WO2012092523A1 - Systems and methods for treatment of allergies and other indications - Google Patents
Systems and methods for treatment of allergies and other indications Download PDFInfo
- Publication number
- WO2012092523A1 WO2012092523A1 PCT/US2011/067987 US2011067987W WO2012092523A1 WO 2012092523 A1 WO2012092523 A1 WO 2012092523A1 US 2011067987 W US2011067987 W US 2011067987W WO 2012092523 A1 WO2012092523 A1 WO 2012092523A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- concentration
- weight
- antihistamine
- salt
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention generally relates to transdermal delivery and, in particular, to the transdermal delivery of Hi antihistamines and other compounds.
- a histamine antagonist is an agent that inhibits action of histamine via histamine receptors.
- Hi antihistamines are used as treatment for symptoms of allergies such as runny nose. Allergies are caused by an excessive type 1 hypersensitivity response of the body to allergens, such as pollen released by plants. An allergic reaction, which if severe enough can lead to anaphylaxis, results in excessive release of histamines and other mediators by the body.
- Other uses of Hi antihistamines help with symptoms of local inflammation that results from various conditions, such as insect stings, even if there is no allergic reaction.
- the present invention generally relates to the transdermal delivery of Hi antihistamines and other compounds.
- the subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.
- compositions for delivering an Hi antihistamine and/or a salt thereof to a subject comprising an Hi antihistamine and/or a salt thereof in a hostile biophysical environment for topical delivery to the skin of a subject.
- a composition also comprises a nitric oxide donor.
- a composition further comprises one or more compounds that stabilize and/or otherwise promote the efficacy of storage and/or delivery (e.g., with or without a nitric oxide donor).
- compositions of the invention increase the efficiency of direct compound delivery to a target site by using transdermal delivery thereby significantly lowering the systemic exposure and reducing potential side effects.
- a transdermal delivery according to the invention can reduce systemic exposure to less than 10% (e.g., less than 5%, or between 0.1% and 1%, or even less) of the systemic exposure resulting from an oral dosage required for effective delivery of the compound.
- sedation effects produced by systemic diphenhydramine can be avoided by using a topical formulation of the invention that provides sufficient local levels near the site of topical administration to be effective without producing sedation side-effects associated with the systemic levels that result from oral administration.
- compositions of the invention provide for unexpectedly high speeds of action of the compound being delivered (e.g., relative to oral delivery or other delivery techniques used for the compound). Accordingly, in some
- aspects of the invention are useful for rapid therapy when delivery of a therapeutic amount of a compound within a short period of time is required.
- Topical delivery formulations described herein can deliver a compound to a target tissue more rapidly than an oral formulation, for example.
- Topical delivery formulations also allow for targeted local delivery of a therapeutically effective amount of compound without requiring a significant systemic increase in the amount of compound.
- topical formulations can be used for systemic delivery if so required.
- compositions for topical delivery to the skin of a subject.
- the composition includes a nitric oxide donor, a hostile biophysical environment, a stabilization polymer, propylene glycol, a polysorbate surfactant, and an Hi antihistamine and/or a salt thereof.
- at least about 80% by weight of the composition comprises water, at least one chloride salt, a nitric oxide donor, a stabilization polymer, propylene glycol, a polysorbate surfactant, and an Hi antihistamine and/or a salt thereof.
- the composition includes a nitric oxide donor, a hostile biophysical environment, and an Hi antihistamine and/or a salt thereof.
- the composition in still another set of embodiments, comprises or consists essentially of water, sodium chloride, a nitric oxide donor, glyceryl stearate, magnesium sulfate and/or magnesium chloride, squalane, a stabilization polymer, isopropyl myristate, oleic acid, propylene glycol, a polysorbate surfactant, and an Hi antihistamine and/or a salt thereof.
- the composition may also comprise or consist essentially of an antioxidant.
- the composition comprises or consists essentially of water, sodium chloride, a nitric oxide donor, glyceryl stearate, cetyl alcohol, magnesium sulfate and/or magnesium chloride, squalane, a stabilization polymer, isopropyl myristate, oleic acid, propylene glycol, a polysorbate surfactant, and an Hi antihistamine and/or a salt thereof.
- the composition may also comprise or consist essentially of an antioxidant.
- the composition comprises each of the following compounds at concentrations of no more than +20% of the stated concentrations: water at a concentration of about 35% to about 55% by weight, sodium chloride at a
- a nitric oxide donor at a concentration of about 2.5% to about 15% by weight
- glyceryl stearate at a concentration of about 4% to about 10% by weight
- cetyl alcohol at a concentration of about 4% to about 10% by weight
- magnesium chloride at a concentration of about 2.5% to about 15% by weight
- squalane at a concentration of about 1% to about 8% by weight
- a polysorbate surfactant at a concentration of about 0.2% to about 2% by weight
- isopropyl myristate at a concentration of about 0.1% to about 5% by weight
- oleic acid at a concentration of about 0.1% to about 5% by weight
- propylene glycol at a concentration of about 1% to about 10% by weight
- a stabilization polymer at a concentration of about 1% to about 10% by weight
- an Hi antihistamine and/or a salt thereof at a concentration of about 0.1% to about 5% by weight.
- the composition may also comprise an antioxidant at a concentration of about 0.1 to about 1% by weight.
- the composition in yet another set of embodiments, comprises each of the following compounds at concentrations of no more than +20% of the stated concentrations: water at a concentration of about 35% to about 55% by weight, sodium chloride at a concentration of about 2.5% to about 15% by weight, a nitric oxide donor at a concentration of about 2.5% to about 15% by weight, glyceryl stearate at a concentration of about 4% to about 10% by weight, magnesium chloride at a concentration of about 2.5% to about 15% by weight, squalane at a concentration of about 1% to about 8% by weight, a polysorbate surfactant at a concentration of about 0.2% to about 2% by weight, isopropyl myristate at a concentration of about 0.1% to about 5% by weight, oleic acid at a concentration of about 0.1% to about 5% by weight, propylene glycol at a concentration of about 1% to about 10% by
- a composition comprises approximately 7.5% (e.g., 1% to 15%, or more or less) by weight of antihistamine (e.g., diphenhydramine or other antihistamine) in an oil/water emulsion further comprising about 10% sodium chloride, and about 5% magnesium chloride.
- antihistamine e.g., diphenhydramine or other antihistamine
- the antihistamine may be an Hi antihistamine and/or a salt thereof.
- the pH of a composition is optimized to ionize the antihistamine while remaining compatible with acceptable pH ranges for contact with the skin (e.g., within a range of about pH 5 to about pH 8).
- a pH at least about 1 pH unit above or below e.g., at least about 2 pH units above or below
- the pKa of diphenhydramine of 9.0 is sufficient to ionize the antihistamine.
- a pH of 7 (+/- 1.0) is effective.
- a pH of 7.2 e.g., +/- 0.5
- a pH at least about 1 pH unit above or below the pKa of an antihistamine may be used, particularly if the pH is within the range of about pH 5.0-8.0 that is particularly compatible for direct topical contact with skin.
- the antihistamine may be, for instance, an Hi antihistamine and/or a salt thereof, or any antihistamine discussed herein.
- a relatively high salt concentration for example at least about 2% (e.g., about 5%, about 10% about 15%, about 20% about 25%, about 25-50%, weight %) is useful to provide a hostile biophysical environment that promotes transdermal migration of an antihistamine (e.g., diphenhydramine).
- an antihistamine e.g., diphenhydramine
- emulsions described herein for example, containing a stabilization polymer and/or a polysorbate surfactant and/or propylene glycol (or a low molecular weight glycol, or a polyglycol such as polyethylene glycol or other polyglycol - however it should be appreciated that glycols with even numbers of carbons can be toxic, particularly for smaller glycols such as ethylene glycol and butylene glycol, and should be avoided or excluded) are unexpectedly effective at stabilizing the antihistamine in the high salt composition in a form that remains effective for an extended period - for example, retaining rapid transdermal delivery of the antihistamine for at least several weeks or months.
- the antihistamine is an Hi antihistamine (e.g., diphenhydramine) and/or a salt thereof.
- the composition includes a stabilization polymer, propylene glycol, a polysorbate surfactant; and an Hi antihistamine and/or a salt thereof.
- At least about 80% by weight of the composition comprises water, at least one chloride salt, a stabilization polymer, propylene glycol, a polysorbate surfactant, an antioxidant, and an Hi antihistamine and/or a salt thereof.
- the invention in accordance with another aspect, is generally directed to a method.
- the method is a method of applying any of the compositions described herein to a subject, e.g., to the skin of a subject.
- the method in accordance with another set of embodiments, includes an act of applying, to a portion of the skin of a subject, a delivery vehicle comprising an Hi antihistamine and/or a salt thereof in a hostile biophysical environment.
- the method includes an act of applying, to at least a portion of the skin of a subject, a composition comprising a nitric oxide donor, a hostile biophysical environment, a stabilization polymer, propylene glycol, a polysorbate surfactant, and an Hi antihistamine and/or a salt thereof.
- the present invention encompasses methods of making one or more of the embodiments described herein, for example, a composition comprising an Hi antihistamine. In still another aspect, the present invention encompasses methods of using one or more of the embodiments described herein, for example, a composition comprising an Hi antihistamine. In yet another aspect, the present invention encompasses various uses of a composition including an Hi antihistamine. For example, the composition may be used to treat an allergy.
- aspects of the invention relate to a patch that comprises a composition of the invention (e.g., with or without a nitric oxide donor, and with or without one or more stabilizing compounds).
- a composition is in the form of a cream or ointment that is incorporated into the patch.
- other configurations also may be used.
- aspects of the invention relate to methods and formulations for delivering a compound locally at a fraction of the systemic dose required using oral delivery.
- a hostile biophysical environment may be evaluated for enhancing local delivery through a topical application.
- an appropriate delivery configuration e.g., a combination of compound concentration, hostile biophysical environment, cream, patch, etc.
- aspects of the invention relate to topical formulations and methods that can be used (e.g., when treating skin allergies) to reduce or avoid drowsiness often associated with oral administration of a compound described herein.
- Topical formulations described herein also are faster acting than oral formulations.
- the present invention generally relates to the transdermal delivery of various compounds.
- transdermal delivery may be facilitated by the use of a hostile biophysical environment.
- One set of embodiments provides a composition for topical delivery comprising an Hi antihistamine and/or an Hi antihistamine salt, and optionally, a hostile biophysical
- the composition may be stabilized using a combination of a stabilization polymer (such as xanthan gum, KELTROL ® BT and/or
- compositions comprising a relatively high salt composition are unexpectedly effective for topical delivery of an Hi antihistamine (including salts thereof), for example diphenhydramine.
- a salt-enhanced delivery (e.g., in a composition having at least 2% salt, at least 5% salt, at least 10% salt, at least 15% salt, or higher as described herein) is particularly effective when the pH of the composition is optimized to ionize the compound being delivered (e.g., at least about 80%, at least about 90%, at least about 95%, or about 99% or more) is ionized.
- the ionized form may be anionic or cationic (e.g., due to protonation).
- a compound may contain several ionizable groups each having a different pKa.
- an ionizable group is sufficiently ionized if the pH of the composition is at least 1 pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or more pH units) below the pKa of the group and it is cationic (due to protonation) below its pKa.
- an ionizable group is sufficiently ionized if the pH of the composition is at least 1 pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or more pH units) above the pKa of the group and it is anionic (due to deprotonation) above its pKa.
- the presence of magnesium chloride for example at 0.1-5% by weight, can help stabilize composistions containing compounds with relatively high pKas (e.g., above 8.0, above 9.0, above 10.0 or higher).
- the pH of a composition may be maintained using a buffer. However, the pH of compositions of the invention are surprisingly stable without a buffer.
- a desired pH can be established by titrating the mixture with an acid (e.g., HC1) or a base (e.g., NaOH).
- the pH of the resulting composition e.g., when formulated as an emulsion as described herein
- can be stable e.g., sufficiently for the composition to be effective for transdermal delivery
- extended periods of time e.g., weeks, months, or 1 or more years.
- a high salt composition containing an Hi antihistamine is unexpectedly stable when formulated as an emulsion (e.g., a water in oil emulsion or an oil in water emulsion, for example, including one or more of a stabilization polymer and/or a polysorbate surfactant and/or propylene glycol (or other low molecular weight glycol, or a polyglycol) as described herein).
- an emulsion e.g., a water in oil emulsion or an oil in water emulsion, for example, including one or more of a stabilization polymer and/or a polysorbate surfactant and/or propylene glycol (or other low molecular weight glycol, or a polyglycol) as described herein.
- the pH of the composition comprising the emulsion and high salt concentration is selected to ionize the compound being delivered as described herein.
- topical delivery according to the invention provides a surprisingly rapid effect (within about 1-5 minutes) on symptoms (e.g., hives or other allergic rashes or other symptoms).
- symptoms e.g., hives or other allergic rashes or other symptoms.
- current formulations of diphenhydramine take significantly longer (e.g., about 40 minutes or more) to take effect.
- aspects of the invention provide methods and compositions for delivering an effective treatment to a subject to treat or prevent an allergy.
- a topical composition is applied to a region of inflamed skin (or skin that has a rash, or other signs of allergy, including, for example, hives).
- a composition is provided to produce relief from symptoms of allergy in less than 1 hour, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes.
- compositions for the topical delivery of substances such as pharmaceutical agents e.g., drugs, biological compounds, etc.
- the pharmaceutical agents may be applied to the skin of a subject, e.g. a human, to aid in treatment of medical conditions or diseases, and/or the symptoms associated thereof.
- the invention provides for the treatment of medical conditions or diseases and/or ailments using pharmaceutical agents (for example, to treat a subject diagnosed with a medical condition or disease, as described herein), and in some cases, the invention provides for the delivery of a minimum amount of pharmaceutical agents to provide effective levels of medication to an effected area topically while limiting side effects.
- the effective dosage of the pharmaceutical agent may be lower than the effective dosage of the pharmaceutical agent when taken orally.
- the Hi antihistamine may have a structure:
- X is CH, N, C(CH 3 ), or C(OH);
- the "Spacer” is usually 2-3 carbons in length, and may be linear, ring, branched, saturated or unsaturated; and R 1 and R 2 each independently may be -H, or a substituted or unsubstituted alkyl group, e.g., -CH 3 .
- X may be a chiral center.
- the two aromatic rings can be orientated in different planes; for example, the tricyclic ring system may be slightly puckered and the two aromatic rings may be arranged to lie in different geometrical planes.
- Hi antihistamines include, but are not limited to, fexofenadine
- compositions including an Hi antihistamine for transdermal delivery or topical application to a subject are directed to compositions including an Hi antihistamine for transdermal delivery or topical application to a subject.
- Hi antihistamine other compounds such as salts or derivatives of Hi antihistamines are also included in other embodiments; thus, it should be understood that in any embodiment described herein using an Hi antihistamine, this is by way of example only, and other embodiments of the invention are directed to Hi antihistamine salts, Hi antihistamine derivatives, etc., instead of and/or in addition to Hi antihistamines.
- Hi antihistamines or other pharmaceutical agents may be present at any suitable concentration.
- the pharmaceutical agent may be present at a concentration of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about
- the pharmaceutical agent may be present at a concentration of no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, no more than about 5%, no more than about 6%, no more than about 7%, no more than about 8%, no more than about 9%, no more than about 10%, no more than about 12%, no more than about 15%, or no more than about 20% by weight of the composition.
- the pharmaceutical agent may be present in native form and/or as one or more salts.
- an Hi antihistamine may be used in its native form, and/or as one or more salts, e.g., the sodium salt, the potassium salt, the magnesium salt, the lysine salt, the arginine salt, the hydrochloride salt, the tannate salt, the citrate salt, the acefylline salt, the maleate salt, etc. of an Hi antihistimate, e.g., fexofenadine, cetirizine (or levocertrizine), clemastine, diphenhydramine, doxylamine, pheniramine, ebastine, chlorpheniramine, meclizine, embramine,
- salts e.g., the sodium salt, the potassium salt, the magnesium salt, the lysine salt, the arginine salt, the hydrochloride salt, the tannate salt, the citrate salt, the acefylline salt, the maleate salt, etc.
- an Hi antihistimate e.g
- "by weight of the composition” includes the entire salt form of the pharmaceutical agent, e.g., the agent itself as well as any counterions such as sodium, potassium, etc.
- the amount of the pharmaceutical agent may be determined in a composition, for example, using techniques such as HPLC or HPLC/MS that are known to those of ordinary skill in the art.
- Hi antihistamines are readily commercially available.
- the Hi antihistamine may be obtained as a racemic mixture, for example, for fexofenadine (e.g., (R)- fexofenadine and (S)-fexofenadine), or cetirizine (e.g., (R)-cetirizine and (S)-cetirizine).
- one of the enantiomers may be present in an amount greater than the other.
- at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the Hi antihistamine within the composition may be present as one of the enantiomers.
- the composition may also comprise a nitric oxide donor in some embodiments, for example, L-arginine and/or L-arginine hydrochloride.
- a nitric oxide donor may be used to increase localized blood flow at the site where the composition is applied, which may enhance delivery of the pharmaceutical agent.
- the nitric oxide donor may be present at any suitable concentration within the composition. For instance, in some cases, the nitric oxide donor is present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition.
- one or more nitric oxide donors may be used. In some cases, there may be no more than 3, 5, 7, or 10 nitric oxide donors present within the composition.
- nitric oxide donor is a compound that is able to release nitric oxide and/or chemically transfer the nitric oxide moiety to another molecule, directly or indirectly, for example, through a biological process.
- the nitric oxide donor may release nitric oxide into the skin, and/or tissues such as muscles and/or elements of the circulatory system in close proximity to the surface of the skin.
- Non-limiting examples of nitric oxide donors include arginine (e.g., L-arginine and/or D-arginine), arginine derivatives (e.g., L-arginine hydrochloride and/or D- arginine hydrochloride), nitroglycerin, polysaccharide-bound nitric oxide-nucleophile adducts, N-nitroso-N-substituted hydroxylamines, l,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc., and/or any combination of these and/or other compounds.
- arginine e.g., L-arginine and/or D-arginine
- arginine derivatives e.g., L-arginine hydrochloride and/or D- arginine hydrochloride
- nitroglycerin polysaccharide-bound nitric oxide-nucleophile adducts
- nitric oxide donors include D,L-arginine, D-arginine, or alkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl, iert-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., a methyl ester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or salts thereof, as well as other derivatives of arginine and other nitric oxide donors.
- alkyl e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl, iert-butyl, etc.
- esters of L-arginine and/or D-arginine e.g., a methyl ester, an ethyl ester, a propyl ester, a but
- non-limiting examples of pharmaceutically acceptable salts include hydrochloride, glutamate, butyrate, or glycolate (e.g., resulting in L- arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D- arginine glutamate, etc.).
- nitric oxide donors include L-arginine-based compounds such as, but not limited to, L-homoarginine, N-hydroxy-L-arginine, nitrosylated L- arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L- arginine, citrulline, ornithine, linsidomine, nipride, glutamine, etc., and salts thereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.), and/or any combination of these and/or other compounds.
- L-arginine-based compounds such as, but not limited to, L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, orni
- nitric oxide donors include S-nitrosothiols, nitrites, 2-hydroxy-2-nitrosohydrazines, or substrates of various forms of nitric oxide synthase.
- the nitric oxide donor may be a compound that stimulates endogenous production of nitric oxide in vivo. Examples of such compounds include, but are not limited to, L-arginine, substrates of various forms of nitric oxide synthase, certain cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, OH-arginine, or endothelein, and/or any combination of these and/or other compounds.
- the concentration of the nitric oxide donor within the composition may be tailored to have a duration of effective treatment of at least about 3 hours, at least about 5 hours, or at least about 8 hours or more in certain instances.
- the duration may also be controlled, for instance, by controlling the concentration of a penetrating agent used in conjunction with the nitric oxide donor.
- Penetration agents are discussed in detail herein.
- the actual concentration for a particular application can be determined by those of ordinary skill in the art using no more than routine experimentation, for example, by measuring the amount of transport of the nitric oxide donor as a function of concentration in vitro across cadaver skin or suitable animal models, skin grafts, synthetic model membranes, human models, or the like.
- nitric oxide is provided using L-arginine, for example, at a concentration of at least about 0.5% by weight (wt% or w/v) of L-arginine (optionally with one or more penetrating agents as discussed herein, for example, a penetrating agent able to create a hostile biophysical environment), at least about 0.75 wt%, at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 5 wt%, at least about 7 wt%, at least about 10 wt%, or at least about 15 wt%.
- L-arginine for example, at a concentration of at least about 0.5% by weight (wt% or w/v) of L-arginine (optionally with one or more penetrating agents as discussed herein, for example, a penetrating agent able to create a hostile biophysical environment), at least about 0.75 wt%, at least about 1 wt%, at least
- the L-arginine may be present in a suitable delivery vehicle, such as a cream or a lotion. L-arginine may be particularly useful in some cases due to its low toxicity, its high solubility, and/or its low cost.
- a suitable delivery vehicle such as a cream or a lotion.
- L-arginine may be particularly useful in some cases due to its low toxicity, its high solubility, and/or its low cost.
- Other examples of nitric oxide donors are discussed in International Patent Application No. PCT/US2005/005726, filed February 23, 2005, entitled “Topical Delivery of a Nitric Oxide Donor to Improve Body and Skin Appearance," by E.T. Fossel, published as WO 2005/081964 on September 9, 2005, incorporated herein by reference.
- the flow of the pharmaceutical agent across the skin may slow as it builds up within the tissue. Fick's first law of diffusion suggests that when the concentration inside becomes substantially equal to that outside, passive flow stops. The increased local blood flow may prevent or at least decrease the stoppage of the flow of the pharmaceutical agent.
- the pharmaceutical agent exits the vehicle into the tissue more readily, as the pharmaceutical agent is dispersed by flow and does not build up in concentration in the tissue.
- pharmaceutical agents may be introduced into the skin, for example, an Hi antihistamine and/or a salt or derivative of an Hi antihistamine, such as fexofenadine, cetirizine (or levocertrizine), clemastine, diphenhydramine, doxylamine, pheniramine, ebastine, chlorpheniramine, meclizine, embramine, dexchlorpheniramine, or loratadine.
- the composition may be delivered locally and/or systemically; initially, much of the delivery is at first local (i.e., through the skin), but in some cases, the pharmaceutical agents may also be distributed systemically, e.g., upon reaching the blood supply.
- the composition may also comprise a hostile biophysical environment to an Hi antihistamine in some embodiments.
- a hostile biophysical environment the environment surrounding the pharmaceutical agent (e.g., an Hi antihistamine, etc.) may be such that the pharmaceutical agent is in a chemically and/or energetically unfavorable environment, relative to the skin (e.g., the chemical potential and/or the free energy of the pharmaceutical agent within the hostile biophysical environment is significantly greater than the chemical potential and/or the free energy of the pharmaceutical agent within the skin, thus energetically favoring transport into the skin), especially the stratum corneum.
- embodiments of the invention are generally directed to compositions for topical delivery to the skin of a subject comprising a nitric oxide donor, a hostile biophysical environment, and a pharmaceutical agent such as an Hi antihistamine, or a salt or a derivative of an Hi antihistamine, or the like.
- a hostile biophysical environment of the invention can comprise, in various aspects
- high ionic strength a high concentration of osmotic agents such as ureas, sugars, or carbohydrates
- a high pH environment e.g., greater than about 7, greater than about 8, greater than about 9, greater than about 10, greater than about 11, greater than about 12, or greater than about 13
- a low pH environment less than about 5, less than about 4, less than about 3 or less than about 2
- highly hydrophobic components or highly hydrophilic components or other substances that cause an increase in the chemical potential and/or free energy of the pharmaceutical agent, or any combination of two or more of these and/or other compounds.
- a hydrophobic component may, in some embodiments, have an octanol- water partition coefficient of at least about 100, at least about 1000, at least about 10 4 , at least about 10 5 , or more in some cases.
- a hydrophilic component may have an octanol- water partition coefficient of less than about 0.01, less than about 10 "3 , less than about 10 "4 , or less than about 10 "5 in some cases.
- the composition defines the biophysical hostile environment.
- a pharmaceutical agent may be packaged in such a way that it is carried into tissue and/or its charge is neutralized by derivitization and/or by forming a neutral salt.
- biophysically hostile environments include, but are not limited to, high ionic strength
- ureas, sugars, carbohydrates, and/or ionic salts such as lithium chloride, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, sodium fluoride, lithium bromide, etc.
- high ionic strengths for example, greater than about 0.25 M, greater than about 1 M, greater than about 2 M, greater than about 3 M, greater than about 5 M, greater than about 10 M, greater than about 15 M, greater than about 20 M, greater than about 25 M, etc., or in some cases, between about 0.25 M and about 15 M, between about 5 M and about 15 M, between about 10 M and about 15 M, etc.
- high or low pH environments e.g., by adding pharmaceutically acceptable acids or bases, for example, such that the pH is between about 3 and about 7, between about 3 and about 6, between about 3 and about 5, between about 4 and 8, between about 5 and about 8, between about 5 and 8.5, between about 7
- the ionic strength is any amount greater than two times the physiological ionic strength of blood.
- the ionic strength of a composition can be readily controlled in certain embodiments by controlling the amounts or concentrations of one or more of the salts present in the composition, e.g., by controlling the amount of sodium chloride, magnesium chloride, choline chloride, etc., and/or other salts.
- Non-limiting examples of delivery vehicles which would be carried into tissue includes liposomes or emulsions of collagen, collagen peptides or other components of skin or basement membrane.
- Non-limiting examples of neutralization of charge include delivery of the pharmaceutical agent in the form or an ester or salt which is electronically neutral.
- the hostile biophysical environment may include any two or more of these conditions.
- the hostile biophysical environment may include high ionic strength and a high pH or a low pH, a highly hydrophobic environment and a high pH or a low pH, a highly hydrophobic environment that includes liposomes, or the like.
- a hostile biophysical environment may also be created in some embodiments by placing a pharmaceutical agent that is relatively highly charged into a hydrophobic, oily environment such as in an oil-based cream or lotion containing little or no water. Absorption may further be aided by combining the use of hostile biophysical environments with the use of penetrating agents, as further described herein.
- the composition may be present as an emulsion.
- an emulsion typically includes a first phase (e.g., a discontinuous phase) contained within a second fluid phase (e.g., a continuous phase).
- the pharmaceutical agent e.g., an Hi antihistamine
- other materials such as those described herein may be present in the same phase as the pharmaceutical agent.
- an emulsion may be prepared to contain a drug (or other pharmaceutical agent) of interest in a hostile biophysical environment, and optionally one or more of a stabilization polymer, propylene glycol, and/or a polysorbate surfactant.
- An emulsion may also comprise a nitric oxide donor in some embodiments, for example, L-arginine and/or L- arginine hydrochloride.
- compositions for preparing and/or manufacturing drug formulations for topical delivery are generally directed to emulsions that contain one or more drugs or other pharmaceutical agents described herein for topical application.
- certain aspects of the invention are useful for preparing emulsions that contain one or more drugs (or other pharmaceutical agents) in a hostile biophysical environment.
- the hostile biophysical environment is a high salt concentration (e.g., a high concentration of one or more salts), for example, as described herein.
- an emulsion is prepared by mixing a first aqueous preparation (e.g., a water phase) with a second non-aqueous preparation (e.g., an oil or lipid phase).
- a first aqueous preparation e.g., a water phase
- a second non-aqueous preparation e.g., an oil or lipid phase
- Drugs or other pharmaceutical agents that are water-soluble may be added to the first aqueous preparation (e.g., prior to mixing with the second non-aqueous preparation).
- Drugs or other pharmaceutical agents that are water insoluble may be added to the second non-aqueous preparation (e.g., prior to mixing with the first aqueous preparation).
- Drugs or other pharmaceutical agents that are partially water soluble may be added to one phase, or may be split between the two phases prior to mixing.
- the split between the two phases will depend on the amount of drug (or other pharmaceutical agent) that is being added, the composition (e.g., the nature and the amount of other chemicals or agents) of the first and second preparations, the pH, the temperature, other physical or chemical factors, and/or a combination thereof. For example, if a drug of interest is soluble at a 1% level in the aqueous (e.g., water or buffer) phase, but a 2% level of the drug is required in the emulsion, then the drug may also be added to the non-aqueous (e.g., lipid) phase at a 1% level. In some embodiments, a drug that is less than 1% soluble in an aqueous phase is provided in the non-aqueous phase prior to mixing. However, it should be appreciated that other percentages and/or splits between the two phases may be used.
- the pH of one or both of the first and second preparations is adjusted to optimize the solubility of the drug being used.
- a high salt concentration is used.
- one or more emulsifying agents may be used in some cases.
- the mixing time may be adjusted to promote appropriate mixing and/or emulsion formation.
- the temperature of the first and/or second preparation may be controlled to promote solubility, mixing, and/or emulsion formation.
- the temperature of one or both preparations and/or of the mixing may be set at 25 °C or higher (e.g., 30 °C or higher, 40 °C or higher, 50 °C or higher, 60 °C or higher, 70 °C or higher, or 80 °C or higher).
- the temperature may be at between 30 °C and 90 °C, between 40 °C and 80 °C, at around 50 °C, at around 60 °C, or at around 70 °C. It should be appreciated that methods and compositions of the invention may be used with any suitable drug or pharmaceutical agent.
- an oral drug may be formulated for topical delivery using one or more compositions or methods described herein.
- a topical formulation may be useful to deliver a locally effective amount of a drug (or other pharmaceutical agent) to a subject (e.g., a human) without causing unwanted side effects associated with systemic levels required for effectiveness when the drug is administered orally.
- a topical formulation may be useful to deliver an amount of a drug that is sufficient to cause a desired effect (e.g., a therapeutic effect) but that is lower than the total amount of the drug that would be administered to a subject (e.g., a human) if it were provided orally.
- Emulsions of the invention may be packaged using any suitable format (e.g., in a tube, a pump-actuated container, or any other suitable form), in certain embodiments of the invention.
- an emulsion may be added to a surface of a patch or bandage.
- the emulsion may also be applied to the skin of a subject as a cream, gel, liquid, lotion, spray, aerosol, or the like.
- compositions such as any of those discussed herein may be used to prepare a composition that is sterile or that has a low microbial content, in some embodiments.
- a composition of the invention is administered to a subject using a delivery vehicle such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch.
- a composition of the invention may be applied or impregnated in a bandage or a patch applied to the skin of a subject.
- a patch has a skin contacting portion made of any suitable material that is covered or impregnated with a cream or emulsion described herein, wherein the skin contacting portion may be supported by a backing, one or both of which may have an adhesive segment or other configuration for attaching to the skin surface of a subject.
- a "subject,” as used herein, means a human or non-human animal.
- subjects include, but are not limited to, a mammal such as a dog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guinea pig, a hamster, a primate (e.g., a monkey, a chimpanzee, a baboon, an ape, a gorilla, etc.), or the like.
- a mammal such as a dog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guinea pig, a hamster, a primate (e.g.
- the delivery vehicle may promote transfer into the skin of an effective concentration of the nitric oxide donor and/or the pharmaceutical agent, directly or indirectly.
- the delivery vehicle may include one or more penetrating agents, as further described herein.
- penetrating agents such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch.
- the concentration of the nitric oxide donor, and/or a pharmaceutical agent in the delivery vehicle can be reduced with the inclusion of a greater amount or concentration of penetrating agent, or increased to lengthen the beneficial effect.
- the nitric oxide donor and/or the pharmaceutical agent may be used in conjunction with an adjunct, such as theophylline (for example, at 10% weight by volume).
- the cream may include one or more of water, mineral oil, glyceryl stereate, squalene, propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropyl myristate, steryl stearate, polysorbate 60, propylene glycol, oleic acid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D, triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea, propylparaben, PND, and/or BHA.
- a cream may have one or more of (w/v): water (20-
- each compound can vary (or the compound may be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.
- the cream may include a pharmaceutical agent, for instance, an
- Hi antihistamine and one or more of the following, in any suitable amount: water (e.g., 20- 80%), L-arginine hydrochloride (e.g., 0-25%), sodium chloride (e.g., 0-25%), potassium chloride (e.g., 0-25%), glyeryl steareate (e.g., 0-15%), cetyl alcohol (e.g., 0-15%), squalene (e.g., 0-15%), isopropyl mysterate (e.g., 0-15%), oleic acid (e.g., 0-15%), Tween 20 (e.g., 0-10 %), and/or butanediol (e.g., 0-10%).
- water e.g. 20- 80%
- L-arginine hydrochloride e.g., 0-25%)
- sodium chloride e.g., 0-25%)
- potassium chloride
- each compound can vary (or the compound may be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.
- the cream may include a pharmaceutical agent, and one or more ionic salts at a concentration at least sufficient to produce a hostile biophysical environment with respect to the pharmaceutical agent.
- the cream may include one or more of (w/v): a charged and/or hydrogen bonding entity (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%), and/or magnesium chloride (1-20% w/v).
- the cream may include one or more of (w/v): L-arginine hydrochloride (2.5-25%), choline chloride (10-30%), sodium chloride (5-20%), and/or magnesium chloride (5-20%).
- the cream may include one or more of (w/v): creatine (0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%), and/or theophylline (0.1-20%).
- the cream may also contain L-arginine
- hydrochloride (0-12.5% w/v) and/or theophylline (0-10% w/v).
- the percentages of each compound can vary (or the compound may be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.
- choline chloride, sodium chloride, and/or magnesium chloride can be used to provide a high ionic strength environment.
- the composition may include an antioxidant, which may be able to reduce or inhibit the oxidation of other molecules within the composition.
- suitable antioxidants include, but are not limited to, glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide dismutase and various peroxidases.
- the antioxidant may be present in any suitable concentration.
- the antioxidant may be present at a concentration of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% by weight of the composition.
- the pharmaceutical agent may be present at a concentration of no more than about 0.2%, no more than about 0.5%, no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, or no more than about 5% by weight of the composition.
- the composition may also be light-sensitive, in certain embodiments. Thus, in some cases, the composition may be contained within a dark or opaque container. In certain embodiments, the composition is also prepared under low-light conditions. Another set of embodiments is generally directed to compositions having relatively high temperature stability. For example, the composition may be stable at elevated temperatures such as at least 40 °C (at least about 104 °F) for periods of time of at least about a day.
- a composition of the present invention may further include a stabilization polymer, propylene glycol, and a polysorbate surfactant.
- stabilization polymers include xanthan gum, KELTROL ® BT and/or KELTROL ® RD; an example of a polysorbate surfactant is Polysorbate 20. Additional examples are discussed herein.
- compositions involving any two of these components were found to lack such high temperature stabilization properties. It is not currently known why this combination of components is remarkably effective at facilitating relatively high temperature stability of the compositions discussed herein, as these components are not known to participate in any significant chemical reactions with each other, and high temperature stability is greatly reduced when one of the components is removed.
- propylene glycol is not known to work in pharmaceutical compositions as a stabilizing agent.
- a composition may be determined to be one that has high temperature stability by determining whether the composition exhibits phase separation over a relatively long period of time, e.g., over at least an hour, at least about 2 hours, at least a day, at least about a week, at least about 4 weeks, etc.
- a composition is exposed to ambient temperature and pressure for at least 1 hour, and the composition is then analyzed to determine whether the composition exhibits phase separation or a change in phase.
- a stable compound is one that exhibits no phase separation, whereas an unstable compound may exhibit phase separation. Such stability may be useful, for example, for storage of the composition, transport of the composition, shelf life, or the like.
- a "stabilization polymer” is a polymer that comprises xanthan gum, a xanthan gum derivative, and/or a xanthan gum equivalent, for example, KELTROL ® BT and/or KELTROL ® RD, KELZAN ® XC, KELZAN ® XCD, KELZAN ® D, KELZAN ® CC,
- the stabilization polymer is chosen to be one which is at least generally regarded as safe for use in humans.
- the stabilization polymer is produced synthetically, and/or one which has been purified to some degree.
- the stabilization polymer may have any suitable molecular weight, for example, at least about 1 million, at least about 2 million, at least about 5 million, at least about 10 million, at least about 25 million, or at least about 50 million.
- the stabilization polymer may be present at any suitable concentration within the composition.
- the stabilization polymer may be present at a concentration of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1% by weight of the composition.
- the stabilization polymer may be present at a concentration of no more than about 0.1%, no more than about 0.2%, no more than about 0.4%, no more than about 0.6%, no more than about 0.8%, no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, no more than about 5%, no more than about 7%, no more than about 10%, no more than about 12%, no more than about 15%, or no more than about 20% by weight of the composition.
- more than one stabilization polymer may be present, and each stabilization polymer may be present in any suitable amount.
- the stabilization polymer consists essentially of KELTROL ® BT and/or KELTROL ® RD.
- the stabilization polymer may have a fixed ratio of KELTROL ® BT and/or KELTROL ® RD, for example, 1: 1 or 3:5 by weight.
- the KELTROL ® BT may be present at a concentration of about 0.3% by weight and the KELTROL ® RD may be present at a
- concentration of 0.5% by weight of the composition may be present at one of the other concentrations described above. Combinations of these and/or other
- stabilization polymers are also contemplated in other embodiments, e.g., KELTROL ® BT and xanthan gum, KELTROL ® RD and xanthan gum, etc.
- thickening agents can be used instead of, or in conjunction with a stabilization polymer.
- Many thickening agents can be obtained commercially.
- Thickening agents include those used in the food industry, or are GRAS agents (generally regarded as safe), e.g., alginin, guar gum, locust bean gum, collagen, egg white, furcellaran, gelatin, agar, and/or carrageenan, as well as combinations of these and/or other stabilization polymers. It should thus be appreciated that, in the specification herein, references to stabilization polymers, in other embodiments, should be understood to also include thickening agents in conjunction or instead of stabilization polymers,
- Propylene glycol can be obtained commercially, and can be present as any stereoisomer or racemic mixture of isomers. It may also be present at any suitable concentration. For instance, propylene glycol may be present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition.
- propylene glycol may be present at a concentration of no more than about 2%, no more than about 4%, no more than about 6%, no more than about 8%, no more than about 10%, no more than about 12%, no more than about 15%, no more than about 20%, or no more than about 25% by weight of the composition.
- other glycols can be used in conjunction or instead of propylene glycol, such as butylene glycol. Accordingly, it should thus be appreciated that, in the specification herein, references to propylene glycol, in other embodiments, should be understood to also include other glycols (e.g., a low molecular weight glycol, or a polyglycol, as described herein) in conjunction or instead of propylene glycol.
- a polysorbate surfactant can also be present any suitable concentration within the composition.
- the polysorbate surfactant may be present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition.
- the polylsorbate surfactant may be present at a concentration of no more than about 2%, no more than about 4%, no more than about 6%, no more than about 8%, no more than about 10%, no more than about 12%, no more than about 15%, no more than about 20%, or no more than about 25% by weight of the composition
- a "polysorbate surfactant,” as used herein, is a surfactant comprising a polysorbate.
- the surfactant may comprise sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, or another sorbitan salt.
- the polysorbate surfactant has a molecular formula:
- w, x, y, and z are any suitable positive integers, w, x, y, and z may also each be independently the same or different. In one set of embodiments, w+x+y+z is 20 (e.g., as in Polysorbate 20). In some cases, other polymeric sugars can be used instead of, or in conjunction with, a polysorbate surfactant. Thus, it should be appreciated that, in the specification herein, references to a polysorbate surfactant are by way of example, and in other embodiments, it should be understood that references to a polysorbate surfactant may include other polymeric sugars in conjunction or instead of a polysorbate surfactant.
- the composition may have a fixed ratio of the stabilization polymer to propylene glycol to the polysorbate surfactant.
- the ratio of these may be about 1: 1: 1, about 1:6:3, about 1:6:2, about 1:7:2, about 1:7:3, about 1.5: 1: 1, about 1.5:6:3, about 1.5:6:4, about 1:6:2.5, about 1:6.25:2.5, about 1:6.25:2.5, etc.
- such ratios may be useful, in certain embodiments of the invention, in providing temperature stability to the composition.
- a pharmaceutical agent may be combined with a penetrating agent, i.e., an agent that increases transport of the pharmaceutical agent into the skin, relative to transport in the absence of the penetrating agent.
- a penetrating agent i.e., an agent that increases transport of the pharmaceutical agent into the skin, relative to transport in the absence of the penetrating agent.
- the penetrating agent may define and/or be combined with a hostile biophysical environment.
- penetrating agents examples include oleoresin capsicum or its constituents, or certain molecules containing heterocyclic rings to which are attached hydrocarbon chains.
- Non-limiting examples of penetrating agents include, but are not limited to, cationic, anionic, or nonionic surfactants (e.g., sodium dodecyl sulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g., benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane); amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g., n-butyrate); organic acids (e.g., citric acid); polyols (e.g., ethylene glycol, glycerol); sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g., cyclohexen
- another aspect of the invention provides for the delivery of pharmaceutical agents (e.g., drugs, biological compounds, etc.) into the body, and such treatments may be systemic or localized, e.g., directed to a specific location of the body of a subject, such as the head, one or more specific muscles, an arm, a leg, the genitals, etc., depending on the specific application.
- pharmaceutical agents e.g., drugs, biological compounds, etc.
- treatments may be systemic or localized, e.g., directed to a specific location of the body of a subject, such as the head, one or more specific muscles, an arm, a leg, the genitals, etc., depending on the specific application.
- pharmaceutical agents are introduced to aid in treatment of medical conditions or diseases, and the symptoms associated thereof.
- the invention provides for the treatment of medical conditions or diseases and/or ailments using pharmaceutical agents (for example, to treat a subject diagnosed with a medical condition or disease), and in some cases, the invention provides for the delivery of a minimum amount of pharmaceutical agents to provide effective levels of medication to an effected area topically while limiting side effects.
- the effective dosage of the pharmaceutical agent may be lower than the effective dosage of the pharmaceutical agent when taken orally.
- Other embodiments of the invention provide methods for treating pain, for example, pain from migraine, pain from arthritis, other headaches, joint pain, muscle pain and other types of pain.
- a composition may be topically applied to a specific location of the body, e.g., to a site of pain.
- a composition as described herein may be used in the preparation of a medicament for treatment of pain, or other diseases or conditions as discussed herein.
- kits typically defines a package or an assembly including one or more of the compositions of the invention, and/or other compositions associated with the invention, for example, as described herein.
- kits typically defines a package or an assembly including one or more of the compositions of the invention, and/or other compositions associated with the invention, for example, as described herein.
- Each of the compositions of the kit may be provided in liquid form (e.g., in solution), or in solid form (e.g., a dried powder).
- some of the compositions may be constitutable or otherwise processable (e.g., to an active form), for example, by the addition of a suitable solvent or other species, which may or may not be provided with the kit.
- compositions or components associated with the invention include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binding agents, bulking agents, preservatives, drying agents, antimicrobials, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps, patches, containers, and the like, for example, for using, administering, modifying, assembling, storing, packaging, preparing, mixing, diluting, and/or preserving the compositions components for a particular use, for example, to a sample and/or a subject.
- a kit of the invention may, in some cases, include instructions in any form that are provided in connection with the compositions of the invention in such a manner that one of ordinary skill in the art would recognize that the instructions are to be associated with the compositions of the invention.
- the instructions may include instructions for the use, modification, mixing, diluting, preserving, administering, assembly, storage, packaging, and/or preparation of the compositions and/or other compositions associated with the kit.
- the instructions may also include instructions for the delivery and/or administration of the compositions, for example, for a particular use, e.g., to a sample and/or a subject.
- the instructions may be provided in any form recognizable by one of ordinary skill in the art as a suitable vehicle for containing such instructions, for example, written or published, verbal, audible (e.g., telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) or electronic communications (including Internet or web-based communications), provided in any manner.
- verbal e.g., telephonic
- digital e.g., optical, visual
- visual e.g., videotape, DVD, etc.
- electronic communications including Internet or web-based communications
- the present invention is directed to methods of promoting one or more embodiments of the invention as discussed herein, for example, methods of promoting the making or use of compositions such as those discussed above, methods of promoting kits as discussed above, or the like.
- “promoted” includes all methods of doing business including, but not limited to, methods of selling, advertising, assigning, licensing, contracting, instructing, educating, researching, importing, exporting, negotiating, financing, loaning, trading, vending, reselling, distributing, repairing, replacing, insuring, suing, patenting, or the like that are associated with the systems, devices, apparatuses, articles, methods, compositions, kits, etc. of the invention as discussed herein.
- Methods of promotion can be performed by any party including, but not limited to, personal parties, businesses (public or private), partnerships, corporations, trusts, contractual or sub-contractual agencies, educational institutions such as colleges and universities, research institutions, hospitals or other clinical institutions,
- Promotional activities may include communications of any form (e.g., written, oral, and/or electronic communications, such as, but not limited to, e-mail, telephonic, Internet, Web-based, etc.) that are clearly associated with the invention.
- the method of promotion may involve one or more instructions.
- "instructions” can define a component of instructional utility (e.g., directions, guides, warnings, labels, notes, FAQs or "frequently asked questions,” etc.), and typically involve written instructions on or associated with the invention and/or with the packaging of the invention.
- Instructions can also include instructional communications in any form (e.g., oral, electronic, audible, digital, optical, visual, etc.), provided in any manner such that a user will clearly recognize that the instructions are to be associated with the invention, e.g., as discussed herein.
- instructional communications in any form (e.g., oral, electronic, audible, digital, optical, visual, etc.), provided in any manner such that a user will clearly recognize that the instructions are to be associated with the invention, e.g., as discussed herein.
- PCT/US2005/005726 filed February 23, 2005, entitled “Topical Delivery of a Nitric Oxide Donor to Improve Body and Skin Appearance," by E. Fossel, published as WO 2005/081964 on September 9, 2005; International Patent Application No. PCT/US2005/013228, filed April 19, 2005, entitled “Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment,” by E. Fossel, published as WO 2005/102282 on November 3, 2005; International Patent Application No. PCT/US2005/013230, filed April 19, 2005, entitled “Beneficial Effects of Increasing Local Blood Flow,” by E. Fossel, published as WO 2005/102307 on November 3, 2005; U.S. Patent Application Serial No.
- compositions for Preparing Emulsions for Topical Drug Delivery by E.T. Fossel.
- This prophetic example illustrates one method of preparing a transdermal formula of the invention including fexofenadine, cetirizine, diphenhydramine, or loratadine.
- the final composition is shown in Table 1.
- percentages other than the ones listed below are also possible, according to other embodiments of the invention.
- sodium chloride, potassium chloride, L- arginine and fexofenadine, cetirizine, diphenhydramine, or loratadine were mixed in water, then heated to 74 °C with rapid mixing. In a separate container, the remaining ingredients were mixed together and heated to 74 °C. The other ingredients were then added to the water phase at 74 °C with rapid mixing. The mixture was then cooled to room temperature with continued mixing. At this point, an emulsion formed with a relatively thin consistency. The emulsion was then homogenized at high speed at room temperature to thicken the consistency.
- compositions described in this example for the first aqueous and second non-aqueous preparations for use with ibuprofen may be used for other drugs or other pharmaceutical agents such as those described herein (e.g., an Hi antihistamine), or may be modified to contain equivalent or similar compounds (or a subset thereof) for use with different drugs or other pharmaceutical agents , and each drug or other pharmaceutical agent may individually be provided in the first preparation, the second preparation, or both.
- drugs or other pharmaceutical agents such as those described herein (e.g., an Hi antihistamine)
- each drug or other pharmaceutical agent may individually be provided in the first preparation, the second preparation, or both.
- Ibuprofen sodium salt is water soluble at pH 7.0 and is added to the water phase. Any suitable ibuprofen salt may be used. For example, a commercially available ibuprofen salt may be used. In some embodiments, an ibuprofen preparation is manufactured to have the following relative composition (Table 2).
- Polysorbate-20 NF 2.0 The basic manufacturing process is to form an emulsion by mixing a water phase and an oil phase at elevated temperature with rapid mixing. Once the two phases are mixed the mixture is cooled to room temperature. While cooling is being accomplished homomixing is
- Step 1 disperse xanthan gum in the propylene glycol and water and mix to fully hydrate.
- Step 2 To the above mixture add ibuprofen and sodium hydroxide to produce sodium ibuprofen, add sodium chloride, potassium chloride and 1-arginine HCl. Heat this mixture to 75 °C to 80 °C.
- Step 3 Add glyceryl stearate SE, cetyl alcohol, squalane, isopropyl myristate, oleic acid and polysorbate-20 and heat this mixture to 75 °C to 80 °C.
- Step 4 Combine the mixtures produced in Step 2 and Step 3 and mix well maintaining temperature.
- Step 5 Cool the mixture of Step 4 to 25 °C to 30 °C while circulating through the vertical colloid mill.
- the resulting smooth emulsion has a pH of 6.50 to 7.50.
- the preparation can be manufactured under conditions to minimize microbial content (e.g., completely sterile or with a microbiological content of less than about 100 CFU/g).
- a transdermal ibuprofen cream is packaged in 100 ml "Magic Star Dispensers" which are airless pumps. The pump dispenses 1.45 ml with each depression of the pump head.
- the active compound e.g., diphenhydramine
- the active compound may be added to the aqueous phase prior to mixing with the oil phase.
- other compounds may be added to the oil phase prior to mixing with the aqueous phase.
- a 19 year old male with a tendency to develop hives was given a cream containing 7.5% diphenhydramine in an oil/water emulsion to which 10% sodium chloride and 5% magnesium chloride was added.
- the pH of the cream was 7.2.
- the subject was at an outdoor sporting event when he developed a moderate case of hives over the exposed upper part of his body.
- the formula for the topical composition that was used for diphenhydramine is provided in Table 3 below (shown as % weight). It should be appreciated that the relative amounts of each component may be varied (e.g., by about 10 %) in some embodiments. It also should be appreciated that this topical composition may be used for other antihistamines (e.g., one or more examples of Hi antihistamines including, but not limited to, fexofenadine, cetirizine (or levocertrizine), clemastine, diphenhydramine, doxylamine, pheniramine, ebastine,
- Hi antihistamines including, but not limited to, fexofenadine, cetirizine (or levocertrizine), clemastine, diphenhydramine, doxylamine, pheniramine, ebastine,
- chlorpheniramine meclizine, embramine, dexchlorpheniramine, and loratadine).
- the active compound may be added to the oil phase prior to mixing with the aqueous phase.
- other compounds e.g., diphenhydramine
- diphenhydramine may be added to the aqueous phase prior to mixing with the oil phase.
- Polysorbate 20 2 While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used.
- a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
- the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
- This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
- At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/977,511 US9289495B2 (en) | 2010-12-29 | 2011-12-29 | Systems and methods for treatment of allergies and other indications |
EP11854321.4A EP2658554A4 (en) | 2010-12-29 | 2011-12-29 | Systems and methods for treatment of allergies and other indications |
JP2013547682A JP2014501283A (en) | 2010-12-29 | 2011-12-29 | Systems and methods for the treatment of allergies and other indications |
CN2011800686275A CN103442723A (en) | 2010-12-29 | 2011-12-29 | Systems and methods for treatment of allergies and other indications |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201061428213P | 2010-12-29 | 2010-12-29 | |
US201061428003P | 2010-12-29 | 2010-12-29 | |
US61/428,213 | 2010-12-29 | ||
US61/428,003 | 2010-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012092523A1 true WO2012092523A1 (en) | 2012-07-05 |
Family
ID=46383539
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/067987 WO2012092523A1 (en) | 2010-12-29 | 2011-12-29 | Systems and methods for treatment of allergies and other indications |
Country Status (5)
Country | Link |
---|---|
US (1) | US9289495B2 (en) |
EP (1) | EP2658554A4 (en) |
JP (1) | JP2014501283A (en) |
CN (2) | CN103442723A (en) |
WO (1) | WO2012092523A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7629384B2 (en) * | 1997-09-17 | 2009-12-08 | Strategic Science & Technologies, Llc | Topical delivery of L-arginine to cause beneficial effects |
ES2429443T3 (en) | 2004-04-19 | 2013-11-14 | Strategic Science & Technologies, Llc | Transdermal supply of beneficial substances by means of an environment of high ionic strength |
US9226909B2 (en) | 2004-04-19 | 2016-01-05 | Strategic Science & Technologies, Llc | Beneficial effects of increasing local blood flow |
US8604081B2 (en) | 2009-06-24 | 2013-12-10 | Strategic Science & Technologies, Llc | Topical composition containing ibuprofen |
WO2010151241A1 (en) | 2009-06-24 | 2010-12-29 | Strategic Science & Technologies, Llc | Topical composition containing naproxen |
US11684624B2 (en) | 2009-06-24 | 2023-06-27 | Strategic Science & Technologies, Llc | Treatment of erectile dysfunction and other indications |
PT2658551T (en) | 2010-12-29 | 2020-07-24 | Strategic Science & Tech Llc | Treatment of erectile dysfunction and other indications |
EP3468530A4 (en) | 2016-06-10 | 2020-03-11 | Clarity Cosmetics Inc. | Non-comedogenic hair and scalp care formulations and method for use |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080233183A1 (en) * | 2007-03-22 | 2008-09-25 | Pathfinder Management, Inc. | Topical formulations having enhanced bioavailability |
US20100280122A1 (en) * | 2004-04-19 | 2010-11-04 | Strategic Science & Technologies, Llc | Transdermal delivery of beneficial substances effected by a hostile biophysical environment |
US20110182977A1 (en) * | 2009-06-24 | 2011-07-28 | Strategic Science & Technologies, Llc | Topical composition containing ibuprofen |
Family Cites Families (188)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR5799M (en) | 1966-03-22 | 1968-03-25 | ||
FR5940M (en) | 1966-10-18 | 1968-04-08 | ||
FR1553063A (en) | 1967-11-28 | 1969-01-10 | ||
US3960782A (en) | 1974-09-27 | 1976-06-01 | The Procter & Gamble Company | Shampoo compositions which impart high luster and manageability to hair |
US4185100A (en) | 1976-05-13 | 1980-01-22 | Johnson & Johnson | Topical anti-inflammatory drug therapy |
JPS5753404A (en) | 1980-09-17 | 1982-03-30 | Kao Corp | External preparation for skin obtained by blending plant extract |
GB2094142B (en) | 1981-03-06 | 1984-09-26 | Lab For Applied Biology Ltd | Injectable solution containing theophylline and a basic amino acid |
GB2126868B (en) | 1982-09-20 | 1986-03-19 | Ralston Purina Co | Method of improving the shelf life of processed meat products |
DE3327840C1 (en) | 1983-08-02 | 1984-09-20 | Blendax Werke Schneider Co | Skin care products |
FR2557452B1 (en) | 1983-12-28 | 1986-08-14 | Roussel Uclaf | NOVEL COMPOSITIONS FOR SKIN CARE CONTAINING PRIMER OIL AND RATE TISSUE TRAITS |
US4681897A (en) | 1984-01-16 | 1987-07-21 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
JPS60252412A (en) | 1984-05-29 | 1985-12-13 | Nichiban Co Ltd | Therapeutic poultice preparation |
US4722837A (en) | 1984-05-29 | 1988-02-02 | Derma-Cure, Inc. | Medicated shampoo composition |
US4692462A (en) | 1985-03-18 | 1987-09-08 | Menley & James Laboratories, Ltd. | Compositions and method of controlling transdermal penetration of topical and systemic agents |
US4732892A (en) | 1985-07-12 | 1988-03-22 | American Home Products Corporation | L-α-amino acids as transdermal penetration enhancers |
DE3684564D1 (en) | 1985-11-18 | 1992-04-30 | Beecham Group Plc | VETERINAERE COMPOSITIONS. |
GB8606368D0 (en) | 1986-03-14 | 1986-04-23 | Unilever Plc | Skin treatment composition |
FR2602678B1 (en) | 1986-08-13 | 1992-06-05 | Drouault Guy | AQUEOUS PHARMACEUTICAL COMPOSITION BASED ON MAGNESIUM, SODIUM AND POTASSIUM SALTS FOR THE REGULATION OF LOCAL CIRCULATIONS |
US4940456A (en) | 1987-02-10 | 1990-07-10 | Dan Sibalis | Electrolytic transdermal delivery of proteins |
US4885157A (en) | 1987-02-13 | 1989-12-05 | Fiaschetti Mary G | Dermal cosmetic composition and applications therefor |
DE3715576A1 (en) | 1987-05-09 | 1988-11-24 | Wella Ag | NEW MACROMOLECULAR, SURFACE-ACTIVE, QUATERNAIRE N-SUBSTITUTED CHITOSAN DERIVATIVES AND COSMETIC AGENT BASED ON THESE NEW CHITOSAN DERIVATIVES |
KR900004875Y1 (en) | 1987-10-02 | 1990-05-31 | 삼성전자 주식회사 | Horizontal window signal generating circuit for pip |
JPH045231Y2 (en) | 1987-12-16 | 1992-02-14 | ||
US5925372A (en) | 1987-12-16 | 1999-07-20 | Novartis Corporation | Mixed solvent mutually enhanced transdermal therapeutic system |
US4871718A (en) | 1987-12-29 | 1989-10-03 | Raymond A. Roncari | Composition of matter for increasing intracellular ATP levels and physical performance levels and for increasing the rate of wound repair |
GB2217595B (en) | 1988-04-21 | 1991-11-20 | American Cyanamid Co | Antiinflammatory gel |
DE3827362A1 (en) | 1988-08-12 | 1990-02-15 | Basf Ag | POWDERY, HYDROPHILE THEOPHYLINE FORMULATION AND METHOD FOR THE PRODUCTION THEREOF |
BR8907107A (en) | 1988-09-30 | 1991-02-05 | Kazuo Watanabe | ANTI-INFLAMMATORY AND ANALGESIC COMPOUNDS, RELATED COMPOSITIONS AND METHODS FOR THE PREPARATION AND USE OF THE SAME |
US4945901A (en) | 1989-03-22 | 1990-08-07 | Burcke Jr Harry J | Hand therapy apparatus and method therefor |
US5158761A (en) | 1989-04-05 | 1992-10-27 | Toko Yakuhin Kogyo Kabushiki Kaisha | Spray gel base and spray gel preparation using thereof |
US5476852A (en) | 1989-05-03 | 1995-12-19 | Janssen Pharmaceutica N.V. | Method of topically treating acne vulgaris, hyperkeratotic dermatoses, and photo-aging of the skin |
US5028435A (en) | 1989-05-22 | 1991-07-02 | Advanced Polymer Systems, Inc. | System and method for transdermal drug delivery |
JP2761939B2 (en) | 1989-09-04 | 1998-06-04 | 株式会社コーセー | Oil-in-water emulsion cosmetic |
DE69022678T2 (en) | 1989-10-17 | 1996-03-21 | Merck & Co Inc | S (+) - ibuprofen-L-amino acid and S (+) - ibuprofen-D-amino acid as analgesics with greater pharmacological potential. |
US5576351A (en) | 1989-12-29 | 1996-11-19 | Mcgaw, Inc. | Use of arginine as an immunostimulator |
EP0441119A3 (en) | 1990-01-09 | 1992-10-14 | Richard D. Levere | The use of l-arginine in the treatment of hypertension and other vascular disorders |
US5332758A (en) | 1990-07-13 | 1994-07-26 | Kanebo, Ltd. | Collagen metabolism ameliorant and its use |
US5824658A (en) | 1990-09-18 | 1998-10-20 | Hyal Pharmaceutical Corporation | Topical composition containing hyaluronic acid and NSAIDS |
DE69108402T2 (en) | 1990-11-14 | 1995-10-05 | Upjohn Co | 5-FLUOR-2,4,6-PYRIMIDINTHIAMINE DERIVATIVES TO PREVENT HAIR LOSS. |
DE4100975A1 (en) | 1991-01-15 | 1992-07-16 | Weuffen Wolfgang | Cosmetic or pharmaceutical preparations for improving hair quality and promoting hair growth |
US5210099A (en) | 1991-02-11 | 1993-05-11 | American Home Products Corporation | Analgesic compositions |
EP0531495B1 (en) | 1991-03-01 | 1997-08-20 | Atherton Investments, Ltd. | Therapeutic and cosmetic compositions for treatment of skin |
BR9205713A (en) | 1991-03-01 | 1994-06-07 | Atherton Investments Ltd | Active ingredient of gastropod secretion, process for its preparation, and composition of active ingredient |
US5498420A (en) | 1991-04-12 | 1996-03-12 | Merz & Co. Gmbh & Co. | Stable small particle liposome preparations, their production and use in topical cosmetic, and pharmaceutical compositions |
DE69202098T2 (en) | 1991-05-27 | 1995-08-17 | Fujisawa Pharmaceutical Co | N-pentadecyl nicotinate N-oxide and hair restorer containing it. |
JP2636118B2 (en) | 1991-09-10 | 1997-07-30 | 三省製薬株式会社 | Hair restorer |
US5254331A (en) | 1991-09-12 | 1993-10-19 | Chanel, Inc. | Skin cream composition |
US5215759A (en) | 1991-10-01 | 1993-06-01 | Chanel, Inc. | Cosmetic composition |
US5217652A (en) | 1991-10-04 | 1993-06-08 | The Gillette Company | Conditioning shampoo |
IT1252061B (en) | 1991-11-22 | 1995-05-29 | Gentili Ist Spa | COMPOSITIONS FOR DERMATOLOGICAL AND COSMETIC USE |
DE69320378T2 (en) | 1992-01-21 | 1999-04-29 | Macrochem Corp | Iontophoretic improved drug delivery |
JP3302995B2 (en) | 1992-04-01 | 2002-07-15 | 株式会社ダイゾー | Aerosol composition |
US5632981A (en) | 1992-08-24 | 1997-05-27 | The United States Of America As Represented By The Department Of Health And Human Services | Biopolymer-bound nitric oxide-releasing compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same |
US5691423A (en) | 1992-08-24 | 1997-11-25 | The United States Of America As Represented By The Department Of Health And Human Services | Polysaccharide-bound nitric oxide-nucleophile adducts |
US5405919A (en) | 1992-08-24 | 1995-04-11 | The United States Of America As Represented By The Secretary Of Health And Human Services | Polymer-bound nitric oxide/nucleophile adduct compositions, pharmaceutical compositions and methods of treating biological disorders |
US5464954A (en) | 1992-08-31 | 1995-11-07 | Idec Izumi Corporation | Safety switch assembly |
GB9222772D0 (en) | 1992-10-30 | 1992-12-09 | Unilever Plc | Cosmetic composition |
US5573776A (en) | 1992-12-02 | 1996-11-12 | Alza Corporation | Oral osmotic device with hydrogel driving member |
JP3191833B2 (en) | 1993-02-24 | 2001-07-23 | 三菱東京製薬株式会社 | Hair restorer |
JPH06287135A (en) | 1993-04-01 | 1994-10-11 | Lion Corp | External agent composition for skin |
US5439938A (en) | 1993-04-07 | 1995-08-08 | The Johns Hopkins University | Treatments for male sexual dysfunction |
US5428070A (en) | 1993-06-11 | 1995-06-27 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of vascular degenerative diseases by modulation of endogenous nitric oxide production of activity |
US5852058A (en) | 1993-06-11 | 1998-12-22 | The Board Of Trustees Of The Leland Stanford Junior University | Intramural delivery of nitric oxide enhancer for inhibiting lesion formation after vascular injury |
US5891459A (en) | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
DE4338793A1 (en) | 1993-11-12 | 1995-05-18 | Froelich Juergen C | L-arginine and analogues as platelet aggregation inhibitors |
DE4341000A1 (en) | 1993-12-02 | 1995-06-08 | Beiersdorf Ag | Use of L-arginine, L-ornithine or L-citrulline and topical preparations with these substances |
US5714472A (en) | 1993-12-23 | 1998-02-03 | Nestec Ltd. | Enternal formulation designed for optimized nutrient absorption and wound healing |
GB9409281D0 (en) | 1994-05-10 | 1994-06-29 | Svedman Paul | Transdermal device |
JPH07316075A (en) | 1994-05-26 | 1995-12-05 | Pola Chem Ind Inc | External preparation for skin |
US6190704B1 (en) | 1994-09-23 | 2001-02-20 | New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Regulation of wound healing by nitric oxide |
US5543430A (en) | 1994-10-05 | 1996-08-06 | Kaesemeyer; W. H. | Method and formulation of stimulating nitric oxide synthesis |
US5505958A (en) | 1994-10-31 | 1996-04-09 | Algos Pharmaceutical Corporation | Transdermal drug delivery device and method for its manufacture |
MX9703184A (en) | 1994-11-04 | 1997-12-31 | Polymun Scient Inmunbiologisch | Application of superoxide dismutase in liposomes. |
US5594032A (en) | 1994-11-10 | 1997-01-14 | Gonzalez-Cadavid; Nestor F. | Amelioration of human erectile dysfunction by treatment with iNOS, inducers of iNOS or iNOS cDNA |
US5648101A (en) | 1994-11-14 | 1997-07-15 | Tawashi; Rashad | Drug delivery of nitric oxide |
US5562917A (en) | 1994-12-23 | 1996-10-08 | Pentech Pharmaceuticals, Inc. | Transdermal administration of apomorphine |
US5853768A (en) | 1995-03-01 | 1998-12-29 | Altadonna; James | Topical preparation and method for pain relief |
US5654337A (en) | 1995-03-24 | 1997-08-05 | II William Scott Snyder | Topical formulation for local delivery of a pharmaceutically active agent |
US5595753A (en) | 1995-04-14 | 1997-01-21 | President And Fellows Of Harvard College | Topical formulations and methods for treating hemorrhoidal pain and sphincter and smooth muscle spasm in the gastrointestinal tract |
US5643586A (en) | 1995-04-27 | 1997-07-01 | Perricone; Nicholas V. | Topical compositions and methods for treatment of skin damage and aging using catecholamines and related compounds |
US5698738A (en) | 1995-05-15 | 1997-12-16 | Board Of Regents, The University Of Texas System | N-nitroso-N-substituted hydroxylamines as nitric oxide donors |
US5762963A (en) | 1995-06-07 | 1998-06-09 | Emory University | Method and compositions for controlling oral and pharyngeal pain using capsaicinoids |
US5645859A (en) | 1995-10-02 | 1997-07-08 | Isp Investments Inc. | Process for producing an alpha or beta-hydroxy acid-vinylpyrrolidone polymer, copolymer or graft polymer complex in the form of free-flowing powders having a high acid loading |
US5605685A (en) | 1995-09-13 | 1997-02-25 | Isp Investments Inc. | Non-irritating skin and hair rejuvenating compostion having a pH between 1 and 6.5 |
US5734080A (en) | 1995-09-22 | 1998-03-31 | Anihealth Corporation | Reaction product of arginine and p-aminobenzoic acid, cosmetic, and human and animal health compositions thereof |
US6036977A (en) | 1995-09-29 | 2000-03-14 | L.A.M. Pharmaceutical Corp. | Drug preparations for treating sexual dysfunction |
FR2740339B1 (en) | 1995-10-26 | 1997-12-05 | Oreal | USE OF AT LEAST ONE NO-SYNTHASE INHIBITOR IN THE TREATMENT OF SENSITIVE SKIN |
FR2740453B1 (en) | 1995-10-27 | 1998-01-16 | Bieurope | PEPTIDE MIXTURES, THEIR PREPARATION AND COSMETIC COMPOSITIONS CONTAINING THEM |
JP2681881B2 (en) | 1995-11-24 | 1997-11-26 | ナショナル サイエンス カウンシル | Percutaneous absorption preparation of antiviral agent acyclovir |
US5789442A (en) | 1996-01-18 | 1998-08-04 | Schering Aktiengesellschaft | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents |
JPH09208460A (en) | 1996-01-31 | 1997-08-12 | Lion Corp | Cataplasm |
JP4020989B2 (en) | 1996-03-06 | 2007-12-12 | 株式会社ノエビア | Blood flow promoting agent and external preparation for skin comprising the same |
GB9608408D0 (en) | 1996-04-23 | 1996-06-26 | Adams Michael A | Treatment of erectile dysfunction |
US5911980A (en) | 1996-06-27 | 1999-06-15 | Macrochem Corporation | Lipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin |
US5985317A (en) | 1996-09-06 | 1999-11-16 | Theratech, Inc. | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents |
US20020015713A1 (en) | 1996-10-24 | 2002-02-07 | Murdock Robert W. | Methods and transdermal compositions for pain relief |
US5891472A (en) | 1996-11-19 | 1999-04-06 | Meri Charmyne Russell | Treatment of equine laminitis |
JPH10167953A (en) | 1996-12-06 | 1998-06-23 | Daicel Chem Ind Ltd | Cosmetic composition |
US5807957A (en) | 1996-12-23 | 1998-09-15 | Macrochem Corporation | Cationic film-forming polymer compositions, and use thereof in topical agents delivery system and method of delivering agents to the skin |
IL120531A (en) | 1997-03-26 | 2006-12-31 | Yissum Res Dev Co | Nitric oxide donors and pharmaceutical compositions containing them |
FR2762782B1 (en) | 1997-05-05 | 1999-06-11 | Oreal | COMPOSITION COMPRISING A MICROORGANISM CULTURE MEDIUM AND USE THEREOF |
AU726861B2 (en) | 1997-07-03 | 2000-11-23 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Novel nitric oxide-releasing amidine- and enamine-derived diazeniumdiolates, compositions and uses thereof and method of making same |
US5976566A (en) | 1997-08-29 | 1999-11-02 | Macrochem Corporation | Non-steroidal antiinflammtory drug formulations for topical application to the skin |
US6207713B1 (en) | 1997-09-17 | 2001-03-27 | Eric T. Fossel | Topical and oral delivery of arginine to cause beneficial effects |
US5895658A (en) | 1997-09-17 | 1999-04-20 | Fossel; Eric T. | Topical delivery of L-arginine to cause tissue warming |
US5922332A (en) | 1997-09-17 | 1999-07-13 | Fossel; Eric T. | Topical delivery of arginine to overcome pain |
US7914814B2 (en) | 1997-09-17 | 2011-03-29 | Strategic Science & Technologies, Llc | Topical delivery of arginine of cause beneficial effects |
US7629384B2 (en) | 1997-09-17 | 2009-12-08 | Strategic Science & Technologies, Llc | Topical delivery of L-arginine to cause beneficial effects |
ES2340450T3 (en) | 1997-09-17 | 2010-06-02 | STRATEGIC SCIENCE & TECHNOLOGIES, LLC | A SUPPLY OF ARGININE FOR THE WARMING OF COLD / COLD FABRICS. |
US6096759A (en) | 1997-09-19 | 2000-08-01 | Georgetown University | Method for treating essential hypertension |
US5906822A (en) | 1997-09-25 | 1999-05-25 | Macrochem Corporation | Cationic film-forming polymer compositions, and use thereof in topical agents delivery system and method of delivering agents to the skin |
US6046244A (en) | 1997-11-05 | 2000-04-04 | Nexmed Holdings, Inc. | Topical compositions for prostaglandin E1 delivery |
GB9801398D0 (en) | 1998-01-22 | 1998-03-18 | Anggard Erik E | Chemical compounds |
EA003741B1 (en) | 1998-06-01 | 2003-08-28 | Энтони Дж. Вербискар | Topical transdermal treatments |
US6103275A (en) | 1998-06-10 | 2000-08-15 | Nitric Oxide Solutions | Systems and methods for topical treatment with nitric oxide |
US6117872A (en) | 1998-06-23 | 2000-09-12 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of exercise performance by augmenting endogenous nitric oxide production or activity |
DE69939019D1 (en) | 1998-07-07 | 2008-08-14 | Transdermal Technologies Inc | COMPOSITIONS FOR THE RAPID AND NON-IRRITANT TRANSDERMAL ADMINISTRATION OF PHARMACEUTICALS AND METHOD FOR FORMULING THEREOF AND THEIR ADMINISTRATION |
DE19830649C2 (en) | 1998-07-09 | 2003-04-10 | Lohmann Therapie Syst Lts | Topical patch with nonsteroidal anti-inflammatory drugs with acid group |
DE19831798A1 (en) | 1998-07-15 | 2000-01-27 | Mandorlo Investment Gmbh Luxem | Microcirculation improving skin and tissue care or treatment composition, containing salts, aminoacids and peroxide, used as cosmetic, medicament or nutrient supplement |
JP2002528400A (en) | 1998-10-26 | 2002-09-03 | ユニバーシティー オブ マサチューセッツ | Skin treatment with adenosine or adenosine analogues |
US6261594B1 (en) | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
JP2000186028A (en) | 1998-12-21 | 2000-07-04 | Nobuko Koga | Cosmetic |
FR2787996B1 (en) | 1998-12-30 | 2002-05-10 | Dior Christian Parfums | COSMETIC OR DERMATOLOGICAL COMPOSITION CONTAINING AN ACTIVE INGREDIENT THAT STIMULATES THE SYNTHESIS OF HSP 32 PROTEIN IN THE SKIN AND COSMETIC PROCESSING METHOD |
US6852739B1 (en) | 1999-02-26 | 2005-02-08 | Nitromed Inc. | Methods using proton pump inhibitors and nitric oxide donors |
AU3490300A (en) | 1999-03-12 | 2000-10-04 | Nitromed, Inc. | Dopamine agonists in combination with nitric oxide donors, compositions and methods of use |
AU777395B2 (en) | 1999-03-12 | 2004-10-14 | Mt Industries, Inc. | Misting apparatus for application of coating materials to skin surface |
US6375672B1 (en) | 1999-03-22 | 2002-04-23 | Board Of Trustees Of Michigan State University | Method for controlling the chemical and heat induced responses of collagenous materials |
FR2794974B1 (en) | 1999-06-16 | 2001-08-17 | Exsymol Sa | COSMETIC COMPOSITION FOR SLIMMING BASED ON L-ARGININE, AN ANALOG OF L-ARGININE OR A DERIVATIVE THEREOF, APPLICABLE TOPICALLY |
WO2001017499A1 (en) | 1999-09-07 | 2001-03-15 | Kabushiki Kaisha Soken | Skin normalizing agents |
US6558695B2 (en) | 1999-12-16 | 2003-05-06 | Dermatrends, Inc. | Topical and transdermal administration of peptidyl drugs using hydroxide releasing agents as permeation enhancers |
US6719997B2 (en) | 2000-06-30 | 2004-04-13 | Dermatrends, Inc. | Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers |
US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
US6582724B2 (en) | 1999-12-16 | 2003-06-24 | Dermatrends, Inc. | Dual enhancer composition for topical and transdermal drug delivery |
US6562370B2 (en) | 1999-12-16 | 2003-05-13 | Dermatrends, Inc. | Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers |
US6586000B2 (en) | 1999-12-16 | 2003-07-01 | Dermatrends, Inc. | Hydroxide-releasing agents as skin permeation enhancers |
US6565879B1 (en) | 1999-12-16 | 2003-05-20 | Dermatrends, Inc. | Topical and transdermal administration of peptidyl drugs with hydroxide-releasing agents as skin permeation enhancers |
FR2802414B1 (en) | 1999-12-20 | 2003-06-27 | G Pharm Lab | COMPOSITION, ESPECIALLY COSMETIC OR DERMATOLOGICAL, CONTAINING OLIGOSACCHARIDES, METHOD FOR THE PREPARATION THEREOF AND METHOD FOR THE COSMETIC TREATMENT |
JP2001288068A (en) | 2000-04-06 | 2001-10-16 | Nof Corp | Skin cosmetic |
FR2810540B1 (en) | 2000-06-21 | 2004-04-30 | C3D | NEW COSMETIC OR HYGIENIC PREPARATIONS IN THE FORM OF DISPERSION |
JP2002003373A (en) | 2000-06-27 | 2002-01-09 | Shiseido Co Ltd | Skin care preparation |
HUP0002628A2 (en) | 2000-07-14 | 2002-06-29 | Keri Pharma Kft | Pharmaceutical combinations for treating diabetes |
US6538033B2 (en) | 2000-08-29 | 2003-03-25 | Huntington Medical Research Institutes | Nitric oxide donor compounds |
US6468557B1 (en) | 2001-01-05 | 2002-10-22 | Alphamed Pharmaceutical Corp. | Method for treating infectious viral diseases |
WO2002062306A1 (en) | 2001-01-25 | 2002-08-15 | The General Hospital Corporation | Nos inhibitors for treatment of wrinkles |
WO2002087700A1 (en) | 2001-04-26 | 2002-11-07 | The Procter & Gamble Company | Method, kit and device for the treatment of cosmetic skin conditions |
DE10128910A1 (en) | 2001-06-15 | 2002-12-19 | Beiersdorf Ag | Combination of arginine and ascorbic acid is used in the production of cosmetic or dermatological compositions for tightening and/or strengthening the skin, especially in cellulite treatment |
ATE450187T1 (en) | 2001-12-06 | 2009-12-15 | Univ Duke | PREVENTION OF SKIN FLAPE NECROSIS IN PLASTIC SURGERY |
US20030157185A1 (en) | 2002-02-08 | 2003-08-21 | Lou Paradise | Topical treatment of neuropathy |
WO2003072039A2 (en) | 2002-02-22 | 2003-09-04 | Essentia Biosystems, Inc. | Cosmetic formulations containing l-arginine oligomers |
CA2479098A1 (en) | 2002-03-20 | 2003-09-25 | Maree Therese Smith | Methods and compositions comprising nitric oxide donors and opioid analgesics |
KR20050004809A (en) | 2002-03-22 | 2005-01-12 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Use of il-18 inhibitors for the treatment and/or prevention of peripheral vascular diseases |
JP2003286129A (en) | 2002-03-27 | 2003-10-07 | Hakugen:Kk | Slimming sheet material |
AU2003223491A1 (en) | 2002-04-05 | 2003-10-27 | Nitromed, Inc. | Nitric oxide donors, compositions and methods of use |
RU2229286C2 (en) | 2002-05-27 | 2004-05-27 | Пятигорская государственная фармацевтическая академия | Ibuprofen ointment prepared on polyethylene oxide base and eliciting anti-inflammatory effect |
JP4419368B2 (en) | 2002-07-25 | 2010-02-24 | 小野薬品工業株式会社 | Prostaglandin derivatives and drugs containing the derivatives as active ingredients |
US20020168424A1 (en) | 2002-07-31 | 2002-11-14 | Dr. Mohsen Shahinpoor | Nitric oxide (NO) donor+cGMP-PDE5 inhibitor as a topical drug for glaucoma |
US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
US7241456B2 (en) | 2002-10-25 | 2007-07-10 | Australian Importers Ltd. | Formulations for topical delivery of bioactive substances and methods for their use |
KR100673044B1 (en) | 2003-05-16 | 2007-01-22 | 로터스 파마세티컬 리미티드 컴퍼니 | The composition for external use by percutaneous administration |
AU2003903037A0 (en) | 2003-06-17 | 2003-07-03 | Institute Of Nutraceutical Research | Connective tissue derived polypeptides |
US20070065463A1 (en) | 2003-06-20 | 2007-03-22 | Ronald Aung-Din | Topical therapy for the treatment of migranes, muscle sprains, muscle spasms, spasticity and related conditions |
US20050069590A1 (en) | 2003-09-30 | 2005-03-31 | Buehler Gail K. | Stable suspensions for medicinal dosages |
JP2005200370A (en) | 2004-01-16 | 2005-07-28 | Nikko Chemical Co Ltd | Nitrogen monoxide production promotor and its utilization |
JP5376761B2 (en) | 2004-02-23 | 2013-12-25 | ストラテジック サイエンス アンド テクノロジーズ, エルエルシー | Topical delivery of nitric oxide to improve body and skin appearance |
US20050196418A1 (en) | 2004-03-04 | 2005-09-08 | Yu Ruey J. | Bioavailability and improved delivery of alkaline pharmaceutical drugs |
US9205062B2 (en) | 2004-03-09 | 2015-12-08 | Mylan Pharmaceuticals, Inc. | Transdermal systems containing multilayer adhesive matrices to modify drug delivery |
US20110028548A1 (en) | 2004-04-19 | 2011-02-03 | Strategic Science & Technologies, Llc | Beneficial effects of increasing local blood flow |
US9226909B2 (en) | 2004-04-19 | 2016-01-05 | Strategic Science & Technologies, Llc | Beneficial effects of increasing local blood flow |
US20090105336A1 (en) | 2004-04-19 | 2009-04-23 | Strategic Science & Technologies, Llc | Beneficial Effects of Increasing Local Blood Flow |
ITMI20041492A1 (en) | 2004-07-23 | 2004-10-23 | Italiano Biochimico Far Maceut | NEW DEVICE FOR THE RELEASE OF ACTIVE PRINCIPLES |
US20070087977A1 (en) | 2004-11-16 | 2007-04-19 | Wendye Robbins | Methods and compositions for treating pain |
EP1858503B1 (en) | 2005-03-03 | 2013-09-04 | Green, Monique Renata | Topical gels compositions |
US7442690B2 (en) | 2005-03-14 | 2008-10-28 | P & L Enterprise Llc | Topical treatment for psoriasis |
EP1770086A1 (en) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Selected CGRP antagonists, process for their preparation as well as their use as medicaments |
KR101121529B1 (en) * | 2005-12-22 | 2012-02-28 | 코와 가부시키가이샤 | Preparation for external use having improved temporal stability of steroid |
CA2660658A1 (en) | 2006-08-11 | 2008-02-14 | The University Of Warwick | Osmium compounds |
EP2117506A2 (en) | 2006-12-13 | 2009-11-18 | Stephen M. Tuel | Methods of making pharmaceutical components for customized drug products |
US8686040B2 (en) | 2008-03-31 | 2014-04-01 | Rdd Pharma Ltd. | Method for treating anal pruritis and other perianal disorders |
US20100099766A1 (en) | 2008-10-16 | 2010-04-22 | Novartis Ag | Topical NSAID compositions having sensate component |
US8969081B2 (en) | 2008-12-10 | 2015-03-03 | The Trustees Of Columbia University In The City Of New York | Caudal motor neuron derived from embryonic stem cells under conditions essentially free of any retinoid |
EP2406399B1 (en) | 2009-03-09 | 2018-02-14 | Bioatla, LLC | Mirac proteins |
WO2010151241A1 (en) | 2009-06-24 | 2010-12-29 | Strategic Science & Technologies, Llc | Topical composition containing naproxen |
US20120027876A1 (en) * | 2010-07-27 | 2012-02-02 | Sara Beth Ford | Composition and Method for the Topical Treatment of Dermatitis |
JP2014501286A (en) | 2010-12-29 | 2014-01-20 | ストラテジック サイエンス アンド テクノロジーズ, エルエルシー | Transdermal delivery of treatment for fungal infections and other indications |
PT2658551T (en) | 2010-12-29 | 2020-07-24 | Strategic Science & Tech Llc | Treatment of erectile dysfunction and other indications |
WO2012092525A1 (en) | 2010-12-29 | 2012-07-05 | Strategic Science & Technologies, Llc | Cox-2 inhibitors and related compounds, and systems and methods for delivery thereof |
US20140010866A1 (en) | 2010-12-29 | 2014-01-09 | Strategic Science & Technologies, Llc | Methods and systems for treatment of migraines and other indications |
US20140038205A1 (en) | 2011-02-18 | 2014-02-06 | Precision Biologic Inc. | Methods and compositions relating to coagulation assays |
-
2011
- 2011-12-29 CN CN2011800686275A patent/CN103442723A/en active Pending
- 2011-12-29 US US13/977,511 patent/US9289495B2/en active Active
- 2011-12-29 CN CN201610220580.4A patent/CN105878172A/en active Pending
- 2011-12-29 JP JP2013547682A patent/JP2014501283A/en active Pending
- 2011-12-29 EP EP11854321.4A patent/EP2658554A4/en not_active Withdrawn
- 2011-12-29 WO PCT/US2011/067987 patent/WO2012092523A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100280122A1 (en) * | 2004-04-19 | 2010-11-04 | Strategic Science & Technologies, Llc | Transdermal delivery of beneficial substances effected by a hostile biophysical environment |
US20080233183A1 (en) * | 2007-03-22 | 2008-09-25 | Pathfinder Management, Inc. | Topical formulations having enhanced bioavailability |
US20110182977A1 (en) * | 2009-06-24 | 2011-07-28 | Strategic Science & Technologies, Llc | Topical composition containing ibuprofen |
Non-Patent Citations (1)
Title |
---|
See also references of EP2658554A4 * |
Also Published As
Publication number | Publication date |
---|---|
CN105878172A (en) | 2016-08-24 |
EP2658554A1 (en) | 2013-11-06 |
EP2658554A4 (en) | 2015-01-07 |
US9289495B2 (en) | 2016-03-22 |
CN103442723A (en) | 2013-12-11 |
US20140044774A1 (en) | 2014-02-13 |
JP2014501283A (en) | 2014-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10898489B2 (en) | Treatment of erectile dysfunction and other indications | |
US20140004176A1 (en) | Delivery of treatments transdermally for fungal infections and other indications | |
US9289495B2 (en) | Systems and methods for treatment of allergies and other indications | |
CA2766354A1 (en) | Topical compositions containing ibuprofen or sildenafil | |
EP2658553A1 (en) | Cox-2 inhibitors and related compounds, and systems and methods for delivery thereof | |
WO2014152382A1 (en) | Transdermal delivery of sildenafil and other phosphodiesterase type 5 inhibitors | |
WO2012092526A1 (en) | Methods and systems for treatment of migraines and other indications | |
US20160081915A1 (en) | Transdermal formulations of fluticasone | |
US20230372351A1 (en) | Treatment of erectile dysfunction and other indications |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11854321 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013547682 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2011854321 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011854321 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13977511 Country of ref document: US |