Nsaid spray formulation and method

Abstract

The present invention relates to compositions and methods of administration of a non-steroidal anti-inflammatory (NSAID) drugs, including diclofenac, and particularly the epolamine salt of diclofenac, as diclofenac epolamine, in topically applied formulations. The topically applied formulations of the present invention provide for film-forming spray applications.

Description

[0001] NSAID Spray Formulation and Method

[0002] Related Application

[0003] This application claims priority to U.S. Ser. No. 63 / 531,595 filed on August 9, 2023, which is incorporated herein in its entirety.

[0004] Description of the Invention

[0005] The present invention relates to compositions and methods of administration of a non-steroidal anti-inflammatory (NSAID) drugs, including diclofenac, and particularly the epolamine salt of diclofenac, as diclofenac epolamine, in topically applied formulations. The topically applied formulations of the present invention provide for film-forming spray applications.

[0006] Background of the Invention

[0007] Inflammation and pain due to conditions such as rheumatoid arthritis and osteoarthritis, including degenerative joint disease of the Hip and knees, minor strains, sprains, and contusions are common occurrences in both animals and human beings. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently administered for the treatment of such conditions. Main classes of NSAIDs include salicylates (e.g. aspirin, trolamine salicylate, methyl salicylate), propionic acid derivatives (e.g. ibuprofen, ketoprofen), aniline derivatives (e.g. aminophenolacetaminophen, acetaminophen [TYI--ENOL®]), pyrazole derivatives (such as phenylbutazone), fenamates (e.g. meclofenamate), indole derivatives (e.g. indomethacin), acetic acid derivatives (e.g. diclofenac), oxicam derivatives (e.g. piroxicam), and cylooxygenase-2 (COX-2) inhibitors (e.g. celecoxib). The most common route of drug administration is oral ingestion of tablets or capsules. Oral administration of most of the NSAIDS can cause severe side reactions such as gastrointestinal bleeding and ulceration, liver and kidney damage, and central nervous system and cutaneous disturbances, particularly after extended use. The oral administration of most of the NSAIDS is also systemic exposure.

[0008] Thus, there is an established need to develop modes of administration of NSAIDs that circumvent the deleterious effects of oral NSAID dosing and first pass metabolism. Topical NSAIDs present a safer potential alternative to oral therapy, with decreased systemic exposure to the active NSAID molecule. The skin provides a protective barrier against foreign materials and infection. In mammals this barrier is created primarily by the outermost epidermal layer, the stratum corneum. The stratum corneum is extremely thin ( some 20 microns) but provides a substantial barrier to penetration by topical administration of drugs, Various transdcrmal delivery systems achieve permeation by using a skin penetration enhancing vehicle.

[0009] Transdcrmal dosage of NSAIDs include plaster, patch, gel. and solution of the drug formulated with pharmaceutically acceptable ingredients. These preparations also include permeation or penetration enhancers for accelerating the rate of permeation of the drug through the skin, Topical formulations of NSAIDs for analgesic effect at the site of application are commercially available and include Feldene^ Gel with piroxicam, Fleeter09Patch with diclofenac epolamine, Voltaren0* Gel with diclofenac sodium, and Pennsaid* (Nuvo Research) solution containing diclofenac sodium with dimethyl sulfoxide (DM SO) as the skin penetration enhancer. Diclofenac has been used, most commonly, as the sodium or potassium salt for relief from pain and inflammation such as musculoskeletal and joint disorders including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Diclofenac epolamine has only been used in a topically applied patch as a hydrogel commercially.

[0010] The transdcrmal administration of NSAIDs such as diclofenac has been accomplished primarily through the use of gels, creams or patches each of which has its drawbacks. Patches are often difficult to apply and frequently do not remain on the skin especially in joint areas such as the elbow or the knee which are prone to constant movement. Gels and creams can be messy and the active ingredient may remain on the hands after application. Gels and creams may also stain clothing or cross-contaminate and transfer to areas or people by contact. The advantage of filmforming dosage forms is the ability to improve pharmacokinetics and provide prolonged release in topical therapy. The use of aerosol systems for the delivery of film-forming components eliminates the risks of contamination during subsequent storage that remain when using other types of dressings, as well as special devices for application. Thus, there is a need for compositions and methods of applying NSAIDs that will avoid the deleterious effects of oral administration and provide ease of application, fast drying time, adherence, and retention, which can result in improved drug delivery, be of therapeutic value and elicit patient compliance. Summary of the Invention

[0011] The present invention relates to compositions and methods of administration of a diclofenac and in particular diclofenac epolamine (DHEP, diclofenac-N-(2-hydroxyethyl) pyrrolidine) formulation for the management of pain. In particular, the compositions of the present invention relate to a film-forming topical spray which are water resistant, exhibit a fast film drying time of less than about 2 minutes and in which the drug was chemically and physically stable at a concentration of at least 1.3% w / w. The films may be formed by using a traditional aerosol with inherent propellant or as a topical spray (manual pump actuated) or a topical aerosol spray with pressurized canister outside of the bag placed within a canister.

[0012] The present invention relates to pharmaceutical compositions comprising from 0.1 to 10.0 % w / w diclofenac epolamine; 1 to 25% w / w film-forming polymer, 1 to 20% permeation enhancer, 1 to 25% plasticizer, and 10 to 85% w / w solvent, and is substantially free of added water.

[0013] The present invention relates to pharmaceutical compositions where the diclofenac epolamine, plasticizer, film-forming polymer and permeation enhancer are dissolved in solution.

[0014] The present invention relates to pharmaceutical compositions where the composition additionally comprising a propellant.

[0015] The present invention relates to pharmaceutical compositions where the propellant is selected from the group comprising HFA-134a, HFA-152a, HFO-1234ze, dimethyl ether, propane(s) and or butane(s) and combinations thereof.

[0016] The present invention relates to pharmaceutical compositions where the propellant is HFA-134a or HFA-152a or combination thereof

[0017] The present invention relates to pharmaceutical compositions where the composition contains an inherent propellant which is contained within a pressurized container.

[0018] The present invention relates to pharmaceutical compositions where the propellant comprises from 50 to 90% w / w of the composition within a pressurized container. The present invention relates to pharmaceutical compositions where the volatile organic solvent is selected from the group consisting of an alcohol or an ester or a ketone or combinations thereof.

[0019] The present invention relates to pharmaceutical compositions where the alcohol, as a volatile organic solvent, is either ethanol or isopropyl alcohol or combinations thereof.

[0020] The present invention relates to pharmaceutical compositions where the ester, as a volatile organic solvent, is selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate or combinations thereof.

[0021] The present invention relates to pharmaceutical compositions where the ketone, as a volatile organic solvent, is acetone.

[0022] The present invention relates to pharmaceutical compositions where the volatile organic solvent is isopropyl alcohol.

[0023] The present invention relates to pharmaceutical compositions where the permeation enhancer is selected from the group consisting of dietheylene glycol monoethyl ether (Transcutol P or HP) and or a glycol, such as propylene glycol, dipropylene glycol, polyethylene glycol or combinations thereof,

[0024] The present invention relates to pharmaceutical compositions where the permeation enhancer is dietheylene glycol monocthyl ether.

[0025] The present invention relates to pharmaceutical compositions where the film forming agent is selected from the group consisting of acrylic acid derivatives, such as Eudragit® El 00, Si 00, RL1(X), RS 100 or LI 00, polyacrylamides, such as Oleocraft® LP-20, MP-30, MP-32, or HP-31, ethylcellulose, such as Ethocel® 4, 7, 10. 20, 45, 100, 200, 300 or Aquaion™ EC-N7, EC-N10, EC-N14, EC-N20, EC-N22, EC-N50, EC-N100, EC-N200, EC-N300, hydroxypropyl cellulose (HPC) and derivatives thereof, hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC) and derivatives thereof, such as, Klucel HXF, MXF, GXF, JXF, F.XF, EXF, ELF, HF, MF, GF, JF, or LF, polyfvinyl pyrrolidone) (PVP), poly(vinylpyrroiidone)-vinyl acetate copolymer (PVP-VA), poly (vinyl acetate or derivatives thereof, such as Kollidon® K-25, K-30, K-90 or Plasdone K-25, K -29 / 32, K-30, S-630 or K-90, poly (vinyl alcohol) (PVA or PVOH) or derivatives thereof, and combinations thereof. The present invention relates to pharmaceutical compositions where the film-forming agent is Eudragit® El 00.

[0026] The present invention relates to pharmaceutical compositions where the plasticizer is selected from the group consisting of water, humectants, such as glycerol, fatty acids, such as oleic acid, fatty alcohols, such as oleyl alcohol, citric acid, fatty acid esters, such as ethyl oleate, glycol derivatives, such as polyethylene glycol, hydrocarbons and hydrocarbon derivatives, mineral oil, propylene glycol, citric acid esters, such as triethyl citrate, castor oil, or triacetin..

[0027] The present invention relates to pharmaceutical compositions where the plasticizer is propylene glycol.

[0028] The present invention relates to pharmaceutical compositions which comprise from about 1 to 3 % w / w diclofenac epolamine (equivalent to about 0.7% to about 2.2% diclofenac); 10 to 25% w / w isopropanol; 0.5 to 1.5% w / w propylene glycol; 0.5 to 1.5% w / w Eudragit E100; and 0.5 to 1.5% w / w Transcutol P (diethylene glycol ethyl ether) in the presence of a propellant 65 to 85% w / w HFA 134a or HFA 152a for topical application as an aerosol.

[0029] The present invention relates to pharmaceutical compositions where the diclofenac epolamine is present less than 60% saturation under conditions of use, and wherein there is no undissolved diclofenac epolamine in the formulation.

[0030] The present invention relates to pharmaceutical compositions where the diclofenac epolamine is present at less than 50% saturation.

[0031] The present invention relates to pharmaceutical compositions where the diclofenac epolamine is present at less than 80% saturation.

[0032] The present invention relates to pharmaceutical compositions where the composition forms a film on topical administration.

[0033] The present invention relates to pharmaceutical compositions where the composition is a true solution.

[0034] The present invention relates to pharmaceutical compositions where the composition further comprises 0.01 to 0.1% wt / wt menthol. The present invention relates to pharmaceutical compositions where the composition has a drying time on a human’s skin of less than about 2 minutes.

[0035] The present invention relates to pharmaceutical compositions where the composition has a drying time on a human’s skin of less than about 5 minutes.

[0036] The present invention relates to pharmaceutical compositions where the composition has a drying time on a human’s skin of between about 1 to about 2 minutes.

[0037] The present invention relates to pharmaceutical compositions where the diclofenac epolamine is present in the formulation at a level of from between about 90-110% of target concentration when stored for 4 weeks at 25 °C.

[0038] The present invention relates to pharmaceutical compositions filled in aerosol dispensers comprising a reservoir for the compositions of the present invention.

[0039] The present invention relates aerosol dispensers where the composition is delivered to a human skin surface by spraying.

[0040] The present invention relates aerosol dispensers where the spray is a metered fixed dose actuation which each actuation of the dispensing button controls the administration of the drug product with a fixed amount of volume administered from a single actuation and eliminates the need to rub with hand and mitigates environmental exposure.

[0041] The present invention relates aerosol dispensers where the spray is a metered spray.

[0042] The present invention relates aerosol dispensers where the spray is a metered fixed dose actuation which each actuation of the dispensing button controls the administration of the drug product with a continuous spray volume administered from a single press and hold actuation and eliminates the need to rub with hand and mitigates environmental exposure.

[0043] The present invention relates aerosol dispensers where the spray is a continuous spray. The present invention relates methods for the treatment of pain comprising applying an effective amount of said drug to a patient in need thereof by administering the composition of claim 1 to a topical surface of the patient. The present invention relates methods where the treatment is for the relief of pain due to osteoarthritis.

[0044] The present invention relates methods where the treatment is for acute pain due to minor strains, sprains, and contusions.

[0045] The present invention relates methods where the treatment is for relief of pain associated with po s t-herpeti c neural gi a .

[0046] The present invention relates methods where the compositions of the present invention are sprayed onto the topical surface of a patient.

[0047] The present invention relates methods where the compositions of the present invention are sprayed onto the topical surface of a patient at a rate of between about 25 mcL to 3.5 mL / spray.

[0048] The present invention relates methods where the compositions of the present invention are sprayed onto the topical surface of a patient at a rate of between about 25 mcL to 200 mcL / spray from a fixed metered dose spray canister.

[0049] The present invention relates methods where the amount of diclofenac epolamine delivered to the topical surface of a patient is about 0.005 mg to 20 mg per square centimeter.

[0050] The present invention relates to pharmaceutical compositions comprising from 0.1 to 10.0 % w / w diclofenac epolamine; 1 to 25% w / w film-forming polymer, 1 to 20% permeation enhancer, 1 to 25% plasticizer, and 10 to 85% w / w solvent and does not contain a propellant.

[0051] The present invention relates to pharmaceutical compositions where the composition is delivered to a human skin surface by an aerosol spray.

[0052] The present invention relates to pharmaceutical compositions where the spray is a continuous spray.

[0053] The present invention relates to pharmaceutical compositions where the spray is a metered spray. The present invention relates to pharmaceutical compositions comprising from 1 .0 to 1.6 % w / w diclofenac cpolaminc; 90 to 97% w / w isopropyl alcohol, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, 1.0 to 2.0% Eudragit 100.

[0054] The present invention relates to pharmaceutical compositions comprising 1.3% w / w diclofenac cpolaminc; 20.62% w / w isopropyl alcohol, 1.0% propylene glycol, 1.0% Transcutol P, 1.0% Eudragit 100 and 75.08% w / w HFA-134a.

[0055] The present invention relates to pharmaceutical compositions comprising 1.3% w / w diclofenac epolamine; 20.62% w / w isopropyl alcohol, 1.0% propylene glycol, 1.0% Transcutol P, 1.0% Eudragit 100 and 75.08% w / w HFA-152a.

[0056] The present invention relates to pharmaceutical compositions comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 90 to 97% w / w isopropyl alcohol, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, and 1.0 to 2.0% Eudragit 100.

[0057] The present invention relates to pharmaceutical compositions comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 90 to 97% w / w isopropyl alcohol / ethyl acetate, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, 1.0 to 2.0% Eudragit 100 and 72.4 to 80.0% w / w HF A- 152a.

[0058] Brief Description of the Figures

[0059] Figure 1 - Mean cumulative amount of drug permeated through human skin (ng) between the 0 and 24 h experimental period from formulations of the present invention and the Fleeter patch. Data is presented as mean ± standard deviation (n=5).

[0060] Figure 2 - Mean cumulative amount of drug permeated through human skin (ng) at 24 h experimental period from formulations of the present invention and the Flector patch. Data is presented as mean ± standard deviation (n=5).

[0061] Figure 3 is a graph of the mean cumulative amount of diclofenac (ng / cm2) delivered to the receptor solution 24 h post-application of 2 formulations. Figure 4 is a representative chromatogram of the premix MS I at t=8 weeks at 50 °C (black) overlaid with MS-77 at t=12 months 25 °C / 60%RH (blue) and diluent blank, 100% methanol (green)

[0062] Figure 5 is a graph of the mean cumulative amount of diclofenac (ng / cm2) delivered to the receptor solution 24 h post-application of Voltaren and MS77.

[0063] Detailed Description of the Invention

[0064] The formulations of the invention are suitable for administration as aerosols or as solutions that form films where applied to the surface of the skin. These films may be formed by using a traditional aerosol with an inherent propellant or as a topical spray, such as activated by a manual pump or as a topical aerosol spray with a pressurized canister separated from the solution and placed within a canister where CO2 may be used as a propellant. In the case of the use of a propellant to deliver the formulations, the high volatility of the propellant will generally require that the formulation be kept pressure-sealed, such as by a simple, manually operable valve for example, until use. Particularly useful dosage delivery devices are aerosol canisters, and the formulation may be sprayed or delivered by tube, for example. The formulation, after delivery, will tend io form a film, and the amount of film-forming agent and other excipients may be adjusted to determine whether the resulting film will be loose or tight, and whether the film may run before setting, or set straight away. These and settings in between may be adopted, as appropriate or desired. The formulations may be delivered as a continuous spray or as a metered spray. The metered spray could deliver an amount from about 25 to 3500 pL, also from about 50 to 250 pL and about 75 to 200 pL per actuation. The continuous spray could deliver an amount based on time of depression of the actuator button and up to the full amount of the container.

[0065] The compositions of the present Invention may include various active pharmaceutical ingredients including but not limited to include salicylates (e.g. aspirin, trolamine salicylate, methyl salicylate), propionic acid derivatives (e.g. ibuprofen, ketoprofen), aniline derivatives (e.g. aminophenolacetarninophen, acetaminophen [TYLENOL.®]), pyrazole derivatives (such as phenylbutazone). fenamates (e.g. meclofenamate), indole derivatives (e.g. indomethacin), acetic acid derivatives (e.g. diclofenac), oxicam derivatives (e.g. piroxicam), cylooxygenase-2 (COX-2) inhibitors (e.g. cclecoxib), menthol, camphor and benzyl alcohol. The present invention relates to compositions and formulations incorporating diclofenac and its structural analogues including but not limited to phenylbutazone, mefenamic acid and indomethacin as well as to other structural analogues such as disclosed in '‘Structure -based design of new diclofenac: Physiochemical, spectral, molecular docking, dynamics simulation and ADMET studies”, M. Uzzatnan, et al. Informatics in Medicine Unlocked (2021) 25: 100677 which is incorporated by reference. The present invention relates in particular to compositions and formulations incorporating diclofenac epolamine which are suitable for administration as aerosols or as solutions and form films applied to the surface of the skin.

[0066] The compositions of the present invention may include the API such as diclofenac epolamine at a concentration of 0.1% w / w. 0.2% w / w or 0.3 w / w or 0.4% w / w. 0.5% w / w or 0.6% w / w, or 0.7% w / w, or 0.8% w / w, or 0.9% w / w, 1.0%’ w / w or 1.1% w / w, or 1.2% w / w or 1 .3% w / w or 1.4% w / w 1.5% w / w or 1.6% w / w, or 1.7% w / w or 1.8%’ w / w or 1.9% w / w 2.0% w / w or 2.1%’ w / w, or 2.2% w / w or 2.3% w / w or 2.4% w / w 2.5% w / w or 2.6%' w / w, or 2.7% w / w or 2.8%’ w / w or 2.9% w / w or 3.0% w / w or 3.5% w / w, or 4.0% w / w or 4.5'71? w / w or 5.0% w / w or 5.5% w / w or 6.0% w / w. The compositions of the present invention may include the A PI such as diclofenac epolamine at a concentration of 0.1 to 10% w / w or from 0.1 to 9% w / w of from 0.1 to 8% w / w or from 0.1 to 7% w / w or 0.1 to 6% w / w or from 0.1 to 5% w / w or from 0.1 to 4% w / w or from 0.1 to 3% w / w or 0.1 to 2% w / w or from 0.1 to 1% w / w or 0.5 to 10% w / w or from 0.5 to 9% w / w of from 0.5 to 8% w / w or from 0.5 to 1% w / w or 0.5 to 6% w / w or from 0.5 to 5% w / w or from 0.5 to 4% w / w or from 0.5 to 3%' w / w or 0.5 to 2% w / w or from 0.5 to 1 % w / w or 1 to 10% w / w or from 1 to 9% w / w of from 1 to 8% w / w or from I to 7% w / w or 1 to 6% w / w or from 1 to 5% w / w or from 1 to 4% w / w or from to 3% w / w or 1 to 2% w / w.

[0067] Hydrofluoroalkane (FIFA) solvents (propellants) have been approved for human use in pressurized metered dose inhalers (pMDIs) since the mid 1990‘s (Vervaet and Byron, 1999). These solvents arc highly volatile, like hydrocarbons, but are non-combustiblc. The HF A will normally play more of a part than a merely neutral and unreactive diluent, and will generally act as a cosolvent, albeit a poor one, for the most part. For purposes of convenience, it will also be appreciated that the propellant will normally be added last. A preferred hydrofluoroalkane solvent is HFA134a. The amount of HTA solvent in the compositions of the present invention may be up to about 60% or about 65% or about 70% or about 75% or about 80 % or about 85% or about 90% wt / wt. The amount of HF A solvent in the compositions of the present invention may be from about 60% to about 90% or from about 60% to about 85% or from about 60% to about 80% or from about 60%; to about 75%’ or from about 60% to about 70% or from about. 60% to about. 65% or from about 65%' to about 90% or from about 65% to about 85% or from about 65% to about 80% or from about 65% to about 75% or from about 65% to about 70% or from about 70% to about 90%’ or from about 70% to about 85% or from about 65% to about 80% or from about 65% to about 75% or from about 65% to about 70% or from about 70% to about 90% or from about 70% to about 85% or from about 70% to about 80% or from about 70% to about 75% or from about 75% to about 90% or from about 70% to about 85% or from about 70% to about 80%.’ or from about 70% to about 75%' or from about 75% to about 90% or from about 75% to about 85% or from about 75% to about 80%- or from about 80% to about 90%- or from about 80%- to about 85% or from about 85% to about 90% wt / wt.

[0068] Suitable solvents for the compositions of the present invention include: water, cyclornethicone, cyclopentasiloxane, benzyl alcohol, propylene glycol, polyethylene glycol, propylene carbonate, ethanol, dimethyl sulphoxide, glycerin, isopropyl alcohol, Isopropyl myristate, and oleic acid and combinations thereof. Volatile alcohol, as ethanol or isopropanol, is particularly preferred at an amount of about. 10% to 25% wt / wt, as it is capable of dissolving therapeutically useful amounts of most drugs suitable for topical administration. Volatile ester, as ethyl acetate, in an amount of about 10% to 25% w / w, as it is capable of dissolving therapeutically useful amounts of most drugs suitable for topical administration. The amount of solvent in the compositions of the present invention may be up to about 10% or about 15%’ or about 20% or about 25%’ or about 30 % or about 40% wt / wt. The amount of solvent in the compositions of the present invention may be from about 5% to about 40% or from about 5% to about 35% or from about 5% to about 30% or from about 5%- to about 25%;orfrom about 5% to about 20% or from about 5%’ to about 15% or from about 10% to about 40% or from about 10%’ to about 35%- or from about 10% to about 30%> or from about 10% to about 25% or from about 10%; to about 20% or from about 10% to about 15%; or from about 15% to about 40% or from about 15% to about 35%; or from about 15% to about 30%; or from about 15% to about 25% or from about 15% to about 20% wt / wt. Creating supersaturated systems using volatile solvents is a very effective method of increasing thermodynamic activity. However, the volatile solvent must ideally be non-toxic, noncombustible, have excellent solubility properties for a wide range of drugs, and be inert. In addition, the final supersaturated system should contain an anti-nucleating agent to slow down the process of crystallization to retain optimal thennodynamic activity, It has been shown that the addition of polymers / plasticizers can be used to slow the process of recrystal lisation. The following polymers have previously been used to effectively prevent re-crystallisation of a number of drugs in supersaturated solutions: acrylic acid derivatives, such as Eudragit® (these are copolymers of methyl acrylate combined with different acidic or alkaline end groups), polyacrylamides, such as Olcocraft®, cthylccllulosc, hydroxypropyl cellulose (HPC) and derivatives thereof, hydroxypropyl methylcellulose (HPMC) and derivatives thereof, poly( vinyl pyrrolidone) (PVP). poly(vinylpyrrolidone) -vinyl acetate copolymer (PVP-VA), poly (vinyl acetate or derivatives thereof, poly (vinyl alcohol) (PVA or PVOH) or derivatives thereof, and combi nations thereof.

[0069] Supersaturated formulas are, generally, best stabilized by polymers having similar solubility parameters to the drugs themselves, since those having higher values can have a destabilizing effect. Eudragit E l 00 (cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1 :1) is particularly preferred at an amount of about 0.5 to 1.5% wt / wt. The amount of anti -nucleating agent in the compositions of the present invention may be up to about 3% or about 2.5% or about 2% or about 1.5% or about 1.0% or about 0.5%- wt / wt. The amount of antinucleating agent in the compositions of the present invention may be from about 0,25% to about 3% or from about 0,25% to about 2.5% or from about 0.25% to about 2.0% or from about 0.25% to about 1.5% or from about 0.25%' to about 1.0% or from about 0.25% to about 0.5% or from about 0.5% to about 3% or from about 0.5% to about 2.5% or from about 0.5% to about 2.0% or from about 0.5% to about 1.5% or from about 0.5% to about 1 .0% or from about 0.75% to about 3% or from about 0.75% to about 2.5% or from about 0.75% to about 2,0% or from about 0.75% to about 1.5% or from about 0.75% to about 1,0% or from about 1 ,0% to about 3%' or from about 1.0% to about 2.5% or from about 1.0% to about 2.0% or from about 1.0% to about 1.5% or from about 1.5% to about 3% or from about 1.5% to about 2.5% or about 1 .5%- to about 2.0% or about 2.0% to about 3,0% wt / wt. The compositions disclosed herein generally contain one or more penetration enhancers which promote the transdcrmal delivery of diclofenac through the skin. Examples of suitable penetration enhancers include, but are not limited, to: alkyl methyl sulfoxides (such as dimethyl sulfoxide, decylmethyl sulfoxide, tetradecylmethyl sulfoxide, and the like): pyrrolidones (such as 2- pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)-pyrrolidone, and the like); laurocapram; acetone; dimethyl acetamide; dimethyl formamide; tetrahydrofurfuryl alcohol; clofibric add amides; hexamethylene lauramide; urea; N,N-diethyl-m-toluamide; propylene glycol; fatty acid esters of propylene glycol; fatty acid esters of polyethylene glycol; glycol ethers and combinations thereof.

[0070] Exemplary fatty acid esters of propylene and polyethylene glycol include, but are not limited to. propylene glycol monocaprylate (e.g., CAPM UL PG-8 or CAPMUL PG-8 NF); propylene glycol monocaprate (e.g., CAPMUL PG-10); propylene glycol monolaurate (e.g., CAPMUL PG-12 EP / NF, LAUROGLYCOL 90); propylene glycol dicaprylate; propylene glycol dicaprate; propylene glycol dicaprylate / dicaprate (e.g,, MIGLYOL 840); and propylene glycol dilaurate (e.g.. CAPMUL PG-2L EP / NF). Exemplary glycol ethers include, but are not limited to, 2- isopropoxyethanol, ethylene glycol monobutyl ether, and diethylene glycol monoethers (e.g., butoxy diglyco]; dipropylene glycol methyl ether; diethylene glycol monoethyl ether, also referred to as 2-(2-ethoxyethoxy)ethanol and Transcutol®, GATTEFOSSE SAS, Saint-Priest, France; and the like). Diethylene glycol monoethyl ether” refers to 2-(2-ethoxyet.hoxy)ethanol, which is also known by synonyms including Transcutol® and CARB1TOL™.

[0071] Transcutol P and propylene glycol are particularly preferred at an amount of about 0.5 to 1.5% wt / wt of each. The total amount of permeation enhancer in the compositions of the present invention may be up to about 5% or about 4% or about 3% or about 2.5% or about 2% or about 1.5% or about 1.0% or about 0.5% wt / wt. The amount of permeation enhancer in the compositions of the present invention may be from about 0.5% to about 5% or from about 0.5% to about 4.5% or from about 0.5% to about 4.0% or from about 0.5% to about 3.5% or from about 0.5% to about 3.0% or from about 0.5% to about 2.5% or from about 0.5% to about 2.0% or from about 0.5% to about 1.5% or from about 1.0% to about 5.0% or from about 1.0% to about 4.5%' or from about 1,0% to about 4.0% or from about 1.0% to about 3.5% or from about 1.0% to about 3.0% or from about 1.0%' to about 2.5%' or from about 1.0%' to about 2.0% or from about 1.0% to about 1.5% or from about 1.5% to about 5.0% or from about ! .5% to about 4.5% or from about 1.5% to about 3.0% or from about 1.5% to about 2.5% or from about 1.5% to about 2.0% or from about 2.0% to about 5.0% or about 2.0% to about. 4.5% or about 2.0% to about 3.5% or from about 2.0% to about 3.0% or from about 2.0% to about 2.5% or from about 2.5% to about 5.0% or from about 2.5% to about 4,5% or from about 2.5% to about 4.0% or from about 2.5% to about 3.5% or from about

[0072] 2.5% to about 3.0% or from about 3.0% to about 5.0% or from about 3.0% to about 4.5% or from about 3.0% to about 4.0% or about 3.0% to about 3.5% or about 3.5% to about 5.0% or from about

[0073] 3.5% to 4.5% or from about 3.5% to 4.0%' or from about 4.0% to about 5.0% or from about 4.0% to about 4.5% or from about 4.5% to about 5.0% wt / wt.

[0074] The formation of a film serves to occlude the skin, and to encourage the retention of water in the skin. This has the advantage that water in the skin may continue to interact with the drug after evaporation of the solvents, thereby to continue permeation of the drug. Thus, a film-forming agent that is capable of forming a hydrogel is preferred. In this respect, PVP and PVA are preferred. Other suitable, film forming agents include: acrylic polymers or copolymers, methacrylate polymers and copolymers, poly (vinyl acetate), and cellulose based polymers and co- polymers.

[0075] The film-forming agent typically also serves the role of anti-nucleating agent as the formulation grows more concentrated once it has been dispensed. However, it may be desired to further inhibit nucleation of the drug, in which case a further component may be added to the formulation for this purpose, always provided that the formulation is raonophasic and saturated with drug under conditions of use. Suitable anti -nucleating agents are well known in the art and may include PVA when PVP is used as the film-forming agent. Other suitable anti nucleating agents include methyl cellulose, ethyl cellulose, hydroxyalkylcelluloses, such as hydroxypropylrnethylcellulose and hydroxypropylcellulose, glycol esters, polyacrylic aeid, and derivatives thereof.

[0076] Plasticizers may also usefully be added to the formulation, where the resulting film would be less flexible than desirable. In particular, plasticizers that do not readily evaporate, such as polymers, including PEG, are useful for this purpose. A combination of Eudragit and PVP has been shown to be useful for controlling drug release. Plasticizers are well known in the art, and include water, glycerol, oleic acid, citric acid, phosphate esters, fatty acid esters, glycol derivatives, hydrocarbons and hydrocarbon derivatives, adipic acid / butanediol polyesters, epoxidized soya oils, diethyl phthalate, dibutyl phthalate, citric acid esters such as triethyl citrate and the like, castor oil, triacetin and chlorinated paraffins.

[0077] The spray formulations of the present invention can be sprayed onto the skin of a human patient and dry into a film that may be water resistant. The time that it takes for the spray formulation to dry onto the skin after it has been applied may be less than five minutes, less than four minutes, less than three minutes, less than two minutes or less than a minute. The time that it takes for the spray formulation to dry onto the skin after it has been applied may be between about 30 seconds to about 5 minutes or about 30 seconds to about 4 minutes or from about 30 seconds to about 3 minutes or about 30 seconds to about 2 minutes or from about 30 seconds to about 1 minute and 30 seconds or about 30 seconds to about 1 minute or from about 45 seconds to about 5 minutes or about 45 seconds to about 4 minutes or from about 45 seconds to about 3 minutes or about 45 seconds io about 2 minutes or from about 45 seconds to about 1 minute or from 1 minute to about 5 minutes or about I minute to about 4 minutes or from about 1 minute to about 3 minutes or about

[0078] 1 minute to about 2 minutes or from about 1 minute to about 1 minute and 30 seconds or from 1 minute and 30 seconds to about 5 minutes or about 1 minute and 30 seconds to about 4 minutes or from about 1 minute and 30 seconds to about 3 minutes or about 1 minute and 30 seconds to about

[0079] 2 minutes or from about 2 minutes to about 5 minutes or from about 2 minutes to about 4 minutes or from about 2 minutes to about 3 minutes or from about 3 minutes to about 5 minutes or from about 4 minutes to about 5 minutes.

[0080] The spray formulations of the present invention should be stable for extended periods of time as measured by the stability of the API in particular diclofenac epolamine over time. The formulations of the present invention have al least 50% or al least 60% or at least 70% or al least 80% or al least 85% or at least 90% or at least 95% or at least 99% recovery of the API after being stored 4 weeks at 25°C. The formulations of the present invention have at least 50% or at least 60% or at least 70% or at least 80% or at least 85% or at least 90% or at least 95% or at least 99% recovery of the API after being stored 4 weeks at 40°C. The formulations of the present invention have from about 50% to about 99% or from about 50% to 90% or from about 50% to about 80% or from about 50% to about 70%- or from about 50% to 60% or from about 60% to about 99% or from about 60% to 90% or from about 60% to about 80% or from about 60% to about 70% or from about 70% to about 99% or from about 70%' to 90% or from about 70% to about 80% or from about 80%' to about 99%- or from about 80%- to about 90% or from about 90% to about 99% recovery of the API after being stored 4 weeks at 25°C. The formulations of die present invention have from about 50% to about 99% or from about 50% to 90% or from about 50% to about 80% or from about 50% to about 70% or from about 50% to 60% or from about 60% to about 99% or from about 60% to 90% or from about 60% to about 80% or from about 60%' to about 70% or from about 70%' to about 99% or from about 70% to 90% or from about 70% to about 80% or from about 80% to about 99% or from about 80% to about 90% or from about 90% to about 99% recovery of the API after being stored 4 weeks at 40°C.

[0081] The compositions of the present invention may also contain other physiologically acceptable excipients or other minor additives, particularly associated with organoleptic properties, such as fragrances, dyes, emulsifiers, buffers, warming agents (e.g. capsaicin, capsicum extract, vanillyl butyl ether, such as HotAct® VBE, vanillin, cooling agents (e.g. isopulegol, methoxy-propanediol, menthanediol, or menthol), where some agents may impart warming or cooling effects without odor or the like. The excipients and minor additives will be present in conventional amounts ranging from about 0.01)01 % to 5%, or from about 0.0001 to 4% or from about 0.0001% to 3% or from about 0.0001% to 29b, or from about 0.0001 to 1% or from about 0.0001% to 0.5% or from about 0.001% to 5%. or from about 0,001 to 4% or from about 0.001% to 2% or from about 0.001% to 2%, or from about 0.001 to 1 % or from about 0.001% to 0.5% or from about 0.01% to 5%, or from about 0.01 to 4% or from about 0.01 % to 3% or from about 0,01% to 2%, or from about 0.01 to 1% or from about 0.01% to 0.5% or from about O.OOOI % to 5%, or from about 0.1 to 4%' or from about 0.1 % to 3% or from about 0.1 % to 2%, or from about 0.1 to 1 % or from about 0.1 % to 0.5%- , by weight, usually not exceeding a total of 10%- by weight.

[0082] The formulations of the invention are suitable for administration as aerosols or as solutions that form films where applied to the surface of the skin. These films may also be formed by a topical spray, such as activated by a manual pump or as a topical aerosol spray with a pressurized canister separated from the spray solution and placed within a canister where CO? may be used as a propellant. Such spray film-forming systems (SFFS) has a liquid carrier with active substances and excipients sprayed onto the skin directly using gas (aerosol) or without a gas or propellant (spray). Aerosol sprays contain propellant and are atomized by valve activation. Spraying takes place continuously as long as pressure is applied until there is a metered-dose valve. A spray does not contain propellant and is atomized by forcing a vacuum by pressing. The dose depends on the pump. The formulation for those compositions which will be delivered via a canister with a propellant inherent in the formulation can be altered to be delivered by a propellant-less device such as a spray bottle by replacing the propellant with isopropyl alcohol or a combination of isopropyl alcohol and ethyl acetate. 1 Example 1

[0083] Excipient Selection

[0084] Pre-formulation experiments were performed to understand the solubility and stability of the drug in a range of individual excipients, binary systems with propellant and solvent systems suitable for use in a formulation. Solvents (e.g. ethanol, Transcutol P and propylene glycol) and nonsolvents (IPM, diisopropyl adipate and HFO134ze propellant) were identified, and this informed the development of suitable solvent systems which were designed to accommodate a drug loading of 1.3% w / w DHEP to match a commercially available comparator product, Elector® topical patch 1 .3% DHEP. Multiple rounds of formulation development were performed to assess different filmforming polymers, propellants and residual phases and concentrations thereof in order to achieve the target product profile. The formulation development yielded a selection of formulations which were, in terms of composition, different enough to mitigate the risk of physical, chemical or performance issues when subjected to formulation stability, in vitro release testing or in vitro skin permeation experiments.

[0085] Non-volatile solvent / penetration enhancers included dimethyl isosorbide, diisopropyl adipate (less than 15% w / w), propylene glycol (less than 20% w / w), diethylene glycol monoethyl ether (Transcutol P) (less than 25% w / w), isopropyl myristate (less than 3% w / w). Volatile solvent ethanol (less than 50% w / w); isopropyl alcohol (less than 50% w / w). Non-volatile benzyl alcohol (less than 2% w / w) and polyethylene glycol 400 (less than 69.9% w / w). Non-volatile skin conditioner less than 15% w / w).

[0086] Example 2

[0087] In vitro Permeation Testing versus Elector

[0088] In vitro permeation testing was performed to compare eleven formulations all containing 1.3% w / w diclofenac epolamine to Elector (1% w / w diclofenac sodium gel). Human skin from cosmetic reduction surgery was used (from a single donor). Subcutaneous fat was removed mechanically and the skin was then dermatomed to a thickness of 500 ± 50 pm using a Integra Life Sciences Model SB Slimline Dermatome. Skin was stored at -80°C until needed and then allowed to thaw at room temperature prior to placement into the diffusion cells. In order to determine the appropriate spray dosing procedure and ensure a suitable amount of formulation was delivered to the membrane, a dose verification experiment was performed. MS44 and MS47 formulations were selected for dosing experiments. In brief: (i) filter paper was mounted between the dosing and receptor chambers of 5 cells of the Medflux-HT™. (ii) a mask was used to block the 2 cells on either side or a central target cell, (iii) formulation was allowed to dry, and all 5 filter paper pieces were extracted (iv) total quantity of drug delivered to the central filter paper was calculated following LC-MS / MS analysis, (v) this was used to calculate the number of sprays required to provide an appropriate dose of DHEP for a permeation experiment, (vi) Adjacent chambers were analyzed to ensure the blocking mask was working effectively. It was determined that, to match the amount of drug in the Elector patch per cm2, 6 sprays from a distance of 5 cm was necessary, while 1 spray achieved a practical in-use dose of formulation of 10 mg / cm2.

[0089] The formulations detailed in Table 1 were selected for the full scale IVPT experiment. A range of penetration enhancers (propylene glycol, Transcutol P, isopropyl myristate, Arlasolve DMI and diisopropyl adipate) and film-forming agents (Eudragit El 00 and Eudragit RL PO) at different levels were represented in the formulations chosen. Additionally, based on the small-scale permeation data a 5% w / w DHEP formulation for use in the experiment was used to examine the impact of drug loading on permeation. Formulations were packaged in 19 mL Presspart plasma lined canisters fitted with Coster 150 uL valves. The receptor solution was pbs; sampling time points were every 2 hours over a 24 hour period; number of replicates was five and the dosing regimen was one spray (practical in-use dose formulation 10mg / cm2).

[0090] Table 1 - Formulations Containing 1.3% DHEP Table 2

[0091] DMI - Dimethyl isosorbide

[0092] After 24 h, DHEP permeation was greatest from MS79 (containing 5 penetration enhancers and the highest level of residual phase of any of the developed formulations), followed by MS 82 (5% w / w DHEP) and then the Elector topical patch. Data from the MS82 formulation (containing 5% diclofenac epolamine) was highly variable, suggesting that the drug was at its limit of thermodynamic activity in the residual phase (i.e. the DHEP precipitates out following the evaporation of ethanol). The data was log transformed for statistical analysis, and outliers were removed from MS61, MS72, MS75, MS76, MS19 and MS82 using a Dixon’s Q test at 95% confidence. Data was analyzed by Tukey-Kramer HSD (Honest Significant Differences) and the results of the pairwise analysis are presented in Appendix 5 (Section 15.2). The results of the analysis are summarized below: The results of the analysis show that 7 of the 11 formulations were not significantly different (P > 0.05) from the Elector patch by cumulative amount of drug permeated through the skin after 24 h. While MS79 and MS82 appeared to exhibit levels of drug permeation higher than Flector, due to the enhanced variability no statistical difference was observed.

[0093] Figure 1 is a graph of the mean cumulative amount of drug permeated through human skin (ng) between the 0 and 24 h experimental period from the formulations listed in Table 1 and the Flector patch. Data is presented as mean ± standard deviation (n=5).

[0094] Figure 2 is a graph of the mean cumulative amount of drug permeated through human skin (ng) at 24 h experimental period from the formulations listed in Table 1 and the Flector patch. Data is presented as mean ± standard deviation (n=5).

[0095] Figure 3 is a graph of the mean cumulative amount of diclofenac (ng / cm2) delivered to the receptor solution 24 h post-application of 2 formulations (MS77 and Flector). Data points represent the cumulative amount of diclofenac from 5 replicates and 1 donor. Error bars represent one standard deviation.

[0096] Example 3

[0097] Pre-formulation

[0098] Saturated solubility experiments were performed for both the MS-77 premix and MS-1 premix. MS-1 premix replaces the ethanol of MS-77 with IP A), to quantify the expected decrease in saturated solubility following the inclusion of IPA. Premix systems were loaded at 7% w / w DHEP on a 1 g scale, and both systems were visually unsaturated within about 2 hours. Premix systems were loaded further with 70 mg of DHEP to bring API loading to 13.08% w / w. MS-77 premix became visually unsaturated within about 1 hour and remained so for the duration of the stir period and therefore was not extracted. MS-1 premix was visually saturated after 24 h of stirring (350 RPM, T=20 °C) and was extracted for HPLC analysis. HPLC assessment confirmed that solubility dropped with the change of ethanol to IPA (>13.084% — > 11.325%). Example 4

[0099] Solubility: of Diclofenac Epolamine in Propellants

[0100] The visual solubility of DHEP in various propellants was assessed by adding 5 mg of DHEP to a 20 mL plastic transparent canister, crimping, and filling with the respective propellant in 1 g intervals. At the point of solubilization, filling was stopped and the effective API % w / w calculated. For propane and butane propellants, canister filling stopped early (8 - 10 g) due to differences in densities.

[0101] Table 2 Example 5

[0102] Effect of IP A

[0103] Ethanol was replaced with IPA to determine the effect on the solubility of DHEP within the canister, MS-1 (MS-77 like-for-like swap with IPA) at 100% of target drug loading (1.30% w / w DHEP) was manufactured. No precipitation was observed within the canister and the formulation was stable at 2-8 °C. Given that DHEP solubility is lower in IPA (ca. 7.17% w / w) than ethanol (ca. 27.78% w / w), the solubility observed of DHEP in MS-1 was unexpected. As such, MS-1 was re-prepared with a 120% of target drug loading (1.56% w / w DHEP) to further understand the level of saturation in the canister. No precipitation was observed within the canister and the formulation was stable at 2-8 °C. MS-2 (18.36% w / w IPA), MS-3 (22.36% w / w IPA) and MS-4 (15.36% w / w IPA) formulations were designed and manufactured with the intent of modifying the HFA-134a : IPA ratio of MS-1 (120% drug loading) to investigate the impact on DHEP solubility in the canister. No precipitation in the canister was observed for MS-2 and MS-3 and the formulations were stable at 2-8 °C. Precipitation in the canister was observed for MS-4 after > 2 weeks at 2-8 °C. MS- 1-4 premixes were also progressed for stability assessment at 50 °C (see HPLC analysis of MS-1 - 4 premixes stored at 50 °C). MS-4 variants were manufactured with 12.5% (MS-9) and 10% (MS- 10) IPA to push the solubility limit even lower. Premixes for both were successfully manufactured with no API solubilization issues. Crystals were observed in the canister for MS-9 (1.30% and 1.56% w / w DHEP) following about 11 - 13 days at 2-8 °C, suggesting the saturation point lies near 12.5% IPA, however MS- 10 was turbid upon manufacture. Overall, the IPA variants produced clear, non-tacky and water-resistant films, with reduced drying time (< 67 s) compared to MS-77 (around 139 s).

[0104] Table 3 - Formulations

[0105] Table 4 Table 5 - Characterization

[0106] Table 6

[0107] Example 6

[0108] Alternative Propellants

[0109] HFA-152a (MS-5), HFO-1234ze (MS-6), Propane (MS-7). Dimethyl ether and N-butane (MS-8) were tested at 75% w / w and 120% drug loading (1.56% w / w DHEP) to assess the effect on DHEP canister solubility and compatibility. No precipitation within the canister was observed for MS-5 (HFA-152a) and the formulation has remained stable at 2-8 °C. Precipitation in the canister was observed for MS-6 (HFO-1234ze) after > 2 weeks at 2-8 °C. Both MS-5 and MS-6 produced clear, colorless spray with a non-tacky, water-resistant film with a drying time of 23 and 28 s, respectively. Propane and N-butane led to turbidity upon propellant addition. Characterization of MS-7 (active and placebo) and MS-8 (active and placebo) was not performed. The turbidity was assumed to be the Eudragit as placebo formulations showed the same effect, and this was not observed when the Eudragit was removed from the formulations (MS-11 and MS- 12). Alternative film formers were investigated to assess compatibility with Propane and Butane propellants however these were still unsuccessful and therefore no further work was performed with Propane or Butane, however they may be combined with other propellants for a commercially viable formulation.

[0110] Table 7 Table 8

[0111] Table 9

[0112] Example 7

[0113] Alternative Film Formers

[0114] MS- 13 and MS- 14 (Placebo) were designed with 2.5% Gantrez ES-435 (version of Gantrez that contains IPA rather than EtOH) for testing compatibility with Propane and Butane propellants. MS- 13 became turbid on propellant (Propane) addition, MS- 14 also became turbid on propellant (Butane) addition, although to a lesser extent. Therefore, Gantrez ES-435 was not progressed for further investigation. MS-15 and MS-16 (Placebo) were designed with 1.5% Oleocraft HP 31 (polyacrylamide) MS- 15 became turbid on propellant (Propane) addition. MS- 16 became slightly turbid towards the end of the propellant (Butane) addition, however quickly recovered to a clear formulation in the canister, indicating that miscibility takes a small amount of time to achieve and is not instant. MS- 16 was characterized however it produced a weak spray and non- water-resistant film and therefore Oleocraft HP 31 was not selected for further investigation. Eudragit RS PO was selected as alternative Eudragit grade, as literature suggested solubility in IPA, water resistance, and pH independent swelling. Eudragit RS PO did not solubilize in the premix. Table 10

[0115] Table 11

[0116] Example 8

[0117] Methanol

[0118] Menthol was incorporated into the formulation (MS-77) as an organoleptic. An initial non-menthol variation (MS-22) was designed based on MS-9 (12.5% w / w IPA), to assess the odor of the IPA- based formulation in the absence of menthol, but the formulation precipitated out at 2-8 °C (2 days) as the level of IPA at 12.5% w / w is close to the saturation point. A second non-menthol variant with IPA increased slightly to 13% w / w (MS-30) was designed. At 100 % drug loading, MS-30 (1.3% w / w DHEP) was manufactured successfully and has remained stable at 2-8 °C. MS- 30 (1.3% w / w) produced a clear, colorless spray with a strong IPA odor and a non-tacky, water- resistant film with a drying time of approximately 37 s. At 120 % drug loading, MS-30 (1.56% w / w DHEP) was manufactured successfully but precipitated after 1 day at 2-8 °C. This suggests the saturation point of DHEP in the canister is approximately 13% IPA with HFA-134a and MS- 30 (1.3% w / w) is thermodynamically optimized. Further, a non-menthol variant with HFO-1234ze (MS-70) was manufactured successfully and has remained stable at 2-8 °C.

[0119] Table 12 Table 13

[0120] Example 9

[0121] HF-134a Formulalions

[0122] Based on the DHEP solubility in the canister observed in MS-9, MS-19 was designed with the replacement of 1PA with ethanol at 12.5% w / w. At 120% drug loading, MS- 19 (1.56% w / w DHEP) was successfully manufactured however precipitated out at 2-8 °C after 1 day. MS-19 was then reprepared at 100% drug loading (1.3% w / w DHEP) and has remained stable at 2-8 °C. The saturation point of DHEP in the canister is approximately 12.5% w / w ethanol with HFA-134a and MS- 19 (1.3% w / w DHEP) is thermodynamically optimized. MS- 19 (1.3% w / w DHEP) was characterized as a clear, colorless spray which produced a non-tacky, water-resistant film with a drying time of ca. 39 s.

[0123] Based on the DHEP solubility in the canister observed in MS-30, MS-62 was designed with IPA at 13% w / w. MS-62 was successfully prepared at 100% (1.3% w / w DHEP) and 120% (1.56% w / w DHEP) drug loading and both have remained stable thus far at 2-8 °C (8 days). Table 14

[0124] Table 15

[0125] Example 10

[0126] HF-152a Formulations

[0127] Based on the DHEP solubility in the canister observed in MS-9, MS-21 was designed with IPA at 12.5% w / w and with the replacement of HFA-134a for HFA-152a. MS-20 was successfully manufactured at 120% (1.56% w / w) drug loading and has remained stable at 2-8 °C, suggesting that HFA-152a has a solvent effect on API solubility in the canister. MS-20 valiants were manufactured with 12% w / w (MS-28) and 11% w / w (MS-29) IPA to push the solubility limit lower. Premixes for both were successfully manufactured at 100% and 120% drug loading with no API solubilization issues, and the formulations have remained stable at 2-8 °C. Therefore, further variants of MS-20 were designed to push the solubility limit even lower, with 10% w / w (MS-39), 7.5% w / w (MS-45) and 5% w / w (MS-46) IPA. Both MS-45 and MS-46 were turbid upon manufacture and were therefore not characterized. MS-39 was successfully manufactured, however became turbid at 2-8 °C after 6 days and >2 weeks for 1.56% and 1.3% w / w DHEP respectively. Overall, thermodynamic optimization could not be achieved due to the solvent effect of HFA-152a on DHEP and the need for a baseline level of IPA (>10%) to maintain system miscibility.

[0128] Table 16 Table 17

[0129] Table 18

[0130] Table 19

[0131] Example 11

[0132] HF-1234ze Formulations

[0133] Based on the DHEP solubility in the canister observed in MS-9, MS-20 was designed with IPA at 12.5% w / w and with the replacement of HFA-134a for HFO-1234ze. MS-20 was successfully manufactured at both 100% (1.3% w / w DHEP) and 120% (1.56% w / w) drug loading however they crashed out at 2-8 °C after 6 and 2 days respectively, suggesting MS-20 was close to the solubility limit at 12.5% w / w IPA. MS-44 and MS-51 were designed with 14% and 15% w / w IPA respectively, to improve thermodynamic optimization. Although successfully manufactured, MS- 44 and MS-51 precipitated out at 2-8 °C. Only a single small crystal was observed in MS-51 (1.3% w / w DHEP) suggesting 15% w / w IPA is closer to the saturation point. Therefore, the IPA levels were increased again slightly to 15.5% w / w in MS-63. Again, MS-63 was manufactured successfully however precipitated out after 4 days at 2-8 °C. IPA levels were increased further to 16% (MS-64) and 17% (MS-71), both were manufactured successfully and have remained stable at 2-8 °C at 1.3% w / w, however precipitated when refrigerated after 1 day at 1.56% w / w DHEP.

[0134] Table 20 Table 21

[0135] Table 22

[0136] Table 23

[0137] Example 12

[0138] Antioxidant Formulations

[0139] MS-9 (HFA-134a and 12.5% w / w IP A) variants were designed with the inclusion of BHT (MS- 23) and BHA (MS-24), to assess the feasibility of including an antioxidant into the formulation to potentially reduce API degradation with IPA from oxidative stress. MS-23 and MS-24 were successfully manufactured at 1 .3% w / w DHEP, but the API precipitated out after 2 days at 2-8 °C. Placebo variants were prepared to rule out the antioxidants being the source of the precipitate, as anticipated no precipitation was observed at 2-8 °C, confirming the precipitate to be API. The IPA levels were increased to 14 % w / w in MS-37 (BHT) and MS-38 (BHA) to account for the competing API / antioxidant solubilities. Both were manufactured successfully at 1.3% w / w DHEP and characterized as clear, colorless sprays which produced a non-tacky, water-resistant film, with a drying time of approximately 26 s (MS-37) and 42 s (MS-38). MS-38 (BHA) has remained stable at 2-8 °C, however MS-37 (BHT) precipitated out after 5 days. Therefore, the IPA levels were increased further to 15 % and 16% w / w IPA in MS-47 and MS-48 (BHT), both were prepared and characterized, and have remained stable at 2-8 °C. Antioxidant formulations with HFO-1234ze were also tested. As a result, MS-60 (BHT) and MS-61 (BHA) were designed with 16% w / w IPA with HFO-1234zc. Both were successfully prepared at 100% (1.3% w / w DHEP) and 120% (1.56% w / w DHEP) drug loading, however MS-60 (BHT) precipitated out after 1 day at 2-8 °C at both strengths, suggesting that the BHT formulation is still unoptimized with HFO-1234ze. MS-61 (BHA) also precipitated out after 1 day at the higher drug strength, however, has remained stable at the lower drug strength at 2-8 °C, suggesting MS-61 1.3% w / w at 16% w / w IPA with HFO- 1234ze is thermodynamically stable. BHT formulation with HFO-1234ze included formulations with IPA levels increased to 16.5% (MS-65) and 17% w / w (MS-66). Both were prepared successfully at 1.3% w / w DHEP and have remained stable at 2-8 °C.

[0140] Table 24

[0141] Table 25

[0142] Table 26 Table 27

[0143] Example 13

[0144] Transcutol P / Propylene Glycol Formulations

[0145] Based on MS-9 (12.5% w / w IPA with HFA-134a), further compositional changes were made by decreasing and increasing Transcutol P, Propylene Glycol, or both to further decrease drying time and to assess potential impact on performance. When reducing Propylene Glycol to 0.5% w / w (MS-25), API solubility in the canister decreased, as DHEP crystallized at 2-8 °C after 5 and 2 days at 1.3% and 1.56% w / w respectively. However, when reducing Transcutol P to 0.5% w / w (MS-26), API solubility did not seem to be impacted in the 1 .3% w / w DHEP variant, however the 1.56% w / w DHEP variant precipitated out after 1 day at 2-8 °C. Lastly, when reducing both Propylene Glycol and Transcutol P to 0.5% w / w (MS-27), DHEP crystallized at 2-8 °C after 14 and 2 days at 1.3% and 1.56% w / w respectively. Propylene Glycol has greater API solubility in the canister compared to Transcutol P with HFA-134a. MS-31 was designed with IPA reduced to 12% w / w, to assess whether the reduced Transcutol P variant (MS-26) was thermodynamically optimized. The API precipitated out in MS-31 at 120% drug loading after 1 day at 2-8 °C as anticipated, however remained stable at 100% drug loading for 27 days at 2-8 °C, after which became turbid upon shaking. Reducing Transcutol P (0.5% w / w) between 12 - 12.5% w / w IPA with HFA-134a may improve performance. MS-26 and MS-31 (1.3% w / w DHEP) with reduced Transcutol P were characterized as clear-, colourless sprays which produced a non-tacky, water- resistant film, with a drying time of approximately 28 s and 27 s respectively. Prior to precipitating out after 14 days at 2-8 °C, MS-27 (1.3% w / w DHEP) with reduced Propylene Glycol and Transcutol P was also characterized as a clear, colorless spray which produced a non-tacky, water- resistant film, with a drying time of approximately 24 s. Increasing Propylene Glycol and / or Transcutol P may improve penetration. MS-32 was designed to test Propylene Glycol increased to 1.5% w / w and IPA decreased to 10% w / w. MS-32 1.56% w / w DHEP crystallized within 1 day at 2-8 °C and MS-32 1.3% w / w DHEP was turbid upon manufacture. MS-33 was designed to test Transcutol P increased to 1.5% w / w and IPA decreased to 10% w / w. As anticipated, MS-33 precipitated out at 2-8 °C at both 1.3% w / w DHEP (2 days) and 1.56% w / w DHEP (1 day). MS- 34 was designed to test Propylene Glycol and Transcutol P increased to 1.5% w / w and IPA decreased to 10% w / w. MS-34 at 1.56% w / w DHEP crystallised after 1 day at 2-8 °C, MS-34 at 1.3% w / w DHEP did not crystallize at 2-8 °C however was turbid at upon removing from refrigerated conditions to room temperature.

[0146] Table 29

[0147] Table 30

[0148] Table 31

[0149] Table 32

[0150] Table 33

[0151] Example 14

[0152] Transcutol P / Propylene Glycol Formulations with HFA-152a

[0153] Formulations with increased Propylene Glycol (MS-41) and Transcutol P (MS-42) combined with HFA-152a, rather than HFA-134a as previously in MS-32 and M-33 were designed to keep the API solubilized within the canister without further changes to the residual phase. MS-41 and MS- 42 were manufactured successfully, though at 120% drug loading became turbid at room temperature (clear at 2-8 °C). At 100% drug loading, MS-41 and MS-42 remained stable at 2-8 °C but turbidity was observed in MS-42 after 3 weeks. Both were characterized as clear, colorless sprays which produced non-tacky, water-resistant films, however film drying time was difficult to assess as the formulations produced a weak, diffuse spray from the actuator. Table 34

[0154] Table 35

[0155] Example 15

[0156] Transcutol P / Propylene Glycol Formulations with HFO-1234ze

[0157] HFO-1234ze formulations with decreased and increased Transcutol P, Propylene Glycol, or both to were developed to decrease drying time and to assess potential impact on performance. MS-52 and MS-53 were based on MS-34 (HFA-134a), but with HFO-1234ze as an alternative propellant and IPA increased to 13% and 15% w / w respectively to maintain miscibility and stability with the propellant. MS-52 (13% w / w IPA) was turbid upon manufacture and MS-53 (15% w / w IPA) crystallised at 2-8 °C after 1 and 3 days at 1.56% and 1.3% w / w DHEP respectively. MS-76 and MS-78 were designed with increased TPA to 16% and 17% w / w respectively. Both were manufactured successfully and have remained stable at 2-8 °C. Both were clear, colorless sprays which produced non-tacky films however the film drying time was significantly increased (> 180 s) and lacked water-resistance. MS-54 and MS-55 were based on MS-27 (HFA-134a), but with HFO-1234ze as an alternative propellant and IPA increased to 15% and 17% w / w respectively to maintain miscibility and stability with new propellant. MS-54 (15% w / w IPA) crystallized at 2-8 °C after 1 day and MS-55 (17% w / w IPA) crystallized at 2-8 °C after 1 and 2 days at 1.56% and 1.3% w / w DHEP respectively. MS-67, MS-73, MS-80 and MS-81 were designed with increased IPA to 19%, 20%, 21% and 22% w / w respectively. All were manufactured successfully, at 2-8 °C MS-67 and MS-73 precipitated out after < 2 days however MS-80 and MS-81 have remained stable. Both were clear, colorless sprays which produced non-tacky, water-resistant films with drying times of 45s and 47s respectively.

[0158] MS-56 and MS-57 were based on MS-26, but with HFO-1234ze as an alternative propellant and IPA increased to 15% and 17% w / w respectively to maintain miscibility and stability with the alternate propellant. MS-56 (15% w / w IPA) crystallized at 2-8 °C after 1 day and MS-57 (17% w / w IPA) crystallized at 2-8 °C after 1 and 2 days at 1.56% and 1.3% w / w DHEP respectively. Therefore, MS-72 and MS-68 were designed with increased IPA to 18% and 19% w / w respectively. Both were manufactured successfully and have remained stable at 2-8 °C thus far. Of note, both were clear, colorless sprays which produced water resistant films however for MS-72 the film drying time was slightly longer (54 s) and resulted in a slightly tacky film.

[0159] MS-58 and MS- were based on MS-25, but with HFO-1234ze as an alternative propellant and IPA increased to 15% and 17% w / w respectively to maintain miscibility and stability with new propellant. MS-58 (15% w / w IPA) crystallized at 2-8 °C after 1 day whereas MS-59 (17% w / w IPA) crystallized at 2-8 °C after 1 days at 1.56% but remained stable at 1.3% w / w DHEP respectively. The solubility of DHEP in the canister is close to 17% w / w IPA with decreased Propylene Glycol (0.5% w / w) and HFO-1234ze. Therefore, MS-69, MS-74 and MS-75 were designed with increased IPA to respectively. All were manufactured successfully, at 2-8 °C MS- 69 precipitated out after 2 days however MS-74 and MS-75 have remained stable. Both were clear, colorless sprays which produced films with a drying time of 48 s and 37 s for MS-80 and MS-81 respectively, however the MS-74 film was slightly tacky and lacked water resistance.

[0160] Table 36

[0161] Table 37

[0162] Table 38

[0163] Table 39 Table 40

[0164] Table 41

[0165] Table 42

[0166] Table 43

[0167] Table 44

[0168] Table 45 Example 16

[0169] Ethyl Acetate Formulations

[0170] A formulation with ethyl acetate (10% w / w) was designed to trial an alternative volatile solvent (MS-10). Ethyl acetate was observed to solubilize the API and Eudragit more rapidly than IPS. Originally, MS-40 was to be prepared at 1.56% and 1.3% w / w DHEP however upon the manufacture of the 1.56% variant the polymer precipitated out of the premix instantly after propellant (HFA-34a) addition and the API crystallized after 1 day at 2-8 °C. Therefore, the manufacture of the 1.3% variant was stopped, and the premix was instead combined with HFO- 1234ze (MS-43) and HF A- 152a (MS-79) to test compatibility with alternative propellants. MS-43 and MS-79 also became turbid upon propellant addition due to polymer precipitation. Ethyl acetate therefore considered not fit for use as an alternative volatile.

[0171] Example 17

[0172] HPLC Stability Analysis

[0173] MS- 1-4 premixes (Sol 1 - 4) were tested for stability assessment at 50 °C, an extreme accelerated storage condition which is indicative of storage at ICH standard room temperature condition of 25°C / 60% RH for a longer period of time where Arrhenius concluded a 10°C increase in temperature imparts double the reaction rates for API degradation as a general rule Each premix was extracted for HPLC analysis at intervals over an 8-week stability period with the aim of identifying the growth of impurity RRT at around 1 .4, observed in the previous lead formulation (MS-77). DHEP recovery (%) decreased for all premixes (Sol 1 - 4) over 8 weeks at 50 °C (by about 2 - 6 %) but all remained acceptable range (95 - 105%). This loss in recovery is accompanied by a representative loss in DHEP peak area, mainly due to three growing impurity peaks at ca. RRT 1.10, RRT 1.11 and RRT 1.37 (corresponds to RRT 1.09, 1.11 and 1.38 seen at t=8 weeks). The t=12-month (25 °C) MS-77 (ethanol) ICH stability minimum fill canisters that were extracted and run alongside the t=8 weeks samples for a direct comparison. The t=12-month (25 °C) samples have a large peak present at RRT 1.28 which does not correspond to any peak found in the premixes (Figure 1). Therefore, the previous impurity peak at RRT around 1.4 was not observed in Sol 1 - 4, however new impurity peaks are growing under heat conditions with replacement with IPA. Figure 4 is a representative chromatogram of the premix MSI at t=8 weeks at 50 °C (black) overlaid with MS-77 at t=12 months 25 °C / 60%RH (blue) and diluent blank, 100% methanol (green).

[0174] Table 46

[0175] Table 47 Example 18

[0176] In vitro Permeation Testing versus Voltaren

[0177] In vitro permeation testing was performed to compare a MS77 (1.3% w / w diclofenac epolamine) to Voltaren (1% w / w diclofenac sodium gel). The permeation experiment was conducted in a manner similar to that in Example 2. Parameters: Human abdominal skin, 500 + / - 50 microns; No. of donors 3; 4 replicates per donor; Dose amount 14 mg / cm2; Flow rate lOuL / min and RS collection every 2 hours for 24 hours.

[0178] Table 48 - MS 77 formulation

[0179] Mean cumulative amount of diclofenac (ng / cm2) delivered to the receptor solution at 24 h and peak flux (ng / cm2 / hr), following application of the 2 formulations.

[0180] Table 49

[0181] When comparing MS77 to Voltaren, there were no significant (p > 0.05) differences in the mean cumulative amounts of diclofenac delivered to the receptor solution at 24 hr.

[0182] Two methods were assessed to verify the dosing method for MS77 and ensure a sufficient amount of API was delivered to the membrane (target dose: ca. 10 mg / cm2) • Method 1 : A dosing apparatus was utilized for dosing MS77

[0183] • Method 2: A canister holder was utilized for dosing MS77

[0184] • Five adjacent flow-through cells were mounted with filter paper and the outside cells were masked, leaving only the center cell unmasked. The unmasked center flow-through cell was was dosed using either method 1 or method 2 and allowed to dry. The filter papers were extracted using ethanol, shaken for ca. 3 hr and analyzed by EC-MS / MS

[0185] Table 50

[0186] Figure 5 is a graph of the mean cumulative amount of diclofenac (ng / cm2) delivered to the receptor solution 24 h post-application of Voltaren and MS77. Data points represent the cumulative amount of diclofenac from 4 replicates and 3 donors (n=12). Outliers were removed. Error bars represent one standard error of the mean.

[0187] One-way analysis of the In-transformed diclofenac peak flux (PF, ng / cnrby formulation (n= 11- 12) using Tukey-Kramer. C / hr) connecting letters reports show that levels not connected by the same letter are significantly different. Voltaren 4.4366700; MS77 3.7123785.

[0188] One-way analysis of the In-transformed total cumulative amount of diclofenac (AUC, ng / cm2) by formulation (n= 11-12) using Tukey-Kramer. Connecting letters reports show that levels not connected by the same letter are significantly different. Voltaren 7.256148 and MS77 6.325305. Example 19

[0189] Toxicity Study in Minipigs

[0190] The objectives of this study were to determine the potential toxicity of DSF100, when given dermally for 28 days to minipigs and to evaluate the potential reversibility of any findings. In addition, the toxicokinetic characteristics of DSF100 were determined.

[0191] The study design was as follows:

[0192] Table 51

[0193] Experimental Design - Main and Recovery

[0194] - = Not applicable.aEach canister of formulation was primed by spraying 7 times prior to the initial use. To deliver the appropriate dose level, the weight of diclofenac epolamine was expelled per spray (approximately 1.7 mg); therefore, 6, 18, and 35 sprays of material were administered directly to clipped skin over each designated area using the transdermal delivery system (via canister) for Groups 2, 3, and 4, respectively. Group 1 received the same number of sprays as Group 4 (35 sprays).bThe test materials were applied dermally once daily from Days 1 to 28. The target area (10 cm x 14 cm on 1 side of the animal’s dorsum) was covered with the appropriate dosing material for 24 hours (+ 1 hour).cDiclofenac Epolamine PBO Medspray.

[0195] The following parameters and end points were evaluated in this study: mortality, clinical observations, dermal observations, body weights, body weight gains, ophthalmology, electrocardiology, clinical pathology parameters (hematology, coagulation, clinical chemistry, and urinalysis), toxicokinetic parameters, organ weights, and macroscopic and microscopic examinations.

[0196] There were no DSFlOO-related early deaths, clinical observations, body weight changes, body weight gain changes, ophthalmic findings, quantitative electrocardiography changes, qualitative electrocardiography changes, hematology changes, coagulation changes, clinical chemistry changes, or urinalysis changes. Test article-related dermal irritation including very slight erythema was observed in 1 of 3 males at 10 mg / day, slight edema was observed in all males and females at 60 mg / day, and skin flaking was observed in all males and females at > 30 mg / day.

[0197] There were no DSF 100-related organ weight changes at terminal or recovery euthanasia. DSF 100- related gross changes at terminal and recovery necropsy included skin scaling at the administration site in males and females, with a microscopic correlate of orthokeratotic hyperkeratosis.

[0198] There was DSF 100-related mild kidney papilla necrosis in 1 high-dose female, as well as minimal to mild single cell apoptosis / necrosis and vacuolation of the kidney epithelial papilla and minimal to mild neutrophil infiltration within the kidney papilla at dosages of > 60 mg in males and females, and minimal mononuclear cell infiltration in high-dose females only. There was complete recovery of microscopic kidney findings by Day 43. At the dermal administration site, there was DSF100- related minimal to mild orthokeratotic hyperkeratosis in males and females similarly at terminal and recovery necropsy.

[0199] In conclusion, DSF100 by once daily dermal administration for 28 days was well tolerated in minipigs at levels of 10, 30, and 60 mg / day, with no adverse findings at any dose level. Based on these results, the no-observed-adverse-effect level (NOAEL) was considered to be 60 mg / day.

[0200] Example 20

[0201] Formulations selected for stability testing.

[0202] A total of 30 premixes, 15 actives and 15 corresponding placebos, were manufactured on a approximately 550 g scale and progressed for stability testing. Following manufacture, each premix was filled into vials and canisters. The compositions for the premix, placebo and within the canister are detailed in Tables 51-63).

[0203] The rationale for each of the formulations tested is as follows:

[0204] 1 MS-77 formulation from previous studies

[0205] 2 MS-1 is identical to MS-77, but with IPA replacing ethanol.

[0206] 3 MS-84 is identical to MS-1, but with HFO-1234ze as an alternative propellant. 4 MS-71 is identical to MS-84, but thermodynamically optimized for DHEP canister solubility at 17% w / w IPA.

[0207] 5 MS-91 is identical to MS-71, but with the removal of menthol to assess sensory impact.

[0208] 6 MS-93 identical to MS-71, but with inclusion of BHT as an antioxidant.

[0209] 7 MS-90 is identical to MS-71, but with inclusion of BHA as an antioxidant.

[0210] 8 MS-92 is identical to MS-71, but with HFA-152a as an alternative propellant.

[0211] 9 MS-87 is identical to MS-77 but with reduced ethanol to assess impact on impurity growth and with HFO-1234ze as an alternative propellant.

[0212] 10 MS-98 is identical to MS-84, but with Transcutol® P increased to 1.5% w / w and propylene glycol decreased to 0.5% w / w.

[0213] 11 MS-80 is identical to MS-84, but with propylene glycol and Transcutol® P both decreased by 0.5% w / w each, and with IPA increased to 21% w / w due to observed reduced DHEP solubility with lower propylene glycol and Transcutol® P levels.

[0214] 12 MS-99 is identical to MS-84, but with Transcutol® P decreased by 0.5% w / w.

[0215] 13 MS-100 is identical to MS-84, but with propylene glycol decreased by 0.5% w / w.

[0216] 14 MS-101 is identical to MS-84, but with propylene glycol increased to 1.5% w / w and Transcutol® P decreased to 0.5% w / w.

[0217] 15 MS-102 is identical to MS-84, but with both Transcutol® P and propylene glycol increased to 1.5% w / w.

[0218] Each premix was manufactured as follows:

[0219] 1. (-)-Menthol, BHT and BHA (for relevant formulations) was weighed and transferred via weigh boats into the manufacturing vessel.

[0220] 2. Transcutol® P and propylene glycol were weighed into the vessel via syringe. 3. Volatile solvent (isopropyl alcohol / ethanol) was weighed into the vessel via syringe.

[0221] 4. The premix was placed on stir using a PTFE stirrer bar and multiplate or hotplate stirrer at

[0222] 500 RPM for ca. 5 min, at which point the solution was checked for visual homogeneity.

[0223] 5. The premix stir speed was increased to 650 RPM to generate a vortex.

[0224] 6. Whilst the premix was on stir, the film former (Eudragit) was weighed and transferred via weigh boat, ensuring addition was slow to minimise ‘clumping’ of the pellets.

[0225] 7. The premix solution was stirred at 600 RPM until the Eudragit pellets were observed to have completely dissolved. The vessel lid was sealed with parafilm whilst on stir.

[0226] 8. For active formulations only, diclofenac epolamine (DHEP) was weighed and transferred via weigh boat to the vessel. The vessel lid was re-sealed with Parafilm.

[0227] 9. The premix was placed back on stir at 600 RPM until DHEP had visually dissolved; this was confirmed via use of the Apollo I liquid viewer.

[0228] Table 52 Theoretical composition (% w / w) in canister of active formulations for stability testing

[0229] Table 53 Theoretical composition (% w / w) in canister of active formulations for stability testing

[0230] Table 54 Theoretical composition (% w / w) in canister of active formulations for stability testing

[0231]

[0232] Table 55 Theoretical composition (% w / w) in canister of placebo formulations for stability testing

[0233] Table 56 Theoretical composition (% w / w) in canister of placebo formulations for stability testing

[0234]

[0235] Table 57 Theoretical composition (% w / w) in canister of placebo formulations for stability testing Table 58 Theoretical composition (% w / w) in canister of premix of active formulations for stability testing

[0236] Table 59 Theoretical composition (% w / w) in canister of premix of active formulations for stability testing Table 60 Theoretical composition (% w / w) in canister of premix of active formulations for stability testing

[0237] Table 61 Theoretical composition (% w / w) in canister of premix of placebo formulations for stability testing

[0238] Table 62 Theoretical composition (% w / w) in canister of premix of active formulations for stability testing

[0239] Table 63 Theoretical composition (% w / w) in canister of premix of active formulations for stability testing

[0240] The premixes were filled into 19 mL FCP-lined aluminium canisters, and 15 mL glass canisters, fitted with 120 pL metered dose valves crimped to the canisters using the Pamasol aerosol filler. Each canister was then filled with propellant before being allocated for stability. The total number of canisters filled for each formulation is detailed in Table 37. Of note, formulations were actuated using an NM33 actuator (manufacturer: Presspart, product code: 000423BV), where required, during stability assessment.

[0241] Additionally, the premixes were filled into 10 mL clear and amber (non-screw neck) vials and also allocated for stability. Any premix remaining after allocation for stability testing was transferred into appropriately sized amber borosilicate containers and stored as excess at ambient uncontrolled laboratory conditions.

[0242] The canisters were filled as follows:

[0243] 1. An empty 19 mL FCP-lined aluminium canister or 15 mL glass canister, as appropriate, was placed on an analytical balance alongside a K-120 D20SAL STDAA FCA7000 56LPS valve and tared.

[0244] 2. The relevant amount of premix was weighed into the canister, and the valve placed on top, to prevent solvent evaporation. The weight of premix added was recorded.

[0245] 3. The valve was crimped onto the canister to create an airtight seal using the 15 mm Pamasol crimp head.

[0246] 4. The canister was filled with the relevant mass of propellant using the Pamasol, and the weight of propellant addition was recorded using an analytical balance (weighing tolerance of ± 5% w / w).

[0247] 5. The canister was vortexed for ca. 30 s at maximum speed to mix. 6. The canister was inverted, and the valve submerged in warm water (approximately 50 °C) for about 1 min to observe for the presence of leaking (indicated by bubbles releasing from the crimped edge of the valve). Any canisters that visually failed this test were re-crimped and checked again, canisters which still failed this test after re-crimping were discarded.

[0248] The premix vials were filled as follows:

[0249] 1. Premix (about 3 mL) was filled via syringe into 10 mL amber / clear borosilicate vials.

[0250] 2. The vials were sealed with a silicone injection stopper and a metal lid; the lid was crimped in place with a handheld 20 mm crimper.

[0251] Table 64: Number of canisters / vials filled per formulation for stability testing.

[0252] The premixes were stored as per the stability conditions, and tested for the specific tests, as detailed in Table 65. At each timepoint, premix vials were tested according to the following parameters (where applicable):

[0253] • Diclofenac epolamine content and related substances (premix analysis) n=2 for active and. n=l for placebo for integration purposes

[0254] • Macroscopic appearance; n=l for active and placebo

[0255] • Microscopic appearance; n=l for active and placebo Table 65: Summary of stability storage conditions, timepoints, and testing performed at each timepoint

[0256] X = Diclofenac epolamine content and related substances, macroscopic and microscopic appearance.

[0257] Y = Back-up only to be tested.

[0258] [1] no testing was performed on MS-84, MS-71. MS-93, MS-90 and MS-

[0259] 87 premixes (both active and placebo) at t=6 months, following the results of IVPT.

[0260] Diclofenac epolamine content and related substances (premix analysis)

[0261] The premix formulations were analyzed at t=0 and over stability for diclofenac epolamine content and related substances by HPLC. DHEP content as percentage of label claim (%) throughout 6 months stability, the DHEP content of the premixes decreased from 1=0, with the decrease being greater for samples stored under accelerated conditions. Overall, the average DHEP content remained within 90 - 110% at all timepoints for samples stored at 25 °C / 60%RH, 30 °C / 65%RH and 40 °C / 75%RH, with the exception of MS-98 at 1=4 weeks 40 °C / 75%RH (111.63%), however the average was skewed by one high replicate (120.06%). The MS-77 premix obtained the lowest recovery at t=6-month 40 °C / 75%RH (92.87%). At 65 °C, the average DHEP content of the premixes remainedwithin 90 - 110%, with the exception of MS-77 (89.65%) and MS-87 (89.82%) at t=4 weeks. Both variants contain ethanol as the main solvent and the lower level of ethanol in MS-87 (76.17% w / w) compared to MS-77 (82.48% w / w) did not delay the decrease in DHEP content observed.

[0262] DHEP purity (% area)

[0263] Overall, the purity of DHEP was between 95 - 100% area for all premixes stored at 25 °C / 60%RH, 30°C / 65%RH and 40 °C / 75%RH across 6 months stability, with the exception of MS-77 (with ethanol) which reported a purity of DHEP of 91.97% area at t=6 month 40 °C / 75%RH. At 65 °C, the purity of DHEP remained within 90 - 100% area for all IPA containing premixes, however fell below 90% area for the ethanol containing premixes at t=4 weeks (88.33 and 87.34% area for MS- 77 and MS-87, respectively). DHEP related substances

[0264] At t=0, no reportable impurities (> 0.05% area) were observed in any of the IPA containing premixes, however, in the ethanol containing premixes (MS-77 and 87) an unknown impurity peak at RRT ca.1.31 (Peak X) was reported at the reportable threshold. Of note, this unknown impurity peak was previously observed to grow during stability assessment under prior studies. Over 6 months stability, the total reportable impurities increased for all premix formulations, with the increase being greater for samples stored under accelerated heat conditions. At t=6 months 40°C / 75%RH, the total reportable impurities for all IPA containing premixes remained < 5% area, however, was about 8% area for MS-77 (with ethanol) with the predominant unknown impurity peak, Peak X contributing 7.02% area of this total. The predominant impurities (> 0.5% area) observed in the IPA containing premixes include unknown impurity peaks at RRT ca. 1.10 (Peak U), RRT ca. 1.12 (Peak V) and RRT ca. 1.33 (Peak Y), and a known impurity peak at RRT ca. 1.37 (Diclofenac Impurity 4). Peak X was only observed in the ethanol containing premixes, and not in those containing IPA. Moreover, Peaks U, V and Y were present in the impurity profile of MS-77 and 87 (ethanol), however at lower levels (NMT ca. 0.15% area for each peak after 6 months at 40 °C / 75%RH) compared to the IPA premixes (NMT ca. 1.4% area for each peak after 6 months at 40 °C / 75%RH).

[0265] In addition, no obvious differences were observed in the impurity profile between MS-90 and 93 (with antioxidants BHA and BHT, respectively) and compared to the other IPA containing premixes (without antioxidants).

[0266] These observations have been summarized below, with some additional potential trends:

[0267] • Presence of antioxidants (MS-90 and 93) did not appear to reduce the level of degradation.

[0268] • Peak W was only present in IPA containing formulations above the reportable threshold (0.05% area). Peak W was present in ethanol containing formulations (MS-77 and 87), but below the reportable threshold.

[0269] • The growth of Imp 4 appears to be retarded in the ethanol containing formulations compared to the IPA containing formulations as it never reached the reportable threshold. • Peaks U, V and Y are present in all premixes but lower in ethanol containing formulations (MS- 77 and 87).

[0270] • Peak X (previously observed under 487-2101-01) was only present in ethanol containing formulations (MS-77 and 87).

[0271] • Increased Transcutol P may potentially exacerbate Peak Y (MS-98 vs 99).

[0272] • Comparing MS-90 and 93 (antioxidants) to MS-71 (no antioxidants), both BHT and BHA seem to reduce the unknown imps as peaks are below threshold / not present, e.g., RRT 0.92, 1.06 and 1.15, which may suggest these smaller peaks are potential oxidation. This trend is more apparent with BHT (MS-93).

[0273] • Overall, the IPA containing premixes performed better than the ethanol containing premixes.

[0274] The lower ethanol level in MS-87 did not appear to impede degradation compared to the higher ethanol level in MS -77.

[0275] Macroscopic appearance

[0276] The premixes were visually assessed over stability. At t=0, all premixes were faint yellow and clear with the visual viscosity of a solution. Generally, the active premixes had a more apparent yellow hue compared to their placebo counterparts. Exceptions to this were the MS-99 and 100 premixes, which did not present a noticeable difference in color between their active and placebo equivalents. In addition, MS-87 and 90 premixes (active and placebo) had a more apparent yellow hue in comparison to the other premix formulations, however the difference in color was not significant enough to warrant a difference in color classification. This may be attributed to the higher concentration of Eudragit E100 in the MS-87 premix and the presence of BHA in the MS- 90 premix, as both excipients have a yellow color.

[0277] After 2 and 4 weeks storage at 65 °C, most placebo premixes remained visually comparable to t=0, except for MS-90 which became increasingly more yellow / beige over time. Again, MS-90 contains BHA, and this unique color change may be linked to the color of this excipient. All active premixes remained clear with the visual viscosity of a solution; however, they all possessed a dramatically darker yellow color following 2 and 4 weeks storage at 65 °C. MS-77 and 87 also became slightly tinted orange which is likely attributed to increased API degradation due to the presence of ethanol in the premix.

[0278] The placebo premixes remained visually comparable to t=0 across 6 months stability at 25°C / 60%RH, 30 °C / 65%RH and 40 °C / 75%RH, except MS-90 which developed a beige color; likely associated to the presence of BHA. Conversely, the yellow hue of the active premixes deepened over 6 months stability at 25 °C / 60%RH, 30 °C / 65%RH and 40 °C / 75%RH, with the change in color being more apparent at accelerated heat conditions. MS-77 and 87 developed an orange tone which is likely attributed to increased API degradation due to the presence of ethanol in these premix formulations. The macroscopic observations of the premixes stored at ICH conditions were consistent with the trends observed in the premixes at 65 °C.

[0279] At t=6 months, some fibrous material was observed settled at the bottom of the MS-80 active vial at 40 °C / 75%RH, which was attributed to vial contamination (e.g., lint or dust). This contamination was also observed microscopically.

[0280] The yellowing of the MS-92, MS-98, MS-80, MS-99, MS- 100, MS- 101 and MS- 102 active premixes was less apparent at 30 °C / 65%RH than at 25 °C / 60%RH at t=6 months, which conflicts the trend observed at previous timepoints that the yellowing of the premixes is exacerbated under heat conditions.

[0281] Microscopic appearance

[0282] The microscopic appearance of the premixes was assessed over stability, using the Olympus BX53M light microscope. At t=0, and across 6 months stability, no API or excipient particulates were observed in any of the premix formulations. Some fibers were observed in the MS-80 active sample at t=6 months 40 °C / 75%RH, however these were attributed to vial contamination (e.g., lint or dust) rather than API or excipient. This is consistent with the macroscopic observations.

[0283] Formulation stability - Canisters

[0284] The formulations were stored as per the stability conditions, and tested for the specific tests, as detailed in Table 66. At each timepoint, the canisters were tested according to the following parameters (where applicable): • Diclofenac epolamine content and related substances (delivered dose uniformity (DDU)) For active formulations n=3 canisters were assessed, with n=3 replicates at both start and end of canister life for n=l canister (totaling n=6 samples), and n=l replicate from stall of canister life only for n=2 and n=3 canister. For placebo formulations n=l canister was assessed with n=l replicate from start of canister life only. Related substances analysis was reported from n=l replicate at start of canister life.

[0285] • Macroscopic appearance; n=l for active and placebo

[0286] • Film characteristics; n=l for active and placebo

[0287] • Microscopic appearance; n=l for active and placebo

[0288] • Leak rate by weight loss; n=10 for MS-71 active only

[0289] • Discharges per container; n=l for active only

[0290] The canisters were visually inspected for any damage or leakage after removal from stability. During chemical testing at t=4 weeks 40 °C / 75%RH, significant DHEP degradation (loss of 60 - 80% area) was observed in the formulations containing HFO-1234ze, highlighting an incompatibility between DHEP and HFO-1234zc propellant. The degradation of DHEP in the corresponding premix solutions without propellant was far less, further supporting that HFO- 1234ze exacerbates degradation of DHEP. Therefore, further stability testing, including additional temperatures at t=4 weeks, of MS-84, 71, 91, 93, 90, 87, 98, 80, 99, 100, 101 and 102 was withdrawn.

[0291] The samples for macroscopic assessment were filled and placed on stability later than the other stability samples. In addition, the decision to withdraw the formulations containing HFO-1234ze from the stability program was implemented prior to the delivery of the glass canister packaging, therefore no macroscopic samples were prepared or tested for MS-84, 71, 91, 93, 90, 87, 98, 80, 99, 100, 101 and 102. Table 66: Summary of stability storage conditions, timepoints, and testing performed at each timepoint.

[0292] X = Diclofenac epolamine content and related substances (delivered dose uniformity (DDU)), macroscopic appearance, film characteristics, and microscopic appearance.

[0293] W = Weight loss (MS-71 active only).

[0294] D = Discharges per container (performed in conjunction with DDU analysis, on active formulations only).

[0295] Y = Back-up.

[0296] * The discharges per container test was repeated for MS-77, 1 and 92 (active only) at t=6 month 25°C / 60% RH (refer to Section 2.5.6).

[0297] Diclofenac epolamine content and related substances (DDU)

[0298] The formulations were analyzed at t=0 and over stability (where applicable) for diclofenac epolamine content (delivered dose uniformity) and related substances by HPLC. During chemical testing at t=4 weeks 40°C / 75%RH, significant DHEP degradation (loss of 60 - 80% area) was observed in the formulations containing HFO-1234ze, highlighting an incompatibility between DHEP and HFO-1234ze propellant. The degradation of DHEP in the corresponding premix solutions without propellant was far less, further supporting that HFO- 1234ze exacerbates degradation of DHEP. Further stability testing, including additional temperatures at t=4 weeks, of MS-84, 71, 91, 93, 90, 87, 98, 80, 99, 100, 101 and 102 was withdrawn.

[0299] Throughout stability testing, elevated RSD values were observed on the DDU method (particularly the end of canister life n=l replicate). Therefore, the number of actuations per extraction was increased from 1 to 2, increasing the volumetric size accordingly to maintain the same target concentration (about 200 pg / mL). The adjusted extraction procedure (detailed in Appendix 2, Section 4.2.1.2) was employed at t=3 months and subsequent stability timepoints.

[0300] DHEP delivered dose uniformity (DDU)

[0301] Across 6 months stability, the average DDU of DHEP from the formulations containing HFA- 134a or HFA-152a (MS-77 and 1, and MS-92, respectively) fluctuated from t=0, but generally remained within the acceptable range of 85.0 - 115.0%. Exceptions to this were: MS-1 t=0 Canister 1 end of life (118.93%) and MS-92 t=6 months 40 °C / 75%RH Canister 2 start of life (83.49%). This trend was consistent across storage conditions, however the decrease in recovery was more apparent under accelerated conditions. At t=0, the recovery of DEEP was lower at the start of canister life compared to the end of canister life for the Canister 1 sample.

[0302] DHEP purity (% area)

[0303] Overall, the reported purity of DHEP was between 95 - 100% area for the MS-77, 1 and 92 canisters stored at 25 °C / 60%RH, 30 °C / 65%RH and 40 °C / 75%RH across 6 months’ stability, with the exception of MS-77 (with ethanol) which reported a purity of DHEP of 92.79% area at t=6 month 40 °C / 75%RH.

[0304] DHEP related substances

[0305] At t=0, no reportable impurities (> 0.05% area) were observed in any of the canisters containing HFA-134a and HFA-152a propellant (MS-77 and 1, and MS-92, respectively). Over 6 months stability, the total reportable impurities increased, with the increase being greater for samples stored under accelerated conditions. At t=6 months 40 °C / 75%RH, the total reportable impurities for the MS-1 (HFA-134a) and MS-92 (HFA-I 52a) canisters with IPA remained < 5% area, however, was about 7% area for MS-77 (HFA-134a) with ethanol, with the predominant unknown impurity peak, Peak X, contributing 6.47% area of this total. Of note, this unknown impurity peak (Peak X) was previously observed to grow during stability. The predominant impurities (> 0.5% area) observed in the IPA containing MS-1 and 92, include unknown impurity peaks at RRT ca. 1.10 (Peak U) and RRT ca. 1.12 (Peak V), and a known impurity peak at RRT ca. 1.37 (Diclofenac Impurity 4). Peak X was not observed during stability testing for MS-1 and 92; consistent with the data obtained for the corresponding premix solutions.

[0306] Overall, MS-1 and 92 (with IPA) performed better than MS-77 (with ethanol) with respect to DHEP purity and related substances. Some additional observations with regards to the formulations containing HFO-1234ze propellant are summarized below:

[0307] All formulations where significant degradation (loss of 60 - 80% area) occurred contained HFO- 1234ze as the propellant, suggesting that this propellant is the main driving factor behind the degradation. MS-77 and MS-1 , and MS-92 (HFA-134a / 152a, respectively) were the only formulations kept on stability and did not sustain as substantial degradation (loss of < 8% area).

[0308] The degradation of DHEP in the MS-84, 71, 91, 93, 90, 87, 98, 80,99, 100, 101 and 102 premix solutions was far less than their corresponding canisters, lending more support to the theory that the HFO-1234ze was exacerbating the loss in % area.

[0309] Peak X (previous impurity observed under 487-2101-01) was present in the formulations containing IPA and HFO at t=4 weeks 40 °C / 75%RH, however, this peak was not observed in the corresponding premixes without propellant (even below reportable threshold).

[0310] Peak X was also observed to be exacerbated by HFO-1234ze in the MS-87 ethanol containing formulation (29.77% area at t=4 weeks 40 °C / 75%RH).

[0311] The key impurities (> 5% area) in the canisters containing HFO-1234ze were Imp A and 4, and unknown peaks W, U and V. Peaks Y and X were also present at > 0.5% area but remained generally < 5% area. Exceptions to this include MS-98 (Peak Y at 5.38% area) and MS-87 (Peak X at 29.77% area) at t=4 weeks 40 °C / 75%RH.

[0312] Macroscopic appearance

[0313] The macroscopic appearance of MS-77, 1 and 92 (active and placebo) in 15 mL glass canisters (with propellant) was assessed over stability. The samples for macroscopic assessment were filled and placed on stability later than the other stability samples. The decision to withdraw the formulations containing HFO-1234ze propellant from the stability program, due to the API degradation observed at t=4 weeks 40 °C / 75%RH was implemented prior to the delivery of the glass canister packaging. Therefore, no macroscopic samples were prepared or tested for MS-84, 71, 91, 93, 90, 87, 98, 80, 99, 100, 101 and 102.

[0314] At t=0, all samples (active and placebo) were classified as clear- and colorless with the visual viscosity of a solution. Over 6 months stability at 25 °C / 60%RH, 30°C / 65%RH and 40 °C / 75%RH, yellowing of the formulations was observed, this was more apparent in the active formulations compared to their placebo counterparts, likely attributed to API degradation, and seemingly exacerbated at higher temperatures. Overall, no significant differences in macroscopic appearance were observed between MS-77, 1 and 92, suggesting the differences in composition (e.g., solvent levcl / typc and propellant type) between the formulations did not impact their visual appearance in the canister.

[0315] Film characteristics

[0316] The drying time (sec), tackiness (Y / N) and water resistance (Y / N) of the dried films were assessed at t=0 and across 6 months stability (where applicable). The dried films were assessed by actuating the formulations, n=l per sample, onto a gloved hand and the below characteristics were assessed: Drying time: Upon actuation a timer was started and was stopped when the film had dried, the time taken to dry was recorded - a dry film was once no residue was transferred to the gloved finger touching the film on the gloved hand. Film tackiness: After film dying, the tackiness of the film was assessed using a gloved finger. Water resistance: A few drops of water were applied to the dried film on the gloved hand, the film was then gently rubbed to assess if the film is water- resistant.

[0317] At t=0, all formulations produced water resistant films with drying times ranging from about 40 - 70 s. In general, the films were non-tacky, however slight tackiness was reported for MS-91 (active only), 93 (active only), 90 (active and placebo) and 87 (active and placebo).

[0318] A slight decrease in drying time was observed over 6 months stability for all conditions (25 °C / 60%RH, 30 °C / 65%RH and 40 °C / 75%RH), however at the final timepoint the majority were within about 5 s of t=0.

[0319] This trend was more apparent in the active formulations compared to the placebos. Some fluctuation in film tackiness was observed, however, this is again likely attributed to the variability / subjectivity of the method. No change in water resistance was observed.

[0320] Microscopic appearance

[0321] The canister was actuated once onto a glass slide and allowed to dry prior to examination. The microscopic appearance of the dry film was then assessed using the Olympus BX53M light microscope. The microscopic appearance of the dried films was assessed at t=0 and across 6 months' stability (where applicable). At t=0, all dried films were absent of API particulates. Across 6 months stability at 25 °C / 60%RH, 30°C / 65%RH and 40 °C / 75%RH, all dried films assessed remained free of API particulates in accordance with t=0. Of note, some excipient particulates, postulated to be Eudragit, were observed in the dried films of MS-98 - 102 at t=0, and MS-77, 1 and 92 (active and placebo) at t=3 and 6 months.

[0322] Leak rate by weight loss

[0323] At t=0 and each subsequent timepoint (25 °C / 60% RH and 40 °C / 75% RH), the specific weight loss canisters (MS-71 active only) were removed from their ICH conditions and allowed to equilibrate to room temperature. Once the canisters were at room temperature, they were weighed to obtain their gross weight. To assess leak rate, the gross weights obtained at each timepoint / condition were compared with the gross weights obtained at t=0 using the calculation below. The average (n=10) % change from t=0 was reported.

[0324] % change from t = 0 =(Canister weight at timepoint (g)-Canister weight at t = 0 (g) / Canister weight at t = 0 (g) x 100.

[0325] The canister weights (g) and the average (n=10) change in canister weight from t=0 (%) over stability were recorded. This test was performed on one active formulation only (MS-71) to assess the integrity of the formerly anticipated final packaging (19 mL FCP-lined aluminum canister and 120 pL metered dose valve) under ICH conditions 25 °C / 60% RH and 40 °C / 75% RH.

[0326] Overall, slight (NMT 0.07%) weight loss was reported for canisters stored at 40 °C / 75% RH but not at 25 °C / 60% RH, and this was more apparent over time. This may be attributable to a decrease in the packaging integrity under higher temperatures, however the % loss observed is not considered to be significant. The same trend was observed during stability testing of MS-77 toxicology material.

[0327] Discharges per container

[0328] The discharges per container test was performed on all active formulations at t=0, in conjunction with DDU analysis. Prior to any actuations (including priming), a 5-place balance was tared and the gross weight of the canister obtained. The canister was then actuated, and the gross weight obtained after each actuation. The process of actuating and weighing was continued until the end point was reached. The end point was determined by at least n=3 actuations consistently below 130 mg. At t=0, differences in the average actuation weight were observed between the formulations on stability. In addition, fluctuations in extraction weights were observed for some formulations, with the actuation weight dropping below the average before returning to average levels during subsequent actuations. This is discussed further in Section 2.5.5. Therefore, with the aim to reduce the observed variability and improve method repeatability, the discharges per container test was performed for MS-77, 1 and 92 (active only) at t=6 month (25 °C / 60% RH) in accordance with the updated method detailed below. Again, this test was performed in conjunction with DDU analysis. Prior to any actuations (including priming), a 5-place balance was tared and the gross weight of the canister obtained. • After shaking for at least 5 seconds, the canister was then actuated, and the gross weight obtained after each actuation.

[0329] The gross weight obtained after each actuation was recorded. The process of actuating and weighing continued until the end point was reached. The end point was determined by at least n=3 actuations consistently below 130 mg. The number of discharges before the end point was reached was recorded.

[0330] The process of actuating and weighing continued until the end point was surpassed. The end point was determined when at least n=3 consecutive actuations fell below the average actuation weight (mean actuation weight of the first 90 discharges) minus 10 mg. E.g., if the average actuation weight for a formulation was 115 mg, the end point was determined when n= 3 consecutive actuations fell below 105 mg. Note: A 10 mg variation in actuation weight was considered acceptable when the average for the canister was > 100 mg, as a DHEP recovery of 90 - 110% could still be achieved theoretically for the actuation. The canister was actuated, and the gross weight obtained, a further 5 times after the end point was reached. This was to ensure the lower actuation weights (n=3) obtained were by means of reaching the end of the canister’s life, and not experimental variation. Overall, at t=0, the formulations were actuated between 91 - 101 times before the end of canister life was reached. MS-92 actuated lower on average (about. 115 mg) compared to the other formulations (about 130 mg); this is likely attributed to the HFA-152a propellant. Of note, the t=0 end point criteria of 3 consecutive actuations < 130 mg were generated from data obtained from the previous lead formulation (MS-77) with HFA-134a. In addition, with MS-71 sporadic low actuation weights (about 30 - 105 mg) were observed, with the actuation weight dropping below the average before returning to average levels during subsequent actuations.

[0331] Discharges per container test was repeated for MS-77, 1 and 92 (active only) at t=6 month (25 °C / 60% RH) in accordance with an updated method in which the following modifications were made:

[0332] The end point was adjusted to account for the lower average weights observed for MS-92 at t=0.

[0333] The new end point criteria was n-3 consecutive actuations below the average actuation weight (mean actuation weight of the first 90 discharges) minus 10 mg.

[0334] Stipulation was introduced to the methodology surrounding the minimum depression and wait time required during each actuation with the aim to minimize experimental variation.

[0335] Actuations were continued beyond the end point to ensure the drop in actuation weights (n=3) obtained were by means of reaching the end of the canister’s life, and not experimental variation.

[0336] As t=0, this test was performed in conjunction with DDU analysis. The number of discharges before the end point was reached was recorded for the formulations at t=6 month (25 °C / 60% RH). MS-1 and 77 were actuated 96 and 94 times respectively before the end of canister life was reached, which is in-line with t=0. Though, MS-92 was actuated 131 times (about 35 more discharges than MS-1 and 77) before the end of canister life was reached due to the lower average actuation weight (108.63 mg).

[0337] Despite the modifications to the method (described above), a fluctuation in actuation weight was recorded for MS-77. The actuation weight fell below the endpoint criteria for 4 consecutive sprays, before returning to average levels for a further 6 sprays and dropped back below the threshold without returning. The recorded fluctuations may be attributable to a fault with the valve and / or the dip tube not drawing up the full amount as the end of canister life is approached and there is less formulation in the canister.

[0338] Formulation stability - premix

[0339] Premix samples, in 10 mL non-screw neck vials, were stored at 25 °C / 60% RH, 30 °C / 65% RH and 40 °C / 75% RH and assessed over a 6-month period. Simultaneously, premix samples were also stored under heat conditions (65 °C) for assessment over a 4-week period. At each timepoint, premixes were assessed for DHEP content and related substances, and macroscopic and microscopic appearance. Testing of MS-84, MS-71, MS-93, MS-90 and MS-87 at 6 months was not conducted.

[0340] At all storage conditions, the DHEP content of the premixes decreased over time, however, generally remained within 90 - 110% of the label claim. Exceptions to this were MS-77 (89.65%) and MS-87 (89.82%) at t=4 weeks 65 °C, both variants contain ethanol as the main solvent, and the lower level of ethanol in MS-87 (76.17% w / w) compared to MS-77 (82.48% w / w) seemingly did not delay the decrease in DHEP content. Overall, the decrease in DHEP content observed was more apparent at higher temperatures. Similarly, the purity of DHEP (% area) in the premixes decreased over time, at all storage conditions, but remained within 90 - 100%, apart from the ethanol containing premixes at t=4 weeks 65 °C (88.33 and 87.34% area for MS-77 and MS-87, respectively). Moreover, a corresponding increase in the total reportable impurities was observed for all premix formulations, with the increase being greater for samples stored at higher temperatures. At t=6 months 40°C / 75%RH, the total reportable impurities for the IP A containing premixes remained < 5% area, however, was about 8% area for MS-77 (with ethanol), with the predominant unknown impurity peak, Peak X (previously observed to grow during stability assessment, contributing 7.02% area to the total. The predominant impurities (> 0.5% area) observed in the IPA containing premixes were unknown impurity peaks at RRT ca. 1.10 (Peak U), RRT ca. 1.12 (Peak V) and RRT ca. 1.33 (Peak Y), and a known impurity peak at RRT ca. 1.37 (Diclofenac Impurity 4). Peak X was only observed in the ethanol containing premixes, and not in those containing IPA. Peaks U, V and Y were present in the impurity profile of MS-77 and 87 (ethanol), however at lower levels (NMT ca. 0.15% area for each peak after 6 months at 40 °C / 75%RH) compared to the IPA premixes (NMT ca. 1.4% area for each peak after 6 months at 40 °C / 75%RH). No obvious differences were observed in the impurity profile between MS-90 and 93 (with antioxidants BHA and BHT, respectively), and compared to the other IPA containing premixes (without antioxidant).

[0341] At t=0, all premixes (active and placebo) were faint yellow and clear, with the visual viscosity of a solution. Over stability at all storage temperatures, the macroscopic appearance of the placebo premixes generally remained as 1=0, except for MS-90 which became increasingly more yellow / beige over time. This unique color change is likely attributed to the presence of BHA. In addition, yellowing of all active premixes was observed, with MS-77 and 87 also displaying a slight orange tint, which is likely attributed to increased API degradation due to the presence of ethanol. Overall, the color changes observed were more apparent for samples stored at higher temperatures.

[0342] Microscopically, no API or excipient particulates were observed in any of the premixes across stability. Some fibers were observed in the MS-80 active sample at t=6-months 40 °C / 75%RH, however these were attributed to vial contamination (e.g., lint or dust) rather than API or excipient. This contamination was also observed macroscopically.

[0343] Example 21

[0344] I PVT Study

[0345] Voltaren® gel was aliquoted to 14 mg / cm2by weight to the 1 cm2area. Dose justification from Voltaren product label states 2g to 4g to affected area up to 4 times daily. If affected area is the knee with average surface area of -100 cm2or -4” x 4” area, then 2000 mg / 100 cm2= 20 mg / cm2. The dose range of 14 mg / cm2was bracketed. Topical spray (non-propellant formulations) were aliquoted to 14 mg / cm2by weight to the 1 cm2area. Formulations had one actuation from a NM33 canister with 120 pL metered dose valve. Multiple actuations to prime the devices were performed prior to application.

[0346] In vitro skin permeation experiments involve the use of a diffusion cell designed to mimic the physiological and anatomical conditions of skin in situ. The model used in this experiment was be the flow-through cell, where ex vivo human skin was placed between the donor and receptor compartments. Human abdominal skin from cosmetic reduction surgery was used from a single donor. The subcutaneous fat was removed mechanically, and the skin was dermatomed to a thickness of 500 ± 100 pm and stored frozen at -80°C. The skin was thawed at room temperature prior to cutting and placement onto the diffusion cells.

[0347] The in vitro permeation investigation was performed using seven formulations (three propellant formulations, three non-propellant pump spray formulations and one comparison marketed product (Voltaren®)). A summary of the experimental conditions is shown in Table X.

[0348] Table 67 - IPVT Experimental conditions

[0349] **Nominal value for propellant MedSpray® formulations is 120 pL spray volume * 25% formulation (-75% propellant) = 30 mg / cm2of drug product, of which 5.2% is DHEP in premix or the (25%) remaining, however, as not all formulation is able to be applied to the surface, a dosing value of 14.12 mg was used for formulation calculations based upon previous dosing verification.

[0350] For Voltaren® gel, nominal applied dose was weighed accurately thus 14 mg / cm2drug product applied as 1 % Diclofenac sodium.

[0351] For nonpropelled sprays, nominal dose was weighed accurately thus, 14 mg / cm2drug product applied as 1.3% Diclofenac epolamine. Table 68: Summary of formulations tested in the IVPT experiment

[0352] Table 69: Summary of formulations tested in the IVPT experiment

[0353] A finite dosing value of 14.12 mg per actuation (one actuation used per dose) was used for the propellant formulation calculations based upon the previous dosing verification. Subsequently, 14 mg was used as the dose amount for Voltaren® gel. The overall trend shows more diclofenac (as a cumulative amount and percentage of applied dose), permeated into the receptor solution from Voltaren® gel as compared to each of the propellant and non -propellant formulations. None of the formulations exceeded approximately 0.5% permeation as a percent of applied dose, except for Voltaren® gel which exhibited permeation of about 1.5% of the applied dose over 24 hours. Voltaren® gel produced the highest peak and average flux as compared developed formulations as either a propelled or unpropelled product. MS62 (P) appeared to be the highest permeating formulation. Additionally, as a general trend, in terms of cumulative amount, peak flux, and average flux, in this study, the formulations with propellant were not statistically different in comparison to the non-propelled formulations except MS62 (P).

[0354] The results of cumulative permeation in ng / cm2are ordered from highest to lowest as follows:

[0355] Voltaren® > MS62 (P) > MSI (P) ~ MS 166 (NP) « MS77 (P) ~ MSI (NP) ~ MS 167 (NP)

[0356] When comparing the delivery of diclofenac in this study between the reference Voltaren® and the formulations, Voltaren® is statistically different from each of the formulations except for MS62 (P). When comparing the formulations to one another, there was no statistical difference observed in the cumulative results.

[0357] The results of peak permeation rates in ng / cm2 / hr are ordered from highest to lowest as follows:

[0358] Voltaren® > MS62 (P) > MSI (P) ~ MS77 (P) ~ MS 166 (NP) ~ MS 167 (NP) ~ MSI (NP)

[0359] The peak flux of Voltaren® was about 1.5 times higher than MS62 (P) and the results were not found to be statistically different. The results of average permeation rates in ng / cm2 / hr for 0 to 24 hours are ordered from highest to lowest as follows:

[0360] Voltaren® > MS62 (P) > MSI (P) ~ MS166 (NP) = MS77 (P) ~ MSI (NP) = MS167 (NP)

[0361] The average flux of Voltaren® gel was about 2.5 times higher than MS62 (P) and was found to be statistically different which confirms Voltaren® gel exhibits a higher potential for permeation. Among the Medpharm formulations, each of the developed formulations is statistically similar except for MS62 (P) which is higher than the other developed formulations in this study and found to be statistically different. An investigation by use of a “Sans Study” showed the unknown impurity peak was attributable to DHEP degradation in the presence of ethanol, therefore ethanol present in MS-77 was replaced with isopropanol (IPA). IPA concentration in formulations is robust at about 21%, where MS-47 through MS-50 with 15% IPA or 16% IPA were also free from crystal growth or turbidity even with presence of BHT or BHA. Therefore, 20.62% in MS-1 or 17% in MS-92 may be appropriate for maintaining solubility of polymer and DHEP. BHT or BHA had little impact on degradation profile and thus may not necessary in the formulations. HFA134a or HFA152a are viable propellants whereas 1234ze, dimethyl ether (DME), propanes and butanes are less desirable due to compatibility and or solubility issues. Formulation may be prepared with or without menthol as organoleptic with little impact to overall formulation. The stability of MS-1 (20.62% IPA) and MS-92 (17% IPA) are quite good relative to MS-77 (20.62% EtOH) with a total degradation reduction from 1.27% for MS-77 to 0.71% for MS-1 at 6 months 25°C / 60% RH. MS-77 has a single primary degradant which accounted for 1.22% of the 1.27% degradation. In the MS-1 formulation, no individual degradant exceeded 0.24%. Six month 40°C / 75% RH had about 40% reduction in total degradation with MS-77 having the one peak exceeding 7 % and in MS- 1 no peak exceeded 1.30% From an appearance perspective, no significant difference between MS-1 and MS-92. Both MS-1 and MS-92 dried in about 60 seconds and left a non-tacky water resistant film

[0362] Desired excipients and ranges to support a DHEP sprayable formulation include:

[0363] DHEP about 1 .3%

[0364] Menthol - about 0 or 0.08%, depending on organoleptic need

[0365] IPA - about 17 to 21%, about 20.62% target

[0366] Propylene Glycol - about 0.5 to 1.5%, about 1.0% target

[0367] Trancutol P - about 0.5 to 1.5%, about 1.0% target

[0368] Eudragit E100 - about 1.0 to 2.0%, about 1.0% target

[0369] Preferred propellants for the above range of excipients are HFA-134a or HFA-152a.

[0370] Alternatively, unpropelled (manual pump actuation) versions of formulations, may be prepared by replacement of the propellant at specified levels with one of the following: IPA and / or IPA / Ethyl acetate Within this disclosure, any indication that a feature is optional is intended provide adequate support (c.g., under 35 U.S.C. 112 or Art. 83 and 84 of EPC) for claims that include closed or exclusive or negative language with reference to the optional feature. Exclusive language specifically excludes the particular recited feature from including any additional subject matter. For example, if it is indicated that A can be drug X, such language is intended to provide support for a claim that explicitly specifies that A consists of X alone, or that A does not include any other drugs besides X. "Negative" language explicitly excludes the optional feature itself from the scope of the claims. For example, if it is indicated that element A can include X, such language is intended to provide support for a claim that explicitly specifies that A does not include X. Non-limiting examples of exclusive or negative terms include "only," "solely," "consisting of," "consisting essentially of," "alone," "without", "in the absence of (e.g., other items of the same type, structure and / or function)" "excluding," "not including", "not", "cannot," or any combination and / or variation of such language.

[0371] Similarly, referents such as "a," "an," "said," or "the," are intended to support both single and / or plural occurrences unless the context indicates otherwise. For example "a dog" is intended to include support for one dog, no more than one dog, at least one dog, a plurality of dogs, etc. Nonlimiting examples of qualifying terms that indicate singularity include "a single", "one," "alone", "only one," "not more than one", etc. Non-limiting examples of qualifying terms that indicate (potential or actual) plurality include "at least one," "one or more," "more than one," "two or more," "a multiplicity," "a plurality," "any combination of," "any permutation of," "any one or more of," etc. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

[0372] Where ranges are given herein, the endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0373] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that the various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition comprising from 0.1 to 10.0 % w / w active pharmaceutical ingredient; 1 to 25% w / w film-forming polymer(s), 1 to 20% permeation enhancer(s), 1 to 25% plasticizer(s), 0.01 to 2% w / w organoleptic sensate(s), and 10 to 85% w / w solvent(s), substantially free of added water2. The composition of claim 1 wherein the active pharmaceutical ingredient is selected from the group consisting of aspirin, trolamine salicylate, methyl salicylate, ibuprofen, ketoprofen, aminophcnolacetaminophcn, acetaminophen , phenylbutazone, mcclofenamatc, indomethacin, diclofenac, piroxicam, and celecoxib and / or salts and / or derivatives or combinations thereof.

3. The composition of claim 2 wherein the active pharmaceutical ingredient is diclofenac.

4. The composition of claim 3 wherein the active pharmaceutical ingredient is diclofenac epolamine.

5. The composition of claim 4 wherein the diclofenac epolamine, film- forming polymer, permeation enhancer and plasticizer are dissolved in the solvent.

3. The pharmaceutical composition of claim 1 additionally comprising a propellant.

4. The pharmaceutical composition of claim 3 wherein the propellant is selected from the group comprising HFA-134A, HFA-152a, HFO-1234ze, dimethyl ether, propane(s) and or butane(s) and combinations thereof.

5. The pharmaceutical composition of claim 4 wherein the propellant is HFA-134a or HFA-152a.

6. The pharmaceutical composition of claim 3 wherein the formulation is contained within a pressurized container.

7. The pharmaceutical composition of claim 3 wherein the propellant comprises from 50 to 90% w / w of the composition.

8. The composition of claim 1 wherein the volatile organic solvent is selected from the group consisting of alcohol(s) or ester(s) or combinations thereof.

9. The composition of claim 8 wherein the volatile organic solvent is either ethanol or isopropyl alcohol or combinations thereof.

10. The composition of claim 1 wherein volatile organic solvent is selected from the group consisting of ethyl acetate, butyl acetate, isopropyl acetate or combinations thereof.

11. The composition of claim 9 wherein the volatile organic solvent is isopropyl alcohol.

12. The composition of claim 1 wherein the permeation enhancer is selected from the group consisting of dietheylene glycol monoethyl ether (Transcutol P or HP) and or a glycol, such as propylene glycol, dipropylene glycol, polyethylene glycol or combinations thereof.] 3. The composition of ciaim i 2 wherein the permeation enhancer is dietheylene glycol monoethyl ether.

14. The composition of claim 1 further comprising organoleptic compounds, fragrances, dyes, emulsifiers, buffers, warming agents and combinations thereof.

15. The composition of claim 14 wherein the wanning agents are selected from the group consisting of capsaicin, capsicum extract, or vanillyl butyl ether(VBE)..

16. The composition of claim 14 wherei n the cooling agents are selected from the group consisting of isopulegol, methoxy-propanediol, menthanediol, and menthol.

17. The composition of claim 14, wherein the composition further comprises 0.01 to 0.1% wt / wt menthol.

18. The composition of claim 1 wherein the film forming agent is selected from the group consisting of acrylic acid derivatives, such as Eudragit®, polyacrylamides, such as Oleocraft®, ethylcellulose, hydroxypropyl cellulose (HPC) and derivatives thereof, hydroxypropyl methylcellulose (HPMC) and derivatives thereof, poly(vinyl pyrrolidone) (PVP), poly(vinylpyrrolidone)-vinyl acetate copolymer (PVP-VA), poly (vinyl acerate or derivatives thereof, poly (vinyl alcohol) (PVA or PVOIf) or derivatives thereof, and combinations thereof.

19. The composition of claim 18 wherein the film-forming agent is Eudragit.

20. The composition of claim 1 wherein the plasticizer is selected from the group consisting of water, glycerol, oleic acid, citric acid, phosphate esters, fatty acid esters, glycol derivatives, hydrocarbons and hydrocarbon derivatives, adipic acid / butanediol polyesters, epoxidized soya oils, diethyl phthalate, dibutyl phthalate, citric acid esters such as triethyl citrate and the like, castor oil, triacetin and chlorinated paraffin.

21. The composition of claim 20 wherein the plasticizer is propylene glycol.

22. A pharmaceutical composition comprising from about 1 to 2 % w / w diclofenac epolamine; 10 to 25% w / w isopropanol; 0.5 to 1.5% w / w propylene glycol; 0.5 to 1.5% w / w Eudragit E100; and 0.5 to 1.5% w / w Transcutol P (diethylene glycol ethyl ether) in the presence of a propellant 65 to 85% w / w HFA 134a or HFA 152a for topical application as an aerosol.

23. The composition of claim 22 wherein the diclofenac epolamine is present at at least 30% saluration under conditions of use, and wherein there is no undissolved diclofenac epolamine in the formulation.

24. The composition of claim 22, wherein the diclofenac epolamine is present at at least 50% saturation.

25. The composition of claim 22, wherein the diclofenac epolamine is present at 50% to 100% saturation.

26. The composition of claim 22, wherein the composition forms a film on topical administration.

27. The composition of claim 22, wherein the composition is a true solution.

28. The composition of claim 22, wherein the composition further comprises 0.01 to 0.1 % wt / wt menthol.29.The composition of claim 22, wherein the composition has a drying time on a human’s skin of between 30 seconds and 3 minutes.

30. The composition of claim 22, wherein the composition has a drying time on a human’s skin of between 1 minute and 2 minutes.

31. The composition of claim 22 further comprising compounds with organoleptic properties, fragrances, dyes, emulsifiers, buffers, warming agents (e.g., cooling agents (e.g. )32. The composition of claim 31 wherein the warming agents are selected from the group consisting of capsaicin, capsicum extract, and vanillyl butyl etherfVBE)..

33. The composition of claim 31 wherein the cooling agents are selected from the group consisting of isopulegol, methoxy-propanediol, menthanediol, and menthol.

34. The composition of claim 33, wherein the composition further comprises 0.01 to 0.1% wt / wt menthol.

35. The composition of claim 1 wherein the diclofenac epolamine is present in the formulation at a level of from between about 70% to about 99% when stored for 4 weeks at 25°C.

36. An aerosol dispenser comprising a reservoir of the composition of claim 1.

37. The aerosol dispenser of claim 35 wherein the composition is delivered to an animal skin surface by spraying.

38. The composition of claim 36 wherein the spray is a continuous spray.

39. The composition of claim 36 wherein the spray is a metered spray.

40. A method for the treatment of pain comprising applying an effective amount of said drug to a patient in need thereof by administering the composition of claim 1 to a topical surface of the patient.

41. The method of treatment of claim 40 wherein the treatment is for the relief of pain due to osteoarthritis.

42. The method of treatment of claim 40 wherein the treatment is for acute pain due to minor strains, sprains, and contusions.

43. The method of treatment of claim 40 wherein the treatment is for relief of pain associated with post-herpetic neuralgia.

44. The method of treatment of claim 40 wherein the composition of claim 1 is sprayed onto the topical surface of a patient.

45. The method of treatment of claim 40 wherein the composition of claim 1 is sprayed onto the topical surface of a patient at a rate of between about 25-3500mcL / spray.

46. The method of treatment of claim 40 wherein the composition of claim 1 is sprayed onto the topical surface of a patient at a rate of between about 25-200mcL / spray47. The method of treatment of claim 40 wherein the amount of diclofenac epolamine delivered to the topical surface of a patient is about 0.005 mg to 20 mg per square centimeter of the topical surface.

48. A pharmaceutical composition comprising from 0.1 to 10.0 % w / w diclofenac epolamine; 1 to 25% w / w film-forming polymer, 1 to 20% permeation enhancer, 1 to 25% plasticizer, and 10 to 85% w / w solvent and does not contain a propellant.

49. The pharmaceutical composition of claim 48 wherein the composition is delivered to an animal skin surface by an aerosol spray.

50. The composition of claim 48 further comprising compounds with organoleptic properties, fragrances, dyes, emulsifiers, buffers, wanning agents and cooling agents.

51. The composition of claim 48 wherein the warming agents are selected from the group consisting of capsaicin, capsicum extract, and vanillyl butyl ether(VBE).,52. The composition of claim 48 wherein the cooling agents are selected from the group consisting of isopulegol, methoxy-propanediol, meuth an ediol, and menthol.

53. The composition of claim 48, wherein the composition further comprises 0.01 to 0.1% wt / wt menthol.54.The composition of claim 49 wherein the spray is a continuous spray55. The composition of claim 49 wherein the spray is a metered spray.

56. The composition of claim 55 wherein the metered spay delivers a volume of about 25 to 3500pl or 50 to 250pl or 75 to 200pl per actuation.

57. A pharmaceutical composition comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 17 to 21% w / w isopropyl alcohol, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, 1.0 to 2.0% Eudragit 100 and 72.4 to 80.0% w / w HFA-134a.

58. A pharmaceutical composition comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 17 to 21% w / w isopropyl alcohol, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, 1.0 to 2.0% Eudragit 100 and 72.4 to 80.0% w / w HFA-152a.

59. A pharmaceutical composition comprising 1.3% w / w diclofenac epolamine; 20.62% w / w isopropyl alcohol, 1.0% propylene glycol, 1.0% Transcutol P, 1.0% Eudragit 100 and 75.08% w / w HFA-134a.

60. A pharmaceutical composition comprising 1.3% w / w diclofenac epolamine; 20.62% w / w isopropyl alcohol, 1.0% propylene glycol, 1.0% Transcutol P, 1.0% Eudragit 100 and 75.08% w / w HFA-152a.

61. The pharmaceutic composition of any of claims 57-58 further comprising 0.01 to 0.1 % menthol.

62. A pharmaceutical composition comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 90 to 97% w / w isopropyl alcohol, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, and 1.0 to 2.0% Eudragit 100.

63. A pharmaceutical composition comprising from 1.0 to 1.6 % w / w diclofenac epolamine; 90 to 97% w / w isopropyl alcohol / ethyl acetate, 0.5 to 1.5% propylene glycol, 0.5 to 1.5% Transcutol P, 1.0 to 2.0% Eudragit 100 and 72.4 to 80.0% w / w HFA-152a.

64. The pharmaceutic composition of any of claims 62 to 63 further comprising 0.01 to 0.1% menthol.

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