FIELD OF THE INVENTION
The present invention relates to transdermal drug delivery system of antimuscarinic drug or its pharmaceutically acceptable salts, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s). In particular, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, the present invention provides a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and process for preparing these compositions to increase permeation, flux rate and bioavailability.
BACKGROUND OF THE INVENTION
Overactive bladder is a condition, which is characterized by involuntary sudden urge to urinate. The symptoms like urgency to pass urine, urinary frequency, nocturia and further accompanied with or without urge incontinence. There is another type of condition associated with overactive bladder called “stress induced incontinence”. Patients suffering from stress urinary incontinence leaks urine, particularly when the pressure increases on patient’s bladder such as while exercising, sneezing, laughing, coughing or doing other physical activities. Thus, overactive bladder affects overall quality of life of a patient and can further lead to other diseases like emotional distress, depression, anxiety, interrupted sleep cycles, social isolation, impairment in work related productivity and/or issues with sexuality.
Different classes of medications have been used for the treatment of the overactive bladder condition, such as anticholinergic, antiadrenergic, adrenergic and acetylcholinesterase inhibitors. Anticholinergic agents are the first choice for the treatment of overactive bladder, which acts at muscarinic receptors and suppress the intensity of involuntary muscle contractions. Most commonly used anticholinergic agents are tolterodine, oxybutynin, trospium, solifenacin, darifenacin and fesoterodine.
Solifenacin is an anticholinergic agent, which acts on selective muscarinic receptors and used in the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. Solifenacin is chemically known as [(3R)-1-azabicyclo [2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate. Solifenacin succinate is marketed in USA as Vesicare® by Astellas Pharmaceuticals as an immediate release oral tablets in the strengths of 5 mg and 10 mg. The recommended oral dose of solifenacin succinate is 5 mg or 10 mg once daily.
Conventionally, anticholinergic agents such as solifenacin is administered orally. However, oral administration of these agents not always remain as first choice of treatment due to various restrictions associated with oral dosage forms, such as difficulty in swallowing for geriatric, pediatric, nauseous, unconscious and bedridden patients. Moreover, oral administration of solifenacin succinate is associated with various side effects such as dry mouth, constipation, blurred vision and other anticholinergic central nervous system side effects including headache, confusion, hallucinations and somnolence. Thus, patients monitoring is required for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose for solifenacin succinate. Furthermore, there is a need of dosage adjustment(s) and/or cautionary use of solifenacin in patients with renal and hepatic impairment and when patients are prescribed other medication(s) that may potentially inhibit cytochrome P450 3A4 enzyme.
Transdermal drug delivery system delivers the active substance into body via the skin. In contrary to above-mentioned shortcomings associated with oral dosage forms, transdermal drug delivery system, as per present invention, provides a suitable and alternate route for the delivery of solifenacin or its pharmaceutically acceptable salts. The objective of the present invention was therefore to overcome the above-mentioned disadvantages. Thus, the present inventors enabled a transdermal drug delivery system of solifenacin or its combination with at least one antiadrenergic, adrenergic, acetylcholinesterase inhibitor. The transdermal drug delivery system of the present invention not only improves the patient compliance in case of geriatric, pediatric, nauseous, unconscious and bedridden patients but also provides other advantages such as the avoidance of first-pass metabolism, reduction in gastro irritation, distress, ulcer, frequency of daily oral administration, provides convenient dosing schedules, improved and controlled pharmacokinetics, offers more uniform plasma dosing of the drug and allows prompt interruption of dosing.

Following patent publications pertain to transdermal drug delivery system of solifenacin.
US patent publication No. 20050181031 assigned to Astellas Pharma discloses transdermal preparation of solifenacin. This patent publication reveals that it is difficult to deliver solifenacin into body via skin and thus used one transdermal permeation enhancer i.e. a fatty acid ester and a terpene to enhance transdermal permeability of solifenacin.
US patent No. 7425340 assigned to Antares Pharma discloses non-occlusive transdermal composition of anticholinergic or antispasmodic agent with urea containing compound as a permeation enhancer and a carrier.
US patent publication No. 20150030666 assigned to KM Transderm discloses adhesive patch of anticholinergic drug containing a support and an adhesive layer containing a thermoplastic elastomer, liquid component and a drug.
PCT publication No. 2017006974 assigned to OJI Holdings Corporation discloses a transdermal patch having a support and a drug-containing layer containing pharmaceutically acceptable salts and inorganic bases of solifenacin.
Though, above-mentioned patent publications disclose transdermal dosage forms, yet there remains a scope and unmet need for a commercially viable transdermal drug delivery system of antimuscarinic drugs such as solifenacin or its pharmaceutically acceptable salts, alone or in combination with at least one antiadrenergic, adrenergic, acetylcholinesterase inhibitor with improved flux characteristics.
OBJECT AND SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a transdermal drug delivery system comprising an antimuscarinic drug or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide a transdermal drug delivery system comprising an antimuscarinic drug or its pharmaceutically acceptable salts, in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide a process for the preparation of a transdermal drug delivery system comprising an antimuscarinic drug or its pharmaceutically acceptable salts, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients and process for preparing the same.

It is another object of the present invention to provide a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and one or more pharmaceutically acceptable excipients.

It is another object of the present invention to provide a transdermal drug delivery system comprises of solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the system comprises of about 0.1% to about 90% by weight of solifenacin or its pharmaceutically acceptable salts thereof and/or about 0.1% to about 90% of at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) such as donepezil, mirabegron, tamsolusin and combinations thereof.
It is another object of the present invention to provide a transdermal drug delivery system comprises of solifenacin and pharmaceutical acceptable excipients, wherein the transdermal drug delivery system is free or substantially free from inorganic acid salt(s) and/or permeation enhancer(s) including but not limited to urea, fatty acid and terpenes based penetration enhancer.
It is another object of the present invention to provide a transdermal drug delivery system in the form of a transdermal patch comprising solifenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide a transdermal drug delivery system, which can be formulated into a transdermal patch having a size range of at least about 2.5cm2 and thickness of at least about 0.01 microns.
It is another object of the present invention to provide a transdermal drug delivery system in form of a transdermal patch comprising solifenacin or its pharmaceutically acceptable salts in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) such as donepezil, mirabegron, tamsolusin and one or more pharmaceutically acceptable excipients.
It is another object of the present invention to provide a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, wherein transdermal drug delivery system of the present invention can be administered with dosage regimen of at least once daily or twice weekly or once weekly or once monthly.
It is another object of the present invention to provide a transdermal drug delivery system of solifenacin or its pharmaceutically acceptable salts, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s), wherein transdermal drug delivery system of the invention exhibits desired formulation and pharmacokinetic attributes such as improved flux characteristics and/or Cmax and/or area under the curve (AUC) or bioequivalence to the oral route or other parameters as known to the person having ordinary skill in the art.
It is another object of the present invention to provide use of transdermal drug delivery system for the prevention and treatment of disease(s) such as urologic diseases, overactive bladder or its associated symptoms, increased urinary frequency, urinary incontinence, bladder instability, painful or difficult urination, pollakisuria, neurogenic bladder, nocturia, nocturnal enuresis, irritable bowel syndrome, cystospasm, chronic cystitis or respiratory diseases (chronic obstructive respiratory disease, chronic bronchitis, asthma, rhinitis and the like) and various other diseases.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “transdermal” refers to administration, delivery or application of a drug by means of direct contact with mucosa or skin. Such administration, delivery or application is also termed as percutaneous, dermal and transmucosal. As used herein, the term “transdermal drug delivery system” or “transdermal delivery system” refers to a delivery system or formulation or composition or dosage form that releases active ingredient upon application to the skin. Transdermal delivery system of the invention includes, but is not limited to, patch (matrix or reservoir), bandage, tape, spray, cream, liquid, paste, plaster, poultice, ointment, lotion, gel, emulsion, foam, film, microsphere, aerosol, nanaosphere, microcapsule, nanocapsule, liposome, micelle and/or the like. Preferably, the transdermal drug delivery system refers to transdermal patch. Preferably, the transdermal patch of the present invention may further comprise at least one adhesive layer, a release liner layer, an active ingredient layer, a release controlling layer and/or a backing layer and/or any other component as known in the art.
As used herein, the term "Solifenacin" is used in broad sense to include not only "Solifenacin" per se (free base) but also its salt(s) or pharmaceutically acceptable salt(s) (including but not limited to acid addition salts such as succinate, hydrochloride, sulfate, hydrobromide, acetate, oxalate, maleate, fumarate, citrate, lactate or like), pharmaceutically acceptable solvate(s), pharmaceutically acceptable hydrate(s), pharmaceutically acceptable isomer(s), pharmaceutically acceptable stereoisomer(s), pharmaceutically acceptable enantiomer(s), pharmaceutically acceptable racemate(s), pharmaceutically acceptable ester(s), pharmaceutically acceptable analogue(s), pharmaceutically acceptable derivative(s), pharmaceutically acceptable metabolite(s), pharmaceutically acceptable complex(es), pharmaceutically acceptable polymorph(s), pharmaceutically acceptable prodrugs thereof and also its various crystalline and amorphous forms and/or mixture of any.
As used herein, “anticholinergic” or “anticholinergic agent” refers to agent or chemicals or drugs that blocks the action of acetylcholine neurotransmitter in central and peripheral nervous system. These agents are used to treat various medical conditions that involve contraction and relaxation of muscles. Some medical conditions include overactive bladder, muscle spasms, breathing problems, diarrhea, gastrointestinal cramps, movement disorders. Anticholinergic agents are selected from the group comprises of tolterodine, oxybutynin, trospium, solifenacin, darifenacin, fesoterodine and the like.

As used herein, “adrenergic” or “adrenergic agent” refers to agents or chemicals or drugs that mediated their response from the adrenergic receptors such as Mirabegron. As used herein, “antiadrenergic” or “antiadrenergic agent” refers to agents or chemicals or drugs that inhibit the adrenergic receptor response such as Tamsulosin. As used herein, “acetylcholinesterase inhibitor” refers to agents or chemicals or drugs that inhibit acetylcholinesterase enzyme to prevent break down of acetylcholine, leads to increases in the level and action of the acetylcholine in central nervous system as well as peripheral such as Donepezil. Other active drug ingredients from the above-mentioned therapeutic class can also be covered under the ambit of this patent.
As used herein, the term "pharmaceutical acceptable excipients" refers to any inert substance that is used in the composition. Excipient may include at least one excipient or one or more pharmaceutically acceptable excipients, any known substance in the pharmaceutical industry useful for preparing transdermal drug delivery system such as polymer, filler, adhesive, plasticizer, penetration enhancer, permeation enhancer, solvent (any solvent), carrier, bases, crystallization inhibitor, gelling agent, pH regulator, stabilizer, solubilizing agent, dispersing agent, antioxidant, surfactant, buffering agent, thickening agent, irritation suppressant, emollient, humectant, cooling agent, antimicrobial, antiseptic, colorant, opacifier, preservative, sequestering agent, complexing agent, moisturizer, emulsifier, softener, tackifier, ultraviolet absorber, aromatic agent, flavoring agent and/or other pharmaceutical excipient(s) or their mixture and/or combination thereof. The amount of excipient(s) may vary from 0-90% based on the total weight of the composition based on the type of excipient(s), as known by one skilled in the art.
As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more process, and/ or steps of the type described herein and/ or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
"Substantially free" as used herein refers to the transdermal drug delivery system as per present invention, which contains less than 5% w/w of intended excipient(s).
Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition or formulation.
As used herein, the term “transdermal patch” may include “reservoir patch” or “reservoir system” refers to pharmaceutical composition comprising an effective amount of drug present in separate compartment within transdermal drug delivery system or “matrix patch” or “matrix system” refers to pharmaceutical composition comprising an effective amount of a drug dissolved or dispersed in a polymeric composition within adhesive layer.
The pharmaceutical compositions of the present invention comprise about 1 mg to about 500 mg of solifenacin or its pharmaceutically acceptable salts. Preferably, from about 1 mg to about 50 mg of solifenacin. More preferably, from about 1 mg to about 25 mg of solifenacin. In one embodiment of the invention, the dosage administered may conveniently be in the range of between about 0.25 mg to about 25 mg, about 0.5 mg to about 23 mg, about 0.5 mg to about 22 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 18 mg, about 0.5 mg to about 16 mg, about 0.5 mg to about 14 mg, about 0.5 mg to about 12 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 1 mg. In one embodiment, the pharmaceutical composition comprises solifenacin in the range of about 1% to about 97% by weight, preferably in the range of about 0.5% to about 50% by weight, more preferably in the range of about 0.5% to about 25% by weight, more preferably in the range of about 0.5% to about 10% by weight on the basis of the total weight of the composition.
The transdermal drug delivery system of the present invention comprises an antimuscarinic drug or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
In another embodiment, the transdermal drug delivery system of the present invention includes an antimuscarinic drug or its pharmaceutically acceptable salts thereof, in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention includes a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention includes a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and process for preparing the same.
In another embodiment, the present invention includes a transdermal drug delivery system, wherein the system comprises one or more pharmaceutically acceptable excipients selected from one or more of a polymer, penetration enhancer, solubilizing agent, buffer, surfactant, solvent and/or mixtures thereof.
In another embodiment, the present invention includes a transdermal drug delivery system comprising solifenacin, wherein solifenacin is in the form of its free base or as a pharmaceutically acceptable salt thereof selected from the group comprising of succinate, hydrochloride, hydrobromide, sulfate, acetate, maleate, fumarate, citrate and lactate.
In another embodiment of the invention, the transdermal drug delivery system of the present invention comprising antimuscarinic drug can be prepared by melt extrusion, solvent casting, circular teflon mould method, mercury substrate method, glass substrate method, ethylene vinyl acetate copolymer membranes method, asymmetric TPX (Poly – 4 methyl -1 - pentane) method, using aluminum backing layer and/or any method known in the art.
In another embodiment, the present invention includes a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and at least one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention includes a transdermal patch composition comprising:
a) solifenacin or its pharmaceutically acceptable salts thereof; and
b) optionally one or more drug selected from the group comprising of donepezil, mirabegron and/or tamsulosin; and
c) at least one or more pharmaceutical acceptable excipients.
In another embodiment, the transdermal drug delivery system of the present invention includes solifenacin or its pharmaceutically acceptable salts thereof, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) and one or more pharmaceutically acceptable excipients, wherein the transdermal drug delivery system exhibits improved flux characteristics range from about 50 to about 200 µg/cm2/h. In another embodiment of present invention, the transdermal drug delivery system exhibits improved flux characteristics range from about 50 to about 100 µg/cm2/h.
In another embodiment, the present invention includes a transdermal drug delivery system comprises of improved solifenacin formulations allowing a reduced frequency of administration.
In another embodiment, the present invention includes a transdermal drug delivery system comprises of solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition comprises of about 0.1% to about 90% by weight of solifenacin or its pharmaceutically acceptable salts thereof and/or about 0.1% to about 90% of at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) such as donepezil, mirabegron, tamsolusin and combinations thereof. In one embodiment, transdermal drug delivery system of this invention comprises a therapeutically effective amount of solifenacin, wherein that amount is from about 1% to 10% percent by weight.
In another embodiment, the present invention includes a transdermal patch composition comprising: a) about 0.1% to about 30% by weight of solifenacin or its pharmaceutically acceptable salts thereof, b) about 5% to about 30% by weight of diethylene glycol monoethyl ether, c) about 10% to about 85% by weight of polysiloxane / polyisobutylene, d) about 0.1% to about 5% by weight of ethylcellulose or hydropropylcellulose, e) at least one or more pharmaceutical acceptable solvents.
In one embodiment, the active ingredient solifenacin is in micronized form, which refers to extremely fine particles that are a few microns in diameter. In one embodiment, the mean particle size of solifenacin used in the compositions is less than about 50 µm, less than about 30 µm, less than about 20 µm, less than about 10 µm, less than about 5 µm, or less than about 1 µm, e.g., about 0.5 µm or even less.
In another embodiment, the present invention includes a transdermal patch comprising: a) a backing layer; b) a drug-containing adhesive layer comprising: 10-30 wt % of solifenacin or a pharmaceutically acceptable salt thereof; 20-80 wt % of a pressure sensitive adhesive; 0.01-10 wt % of one or more of skin penetration enhancers; and 0.01-10 wt % of a tacking agent; and c) a release layer, wherein the drug-containing adhesive layer is disposed between the backing layer and the release liner.
In another embodiment, the present invention includes a process of manufacturing a transdermal patch for the delivery of solifenacin. In the method, solifenacin or a pharmaceutically acceptable salt thereof is dissolved in a solvent. The solifenacin solution is combined with a permeation enhancer and other excipients. A matrix modifier is added and the resulting solution is homogenized. The solution is then mixed with an adhesive in a suitable solvent. It may be solvent cast or extruded.
In one embodiment of the present invention, the transdermal drug delivery system comprises of solifenacin or its pharmaceutically acceptable salts thereof and at least one pharmaceutical acceptable excipient, wherein the transdermal drug delivery system is free or substantially free from inorganic acid salt(s) and/or permeation enhancer(s) including but not limited to urea, fatty acid and terpenes based penetration enhancer.
In another embodiment of the invention, the transdermal drug delivery system is in the form of transdermal patch, tape or bandage.
In another embodiment of the invention, there is provided a transdermal drug delivery system in the form of a transdermal patch comprising solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients. The patch disclosed in the present invention can be a matrix or a reservoir type patch or monolithic drug in adhesive or multi-laminate drug in adhesive type patch.
In another embodiment of the invention, there is provided a transdermal drug delivery system in the form of a transdermal patch comprising solifenacin or its pharmaceutically acceptable salts thereof in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s) such as donepezil, mirabegron, tamsolusin and one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention, there is provided a transdermal drug delivery system, which can be formulated into a transdermal patch having a size range of at least about 2.5cm2 and thickness of at least about 0.01 microns. Preferably, the transdermal patch as per present invention is having a size range of at least about 2.5cm2 to about 55 cm2.
In another embodiment of the present invention, there is provided a transdermal drug delivery system comprises of combination of solifenacin or its pharmaceutically acceptable salts thereof and at least one acetylcholinesterase inhibitor (preferably donepezil) or at least one antiadrenergic agent (preferably tamsulosin) or at least one adrenergic agent (preferably mirabegron) with at least one pharmaceutical acceptable excipient, wherein the composition comprises of a) about 0.1% to about 90% by weight of solifenacin or its pharmaceutically acceptable salts thereof, b) about 0.1% to about 90% by weight of donepezil or tamsulosin or mirabegron or its pharmaceutically acceptable salts thereof.
In another embodiment of the present invention, the transdermal drug delivery system can be formulated with biocompatible polymers, which are selected from the group comprising natural and synthetic rubbers, polyisobutylene, neoprenes, polybutadienes, polyisoprenes, polysiloxane, polysiloxanes vinyl acetate adhesives, polyacrylate, plasticized styrene-rubber block copolymers, silicones¸ ethylene vinyl acetates, styrene-isoprene copolymers, polyurethanes, polyether block amide copolymers, acrylic adhesives including cross-linked and uncross-linked acrylic copolymers and/or combination thereof.
In another embodiment of the present invention there is provided a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein transdermal drug delivery system of the present invention can be administered with dosage regimen of at least once daily or twice weekly or once weekly or once monthly.
In another embodiment of the present invention there is provided a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein transdermal drug delivery system provides delivery of solifenacin to a subject through skin over an extended period of time.
In another embodiment of the present invention, the transdermal drug delivery system as per present invention are able to provide sustained anticholinergic effect in a subject from about 1 to about 15 days. Preferably, the transdermal drug delivery system as per present invention are able to provide sustained anticholinergic effect in a subject from about 1 to about 7 days, about 1 to about 6 days, about 1 to about 5 days, about 1 to about 4 days, about 1 to about 3 days, about 1 to about 2 days.
In another embodiment of the present invention, the transdermal delivery system as per present invention comprising solifenacin as the active ingredient, when applied onto the skin of patients provides a release rate of solifenacin over from about 10 hours to 180 hours. Preferably, transdermal delivery system as per present invention comprising solifenacin as the active ingredient, when applied onto the skin of patients provides a release rate of solifenacin over from about 24 hours to 168 hours.
In another embodiment of the present invention, there is provided a method for enhanced delivery of solifenacin. In one embodiment, methods include the use of iontophoresis, a battery powered electronic stimulant, magnetophoresis, electroporation, photochemical stimulation and phonophoresis for enhanced delivery of solifenacin.
Embodiments of the present invention also relate to transdermal drug delivery system of solifenacin or its pharmaceutically acceptable salts thereof, alone or in combination with at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor(s), wherein transdermal drug delivery system of the invention exhibits desired formulation and pharmacokinetic attributes such as improved flux characteristics, Cmax, area under the curve (AUC) and/or bioequivalence to the oral route or other parameters as known to the person having ordinary skill in the art.
In another embodiment of the present invention, the transdermal delivery system reduces caregiver burden and improves dosing compliance. Furthermore, transdermal delivery of solifenacin also results in less gastrointestinal exposure compared to oral administration and could decrease the incidence of gastrointestinal side effects. Increases plasma levels over several days obtained by improved flux rates may reduce the need for dosing titration. Thus, the transdermal delivery system as per present invention exhibits greater efficacy.
In another embodiment of the present invention, the transdermal delivery system as per present invention on application to the skin, diffuses the drug into the skin to absorbed into the bloodstream to produce a systemic therapeutic effect. The therapeutic action depends on multiple factors, such as, potency of the solifenacin, solubility and diffusivity of solifenacin in the skin, skin thickness, drug concentration within the application site and/or drug concentration in the reservoir.
In another embodiment of the present invention, there is provided a transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and at least one or more pharmaceutically acceptable excipients, wherein the transdermal drug delivery system is stable.
In another embodiment of the present invention, there is provided a transdermal patch comprising solifenacin or its pharmaceutically acceptable salts thereof and at least one or more pharmaceutically acceptable excipients, wherein the transdermal patch exhibits favorable drug permeability.
In another embodiment of the present invention, there is provided a method of treating overactive bladder disease or its associated symptoms in a patient comprising: a) applying transdermal patch comprising solifenacin or its pharmaceutically acceptable salts thereof in amount from 1 mg to 6.5 mg; b) removing the patch of step a) and applying another patch comprising solifenacin or or its pharmaceutically acceptable salts thereof in amount from 1 mg to 6.5 mg to the patient at an interval so as to produce in the human patient a mean maximum plasma concentration of solifenacin effective to alleviate the symptoms of overactive bladder disease or its associated symptoms.
Embodiments of the present invention relate to the use of transdermal drug delivery system for the treatment or prevention of overactive bladder disease or its associated symptoms, wherein the administration of said system does not require any dosage adjustment(s), in patients with renal and hepatic impairment and/or patients who are prescribed with other medication(s) that may potentially inhibit cytochrome P450 3A4 enzyme.
Embodiments of the present invention relate to use of transdermal drug delivery system for prevention and treatment of disease(s) such as urologic diseases, overactive bladder or its associated symptoms, increased urinary frequency, urinary incontinence, bladder instability, painful or difficult urination, pollakisuria, neurogenic bladder, nocturia, nocturnal enuresis, irritable bowel syndrome, cystospasm, chronic cystitis or respiratory diseases (chronic obstructive respiratory disease, chronic bronchitis, asthma, rhinitis and the like) and various other diseases and can be administered to geriatric, pediatric and bedridden patients or hospitalized patients or patients who are nauseous, unconscious and suffering from dysphagia or the like.
In another embodiment of the present invention, the transdermal drug delivery system can be packed into a primary packaging system and/or secondary packaging system and/or in a kit alone or with instructions of use to the patient.
Bioavailability refers to the proportion of the drug administered that reaches the physiological site where the drug exerts its therapeutic effect, which is generally regarded as the blood stream for many drugs. The bioavailability of a drug is most readily expressed as the concentration of the drug or its active metabolites in the blood plasma integrated over time. This quantity is commonly referred to as the "area under the curve" or "AUC". Transdermal drug delivery system of solifenacin according to this invention preferably increases the drug's bioavailability at least 1% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, or 50% or more. In a further embodiment, bioavailability studies can be performed to compare the bioavailability of the oral dosage form. The transdermal drug delivery system of solifenacin prepared as per present invention is expected to exhibit improved in-vivo pharmacokinetic profile, desired skin adhesion, skin irritation and skin sensitization properties.
Skin permeation and flux study was performed in vitro, using intact human skin mounted on a static diffusion cell (Franz-cell type). The human skin was stored in a deep freezer at a temperature of about -70° C, then thawed for use and immersed in 0.9% saline solution. For testing, the thawed skin was cut into squares of a suitable dimensional size. The release liner was removed from the test patch, and adhesive side surface of patch was applied to the epidermal side skin placed on Franz diffusion cell. Suitable buffer medium (such as phosphate buffer) was used in the donor cell and in the receptor cell of Franz diffusion cell. For continuous stirring a magnetic stirring rod was placed in each cell and the temperature of the filled buffer medium was maintained at a temperature of about 30±5° to 37±5° C throughout the testing period. A sample of suitable amount (from 1 ml to 30 ml) was collected at suitable time period and assayed for the amount of drug release using any appropriate chromatographic procedure. The transdermal drug delivery system of solifenacin prepared as per present invention is expected to exhibit improved flux characteristics from about 50 to about 100 µg/cm2/h.
As used herein, the term “backing layer”, “backing liner” or “backing” refers to protective layer present in the transdermal delivery system. The backing layer holds entire system together and protects the drug, which is present in matrix or reservoir type of system. The backing layer material may comprise of vinyl esters, polyethylene polyester, aluminized polyethylene terapthalate, siliconized polyethylene terapthalate, polyester polypropylene, polypropylene resin, polyethylene resin, polyurethylene, polyolefin monolayer film, ethylene-vinyl acetate, aluminized plastic laminate, polyolefin and aluminum foil of metalized polyester laminated with polyethylene material and/or combinations thereof or any other as known by one skilled in the art. The backing layer is preferably in the range of about 1 micron to about 300 microns in thickness, preferably in the range of about 2 microns to about 260 microns.
As used herein, the term “release layer”, “release liner” or “release film” refers to a peel strip, which protects adhesive layer from external contamination. The release layer may be non-occlusive or occlusive type. Release layer material comprises of paper fabric, polyethylene, polyvinylchloride, silicon, teflon and/or combinations thereof or any other as known by one skilled in the art.
As used herein, the term “occlusive” refers to type of release layer, which prevent water loss or water evaporation from the transdermal drug delivery system. As used herein, the term “non-occlusive” refers to type of release layer, which allows air, moisture or water vapor to pass through transdermal drug delivery system.
As used herein, the term “adhesive layer” refers to the adherence strip, which possess sufficient adhesion property. The adhesive layer firmly secures the transdermal drug delivery system to the applied or administered skin surface. The adhesive layer materials are pressure sensitive material comprising polyacrylamates, polyacrylates, polysiloxane, polyisobutylene, silicone and/or combinations thereof or any other as known by one skilled in the art. The adhesive layer may be present in separate layer or with active ingredient matrix. Commercially available acrylic-based pressure sensitive adhesives are also included in the ambit of present invention such as various commercial grades of Duro-Tak® and their combinations.
As used herein, the term “rate controlling layer” refers to drug release controlling layer. This delivers active ingredient in controlled manner as per programmed delivery rate. The rate controlling polymers may selected from the group comprising chitosan, alginate, polylactide polyglycolide, polycaprolactone /polyvinylpyrrolidone (PCL/PVP) composites, cellulose based excipients (hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or like) or acrylic-based polymers, acrylic acid, co-2-(diethylamino)ethyl methacrylate, polyethylene, ethylene vinyl acetate, nylon, polyacrylate, rubber (natural or synthetic), silica and/ or combination thereof or any other as known by one skilled in the art.
As used herein, the term “plasticizer” refers to the inert ingredients, which are added to create plasticity, flexibility and to reduce brittleness in transdermal drug delivery system. The plasticizers are selected from the group comprising glycerol, dibutyl pthalate, triethyl citrate, propylene glycol, polyethylene glycol and esters of phthalic acid, sebacic acid, oleic acid, citric acid, tartaric acid and/or combinations thereof or any other as known by one skilled in the art.
As used herein, the term “penetration enhancer” or “permeation enhancer” refers to an agent, which improves the rate of transport of active ingredient across the skin or mucosa. The penetration enhancer are selected from the group comprising of surfactants (any surfactant), including but not limited to sodium-lauryl-sulfate, polyoxyethylene-9-laurylether, bile salts, sodium-deoxycholate, sodium glycocholate, sodium-taurocholate, sorbitan monolaurate, pluronic and the like; water, propylene glycol, 2- pyrrolidone, isopropyl myristate, isopropyl palmitate, transcutol, N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate, oleic acid, glyceryl oleate and sodium lauryl sulfoacetate, fatty acid, essential oils, oxazoldines, polyols, enzymes, glyceryl monoesters, glyceryl monolaurate, laurocapram (azone) and the like; alcohols selected from methanol, ethanol, propanol, butanol, pentanol, hexanol, octanol and the like; fatty alcohol selected from caprylic, decyl, lauryl, stearyl derivative and the like; alkanones selected from n-heptane, n-octane, n-nonane, n-decane derivative and the like; amides cyclic amide: 1-dodecylazacycloheptane-2-one (azone), pyrrolidone derivate (1-methyl-2- pyrrolidone), sulfoxides selected from decylmethylsulfoxide, dimethylsulfoxide, urea-containing compound can be urea, or a derivative or analogue selected from 1,3-Dimethylurea, 1,1-Diethylurea, 1-Acetyl-1-phenylurea, Isopropylideneurea, allophanic acid, hydantoic acid, allophanoyl, pyrrolidone carboxylic acid, biuret, thiobiuret, dithiobiuret, triuret and 2-(3-Methylureido)-1-naphthoic acid; terpenes selected from 1-menthol, limonene, cineole, menthone, peppermint oil, orange oil, turpentine oil, eucalyptus oil, Di(ethylene glycol) ethyl ether, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl monoleate, glyceryl palmitate, glyceryl rincoleate, glyceryl stearate-laureth, glyceryl ricinoleate, glyceryl caprylate, glyceryl dilaurate, hexylene glycol, di ethyl sebacate, ammonium lauryl sulfate, diisopropyl dilinoleate, ethyl acetate, ethyl oleate, diisopropyl adipate, isopropyl isostearate, lauryl acetate, methyl salicylate, myristyl lactate, disodium cocamphodiacetate, dioctyl phthalate, disodium laureth sulfosuccinate, sodium lactate, sodium laureth sulfate, sorbitan isostearate, sorbitan monooleate, sorbitan monoplamitate, sorbitan monostearate, sorbitan tristearate, sodium lauryl ether sulfate, sodium dodecyl sulfatesodium n-lauroyl sarcosinate, triethanolamine lauryl sulfate, sorbitan monopalmitate, octyldodecanol, alpha-terpineol, choleth-24, cocodiethanolamide, coco-caprylate/caprate, dichlorodifluoromethane, diethanolamine, diisopropanolamine, dimethyl isosorbide, glycerin, isoceteth-20, lactic acid, lauramine oxide, laureth, lauric diethanolomide, lauric/myristic diethanolol amide, levulinic acid, methoxy PEG-16, methyl gluceth-10, oleth oleyl oleate, PEG methyl ether, pentadecalactone, polysorbate, propylene carbonate, SD alcohol 408, spermaceti, squalene, steareth, tocopherol or related compound, trideceth-10, trolamine, cyclomethicone, ceteareth, triglycerides, chloro-m-cresol, chloroxylenol, L-a-lecithin, phenoxyethanol, Triton x (octoxynol 9), benzyl dimethyl dodecyl ammonium bromide, cocamidopropyl hydroxysultaine, oleyl betaine, cyclopentadecanolide, dodecyl amine, dodecyl methyl sulfoxide, dodecyl pyridinium chloride, nicotine sulfate, octyl salicylate, octyl trimethyl ammonium bromide, 1-phenyl piperazine, salicylic acid, sodium cocoyl glutamate, sodium oleate, cocoyl hydrolyzed collagen, tetracaine, 1,2 hexanediol, hexadecyl dimethyl ammoniopropane sulfonate, lauric acid, lauroylcholine chloride, linoleic acid, linolenic acid, lauryl lactate and the like and/or combination/mixture thereof or any other as known by one skilled in the art.
As used herein, the term “crystallization inhibitors” refers to an agent, which inhibits the crystallization process of active ingredient present in transdermal drug delivery system so as to maintain the stability of system throughout shelf life. The crystallization inhibitors are selected from the group comprising silica, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and/or combination thereof or any other as known by one skilled in the art.
As used herein, the term “skin irritation reducing agents” refers to an agent, which are capable to suppress the irritation caused by any of the active or inactive ingredient present in transdermal drug delivery system. The skin irritation reducing agents are selected from the group comprising of crotamiton, glycerol, antioxidants suitable for use as a skin irritation reducing agent include pantethine, a-bisobolol, rosamarinic acid, quercetin, hamamelitanin, aluminum acetate, curcumin, glycyrrhizin, retinol acetate, 1-ascorbyl palmitate, tocopherol, calcipotriol, tacalcitol, resveratrol, silibinin, ginsenoside, squalene, aluminum hydroxide, titanium oxide, ethylene diamine tetraacetic acid (EDTA), puerarin, tranexamic acid, glycerin and/or combination thereof or any other as known by one skilled in the art.
Suitable solvents or vehicles according to the present invention include aqueous or organic solvents. Preferable solvents or vehicles include, but not limited to, water, methanol, ethanol, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, isopropanol, chloroform, acidified ethanol, acetone, polyols, polyethers, oils, esters, ketones, alkyl ketones, methylene chloride, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl formamide, tetrahydrofuran, acetaldehyde, acetone, benzene, carbon disulphide, 1,2 dichloroethane, dichloromethane, N,N-dimethylformamide, ethyl ether, ethylene glycol, perchloroethylene, toluene, trichloroethylene, propylene glycol, triacetin, polyethylene glycol, tributyl citrate or triethyl citrate, glycerine, hexane glycol, sorbitans and mixtures thereof.

As used herein, the term “primary packing system” or “primary packing” refers to a type of packing, wherein packing material is an immediate contact with the drug product.

As used herein, the term “secondary packing system” or “secondary packing/packaging” refers to a type of packing material that is in immediate contact with the primary packing system. The packing material of transdermal drug delivery system comprises of polyvinylidene, polyamide, vinyl acetate resins, polyethylenes, polyesters, polypropylenes, polyurethanes, polyolefin, polyvinyl alcohol, polyvinyl chloride, nitrile rubber, modified acrylonitrile methyl acrylate copolymers, expanded synthetic resin sheets or films, non-woven fabrics, foils, papers, ethylene/vinyl acetate copolymers, ethylene/ethylacrylate copolymers, metal vapor deposited films or sheets, cotton clothes, rubber sheets or films and/or combination thereof or any other as known by one skilled in the art.
The used herein, the term “stable” refers to the compositions of present invention, wherein the amount of the active ingredient of a formulation do not deviate from the initial amount by more than the values given in the specification or the guidelines of the common Pharmacopoeias or loss in active ingredient is less than 50% (40%, 30%, 20%, 10%, 5%) of the initial content after being stored for at least 1 month, preferably for at least 2 months, preferably for at least 3 months, more preferably for at least 6 months, more preferably for at least 12 months or more preferably for at least 24 months. The stability of the composition may be evaluated at “long term” conditions 25°C/60% RH, at intermediate condition 30°C/65% RH, at “accelerated conditions” 40°C/75% RH, in the final packaging either measured as the loss in content of active ingredient. Stability testing may be conducted according to the current guidelines by ICH and FDA. The purity of solifenacin in compositions as per the present invention ranges from at least 99.99%, 99%, 98%, 97%, 96% or 95%.
As used herein, the term "about" means ± approximately 10% of the indicated value.
Having described the invention with reference to certain preferred embodiment, other embodiment will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following example describing in detail method for the preparation of transdermal drug delivery system. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following example are set out to illustrate the invention and do not limit the scope of the present invention.
Table 1
Ingredients Example 1 Example 2 Example 3 Example 4
% W/W
Solifenacin 0.1-90 0.1-90 0.1-90 0.1-90
Donepezil - 0.1-90 - -
Mirabegron - - 0.1-90 -
Tamsulosin - - - 0.1-90
Polymer 0-50 0-50 0-50 0-50
Plasticizer 0-15 0-15 0-15 0-15
Penetration enhancer 0-40 0-40 0-40 0-40
Crystallization inhibitor 0-10 0-10 0-10 0-10
Solvent q.s q.s q.s q.s
Table 2
Ingredients Example 5
% W/W
Solifenacin 0.1-30
Diethylene glycol monoethyl ether 5-30%
Polysiloxane / Polyisobutylene 10-85%
Ethylcellulose or Hydropropylcellulose 0.1-5%
Solvent q.s
Preparation of transdermal drug delivery system: i. Preparation of mass / dispersion comprising active ingredient and at least one pharmaceutical acceptable excipient; ii. Formation of uniform, homogenous film by spreading the prepared mass / dispersion over release liner layer; iii. Addition of backing layer; iv. Drying; and v. Prepared film are sectioned into appropriate dimensions and packed.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope, and spirit of this invention.

CLAIMS:WE CLAIM:
1. A transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and at least one pharmaceutical acceptable excipient.

2. A transdermal drug delivery system comprising combination of solifenacin or its pharmaceutically acceptable salts thereof and at least one other drug selected from antiadrenergic, adrenergic, acetylcholinesterase inhibitor and at least one pharmaceutical acceptable excipient.

3. A transdermal drug delivery system comprising solifenacin or its pharmaceutically acceptable salts thereof and at least one pharmaceutical acceptable excipient, wherein the transdermal drug delivery system is free of urea, fatty acid and terpenes based penetration enhancer.

4. The transdermal drug delivery system as claimed in claim 1 to 3, wherein solifenacin is in the form of its free base or as a pharmaceutically acceptable salt selected from the group comprising of succinate, hydrochloride, hydrobromide, sulfate, acetate, maleate, fumarate, citrate and lactate.

5. The transdermal drug delivery system as claimed in claim 1 to 4, wherein said system is in the form of transdermal patch, tape or bandage.

6. The transdermal drug delivery system as claimed in claim 1 to 5, wherein said system is a transdermal patch in the form of reservoir or matrix or monolithic drug in adhesive or multi-laminate drug in adhesive type patch.

7. The transdermal drug delivery system as claimed in claim 2, wherein at least one antiadrenergic, adrenergic, acetylcholinesterase inhibitor selected from group comprising of tamsulosin, mirabegron, donepezil and/or combination thereof.

8. The transdermal drug delivery system as claimed in claim 1 to 7, wherein the system comprises one or more pharmaceutically acceptable excipients selected from one or more of a polymer, penetration enhancer, solubilizing agent, buffer, surfactant, solvent and/or mixture thereof.

9. A transdermal patch composition comprising:
a) solifenacin or its pharmaceutically acceptable salts thereof; and
b) optionally one or more drug selected from the group comprising of donepezil, mirabegron and/or tamsulosin; and
c) at least one pharmaceutical acceptable excipient.

10. The transdermal drug delivery system as claimed in claim 1 to 9, wherein said system is used for the treatment or prevention of a disease in patients with overactive bladder, or its associated symptoms and/or increased urinary frequency, urinary incontinence, bladder instability, painful or difficult urination, pollakisuria, neurogenic bladder, nocturia, nocturnal enuresis, irritable bowel syndrome, cystospasm, chronic cystitis and/or respiratory diseases.

Dated this the 18rd day of June, 2019

[Digitally Signed]
Dr. Dinesh Kumar
Head IPR - Generics,
JUBILANT GENERICS Ltd.
D-12, Sector 59, Noida, Uttar Pradesh, India