Topical composition containing ibuprofen

FIELD: medicine.

SUBSTANCE: invention represents a composition for the topical delivery of a composition containing a nitrogen oxide donor specified in L-arginine or its derivative; an adverse biophysical medium containing an ionic salt; a stabilisation polymer containing xantham gum; propylene glycol; a polysorbate surfactant containing Polysorbate 20; and ibuprofen and/or an ibuprofen salt, to the individual's skin.

EFFECT: creating the composition possessing temperature stability at high temperatures.

20 cl, 1 ex, 1 tbl

 

The technical field to which the invention relates.

The present invention generally relates to transdermal delivery compositions.

Prior art

Local transdermal delivery of drugs, although desirable, is limited by the modern technology. A small number of pharmaceutical objects successfully deliver transdermal in effective doses. For example, a limited number of drugs, such as steroids, nicotine and nitroglycerin, which are uncharged and do not form hydrogen bonds, successfully delivered by passive diffusion, based on the concentration gradient between the external and internal parts of the skin to deliver drugs in accordance with the first law of diffusion Fika. The amount of pharmaceutical agent that can be delivered by simple diffusion, is also limited. For example, as soon as the concentration inside the stratum corneum of the epidermis becomes equal to the concentration outside the flow of the pharmaceutical agent may stop. Thus, it is necessary to improve transdermal delivery compositions, either locally or systemically.

The invention

The present invention generally relates to transdermal delivery compositions, locally or systemically, and in some variant of the x implementation for transdermal delivery compositions due to adverse biophysical environment. Examples include ibuprofen, or other pharmaceutical agents. The object of the present invention in some cases includes interrelated products, alternative solutions to specific problems and/or many different applications in one or more systems and/or products.

In one series of embodiments of the proposed compositions having relatively high thermal stability. In some embodiments, the implementation of the composition of the present invention may include a polymer to stabilize, propylene glycol and Polysorbate surfactant. Non-limiting examples of stabilizing polymers are xanthan gum, KELTROLBT and/or KELTROLRD; example Polysorbate surfactant is Polysorbate 20 (Polysorbate 20). This combination of components to create high-temperature stability is unexpected, as the composition, including any of these two components (but not the third), as installed, does not provide the properties of high temperature stability. Currently it is not known why this combination of components is extremely effective in providing a relatively high thermal stability of the compositions discussed in this case, since such components, as is known, do not accept Uch the participation in any noticeable chemical reactions with each other, and high temperature stability collapses when one of the components removed. In addition, propylene glycol, as we know, does not work in the pharmaceutical compositions as a stabilizing agent.

Thus, in one aspect the present invention relates to compositions for topical delivery to the skin object. In one series of embodiments, the composition includes a donor of nitric oxide, adverse biophysical environment, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another series of embodiments, at least 80% of the mass. the composition comprises water, at least one chloride salt, a donor of nitric oxide, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another series of embodiments, the composition comprises water, sodium chloride, a donor of nitric oxide, literallayout, cetyl alcohol, potassium chloride, squalane, polymer stabilization, isopropylmyristate, oleic acid, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another series of embodiments, the composition comprises each of the following compounds in concentrations of not more than 20 from certain concentrations: water at a concentration of approximately 44.2% wt., sodium chloride at a concentration of about 10 wt. -%, the donor of nitric oxide in a concentration of about 7.5 wt. -%, literallayout at a concentration of approximately 7 wt. -%, cetyl alcohol in a concentration of about 7% wt., potassium chloride in a concentration of approximately 5.5 wt. -%, propylene glycol at a concentration of approximately 5 wt. -%, squalane at a concentration of about 4 wt. -%, Polysorbate surfactant at a concentration of approximately 2% of the mass. and isopropylmyristate at a concentration of approximately 1 wt. -%, oleic acid at a concentration of approximately 1 wt. -%, the polymer for stabilization at a concentration of about 0.8 wt. -%, ibuprofen and/or salt of ibuprofen at a concentration of approximately 5.0% of the mass.

The composition in another series of embodiments includes a donor of nitric oxide, adverse biophysical environment, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen. In another series of embodiments, the composition includes a polymer to stabilize, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen. In another series of embodiments, at least about 80% of the mass. the composition comprises water, at least one chloride salt, polymer DL the stabilization propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another aspect, the present invention relates to the use of a composition when getting medicines to treat diseases or conditions discussed in this invention. In one series of embodiments, the composition for the medicinal product contains a donor of nitric oxide, adverse biophysical environment, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another series of embodiments, at least about 80% of the mass. compositions for medicines comprise water, at least one chloride salt, a donor of nitric oxide, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

Composition for the medicinal product in another series of embodiments includes water, sodium chloride, a donor of nitric oxide, literallayout, cetyl alcohol, potassium chloride, squalane, polymer stabilization, isopropylmyristate, oleic acid, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

Composition for the medicinal product in another behold the AI of embodiments includes each of the following compounds in concentrations of not more than 20% from the determined concentrations: water at a concentration of approximately 44.2% wt., sodium chloride at a concentration of about 10 wt. -%, the donor of nitric oxide in a concentration of about 7.5 wt. -%, literallayout at a concentration of approximately 7 wt. -%, cetyl alcohol in a concentration of about 7% wt., potassium chloride in a concentration of approximately 5.5 wt. -%, propylene glycol at a concentration of approximately 5 wt. -%, squalane at a concentration of about 4 wt. -%, Polysorbate surfactant at a concentration of approximately 2% of the mass. and isopropylmyristate at a concentration of approximately 1 wt. -%, oleic acid at a concentration of approximately 1 wt. -%, the polymer for stabilization at a concentration of about 0.8 wt. -%, ibuprofen and/or salt of ibuprofen at a concentration of approximately 5.0% of the mass.

Composition for the medicinal product in another series of embodiments includes a donor of nitric oxide, adverse biophysical environment, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen. In another series of embodiments, the composition for a medicinal product includes a polymer to stabilize, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen. In another series of embodiments, at least 80% of the mass. composition for medicinal cf is DSTV comprise water, at least one chloride salt, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen.

In another aspect, the present invention relates to a method of implementing one or more embodiments described in the invention. In another aspect the present invention relates to a method for applying one or more of the embodiments described in the invention. In another aspect the present invention relates to a method of promoting one or more of the embodiments described in the invention.

Other advantages and new features of the present invention will be apparent from the following detailed description of various non-limiting embodiments of the present invention. In cases where the present description and the document included by reference, include conflicting and/or inconsistent data, the present description will control. If two or more documents, introduced by reference, include conflicting and/or inconsistent data with respect to each other, the document having the latest date of entry into force, will control.

Detailed description

The present invention generally relates to the transdermal delivery of various comp the positions. In some aspects, transdermal delivery can be facilitated through the use of adverse biophysical environment. One series of embodiments provides a composition for topical delivery containing ibuprofen and/or salt of ibuprofen, and not necessarily unfavourable biophysical environment and/or the donor of nitric oxide. In some cases, the composition may be stabilized using a combination of polymer for stabilization (such as xanthan gum, KELTROLBT and/or KELTROLRD), propylene glycol and Polysorbate surfactants, such as Polysorbate 20; and this combination is unexpectedly provides temperature stability of the composition, for example, at elevated temperatures, such as at least 40C. (at least about 104F), compared to compositions that do not contain one or more of such components.

One aspect of the present invention provides compositions for topical delivery of substances such as pharmaceutical agents (e.g., drugs, biological substances and other). Pharmaceutical agents can be applied on the skin of the subject, for example, a person to assist in the treatment of painful conditions or diseases and/or symptoms associated with them. In some embodiments, implementation of Britanie offers the treatment of painful conditions or diseases and/or ailments with the use of pharmaceutical agents (e.g., for the treatment of a subject who has been diagnosed with a painful condition or disease described in this case); and in some cases, the invention provides a delivery of a minimum number of pharmaceutical agents to provide effective levels of medication to the affected area tapicerki while limiting side effects. In some cases, the effective dose of the pharmaceutical agent can be lower than the effective dose of the pharmaceutical agent by oral administration.

For example, in one series of embodiments, the pharmaceutical agent is a ibuprofen and/or salt of ibuprofen. Although ibuprofen is an effective agent against pain when administered orally, it can irritate the lining of the stomach, and people prone to developing sores or irritated with upper gastrointestinal tract, usually informed about the exception of ibuprofen. Thus, the present invention in one series of embodiments provides the ability topical application of ibuprofen to a site of inflammation or pain, excluding in the rest of the body, especially the stomach. The composition may also include a donor of nitric oxide, such as L-arginine, which can be useful, for example, to enhance the localized blood flow and realized who and the delivery site, that, in turn, may increase the delivery of pharmaceutical agent, e.g., locally or systemically. In some cases, the enhancement may be due to maintain an appropriate concentration gradient at the delivery site.

In addition, in some cases, the composition may be formulated in such a way that it creates a hostile biophysical environment for the pharmaceutical agent (for example, ibuprofen). In the event of adverse biophysical environment surrounding the pharmaceutical agent may be such that the pharmaceutical agent will be chemically and/or energetically unfavorable environment relative to the skin (e.g., chemical potential and/or the free energy of the pharmaceutical agent in hostile biophysical environment is much larger than the chemical potential and/or the free energy of the pharmaceutical agent in the skin, which is energetically promotes the transition into the skin), especially relative to the stratum corneum of the epidermis.

Examples of such compositions are discussed in international patent application number PCT/US2005/013228, filed April 19, 2005, entitled "Transdermal delivery of medicinal substances achieved with the help of adverse biophysical environment" (E. Fossel); published as WO 2005/102282 November 3, 2005 (incorporated by reference). Other methods for sky is appopriate biophysical environments discussed in detail in this description. However, such compositions are often not stable at relatively high temperatures, for example, at elevated temperatures, such as at least 40C. (at least about 104F) during the period of time of at least about one day. Thus, in one series of embodiments in this case, the proposed compositions having relatively high thermal stability. In some embodiments, implement, for example, the composition of the present invention may additionally include a polymer to stabilize, propylene glycol and Polysorbate surfactant. Non-limiting examples of polymers for stabilization are xanthan gum, KELTROLBT and/or KELTROLRD; example Polysorbate surfactant is Polysorbate 20. Other examples discussed in the description.

This combination of components to ensure high temperature stability is unexpected, as compositions comprising any two of these components (but not the third), as installed, does not provide such properties of such high-temperature stabilization. Currently it is not known why this combination of components is extremely effective in promoting a relatively high temperature stability of the compositions discussed the x in this case, as such components, as is known, do not participate in any noticeable chemical reactions with each other, and high temperature stability collapses when one of the components removed. In addition, propylene glycol, as we know, does not work in the pharmaceutical compositions as a stabilizing agent.

For example, in one series of embodiments, the composition can be defined as a composition that has high temperature stability, by definition, does the composition phase separation over a relatively long period of time; for example, for at least one hour, at least about 2 hours, at least for one day, at least about one week, at least about 4 weeks, etc. for Example, in some embodiments, the implementation of the composition is exposed to room temperature and room pressure for at least 1 hour, and composition then analyze to determine, does the composition phase separation or change in phase. Stable mixture is a mixture that does not show phase separation, whereas unstable mixture can show phase separation. Such stability may be useful, for example, for storage of the composition, transport is the legacy of the composition, ensure retention or other

The pharmaceutical agent (e.g., ibuprofen and/or salt of ibuprofen) may be present in any suitable concentration. For example, in some cases, the pharmaceutical agent may be present in 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% mass. based on the composition. In addition, the pharmaceutical agent may be present in native form and/or in the form of a salt. For example, if there is a ibuprofen, it can be used in native form and/or in the form of one or more salts of ibuprofen, for example, in the form of a sodium salt of ibuprofen, potassium salt of ibuprofen lysine salt of ibuprofen, arginine salt of ibuprofen, etc. Ibuprofen is commercially easily available means.

As used in this case, "polymer stabilization" is a polymer that contains xanthan gum, derived xanthan gum and/or equivalent xanthan gum, for example, KELTROLBT and/or KELTROL RD, KELZANXC, KELZANXCD, KELZAND, KELZANCC, XANTURAL180, XANTURAL75 or so on, all of which can be obtained commercially from various suppliers. In some embodiments, the implementation of possible combinations and/or other polymers. In some cases, the polymer stabilization is chosen so that it represents a polymer to stabilize, which, at least generally regarded as safe for human use. In addition, in some embodiments, the implementation of the polymer to stabilize produced synthetically and/or is a polymer, which is purified to a certain extent. The polymer for stabilization can have any suitable molecular weight, such as at least about 1 million, at least approximately 2 million, at least approximately 5 million at least approximately 10 million, at least about 25 million or, at least, approximately 50 million.

The polymer for stabilization may be present in the composition in any suitable concentration. For example, the polymer for stabilization may be present in a concentration of at least about 0.1%, at least about 0.2%, at least approximately 0.3%, at least about 0.4%, by ENISA least about 0.5%of at least approximately 0.6%of at least approximately 0.7%, at least about 0.8%, at least about 0.9% or at least about 1% of the mass. based on the composition. In some cases it may be more than one polymer to stabilize, and each polymer for stabilization may be present in any suitable amount. As a specific example, in some embodiments, the implementation of the polymer to stabilize essentially consists of KELTROLBT and/or KELTROLRD. In some cases, the polymer for stabilization may be a fixed ratio KELTROLBT and/or KELTROLRD, for example, 1:1 or 3:5 by weight. In another example, KELTROLBT may be present in a concentration of approximately 0.3 wt. -%, and KELTROLRD may be present in a concentration of 0.5% wt. based on the composition, and one or both of them may be present in one of the other concentrations described above. Combinations of these and/or other polymers for stabilization are also planned in other embodiments, implementation of, for example, KELTROLBT and xanthan gum, KELTROLRD and xanthan gum, etc. In some cases can be used instead of polymer thickeners for stabilization or in combination with a polymer to stabilize. Many of the thickeners can be obtained commercially. Thickeners thickeners include those that are used in the food industry or are the agents on the list of GRAS (generally considered to be safe), for example, arginine, guar gum, carob bean gum, collagen, egg whites, furcellaran, gelatin, agar and/or carrageenan, and combinations thereof and/or other polymers for stabilization. Thus, it is necessary to take into account that in this case links to the polymers to stabilize in other embodiments, the implementation should be understood as including thickeners in combination with or instead of the polymers to stabilize.

Propylene glycol can be obtained commercially and can be present in the form of any stereoisomer or racemic mixture of isomers. It can also be present in any suitable concentration. For example, propylene glycol can be present in 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% of the mass. based on the composition. In some cases, other glycols can be used in combination is or instead of propylene glycol, for example, butyleneglycol. Accordingly, it is necessary to note that in this specification, references to propylene glycol in other variants of implementation, as can be understood, also include other glycols in combination with or instead of propylene glycol.

In addition, Polysorbate surfactant may also be present in the composition in any suitable concentration. For example, in some cases Polysorbate surfactant may be present in 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% of the mass. based on the composition. In this case, "Polysorbate surface-active agent is a surfactant containing Polysorbate. For example, the surfactant may include sorbitanoleat, servicemanagement, servicemonitor, servicemanual or other salts sorbitan. In some cases Polysorbate surfactant has a molecular formula:

g is e, w, x, y and z are any appropriate positive integers. Also w, x, y and z each independently from each other may be the same or different. In one series of embodiments, the sum of w+x+y+z is equal to 20 (such as Polysorbate 20). In some cases, other polymeric sugar can be used instead Polysorbate surfactant or in combination with him. Thus, it should be noted that in this description, references to Polysorbate surfactant is given as an example and in other embodiments, the implementation should be understood that references to Polysorbate surfactant may include other polymeric sugars in combination with or instead of Polysorbate surfactants.

In some cases, the composition may have a fixed ratio of polymer to stabilize the propylene glycol and Polysorbate a surfactant. For example, the ratio may be approximately 1:1:1, about 1:6:3, about 1:6:2, about 1:7:2, about 1:7:3, is approximately 1.5:1:1, about 1.5:6:3, is approximately 1.5:6:4, about 1:6:2.5 to about 1:6,25:2.5 to about 1:6,25:2,5, etc. As mentioned above, in some embodiments, the implementation of such relationships can be useful for providing t mperatures stability of the composition.

As discussed, the composition may also contain a donor of nitric oxide, for example, L-arginine and/or hydrochloride of L-arginine. In some cases, a donor of nitric oxide can be used to increase localized blood flow at the site where the applied composition, which may increase the delivery of the pharmaceutical agent. The donor of nitric oxide may be present in the composition in any suitable concentration. For example, in some cases, a donor of nitric oxide is present in 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% mass. based on the composition. In some cases, you can use one or more nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 etc. of nitric oxide donors).

"The donor of nitric oxide", as used here, is a compound that is capable of releasing nitric oxide and/or chemically to transfer the balance of nitric oxide to another molecule, directly or indirectly, for example through a biological process is. The donor of nitric oxide can release nitric oxide in the skin and/or tissue such as mucous and/or elements of the circulatory system in close proximity to the skin surface. Non-limiting examples of nitric oxide donors are arginine (for example, L-arginine and/or D-arginine), derivatives of arginine (for example, hydrochloride, L-arginine and/or hydrochloride D-arginine), nitroglycerin, adducts associated with the polysaccharide of nitric oxide and the nucleophile, N-nitroso-N-substituted hydroxylamine, 1,3-(nitroxymethyl)-phenyl-2-hydroxybenzoate, etc. and/or any combination thereof and/or other compounds.

In addition to L-arginine hydrochloride and L-arginine other non-limiting examples of nitric oxide donors are D,L-arginine, D-arginine or alkalemia (for example, ethyl, methyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., methyl ether, ethyl ether, propyl ether, butyl ether, etc. and/or their salts and other derivatives of arginine and other nitric oxide donors. For example, non-limiting examples of pharmaceutically acceptable salts are the hydrochloride, glutamate, butyrate or glycolate (for example, glutamate L-arginine butyrate L-arginine, glycolate L-arginine hydrochloride, D-arginine, glutamate, D-arginine and others). Other examples of nitric oxide donors are the soedineniya on the basis of L-arginine, such as, but without limitation, L-homoarginine, N-hydroxy-L-arginine, nitrosocarbaryl L-arginine, nitrosocarbaryl L-arginine, nitrosocarbaryl N-hydroxy-L-arginine, nitrosocarbaryl N-hydroxy-L-arginine, citrulline, ornithine, linsidomine, nipride, glutamine, etc. and their salts (e.g. hydrochloride, glutamate, butyrate, glycolate etc); and/or any combination thereof and/or other compounds. Other non-limiting examples of nitric oxide donors are S-nitrosothiol, nitrite, 2-hydroxy-2-nitrosoguanidine or substrates of various forms synthase nitric oxide. In some cases, a donor of nitric oxide may be a compound that stimulates endogenous production of nitric oxidein vivo. Examples of such compounds include, but without limitation, L-arginine, the substrate of various forms synthase nitric oxide, some cytokines, adenosine, bradykinin, calreticulin, Bisacodyl, phenolphthalein, HE-arginine or endothelin, and/or any combination thereof and/or other compounds.

Accordingly, it should be understood that in any of the embodiments described in this case, which describe L-arginine and/or hydrochloride of L-arginine, in other embodiments, the implementation can also be used by other nitric oxide donors instead of L-arginine and/or hydrochloride of L-arginine or in combination with L-arginine and/or guide what uflorida L-arginine.

In some cases, the concentration of the donor of nitric oxide in the composition can be chosen to have a duration of effective treatment, at least about 3 hours, at least about 5 hours, or at least about 8 hours or more in some cases. The duration can also be controlled, for example, by adjusting the concentration of the penetrating agent used in combination with a donor of nitric oxide. Penetrating agents discussed in detail in the description. Real concentration for a particular application can be determined by a qualified in this field by the technician using no more than routine experimentation, for example, by measuring the amount of transport of the donor of nitric oxide, as a function of concentration ofin vitrothrough cadaver skin or suitable animal models, skin grafts, synthetic model membranes, the human model or other

As a specific non-limiting example, in some embodiments, the implementation of nitric oxide provide through the use of L-arginine, for example, at a concentration of at least about 0.5% of the mass. (% of the mass. or mass./about.) L-arginine (optional with one or more discussed penetrating agents, for example, penetrating agent, capable of izdavati adverse biophysical environment), at least approximately a 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% of the mass. or, at least, approximately 15% of the mass. L-Arginine may be in a suitable carrier for delivery, such as a cream or lotion. L-arginine may be particularly useful in some cases due to its low toxicity, high solubility and/or low cost. Other examples of nitric oxide donors discussed in international patent application number PCT/US2005/005726, filed February 23, 2005, entitled "Topical delivery of a donor of nitric oxide to improve the appearance of the body or skin (E.T. Fossel); published as WO 2005/081964 September 9, 2005 and incorporated by reference.

Not being tied to any theory, in General, believe that the flow of the pharmaceutical agent through the skin may slow down as the agent accumulates in the tissue. First law of diffusion Fika has confirmed that when the concentration inside becomes essentially equal to the concentration outside, passive flow stops. Increased localized blood flow can prevent or at least reduce the stop flow farmaceuticas the CSOs agent. Therefore, when the composition is applied to the skin, the pharmaceutical agent is released from the carrier into the fabric easier, as the pharmaceutical agent is distributed stream and does not accumulate in concentration in the tissue. Thus, in some embodiments, the implementation of pharmaceutical agents, for example, ibuprofen and/or salt of ibuprofen, can be introduced into the skin.

In various embodiments, the implementation of adverse biophysical environment of the present invention may contain a high concentration of osmotic agents high ionic strength, such as urea, sugar or carbohydrates environment with a high pH value (for example, greater than about 9, greater than about 10, greater than about 11, more than about 12 or greater than about 13), an environment with a low pH value (less than about 5, less than about 3, less than about 2), highly hydrophobic components or highly hydrophilic components or other substances, which cause the increase of the chemical potential and/or free energy, pharmaceutical agent, or any combination of two or more of these and/or other compounds. The hydrophobic component in some embodiments may not have the distribution coefficient octanol/water, at least about 100, at least around is about 1000, at least approximately 104at least approximately 105or more in some cases. Similarly, the hydrophilic component may have a distribution coefficient octanol/water less than about 0.01, less than about 10-3less than approximately 10-4or less than approximately 10-5in some cases.

In some cases, the composition defines adverse biophysical environment. In other cases, the pharmaceutical agent can be Packed in such a way that it endured in the fabric and/or the charge was neutralized by derivatization and/or formation of neutral salts. Examples biophysicist adverse environments are, but without limitation, solutions with a high ionic strength (e.g., by adding urea, sugars, carbohydrates and/or ionic salts such as lithium chloride, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, sodium fluoride, lithium bromide, and so on); as well as combinations and/or other agents, e.g., high ionic strength (e.g., greater than approximately 0.25 M, greater than about 1 M, more than about 2 M, more than approximately 3 M, greater than about 5 M, more than approximately 10 M, more than approximately 15 M, greater than about 20 M, more than approx the tion 25 M, and more in some cases; from about 0.25 to 15 M, from about 5 to 15 M, from about 10 to 15 M and so on); the environment with high or low pH value (for example, by adding pharmaceutically acceptable salts or bases, for example, so that the pH value was in the range from about 3 to 7, from about 3 to about 6, about 3 to 5, from about 7 to 11, approximately 8 to 11, from about 9 to 11 and so on); or highly hydrophobic environment (for example, by reducing the water content and increase in the content of lipid, oil and/or wax in the environment). In some embodiments, the implementation of the ionic strength is any amount greater than twice the magnitude of the physiological ionic strength of blood.

Other highly charged molecules, such as polylysine, polyglutamine, polyaspartate etc. or copolymers such highly charged amino acids, can also be used in some embodiments of implementation to create adverse biophysical environment. Non-limiting examples of carriers for shipping, which could be transferred to the fabric include liposomes or emulsions of collagen, collagen peptides or other components of the skin or the basal membrane. Non-limiting examples of the charge neutralization are shipping pharmaceutical agent in the form or the false ester or salt, which are electrically neutral. In some embodiments, the implementation of adverse biophysical environment can include any two or more of these conditions. For example, adverse biophysical environment can comprise a highly hydrophobic environment of high ionic strength and high pH or low pH value and highly hydrophobic environment with a high pH or a low pH value, which contains liposomes, or other

In some embodiments, the implementation of adverse biophysical environment can also be created through the facilities of pharmaceutical agent that is relatively highly charged, hydrophilic, oily medium, for example, cream is oil-based or a lotion containing a small amount of water or not containing water. Absorption can be further facilitated by the combined use of adverse biophysical environment with the use of penetrating agents, which is also documented in this case.

In one series of embodiments, the composition may be presented in the form of an emulsion. As known to a person skilled in the technical field, the emulsion typically comprises a first phase (e.g., dispersed phase)within the second liquid phase (for example, dispersion (continuous) phase). Pharmacological agent (in the example, ibuprofen) may be in any or in both phases. In addition, other materials such as the materials described in the invention can be present in the same phase, as a pharmacological agent. For example, when they are present, the donor of nitric oxide, polymer stabilization, propylene glycol and/or Polysorbate surfactant can all be in the same phase, as a pharmacological agent, for example, in the dispersed phase and/or in the dispersion phase.

Another aspect of the present invention generally relates to compositions for topical delivery, having, by weight, at least about 50%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or essentially the entire composition comprising water, at least one chloride salt, a donor of nitric oxide, polymer stabilization, propylene glycol, Polysorbate surfactant and ibuprofen and/or salt of ibuprofen. The composition may also include other components, for example, literallayout, cetyl alcohol, squalane, isopropylmyristate and/or oleic acid, which may form part or all of the remainder of the composition. Examples and/or other components described in this invention.

In the Yes may be present in any suitable concentration, for example, in a concentration of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50 wt%. based on the composition. In some embodiments, the implementation of water is present in a concentration of approximately 40.9% of the masses. based on the composition.

Non-limiting examples of the chloride salts are sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, etc. In some cases it may be more than one chloride salt, such as sodium chloride and potassium chloride. Chloride(s) g(and) may(can) be present in any suitable concentration, and in some cases chloride(s) g(and) may create adverse biophysical environment. For example, chloride(s) g(and) may present in 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%, at least priblizitel is but 10%, at least about 12%, at least about 15%, at least about 17% or at least about 20% of the mass. based on the composition.

In one series of embodiments as a non-limiting example, the composition may consist essentially of water, sodium chloride, a donor of nitric oxide, glycerylmonostearate, cetyl alcohol, potassium chloride, squalane, polymer stabilization, isopropylmyristate, oleic acid, propylene glycol, Polysorbate surfactants and ibuprofen and/or salt of ibuprofen.

In some cases, as non-limiting examples literallayout is present in a concentration of approximately 7% of the mass. based on the composition. In some cases, cetyl alcohol is present in a concentration of approximately 7% of the mass. based on the composition. In one series of embodiments squalene is present in a concentration of approximately 4% of the mass. based on the composition. In some cases, the potassium chloride is present at a concentration of approximately 5% of the mass. based on the composition. In one series of embodiments isopropylmyristate is present in a concentration of approximately 1% of the mass. based on the composition. In some cases, the oleic acid is present in a concentration of approximately 1% of the mass. from the calculations is that for the track.

In some embodiments implementing the present invention relates to compositions containing each of the following compounds in concentrations of not more than 20% from the determined concentrations: water at a concentration of approximately 40.9% of mass., sodium chloride at a concentration of about 10 wt. -%, the donor of nitric oxide in a concentration of about 7.5 wt. -%, literallayout at a concentration of approximately 7 wt. -%, cetyl alcohol in a concentration of about 7% wt., potassium chloride in a concentration of approximately 5 wt. -%, squalane at a concentration of about 4 wt. -%, the polymer for stabilization at a concentration of about 0.8 wt. -%, isopropylmyristate at a concentration of approximately 1 wt. -%, oleic acid at a concentration of approximately 1 wt. -%, propylene glycol at a concentration of approximately 5 wt. -%, Polysorbate surfactant at a concentration of approximately 2% of the mass. and ibuprofen and/or salt of ibuprofen at a concentration of about 7.5% of the mass.

In some aspects of the invention the composition of the present invention is administered to a subject using a media delivery, such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch. In one series of embodiments, the composition of the invention can be applied to the tire or may be impregnated bandage or VL is Styr, applied on the skin of the subject. The definition of "subject", as used here, means any person or animal. Examples of subjects include, but without limitation, mammals such as dog, cat, horse, donkey, rabbit, cow, pig, sheep, goat, rat (e.g., Rattus Norvegicus), mouse (e.g., Mus musculus), Guinea pig, hamster, Primate (e.g., macaque, chimpanzee, baboon, APE, gorilla, etc. or other Such media for delivery can be applied on the skin of the subject, such as people. Examples of carriers for delivery discussed in the description. The media delivery can stimulate migration to the skin an effective concentration of a donor of nitric oxide and/or pharmaceutical agent, directly or indirectly. For example, the media delivery may include one or more penetrating agents, which is also documented in this case. Specialist in the art will understand the system and method of introducing the donor of nitric oxide and/or pharmaceutical agent in media for delivery, such as cream, gel, liquid, lotion, spray, aerosol, or transdermal patch. In some cases, the concentration of the donor of nitric oxide and/or pharmaceutical agent in the carrier for delivery may be reduced by the inclusion of a higher number or higher concentrations of penet youseo agent, or increased to lengthen a positive effect. In one series of embodiments, the donor of nitric oxide and/or pharmaceutical agent can be used in combination with an adjuvant, such as theophylline (for example, when 10% of the mass. for volume).

Other materials may be present in the carrier for delivery, for example, buffers, preservatives, surfactants, etc. for Example, the cream may include one or more components from among water, mineral oil, glycerylmonostearate, squalane, propylene glycol stearate, oil of wheat germ, glycerylmonostearate, isopropylmyristate, storystart, Polysorbate 60, propylene glycol, oleic acid, tocopherol acetate, collagen, servicestart, vitamin a and D, triethanolamine, methylparaben, aloe Vera extract, imidazolidinethione, propyl paraben, PND and/or BHA.

As a specific non-limiting examples, the cream may contain one or more components (wt./about.): water (20-80%), white oil (3-18%), literallayout (0.25 to 12%), squalane (0.25 to 12%), cetyl alcohol (0.1 to 11%), propylene glycol stearate (0.1 to 11%), wheat germ oil (0.1 to 6%), Polysorbate 60 (0,1-5%), propylene glycol (0.05 to 5%), collagen (0.05 to 5%), servicestart of 0.05-5%), vitamin a (0.02 to 4%), vitamin D (0.02 to 4%), vitamin E (0.02 to 4%), triethanolamine (0.01 to 4%), methylparaben (0.01 to 4%), aloe Vera extract (0.01 to 4%), imidazolidinyl the well (in 0.01-4%), propylparaben (0.01 to 4%), BHA (0.01 to 4%), the hydrochloride of L-arginine (0.25 to 25%), sodium chloride (0.25 to 25%), magnesium chloride (0.25 to 25%) and/or choline chloride (0.25 to 25%). The percentage of each connection can be changed (or in some cases the connection may be absent), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20% etc.

In another embodiment, the cream may include a pharmaceutical agent, such as ibuprofen, and one or more components selected from among the following components in any suitable quantity of water (e.g., 20-80%), the hydrochloride of L-arginine (e.g., 0-25%), sodium chloride (e.g., 0-25%), potassium chloride (e.g., 0-25%), literallayout (for example, 0-15%), cetyl alcohol (for example, 0-15%), squalane (for example, 0-15%), isopropylmyristate (for example, 0-15%), oleic acid (for example, 0-15%), Tween 20 (e.g., 0-10%) and/or butanediol (e.g., 0-10%). The percentage of each connection can be changed (or in some cases the connection may be absent), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20% etc.

In some embodiments, the implementation of the cream may contain a pharmaceutical agent and one or more ionic salts in a concentration at least sufficient to create adverse biophysical environment relative to the pharmaceutical agent. For example, the cream may contain one or more components (wt./about.): araginy and/or associated hydrogen bond object (0.001 to 30%), choline chloride (1-30%), sodium chloride (2-30%) and/or magnesium chloride (1-20%) wt./vol.). In another example, the cream may include one or more components (wt./about.): the hydrochloride of L-arginine (2.5 to 25%), choline chloride (10-30%), sodium chloride (5-20%) and/or magnesium chloride (5-20%). In another example, the cream may contain one or more components (wt./about.): creatine (0.001 to 30%), inosine (0.001 to 30%), choline chloride (1-30%), sodium chloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1 to 25%) and/or theophylline (0.1 to 20%). In some cases, the cream may also contain the hydrochloride of L-arginine (0-12,5%) and/or theophylline (0-10%) (wt./vol.). The percentage of each connection can be changed (or in some cases the connection may be absent), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20% etc. In such examples, chlorinated, sodium chloride and/or magnesium chloride can be used to create solutions with a high ionic strength.

Although in this case described ibuprofen and/or salt of ibuprofen, it should be understood that they are only an example, and in other embodiments, the implementation can be used with other pharmaceutical agents instead of ibuprofen and/or its salts, or in addition to the ibuprofen and/or its salts. Non-limiting examples of pharmaceutical agents are small molecules (e.g., having a molecular weight less than about 2000 daltons, less than p is blithedale 1500 daltons, or less than about 1000 daltons), peptides (e.g., having less than about 10, less than about 15, less than about 20, or less than about 25 amino acids), proteins (usually more than peptides, hormones, vitamins, nucleic acids or other Additional examples of suitable pharmaceutical agents for use in the present invention include, but without limitation, NSAID (non-steroidal anti-inflammatory drugs), such as acetylsalicylic acid, naproxen, celecoxib, refecoxib and others; pharmaceutical agents hypnotics, such as morphine, codeine, propoksifen, oxycodone, hydrocodone and other similar drugs; pharmaceutical agents for erectile or sexual dysfunction, such as yohimbe, alprostadil, sildenafil, cialis, uprima, vardenafil or other; pharmaceutical agents for migraine, such as digidroergotamin and its salts ergotamine and its salts, sumatriptan and its salts, rizatriptan and its salts, zolmitriptan and its salts, and others; pharmaceutical agents for hair treatments such as finasteride, eflornithine, Minoxidil or others; or other pharmaceutical agents, such as Niacin, lidocaine, benzocaine, naproxen, and other Additional examples are improving muscle activity agents for example, creatine or precursors of creatine (for example, to eatin-phosphate), arginine and/or other nitric oxide donors, and/or precursors of ATP, such as inosine, adenosine, inosine, adenine, gipoksantin, ribose, phosphate (e.g., monolatrist) and others, and/or anabolic steroid agents, such as androsten, DHEA, androstenediol, Androstenedione, or other Another example is ephedra or its components, such as ephedrine and pseudoephedrine. Another example is chemotherapeutic agents or agents for treating cancer and/or viral infections, for example, but without limitation, tamoxifen (for example, for the treatment of breast cancer), cisplatin, carboplatin, and related molecules, cyclophosphamide and related molecules, Vinca alkaloids, epipodophyllotoxins, including Taxol, acyclovir or other for Example, cancer and/or viral infection can be a skin cancer, breast cancer, penile cancer, testicular cancer or other localized cancers or viral infections such as herpes.

In some aspects of the invention, the pharmaceutical agent may be combined with penetrating agent, i.e. an agent that increases the transport of the pharmaceutical agent into the skin relative to transport in the absence of a penetrating agent. In some embodiments, the implementation of the penetrating agent may determine and/or may be mixed with adverse biophysical environment. Examples of the penetrating agent is in are oleoresin of capsicum or its components, or some molecules containing heterocyclic ring, which is attached to the hydrocarbon chain.

Non-limiting examples of penetrating agents include, but without limitation, cationic, anionic or non-ionic surfactants (e.g. sodium dodecyl sulphate, poloxamer and others), fatty acids and alcohols (e.g. ethanol, oleic acid, lauric acid, liposomes and other); anticholinergic agents (e.g., benzylaniline, bromide, oxetanone); alkenone (for example, n-heptane); amides (for example, urea, N,N-dimethyl-m-toluamide); fatty acid esters (for example, n-butyrate); organic acids (for example, citric acid); polyols (e.g. ethylene glycol, glycerin); sulfoxidov (e.g., dimethylsulfoxide); terpenes (for example, cyclohexane); urea; sugar; a carbohydrate or other agents. In some embodiments, the implementation of the penetrating agent include salts, for example, described in this invention.

Thus, another aspect of the invention provides the delivery of pharmaceutical agents (e.g., drugs, biological compounds, etc. in the body, and such treatment may be systemic or localized, for example, directed to a specific location of the body, such as the head, one and a few specific muscles, genitals, etc. depending on the concrete in the version of the application.

In one series of embodiments the pharmaceutical agents is administered to facilitate the treatment of painful conditions or diseases and associated symptoms. In some embodiments, implementation of the invention provides the treatment of painful conditions or diseases and/or ailments with the use of pharmaceutical agents (e.g., for treatment of a subject who has been diagnosed with a painful condition or disease), and in some cases, the invention provides a delivery of a minimum number of pharmaceutical agents to provide effective levels of medication to the affected area tapicerki while limiting side effects. In some cases, the effective dose of the pharmaceutical agent may be lower than the effective dose of the pharmaceutical agent by oral administration. Other embodiments of the invention propose methods of treating pain, for example, pain due to migraine, pain due to arthritis, other headaches, joint pain, muscle pain and other types of pain. Accordingly, in some embodiments, the implementation of the composition may be tapicerki put on a specific location of the body, for example, at the site of pain. In addition, in some cases, the compositions described in this invention, can be IP is alsomany when getting medicines for treatment of pain or other diseases or conditions, discussed in the invention.

In another aspect, the present invention relates to a kit including one or more compositions referred to in the invention. The definition of "set"as used in this case, typically defines a package or kit comprising one or more compositions of the invention and/or other compositions associated with the invention, for example, which are discussed in the invention. Each of the compositions set can be presented in liquid form (e.g., in solution or in solid form (for example, in the form of dried powder). In some cases, some songs can make or otherwise transform (for example, in an active form), for example, by adding a suitable solvent or other samples that may or may not be provided with the set. Examples of other compositions and components associated with the invention include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binding agents, giving the amount of fillers, preservatives, drying agents, antimicrobial agents, needles, syringes, packaging materials, tubes, vials, flasks, glasses, cups, Frits, filters, rings, clips, covers, patches, containers, etc. on the example, to apply, entering, modifying, compiling, storing, packing, receiving, mixing, dilution and/or preservation of compositions, components for specific applications, for example, the model and/or entity.

The kit of the present invention in some cases may include instructions in any form, which is submitted in connection with the compositions of the invention so that any ordinary specialist in the art could understand that the instructions should be associated with the compositions of the invention. For example, the instructions can include instructions for use, modification, mixing, dilution, preservation, introduction, preparation, storage, packaging and/or the preparation of compositions and/or other compositions associated with the set. In some cases, the instructions may also include instructions for delivery and/or the introduction of the composition, for example, in the case of specific applications, for example, the model and/or the subject. The instructions may be presented in any form that is perceived by a specialist in the art as a suitable medium for such statements; for example, using written or printed, verbal, auditory (e.g., phone), digital, optical, visual (e.g., a video tape, DVD and others), or electronic communications (including the Internet or web link), the war is undertaken in any way.

In some embodiments implementing the present invention relates to a method of promoting one or more embodiments of the present invention described in this case, to methods of promotion receipt or application of the compositions, such as compositions described in the invention, to methods of promotion of the sets described above, etc. As used in this case, the definition of "promotion" includes all methods of doing business, including, but without limitation, sales methods, advertising, allocation, licensing, Contracting, information, education, research, import, export, negotiate and purchase the sale, financing, lending, trading, sales through vending machines, resale, distribution, reimbursement, refund, insurance, patent, or other, related systems, devices, tools, products, methods, compositions, kits, etc. of the invention, which are discussed in the description. Methods of promotion can be made by any party, including, but without limitation, private parties, companies (public or private), partners, corporations, trusts, contractors or subcontractors, educational institutions such as colleges and universities, the researcher is Kimi institutions, hospitals or other clinics, government agencies, etc. of the promotion may include the transmission of information in any form (for example, using written, oral and/or electronic messages, such as, but without limitation, e-mail, telephone, Internet, web link), which is uniquely associated with the invention.

In one series of embodiments, the method of promotion may include one or more instructions. As used in this case, the definition of "statement" can identify the component of the training program (e.g., manuals, guides, warnings, labels, notes, FAQ or "frequently asked questions, and other), and usually includes written instructions according to the invention or related to the invention and/or with the packaging of the invention. The instructions may include training information message in any form (e.g., verbal, electronic, acoustic, digital, optical, visual, etc), provide in any way, so that the user clearly understood that instructions should be associated with the invention, for example, discussed in this case.

The following documents are included in the description by reference: international patent application number PCT/US98/19429, filed September 17, 1998, entitled "delivery of arginine to ensure positive is ffectiv" (E. Fossel, published as WO 99/13717 25 March 1999; international patent application number PCT/US2005/005726, filed February 23, 2005, entitled "Topical delivery of a donor of nitric oxide to improve the appearance of your body and skin" (E. Fossel, et al.), published as WO 2005/081964 9 September 2005; international patent application number PCT/US2005/013228, filed April 19, 2005, entitled "Transdermal delivery of medicinal substances achieved with the help of adverse biophysical environment" (E. Fossel, published as WO 2005/102282 November 3, 2005; and international patent application number PCT/US2005/013230 filed April 19, 2005, entitled "Positive effects of increasing local blood flow" (E. Fossel, published as WO 2005/102307 November 3, 2005

Also in this description by reference included: patent application U.S. reg. number 08/932227, filed September 17, 1997, entitled "Topical delivery of arginine to ensure positive effects (E.T. Fossel, published as 2002/0041903 11 April 2002; patent application U.S. reg. number 10/201635 filed July 22, 2007, entitled "Topical delivery of L-arginine with the purpose of ensuring positive effects (E.T. Fossel, published as 2003/0028169 6 February 2003; patent application U.S. reg. number 10/213286, filed August 5, 2002, entitled "Topical and oral delivery agrinine to ensure positive the effects, (E.T. Fossel, published as 2003/0018076 January 23, 2003; U.S. patent No. 5895658, issued April 20, 1999, entitled "Topical delivery of L-arginine to ensure heat the tissue" (E.T. Fossel; U.S. patent No. 5922332, issued July 13, 1999, entitled "Topical delivery of arginine for the relief of pain" (E.T. Fossel; U.S. patent No. 6207713, issued March 27, 2001, entitled "Topical and oral delivery of arginine to ensure positive effects" (E.T. Fossel); and U.S. patent No. 6458841, issued October 1, 2002, entitled "Topical and oral delivery of arginine to ensure positive effects" (E.T. Fossel).

The following example is intended to illustrate certain embodiments of the present invention, but is not an example of the total volume of the invention.

EXAMPLE 1

This example illustrates one way to obtain a transdermal composition of the present invention, including ibuprofen. The resulting composition are shown in table 1. Of course, the specialist in the art will understand that the percentage composition different from the following percentage composition, it is also possible in accordance with other options implementation.

% wt./mass.
Table 1
Ingredient
Waterof 40.9
Sodium chloride10,0
The hydrochloride of L-arginine7,5
Ibuprofen (sodium salt)7,5
Literallayout (SE)7,0
Cetyl alcohol7,0
Potassium chloride5,0
Squalane4,0
Xanthan gum0,8
Isopropylmyristate1,0
Oleic acid1,0
Propylene glycol5,0
Polysorbate 20 (Polysorbate-20)2,0

To obtain the drug in this example sodium chloride, potassium chloride, L-arginine and ibuprofen mixed in water, then heated to 74C. with rapid stirring. In a separate container the rest of the ingredients are mixed together and heated to 74C. Other ingr dirty then added to the aqueous phase at 74C with rapid stirring. The mixture was then cooled to room temperature with constant stirring. At this stage, the emulsion is formed with a relatively thin consistency. The emulsion is then homogenized at high speed at room temperature to a thinner consistency.

Although in the description described and illustrated several embodiments of the present invention, a specialist in the art will easily see a number of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described in the invention; and each of such variations and/or modifications believed to be within the scope of the present invention. In General, the specialist in the art will easily understand that all parameters, dimensions, materials and configurations described in the invention, should be considered only as examples, and that the actual parameters, dimensions, materials and/or configurations will depend on the specific application or applications for which the use instructions of the present invention. Specialist in the art will understand, or he will be able to detect using no more than routine experimentation, many equivalents of the specific embodiments of the invention described in the data is m description. Therefore, it should be understood that the above described embodiments of presented only as examples and that within the scope of the attached claims and their equivalents, the invention may be implemented otherwise than is specifically described and claimed. The present invention relates to each individual feature, system, article, material, kit and/or method, described in this description. In addition, the combination of two or more such features, systems, articles, materials, kits and/or methods, if such features, systems, articles, materials, kits and/or methods are not mutually inconsistent, is included in the scope of the present invention.

All definitions that are designated and which are used in this case, as can be understood, checked the dictionary definitions, definitions in the documents incorporated by reference, and/or typical values of the identified concepts.

Union "and/or"used in the description and in the claims, as should be understood, means "either or both" element is connected in such a way, that is, elements that in some cases are present together and in other cases are present separately. Many of the items listed using the Union "and/or"should be considered in the same way, that is, "the Dean or more elements, the United way. Optional can be other elements other than the elements specifically defined using the terms "and/or", regardless of whether related or not related these elements with specific elements. Thus, as a non-limiting example, the reference to "and/or" when used in conjunction with the wording with the possibility of extension, such as "contains", can be treated in one embodiment, only A (optionally including elements other than B); in another embodiment, only In the (optionally including elements other than A); in yet another embodiment, both a and B (optionally including other elements); etc

As used in the description and in the claims, the term "or"how to understand, has the same meaning as the term "and/or"defined above. For example, if the split position in the enumeration unions "or" or "and/or" should be interpreted as including, that is, the inclusion of at least one element, but also with more than one number or list of elements and, optionally additional non-listed positions. Only determine uniquely the opposite, such as "only one" or "just one", or when used in the formula and is gaining, "comprising", will be treated to the inclusion of only a single item number or list of elements. In General, the conjunction "or", as used in this case should be interpreted as pointing to exclusive alternatives (i.e., "one or the other, but not both")when they are preceded by definition of exclusivity, such as "any", "one", "only one" or "just one". The expression "consisting essentially of"when used in the claims, will be the normal value used in the patent law.

In this case, in the description and in the claims, the expression "at least" in reference to a list of one or more elements, as can be understood, means at least one element selected from any one or more items in the item list, but not necessarily including at least one of each and any specifically listed within the list of elements and do not exclude other combinations of elements in the list of items. This definition also acknowledges that may not necessarily be the elements other than the elements specifically identified in the list of elements, which include the phrase "at least", regardless belong or not belong to those elements that are defined to ncrete. Therefore, as a non-limiting example, the expression "at least one of a and b (or, equivalently, "at least one of a or b", or equivalently "at least one of a and/or B") can be treated in one embodiment, at least one, optionally including more than one element, And, in the absence of (and optionally including elements other than B); in another embodiment, at least one, not necessarily includes more than one element, in the absence of A (and optionally including elements other than A); in yet another embodiment, at least one, optionally including more than one element, And, at least, optionally including more than one element (and optionally including other elements); etc

It should be understood that, unless expressly otherwise stated to the contrary, in any of the ways stated in this case that include more than one stage or action, order, stages or actions of the method is not necessarily limited to the order in which the stages or steps listed in this method.

In the claims and the description above, all transitional expressions, such as "comprising", "includes", "carrying", "having", "containing", "involving", "holding", "the purposes of" and so on, as should be understood, have the opportunity to expand; that is, mean inclusion, not limitation. Only the transitional phrase "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional expressions, respectively, as presented in publication United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

1. Composition for topical delivery of ibuprofen to the skin of a subject, comprising:
the donor of nitric oxide selected from L-arginine or its derivative; adverse biophysical environment, including ionic salt; polymer for stabilization, including xanthan gum; propylene glycol;
Polysorbate surfactant comprising Polysorbate 20; and
ibuprofen and/or salt of ibuprofen.

2. The composition according to claim 1, where the composition is stable when exposed to temperatures of 40C for a time selected from at least one day, at least one week, and at least 4 weeks.

3. The composition according to claim 1, where the composition is a cream, a gel, a lotion or a transdermal patch.

4. The composition according to claim 1, where the donor of nitric oxide is present in a concentration selected from the group comprising at least 0.5 wt.% based on the composition, of at least 5 wt.% based on the composition, and at least 7 wt.% based on the composition.

5. The composition according to claim 1 where the ionic salt is present in a concentration selected from the group comprising at least 5 wt.% based on the composition, of at least 7 wt.% based on the composition, and at least 10 wt.% based on the composition.

6. The composition according to claim 1, where adverse biophysical environment includes one or more salts selected from the group comprising sodium chloride, choline chloride, magnesium chloride and calcium chloride.

7. The composition according to claim 1, where adverse biophysical environment has an ionic strength selected from the group comprising at least 0.25 M and at least 1 M

8. The composition according to claim 1, where adverse biophysical environment has a pH selected from the group including at least 9 and less than 5.

9. The composition according to claim 1, where the composition further comprises packaging, containing a donor of nitric oxide, and packaging selected from the group comprising liposomes, emulsion collagen, collagen peptides, and combinations thereof.

10. The composition according to claim 1, where the polymer for stabilization is present in a concentration selected from the group comprising at least 0.5 wt.% based on the composition and at least 0.8 wt.% based on the composition.

11. The composition according to claim 1, where the propylene glycol is present at a concentration selected from the group comprising at least 3 wt.% israsoma on the composition and at least 5 wt.% based on the composition.

12. The composition according to claim 1, where Polysorbate surface-active substance is present in a concentration selected from the group comprising at least 1 wt.% based on the composition and at least 2 wt.% based on the composition.

13. The composition according to claim 1, where Polysorbate surfactant has the formula:

14. The composition according to item 13, where the sum of w+x+y+z is equal to 20.

15. The composition according to claim 1, where the ibuprofen and/or salt of ibuprofen is present in a concentration selected from the group comprising at least 1 wt.% based on the composition, of at least 3 wt.% based on the composition, of at least 5 wt.% based on the composition and at least 7 wt.% based on the composition.

16. A method of treating pain, comprising applying to a subject a composition according to claim 1.

17. The composition according to claim 1, where the composition further comprises literallayout, cetyl alcohol, squalane, isopropylmyristate and oleic acid.

18. The composition according to claim 1, additionally containing water in a concentration selected from the group comprising at least 35 wt.% based on the composition and at least 40 wt.% based on the composition.

19. The composition according to claim 1, where the donor of nitric oxide contains L-arginine.

20. The composition according to claim 1, where the donor of nitric oxide content is it the hydrochloride of L-arginine.



 

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Film oral base // 2488385

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, more specifically to a film base with dispersed fine particles of one or more sugars or sugar alcohols, and also refers to a film preparation containing the base and medicinal agent. The method for preparing the base consists in dissolving an edible polymer soluble in water or an organic solvent in an organic solvent of a solubility parameter of 9.7 (cal/cm3)1/2 or higher, and dispersing one or two or more compounds specified in a group consisting of sugars, including mono- to hexasaccharides, and sugar alcohols thereof having an average particle size of 0.1 mcm to 60 mcm, and insoluble in an organic solvent.

EFFECT: invention may create the film oral base and preparation having a fast profile of oral solubility and adequate film strength, and provide a reduced oral adhesiveness of the water-soluble polymer, and improved feeling if held in fingers.

12 cl, 26 ex, 12 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a percutaneously absorbable preparation comprising 2-[(1-benzylpiperidin-4-yl)methyl]-5,6~dimethoxyindan-1-one and/or its hydrochloride in a pressure-sensitive adhesive layer, wherein the percutaneously absorbable preparation may be administered into a patient so that Cmax per a surface area unit of the percutaneously absorbable preparation is 0.025 to 0.5 ng/mlcm2 in the plasma concentration profile. The preparation has a favourable plasma concentration profile of 2-[(1-benzylpiperidin-4-yl)methyl]-5,6~dimethoxyindan-1-one and/or its hydrochloride with no jump of the plasma concentration.

EFFECT: what is presented is the percutaneously absorbable preparation.

29 cl, 1 tbl, 2 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is system of transdermal delivery of medication for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject. System of transdermal medication delivery includes carrying substrate and layer of active agent. Layer of active agent includes thickening agent, plasticiser and therapeutically efficient quantity of ionised active agent.

EFFECT: claimed is novel system of transdermal medication delivery for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject.

23 cl, 32 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention represents adhesive medication, consisting of applied on at least one base surface adhesive layer, which consists of donepezil and acrylic adhesive agent, water content in active layer constituting 1000-8000 fractions/mln.

EFFECT: improved release of donepezil from adhesive layer is achieved and change of adhesive layer colour with the course of time is prevented.

2 cl, 23 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a water suspension of silicon nanocrystalline particles for biomedical applications. The declared method is characterised by the fact that a porous silicon film of the thickness of 1 to 100 mcm and the porosity of 50 to 80% is formed on the surface of silicon plates. The film is formed by electrochemical etching in a solution containing 40-50% aqueous solution of fluoric acid and alcohol in ratio 1:1 to 1:5 for a period of time of 10 to 60 minutes at specific current 20 to 60 mA/cm2. The prepared silicon plates coated with a porous silicon layer is washed in distilled water, dried and placed in a container with distilled water. Then, they are exposed to ultrasound for more than 10 minutes at the intensity of the silicon plate exposure in water of 100 Wt/cm2 at frequency 23 kHz. This provides forming the stable suspension in distilled water from nanoparticles of the lateral dimension of 10 to 500 nm.

EFFECT: invention provides preparing the biocompaticle suspension of silicon nanoparticles that penetrate into living cells preserving its useful biological properties and luminescence.

4 dwg, 1 ex

Biogel // 2503464

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics. There are developed agent for forming a biogel, biogels for hemostasis, wound closure, tissue engineering and targeted drug delivery. The agent contains a soluble carrier whereon a number of fibrinogen-binding groups is immobilised. The biogel that contains fibrinogen molecules and a number of soluble carriers applicable for intravenous and/or local administration; each carrier comprises a number of fibrinogen-binding groups immobilised on the carrier, and each fibrinogen molecule is bound to at least two fibrinogen-binding groups so that the fibrinogen molecules occurs to be bound to each other through the carriers by non-covalent bonds between the fibrinogen-binding groups and the fibrinogen molecules. The biogel containing fibrin monomers and a number of soluble carriers applicable for intravenous and/or local administration, wherein each carrier comprises a number of fibrinogen-binding groups immobilised on the carrier, while the fibrin monomers are bound to each other through the carriers by non-covalent bonds between the fibrinogen-binding groups and the fibrinogen monomers. The biogel containing fibrin and a number of soluble carriers applicable for intravenous and/or local administration, wherein each carrier comprises a number of fibrinogen-binding groups immobilised on the carrier with the fibrin monomers in fibrin are covalently bound to each other by peptide bonds, and the fibrin monomers in fibrin are bound to each other through the carriers by non-covalent bonds between the fibrinogen-binding groups and the fibrinogen monomers. A method for forming the biogel involving a contact of the fibrinogen molecules with a number of soluble carriers. A method for hemostasis by topical administration of the biogel at a haemorrhage or a wound. Using a number of soluble carriers applicable for intravenous and/or local administration. A pharmaceutical formulation for topical administration containing the biogel, agent or a number of soluble carriers.

EFFECT: using the declared invention enables preparing the agents requiring no toxic reagents to be used, have a minimal risk of allergic reactions, and are easy to prepare and use.

2 tbl, 4 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and cosmetology, and represents a composition for treating or preventing alopecia in the form of a gel containing sodium salt of non-fractionated heparin 0.08-0.8% , lipid nanocomplex emulsion 0.15-3%, gel former 0.5-2%, emulsifier 0.1-0.2%, neutralising agent 0.03-1.3%, preserving agent 0.01-0.03%, and a solvent specified in a group consisting of water, or polyol - the rest.

EFFECT: invention provides extending the range of products for treating alopecia with no side effects.

25 cl, 6 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition for treating oxidative stress comprises ball-shaped lipoic acid or one of salts thereof, and at least one lipophilic medium. The lipoic acid balls represent particles consisting of an inert core (a nucleus) coated with lipoic acid which is coated with a first layer of an isolating polymer, and with a second polymer layer resistant (stable) at gastric pH. What is also described is a preparation for treating oxidative stress with an unified dose containing the above composition. The preparation is presented in the form of a soft gelatin capsule.

EFFECT: compositions according to the invention are stable in the lipophilic medium.

22 cl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to biotechnology and immunology. What is presented is a method for preparing a vaccine with using reverse latex. The first stage involves preparing an adjuvant composition by dispersion of reverse latex or polymer powder prepared by reverse latex spraying, in a physiologically acceptable solution. The second stage involves mixing the prepared adjuvant composition with an antigen-containing medium for preparing the vaccine composition.

EFFECT: reverse latex adjuvant is characterised by higher safety and possesses the high adjuvant effect both at the level of the humoral response, and at the level of the cell response.

8 cl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and represents a method for introducing gold nanoparticles into the body by the local skin application, differing by applying the preparation of the following composition: 96% dimethyl sulphoxide 0.1 ml per a gel base 1 ml with gold nanoparticles d=140 nm, or the preparation of the following composition: 20% thiophane sulphoxide 0.1 ml per a gel base 1 ml with gold nanoparticles d=40 nm; the skin areas coated with gold nanoparticles in complex with organic sulphur compounds shall be exposed to ultrasound at frequency 1 MHz, power 2 Wt and length 2 minutes.

EFFECT: invention provides higher transdermal permeability of gold nanoparticles and no nanoparticle accumulation in the internal organs.

8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. A composition for treating an ear disease is introduced into the tympanic cavity, contains a polyoxyethylene-polyoxypropylene copolymer, an active substance specified in an immunomodulator, a vasopressin antagonist, an ion channel antagonist, a neurokinin receptor antagonist, a serotonin reuptake inhibitor, an NMDA-receptor antagonist, a prostaglandin analogue, a preparation having an effect on the central nervous system, a GABA receptor modulator, a cytotoxic agent, an antioxidant, a glutamate receptor modulator or a calcineurin inhibitor.

EFFECT: invention provides the prolonged release of the active substance into the internal ear for a period of time of at least 7 days.

14 cl, 3 dwg, 114 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: aqueous suspensions contain riluzol or a pharmaceutical acceptable salt, at least one surfactant, and at least one suspending agent. Riluzol is found in the amount of approximately 0.1% to approximately 20% (weight/volume) and characterized by a particle size less than approximately 200 mcm. The surfactant is specified in anionic surfactants, nonionic surfactant or a mixture thereof. The suspending agent is specified in smectic clays, microcrystalline cellulose, natural gums or a mixture thereof.

EFFECT: suspension of riluzol according to the invention are physically and chemically stable, has the common local (oral) anaesthetic effect specific for riluzol.

19 cl, 16 ex

Topical composition // 2497516

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a topical pharmaceutical composition in the form of an opaque emulsion gel. The composition contains 1.2-4 wt % of diclofenac diethylammonium salt, saturated or unsaturated C10-C18fatty alcohol, at least 40 wt % of water, C2-C4alkanol, glycol solvent, gelling agent, liquid lipid forming an oil phase of the emulsion gel, non-ionic surfactant and agent with the primary properties to reduce pH of the prepared composition to 6-9.

EFFECT: compositions under the invention are characterised by high skin permeability, extremely low systemic absorption, absence of human skin irritation after application, high chemical and physical stability, complete solubility of the active component and considerable relief of pain intensity.

8 cl, 4 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents an ophthalmic pharmaceutical composition containing: an amount of prostaglandine applicable for treating glaucoma; a polymer compound of quarternary ammonium for preserving the composition; a surfactant, wherein the surfactant is ethoxylated and/or hydrogenated vegetable castor oil in the concentration of at least 0.05 wt/vol %, but not less than 0.4 wt/vol % of the composition, wherein i) the surfactant representing the ethoxylated and/or hydrogenated vegetable castor oil is the one surfactant in the composition fully or substantially fully; and ii) the composition is free from benzalkonium chloride; and water, wherein the composition is applicable locally on an individual's eye.

EFFECT: invention provides the better bioavailability of the composition and the reduced amount of the surfactant.

17 cl, 6 dwg

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