PATCH

Abstract

The invention relates to an adhesive composition comprising a crosslinked silyl-containing telechelic polyurea polymer and methods for making the same. Typically, the composition is formed into a patch which shows excellent adhesion to the skin even when drugs and other additives are dissolved into the composition.

Claims

1. An adhesive composition comprising a crosslinked silyl-containing telechelic polyurea polymer, wherein G and G are less than 1000 Pa at a frequency of 0.1 rad/s at 25 C.

2. The adhesive composition of claim 1, wherein the adhesive composition has a G and G of less than 50,000 Pa at a frequency of 100 rad/s at 25 C.

3. The adhesive composition of claim 1, wherein the adhesive composition has a tan delta between 0.90 and 1.10 at least one frequency between 0.01 and 100 rad/s at 25 C., and wherein the tan delta is not above 1.10 for any frequency between 0.01 rad/s and 100 rad/s.

4. (canceled)

5. The adhesive composition of claim 1, wherein the telechelic polyurea comprises a structure according to formula (IV): ##STR00008## wherein R1 is a polyether; R2 and R3 are each independently a spacer; n is an integer in the range of 1 to 100; m is an integer in the range 0 to 1; p is an integer in the range 0 to 10; and wherein the sum of m and p is >0.

6. The adhesive composition of claim 5, wherein polyether possesses a weight average molecular weight in the range 2000 Da to 10,000 Da.

7. (canceled)

8. The adhesive composition of claim 5, wherein the polyurea has a structure according to formulae (VII) or (VIII): ##STR00009## R.sup.1 is a polyether; R.sup.2 is a spacer; L is a linker selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl each of which may be optionally substituted; R.sup.6 is selected from: alkyl, alkenyl, alkynyl, aryl, heteroaryl each of which may be optionally substituted; R.sup.7 is selected from: hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; n is an integer in the range of 1 to 100; and j is an integer in the range of 0 to 2.

9. The adhesive composition of claim 5, wherein the spacer is selected from: optionally substituted alkyl, optionally substituted alkoxyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl.

10. The adhesive composition of claim 1, wherein the composition does not comprise a tackifier.

11. The adhesive composition of claim 1, wherein the adhesive composition is a pressure sensitive adhesive.

12. A method of making an adhesive composition comprising a crosslinked silyl-containing telechelic polyurea, the method comprising the steps of: a) reacting a first reagent with a second reagent to form a telechelic polyurea, wherein the first reagent comprises at least one polyetherdiamine or at least one polyetherdiisocyanate, and wherein the second reagent comprises at least one diisocyanate or at least one diamine respectively; b) reacting the telechelic polyurea from step a) with a silyl containing species to form a silyl-terminated telechelic polyurea; and c) crosslinking the silyl-terminated telechelic polyurea; wherein the first reagent is provided in an excess in the range of 2 mol % to less than 100 mol % with respect to the second reagent.

13. The method of claim 12, wherein the first reagent is a polyetherdiamine comprising poly(ethylene glycol), poly(propylene glycol) or a combination thereof, and the second reagent is a diisocyanate selected from isophorone diisocyanate, toluene diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, hexamethyl diisocyanate, bis-(4-cyclohexylisocyanate) or combinations thereof.

14. (canceled)

15. (canceled)

16. The method of claim 12, wherein the first reagent is provided in an excess in the range 5 mol % to 90 mol % with respect to the second reagent.

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. The method of claim 12, wherein the second reagent is added to the first reagent at a rate of addition of first reagent to second reagent is less than or equal to 10 mol % per minute.

22. The method of claim 12, wherein the second reagent is added to the first reagent in a series of steps, wherein each step is allowed to react until substantially no further second agent is present.

23. (canceled)

24. (canceled)

25. The method of claim 12, wherein the polyetherdiamine possess a weight average molecular weight in the range 2000 Da to 10,000 Da.

26. (canceled)

27. The method of claim 12, wherein the method is performed without solvent.

28. (canceled)

29. The method of claim 12, wherein the telechelic polyurea is moisture cured.

30. (canceled)

31. A transdermal drug delivery patch comprising: a substrate; and an adhesive composition comprising: (i) a crosslinked silyl-containing telechelic polyurea polymer, wherein G and G are less than 1000 Pa at a frequency of 0.1 rad/s at 25 C., and (ii) at least one drug suitable for transdermal delivery, wherein the adhesive composition is applied as a layer to the substrate.

32. (canceled)

33. (canceled)

34. (canceled)

35. The transdermal drug delivery patch of claim 31, wherein the drug is hydrophobic.

36. A method of treating a disease in a user in need of treatment comprising applying the transdermal drug delivery patch according of claim 31 to the skin of the user.

Description

DESCRIPTION OF FIGURES

[0105] FIG. 1 showsPermeation of cannabidiol (CBD) through synthetic membranes (Strat-M) from formulations F14 and F3 with cannabidiol.

[0106] FIG. 2 showsPermeation of varenicline through human skin from formulations F14 and F4 with varenicline.

[0107] FIG. 3 showsthe % strain where the storage modulus G plateaus for a number of different compositions according to the invention,

[0108] FIG. 4 showsthe G, G at different angular frequency for an example composition (D5.2) at 9922 (130 m) and 9942 (50 m) thickness.

[0109] FIG. 5 showsthe G, G at different angular frequency for an example composition (D5.3) at 9942 (50 m) and 9922 (130 m) thickness.

[0110] FIG. 6 showsthe viscosity for different polymer compositions.

[0111] FIG. 7 showsfrequency sweep experiments on different polymers at a thickness of 9942 (50 m) with a constant strain (%) of =1.0% at 25 C.

[0112] FIG. 8 showsthe tan change during frequency sweep experiments.

[0113] FIG. 9 showsfrequency sweep comparison between D5.0, D5.2 and D5.4 compositions highlighting the different G and G trends at high angular frequencies. Experiments conducted at a constant strain (%) of =1.0% at 25 C.

[0114] FIG. 10 showsG values at low and high angular frequencies for different compositions. The G at low frequencies represents adhesion and at high frequency represents the debonding process.

[0115] FIG. 11 showsThe effect of temperature by frequency sweep experiments.

[0116] FIG. 12 showsRheological comparison of compositions made from a different molecular weight starting materials.

[0117] FIGS. 13(a) and (b) show-A comparison of the viscoelastic windows of different compositions at 25 C. and at a frequency of 0.01 rad/s (a) and 0.05 rad/s (b) to the Chang's viscoelastic window for adhesives shown as black lines. The dashed line corresponds to the Dahlquist criterion.

[0118] FIG. 14 showsthe results of a rolling ball tack test for various S-PURE variants.

[0119] FIG. 15 showsthe results of a 90 peel back test for various compositions of the invention.

EXAMPLES

[0120] Scheme 1 shows an exemplary embodiment of a method for making a polymer according to the invention. A diisocyanate is added to a polyether diamine in a gradual fashion in step i) in order to exclusively form a first diamine intermediate. That intermediate can then be reacted again in step ii) with more of the diisocyanate, again in a gradual fashion to exclusively create a second intermediate. Step ii) can be repeated numerous times where, each time, the diamine products of the previous step serve as the starting material to which the diisocyanate is added. As such, the value of k theoretically increases by a factor of two plus 1 each time step ii) is repeated. In other words, if the starting k value is k.sub.1 and the new k value is k.sub.2, one could state that k.sub.2 is approximately equal to 2k.sub.1+1. If k grows too large, i.e. around 100 or 150 for example, this is less desirable as the polymers often become too viscous to be practically useful. The total amount of diisocyanate added in each step is reduced by around half each time as the number of moles of intermediate each time is reduced as precursor diamines from previous steps are incorporated into the structure of subsequent diamines.

[0121] Finally, in step iii), the propagation of the polymer is terminated through the addition of a trimethoxylsilyl isocyanate. In Scheme 1 poly(propylene glycol) diamine, toluene diisocyanate and trimethoxylsilyl propyl isocyanate are used to illustrate the process.

##STR00006##

[0122] As can be seen from Scheme 1, the polyurea of the invention is synthesised in various stages. The adhesion properties of the different versions of the PSA were compared using two adhesion tests, 90 peel and loop tack. The polymers of the invention were compared with existing polymer patch technology that require tackifiers in their formulation. Results are shown in the tables below.

##STR00007##

[0123] The process shown in Scheme 2 is an alternative method wherein a diamine is added to the diisocyanate. The same exemplary agents from step i) of Scheme 1 have been used in step iv). However, step v) introduces an ethyl group into the polymer structure using an ethylenediamine monomer. The resulting diisocyanate is then reacted with further amounts of the diamine from step iv) in multiple step-wise additions in step vi). The number of step-wise additions performed in step vi) determines the number average integer value of q. Finally, the polymer propagation is terminated using trimethoxylsilyl propyl amine.

Example 1Production of Silyl-Terminated Polyurea

[0124] To a vessel of 4707.67 g of polyetheramine (Jeffamine D-4000, a polyoxypropylene diamine), 124.26 g of isophorone diisocyanate was added whilst stirring at a temperature of 75 C. The solution was continuously mixed and sampled to monitor the NCO bond concentration until it was no longer detected. Once no further isocyanate was detected, the step was repeated by addition of a further 59.02 g of isophorone diisocyanate and reacted until no further isocyanate was detected. This process was repeated twice more with 28.04 g and 13.32 g of isophorone diisocyanate respectively at each subsequent step. Once all diisocyanate had been reacted, 64.86 g of 3-isocyanatopropyl trimethoxysilane was added to the reaction vessel and left to react to form the silyl-terminated polyurea. 2.83 g of (3-aminopropyl) trimethoxysilane is added to react with any residual isocyanate species.

[0125] By way of contrast, table 1 shows polymer compositions wherein the silyl-terminated polyurea is made by the above method but without an excess of polyetheramine and wherein only a single addition of isophorone diisocyanate is employed.

[0126] The percentage molar excess of the first reagent compared with the second reagent is calculated using the formula below:

The formula for a single addition of isophorone diisocyanate or for every first step of isophorone diisocyanate addition is:

[00005]$n_{\mathrm{IPDI}\mathrm{Step},1}=\left(\frac{m_{\mathrm{polyetheramine}}{A}_{T}0.5)}{1000}\right)0.50.95$

For the rest Steps when required the moles of isophorone diisocyanate are calculated as:

[00006]$n_{\mathrm{IPDI}\mathrm{Step},x}=\left[n_{{\mathrm{IPDI}}_{\mathrm{Step},x-1}}0.50.95\right]/222.28$ [0127] where m.sub.polyetheramine-mass of polyetheramine added into the vessel, A.sub.T-total amine content of polyetheramine used provided in the material's certificate of analysis.

Example 2Production of Adhesive Composition without Tackifiers (F1)

[0128] To a vessel containing 9.9 g of the silyl terminated polyurea of Example 1, 0.1 g of titanium (IV) butoxide was added. The mixture was heated to 55 C. and cast on a PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 6 minutes in a humid atmosphere, with greater than 50% relative humidity. The thin layer of liquid polyurea crosslinked into the form of a pressure sensitive adhesive.

Example 3Production of Adhesive Composition with Tackifiers (F2)

[0129] A vessel containing 19.8 g Arakawa KE311 tackifying resin was heated to 120 C. under a nitrogen atmosphere. To the heated resin 79.2 g of the silyl terminated polyurea of Example 1 was added and left stirring at 120 C. for 3 hours until the mixture was homogenous. The vessel was then cooled to 80 C. 1 g of titanium (IV) butoxide was added and the solution was cast on to a PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 6 minutes in a humid atmosphere, with greater than 50% relative humidity. The thin layer of liquid polyurea crosslinked into the form of a pressure sensitive adhesive.

Example 4Production of Adhesive Composition with Tackifiers (F3)

[0130] A vessel containing 39.6 g Arakawa KE311 tackifying resin was heated to 120 C. under a nitrogen atmosphere. To the heated resin 59.4 g of the silyl terminated polyurea of Example 1 was added and left stirring at 120 C. for 3 hours until the mixture was homogenous. The vessel was then cooled to 80 C. 1 g of titanium (IV) butoxide was added and the solution was cast on to a PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 6 minutes in a humid atmosphere, with greater than 50% relative humidity. The thin layer of liquid polyurea crosslinked into the form of a pressure sensitive adhesive.

Example 5Production of Adhesive Composition with Tackifiers (F4)

[0131] A vessel containing 49.5 g Arakawa KE311 tackifying resin was heated to 120 C. under a nitrogen atmosphere. To the heated resin 49.5 g of the silyl terminated polyurea of Example 1 was added and left stirring at 120 C. for 3 hours until the mixture was homogenous. The vessel was then cooled to 80 C. 1 g of titanium (IV) butoxide was added and the solution was cast on to a PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 6 minutes in a humid atmosphere, with greater than 50% relative humidity. The thin layer of liquid polyurea crosslinked into the form of a pressure sensitive adhesive.

90 Peel Test on a Stainless Steel Plate 20 Minutes:

[0132] The adhesive strength is evaluated by the 180 peel test on a stainless steel plate as described in FINAT method No. 1 published in the FINAT Technical Manual, 6.sup.th edition, 2001. FINAT is the international federation for self-adhesive label manufacturers and converters. The principle of this test is the following.

[0133] A test specimen in the form of a rectangular strip (25 mm175 mm) is cut from the PET carrier coated with the cured composition obtained previously. This test specimen is, after the preparation thereof, stored for 24 hours at a temperature of 23 C. and in a 50% relative humidity atmosphere. It is then fastened over two-thirds of its length to a substrate constituted of a stainless steel plate. The assembly obtained is left for 20 minutes at room temperature. It is then placed in a tensile testing machine capable, starting from the end of the rectangular strip that is left free, of peeling or debonding the strip at an angle of 90 and with a separation rate of 300 mm per minute. The machine measures the force required to debond the strip under these conditions.

Loop Tack Test

[0134] A test specimen in the form of a rectangular strip (25 mm175 mm) is cut from the PET carrier coated with the cured composition obtained previously. This test specimen is, after the preparation thereof, stored for 24 hours at a temperature of 23 C. and in a 50% relative humidity atmosphere. The 2 ends of this strip are joined so as to form a loop, the adhesive layer of which is facing outward. The 2 joined ends are placed in the movable jaw of a tensile testing machine capable of imposing a rate of displacement of 300 mm/minute along a vertical axis with the possibility of moving back and forth. The lower part of the loop placed in the vertical position is firstly put into contact with a horizontal glass plate measuring 25 mm by 30 mm over a square area measuring around 25 mm per side. Once this contact has occurred, the displacement direction of the jaw is reversed. The tack is the maximum value of the force needed for the loop to be completely debonded from the plate.

Rolling Ball Tack Test

[0135] The tackiness of patches was determined utilising a ChemInstruments RBT-100 ramp that meets PSTC-6 test method standards. A ball bearing was used as the test substrate. Samples were cut to give a 150 mm25 mm test area and the distance travelled by the ball along the strip was recorded. An average of three measurements (n=3) was accepted as a statistically robust value of adhesion.

Viscosity

[0136] Viscosity of compositions was determined using a Brookfield viscometer utilising spindle number 27 and a Thermosel. the composition at 80 C. was added to a preheated crucible, 10.5 g for each measurement were required. Measurements were recorded by the instrument every minute for ten minutes. The test was repeated until concordant results were observed. The average of these ten concordant results were reported as the viscosity value for the measured batch.

Rheology Analysis

[0137] Rheological analysis was performed on an Anton Parr MCR 302 rheometer using a measuring parallel plate configuration (diameter of 25 mm) at 25 C. For all oscillatory sweep experiments, cured adhesive discs of 25 mm diameter were used. Amplitude sweep measurements were carried out using a strain (%) range of =0.01-710% at a constant angular frequency of =10 rad/s. Frequency sweep experiments were conducted at an angular frequency range of =0.5-100 rad/s and at a constant strain (%) of =1.0%. An average of at least three measurements (n=3) was accepted as a statistically robust run.

TABLE-US-00001 TABLE 1 Formulations containing tackifiers Excess Silylated 90 peel, Viscosity Amine, Polyurea, Tackifiers, N/25 Loop at 80 C., mol % wt % wt % mm tack, N cP F1 100 100 0 2.0 0.16 2600 F2 100 80 20 1.6 0.26 3300 F3 100 60 40 3.7 4.01 4000 F4 100 50 50 13.9 7.13 6000 F5 100 40 60 31.8 14.61 9900 F6 100 20 80 0.5 0.01 56500 F7 100 45 55 30.9 11.3 5400 F8 100 47.5 52.5 21.3 12.6 4700 F9 100 52.5 47.5 18.4 8.4 4450

[0138] F4 to F9 were found to be unstable. That is, phase separation occurs after a week of storage at room temperature.

Example 6Formulations Prepared with Varying Additions

[0139] Formulation F10 represents a silyl-terminated polyurea formulated as per Example 1 but without any addition of diisocyanate. Formulation F11 to F15 represent compositions with varying amounts of isophorone diisocyanate added to the reaction, such that the molar excess of primary amine to isocyanate is varied. An adhesive film was formed as in Example 2.

TABLE-US-00002 TABLE 2 Adhesive properties with respect to excess primary amine Viscosity Excess amine, 90 peel, Loop tack, at 80 C., mol % N/25 mm N cP F10 0.0 0.0 <500 F11* 100 2.0 0.2 2000 F12 33 2.7 3.0 9500 F13 23 4.4 4.4 15000 F14 16 4.9 11.2 22000 F15 15 6.7 13.2 30000 *a repeat of F1

[0140] As can be seen from the above data, the adhesive properties of the composition increase as the molar excess of primary amine decreases. Comparable adhesive properties are achieved despite the absence of a tackifier. Moreover, the compositions are stable.

TABLE-US-00003 TABLE 3 Adhesive properties with respect to rate of addition Excess Viscosity amine, 90 peel, Loop tack, at 80 C., Addition Rate mol % N/25 mm N cP F14 4 slow constant 16 4.9 11.2 22,000 additions over 15 minutes, spread over a total 80 minutes F16 Slow constant addition 16 Cohesion Cohesion 54420 over 60 minutes failure failure F17 Slow constant addition 16 Cohesion Cohesion 46500 over 40 minutes failure failure F18 Slow constant addition 16 Cohesion Cohesion 45500 over 30 minutes failure failure F19 Slow constant addition 16 Cohesion Cohesion 49200 over 20 minutes failure failure F20 Addition over 1 minute 16 4.3 4.8 16050 duration

[0141] As can be seen from the data above, the addition rate of diisocyanate into the reactor containing amines affects the resultant peel, tack and viscosity of the adhesive.

TABLE-US-00004 TABLE 4 Comparison with commercially available patches. 90 peel, Type N/25 mm F2 Silyl terminated polyurea with 1.6 tackifiers matrix F3 Silyl terminated polyurea with 3.7 tackifiers matrix F13 Silyl terminated polyurea no 4.4 tackifiers matrix F14 Silyl terminated polyurea no 4.9 tackifiers matrix F15 Silyl terminated polyurea no 6.7 tackifiers matrix F14 with cannabidiol Silyl terminated polyurea no 1.1 patch tackifiers matrix F14 with varenicline Silyl terminated polyurea no 3.5 patch tackifiers matrix Nurofen patch 1.0 Lidocare patch 1.1 Salonpas patch 1.1 KefenTech patch 2.4 Kinesiology tape 2.6 Surgical tape 2.5 Elastoplast 3.5

[0142] As evidenced by the data in table 4, the compositions of the invention provide adhesion comparable to many existing transdermal drug patches without the requirement for a tackifier.

[0143] Since one of the main applications of this novel adhesive is to be used in the manufacturing of transdermal patches, the permeation of a model drug through human skin mimicking membranes (Strat-M) was investigated. The permeation rate of a cannabidiol patch synthesized with the two different adhesive types (with and without tackifiers) was compared. As it can be seen in FIGS. 1 and 2 the exclusion of tackifiers from the adhesive formula had no effect on the permeation of the drug through human skin mimicking membranes.

Example 7Silyl Terminated Polyurea (F14 with Cannabidiol)

[0144] 5 g of cannabidiol, 2 g of titanium (IV) butoxide, 12 g of diethylene glycol monoethyl ether, 3 g of octadecanol were added to a vessel containing 78 g of silyl terminated polyurea. The mixture was homogenised at 80 C. by stirring at 120 rpm for 30 minutes. Once homogenised, the mixture was cast on PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 5 minutes in a humid atmosphere, with greater than 50% relative humidity. The film of liquid mixture crosslinked into the form of pressure sensitive adhesive containing cannabidiol with excipients.

Example 8Silyl Terminated Polyurea with Tackifiers (F3 with Cannabidiol)

[0145] A vessel containing 46.8 g of hydrogenated rosin ester (Arakawa KE311) tackifying resin and 31.2 g of silyl terminated polyurea was heated to 120 C. under a nitrogen atmosphere. The mixture was homogenised by stirring at 120 rpm for 3 hours. The vessel was then cooled to 80 C. 5 g of cannabidiol, 2 g of titanium (IV) butoxide, 12 g of diethylene glycol monoethyl ether, 3 g of octadecanol were added to the vessel now containing 78 g of homogenised silyl terminated polyurea and Arakawa KE311 tackifying resin. The mixture was homogenised at 80 C. by stirring at 120 rpm for 30 minutes. Once homogenised, the mixture was cast on PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 5 minutes in a humid atmosphere, with greater than 50% relative humidity. The film of liquid mixture crosslinked into the form of pressure sensitive adhesive containing cannabidiol with excipients.

Example 9Permeation Experiment with Synthetic Membrane

[0146] 0.5 cm.sup.2 sample discs were cut from the mother rolls of the above formulations and attached to Strat-M membranes. Obtained test specimens were placed into a diffusion cell (Franz cell) to measure the amount of cannabidiol permeated across Strat-M membranes over 24 hours. The acceptor solution and diffusion cells were kept at 36 C. Acceptor solution samples were regularly taken from the diffusion cell and analysed on a HPLC instrument using a validated method. See FIG. 1.

Example 10Silyl Terminated Polyurea (F14 with Varenicline)

[0147] 0.15 g of varenicline, 0.2 g of titanium (IV) butoxide, 0.3 g of propylene glycol, 0.5 g of diethylene glycol monoethyl ether, 0.5 g of dimethyl sulfoxide were added to a vessel containing 8.35 g of silyl terminated polyurea. The mixture was homogenised at 80 C. by stirring at 120 rpm for 30 minutes. Once homogenised, the mixture was cast on PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 5 minutes in a humid atmosphere, with greater than 50% relative humidity. The film of liquid mixture crosslinked into the form of pressure sensitive adhesive containing varenicline with excipients.

Example 11Silyl Terminated Polyurea with Tackifiers (F4 with Varenicline)

[0148] A vessel containing 4.175 g of hydrogenated rosin ester (Arakawa KE311) tackifying resin and 4.175 g of silyl terminated polyurea was heated to 120 C. under a nitrogen atmosphere. The mixture was homogenised by stirring at 120 rpm for 3 hours. The vessel was then cooled to 80 C. 0.15 g of varenicline, 0.2 g of titanium (IV) butoxide, 0.3 g of propylene glycol, 0.5 g of diethylene glycol monoethyl ether, 0.5 g of dimethyl sulfoxide were added to a vessel containing 8.35 g of silyl terminated polyurea. To the vessel now containing 8.35 g of homogenised silyl terminated polyurea, a hydrogenated rosin ester (Arakawa KE311) tackifying resin was added. The mixture was homogenised at 80 C. by stirring at 120 rpm for 30 minutes. Once homogenised, the mixture was cast on PET substrate as a thin film of 130 micron by passing under a heated blade. The film was kept at a temperature of 80 C. for 5 minutes in a humid atmosphere, with greater than 50% relative humidity. The film of liquid mixture crosslinked into the form of pressure sensitive adhesive containing varenicline with excipients.

Example 12Permeation Experiment with Human Skin

[0149] 0.5 cm.sup.2 sample discs were cut from the mother rolls of the above formulations and attached to 750 m human skin. Obtained test specimens were placed into a diffusion cell (Franz cell) to measure the amount of varenicline permeated across human skin over 24 hours. The acceptor solution and diffusion cells were kept at 36 C. Acceptor solution samples were regularly taken from the diffusion cell and analysed on a HPLC instrument using a validated method. See FIG. 2.

Example 13S-PURE Synthesis

[0150] Additional adhesive compositions according to the invention were prepared as set out below. S-PURE is a trade name for the adhesives of the invention.

Synthesis of S-PURE D5.0

[0151] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with an initial stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 ml/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, IPTMS (235.79 g, 1.19 mol, 0.99 eq.) was added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (10.30 g, 0.06 mol, 0.05 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.1

[0152] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with an initial stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react for 15 min from the addition of the IPDI. IPTMS (134.45 g, 0.70 mol, 0.59 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (5.87 g, 0.03 mol, 0.03 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.2

[0153] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 eq.) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (86.32 g, 0.47 mol, 0.40 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (3.77 g, 0.02 mol, 0.02 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.3

[0154] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 eq.) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 eq.) was conducted at a flow rate of 2.5 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (63.46 g, 0.35 mol, 0.30 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (2.77 g, 0.01 mol, 0.01 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.4

[0155] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 eq.) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 eq.) was conducted at a flow rate of 2.5 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fifth addition of IPDI (6.19 g, 0.03 mol, 0.03 eq.) was performed at a flow rate of 1.2 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (52.60 g, 0.30 mol, 0.25 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (2.30 g, 0.01 mol, 0.01 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.5

[0156] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 eq.) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 eq.) was conducted at a flow rate of 2.5 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fifth addition of IPDI (6.19 g, 0.03 mol, 0.03 eq.) was followed at a flow rate of 1.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A sixth addition of IPDI (2.94 g, 0.01 mol, 0.01 eq.) occurred at a flow rate of 0.6 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (47.44 g, 0.28 mol, 0.24 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (2.07 g, 0.01 mol, 0.01 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanategroups and stored under a nitrogen blanket.

Synthesis of S-PURE D5.6

[0157] Jeffamine D-4000 (amine content: 0.49, 4700 g, 1.18 mol, 1 eq.) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 eq.) was added using a metering pump at a flow rate of 20 mL/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 eq.) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 eq.) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 eq.) was conducted at a flow rate of 2.5 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fifth addition of IPDI (3.09 g, 0.01 mol, 0.01 eq.) was followed at a flow rate of 0.6 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (58.04 g, 0.33 mol, 0.28 eq.) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (2.53 g, 0.01 mol, 0.01 eq.) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

Synthesis of S-PURE D6.2AComparative

[0158] A mixture of 90:10 molar ratio of Jeffamine D-4000 (amine content: 0.49, 4463.1 g, 1.12 mol) and Jeffamine D-2000 (amine content: 1.01, 240.6 g, 0.12 mol) was charged in a reactor vessel and heated to 852 C. under dry nitrogen with a stirring speed of 120 rpm. After the required temperature was reached, the stirring speed was increased at 180 rpm and IPDI (128.28 g, 0.72 mol, 0.58 eq. with the respect to the total moles of poly(etheramines)) was added using a metering pump at a flow rate of 20 ml/min ensuring the addition was between 5 and 7 min. The mixture was allowed to react such that the entire step took 15 min from the start of the IPDI addition. Then, a second addition of IPDI (60.93 g, 0.34 mol, 0.27 eq. with the respect to the total moles of poly(etheramines)) occurred at a flow rate of 11 ml/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A third addition of IPDI (28.94 g, 0.16 mol, 0.13 eq. with the respect to the total moles of poly(etheramines)) was followed at a flow rate of 5.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fourth addition of IPDI (13.75 g, 0.08 mol, 0.06 eq. with the respect to the total moles of poly(etheramines)) was conducted at a flow rate of 2.5 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. A fifth addition of IPDI (6.53 g, 0.04 mol, 0.03 eq. with the respect to the total moles of poly(etheramines) was performed at a flow rate of 1.2 mL/min ensuring the addition was between 4 and 6 min. The mixture was allowed to react such that the entire step took 15 min from the addition of IPDI. IPTMS (55.50 g, 0.27 mol, 0.22 eq. with the respect to the total moles of poly(etheramines)) was then added using a syringe in bulk and the reaction was allowed to proceed for 20 min from the addition of IPTMS. Finally, APTMS (2.42 g, 0.01 mol, 0.01 eq. with the respect to the total moles of poly(etheramines)) was added using a syringe in bulk and the reaction was also allowed to proceed for 20 min from the addition of APTMS. The final product was analysed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0159] The different compositions and ratios of D4000:IPDI are summarised below.

TABLE-US-00005 TABLE 5 conditions for preparing S-PURE adhesive compositions. D4000:IPDI content Number of IPDI S-PURE Variant (mol ratio) Additions S-PURE-D5.0 1:0.47 1 S-PURE-D5.1 1:0.69 2 S-PURE-D5.2 1:0.79 3 S-PURE-D5.3 1:0.84 4 S-PURE-D5.4 1:0.87 5 S-PURE-D5.5 1:0.88 6 S-PURE-D5.6 1:0.85 5

Example 14Preparation of Adhesive Patches

[0160] Titanium (IV) butoxide catalyst (1%) was added to a representative amount of the S-PURE compositions described above and the resultant mix was spread using an RK K-Control coater set at 80 C. using a K-Bar. The resultant patch was subjected to 1.5 minutes of steam and a further 3.5 minutes of heat to induce curing of the prepolymer. Curing was assessed after 5 min total time.

Example 15Amplitude Sweep Experiments

[0161] The table below shows the strain (%) range where the storage modulus (G) plateaus. At high strains (%) (>30%), sample slippage was observed, and viscoelastic characteristics could not be measured further. The results are shown in FIG. 3 and in Table 6 below:

TABLE-US-00006 TABLE 6 LVER regions based on amplitude sweep experiments. Entry LVER-Strain (%) Range S-PURE-D5.0 0.01-28 S-PURE-D5.1 0.01-20 S-PURE-D5.2 0.01-28 S-PURE-D5.3 0.01-13 S-PURE-D5.4 0.01-28 S-PURE-D5.5 S-PURE-D6.2 0.01-39

[0162] The effect of patch thickness was studied where 9922 (130 m)>9942 (50 m). Frequency sweep experiments were performed at a constant strain (%) of =1.0% (as dictated by the previously found LVER regions). As expected, the results showed that an increase in the thickness led to larger G values indicative of stiffer and more elastic materials. Despite the difference in thickness, samples demonstrated similar viscoelastic profiles up to =100 rad/s where the value of G almost equalled the value of G. A continues increase in the G values was noticed by increasing the frequency of deformation attributed to the existence of polymer entanglements. The results for the S-PURE D5.2 and D5.3 formulations are shown in FIGS. 4 and 5 respectively.

[0163] The effect of different average molecular weights between crosslinks (Mc) was investigated by analysing formulations made from polymers with various molecular weights. Initially viscometry was used to assess the difference in molecular weight. Polymers formed from higher IPDI to Jeffamine D4000 ratios had longer polymer chains during the step-growth polymerization process, which leads to higher average molecular weights and thus higher viscosities. The results are shown in FIG. 6.

[0164] Frequency sweep experiments were performed on different S-PURE variants at a thickness of 9942 (50 m). The results in FIG. 7 show that higher molecular weight S-PURE variants had lower G values indicative of softer, more wettable and thus more adhesive surfaces. Generally, the average molecular weight of the polymers is expected to be analogous to the average molecular weight between crosslinks (Mc) the increase of which leads to lower crosslink densities. D5.0 demonstrated a constant rheological profile with the G values plateauing by increasing angular frequency in contrast to the rest of the formulations where the G kept increasing by the frequency of deformation a result of polymer entanglements and higher average molecular weight. In addition, D5.5, which had the highest molecular weight, demonstrated the lowest G and G values which cross over at a frequency of 1.1 turning the adhesive into a viscous fluid with the G exceeding the G throughout. This was also showcased by the values of tan which were >1 for D5.5 and lower <1 for the lower molecular weight S-PURE variants which showed a more viscoelastic type of character (FIG. 8).

[0165] The different trends of G and G at high angular frequencies are shown in FIG. 9 where the increase in molecular weight brought the two values closer to each other in a parallel way though without crossing over to turn into a fluid like state. An overall chart of the G values at low (indicative of adhesion) and high (indicative of peeling) angular frequencies is illustrated in FIG. 10.

[0166] The effect of temperature was also investigated on D5.3 9942 samples by comparing their viscoelastic behaviour at 25 and 37 C. The results are shown in FIG. 11. An increase in temperature can affect the viscoelastic characteristics by lowering both the G and G values. Despite the temperature raise, the viscoelastic profiles remained the same with the G approaching the G at high angular frequencies without crossing indicative that the covalent crosslinked network doesn't break at the examined frequencies. The drop in G by increasing temperature was attributed to a larger free volume of the polymer chains which makes them more mobile along with the thermal rupture of hydrogen bonds.

[0167] Finally, S-PURE formulations containing a mixture of Jeffamine D-4000 and Jeffamine D-2000 (D6.2A) were compared with those containing Jeffamine D4000 (D5.2) at the same thickness (9942), Frequency sweep results indicated that D6.2A had a lower G value than D5.2 at low angular frequencies showing that D6.2A had a better adhesion as a result of the higher amount of urea moieties per chain. At high angular frequencies the G values of D6.2A were higher indicative of a higher peel strength than D5.2.

[0168] The tabulated results are shown in Tables 7 and 8 below.

TABLE-US-00007 TABLE 7 G.sub.plateau G.sub.0.5 rad/s G.sub.1 rad/s G.sub.100 rad/s G = G Entry (Pa) (Pa) (Pa) (Pa) (rad/s) SPURE D6.2A 9942 No plateau 1,551 171 2,051 215 20,811 3253.sup. 4.9 1.6 SPURE D6.2A 9922 No plateau 1,864 500 2,406 602 31,461 8144.sup. 1.7 0.3 SPURE D5.0 9942 12,711 910 Plateau Plateau Plateau No crossing SPURE D5.1 9942 No plateau 15,293 6019 16,877 6614 40,950 16,851 No crossing SPURE D5.2 9942 No plateau 1,945 66 2,321 199 14,950 1974.sup. Parallel SPURE D5.2 9922 No plateau 2,891 887 3,501 1074 22,296 8,321 Parallel SPURE D5.3 9942 No plateau 1,027 293 1599 488 16,501 4053.sup. Parallel SPURE D5.3 9922 No plateau 2,441 981 3,284 1209 24,720 13,021 Parallel SPURE D5.4 9922 No plateau 1,650 796 2,132 1025 26,501 13,800 2.0 0.2 SPURE D5.4 9942 No plateau 1,143 67 1,620 138 8,664 5,181 Parallel SPURE D5.5-9942 No plateau 235 25 316 23 4,750 373.sup. 1.1 0.3 SPURE D5.5-9922 No plateau 239 89 352 125 6,370 1,705 0.7 0.1

TABLE-US-00008 TABLE G G G G G G (0.01 (0.01 (0.5 (0.5 (100 (100 rad/s) rad/s) rad/s) rad/s) rad/s) rad/s) Entry (Pa) (Pa) (Pa) (Pa) (Pa) (Pa) SPURE D6.2A 309 11 30 8 1,551 171 836 120 20,811 3253.sup. 18,334 3,468 SPURE D5.0 7,932 664 1150 462 12,711 910 401 273 12,711 910 3,259 400 SPURE D5.1 2,255 147 161 93 15,293 6,019 1,266 380 40,950 16,851 22,751 8,215 SPURE D5.2 563 18 29 2 1,945 66 603 36 14,950 1,974 12,646 1,572 SPURE D5.3 315 30 36 7 1,027 293 558 97 16,501 4053.sup. 14,420 2,963 SPURE D5.4 275 47 17 3 1,143 67 597 21 8,664 5,181 11,673 428.sup. SPURE D5.5 197 50 74 16 235 25 187 21 7,334 2,107 4,657 974

[0169] Based on the G and G values, viscoelastic windows were attained at 0.01 and 0.05 rad/s (FIGS. 13(a) and (b)). For the viscoelastic windows the following coordinates were used: G, G=> (100, 0.5), (100, 100), (0.5, 0.5) and (0.5, 100) or (100, 0.01), (100, 100), (0.01, 0.01) and (0.01, 100). To assess the type of adhesive, the viscoelastic windows were compared against Chang's viscoelastic windows and the Dahlquist criterion for a good adhesive. A frequency of 0.5 rad/s is equivalent to the deformation that an adhesive experiences on skin.

[0170] According to FIGS. 13(a) and (b), all S-PURE variants fulfilled the Dahlquist criterion for a good PSA with a good contact efficiency. Surprisingly, increasing molecular weight (5.0=>5.5), the viscoelastic windows shifted to the lower left quadrant 3 characteristic of removable PSAs for medical applications characterized by a low G with most of them exceeding the limits of the Chang's windows.

[0171] The adhesion and rolling ball tack test for the S-PURE compositions was measured and is shown below in table 9 and in FIGS. 14 and 15:

TABLE-US-00009 TABLE 9 90 Peel Adhesion Rolling Ball Tack Test S-PURE Variant Test (N) (mm) S-PURE-D5.0 0.70 0.15 70 11 S-PURE-D5.1 1.46 0.13 52 15 S-PURE-D5.2 2.99 0.13 34 8 S-PURE-D5.3 4.20 0.31 24 11 S-PURE-D5.4 5.71 0.10 21 4 S-PURE-D5.5 6.25 0.22 17 6 S-PURE-D5.6 5.19 0.30 17 12
The force required to peel a patch from a stainless-steel surface increased by raising the amount of IPDI added (D5.0 to D5.5). Results indicated that 90 peel adhesion testing can be used as a method to differentiate different S-PURE formulations. The average distance travelled by the ball after it exits the ramp decreased as tackiness increased. The higher the amount of IPDI added, the greater the tackiness of S-PURE as the lower was the travelling distance of the ball. However, the differences in tackiness between the variants of S-PURE were not large enough to be able to use this parameter to distinguish between S-PURE variants.