WO2013048453A1

WO2013048453A1 - Compounded transdermal pain management

Info

Publication number: WO2013048453A1
Application number: PCT/US2011/054324
Authority: WO
Inventors: Jay Richard II RAY
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-09-30
Filing date: 2011-09-30
Publication date: 2013-04-04
Anticipated expiration: 2014-03-30

Abstract

The present embodiments relate to topically delivered medication for treatment of pain, inflammation, muscle fatigue, spasming, and/or other ailments. A transdermal cream may provide the effective topical administration of multiple medications simultaneously. The transdermal cream may include a salt load of approximately 30% or greater. The transdermal cream may include a unique base composition such that the transdermal cream may be able to remain stable and avoid degradation for six months or more and capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight of the transdermal cream and/or base composition. The transdermal cream may be able to withstand extreme temperatures and avoid separation of the active ingredients from the base. In oneembodiment, the trans dermal cream may comprise ketamine HCL, gabapentin, clonidine BCL and baclofen. The transdermal cream may deliver an enhanced topical delivery flux of ketamine via a single trans dermal application.

Description

COMPOUNDED TRANSDERMAL PAIN MANAGEMENT

FIELD OF THE INVENTION

[0001] The present application relates to pain management. In particular, the present application relates to compounded transdermal pain management.

BACKGROUND

[0002] Transdermal creams are employed to deliver medication to the skin of a patient. However, conventional transdermal creams may include various drawbacks. For instance, conventional transdermal creams may not support and/or include high concentrations of an active ingredient. Conventional transdermal creams may also exhibit low rates and/or total amounts of absorption for certain active ingredients into the skin, and/or separation of an active ingredient from a base when exposed to environmental extremes.

SUMMARY

[0003] The present embodiments may relate to topically delivered compounded medications for treatment of pain, inflammation, muscle fatigue, spasming, and/or other ailments. In one aspect, a transdermal cream for the effective administration of multiple medications simultaneously for one or more ailments may be provided. The transdermal cream may include a high concentration of one or more active ingredients. The transdermal cream may include a unique base composition and satisfactorily carry a salt load of approximately 30% or greater. The transdermal cream may be able to remain stable and/or avoid degradation for six months or longer, and be capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight of the transdermal cream. The transdermal cream may be able to withstand extreme temperatures and avoid separation of the active ingredients from the base during storage. In one embodiment, the transdermal cream may comprise a base composition and multiple active ingredients, such as ketamine HCL, gabapentin, clonidine HCL, and/or baclofen.

[0004] In one aspect, a pharmaceutical composition for a transdermal cream may be provided. The pharmaceutical composition may permit the topical administration of multiple medications simultaneously to address one or more ailments. The

pharmaceutical composition may (1) exhibit resiliency in the presence of at least a 30% salt load, and (2) be able to remain stable and/or avoid degradation for six months or more. The pharmaceutical composition may be capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight.

[0005] In another aspect, a transdermal cream may be provided. The transdermal cream may provide for the topical administration of multiple medications simultaneously. The transdermal cream may comprise a salt load of approximately 30% or greater. The transdermal cream may be able to remain stable and/or avoid degradation for six months or more. The transdermal cream may be capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight of the transdermal cream.

[0006] In another aspect, a transdermal cream may be provided. The transdermal cream may provide for the topical administration of multiple medications simultaneously, including ketamine, via a base composition to address various ailments. The transdermal cream may provide for greater than 50% permeation of ketamine beyond the stratum corneum after a single dose is administered topically via the base composition. The transdermal cream may facilitate a maximum mean flux of greater than approximately 3.5 μg/cm²/hr of percutaneous absorption of ketamine through the human skin within approximately 4 to 10 hours after commencing a single dose via a topical administration using the transdermal cream. The transdermal cream may comprise the base composition and multiple active ingredients, such as ketamine HCL, gabapentin, clonidine HCL, and/or baclofen.

[0007] In another aspect, a compounded transdermal pain management program may be provided. The compounded transdermal pain management program may include providing a base composition, such as the unique base composition disclosed herein. The compounded transdermal pain management program may include providing, within the base composition, several medications that address different ailments. The medications may be mixed with the base composition for topical administration to a patient. The medications may include one or more NSAIDs, such as propionic or acetic acids; one or more muscle relaxants, such as baclofen or cyclobenzaprine; one or more opiad agonists, such as C2 or C3 opiate agonists, or tramadol; one or more local anesthetics, such as lidocaine, prilocaine, or benzocaine; one or more NMDA (N-methyl-D-aspartate) receptor antogonists, such as ketamine; and/or one or more nerve depressants, such as gabapentin, topirimate, or lamotrigine.

[0008] The above-described and other features and advantages of the present disclosure will be appreciated and understood by those skilled in the art from the following detailed description, drawings, and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] There is shown in the drawings embodiments which are presently preferred, it being understood, however, that the invention can be embodied in other forms without departing from the spirit or essential attributes thereof.

[00010] Figure 1 depicts an exemplary method of employing a compounded transdermal pain management program;

[0001 1] Figure 2 depicts ketamine flux versus time exhibited during an exemplary evaluation of the exemplary transdermal cream embodiments discussed herein;

[00012] Figure 3 depicts gabapentin flux versus time exhibited during the exemplary evaluation;

[00013] Figure 4 depicts baclofen flux versus time exhibited during the exemplary evaluation;

[00014] Figure 5 depicts clonidine flux versus time exhibited during the exemplary evaluation; and

[00015] Figure 6 depicts the total percentage permeation of the applied dose beyond the stratum corneum after a single dose of an exemplary transdermal cream is topically applied.

DETAILED DESCRIPTION OF THE INVENTION

[00016] The present embodiments may relate to topically delivered compounded medications, such as for the treatment of pain, inflammation, muscle fatigue, spasming, and/or other ailments. In one aspect, the present embodiments relate to a transdermal cream for the topical administration of multiple medications for different ailments simultaneously. The transdermal cream may include a salt load of approximately 30% of the transdermal cream or greater. The transdermal cream may include a unique base composition that allows the transdermal cream to remain stable and avoid degradation for six months or longer. The transdermal cream may be capable of providing enhanced effective delivery of active ingredient concentrations exceeding approximately 20% of the total formulation weight of the transdermal cream and/or base composition. The transdermal cream may be able to withstand extreme temperatures and avoid separation of the active ingredients from the base composition. For instance, the transdermal cream may be able to withstand extreme temperatures exceeding approximately 72°F and still remain stable and avoid separation of a base and the active ingredients. In one embodiment, the transdermal cream may comprise ketamine HCL, gabapentin, clonidine HCL, baclofen, and/or other active ingredients.

[00017] In one aspect, a pharmaceutical composition for a transdermal cream may be provided. The pharmaceutical composition may permit the topical administration of multiple medications simultaneously to address one or more ailments. The

pharmaceutical composition may (1) exhibit resiliency in the presence of a salt load of approximately 30% of the pharmaceutical composition or greater, and (2) be able to remain stable and/or avoid degradation for six months or more. The pharmaceutical composition may be capable of effective delivery of active ingredient concentrations exceeding approximately 20% of the total formulation weight. The pharmaceutical composition may provide for approximately 50% or greater permeation of an active ingredient beyond the stratum corneum.

[00018] In another aspect, a transdermal cream may be provided. The transdermal cream may provide for the topical administration of multiple medications simultaneously, including ketamine, to address one or more ailments. The transdermal cream may provide for greater than approximately 50% permeation of ketamine beyond the stratum corneum after a single dose is administered topically via a base composition. The transdermal cream may facilitate a maximum mean flux of greater than approximately 3.5 μg/cm²/hr of percutaneous absorption of ketamine through the human skin within approximately 4 to 10 hours after commencing a single dose via a topical administration using the transdermal cream. The transdermal cream may comprise ketamine HCL, gabapentin, clonidine HCL, baclofen, and/or other active ingredients.

[00019] A compounded transdermal pain management program may be provided. The compounded transdermal pain management program may include providing a base composition, such as the unique base composition disclosed herein. The compounded transdermal pain management program may include providing, within the base composition, several medications that address different ailments. The medications may be mixed with the base composition for topical administration to a patient. The medications may include one or more NSAIDs, such as propionic or acetic acids; one or more muscle relaxants, such as baclofen or cyclobenzaprine; one or more opiad agonists, such as C2 or C3 opiate agonists, or tramadol; one or more local anesthetics, such as lidocaine, prilocaine, or benzocaine; one or more nerve depressants, such as gabapentin, topirimate, or lamotrigine; and/or one or more MDA (N-methyl-D-aspartate) receptor antagonists, such as ketamine.

I. Compounded Transdermal Pain Management

[00020] The present embodiments may relate to a compounded transdermal pain management program. A compounded transdermal pain management program may address a several ailments simultaneously. The program may provide pain treatments that (1) may not include oral therapies; (2) may have minimal side effects; and (3) may avoid drug-drug interactions from concomitant therapies. The latter may become a greater concern with an aging population that may have poorer blood circulation and be using an increased number of oral therapies resulting in ever increasing drug-drug interactions - both of which may cause pain management therapies to be difficult to be prescribed. The program may provide patients with the highest quality-of-life possible with the lowest side-effect profile possible.

[00021] Figure 1 depicts an exemplary method of employing a compounded transdermal pain management program 100. The compounded transdermal pain management program 100 may include providing a base composition 102; and within the base composition, providing: one or more NSAIDs 104; one or more muscle relaxants 106; one or more opiad agonists 108; one or more local anesthetics 110; one or more nerve depressants 112; and/or one or more NMDA receptor antagonists 1 14. The compounded transdermal pain management program may include additional, fewer, or alternate steps and/or ingredients.

[00022] The compounded transdermal pain management program 100 may include providing a base composition 102. The base composition may include the base ingredients discussed herein below, including the base ingredients identified in Table I below. The base composition may include additional, fewer, or alternate ingredients.

[00023] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more NSAIDs (non-steroidal anti-inflammatory drugs/medications) 104. NSAIDs may block the synthesis of prostaglandins by inhibiting cyclooxygenase-2 (COX-2) and/or cyclooxygenase-1 (COX-1). All classes of NSAIDs may block both COX-1 and COX-2 except for the last class which is specifically delineated out as COX-2 inhibitors. Inhibition of COX-2 may produce the positive effects of NSAIDs, while blocking COX- 1 may cause the side effects of stomach upset, increased stomach acid, and the like. The compounded transdermal pain management program may include COX-1 and/or COX-2 inhibitors.

[00024] Blocking the synthesis of prostaglandins (COX-2 specifically) may decrease inflammation, swelling, and pain associated with the production of the same. When one class of NSAIDs fails to produce the desired response, it may appropriate to shift a patient to a different class of non-steroidal anti-inflammatory medications. A patient who is prescribed a medication in one particular class that fails to achieve the desired response may also fail therapy on a medication that is in that same class. Switching classes of NSAIDs may be appropriate when a failure in one subset is seen.

[00025] NSAIDs that may be used with the compounded transdermal pain management program, as well as the transdermal creams and/or base composition disclosed herein, may include: (1) salicylic acid derivatives - aspirin, diflunisal, salsalate, and trilisate; (2) propionic acids - flurbiprofen, ibuprofen, ketoprofen, naproxen, and oxaprozin; (3) acetic acids - diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac, and tolmetin; (4) fenamates - meclofenamate; (5) oxicams - meloxicam and piroxicam; and (6) COX-2 inhibitors - celecoxib, rofecoxib, and valdecoxib.

[00026] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more muscle relaxants 106. Muscle relaxant medications may produce muscle relaxation by blocking interneuronal activity in the descending reticular formation and/or spinal cord. Each different medication may have it's own set of nuances with the most dominant ones (at least in reference to oral therapies) being carisoprodol and cyclobenzaprine. Available muscle relaxants that the compounded transdermal pain management program, as well as the transdermal creams and base composition disclosed herein, may employ include, but are not necessarily limited to, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, quinine sulfate, and/or tizanidine.

[00027] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more opiate agonists 108. Opiate agonists include medications that may directly bind to opiate receptors in the body whose principal therapeutic action is analgesia. Pharmacological effects of opioid agonists may include anxiolysis, euphoria, feelings of relaxation, respiratory depression, constipation, miosis, and cough suppression, as well as analgesia. C2 opiate agonists may include oxycodone, morphine, methadone, hydromorphone, and fentanyl. C3 opiate agonists may include hydrocodone, codeine, propoxyphene, butalbital, and pentazocine. Tramadol, although not a narcotic medication, may act on the opiate receptor site to cause pain relief with the same identified mechanism of action of C2 and C3 opiate agonists. However, the levels of effectiveness, as well as physical dependency, may be more depressed with tramadol than with the others. The compounded transdermal pain management program, as well as the transdermal creams and base composition disclosed herein, may employ C2 and C3 opiate agonists, such as the ones named above, and/or tramadol.

[00028] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more local anesthetics 1 10. Local anesthetics may include medications that are applied to intact skin and provide dermal analgesia by the release of the medication(s) from the cream base (or from a patch) into the epidermal and dermal layers of the skin, and by the accumulation of the drug in the vicinity of the dermal pain receptors and nerve endings. Local anesthetics may stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. Primary examples of local anesthetics that the compounded transdermal pain management program, as well as the transdermal creams and base composition disclosed herein, may employ include, but are not limited to, lidocaine, prilocaine, benzocaine, and/or tetracaine.

[00029] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more nerve depressants 112. Nerve depressants include medications that may have a mechanism of action largely unknown. In animal models of analgesia, nerve depressants may prevent allodynia (pain related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Nerve depressants may also decrease pain-related responses after peripheral inflammation.

[00030] The compounded transdermal pain management program may provide for therapy with regard to a host of different localized nerve problems. The mechanism by which gabapentin works orally may also work with some topical therapies, such as the base composition disclosed herein. Nerve depressants that the compounded transdermal pain management program, as well as the trandermal creams and base composition disclosed herien, may employ include gabapentin, topirimate, lamotrigine, and/or others.

[00031] The compounded transdermal pain management program 100 may provide, such as within the base composition, one or more NMDA receptor antagonist 1 14, such as ketamine. Ketamine is a drug used in human and veterinary medicine. Pharmacologically, ketamine is classified as a NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine may bind to opioid μ receptors and sigma receptors. Like other drugs of this class, such as tiletamine and phencyclidine (PCP), ketamine may induce a state referred to as "dissociative anesthesia." Because ketamine is a phencyclidine analogue, it may have psychological adverse effects found with that hallucinogen. Although ketamine is frequently used as a veterinary anesthetic, it is used more frequently in children than in adults. The

psychotomimetic effects have prompted the DEA to classify ketamine as a Schedule III

Controlled Substance. However, it is believed that ketamine may demonstrate no or only mild psychotomimetic effects when dosed at sub-anesthetic doses.

[00032] Neuropathic pain may be resistant to opioids, so the compounded transdermal pain management program may also use other medication classes, such as tricyclic antidepressants, anticonvulsants, non-steroidal anti-inflammatories, and/or local anesthetics. Still, ketamine may be useful because of its NMDA receptor activity (antagonism). Activity on NMDA receptor may be the same as that produced by dextromethorphan. The current application of ketamine in the base composition/topical gel disclosed herein stems from the theoiy that ketamine has peripheral action at both opioid and Na+ and K+ channels.

[00033] Generally, ketamine should only be recommended for refractory pain, i.e. , pain that goes beyond the scope and bounds of traditional treatment therapies. FDA approved usages should also be kept in mind. The FDA approved adult usage is dissociative sedation with dosing of l-2mg/kg IV over 1-2 minutes or 4-5mg/kg IM, and the FDA approved pediatric usage is dissociative sedation with dosing of l-2mg/kg IV over 1-2 minutes or 4-5mg/kg IM, The standard dosing of ketamine may be around 400 mg, and not more often than 5 times daily, based upon a patient that weights about 176 pounds.

II. Exemplary Base Composition

[00034] The present transdermal cream embodiments include a unique base composition that is an extension of the popular and trusted base Lipoderm®. The base composition may provide superior emulsion stability with high active ingredient concentrations. The base composition was engineered to improve and enhance the active ingredient carrying capacity of Lipoderm®. Enhanced active ingredient carrying capacity may be desirable when transdermally treating certain conditions, such as neuropathic pain, and/or multiple conditions via a single transdermal cream.

[00035] The base composition may allow physicians to prescribe increased amounts of multiple active ingredients to be administered topically. The base composition may also allow for higher single active ingredient percentages to reduce the amount of applied cream needed by patients to reach a given amount of medication administered.

[00036] With conventional base compositions, medicine providers who ship medications to patients, or serve patients who carry their creams with them all the time, may experience issues with the creams separating (base from active) when exposed to environmental extremes. The base composition of the present embodiments may address these types of challenges without sacrificing the cosmetically elegant feel of Lipoderm®. The unique base composition disclosed herein has the trade name Lipoderm®

ActiveMax™. [00037] The base composition of the present embodiments was developed in part to show resiliency in the presence of high salt loads. For example, 30% Ketamine HCL in the base composition disclosed herein demonstrated superior physicochemical attributes, such as remaining stable and elegant for six (6) months. The base composition may be used with a transdermal cream that may provide a formulation with active ingredient concentrations exceeding 20%> of the total formulation weight of the transdermal cream, and/or alleviate separation issues. The base composition may provide for increased stability in the presence of high active ingredient percentages.

[00038] Table I below lists the base ingredients for the preferred embodiment of the base composition disclosed herein. Other ingredient lists with additional, fewer, or alternate ingredients may be used.

Table I. Base Lipoderm® ActiveMax™ Ingredients

Water

Cetearyl Alcohol

Plukenetia Volubilis Seed Oil

Isopropyl Myristate

Propylheptyl Caprylate

Sodium Stearoyl Glutamate

PEG-8/SMDI Copolymer

PEG- 100 Stearate

Glyceryl Stearate

Glycerin

Tocopheryl Acetate

Lecithin

Hydrogenated Lecithin

Populus Tremuloides Bark Extract

Lonicera Japonica (Honeysuckle) Flower Extract

Lonicera Caprifolium (Honeysuckle) Flower Extract

Leuconostoc/Radish Root Ferment Filtrate

Pentaclethra Macroloba Seed Oil

Butyrospermum Parkii (Shea) Butter

Carthamus Tinctorius (Safflower) Seed Oil

Cocos Nucifera (Coconut) Oil

Tocopherol

Ascorbyl Palmitate

Squalane

Ceramide 3

Alcohol

Glyceryl Stearate

Caprylic/Capric Triglyceride

Xanthan Gum

Gluconolactone

Sodium Dehydroacetate

Disodium EDTA

BHT

III. Evaluation of Exemplary Transdermal Cream Compositions

[00039] The base composition disclosed herein, Lipoderm® ActiveMax™, has been proven to deliver four drugs, intact, simultaneously. An evaluation of the percutaneous absorption of ketamine HCL, gabapentin, clonidine HCL, and baclofen in both Lipoderm^® and Lipoderm^® ActiveMax^IM into human trunk skin, in vitro, using the Franz skin finite dose model was performed. The study was designed to evaluate the percutaneous absorption harmacokinetics of ketamine HCL, gabapentin, clonidine HCL, and baclofen. Absorption was measured in human cadaver skin, in vtiro, using the finite dose technique and Franz diffusion cells.

[00040] Ketamine HCL 5% w/w, gabapentin 10% w/w, clonidine HCL 0.2% w/w and baclofen 2% w/w, in Lipoderm® and Lipoderm® ActiveMax, were tested on triplicate sections from three different cadaver skin donors for the percutaneous absorption of ketamine HCL, gabapentin, clonidine HCL, and baclofen over a 48-hour dose period. At pre-selected times after dose application, the dermal receptor solution was removed in its entirety, replaced with fresh receptor solution, and an aliquot saved for subsequent analysis. In addition, the epidermis and dermis were recovered and evaluated for drug content. The samples were analyzed for ketamine HCL, gabapentin, clonidine HCL, and baclofen content by High Performance Liquid Chromatography (HPLC)/MS.

A. Methods and Procedures Utilized for Evaluation

[00041] The in vitro Franz skin finite dose model has proven to be a valuable tool for the study of percutaneous absorption and the determination of the pharmacokinetics of topically applied drugs. The model uses ex vivo animal, human cadaver, or surgical skin mounted in specially designed diffusion cells that allow the skin to be maintained at a temperature and humidity that match typical in vivo conditions. (See Franz, T.J., Percutaneous Absorption: On the Relevance of In Vitro Data. J. Invest. Dermatol, 1975, 64:190-195.)

[00042] A finite dose (e.g., 4-7 mg/cm²) of formulation may be applied to the outer surface of the skin and drug absorption may be measured by monitoring its rate of appearance in the receptor solution bathing the inner surface of the skin. Data defining total absorption, rate of absorption, as well as skin content may be accurately determined in this model. The method has historic precedent for accurately predicting in vivo percutaneous absorption kinetics. (See Franz T.J., The Cadaver Skin Absorption Mode and the Drug Development Process. Pharmacopeial Forum 34(5): 1349-1356, 2008; see also Franz T.J., Lehman P.A., and Raney S., Use of Excised Human Skin to Assess the Bioequi valence of Topical Products. Skin Pharmacol Physiol 22:276-286, 2009.)

[00043] During the evaluation, percutaneous adsorption was measured using the in vitro cadaver skin finite dose technique. Human cadaver trunk skin without obvious signs of skin disease, obtained within approximately 24 to 48 hours of death, was used in this study. The skin was dermatomed, cryopreserved, sealed in a water-impermeable bag and stored at approximately -70°C until the day of the experiment. Prior to use, the skin was thawed in approximately 37°C water, then rinsed in water to remove any adherent blood or other material from the surface.

[00044] Skin from three donors was cut into multiple smaller sections large enough to fit on an approximately nominal 0.8 cm² Franz diffusion cells. The dermal chamber was filled to capacity with a reservoir solution of phosphate-buffered isotonic saline (PBS), pH 7.4 ± 0.1, with 0.1 % Oleth-20 and 0.008% Gentamicin, and the epidermal cell (chimney) left open to ambient laboratory conditions. All cells were mounted in a diffusion apparatus in which the dermal bathing solution was stirred magnetically at approximately 600 RPM and the skin surface temperature maintained at 32.0° ± 1.0°C.

[00045] To assure the integrity of each skin section, its permeability to tritiated water was determined before application of the test products. (See Franz T.J. and Lehman P.A., The Use of Water Permeability as a Means of Validation for Skin Integrity in In Vitro Percutaneous Absorption Studies. Abst. J. Invest. Dermatol 1990, 94:525.) Following a brief (0.5-1 hour) equilibrium period, ³H₂0 (NEN, Boston, MA, sp. Act. ~ 0.5 μα/mL) was layered across the top of the skin so that the entire exposed surface was covered (approximately 250 to 500 μΐ,). After 5 minutes the ³H₂0 aqueous layer was removed. At 30 minutes, the receptor solution was collected and analyzed for radioactive content by liquid scintillation counting.

[00046] Just prior to dosing, a pre-dose sample was taken and the reservoir solution was replaced with a fresh solution of IX PBS with 0.1% Oleth-20 and 0.008% Gentamicin. The chimney was removed from the Franz cell to allow full access to the epidermal surface of the skin. All formulations were then applied to the skin sections using a positive displacement pipette set to deliver 5 formulation/cm². The dose was spread across the surface with a glass rod. Five to ten minutes after application the chimney portion of the Franz cell was replaced. At pre-selected times after dosing (2, 4, 8, 12, 24, 32, and 48 hours), the reservoir solution was removed in its entirety, replaced with fresh reservoir solution, and a predetermined volume aliquot saved for subsequent analysis.

[00047] After the last sample was collected, the surfaces were washed twice (0.5 mL volume each) with 80:20 methanol: water to collect un-absorbed formulation from the surface of the skin. Following the surface cleanse, the skin was then removed from the diffusion cell, split into epidermis and dermis, and each skin sample extracted overnight using an appropriate extraction solvent, and analyzed for ketamine HCL, gabapentin, clonidine HCL, and baclofen content. Ketamine HCL, gabapentin, clonidine HCL, and baclofen concentrations were quantified in study samples using an HPLC/MC analytical method. Donor demographics are listed in Table II below.

Table Π. Donor Demographics

[00048] The formulation used during the evaluation involved ketamine HCL, gabapentin, clonidine HCL, and baclofen, in an amount necessary to result in a concentration of 5% w/w, 10% w/w, 0.2% w/w and 2% w/w respectively, being added to the base

compositions, along with 10% propylene glycol as a wetting agent, and mixed with the aid of an electronic mortal¹ and pestle (EMP, 3 minutes at a setting of 7). The formulation was sheared twice using an ointment mill, at a setting of 2, and remixed with the EMP (1 minute at a setting of 5) to achieve accurate content uniformity. Potency was confirmed through the use of a High Performance Liquid Chromatograph (HPLC) with a photo diode array detector or Ultra High Performance Liquid Chromatograph (UHPLC) with a CAD detector.

B. Results

[00049] The data indicates that the base composition, Lipoderm^® ActiveMax^1M, delivered ketamine HCL, gabapentin, clonidine HCL and baclofen, simultaneously (and intact), into and through human cadaver skin, in vitro. The data shows that ketamine HCL, gabapentin, clonidine HCL, and baclofen in the base composition may penetrate into and through ex vivo human trunk skin using the Franz finite dose model. [00050] In particular, the absorption profiles indicate a rapid penetration to a peak flux for gabapentin and baclofen occurring approximately one hour after dose application, and between approximately four to ten hours after dose application for ketamine HCL.

Clonidine HCL exhibited a rapid penetration to an initial peak flux occurring one hour after dose application, but also a secondary peak at between approximately 28 and 40 hours, possibly due to a depot of some of the applied dose in the epidermis, followed by a slow decrease in flux afterward. (See Figures 2-6.) This one-of-a-kind study validates the ability of the base composition to deliver four drugs simultaneously through human skin and intact. This information is potentially of great value for pharmacists and physicians utilizing topical preparations for various pain syndromes.

[00051] Figure 2 depicts ketamine flux versus time exhibited during the exemplary evaluation of the exemplary transdermal cream embodiments discussed herein. In particular, Figure 2 depicts a summary 200 of the mean flux ^g/cm²/hr) results 202 of percutanous absorption of ketemine through ex vivo, human trunk skin over 48 hours 204 from a single application. The ketamine mean flux graph using the base composition, Lipoderm^® ActiveMax™ 206, yielded a ketamine flux of approximately 0.75 μg/cm²/hl· at about 1 hour after application, approximately 3.0 μg/cm²/hr at about 3 hours after application, approximately 4.1 μg/cm²/hr at about 6 hours after application, approximately 4.3 μg/cm²/hr at about 10 hours after application, approximately 2.4 μg/cm²/hr at about 18 hours after application, approximately 2.5 μg/cm²/hr at about 28 hours after application, and approximately 1.9 μg/cm /hr at about 40 hours after application.

[00052] As shown in Figure 2, the mean flux of ketamine through the skin using the base composition, Lipoderm^® ActiveMax™ 206, was proven to exceed the mean flux of ketamine through the skin using Lipoderm" 208 for most of the 48 hours after a single application. As depicted, the mean flux of ketamine through the skin using the base composition, Lipoderm^® ActiveMax™ 206, exceeded the mean flux of ketamine through the skin using Lipoderm^® 208 within about 2 hours after a single application.

[00053] The maximum mean flux of ketamine 210 using the base composition 206 exceeded the maximum mean flux of ketamine 212 through the skin using Lipoderm^® 208. The maximum mean flux of ketamine 210 using the base composition 206 was approximately 4.3 μg/cm²/hr at about 10 hours after application, which occurred later after application than the maximum mean flux of ketamine 212 using Lipoderm^® 208.

[00054] Figure 3 depicts gabapentin flux versus time exhibited during the exemplary evaluation. In particular, Figure 3 depicts a summary 300 of the mean flux ^g/cm²/hr) 302 results of percutanous absorption of gabapentin through ex vivo, human trunk skin over 48 hours 304 from a single application. Depicted are the mean flux of gabapentin through the skin using the base composition, Lipoderm^® ActiveMax™ 306, and

Lipoderm^® 308.

[00055] Figure 4 depicts baclofen flux versus time exhibited during the exemplary evaluation. In particular, Figure 4 depicts a summary 400 of the mean flux ^g/cm²/hr) 402 results of percutanous absorption of baclofen through ex vivo, human trunk skin over 48 hours 404 from a single application. Depicted is the mean flux of baclofen through the skin using the base composition, Lipoderm^® ActiveMax™ 406, and Lipoderm^® 408.

[00056] Figure 5 depicts clonidine flux versus time exhibited during the exemplary evaluation. In particular, Figure 5 depicts a summary 500 of the mean flux ^g/cm /hr) 502 results of percutanous absorption of clonidine through ex vivo, human trunk skin over 48 hours 504 from a single application. Depicted is the mean flux of clonidine through the skin using the base composition, Lipoderm^® ActiveMax™ 506, and Lipoderm^® 508.

[00057] The clonidine mean flux graph using the base composition, Lipoderm^®

ActiveMax™ 506, yielded a clonidine flux of approximately 0.005 g/cm²/hr at about 1 hour after application, approximately 0.007 μg/cm²/hr at about 3 hours after application, approximately 0.006 μg/cm²/hr at about 6 hours after application, approximately 0.008 μg/cm²/hr at about 10 hours after application, approximately 0.008 μg/cm²/h at about 18 hours after application, approximately 0.011 μg/cm²/hr at about 28 hours after application, and approximately 0.011 μg/cm /hr at about 40 hours after application.

[00058] As shown in Figure 5, the mean flux of clonidine through the skin using the base composition, Lipoderm^® ActiveMax™ 506, was proven to exceed the mean flux of clonidine through the skin using Lipoderm^® 508 from about two hours after application to about 40 hours after application. Also, the minimum mean flux of clonidine observed using the base composition 510 (at approximately 1 hour after application) also exceeded the minimum mean flux of clonodine through the skin observed using Lipoderm^® 512 (at approximately 3 hours after application).

[00059] Figure 6 depicts the total percentage permeation of multiple drugs (intact) beyond the stratum corneum simultaneously after a single dose of the exemplary transdermal cream embodiments is applied topically 600. In particular, Figure 6 depicts comparisons of percent permeation 602 for four intact drugs topically applied in combination 604 via the base composition and Lipoderm^® - comparisons for ketamine 606, clonidine 608, bacofen 610, and gabepentin 612. [00060] As shown, the percent permeation for ketamine using the base composition, Lipoderm^® ActiveMax™ , was approximately 53.4%, which was substantially better than the approximately 44.8%) percent permeation for ketamine achieved using Lipoderm^® as a base. Also, the approximately 5.5%o permeation of baclofen using the base composition, Lipoderm^® ActiveMax™ , was better than the approximately 3.95% permeation for baclofen achieved using Lipoderm^® as a base. The base composition also yielded approximately 17.9% permeation for clonidine and approximately 2.6% permeation for gabapentin.

[00061] Exemplary formulations that were tested during the exemplary evaluation are listed below in Tables III and IV. "PCCA" identified below is the Professional

Compounding Centers of America.

Table III. Exemplary Lipoderm^® Formula

Table IV. Exemplary Lipoderm ActiveMax Formula

IV. Other Exemplary Transdermal Cream Compositions

[00062] The base composition disclosed herein may be used with various total transdermal cream compositions. An exemplary transdermal cream composition may include approximately 30% ketamine HCL in the base composition. The trandermal cream composition may remain stable for six months or longer, and include active ingredient concentrations exceeding 20% of the total formulation weight. The transdermal cream compositions may include vitamin E acetate, sodium metabisulfite, butylated hydroxytoluene, and Dow Corning© 200 Fluid. Exemplary ingredients to make 100 gm of transdermal cream are listed in Table V below.

Table V. 30% Ketamine HCL Formulation

[00063] Another exemplary transdermal cream composition may include approximately 79% of the base composition, along with approximately 10% flurbiprofen, approximately 1% amitriptyline, approximately 6% gabapentin, approximately 2% lidocaine, and/or approximately 2% prilocaine. Exemplary ingredients are listed in Table VI below.

Table VI. FIurbiprofen/Amitriptyline/Gabapentin Lidocaine Prilocaine

Formulation

[00064] An exemplary transdermal cream composition may include approximately 79% of the base composition, along with approximately 10% flurbiprofen, approximately 1% cyclobenzaprine, approximately 6% gabapentin, approximately 2% lidocaine, and/or approximately 2% prilocaine. Exemplary ingredients are listed in Table VII below.

Table VII. Flurbiprofen/Cyclobenzaprine/Gabapcntin/Lidocaine Prilocaine

Formulation

[00065] An exemplary transdermal cream composition may include approximately 86%> of the base composition, along with approximately 10% gabapentin, approximately 2% lidocaine, and/or approximately 2% prilocaine. Exemplary ingredients are listed in Table VIII below. Table VIII. Gabapentin/Lidocaine/Prilocaine Formulation

[00066] An exemplary transdermal cream composition may include approximately 70% of the base composition, along with approximately 30% ketamine. Ketamine may be provided as a 30% stand-alone compounded therapy to allow combination with a wide range of other therapies. Exemplary ingredients are listed in Table IX below.

Table IX. 30% Ketamine Formulation

[00067] An exemplary compounded medication may include (1) an anti- inflammatory (non-steroidal), such as flurbiprofen, ibuprofen, meloxicam, and/or piroxicam; (2) a muscle relaxant, such as cyclobenzaprine; (3) a nerve pain depressant, such as gabapentin and/or topiramate; (4) a tri-cyclic, such as amitriptyline; (5) a local anesthetic, such as lidocaine and/or prilocaine; and/or (6) other anesthetics and/or pain suppressants, such as ketamine.

[00068] In general, the compounded medications may be used to treat generalized pain and/or muscle spasms. The combination therapies may assist patients by providing many different lines of medication in each application often without causing as many side effects as oral therapies. Each compounded transdermal cream may be applied in a small amount, such as the size of a quarter, to the site where the pain, inflammation, and/or swelling are localized.

V. Additionally Exemplary Compounded Formulas

[00069] The compounded formulas may be mixed to provide for formula quantities of 24,000 gm. For instance, an exemplary compound formula may include approximately 10% flurbiprofen, approximately 1% amitriptyline, approximately 6% gabapentin, approxiamtely 2% lidocaine, and approximately 2% prilocaine in a transdermal gel. Exemplary ingredients are listed in Table X below.

Table X. Flurbiprofen/ Anutruotyline/Gabapentin/Lidocaine/Prilocaine Formulation

[00070] With the above formula, lidocaine HCL monohydrate 1.23 gm = 1 gm lidocaine base, and prilocaine HCL 1.165 gm = 1 gm prilocaine base. The amount of each active ingredient needed should be calculated and weighed based on activity and adjust

Lipoderm® ActiveMax™ accordingly. All ingredients should be combined in a 30 quart mixing bowl with at least 4000 grams of Lipoderm® ActiveMax™ on the bottom.

[00071] With a Globe SP30P set on the lowest speed of "1", a person preparing the mixture may set timer on the mixer to zero minutes and pulse slightly 1/4 second per pulse until the powders are wet. The preparer should continue to stir on low for 15 minutes, and then allow the mixture to set for 45 minutes to thicken. The preparer should then stir for another 15 minutes. After which, mill in Exakt 120S-450 ointment mill with both rollers set to "1". The preparer should slowly adjust a rear roller to a setting of "3" to ensure that the product flows down the scraper plate appropriately. Then, the preparer should stir the milled product with the mixer set on "1" for 15 minutes and then package as desired in air-tight containers. The general procedure may be used with the formulations mentioned below as well.

[00072] Another exemplary compounded formula may include approximately 10% flurbiprofen, approximately 1% cyclobenzaprine, approximately 6% gabapentin, approximately 2% lidocaine, and approximately 2% prilocaine in a transdermal gel. The mixing or preparation instructions noted above may also be followed. Exemplary ingredients are listed in Table XI below.

Table XI. Flurbiprofen/Cyclobenzaprine/Gabapentin Lidocain/Prilocaine

Formulation

[00073] Another exemplary compounded formula may include gabapentin, prilocaine, and/or other ingredients in a transdermal gel. The instructions noted previously may be followed to prepare the formula composition. Exemplary ingredients are listed in Table XII below.

Table XII. Gabapention/Lidocaine/Prilocaine Formulation

[00074] Another exemplary compounded formula may include approximately 30% ketamine in a transdermal gel. The instructions noted previously may be followed to prepare the formula composition. Exemplary ingredients are listed in Table XIII below.

Table XIII. Ketamine HCL Formulation

[00075] The present invention may be embodied in other forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be had to the following claims rather than the foregoing specification as indicating the scope of the invention. Further, the illustrations of arrangements described herein are intended to provide a general understanding of the structure of various embodiments, and they are not intended to serve as a complete description of all the elements and features of apparatus and systems that might make use of the structures described herein. Many other arrangements will be apparent to those of skill in the art upon reviewing the above description. Other arrangements may be utilized and derived therefrom, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Figures are also merely representational and may not be drawn to scale. Certain proportions thereof may be exaggerated, while others may be minimized. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense.

[00076] Thus, although specific arrangements have been illustrated and described herein, it should be appreciated that any arrangement calculated to achieve the same purpose may be substituted for the specific arrangement shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments and arrangements of the invention. Combinations of the above arrangements, and other arrangements not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description. Therefore, it is intended that the disclosure not be limited to the particular arrangement(s) disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments and arrangements falling within the scope of the appended claims.

[00077] The Abstract of the Disclosure is provided to comply with 37 C.F.R. § 1.72(b), requiring an abstract that will allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

Claims

What is claimed is:

1. A pharmaceutical composition for a transdermal cream that permits the

administration of multiple medications, wherein the pharmaceutical composition exhibits (a) resiliency in the presence of at least a 30% salt load and (b) is able to remain stable for six months, the pharmaceutical composition further capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight.

2. The transdermal cream of claim 1 , wherein the transdermal cream comprises

approximately 30% or more ketamine HCL and allows for approximately 50% or greater permeation of the ketamine HCL beyond the stratum corneum after a single dose is administered topically.

3. The transdermal cream of claim 1, wherein the transdermal cream comprises

ketamine HCI, gabapentin, clonidine HCL and baclofen.

4. The pharmaceutical composition of claim 1, wherein the transdennal cream is able to withstand extreme temperatures exceeding approximately 72°F and still remain stable and avoid separation of a base and the active ingredients.

5. The transdermal cream of claim 1, wherein the transdermal cream comprises a base having ingredients listed in Table I.

6. The transdermal cream of claim 1, wherein the transdermal cream comprises a base comprising ingredients listed in Table I and ketamine HCI, gabapentin, clonidine HCL and baclofen.

7. A transdermal cream for the administration of multiple medications, the

transdermal cream comprising approximately a 30% salt load or greater, wherein the transdermal cream is able to remain stable for six months and is capable of effective delivery of active ingredient concentrations exceeding 20% of the total formulation weight of the transdermal cream.

8. The transdermal cream of claim 7, wherein the transdermal cream comprises approximately 30% or more ketamine HCL.

9. The transdermal cream of claim 7, wherein the transdermal cream comprises ketamine HCI, gabapentin, clonidine HCL and baclofen, and provides for 50% or greater permeation of ketamine HCL and for 5% or greater permeation of baclofen beyond the stratum corneum after a single dose is administered topically.

10. The transdermal cream of claim 7, wherein the transdermal cream comprises a base having ingredients listed in Table I.

11. The transdermal cream of claim 7, wherein the transdermal cream comprises a base comprising ingredients listed in Table I and ketamine HCI, gabapentin, clonidine HO and baclofen.

12. A transdermal cream for the topical administration of multiple medications

simultaneously, the transdermal cream comprising:

at least 30% ketamine HCL by weight; and

a base composition,

wherein the base composition provides for greater than 50% permeation of the ketamine beyond the stratum corneum after a single dose is administered topically via the base composition.

13. The transdermal cream of claim 15, wherein the base composition provides a maximum mean flux of greater than approximately 3.5 μg/cm²/hr of percutaneous absorption of ketamine through the human skin within approximately 4 to 10 hours after commencing a single dose via a topical administration using the transdermal cream.

14. The transdermal cream of claim 16, wherein the transdermal cream comprises multiple active ingredients, including gabapentin, clonidine HCL, and baclofen.

15. A compounded transdermal pain management program for the topical administration of multiple medications simultaneously, the compounded transdermal pain management program comprising:

providing a base composition;

providing several medications within the base composition for topical administration to a patient, wherein the several medication include at least one NSAID; at least one opiad agonist; at least one local anesthetic; at least one NMDA receptor antogonist; and at least one nerve depressant.

16. The compounded transdermal pain management program of claim 15, wherein the at least one NMDA receptor antogonist comprises ketamine.

17. The compounded transdermal pain management program of claim 16, wherein the at least one opiad agonist comprises tramadol.

18. The compounded transdermal pain management program of claim 17, wherein the at least one nerve depressant comprises gabapentin.

19. The compounded transdermal pain management program of claim 18, wherein the at least one muscle relaxant comprises baclofen or cyclobenzaprine.

20. The compounded transdermal pain management program of claim 19, wherein the at least one NSAID comprises flurbiprofen.