RU2831467C2 - Plaster - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to compositions containing urea and amine functionalised silyl-containing polymers, which in combination with tackifying resins are used as pressure-sensitive adhesives and, more specifically, plasters for drug delivery. Disclosed is a composition for use for drug delivery to skin, which contains a cross-linked silyl-containing polymer and one or more drugs, wherein said polymer can be obtained by polymerising a first difunctional compound and a second difunctional compound, wherein the first and second difunctional compounds together contain a terminal amine group and a terminal isocyanate group, and where the first and second difunctional compounds have structures according to Formulas III and IV, respectively, or Formulas IIIa and IVa, respectively, where the silyl-containing group is provided on the ends of the silyl-containing polymer obtained by polymerising the first and second difunctional compounds; where said silyl-containing group has the structure Si(OR⁶)_p(R⁶)_3-p; where "p" is integer from 1 to 3, and each R⁶ is independently selected from C₁-C₁₀-alkyl or C₁-C₁₀-heteroalkyl group; and wherein said composition further comprises a tackifying resin. Also disclosed is an embodiment of said composition and a patch for transdermal drug delivery containing said composition. Disclosed compositions can be synthesized with less difficulty compared to urethane analogues and are compatible with a wide range of different drugs in the plaster system.

EFFECT: disclosed compositions are capable of not only preserving and transmitting active compounds to the skin, but also providing maximum efficacy of the delivered compounds for a certain period of time.

18 cl, 4 dwg, 5 tbl, 7 ex

Description

Field of technology

The present invention relates to compositions intended for use as adhesives and for transdermal drug delivery (more particularly to patches) in combination with one or more drugs intended for transdermal drug delivery, and to methods for producing these compositions.

Prior art

Transdermal drug delivery is a well-known method of administering drugs to a patient. This method is mainly recognized as different from injections because the drugs penetrate the skin barrier according to their solubility and size rather than using devices that facilitate their penetration through the dermis.

Transdermal drug delivery is often the preferred method of administering medications to patients, as many patients dislike more invasive procedures such as injections. Therefore, patient compliance and preference are usually higher with patch delivery methods. However, there are challenges associated with these technologies.

One of the problems associated with drug delivery patches is that they are often unable to adequately retain and transport the desired active agents onto, into and/or through the skin. This problem is less common with alternative transdermal delivery systems such as gel formulations. However, gel formulations are often difficult to apply and/or do not facilitate gradual diffusion of the active agents. Drugs contained in gels are rapidly transferred to the skin and therefore do not provide a long-term therapeutic effect. Also, when using gels, it is difficult to control the dosage of drugs.

Accordingly, it is desirable to provide a system, preferably a patch system, that is capable of not only storing and delivering active compounds to the skin, but also does so with a suitable diffusion profile over time to ensure maximum efficacy of the delivered compounds over a period of time. Ideally, the system should have good adhesion to the skin so that the system remains in place, but can be easily removed without causing significant discomfort, and without leaving residues on the skin.

Publication WO 2017077284 describes a transdermal drug delivery patch with excellent properties that overcomes the above-mentioned problems. However, this system has some disadvantages.

Firstly, the reaction between polyols and diisocyanates described in WO 2017077284 is a relatively slow process and therefore requires the use of catalysts, which may be undesirable in some commercial products and intended applications, even in small quantities.

Second, the temperatures required to achieve acceptable polymerization and curing reaction rates for these polymers (even in the presence of catalysts) are often high, increasing the costs of large-scale industrial production and creating the potential for thermal reaction and/or degradation of the drug and excipients.

It is therefore desirable to find a polymer composition that provides the said advantages, ideally without compromising the primary properties of the polymer, such as adhesion, and that these compositions are not incompatible with target applications, such as drug delivery (e.g. due to reduced drug storage capacity, etc.).

The present invention aims to overcome or at least alleviate the said problems.

The essence of the invention

In a first aspect of the present invention, there is provided a composition for use as a pressure-sensitive adhesive, which comprises: a silyl-containing polymer which can be obtained by polymerising a first difunctional compound and a second difunctional compound, wherein the first and second difunctional compounds together comprise a terminal amino group and a terminal isocyanate group, and wherein the composition further comprises a tackifying resin.

The present inventors have discovered that the incorporation of urea moieties into the polymer backbone of crosslinked silyl-containing polymers results in an increase in the rate of polymerization, allows the use of lower temperatures, and in many cases eliminates the need for a catalyst.

Accordingly, typically the first and second difunctional compounds are polymerized in the absence of a polymerization catalyst. As is known to those skilled in the art, although catalysts are often present in small amounts, residual amounts of catalyst in the reaction mixture can be problematic. This often occurs during polymerization reactions because the resulting polymers can sometimes trap material, making it difficult to filter out the remaining catalyst. Moreover, although only small amounts of catalyst are typically needed to provide satisfactory rate enhancement for many polymerization reactions, the presence of residual amounts of catalyst and/or catalyst-derived compounds (even in very small amounts) can render polymers containing residual amounts of catalyst unsuitable for certain commercial applications (particularly in the fields of pharmaceuticals and medical devices).

Although there is no particular limitation in the choice of polymerization catalysts, representative catalysts may include substances such as tin (which may include elemental tin and tin in various oxidation states) or 1,4-diazabicyclo[2.2.2]octane (DABCO; from English: 1,4-diazabicyclo[2.2.2]octane). Of these available catalysts, tin is commonly used in the processes according to the prior art, since it is an effective catalyst for many polymerization reactions and is relatively inexpensive. In the present invention, no catalyst is required, which simplifies the process.

The crosslinking of silyl-containing polymers described in this publication allows the polymers to form a network of covalently interconnected macromolecules, which improves their properties related to both adhesion and drug delivery. The silyl groups of adjacent molecules interact with each other under suitable conditions in the presence of moisture to form covalent bonds between the molecules. A catalyst is typically used in the crosslinking process, although there are no particular restrictions on the choice of catalyst.

As used in the context of the present invention, the term "difunctional" refers to the presence of two functional groups, preferably located at different ends of the connection. However, these groups may also be located at other points in the connection, provided that this does not hinder chain growth. As is known to those skilled in the art, amines react with isocyanates to form urea groups. Typically, one of the compounds used to prepare the polymer contains an isocyanate group, and the second contains an amino group. Both functional groups of the first or second difunctional compounds do not necessarily have to be amine or isocyanate. Other functional groups may be present in combination with the amine or isocyanate. Moreover, the term "difunctional" should not be understood as meaning only two groups. Additional groups may be provided.

When used in the context of the present invention, the terms "alkyl group", "heteroalkyl group", "cycloalkyl group", "alkenyl group", "heteroalkenyl group", "aryl group" and "heteroaryl group" have their art-specific meanings. However, provided that no adverse reactions occur that may hinder the polymerization or curing of the polymers described in this publication, it is possible to replace one or more hydrogen atoms with halogen atoms, such as fluorine.

Although it is possible that only one compound is used that contains both an amine group and an isocyanate group, typically the compound containing the isocyanate group is different from the compound containing the amino group, and therefore the first and second compounds may alternately contain the amino group and the isocyanate group.

It is often the case that one of the first or second difunctional compounds is polymeric and the other is monomeric. The polymeric compound can be modified and functionalized to meet the characteristics of a particular drug or a desired dosing regimen. This can include adding additional functionality to the structure (e.g., to increase hydrophilicity or increase rigidity) or changing the molecular weight of the polymeric compound to further modify its physical characteristics. Typically, the polymeric compound has a molecular weight in the range of from about 500 Daltons to about 10,000 Daltons, more typically from about 1,000 Daltons to about 8,000 Daltons, even more typically from about 1,500 Daltons to about 6,000 Daltons, and most typically from about 2,000 Daltons to about 4,000 Daltons. Most typically, this polymer group is a polyether, a polyester, a polythioether, a polycarbonate, or combinations thereof. It is often a polyether such as polyethylene glycol or polypropylene glycol.

Typically, the first or second difunctional compound containing the amine is polymeric, and therefore often the first or second compound containing the isocyanate group is monomeric.

Although each of the difunctional compound containing an amine group and the difunctional compound containing an isocyanate group may contain another group that contributes to the extension of the polymer chain (i.e., not an amine group and not an isocyanate group, respectively), typically the difunctional compound containing an isocyanate group is a diisocyanate, i.e., both groups that contribute to the extension of the chain are isocyanate. One of the two functional groups may be an electrophilic group similar to an isocyanate, but this is less common than the use of a diisocyanate. Additionally, the difunctional compound containing an amine group may contain an amine group and another nucleophilic group capable of attacking an isocyanate to contribute to the extension of the polymer. Typical nucleophilic groups include, but are not limited to, alcohols, thiols, amides, or carboxylic acids. Of these, the most common non-amine groups are alcohols and thiols. However, typically the first or second compound containing an amino group contains two amino groups, i.e. is a diamine.

Typically, amino groups are primary or secondary amines. The amine may be a secondary amine, which may have the structure -NRH, in which R is selected from alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl, and cycloalkyl groups. Most typically, R is an alkyl or cycloalkyl group, and most typically is an alkyl group containing from C ₁ to C ₁₀ , often selected from methyl, ethyl, propyl, and butyl. Typically, R is a methyl group. In most situations, the amino group is a primary amine, i.e., -NH ₂ .

Often the first and second difunctional compounds are alternatively a diamine and a diisocyanate. This maximizes the amount of urea functionality in the polymer structure.

Typically, the first and second difunctional compounds have structures according to Formulas I and II, respectively, or Formulas Ia and IIa, respectively, and the silyl-containing polymer is obtained by polymerizing the first and second difunctional compounds according to Formulas I and II or by polymerizing the first and second difunctional compounds according to Formulas Ia and IIa:

in which:

R ¹ is selected from alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl and cycloalkyl groups;

R ² is selected from polyethers, polyesters, polythioethers, polycarbonates, or combinations thereof;

R ³ and R ⁴ are independently selected from an H atom, an alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl and cycloalkyl group.

Typically, R ¹ is an alkyl, heteroalkyl, or cycloalkyl group. Provided that the structure of R ¹ is capable of containing two isocyanate groups and does not contain groups that can react intramolecularly with one or both of the isocyanate groups, there is no particular limitation on the alkyl, heteroalkyl, or cycloalkyl groups from which R ¹ may be selected.

With respect to R ² , the specific R ² may be selected depending on the drug to be delivered. However, in cases where R ² was a polyalkyl ether, the present inventors observed excellent properties. There is no particular limitation in the choice of polyalkyl ether, but C ₁ -C ₁₀ polyalkylene glycols are typically used, and of these, polyethylene glycol, polypropylene glycol and polybutylene glycol are preferred. Polypropylene glycol is most typically used. Although R ² may be a polyether, a polyester, a polythioether, a polycarbonate or combinations thereof, this does not mean that additional monomers cannot be included in these polymers. For example, non-ether moieties can be included in a polyether, and ether moieties can be included in a polythioether. Polymers may be copolymers (e.g., combinations of polyether and polyester) and may have block, random, or alternating configurations. Therefore, reference to a specific polymer should be understood as describing most of its properties and structure. However, pure forms of the polymers mentioned are also possible (e.g., polyethers containing only polyether linkages).

Each of the radicals R ³ and R ⁴ is usually a small group, such as an H atom or a C ₁ -C ₁₀ alkyl group. Often, R ³ and R ⁴ are selected from a hydrogen atom, methyl, ethyl, propyl and butyl groups. Typically, R ³ and R ⁴ are independently an H atom or a methyl group. Small groups such as an H atom or a methyl group do not sterically hinder the polymerization reaction. Most typically, both radicals R ³ and R ⁴ are hydrogen atoms.

The present invention encompasses not only compositions containing silyl-containing polymers that can be obtained by polymerizing the first and second difunctional compounds described in this publication, but also situations in which additional compounds are included in the polymer structure.

Compounds additional to the first and second difunctional compounds described in this publication may be included in the silyl-containing polymer. These additional compounds may be difunctional compounds containing amine or isocyanate groups, but different from the first and second compounds. These additional compounds may also contain completely different groups than the first and second compounds, although they are typically also difunctional. These additional compounds may be included during or after the polymerization of the first and second compounds, depending on whether an alternating, random, or block copolymer structure is desired. However, typically the silyl-containing polymer is prepared without the use of such additional compounds.

Often, the ratio of the first and second difunctional compounds is in the range of about 1:2 to about 2:1, more typically about 3:2 to about 2:3, and most typically about 1:1. In some embodiments of the present invention, it is desirable to have a mixture of the first and second compounds in approximately equal amounts, since this often facilitates the formation of polymers with high molecular weights. However, it may be desirable to have an excess of one of the two compounds to reduce the molecular weight and provide identity of the end groups allowing an optimal choice of the silyl-containing capping ligand. Accordingly, in some embodiments, one of the first and second difunctional compounds can be present in an excess ranging from about 200% to about 25%, more typically from about 150% to about 50%, even more typically from about 80% to about 120%, and most typically in an excess of about 100%.

As indicated above, the silyl-containing polymer can be prepared by polymerizing the first and second difunctional compounds. The silyl-containing group may already be provided as part of the first and second difunctional compounds, but typically the silyl group or silyl groups are provided at the ends of the silyl-containing polymer. Accordingly, often after the polymerization of the first and second difunctional compounds is completed, "capping ligands" are used to add one or more silyl groups to the ends of the silyl-containing polymer.

Often, two silyl groups are present, and typically they are at each end of the polymer chain. Typically, polymers contain two or more silyl groups. Although only one silyl group is necessary to provide crosslinking between two adjacent polymer chains, it has been shown that the presence of two or more silyl groups increases the degree of crosslinking that can occur. The degree of crosslinking can be varied by increasing the number of silyl groups, allowing one skilled in the art to adjust the desired level of crosslinking to suit a particular application (e.g., depending on the dose of drug to be delivered, the period of time over which drug release is required, and the particular type of drug being delivered).

In an embodiment of the present invention, the first and second difunctional compounds have structures according to Formulas III and IV, respectively, or according to Formulas IIIa and IVa, respectively:

in which:

"n" is an integer ranging from about 20 to about 200, typically from about 30 to about 140, and more typically from about 40 to about 80. In an alternative embodiment of the present invention, each of the methyl groups present in formulas III and IIIa may, independently of the other groups, be replaced by a hydrogen atom.

The silyl group used in the present invention is not particularly limited, and it may be attached to the polymer via a linker which typically comprises a _C1 - _C10 alkyl or _C1 - _C10 heteroalkyl chain, and the silyl group may typically comprise three _C1 - _C10 alkyl and/or _C1 - _C10 alkoxy groups. Typical terminal silyl groups which can react with the above-described polymer to form a silyl-containing polymer are shown in Formulas V and Va:

in which:

"p" is an integer between 3 and 0;

R ⁵ is independently selected from an H atom, an alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl and cycloalkyl group;

R ⁶ is a C ₁ -C ₁₀ alkyl group; and

"j" is an integer ranging from 1 to 10.

It will be apparent to one skilled in the art that the choice of compound used to incorporate the silyl group into the polymer is largely determined by the ratio of the first and second difunctional compounds used in the polymerization reaction (since this determines the end groups available for reaction with the so-called "blocking" ligands). However, the final structure is essentially the same. However, typically "j" is in the range of 2 to 5, and more typically it is 3 or 4. In addition, "p" is typically 3, and R ⁶ can be independently selected from methyl, ethyl, propyl or butyl groups, most typically R ⁶ is a methyl or ethyl group.

The general structure of a silyl-containing polymer may typically correspond to Formulas VI and/or VIa:

in which:

"p" is an integer between 3 and 0;

"m" is an integer ranging from about 1 to about 300;

each of the groups A' and A is independently selected from -NR ⁴ -, -NR ³ -, -O- or -S-, provided that at least one of the groups A' and A is -NR ⁴ -, -NR ³ -;

B is a nucleophilic group;

B' is an electrophilic group;

each of the radicals R ⁶ and R ⁷ is independently a C ₁ -C ₁₀ -alkyl or C ₁ -C ₁₀ -heteroalkyl group; and

R ¹ , R ² , R ³ and R ⁴ are as described above.

Typically, both groups A' and A are -NR ⁴ - groups, and R ⁴ can be selected from an H atom or a C ₁ -C ₅ alkyl or C ₁ -C ₅ heteroalkyl group. However, most typically R ₄ is a hydrogen atom. Furthermore, the group B is typically selected from -NR ⁵ -, -O-, or -S-, since all of these groups can be readily prepared by reacting a terminal isocyanate with a silyl-containing capping ligand containing -NR ⁵ H, -OH, or -SH, respectively (with R ⁵ being as described above). Typically, B is -NR ⁵ -, and most typically -NH-. As for B', this element is typically any group capable of reacting with the nucleophile A', and most often it is derived from an isocyanate, i.e., B' can be -C(O)NH-. The groups B and B' serve to provide attachment of the silyl-containing capping ligand to the end of the polymerized diamine diisocyanate.

The precise length of the blocking silyl group (and hence the identity of R ⁷ ) is not particularly limited within the range of R ⁷ being C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ heteroalkyl groups. R ⁷ preferably functions as a spacer between the functional group capable of attaching the blocking ligand to the polymer backbone and the silyl group itself. Typically, however, R ⁷ is a C ₂ -C ₈ alkyl or C ₂ -C ₈ heteroalkyl group, more typically a C ₃ -C ₅ alkyl or C ₃ -C ₅ heteroalkyl group, and most typically it is a C ₃ alkyl or C ₃ heteroalkyl group. Typically, R ⁷ is an alkyl group.

"p" is typically an integer equal to 3, 2, or 1; more typically equal to 2 or 3; and most typically equal to 3. Additionally, R ⁶ is often a C ₁ -C ₄ alkyl or C ₁ -C ₄ heteroalkyl group. More typically, R ⁶ is an alkyl group, and even more typically, R ⁶ is a methyl or ethyl group. Most typically, R ⁶ is a methyl or ethyl group.

The value of "m" is not particularly limited in the range from about 1 to about 200. However, typically "m" is an integer in the range from about 10 to about 150; more typically in the range from about 15 to about 120; even more typically in the range from about 20 to about 80; and still more typically in the range from about 25 to about 50. The exact molecular weight of the silyl-containing polymer can be varied by changing the value of "m" to suit a particular application.

As explained above, additional compounds can be incorporated into this structure to produce a variety of copolymers. For example, structures according to the general formula VIIa can be obtained:

in which:

A', A, R ¹ , R ² and "m" are as described above;

each of the numbers I and I' is an integer independently selected from the range from 0 to 200;

each of the radicals R ^1a and R ^2a is independently selected from alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl and cycloalkyl groups; polyethers, polyesters, polythioethers, polycarbonates or combinations thereof.

This structure is analogous to Formula VIa, in which additional compounds are included and the terminal silyl groups described in Formula VIa are abbreviated using the term "silyl". A corresponding structure based on Formula VI (where an excess of isocyanate is used) is also provided.

Typically, one or both of I and I' are 0. In some embodiments of the present invention, I is 1. It is possible that I' is "m". Additionally, R ² may be equivalent to R ^2a , and/or R ¹ may be equivalent to R ^1a . In some cases, each of I and I' may be an integer independently selected from the range of 1 to about 180; typically, from about 20 to about 180; more typically, from about 40 to about 160; even more typically, from about 60 to about 140; even more typically, from about 80 to about 120; and even more typically, from about 90 to about 110. Often, one or both of I and I' may be an integer independently selected from the range of 1 to about 60, more typically, from 1 to about 40, and even more typically, from 1 to about 20.

In an embodiment of the present invention, the silyl-containing polymer may be capped with a silyl group at one end and the other end may be linked to a multivalent linker group. When used in the context of the present invention, the term "multivalent linker" encompasses molecules that contain two additional groups capable of reacting with other groups, thereby effectively forming a molecular unit to which two or more compounds may be attached. In this case, two or more polymers obtained by polymerizing a first and second difunctional compound may be attached to a multivalent linker and then capped at one remaining end with a silyl group. This is represented in Formulas VIII and VIIIa:

in which:

A', A, B, B', R ¹ , R ² , R ⁶ , R ⁷ , "m" and "p" are as described above;

q is an integer between 2 and 4; typically it is 3 or 4; more typically it is 2 or 3; still more typically it is 3; still more typically it is 2; and in some circumstances it is 4;

D is a multivalent linker containing 2 to 4 nucleophilic groups;

And

D' is a multivalent linker containing 2 to 4 electrophilic groups.

Typically, D comprises 2 to 4 groups independently selected from -NR ⁵ -, -O-, or -S-, which form bonds with the polymer backbone by reaction of the terminal isocyanate group (in this case) with -NR ⁵ H, -OH, or -SH, respectively. Typically, D comprises 2 to 4 -NR ⁵ - groups (with R ⁵ being as described above), and more typically, D comprises -NH- groups. As for D', this multivalent linker typically comprises 2 to 4 electrophilic groups capable of reacting with the nucleophile A', and this electrophilic group is most often derived from an isocyanate, i.e., D' may comprise -C(O)NH- groups. Each of the D and D' groups may typically comprise 3 or 4 nucleophilic or electrophilic groups, respectively, more typically 2 or 3, and most typically 3. However, 2-group configurations and 4-group configurations are also contemplated.

In an alternative embodiment of the present invention, there is provided a composition for use as a pressure sensitive adhesive, which comprises a crosslinked silyl-containing polymer, wherein the polymer has a structure according to Formula IX:

in which:

A', A, B', ^R2 , ^R6 , ^R7 and "p" are as described above; and the composition further comprises a tackifying resin.

The inventors of the present invention have found that, in addition to the copolymer described in the first aspect of the invention, crosslinked polymers having a structure according to formula IX (containing one difunctional polymer compound functionalized with two silyl groups), in combination with a tackifying resin, can also function successfully as pressure-sensitive adhesives, despite the absence of multiple urea groups. This is advantageous since the polymerization process requires fewer steps.

As described above in connection with the first embodiment of the present invention, one or more additional monomers may be included in the polymer structure. In addition, situations are also envisaged in which the multivalent molecule is functionalized such that it can accept several polymers in a manner similar to that described in connection with Formulas VIII and VIIIa above. Accordingly, the polymer may have a structure according to Formula X:

in which D', A', A, B', R ² , R ⁶ , R ⁷ , "p" and "q" are as described above.

As explained above, A', A, B', ^R2 , ^R6 , ^R7 and "p" are as described above, and the characteristic structure of said compound is shown below in Formula XI:

In an alternative embodiment of the present invention, any of the methyl groups ( _-CH3 ) present in Formula XI may be independently replaced by a hydrogen atom.

With respect to any of the embodiments of the present invention described above, it is also characteristic that the polymers further comprise at least one group intended to dissolve or disperse at least one drug for drug delivery to the skin. The polymers can be functionalized so that they contain a variety of functional groups to impart various properties to the polymer, for example, to improve the drug delivery characteristics. More specifically, monomer units or side groups can be included in the polymer that increase the solubility or dispersibility of a particular drug to be delivered. Depending on the drug to be delivered and the desired drug delivery profile, a wide range of monomer units and functional groups can be included to provide the desired characteristics. For example, the polymer can contain polyethylene glycol moieties in its structure to increase hydrophilicity.

The compositions of the present invention have been found to function successfully as adhesives, and in particular as adhesive patches. In addition, in an embodiment of the present invention, the compositions may contain ingredients for delivery to the skin of the user.

In a preferred embodiment of the present invention, the compositions of the present invention may further comprise one or more drugs and may be used to deliver drugs "to the skin." When used in the context of the present invention, the term "to the skin" means that the drugs are applied to the skin surface, introduced into the skin, or delivered into the body transdermally, i.e. through the skin into the bloodstream.

The term "drug" as used in the context of the present invention refers to a biologically active substance. There is no particular limitation on the type of compound from which the drug is prepared. Drugs used in the present invention are typically low molecular weight molecules, particularly if the drug is intended for transdermal delivery. However, larger molecules and macromolecules are also possible, including biological compounds such as peptides and proteins. The term "drug" also covers pharmaceutically acceptable salts of biologically active substances. It is also envisaged that the drug may have a physical effect on the body, such as heating or cooling, which may have a therapeutic effect.

When used in the context of the present invention, the term "small molecule drugs" encompasses compounds typically prepared by chemical synthetic methods that typically have a molecular weight of less than 1000 Da, more typically less than 700 Da.

When used in the context of the present invention, the term "polymer" refers to macromolecules containing a plurality of repeating monomer units, typically having a weight average molecular weight greater than 600 Da, preferably greater than 2000 Da.

As used in the context of the present invention, the term "crosslinked" refers to a covalent relationship between the polymers in the compositions, either direct (polymer to polymer) or indirect (polymer to polymer via an intermediate bridging group), typically resulting from a reaction between certain pendant groups of one polymer and corresponding pendant groups of adjacent polymers or intermediate bridging groups. This may be achieved using a catalyst and/or in the presence of coreactants such as water. In addition, elevated temperatures, irradiation such as ultraviolet (UV) radiation or electron beam (EB) radiation may be used to promote the crosslinking reaction. If a catalyst is used, at least one catalyst is typically present in the composition in an amount ranging from 0.001 wt.% to 5 wt.%, more typically from 0.01 wt.% to 3 wt.%, based on the weight of the composition. The catalyst may remain in the composition or be completely consumed during the crosslinking process.

When used in the context of the present invention, the term "curing" should be understood as "crosslinking" (described above) the components of the composition with each other until the desired properties of the cured material are achieved. In the present invention, such crosslinking typically occurs between the silyl groups of adjacent silyl-containing polymers, described above.

Typically, the silyl-containing polymers described above have a weight average molecular weight ranging from 700 Da to 250 kDa, more typically from 6 kDa to 100 kDa, and still more typically from 8 kDa to 50 kDa.

The dispersion of silyl-containing polymers is typically less than 3, more typically less than 2, and most typically it lies in the range from 1.0 to 1.6, typically from 1.1 to 1.4.

The compositions of the present invention contain a compatible tackifying resin. It improves the adhesive properties of the composition and allows the composition to be included in a pressure sensitive adhesive (PSA). The compositions containing the compatible tackifying resin provide good adhesion to the skin and can be easily removed, leaving a negligible residue on the skin. Without being bound by a particular theory, it is believed that there is a synergistic interaction between the silyl-containing polymers described above and the tackifying resin, which minimizes the decrease in adhesive properties when the compounds are solubilized in the material. Accordingly, the present invention also encompasses pressure sensitive adhesives containing the composition described above.

The ratio of tackifying resin to silyl-containing polymer is typically in the range of 1:10 to 10:1, more typically in the range of 1:2 to 2:1, and typically about 1:1. Typically, the composition comprises: a) 20 wt.% to 85 wt.%, or more typically 30 wt.% to 60 wt.%, of at least one silyl-containing polymer described above; and b) 15 wt.% to 80 wt.%, or more typically 30 wt.% to 60 wt.%, of at least one tackifying resin. Typically, the composition comprises about 50% silyl-containing polymer and about 50% tackifying resin.

The tackifying resin may be selected from phenol-modified terpene resins (typically polyterpenes), hydrocarbon resins (typically hydrocarbons are aromatic, i.e. contain one or more aromatic groups), esterified rosin resins, modified esterified rosin resins and acrylic resins. Typically, the phenol-modified terpene resins have a softening point in the range of from 70°C to 150°C or, more typically, from 110°C to 130°C; the hydrocarbon resins have a softening point in the range of from 10°C to 150°C and, more typically, from 70°C to 120°C; and esterified rosin resins have a softening point ranging from 10°C to 130°C, more typically from 90°C to 110°C.

The softening temperature of the silyl-containing polymer and/or tackifying resin can be measured according to ASTM E28.

Tackifying resins are generally compatible with skin, non-irritating, and essentially non-cytotoxic. In addition, tackifying resins are generally resistant to degradation. If tackifying resins do degrade over time (e.g., by photolysis or hydrolysis during use or storage), the degradation products are generally essentially non-toxic and typically do not penetrate the skin.

Typically, phenol-modified terpene resins are prepared by polymerization of terpene hydrocarbons and phenols in the presence of Friedel-Crafts catalysts.

According to an embodiment of the present invention, the hydrocarbon resins are selected from resins obtained by a process comprising the polymerization or copolymerization of alpha-methylstyrene, which process may also comprise a reaction with phenols, resins obtained by hydrogenation, polymerization or copolymerization (with an aromatic hydrocarbon) of mixtures of unsaturated aliphatic hydrocarbons containing less than 10 or 10 carbon atoms obtained from petroleum fractions, optionally grafted with maleic anhydride, terpene resins, typically obtained by polymerization of terpene hydrocarbons, such as monoterpene (or pinene), in the presence of Friedel-Crafts catalysts, copolymers based on natural terpenes, such as copolymers of styrene and terpene, alpha-methylstyrene and terpene and vinyltoluene and terpene.

According to an embodiment of the present invention, the esterified rosin resins are selected from natural or modified rosins, such as rosin extracted from pine resin, wood rosin extracted from tree roots, and derivatives thereof that are hydrogenated, dimerized, polymerized or esterified with monoalcohols or polyols such as glycerol.

According to an embodiment of the present invention, the molecular weight of the non-acrylic resins mentioned above is less than or equal to 10,000 Da, typically less than or equal to 2,000 Da, more typically less than or equal to 1,000 Da.

An acrylic resin is defined as a polymer or oligomer containing in the polymer chain a significant amount of (meth)acrylic and/or (meth)acrylate monomers, usually at least 5 wt.%, more often at least 10 wt.%, even more often at least 20 wt.%, typically at least 30 wt.%.

According to an embodiment of the present invention, the (meth)acrylic monomers are selected from acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, isobutyl acrylate, isobutyl methacrylate, n-hexyl acrylate, n-hexyl methacrylate, 2-ethylhexyl acrylate, ethylhexyl methacrylate, n-heptyl acrylate, n-heptyl methacrylate, stearyl acrylate, stearyl methacrylate, glycidyl methacrylate, alkyl crotonates, vinyl acetate, di-n-butyl maleate, dioctyl maleate, acetoacetoxyethyl methacrylate, acetoacetoxyethyl acrylate, acetoacetoxypropyl methacrylate, acetoacetoxypropyl acrylate, Diacetone acrylamide, acrylamide, methacrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, allyl methacrylate, tetrahydrofurfuryl methacrylate, tetrahydrofurfuryl acrylate, cyclohexyl methacrylate, cyclohexyl acrylate, n-hexyl acrylate, n-hexyl methacrylate, 2-ethoxyethyl acrylate, 2-ethoxyethyl methacrylate, isodecyl methacrylate, isodecyl acrylate, 2-methoxy acrylate, 2-methoxy methacrylate, 2-(2-ethoxyethoxy)ethyl acrylate, 2-phenoxyethyl acrylate, 2-phenoxyethyl methacrylate, isobomyl acrylate, isobomyl methacrylate, caprolactone acrylate, caprolactone methacrylate, polypropylene glycol monoacrylate, polypropylene glycol monomethacrylate, polyethylene glycol(400) acrylate, polypropylene glycol(400) methacrylate, benzyl acrylate, benzyl methacrylate, N-vinylpyrrolidone or N-vinyl lactam.

Typically (meth)acrylic monomers contain up to 20 carbon atoms and are typically selected from acrylic acid, methacrylic acid, butyl acrylate, 2-ethylhexyl acrylate and hydroxyethyl acrylate.

According to an embodiment of the present invention, the acrylic resins are selected from polymers containing at least one (meth)acrylic functional group or chain moiety and at least one hydrocarbon chain moiety; such polymers may be in the form of copolymers, grafted, reacted or block polymers.

The above resins have a viscosity, measured at 100°C, significantly greater than or equal to 100 Pa⋅s and less than or equal to 100 Pa⋅s at 150°C. The acrylate resins may contain repeating units consisting of at least one hydrocarbon monomer and at least one acrylate monomer. The hydrocarbon monomers are selected from the group consisting of styrene, alpha-methylstyrene, vinyltoluene, indene, methylindene, divinylbenzene, dicyclopentadiene and methyldicyclopentadiene and polymerizable monomers contained in _C5 -piperylene, _C5 -isoprene and _C9 -aromatic products of the petrochemical industry. These hydrocarbon monomers are usually polymerized together in various ratios by cationic polymerization using Lewis acid catalysts. Acrylate monomers have the general formula R _a -CH=CR _b -COOR _c , in which R _a , R _b and R _c are independently selected from a hydrogen atom, aliphatic groups and aromatic groups. The acrylate monomers are selected from the group consisting of methyl acrylate, acrylic acid, methacrylic acid, methyl methacrylate, ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate, isobutyl acrylate, isobutyl methacrylate, n-hexyl acrylate, n-hexyl methacrylate, ethylhexyl acrylate, ethylhexyl methacrylate, n-heptyl acrylate, n-heptyl methacrylate, 2-methylheptyl (meth) acrylate, octyl acrylate, octyl methacrylate, isooctyl (meth) acrylate, n-nonyl (meth) acrylate, isonyl (meth) acrylate, decyl (meth) acrylate, isodecyl acrylate, isodecyl methacrylate, dodecyl (meth) acrylate, isobomyl(meth)acrylate, lauryl methacrylate, lauryl acrylate, tridecyl acrylate, tridecyl methacrylate, stearyl acrylate, stearyl methacrylate, glycidyl methacrylate, alkyl crotonates, vinyl acetate, di-n-butyl maleate, di-octyl maleate, acetoacetoxyethyl methacrylate, acetoacetoxyethyl acrylate, acetoacetoxypropyl methacrylate, acetoacetoxypropylacrylate, diacetone acrylamide, acrylamide, methacrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, allyl methacrylate, tetrahydrofurfuryl methacrylate, tetrahydrofurfuryl acrylate, cyclohexyl methacrylate, cyclohexyl acrylate, n-hexyl acrylate, n-hexyl methacrylate, 2-ethoxyethyl acrylate, 2-ethoxyethyl methacrylate, isodecyl methacrylate, isodecyl acrylate, 2-methoxyacrylate, 2-methoxymethacrylate, 2-(2-ethoxyethoxy)ethyl acrylate, 2-phenoxyethyl acrylate, 2-phenoxyethyl methacrylate, isobornyl acrylate, isobornyl methacrylate, caprolactone acrylate, caprolactone methacrylate, polypropylene glycol monoacrylate, polypropylene glycol monomethacrylate, polyethylene glycol (400) acrylate, polypropylene glycol (400) methacrylate, benzyl acrylate, benzyl methacrylate, sodium 1-allyloxy-2-hydroxypropyl sulfonate, acrylonitrile and mixtures thereof.

Typically, the hydrocarbon monomers are selected from the group of aromatic monomers or polymerizable monomers from _C9 -aromatic petrochemical sources, dicyclopentadiene or polymerizable monomers from C5 _- piperylene or C5 _- isoprene petrochemical sources.

Acrylate monomers are typically acrylic acid and 2-ethylhexyl acrylate, hydroxyethyl acrylate, methacrylic acid, butyl acrylate. The softening point of these resins typically ranges from room temperature to 180°C, the weight average molecular weight typically ranges from 200 Da to 25,000 Da, and the acid number typically ranges from 0 mg KOH⋅g ^-1 to 300 mg KOH⋅g ^-1 . Typical resins may have a molecular weight less than or equal to 10,000 Da, more commonly less than or equal to 2,000 Da, most typically less than or equal to 1,000 Da; a softening point less than or equal to 150°C, more typically less than or equal to 120°C, most typically in the range from 70°C to 120°C; an acid number less than or equal to 150 mg KOH⋅g ^-1 , more typically less than or equal to 100 mg KOH⋅g ^-1 , and most typically in the range from 10 mg KOH⋅g ^-1 to 100 mg KOH⋅g ^-1 .

According to an embodiment of the present invention, the molecular weight of the acrylic resin is less than or equal to 300,000, if only one resin is present in the composition, typically it is less than or equal to 100,000, most typically it is less than or equal to 20,000.

Non-acrylic resin may contain acrylic functional groups in small amounts, which are the result of a chemical polymerization reaction or are grafted or functionalized groups on the monomers or polymer chains.

Examples of suitable resins include phenol-modified terpene resins such as DERTOPHENE (RTM) H150, available from DRT, with a molecular weight Mn of about 630 Da, DERTOPHENE (RTM) T, having a molecular weight of about 500 Da, available from the same company; hydrocarbon resins such as NORSOLENE (RTM) WHO, available from Cray Valley, which is obtained by polymerizing alpha-methylstyrene without the influence of phenols, with a number average molecular weight of 1000 Da and a softening point of 110°C, NORSOLENE (RTM) W80, having the same structure as NORSOLENEO WHO but with a lower molecular weight, resulting in a softening point of 80°C; esterified rosin resins such as KaKSYLVALITE (RTM) RE 100, which is a pentaerythritol ester of rosin available from Arizona Chemical and has a molecular weight Mn of about 1700 Da; and acrylic resins such as KOLON (RTM) PX95 (available from Kolon industries inc.) or Eastman (RTM) resin described in U.S. Patent Publication No. 7,332,540 (Composition 1, Table 3, Column 14), which are polymers containing at least one functional (meth)acrylic group or chain moiety and at least one hydrocarbon chain moiety, said polymers being in the form of copolymers, grafted, reacted or block polymers, Acronal (RTM) 4F, available from BASF Company, Germany, obtained by polymerization of butyl acrylate monomers.

Accordingly, the tackifying resin may be selected from a vinylpyrrolidone-vinyl acetate copolymer such as Kollidon VA 64; a glycerol ester of hydrogenated wood rosin such as Foral 85; a polyisobutylene such as Oppanol B10 or Oppanol B11; poly(methyl methacrylate-co-butyl methacrylate-co-dimethylaminoethyl methacrylate), such as Eudragit E 100 or Eudragit E PO; poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), such as Eudragit RL 100 or Eudragit RS; a glycerol ester of partially dimerized rosin such as Pexaiyn Ester 10; a copolymer of vinyl chloride and vinyl acetate such as Kanevinyl MB 1008; stabilized pentaerythritol ester of tall oil rosin such as Sylvaiite RE100; a copolymer of ethenylbenzene with 1-methylethylbenzene such as Cleartak W-110; polyvinylpyrrolidone such as Kollidon 90F; sucrose acetate isobutyrate such as Eastman SAIB-100; or combinations thereof.

The curing catalyst that can be used in the composition of the present invention can be any catalyst known to those skilled in the art that is used for silanol condensation. Examples of such catalysts include organic derivatives of titanium, such as titanium acetylacetonate (commercially available under the name TYZOR (RTM) AA75 from DuPont), aluminum, such as aluminum chelate (commercially available under the name K-KAT (RTM) 5218 from King industries), or amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene or DBU.

Optionally, the composition of the present invention may also include, in combination with the silyl-containing polymer, thermoplastic polymers often used to produce HMPSA, such as ethylene vinyl acetate (EVA) or styrene block copolymers.

The composition of the present invention may also contain up to 3% of hydrolyzable alkoxysilane derivatives as a desiccant, typically a trimethoxysilane derivative. Such an agent provides the advantage of extending the shelf life of the composition of the present invention during storage and transportation prior to use. Examples of additives include gamma-methacryloxypropyltrimethoxysilane, available under the trade name SiLQUEST (RTM) A-174 from US Momentive Performance Materiais Inc.

The composition of the present invention may also contain a plasticizer, such as a phthalate such as diisononyl phthalate (DINP) or benzoate, a paraffin and naphthenic oil (such as PREVIOL® 352 from Esso), or a polyethylene homopolymer wax (such as A-C® 617 from Honeyweil), or a polyethylene/vinyl acetate copolymer wax, as well as pigments, dyes or fillers.

In addition, the composition of the present invention typically includes from 0.1% to 3% of one or more stabilizers (or antioxidants). Such compounds are added to protect the composition against degradation. Such compounds may include primary antioxidants that capture free radicals and are, in particular, substituted phenols, such as IRGANOX (RTM) 1076 or IRGANOX (RTM) 1010 from Ciba. Primary antioxidants may be used alone or in combination with other secondary antioxidants or UV stabilizers.

There are no particular limitations on the choice of drugs that can be used together with the composition described above, provided that these drugs are soluble or dispersible in the composition. Although reference is made throughout the publication to "skin", it is assumed that the composition can also be applied to wounds and mucous membranes (e.g., the mucous membranes of the eyes and gums). However, the composition is typically applied to the skin.

Although there are no particular restrictions on the choice of drugs, the drug typically has a molecular weight greater than 100 Da, typically in the range of 500 Da to 20,000 Da, more typically in the range of 500 Da to 10,000 Da, and still more typically in the range of 500 Da to 5,000 Da. Often, the molecular weight is in the range of 100 Da to 5,000 Da, more typically in the range of 100 Da to 500 Da. As explained above, small molecule drugs are particularly preferred for transdermal drug delivery, in which the drug must penetrate the skin to enter the bloodstream.

Drugs are often hydrophilic, as this increases the possibility of drug absorption into the bloodstream (in transdermal drug delivery). Obviously, the drug must be a compound capable of dissolving (at least partially) in a cross-linked polymer matrix, either alone or with the help of a co-solvent. The use of hydrophobic and amphoteric drugs is also envisaged, in particular - in cases where drugs are intended for application to the skin.

The medicinal products described in this publication are not limited to small molecule medicinal products and may also include biological compounds such as proteins, peptides, enzymes, DNA, RNA, short interfering RNA, antibodies or fragments thereof, vitamins, minerals or combinations thereof.

Other compounds or excipients may be added to enhance the efficacy or improve the distribution profile of the drugs. For example, dyes, pigments, antioxidants, desiccants, buffers that regulate pH to maintain the stability of the drugs intended for delivery, or the drugs themselves may be encapsulated in carriers such as micelles to further improve their delivery. Polymeric materials other than those described above may also be provided, for example - to modify the physical characteristics of the composition.

The drugs used are typically selected from the group consisting of analgesics, anti-inflammatory agents, hormones, anti-addiction agents such as nicotine, antihypertensive agents, antidepressants, anti-Alzheimer's drugs, anti-infective agents, anti-scarring agents, antipsychotics, metabolic modulators, anti-pigmentation agents, nutrients, minerals and vitamins.

A typical drug used is an analgesic and may be selected from the group consisting of capsaicin, isobutylphenylpropanoic acid (ibuprofen), flurbiprofen, methyl salicylate, diclofenac, diclofenac epolamine, levomenthol, salicylic acid, ketoprofen, ketamine, fenbufen, fentanyl, buprenorphine, prilocaine, lidocaine, piroxicam, sufentanil, trolamine, or combinations thereof.

If the drug is an anti-infective agent, it is typically an antiviral, antibacterial, or antifungal agent, and examples of typical anti-infective drugs include chlorhexidine, iodine, silver nitrate, chlorquinaldol, or combinations thereof.

Alternatively, the drug used may be a hormone. There is no particular limitation on the specific hormone or combination of hormones that may be used in the present invention. However, the hormone is typically selected from buprenorphine, clobetasol butyrate, clonidine, dexamethasone, diflucortalone valerate, estradiol, estrogen, ethinyl estradiol, gestodene, hydrocortisone, levonorgestrel, norelgestromin, norethisterone, prednisolone, teriparatide, testosterone, triamcinolone or combinations thereof.

Other drugs that may be used are drugs that act on the central nervous system (CNS drugs), typical examples of which include olanzapine, memantine, and donepezil.

In another embodiment of the present invention, the drug used may be an anti-addiction agent such as nicotine, an anti-emetic agent such as cannabinoids (eg, dronabinal), and it may also be selected from vitamins, nutrients, minerals, or combinations thereof.

Other examples of drugs suitable for use in the composition of the present invention include anticancer agents, in particular antiskin cancer agents.

The drugs used in the composition of the present invention often comprise one or more drugs selected from nicotine, ibuprofen, meloxicam, olanzapine, memantine, donepezil, dronabinol, lidocaine, fentanyl, diclofenac, methyl salicylate, testosterone, luflonomide, terflunomide, apomorphine, ketamine, esketamine, amitriptyline, aripiprazole, colchicine, hydrocortisone, lamotrigine, loratadine, ketoprofen, naltrexone, ketorolac, granisetron, celecoxib, fulvestrant, indomethacin, agomelatine, escitalopram, flurbiprofen, galantamine, methylphenidate, mometasone, propafenone, clobazam, pramipexole, ropinirole, bisoprolol, levonorgestrel, ziprasidone, verapamil, mevrafenib, propylthiouracil, methotrexate, pazopanib, maraviroc, lithium, lisdexamfetamine, huperzine A, calcitrol, temazolamib, bupropion, domperidone, lurasidone, tetracycline, progesterone, prilocaine, ivermectin, cannabidiol, artesunate, artemisinin, salsalate, or combinations thereof.

In an alternative embodiment of the present invention, the composition of the present invention can be used to deliver "non-drug" agents. The term "non-drug" as used in the context of the present invention refers to compounds that, although not directly therapeutic or prophylactic against disease, provide some benefit to the user. Depending on the circumstances, there may be some overlap between the "drugs" and "non-drugs" described herein. For example, delivering a vitamin to alleviate a disorder associated with an acute vitamin deficiency may be considered a "drug" delivery, while providing vitamins for general well-being may be considered a "non-drug" circumstance. There is no particular limitation on the type of non-drug that can be used in conjunction with the composition of the present invention. However, representative examples include nutraceuticals, cosmetics, stimulants, skin protectants, or combinations thereof. Of these, nutraceuticals and cosmetics are often used. A person skilled in the art will understand how the compatibility of the composition of the present invention can be increased with a particular non-drug or combination of non-drugs. In addition, drugs and non-drugs can be provided together.

Cosmetics that can be used in combination with the present invention are not particularly limited. They can include transdermal cosmetics or traditional cosmetics for application to the skin surface. The types of cosmetic products that may be desirable for delivery to the skin can be selected from anti-aging creams, anti-wrinkle creams, serums, oils, moisturizers, toners, etc.

Some non-drugs may also interfere with the excipients prescribed with the drug. For example, if the non-drug is a stimulant, it may increase the speed at which the drug used with the stimulant begins to work in the body. However, such compounds can be used with the drug component.

It may also be desirable for the "non-drug" to be a skin protectant, i.e. a compound that protects the skin from harmful effects, such as chemicals or ultraviolet radiation. A skin protectant is typically a sunscreen (i.e. a compound that minimizes skin damage caused by sunlight).

Various auxiliary substances and preservatives can be included in the composition of the present invention depending on the choice of specific substances for use in the composition. Excipients can be included to modify the drug release properties of the composition or other properties of the composition, such as the stickiness or color of the composition. Some auxiliary substances can also have a biological effect on the body, for example, caffeine, which synergizes with other drugs contained in the composition and increases the overall effectiveness of the composition. Excipients can also be used to modify the physical characteristics of the composition, including to provide warming or cooling effects when applied to the skin or to soften the skin when using moisturizing substances.

For example, it may be necessary to deliver an excipient to the skin that creates a sensation of cold or heat. For example, a volatile topical analgesic such as menthol may be added to the composition to create a sensation of cold.

The composition may also contain a solvent or co-solvent intended to increase the solubility of the drugs used in the composition of the present invention. There are no particular limitations on the choice of solvent or co-solvent, provided that it is compatible with the composition and increases the solubility and/or release of drugs from the composition during its use. Typically, the solvent or co-solvent is an organic solvent, typically an essentially safe organic solvent. The solvent can be used to reduce the viscosity of the polymer composition, and therefore it can be used to facilitate the incorporation of drugs into the polymer matrix.

Typically, the composition of the present invention is in the form of a patch for drug delivery. Typically, the patch is a patch for transdermal drug delivery. The inventors have found that the composition of the present invention is capable of forming thin films with excellent drug retention and excellent drug delivery profiles, which also exhibit excellent skin adhesion and removal properties. The patches typically comprise a thin layer of cured composition, typically having a thickness of less than 10 mm, typically less than 5 mm. The patches may comprise a layer of cured composition and at least one base layer onto which the layer of composition is applied. The base layer is typically non-sticky on one side, which allows the patch to be applied to the user's skin manually.

The patch of the present invention has several advantages over existing patch designs. As explained above, many patch adhesives do not effectively dissolve some drugs or do not provide delivery of a dose over an extended period of time. Accordingly, many patches require the use of a separate drug reservoir to perform this function. However, this typically requires the inclusion of additional layers in the patch structure, and drugs often need to penetrate the adhesive layer to reach the skin. Some designs to overcome this problem use a centrally located reservoir and an adhesive located around its perimeter. However, this often results in poor contact between the reservoir and the skin surface, which reduces the effectiveness of the patch, and the adhesion can often be ineffective. In the case of the present invention, this is not a problem, since the composition can be formulated in the form of a single layer that provides good adhesion and good delivery of the drug to the skin. In addition, the patches of the present invention can be manufactured using less stringent conditions and therefore can contain a wider range of drugs.

Typically, the patch comprises a continuous or semi-continuous layer of the composition described above, enclosed between two base layers. Typically, at least one of the base layers consists of a release material that can be easily separated, typically by hand, from the layer of the composition before application of the patch. Both base layers may be made of a release material. This release layer or non-removable "back liner" may also prevent the layer of the composition from drying out or leaking the drug contained therein when the patch is not in use and provides for easier handling of the layer of the composition.

Typically, one of the layers may be made of a non-removable material or "bottom liner" that is firmly bonded to the layer of the composition. An additional backing layer containing a removable layer may be applied to the other surface of the layer of the composition opposite the bottom liner layer. This provides the patch with a patch-type structure that prevents the layer of the composition from adhering to surfaces when the patch is not in use and from adhering to the user's clothing when the patch is in use.

The base is intended to accommodate the composition and may be a protective film, a carrier film or a nonwoven material. Often, the release layer has a siliconized surface covering the entire or substantially entire surface and/or is made of a siliconized material. The release layer may be any polymer film that allows separation from the composition layer, such as a film made of polytetrafluoroethylene (PTFE) or similar materials.

In a second aspect of the present invention, there is provided a method for producing a composition according to the first aspect of the present invention; this method comprises: a first step of producing a silyl-containing polymer and a tackifying resin according to the first aspect of the present invention; a second step of dissolving a drug requiring delivery to the skin in the mixture; and a third step of curing the mixture.

Alternatively, the drug may be added after the third stage of curing of the mixture. However, typically the drug is added before curing.

Although the tackifying resin is typically used during the first step of the process, it can be used in subsequent steps. Additionally, a catalyst is typically used in the first, second, or third step of the process. If the catalyst is added during the second step, it is typically done after the drug to be delivered to the skin has been added, and typically after any additional excipients have been added. Typically, the catalyst is added either at the end of the second step or at the beginning of the third step. Typically, the catalyst promotes silanol condensation. Typical catalysts include, but are not limited to, organic derivatives of titanium(III), titanium(IV), or aluminum(III), such as aluminum triacetylacetonate, titanium tetraalkoxides, such as titanium tetrabutoxide and titanium tetraethoxide; and amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene.

The third stage of curing the polymer is typically carried out in a humid environment, i.e. in the presence of water. According to an embodiment of the present invention, the composition is cured in a humid atmosphere characterized by a certain level of humidity. The level of humidity is typically controlled using a suitable device, typically comprising a humidity generator, a sensor and a control system. Examples of suitable devices are described, for example, in the publication EP 2856 937. Typically, the humidity during the curing stage is such that from 1% to 100% of the molecules in the curing atmosphere are water molecules, more typically from 2% to 95%, even more typically from 5% to 90%, even more typically from 10% to 80%, even more typically from 15% to 70%. Often, the humidity is in the range of from 20% to 50% or more typically in the range of from 25% to 40%. In some cases, humidity ranges from 1% to 90%, often from 1% to 10%, and in some cases from 2% to 8%.

The second step may include heating the first component to a temperature in the range of from 30°C to 150°C, typically from 50°C to 130°C, and most typically from 70°C to 100°C.

The second step of the method typically includes a mixing step to facilitate dissolution of the drug and ensure a homogeneous mixture. This step can be performed using one or more solvents or cosolvents to improve dissolution of the drugs in the first component. Suitable solvents and cosolvents are described above. Typically, the solvents are substantially free of water to prevent premature solidification.

In addition, preservatives, fillers and other auxiliary substances may be added to the composition, and this is usually carried out together with the addition of the drug, typically during the second stage. The first and/or second stage may be carried out in an inert atmosphere.

The curing step is typically carried out at a temperature above room temperature, typically at a temperature above 20°C, often at a temperature in the range of 20°C to 200°C, and more typically at a temperature in the range of 40°C to 120°C. Often the temperature is in the range of 50°C to 80°C, and most typically it is about 60°C. Typically a catalyst is used. However, it should be noted that a lower temperature can be used if a catalyst is used.

Typically, during the second step, after obtaining a substantially homogeneous mixture, the mixture is applied to a lower liner or a release liner before curing. Typically, the mixture is formed into a layer that can be placed between two lower liners or two release liner substrates or a combination thereof. There are no particular limitations on the shape or material of the lower liner or release layer. The lower liner is typically a thin, flexible material, typically less than 5 mm thick, and often less than 1 mm thick. The lower liner is typically firmly bonded to the layer of the composition. Typical examples of release materials include siliconized surfaces, polyolefin films or coatings such as high-density polyethylene or polypropylene films, stretchable or deformable films or coatings such as fluorosilicones or polytetrafluoroethylene films, and acetate films.

Although the drug for delivery to the skin is typically included in the composition before it is cured, the drug can be included after the composition is cured, depending on the thermal and chemical stability of the drug to be delivered. The drug can be a solid, liquid, or solution containing the drug when added to the composition.

There is no particular limitation on the duration of the curing step. The time required for the curing step may vary widely depending on the mass of the composition deposited on the unit area of the base, the heating temperature, the humidity and the specific composition of the composition concerned. Typically, the duration of the curing step is in the range of 1 second to 24 hours, and more typically it is in the range of 5 minutes to 24 hours. However, in the case of the silyl-containing polymers of the present invention, the curing time may be in the range of 2 minutes to 30 minutes, more typically in the range of 5 minutes to 15 minutes, and in many cases it is less than about 10 minutes or even less.

Without being bound by a particular theory, it is believed that this curing step has the effect of forming siloxane-type bonds between the polymer chains under the influence of atmospheric moisture, which results in the formation of a three-dimensional polymer network. Accordingly, the cured composition acts as a pressure-sensitive adhesive layer that imparts the desired bond strength and tack to the substrate to which such a coating is applied.

The method can be carried out as a batch process or a continuous process. A continuous process can include the use of heated rollers to form and heat the composition, and steam jet sprayers can be used to provide moisture to promote the crosslinking reaction.

In a third aspect of the present invention, there is provided the use of the composition described above as pressure sensitive adhesives, and more typically for transdermal drug delivery.

The inventors of the present invention have found that compositions containing a crosslinked silyl-containing polymer are extremely effective as adhesives and in storing and delivering drugs to the skin. This is especially true when these polymers are combined with the tackifying resin described above, which promotes adhesion to the skin.

The composition used in the use according to the third aspect of the present invention is typically a patch for delivering a drug. Typically, it is a patch for delivering a drug to the skin.

Typically, the drugs used in the composition according to the third aspect of the present invention are as described above.

In a fourth aspect of the present invention, there is provided a method for treating a disease, comprising producing a composition or patch as described above, and applying the composition or patch to a user. Typically, the composition or patch is applied to the skin of the user.

There are no particular limitations on the types of diseases that can be treated using this method. The only limitation is that the drugs used to treat a particular condition must be effective when applied to the skin. Typical uses of the composition of the present invention include the treatment of diseases selected from: analgesia, hypertension, addiction, such as nicotine, hormonal imbalance, cancer, such as skin cancer, bacterial, viral or fungal infections, Alzheimer's disease, affective disorders, Parkinson's disease, metabolic diseases, tissue scarring or combinations thereof.

In addition, the method of treatment of the present invention can be used to deliver vaccines and/or to accelerate wound healing.

In a fifth aspect of the present invention, there is provided a composition or patch according to the first aspect of the present invention for use in therapy. Typically, conditions that can be treated using the composition or patches of the present invention are: analgesia, hypertension, addiction, for example - nicotine, hormonal imbalance, cancer, for example - skin cancer, bacterial, viral or fungal infections, Alzheimer's disease, affective disorders, Parkinson's disease, metabolic diseases, tissue scarring or combinations thereof. Most typically, the compositions and patches of the present invention are intended for use in the treatment of analgesia.

In addition, the composition and patches of the present invention can also be used as vaccine delivery vehicles and/or as wound healing accelerators.

The present invention will now be described with reference to the accompanying drawings and examples of its implementation.

Brief description of graphic materials

Fig. 1 shows the IR spectra of the composition JSAD001 with reference to the reduction of the IR peak associated with isocyanate groups.

Fig. 2 shows the IR spectra of the composition JSAD005 with reference to the reduction of the IR peak associated with isocyanate groups.

Fig. 3 shows the IR spectra of the JSAD006 composition with reference to the reduction of the IR peak associated with isocyanate groups.

Fig. 4 shows the molecular weight distribution of JSAD006.

Description of examples of implementation of the invention

Example 1

Peel strength properties

API (from English: active pharmaceutic ingredient) - active pharmaceutical ingredients,

DEGEE (from English Diethylene glycol monoethyl ether) is diethylene glycol monoethyl ether.

The peel strength properties of the compositions of the present invention were tested in comparison with polyol-polyurethane equivalents. The peel test was conducted according to the FINAT method No. 2 by means of a 90° peel and the ASTM 3330-34 (2010) method for testing adhesive tapes on stainless steel using a speed of 100 mm/min. The results of these tests are presented below in Table 1.

The reference in Table 1 to compositions “without drug” may be considered as describing adhesive compositions.

Example 2

Ibuprofen release

The ibuprofen release properties of the compositions of the present invention were tested in comparison with polyol-polyurethane equivalents. The results of these tests are shown in Table 2 below.

Example 3

Lidocaine release

The lidocaine release properties of the compositions of the present invention were tested in comparison with polyol-polyurethane equivalents. The results of these tests are shown in Table 3 below.

Example 4

Release of methyl salicylate

The methyl salicylate release properties of the compositions of the present invention were tested in comparison to polyol-polyurethane equivalents. The results of these tests are shown in Table 4 below.

Example 5

Diclofenac release

The release properties of diclofenac from the compositions of the present invention were tested in comparison with polyol-polyurethane equivalents. The results of these tests are shown in Table 5 below.

Example 6

Production method Synthesis JSAD0 =01

Step 1 - Isophorone diisocyanate (IPDI; from English: Isophorone Diisocyanate) (2.27 g, 2.05 equiv.) was heated to 60 °C with stirring, Jeffamine D-4000 (Mw=4000 Da, NH functionality = 2) (20.0 g, 1 equiv.) was added dropwise to the isocyanate and stirred at 60 °C for 5 minutes. No catalyst was required, IR data showed the completion of the reaction after 5 minutes as a decrease in the NCO peak at ≈ 2240 cm ^-1 (see Fig. 1), with longer reaction times this peak did not decrease to a greater extent than after 5 minutes.

The reaction of Step 1 is possible at room temperature, but a higher temperature was used to reduce viscosity and facilitate stirring.

Step 2 - 3-Aminopropyltrimethoxysilane (2.38 g, 2.05 equiv) was added to the reaction mixture at 60 °C and stirred for 10 min. The reaction was monitored for disappearance of the NCO peak, which occurred after 10 min.

Synthesis of JSAD002

Step 1 - Isophorone diisocyanate (IPDI) (1.71 g, 1.53 equiv) was stirred at 60°C, Jeffamine D-4000 (20.00 g, 1.0 equiv) was added dropwise and stirred for 5 minutes.

Step 2 - 3-aminopropyltrimethoxysilane (1.70 g, 1.53 equiv) was added to the reaction mixture and stirred for 10 min.

Synthesis of JSAD003

Step 1 - Isophorone diisocyanate (IPDI) (2.39 g, 1.53 equiv) was heated to 60°C, Jeffamine D-4000 (14.0 g, 0.5 equiv) and Jeffamine D-2000 (Mw=2000 Da, _NH2 functionality = 2) (7.0 g, 0.5 equiv) were mixed, added dropwise to the isocyanate and stirred for 5 minutes.

Step 2 - 3-aminopropyltrimethoxysilane (2.38 g, 1.53 equiv) was added to the reaction mixture and stirred for 10 min.

Synthesis of JSAD0005.3

Step 1 - Jeffamine D-4000 (10.0 g, 1 equiv) was heated to 60 °C, IPDI (0.285 g, 0.51 equiv) was added dropwise and the reaction mixture was stirred at 60 °C for 5 min, monitoring the complete disappearance of the NCO peak at 2240 cm ^-1 (see Fig. 2).

Step 2 - 3-Isocyanatopropyltriethoxysilane (0.325 g, 0.51 equiv) was added to the reaction mixture and stirred for 10 minutes.

Additional reactions showed that the molecular weight distribution was not affected by the addition of amine to isocyanate or by the addition of isocyanate to amine.

Synthesis of JSAD006

Step 1 - 3-Isocyanatopropyltriethoxysilane (1.903 g, 2.05 equiv) was added dropwise to Jeffamine D-4000 (15 g, 1 equiv) at 60°C, the reaction was complete after 5 min.

Example 7

Curing method

To prepare the adhesive (e.g. JSAD002A), the base polymer (e.g. JSAD002) was mixed with a resin solution. The resin solution contained Norsolene W110 and Sylvaiite RE100s in a 50:50 ratio, dissolved in methyl ethyl ketone (MEK) (e.g. with a solids content of 66.2%). The resin solution was mixed with the polymer and the MEK was removed by rotary evaporation to obtain equal weight fractions of resin and polymer - e.g. 2.57 g of JSAD002 was mixed with 4.195 g of resin solution (1.285 g of Sylvalite, 1.285 g of Norsolene, 1.625 g of MEK).

To cure the patches, the adhesive composition was heated to 75°C, then all active pharmaceutical ingredients (API) and/or excipients were added and thoroughly mixed/homogenized. A curing catalyst (e.g., 7.17 g, 97 wt.%, JSAD002A mixed with 0.1109 g, 3 wt.% Ti(IV) butoxide) was added. The catalyst was mixed for 5 minutes at 75°C, after which the composition was poured onto a heated coater, the film was stretched to a thickness of 30 μm, steam was applied, and the curing chamber was maintained on the heated coater until curing was complete.

Claims (46)

1. A composition for use in delivering a drug to the skin, which comprises a cross-linked silyl-containing polymer and one or more drugs, wherein said polymer can be obtained by polymerization of: the first difunctional compound and the second difunctional compound, wherein the first and second difunctional compounds together comprise a terminal amino group and a terminal isocyanate group, and wherein the first and second difunctional compounds have structures according to Formulas III and IV, respectively, or Formulas IIIa and IVa, respectively wherein the silyl-containing group is provided at the ends of a silyl-containing polymer obtained by polymerizing the first and second difunctional compounds; wherein said silyl-containing group has the structure Si(OR ⁶ ) _p (R ⁶ ) _3-p ; where "p" is an integer from 1 to 3, and each R ⁶ is independently selected from a C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ heteroalkyl group; and wherein said composition further comprises a tackifying resin. 2. The composition according to claim 1, wherein the first and second difunctional compounds are polymerized in the absence of a catalyst. 3. The composition according to claim 1 or 2, wherein the first or second difunctional compound containing a terminal amino group has a molecular weight lying in the range from 500 Da to 10,000 Da, typically from 2,000 Da to 5,000 Da. 4. The composition according to any one of claims 1-3, wherein one or more additional difunctional compounds are polymerized together with the first and second difunctional compounds. 5. The composition of claim 4, wherein one or more additional difunctional compounds are selected from polyols, diamines, dithiols, diisocyanates, dicarboxylic acids, diamides, or combinations thereof. 6. The composition according to any one of claims 1 to 5, wherein the silyl-containing polymer has a structure according to Formulas VI and/or VIa: in which: "p" is an integer between 3 and 0; "m" is an integer ranging from about 1 to about 200; each of the groups A' and A is independently selected from -NR ⁴ -, -NR ³ ; B is a nucleophilic group; B' is an electrophilic group; R ¹ represents a cycloalkyl group; R ² is a polyether; R ³ and R ⁴ are independently selected from an H atom, an alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl, heteroaryl and cycloalkyl group; and each of the radicals R ⁶ and R ⁷ is independently a C ₁ -C ₁₀ alkyl or C ₁ -C ₁₀ heteroalkyl group. 7. A composition for use in delivering a drug to the skin, which comprises a cross-linked silyl-containing polymer having a structure according to Formula IX in which each of the groups A' and A is independently selected from -NR ⁴ ; B' is =NH-C(O)-; R ² is selected from polyethers; R ⁴ is independently selected from the H atom; and each of the radicals R ⁶ and R ⁷ is independently a C ₁ -C ₁₀ alkyl group; wherein said composition additionally contains a resin that increases adhesiveness. 8. The composition according to claim 7, additionally containing one or more medicinal agents. 9. The composition according to any one of claims 1 to 8, wherein the polymer further comprises at least one group intended to dissolve or disperse at least one drug for delivering the drug to the skin. 10. The composition of claim 9, wherein said composition comprises from 20% to 85% of a silyl-containing polymer and from 15% to 80% of a tackifying resin; more typically 50% of a silyl-containing polymer and 50% of a tackifying resin. 11. A composition according to any one of claims. 1-10, wherein said one or more drugs are selected from nicotine, ibuprofen, meloxicam, olanzapine, memantine, donepezil, dronabinol, lidocaine, fentanyl, diclofenac, methyl salicylate, testosterone, luflonomide, terflunomide, apomorphine, ketamine, esketamine, amitriptyline, aripiprazole, colchicine, hydrocortisone, lamotrigine, loratadine, ketoprofen, naltrexone, ketorolac, granisetron, celecoxib, fulvestrant, indomethacin, agomelatine, escitalopram, flurbiprofen, galantamine, methylphenidate, mometasone, propafenone, clobazam, pramipexole, ropinirole, bisoprolol, levonorgestrel, ziprasidone, verapamil, meurafenib, propylthiouracil, methotrexate, pazopanib, maraviroc, lithium, lisdexamfetamine, huperzine A, calcitrol, temazolamib, bupropion, domperidone, lurasidone, tetracycline, progesterone, prilocaine, ivermectin, cannabidiol, artesunate, artemisinin, salsalate, buprenorphine, clobetasol butyrate, clonidine, dexamethasone, diflucortalone valerate, estradiol, estrogen, ethinyl estradiol, gestodene, norelgestromin, norethisterone, prednisolone, teriparatide, triamcinolone or their combinations. 12. The composition according to any one of claims 8-11, wherein the medicinal product is hydrophilic. 13. The composition according to any one of claims 1 to 12, wherein said delivery of the drug to the skin is transdermal delivery of the drug. 14. The composition according to any one of claims 8-13, wherein the drug is selected from lidocaine, nicotine, ibuprofen, diclofenac, methyl salicylate or combinations thereof. 15. The composition according to any one of claims 1-13, wherein the drug is selected from donepezil, testosterone, loratadine, progesterone, estrogen or combinations thereof. 16. A patch for transdermal delivery of drugs, comprising a composition as defined in any one of claims 1-15. 17. A transdermal drug delivery patch according to claim 16 for use in treating a disease, wherein said treatment comprises the steps of obtaining a transdermal drug delivery patch and applying said patch to the skin of a user. 18. A patch for transdermal delivery of drugs according to claim 17, wherein the disease is selected from hormonal imbalance and Alzheimer's disease.

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