patch

Abstract

To provide a PSA that uses as little material as possible while retaining the same overall adhesive and delivery properties. The present invention relates to an adhesive composition containing a crosslinked silyl-containing telechelic polyurea polymer, the adhesive composition having G' and G'' of less than 1000 Pa at 25°C at a frequency of 0.1 rad / s.

Description

[Technical field]

[0001] The present invention relates to an adhesive composition, typically for use in a transdermal drug delivery patch; a transdermal drug delivery patch comprising the composition; a method for making the composition and the patch; a method for treating a disease using the patch; and the use of such a composition as a pressure sensitive adhesive. [Background technology]

[0002] Pressure sensitive adhesives (PSAs) are materials that form a bond to a substrate when applied to the substrate with sufficient pressure. Such materials have a wide range of applications. They can be used in conventional office applications (e.g., adhesive labels) and in more specific situations, such as for vehicle trim. However, one application of particular interest is skin patches, typically designed for transdermal drug delivery. The patch may be pressed onto the skin, and the PSA will adhere to the skin, preventing the patch from falling off.

[0003] There are various requirements for such a PSA. Clearly, the adhesive needs to be strong enough to prevent premature detachment from the skin. However, it is desirable that the PSA allow removal of the patch without causing pain (e.g. pain due to hair loss or skin damage). Furthermore, the residue left on the skin by many adhesives is unpleasant to the user and therefore needs to be minimized.

[0004] In recent years, PSAs have been developed that not only function as adhesives but also as reservoirs of compounds for delivery to the skin. Some PSA compositions have been found to not only have excellent adhesive properties but also be capable of storing large amounts of drugs. Furthermore, some PSAs exhibit excellent drug delivery profiles and have good compatibility with a variety of different drugs (a variety of different drugs with different solubilities).

[0005] One example of such a PSA is shown in WO2017 / 0077284. However, it has been found that in some cases, the best results are achieved when providing an adhesive. As will be appreciated by those skilled in the art, the more materials that are introduced into the composition, the more expensive the composition is to manufacture. Furthermore, the increased complexity of the composition makes it more difficult to obtain regulatory approval for the composition when used in the health care field. The additional materials degrade over time or leach out of the composition over time, changing the properties of the composition.

[0006] The adhesive composition may be defined by the Dahlquist criteria and / or Chang's window as defined below: Dahlquist Criterion: The elastic modulus of an adhesive must be less than 0.3 MPa (3×10) at 25°C and ~1 rad / s to form good adhesive contact with the substrate. 6 dyne / cm 2 ) or less. · Chang window: Chang proposed that adhesive types can be classified into four quadrants, depending on the location of the viscoelastic window. Quadrant 1 (top left) is characterized by high G´, low G´ and corresponds to classical adhesives. Quadrant 2 (top right) is characterized by high G´, high G´ and corresponds to high shear PSAs (moderate peel strength, very high shear and resistance) with applications e.g. for high performance tapes. Quadrant 3 (bottom left) is characterized by low G´ and low G´ and corresponds to removable PSAs (clean removable) for removable medical applications. Quadrant 4 (bottom right) is characterized by low G´ and high G´ and corresponds to low temperature PSAs (low shear, very high peel) for e.g. labels etc. Summary of the Invention [Problem to be solved by the invention]

[0007] It is desirable to produce a PSA that uses as little material as possible while retaining the same overall adhesive and delivery properties. The present invention is intended to solve this problem, or at least provide an improvement over this problem. [Means for solving the problem]

[0008] In a first aspect of the present invention, there is provided an adhesive composition comprising a crosslinked silyl-containing telechelic polyurea polymer, having G′ and G″ less than 1000 Pa at 25° C. and a frequency of 0.1 rad / s. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] G' and G" are measurements of rheological properties commonly used in the art. Rheology studies the deformation and flow of materials. It can be used to establish a direct relationship between polymer properties and article performance. Rheological parameters can be measured using a parallel plate system, and shear strain (γ) and shear stress (τ) are experimentally determined as follows: γ=F γ ω τ=FτT In the formula, F γ (=R / d) is the shear strain factor; Fτ(=2 / πR 3 ) is the shear stress factor; ω is the angular displacement; T is the torsional force; R is the radius of the plate and d is the shear gap.

[0010] Complex dynamic shear modulus (G * ), storage modulus (G´), and loss or plastic modulus (G´´) and loss factor (tan δ) are defined as follows:

number

[0011] Thus, G' and G" can be measured using a rheometer and standard protocols known to those skilled in the art. The temperature and frequency at which G' and G" are measured will affect the values ​​obtained. In this case, the values ​​of G' and G" are obtained at a frequency of 0.1 rad / s and 25°C. For example, one skilled in the art will understand that a polymer will have a G' and G" of less than 11,000 when G' and G" are measured at 0.5 rad / s and 25°C.

[0012] The inventors have found that the adhesive composition defined above not only serves as an excellent drug reservoir and drug delivery system, but also exhibits excellent adhesive properties. These properties allow the composition to be made into an adhesive patch without the need for additives to improve the adhesive properties. The composition according to the invention is also useful as a pressure sensitive adhesive in both medical and non-medical applications where pressure sensitive adhesives are useful. For example, it is useful in food manufacturing and packaging, electrical and medical supplies.

[0013] In additional or alternative aspects of the invention, the adhesive composition has a G' and G'' of less than 50,000 Pa at 25°C at a frequency of 100 rad / s.

[0014] In additional or alternative aspects of the invention, the adhesive composition has a tan delta at 25° C. of 0.90 to 1.10 at at least one frequency between 0.01 and 100 rad / s, and the tan delta is not greater than 1.10 for all frequencies between 0.01 rad / s and 100 rad / s.

[0015] As known to those skilled in the art, tan delta describes the ratio of two parts of the viscoelastic behavior. The following applies: 1. For ideal elastic behavior δ=0°. There is no viscous part. Therefore, G´´=0 and tan δ=G´´ / G´=0. 2. For ideal elastic behavior δ=90°. There is no elastic part. Hence G´=0, so the value of tan delta=G´´ / G´ approaches infinity as we divide by zero.

[0016] In alternative or additional aspects of the invention, the adhesive composition has a tan delta of 0.95 to 1.05 at 25° C. for at least one frequency between 0.01 and 100 rad / s, and the tan delta is less than 1.05 for all frequencies between 0.01 rad / s and 100 rad / s.

[0017] In some embodiments, the crosslinked silyl-containing telechelic polyurea is prepared by a method comprising the steps of: (a) reacting a first reagent with a second reagent to form a telechelic polyurea, where the first reagent comprises at least one polyether diamine or at least one polyether diisocyanate, and 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, where the first reagent is provided in an excess relative to the second reagent in the range of 2 mol % to less than 100 mol %.

[0018] Further described herein is a method of making 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, where the first reagent comprises at least one polyether diamine or at least one polyether diisocyanate, and 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, where the first reagent is provided in an excess relative to the second reagent in the range of 2 mol % to less than 100 mol %.

[0019] The present inventors have found that by adjusting the polymerization process so that the first reagent (i.e., polyether diamine or polyether diisocyanate) is provided in excess relative to the second reagent (i.e., diisocyanate or diamine), the resulting composition not only serves as an excellent drug reservoir and drug delivery system, but also exhibits excellent adhesive properties, such that the composition can be made into an adhesive patch without the need for additives to enhance the adhesive properties.

[0020] For the avoidance of doubt, references to "excess" as used in this disclosure refer to a molar excess, i.e., a molar ratio of a first reagent to a second reagent that is greater than 1:1. Furthermore, references to "excess" in this description, for example with respect to a first and second reagent, refer to the total amount of these reagents used in the process, allowing for some of the reactive groups (e.g., amines and isocyanates) associated with a given first and second reagent to remain unreacted. Thus, the percentage of molar excess of a first reagent compared to a second reagent is calculated using the following formula: ((100 / N2) * N1)-100 N1 is the number of moles of the first reagent added to the reactor and N2 is the number of moles of the second reagent added to the reactor.

[0021] As will be appreciated by those skilled in the art, while diamines and diisocyanates have two amine moieties and two isocyanate moieties, respectively, in a given reagent sample, some of these moieties may decompose or otherwise not participate in urea formation. This ratio will be different for different reagents, however, one skilled in the art will be able to take this behavior into account and adapt their calculations as necessary.

[0022] As will be appreciated by those skilled in the art, the polyureas resulting from the reaction of polyetherdiamines with diisocyanates are essentially identical to the polymers obtained by the reaction of the corresponding polyetherdiisocyanates with the corresponding diamines, both of which form a series of urea linkages between the respective reagents.

[0023] The term "crosslinking" as used in this description is intended to refer to the direct (polymer to polymer) or indirect (polymer to polymer intermediate bridging species) covalent interaction of polymers in the composition, which typically results from a reaction between a particular polymer side group (or end group) of adjacent polymers or intermediate bridging species and another corresponding side group (or end group). This can be achieved using a catalyst and / or in the presence of a co-reactant, such as water. Additionally, elevated temperature, radiation, such as ultraviolet (UV) radiation or electron beam (EB) radiation, may be used to promote the crosslinking reaction. When a catalyst is used, at least one catalyst is typically present in the composition in an amount ranging from 0.001 to 5% by weight of the composition, more typically 0.01 to 3% by weight. The catalyst may remain in the composition, or may be consumed, or may change during the crosslinking process. A typical example of a catalyst is a crosslinking promoter, such as titanium (IV) butoxide.

[0024] The term "curing" as used in this description is understood as crosslinking the components of the composition together until the desired properties of the cured material are obtained. This crosslinking in the present invention typically occurs between the silyl groups of the silyl-terminated telechelic polyureas described above.

[0025] While the telechelic polyureas formed in step (a) are typically linear polyureas, some of the telechelic polyureas may be at least partially branched. Thus, the polyureas may have more than two end groups that can be crosslinked in step (c). However, most conventional telechelic polyureas are linear.

[0026] The term "telechelic polyurea" is intended to have its ordinary meaning in the art, i.e., a polymer or oligomer that is capable of undergoing further polymerization or other reactions via its reactive end groups.

[0027] Typically, the diisocyanate and diamine species used as the second reagent have two isocyanate groups and two amine groups, respectively, which are attached to a spacer. The isocyanate and amine groups are typically located at the ends of the spacer. Some of the diisocyanates and / or diamines may have only a single isocyanate or amine group. However, the concentration of such mono-substituted species is typically low, e.g., less than 5% by weight, more typically less than 1% by weight.

[0028] The term "spacer" is intended to have its usual meaning in the art. In particular, it describes a moiety that provides a covalent bond between two groups in a structure. The main function of this spacer is to separate the two groups at a predetermined distance from each other. Therefore, the chemistry of the spacer is flexible, provided that the desired spacing is achieved and does not adversely affect the reaction between the first and second reagents. There is no particular limit to the choice of spacer, but it is typically not polymeric.

[0029] Typically, the spacer is not a polyether. The spacer may be selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, each of which may be optionally substituted. Of these, alkyl, aryl, and heteroaryl groups are most typically used. In many cases, the spacer will be an alkyl group or an aryl group. In many cases, the spacer will be an alkyl group. The alkyl group will be a C1-C 20 and more typically, C2 to C 15 , and more typically C3-C 10The alkyl group may be linear, branched, or cyclic alkyl. The alkyl group may have one or more heteroatoms selected from S, N, and O. Typical examples of spacer groups include isophorone, phenyl or biphenyl, cyclohexyl or bicyclohexyl, and C2-C8 alkyl (e.g., ethyl, propyl, butyl, or hexyl), each of which may be optionally substituted. The term "optionally substituted" is intended to mean structural modifications to a species in the present description that do not materially affect the function of the species in question.

[0030] The diisocyanate is typically selected from aromatic diisocyanates, aliphatic diisocyanates, or combinations thereof. As will be appreciated by those skilled in the art, a wide range of molecules having two isocyanate groups may be used, provided that the molecules do not have groups that inhibit the intermolecular interaction between the isocyanate and amine groups present in the polyether diamine.

[0031] However, typical examples of diisocyanates may be selected from isophorone diisocyanate, toluene diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, hexamethyl diisocyanate, bis-(4-cyclohexyl isocyanate) or combinations thereof.

[0032] Similarly, the diamine is typically selected from aromatic diamines, aliphatic diamines, or combinations thereof. As will be appreciated by those skilled in the art, a wide variety of molecules having two amine groups may be used, provided that the molecules do not contain groups that inhibit the intermolecular interaction between the amine groups and the isocyanate groups present in the polyether diisocyanate.

[0033] However, typical examples of diamines may be selected from isophorone diamine, toluene diamine, diaminonaphthalene, diphenylmethane diamine, hexamethyl diamine, bis-(4-cyclohexylamine) or combinations thereof.

[0034] As explained above, the first reagent is provided in excess relative to the second reagent. Often, the upper limit of the excess is selected from 95 mol%, 90 mol%, 85 mol%, 80 mol%, 75 mol%, 70 mol%, 65 mol%, 60 mol%, or 55 mol%. Furthermore, the corresponding lower limit is often selected from 5 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, or 45 mol%, respectively. Often, the first reagent is provided in an excess in the range of 5 mol% to 90 mol% relative to the second reagent. More typically, the first reagent is provided in an excess of less than 10 mol% to 80 mol% relative to the second reagent. Even more typically, the first reagent is provided in an excess of less than 10 mol% to 30 mol% relative to the second reagent. In some embodiments, the first reagent is provided in less than 15 mol % to 20 mol % excess relative to the second reagent, while in other cases, the first reagent may be provided in less than 40 mol % to 60 mol % excess relative to the second reagent.

[0035] Furthermore, in many cases, a second reagent is added to the first reagent. Furthermore, the reaction between the first and second reagents typically proceeds by gradually combining the reagents, typically in a dropwise manner. For the avoidance of doubt, this gradual addition is typically in the form of a dropwise addition of 20 mol% min -1 Hereinafter, more typically, 10 mol% min -1 In some cases, it is 5 mol% min -1 In most cases, the rate of addition is 1 mol% min -1 ~15mol%min -1 , more typically 3 mol% min -1 ~12mol%min -1 , most typically 5 mol% min -1 ~10mol%min -1 It is.

[0036] Moreover, in many cases, the second reagent is added to the first reagent in a series of steps. Thus, a first amount of the second reagent may be added to the first reagent and allowed to react until there is substantially no further second reagent present. This may be followed by adding a second amount of the second reagent to the reaction mixture. This process may be repeated multiple times, such that the method may involve 1-10 additions, 2-8 additions, or even more typically 3-6 additions, and often 4 or 5 additions. This type of addition is referred to in this disclosure as a "staged" addition. This should not be confused with steps (a)-(c) referred to in this disclosure, which characterize different steps in the polymer manufacturing process. In possible embodiments, the mass of the second reagent present in each subsequent addition is less than the previous addition. In some cases, the subsequent mass is about half that used in the previous amount of the second reagent. As will be appreciated by those skilled in the art, each addition of the second reagent promotes further chain extension and reduces the number of moles of the polymer intermediate formed in the previous step. This polymer intermediate then forms the basis on which further portions of the second reagent can react. For the avoidance of doubt, the first reagent is provided in excess relative to the total amount of the second reagent used in all steps where stepwise addition is employed. Each step is typically allowed to proceed to substantial completion. This can be monitored in various ways known to those skilled in the art, for example, by dynamically monitoring the disappearance of a characteristic signal in the spectrum of the test sample.

[0037] As described above, the first reagent is a polyether diamine or a polyether diisocyanate. Typically, the first reagent has a weight average molecular weight in the range of 2000 Da to 10,000 Da. In many cases, the first reagent has a weight average molecular weight in the range of 2500 Da to 8000 Da, more typically in the range of 3000 Da to 6000 Da, and most typically in the range of 3500 Da to 5000 Da.

[0038] Both polyether diamines and polyether diisocyanates have a polyether moiety that is terminated at both ends with an amine group and an isocyanate group, respectively. Typically, the polyether moiety has a structure according to formula (I):

[0039] [ka]

[0040] where R is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, which may be optionally substituted, and l is an integer ranging from 2 to 100. Typically, R is an alkyl or alkenyl, more typically an alkyl. Usually, R is a small group, C1-C 10 R ranges in length from 1 to 5, more typically from C1 to C8, even more typically from C2 to C6, and in some cases from C2 to C4. Typically, R is a C1, C2 or C3 group, and most typically a C2 or C3 group. Often, R is selected from methyl, ethyl, propyl, and butyl, and more typically is ethyl or propyl.

[0041] Furthermore, while in many cases only a single type of ether monomer is used in the polyether moiety, a variety of different monomers may additionally be used. For example, a mixture of different ether monomers may be used, thereby forming a polyether moiety containing different ether monomer units in the structure of the polyether moiety. The polyether moiety may be a copolymer comprising one or more blocks of polyether subunits and / or additional polymer subunits. Thus, alternating copolymers and block copolymers are also contemplated as suitable polyether moieties. For example, the polyether moiety may include a poly(propylene glycol) moiety and a poly(ethylene glycol) moiety. Alternatively, the polyether moiety may be a copolymer formed from a mixture of ethyl ether and propyl ether monomers, thereby forming an alternating copolymer of these two monomers.

[0042] In some examples, the polyether moiety is selected from polyoxymethylene, poly(ethylene glycol), poly(propylene glycol), poly(1,2-butylene glycol), poly(tetramethylene glycol), or combinations thereof. Of these, poly(ethylene glycol) and poly(propylene glycol) or combinations thereof are most typically used. Reference to "combinations thereof" as used in this disclosure is intended to encompass both copolymers and mixtures of polymers. While polyethers are typically formed only from ether monomers (most typically ethylene glycol and / or propylene glycol), the polyether moiety may additionally contain non-ether monomers in its structure. The concentration of these monomers in the polyether is usually relatively small compared to the ether monomers. Typically, the concentration of non-ether monomers present in the polyether moiety is 20% mol or less, more typically 10% mol or less, even more typically 5% mol or less, and commonly 1% mol or less. In some embodiments, the polyether moiety is formed only from ether monomers.

[0043] In addition to the diisocyanates or diamines mentioned above, the second reagent may also further comprise one or more additional diisocyanates or diamines. As will be appreciated by those skilled in the art, the introduction of additional monomers into the process will result in the monomers being inserted into the resulting telechelic polyurea, whether they contain isocyanate or amine groups. These monomers will insert themselves into the structure of the telechelic polyurea.

[0044] The telechelic polyurea formed in step (a) may be formed using either a polyetherdiamine or a polyetherdiisocyanate as the first reagent, but typically the first reagent is a polyetherdiamine, and thus typically the second reagent is a diisocyanate.

[0045] In many cases, the method of the first aspect of the present invention is carried out without solvent.In many circumstances, the first and / or second reagent can act as both a reagent and a solvent, eliminating the need for a separate solvent.This is particularly useful when producing compositions for use in medical applications, due to the strict regulations imposed on such products, where even low levels of impurities can prevent approval.

[0046] The processes in steps (a) and (b) at least typically do not require a catalyst.

[0047] The process of the first aspect of the present invention is not limited to any particular temperature. However, as will be appreciated by those skilled in the art, the reaction rate of the polymerization reaction (as with many chemical reactions) is determined in part by the temperature of the process. Thus, typically, the temperature of the process ranges from 5°C to 150°C, more typically from 10°C to 100°C. In some embodiments, the process may be carried out at room temperature (e.g., in the range of 15°C to 30°C).

[0048] To form a crosslinked silyl-containing polyether polyurea, the silyl-terminated telechelic polyether polyurea formed in step (b) must be cured, thereby connecting the silyl groups of adjacent silyl-terminated telechelic polyether polyurea molecules together. There are numerous methods for promoting such a reaction, including radiation curing, thermal curing, and moisture curing. In each of these processes, an appropriate catalyst may be used. However, typically, the telechelic polyurea is moisture cured.

[0049] The polymerization reaction of step (a) may be completed by the start of step (b), i.e., by the introduction of a silyl-containing species, which reacts with the terminal amine or isocyanate at the end of the growing chain. The silyl-containing species is typically an amine or alcohol (in which case it is intended to react with the terminal isocyanate), or an isocyanate (in which case it is intended to react with the terminal amine). The amine is usually a primary amine, although secondary amines are also contemplated. Typically, the silyl-containing species reacts to form a silyl group at each of the ends of the polyurea. In many circumstances, the silyl-containing species has a formula according to formula (II):

[0050] [ka]

[0051] During the ceremony, R 5 contains a silyl group, A is either an amine, an alcohol, or an isocyanate; and L is an optional linker or bridging group.

[0052] As will be appreciated by those skilled in the art, a linker or bridging group connects two groups together. For the avoidance of doubt, this linker is optional and therefore a single bond connects A and R 5may be directly bonded together. There is no substantial limit as to the characteristics of the linker, so long as it does not inhibit the reaction of the silyl-containing species. Typically, L is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, each of which may be optionally substituted. Typical examples of linkers are alkyl and aryl groups, and the linkers are usually short, usually C1-C 10 The range is.

[0053] R 5 Typically has a structure according to formula (III):

[0054] [ka]

[0055] In the formula, R 6 is independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, each of which may be optionally substituted; and j is an integer ranging from 0 to 2. In some circumstances, j is 1 or 2. Most typically, R 6 are independently an alkyl group, typically a C1 to C6 alkyl group. Of these, butyl, propyl, ethyl and methyl are preferred. In many cases, R 6 are independently either ethyl or methyl, and in most cases R 6 is methyl.

[0056] In many cases, the method for producing crosslinked silyl-containing telechelic polyurea is carried out without solvent.One of the advantages of this method is that the reagent itself can function as the solvent for the reaction.This is advantageous from a commercial point of view, because the process requires relatively few materials, and also from a structural point of view, because residual solvent does not get into the crosslinked polyurea during the curing process.

[0057] In some cases, after applying the silyl groups to the polyurea, residual silylating agent is present in the solution. This can cause problems in downstream applications, and therefore the process often includes a step to remove this residual silylating agent. A variety of reagents may be used to achieve this removal, and the choice of compound used will vary depending on the particular choice of silylating agent used. For example, a conventional silylating agent that can be used in the present invention is (3-isocyanopropyl)trimethoxysilane, often abbreviated as "IPTMS". To remove excess IPTMS, a typical compound is (3-aminopropyl)trimethoxysilane, often abbreviated as APTMS. These two components react to form terminally silylated species, which may also be crosslinked in step (b). Such a process is typically carried out before step (c), but after step (b).

[0058] The process for producing crosslinked silyl-containing telechelic polyureas is typically carried out at a temperature in the range of 10° C. to 100° C. More typically, the temperature is in the range of 40° C. to 90° C., and more typically, 50° C. to 75° C. At temperatures lower than this, the agitation speed of the mixture becomes less than optimal, and at higher temperatures, the energy consumption begins to become commercially impractical.

[0059] The curing process used in the present invention (step (c) above) is not particularly limited. As will be appreciated by those skilled in the art, there are numerous techniques that result in crosslinking of the silyl groups, thus forming a matrix of interconnected silyl-containing polymer chains. For example, the curing process can be radiation curing or moisture curing. The choice of cure often depends on the choice of materials to be introduced into the crosslinked polymer. For example, if the composition is used for drug delivery, a radiation curing method may be used if the drug to be delivered is not thermally stable (and therefore cannot be subjected to a practical moisture curing process). Conversely, if the additive is not radiation stable, a moisture curing method will be used. Typically, however, a moisture curing process will be used. Such processes are known to those skilled in the art.

[0060] In many cases, the silyl-containing non-crosslinked polyureas formed in the process of the present invention will have a viscosity (measured at 80° C.) measured using a rotational viscometer, e.g., a Brookfield viscometer, in the range of 2,000 cP (centipoise) to 55,000 cP, more typically from 4,000 cP to 45,000 cP, even more typically from 8000 cP to 40,000 cP, and most typically from 15,000 cP to 35,000 cP.

[0061] In a second aspect of the invention there is provided an adhesive composition containing a crosslinked polyurea obtainable by the process according to the first aspect of the invention.

[0062] The present inventors have found that the adhesive composition of the present invention has excellent transdermal drug delivery properties and also exhibits excellent adhesive properties as a PSA. In fact, the properties of such crosslinked polyureas are at least comparable to those of prior art polymer compositions using pressure sensitive adhesives (see, for example, those specified in WO2017 / 077284, pages 40-44).

[0063] Often, each of the crosslinked silyl-containing telechelic polyureas has a structure according to formula (IV):

[0064] [ka]

[0065] In the formula, R 1 is a polyether as defined above, R 2 is the spacer defined above, R 3 is a spacer or polyether, n is an integer ranging from 1 to 100; m is an integer ranging from 0 to 1; and p is an integer ranging from 0 to 10; The sum of m and p is >0.

[0066] In many cases, R 3 is R 1 and R 2 Typically, p is 0 or 1, and most typically, p is 0. Furthermore, m is often 1. Usually, R 3 is a spacer. Furthermore, n is typically in the range of 5 to 90, more typically 10 to 80, and even more typically 20 to 70.

[0067] As explained above, the preparation of polymers using methods according to aspects of the present invention results in the formation of mixtures of polyureas that provide compositions with excellent physical properties for use in transdermal drug delivery devices. The polyureas typically contain this structure, i.e., this structure is present in the polyurea.

[0068] Typically, the crosslinked silyl-containing polyurea has a structure according to formula (V):

[0069] [ka]

[0070] In the formula, R 1 , R2 , R 3 , n and p are as defined above; R 4 is a spacer, R 4 is R 1 , R 2 and R 3 is different.

[0071] Often, the silyl-terminated telechelic polyurea has a structure according to formula (VI):

[0072] [ka]

[0073] In the formula, R 1 , R 2 , R 3 , R 5 , n, m and p are as defined above.

[0074] Often, the silyl-terminated telechelic polyurea has a structure according to formula (VII) or (VIII):

[0075] [ka]

[0076] In the formula, R 1 , R 2 , L, R 6 , R 7 , n and j are as defined above; R 8 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, each of which may be optionally substituted. Most typically, R 4 is hydrogen or C1-C5 alkyl, more typically hydrogen, methyl or ethyl, and most typically hydrogen.

[0077] Typically, the composition is a pressure sensitive adhesive (PSA). As will be understood by those skilled in the art, a pressure sensitive adhesive is a non-reactive adhesive that forms a physical bond to a surface when pressure is applied to it.

[0078] In many cases, the composition is substantially free of tackifiers. The term "substantially free" typically means that less than 5% by weight of the composition is tackifier. More typically, less than 3% by weight of the composition is tackifier, often less than 2%, and most often less than 1%. Usually, there is no tackifier present. The term "tackifier" is intended to describe a composition that modifies the tack of the composition, typically imparting improved adhesive properties to the composition. Tackifiers typically do not have the same function as the polymers of the present invention. In the present invention, the adhesive properties of the crosslinked polymer alone are sufficient for various PSA applications. Thus, no additional tackifier is required. Typical tackifiers include tackifier resins. Examples of tackifier resins include, but are not limited to, phenol-modified terpene resins (typically polyterpenes), hydrocarbon resins (typically hydrocarbons having aromatic character, i.e., having one or more aromatic groups), rosin ester resins, modified rosin ester resins, and acrylic resins.

[0079] Additionally, the ability to eliminate adhesives and similar components means that more favorable process temperatures can be used. Additionally, the presence of less material in the composition results in a cleaner profile of leachable compounds (such as drugs) because there is less material that can be leached out.

[0080] Typically, the pre-cured composition has a viscosity (measured at 80° C.) in the range of 1,000 to 55,000 cP, typically 6,000 to 40,000 cP, and even more typically 8,000 to 35,000 cP. In some embodiments, the viscosity of the composition may be lower than that of the silyl-containing non-crosslinked polyurea.

[0081] Moreover, typically, the composition is substantially free of plasticizers. That is, other types of additives can be used. Additional additives can be incorporated into the composition as known to those skilled in the art, such as penetration enhancers (i.e., species that regulate the ability of drugs to move across the skin barrier), pH adjusters, and surfactants, provided that these additional components do not interfere with the drug delivery or adhesive properties of the composition. Typical examples of penetration enhancers include, but are not limited to, propylene glycol, diethylene glycol ethyl ether, dimethyl sulfoxide, ethanol, octadecanol, and combinations thereof.

[0082] In some aspects, the composition is substantially free of antioxidants.

[0083] In a further aspect of the invention, there is provided a transdermal drug delivery patch containing the composition of the second aspect of the invention, the composition comprising one or more drugs suitable for transdermal drug delivery. The inventors have found that these compositions function well as reservoirs and delivery vehicles for transdermally deliverable drugs, and provide excellent adhesive properties.

[0084] The term "drug" as used in the present invention is intended to refer to a biologically active substance. The type of compound from which the drug is produced is not particularly limited. The drugs used in the present invention are typically small molecule drugs. However, larger molecules and macromolecules are also contemplated, including biological substances such as peptides and proteins. The term "drug" is also intended to include pharma- ceutically acceptable salts of biologically active substances. It is further contemplated that the drug may provide a physical effect on the body, such as heating or cooling, which may have a therapeutic effect. The term "drug" is also intended to include compounds useful for health, such as vitamins, functional foods, menthol, capsaicin, cannabidiol (CBD), etc. Such compounds are useful for maintaining health, not necessarily treating the disease itself.

[0085] The term "small molecule drug" is intended to encompass compounds that are typically produced by synthetic chemical processes having a molecular weight of less than 1000 Da, more typically less than 700 Da, and most typically less than 500 Da.

[0086] Typically, the patch comprises: a substrate, a layer of the composition according to the second aspect of the present invention applied to the substrate, the composition comprising one or more drugs for transdermal drug delivery. The substrate typically has a non-adhesive surface, which allows the user to handle the patch. Typically, the substrate is a backing liner. As will be understood by those skilled in the art, the backing liner is a layer of material to which the active ingredients of the patch are applied. In the present case, the backing liner provides a non-adhesive surface that allows the patch to be handled. Typically, the backing liner is substantially non-porous, i.e., it prevents ingredients from the composition from leaching through the backing layer. The backing liner can provide structural support to the patch, thereby ensuring that the patch retains its shape or at least resists excessive structural deformation. However, non-porous backing liners are also envisaged, and in some embodiments, it is advantageous for the backing liner to be made of a flexible material, such as a stretchable fabric.

[0087] Typically, the patch comprises a backing liner, a release liner, and a layer of the composition according to the second aspect of the present invention, the composition containing one or more drugs suitable for transdermal drug delivery. As will be understood by those skilled in the art, the release liner is a layer of material that sandwiches the active ingredients of the patch between itself and the backing liner. The release liner also has a non-adhesive surface, allowing the patch to be easily handled before use. The release liner is typically formed of a material that can be cleanly peeled away from the working layer of the patch, leaving the adhesive working layer exposed for attachment to the user. Thus, the adhesive quality of the release liner is typically low, thereby ensuring easy removal, but sufficient to hold the layer in place before use. The backing liner and the release liner are adjacent to the layer of the composition, although one or more intermediate sheets of material may be placed between the backing liner and the layer of the composition and / or between the release liner and the layer of the composition. In most cases, however, the backing liner and the release liner are directly adjacent to the layer of the composition. There is no particular method or order for assembling the patch. In many cases, however, the composition is provided on a release liner which is subsequently attached to a backing liner.

[0088] There are no particular limitations regarding the choice of drugs that may be included in the patch of the present invention. However, typically, the drugs used are hydrophobic. Typical examples of hydrophobic drugs include apomorphine, artemisinin, artesunate, aspirin, azathioprine, azelastine, bisoprole, buprenorphine, kallitrol, calciferol, cannabinoids, capsaicin, carbamazepine, cetirizine, chlorhexidine, clobetasone butyrate, clonidine, clotrimazole, cyclosporine, desloratadine, dexamethasone, diflucortolone valerate, diclofenac epolamine, ergotamine, donepezil, β-estradiol, fenbufen, fentanyl, flurbiprofen, gestode. , hydrocortisone, ibuprofen, indomethacin, iodine, ivermectin, ketoprofen, lamotrigine, levomenthol, levonorgestrel, loratadine, melatonin, naproxen, norelgestromin, norethisterone, penicillin, piroxicam, pramipexole, praziquantel, prednisolone prilocaine, progesterone, propylthiouracil, quinidine, risperidone, salbutamol, methyl salicylate, salsalate, saquinavir, simvastatin, teriparadtide, testosterone, tetrabenazine, triamcinolone, trimethoprim, and varenicline.

[0089] Alternatively, the drug may be hydrophilic. Typical examples of hydrophilic drugs include: acyclovir, allopurinol, amoxicillin, caffeine, ceftriaxone, cisplatin, cyclophosphamide, dopamine, dopamine hydrochloride, doxycycline, fluoxetine, fluorouracil, gabapentin, gentamicin, lamivudine, lidocaine, methotrexate, nicotine, nystatin, paracetamol, penicillamine, silver nitrate, sufentanil citrate, temozolomide, tetracycline, and triamcinolone. In one embodiment, the drug may be lidocaine. It is also envisaged that the drug contains one or more cannabinoids.

[0090] The drug is typically present in the composition in an amount of from 0.1% to 40% by weight of the composition, more typically from 1% to 35% by weight of the composition, even more typically from 5% to 30% by weight of the composition, more typically from 8 to 20% by weight of the composition, even more typically from 10 to 15% by weight of the composition, and often about 12.5% ​​of the composition.

[0091] In an embodiment of the present invention, a pressure sensitive adhesive is provided that contains the composition according to the first embodiment of the present invention. While one preferred embodiment relates to transdermal drug delivery, the composition according to the second embodiment of the present invention is useful as a pressure sensitive adhesive by itself. Thus, the composition according to the second embodiment of the present invention can be used in a wide variety of applications that require a PSA. Typical applications include, but are not limited to, glues, labels, tapes, protective films, medical devices (e.g., EKG monitors and wound dressings), skin patches, i.e., patches that may not contain an active agent (but may contain agents designed to provide various physical effects, such as a heating or cooling sensation), notepads, automotive trim, and the like.

[0092] In a further aspect of the present invention, a method of treating a disease is provided, which comprises applying to a user a patch according to the third aspect of the present invention. There is no particular limitation on the type of disease that can be treated using this method. The only limitation would be that the drug used to treat the particular disease would be effective when applied to the skin. Typical applications for the compositions of the present invention include treating diseases selected from the following: pain relief, high blood pressure, addiction, e.g. nicotine addiction, hormonal imbalance, cancer, e.g. skin cancer, bacterial, viral or fungal infections, Alzheimer's disease, mood disorders, Parkinson's disease, metabolic diseases, tissue scarring, or combinations thereof.

[0093] Additionally, the methods of treatment of the present invention may be for the delivery of a vaccine and / or for improving wound healing.

[0094] Further provided in the present invention is a composition or patch for use in treatment.Typically, the diseases that can be treated with the composition or patch of the present invention are: analgesia, hypertension, addiction, such as nicotine addiction, hormonal imbalance, cancer, such as skin cancer, bacterial, viral or fungal infections, Alzheimer's disease, mood disorders, Parkinson's disease, metabolic diseases, tissue scarring, or combinations thereof.Most typically, the composition and patch of the present invention are for use in the treatment of analgesia.Furthermore, the composition and patch of the present invention can also be used as a means of delivering vaccines and / or as a means of improving wound healing.

[0095] Numerical values ​​provided in this disclosure are intended to be modified by the term "about." Moreover, the disclosure of a range is intended to disclose that range, specific values ​​between the upper and lower limits of that range, and specifically integers between the upper and lower limits.

[0096] Furthermore, even if a feature is described as being "included" in the invention, any feature described in the present disclosure can also be envisaged as the invention "consists of" or "consists essentially of" that feature. [Brief description of the drawings]

[0097] Description of the drawings

[0098] FIG. 1 shows the permeation of cannabidiol (CBD) through a synthetic membrane (Strat-M) from formulations F14 and F3 with cannabidiol.

[0099] FIG. 2 shows the permeation of varenicline through human skin from formulations F14 and F4 with varenicline.

[0100] FIG. 3 shows the % strain at the storage modulus G′ plateau for various compositions according to the invention.

[0101] FIG. 4 shows G′, G″ at different angular frequencies for the exemplary composition (D5.2) at 9922 (130 μm) and 9942 (50 μm) thicknesses.

[0102] FIG. 5 shows G′, G″ at different angular frequencies for the exemplary composition (D5.3) at 9942 (50 μm) and 9922 (130 μm) thicknesses.

[0103] FIG. 6 shows the viscosities for various polymer compositions.

[0104] FIG. 7 shows frequency sweep experiments at steady strain (%) γ=1.0% (25° C.) for various polymers at a thickness of 9942 (50 μm).

[0105] FIG. 8 shows the change in tan δ during the frequency sweep experiment.

[0106] Figure 9 shows a frequency sweep comparison between the D5.0, D5.2 and D5.4 compositions, highlighting the various G' and G'' trends at high angular frequencies. The experiments were performed at a steady strain (%) γ = 1.0% (25°C).

[0107] Figure 10 shows the G' values ​​at low and high angular frequencies for various compositions. G' at low frequencies indicates adhesion and high frequencies indicate the debonding process.

[0108] FIG. 11 shows the effect of temperature on a frequency sweep experiment.

[0109] FIG. 12 shows a rheological comparison of compositions formed from different molecular weight starting materials.

[0110] 13(a) and (b) show a comparison of the viscoelastic window of various compositions at 25° C. and frequencies of 0.01 rad / s (a) and 0.05 rad / s (b) against the Chang viscoelastic window for the adhesive, shown as a black line. The dotted line corresponds to the Dahlquist criterion.

[0111] FIG. 14 shows the results of the rolling ball tack test for various S-PURE deformation embodiments.

[0112] FIG. 15 shows the results of 90° peel testing for various compositions of the present invention. EXAMPLES

[0113] Scheme 1 shows an exemplary embodiment of the method for preparing the polymer according to the present invention. Diisocyanate is added to polyether diamine in a stepwise manner in step (i) so that only the first diamine intermediate is formed. This intermediate can then be reacted again in step (ii) with additional diisocyanate, again in a stepwise manner, so that only the second intermediate is produced. Step (ii) can be carried out repeatedly, where each time the diamine product of the previous step serves as the starting material to which diisocyanate is added. In this way, the value k is theoretically increased by 2+1 each time step (ii) is repeated. In other words, if the starting k value is k1 and the new k value is k2, then k2 is approximately equal to 2k1+1. If k is too large, i.e., for example, about 100 or 150, this is undesirable, because in many cases the polymer will have too much viscosity and cannot be practically used. The total amount of diisocyanate added in each step is reduced by about half each time because the number of moles of intermediate is reduced each time as precursor diamine from the previous step is incorporated into the structure of the subsequent diamine.

[0114] Finally, in step (iii), polymer elongation is terminated via the addition of trimethoxysilyl isocyanate. Scheme 1 illustrates the process using poly(propylene glycol) diamine, toluene diisocyanate, and trimethoxysilylpropyl isocyanate.

[0115] [ka]

[0116] As seen in scheme 1, the polyurea of ​​the present invention is synthesized in various steps. The adhesive properties of different versions of PSA were compared by two adhesion tests, 90° peel and loop tack. The polymer of the present invention was compared with existing polymer patch technology that requires adhesive in the formulation. The results are shown in the table below.

[0117] [ka]

[0118] The process shown in scheme 2 is an alternative method, in which a diamine is added to a diisocyanate. The same exemplary reagent as in step (i) of scheme 1 was used in step (iv). However, in step (v), an ethyl group was introduced into the polymer structure using ethylenediamine monomer. The resulting diisocyanate is then reacted in step (vi) with an additional amount of the diamine from step (iv) in multiple stepwise additions. The number of stepwise additions carried out in step (vi) determines the number-average integer value q. Finally, the polymer extension was terminated using trimethoxysilylpropylamine.

[0119] Example 1 - Preparation of Silyl Terminated Polyurea To a vessel of 4707.67 g of polyetheramine (Jeffamine D-4000™, polyoxypropylene diamine) was added 124.26 g of isophorone diisocyanate while stirring at a temperature of 75°. The solution was continuously mixed and sampled to monitor the -NCO bond concentration until it was no longer detectable. When no further isocyanate was detected, the process was repeated by adding an additional 59.02 g of isophorone diisocyanate and allowed to react until no further isocyanate was detected. This process was repeated two more times, with 28.04 g and 13.32 g of isophorone diisocyanate in each subsequent step. When all of the diisocyanate had reacted, 64.86 g of 3-isocyanatopropyltrimethoxysilane was added to the reaction vessel and allowed to react to form the silyl terminated polyurea. 2.83 g of (3-aminopropyl)trimethoxysilane was added to react with any remaining isocyanate species.

[0120] For comparison, Table 1 shows polymer compositions in which silyl-terminated polyureas were formed in the manner described above, but without excess polyetheramine, and using only a single addition of isophorone diisocyanate.

[0121] The percent molar excess of the first reagent compared to the second reagent is calculated using the following formula: The equation for the single addition of isophorone diisocyanate or for the first step of each isophorone diisocyanate addition is:

[0122] [ka]

[0123] For the remaining steps, where necessary, the moles of isophorone diisocyanate are calculated as follows:

[0124] [ka]

[0125] In the formula, m ポリエーテルアミン is the mass of polyetheramine added to the vessel, A T is the total amine content of the polyetheramine used, as provided in the material certificate of analysis.

[0126] Example 2 - Preparation of adhesive composition (F1) without adhesive 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 as a 130 micron thin film on a PET substrate by passing under a heated blade. The film was kept in a humid atmosphere with a relative humidity of greater than 50% at a temperature of 80° C. for 6 minutes. The thin layer of liquid polyurea was crosslinked into the form of a pressure-sensitive adhesive.

[0127] Example 3 - Preparation of adhesive composition with pressure-sensitive adhesive (F2) A container with 19.8 g of Arakawa KE311 adhesive resin was heated to 120° C. under a nitrogen atmosphere. 79.2 g of the silyl-terminated polyurea of ​​Example 1 was added to the heated resin and stirred at 120° C. for 3 hours until the mixture was homogenous. The container was then cooled to 80° C., 1 g of titanium (IV) butoxide was added, and the solution was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% at a temperature of 80° C. for 6 minutes. The thin layer of liquid polyurea was crosslinked into the form of a pressure-sensitive adhesive.

[0128] Example 4 - Preparation of adhesive composition with pressure sensitive adhesive (F3) A container with 39.6 g of Arakawa KE311 adhesive resin was heated to 120° C. under a nitrogen atmosphere. 59.4 g of the silyl-terminated polyurea of ​​Example 1 was added to the heated resin and stirred at 120° C. for 3 hours until the mixture was homogenous. The container was then cooled to 80° C., 1 g of titanium (IV) butoxide was added, and the solution was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% at a temperature of 80° C. for 6 minutes. The thin layer of liquid polyurea was crosslinked into the form of a pressure-sensitive adhesive.

[0129] Example 5 - Preparation of adhesive composition with pressure-sensitive adhesive (F4) A container with 49.5 g of Arakawa KE311 adhesive resin was heated to 120° C. under a nitrogen atmosphere. 49.5 g of the silyl-terminated polyurea of ​​Example 1 was added to the heated resin and stirred at 120° C. for 3 hours until the mixture was homogenous. The container was then cooled to 80° C., 1 g of titanium (IV) butoxide was added, and the solution was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% at a temperature of 80° C. for 6 minutes. The thin layer of liquid polyurea was crosslinked into the form of a pressure-sensitive adhesive.

[0130] 20 minute 90° peel test on stainless steel plate: The adhesive strength is evaluated by a 180° peel test on a stainless steel plate as described in FINAT Method No. 1 published in the FINAT Technical Manual, 6th Edition, 2001. FINAT is the International Union for Manufacturers and Converters of Self-Adhesive Labels. The principle of this test is presented below.

[0131] Test specimens in the form of rectangular strips (25 mm x 175 mm) were cut out from the PET carrier coated with the cured composition obtained above. After its preparation, the test specimens were stored for 24 hours at a temperature of 23°C and in an atmosphere of 50% relative humidity. They were then fixed over 2 / 3 of their length to a substrate consisting of a stainless steel plate. The assembly obtained was left to stand at room temperature for 20 minutes. It was then placed in a tensile testing machine, which, starting from the end of the rectangular strip that was left as a free end, was able to peel or debond the strip at an angle of 90° and with a separation speed of 300 mm / min. The machine measured the force required for the strip to be debonded under these conditions.

[0132] Loop Tack Test Test specimens in the form of rectangular strips (25 mm x 175 mm) were cut out from the PET carrier coated with the cured composition obtained above. After its preparation, the test specimens were stored for 24 hours at a temperature of 23°C and in an atmosphere of 50% relative humidity. The two ends of the strip were joined, thereby forming a loop, with its adhesive surface facing outwards. The two joined ends were placed in the movable jaws of a tensile testing machine, which can impose a displacement speed of 300 mm / min along the vertical axis and can move back and forth. The lower part of the loop, placed in a vertical position, was first brought into contact with a horizontal glass plate of 25 mm x 30 mm over a square area of ​​about 25 mm per side. After this contact had occurred, the displacement direction of the jaws was reversed. The tack was the maximum force required for the loop to completely debond from the plate.

[0133] Rolling ball tack test The adhesion of the patches was determined using a ChemInstruments RBT-100 lamp conforming to the PSTC-6 test method standard. A ball bearing was used as the test substrate. Samples were cut to provide a 150mm x 25mm test area and the distance the ball traveled along the strip was recorded. The average of 3 measurements (n=3) was accepted as a statistically strong adhesion value.

[0134] viscosity The viscosity of the compositions was determined using a Brookfield Viscometer using spindle number 27 and a Thermosel. The compositions at 80° C. were added to a preheated crucible. Each measurement required 10.5 g. Measurements were recorded by the instrument every minute for 10 minutes. The test was repeated until a consistent result was observed. The average of these 10 consistent results was reported as the viscosity value for the measured batch.

[0135] Rheological analysis Rheological analyses were performed on an Anton Parr MCR 302 rheometer in a parallel plate configuration (25 mm diameter) at 25°C. For all oscillatory sweep experiments, 25 mm diameter cured adhesive disks were used. Amplitude sweep measurements were performed at a steady angular frequency ω = 10 rad / s with a strain (%) range γ = 0.01-710%. Frequency sweep experiments were performed at an angular frequency range ω = 0.5-100 rad / s and a steady strain (%) γ = 1.0%. The average of at least three measurements (n = 3) was accepted as a statistically robust run.

[0136] [Table 1]

[0137] F4-F9 were unstable, i.e. phase separation occurred after 1 week of storage at room temperature.

[0138] Example 6 - Formulations prepared with various additives Formulation F10 is a silyl-terminated polyurea prepared according to Example 1, but without additional diisocyanate. Formulations F11-F15 are compositions in which various amounts of isophorone diisocyanate were added to the reaction, thereby resulting in different molar excesses of primary amine to isocyanate. Adhesive films were formed in the same manner as in Example 2.

[0139] [Table 2]

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

[0141] [Table 3]

[0142] As can be seen from the data above, the rate at which the diisocyanate is added to the amine-containing reactor affects the release, tack, and viscosity of the resulting adhesive.

[0143] [Table 4]

[0144] As shown by the data in Table 4, the compositions of the present invention provide adhesion comparable to many existing transdermal drug patches, without the need for adhesives.

[0145] Since one of the primary applications of this novel adhesive is in the manufacture of transdermal patches, the permeation of a simulated drug through a human skin imitation membrane (Strat-M) was investigated. The permeation rates of cannabidiol patches made with two different adhesive types (with and without adhesive) were compared. As can be seen in Figures 1 and 2, removing the adhesive from the adhesive formulation did not affect the permeation of the drug through the human skin imitation membrane.

[0146] Example 7 - Silyl Terminated Polyurea (F14 with Cannabidiol) 5g of cannabidiol, 2g of titanium (IV) butoxide, 12g of diethylene glycol monoethyl ether, 3g of octadecanol were added to a vessel containing 78g of silyl-terminated polyurea. The mixture was homogenized by stirring at 120 rpm for 30 minutes at 80°C. After homogenization, the mixture was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% at a temperature of 80°C for 5 minutes. The film of the liquid mixture was crosslinked into a pressure-sensitive adhesive containing cannabidiol with additives.

[0147] Example 8 - Silyl Terminated Polyurea with Adhesive (F3 with Cannabidiol) A vessel containing 46.8 g of hydrogenated rosin ester (Arakawa KE311) adhesive resin and 31.2 g of silyl-terminated polyurea was heated to 120° C. in a nitrogen atmosphere. The mixture was homogenized 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, and 3 g of octadecanol were added to a vessel containing 78 g of homogenized silyl-terminated polyurea and Arakawa KE311 adhesive resin. The mixture was homogenized by stirring at 120 rpm at 80° C. for 30 minutes. After homogenization, the mixture was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a high humidity atmosphere with a relative humidity of more than 50% for 5 minutes at a temperature of 80° C. A film of the liquid mixture was crosslinked into a pressure sensitive adhesive containing cannabidiol along with additives.

[0148] Example 9 - Permeation experiments on synthetic membranes 0.5cm 2Sample disks were cut from the parent roll of the formulation and attached to a Strat-M™ membrane. The resulting test samples were placed in a diffusion cell (Franz cell) to measure the amount of cannabidiol that permeated through the Strat-M™ membrane over a 24 hour period. The receptor solution and diffusion cell were kept at 36° C. Receptor solution samples were taken from the diffusion cell at regular intervals and analyzed on an HPLC instrument using a validated method. See FIG. 1.

[0149] Example 10 - Silyl Terminated Polyurea (F14 with Varenicline) 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, and 0.5 g of dimethyl sulfoxide were added to a vessel containing 8.35 g of silyl-terminated polyurea. The mixture was homogenized by stirring at 80° C. and 120 rpm for 30 minutes. After homogenization, the mixture was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% at a temperature of 80° C. for 5 minutes. The film of the liquid mixture was crosslinked into the form of a pressure-sensitive adhesive containing varenicline with additives.

[0150] Example 11 - Silyl Terminated Polyurea with Adhesive (F4 with Varenicline) A vessel containing 4.175 g of hydrogenated rosin ester (Arakawa KE311) adhesive resin and 4.175 g of silyl-terminated polyurea was heated to 120° C. under a nitrogen atmosphere. The mixture was homogenized 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, and 0.5 g of dimethyl sulfoxide were added to the vessel containing 8.35 g of silyl-terminated polyurea. The hydrogenated rosin ester (Arakawa KE311) adhesive resin was added to the vessel now containing 8.35 g of homogenized silyl-terminated polyurea. The mixture was homogenized by stirring at 120 rpm for 30 minutes at 80° C. After being homogenized, the mixture was cast as a 130 micron thin film on a PET substrate by passing it under a heated blade. The film was kept in a humid atmosphere with a relative humidity of more than 50% for 5 minutes at a temperature of 80° C. The film of the liquid mixture was crosslinked into the form of a pressure sensitive adhesive containing varenicline along with additives.

[0151] Example 12 - Permeation studies in human skin 0.5cm 2 Sample disks were cut from the above formulation mother roll and attached to 750 μm human skin. The resulting test samples were placed in a diffusion cell (Franz cell) to measure the amount of varenicline that permeated through human skin over a period of 24 hours. The receptor solution and diffusion cell were kept at 36° C. Receptor solution samples were taken from the diffusion cell at regular intervals and analyzed on an HPLC instrument using a validated method. See FIG. 2.

[0152] Example 13 - S-PURE synthesis Additional adhesive compositions according to the present invention were prepared as described below: S-PURE is the trade name for the adhesive of the present invention.

[0153] Synthesis of S-PURE D5.0 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv) was added using a metering pump at a flow rate of 20 mL / min, with the addition taking between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. IPTMS (235.79 g, 1.19 mol, 0.99 equiv) was then added in bulk using a syringe and the reaction was allowed to proceed for 20 minutes from the addition of IPTMS. Finally, APTMS (10.30 g, 0.06 mol, 0.05 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0154] Synthesis of S-PURE D5.1 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. A second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv) was then made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react for 15 minutes from the addition of IPDI. Then IPTMS (134.45 g, 0.70 mol, 0.59 equiv.) was added in bulk via syringe 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 equiv.) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0155] Synthesis of S-PURE D5.2 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv.) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv.) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv.) was made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 equiv) was then made at a flow rate of 5.2 mL / min with the addition occurring between 4 and 6 min. The mixture was allowed to react with the entire process taking 15 min from the addition of IPDI. IPTMS (86.32 g, 0.47 mol, 0.40 equiv) was then added in bulk via syringe 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 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0156] Synthesis of S-PURE D5.3 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv) was made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 equiv) was then made at a flow rate of 5.2 mL / min with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 equiv) was then made at a flow rate of 2.5 mL / min with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. IPTMS (63.46 g, 0.35 mol, 0.30 equiv) was then added in bulk using a syringe and the reaction was allowed to proceed for 20 minutes from the addition of IPTMS. Finally, APTMS (2.77 g, 0.01 mol, 0.01 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0157] Synthesis of S-PURE D5.4 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv) was made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 equiv) was then made at a flow rate of 5.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 equiv) was then made at a flow rate of 2.5 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fifth addition of IPDI (6.19 g, 0.03 mol, 0.03 equiv) was then made at a flow rate of 1.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. Then IPTMS (52.60 g, 0.30 mol, 0.25 equiv.) was added in bulk via syringe 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 equiv.) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0158] Synthesis of S-PURE D5.5 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv.) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv.) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv.) was made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 equiv) was then made at a flow rate of 5.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 equiv) was then made at a flow rate of 2.5 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fifth addition of IPDI (6.19 g, 0.03 mol, 0.03 equiv) was then made at a flow rate of 1.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A sixth addition of IPDI (2.94 g, 0.01 mol, 0.01 equiv) was then added at a flow rate of 0.6 mL / min with the addition occurring between 4 and 6 min. The mixture was allowed to react with the entire process taking 15 min from the addition of IPDI. IPTMS (47.44 g, 0.28 mol, 0.24 equiv) was then added in bulk via syringe 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 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS.The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0159] Synthesis of S-PURE D5.6 Jeffamine D-4000™ (amine content: 0.49, 4700 g, 1.18 mol, 1 equiv.) was charged into the reaction vessel and heated to 85±2° C. under dry nitrogen with an initial stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (121.58 g, 0.55 mol, 0.47 equiv.) was added using a metering pump at a flow rate of 20 mL / min such that the addition took place between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. Then, a second addition of IPDI (57.75 g, 0.26 mol, 0.22 equiv.) was made at a flow rate of 11 mL / min such that the addition took place between 4 and 6 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the addition of IPDI. A third addition of IPDI (27.43 g, 0.12 mol, 0.10 equiv) was then made at a flow rate of 5.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total process time of 15 minutes from the addition of IPDI. A fourth addition of IPDI (13.03 g, 0.06 mol, 0.05 equiv) was then made at a flow rate of 2.5 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total process time of 15 minutes from the addition of IPDI. A fifth addition of IPDI (3.09 g, 0.01 mol, 0.01 equiv) was then made at a flow rate of 0.6 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total process time of 15 minutes from the addition of IPDI. Then IPTMS (58.04 g, 0.33 mol, 0.28 equiv) was added in bulk via syringe 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 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0160] Synthesis of S-PURE D6.2A - Comparison A 90:20 molar mixture 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 into a reaction vessel and heated to 85° C.±2° C. under dry nitrogen at a stirring rate of 120 rpm. After the required temperature was reached, the stirring rate was increased to 180 rpm and IPDI (128.28 g, 0.72 mol, 0.58 equivalents, based on total moles of poly(ether amine)) was added using a metering pump at a flow rate of 20 mL / min such that the addition took between 5 and 7 minutes. The mixture was allowed to react such that the entire process took 15 minutes from the start of the IPDI addition. A second addition of IPDI (60.93 g, 0.34 mol, 0.27 eq., based on total moles of poly(etheramine)) was then made at a flow rate of 11 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A third addition of IPDI (28.94 g, 0.16 mol, 0.13 eq., based on total moles of poly(etheramine)) was then made at a flow rate of 5.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total period of 15 minutes from the addition of IPDI. A fourth addition of IPDI (13.75 g, 0.08 mol, 0.06 eq., based on total moles of poly(etheramine)) was then made at a flow rate of 2.5 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total of 15 minutes from the addition of IPDI, and a fifth addition of IPDI (6.53 g, 0.04 mol, 0.03 eq., based on total moles of poly(etheramine)) was added at a flow rate of 1.2 mL / min, with the addition occurring between 4 and 6 minutes. The mixture was allowed to react for a total of 15 minutes from the addition of IPDI, and IPTMS (55.50 g, 0.27 mol, 0.22 eq., based on total moles of poly(etheramine)) was added in bulk via syringe, and the reaction was allowed to proceed for 20 minutes from the addition of IPTMS.Finally, APTMS (2.42 g, 0.01 mol, 0.01 equiv) was added in bulk via syringe and the reaction was again allowed to proceed for 20 min from the addition of APTMS. The final product was analyzed by FT-IR to confirm the absence of residual isocyanate groups and stored under a nitrogen blanket.

[0161] The various compositions and ratios of D4000:IPDI are summarized below.

[0162] [Table 5]

[0163] Table 5: Conditions for preparing S-PURE adhesive composition

[0164] Example 14 - Preparation of Adhesive Patches Titanium (IV) butoxide catalyst (1%) was added to a representative amount of the S-PURE composition above, and the resulting mixture was spread using a K-bar at 80° C. with a RK K-Control coater set. The resulting patch was subjected to 1.5 minutes of flow and an additional 3.5 minutes of heating to induce cure of the prepolymer. Cure was evaluated after a total time of 5 minutes.

[0165] Example 15 - Amplitude Sweep Experiment The table below shows the strain (%) range (>30%) at the storage modulus (G´) plateau. At high strains (%), slippage of the samples was observed and it was not possible to measure the viscoelastic properties further. The results are shown in Figure 3 and reported in Table 6 below.

[0166] [Table 6]

[0167] The effect of patch thickness was investigated at 9922 (130 μm) > 9942 (50 μm). Frequency sweep experiments were performed at a steady strain (%) γ = 1.0% (determined by the LVER region found previously). As expected, the results show that an increase in thickness results in a higher G', indicating a harder and more elastic material. Despite the difference in thickness, the samples show similar viscoelastic profiles up to ω = 100 rad / s, with values ​​of G' being nearly similar to those of G''. The continuous increase in G' values ​​appears due to the increasing frequency of deformation, which is attributed to the presence of polymer entanglements. The results for S-PURE D5.2 and D5.3 formulations are shown in Figures 4 and 5, respectively.

[0168] The effect of different average intercrosslink molecular weights (Mc) was investigated by analyzing formulations made from polymers with different molecular weights. First, a viscometer was used to evaluate the differences in molecular weight. Polymers made from higher IPDI to Jeffamine™ D4000 ratios had longer polymer chains during the step-growth polymerization process, which resulted in higher average molecular weights and therefore higher viscosities. The results are shown in Figure 6.

[0169] Frequency sweep tests were performed on different S-PURE variants at a thickness of 9942 (50 μm). The results in FIG. 7 show that the S-PURE variants with higher molecular weight have lower G' values, which indicates a softer, more wettable, and therefore higher adhesive surface. In general, the average molecular weight of the polymer is expected to be similar to the average intercrosslink molecular weight (Mc), and an increase in this leads to a lower crosslink density. D5.0 showed a steady rheological profile, with the G' value reaching a plateau with increasing angular frequency. This is in contrast to the remaining formulations, where G' continues to increase with the frequency of displacement, a result of polymer entanglement and the higher average molecular weight. Furthermore, D5.5, which has a higher molecular weight, showed the lowest G' and G''. These values ​​cross over at a frequency of ∼1.1, where the adhesive turns into a viscous fluid and G'' continues to exceed G'. This was also shown by the values ​​of tan δ, which were >1 for D5.5 and relatively low <1 for the lower molecular weight S-PURE deformation forms, which exhibited relatively high viscoelastic type properties (FIG. 8).

[0170] The different trends of G' and G" at high angular frequencies are shown in Figure 9, where an increase in molecular weight brings the two values ​​closer to each other in a "parallel" manner, but does not cross over to change to a fluid-like state. A complete chart of G' values ​​at low angular frequencies (indicating adhesion) and high angular frequencies (indicating peeling) is shown in Figure 10.

[0171] The effect of temperature was also investigated for the D.5.3 9942 samples by comparing their root viscoelastic behavior at 25°C and 37°C. The results are shown in Figure 11. An increase in temperature can affect the viscoelastic properties by lowering both the G' and G'' values. Despite the increase in temperature, the viscoelastic profile remains the same and at high angular frequencies G' approaches and does not cross G'', indicating that the covalent crosslink network is not destroyed at the experimental frequencies. The decrease in G' with increasing temperature is attributed to the relatively large free volume of the polymer chains, which gives them a relatively high mobility along with the thermal breaking of the hydrogen bonds.

[0172] Finally, an S-PURE formulation containing a mixture of Jeffamine D-4000™ and Jeffamine D-2000™ (D6.2A) was compared to one containing Jeffamine™ D4000 (D5.2) at the same thickness (9942). Frequency sweep results showed that D6.2 had better adhesion as a result of more urea moieties per chain. At high angular frequencies, the G' value of D6.2A was higher, indicating a higher peel strength than D5.2.

[0173] The summarized results are shown in Tables 7 and 8 below.

[0174] [Table 7]

[0175] [Table 8]

[0176] Based on the values ​​of G' and G'', the viscoelastic window was achieved at 0.01 and 0.05 rad / s (Figures 13(a) and (b)). The following coordinates were used for the viscoelastic window: 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 evaluate the adhesive type, the viscoelastic window was compared against the Chang viscoelastic window and the Dahlquist criterion for good adhesion. The frequency of 0.5 rad / s is equal to the displacement that the adhesive undergoes on the skin.

[0177] According to Figures 13(a) and (b), all S-PURE variants meet the Dahlquist criteria for a good PSA and have good contact efficiency. Surprisingly, with increasing molecular weight (5.0 => 5.5), the viscoelastic window shifts to the lower left quadrant 3, which is characteristic of removable PSAs for medical applications and is characterized by low G', most of which are beyond the Chang window.

[0178] Adhesion and rolling ball tack tests for the S-PURE compositions were evaluated and are shown below in Table 9 and in Figures 14 and 15.

[0179] [Table 9]

[0180] The force required to peel the patch from the stainless steel surface increases with increasing amounts of IPDI added (D5.0 to D5.5). The results show that the 90° peel adhesion test can be used as a method to distinguish different S-PURE formulations. The average distance traveled by the ball after leaving the ramp decreases with increasing tack. The higher the amount of IPDI added, the more tacky the S-PURE becomes and the less distance the ball travels. However, the difference in tackiness between the S-PURE variants was not large enough to allow this parameter to be used to distinguish between the S-PURE variants.

Claims

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

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

3. 3. The adhesive composition of claim 1 or 2, wherein the adhesive composition has a tan delta at 25°C of 0.90 to 1.10 at at least one frequency between 0.01 and 100 rad / s, and wherein the tan delta does not exceed 1.10 for all frequencies between 0.01 rad / s and 100 rad / s.

4. 3. The adhesive composition of claim 1 or 2, wherein the tan delta of the adhesive composition is from 0.95 to 1.05 at 25°C at at least one frequency between 0.01 and 100 rad / s, and wherein the tan delta does not exceed 1.05 for all frequencies between 0.01 rad / s and 100 rad / s.

5. The telechelic polyurea has the formula (IV): 【Chemical 1】 and having a structure according to During the ceremony, R １ is a polyether; R ２ and R ３ are each independently a spacer; n is an integer ranging from 1 to 100; m is an integer ranging from 0 to 1; p is an integer ranging from 0 to 10; and the sum of m and p is >0, The adhesive composition according to claim 1 or 2.

6. 6. The adhesive composition of claim 5, wherein the polyether has a weight average molecular weight in the range of 2000 Da to 10,000 Da, typically the polyether has a weight average molecular weight in the range of 2500 Da to 8000 Da, more typically the polyether has a weight average molecular weight in the range of 3000 Da to 6000 Da, and most typically the polyether has a weight average molecular weight in the range of 3500 Da to 5000 Da.

7. The adhesive composition of claim 5 , wherein the polyether is polyethylene glycol, polypropylene glycol, or a combination thereof.

8. The polyurea has formula (VII) or (VIII): 【Chemistry 2】 and having a structure according to During the ceremony, R １ is a polyether, R ２ is the spacer, L is a linker selected from alkyl, alkenyl, alkynyl, aryl, and heteroaryl, each of which is optionally substituted; R ６ is selected from alkyl, alkenyl, alkynyl, aryl, and heteroaryl, each of which is optionally substituted; R 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 ranging from 1 to 100, and j is an integer ranging from 0 to 2; The adhesive composition of claim 5.

9. 6. 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 or 2, wherein the composition does not contain a pressure-sensitive adhesive.

11. The adhesive composition of claim 1 or 2, wherein the adhesive composition is a pressure sensitive adhesive.

12. 1. An adhesive composition comprising a crosslinked silyl-containing telechelic polyurea, the crosslinked silyl-containing telechelic polyurea (a) reacting a first reagent with a second reagent to form a telechelic polyurea, wherein the first reagent comprises at least one polyether diamine or at least one polyether diisocyanate, and 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 and The adhesive composition, wherein the first reagent is provided in excess of the second reagent in the range of 2 mol % to less than 100 mol %.

13. 13. The adhesive composition of claim 12, wherein the first reagent is a polyether diamine and the second reagent is a diisocyanate.

14. 14. The adhesive composition of claim 12 or 13, wherein the diisocyanate is selected from aromatic diisocyanates, aliphatic diisocyanates, or combinations thereof.

15. 15. The adhesive composition of claim 14, wherein the diisocyanate is selected from isophorone diisocyanate, toluene diisocyanate, naphthalene diisocyanate, diphenylmethane diisocyanate, hexamethyl diisocyanate, bis-(4-cyclohexyl isocyanate), or combinations thereof.

16. 13. The adhesive composition of claim 12, wherein the first reagent is provided in excess relative to the second reagent in the range of 5 mol % to 90 mol %.

17. 17. The adhesive composition of claim 16, wherein the first reagent is provided in an excess of 10 mol % to 80 mol % relative to the second reagent.

18. 18. The adhesive composition of claim 17, wherein the first reagent is provided in an excess of 10 mol % to 30 mol % relative to the second reagent.

19. 20. The adhesive composition of claim 18, wherein the first reagent is provided in an excess of 15 mol % to 20 mol % relative to the second reagent.

20. 17. The adhesive composition of claim 16, wherein the first reagent is provided in an excess of 40 mol % to 60 mol % relative to the second reagent.

21. 14. The adhesive composition of claim 12 or 13, wherein the rate of addition of the first reagent to the second reagent is 10 mol % or less per minute.

22. 14. The adhesive composition of claim 12 or 13, wherein the second reagent is added to the first reagent in a series of steps.

23. 23. The method of claim 22, wherein the series of steps comprises in the range of 1 to 10 additions.

24. 23. The adhesive composition of claim 22, wherein the reaction is carried out in each step until substantially no additional second reagent is present.

25. 14. The adhesive composition according to claim 12 or 13, wherein the polyetherdiamine has a weight average molecular weight in the range of 2000 Da to 10,000 Da, typically the polyetherdiamine has a weight average molecular weight in the range of 2500 Da to 8000 Da, more typically the polyetherdiamine has a weight average molecular weight in the range of 3000 Da to 6000 Da, and most typically the polyetherdiamine has a weight average molecular weight in the range of 3500 Da to 5000 Da.

26. 14. The adhesive composition of claim 12 or 13, wherein the polyether diamine comprises poly(ethylene glycol), poly(propylene glycol), or a combination thereof.

27. 14. The adhesive composition of claim 12 or 13, wherein the method is carried out without the use of a solvent.

28. The adhesive composition according to claim 12 or 13, wherein the process temperature is in the range of 10°C to 100°C.

29. 14. The adhesive composition of claim 12 or 13, wherein the telechelic polyurea is moisture cured.

30. 1. A method for making a composition comprising a crosslinked telechelic polyurea, comprising: The method comprises: (a) reacting a first reagent with a second reagent to form a telechelic polyurea, wherein the first reagent comprises at least one polyether diamine or at least one polyether diisocyanate, and 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. The process includes the steps of: The method, wherein the first reagent is provided in excess relative to the second reagent in the range of 2 mol % to less than 100 mol %.

31. A transdermal drug delivery patch comprising the composition of claim 1 or 2, wherein the composition further comprises one or more drugs suitable for transdermal drug delivery.

32. A transdermal drug delivery patch comprising the composition of claim 1 or 2, wherein the composition further comprises one or more drugs suitable for transdermal drug delivery; The patch: a substrate; and 20. A layer of the composition of claim 19 applied to the substrate. and A transdermal drug delivery patch, wherein the composition comprises one or more drugs suitable for transdermal drug delivery.

33. A transdermal drug delivery patch comprising the composition of claim 1 or 2, wherein the composition further comprises one or more drugs suitable for transdermal drug delivery; Backing liner, a release liner, and A layer of the composition of claim 19. and A transdermal drug delivery patch, wherein the composition comprises one or more drugs suitable for transdermal drug delivery.

34. 32. The transdermal drug delivery patch of claim 31, wherein the drug is hydrophilic.

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

36. The transdermal drug delivery patch of claim 31, wherein the drug is selected from beta-estradiol, testosterone, progesterone, desloratadine, loratadine, and donepezil.

37. A transdermal drug delivery patch as described in claim 31 for hormonal imbalance and / or Alzheimer's disease.

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