diameter to the inner lumen of the coated test specimen was inserted fully into the test specimen. The tube was positioned such that a clamp was placed on the section that had a clean level cut (the angled tube cut faced towards the water container of the friction testing machine).

(35) 4. The clamping pads were of 60 DURO supplied by Harland; (Part Number 102149).

(36) 5. This test assembly was mounted onto the Harland Friction Tester FTS 5000 after it had been calibrated.

(37) 6. A container was filled with water to a predetermined mark so that the coated test specimen and clamps were submerged prior to testing. The clamp section of the specimen remained out of the water while the angled cut end of the specimen was submerged in the water.

(38) 7. The test was started after 30 seconds had elapsed to ensure that the coating was fully hydrated.

(39) 8. The force expressed into the clamps was automatically recorded in the form of a graph of gram force versus time.

(40) 9. After the test was completed, a reading of average gram force and maximum gram force was presented by the instrument.

(41) 10. The COF was calculated by dividing the average gram force reading by 300 grams 11. After each test, a wetted cloth was used to remove any residual coating that may have accumulated on the pads.

ABBREVIATIONS

(42) PG=propyl gallate; supplied by Sigma Aldrich in the form of powder

(43) Na-CMC=sodium carboxymethyl cellulose

(44) PPG=propylene glycol

(45) DW=distilled water

(46) Buffer:

(47) HPCE grade buffer solution with a pH value of 4.0 at 25° C. with a concentration of 20 mM sodium citrate (supplied by Sigma Aldrich).

Results

Example 1: Propyl Gallate Solutions

(48) a) Effects of Glycerol on Coating Integrity

(49) TABLE-US-00001 TABLE 1 COF (Number of pH Friction Cycles; 300 g Dosage PG PVP PPG Buffer Carrier Glycerol clamp force) (kGy) (wt %) (wt %) (wt %) (wt %) Solution (wt %) 0 5 10 20 25 45 0.2 5 0 0 DW 5 4.2 4.1 4.1 4.1 4.1 45 0.2 5 0 0 DW 0 4.5 4.3 4.3 4.3 4.3

(50) b) Effects of PG Concentration on Coating Integrity

(51) TABLE-US-00002 TABLE 2 COF (Number of Friction pH Cycles; 300 g clamp Dosage PG PVP PPG Buffer Carrier Glycerol force) (kGy) (wt %) (wt %) (wt %) (wt %) Solution (wt %) 0 5 10 20 25 45 0 10 0 0 DW 5 30 90 120 160 190 45 0.2 10 0 0 DW 5 4 4.3 4.2 4.2 4.3 45 0.5 10 0 0 DW 5 4 4.3 4.3 4.3 4.3 45 0.2 5 0 0 DW 5 4.3 4.1 4.1 4.1 4.1

(52) c) Effects of PG concentration on coating integrity

(53) TABLE-US-00003 TABLE 3 COF (Number of Friction pH Cycles; 300 g clamp Dosage PG PVP PPG Buffer Carrier Glycerol force) (kGy) (wt %) (wt %) (wt %) (wt %) Solution (wt %) 0 5 10 20 25 45 0 5 0 0 DW 0 30 70 130 170 220 45 0.2 5 0 0 DW 0 4.2 4.1 4.1 4.1 4.1

(54) d) Effects of PPG concentration on coating integrity

(55) TABLE-US-00004 TABLE 4 COF (Number of pH Friction Cycles; 300 g Dosage PG PVP PPG Buffer Carrier Glycerol clamp force) (kGy) (wt %) (wt %) (wt %) (wt %) Solution (wt %) 0 5 10 20 25 45 0.2 0 0 4 (10) saline 0 8.0 6.0 6.0 6.0 6.0 45 0.2 0 5 4 (10) saline 0 6.0 4.5 4.5 4.5 4.5
e) Effects of carrier solution on coating integrity

(56) TABLE-US-00005 TABLE 5 COF (Number of pH Friction Cycles; 300 g Dosage PG PVP PPG Buffer Carrier Glycerol clamp force) (kGy) (wt %) (wt %) (wt %) (wt %) Solution (wt %) 0 5 10 20 25 45 0.2 0 5 4 (10) saline 0 5.0 4.5 4.5 4.5 4.6 45 0.2 0 5 4 (10) DW 0 7.0 7.0 6.5 6.5 6.5

(57) As can be seen from the test results, in the absence of propyl gallate, the coefficient of friction (COF) is much higher than in the presence of propyl gallate. Furthermore, the COF increases with increase in the number of cycles. If propyl gallate is present, the COF is low and maintains almost constant (Table 2, Table 3).

(58) Furthermore, the COF can be adjusted by adding further additives or by selecting the carrier solution and/or the pH.

Example 2: CMC Solutions

(59) Formulations based on propyl gallate (PG) and sodium carboxymethyl cellulose (Na-CMC) were developed to further enhance the wetting agent performance. The samples were prepared with polypropylene glycol and buffer content maintained constant throughout the study to demonstrate the influence of the main stabilizing component ingredients, i.e. propyl gallate and sodium carboxymethyl cellulose.

(60) The coating integrity and hydrolytic stability of the coating were tested after subjecting the hydrated specimens to 45 kGy gamma irradiation dosages. The primary objective of the wetting agent is to protect the hydrated hydrophilic coating during the sterilization cycles and secondarily, to provide hydrolytic stability to the coating, reflecting real-world shelf-life product indication.

(61) The hydrolytic stability of the coating was assessed by interpreting the coating frictional stability performance over the 25 frictional cycles after subjecting coated hydrated specimens to accelerated aging for periods of 15 days (T15) and 30 days (T30), respectively, at an ageing temperatures of 50° C. All specimens were subjected to 45 kGy irradiation dosages. Time Zero (T0) directly after exposure captures the isolated effects of gamma irradiation on the coating integrity.

(62) TABLE-US-00006 TABLE 6 Stability of wetting agent formulations after 45 kGy exposure Sample 1 Sample 2 Sample 3* Sample 4 PG (wt %) 0.02 0.20 0.02 0.10 PPG (wt %) 5.00 5.00 5.00 5.00 Na-CMC (wt %) 0.20 0 0.20 0.10 Buffer (wt %) 5.00 5.00 5.00 5.00 T0 Meta-stable stable stable stable T15 Not stable stable stable stable T30 Meta-stable stable stable stable *= ultrasonic agitation; T0 = directly after exposure; T15 = after 15 days at 50° C.; T30 = after 30 days at 50° C.

(63) After 15 days ageing at 50° C. in a hydrated state after 45 kGy exposure, the data indicate that PG provides further stability within the formulation. When comparing Samples 1 and 3, the formulations are identical, but Sample 3 was ultrasonically agitated to promote the dissolution of the propyl gallate (PG) and enhances the efficacy of the PG within the solution and coating. Comparing Sample 3 to Sample 5, suggests that 0.1 wt % of PG and 0.1 wt % of CMC are sufficient to deliver coating stability after irradiation and ageing of the product specimens.

(64) After 30 days ageing at 50° C. in a hydrated state after 45 kGy exposure, the data highlights: PG at concentrations of 0.2 wt % provide adequate stability alone (Sample 2) Ultrasonic agitation enhances the efficacy of PG dissolution (Samples 1 and 3) A relative low 1:1 ratio of PG to Na-CMC delivers adequate coating stability (Sample 4).

(65) Further developments were focused on increasing the percentage of Na-CMC within the formulation. The following results depict Na-CMC concentrations of 2 wt % and 5 wt % and assessing the influence of PG.

(66) TABLE-US-00007 TABLE 7 Stability of wetting agent formulations after 45 kGy exposure Sample 5 Sample 6 Sample 7 Sample 8 PG (wt %) 0.20 0 0.02 0 PPG (wt %) 5.00 5.00 5.00 5.00 Na-CMC (wt %) 2.00 2.00 5.00 5.00 Buffer (wt %) 5.00 5.00 5.00 5.00 T0 stable stable stable stable T15 stable stable stable stable T30 stable stable stable stable T0 = directly after exposure; T15 = after 15 days at 50° C.; T30 = after 30 days at 50° C.

(67) At T0 after 45 kGy exposure, all formulations exhibited optimum coating friction and wear characteristics. After 15 days ageing at 50° C. in a hydrated state after 45 kGy exposure, all formulations exhibited optimum coating friction and wear characteristics. After 30 days ageing at 50° C. in a hydrated state after 45 kGy exposure, all formulations exhibited optimum coating friction and wear characteristics.

(68) Na-CMC delivers excellent stability to the coating and can be used in conjunction with low concentration of PG to further improve the coating stability as indicated by results obtained in Tables 6 and 7.