Non-pharmaceutical solutions and use thereof for transdermal delivery of active agents

Abstract

The present application discloses non-pharmaceutical solutions intended to solubilize an active agent by a pharmacist or a pharmaceutist to produce transdermal pharmaceutical compositions comprising known concentration of an active agent for metered transdermal delivery of the agent. In addition, the present application discloses methods of making the transdermal pharmaceutical compositions and methods of treating various conditions or diseases comprising applying the compositions.

Description

[0001] NON-PHARMACEUTICAL SOLUTIONS AND USE THEREOF FOR

[0002] TRANSDERMAL DELIEVRY OF ACTIVE AGENTS

[0003]

[0001] TECHNICAL FIELD

[0004]

[0002] This application relates to a non-pharmaceutical solution intended to be used by a pharmacist or pharmaceutist to solubilize an active agent, such as a pharmaceutical agent or a biological agent and methods for preparing the non-pharmaceutical solution. In addition, this application relates to a method of using the non-pharmaceutical solution for transdermal deliver}' of the active agent to a patient in need thereof.

[0005]

[0003] BACKGROUND OF THE INVENTION

[0006]

[0004] Transdermal drug delivery', delivery' of drugs through the skin, provides many advantages. Primarily, it is a comfortable, convenient, and non-invasive way of administering drugs. Drugs delivered transdermally directly enter subdermal blood vessels and are transported to the target site via by-passing the first-pass liver metabolism and decomposition. As such, it allows for high drug bioavailability. Moreover, such a means of delivery' provides uninterrupted therapy and a higher degree of control over drug concentrations in the blood. These characteristics help avoid side effects caused by temporarily high blood concentrations of drugs which accompany administration of oral dosage forms and injections.

[0007]

[0005] In addition, as the population ages and health and end-of-life care evolves, the ability to formulate individualized products in small quantities to physician order has become more needful. Transdermal, transmucosal (Nasal & rectal) and oral suspension delivery is being increasingly utilized for formulation.

[0008]

[0006] Compounded transdermal formulations are typically extremely limited in their applicability due to the ordinary limitations of forming uncontrolled solutions / suspensions without regard to the dielectric parameters necessary' to accomplish bolus delivery of medicaments.

[0009]

[0007] A system that lends itself readily to the rapid formulation of less-than-1 -liter batches would be widely applicable to the practice of individualized medicine compounded per patient by physician order. Speed of production via utilization of pre-formulated transdermal vehicle, manufactured to cGMP standards can enable safer, more reliable individualized formulation outcomes.

[0008] Additionally, the process of drug development as practiced in the developed world is a time-consuming and painstaking process. Much of the effort is aimed at determining not only the efficacy of various dose concentrations but the interaction between the dose form and tissues of the medicated body. With any form of delivery, a unique set of challenges present A system, which safety and efficacy was previously established, and which could be reliably produced to current Good Pharmaceutical Manufacturing Practice (cGMP) could readily enable formulation of an active ingredient into a measurable, readily dispensable drug product.

[0010]

[0009] There remains a long felt need for a better means of transdermal delivery of active pharmaceutical or biological agent(s) to patients in need thereof in addition to compounding transdermal formulations comprising therapeutically effective amount of- pharmaceutical or biological agents.

[0011]

[0010] SUMMARY

[0012]

[0011] The instant application relates to a non-pharmaceutical solution intended to solubilize an active agent by a pharmacist or a pharmaceutist to produce a pharmaceutical composition comprising known concentration of the agent for metered transdermal delivery of the agent.

[0013]

[0012] In one example, the non-pharmaceutical solution comprises two or more solvents.

[0014]

[0013] In yet another example, the non-pharmaceutical solution comprises at. least one solvent modifier.

[0015]

[0014] In yet another example, the non-pharmaceutical solution comprises at least one solute modifier.

[0016]

[0015] In yet another example, the non-pharmaceutical solution comprises at least one source of cellular activation energy.

[0017]

[0016] In yet another example, the non-pharmaceutical solution comprises at least one skin stabilizer.

[0018]

[0017] In yet another example, the non-pharmaceutical solution comprises one or more ingredients selected from the group consisting of two or more solvents, at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof.

[0019]

[0018] The two or more solvents are selected from the group consisting of ethanol, ethylene glycol, propylene glycol, propylene carbonate, butylene glycol, acetone, glycerol, water, and a mixture thereof.

[0020]

[0019] The at least one solvent modifier is selected from the group consisting of lemon oil (or / and d-limonene), Vitamin E, Pro-Vitamin B, D-panthenol, methylsulfonylmethane (MSV 1, and a mixture thereof

[0021]

[0020] The at least one solute modifier is selected from the group consisting of a terpene, a polyphenolic flavinoid, a sugar adduct gluconuride, a sterol, an isoflavone, 33'- thiodi propionic acid (sulfurated propionic acid), phosphatidyl serine, choline, Vitamin Ds, Vitamin Ki, dehydroepiandosterone (DHEA), and a mixture thereof.

[0022]

[0021] The at least one source of cellular activation energy can be selected from the group consisting of forskolin, colforsin, a methylxanthine, saikogenin, saikosaponin, angelic acid, phellopterin, oxypeucedanin, acetylcholine, cytidine diphosphocholine, ascorbic acid (Vitamin C), and a mixture thereof.

[0023]

[0022] The at least one skin stabilizer is selected from the group consisting of glycerin monolaurate, Vitamin B?,, alkoxy glycerols, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), gamma-linolenic acid (GLA), Vitamin E, D-panthenol, phytantriol, dehydroepiandrosterone (DHEA), pregnenolone, pregnenolone acetate, esculin, allantoin, ascorbyl palmitate, and a mixture thereof.

[0024]

[0023] In one example, the total amount of two or more solvents ranges from about 85% (wt / wt) to about 99% (wt / wt) of the total weight of the non-pharmaceutical solution.

[0025]

[0024] In another example, the total amount of one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof ranges from about 1% (wt / wt) to about 15% (wt / wt) of the total weight of the non- pharmaceuti cal soluti on .

[0026]

[0025] In one example, the present application discloses a transdermal pharmaceutical composition comprising a non-pharmaceutical solution as described herein and a therapeutically effective amount of at least one active agent.

[0027]

[0026] The at least one active agent is selected from the group consisting of a pharmaceutical agent, a biological agent, and a mixture thereof

[0028]

[0027] In one example, the transdermal pharmaceutical composition disclosed herein comprises the at least one active agent in an amount ranging from about 0.1 gram to about 100 grams.

[0029]

[0028] In one aspect, the at least one active agent is selected from the group consisting of an antibiotic agent, antihistamine agent, decongestant, anti-inflammatory agent, antiparasitic agent, antiviral agent, an anesthetic agent, antifungal agent, amoebicidal agent, trichomonocidal agent, analgesic agent, anti-arthritic agent, anti-asthmatic agent, anticoagulant agent, anticonvulsant agent. anti-Alzheimer's disease agent, antidepressant agent, antidiabetic agent, antineoplastic agent, anti-psychotic agent, neuroleptic agent, antihypertensive agent, hypnotic agent, sedative agent, anxiolytic energizer agent, anti -Parkinson agent, muscle relaxant agent, antimaiarial agent, hormonal agent, contraceptive agent, sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmic agent, electrolytic agent, diagnostic agent, prokinetic agent, gastric acid secretion inhibitor agent, anti-ulcerant agent, anti -flatulent agent, anti-incontinence agent, and cardiovascular agent, a cannabinoid, and a mixture thereof.

[0030]

[0029] In another aspect, the at least one active agent is selected from the group consisting of Acetaminophen, Amitriptyline, Atropine, Baclofen, Bumetanide, Captopril, Carbamazepine, Carbidopa / Levodopa, Carvedilol, Chlorpromazine, Clindamycin, Clonazepam, Clonidine, Cyclobenzaprine, Diazepam, Diphenydramine / Maaloxm / Lidocaine, Dexamethasone, Diltiazem, Famotidine, Fluconazole, Glycopyrrolate, Haloperidol, Hydrocodone / APAP, Hydrocodone, Hydromorphone, Hydroxyzine, Ibuprofen, Ketoprofen, Ketamine, Levetiracetam, Lidocaine, Lansoprazole, Lorazepam, Dextromethorphan, Methadone, Metodopramide, Metoprolol,

[0031] Metronidazole, Morphine, Naproxen Na, Nortriptyline, ORH, Omeprazole, Oxycodone, Phenobarbital, Pilocarpine, Prednisone, Prodtlorperazine, Procl orperazine, Promethazine, Quetiapine, Quinidine, Spironolactone, Topiramate, Trazodone, Ursodiol, Valproic Acid, a cannabinoid, and a mixture thereof.

[0032]

[0030] In one example, the instant application discloses a method for preparing a transdermal pharmaceutical composition described herein. In one aspect, the method comprises adding a therapeutically effective amount of at least one active agent to a nonpharmaceutical solution described herein to obtain the transdermal pharmaceutical composition.

[0033]

[0031] In another example, the instant application discloses a method for preparing a transdermal pharmaceutical composition described herein, the method comprising adding phosphoric acid and a therapeutically effective amount of at least one active agent to a non-pharmaceutical solution described herein to obtain the transdermal pharmaceutical composition.

[0034]

[0032] In one example, the transdermal pharmaceutical composition described herein is in a liquid form.

[0035]

[0033] In another example, the transdermal pharmaceutical composition described herein is in a sprayable liquid form.

[0036]

[0034] In one example, the instant application discloses a method for treating a disease or condition in a subject, the method comprising applying a transdermal pharmaceutical composition described herein to a subject in need thereof.

[0037]

[0035] In another example, the instant application discloses a method for treating a disease or condition in a subject, the method comprising applying a transdermal pharmaceutical composition described herein to a subject in need thereof, within about 5 minutes to about 5 hours of preparation of the composition.

[0038]

[0036] In another example, the instant application discloses a kit comprising a non- pharmaceutical solution described herein. In one aspect of the embodiment, the kit comprises instructions for using the non-pharmaceutical solution.

[0039]

[0037] In another example, the instant application discloses a kit comprising a first container and a second container, wherein the first container comprises a non-pharmaceutical solution described herein, and the second container comprises an active agent. In one aspect of the embodiment, the kit comprises instructions for preparing a transdermal pharmaceutical composition as described herein.

[0040]

[0038] BRIEF DESCRIPTION OF DRAWINGS

[0041]

[0039] FIG. 1 is diagrammatical representation of the Ion surface interactions.

[0042]

[0040] FIG. 2 shows mean serum concentrations of testosterone (ng / mL) versus time (h).

[0043]

[0041] FIG. 3A shows serum levels of Lidocaine prepared using a non-pharmaceutical solution as described herein.

[0044]

[0042] FIG. 3B shows serum levels of Lidocaine prepared using another non-pharmaceutical solution described herein.

[0045]

[0043] FIG. 4 shows serum levels of morphine sulphate prepared using a non-pharmaceutical solution as described herein.

[0046]

[0044] FIG. 5 shows serum levels of morphine-3 -glucuronide prepared using a non- pharmaceutical solution as described herein.

[0047]

[0045] FIG. 6 shows serum levels of acyclovir prepared using a non-pharmaceutical solution as described herein.

[0048]

[0046] FIG. 7 shows serum levels of hydroxyzine prepared using a non-pharmaceutical solution as described herein.

[0049]

[0047] FIG. 8 shows clinical data comparing equivalent doses of Diazepine delivered trans rectally (“Diastat”) and transdermally by means of analysis of the active metabolite, dimethyl diazepam.

[0050]

[0048] FIG. 9 show's dose response curves to 3 different formulation variations designed to modify the absorption curve from rapidly absorbed, higher blood level to a longer area under curve and presumable longer efficacy.

[0051]

[0049] FIG. 10 show's that the transdermal ibuprofen formulation reduces exudate formation in rat pleurisy model.

[0052]

[0050] FIG. 11 show's that the transdermal ibuprofen formulation reduces reduced inflammatory cell migration in rat pleurisy model.

[0053]

[0051] FIG. 12 show's stability of transdermal progesterone formulation at 25 °C.

[0054]

[0052] FIG. 13 shows stability of transdermal progesterone formulation at 40 °C.

[0055]

[0053] FIG. 14 show's transdermal progesterone formulation comparison of 7-year sample with newly produced.

[0056]

[0054] FIG.15 show's stability of freshly prepared transdermal progesterone formulation.

[0057]

[0055] FIG. 16 shows results of a 5-day UV exposure test showing no degradation of Testosterone.

[0058]

[0056] FIG. 17 shows stability of transdermal diclofenac sodium formulation at 25 °C.

[0059]

[0057] FIG. 18 shows stability of transdermal progesterone formulation at 40 °C.

[0060]

[0058] FIG. 19A show's time-profile of the plasma concentrations of Acetaminophen following the oral administration of 200mg / kg Acetaminophen to male C57BL / 6 mice,

[0059] FIG. 19B show's time-profile of the brain concentrations of Acetaminophen following the oral administration of 200mg / kg Acetaminophen to male C57BL / 6 mice, n= 6.

[0061]

[0060] FIG. 20 / X shows time-profile of the plasma, concentrations of Acetaminophen following the subcutaneous administration of 200mg / kg Acetaminophen to male C57BL / 6 mice, n::::6.

[0062]

[0061] FIG. 20B show's time-profile of the brain concentrations of Acetaminophen following the subcutaneous administration of 200mg / kg Acetaminophen to male C57BL / 6 mice, n= 6.

[0063]

[0062] FIG. 21 A shows time-profile of the plasma concentrations of Acetaminophen following the application of lOOpl of SOmg / ml NPS transdermal Acetaminophen formulation to male C57BL / 6 mice, n= 6. This represents approximately half the oral and injected dose.

[0064]

[0063] FIG. 21 B shows time-profi le of the brain concentrations of Acetaminophen following the application of lOOpl of 50mg / ml NPS transdermal Acetaminophen formulation to male C57BL / 6 mice, n= 6. This represents approximately half the oral and injected dose.

[0065]

[0064] FIG. 22A shows mean plasma concentration for each formulation (n=3 / group).

[0066]

[0065] FIG 22B shows mean dose-correlated melanotan levels in plans for the formulations.

[0067]

[0066] FIG. 23 A. shows pharmacokinetic curves of 5 mg cannabidiol (CBD) over a 24-hour period from dose to euthanasia.

[0068]

[0067] FIG. 23B shows pharmacokinetic curves of 15 mg cannabidiol (CBD) over a 24-hour period from dose to euthanasia.

[0069]

[0068] FIG. 23 C shows pharmacokinetic curves of 30 mg cannabidiol (CBD) over a 24-hour period from dose to euthanasia.

[0070]

[0069] FIG. 24A shows mean of the human insulin levels measured in the plasma of nondiabetic rats during the time course of the kinetic study after treatment with placebo (1 ml / kg), or insulin solutions (0,4 lU / kg and 0.8 lU / Kg).

[0071]

[0070] FIG. 24B shows mean of the human insulin levels measured in the plasma, of diabetic rats during the time course of the kinetic study after treatment with placebo (1 ml / kg), or insulin solutions (0.4 lU / kg and 0.8 lU / Kg).

[0072]

[0071]

[0072] DETAILED DESCRIPTION

[0073]

[0073] Definitions

[0074]

[0074] The examples herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting examples that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known features and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0075]

[0075] Unless otherwise indicated, the definitions and embodiments described in this, and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0076]

[0076] The singular forms "a", "an" and "the" as used herein include plural references unless the content clearly dictates otherwise. For example, an embodiment including "an agent" should be understood to present certain aspects with one compound or two or more additional compounds.

[0077]

[0077] The terms "about", "substantially", and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5%, at least ±10%, at least ±15%, at least ±20%, or at least ±25% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0078]

[0078] The term "suitable" as used herein means that the selection of the compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0079]

[0079] The terms “agent” and "ingredient" as used herein are interchangeable and refer to a compound or mixture of compounds that, when added to a formulation, tend to produce a particular effect on the formulation's properties.

[0080]

[0080] The term "and / or" as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that "at least one of or "one or more" of the listed items is used or present.

[0081]

[0081] The terms “non-pharmaceutical solution” or “solution” as used herein are interchangeable and refer to combination of solvents and / or excipients in particular ratios and ranges of ratios relative to each other and a value determined for the solution into which pharmaceutical active ingredients are stably dissolved in order serve as a vehicle for the introduction of said active pharmaceutical ingredient(s) into physiology across the skin. The solvents and / or excipients have been registered as a Type 4 Drug Master File with the U.S. Food and Drug Administration (FDA) and does not contain an active agent or an active ingredient.

[0082]

[0082] The terms “active agent”, “active ingredient” “medicament” and “solute” as used herein are interchangeable and refer to a pharmaceutical agent or a biological agent and can be selected from the group consisting of a small molecule, a large molecule, a peptide, and a mixture thereof

[0083]

[0083] The term "transdermal pharmaceutical composition" or “transdermal pharmaceutical formulations” as used herein are interchangeable and refer to a liquid or semi-solid mixture of chemicals that can be broadly classified as solvents, solvent modifiers and / or the other chemical inclusions into which pharmaceutical active ingredients are stably dissolved to serve as a vehicle for the introduction of said active pharmaceutical ingredient(s) into physiology, whether by injection, ingestion or across the skin.

[0084]

[0084] The terms "formulation," "composition," "pharmaceutical formulation," and "pharmaceutical composition" as used herein are interchangeable and refer to a formulation for pharmaceutical use.

[0085] The term "pharmaceutically acceptable" as used herein, refers to a material that does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic (i e., the toxicity of the material significantly outweighs the benefit of the material). In some instances, a pharmaceutically acceptable material is administered to an individual without causing significant undesirable biological effects or significantly interacting in a deleterious manner with any of the components of the formulation in which it is contained . The term "pharmaceutically acceptable" also refer to being compatible with the treatment of animals, for example, humans

[0085]

[0086] The term "therapeutically effective amount" as used herein means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art.

[0086]

[0087] The term "treating", and "treatment" as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e., not worsening) the state of disease, prevention of disease spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. "Treating" and "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. "Treating" and "treatment" as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of a formulation as described herein and optionally consists of a single administration, or alternatively comprises a series of applications. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active ingredient or agent, the activity of the formulations described herein, and / or a combination thereof. It will also be appreciated that the effective dosage of a formulation used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required, t or example, the formulations are administered to the subject in an amount and for duration sufficient to treat the patient.

[0087]

[0088] The term "topical formulation" as used herein includes a formulation that is suitable for topical application to the skin. A topical formulation may, for example, be used to confer a therapeutic benefit to its user. Specific topical formulations can be used for local, regional, or transdennal application of substances.

[0088]

[0089] The term "transdermal" as used herein includes a process that occurs through the skin. The terms "transdennal," "percutaneous" and "transcutaneous" can be used interchangeably. In certain embodiments, "transdermal" also includes epicutaneous. Transdennal administration is often applied where systemic delivery of an active is desired, although it may also be useful for delivering an active to tissues underlying the skin with minimal systemic absorption.

[0089]

[0090] The term "transdermal application" as used herein includes administration through the skin. Transdermal application can be used for systemic delivery of an active agent; however, it is also useful for delivery of an active agent to tissues underlying the skin with minimal systemic absorption. In certain embodiments, "transdermal application" can also include epicutaneous application.

[0090]

[0091] The term "pharmaceutically acceptable salt" means an acid addition salt or basic addition salt which is suitable for, or compatible with the treatment of subjects, including human subjects.

[0091]

[0092] The term “disease” or “condition” means the scope of illness or treatable physiological dysfunction, condition or syndrome associated with the active pharmaceutical, cosmetic or nutritional ingredient referred to in the example.

[0092]

[0093] Numerical ranges as used herein are intended to include every' number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.

[0093]

[0094] Tire non-pharmaceutical solution described herein is a combination of solvents and excipients that have been registered as a Type 4 Drug Master File with the U.S. Food and Drug Adm mi station (FT) A ) ,

[0095] It is understood that all ingredients used in the formulations of this invention must within the applied and recommended dosages, be non-toxic and safe for human use. Also, all amounts, parts and percentages in the following description and appended claims are on a weight basis unless otherwise noted.

[0094]

[0096] It is also understood that all active agents (pharmaceutical and / or biological) listed herein have been approved at one time or another as either an injectable, oral, topical, transbuccal or transmucosal and that any medicament developed in future may be formulated by this method.

[0095]

[0097] The inventors of the instant application surprisingly found that the non-pharmaceutical solutions described herein can be used to solubilize active agents, including small molecules, peptides, and proteins, to form stable pharmaceutical compositions and that such pharmaceutical compositions can be applied transdermally resulting in a therapeutic effect.

[0096]

[0098] The present application relates to non-pharmaceutical solutions and methods of use thereof. Specifically, the present application relates to a non-pharmaceutical solution or solutions intended to be used by a pharmacist or pharmaceutist to solubilize an active agent to produce a pharmaceutical composition, of known concentration, capable of metered transdermal drug deliver}'. The pharmaceutical composition has specific dielectric properties that facilitate administration of a dissolved pharmaceutical agent across the skin. The composition may also be designed for transdermal delivery' of an active biologic ingredient. The composition can be manufactured in large volumes for batch application or provided in a bulk container. After application it cannot be reused.

[0097]

[0099] The practice of compounding pharmacy is well-used to mixing small batches of liquid and semi-solid dose forms for oral, spray-on or perianal purposes. These pharmacists serve specialty populations such as hospice, pediatric, frail elderly, and end-stage renal disease. Increasingly, physicians are prescribing compounded preparations at patient request when there is no viable commercially manufactured remedy fitting that patient’s needs. The process for weighing, measuring, and mixing an active pharmaceutical ingredient (API) into such preparations can be time-consuming and costly. These non-pharmaceutical solutions described herein can be prepared to cGMP quality, packaged in small units such as 500 milliliters or 1 liter and can be provided to a pharmacist or a pharmaceutist for preparation and dispensing to prescription order of a pharmaceutical composition. The inventors of the instant application found that batches of various pharmaceutical composition prepared using the non-pharmaceutical solutions described herein as a base can be built much more rapidly than traditional compounded remedies.

[0098]

[0100] The instant application discloses a non-pharmaceutical solution comprising one or more ingredients selected from the group consisting of two or more solvents, at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof.

[0099]

[0101] In one example, the two or more solvents are selected from the group consisting of ethanol, ethylene glycol, propylene glycol, propylene carbonate, butylene glycol, acetone, glycerol, water, and a mixture thereof.

[0100]

[0102] Solvents

[0101]

[0103] The solvent is the principal component of the carrier for the active agent and, preferably, is one in which the active agent is soluble or at least substantially soluble or can be made soluble or become more soluble, by addition of one or more additional solvents or solvent-modifying agents. As used herein, by “substantially soluble” is meant that the minimum effective dose of the active agent, generally at least about 0.25 mg, preferably at least about 0.5 mg, especially preferably about 1 mg, or more, will dissolve in 1 cc of the solvents) or in 1 cc of a mixture of the solvents) with solvent modifying agem(s). Suitable solvents may be selected from any of the solvents normally used for medicaments, cosmetics, nutrients or other active agents to be delivered transdermally.

[0102]

[0104] Preferred solvents include lower alcohols of from about 2 to about 6 carbon atoms, preferably from 2 to 4 carbon atoms and may be monoalcohols, such as, for example, ethanol, isopropanol, sec-butanol, or polyols, such as, for example, ethylene glycol, propylene glycol, butylene glycol, glycerol. Mixtures of solvents may be used. Other solvents, such as ketones, e g., acetone, methylethyl ketone, ethers, e.g., ethyl ether, may also be used, in amounts which will be safe and non-toxic in use.

[0103]

[0105] While the non-pharmaceutical solution is generally non-aqueous, water may be used for water- soluble active agents and for those drugs or other active agents which are stable in the presence of and not denigrated by the presence of water. Water may also be introduced as a. component of one of the other ingredients, for example, as an alcohol: water azeotrope, etc When water is present in the solvent it will usually constitute less than about 50 percent, preferably less than about. 10 percent, especially, preferably, less than about 2 percent, by weight of the total solvent although more or less may be used depending on the active agent and so long as the objectives of the invention can be met. Furthermore, as will become apparent by the examples to follow, the compositions of this invention and utilizing the principles which will be described in more detail, hereinafter, may also be formulated as aqueous emulsions, including wherein the aqueous phase is the major and continuous phase. Such aqueous emulsions, as is the case with non-aqueous (usually less than about 5%, especially less than about 2%, of wa ter) non-nhatrnaceutical solution, will be rapidly absorbed by and relea se the active agent or agents in, typically, less than one minute.

[0104]

[0106] The total amount of solvents) will be selected to assure dissolution of the solute and other additives and provide suitable product viscosity. As such, the total amount of solvents) present in the non-pharmaceutical solution fall within the range of about 85% (wt / wt) to 99% (wt / wt) of the total weight of the non-pharmaceutical solution.

[0105]

[0107] In one example, the total amount of two or more solvents in a non-pharmaceutical solution described herein ranges from about 85% (wt / wt) to about 99% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of the two or more solvents is about 85% (wt / wt), about 85,25% (wt / wt), about 85.5% (wt / wt), about 85.75% (wt / wt), about 86% (wt / wt), about 86.25% (wt / wt), about 86.5% (wt / wt), about 86 / 75% (wt / wt), about 87% (wt / wt), about 87.25% (wt / wt), about 87.5% (wt / wt), about 87.75% (wt / wt), about 88%> (wt / wt), about 88.25% (wt / wt), about 88.5% (wt / wt), about 88.75% (wt / wt), about 89% (wt / wt), about 89.25% (wt / wt), about 89.5% (wt / wt), about 89.75% (wt / wt), 90% (wt / wt), about 90.25% (wt / wt), about 90.5% (wt / wt), about 90.75% (wt / wt), about 91% (wt / wt), about 91.25% (wt / wt), about 91.5% (wt / wt), about 91.75%) (wt / wt), about 92% (wt / wt), about 92.25% (wt / wt), about 92.5% (wt / wt), about 92.75% (wt / wt), about 93% (wt / wt), about 93.25% (wt / wt), about 93.5% (wt / wt), about 93.75% (wt / wt), about 94% (wt / wt), about 94.25% (wt / wt), about 94.5% (wt / wt), about 94.75% (wt / wt), about 95% (wt / wt), about 95.25% (wt / wt), about 95.5% (wt / wt), about 95.75% (wt / wt), about 96% (wt / wt), about 96.25%) (wt / wt), about 96.50% (wt / wt), about 96.75% (wt / wt), about 97% (wt / wt), about 97.25% (wt / wt), about 97.5% (wt / wt), about 97.75% (wt / wt), about 98% (wt / wt), about 98.25% (wt / wt), about 98.5% (wt / wt), about 98.75% (wt / wt), or about 99% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of ethanol, acetone, and propylene glycol is in an amount within a range of the amounts described in this paragraph.

[0106]

[0108] In another example, the non-pharmaceutical solution comprises ethanol in an amount ranging from about 40% (wt / wt) to about 60% (wt / wt) of the total weight of the non- pharmaceutical solution. In some examples, the ethanol is present in an amount of about 40% (wlAvt), about 40.25% (wt / wt), about 40.5% (wt / wt), about 40.75% (wt / wt), about 41% (wt / wt), about 41.25% (wt / wt), about 41.5% (wt / wt), about 41.75% (wt / wt), about 42% (wt / wt), about 42.25% (wt / wt), about 42.5% (wt / wt), about 42.75% (wt / wt), about 43% (wt / wt), about 43.25% (wt / wt), about 43.5% (wt / wt), about 43.75% (wt / wt), about 44% (wt / wt), about 44.25% (wt / wt), about 44.5% (wt / wt), about 44.75% (wt / wt), about 45% (wt / wt), about 45.25% (wt / wt), about 45.5% (wt / wt), about 45.75% (wt / wt), about 46% (wt / wt), about 46.25% (wt / wt), about 46.50% (wt / wt), about 46.75% (wt / wt), about 47% (wt / wt), about 47.25% (wt / wt), about 47.5% (wt / wt), about 47.75% (wt / wt), about 48% (wt / wt), about 48.25% (wt / wt), about 48.5% (wt / wt), about 48.75% (wt / wt), about 49% (wt / wt), about 49.25% (wt / wt), about 49.5% (wt / wt), about 49.75% (wt / wt), about 50% (wt / wt), about 50.25% (wt / wt), about 50.5% (wt / wt), about 50,75% (wt / wt), about 51% (wt / wt), about 52.25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 52% (wt / wt), about 52 25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 53% (wt / wt), about 53.25% (wt / wt), about 53.5% (wt / wt), about 53.75% (wt / wt), about 54% (wt / wt), about 54.25% (wt / wt), about 54.5% (wt / wt), about 54.75% (wt / wt), about 55% (wt / wt) about 55.25% (wt / wt), about 55.5% (wt / wt), about 55.75% (wt / wt), about 56% (wt / wt), about 56.25% (wt / wt), about 56.50% (wt / wt), about 56.75% (wt / wt), about 57% (wt / wt), about 57.25% (wt / wt), about 57.5% (wt / wt), about 57.75% (wt / wt), about 58% (wd / wd), about 58.25% (wt / wd), about 58.5% (wt / wt). about 58.75% (wt / wt), about 59% (wt / wt), about 59.25% (wt / wt), about 59.5% (wt / wt), about 59.75% (wl / wt), or about 60% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of ethanol is in an amount within a range of the amounts described in this paragraph.

[0107]

[0109] In yet another example, the non-pharmaceutical solution comprises propylene glycol in an amount ranging from about 40% (wt / wt) to about 60% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the propylene glycol is present in an amount of about 40% (wt / wt), about 40.25% (wt / wt), about 40.5% (wt / wt), about 40.75% (wiAvt), about 41% (wt / wt), about 41.25% (wl / wt), about 41.5% (wtAvt), about 41.75% (wt / wt), about 42% (wt / wt), about 42.25% (wt / wt), about 42.5% (wt / wt), about 42.75% (wt / wt), about 43% (wt / wt), about 43.25% (wt / wt), about 43.5% (wt / wt), about 43.75% (wt / wt), about 44% (wt / wt), about 44.25% (wt / wt), about 44.5% (wt / wt), about 44.75% (wt / wt), about 45% (wt / wt), about 45.25% (wt / wt), about 45.5% (wt / wt), about 45.75% (wt / wt), about 46% (wt / wt), about 46.25% (wt / wt), about 46.50% (wt / wt), about 46.75% (wt / wt), about 47% (wt / wt), about 47.25% (wt / wt), about 47.5% (wt / wt), about 47.75% (wt / wt), about 48% (wt / wt), about 48.25% (wt / wt), about 48.5% (wt / wt), about 48.75% (wt / wt), about 49% (wt / wt), about 49.25% (wt / wt), about 49.5% (wt / wt), about 49.75% (wt / wt), about 50% (wt / wt), about 50.25% (wt / wt), about 50.5% (wt / wt), about 50.75% (wt / wt), about 51% (wt / wt), about 52.25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 52% (wt / wt), about 52.25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 53% (wt / wt), about 53.25% (wt / wt), about 53.5% (wt / wt), about 53.75% (wt / wt), about 54% (wt / wt), about 54.25% (wt / wt), about 54.5% (wt / wt), about 54.75% (wt / wt), about 55% (wt / wt) about 55.25% (wt / wt), about 55.5% (wt / wt), about 55.75% (wt / wt), about 56% (wt / wt), about 56.25% (wt / wt), about 56.50%

[0108] (wt / wt), about 56.75% (wt / wt), about 57% (wt / wt), about 57.25% (wt / wt), about 57.5%

[0109] (wt / wt), about 57.75% (wt / wt), about 58% (wt / wt), about 58.25% (wt / wt), about 58.5%

[0110] (wt / wt), about 58.75% (wt / wt), about 59% (wt / wt), about 59.25% (wt''wt), about 59.5%

[0111] (wt / wt), about 59.75% (wt / wt), or about 60% (wt / wt) of the total weight of the non- pharmaceutical solution. In some examples, the total amount of propylene glycol is in an amount within a range of the amounts described in this paragraph.

[0112]

[0110] In yet another example, the non-pharmaceutical solution comprises propylene carbonate in an amount ranging from about 40% (w4 / wt) to about 60% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the propylene carbonate is present in an amount of about 40% (wt / wt), about 40.25% (wl / wl), about 40.5% (wt / wt), about 40.75% (wt / wt), about 41% (wt / wt), about 41.25% (wt / wt), about 41.5% (wt / wt), about 41 .75% (wt / wt), about 42% (wt / wt), about 42.25% (wt / wt), about 42.5% (wt / wt), about 42.75% (wt / wt), about 43% (wt / wt), about 43.25% (wt / wt), about 43.5% (wt / wt), about 43.75% (wt / wt), about 44% (wt / wt), about 44.25% (wt / wt), about 44.5% (wt / wt), about 44.75% (wl / wt), about 45% (wt / wt), about 45.25% (wt / wt), about 45.5% (wt / wt), about 45.75% (wt / wt), about 46% (wt / wt), about 46.25% (wt / wt), about 46.50% (wt / wt), about 46.75% (wt / wt), about 47% (wt / wt), about 47 25% (wt / wt), about 47.5% (wt / wt), about 47.75% (wt / wt), about 48% (wt / wt), about 48.25% (wt / wt), about 48.5% (wt / wt), about 48.75% (wt / wt), about 49% (wt / wt), about 49.25% (wt / wt), about 49.5% (wt / wt), about 49.75% (wt / wt), about 50% (wt / wt), about 50.25% (wt / wt), about 50.5% (wt / wt), about 50.75% (wt / wt), about 51% (wt / wt), about 52.25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 52% (wt / wt), about 52.25% (wt / wt), about 52.5% (wt / wt), about 52.75% (wt / wt), about 53% (wt / wt), about 53.25% (wt / wt), about 53.5% (wt / wt), about 53.75% (wt / wt), about 54% (wt / wt), about 54.25% (wt / wt), about 54.5% (wt / wt), about 54.75% (wt / wt), about 55% (wt / wt) about 55.25% (wt / wt), about 55.5% (wt / wt), about 55.75% (wt / wt), about 56% (wt / wt), about 56.25% (wt / wt), about 56.50% (wt / wt), about 56.75% (wt / wt), about 57% (wt / wt), about 57.25% (wl / wl), about 57.5% (wt / wt), about 57.75% (wt / wt), about 58% (wt / wt), about 58.25% (wt / wt), about 58.5% (wt / wt), about 58.75% (wt / wt), about 59% (wt / wt), about 59.25% (wt / wt), about 59.5% (wt / wt), about 59.75% (wt / wt), or about 60% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of propylene carbonate is in an amount within a range of the amounts described in this paragraph.

[0113] [Ill] In yet another example, the non-pharmaceutical solution comprises acetone in an amount ranging from about 1% (wt / wt) to about 10% (wt / wt) of the total weight of the non-pharmaceutical solution. In one aspect of the example, the total amount of acetone is about 1% (wl / wt), about 1.25% (wt / wt), about 1.5% (wt / wt), about 1.75% (wt / wt), about 2% (wl / wt), about 2.25% (wl / wt), about 2.5% (wt / wt), about 2.75% (wtrivt), about 3% (wt / wt), about 3.25% (wt / wt), about 3.5% (wl / wt), about 3 75% (wt / wt), about 4% (wt / wt), about 4.25% (wt / wt), about 4.5% (wt / wt), about 4.75% (wt / wt), about 5% (wt / wt), about 5.25% (wt / wt), about 5.5 % (wt / wt), about 5.75% (wt / wt), about 6% (wt / wt), about 6.25% (wt / wt), about 6.5% (wt / wt), about 6.75% (wt / wt), about 7% (wt / wt), about 7.25% (wt / wt), about 7.5% (wt / wt), about 7.75% (wt / wt), about 8% (wt / wt), about 8.25% (wt / wt), about 8.5% (wt / wt), about 8.75% (wt / wt), about 9% (wt / wt), about 9.25% (wt / wt), about 9.5% (wt / wt) about 9.75% (wt / wt), or about 10% (wl / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of acetone is in an amount within a range of the amounts described in this paragraph.

[0114]

[0112] In yet another example, the non-pharmaceutical solution comprises water in an amount ranging from about 5% (wt / wt) to about 50% (wi / wt) of the total weight of the non- pharmaceutical solution. In some examples, the water is present in an amount of about 1 % (wt / wt), 2% (wt / wt), 3% (wt / wt), 4% (wt / wt), 5% (wt / wt), 6% (wt / wt), 7'% (wt / wt), 8% (wt / wt), 9% (wt / wt), 10% (wt / wt), 11% (wt / wt), 12% (wt / wt), 13% (wt / wt), 14% (wt / wt), 15% (wt / wt), 16% (wt / wt), 17% (wt / wt), 18% (wt / wt), 19% (wt / wt), 20%

[0115] (wt / wt), 21% (wt / wt), 22% (wt / wt), 23% (wt / wt), 24% (wt / wt), 25% (wt / wt), 26%

[0116] (wt / wt), 27% (wt / wt), 28% (wt / wt), 29% (wt / wt), 30% (wt / wt), 31% (wt / wt), 32%

[0117] (wt / wt), 33% (wt / wt), 34% (wt / wt), 35% (wt / wt), 36% (wt / wt), 37% (wt / wt), 38%

[0118] (wt / wt), 39% (wt / wt), 40% (wt / wt), 41% (wt / wt), 42% (wt / wt), 43% (wt / wt), 44%

[0119] (wt / wt), 45% (wt / wt), 46% (wt / wt), 47% (wt / wt), 48% (wt / wt), 49% (wt / wt), or 50% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of water is in an amount within a range of the amounts described in this paragraph.

[0120]

[0113] In yet another example, the non-pharmaceutical solution further comprises one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof. In one aspect of the example, the total amount of one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof ranges from about 1% (wt / wt) to about 15% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of one or more ingredients selected from the group consisting of a solvent modifier, a solute modifier, a source of cellular activation energy, a skin stabi lizer, and a mixture thereof is about 1% (wt / wt), about 1.25% (wtAvt), about 1.5% (wtwvt), about 1.75% (w1 / wt), about 2% (wt / wt), about 2.25% (wt / wt), about 2.5% (wt / wt), about 2 75% (wt / wt), about 3% (wt / wt), about 3.25% (wt / wt), about 3.5% (wt / wt), about 3.75% (wt / wt), about 4% (wt / wt), about 4.25% (wt / wt), about 4.5% (wt / wt), about 4.75% (wt / wt), about 5% (wt / wt), about 5.25% (wtAvt), about 5.5.% (wt / wt), about 5.75% (wt / wt), about 6% (wt / wt), about 6.25% (wt / wt), about 6.5% (wt / wt), about 6.75% (wt / wt), about 7% (wt / wt), about 7.25% (wt / wt), about 7.5% (wd / wt), about 7 75% (wt / wt), about 8% (wt / wt), about 8.25% (wt / wt), about 8.5% (wt / wt), about 8.75% (wt / wt), about 9% (wt / wt), about 9.25% (wt / wt), about 9.5% (wt / wt) about 9.75% (wt / wt), about 10% (wtAvt), about 10.25% (wt / wt), about 10.5% (wt / wt), about 10.75% (wt / wt), about 11% (wt / wt), about 11.25% (wt / wt), about 11.5.% (wt / wt), about 1 1 75% (wt / wt), about 12% (wt / wt), about 12.25% (wt / wt), about 12.5% (wt / wt), about 12.75% (wt / wt), about 13% (wt / wt), about 13.25% (wl / wt), about 13.5% (wt / wt), about 13.75% (wt / wt), about 14% (wt / wt), about 14.25% (wt / wt), about 14.5% (wt / wt), about 14.75% (wt / wt), or about 15% (wt / wt) of the total weight of the non-pharmaceutical solution. In some examples, the total amount of one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof is in an amount within a range of the amounts described in this paragraph.

[0121]

[0114] Solvent modifiers

[0122] [115 J A solvent modifier is selected to modify the polarity of the non -pharmaceutical solution to balance that of the active ingredient (solute). Therefore, solvent modifiers will usually be polar compounds (i.e. form polar ions in solution) and will usually contain a functional group containing oxygen, sulfur or nitrogen in its molecular form. Also, if the active agent is unsaturated the solvent modifier will usually also contain double bonds in the straight-chain or cyclic portion to match the structure of the solute (i.e., active agent). Most importantly, the solvent modifier or mixture of solvent modifiers enables the solvents) and solvent modifiers) to form a weak complex with the active agent, i e., an association via van der Waals forces and / or hydrogen bonding, thus yielding a stable pharmaceutical composition with a high solute / solvent ratio. As used herein, “stable” is intended to have its normal and usual meaning, namely, that the pharmaceutical composition may be stored at room or elevated temperature for one or more days, usually 30 or more days, without undergoing phase separation. By ‘‘high sok.de / solvent’ ratio is meant at least 0.25 mg solute per cubic centimeter of solvent (or solvent plus modifying agents) and, more generally, often amounts of solute exceeding the solubility of the solute in the solvent alone, or in each solvent of a multi-solvent system.

[0123]

[0116] As noted above, solvent modifiers may be individually (or as a group) selected from substances having structural elements in common with the active agent. However, it has been found that for many bio-active compounds and other active agents, a relatively small group of solvent modifiers can facilitate the dissolution of the active agent and formation of the weak association which enable the complex of active agent-modifier to pass the defenses of the skin with minimal irritation without modification of the chemical structure or stereoscopic configuration of the active agent.

[0124]

[0117] Thus, particularly favorable results have been obtained by using as the solvent modifier one or more of lemon oil (or / and d-limonene), Vitamin E, Pro-Vitamin B, Vitamin B\ D-panthenol and methylsulfonylmethane (MSM).

[0125]

[0118] The amount of solvent modifier will be selected to result in the desired solute / sol vent ratio, and will depend on various factors, including, for example, primarily, the polarities, and polarizabilities, dipole moments, van tier Waals forces of each component, including the solvent, solvent modifier, and solute (i.e., active agent).

[0126]

[0119] In this regard, in order to match the polarities, dipole moments, of the solute to that of the solvent system the amount of the individual components of the solvent system will be selected such that the weighted (molar) average of the dipole moments of the individual components will be substantially the same as the dipole moment of the solute in solution.

[0127]

[0120] The amount of solvent modifier(s) to achieve the desired sol ute / soi vent ratio ranges from about 0.0001 to about 50% (wt / wt), preferably, from about 0.1 to about 35%, more preferably, from about 0,1 to about 5% (wt / wt), based on the total solution.

[0128]

[0121] Solute modifiers

[0129]

[0122] The solute modifier may be included in the non-pharmaceutical solution where necessary to facilitate dissolution of insoluble or sparingly soluble solutes at higher concentrations. Solute modifiers which form reversible or temporary complexes with the solute to facilitate passage through the skin while minimizing immunological response are especially effective. The solute modifier will also, optimally, be a nutritional compound which will be metabolized by the body once the solute is released from the complex.

[0130]

[0123] Examples of solute modifiers include, but are not limited to, terpenes, polyphenolic flavinoids, and other sugar adduct glucoimndes, sterols, such as, for example, cholesterol and cholesterol-like compounds and hormones, such as isoflavones, 3,3'- tmodi propionic acid (sulfurated propionic acid), phosphatidyl serine and choline, Vitamin Ds, Vitamin Ki, dehydroepi andosterone (DHEA) and water. Another group of solute modifiers include bosweiiic acid, hypericum, phytic acid and water

[0131]

[0124] The amount of solute modifier can be about 0.003% (wt / wt), such as, for example, from about 0.003% (wt / wt) to about 5% (wt / wt) of the total amount of the nonpharmaceutical solution, preferably from about 0.1% (wt / wt) to about 5% (wt / wt) of the total weight of the non-pharmaceutical solution, more preferably from about 0 / 1. % (wt / wt) to about 4% (wt / wt) of the total weight of the non-pharmaceutical solution.

[0132]

[0125] Source of cellular activation energy

[0133]

[0126] The process by which transderm al drug delivery operates involves moving molecules across chemical and electrical gradients. Under ordinary tonic conditions, the introduction of materials through the skin results in chemical cascades that consume relatively large amounts of energy as the body seeks to defend itself against the challenge. Therefore, the non-pharmaceutical solution used for preparation of transdermal pharmaceutical composition as described herein, according to one preferred embodiment, includes a substance which brings stored energy or the stimulus for release of stored energy on a cellular level, thereby minimizing energy-negative reactions, which could lead to sensitization, ACD or anaphylaxis. The inclusion such a stored energy substance results in a multiplied net increase in available cellular energy- arid, accordingly, the potential acceleration of those reactions which result in the active agent ultimately reaching its target and being effectively utilized by the body.

[0134]

[0127] One example of a. source of cellular activation energy includes extracts of the plant Coleus Forskohlii, and especially, Forskolin, a labdane di terpenoid Other extracts of Coleus Forskohlii, such as, Colforsin or Coleonol, for example, can also be used.

[0135]

[0128] Other examples of cellular activation energy sources for stimulating generation of cAMP, either via. precursors or cellular activators, include, for example, methyl xanthines, Saikogenin and Saikosaponin, Angelicae dahuricae radix (yielding angelic acid), phellopterin, oxypeucedanin.

[0136]

[0129] Examples of substances which stimulate cellular production of cGMP can also be used and can be selected from the group consisting of acetylcholine, cytidine diphosphocholine, and ascorbic acid (vitamin C).

[0137]

[0130] The amount of the source of cellular acti vation energy can range from 0.001% to 0.1%, preferably, from about 0.001% (wt / wt) to about 0.01% (wt / wt) of the total weight of the non -pharmaceutical solution, more preferably, from about 0.001 % (wt / wt) to about 0.005% (wt / wt) of the total weight of the nou-pharmaceutical solution.

[0138]

[0131] Skin Stabilizers

[0139]

[0132] Skin stabilizers may be included in the non-pharmaceutical solutions described herein to stabilize the skin prior to passage and to assi st the skin to repair any damage resulting from the transmigration of the active agent and solvent and other components of the solution.

[0140]

[0133] Suitable skin stabilizers may provide one or more of the following attributes to facilitate safe and effective dosing of the active agent while avoiding local or systemic sensitization: form hydrogen bonds and complex with free radicals; act as a bridge for coHagen, keeping the strand intact temporarily during repair; stimulate the body's repair mechanisms, modulating prostaglandins, cytokines and die like, re-stabilize the Elastin complex after the composition passes through the skin, carry cationic potential, stimulating nerve transmission, i.e., decreasing nerve repolarization time at synapses. In addition, preferred skin stabilizers should be able to be metabolized by the body and should also shield a medicament or other active agent(s) from, the skin's defense mechanisms by forming suitable complexes which wi 11 be readily uncomplexed when the active agent reaches its intended site.

[0141]

[0134] Examples of substances which may function as skin stabilizers and which may be included in a son-pharmaceutical solution as described herein include glycerin monolaurate (e.g., as Lauricidin®) and similar fatty acid esters, Vitamin Ds, alkoxy glycerols, unsaturated fatty acids, such as, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA ), Vitamin E (alpha tocopherol) and the esters, e.g., acetate, and derivatives thereof, e.g., tocotrienoh D- pantnenol, phytantrioi, Dehydroepiandosterone (DHEA), pregnenolone, pregnenolone acetate, ascorbyl palmitate, and the like.

[0142]

[0135] The skin stabilizer can be present in an amount ranging from about 0.05% to about 5%, preferably, from about 0.1% (wt / wt) to about 5% (wt / wt) of the total weight of the non- pharmaceutical solution, more preferably, from about 0.1 % (wt / wt) to about 2% (wt / wt) of the total weight of the non-pharmaceutical solution It is preferred to select stabilizers which will be effective in stabilizing the skin at as low a concentration as possible.

[0143]

[0136] In one example, a non-pharmaceutical solution described herein comprises two or more solvents selected from ethanol, propylene glycol, propylene carbonate, acetone, and a mixture thereof.

[0144]

[0137] In another example, a non-pharmaceutical solution described herein further comprises one or more ingredients selected from the group consisting of lemon oil vitamin E, D- panthenoh Methyl sulphonyl methane, phytantrioi, glycerin monolaurate, forskolin, and a mixture thereof.

[0145]

[0138] In one preferred example, the non-pharmaceutical solution (herein referred to as NPS- A.) comprises ethanol in an amount of about 47% (wt / wt), propylene glycol in an amount of about 49% (wl / wt), acetone in an amount of about 3% (wl / wt), and one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof in an amount of 1% (wl / wt) of the total weight of the non -pharrn aceuti cal sol uti on .

[0146]

[0139] In another preferred example, the non-pharmaceutical solution (herein referred to as NPS-B) comprises ethanol in an amount of about 44% (wt / wt), propylene carbonate in an amount of about 50% (wt / wt), acetone in an amount of about 2% (wt / wt), and one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof in an amount of 4% (wt / wt) of the total weight of the non-pharmaceutical solution.

[0147]

[0140] Various non-pharmaceutical solutions for solubility experiments and pre-clinical and clinical batches were prepared. The inventors surprisingly found thatNPS-A and NPS- B and variations thereof can incorporate many active ingredients without further optimizing the solution, or with minimal additions of amounts of alternative solvents such as water, glycerol, or additional excipients. These variations are readily reproduceable at small scale and can be reduced to batching instructions.

[0148]

[0141] Non-Pharmaceutical Solution A (NPS-A):

[0149]

[0142] Non-Pharmaceutical Solution B: (NPS-B):

[0150]

[0143] Variations of the above two non-pharmaceutical solutions A and B are shown in Table

[0151]

[0144] Using preferred non-pharmaceutical solutions, experiments were conducted in animal models then in single patients then multiple patients and the analyzed results of the experiments unequivocally establish the ability of the non-pharmaceutical solutions described herein to deliver active agent(s) across intact skin and create a physiological reaction once in tissue in the subject.

[0152]

[0145] The instant application provides non-pharmaceutical solutions, to which upon adding an active agent, can quickly introduce an active agent through intact skin or mucous membrane or other viable membrane or external covering of animal, including humans, or plants, while minimizing damage and, therefore, minimizing the immune response of the skin or membrane to this introduction / challenge.

[0153]

[0146] Most active agents require a critical amount of the compound of interest to be introduced into the body of the patient all at once. This is referred to in the literature as the bolus dose effect. If this critical mass is not reached the medicament is ignored by physiology. The instant application provides non-pharmaceutical solutions, to which upon adding an active agent, can quickly introduce a bolus of medicament or other active agent through intact skin or mucous membrane or other viable membrane or external covering of animal, including human, or plant, engaging the body’s bolus response enabling many more medicaments to be dosed transdermally

[0154]

[0147] Rapid introduction of the active agent enables: (a) minimal immune response or anaphylaxis, and (b) repetitive dosing over the same area of skin over a short term or, if needed, for a longer course of therapy.

[0155]

[0148] It is understood that all ingredients used in the compositions of this invention must, within the applied and recommended dosages, be non-toxic and safe for animal and human use. Also, all amounts, parts and percentages in the following description and appended claims are on a weight basis unless otherwise noted.

[0156]

[0149] Transdermal Pharmaceutical compositions

[0157]

[0150] The instant application discloses transdermal pharmaceutical compositions comprising a non-pharmaceutical solution as described herein and an active agent, in addition to the methods of preparing and using such pharmaceutical composition(s).

[0158]

[0151] In one example, the method of preparing a transdermal pharmaceutical composition described herein comprises adding a therapeutically effective amount of an active agent to the non-pharmaceutical solution to obtain the transdermal pharmaceutical composition.

[0159]

[0152] In another example, the method of preparing a transdermal pharmaceutical composition described herein further comprises adding phosphoric acid.

[0160]

[0153] The active agent can be selected from the group consisting of an antibiotic agent, antihistamine agent, decongestant, anti-inflammatory agent, antiparasitic agent, antiviral agent, an anesthetic agent, antifungal agent, amoebicidal agent, trichomonocidal agent, analgesic agent, anti -arthritic agent, anti-asthmatic agent, anticoagulant agent, anticonvulsant agent, anti-Alzheimer's disease agent, antidepressant agent, antidiabetic agent, antineoplastic agent, anti-psychotic agent, neuroleptic agent, antihypertensive agent, hypnotic agent, sedative agent, anxiolytic energizer agent, anti -Parkinson agent, muscle relaxant agent, antimalarial agent, hormonal agent, contraceptive agent, sympathomimetic agent, hypoglycemic agent, antilipemic agent, ophthalmic agent, electrolytic agent, diagnostic agent, prokinetic agent, gastric acid secretion inhibitor agent, anti-ulcerant agent, anti -flatulent agent, anti-incontinence agent, and cardiovascular agent, a cannabinoid, and a mixture thereof.

[0161]

[0154] In one example, the active agent can be selected from the group consisting of large and small molecules up to and including peptides, and a mixture thereof. In another example, the active agent is a biologic agent, such as human insulin. The insulin comprised in a formulation described herein can have a molecular weight ranging from 340 Daltons to 22,000 Daltons. In yet another example, the active ingredient is a biologic agent, such as an Incretin. In yet another example, the active is a biologic agent classified as a melanocortin such as alpha Melanocyte Stimulating Hormone (aMSH). In another example the active agent is a Caine anesthetic such as Bupivacaine (Marcaine), Bupivacaine (Sensorcaine), Chloroprocaine (Nesacaine), Lidocaine (Xylocaine), Tetracaine, Mepivacaine (Carbocaine), etc. The at least one Caine anesthetic comprised in a formulation described herein can have a molecular weight ranging from 334 Daltons to 290 Daltons, In yet another example the active agent is a Non-Steroidal Anti-Inflammatory Drug or NS AID such as Aspirin, Ibuprofen, Diclofenac Sodium, Naproxen Sodium, Celecoxib, Indomethacin, Mefenamic acid, Nambumetone, Rofecoxib, Valdecoxib and Etoricoxib. In yet another example the active agent is an anesthetic drug such as Ketamine or Acetaminophen. In yet another example the active agent is an Anti -addict! on agent for example Naloxone, Nalmefene or Methadone. In yet another example the at least one active ingredient is an Antibacterial such as Clindamycin, Ciprofloxacin, Metronidazole or Omeprazole. In another example the active agent is an Anticonvulsant such as Carbamazepine, Phenytoin and Valproic Acid. In yet another example the at least one active ingredient is an Anti Parkinson’s agent such as L-DOPA, Levodopa and Carbidopa. In yet another example the active agent is an Antipsychotic such as risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole and clozapine. In yet another example the active agent is an Anti-spasticity agent such as gabapentin, Clonidine and the Cannabinoids In yet another example the active agent is an antiviral agent such as Vidarabine, Acyclovir, Gancyclovir, Ribavirin, Tamiflu and Interferons. In yet another example the active agent is an Anxiolytic such as Diazepam, Lorazepam, Clonazepam, or Oxazepam . In yet another example the active agent i s a hormonal agent for Pituitary disease such as Corticotrophin-releasing hormone (CRH), Dopamine, Gonadotrophinreleasing hormone (GnRH), Growth hormone-releasing hormone (GHRH), Somatostatin and Thyrotropin-releasing hormone (TRH). In another example the active agent is a Hormonal agent for prostaglandins such as PGA, PGB, PGE, PGF, and PGI. In yet another example the active agent is a hormonal agent for sex hormones such as Estrogen, Progesterone and Testosterone. In yet another example the active agent is a hormonal agent for Thyroid disease such as Thyroid Stimulating Hormone, Thyroid Releasing Hormone, T3 & T4. In yet another example the active agent is a hormonal agent for hormonal suppression or excitation such as Epinephrine and Cortico-steroids. In yet another example the active agent is a neurotonic agent such as Suramin.

[0162]

[0155] As such, some of the transdermal pharmaceutical compositions described herein comprise one or more active agents selected from the group consisting of AB HR 0.5 / 12.5 / 0.5 / 10mg, ASH 0.5 / 12.S / 0.5mg, Acetaminophen, Amitriptyline, Atropine, Baclofen, Bumetanide, Captopril, Carbamazepine, Carbidopa / Levodopa, Carvedilol, Chlorpromazine, Clindamycin, Clonazepam, Clonidine, Cyclobenzaprine, Diazepam, Diphenydramine / Meloxicam I Lidocaine, Dexamethasone, Diltiazem, Famotidine, Fluconazole, Glycopyrrolate, Haloperidol, Hydrocodone / APAP, Hydrocodone, Hydromorphone, Hydroxyzine, Ibuprofen, Ketoprofen, Ketamine, Levetiracetam, Lidocaine, Lansoprazole, Lorazepam, Dextromethorphan, Methadone, Metodopramide, Metoprolol, Metronidazole, Morphine, Naproxen Na, Nortriptyline, ORH, Omeprazole, Oxycodone, Phenobarbital, Pilocarpine, Prednisone, , Proclorperazine, Promethazine, Quetiapine, Quinidine, Spironolactone, Topiramate, Trazodone, Ursodiol, Valproic Acid, a cannabinoid, and a mixture thereof.

[0163]

[0156] The cannabinoid is selected from the group consisting of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinoic acid), CBD (cannabidiol), CBDA (cannabidiol), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabicyclophenol), CBV (secondary cannabinol), THCV (tetrahydrocannabinol), CBDV (secondary' cannabidiol), CBCV (cannabinol), CBGV (secondary' cannabigerol), CBGM (cannabigerol monomethyl ether), CBE (cannabigerol), CBT (cannabidopyranocyclone), and a mixture thereof.

[0157] The transdermal pharmaceutical composition described herein may further, as active agents, isolated terpenes selected from the group consisting of alpha-bisabolol, borneol, camphene, camphor, beta-caryophyllene, delta-3 -carene, caryophyllene oxide, alpha- cedrene, beta-eudesmol, fenchol, geraniol, guaiol, alpha-humulene, isoborneol, limonene, linalool, menthol, myrcene, nerol, nerolidol, cis-ocimene, trans-ocimene, alpha-phellandrene, alpha-pinene, beta-pinene, sabinene, alpha-terpinene, alphaterpineol, terpinolene, alpha-guaiene, elemene, farnesene, farnesol, germacrene B, guaia-l(10),11 -diene, trans-2-pinanol, selina-3,7(l l)-diene, eudesm-7(l 1)-en-4-ol, valencene, and a mixture thereof.

[0164]

[0158] The amount of active agent(s) ranges from about 1 mg to about 100 mg.

[0165]

[0159] In one example, the transdermal pharmaceutical composition described herein is in a liquid form.

[0166]

[0160] In another example, the transdermal pharmaceutical composition described herein is in a sprayable liquid form.

[0167]

[0161] In one example, the instant application discloses a method for treating a disease or condition in a subject, the method comprising applying a transdermal pharmaceutical composition described herein to a subject in need thereof.

[0168]

[0162] In another example, the instant application discloses a method for treating a disease or condition in a subject, the method comprising applying a transdermal pharmaceutical composition described herein to a subject in need thereof within about 5 minutes to about 5 hours of preparation of the composition.

[0169]

[0163] In another example, the instant application discloses a kit comprising a nonpharmaceutical solution described herein. In one aspect of the embodiment, the kit comprises instructions for using the non-pharmaceutical solution.

[0170]

[0164] In another example, the instant application discloses a kit comprising a first container and a second container, wherein the first container comprises a non-pharmaceutical solution described herein, and the second container comprises an active agent. In one aspect of the embodiment, the kit comprises instructions for preparing and / or applying a transdermal pharmaceutical composition as described herein.

[0171]

[0165] In another example, the instant application discloses a kit comprising a first container a second container, and a third container, wherein the first container comprises a non- pharmaceutical solution described herein, and the second container comprises an active agent, and. the third container comprises phosphoric acid. In one aspect of the embodiment, the kit comprises instructions for preparing and / or applying a transdermal pharmaceutical composition as described herein.

[0172] Although not wishing to be bound by any particular theory of operation, it is behoved that the most adequate theory describing how the active agent (i.e., a pharmaceutical / biotogical agent) rinds its way, once inside the body, to the intended target site, is the so-called “information theory / '1This theory asserts that the active agent for which the body develops particular affinities when challenge is present due to degenerative disease, infection or trauma. The affected tissues selectively attract and bind these substances as they encounter them in humor or tissue mediums while normal tissues seek to deflect the compounds away. Once the carrier med icam ent-complex arrives in the vicimty of the diseased or “abnormal” tissue, the attraction of the tissue receptors overcomes the weak association between the non-pharmaceutical solution and the medicament and the medicament is released intact and taken by the needy tissue. By a similar mechanism modifying agent components may be stripped from the complex prior to arriving at the needy tissue.

[0173] [16T| Examples of active agents which may be incorporated in the non-pharmaceatical solutions are not particularly limited. Generally, any active agent previously used or suggested as useful for delivery by any means, including transdermaily, whether by patch or ointment or other topical formulation, may be used. Some areas where it is envisioned that the transdermal compositions will have particular benefits include pain relief (for safer dose of a prescription or n on-prescription analgesic locally to the site of pain); antibiotic delivery, e.g., Ciprofloxacin (permitting higher dosages at the locus of the infection to above safe systemic levels); corticosteroids (for treating inflammatory indications with delivery bypassing the liver and minimizing systemic side effects); hormone replacement therapy (e.g., to deliver tri-estrogens to the non- carcinogenic androgen pathway along with the inclusion of mechanisms to offset the negative cosmetic side effects of this pathway); isofiavinoid cancer therapies (allowing high concentrations); hypertoxic chemotherapies (io raise local concentrations with reduced impact systemically).

[0168] The embodiments also offer benefits in connection with active agents of high molecular weights for which prior known topical transdennal delivery systems were not effective or applicable. The transdermal pharmaceutical compositions described herein were found effective for active agents having molecular weights in excess of about 325 Daltons, especially higher than about 350 D, more especially higher than about 375 D and most especially higher than about 400 D, for example, 500 D and higher. Extremely high molecular weight substances such as calcitonin (MW-4500) human insulin (MW--6,000) and other hormones, polypeptides, and protein, may be solubilized in the non-pharmaceutical solutions described herein.

[0174]

[0169] The transdennal pharmaceutical compositions as described herein can be formulated to delivery, per unit dosage, usually about 1 cc, at least about 0.25 mg, especially at least about 0.5 mg, especially, up to about 1 mg or higher of active ingredient, including such high molecular weight substances as described above.

[0175]

[0170] The transdennal pharmaceutical compositions were developed in series and tested on in vitro constructs, a single animal, then several animals in controlled conditions measuring pharmacokinetics and subsequently, pharmacodynamics of several formulations. Safety of the compositions was tested in a standard accepted model for inducing irritation from topically applied products. The compositions were subsequently tested in a single patient, several patients and eventually many patients.

[0176]

[0171] The effective dosage of the active agents was observed to be substantially less than the effective dosage when administered orally or intravenously or intramuscularly. However, higher, or lower dosages may be required or advantageous depending on the condition or disease to be treated, whether intended for local or systemic administration, etc.

[0177]

[0172] EXAMPLE 1: TRANSDERMAL TESTOSTERONE FORMULATION

[0178]

[0173] Three lots of transdermal testosterone formulations were prepared by adding 50 mg of testosterone to 1 ml of NPS-A.

[0179]

[0174] One demo lot was placed on stability and monitored at the intended long-term storage condition (25 °C) and at the accelerated storage condition (40 °C). A limited photo stability study was conducted for 7 days.

[0180]

[0175] One development lot was placed on stability and monitored at the intended long-term storage condition (25 °C / 60%RH) and at the accelerated storage condition (40 °C / 75%RH).

[0181]

[0176] A third development lot was placed on stability and monitored at the intended longterm storage condition (25 °C / 60%RH) and at the accelerated storage condition (40 °C / 75%RH).

[0182]

[0177] The transdermal testosterone formulations from these 3 studies were stored in a single packaging configuration consisting of a 30 ml PE bottle with integral pump spray snap cap. Each 30 ml PE bottle contained 30 ml @ 50 mg / ml dosage.

[0183]

[0178] Stability data through a 6-month time point were analyzed.

[0184]

[0179] The drug product exhibited no significant decrease in purity. No adventitious impurities were detected. For all storage conditions, appearance and assay remained unchanged.

[0185]

[0180] Preclinical experiments showed an increase in serum concentration levels of testosterone between the zero-time point and 30 minutes. # of the 5 animals tested continued to show increased serum levels up to the 1-hour timepoint.

[0186]

[0181] Clinical Experiments

[0187]

[0182] Study treatment and design

[0188]

[0183] A single dose, open label, non-crossover study involving 5 healthy volunteers was conducted to study the transdermal testosterone formulation at five escalating doses of 10, 20, 30, 40, and 50 nigs dosed by means of 1-5 metered sprays. The subjects were randomized to one of the five doses stated above by computer-generated randomization.

[0189]

[0184] Five healthy male subjects successfully participated in this study according to the protocol. Of the 5 subjects enrolled In the study, three were Caucasian, and another two from other ethnics. The mean (SD) age of the subjects was 29.0 (6.2) years old, and the mean (SD) BMI was 24.1 (3.2) kg / m2. The study was approved by the East London and The City Health Authority Research Ethics Committee. All the subjects gave written informed consent before participated in the study. All the subjects were admitted to this study having fulfilled all entry criteria as outline in inclusion / exclusion criteria and the physical examination, medical history, and the clinical laboratory test.

[0190]

[0185] All 5 healthy subjects successfully completed the study according to the protocol. The concentrations of testosterone in serum were obtained from the calibration curve from the individual absorbance value.

[0191]

[0186] FIG. 2 show's the plot of mean serum concentrations of testosterone (ng / mL) versus time (h) from -0.5 to 24 hours post dose for five subjects for all the treatments given. The individual serum concentration plot shows the testosterone concentrations fluctuated in most of the subjects treated by the transdermal testosterone formulation.

[0192]

[0187] No serious or unexpected adverse events were reported or observed during the study day. The applied dosages and protocol requirements were well tolerated by all subjects.

[0193]

[0188] In conclusion, the transdermal testosterone formulation prepared according to the method described herein delivered testosterone systemically in humans and the concentrations of hormone in the first 12 hours following administration of the transdermal testosterone formulation were bioequivalent to an existing topical deliverygel.

[0194]

[0189] Further studies at a set comparable dose were engaged. A single dose, 3 crossover, 3 treatment 6 sequences comparative study was organized with one arm dosed with placebo, another arm dosed with AndroGel® 50 mg and a 50 dose of transdermal testosterone formulation prepared as described herein. Subjects were cannulized on test days and 17 4-mL blood samples taken and tested via ELISA. All subjects consistently showed higher response to the transdermal testosterone formulation prepared as described herein. FIG. 2 shows the net change from baseline.

[0195]

[0190] EXAMPLE 2: TRANSDERMAL LIDOCAINE FORMULATION

[0196]

[0191] This placebo controlled, double blind trial compared anaesthetic properties of two transdermal lidocaine formulations (prepared using NPS-A and NPS-B) with placebo. The active and placebo treatments were applied to the dorsum of the hands, bilaterally and simultaneously for 5 min on 100 healthy volunteers. Following cannulation, pain perception was measured using the verbal rating score (VRS) and visual analogue score (VAS). Lidocaine plasma levels were assessed at 0 and 2 h and the results are shown in FIG. 3A and FIG. 3B. The VRS and VAS results show that the transdermal formulation prepared using NPS-B significantly decreased pain score compared to placebo (p < 0.02). Blood lidocaine at 2 h post application was also higher for transdermal formulation prepared using NPS-B than for transdermal formulation prepared using NPS-A, suggesting that a 5 min application of transdermal formulation prepared using NPS-B was effective in delivering local anaesthetic and accelerating the onset of skin anesthesia prior to venous cannulation in adults.

[0197]

[0192] Study design and subjects

[0198]

[0193] This study was prospective, double blinded and placebo controlled, with a 1-week washout period, involving 100 healthy volunteers. Based on our previous study, 100 subjects recruited in this study would have an 80% power to detect a difference of 25% in the primary outcome measures at p < 0.05. Prior to enrolment, each subject was screened for standard blood biochemistry', drugs of abuse, and answered a questionnaire for demographics. Skin was assessed for erythema, edema, itching, broken skin, or other signs of pathology. Body mass, height, body mass index, systolic and diastolic blood pressure, and heart rate were recorded. Subjects outside the age range of 20- 40 years, with signs of skin pathology, hematology ‘out of standard limits’ or with positive drug abuse tests were excluded. Subjects were not permitted any form of analgesia within 1 week of the trial. The study was approved by the East London and City Authority Research Ethics Committee and received a Doctors and Dentists Exemption Certificate (DDX) from the MHRA (Medicines and Healthcare Products Regulatory Agency, LTK). Subjects were admitted to the investigation having been provided with a verbal and written explanation and signed a consent form.

[0199]

[0194] Admission and procedure

[0200]

[0195] Subjects were admitted to the Study Unit having fulfilled all the inclusion criteria. Blood pressure and heart rate were measured after subjects rested for 10 min. A sample was taken from an antecubital vein to establish a baseline measurement of plasma lidocaine concentration. All subjects were dosed according to the randomization schedule. In the Phase 1 study, the transdermal formulation prepared using NPS-B was applied to the dorsal surface of a randomly selected hand and NPS-B (placebo) was simultaneously applied on the contralateral hand. Administrations of the formulations were achieved by metered pump spray of 1 ml to the area of 4 cm2. Five minutes after application, the hands were routinely cleaned using alcohol wipes prior to venepuncture.

[0201]

[0196] A vein on each hand within the treatment area was then cannulated using a 20G butterfly needle. The success of cannulation was confirmed by the ability to withdraw 1-2 ml of blood. Two methods of pain assessment, Verbal Rating Score (VRS) and Verbal Analogue Score (VAS), were used to assess the pain of the procedure. Following successful bilateral cannulation, a VRS pain classification was used for each hand. The volunteers were asked the following question: 'How strong was the pain of the procedure?' and provided with a choice of five categories:

[0202] ® no pain

[0203] ® minimal sensation

[0204] ® mild pain

[0205] ® moderate n A ain

[0206] ® severe pain

[0207] The volunteer selected one answer for each hand by circling the number.

[0208]

[0197] In the VAS assessment, a 100 mm horizontal line with endpoints that are anchored by descriptors 'no pain’ and 'severe pain' was used. For each hand, the volunteer was asked 'What did the procedure feel like?' and then requested to make a vertical line on the horizontal line which represented the intensity or unpleasantness of their pain by the procedure. Values were measured in millimeters from the left-hand edge of the horizontal line.

[0209]

[0198] Two hours after the treatment application, another blood sample was taken to assess the systemic level of lidocaine. The plasma was transferred to cryo-vials and stored at 20 °C until analysis. All the procedures, including treatment applications, bilateral cannulation and data recording were each performed blindly by separate investigators. One week later, the volunteers repeated the above procedure with the transdermal formulation prepared using NPS-B.

[0210]

[0199] Analytical method

[0211]

[0200] Plasma concentration of lidocaine was analysed by using the liquid chromatographymass spectrometry (LC-MS / MS) method. Sample separation and detection was achieved on a Supel cosil LC-Si 10 cm column and PE SCIEX API 2000 mass spectrometer. The method was validated to demonstrate adequate sensitivity, specificity, accuracy and precision. The lower limit of quantification (LOQ) was 0.5 ng.ml and bupivacaine was used as an internal standard.

[0201] Statistical analysis

[0212]

[0202] All the data were analyzed using GraphPad Prism 4.0

[0213] (h ttp : Z / www . graph pad . com / pri sm / Pri sm . htm )an dMi ni tab 14 stati sti cal software

[0214] (http: / / www.minitab.com / ). The active treatments were compared to the placebo control using Wilcoxon’s Signed Rank test. The lidocaine concentrations at 2 h for transdermal formulations prepared using NPS-A and NPS-B were compared using Student’s paired t-test.

[0215]

[0203] Formulation Effectiveness

[0216]

[0204] One hundred healthy volunteers were successfully recruited, and the demographics data are presented in Table 1. Of the 100 subjects, 65 were Caucasian, 22 Asian, four African / Caribbean, and nine from other ethnic groups. The cannulation procedures were successfully completed at the first attempt for ah 100 volunteers. All the subjects tolerated the procedure well and complied with the study protocol.

[0217]

[0205] The median for VRS and VAS scores were different between active and placebo for both transdermal formulations prepared using NPS-A and NPS-B.

[0218]

[0206] The result from this exploratory' study showed that immediately following application of a transdermal lidocaine formulations prepared as described herein, there is a fast onset of effective anaesthesia for the venous cannulation in adults.

[0219]

[0207] In conclusion, topical application of the transdermal lidocaine formulations prepared as described herein was effective in providing skin anaesthesia for dorsal hand vein cannulation in healthy subjects, after 5 min of application. These findings also indicate the rapid transdermal drug delivery7by the transdermal lidocaine formulations prepared as described herein

[0220]

[0208] EXAMPLE 3: TRANSDERMAL MORPHINE FORMULATION

[0221]

[0209] Morphine Sulfate is a highly lipophilic compound that binds in the skin and can cause skin irritation adjacent to the sight w'here intravenous dosing occurs. Morphine is typically dosed orally before IV to manage chronic or terminal condition pain and because of its effects on the cholinergic pathway can cause modified cognition and slowing or stoppage of the peristaltic activity of the gut leading to constipation and even impacted bowel syndrome.

[0222]

[0210] A transdermal morphine sulfate formulation prepared using NPS-A was administered to rats FIG. 4 and FIG. 5 show equivalence of the transdermal system in delivering the compound as well as an enhanced result with the active glucuronide.

[0223]

[0211] EXAMPLE 4: TRANSDERMAL ACYCLOVIR FORMULATION

[0224]

[0212] Acyclovir is an anti-viral targeting the varicella Zoster virus which causes Chicken Pox and Shingles in adults. FIG. 6 shows the response to dosing of transdermal acyclovir formulation prepared using NPS-A in a racine model. Seram concentrations were at levels considered to be therapeutic.

[0225]

[0213] EXAMPLE 5: TRANSDERMAL HYDROXYZINE FORMULATION

[0226]

[0214] Hydroxyzine and its metabolite, Citirizine, are anti-histaminic in their effect and also used as a somnolent. FIG. 7 show's Racine response to a 25 rag transdermal dose in a racine model.

[0227]

[0215] EXAMPLE 6: TRANSDERMAL DIAZEPAM FORMULATION

[0228]

[0216] Diazepam is an anxiolytic benzodiazepine. FIG. 8 shows clinical data comparing equivalent doses of Diazepine delivered trans rectally (“Diastat”) and transdermally by means of analysis of the active metabolite, dimethyl diazepam.

[0229]

[0217] EXAMPLE 7: TRANSDERMAL IBUPROFEN FORMULATION

[0230]

[0218] Ibuprofen i s a Non-Steroidal Anti-inflammatory Drug (“NS AID”) used in the treatment of Musculo-skeletal pain arising from inflammation and arthritis. FIG. 9 shows dose response curves to 3 different formulation variations designed to modify the absorption curve from rapidly absorbed, higher blood level to a longer area under curve and presumable longer efficacy. FIG. 10 and FIG. 11 shows two separate measures of reduction in inflammation, (FIG. 10) the amount of Fluid exudate measured and (FIG. 11) Inflammatory / Cell migration. In both cases the transdermal formulation prepared according to a method described herein performed favorable versus the control standard oral dose. This study was conducted under current GLP protocol with each blood sample being analyzed by FIPLC 3 separate time per sample and all results fully audited.

[0231]

[0219] EXAMPLE 8: TRANSDERMAL PROGESTERONE FORMULATION STABILITY

[0232]

[0220] The human pro-gestation hormone, Progesterone, first identified by Nobel Laureate

[0233] Max Born is generally known to be insoluble and unstable in ethanol solutions. FIG. 12 and FIG, 13 show results of a well -controlled stability study with samples stored in appropriate spray-bottle packages at 25 °C and 40 °C over 90 days. There is no detectable change at either temperature with the 40 °C study projecting 3 years shelf life. FIG.14 and FIG. 15 show analysis of a Progesterone sample packaged for commercial distribution 7 years prior to a newly manufactured batch. While there is some degradation of excipients at 7 years show at 2.5 minutes, the principal peak for the Progesterone is nearly identical with equivalent area height and no visible degradation products FIG. 16 also show's results of a 5-day UV exposure test showing no degradation.

[0234]

[0221] EXAMPLE 9: TRANSDERMAL DICLOFENAC SODIUM FORMULATION STABILITY

[0235]

[0222] Diclofenac Sodium is an NSAID that is used to treat musculoskeletal pain. While highly effective when dosed orally at 80 to 100 mgs b.i.d., the drug cannot be tolerated at this dose for more than 14 days. A lower concentration at a fifth of the oral dose has been marketed successfully as an Over-The-Counter Remedy. FIG. 17 and FIG. 18 show assay analysis of samples of transdermal diclofenac sodium prepared according to the method described herein stored at 25 °C and 40 °C for 90 days. No change is noted at 25 degrees and a slight concentration with no degradation shown at 40 degrees.

[0236]

[0223] EXAMPLE 10: TRANSDERMAL ACETAMINOPHEN FORMULATION

[0237]

[0224] Acetaminophen or Paracetamol is an analgesic, body temperature modulator, best known by its trade name Tylenol®. FIG. 19A, FIG, 19B, FIG. 20A, FIG. 20B, FIG, 21 A, and FIG. 21B show the results of a study in a racine model testing the transdermal acetaminophen formulation prepared according to the method described herein against oral and injected controls in blood and brain. It is notable that levels achieved w'ere at one half the oral and injected doses. Also, while delayed 1 hour, brain levels were significantly higher than the other dose forms.

[0238]

[0225] EXAMPLE 11: TRANSDERMAL MELANOTAN FORMULATION

[0239]

[0226] Alpha Melanocyte- Stimulating Hormone is a Melanocortin peptide of about 1200 Daltons with demonstrated efficacy at up-regulating melanin levels in skin and up- regulating libido FIG 22A and FIG. 22B show data from a study, using the transdermal melanotan formulation prepared according to the method described herein, in a racine model showing favorable pharmacokinetic response in 4 animals at increasing doses.

[0240]

[0227] EXAMPLE 14: TRANSDERMAL CANNABIDIOL FORMULATION

[0241]

[0228] Three different doses, 5 mg, 15 mg, and 30 mg of transdermal cannabidiol (CBD) formulations were prepared according to the method described herein and was tested on rats. FIG. 23 A, FIG. 23B, and FIG. 23C show7the individual pharmacokinetic curves over the 24-hour period from dose to euthanasia. The results demonstrate that the transdermal CBD formulation prepared according to the method described herein delivered the active ingredient into the blood compartment of the animals in a dose dependent fashion.

[0242]

[0229] EXAMPLE 15: TRANSDERMAL INSULIN FORMULATION

[0243]

[0230] In another Pharmacokinetic and pharmacodynamic study, the time course dose response effects of the application of transdermal human insulin formulations prepared according to a method described herein on fasted blood glucose, and the corresponding levels of human insulin in the plasma of control male was investigated Wistar rats, and STZ induced Type 1 diabetic rats. A low-dose range was used for non-diabetic control animals and an appropriate larger dose for diabetic animals was employed.

[0244]

[0231] It was observed that the transdermal application of low7doses of human insulin did not induce a decrease of fasted blood glucose in control animals. As is normally the case, normal animals compensated for the increase in serum insulin by decrease in blood glucose by the release of hepatic glucose. In the normoglycemic condition in healthy animals and humans, insulin treatment induces the release of glucagon and epinephrine and consequently the release of glucose by the liver. However, in diabetic rats, treatment with transdermal human insulin formulation resulted in a significant drop in fasted blood glucose levels, particularly in animals treated with 4 lU / kg / ml.

[0245]

[0232] In order to confirm the presence of active potent Human insulin in both model s, diabetic and non-diabetic animals, Serum samples were analyzed by ELISA and Human insulin was detected as early as 5 minutes after the transdermal application with a maximum observed concentration at 30 to 60 minutes later and then was observed to decrease afterwards during the study time course.

[0246]

[0233] FIG. 24A shows mean of the human insulin levels measured in the plasma of non- diabetic rats during the time course of the kinetic study after treatment with placebo (1 ml / kg), or insulin solutions (0.4 lU / kg and 0.8 lU / Kg).

[0247]

[0234] FIG. 24B shows mean of the human insulin levels measured in the plasma of diabetic rats during the time course of the kinetic study after treatment with placebo (1 ml / kg), or insulin solutions (0.4 lU / kg and 0.8 lU / Kg).

[0248]

[0235] The data confirms that the non-pharmaceutical solution described herein acts as a vector or carrier permitting human insulin to cross the animals’ skin barrier and to stimulate physiological activity in a dose dependent manner, reducing blood glucose levels, in an animal model of type 1 diabetes.

[0249]

[0236] The foregoing description of the specific embodiments wall so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art wall recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

Claims

We claim:

1. A non-pharmaceutical solution or Coprocessed Excipient comprising one or more ingredients selected from the group consisting of at least two or more solvents, at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof.

2. The non-pharmaceutical coprocessed excipient according to claim 1, wherein the at least two or more solvents are selected from the group consisting of ethanol, ethylene glycol, propylene glycol, propylene carbonate, butylene glycol, acetone, glycerol, water, and a mixture thereof3. The non-pharmaceutical coprocessed excipient according to claim 1, wherein the at least two or more solvents are present in an amount ranging from about 85% (wt / wt) to about 99% (wt / wt) of total weight of the non-pharmaceutical solution.

4. The non-pharmaceutical coprocessed excipient solution according to claim 1, wherein the total amount of one or more ingredients selected from the group consisting of at least one solvent modifier, at least one solute modifier, at least one source of cellular activation energy, at least one skin stabilizer, and a mixture thereof is in an amount ranging from about 1% (wt / wt) to about 15% (wt / wt) of total weight of the non-pharmaceutical solution.

5. A transdermal pharmaceutical composition comprising the non-pharmaceutical coprocessed excipient according to claim 1 and a therapeutically effective amount of an active agent.

6. The transdermal pharmaceutical composition according to claim 3, wherein the active agent is selected from the group consisting of an antibiotic agent, antihistamine agent, decongestant, anti-inflammatory agent, antiparasitic agent, antiviral agent, an anesthetic agent, antifungal agent, amoebicidal agent, trichomonocidal agent, analgesic agent, anti- arthritic agent, anti-asthmatic agent, anticoagulant agent, anticonvulsant agent, antiAlzheimer's disease agent, antidepressant agent, antidiabetic agent, antineoplastic agent, anti-psychotic agent, neuroleptic agent, antihypertensive agent, hypnotic agent, sedative agent, anxiolytic energizer agent, anti-Parkinson agent, muscle relaxant agent, antimalarial agent, hormonal agent, contraceptive agent, sympathomimetic agent,psychedelic agent, Incretin-memetic agent, hypoglycemic agent, antilipemic agent, ophthalmic agent, electrolytic agent, diagnostic agent, prokinetic agent, gastric acid secretion inhibitor agent, anti-ulcerant agent, anti-flatulent agent, anti-incontinence agent, and cardiovascular agent, a cannabinoid, a terpene, and a mixture thereof.

7. The transdermal pharmaceutical composition according to claim 3, wherein the composition is formulated in a liquid dose form.

8. The transdermal pharmaceutical composition according to claim 3, wherein the composition is a sprayable or droplet-applied pharmaceutical composition.

9. A method for preparing the transdermal pharmaceutical composition according to claim3, the method comprising adding a therapeutically effective amount of the active agent to the non-pharmaceutical solution to obtain the transdermal pharmaceutical composition.

10. A method of treating a disease or a condition in a subject, the method comprising applying the transdermal pharmaceutical composition according to claim 3 to a subject in need thereof.

11. The method according to claim 8, wherein the method comprises applying the transdermal pharmaceutical composition within about 5 minutes to about 5 hours of preparation of the composition.

12. The method according to claim 8, wherein a pharmaceutical composition is identified and designed by an artificial intelligence system for a patient intervention.

13. A kit comprising a non-pharmaceutical coprocessed excipient solution according to claim 1.

14. A kit comprising a first container and a second container, wherein the first container comprises a non-pharmaceutical coprocessed excipient solution according to claim 1, and the second container comprises an active agent selected from a pharmaceutical agent and a biological agent.

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