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WO2025038384A1 - Compositions adhésives pharmaceutiques - Google Patents

Compositions adhésives pharmaceutiques Download PDF

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Publication number
WO2025038384A1
WO2025038384A1 PCT/US2024/041470 US2024041470W WO2025038384A1 WO 2025038384 A1 WO2025038384 A1 WO 2025038384A1 US 2024041470 W US2024041470 W US 2024041470W WO 2025038384 A1 WO2025038384 A1 WO 2025038384A1
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WO
WIPO (PCT)
Prior art keywords
composition
group
pressure sensitive
sensitive adhesive
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/041470
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English (en)
Inventor
Arindam SANNIGRAHI
Pradeep Ratilal VAVIA
Kshitija Milind Phatak
Praveen Mishra
Debarshi DASGUPTA
Sandeep NAIK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Momentive Performance Materials Inc
Original Assignee
Momentive Performance Materials Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Momentive Performance Materials Inc filed Critical Momentive Performance Materials Inc
Publication of WO2025038384A1 publication Critical patent/WO2025038384A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J183/00—Adhesives based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon, with or without sulfur, nitrogen, oxygen, or carbon only; Adhesives based on derivatives of such polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/445—Block-or graft-polymers containing polysiloxane sequences containing polyester sequences
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/452—Block-or graft-polymers containing polysiloxane sequences containing nitrogen-containing sequences
    • C08G77/455—Block-or graft-polymers containing polysiloxane sequences containing nitrogen-containing sequences containing polyamide, polyesteramide or polyimide sequences
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/458—Block-or graft-polymers containing polysiloxane sequences containing polyurethane sequences
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/42—Block-or graft-polymers containing polysiloxane sequences
    • C08G77/46—Block-or graft-polymers containing polysiloxane sequences containing polyether sequences
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
    • C08G77/70—Siloxanes defined by use of the MDTQ nomenclature
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers

Definitions

  • the present invention relates to an adhesive composition comprising a silicone pressure sensitive adhesive for transdermal drug delivery of a steroid drug.
  • This invention also relates to an adhesive composition wherein the steroid drug is resistant to crystallization in the adhesive for not less than a week and to a transdermal delivery system comprising the adhesive composition.
  • PSAs Pressure sensitive adhesives
  • TDDSs transdermal drug delivery systems
  • Common classes of pressure sensitive adhesives used in TDDSs include silicone-based and acrylate-based PSAs.
  • 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.
  • 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).
  • PDMS polydimethylsiloxane
  • 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 chemical inertness, electrical insulating properties, biocompatibility, and the ability to adhere to low surface energy substrates such as silicone release liners, polytetrafluoroethylene, and fluorohalocarbon materials.
  • Transdermal delivery of drugs that is, delivery of drugs through the skin, or mucosa, provides many advantages. The method is a comfortable, convenient, and noninvasive way of administering drugs. Many of the variables and side effects associated with oral administration are eliminated.
  • the silicone-based PSAs generally provide a higher drug flux and a higher active agent utilization compared to acrylate-based PSAs. Silicone adhesives due to their non-irritating and non-sensitizing behavior towards skin is highly sought after as an adhesive for transdermal drug delivery systems. Usually, no interaction between the active agent and the silicone groups occurs. [0009] In the manufacturing of TDDSs polymer blends have been utilized containing 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. However, physical blends may be subject to phase separation.
  • Steroid drugs represent a preferred class of drugs for use in conjunction with the drug delivery device. Steroid drugs have been difficult materials to administer transdermally, historically because of their generally poor (low) skin permeation properties. Historically, skin permeation enhancers have been used to achieve therapeutic blood-levels in patients.
  • Examples of steroid drugs useful herein include: progestogens such as norethindrone, norethindrone acetate, desogestrel, 3-keto desogestrel, gestadene and levonorgestrel; estrogens such as estradiol and its esters, e.g., estradiol valerate, cyprionate, decanoate and acetate, as well as ethinyl estradiol; androgens such as testosterone and its esters; and corticosteroids such as cortisone, hydrocortisone, and fluocinolone acetonide.
  • progestogens such as norethindrone, norethindrone acetate, desogestrel, 3-keto desogestrel, gestadene and levonorgestrel
  • estrogens such as estradiol and its esters, e.g., estradiol valerate, cyprionate, decanoate
  • estradiol is an estrogen steroid hormone being used as a medication in the hormonal therapy.
  • Transdermal delivery of estradiol is a preferred as means of sustained dosage for the patient.
  • concentrations of the dissolved estradiol should be high and repeatedly form supersaturated, thermodynamically metastable, or unbalanced systems that possess a high tendency to crystallize.
  • estradiol is incompatible with silicone pressure sensitive adhesives and tends to crystallize in the adhesive matrix. This limits the use of silicone pressure sensitive adhesives in the transdermal drug delivery patches of estradiol.
  • estradiol drug in polymer matrix either in the dissolved or precipitated state significantly affect the performance of the transdermal patch as such drug release performance and adhesive performance.
  • Conventional attempts to prepare successful transdermal delivery systems for the delivery of Steroid drugs relied on either having the drug in a layer other than the adhesive layer or by utilizing a combination of silicone and acrylate PSAs for preparing the drug delivery system, or by utilization of significant amount of crystallization inhibitors. These are not approaches that are attractive from a manufacturing or commercial standpoint.
  • the conventional transdermal delivery systems for steroid drugs such as Estradiol encounter the difficulty of formulating a composition that can achieve sustained drug delivery (e.g., at therapeutic levels) over a period of time of 7 days.
  • the invention provides a transdermal drug delivery system for delivering at least one steroid drug, the system consisting essentially of: (i) a backing layer; (ii) a Steroid drug- in- adhesive layer; and (iii) a liner layer, wherein the steroid drug in adhesive layer comprised silicone pressure sensitive adhesive.
  • the invention provides a transdermal drug delivery system for delivering at least one steroid drug, the system consisting essentially of: (i) a backing layer; (ii) a Steroid drug in adhesive layer; and (iii) a liner layer, 4 34012696.1 wherein the steroid drug is a steroid hormone dispersed in a silicone pressure sensitive adhesive.
  • composition comprising: (i) a silicone pressure sensitive adhesive comprising (a) a solid MQ resin, (b) a polyorganosiloxane, and (c) a siloxane comprising a hydrophilic group; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive.
  • the hydrophilic group of the siloxane (c) is selected from the group consisting of an ionic group, an ionizable group, a zwitterionic group, or a polar hydrophilic group.
  • the hydrophilic group is selected from a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, and a polycarbonate.
  • the siloxane comprising a hydrophilic group (c) is selected from a compound of the formula: M 1 aM 2 bM 3 cD 1 dD 2 eD 3 fT 1 gT 2 hT 3 iQ 1 jQ 2 kQ 3 lQ 4 oQ 5 p
  • R 10 SiO1/2 M 3 R 11 R 12 R 13 SiO 1/2
  • D 1 R 14 R 15 SiO2/2
  • D 2 R 16 R 17 SiO 2/2
  • D 3 R 18 R 19 SiO2/2
  • T 1 R 20 SiO 3/2
  • Q 1 Si(OR 23 )1O3/2
  • Q 2 Si(OR 24 ) 2 O 2/2
  • Q 3 Si(OR 25 )3O1/2
  • Q 4 Si(OR 26 )4
  • SiO 4/2 SiO 4/2 where:
  • the silicone pressure sensitive adhesive comprises the siloxane comprising a hydrophilic group (c) in an amount of from about 0.1% to about 10% by weight based on the weight of the silicone pressure sensitive adhesive.
  • the silicone pressure sensitive adhesive comprises the solid MQ resin (a) in an amount of from about 30% to about 70% by weight; the polyorganosiloxane (b) in an amount of from about 30% to about 60 % by weight; and the siloxane comprising a hydrophilic group (c) in an amount of from about 0.1% to about 10% by weight based on the weight of the silicone pressure sensitive adhesive.
  • the silicone pressure sensitive adhesive has a cyclosiloxane content of 50 ppm or less.
  • the composition comprises the steroid hormone in an amount of from about 5% to about 20% by weight of the adhesive composition.
  • the steroid hormone is selected from estrogen, estradiol, ethinyl estradiol, esters of estradiol, testosterone, progesterone, or a combination of two or more thereof.
  • the composition further comprises a first additive selected from a crystallization inhibitor.
  • the crystallization inhibitor is selected from the group consisting of polyvinyl pyrrolidone, copolymers of butylmethacrylate, dimethyl aminoethyl methacrylate and methyl methacrylate, povidones, copovidones, crospovidones, or a combination of two or more thereof.
  • the composition further comprises a second additive selected from a solubilizer.
  • the solubilizer is selected from the group consisting of dimethyl sulfoxide, isopropyl myristate, Diethylene glycol monoethyl ether, dipropylene glycol , Polyethylene glycol, polypropylene glycol, or a combination of two or more thereof.
  • the composition further comprises a third additive selected from a permeation enhancer.
  • the permeation enhancer is selected from the group consisting of oleyl alcohol, glycerine, dipropylene glycol, butylene glycol, propylene glycol, oleyl ether, isopropyl myristate allantoin, or a combination of two or more thereof.
  • 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
  • the composition has a storage modulus of the order of 10 4 to 10 6 Dyne/cm 2 measured at an angular frequency of 0.01 rad/s at a temperature of 32 o C.
  • the composition has a storage modulus of the order of 10 6 to 10 8 Dyne/cm 2 measured at an angular frequency of 100 rad/s and at temperature of 32 o C.
  • the composition has a complex viscosity of the order of 10 6 to 10 8 poise measured at an angular frequency of 0.01 rad/s and at temperature of 32 o C.
  • the steroid hormone has a cumulative release of not less than 1 % over a duration of 96 hours measured using a modified USP type V Dissolution apparatus in paddle over disc mode across the cellulosic membrane.
  • a transdermal drug delivery system comprising: (i) a backing layer; and (ii) a drug-in-adhesive layer comprising the composition of any of the previous ebodiments.
  • the system has a residual drug content of not more than 0 to 99 % by weight, in its spent state, compared to the drug content of the system, 8 34012696.1 before drug release, the residual drug content being measured by HPLC after extraction of drug in acetonitrile, from the spent Transdermal delivery system.
  • the system has a skin contact layer wherein the skin contact layer is selected from an acrylate or silicone based pressure sensitive adhesive.
  • the transdermal drug delivery system is packaged in an atmosphere of nitrogen.
  • 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).
  • the system has an f2 value (similarity factor) the range of 50 – 100 as compared to a commercial transdermal system.
  • Figure 1 is a graph showing crystallization inhibition of Estradiol in PSA matrix
  • Figure 2 is graph showing the percent release of drug in transdermal drug delivery systems
  • Figure 3 is a graph showing the percent cumulative permeation of drug in transdermal drug delivery systems.
  • 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).
  • the articles “a” and “an” are generally intended to mean “one or more” unless context suggest otherwise.
  • transdermal delivery is intended both transdermal (or “percutaneous") and transmucosal administration, i.e., delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
  • the term “backing layer” means the layer vertically farthest from the skin.
  • 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.
  • PET Polyethylen-therephthalate
  • Polyethylene Polyethylene
  • Polypropylene Polyurethane
  • the term “Steroid Drug-in-Adhesive Layer” means an adhesive material containing the steroid drug and optionally the additives.
  • the transdermal delivery system is typically a transdermal patch.
  • Steroid drug is typically a steroid hormone which is delivered through the transdermal route.
  • an “additive” is any compound added to the adhesive composition which has no medical use but may provide the adhesive 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.
  • the adhesive material is a silicone PSA
  • the Steroid drug is Estradiol
  • the optional crystallization inhibitor is Eudragits (EPO) from Evonik
  • the optional permeation enhancer in oleyl alcohol is preferred.
  • the term “Release liner” or “liner layer” means a layer which is adhesively bonded to the adhesive layer of the transdermal drug delivery 10 34012696.1 system and removed from the transdermal drug delivery system prior to its application to the skin. 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.
  • Permeation enhancement and “permeation enhancers” relate to the process and added materials which bring about an increase in the permeability of skin to a poorly skin permeating pharmacologically active agent, i.e., so as to increase the rate at which the drug permeates through the skin and enters the bloodstream.
  • the enhanced permeation effected through the use of such enhancers is not required when the matrix compositions of the present invention are employed.
  • Step drug means any steroid drug, suitable for transdermal or transmucosal administration which induces a desired systemic effect.
  • Pressure Sensitive Adhesive is the key component of a mono-layer steroid drug-in-adhesive transdermal patch. Pressure Sensitive Adhesive in such patches is required to compatibilize the drug along with other additives without undergoing significant loss in adhesive properties.
  • the Pressure Sensitive adhesive selected should be such that it provides sufficient adhesion to the skin while the patch is in use.
  • the Pressure Sensitive adhesive should also be non-irritant and non- sensitizing towards skin even while prolonged usage.
  • Silicone pressure sensitive adhesive are regarded to have non-irritating and non-sensitizing properties towards the skin. Acrylic pressure sensitive adhesive also shows good solubility towards drug without losing its adhesion towards skin.
  • Estradiol is an estrogen steroid hormone being used as a medication in the hormonal therapy. Transdermal delivery of estradiol is preferred as means of sustained dosage for the patient. However, estradiol is incompatible with silicone pressure sensitive adhesives and tends to crystallize in the adhesive matrix.
  • the existing transdermal patches for Estradiol either use an acrylate co-polymer adhesive or a 11 34012696.1 hybrid acrylate-silicone system to solubilize estradiol with help of some crystallization inhibitors.
  • crystallization inhibitors and co-solubilizers may be used to further inhibit the crystallization of estradiol in the adhesive matrix. These crystallization inhibitors and co-solubilizers are well-known in the state of the art. Examples of commonly used crystallization inhibitors and co-solubilizers. Commonly used crystallization inhibitors are Polyvinyl pyrrolidone (PVP K30, K25), Eudragits (EPO, RLPO, RSPO, etc.), Kollidon, etc.
  • PVP K30, K25 Polyvinyl pyrrolidone
  • Eudragits EPO, RLPO, RSPO, etc.
  • Kollidon etc.
  • DMSO Dimethyl sulfoxide
  • IPM Isopropyl myristate
  • DPG Dipropylene glycol
  • PEG Polyethylene glycol
  • PPG polypropylene glycol
  • permeation enhancer may also be used for facilitating the drug delivery via transdermal route. These permeation enhancers are well-known in the state of the art.
  • compositions comprising (i) a silicone pressure sensitive adhesive, and (ii) a bioactive agent, where the bioactive agent is dispersed in the silicone pressure sensitive adhesive.
  • the bioactive agent is a steroid hormone.
  • the silicone pressure sensitive adhesive comprises a hydrophilic functional siloxane.
  • the silicone pressure sensitive adhesive is a composition comprising (i) a silicone resin, (ii) a polyorganosiloxane, and (iii) a siloxane comprising a hydrophilic group.
  • the silicone pressure sensitive adhesive is selected from an adhesive as described in U.S. Patent Application 18/128,688, which is incorporated by reference herein in its entirety.
  • the composition includes a silicone resin (i).
  • Silicone resins are typically referred to as MQ silicone resins or MQ resins comprising M units represented by the formula R3SiO1/2, and Q units represented by the formula SiO4/2, where R is 12 34012696.1 generally selected from a C1to C60 hydrocarbon.
  • the hydrocarbon can be selected from an alkyl radical, a cycloaliphatic radical, an unsaturated hydrocarbon radical, and an aromatic radical.
  • R is selected from a C1-C60 alkyl radical, a C2- C60 unsaturated radical, a C5-C60 cycloaliphatic radical, and a C6-C60 aromatic radical.
  • R is selected from a C1-C10 alkyl radical.
  • R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl, heptyl, or octyl.
  • each R group is independently selected from a C1- C6 monovalent hydrocarbon, a C5-C20 cycloaliphatic radical, a C2-C6 olefinic radical, and a C6-C20 aromatic radical.
  • suitable C1-C6 monovalent hydrocarbon radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, and hexyl.
  • suitable cycloaliphatic radicals include, but are not limited to, cyclopyentyl, cyclohyexyl, cycloheptyl, cyclooctyl, etc.
  • suitable C2-C6 olefinic radicals include, but are not limited to, vinyl, allyl, etc.
  • suitable aromatic radicals include, but are not limited to, phenyl.
  • the respective R 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 R groups are methyl. In one embodiment, substantially all the R groups are free of unsaturation. In one embodiment, the MQ resin has from 0 to 0.5 mole % of the R groups contain any unsaturation. [0067] The MQ resin is primarily formed of such M and Q units but may contain some residual D units (R2SiO2/2) and T units (RSiO3/2).
  • 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.
  • the silicone resin may have a ratio of M to Q units of from about 0.2:1 to about 1.7:1, from about 0.4:1 to about 1.5:1, from about 0.6:1 to about 1.2:1, or from about 0.8:1 to about 1:1.
  • the silicone resin may include some residual, free silanol (Si-OH) groups.
  • the silicone resin may have a silanol content of from about 0.5 wt.% to about 12.0 wt.%, from about 0.75 wt.% to about 10 wt.%, from about 1 wt.% to about 7.5 wt.%, or from about 2.5 wt.% to about 5 wt.% based on the weight of the silicone resin.
  • the silicone resin can also be a solid, a liquid, a dispersion, or solution in a solvent.
  • the viscosity of the silicone resin can be based on the silicone resin as a 13 34012696.1 liquid; or in a dispersion or solution, where the solids content of the silicone resin in the dispersion or solution is from about 10% solids to about 98% solids.
  • the silicone resin is provided as a solid resin and is made by removing volatile solvent from the resin to provide a solid, solvent free MQ resin. This can be accomplished via spray drying.
  • the polyorganosiloxane (ii) is selected from a silanol terminate polyorganosiloxane.
  • the polyorganosiloxane (ii) may have a viscosity of from 300 to 200,000,000, from about 500 to about 150,000,000, from about 1,000 to about 100,000,000, from about 2,500 to about 75,000,000, from about 5,000 to about 50,000,000, from about 10,000 to about 25,000,000, from about 20,000 to about 10,000,000, from about 30,000 to about 5,000,000, from about 50,000 to about 1,000,000, from about 75,000 to about 750,000, from about 100,000 to about 500,000, or from about 250,000 to about 400,000 centipoise (cps) at 25°C. and preferably
  • the viscosity of polyorganosiloxane (ii) can be readily measured employing known and conventional viscosity measurement apparatus and techniques.
  • the polyorganosiloxane (ii) has a viscosity of from about 50,000 to about 750,000, from about 75,000 to about 500,000, from about 100,000 to about 400,000, or from about 200,000 to about 300,000 cps.
  • the polyorganosiloxane (ii) can be selected from a mixture of differing polyorganosiloxanes of different viscosities.
  • the polyorganosiloxane (ii) comprises a mixture of a first polyorganosiloxane having alkyl groups, and a second polyorganosiloxane comprising alkyl and aromatic groups.
  • the polyorganosiloxane (ii) comprises a first polyorganosiloxane having a first viscosity, and a second polyorganosiloxane having a second viscosity.
  • the first polyorganosiloxane has a viscosity of greater than 15,000 cPs
  • the second polyorganosiloxane has a viscosity less than 12,000 cPs.
  • the first polyorganosiloxane has a viscosity of from about 15,000 cPs to aout 1,000,000 cPs, from about 25,000 cPs to about 750,000 cPs, from about 50,000 cPs to about 500,000 cPs, or from about 75,000 cPs to about 250,000 cPs; and the second polyorganosiloxane has a viscosity of from about 500 cPs to about 12,000 cPs, from about 1,000 cPs to about 10,000 cPs, from about 2,500 cPs to about 7,500 cPs, or from about 3,000 cPs to about 5,000 cPs.
  • the silicone resin (i) can be present in an amount of from about 40 wt.% to about 70 wt.%, from about 45 wt.% to about 65 wt.%, or from about 50 wt.% to 14 34012696.1 about 55 wt.% based on the total weight of the silicone resin (i) and the polyorganosiloxane (ii).
  • the polyorganosiloxane (ii) can be present in an amount of from about 30 wt.% to about 60 wt.%, from about 35 wt.% to about 55 wt.%, or from about 45 wt.% to about 50 wt.% based on the total weight of the silicone resin (i) and the polyorganosiloxane (ii).
  • A is a bridging unit betw iloxane moiety and the hydrophilic group I, having at least one spacing atom selected from a C1-C60 acyclic hydrocarbon radical, a C4-C60 alicylic radical, an C6-C60 aromatic hydrocarbon radical, a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, a polycarbonate, or a combination of two or more thereof, where the bridging unit may include one or more moieties selected from alkoxy, carboxy, urethane, urea, ketone, or a combination of two or more thereof; [0097] I is an ionic, ionizable, zwitterionic group, or a polar hydrophilic group or moieties; [0098] G is a polymerizable group having the general Formula: 27 R or [0100] a non- F is
  • A is a C1-C10 alkyl, a C1-C10 cycloalkyl, or a C6- C12 aromatic group. In one embodiment, A is a C1-C4 alkyl. It will be appreciated that the radical A will be divalent or trivalent depending on whether G is 0 or 1.
  • I can be selected from an acid or base comprising a carboxylate -COO-, a dicarboxylate (-R(COO-)2) a sulfone —SO2— , a sulfonate —SO3 ⁇ , a sulfate —OSO3 ⁇ , a phosphonate —PO3 2 ⁇ , a phosphate — OPO3 2 ⁇ group, -N + R 30 R 31 H, -N + H2R 32 , -N + H3, or an ammonium salt, each containing a hydrogen or a cation independently selected from an alkali metal, an alkali earth metal, a transition metal, a quaternary ammonium group, and a phosphonium group, where R 30 , R 31 , and R 32 are independently selected from a C1-C30 hydrocarbon.
  • the zwitterionic moiety is selected from a group comprising an anionic group and a cationic group in a covalently bonded compound and having a net neutral charge.
  • the zwitterionic group is selected from a group having the formula —R 33 —N + (R 34 )2—R 35 —I z , where R 33 is a divalent hydrocarbon group having from 1 to 20 carbon atoms, R 34 is a monovalent hydrocarbon group having from 1 to 20 carbon atoms, R 35 is a divalent hydrocarbon group having from 2 to 20 carbon atoms; and I z is an ionic group selected from a carboxylate -COO-, a sulfone —SO2—, a sulfonate —SO3 ⁇ , a sulfate —OSO3 ⁇ , a phosphonate —PO3 2 ⁇ , and a phosphate
  • I is a polar group or moiety.
  • the polar group or moiety refers to a group that is not ionizable or ionic in nature but contains heteroatoms that render the group polar.
  • the polar groups may act as hydrogen bond acceptor, and those having hydrogen atoms directly bonded to a heteroatom may additionally act as hydrogen bond donors.
  • suitable polar groups or moieties include, but are not limited to, a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, and/or a polycarbonate.
  • the siloxane comprising a hydrophilic group (iii), in embodiments, can have a viscosity of from 1 cps to about 10000 cps, from about 10 cps to about 7500 cps, from about 25 cps to about 5000 cps, from about 50 cps to about 2500 cps, or from about 75 cps to about 1000 cps.
  • the siloxane comprising a hydrophilic group (iii), in embodiments can have a viscosity of from about 1 cPs to about 100 cPs, from about 100 cPs to about 1000 cPs, or from about 1000 cPs to about 10000 cPs.
  • the viscosity of the siloxane comprising a hydrophilic group can be based on the siloxane as a liquid; 17 34012696.1 or in a dispersion or in solution, where the solids content of the siloxane comprising a hydrophilic group in the dispersion or solution is from about 10% solids to about 98% solids. In one embodiment, the viscosity is based on siloxane as a liquid.
  • the siloxane comprising a hydrophilic group (iii) can be present in an amount of from about 0.1 wt.% to about 20 wt.%, from about 0.5 wt.% to about 15 wt.% from about 1 wt.% to about 10 wt.%, from about 2 wt.% to about 8 wt.%, or from about 3 wt.% to about 5 wt.% based on the total weight of the composition.
  • the siloxane comprising a hydrophilic group are prepared by the reaction of an olefin bearing at least one polar group, and a silyl hydride in presence of a hydrosilylation catalyst.
  • the silicone pressure sensitive adhesive may exhibit a low concentration of cyclic siloxanes.
  • the pressure sensitive adhesive contains less than about 2500 ppm, 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).
  • D4 octamethylcyclotetrasiloxane
  • D5 decamethylcyclopentasiloxane
  • D6 dodecamethylcyclohexasiloxane
  • the pressure sensitive adhesive contains each of a D4, D5, or D6 cyclic siloxane in an amount of less than 2500 ppm, 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.
  • the bioactive agent is selected from a steroid hormone.
  • the steroid hormone is not particularly limited and can be selected as desired for a particular purpose or intended application.
  • the steroid hormone can be selected from, but is not limited to, estrogen, estradiol, ethinyl estradiol, esters of estradiol, testosterone, progestrone or a combination of two or more thereof [0113]
  • the bioactive agent e.g., a steroid hormone, 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.
  • the silicone pressure sensitive adhesive can be provided by reacting the composition in the presence of heat for a sufficient time to effect condensation of the silicone resin and the silicone polymer to increase molecular weight or crosslinking, or both .
  • the process comprises reacting a polyorganosiloxane and a silicone resin in the presence of a hydrophilic functional siloxane (e.g., a hydrophilic functionalized 18 34012696.1 polyorganosiloxane and/or hydrophilic functionalized silicone resin).
  • a solid silicone resin in the form of a MQ type resin
  • the hydrophilic functionalized polyorganosiloxane and/or hydrophilic functionalized silicone resin are added to the mixture of the polyorganosiloxane and the silicone resin and heated for a period of time sufficient for a condensation reaction to occur to a selected extent.
  • no additional catalyst e.g., metal catalysts such as, but not limited to, platinum based catalysts
  • 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, a crystallization inhibitor, a solubilizer, a permeation enhancer, and the like.
  • the composition includes a crystallization inhibitor selected from, but not limited to, Polyvinyl pyrrolidone, copolymers of butylmethacrylate, dimethyl aminoethyl methacrylate and methyl methacrylate, povidones, copovidones, crospovidones, a combination of two or more thereof.
  • a crystallization inhibitor selected from, but not limited to, Polyvinyl pyrrolidone, copolymers of butylmethacrylate, dimethyl aminoethyl methacrylate and methyl methacrylate, povidones, copovidones, crospovidones, a combination of two or more thereof.
  • the composition includes a solubilizer selected from, but not limited to, dimethyl sulfoxide, Isopropyl myristate, Diethylene glycol monoethyl ether, Dipropylene glycol , Polyethylene glycol, polypropylene glycol, or a combination of two or more thereof.
  • the composition comprises a permeation enhancer selected from, but not limited to, oleyl alcohol, polyhydric alcohols, such as glycerine, dipropylene glycol, butylene glycol, propylene glycol, oleyl ether and isopropyl myristate allantoin, or a combination of two or more thereof.
  • 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. [0119] In one aspect, the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises (i) a MQ silicone resin, (ii) a polyorganosiloxane, and (iii) a siloxane comprising a hydrophilic group.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive wherein the silicone pressure sensitive adhesive comprises (i) a MQ silicone resin, (ii) a polyorganosiloxane, and (iii) a siloxane comprising a hydrophilic group wherein the hydrophilic group is selected from the group consisting of an ionic group, an ionizable group, a zwitterionic group, a polyetheramine group.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive wherein the silicone pressure sensitive adhesive comprises (i) a MQ silicone resin, (ii) a polyorganosiloxane, and (iii) a siloxane comprising a hydrophilic group wherein the hydrophilic group is selected from the group consisting of a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, and a polycarbonate.
  • a bridging unit between the siloxane moiety and the hydrophilic group I having at least one spacing atom selected from a C1-C60 acyclic hydrocarbon radical, a C4-C60 alicylic radical, an C6-C60 aromatic hydrocarbon radical, a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, a polycarbonate, 21 34012696.1 or a combination of two or more thereof, where the bridging unit may include one or more moieties selected from alkoxy, carboxy, urethane, urea, ketone, or a combination of two or more thereof; I is an ionic, ionizable, zwitterionic group, or a polar hydrophilic group; G is a polymerizable group having the general Formula: 27 R - -F-K, wherein F is a linker group chosen from a a C4-C60 alicylic radical, an C6-
  • a bridging unit between the siloxane moiety and the hydrophilic group I having at least one spacing atom selected from a C1-C60 acyclic hydrocarbon radical, a C4-C60 alicylic radical, an C6-C60 aromatic hydrocarbon radical, a polyetheramine, a polyether, a polyamide, a polyester, a polyurethane, a polysulfone, a polycarbonate, 23 34012696.1 or a combination of two or more thereof, where the bridging unit may include one or more moieties selected from alkoxy, carboxy, urethane, urea, ketone, or a combination of two or more thereof; I is an ionic, ionizable, zwitterionic group, or a polar hydrophilic group; G is a polymerizable group having the general Formula: 27 R - -F-K, wherein F is a linker group chosen from a a C4-C60 alicylic radical, an C6-
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises (i) a MQ silicone resin, (ii) a polyorganosiloxane, and (iii) 0.1-10 % by weight of a siloxane comprising a hydrophilic group , 30-70% by weight of a solid MQ resin and 60 – 30% by weight of a polyorganosiloxane, based on total weight of silicone pressure sensitive.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the silicone pressure sensitive adhesive comprises 0.1-10 % by weight of a siloxane comprising a hydrophilic group , 30-70% by weight of a solid MQ resin and 60 – 30% by weight of a polyorganosiloxane, based on total weight of silicone pressure sensitive and wherein the silicone pressure sensitive adhesive has a cyclosiloxane content of less than 50 ppm.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the steroid hormone comprises 5 to 20% by weight of the steroid silicone pressure sensitive adhesive.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the steroid hormone comprises 5 to 20% by weight of the silicone pressure sensitive adhesive the steroid hormone being selected from the group consisting of estrogen, estradiol, ethinyl estradiol, esters of estradiol, testosterone, progestrone or a combination of two or more thereof.
  • the steroid hormone is estradiol.
  • the adhesive composition further comprises a first additive.
  • the adhesive composition further comprises a second additive.
  • the adhesive composition further comprises a third additive. 25 34012696.1
  • the first additive is present in an amount of not less than 1%.
  • the second additive is present in an amount not less than 1%.
  • the third additive is present in an amount not less than 1%.
  • the first additive is a crystallization inhibitor selected from the group consisting of Polyvinyl pyrrolidone, copolymers of butylmethacrylate, dimethyl aminoethyl methacrylate and methyl methacrylate, povidones, copovidones, and crospovidones.
  • the second additive is a solubilizer selected from the group consisting of dimethyl sulfoxide, Isopropyl myristate, Diethylene glycol monoethyl ether, Dipropylene glycol , Polyethylene glycol and polypropylene glycol.
  • the third additive is a permeation enhancer selected from the group consisting of oleyl alcohol, polyhydric alcohols, such as glycerine, dipropylene glycol, butylene glycol, propylene glycol, oleyl ether and isopropyl myristate allantoin.
  • the adhesive composition has storage modulus of the order of 10 4 to 10 6 Dyne/cm 2 measured at an angular frequency of 0.01 rad/s and at temperature of 32 o C.
  • the adhesive composition has a storage modulus of the order of 10 6 to 10 8 Dyne/cm 2 measured at an angular frequency of 100 rad/s and at temperature of 32 o C.
  • the adhesive composition has a complex viscosity of the order of 10 6 to 10 8 poise measured at an angular frequency of 0.01 rad/s and at temperature of 32 o C.
  • the invention provides an adhesive composition comprising: (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the steroid hormone is resistant to crystallization for at least a week at a temperature of 40 ⁇ C and humidity of 75%.
  • the invention provides an adhesive composition comprising (i) silicone pressure sensitive adhesive; and (ii) a steroid hormone, 26 34012696.1 wherein the steroid hormone is dispersed in the silicone pressure sensitive adhesive and wherein the steroid hormone has a cumulative release of not less than 1 % over a duration of 96 hours measured using a modified USP type V Dissolution apparatus in paddle over disc mode across the cellulosic membrane.
  • the invention provides a transdermal drug delivery system for delivering at least one steroid drug, the system consisting essentially of (i) a backing layer (ii) a Steroid drug in adhesive layer; and (iii) a liner layer.
  • the invention provides a transdermal drug delivery system for delivering at least one steroid drug, the system consisting essentially of (i) a backing layer; (ii) a Steroid drug in adhesive layer; and (iii) a liner layer wherein the steroid drug is a steroid hormone.
  • the invention provides a transdermal drug delivery system for delivering at least one steroid drug, the system consisting essentially of a backing layer; a Steroid drug in adhesive layer; and a liner layer, wherein the transdermal drug delivery system has a residual drug content, in its spent state, of not greater than 0 to 99% by weight compared to the drug content of the system, before drug release, the residual drug content being measured by a HPLC after extraction of drug in acetonitrile, from the spent Transdermal delivery system.
  • the transdermal drug delivery system is packaged in an atmosphere of nitrogen.
  • the transdermal drug delivery 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).
  • the invention provides a transdermal delivery system comprising an adhesive composition wherein the adhesive composition comprises (i) a silicone pressure sensitive adhesive; and (ii) a steroid drug, wherein the steroid drug is dispersed in the silicone pressure sensitive adhesive and wherein the system has an f2 value (similarity factor) the range of 50 – 100 as compared to a commercial Vivelle Dot® transdermal system or as compared to Dermestril ® transdermal system.
  • PSA 1 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in the example 5 of U.S. Utility Application No.18/128,688 incorporated herein by reference.
  • PSA 2 Pressure Sensitive Adhesive 2
  • PSA 2 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in the example 7 of U.S. Utility Application No.18/128,688 incorporated herein by reference.
  • PSA 3 Pressure Sensitive Adhesive 3
  • PSA 3 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in the example 10 of U.S. Utility Application No.18/128,688 incorporated herein by reference.
  • Comparative Pressure Sensitive Adhesive 1 is a silicone pressure sensitive adhesive synthesized using a solvent less method as described in Example 11 of patent US 20220325154A1 incorporated herein by reference. In a typical synthetic method, a hydroxyl terminated polydimethylsiloxane gum (153.19 grams) was added followed by MQ silicone resin (206.81 grams) 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 o C under positive nitrogen flow.
  • Probe Tack Measurement In the probe tack test, a probe is pushed forward to contact with the adhesive surface and then retracted at a predefined speed. 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: • Test speed: 0.5 mm/s • Return speed: 0.01–1.00 mm/s • Applied force: 0.9 N • Contact time: 10 second • Temperature: 32° C
  • 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.
  • 180° 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 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 29 34012696.1 • Target type: Distance • Target value: 45 mm • Hold time: 6 second.
  • FIG. 1 shows that the inventive PSAs described here inhibited the crystallization of estradiol much better than the comparative PSA.
  • the inventive proto-types of adhesive compositions were prepared as examples using PSA 1 with the transdermal patch size being same as comparative example 1.
  • Example 1 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate.
  • PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the drug solution. The resulting solution was vortex mixed till a homogenous solution was obtained.100 ⁇ m wet thickness of this solution is coated on fluoro-coated PET release liner and allowed to dry at 50 o C for 50 minutes. After drying the coated side is covered with a PET backing layer and the Transdermal Patch construction is complete. [0167]
  • Example 2 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate. Further, Eudragit EPO (5% w/w of polymer dry weight) was dissolved in the drug solution. PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the above solution.
  • Example 3 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate. Further, Eudragit EPO (10% w/w of polymer dry weight) was dissolved in the drug solution. PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the above solution.
  • Example 4 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate. Further, Eudragit EPO (10% w/w of polymer dry weight), 31 34012696.1 and diprolylene glycol (DPG) (2% w/w of polymer dry weight) was dissolved in the drug solution. PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the above solution.
  • Example 5 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate. Further, Eudragit EPO (10% w/w of polymer dry weight), and Oleyl alcohol (2% w/w of polymer dry weight) was dissolved in the drug solution. PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the above solution.
  • Example 6 Estradiol equivalent to 2.5% w/w of polymer dry weight was dissolved in ethyl acetate. Further, Eudragit EPO (10% w/w of polymer dry weight), and Transcutol P (2% w/w of polymer dry weight) was dissolved in the drug solution. PSA 1 equivalent to 120 mg polymer dry weight was weighed and added in the above solution.
  • Comparative Example 1 A Silicone and Acrylic hybrid estradiol patch marketed as Vivelle Dot® patch is used as comparative example 1.
  • a typical Vivelle Dot® patch adhesive formulation contains estradiol, acrylic and silicone adhesive, oleyl alcohol, povidone, and dipropylene glycol. The physical dimension of the patch is 3.75 cm 2 .
  • Comparative Example 2 An Acrylic co-polymer estradiol patch marketed as Dermestril® patch is used as comparative example 2.
  • a typical Dermestril® patch adhesive formulation contains estradiol dissolved in an acrylic co- polymer adhesive. The physical dimension of the patch is 19.6 cm 2 .
  • the details of the adhesive composition used in described examples are provided in Table 2. 32 34012696.1 [0175] Table 2 S.No. Component Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 PSA 1 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg 120 mg [0177] Viscoelastic Properties of Adhesive composition: The viscoelastic properties of PSA 1 and Example 3 made thereof have been 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 geometry were used in oscillation mode with an angular strain of 0.01% to generate the rheograms.
  • the complex viscosity ( ⁇ *) values on the other hand compare the cold flow properties of these adhesives.
  • Example 3 was taken further for testing the ex vivo permeation. Additionally, different permeation enhancers were screened to see their effect on the permeation profiles of the drug in the presence of the added permeation enhancers which constitute Example 4 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 34 34012696.1 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 PEG 400 (40% v/v) 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 PEG 400 solution (40% v/v). Capacity of each cell: 12 ml.
  • Aliquot volume 1 ml.
  • 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.
  • FIG. 1 shows the results for permeation of drug through the Wistar Skin.
  • the marketed formulation containing estradiol is intended for delivering the drug for a period of 4 days (96 hours).
  • Several permeation enhancers were screened to get estradiol permeation similar to the marketed patches.
  • Example 5 Several permeation enhancers such as dipropylene glycol (DPG), oleyl alcohol and diethylene glycol mono ethyl ether (Transcutol P) were screened at a concentration of 2% to match the skin permeation kinetics of the developed patch to that of the marketed comparator product.
  • DPG dipropylene glycol
  • Transcutol P diethylene glycol mono ethyl ether
  • Example 5 The samples of Example 5 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 35 34012696.1 stability chambers for long term and 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.
  • Table 4 The stability study conditions maintained as per ICH guidelines Q1A (R2) Type of stability Storage conditions Testing frequency (in th [ ] a e : ta ty spec catons an ana yt ca met o o ogy re erences Sr. Test Specifications Method y r ll 36 34012696.1 [0189] Table 6: Results of Stability studies up to 1 month Example number 5 Sr. no.

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Abstract

L'invention concerne une composition adhésive comprenant un adhésif sensible à la pression (PSA) à base de silicone et un médicament stéroïde, le médicament stéroïde étant stable pendant une longue durée.
PCT/US2024/041470 2023-08-11 2024-08-08 Compositions adhésives pharmaceutiques Pending WO2025038384A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986000532A1 (fr) * 1984-07-07 1986-01-30 Flexcon Company, Inc. Adhesif au silicone sensible a la pression et ses utilisations
US5560922A (en) * 1986-05-30 1996-10-01 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process
US20140276479A1 (en) * 2013-03-14 2014-09-18 Noven Pharmaceuticals, Inc. Transdermal drug delivery system with overlay
WO2019079291A1 (fr) * 2017-10-17 2019-04-25 Lubrizol Advanced Materials, Inc. Composition et dispositif pour administrer des agents actifs aux surfaces cutanées
US20220325154A1 (en) 2021-04-05 2022-10-13 Momentive Performance Materials Inc. Silicone pressure sensitive adhesive and method of making the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986000532A1 (fr) * 1984-07-07 1986-01-30 Flexcon Company, Inc. Adhesif au silicone sensible a la pression et ses utilisations
US5560922A (en) * 1986-05-30 1996-10-01 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process
US20140276479A1 (en) * 2013-03-14 2014-09-18 Noven Pharmaceuticals, Inc. Transdermal drug delivery system with overlay
WO2019079291A1 (fr) * 2017-10-17 2019-04-25 Lubrizol Advanced Materials, Inc. Composition et dispositif pour administrer des agents actifs aux surfaces cutanées
US20220325154A1 (en) 2021-04-05 2022-10-13 Momentive Performance Materials Inc. Silicone pressure sensitive adhesive and method of making the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDRÉ COLAS: "Silicones in Pharmaceutical Applications", DOW CORNING HEALTHCARE INDUSTRIES, 14 December 2005 (2005-12-14), XP055264151, Retrieved from the Internet <URL:http://www.dowcorning.com/content/publishedlit/51-993a-01.pdf> [retrieved on 20160411] *

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