In another embodiment, the active agent is a combination of at least two histamine antagonists, which may be directed to the same or different histamine receptors. Administering a single composition containing two different histamine antagonists may permit the effective concentration of each active agent to be lower than if a single active agent is administered to the patient while still achieving the desired therapeutic effects.
In some embodiments, the histamine antagonist is alcaftadine. A person skilled in the art will appreciate that the dosage and application area will vary and can be tailored to the area being treated e. Yet still more preferably, the formulation permits delivery of a daily dosage of about 0. In some embodiments, the composition is at a concentration of active agent from about 0. In some embodiments, the composition is at a concentration of active agent from about 2.
In some embodiments, the composition is at a concentration of from about 0. In some embodiments, the concentration is from about 0. In some embodiments, the concentration is about 0.
Alternatively, the composition can be applied to a skin area of about 1 to 10 cm 2 , about 1 to 50 cm 2 , about 10 to cm 2 , about 50 to cm 2 , or about to cm2. In certain embodiments, the concentration is such that this dosage amount can be provided by application of the composition from one to four times, a day, such as one to two times a day. Alternatively, the composition can be applied to a skin area of about 1 to 10 cm 2 , about 1 to 50 cm 2 , about 10 to cm 2 , about 50 to cm2, or about to cm2.
Urticaria and Other Inflammatory Skin Diseases  In certain embodiments, the compositions, methods, and kits presented herein are useful for treating an inflammatory skin disease e. In some instances, the inflammation can last weeks, months or even years. An extended duration of the inflammatory response is frequently provoked by a persistent stimulus of the inflammatory response.
Chronic inflammation can be the result of progression of acute inflammation. Chronic inflammation can also ensue after repeat episodes of acute inflammation or can develop de novo. The histological appearance of chronic inflammation frequently involves a mixed inflammatory cell infiltrate that is often associated with the presence of macrophages, lymphocytes and plasma cells with neutrophil and eosinophil polymorphs as possible minor components neutrophil and eosinophil polymorphs are associated in greater numbers with acute inflammation.
In certain embodiments, the skin irritation associated with other inflammatory diseases can be treated using the methods of the invention. These include skin inflammation associated with systemic lupus erythematosis, systemic sclerosis or schleroderma, dermatomyosis , vasculitis, sarcoidosis, Behcet's syndrome, and the like. Additional inflammatory diseases are described, e. In certain embodiments, urticaria can be acute immunoglobulin E IGE -mediated urticaria, chemical induced urticaria, non-IGE-mediated urticaria, urticarial vasculitis, autoimmune urticaria, cholinergic urticaria, cold urticaria, dermatological effects of Muckle-Wells syndrome, mastocystosis, and the like.
In certain embodiments, the urticaria may be other varieties of urticaria, such as skin inflammation associated with angioedema, acquired CI esterase inhibitor deficiency i. See, e. Pharmaceutical Preparations  In view of their useful anti-urticaria properties, the histamine antagonists e.
These compositions may be prepared by any of the methods well known in the art of pharmacy and drug delivery. For example, to prepare the compositions for treating urticaria, an effective amount of the active ingredient e. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
In certain embodiments, the penetration enhancers include, but are not limited to, ethyl alcohol, isopropyl alcohol, or octolyphenylpolyethylene glycol. In certain embodiments, the penetration enhancers include oleic acid, polyethylene glycol , propylene glycol, N-decylmethylsulfoxide, fatty acid esters e.
In one aspect, the composition comprises 0. Preferably, the essential oil is eucalyptus oil. Examples of fatty acid ester and fatty alcohol esters include butyl acetate, caproyl glycolate, cetyl lactate, cocoyl glycolate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethyleneglycol oleate, diethyl sebacate, diisopropyl sebacate, dodecyl N,N-dimethylamino acetate, dodecyl N,N-dimethylamino butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2- N,N- dimethylamino propionate, EQoleyl ester, ethyl acetate, ethyl acetoacetate, ethyl propionate, glyceryl dilaurate, glyceryl dioleate, glycerol monoethers, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl palmitate, isostearoyl glycolate, lauroyl glycolate, methyl acetate, methyl caprate, methyl laurate, methyl oleate, methyl propionate, methyl valerate, 1 -monocaproyl glycerol, medium-chain-length monoglycerides,, benzyl or substituted benzyl nicotinate, octyl acetate, octyl N.
N-dimethylamino acetate, oleyl oleate, n-pentyl N-acelylprolinate, propylene glycol monolaurate, sodium lauroyl glycolate, tetradecyl N,N-dimethylamino acetate, tromethamine lauroyl glycolate and the like. Still other examples include sunscreens such as Padimate-O, homosalate, cinnamate esters, octocrylene, and the like.
See Osborne, D. In some embodiments, a composition can contain 0. A variety of preservatives are suitable, including, but not limited to, benzoic acid, benzyl alcohol, benzylhemiformal, benzylparaben, 5-bromonitro- 1,3-diox-ane, 2-bromonitropropane-l,3-diol, butyl paraben, phenoxyethanol, methyl paraben, propyl paraben, diazolidinyl urea, calcium benzoate, calcium propionate, captan, chlorhexidine diacetate, chlorhexidine digluconate, chlorhexidine dihydrochloride, chloroacetamide, chlorobutanol, p-chloro-m-cresol, chlorophene, chlorothymol, chloroxylenol, m-cresol, o-cresol, diethylene glycol dimethyl ether "DEDM" hydantoin, DEDM hydantoin dilaurate, dehydroacetic acid, dibromopropamidine diisethionate, 1,3- bis hydroxymethyl -5,5-dimethylimidazolidine-2,4-dione "DMDM" hydantoin, and the like.
In some embodiments, the composition includes at least about 3, 5, 7, 9. In some embodiments, the composition comprises at least about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, In some embodiments, the composition comprises at least about 50, In some embodiments, the composition comprises at most about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, In some embodiments, the composition comprises at most about 50, In some embodiments, the surfactant is a polysorbate surfactant, such as polysorbate Suitable cellulosic thickening agents include, but are not limited to, hydroxypropyl cellulose HPC of various grades, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, dextran, guar gum, pectin, starch, cellulose, and the like.
The viscosity of the formulation can be optimized using one or more pharmaceutically acceptable thickening agents that do not significantly interact with the components of the formulation, do not significantly reduce flux of the formulation, and do not cause stinging or irritation.
In certain embodiments, one or more of the following thickening agents is used: polyacrylic acid polymers, carbomers, cellulose derivatives, poloxamers, poloxamines, dextrans, pectins, natural gums. In one embodiment, cellulose, hydroxyethyl cellulose "HEC" , hydroxypropyl methyl cellulose "HMPC" , carboxymethyl cellulose, and the like. Alternatively, the composition has a kinematic viscosity of more than about 1 centistokes cSt or a dynamic viscosity of more than about 1 centipoise cP.
In certain aspects, the dynamic viscosity of the composition is at least about 2, 3, 4, 5, 7, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, , , , , , , , , , 10, cP at STP.
In yet other aspects, the composition is thixotropic i. The composition's viscosity can be adjusted by the addition of a cellulosic thickening agent, such as hydroxypropyl cellulose, or other thickening agents.
In certain embodiments, the formulation pH may be too acidic or basic to be applied to the eye without irritation or pain. In certain embodiments, the formulation may include components e. In certain embodiments, the formulation may include a penetration enhancing device e. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as single-application dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
Examples of such dosage unit forms are tablets including scored or coated tablets , capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed.
Tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, e. The tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for controlled release. Additionally, emulsions can be prepared with a non- water miscible ingredient, such as oils, and stabilized with surfactants, such as mono-diglycerides, PEG esters, and the like. Such excipients include, e. The aqueous suspensions may also contain a preservative e.
Aqueous suspensions for oral use may include a flavoring agents or a sweetening agent, such as sucrose or saccharin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. For an oral preparation, sweetening and flavoring agents such as those set forth above may be added to provide a palatable preparation.
These compositions may also be preserved by the addition of an anti-oxidant such as ascorbic acid. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The oily phase may be a vegetable oil, such as olive oil or arachis oil; a mineral oil, such as liquid paraffin; or a mixture.
Suitable emulsifying agents may be naturally-occurring gums, such as gum acacia or gum tragacanth; naturally-occurring phosphatides, such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides e.
Emulsions for oral use may also contain sweetening and flavoring agents. The additives may facilitate the administration to the skin or may be helpful for preparing the desired compositions. Such agents and additives would be included in proportions that would not produce a significant deleterious effect on the skin. These compositions may be administered in various ways, e. Because of their increased water solubility over the corresponding non-salt form, acid or base addition salts of the subject compounds are often more suitable for the preparation of aqueous compositions.
In certain embodiments, acid or base addition salts of the active agent would be used. In addressing urticaria, a transdermal or topical application will likely provide the advantage of faster relief and increased efficacy with less chance of undesired systemic effects. Preferably, an "acceptable time period" is at least about 30 days, at least about six months, at least about one year, or at least about two years. In some embodiments, the rate of degradation is less than 0. The topical formulations of the present invention may, for example, comprise a pH-adjusting agent.
In some embodiments, the pH adjusting agent is a base. Suitable pH-adjusting bases include amines, such as diethanolamine, triethanolamine, or aminopropanol; bicarbonates; carbonates; and hydroxides, such as ammonium hydroxide, alkali or alkaline earth metal hydroxide, or transition metal hydroxides. Alternatively, the pH adjusting agent can also be an acid, an acid salt, or mixtures thereof. Non-limiting examples of amounts of acid or base that may be included in the formulation are about 0.
This amount may be about 0. In certain embodiments, the buffer is an acidic buffer system, such as benzocaine, citric acid, or a citric acid salt. In certain embodiments, the buffer system comprises panthenol, either alone or in combination with 3-aminopropanol.
In certain embodiments, this amount is about 0. In certain embodiments, this amount may be about 0. In certain embodiments, the formulation includes a buffer, and a second pH- adjusting agent e. In certain embodiments, the second pH-adjusting agent comprises two agents e. In some embodiments, the pH is adjusted to about 4.
In certain aspects, the formulation has a pH of below about 7. In certain other aspects, the pH of the formulation may range from about 1. In still other aspects, the pH of the formulation may range from about 1. The formulation may include a buffering or pH-adjusting agent to maintain its acidic pH. In certain aspects, the formulation has a pH value between about 4 and 7, such as 4, 5, 6 or 7 and fractional values between 4 and 7.
In certain aspects, the formulation has a pH of above about 7, 8, 9, 10, 11, or In certain other aspects, the pH of the formulation may range from about 7 to In still other aspects, the pH of the formulation may range from about 9 to This peak would have a singlet splitting patter and would be found at the The hydroxyl hydrogen of the ethanol also does not show up on the 1HNMR data, which would be a doublet peak at 0.
The IR data is not very much different of that of the starting materials besides for one peak. The IR data is a good reference however for the presence of the product, benzocaine. All of the significant peaks are present at The only difference in this IR data from the IR data of the starting materials is the presence of the ester at IR spectra of Fluorescein on sigmaaldrich.
GC data showed one significant peak at GC-MS data also showed one peak at Overall, the product was successfully acquired. References: 1. Demare, P. European Polymer Journal , 49 , 3. Gilpin, R. Pharmaceuticals and Related Drugs. Nusstein, J. Anesth Prog. Rummel, A. Studies in rats indicate that aminoadipic acid along with the three branched-chain amino acids - leucine, valine, and isoleucine levels are elevated in the pre-diabetic phase and so aminoadipic acid may serve as a predictive biomarker for the development of diabetes PMID: Long-term hyperglycemia of endothelial cells can also lead to elevated levels of aminoadipate which is thought to be a sign of lysine breakdown through oxidative stress and reactive oxygen species ROS PMID: Therefore, depending on the circumstances aminoadipic acid can act as an acidogen, a diabetogen, an atherogen and a metabotoxin.
An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A diabetogen is a compound that can lead to type 2 diabetes. An atherogen is a compound that leads to atherosclerosis and cardiovascular disease. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of aminoadipic acid are associated with at least two inborn errors of metabolism including, 2-aminoadipic aciduria and 2-oxoadipic aciduria.The method of paragraph 9, wherein said topical pharmaceutical composition is a non-ophthalmic epidermal pharmaceutical preparation. For example, electrodes can be used to generate micro-channels in the stratum corneum. A small direct current is applied through the electrode positioned on the transdermal patch to urge the botulinum toxin in the composition through the patient's skin. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, the frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration. It is used in various chemical, industrial and manufacturing applications. This may take the form of an inherent property of the device, for example, one in which an amount of the histamine antagonist exposed to blood at the outset is high, so that the influx rate is high.
Typical duration of exposure to ultrasound is between about 1 and about 10 minutes. Sigma Aldrich. A diabetogen is a compound that can lead to type 2 diabetes. Thus, "from about 6 to 8. In certain embodiments, the formulation includes a buffer, and a second pH- adjusting agent e.
Sodium bicarbonate 8mL is then added dropwise to the reaction mixture until the pH of the solution is more than 8. The compositions, methods, and kits presented herein provide solutions for this and other problems. Potassium carbonate Potassium carbonate K2CO3 is a white salt, soluble in water insoluble in ethanol which forms a strongly alkaline solution. The method of paragraph 1 , wherein said urticaria is chronic urticaria 5. It is an intermediate in the metabolism i. Mutations in DHTKD1 dehydrogenase E1 and transketolase domain-containing protein 1 have been shown to cause human 2-aminoadipic aciduria and 2-oxoadipic aciduria via impaired decarboxylation of 2-oxoadipate to glutaryl-CoA, which is the last step in the lysine degradation pathway PMID:
In some embodiments, the composition comprises at least about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, In some embodiments, the topical pharmaceutical composition is a non-ophthalmic, epidermal pharmaceutical preparation. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The administering step may consist of a single administration or may include a series of administrations. The method of paragraph 1 , wherein said urticaria is chronic urticaria 5.
Because the effectiveness of transdermal delivery of the active agent through the skin is at least partially dependent on the polarity of the agent, it may be desirable to change the pH of the composition an impart a charge on the active agent to facilitate the effectiveness of the electrical current in transporting the agent through the skin e. Topical application or administering is also meant to include the use of mouth washes and gargles. In some embodiments, the composition is at a concentration of from about 0.
Without being bound by any particular mechanistic theory, alcaftadine is an HI, H2 and H4 histamine receptor antagonist; decreases chemotaxis, and has been shown to demonstration eosinophil-activation inhibition. Also commonly referred to as caustic potash, it is a potent base that is marketed in several forms including pellets, flakes, and powders.
In certain embodiments, the stratum corneum may be disrupted by applying an adhesive, such as adhesive tape or wax, to the skin, and subsequently removing the adhesive from the skin. In some embodiments, the pH adjusting agent is a base. Emulsions for oral use may also contain sweetening and flavoring agents. The adaptation may involve one or a combination of control of the active agent's concentration, control of solution viscosity and other flow properties, formulation of the active agent with additives which enhance or inhibit transdermal flux, controlling permeability rates through membranes either by selection of membrane material, pore structure, or some combination of both , using microneedles of appropriate number and interior diameter, using drug coated or matrix embedded microstructures, using mechanisms for flow control, and the like, so as to achieve the desired flux rates, blood concentrations, and bioavailability profiles.
Low-frequency ultrasound temporarily disrupts the stratum corneum so that subsequent topical application of an active agent may have greater efficacy. Mixture is then refluxed for 70 minutes. The ultrasound is applied without causing an increase in skin temperature greater than about 1 degree Celsius. Discussion and Conclusion: Benzocaine, an ester, was synthesized from p-aminobenzoic acid, absolute ethanol, and sulfuric acid.
Histamine is the ligand for two membrane-bound receptors, the HI and H4 receptors, which are present on many cell types. The dose will vary depending on a number of factors, including the range of normal doses for a given therapy, the frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration. The transdermal therapy may be directed at administering pharmaceutical agents that are incorporated into a patient's circulatory system, and thus are systemically administered through the skin. Treatment can refer to any delay in onset, e. The skin may be disrupted using any suitable method without imparting significant pain to the patient. In certain aspects, the formulation has a pH value between about 6 and 8.
Furthermore, specific devices may be designed for different patient groups. The ultrasound is applied without causing an increase in skin temperature greater than about 1 degree Celsius. The yielded amount was mg or Approved Matched Description: … It was determined that topical KOH solution was found to be a safe and effective treatment of plane warts … Epinephrine Epinephrine, also known as adrenaline, is a hormone and neurotransmitter and produced by the adrenal glands that can also be used as a drug due to its various important functions.