Composition and treatment of conditions that present with reduced blood flow

Abstract

A composition is provided comprising a calcium channel blocker, a vasodilator, a phosphodiesterase 5 (PDE5) inhibitor and optionally an anti-inflammatory agent. The composition is useful to treat conditions in which blood flow to an area is limited or restricted such as Raynaud's Phenomenon.

Description

COMPOSITION AND TREATMENT OF CONDITIONS THAT PRESENT WITH REDUCED BLOOD FLOWField of the Invention

[0001] The present invention generally relates to the treatment of conditions that would benefit from increased local blood flow, and in particular, to a composition for use to treat such conditions.Background

[0002] Poor circulation occurs when blood flow is significantly reduced due to interference in a part of your body. Obstacles or narrowing of blood vessels can make it more difficult for blood to travel through the body. When blood has difficulty circulating, the cells in the body get less oxygen and nutrients making it harder for them to function properly.

[0003] Raynaud’s phenomenon (RP) is a painful vasospastic condition affecting the extremities, in particular the hands and fingers, that occurs in response to cold or stress. Commonly, it is characterized by a triad of a white decolorization (pallor) of the digits due to vasoconstriction, followed by a cyanosis as a result of deoxygenated blood sequestration and lastly by pain, redness and heat due to reperfusion.

[0004] The cause of most cases of Raynaud’s is unknown, but it may be linked to systemic diseases such as systemic sclerosis, lupus, diabetic neuropathy, scleroderma or Sjogren’s syndrome. A number of medications can also be the cause. The effect on the patient can be debilitating with constant need to avoid cold and other triggers, and in some severe cases the ischemic digits can become ulcerated or become gangrenous requiring amputation.

[0005] Like many conditions that present with reduced blood flow, the pathogenesis of RP is a complex interplay of neural, genetic and vascular factors which therefore requires a multipronged approach to management. Non-pharmacologic methods of treatment (i.e. keeping warm with extra layers of clothing, gloves, cold avoidance, smoking cessation) are indicated for management of all cases of RP, but often those simple measures are not enough.92368649\1Summary

[0006] A pharmacological multimodal composition is provided for the treatment of conditions which require enhanced blood flow to a local area. The composition comprises a combination of ingredients that effectively result in vasodilation and increased blood flow to an affected area.

[0007] In one aspect, a composition is provided comprising a calcium channel blocker, a vasodilator, a phosphodiesterase 5 (PDE5) inhibitor and a pharmaceutically acceptable carrier.

[0008] In another aspect of the invention, a composition for use to treat a condition in a mammal requiring increased blood flow to a local area is provided comprising a calcium channel blocker, a vasodilator, a PDE5 inhibitor and a pharmaceutically acceptable carrier.

[0009] A method of treating a condition in a mammal requiring increased blood flow to a local area is also provided comprising administering to the mammal the composition.

[0010] In a further aspect of the invention, a method of treating a mammal with Raynaud’ s Phenomenon is provided comprising administration of a composition comprising a calcium channel blocker, a vasodilator, a PDE5 inhibitor and a pharmaceutically acceptable carrier to an affected area on the mammal.

[0011] These and other aspects of the invention will become apparent by reference to the detailed description.Detailed Description

[0012] A composition is provided comprising a calcium channel blocker, a vasodilator, a PDE5 inhibitor and a pharmaceutically acceptable carrier.

[0013] The present composition comprises a calcium channel blocker to prevent calcium influx into muscle cells resulting in relaxing and dilating of smooth muscle and improved blood flow. In one embodiment, the calcium channel blocker is a voltage-gated calcium channel inhibitor capable of reducing vasoconstriction and improving peripheral blood flow. In another embodiment, calcium channel blockers suitable for inclusion in the composition include92368649\1dihydropyridine calcium channel blockers such as, but not limited to, amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, cilnidipine, cronidipine, efonidipine, mibefradil, felodipine; nifedipine, amlodipine, flordipine, isradipine, lacidipine, nicardipine, nimodipine, oxodipine, riodipine and pranidipine. The calcium channel blocker may also be non-dihydropyridine calcium channel blocker such as, but not limited to, phenylalkylamines, e.g. verapamil and benzothiazepines, e.g. diltiazem. The composition may also comprise a combination of calcium channel blockers.

[0014] The composition also comprises a vasodilator which functions to relax and widen blood vessels by increasing nitric oxide to result in improved blood flow. The nitric-oxide pathway increases cGMP via activation of guanylate cyclase. Suitable vasodilators for inclusion in the composition include nitric-oxide donors, nitric-oxide precursors, nitric-oxide-releasing compounds, soluble guanylate cyclase (sGC) stimulators or activators, prostacyclin or prostacyclin analogs, endothelin pathway modulators, potassium channel openers, and other agents capable of promoting vascular smooth-muscle relaxation and enhanced blood flow. The composition may also comprise a combination of two or more vasodilators, of the same type or of different types. Examples of suitable vasodilators include, but are not limited to, nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, hydralazine, minoxidil and combinations thereof.

[0015] The composition also comprises a phosphodiesterase 5 (PDE5) inhibitor which functions by blocking phosphodiesterases to result in increased cGMP by preventing the degradation thereof, and this similarly relaxes and dilates smooth muscle. The composition may also comprise a combination of two or more different PDE5 inhibitors. Examples of suitable PDE5 inhibitors include, but are not limited to, tadalafil, sildenafil, vardenafil, avanafil and combinations thereof.

[0016] An anti-inflammatory agent may optionally be included in the composition to enhance the overall therapeutic response of the composition by reducing local inflammation, vascular irritation, or inflammatory contributors to vasospasm. Suitable anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, oxaprozin, naproxen, celecoxib, diclofenac, indomethacin, piroxicam, meloxicam, and salicylates such as acetylsalicylic acid. Corticosteroids, immunomodulatory agents, cytokine92368649\1inhibitors, mast-cell stabilizers, and other agents capable of reducing inflammation, pain, or inflammatory vascular dysfunction associated with Raynaud’s and related conditions are also suitable for use in the present composition. Combinations of two or more anti-inflammatory agents may also be used, of the same type or of different types, e.g. a combination of NSAIDs, or an NSAID with corticosteroid, immunomodulatory agent and / or cytokine inhibitor.

[0017] The amount of each of the components in the present composition will vary based on the nature and characteristics of the selected components. Generally, the present composition will comprise about 0.1 -20 wt% of the calcium channel blocker, 0.1-2 wt% of the vasodilator, 0.1-20 wt% of the PDE5 inhibitor and 0-10 wt% of the anti-inflammatory agent. In embodiments, the composition may comprise 1-10 wt% of the calcium channel blocker, 1-2 wt% of the vasodilator, 1-10 wt% of a PDE5 inhibitor and 1-10 wt% of an anti-inflammatory agent.

[0018] In a particular embodiment of the invention, the present composition comprises nifedipine or diltiazem as the calcium channel blocker, nitroglycerine as the vasodilator, tadalafil or sildenafil as the PDE5 inhibitor and ketoprofen or diclofenac as the anti-inflammatory agent. In another embodiment, the composition comprises 2 wt% nifedipine, 0.13 wt% nitroglycerine, 2 wt% tadalafil and 5 wt% ketoprofen.

[0019] The present composition may be formulated for administration orally (e.g., via tablets, capsules or liquids), sublingually or buccally, topically or transdermally, by injection, or by other systemic or localized delivery formats.

[0020] The components of the composition may be combined with one or more pharmaceutically acceptable adjuvants to facilitate delivery by a selected mode of administration. The expression "pharmaceutically acceptable" means acceptable for use in the pharmaceutical and veterinary arts, i.e. not being unacceptably toxic or otherwise unsuitable. Examples of pharmaceutically acceptable adjuvants include one or more carriers, diluents, excipients, humectants, thickeners, emulsifiers, preservatives and the like. Reference may be made to "Remington's: The Science and Practice of Pharmacy", 21st Ed., Lippincott Williams & Wilkins, 2005, for guidance on drug formulations generally. The selection of adjuvant depends on the intended mode of administration of the composition. Some adjuvants may be added to the composition regardless of how it is to be administered. For example, preservatives such as9236864911stabilizers, anti-oxidants and / or anti-microbial agents may be added to the composition to maintain efficacy and prevent microbial growth over prolonged storage periods. Suitable antioxidants include but are not limited to vitamin C, butylated hydroxytoluene (BHT), sulphites, and vitamin E. Suitable antimicrobial agents include but are not limited to benzoates, benzyl alcohol, sodium benzoate, sorbates, propionates, and nitrites.

[0021] The present composition is useful in the treatment of conditions in a mammal which involves reduced blood flow, and / or conditions which would benefit from enhanced blood flow to a local area. Such conditions include, but are not limited to, wounds and ulcers that require enhanced blood flow to facilitate healing, diabetic neuropathy resulting from microvascular injury that causes pain, paresthesia and dysesthesia, soft tissue injuries, erectile dysfunction, peripheral arterial disease, chilblains, scleroderma, arthritis, frostbite, muscle injury, psoriasis, rosacea, alopecia, chronic pain, hypertension, conditions which otherwise reduce blood flow and exhibit poor circulation, e.g. obesity, high blood pressure, Raynaud’s Phenomenon, and skin aging through wrinkle and cellulite reduction. The terms “treat”, “treating” or “treatment” are used herein to refer to methods that moderate, reverse, reduce the severity of, or protect against, the progression of a condition which involves reduced blood flow, and / or a condition in which enhanced blood flow would be a benefit, or symptoms associated therewith. The term “mammal” as used herein refers to both human and non-human mammals, e.g. domestic animals and / or livestock.

[0022] In an embodiment, the composition is useful to treat a condition that exhibits poor blood circulation and which is beneficially treated using a topical composition such as wounds / ulcers, frostbite, arthritis, rosacea, chronic pain, Raynaud’s Phenonomen and skin aging conditions in a mammal. In this embodiment, the composition may be formulated for topical administration which enables targeted therapeutic benefit while minimizing systemic exposure and associated side effects. Thus, creams, lotions and ointments may be prepared for topical application comprising one or more adjuvants suitable for such application, for example, solubilizing agents, penetration enhancers, surfactants, thickeners and / or gelling agents. Examples of agents that enhance permeation or absorption through the skin or other tissues, include, but are not limited to, medium-chain fatty acids (e.g., caprylic acid, capric acid, lauric acid), fatty acid esters, mono- and di-glycerides, alcohols, glycols (e.g., propylene glycol, polyethylene glycol),92368649\1surfactants, terpenes, lipid-disrupting agents, and other excipients known to improve tissue penetration or local bioavailability. In some embodiments, adjuvants such as glycerin, triglycerides, cetyl or cetostearyl alcohol, polysorbates, DMSO, alkyl polyglucosides, sorbitan monooleate, oils such as coconutjojoba and argan, carbomers, natural gums such as xanthan and guar gum, cellulose derivatives, stearic acid, liposomes and carbohydrate-based compounds may be included. Preferred adjuvants may include one or more of water, glycerin, xanthan gum, disodium EDTA, fractionated coconut oil, isopropryl myristate, Promulgen-D TM, Polawax TM, cetyl alcohol, hydroxylated lecithin, phenoxyethanol and liquid GermallTM Plus. The concentration of such agents may be varied to optimize delivery while maintaining tolerability and safety.

[0023] Topical compositions may also include emollients and moisturizers which function to protect the skin against any adverse effect that may be caused by the active ingredients such as petrolatum, mineral oil, lanolin, dimethocone, hyaluronic acid, urea, propylene glycol, ceramides and the like.

[0024] In another embodiment of the invention, the composition is formulated for administration by infusion, or by injection, either subcutaneously or intravenously, such as peripheral arterial disease or hypertension / high blood pressure. Such a composition may be prepared as an aqueous solution in sterile and pyrogen-free form and optionally buffered or made isotonic. Thus, the composition may be administered in distilled water or, more desirably, in saline, phosphate-buffered saline or 5% dextrose solution.

[0025] The present composition is prepared by combining the selected active ingredients, i.e. the calcium channel blocker, the vasodilator, the PDE5 inhibitor and optionally an antiinflammatory agent with one or more adjuvants suitable to yield the desired composition for a selected mode of administration, for example, an oral composition, an injectable composition or a topical composition.

[0026] For use in the treatment of a condition in accordance with the present invention, the composition is administered to a mammal in need of treatment in a therapeutically effective amount. A “therapeutically effective amount” is an amount sufficient to treat the targeted condition, for example, by increasing blood flow to an affected area which will result in treating9236864911the targeted condition. The therapeutically effective amount will vary with the selected active components of the composition, i.e. the calcium channel blocker, vasodilator and PDE5 inhibitor. In this regard, the therapeutically effective amount of the composition administered to treat a condition will comprise dosages of one or more of the active components that is less than the dosage of the component when used alone since the composition is treating the condition using the same or different modes of action (multimodal) to thereby enhance the treatment. For example, the present composition treats reduced blood flow using the different modes of action of the calcium channel blocker, vasodilator and PDE5 inhibitor to result in a composition which exhibits a synergistic effect, i.e. a therapeutic effect which is greater than the additive therapeutic effect of each component agent on its own. In this regard, reduced dosages of at least one of the components in the composition results, such as a reduction of the dosage of the one or more components by at least about 10%, and preferably, at least about 20%, 30%, 40%, 50%, 75% or more, in comparison to the dosage of the at least one component when used alone. Such a reduced dosage may additionally result in a more favourable or reduced side effect profile. Based on the known dosages of the components of the present composition, one of skill in the art can readily determine the dosage of each of the components to include in the composition using well-established protocols for different administrable forms.

[0027] For topical treatments, a therapeutically effective amount of the composition is applied to the affected area for a period of time to treat the area. For the treatment of an event of Raynaud’s Phenomenon, characterized by symptoms such as intense coldness, numbness, tingling, throbbing pain, or change of color within affected extremities, the composition may be topically applied to the affected extremities such as fingers, toes, ears and nose. In an embodiment, the therapeutically effective amount may be an amount in the range of 0.1-2 grams of the composition applied topically 1-3 times a day for a period of at least 1 week or more, for example, 2-4 weeks.

[0028] The present composition may optionally include one or more additional active ingredients which enhance the efficacy of the composition. For example, the composition may include additional active ingredients that treat symptoms of the condition, including but not limited to analgesic agents such as lidocaine or prilocaine, neuromodulatory or sensory-modulating agents such as alpha-adrenergic modulators, capsaicin or capsaicinoids or agents that affect peripheral nerve signaling, tissue-supportive agents such as antioxidants or agents supporting microvascular9236864911or tissue integrity, endothelial-supporting / nitric oxide-pathway agents such as nitric oxide precursors (L-arginine or L-citrulline), or combinations thereof, provided that such agents do not materially interfere with the primary therapeutic mechanism of the composition.

[0029] The present composition advantageously provides a multimodal approach to treating restricted blood flow, such as that which occurs in Raynaud’s Phenomenon, to result in a treatment having a synergistic effect. In particular, the combination of calcium channel blocker, vasodilator and PDE5 inhibitor each function to enhance blood flow but by different modalities. While the calcium channel blocker prevents calcium influx into muscles, the vasodilator increases nitric oxide to blood vessels which increase cGMP via activation of guanylate cyclase, and the PDE5 inhibitor blocks phosphodiesterase to prevent or at least reduce degradation of cGMP. Thus, each of the components of the present composition function in a complementary manner to result in improved blood flow, and thereby collectively provide an enhanced, synergistic effect that provides a significantly improved treatment of Raynaud’s and related conditions not achieved previously be existing treatments.

[0030] Embodiments of the invention are described by reference to the following specific example which is not to be construed as limiting.Example 1

[0031] The following was mixed together, by weight:500 parts ketoprofen200 parts nifedipine13 parts nitroglycerine200 parts tadalafil9087 parts Permeabase cream

[0032] The ingredients of Permeabase™ cream are shown in Table 1.9236864911Table 1.n CAS Name Common Name Proper name Range Cone % Qty >TOTAL: 100

[0033] The cream is prepared by slowly blending together ingredients #l-#4 in a heat-proof container such as a stainless steel jacket container, and heating to 70° C using a lightnin mixer to form Phase A. In a separate stainless steel vessel, ingredients #5-#10 are combined and also heated to 70° C to form Phase B. Phase B is then slowly added and combined with Phase A with continued mixing using a lightnin mixer to form Phase C. The mixture is then cooled. When the Phase C mixture is cooled to 50° C, ingredient #11 is added, followed by ingredient #12. The mixture is mixed until it reaches a temperature of 40° C, and cooling is continued until it reaches 35° C to yield a cream.

[0034] The Permabase cream was combined with the active ingredients in the noted amounts to yield a medicated cream.Example 2

[0035] The resultant medicated cream was applied to the hands of a patient as follows: 0.5 gram92368649\1was applied to each hand of the patient, every 8 hours for a week.

[0036] Patient 1 was a 31 year old male with RP, otherwise in good health, weight 196 pounds and height 5 feet, 9 inches. He did not want to try other oral forms of treatment for his RP, due to fear of systemic side effects. He presented with excruciating pain and heat in his hands, with discoloration triggered by almost any change in temperature. In particular, when driving a car, even light air conditioning on his hands would trigger an event. He would rather swelter in his car with no air conditioning than risk triggering the Raynaud’s triad in his hands.

[0037] After one week of treatment, Patient 1 was able to happily drive his car in the summer with the A / C on full and no symptoms of pain, pallor or heat in his hands. The effect of this treatment was far superior to any other treatment that had been received to date.Example 3

[0038] Patient 2 was a 49 year old female, in generally good health, but also suffering from the RP triad. Typically her hands were always kept covered, for example by gloves to avoid cooler temperatures. After one week of treatment, her cold tolerance had significantly improved such that she had no fear of triggering a painful or discoloration event. The effect of this treatment was far superior to any other treatment that had been received to date.Example 4

[0039] The objective of this study was to evaluate and compare the in vitro permeation behavior of multiple multi-API topical formulations using Franz diffusion cell methodology. The study specifically aimed to:• quantify cumulative permeation of the combined drug mixture present in each formulation;• compare permeation profiles across formulations with differing co-active compositions;and• assess the influence of formulation composition on overall transmembrane transport. The analytical method employed in this study measured the total UV-detectable drug mixture. Formulations Evaluated

[0040] Five topical formulations were prepared and evaluated as summarized in Table 2. Each formulation contained multiple active pharmaceutical ingredients (APIs) at fixed concentrations.9236864911Table 2.FLOW FLOW FLOW FLOW FLOW(original) DICLO SILD VERAP DILTKetoprofen 5% 5% 5% 5%Diclofenac 5%Nitroglycerin 1.3% 1.3% 1.3% 1.3% 1.3%Nifedipine 2% 2% 2%Tadalafil 2% 2% 2% 2%Diltiazem 2%Sildenafil 2%Verapamil 2%Materials and Methods

[0041] Stock Solution Preparation - Individual drug stock solutions were prepared according to the following concentrations:• Ketoprofen: 5 mg / mL• Diclofenac: 5 mg / mL• Nifedipine, Tadalafil, Sildenafil, Diltiazem or Verapamil: 2 mg / mL• Nitroglycerin (NTG): 0.13 mg / mLSc. StockDrug Cone.Drug + Diluentmg / mLKetroprofen 200 mg + 40 mL 5Diclofenac 200 mg + 40 mL 5NTG 2.70 mL + 34.8 mL 0.13Nifedipine 80 mg + 40 mL 2Tadalafil 80 mg + 40 mL 2Diltiazem 80 mg + 40 mL 2Sildenafil 80 mg + 40 mL 2Verapamil 80 mg + 40 mL 2

[0042] Calibration Curves Preparation - Stock solutions were combined to yield the final formulation compositions such that the final combinations were representative of each9236864911formulation, as set out in Table 3:Table 3.FLOW (original) FLOWDICLO FLOWSILD FLOWVERAP FLOW DILT Drug Cone. Cone. Cone. Cone. Cone.mL mL mL mL mLmg / mL mg / mL mg / mL mg / mL mg / mL Ketroprofen Stock 5 250 5 250 5 250 Diclofenac Stock 5 250 5 250NTG Stock 5 6.5 5 6.5 5 6.5 5 6.5 Nifedipine Stock 5 100 5 100 5 6.5Tadalafil Stock 5 100 5 100 5 100 5 100 5 100 Diltiazem Stock 5 100 Sildenafil StockVerapamil Stock 5 100 5 100Diluent 80 80 80 80

[0043] Subsequently, 1:2 (1 ) dilutions were prepared where required for analytical measurement as shown in the following tables for each formulation:Table 4.Measurable Readings92368649\1Table 6FLOW SILD Concentration of Dilutions (pg / mL)StockFlow , , „ #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11(pg / mL)Ketoprofen 250.00 125.00 62.50 31.25 15.63 7.81 3.91 1.95 0.98 0.49 0.24 0.12 Nifedipine 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Nitroglycerin 6.50 3.25 1.63 0.81 0.41 0.20 0.10 0.05 0.03 0.01 0.01 0.00 Sildenafil 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Total cone 456.50 228.25 114.13 57.06 28.53 14.27 7.13 3.57 1.78 0.89 0.45 0.22Measurable ReadingsTable 7.FLOW VERAP Concentration of Dilutions (pg / mL)StockFlow , , #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11(pg / mL)Ketoprofen 250.00 125.00 62.50 31.25 15.63 7.81 3.91 1.95 0.98 0.49 0.24 0.12 Verapamil 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Nitroglycerin 6.50 3.25 1.63 0.81 0.41 0.20 0.10 0.05 0.03 0.01 0.01 0.00 Tadalafil 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Total cone 456.50 228.25 114.13 57.06 28.53 14.27 7.13 3.57 1.78 0.89 0.45 0.22Measurable ReadingsTable 8.FLOW DILT Concentration of Dilutions (pg / mL)StockFlow , , #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11(pg / mL)Ketoprofen 250.00 125.00 62.50 31.25 15.63 7.81 3.91 1.95 0.98 0.49 0.24 0.12 Diltiazem 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Nitroglycerin 6.50 3.25 1.63 0.81 0.41 0.20 0.10 0.05 0.03 0.01 0.01 0.00 Tadalafil 100.00 50.00 25.00 12.50 6.25 3.13 1.56 0.78 0.39 0.20 0.10 0.05 Total cone 456.50 228.25 114.13 57.06 28.53 14.27 7.13 3.57 1.78 0.89 0.45 0.22Measurable Readings92368649\1

[0044] Franz Diffusion Cell Study Design - The following equipment and conditions were employed to conduct the Franz diffusion cell study:Equipment: Teledyne Hanson Phoenix DB-6 dry heat diffusion systemMembrane: Strat-MReceptor media: Phosphate Buffer Saline pH 7.4 (PBS)Temperature: 32±0.5°CAgitation: 400 rpmApplication volume: 1 gramSampling time points: 30, 60, and 120 minutesAnalytical Methodology: UV- Visible spectrophotometry. The UV absorbance signal reflects the aggregate contribution of all UV-absorbing APIs present in each formulation.

[0045] Calibration curves demonstrated acceptable linearity over the tested concentration ranges for all formulations. Slopes and intercepts were consistent and suitable for comparative quantification of total drug mixture permeation as shown in the Tables below, and Figures 1 A-5A, respectively.Table 9: FLOW : Ketoprofen 5%, Nifedipine 2%, Nitroglycerin 0.13%, Tadalafil 2%Cone Abs(pg / mL) 260 nm9236864911Table 10. FLOW DICLO: Diclofenac 5%, Nifedipine 2%, Nitroglycerin 0.13%, Tadalafd 2% Cone Abs(pg / mL) 278 nmTable 11. FLOW SILD: Ketoprofen 5%, Nifedipine 2%, Nitroglycerin 0.13%, Sildenafil 2%92368649\1Table 12. FLOW VERAP: Ketoprofen 5%, Verapamil 2%, Nitroglycerin 0.13%, Tadalafil 2%Table 13. FLOW DILT: Ketoprofen 5%, Diltiazem 2%, Nitroglycerin 0.13%, Tadalafil 2%

[0046] Cumulative Drug Mixture Permeation - Measurable permeation was observed for the FLOW, DICLO, SILD, and VERAP formulations, with cumulative permeation increasing over the 120-minute study period as summarized below and as shown in Table 14.i) DICLO exhibited markedly higher permeation at all time points, with substantial early transport and continued increase through 120 minutes as shown in Fig. 2B.ii) SILD demonstrated high early permeation followed by a slower increase, suggesting a tendency toward plateauing behavior as shown in Fig. 3B.92368649\1iii) VERAP showed delayed but progressive permeation, resulting in moderate cumulative transport as shown in Fig. 4B.iv) FLOW (original) exhibited minimal early permeation with increased transport observed at later time points as shown in Fig. IB.v) DILT showed minimal permeation at early time points, followed by a clear increase at60 and 120 minutes, indicating a delay ed-onset permeation profile rather than inhibition as shown in Fig. 5B.Table 14. Total UV-Detectable Drug Mixture Permeated (jig) and Permeation ProfilesDiscussion

[0047] The results demonstrate that the present composition may be modified to achieve formulations that exhibit different permeation kinetics, including immediate, delayed, and plateauing behaviors. For example, the diclofenac (DICLO) formulation showed substantially higher permeation relative to other formulations, suggesting a strong enhancement of overall transport that may be attributable to formulation-specific drug-drug or drug-membrane interactions. The sildenafil (SILD) formulation displayed a balanced permeation profile, with significant early transport followed by controlled progression, which may be advantageous for formulations requiring rapid onset without excessive cumulative exposure. The diltiazem (DILT) formulation exhibited a lag-time effect, followed by meaningful transport at later time points. This suggests delayed membrane interaction or release behavior.

[0048] Thus, this study confirms that various combinations of calcium channel blocker, vasodilator, PDE5 inhibitor and optional anti-inflammatory agent have utility in the treatment of conditions requiring enhanced blood flow to a local area.9236864911

Claims

CLAIMS1. A composition comprising a calcium channel blocker, a vasodilator, a phosphodiesterase 5 (PDE5) inhibitor, a pharmaceutically acceptable carrier and optionally an antiinflammatory agent.

2. The composition of claim 1, wherein the calcium channel blocker is selected from the group of dihydropyridines, phenylalkylamines and benzothiazepines.

3. The composition of claim 1 or claim 2, wherein the calcium channel blocker is a dihydropyridine,4. The composition of claim 3, wherein the calcium channel blocker is nifedipine.

5. The composition of claim 1, wherein the calcium channel blocker is a benzothiazepine.

6. The composition of claim 5, wherein the calcium channel blocker is deltiazem.

7. The composition of any one of claims 1-6, wherein the vasodilator is selected from the group of nitric-oxide donors, nitric-oxide precursors, nitric-oxide-releasing compounds, soluble guanylate cyclase (sGC) stimulators or activators, prostacyclin or prostacyclin analogs, endothelin pathway modulators and potassium channel openers.

8. The composition of claim 7, wherein the vasodilator is nitroglycerine, isosorbide dinitrate, isosorbide mononitrate, hydralazine or minoxidil.

9. The composition of claim 8, wherein the vasodilator is nitroglycerine.

10. The composition of any one of claims 1-9, wherein the PDE5 inhibitor is tadalafil, sildenafil, vardenafil, avanafil or a combination thereof.

11. The composition of any one of claims 1-10, comprising an anti-inflammatory agent selected from a non-steroidal anti-inflammatory drug (NSAID), corticosteroid, immunomodulatory agent, cytokine inhibitor and mast-cell stabilizer.

12. The composition of claim 11, wherein the NSAID is ibuprofen, ketoprofen, oxaprozin, naproxen, celecoxib, diclofenac, indomethacin, piroxicam, meloxicam or a salicylate.

13. The composition of claim 1, wherein the composition comprises nifedipine or diltiazem, tadalafil or sildenafil and nitroglycerin.923686491114. The composition of claim 12, which additionally comprises an NSAID.

15. The composition of claim 1, which comprises 0.1-20 wt % of a calcium channel blocker, 0.1-2 wt % of a vasodilator and 0.1-20 wt % of a PDE5 inhibitor, and 0-10 wt % of an anti-inflammatory agent.

16. The composition of claim 1, comprising, by weight: about 5% ketoprofen, about 2% nifedipine, about 0.13% nitroglycerine and about 2% tadalafil.

17. The composition of any one of claims 1-16, which is a topical composition.

18. A method of treating a condition requiring enhanced blood flow to a local area in a mammal comprising administering to the mammal a composition as defined in any one of claims 1-17.

19. The method of claim 18, wherein the composition is a topical composition applied to an affected area.

20. The method of claim 18 or 19, wherein the condition is Raynaud’s Phenomenon.9236864911

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