WO2025038382A1 - Pharmaceutical adhesive compositions - Google Patents

Abstract

A composition comprising silicone pressure sensitive adhesive and an amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive.

Description

PATENT APPLICATION Docket No.: 5072672 TITLE PHARMACEUTICAL ADHESIVE COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to and the benefit of India Patent Application 202311054175, filed on August 11, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF INVENTION [0002] The present invention relates to a composition comprising a silicone pressure sensitive adhesive and a bioactive agent wherein the bioactive agent is dispersed in the adhesive. This invention also relates to an adhesive composition comprising a silicone pressure sensitive adhesive and an amine functional drug wherein the adhesive is resistant to loss of adhesive properties such as tack and peel strength. BACKGROUND [0002] Pressure sensitive adhesives (PSAs) are known in the art and are commercially available. Some of the more common types of PSAs are formulations based on acrylates, silicone, natural rubbers, and synthetic rubbers. These PSAs are typically formulated for removable end use and find utility in a wide variety of applications including use in transdermal drug delivery systems (TDDSs). [0003] Common classes of pressure sensitive adhesives used in TDDSs include silicone-based and acrylate-based PSAs. [0004] Acrylate-based PSAs, also referred to as acrylate PSAs, are broadly used in TDDSs due to the fact that they are relatively low in cost when compared to other PSAs and solubilize many types of functional drugs for TDDSs. TDDSs using acrylate- based PSAs usually provide good adhesion properties. The disadvantages of acrylate- based PSAs include poor high temperature performance, poor low temperature performance, inability to adhere to surfaces with low surface energies, and the potential to build excessive adhesion to the skin in medical tape applications which can result in painful removal for the user and skin irritation. 1 34006165.1 [0005] Silicone-based PSAs, also referred to as silicone PSAs, are typically produced by either blending or condensing together a silicone resin and a silicone polymer, such as polydimethylsiloxane (PDMS). Silicone materials by nature are very stable at high temperatures and the low glass transition temperature (Tg) of PDMS (less than −115° C.) ultimately provides a PSA that can find use in temperatures ranging from −100° C. to 265° C. Silicone-based PSAs also have excellent UV resistance, electrical insulating properties, biocompatibility, and the ability to adhere to low surface energy substrates such as silicone release liners, polytetrafluoroethylene, and fluorohalocarbon materials. In TDDSs the silicone-based PSAs generally provide a higher drug flux and a higher active agent utilization compared to acrylate-based PSAs. The primary disadvantage of silicone-based PSAs is that their utility in TDDSs is limited by their incompatibility with many pharmaceutical active ingredients. [0006] Manufacturing TDDSs polymer blends utilizes both acrylate PSAs and silicone PSAs to combine the advantages of both technologies. Physical blends of PSA may provide better wear adhesion and drug permeation properties but may be subject to phase separation. However, the lower surface energy silicone PSA is usually incompatible with the higher surface energy acrylate PSA resulting in phase separation. [0007] Rivastigmine, (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl- phenyl-carbamate is used for treating Alzheimer's disease, and it is useful as an acetylcholinesterase inhibitor in the central nervous system. [0008] Such rivastigmine is commercially available in the form of a patch. GB Patent No. 2,203,040 discloses a transdermal composition in the form of a patch in Example 2, in which the patch is prepared by mixing rivastigmine with two polymers and a plasticizer to obtain a viscous composition and applying the composition to a foil. [0009] PCT application WO2012/161489 describes a transdermal therapeutic systems containing an acrylate based drug in adhesive layer and a skin contact layer containing silicone acrylic hybrid pressure sensitive adhesive. The transdermal patch for Rivastigmine provides a tack of from 0.6 N to 8.0 N and permeation rate of the drug which is constant within less than 19% points over about the last two-thirds of the administration period. The TDDS of this patent disclosure require an additional (acrylate) layer to disperse the drug which is not desirable, from a manufacturing standpoint, of these TDDSs. [0010] There continues to exist a need in the art for an improved transdermal patch that overcomes the above-mentioned disadvantages. 2 34006165.1 SUMMARY [0011] The following presents a summary of this disclosure to provide a basic understanding of some aspects of the invention. This summary is intended to neither identify key or critical elements nor define any limitations of embodiments or claims. Furthermore, this summary may provide a simplified overview of some aspects that may be described in greater detail in other portions of this disclosure. [0012] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive. [0013] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive and wherein the pressure sensitive agent has a silanol content of less than 8000 ppm. [0014] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive and wherein the pressure sensitive agent has a silanol content of less than 8000 ppm and a cyclosiloxane content of less than 50 ppm. [0015] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive retains tack and peel strength of at least in the range of 60-80% of its initial value over a period of at least six months at temperature in the range of 25 to 30^oC. [0016] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) an amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive. 3 34006165.1 [0017] In one aspect, the invention provides a transdermal drug delivery system comprising: (i) a backing layer (ii) a drug-in-adhesive layer wherein the drug-in-adhesive layer comprises a silicone pressure sensitive adhesive and an amine functional drug and (iii) a liner layer. [0018] In one aspect, provide is a composition comprising:(i) a silicone pressure sensitive adhesive comprising (a) a solid MQ resin, and (b) a polyorganosiloxane; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive. [0019] In one embodiment, the silicone pressure sensitive adhesive (i) comprises from about 40% to about 70% by weight of the solid MQ resin, and from about 30% to about 60% of the polyorganosiloxane based on the weight of the silicone pressure sensitive adhesive. [0020] In one embodiment in accordance with any previous embodiment, the silicone pressure sensitive adhesive has a silanol content of about 8000 or less. [0021] In one embodiment in accordance with any previous embodiment, the silicone pressure sensitive adhesive has a cyclosiloxanes content of about 50 ppm or less. [0022] In one embodiment in accordance with any previous embodiment, the composition comprises the bioactive agent in an amount of from about 5% to about 30% of the composition. [0023] In one embodiment in accordance with any previous embodiment, the bioactive agent is an amine functional drug. [0024] In one embodiment in accordance with any previous embodiment, the amine functional drug is selected from the group consisting of amphetamine, methylphenidate, rivastigmine, rotigotine, fentanyl, paroxetine clonidine, amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, doxepin, ethopropazine, flavoxate, homatropine, imipramine, loxapine, mazaticol, metixene, oxybutinin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, scopolamine, telenzepine, theophylline, 4 34006165.1 tolterodine, trimipramine, trihexyphenidyl, tropatepine, tropicamide, or a combination of two or more thereof. [0025] In one embodiment in accordance with any previous embodiment, the composition further comprises a first additive for preventing degradation of the bioctive agent. [0026] In one embodiment, the first additive is selected from the group consisting of Vitamin E Acetate, α-tocopherol (Vitamin E), Ascorbyl palmitate, butylated hydroxytoluene (BHT), or a combination of two or more thereof. [0027] In one embodiment in accordance with any previous embodiment, the composition further comprises a second additive selected from a tack modifier. [0028] In one embodiment, the tack modifier is selected from the group consisting of amorphous silicon dioxide, rosine ester, synthetic tackifier , isoprene rubber, or a combination of two or more thereof. [0029] In one embodiment in accordance with any previous embodiment, the composition further comprises a third additive selected from a drug delivery additive. [0030] In one embodiment, the third additive is selected from Polyethylene glycol, oleyl alcohol, isopropyl myristate, menthol, Diethylene glycol monoethyl ether (Transcutol P), or a combination of two or more thereof. [0031] In one embodiment in accordance with any previous embodiment, the first additive, the second additive, and third additive are independently present in an amount of from about 0 to about 10 percent by weight or greater based on the weight of the composition. [0032] In one embodiment in accordance with any previous embodiment, the composition retains the tack and peel strength at least in the range of 60-80% of its initial value over a period of at least six months at temperature in the range of 25 to 30^oC. [0033] In one embodiment in accordance with any previous embodiment, the composition has a storage modulus of the order of 10³ to 10⁵ Dyne/cm² measured at an angular frequency of 0.01 rad/s at a temperature of 32 ^oC. [0034] In one embodiment in accordance with any previous embodiment, the composition has a storage modulus of the order of 10⁶ to 10⁷ Dyne/cm² measured at an angular frequency of 100 rad/s and at temperature of 32 ^oC. 5 34006165.1 [0035] In one embodiment in accordance with any previous embodiment, the composition has a complex viscosity of the order of 10⁶ to 10⁸ poise measured at an angular frequency of 0.01 rad/s and at temperature of 32 ^oC. [0036] In one embodiment in accordance with any previous embodiment, the amine functional drug has a cumulative release of not less than 30 % over a duration of 24 hours across a cellulosic membrane. [0037] In another aspect, provided is a transdermal drug delivery system comprising: (i) a backing layer; and (ii) a drug-in-adhesive layer comprising the composition of any of any of the previous embodiments. [0038] In one embodiment, the transdermal drug delivery system has a residual drug content of not more than 5 to 20 % by weight, in its spent state, as compared to its original drug content of an as-prepared transdermal drug delivery system. [0039] In one embodiment in accordance with any previous embodiment, the transdermal drug delivery system has a skin contact layer wherein the skin contact layer is selected from an acrylate or silicone based pressure sensitive adhesive. [0040] In one embodiment in accordance with any previous embodiment, the transdermal drug delivery system is packaged in an atmosphere of nitrogen. [0041] In one embodiment in accordance with any previous embodiment, the system passes stability test at temperature of 40°C ± 2°C and Relative Humidity of 75% ± 5% for at least one month as per ICH guidelines Q1A (R2). [0042] In one embodiment in accordance with any previous embodiment, the system has an f2 value (similarity factor) in the range of 50 to 100 as compared to the commercial rivastigmine transdermal delivery system. [0043] The following description and the drawings disclose various illustrative aspects. Some improvements and novel aspects may be expressly identified, while others may be apparent from the description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS [0044] Figure 1 displays retention of adhesion of adhesive composition containing Rivastigmine; [0045] Figure 2 displays the percent cumulative release of drug in an adhesive composition; [0046] Figure 3 displays the percent residual rivastigmine in the adhesive composition after release of rivastigmine; and 6 34006165.1 [0047] Figure 4 displays the percent cumulative permeation of drug through wistar rat skin. DETAILED DESCRIPTION [0048] Reference will now be made to exemplary embodiments, examples of which are illustrated in the accompanying drawings. It is to be understood that other embodiments may be utilized, and structural and functional changes may be made. Moreover, features of the various embodiments may be combined or altered. As such, the following description is presented by way of illustration only and should not limit in any way the various alternatives and modifications that may be made to the illustrated embodiments. In this disclosure, numerous specific details provide a thorough understanding of the subject disclosure. It should be understood that aspects of this disclosure may be practiced with other embodiments not necessarily including all aspects described herein, etc. [0049] As used herein, the words “example” and “exemplary” means an instance, or illustration. The words “example” or “exemplary” do not indicate a key or preferred aspect or embodiment. The word “or” is intended to be inclusive rather than exclusive, unless context suggests otherwise. As an example, the phrase “A employs B or C,” includes any inclusive permutation (e.g., A employs B; A employs C; or A employs both B and C). As another matter, the articles “a” and “an” are generally intended to mean “one or more” unless context suggest otherwise. [0050] As used herein the term ‘transdermal delivery system’ means a system for delivery of substance across the human skin or across the human mucosa, typically from the exterior of the skin or mucosa. The transdermal delivery system includes a transdermal patch. [0051] As used herein the term, a ‘spent transdermal delivery system’ means a transdermal delivery system from which drug has been allowed to release across any barrier, including a skin, mucosal or a membrane barrier. [0052] As used herein, the term “spent state” means a state after the release of a drug. [0053] As used herein, the term “as-prepared transdermal drug delivery system” means the transdermal delivery system which is not a spent transdermal drug delivery system 7 34006165.1 [0054] As used herein, the term “backing layer” means a layer in the transdermal delivery system that is vertically farthest from the skin. Typically, the backing layer is a flexible layer and is impermeable to the active ingredients of the transdermal patches like the active pharmaceutical ingredient or the drug, additives, tack modifiers etc. A suitable material or combination of materials may be used as backing layer. Some examples of materials used as backing layers includes but not limited to are Polyethylen-therephthalate (PET), Polyethylene, Polypropylene, Polyurethane, etc. [0055] As used herein, the term “Drug-in-Adhesive Layer” means a layer in the transdermal delivery system having an adhesive material containing the active pharmaceutical ingredient (drug) and any additives. For the purpose of this invention the drug- in-adhesive layer comprises the adhesive composition [0056] As used herein, the term drug is an active pharmaceutical ingredient. Additive is any compound added to the adhesive composition which is not a drug but may provide the composition with one of the or combination of properties like drug stability, crystallization inhibition, patch stability, shelf life, modification to adhesion properties, permeation enhancement etc. [0057] In one of the embodiments, the adhesive composition comprises a silicone PSA, the amine-functional drug is Rivastigmine and the additives are α- Tocopheryl acetate (Vitamin E Acetate) (Additive to improve drug stability), amorphous silicon dioxide (Tack modifier), and Polyethylene glycol (Permeation enhancer). The drug in adhesive layer of the transdermal drug delivery system containing the drug and optionally the additives is in direct contact with the skin when the transdermal delivery systems are in use. [0058] As used herein, the term “Release liner” or “liner layer” means a layer of the transdermal delivery system that is adhesively bonded to the adhesive composition that is peeled off from the adhesive composition prior to its application to the skin. Like the backing layer, this layer is preferably impermeable to the active ingredients and the additives used in the transdermal patch. A suitable material or combination of materials may be used as release liner. Some examples of materials used as release liner includes but not limited to are siliconized PET, siliconized Polypropylene, siliconized Polyethylene, fluor-polymer coated PET, fluoropolymer coated Polypropylene, fluoropolymer coated Polyethylene, etc. 8 34006165.1 [0059] The disclosure may identify a number of different ranges for a component or components in the composition. It will be appreciated that the numerical values of the respective ranges can be combined to form new and non-specified ranges. [0060] The drug-in-adhesive layer is a key component of a transdermal drug delivery system. The pressure sensitive adhesive in such layer is required to compatabilise the drug along with other additives without undergoing significant loss in adhesive properties. [0061] Provided is a composition comprising (i) a silicone pressure sensitive adhesive, and (ii) a bioactive agent dispersed in the silicone pressure sensitive adhesive. In one embodiment, the bioactive agent is an amine functional drug. The composition exhibits excellent adhesive properties including excellent tack and peel strength, storage modulus, and complex viscosity. The compositions are suitable for use as a drug-in-adhesive layer of a transdermal delivery system. The composition also provides excellent shelf-life stability. [0062] The silicone pressure sensitive adhesive comprises a solid MQ resin and a polyorganosiloxane. The MQ resin and the polyorganosiloxane are reacted to form the silicone pressure sensitive adhesive. [0063] In embodiments, the silicone pressure sensitive adhesive can be provided as described in accordance with U.S. Patent No. 12,049,576, which is incorporated by reference herein in its entirety. In accordance with the present compositions, following the reaction of the MQ resin and the polyorganosiloxane in the presence of a base catalyst, the composition is then further reacted with a disilazane. [0064] The MQ resin is not particularly limited and comprises a polymer of M units represented by the formula R¹ ₃SiO_1/2 and Q units of the formula SiO4/2. The MQ resin is primarily formed of such M and Q units but may contain some residual D units (R² ₂SiO_2/2) and T units (R³SiO_3/2). Generally, the MQ resin contains less than 20 mole % of D and T units, less than 15 mole % of D and T units, less than 10 mole % of D and T units, less than 5 mole % of D and T units, even less than 1 mole % of D and T units. [0065] In the MQ resin, R¹, R², and R³ are each independently selected from a C1-C6 monovalent hydrocarbon, a C5-C20 cycloaliphatic radical, a C2-C6 olefinic radical, and a C6-C20 aromatic radical. Examples of suitable C1-C6 monovalent hydrocarbon radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl. Examples of suitable 9 34006165.1 cycloaliphatic radicals include, but are not limited to, cyclopyentyl, cyclohyexyl, cycloheptyl, cyclooctyl, etc. Examples of suitable C2-C6 olefinic radicals include, but are not limited to, vinyl, allyl, etc. Examples of suitable aromatic radicals include, but are not limited to, phenyl. The respective R¹, R², and R³ groups can be the same or different within a given M, D, or T unit. In one embodiment, from about 95 to 100% of the R¹, R², and/or R³ groups are methyl. In one embodiment, substantially all the R¹, R², and/or R³ groups are free of unsaturation. In one embodiment, the MQ resin has from 0 to 0.5 mole % of the R¹, R², and R³ groups contain any unsaturation. [0066] In embodiments, the MQ resin is a solid, solventless resin. The solid, solventless MQ resin has a density in the range of 0.3 to 0.9 g/cm³. The ratio of M units to Q units is on the order of 0.2:1 or greater. In one embodiment, the ratio of M units to Q units is from 0.2:1 to 1.7:1. The MQ resin may comprise some free Si-OH groups. In embodiments, the MQ resin comprises from about 2 % to about 12 % free Si-OH functional groups, from about 4 % to about 10 % free Si-OH functional groups, or from about 5 % to about 8 % free Si-OH functional groups. [0067] The polydiorganosiloxane is selected from a hydroxyl functional polydiorganosiloxane. Polydiorganosiloxanes may also be referred to herein as a silicone gum. In accordance with the present technology, the silicone gum may be a low to high molecular weight gum. [0068] In one embodiment, the polydiorganosiloxane has a viscosity of from about 500 cPs to about 200,000,000 cPs; from about 25,000 cPs to about 150,000,000 cPs; from about 50,000 cPs to about 100,000,000 cPs; from about 75,000 cPs to about 75,000,000 cPs; from about 100,000 cPs to about 50,000,000 cPs; from about 125,000 cPs to about 800,000 cPs; from about 150,000 cPs to about 750,000 cPs; from about 200,000 cPs to about 500,000 cPs; or from about 300,000 cPs to about 450,000 cPs. In one embodiment, the polydiorganosiloxane has a viscosity of from about 50,000 cPs to about 150,000 cPs or from about 75,000 cPs to about 100,000 cPs. In another embodiment, the polydiorganosiloxane has a viscosity of from about 100,000 cPs to about 450,000 cPs; from about 150,000 cPs to about 400,000 cPs; or from about 200,000 to about 300,000 cPs. In another embodiment, the polydiorganosiloxane has a viscosity of from about 300,000 cPs to about 750,000 cps; from about 400,000 cPs to about 700,000 cPs; or from about 500,000 cPs to about 600,000 cPs. Viscosity may be evaluated using any suitable method. In one embodiment, viscosity is determined by 10 34006165.1 dissolving the melt obtained PSA into a suitable solvent at 60% solids and measuring the viscosity at 25°C with a Brookfield (DV1) Viscometer. [0069] The polydiorganosiloxane can comprise a blend of polydiorganosiloxanes of different viscosities. In one embodiment, the polydiorganosiloxane comprises a first polydiorganosiloxane of a first viscosity of about 100,000 cPs to about 450,000 cPs, and a second viscosity of from about 300,000 cPs to about 750,000 cPs, where the second polydiorganosiloxane has a viscosity greater than that of the first polydiorganosiloxane. [0070] In forming the adhesive, the solid MQ resin is present in an amount about 40 wt.% to 70 wt.%, from about 45 wt. % to about 65 wt.%, or from about 50 wt.% to about 60 wt. %,; and the polydiorganosiloxane is present in an amount of from about 30 wt.% to about 60 wt.% , from about 35 wt.% to about 55 wt.%, or from about 40 wt.% to about 50 wt.%.The catalyst is not particularly limited and may be selected from any suitable condensation catalyst. The condensation catalyst can, for example, be an acid catalyst or a base catalyst. In one embodiment, the catalyst is a base catalyst. In one embodiment, the base catalyst can be selected from a chain extension reagent or capping agents selected from a metal siloxalonates, a metal silanolate, a silazane, a bis(alkylamino)silane, or a combination of two or more thereof. Examples of suitable alkali metal silanolates include, but are not limited to, potassium silanolate, lithium silanolate, and sodium silanolate. Examples of suitable metal siloxanolates include, but are not limited to, potassium siloxanolate, lithium siloxanolate, and sodium siloxanolate. Examples of silazanes can be, but are not limited to, suitable bis-silazanes, trisilazanes, tetrasilazanes. Examples of such reagents include, but are not limited to, hexamethylcyclotrisilazane, trimethyltrivinylcyclotrisilazane, octamethylcyclotetrasilazane, alkyl or alkenyl substituted cyclosilazanes of ring sizes 6 or 8, linear alkyl or polyalkyl substituted polysilazanes. Some more specific examples of suitable silazanes include, but are not limited to, 1,1,3,3-tetramethyldisilazane, 1,3- diethyl-1,1,3,3-tetramethyldisilazane, hexamethyldisilazane; cyclic disilazane compounds such as 2,2,5,5-tetramethyl-2,5-disila-1-azacyclopentane and 2,2,6,6- tetramethyl-2,6-disila-1-azacyclohexane; cyclic trisilazane compounds such as 2,2,4,4,6,6-hexamethylcyclotrisilazane and 2,4,6-trimethyl-2,4,6- trivinylcyclotrisilazane; and cyclic tetrasilazane compounds such as 2,2,4,4,6,6,8,8- octamethylcyclotetrasilazane.In forming the adhesive, the catalyst is present in an 11 34006165.1 amount about 0.3 wt.% to 10 wt.%, from about 0.5 wt.% to about 5 wt. %, or from about 1 wt.% to about 2 wt%. [0071] The adhesive composition includes reacting the product of the MQ resin and the polyorganosiloxane with a disilazane. The disilazane is not particularly limited. Examples of suitable disilazanes include, but are not limited to, 1,1,1,3,3,3- hexamethyldisilazane, 1,1,3,3-tetramethyldisilazane, 1,3-bis(3,3,3-trifluoropropyl)- 1,1,3,3-tetramethyldisilazane, 1,3-bis(chloromethyl)tetramethyldisilazane, 1,3- diphenyltetramethyldisilazane, 1,3-divinyl-1,1,3,3-tetramethyldisilazane, 2,2,4,4,6,6- hexamethylcyclotrisilazane, 2,4,6-trimethyl-2,4,6-trivinylcyclotrisilazane, heptamethyldisilazane, octamethylcyclotetrasilazane, hexamethyldisilazane lithium, hexamethyldisilazane sodium, and hexamethyldisilazane potassium. [0072] The solids content of the resulting pressure sensitive adhesive can be adjusted as desired with an appropriate solvent. The solids content of the pressure sensitive adhesive can be selected as desired for a particular purpose or intended application. In one embodiment, the solids content of the pressure sensitive can be adjusted to be from about 30% to about 80%, from about 40% to about 70%, or from about 50% to about 60%. The solvent is preferably a non-aromatic solvent and, more preferably a solvent other than a BTX type solvent. Examples of suitable solvents that may be used to dissolve the pressure sensitive adhesive include, but are not limited to, hydrocarbon solvents, silicone solvents, an ester, a ketone, or an ether. [0073] The process for producing the silicone pressure sensitive adhesive comprises (i) mixing the solid, solventless MQ resin with the polydiorganosiloxane to form a first mixture; (ii) adding the catalyst to the first mixture to catalyze the reaction of the MQ resin and the polydiorganosiloxane to form a pressure sensitive adhesive composition; and (iii) removing the catalyst from the pressure sensitive adhesive composition, where the reaction is free of a solvent. The process may further comprise (iv) dissolving the pressure sensitive adhesive composition in a non-aromatic solvent and adjusting the solids content as desired. [0074] Mixing the solid, solventless MQ resin and the polydiorganosiloxnae can be carried out at a suitable temperature to provide sufficient mixing and dispersion of the MQ resin in the polydiorganosiloxane. In embodiments, the mixture of the MQ resin and the polydiorganosiloxane can be heated at a temperature of from about 25 °C to about 200 °C, from about 50 °C to about 150 °C, or from about 75 °C to about 100 12 34006165.1 °C. In one embodiment, the mixture of the MQ resin and the polydiorganosiloxane can be heated at a temperature of from about 120 °C to about 130 °C. [0075] After addition of the catalyst to the mixture of the MQ resin and the polydiorganosiloxane, the mixture can continue to be heated for a period of time sufficient to complete the condensation/crosslinking reaction. In embodiments, the mixture of the MQ resin, polydiorganosiloxane, and catalyst or chain extension agent can be heated at a temperature of from about 60 °C to about 200 °C, from about 75 °C to about 175 °C , or about 100 °C to about 150 °C. The time for heating may vary. In embodiments, heating can be carried out for anywhere from 1 to 10 hours. [0076] The disilazane can then be added to the composition and reacted. The mixture of MQ resin, polyorganosiloxane, catalyst, and disilazane can be heated at a a temperature of from about 60 °C to about 200 °C, from about 75 °C to about 175 °C , or about 100 °C to about 150 °C. The time for heating may vary. In embodiments, heating can be carried out for anywhere from 1 to 10 hours. [0077] In embodiments, the silicone pressure sensitive adhesive has a silanol content of about 8000 ppm or less, about 7000 ppm or less, about 6000 ppm or less, even about 5000 ppm or less. [0078] In embodiments, the pressure sensitive adhesive contains less than 2000 ppm, less than 1800 ppm, less than 1500 ppm, less than 1250 ppm, less than 1000 ppm less than 750 ppm, less than 500 ppm, less than 250 ppm, less than 100 ppm, even less than 50 ppm of one or more of a octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), or dodecamethylcyclohexasiloxane (D6). In one embodiment, the pressure sensitive adhesive contains each of a D4, D5, or D6 cyclic siloxane in an amount of less than 2000 ppm, less than 1800 ppm, less than 1500 ppm, less than 1250 ppm, less than 1000 ppm less than 750 ppm, less than 500 ppm, less than 250 ppm, less than 100 ppm, or less than 50 ppm. [0079] In embodiments, the bioactive agent is selected from an amine functional drug. The amine functional drug is not particularly limited and can be selected as desired for a particular purpose or intended application. Examples of suitable amine functional drugs include, but are not limited to, amphetamine, methylphenidate, rivastigmine, rotigotine, fentanyl, paroxetine clonidine, amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, doxepin, ethopropazine, flavoxate, 13 34006165.1 homatropine, imipramine, loxapine, mazaticol, metixene, oxybutinin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, scopolamine, telenzepine, theophylline, tolterodine, trimipramine, trihexyphenidyl, tropatepine, tropicamide, or a combination of two or more thereof. [0080] The bioactive agent, e.g., the amine functional drug, can be present in the composition in an amount of from about 5 wt.% to about 30 wt.%, from about 10 wt. % to about 25 wt.%, or from about 15 wt.% to about 20 wt.% based on the weight of the composition. [0081] The composition may include other additives or ingredients as desired and may be useful for application in a drug delivery system. Examples can include, but are not limited to, additives that prevent degradation of the bioactive agent (e.g., the amine functional drug), tack modifiers, materials that facilitate transdermal drug delivery, and the like. [0082] In one embodiment, the composition includes an additive that is suitable for preventing degradation of the bioactive agent. Examples include, but are not limited to, Vitamin E Acetate, α-tocopherol (Vitamin E), Ascorbyl palmitate, butylated hydroxytoluene (BHT), or a combination of two or more thereof. In one embodiment, the composition includes a tack modifier. Examples of suitable tack modifiers include, but are not limited to, tack modifier amorphous silicon dioxide, rosine ester, synthetic tackifier , isoprene rubber, or a combination of two or more thereof. [0083] In one embodiment, the composition includes an additive to facilitate drug delivery (e.g., to facilitate transdermal drug delivery). Examples of suitable drug delivery agents include, but are not limited to, Polyethylene glycol, oleyl alcohol, isopropyl myristate, menthol, Diethylene glycol monoethyl ether (Transcutol P), or a combination of two or more thereof. [0084] The respective additives are optional additives that may be included as desired. When added to the composition, such additives can be independently provided in an amount of 0.01 wt.% or greater. In embodiments, additives can be added in an amount of from about 0.01 wt.% to about 10 wt.%, from about 0.05 wt.% to about 5 wt.%, or from about 0.1 wt.% to about 1 wt.% based on the weight of the composition. [0085] In one aspect, the present invention provides a composition comprising: (i) a silicone pressure sensitive adhesive; and 14 34006165.1 (ii) an amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive. [0086] In one aspect, the present invention provides a composition comprising: (i) a silicone pressure sensitive adhesive; and (ii) an amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises 40-70% by weight of a solid MQ resin and 60 – 30% by weight of a polyorganosiloxane, based on total weight of adhesive and wherein, the silicone pressure sensitive adhesive has a silanol content of less than 8000 ppm. [0087] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises 40-70% by weight of a solid MQ resin and 60 – 30% by weight of a polyorganosiloxane, based on total weight of adhesive and wherein, the silicone pressure sensitive adhesive has a cyclosiloxane content less than 50 ppm. [0088] In one aspect, the invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises 5 to 30% amine functional drug. [0089] In one aspect, the invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the amine functional drug is one or more drug (s) selected from the group consisting of amphetamine, methylphenidate, rivastigmine, rotigotine, fentanyl, paroxetine clonidine, amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, 15 34006165.1 doxepin, ethopropazine, flavoxate, homatropine, imipramine, loxapine, mazaticol, metixene, oxybutinin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, scopolamine, telenzepine, theophylline, tolterodine, trimipramine, trihexyphenidyl, tropatepine, and tropicamide. [0090] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine-functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the composition further comprises a first additive, an optional second additive, and optional third additive. [0091] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition further comprises a first additive and an optional second additive and wherein the first additive, the optional second additive, and optional third additive is individually present in an amount of not less than 0.01%. [0092] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition further comprises a first additive and optional second and optional third additives and wherein the first additive is selected from the group consisting of Vitamin E Acetate, α-tocopherol (Vitamin E), Ascorbyl palmitate or butylated hydroxytoluene (BHT), or from any group of chemicals known in the art to prevent degradation of amine functional drugs. [0093] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition further comprises a first additive and optional second and optional third additives and wherein the optional second additive is selected from the group consisting of amorphous silicon dioxide, rosine ester, 16 34006165.1 synthetic tackifier , isoprene rubber, or from any group of materials known in the art to alter the tack. [0094] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition further comprises a first additive and optional second and third additives and wherein the optional third additive is selected from the group consisting of Polyethylene glycol, oleyl alcohol, isopropyl myristate, menthol, Diethylene glycol monoethyl ether (Transcutol P), or from any group of chemicals known in the art to facilitate drug delivery via transdermal route. [0095] In one aspect, the present invention provides a composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the composition retains the tack and peel strength at least in the range of 60-80% of its initial value over a period of at least six months at temperature in the range of 25 to 30^oC. [0096] In one aspect, the present invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition has a storage modulus of the order of 10³ to 10⁵ Dyne/cm² measured at an angular frequency of 0.01 rad/s at a temperature of 32 ^oC. [0097] In one aspect, the present invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the adhesive composition has a storage modulus of the order of 10⁶ to 10⁷ Dyne/cm² measured at an angular frequency of 100 rad/s and at temperature of 32 ^oC. 17 34006165.1 [0098] In one aspect, the present invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the body of the silicone pressure sensitive adhesive and wherein the adhesive composition has a complex viscosity of the order of 10⁶ to 10⁸ poise measured at an angular frequency of 0.01 rad/s and at temperature of 32 ^oC. [0099] In one aspect, the present invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the body of the silicone pressure sensitive adhesive and wherein the amine functional drug has a cumulative release of not less than 30 % over a duration of 24 hrs across a cellulosic membrane. [0100] In one aspect , the invention provides transdermal drug delivery system comprising: (i) a backing layer; (ii) a drug-in-adhesive layer; and (iii) a liner layer, wherein the drug-in-adhesive layer comprises an adhesive composition comprises (i) a silicone pressure sensitive adhesive; and (ii) an amine functional drug, wherein the amine functional drug is dispersed in the body of the silicone pressure sensitive [0101] In one aspect , the invention provides transdermal drug delivery system comprising: (i) a backing layer; (ii) a drug-in-adhesive layer; and (iii) a liner layer, wherein the transdermal drug delivery system has a residual drug content of not more than 5 to 20 % by weight, in its spent state, as compared to its original drug content of an as-prepared transdermal drug delivery system. [0102] In another aspect , the invention provides transdermal drug delivery system consisting essentially of (i) a backing layer; 18 34006165.1 (ii) a drug-in-adhesive layer ; (iii) a liner layer; and (iv) optionally a skin contact layer wherein the skin contact layer is selected from an acrylate or silicone based pressure sensitive adhesive. [0103] In another aspect , the invention provides transdermal drug delivery system consisting essentially of (i) a backing layer; (ii) a drug-in-adhesive layer; and (iii) a liner layer, wherein the transdermal drug delivery system is packaged in an atmosphere of nitrogen [0104] In another aspect , the invention provides transdermal drug delivery system consisting essentially of (i) a backing layer; (ii) a drug-in-adhesive layer; and (iii) a liner layer, wherein the system passes stability test at temperature of 40°C ± 2°C and Relative Humidity of 75% ± 5% for at least one month as per ICH guidelines Q1A (R2). [0105] In one aspect, the present invention provides a transdermal delivery system comprising an adhesive composition wherein the adhesive composition comprises: (i) a silicone pressure sensitive adhesive; and (ii) amine functional drug, wherein the amine functional drug is dispersed in the silicone pressure sensitive adhesive and wherein the system has an f2 value (similarity factor) in the range of 50 – 100 as compared to the commercial rivastigmine Exelon® transdermal delivery system. [0106] The following examples are intended to illustrate aspects and embodiments of the present technology. All parts and percentages are by weight and all temperatures are in Celsius unless explicitly stated otherwise. All patents, other publications, and U.S. patent applications referred to in the instant application are incorporated herein by reference in their entireties. [0107] Examples [0108] Pressure Sensitive Adhesives 1 – 3 19 34006165.1 [0109] Pressure Sensitive Adhesive 1 (PSA 1): PSA 1 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in example 11 of the patent US 20220325154A1, incorporated herein by reference, followed by reaction with 1,1,1,3,3,3-hexamethyldisilazane. In a typical synthetic method, a hydroxyl terminated polydimethylsiloxane gum (153.19 g) was added followed by MQ silicone resin (206.81 g) or vice versa in a 3-liter planetary mixture equipped with helical blade & heating apparatus, thermocouple, sparge tube (for N2 sparging). The reactor temperature was set to 125-130 ^oC under positive nitrogen flow. The above mixture was agitated at 125-130 ^oC until a completely homogeneous solution/dispersion was obtained. The mixing process was continued for 1-4 hours until MQ resin was dissolved or dispersed completely in the gum mixture. 2.0 g of 2,4,6- Trimethyl-2,4,6-trivinylcyclotrisilazane (CAS-No:5505-72-6) was added and reaction continued for another 3 hrs. The reactor temperature was increased to 150 ^oC and hold the temperature for 2-3 hours under N2. Following this, the reactor temperature was brought down to 120 ^oC and N₂ flow was stopped. 18g 1,1,1,3,3,3- hexamethyldisilazane (CAS-No: 999-97-3) was added and reaction was allowed to proceed for 2 hours. The reactor temperature was increased to 150 ^oC and hold the temperature for 2-3 hours under N2. Following this, the reactor was cooled. The solids content was then adjusted to 60% by dissolving the resulting high viscous mass in 40 parts ethyl acetate (~ 200 grams) at 50 ^oC. The GPC of the PSA had multimodal resin and polymer peaks. [0110] Pressure Sensitive Adhesive 2 (PSA 2) : PSA 2 is a silicone pressure sensitive adhesive prepared by the addition of 0.4% fumed silica amorphous silicon dioxide (Aerosil®- 200 from Evonik) in PSA 1 above. In a typical synthetic method, a hydroxyl terminated polydimethylsiloxane gum (153.19 g) was added followed by MQ silicone resin (206.81 g) or vice versa in a 3-liter planetary mixture equipped with helical blade & heating apparatus, thermocouple, sparge tube (for N2 sparging). The reactor temperature was set to 125-130 ^oC under positive nitrogen flow. The above mixture was agitated at 125-130 ^oC until a completely homogeneous solution/dispersion was obtained. The mixing process was continued for 1-4 hours until MQ resin was dissolved or dispersed completely in the gum mixture. 2.0 g of 2,4,6- Trimethyl-2,4,6-trivinylcyclotrisilazane (CAS-No:5505-72-6) was added and reaction continued for another 3 hrs. The reactor temperature was increased to 150 ^oC and hold the temperature for 2-3 hours under N2. Following this, the reactor temperature was 20 34006165.1 brought down to 120 ^oC and N2 flow was stopped. 18 g 1,1,1,3,3,3- hexamethyldisilazane (CAS-No: 999-97-3) was added and reaction was allowed to proceed for 2 hours. The reactor temperature was increased to 150 ^oC and hold the temperature for 2-3 hours under N2. The reactor was brought down to 135 ^oC and 1.44 g Aerosil®-200 was added and allowed to mix for 2 hours. Following this, the reactor was cooled. The solids content was then adjusted to 60% by dissolving the resulting high viscous mass in 40 parts ethyl acetate (~ 200 g) at 50 ^oC. The GPC of the PSA had multimodal resin and polymer peaks. [0111] Comparative Pressure Sensitive Adhesive 3 (PSA 3):PSA 3 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in Example 11 of the patent US 20220325154A1,incorporated herein by reference. In a typical synthetic method, a hydroxyl terminated polydimethylsiloxane gum (153.19 g) was added followed by MQ silicone resin (206.81 g) or vice versa in a 3-liter planetary mixture equipped with helical blade & heating apparatus, thermocouple, sparge tube (for N₂ sparging). The reactor temperature was set to 125-130 ^oC under positive nitrogen flow. The above mixture was agitated at 125-130 ^oC until a completely homogeneous solution/dispersion was obtained. The mixing process was continued for 1-4 hours until MQ resin was dissolved or dispersed completely in the gum mixture. 2.0 g of 2,4,6-Trimethyl-2,4,6-trivinylcyclotrisilazane (CAS-No:5505-72-6) was added and reaction continued for another 3 hrs. Finally, the reactor temperature was increased to 150 ^oC and hold the temperature for 2-3 hours under N2. Following this, the reactor was cooled. The solids content was then adjusted to 60% by dissolving the resulting high viscous mass in 40 parts ethyl acetate (~ 200 g) at 50 ^oC. The GPC of the PSA had multimodal resin and polymer peaks. [0112] Characterization of Adhesive Properties of the Adhesives: To test the suitability of the Pressure Sensitive adhesive to be used in the transdermal patches, Pressure Sensitive adhesive without and with Rivastigmine were prepared by coating 100 um thick layer of 60% adhesive solution on a PET film. For Pressure Sensitive adhesive with Rivastigmine, 9 wt.% Rivastigmine base was dissolved in 60% Pressure Sensitive adhesive solution. The coated Pressure Sensitive adhesive were then dried using Mathis-labcoater-labdryer (Switzerland) at 50 ^oC for 50 minutes to remove the solvent. The dry adhesive film thus formed were clear, transparent and bubble free. [0113] Probe Tack Measurement: In the probe tack test, a probe was pushed forward to contact with the adhesive surface and then retracted at a predefined speed. 21 34006165.1 The force required to break the bond after a short period of contact is plotted as force- time diagram. The probe tack test was performed with the CT3 Texture Analyzer (Brookfield, USA) with the following test parameters: [0114] Test speed: 0.5 mm/s [0115] Return speed: 0.01–1.00 mm/s [0116] Applied force: 0.9 N [0117] Contact time: 10 seconds. [0118] Temperature: 32° C [0119] The cylindrical probe TA 10 (clear acrylic) with a diameter of 12.7 mm and length of 35 mm were used and fixed with fixture TA-ATT. The patches consisting of the backing membrane and adhesive composition were fixed by double-sided adhesive tape on the measuring table. All tests were run in triplicate. [0120] 180^o Peel Strength Measurement: The 180° peel adhesion strength measures the force required to peel away an adhesive once it has been attached to a surface (stainless steel type 314). This test was carried out as per the ASTM D 3330 test guidelines, on a CT3 Texture Analyzer by Brookfield USA with TexturePro CT software. All tests were performed in triplicate. The conditions of the test were as follows: • Test Type: Tension • Target type: Distance • Target value:45 mm • Hold time:6 sec • Triggered load:0.05 N • Test speed:1 mm/s • Probe: TA2/100 • Fixture: TA-DGA • Peel rate: 300mm/min • Dwell time: 5 Minutes [0121] Viscoelastic Properties: The viscoelastic properties of the silicone PSAs with and without rivastigmine have been thoroughly characterized by the dynamic rheological analysis. The experimental process involves casting of PSA onto a suitable release liner and drying at 150 ° C for 1 hour and then transferring from release linear to the DHR3 rheometer (TA Instruments. A 25 mm parallel plate 22 34006165.1 geometry were used in oscillation mode with an angular strain of 0.01% to generate the rheograms. The storage modulus [G′] at lower angular frequency ( ω = 0.01 rad/s) represents the adhesive strength during application of the adhesive whereas the G′ at higher angular frequency ( ω = 100 rad/s) relates to the peel force at debonding. The complex viscosity values on the other hand compare the cold flow properties of these adhesives. [0122] Table 1: Tack Force, Peel Strength and Viscoelastic Properties of PSA without and with Rivastigmine Adhesive Without Rivastigmine With Rivastigmine Tack Peel G' G'(100 Complex Tack Peel G' G'(100 Complex ty x

[0123] From the data presented in Table-1, it is clear that, the inventive PSA (PSA-1 and PSA-2) does not display a noticeable loss of tack force and peel strength or viscoelasticity, as compared to the comparative PSA (PSA 3) upon loading of the amine functional drug, i.e. Rivastigmine. [0124] PSA 1 and PSA 2 were further used to prepare transdermal delivery system of the invention in accordance with examples 1 to 6 below, with the transdermal patch size being same as comparative example 1. [0125] Example 1: Rivastigmine base, Vitamin E acetate, and fumed silica Aerosil®-200 were dissolved in a 60% solution of PSA 1 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro- coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the 23 34006165.1 coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0126] Example 2: Rivastigmine base and Vitamin E acetate were dissolved in a 60% solution of PSA 2 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro-coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0127] Example 3: Rivastigmine base, Vitamin E acetate, and Polyethylene glycol (PEG) were dissolved in a 60% solution of PSA 2 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro- coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0128] Example 4: Rivastigmine base, Vitamin E acetate, and Isopropyl myristate (IPM) were dissolved in a 60% solution of PSA 2 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro- coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0129] Example 5: Rivastigmine base, Vitamin E acetate, and Oleyl alcohol were dissolved in a 60% solution of PSA 2 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro-coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0130] Example 6: Rivastigmine base, Vitamin E acetate, and menthol were dissolved in a 60% solution of PSA 2 in ethyl acetate in predetermined amounts. 100 µm wet thickness of this solution is coated on fluoro-coated PET release liner and allowed to dry at 50 ^oC for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0131] Comparative Example 1: The commercially available product Exelon® is used as a reference (Comparative example 1). Exelon® is a commercially available rivastigmine containing patch having a rivastigmine containing acrylic based layer (60 g/m²) and a rivastigmine-free silicone based skin contact layer (30 g/m²) and 24 34006165.1 contains rivastigmine in an amount of 1.8 mg/cm², provided by Novartis pharma. The physical dimension of the patch is 10 cm². [0132] Rivastigmine adhesive composition Table 2 S.No. Component Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 PSA 1 120 mg - ^{- - - -}

[0133] Drug Release Studies of Adhesive Compositon: The drug release studies for rivastigmine base loaded transdermal patches were carried out as per FDA guidelines (Reference: https://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm).The drug dissolution was carried out using USP Dissolution apparatus type VI (cylinder).The speed of stirring was 50 rpm at 32˚C. The drug release media selected was 500 ml of 0.9% NaCl solution. The fluoro-coated release liner is removed from the transdermal patch. The patch was applied on the side of the cylinder using a double sided adhesive 25 34006165.1 tape with the adhesive layer of the trandermal patch facing outside. The Cuprophan membrane (Cellulose fibre, synthetic non-biocompatible membrane) was applied immediately onto the patch. This cylinder assembly was subjected to the selected media for a period of 24 hours and samples were withdrawn at several timepoints viz, 1, 2, 4, 7, 9, 12, and 24 hours. [0134] Figure 2 shows that the cumulative release of drug in example 2 is not deviant from that of comparative example 1. [0135] Residual Drug Studies of Adhesive Compositon: [0136] After the drug release study, the spent transdermal patches are taken to determine the residual drug content by extracting the drug in an appropriate solvent. The solvent used for the extraction of residual drug was Acetonitrile. The patches after drug release studies were immersed in acetonitrile and subjected to sonication for a period of 10 minutes. The solvent was then filtered and analysed for the dissolved drug content using HPLC. [0137] HPLC method: HPLC system: JASCO HPLC Pump: JASCO PU 2080 Detector: Photodiode array detector (PDA detector) Wavelength: 210 nm Column: ODS C18, 5μm, 4.6 x 250 mm Mobile phase: Phosphate buffer pH 3: Methanol: Acetonitrile (45:30:25) Flow rate: 1 ml/min Injection volume: 10 μL Run time: 10 minutes. [0138] Figure 3 shows that the % residual rivastigmine was considerably less for the transdermal delivery system of example 2 compared to that of comparative example 1. [0139] Drug Permeation Study using Wistar Rat Skin: Ex-vivo skin permeation studies were carried out to test the drug permeation through the skin barrier to reach the systemic circulation. The ex-vivo best model reported to date for the prediction of the in vivo permeation of transdermal products is the use of skin in the Franz Cell apparatus wherein the animal skin was placed between the donor and the receptor compartments. The transdermal patches were placed in the donor compartment such that the drug loaded side faces the skin membrane. Considering the in vitro drug 26 34006165.1 release profiles, Example 2 was taken further for testing the ex vivo permeation. Different permeation enhancers (Additive 3) were screened to see their effect on the permeation profiles of the drug in the presence of the added permeation enhancers which constitute Example 3 to 6. Wistar rats (250-300 grams) were shaved to remove the hair and their abdominal skin was removed carefully. The removed skin was cleaned carefully, and the subcutaneous adhered fatty layer was removed without damaging the skin. The removed whole skin was used fresh or was stored at 0-2˚C and was used within a week. The skin was kept between the donor and the receptor compartment of Franz Diffusion cell as depicted in the figure below. The receptor medium was filled with 0.9% NaCl solution. The skin was continuously kept in contact with the receptor medium. The following conditions were maintained throughout the study as per the following protocol. Instrument: Franz diffusion cell. Membrane: Abdominal skin of Wistar rats. Media: 0.9% NaCl solution. Capacity of each cell: 12 ml. Aliquot volume: 1 ml. Time points (hours): 0, 1, 2, 4, 8, 12, 24. Stirring speed (rpm): 350. [0140] The sample aliquots (1 ml) were withdrawn at the specified time points and the receptor was replaced with fresh media to maintain the sink conditions. The concentration of drug in the aliquots was determined using HPLC method as described above. The amount drug permeated was plotted vs time in days to obtain the permeation profile for each formulation. The permeation profile of the developed patches was compared with the marketed formulation. [0141] Figure 4 shows the results for permeation of drug through the Wistar Skin. The permeation of the marketed formulation was found to be around 50%, indicating that 50% of the drug from the patch permeates the skin over a period of 24 hours. The marketed patch contains 18 mg drug loaded in the patch intended to deliver around 9.5 mg in one day. The permeation data obtained from the above ex-vivo permeation studies can be well correlated with the label claim of the marketed preparation allowing around 9.5 mg drug delivery across the skin barrier in 24 hours of time. Several permeation enhancers such as polyethylene glycol (PEG) in Example 3, isopropyl myristate (IPM) in Example 4, oleyl alcohol in Example 5, and menthol in 27 34006165.1 Example 6 were screened at a concentration of 2% to match the skin permeation kinetics of the developed patch to that of the marketed comparator product. Permeation in Example 3 established a good correlation with the permeation from the comparative example 1, whereas, permeation profile of the drug from Example 2, which is without any permeation enhancer depicted a slow permeation of the drug. Therefore, Example 3 was further selected for accelerated stability. [0142] Accelerated Stability Study: The samples of Example 3 were packed in a primary packaging of heat sealed child resistant multilaminate sachets made of paper (30 micron), polyester (40 micron) and aluminium (40 micron). The sealed packets were then put in a secondary packaging which is a cardboard box, and were kept in stability chambers for accelerated studies and were tested for the listed parameters at the specified time points. All the samples were properly packed in primary and secondary packaging to avoid or minimize the direct contact of samples with external moisture and external temperature. The storage conditions of the batches prior to the start of stability testing were at controlled temperature of not more than 25°C. The samples to be kept in respective stability chambers were labeled properly and with an intact primary and secondary packaging was ensured. The age of samples before placing them in to the stability chambers was 4 days. [0143] Table 3: The stability studies maintained as per ICH guidelines Q1A (R2). Type of stability Storage conditions Testing frequency (in months)

28 34006165.1 [0144] Table 4: Stability specifications and analytical methodology references. Sr. no. Test Specifications Method Optical y r I ll

[0145] Table 5: Results of Accelerated Stability Studies up to 1 month. Example 3 es 4 4

29 34006165.1 [0146] What has been described above includes examples of the present specification. It is, of course, not possible to describe every conceivable combination of components or methodologies for purposes of describing the present specification, but one of ordinary skill in the art may recognize that many further combinations and permutations of the present specification are possible. Accordingly, the present specification is intended to embrace all such alterations, modifications and variations that fall within the spirit and scope of the appended claims. Furthermore, to the extent that the term “includes” is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim. [0147] The foregoing description identifies various, non-limiting embodiments of an aromatic-containing silicone compound and curable compositions comprising such compounds. Modifications may occur to those skilled in the art and to those who may make and use the invention. The disclosed embodiments are merely for illustrative purposes and not intended to limit the scope of the invention or the subject matter set forth in the claims. 30 34006165.1

Claims

CLAIMS What is claimed is: 1. A composition comprising: (i) a silicone pressure sensitive adhesive comprising (a) a solid MQ resin, and (b) a polyorganosiloxane; and (ii) a bioactive agent, wherein the bioactive agent is dispersed in the silicone pressure sensitive adhesive.

2. The composition of claim 1, wherein the silicone pressure sensitive adhesive (i) comprises from about 40% to about 70% by weight of the solid MQ resin, and from about 30% to about 60% of the polyorganosiloxane based on the weight of the silicone pressure sensitive adhesive.

3. The composition of claim 1 or 2, wherein the silicone pressure sensitive adhesive has a silanol content of about 8000 or less.

4. The composition of any of claims 1-3, wherein the silicone pressure sensitive adhesive has a cyclosiloxanes content of about 50 ppm or less.

5. The composition of any of claims 1-4 comprising the bioactive agent in an amount of from about 5% to about 30% of the composition.

6. The composition of any of claims 1-5, wherein the bioactive agent is an amine functional drug.

7. The composition of claim 7, wherein the amine functional drug is selected from the group consisting of amphetamine, methylphenidate, rivastigmine, rotigotine, fentanyl, paroxetine clonidine, amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, doxepin, ethopropazine, flavoxate, homatropine, imipramine, loxapine, mazaticol, metixene, oxybutinin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, scopolamine, telenzepine, theophylline, tolterodine, trimipramine, trihexyphenidyl, tropatepine, tropicamide, or a combination of two or more thereof.

8. The composition of any of clais 1-7 further comprising a first additive for preventing degradation of the bioctive agent. 31 34006165.1

9. The composition of claim 8, wherein the first additive is selected from the group consisting of Vitamin E Acetate, α-tocopherol (Vitamin E), Ascorbyl palmitate, butylated hydroxytoluene (BHT), or a combination of two or more thereof.

10. The composition of any of claims 1-9 further comprising a second additive selected from a tack modifier.

11. The composition of claim 10, wherein the tack modifier is selected from the group consisting of amorphous silicon dioxide, rosine ester, synthetic tackifier , isoprene rubber, or a combination of two or more thereof.

12. The composition of any of claims 1-11 further comprising a third additive selected from a drug delivery additive.

13. The composition of claim 12, wherein the third additive is selected from Polyethylene glycol, oleyl alcohol, isopropyl myristate, menthol, Diethylene glycol monoethyl ether (Transcutol P), or a combination of two or more thereof.

14. The composition of any of claims 8-13, wherein the first additive, the second additive, and third additive are independently present in an amount of from about 0 to about 10 percent by weight or greater based on the weight of the composition.

15. The composition of any of claims 1-14, wherein the composition retains the tack and peel strength at least in the range of 60-80% of its initial value over a period of at least six months at temperature in the range of 25 to 30^oC.

16. The composition of any of claims 1-15, wherein the composition has a storage modulus of the order of 10³ to 10⁵ Dyne/cm² measured at an angular frequency of 0.01 rad/s at a temperature of 32 ^oC.

17. The composition of any of claims 1-16, wherein the composition has a storage modulus of the order of 10⁶ to 10⁷ Dyne/cm² measured at an angular frequency of 100 rad/s and at temperature of 32 ^oC.

18. The composition of any of claims 1-17, wherein the composition has a complex viscosity of the order of 10⁶ to 10⁸ poise measured at an angular frequency of 0.01 rad/s and at temperature of 32 ^oC.

19. The composition of any of claims 1-18, wherein the amine functional drug has a cumulative release of not less than 30 % over a duration of 24 hours across a cellulosic membrane.

20. A transdermal drug delivery system comprising: (i) a backing layer; 32 34006165.1 (ii) a drug-in-adhesive layer comprising the composition of any of claims 1-19.

21. The transdermal drug delivery system of claim 20 having a residual drug content of not more than 5 to 20 % by weight, in its spent state, as compared to its original drug content of an as-prepared transdermal drug delivery system.

22. The transdermal drug delivery system of claim 20 or 21 comprising a skin contact layer wherein the skin contact layer is selected from an acrylate or silicone based pressure sensitive adhesive.

23. The transdermal drug delivery system of any of claims 20-22, wherein the transdermal drug delivery system is packaged in an atmosphere of nitrogen.

24. The transdermal drug delivery system of any of claims 20-23, wherein the system passes stability test at temperature of 40°C ± 2°C and Relative Humidity of 75% ± 5% for at least one month as per ICH guidelines Q1A (R2).

25. The transdermal drug delivery system of any of claims 20-23, wherein the system has an f2 value (similarity factor) in the range of 50 to 100 as compared to the commercial rivastigmine transdermal delivery system. 33 34006165.1