US 20110269.704A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0269704 A1 Seigfried (43) Pub. Date: Nov. 3, 2011
(54) METHOD FOR DEVELOPING ALIQUID A6IP 23/02 (2006.01) COMPOSITION TO BEAPPLIED TO THE A6II 3/196 (2006.01) SKNASA FOAMAND ACOMPOSITION A6IP 29/00 (2006.01) THAT CAN BE APPLIED TOPCALLY A6IP3L/00 (2006.01) A6IP3L/04 (2006.01) (76) Inventor: Bernd G. Seigfried, Limburgerhof A63L/92 (2006.01) (DE) A6II 3/474 (2006.01) (21) Appl. No.: 13/143,740 (52) U.S. Cl...... 514/29: 514/570; 514/626; 514/179; 514/396; 514/567 (22) PCT Filed: Jul. 16, 2010 (86). PCT No.: PCT/DE2O1 O/OOO818 (57) ABSTRACT A liquid pharmaceutical composition to be applied to the skin S371 (c)(1), as a foam and that has at least one solvent, at least one active (2), (4) Date: Jul. 8, 2011 pharmaceutical ingredient, and at least one foaming agent. The foam volume and the foam stability are determined (30) Foreign Application Priority Data according to a standardized SITA measuring method. The foaming agent, the solvent, and the active pharmaceutical Jul. 24, 2009 (DE) ...... 10 2009 O34 603.1 ingredient are varied in regard to the chemical type and/or concentration thereof until the foam thus produced by the Publication Classification SITA measuring method has a foam volume of at least 400 ml (51) Int. Cl. and such foam stability that after a dwell time of up to ten A6 IK3I/7048 (2006.01) minutes the foam still has at least 50% of the foam volume A6 IK3I/I67 (2006.01) that originally existed immediately after the foam was pro A 6LX 3/573 (2006.01) duced. Patent Application Publication Nov. 3, 2011 Sheet 1 of 18 US 2011/0269.704 A1
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METHOD FOR DEVELOPING ALIQUID sive and may suffer from a drawback such that a foam differ COMPOSITION TO BE APPLIED TO THE ing in composition and essentially inhomogeneous can result SKNASA FOAMAND A COMPOSITION from varying the configuration of the aforementioned param THAT CAN BE APPLIED TOPCALLY eters of the mechanical foam applicator. 0008 Thus, one underlying problem of the present inven tion is to provide a method for the development of a liquid 0001. The present invention is directed in part to a method pharmaceutical composition to be applied as foam to the skin, for making or developing liquid pharmaceutical composi by which the development time for such pharmaceutical com tions to be applied as a foam to the skin with the features of the positions is Substantially simplified and shortened. preamble of the patent claim 1 as well as a corresponding 0009 Further, another underlying problem of the present topically applicable compositions with the features of the invention is to provide a topically applicable composition that preamble of the patent claim 9. can be applied as foam and that contains a systemically or 0002 Topically applied pharmaceutical compositions that topically acting pharmaceutical active ingredient, whereby exist in the liquid state and are present as a foam when applied this topically applicable composition is developed preferably are familiar. For example, EP 0510561 B1 describes one by the aforementioned development process. Such pharmaceutical composition applied as foam, wherein 0010. The first stated problem is solved by a method the basic liquid used in the known pharmaceutical composi according to the characteristics of the patent claim 1 and the tion is foamed exclusively by mechanical action. The basic further problem, which is mentioned subsequently, is solved liquid composition that is mechanically foamed contains, as by a topically applicable composition with the features of the ingredients, a surfactant as the foaming agent, a solvent or preamble of the patent claim 9. mixture of solvents, as well as a pharmaceutical active ingre 0011. In the inventive method of development of a liquid dient, wherein this known liquid composition should be pharmaceutical composition to be applied as a foam to the foamable simply by mechanical action, without the use of a skin, having as minimum components a solvent, a pharma propellant. In example 5 of EPO 510561 B1, one such known ceutical active ingredient, and a foaming agent, the method composition is described, containing an aqueous alkylamido includes foam volume and the foam stability to be determined betaine solution as the Surfactant. In addition, the composi by a standardized SITA measurement method, wherein no tion described in this example is provided with lecithin, propellant is used in this measurement method. In the pro which serves solely to form liposomes. vided liquid pharmaceutical composition, the at least one 0003. In order to be able to measure the foaming behavior foaming agent, the at least one solvent and the at least one of liquid compositions, various measurement techniques are pharmaceutical active ingredient are varied in regard to their known and also standardized, such as by DIN Standard chemical nature and/or concentration until the foam created 53902. The particular liquid composition being investigated by the SITA measurement method understandardized condi is subjected to a more or less reproducible mechanical action tions has a foam volume of at least 400 ml, especially a foam for a given time in order to create a foam, whose Volume and volume between 450 and 1400 ml, and preferably a foam stability are measured. Volume between 600 and 1200 ml. Furthermore, the foam 0004. According to DE 197 40 095 A, however, known according to a method of the invention must have Such a foam measurement techniques do not adequately distinguish stability that it still has, after a dwell time of up to ten minutes between the foam volumes and foam stabilities of composi and especially after a dwell time of up to five minutes, at least tions which are similar in terms of their ingredients. 50% of the foam volume and especially between 55% and 0005. Therefore DE 197 40 095 A proposes foaming the 100% of the foam volume and preferably between 85% and liquid composition being measured by using a stirrer with a 99% of the foam volume that was originally present imme given profile, which is driven at a given speed of rotation. The diately after the creation of the foam. In other words, there foam created in this way is visually measured. fore, the development method according to the invention calls 0006. A further embodiment of this foam measuring tech for varying the minimum ingredients (solvent, pharmaceuti nique is described in EP 1092970 B1, wherein the develop cal active ingredient, and foaming agent) contained in the ment differs from the measurement technique previously liquid pharmaceutical composition that is Supposed to form described in reference to DE 197 40 095A by providing an the foam when applied in terms of their chemical nature automatic determination of the height of the foam via mea and/or their concentration until they give rise to a foam by the Suring electrodes. This measurement method, which is called SITA measurement method under standardized conditions the “SITA measurement method’ in the present text, allows whose foam Volume possesses the previously quantified Vol one to determine the foam Volume on the one hand, and on the umes and whose foam stability possesses the previously other hand the foam stability of liquids, especially dyeing and quantified Stabilities. cleaning solutions, electroplating agents, emulsions, rinsing 0012. The above-described method of the invention has a agents, body care products or even beer, so as to obtain a number of advantages. Thus, it has been established, Surpris quality rating of the aforementioned foamable liquids. ingly, that the method of the invention enables an especially 0007 When one needs to develop liquids that are foam easy and rapid development of Such liquid pharmaceutical able and therefore are applied as a foam in the field of phar compositions as can be reproducibly foamed with a number macy, it is usually proposed to proceed by selecting a phar of foam applicators, so that unlike the prior art described at maceutically active liquid and one then attempts to foam it by the outset one can develop pharmaceutical foams that are varying the mechanical foaming technique, in particular, by especially reproducible in terms of their foam consistency varying the air pressure, the geometry and configuration of and their foam composition. For example, if the goal of Such the foam head and the valve of a particular foam applicator. a development is to provide a liquid composition whose foam However, Such a development process for foamable, origi should have a relatively short stability after being foamed by nally liquid, pharmaceutical compositions is very time inten means of a Suitable mechanical foam applicator, so that it US 2011/0269.704 A1 Nov. 3, 2011
quickly breaks down after being applied to the skin, in the via the SITA measurement method. This embodiment of the method of the invention one will vary the chemical nature invented method allows one to develop foams with defined and/or the concentration of the ingredients until a foam foam volumes and foam stabilities, as measured by the SITA results in the SITA measurement method whose foam stabil measurement method, especially easily and quickly by vary ity is distinguished in that, within two to four minutes, the ing the nature and/or the concentration of the ingredients of foam volume still takes on a value between 50% and 70% of the liquid pharmaceutical composition, which then correlate the original foam Volume. In contrast, when the objective is to with the foams that are later applied as foam to the skin by the create an especially stable foam, the chemical nature and/or selected foam applicator. the concentration of the minimum ingredients of the liquid 0016 Especially when the development method of the composition which afterwards forms the foam will be varied invention is used to create afoam from the liquid composition so that a foam results whose foam stability is so high that after that possesses a foam density between 0.05 g/ml and 0.8 g/ml, eight to ten minutes there is still present between 85% and preferably between 0.15 g/ml and 0.4 g/ml by the SITA mea 99% of the foam volume that was originally present imme Surement method, it has been found that such liquid compo diately after the foaming process. If, on the other hand, a sitions provide excellent foams that can be applied with a liquid, foamable composition which has an especially large number of differently designed, mechanical-type foam appli foam Volume is desired, then the nature and/or the concentra CatOrS. tion of the minimum ingredients of the liquid composition 0017 Already above it is referred several times that the will be varied so that an especially high foam volume results chemical nature and/or the concentration of ingredients (sol in the SITA measurement method, i.e., a foam volume that vent, foaming agent, active ingredient) are varied in the varies between 600 ml and 1200 ml or even up to 1400 ml. method of the invention so as to ensure the foam Volume and Thus it should be noted that the method of the invention the foam stability as indicated above in the development proposes a standardized method in which, by variation of the method of the invention. chemical nature of the ingredients and/or their concentration, 0018. In particular, the solvent for the production of the one can develop a foam quantified in the above sense with liquid composition in the method of the invention may be regard to the foam volume and the foam stability, and which chosen from the group consisting of water, at least one alco can accordingly be applied to the skin of humans and animals. hol, especially at least one monovalent to trivalent alcohol, at 0013 The term “and/or used in the present specification least one polyalcohol and mixtures of the aforementioned means that all or some elements of the particular listing are to Solvents. Of course, in choosing the solvent one will make be construed additively or that some or all elements of the sure that these solvents are skin-tolerated and especially do respective listing are to be construed alternatively, whereas not result in any skin irritation, so that they are appropriately the standardized SITA measurement method which is used in pharmaceutically applicable. Preferred solvents are 2-pro the present invention is described in detail at the beginning of panol, propylene glycol, glycerinas well as polyols, while the the examples. Moreover, it should be stated that all terms used term water comprises all aqueous systems, especially also in the singular case in the present specification of invention aqueous pharmaceutical buffer systems. also include the plural of these terms. 0019. In an especially suitable embodiment of the method 0014. A first embodiment of the inventive method for of the invention, the pharmaceutical active ingredient itself is development of a liquid pharmaceutical composition to be used as the foaming agent, so that this embodiment of the applied as a foam to the skin proposes that include producing invented method is based on the fact that it contains, besides a correlation between the foam as specified by the SITA the solvent, only the pharmaceutical active ingredient whose measurement method and the desired pharmaceutical prop concentration and whose chemical nature are varied so that erties. By desired pharmaceutical properties is meant in par the foam volumes and foam stabilities indicated in the method ticular the transport of active ingredient through the layers of of the invention and measured according to the SITA method the foam into and/or through the skin, i.e., the permeation are guaranteed. and/or penetration of the skin and/or the fine distribution of 0020. Alternatively or in addition to this, a modification of the active ingredient and/or the resulting pharmaceutical the method of the invention proposes that the foaming agent effect. For example, if a goal of the development in the for the production of the liquid composition is chosen from method of the invention is, that the active ingredient should the group comprising Surfactants, especially anionic, cat quickly get onto the skin Surface in relatively high concentra ionic, nonionic and ampholytic Surfactants, silicones, fats, tion, one will vary the nature and/or concentration of the fatty acids, fatty acid derivates, phospholipids, Sugar deri ingredients in the liquid composition being foamed by the Vates, lipids, especially sphingolipids and glycolipids, and SITA measurement method so that the resulting foam has a mixtures and derivates of the aforementioned substances. relatively small foam Volume, especially a foam Volume 0021. In principle foaming agents, whether the active between 450 ml and 600 ml, and a relatively low foam sta ingredient itself or the above listed foaming agents, may be bility, especially a foam stability after five minutes between capable of provide the aforementioned foam volumes and 55% and 70% of the foam volume that was originally present foam stabilities as soon as the liquid composition is foamed in immediately after creating the foam. purely mechanical fashion, without the use of a propellant. 0015. In a modification of the above specified embodi Preferred surfactants include the fatty alkyl ether sulfates, the ment of the invented method, another embodiment calls for alkyl phosphates, the alkyl ether phosphates, the alkylben selecting a foam applicator for the mechanical foaming of the Zene Sulfonates, the petroleum Sulfonates, the olefin Sul liquid composition, a foam is created from the liquid compo fonates and/or the esters of SulfoSuccinic acid. Among the sition by the selected foam applicator, and a correlation is silicones, one should mention especially modified siloxanes, produced between the properties, especially the pharmaceu polydialkyl siloxanes and preferably linear or cyclical poly tical properties of the foam created via the foam applicator dimethylsiloxanes. Fats and modified fats, such as fatty acids, and the foam volume and/or the foam stability as determined fatty acid derivates, fatty acid esters, as well as synthetic, US 2011/0269.704 A1 Nov. 3, 2011
plant and animal phospholipids, especially phosphatidylcho on the foam volume and the foam stability, but this can be line and/or hydrogenated phospholipids and preferably determined quite easily and without problem and within the hydrogenated phosphatidylcholine, are among the preferred shortest time in a reproducible manner by the method of the foaming agents, in addition to the sphingolipids, glycolipids invention. and Sugar derivates, preferably Sugar or Sorbitol esters. 0028. As already mentioned above, the present invention 0022. Among the fat derivatives, especially the sulfates of furthermore concerns atopically applicable composition with fatty acids, sulfonates of fatty acids, salts of sulfates of fatty the features of the preamble of patent claim 9. acids, salts of Sulfonates of fatty acids, soaps and mixtures 0029. The topically applicable composition of the inven and derivates of the aforementioned substances are especially tion, which is developed preferably but not exclusively Suitable as foaming agents for use in the method of the inven according to the above described method of the invention, tion. This holds likewise for alkoxylated fatty acids and has, a pharmaceutical active ingredient, a solvent as well as a alkoxylated fatty acid derivates, alkoxylated fatty alcohols, foaming agent. In contrast to the known liquid composition of alkoxylated phenols as well as mixtures and derivates of the EP 0510561 for example, which is applicable as a foam, the aforementioned substances. topically applicable composition of the invention proposes a 0023. Furthermore, preferred surfactant foaming agents phospholipid foaming agent as the foaming agent. Further are chosen from the group consisting of alkylcarboxylates, more, the at least one phospholipid foaming agent, the at least alkylsulfates, alkylsulfonates, alkylethercarboxylates, Sul one solvent and the at least one active ingredient in the com fates of fatty acids, phosphates of fatty acids, Sulfonates of position of the invention are attuned to each other in their fatty acids, salts of sulfates offatty acids, salts of sulfonates of chemical nature and/or their concentration so that the com fatty acids, fatty acid amides, polyalkylenes, fluoroSurfac position can be mechanically foamed exclusively without the tants, soap, metal Soaps, especially alkaline soaps, such as use of an additional propellant. The foam so created by the Sodium, potassium and ammonium salts of aliphatic carboxy mechanical foaming during the application has a foam Vol lic acids, organic amino-Soaps, especially organic amine ume of at least 400 ml, preferably between 450 and 1400 ml Soaps of aliphatic carboxylic acids, quaternary ammonium and especially a foam volume between 600 and 1200 ml. compounds, especially benzalkonium chloride, octadecy Furthermore, the composition according to the invention has lammonium chloride, Sulfonium salts, amidoamines, fatty such a foam stability that the foam still has, after a dwell time acid esters, preferably monoglycerin, diglycerin and triglyc of up to ten minutes and especially after a dwell time of up to erin esters, fatty acid ethers, alkoxylated, especially ethoxy five minutes, at least 50% of the foam volume and especially lated fatty acids, alkoxylated, especially ethoxylated fatty between 55% and 100% of the foam volume and preferably acid derivates, alkoxylated, especially ethoxylated fatty alco between 85% and 99% of the foam volume that was originally hols, alkoxylated, especially ethoxylated phenols, alkoxy present immediately after the creation of the foam, wherein lated, especially ethoxylated fatty acid amides, mono- and both the aforementioned foam volume and the aforemen dialkylalkanolamides or alkylpolyglucosides, especially tioned foam stability can be determined by the standardized coco-mono-ethanolamides, coco-di-ethanolamides, coco SITA foam measurement method. In other words, topically mono-isopropanolamides, coco-diglucosides, betaine, applicable composition of the invention is characterized not betaine derivates, preferably N-alkylbetaine, alkyl-ami only by the nature of its ingredients and/or their concentra dopropylbetaine, Sulfobetaine, alkylsulfobetaine, alkylglyci tion, but also by the foam created from it, wherein the foam is nate and alkylcarboxyglycinates, wherein the alkyl residue specified and quantified in terms of the foam Volume and the each time comprises in particular a carbon skeleton with 8 to foam stability by the standardized SITA measurement 18 carbon atoms, acylamino acid, alkylimidazoline, N-Sub method. stituted alkylamines, acyllactate, N-acylsarkosinate, alkano 0030 The composition of the invention has a number of lamide, aminoxide, polyhydroxyalcohol esters, as well as advantages. When the composition of the invention is applied mixtures and derivates of the aforementioned substances. to human or animal skin, where the term skin as already 0024. As cationic surfactants that are likewise especially defined above covers the mucous membranes of mouth, nose, Suitable as the foaming agent in the method of the invention vagina and foreskin, the skin areas of the ear and especially for the production of the liquid composition, one will select the inner ear, the skin areas of the anus and the rectum, the Substances which contain quaternary ammonium com nails and the eyes, especially the conjunctiva, the cornea and pounds, Sulfonium salts, amidoamides and their mixtures as the lacrimal sac, the foam created from the composition of the well as their derivates. invention has, first of all, an excellent adhesion to these appli 0025 Preferred ampholytic surfactants for the production cation sites, so that it cannot easily be wiped off unintention of the liquid composition will be chosen from the group ally. Moreover, the foam produced in exclusive mechanical comprising betaine and betaine derivates. fashion from the liquid composition of the invention has a 0026. As for the active ingredients used in the method of naturally homogeneous composition, and the pharmaceutical the invention, these will preferably be active ingredients such active ingredient is present in this foam in an especially uni as are described in further detail in connection with the topi formultrafine distribution, so that once the foam breaks down cally applicable composition according to the invention. after being applied this ultrafine distribution is retained in the 0027 Besides the repeatedly aforementioned solvent, the liquid layer formed on the skin surface, with the result that the pharmaceutical active ingredient and the foaming agent, in pharmaceutical active ingredient is transported with a high further embodiments of the invented method for production rate of penetration and/or permeation into and/or through the of the liquid composition that is foamed in purely mechanical skin. This, in turn, means that the active ingredient so applied fashion for its application, there is proposed in particular a has a high pharmaceutical efficacy, so that if desired the complexing agent, a buffer, a thickening agent, an antioxidant concentration of active ingredient in the composition of the and/or a stabilizer. However, one must make pay heed that invention can be reduced as compared to traditional compo these aforementioned ingredients can also have an influence sitions or, alternatively, the time intervals between consecu US 2011/0269.704 A1 Nov. 3, 2011 tive applications can be lengthened appropriately, especially prostaglandin synthesis inhibitors, antiviral-acting or viro since the active ingredient forms a depot in the skin. Due to static-acting Substances, antimicrobial-acting Substances, the fact that a phospholipid foaming agent is present as the active ingredients against prions, immune Suppressants, hor foaming agent in the composition of the invention, this phos mones, active ingredients for treatment of warts or wounds, pholipid foaming agent has the effect of producing a faster especially chronic wounds, vitamins, plant extracts or penetration or permeation into or through the skin, which essences of plant extracts, psychoactive drugs, active ingre proves to be an additional advantage of the composition of the dients influencing sleep, analeptics, general anesthetics, invention. muscle relaxants, antiepileptics, antiparkinson agents, anti 0031) Especially when the foam created from the compo emetics, antiparasitics, ganglion-active ingredients, sympa sition of the invention by the SITA measurement method has thetic-active ingredients, parasympathetic-active ingredients, a foam density between 0.05 g/ml and 0.8 g/ml, preferably antibacterial-acting drugs, calcium antagonists, cardiovascu between 0.15 g/ml and 0.4 g/ml, such embodiments of the lar agents, antiasthmatics, antitussives, expectorants, hepat compositions according to the invention have the aforemen ics, diuretics, choleretics, disinfectants, trace elements, anti tioned advantageous properties to an enhanced degree. infectives, cytostatics, antimetabolites, hormone antagonists, 0032. As already explained above for the method of the immune modulators, as well as derivates and salts of the invention, the composition according to the invention aforementioned active ingredients. includes, as a solvent, especially water, at least one alcohol, 0035 Depending on the particular use of the invented especially at least one polyvalent to trivalent alcohol, and/or composition, the inventive compositions include an active at least one polyalcohol, and Such solvents are chosen in ingredient or a special active ingredient mixture, which is particular for Such phospholipid foaming agents as contain a chosen from the following listed special active ingredients, phospholipid and/or a phospholipid mixture isolated from presented under their particular main groups. plant components, especially soybeans. 0036 Preferably, for the main group of the 5C.-reductase 0033 For clarity it is pointed out that the term phospho inhibitors,alphatradiol and 17C-estradiol can be used; for the lipid mixture orphospholipids in the above description covers main group of weight loss agents, appetite curbing or anti all phospholipids of plant origin, animal origin, or synthetic obesity agents: norephedrine, phenylpropanole amine, origin. In particular, this includes the ester phospholipids, D-norpseudoephedrin, orlistate and Sibutramine; for the main especially phosphatidylcholine, lyso-phosphatidylcholine, group of ACE-inhibitors: benazepril, cilaZapril, quinapril, phosphatidyl ethanolamine, lyso-phosphatidyl ethanola ramipril, spirapril and trandolapril; for the main group of mine, phosphatidyl serine, lyso-phosphatidyl serine, phos acidosis therapeutic or antihypoxemic agents: calcium-so phatidyl inositol, lyso-phosphatidyl inositol, phosphatidyl dium-hydrogen-citrate; for the main group of astringents: glycerin, diphosphatidylglycerin and the phosphatidic acids, aluminium chloride, aluminum diacetate, aluminum formate, the ether phospholipids, especially choline plasmalogen and bismuth chloride oxide, bismuth gallate, polycresulene, tan ethanolaminoplasmalogen, as well as the Sphingosine phos nin and Zinc oxide; for the main group of acne agents: aze pholipids, especially ceramide phosphorylcholine and phy lainic acid and benzoyl peroxide; for the main group of aldos toglycolipid and derivates of the ester phospholipids, the terone antagonists: canrenionic acid, potassium canrenoate, ether phospholipids and/or the sphingosine phospholipids, dolasetrone and eplerenone; for the main group of alcohol withdrawal agents: acamprosate and disulfiram; for the main regardless of whether they have been isolated from natural group of C.1-receptor blockers: alfuZosin, bunaZosin and Substances, such as plants or plant components, especially dihydroergotamine; for the main group of O2-receptor ago plant seeds, or animal components, such as eggs, or syntheti nist: apraclonidine, brimonidine, doxoZosine and moxoni cally produced. Typical derivates of these phospholipids dine; for the main group of C- and B-sympathomimetics: which can be contained in the composition of the invention as adrenaline, dobutamine, dopexamine and epinephrine; for the foaming agent are preferably the hydrogenated or partly main group of aminoglycoside antibiotics: gentamycin, kana hydrogenated phospholipids, especially hydrogenated or mycin, neomycin, netilmycin, Streptomycin and tobramycin; partly hydrogenated phosphatidylcholine. for the main group of amino acids: alanine, aminoacetic acid, 0034 Regarding the active ingredient, it should be noted glycine, arginine, asparagine, asparaginic acid, cysteine, cys that the at least one active ingredient contained in the com tine, glycocoll, ornithine, proline and serine; for the main position of the invention is one that is suitable for use on group of amino acid Substitution: alanylglutamine, arginine humans or animals and especially for topical and systemic glutamate, desmeninol, glycylglutamine and glycyltyrosine; application, especially on the skin, wherein an especially for the main group of analeptics orantihypoxemics: camphor preferred active ingredient is chosen from the group compris and caffeine; for the main group of analgesics or antirheu ing local anesthetics, anti-allergic agents, dermatics, active matics: abatacept, acetylsalicylic acid, acetaminophen, ademetionin, anakinra, aurothiomalate Sodium, buprenor ingredients against flu infections and colds, active ingredients phin, diethylamine Salicylate, etanercept, etoricoxide, fenta for the treatment of neuropathies, active ingredients for the nyl, flufenamine acid, flupirtin, glucosamine, hydromor treatment of disturbed circulation, chemotherapy drugs, qui phone, 2-hydroxybenzoic acid, diethylazane salt, nine, antimycotics, antibiotics, thalidomide, serotonin, hydroxychloroquin, hydroxyethylsalicylate, leflunomide, eicosanoids, analgesics, anticonvulsants, nonsteroidal anti levomethadone, meptazinol, metamizol, methylsalicylate, rrheumatics, leukotrienes, leukotriene inhibitors, androgens, misoprostol, morphine, nalbuphine, sodium aurothiomalate, antiandrogens, corticoids, opiate receptor antagonists, blood nicoboxil, nonivamide, noramidopyrine, novaminsulfone, clotting inhibitory Substances, thrombocyte aggregation oxaceprol, oxycodone, paracetamol, penicillamine, pethi inhibitors, histamine antagonists, regulatory and enzymati dine, phenaZone, piritramide, propylnicotinate, propy cally acting peptides and proteins, nucleic acids (single and phenaZone, Salazosulfapyridine, SulfaSalazine, tilidine, tra double-stranded DNA, single and double-stranded RNA, madol and Ziconotide; for the main group of acidification snRNA, DNA oligonucleotides, RNA oligonucleotides) and agents: malic acid; for the main group of antacids: almasilate, oligopeptides, antipruritics, antidiabetics, prostaglandins, aluminum hydroxide, aluminum hydroxide-magnesium car US 2011/0269.704 A1 Nov. 3, 2011
bonate gel, aluminum phosphate, carbaldrate, magaldrate, human blood clotting factor 1X, blood clotting factor Xll, magnesium carbonate, magnesium hydroxide and magne eptacog alpha (activated), fibrinogen, gelatins, moroctocog sium trisilicate; for the main group of antihelminthics: alpha, nonacog alpha, octocog alpha (BHK), phytomenadi albendaZol, mebendazol, niclosamide, praziquantel, pyrantel one, human plasma proteins, human plasma proteins with and pyrviniumembonate; for the main group of antiallergics: factor VIII inhibitor bypass activity, proconvertin, protamine chromoglycinic acid, lodoxamide, meduitazine, mizolastine hydrochloride, tranexamic acid and troXerutin; for the main and olopatadine; for the main group of antianemics: calcium group of antihistamines: anazolin, azelastin, bamipin, ceti folinate, darbepoeton alpha, iron, iron carboxymaltose, iron rizin, chlorphenamine, chlorphenoxamine, cyproheptadine, (II) chloride, iron (II) fumarate, iron (II) gluconate, iron (II) desloratadine, dexchlorpheniramine, dimenhydrinate, dioxo Succinate, iron (II) sulfate, iron glycine Sulfate, iron (III) promethazine, diphenhydramine, diphenylpyraline, ebastine, hydroxide-dextran complex, iron (III) hydroxide-polymal emedastine, epinastine, fexofenadine, hydroxy Zine, levo tose complex, iron (III) hydroxide-saccharose complex, iron cabastine, levocetirizine, loratadine, rupatadine, terfenadine, (III) sodium-gluconae complex, epoetin alpha, epoetin beta, tripelennamine and triprolidine; for the main group of anti epoetin Zeta, erythropoetin, folic acid and methoxy-polyeth hypertonics: alliskiren, ambrisentan, amiloride--hydrochlo ylglycol-epoetin beta; for the main group of antiandrogens: rothiazide, hydrochlorothiazide--amiloride, bosentan, cande bicalutamide, chlormadione and cyproterone; for the main Sartan, captopril, clonidine, delapril, enalapril, enalaprilate, group of antiarrhythmics: ajmalin, amiodaron, quinidine, eprosartan, hydralazine, imidapril, indapamide, indoramine, detajmium bitartrate, flecainide, lidocaine, mexiletin, orci lercanidipine, manidipine, methyldopa, minoxidil, moex prenalin, prajamalium bitartrate, propafenon and Sotalol; for ipril, nilvadipin, nitrendipin, nitroprusside Sodium, olm the main group of antibiotics or anti-infectives: amikacin, esartan, praZosin, reserpine, nitrogen monoxide, sitaxentan, aminosidine, paromomycin, chloramphenicol, ciprofloxacin, telmisartan, teraZosin, treprostinil and urapidil; for the main clindamycin, colistimethate-sodium, colistin, enfuvirtid, group of antihypoglycemics: diaZOxide and glucagon; for the enoxacin, flucloxacillin, fosfomycin, fusafungin, levofloxa main group of antihypotonics: amezinium methyl sulfate, cin, lineZolid, mefloquin, metronidazol, mezlocillin, moxi cafedrin, dopamine, etillefrin, levarterenol, norepinephrine, floxacin, norfloxacin, ofloxacin, oxacillin, penicillin G, peni midodrin, noradrenaline, oxillofrin and theodrenaline; for the cillin V, phenoxymethylpenicillin, phenoxymethylpenicillin main group of anticoagulants: bivalirudin, certoparin Sodium, benZathin, pipemidinic acid, piperacillin, piperacillin+ dabigatran, dalteparin Sodium, danaparoid sodium, drotreco taZobactam, proguanil, propicillin, pyrimethamine, gin alpha (activated), enoxaparin Sodium, fondaparinux, hep retapamulin, rifaximin, roXithromycin, Sulbactam, Sulbac arin, heparin (low-molecular), nadroparin calcium, reviparin tam+ampicillin, sulfadiazine, spiramycin, Sultamicillin, tazo Sodium, tinZaparin Sodium, lepirudin, nadroparin calcium, bactam-piperacillin, teicoplanin, tellithromycin, tigecyclin pentosanpolysulfate sodium, protein C, reviparin Sodium, and Vancomycin; for the main group of antidementia agents rivaroXaban, tinzaparin Sodium and warfarin; for the main (nootropics): galantamine, nicergolin, nimodipin, pyracetem, group of antimycotics: amorolfin, amphotericin B, anidu pyritinol and rivastigmin: for the main group of antidepres lafungin, bifonazole, caspofungin, ciclopiroX, ciotrimazole, sants: agomelatin, amitriptylin, amitriptylin oxide, bupro econazole, fenticonazole, fluconazole, flucytosin, griseoful pion, citapram, clomipramin, dulloxetin, escitalopram, fluox vin, hexamidine, isoconazole, itraconazole, ketoconazole, etin, fluvoxamin, maprotilin, mianserin, mirtazapin, micafungin, miconazole, naftifin, natamycin, nystatin, oxi nortriptylin, opipramol, paroxetin, reboxetin, Sertralin, tra conazole, posaconazole, Sertaconazole, terbinafin, tiocona nylcypromin, traZodon and trimipramin; for the main group Zole, tolnaftat, undecylenic acid and Voriconazole; for the of antidiabetics: acarbose, exenatid, glibenclamide, gliclacid, main group of antineoplastic agents: alemtuzumab, alitretin glimepirid, gliquidon, insulinaspart, insulinaspart biphasic, oin, bevacizumab, arsenic trioxide, asparaginase, beXaroten, insulindetemir, insulinglargin, insulinglulisin, human insu buserelin, celecoxib, cetuximab and colaspase; for the main lin, human insulin-isophan biphasic, insulin-isophan, insulin group of antiparasitic agents: allethrin 1, acetic acid, per lispro, isophan-insulin, metformin, miglitol, nateglinid, methrin and piperonylbutoxide; for the main group of pioglitazon, repaglinid, rosiglitazon, Sitagliptin and Vilda antiphlogistics: aescin, ammonium bituminosulfonate, gliptin; for the main group of antidotes: bis-Sulfanyl propane ammonium bituminosulfonate bright, benzydamine, bufex Sulfonic acid, deferasirox, deferoxamin, deferipron, dimer amac, cumarin, dimethylsulfoxide, guaiaZulene, sodium capto-propane Sulfonic acid, dimethylaminophenol, diso bituminosulfonate and serrapeptase; for the main group of dium folinate, iron hexacyanoferrate, eserin, flumazenil. antipruriginosics: crotamiton, levomenthol, menthol and coal fomepizol, naloxone, Sodium folinate, sodium thiosulfate, tar; for the main group of antipsoriatics: acitretin, dimethyl obidoxim chloride, pentetic acid, physostigmin, Silbinin and fumarate and ethylhydrogenfumarate; for the main group of tolonium chloride; for the main group of antiemetics or anti antipsychotics: aripiprazole; for the main group of antisep Vertigo agents: aprepitant, beta-histine, domperidon, fluna tics: ethacridin, ethanol, denatured ethanol, fenchon, glyoxal, rizin, fosaprepitant, granisetron, ondansetron, palonosetron hexetidin, hydroxyquinoline Sulfate, potassium thiocyanate, and tropisetron; for the main group of antiepileptic agents: methenamine-silver nitrate 1:2, phenoxyethanol, ionic silver carbamazepin, clonazepam, diphenylhydantoin, phenytoin, and colloidal silver; for the main group of antiscabies agents: dipropylacetic acid, valproic acid, ethoSuximid, felbamat, benzylbenzoate; for the main group of antitussives or expec gabapentin, potassium bromide, lacosamid, lamotrigin, leve torants: anethol, benproperin, cineol, codeine, dextrometho tiracetam, mesuXimid, oXcarbazepin, phenobarbital, primi rphan, dihydrocodeine, dropropizin, eucalyptol, guaifenesin, don, propylvalerianic acid, rufinamide, Sultiam, tiagabin, guajacol glycerine ether, levodropropizin, narcotin, sodium topiramate, valproic acid, vigabatrin and Zonisamide; for the dibunate, noscapin, pentoxyverin, thymol and tyloxapol; for main group of antiestrogens: clomife; for the main group of the main group of anticoagulants: argatroban; for the main antihemorrhagics, antifibrinolytics and other hemostatic group of anxiolytics: buspiron; for the main group of appetite agents: aminomethylbenzoic acid, human blood clotting fac curbing agents: amfepramon and cathine; for the main group tor 1, blood clotting factor Vlla, blood clotting factor Vll of aromatase inhibitors: anastroZole, exemestan and letro (CHO), recombinant blood clotting factor Vll, human blood Zole; for the main group of arteriosclerosis agents: dode clotting factor Vll, recombinant blood clotting factor 1X, cyltetradecylhydroxypolyoxyethylene polyoxypropylene; US 2011/0269.704 A1 Nov. 3, 2011 for the main group of balneotherapeuticals and thermo dequalinium chloride, dibromhydroxybenzene Sulfonic acid, therapy agents: humic acids; for the main group of B-lactam dichlorbenzyl alcohol, dithranol, ethylhexanol, formalde antibiotics: aztreonam, imipenem, cilastatin, doripenem, hyde, glucoprotamine, glutaral, magnesium monoperoxyph ertapenem, loracarbef, meropenem; for the main group of thalate, mecetronium ethylsulfate, oligodiiminoimidocarbo beta-receptor and calcium channel blockers and inhibitors of nyliminohexamethylene, ortho-phthalaldehyde, peracetic the renin-angiotensin-aldosterone system: acebutolol. acid, polyhexanid, povidone iodine, 1-propanol, 2-propanol, atenolol, bisoprolol, betaxolol, bupranolol, carteolol, celip tetrahydrotetrakishydroxymethylimidazoimidazoldione, rolol, esmolol, fosinopril, gallopamil, irbesartan, tosylchloramide Sodium and hydrogen peroxide; for the main levobunolol, lisinopril, losartan, metipranolol, metoprolol. group of deodorants: chlorophyllin; for the main group of nebivolol, nifedipine, nisoldipin, oXprenolol, penbutolol, per dietetics or nutritional Supplements: methyloxobutyric acid, indopril, pindolol, propranolol, talinolol, Valsartan and Vera methyloxovalerianic acid (3), methyloxovalerianic acid (4) pamil, for the main group of bisphosphonates: alendronate, and oxophenylpropionic acid; for the main group of diagnos alendronatic acid, clodronate, clodronic acid, etidronate and tic agents and diagnosis preparation agents: aminolavulinic etidronic acid; for the main group of broadband penicillin: acid, aminolevulinic acid, 5-amino-4OXopentanoic acid, amoxicillin and amplicillin; for the main group of broadband ceruletid, human corticorelin, iron oxide, ferumoxsil, fluo penicillin+B-lactamase inhibitors: clavulanic acid and Sul rescein, gadobenic acid, gadobutrol, gadodiamide, gadofos bactam; for the main group of bronchodilators: aminophyllin veset, gadopentetic acid, gadoteridol, gadoteric acid, gadox and bambuterol; for the main group of broncholytics or anti etic acid, galactose, C-urea, hexylaminooxopentanoate, asthmatics: carbocisteine, ciclesonide, clenbuterol, fenoterol, indocyanine green, mangafodipir, palmitic acid, patent blue formoterol, ipratropium bromide, ketotifen, montelukast, V, perflutren, polyvinyl chloride, protirelin, secretin, starch omalizumab, reproterol, Salbutamol, Salmeterol, terbutalin, hydrolyzate, somatorelin, TRH and tuberculin purified for theophyllin, theophyllin ethylene diamine, tiotropium bro human use; for the main group of direct parasympathomimet mide and tulobuterol; for the main group of calcium antago ics: bethanechol chloride; for the main group of diuretics: nists: amlodipin, diltiazem, felodipin and isradipin; for the bumetanide, furosemide, piretanide, Spironolactone, main group of calcium replacement agents: calcium amino torasemide, triamterene, triamterene--hydrochlorothiazide ethyl phosphate, calcium aspartate, calcium bis-(hydrogen and Xipamide; for the main group of dopamine agonists: aspartate), calcium chloride, calcium citrate, calcium glucon C-dihydroergocryptin; for the main group of circulation pro ate, calcium hydrogen phosphate, calcium hydrogen phos moting agents: alprostadil, cinnarizin, moXaverin, naftidro phate, calcium lactobionate, calcium lactogluconate and cal furyl, pentoxifyllin, prostaglandin E1 and Xanthinol nicoti cium salts; for the main group of carboanhydrase inhibitors: nate; for the main group of iron replacement: ammonium iron acetazolamide, binzolamide and dorzolamide; for the main Sulfate; for the main group of emetics: apomorphine; for the group of cephalosporin: cefaclor, cefadroxil, cefalexin, cefa main group of withdrawal agents/agents for treatment of Zolin, cefepim, cefixim, cefotaxim, cefotiam, cefepodoxim, addictive diseases: maltrexone, nicotine and Vareniclin; for the ceftazidim, ceftibuten, ceftriaxon, cefuroxim and ceph; for main group of enzyme replacement therapy for Fabry's Syn the main group of chemotherapy agents: co-trimoxazole, dap drome: agallsidase alpha and agallsidase beta; for the main son, nifuratel, nitrofural, nitrofurantoin, nitrofurazon, group of enzyme inhibitors, enzyme deficiency products and nitroxolin, octenidin, pentamidin, ulfamethoxazole, tauroli transport proteines: carglumic acid, L-carnitine, levocar din and trimethoprim; for the main group of cholagogues and nitine, C-esterase inhibitor, galsulfase, hyaluronidase, idur bile duct therapeutic agents: menthon, C-pinene, B-pinene Sulfase, imiglucerase, laronidase and miglustat; for the main and ursodesoxycholic acid; for the main group of cholin group of enzyme replacement therapy in Pompe's disease: ergics: acetylcholine chloride, carbachol, distigmin bromide, alglucosidase alpha; for the main group of estrogens: estriol, neostigminand pyridostigmin bromide; for the main group of conjugated estrogens and ethinylestradiol; for the main group corticoids: fludrocortisone for the main group of depot peni of fibrinolytics: alteplase, reteplase, Streptokinase, tenect cillin: benzylpenicillin-benzathin and benzylpenicillin eplase and urokinase; for the main group of film forming procaine; for the main group of dermatic agents: ammonium agents: carbomer and carmellose; for the main group of gall dodecylsulfate, betacarotene, DFMO, eflornithine, difluorm stone dissolvers: chenodesoxycholic acid; for the main group ethylornithine, dodecylbenzene sulfonic acid, nitrilotrietha of gestagens: dienogest, drospirenone, dydrogesterone, nol salt, ectoin, estradiol benzoate, ethyllinolate, framycetin, gestodene, hydroxyprogesterone caproate, levonorgestrel, fusidinic acid, synthetic tannin, phenol-methanal-urea poly medrogestone, medroxyprogesterone, megestrolacetate, condensate Sulfonated, urea, hexamethylene tetramine, hyd norelgestromin, norethisterone, norgestimate and D-norg roquinone, isotretinoin, potassium hydroxide, keratin, copper estrel; for the main group of glaucoma treatment: bimatoprost (II) nitrate, lithium Succinate, methane thelinium bromide, and latanoprost; for the main group of geriatrics: potassium methenamine, methoxypsoralene, mupirocin, nadifloxacin, metabisulfite; for the main group of antipodagrics: pimecrolimus, podophyllotoxin, Salicylic acid, nitric acid, probenecide; for the main group of glucocorticoids: alclom Selenium disulfide, Sulfadiazine-silver, tacalcitol, tretinoin etaSone, amcinonide, beclometaSone, betamethasone, budes and tyrothricin; for the main group of disinfectants: amino onide, clobetasol, clobetaSone, clocortolone, cloprednol, propyldodecylpropane diamine, cocospropylene diamine, deflazacort, desoximetasone, dexamethasone, diflorasone, dodecylpropane diamine, ethylene dioxydimethanol and tri diflucortolone, flumetasone, flunisolide, fluocinolonac closan; for the main group of disinfectants or antiseptics: etonide, fluocinonide, fluocortolone, fluorometholone, flu aethacridin, aluminum acetate tartrate, amylmetacresol, prednidene, fluticaSone, halometasone, hydrocortisone, bibrocathol, benzalkonium chloride, benzethonium chloride, hydrocortisone aceponate, hydrocortisone acetate, hydrocor benzyl alcohol, bishydroxymethyl urea, biphenyl-2-ol, bro tisone-17-butyrate, hydrocortisone hydrogen Succinate, mchlorophen, cetylpyridinium chloride, 8-quinolinol Sulfate, methylprednisolone, mometasonfuroate, prednicarbate, clioquinol, didecyldimethylammonium chloride, didecylm prednisolone, prednisone, rimexolone, triamcinolone, triam ethyloxyethlammonium propionate, quinolinol Sulfate potas cinolone acetonide, triamcinolone-16.21-diacetate and tri sium Sulfate, chlorhexidin, chlorhydroxybenzoic acid, cloro amcinolone hexacetonide; for the main group of gonadorelin fen, cocospropylene diamine guanidinium acetate, inhibitors: cetrorelix; for the main group of gynecologicals: US 2011/0269.704 A1 Nov. 3, 2011 gemeprost, copper, metergolin, methylergometrin, lactic estyramine, cholestyramine, etofibrate, etofyllin clofibrate, acid, nonoxinol, progesterone, prostaglandin E2, quinagolide eZetimib, fenofibrate, fluvastatin, gemfibrozil, lovastatin, and Sulprostone; for the main group of hemopoietic growth magnesium pyridoxal phosphate glutamate, nicotinic acid, factors: becaplermin; for the main group of hemostyptics: omega-3-acid ethyl ester, pravastatin and simvastatin; for the cellulose oxidized regenerated, desmoressin and collagen; main group of topical anesthetics or neural therapeuticals: for the main group of hepatics: acetylmethionine, betaine aethoform, p-aminobenzoic acid ethyl ester, articaine, ben dihydrogen citrate, choline hydrogen tartrate, potassium Zocaine, bupivacaine, carticaine, chlorethane, cinchocaine, iron-phosphate-citrate complex, ornithine aspartate and Zinc ethyl choride, felypressin, macrogol lauryl ether, mepiv acetate; for the main group of cardioglycosides (Digitalis acaine, prilocaine, procaine, proxymetacaine, quinisocaine, lanata): 3-acetyldigoxin, digitoxin and digoxin; for the main ropivacaine and tetracaine; for the main group of gastrointes group of hyperemization agents: benzylnicotinate and tinal agents: hydrotalcit, lanSoprazole, loperamide, methyln isobornylacetate; for the main group of hypnotics or seda altrexone bromide, metoclopramide, sodium alginate, tives: brotizolam, chloralhydrate, clomethiazole, doxy olsalazin, omeprazole, oxetacaine, pancreas powder, pancre lamine, flunitrazepam, flurazepam, lormetazepam, melato atin, pantoprazole, pepsin, pirenzepine, polymethylsiloxane, nin, midazolam, nitrazepam, temazepam, Zaleplon, Zolpidem rabeprazole, racecadotril, ranitidine, silicon dioxide, simethi and Zopiclon; for the main group of pituitary and hypothala cone. Sucralfate, Smectite, tannin-protein and tilactase; for the mus hormones, other regulatory peptides and their inhibitors: main group of magnesium replacement agents: magnesium carbetocin, choriogonadotropin alpha, choriongonadotropin, chloride, magnesium salts and magnesium sulfate; for the tetracosactid, B-1-24-corticotropin, follitropin alpha, fol main group of macrollide antibiotics: azithromycin, bacitra litropin beta, ganirelix, gonadorelin, gonadotrophinum chori cin, clarithromycin, daptomycin and erythromycin; for the onicum, gonadotrophinum hypophysicum, menotropin, lan main group of migraine agents: almotriptan, eletriptan, reotid, LH-RH. lutropin alpha, mecaserim, nafarelin, ergotamine, froVatriptan, naratriptan, rizatriptan, Sumatriptan octreotid, oxytocin, Somatostatin, Somatropin, terlipressin, and Zolmitriptan; for the main group of mineral preparations: thyrotrophin, urofollitropin, urogonatropin and human calcium lactate, calcium saccharate, iron hydrogenaspartate, growth hormone; for the main group of immunomodulators: potassium aminoethylphosphate, potassium citrate, magne eculizumab, glatiramer, lenalidomide, lenograstim, palivi sium aminoethylphosphate, magnesium aspartate, magne Zumab and pegvisomant; for the main group of immune sium bis(hydrogenaspartate), magnesium citrate, magnesium stimulants: aldesleukin, dimepranolacedoben, filgrastim, gluconate, magnesium hydrogen citrate, magnesium hydro inosine, interferon alpha-2a, interferon alpha-2b, interferon gen glutamate, magnesium hydrogen phosphate, magnesium beta-1, interferon beta-1b, interferon gamma-1b, peg orotate and magnesium oxide; for the main group of filgrastim, peginterferon alpha-2a and peginterferon alpha homocysteinuria treatment agents: betaine; for the main 2b; for the main group of immune Suppressants: adalimumab, group of Scleroderma and induratio penis plastica treatment azathioprin, basiliximab, cyclosporine, cladribin, cyclospo agents: 4-aminobenzoic acid; for the main group of mucolyt rine, daclizumab, efalizumab, everolimus, immunglobulin G ics: acetylcysteine; for the main group of mucolytics: desox rabbit antihuman-T-cell, infliximab, muromonab-CD3, yribonuclease and dornase alpha; for the main group of mycophenolate mofetil, mycophenolic acid, natalizumab, muscle relaxants and reversers: alcuronium chloride, atracu Sirolimus, tacrolimus and tocilizumab; for the main group of rium besylate, quinine, cisatracurium besylate, dantrolen, infusion and standard injection Solutions or organ perfusion mivacurium chloride, orphenadrin, pancuronium bromide, Solutions: N-acetyltyrosine, gelatine poly Succinate, glucose, pridinol, rocuronium bromide, Succinyl choline chloride, glutamine, glycerol dihydrogen phosphate, human albumen, suxamethonium chloride, Sugammadex, tetrazepam, tizani potassium hydrogen glutamate, mannitol, Sodium aminoeth din, tolperison and Vecuronium bromide; for the main group ylhydrogen phosphate, Sodium chloride, sodium hydrogen of myotonolytics: baclofen and methocarbamol; for the main carbonate, oleic acid, 2-oxoglutaric acid, polyhydroxyethyl group of narcosis agents: esketamine, etomidate, hydroxybu starch, hydrochloric acid, taurine, trometamol and Xylitol; for tyiric acid, ketamine, propofol, remifentanil, sevofluran, the main group of inhaled narcotics: desfluran, dinitrogen Sufentanil and thiopental-sodium; for the main group of neu monoxide and isofluran; for the main group of intestinal roleptics: amisulpride, aaphenothiazine, pothipendyl, ben antiphlogistics: 5-aminosalicylic acid, mesalazin, (-)-C.-bis peridol, bomperidol, butyrophenone, chlorprothixen, clozap abolol, levomenol, bromelain and choline stearate; for the ine, diphenylbutylpiperidine, droperidol, fluspirilen, main group of potassium replacement agents: potassium pimozide, flupentiXol, fluiphenazine, levomepromazine and acetate, potassium chloride, potassium hydrogen aspartate, melperone; for the main group of neuropathy drugs and other potassium hydrogen carbonate, potassium lactate and potas neurotropic agents: cytidine phosphate, A-liponic acid, thio sium malate; for the main group of potassium-sparing diuret ctic acid, pregabalin, riluzol and uridine phosphate; for the ics: amiloride; for the main group of capillary sealing agents: main group of nonsteroidal anti-inflammatory drugs: flurbi calcium dobesylate; for the main group of cardiacs: enoxi profen, ketorolac-tromethanol, lornoxicam and parecoxib; mon, icatibant, B-methyldigoxin, methyldigoxin, milrinon for the main group of nonsteroidal antirheumatics: ace and oubain; for the main group of caries and parodontosis colfenac, aemetacin, alizapride, chloroquin, dexibuprofen, agents and other dental preparations: dectaflur, sodium fluo diclofenac, etofenamate, ibuprofen, indomethacin, ketopro ride and olaflur, for the main group of carminatives: dimeth fen, meloxicam, nabumeton, naproxen, phenylbutaZone, ylpolysiloxane and dimethicone; for the main group of coro piroXicam, proglumethacin and tiaprofenic acid; for the main nary drugs: ivabradin and molsidomine; for the main group of group of ophthalmics: chondroitin Sulfate, gramicidine, laxatives: bisacodyl, glycerine, glycerol, lactulose, macrogol, hydroxypropyl-guar, hydroxypropylmethylcellulose, magnesium peroxide, Sodium dioctylsulfoSuccinate, sodium hypromellose, inosine phosphate, lomefloxacin, methylhy laurylsulfoacetate, sodium monohydrogen phosphate, droxypropylcellulose, naphazolin, nedrocromil, oxybup Sodium picosulfate, Sodium sulfate, syrupy paraffin, polyeth rocaine, pegaptainib, pilocarpin, polymyxin B, poly(vinylal ylene glycol and white Vaseline oil paraffin, for the main cohol), povidone, ranibiZumab, Scopolamine, Sulfacetamide, group of photoprotective agents: actinoquinol; for the main tafluprost, tetry Zolin, timolol, travoprost, tropicamide, verte group of lipid lowering drugs: atorvastatin, beZafibrate, col porfin and wool wax alcohols; for the main group of US 2011/0269.704 A1 Nov. 3, 2011 osteoporosis/calcium/bone metabolism regulators: alphacal cobalt hydrogen aspartate, iron (III) chloride, copper (II) cidol, calcitonin, disodium fluorophosphate, eptotermin chloride, copper (II) hydrogen aspartate, manganese (II) alpha, hydroxycolecalciferol, ibandronate, ibandronic acid, chloride, manganese (II) hydrogenaspartate, Sodium molyb pamidronate, pamidronic acid, human parathyroid hormone, date, Sodium selenite, Zinc aspartate, Zinc bishydrogenaspar paricalcitol, raloxifen, distrontium ranelate, risedronate, tate, Zinc chloride, Zinc gluconate, Zinc histidine, Zinc orotate risedronic acid, teriparatid, tiludronate, tiludronic acid, and Zinc sulfate; for the main group of replacement agents: Zoledronate and Zoledronic acid; for the main group of oto disodium hydrogen citrate, magnesium acetate, sodium logic agents: docusate-sodium; for the main group of parkin acetate, sodium hydroxide and sodium lactate; for the main son drugs and other agents against extrapyramidal distur group of sympathomimetics: diplivefrin and ephedrine; for the bances: benserazide, bromocriptine, budipine, cabergoline, main group of tetracyclines: chlortetracycline, demeclocy carbidopa, entacapone, levodopa, lisuride, metixene, per cline, doxycycline, meclocycline, minocycline, oxytetracy golide, piribedil, pramipexol, procyclidine, rasagiline, ropin cline and tetracycline; for the main group of platelet clotting irole, rotigotine, selegiline, tetrabenazine, tiapride, tolcapone inhibitors: abciximab, cilostazol, clopidogrel, eptifibatide, and trihexypenidyll; for the main group of penicillins: benzyl iloprost, ticlopidine and tirofiban; for the main group of penicillin and dicloxacillin; for the main group of phosphate thyreostatics: carbimazole, methimazole and thiamazole; for binders: algeldrate, hydrated aluminum oxide, calcium the main group of tocolytics: atosiban; for the main group of acetate and calcium carbonate; for the main group of phos toxoplasmosis, pneumocystis carinii and pneumonia drugs: phate replacement agents: sodium glycerophosphate; for the atovaquone; for the main group of tranquilizers (benzodiaz main group of photosensitizers: ammoidine and methox epin): alprazolam, bromazepam, chlordiazepoxide, cloba salene; for the main group of polyaromatic retinoids: ada Zam, diazepam and dipotassium cloraZepate; for the main palene; for the main group of progestagenics: desogestrel and group of tuberculosis drugs: aminosalicylic acid, ethambutol, etonogestrel; for the main group of protease inhibitors: ata isoniazide, protionamide, pyrazinamide, rifampicin and ter Zanavirandlopinavir, for the main group of proteinase inhibi izidone; for the main group of ulcer therapeuticals: bismuth tors: antithrombin Ill; for the main group of protozoan agents: nitrate, bismuth tetraoxodialuminate, cimetidine, esomepra artemether and lumefantrine; for the main group of psycho Zole and famotidine; for the main group of uricostatics: analeptics: atomoxetin, metamfepramon and methylpheni allopurinol and benzbromarone; for the main group of uro date; for the main group of psychoenergetics: deanol; for the logicals: dutasteride, fesoterodine, finasteride, flavoxate, main group of psychopharmaceuticals: doxepin, haloperidol. potassium aminobenzoate, potassium Sodium hydrogen cit imipramine, lithium salts, lorazepam, medazepam, meman rate, lanthanum (III) carbonate, mercaptamine, methionine, tin, moclobemide, modafinil, olanzapine, oxazepam, pali oxybutynine, phenoxybenzamine, phytosterol, polystyrene peridone, perazine, perphenazine, phenothiazines, pimozide, divinylbenzene Sulfonic acid, polystyrene Sulfonic acid, pipamperone, prazepam, promethazine, prothipendyl, que propiverine, propyl-4-hydroxybenzoate, sevelamer, Solifena tiapine, risperidone, sertindole, Sulpirid, thioridazine, thio cin, tamsulosin, tiopronin, tolterodine, troSpium chloride and canthene, Venlafaxine, Ziprasidone, Zotepine and Zuclo yohimbin; for the main group of uterus agents: dinoprostone; penthixol; for the main group of rhinologics or sinusitis for the main group of vasodilators: adenosine, buflomedil, agents: Emser salt, synthetic Emser salt, natural sea salt, carvedilol, codergocrin, dihydralazine, dihydroergotoxin, oxymetazolin, silver-protein acetyl tannate, tramaZoline, dipyridamol, glycerol trinitrate, isosorbide dinitrate, isosor Xanthan gum and Xylometazoline; for the main group of robo bide mononitrate, nitroglycerin, pentaerythrityl tetranitrate, rants or tonics: iron (III) citrate and glutaminic acid; for the sildenafil, tadalafil, trapidiland Vardenafil; for the main group main group of X-ray contrast agents: amidotrizoic acid, of Venous therapeuticals: heparinoids, mucopolysaccharide barium sulfate, diatrizoate, iobitridol, iodixanol, iohexol, polysulfuric acid esters, oligo(O-sulfo)rutoside, poli iomeprol, iopamidol, iopromide iosarcol, iotrolan, iotroxic docanole, rutin and rutoside; for the main group of vein tonic acid, ioxaglic acid and ioxitalamic acid; for the main group of agents: dioSmin; for the main group of virustatics: abacavir, saluretics: bemetizide, bendroflumethiazide, chlorthalidone, aciclovir, adefovir, amantadine, brivudin, cidofovir, clopamide, hydrochlorothiazide, hydrochlorothiazide-- darunavir, didanosine, efavirenz, emitricitabine, entecavir, amiloride, hydrochlorothiazide+triamterene and mefruside: etravirine, famciclovir, foSamprenavir, ganciclovir, idoxuri for the main group of thyroid therapeutic agents: cinacalcet, dine, imiquimod, indinavir, interferon beta, lamivudine, potassium iodide, levothyroxin, liothyronin, sodium iodide, maraviroc. nelfinavir, nevirapine, oseltamivir, raltegravir, rib Sodium perchlorate, propylthiouracil, thiouracils and L-thy avirin, ritonavir, saquinavir, stavudine, telbivudine, tenofovir, roxin; for the main group of essential amino acids: histidine, tipranavir, trifluridine, tromantadine, Valaciclovir, Valganci isoleucine, leucine, lysine, phenylalanine, threonine, tryp clovir, Zanamivir and Zidovudine; for the main group of Vita tophan, tyrosine and valine; for the main group of secretolyt mins: aneurin, ascorbic acid, benfotiamine, biotin, calcife ics: ambroXol and bromhexine; for the main group of serums, diol, ergocalciferol, calciferol, calcipotriol, calcitriol, immunglobulins and inoculants: immunglobulin (anti-D), calcium pantothenate, collecalciferol, cyanocobalamine, immunglobulin (botulismus), immunglobulin (cytomegalia), dihydrotachysterol, hydroxocobalamine, purified silicon immunglobulin (hepatitis B), immunglobulin (human), dioxide, sodium ascorbate, Sodium pantothenate, nicotina immunglobulin (tetanus), immunglobulin(rabies) and immu mide, nicotinic acid amide, pyridoxin, retinol, riboflavin, nglobulin (varicella-Zoster); for the main group of sexual thiamine, thiamine dihydrogen phosphate-dihydrogen phos hormones and their inhibitors: estradiol, estradiol Valerate, phate (ester salt), thiamine disulfide, thiamine nitrate, C-to mestranol, mifepristone, prasterone, testosterone and copherol, RRR-O-tocopherol, C.-tocopherol acetate, RRR-C- tibolone; for the main group of spasmolytics or anticholin tocopherol acetate, DL-C.-tocopherol hydrogen Succinate, ergics: atropine, atropine Sulfate, biperiden, bornaprine, RRR-C-tocopherol hydrogen Succinate, vitamin A, vitamin borneol, butylscopolaminium bromide, camphen, cyclopen A-acid, Vitamin B, Vitamin B, Vitamin B vitamin B2, tolate, darfenacin, glycopyrronium bromide, hymecromone, vitamin C. vitamin D. Vitamin D. Vitamin E and vitamin K. hyoscine butylbromide, mebeverine and pipenzolate bro for the main group of wound and scar treatment agents: allan mide; for the main group of trace elements: bis(L-histidinato) toin, calcium alginate, dexpanthenol, ethylcyanoacrylate, Zinc, chromium chloride, chromium hydrogen aspartate, lactide-caprolactone copolymers, poly(butylmethacrylate US 2011/0269.704 A1 Nov. 3, 2011 co-methylmethacrylate) (x:y), polyurethane and titanium 0040 Preferred glucocorticoids are chosen from the group dioxide; for the main group of urine acidification agents: consisting of clobetasol-17-propionate, diflucortolone-21 ammonium chloride; for the main group of cytoreductive Valerate, amcinonide, betamethasone-17,21-dipropionate, agents: anagrelid; for the main group of cytostatics, other betamethasone-17-Valerate, desocimethasone, diflucor antineoplastic agents and protectives: adriamycin, amethop tolone-21-valerate, fluocinolone acetonide, fluocinonide, terin, bendamustine, bleomycin, bortezomib, buSulfan, fluocortolone, fluprednidene-21-acetate, fluthicasone-17 capecitabine, carboplatin, CCNU, lomustine, chlorambucil, propionate, halcinonide, hydrocortisone-21-acetate-17-pro cisplatin, cyclophosphamide, cytarabine, dacarbazine, dasa pionate, hydrocortisone-17-butyrate-21-propionate, hydro tinib, daunorubicin, dexraZOXan, docetaxel, doxorubicin, epi cortisone-17-butyrate, methylpredisolonaceponate, rubicin, erlotinib, estramustine, etoposide, fludarabine, fluo rouracil, flutamide, 5-FU, fulvestrant, gemcitabine, momethasone, momethasone furoate, prednicarbate, triamci goserelin, hydroxycarbamide, ibritumomabtiuXetan, idarubi nolonacetonide, clobethasone butyrate, clocortolone-21-piv cin, ifosfamide, imatinib, irinotecan, lapatinib, leuprorelin, alate, fluocortinbutyl, flumethasone-21-pivalate, hydrocorti melphalan, mercaptopurine, mesna, methotrexate, methy Sone and derivates of the aforementioned Substances. laminooxopentanoate, miltefosine, mitomycin, mitotane, 0041 Another embodiment of the composition according mitoxantrone, nelarabine, nilotinib, nimustin, oxaliplatin, to the invention proposes that the composition of the inven paclitaxel, palifermin, panitumumab, pegaspargase, pemetr tion contain, as active ingredient, at least one topical anes exed, porfimer-sodium, procarbazine, rasburicase, rituximab, thetic, especially a topical anesthetic that is chosen from the Sorafenib, Sunitinib, tamoxifen, tegafur, temoporfin, temoZo above indicated special topical anesthetics, and the concen lomide, temsirolimus, thiotepa, thioguanine, topotecan, tration of this topical anesthetic, depending on the particular toremifene, trabectedline, trastuzumab, treosulfan, triptorelin, active ingredient, varies in particular between 3 wt.% and 15 trofosfamide, uracil, vinblastin, Vincristin, Vindesine and wt.%, especially between 6 wt.% and 12 wt.%, in terms of vinorelbine; for the main group of biomaterials or medical the concentration of active ingredient in the liquid composi plastics or various materials: hydroxylapatite, methyl methacrylate, poly(methylacrylate-co-methylmethacrylate) tion. (x:y), tricalcium bisphosphate and Zirconium (IV) oxide as 0042 Especially preferred topical anesthetics are chosen special active ingredient or active ingredient mixture. from the group consisting of benzocaine, procaine, tetra 0037. An especially suitable embodiment of the composi caine, lidocaine, etidocaine, prilocaine, mepivacaine, bupiv tion according to the invention proposes that this embodiment acaine. S-ropivacaine, articaine and their derivates. of the invented composition has, as active ingredient, an anal 0043. Another embodiment of the composition according gesic, especially an analgesic that is chosen from the above to the invention calls for the composition to contain at least indicated special analgesics, and the concentration of this one immunomodulator in a concentration between 0.03 wt.% analgesic in the liquid composition that is mechanically and 0.1 wt.%, and the above indicated special immunomodu foamed is varied in particular between 0.1 wt.% and 20 wt.%. lators are especially preferred. preferably in a concentration between 2 wt.% and 10 wt.%. 0044 An especially suitable modification of the compo 0038 If the composition of the invention is to be used as sition of the invention comprises, as an active ingredient or foam for treatment of fungal infections, then it includes, as mixture of active ingredients, a nonopioid analgesic/antiphlo pharmaceutical active ingredient, at least one antimycotic, gistic agent, especially a non-opioid analgesic/antiphlogistic especially an antimycotic that is chosen from the above indi that is chosen from the above indicated special non-opioid cated special antimycotics. Preferably this antimycotic is analgesics/antiphlogictics. These include in particular the chosen from the group comprising chlotrimaZol, biphonaZol. salicylates, preferably acetylsalicylic acid and/or diflunisal, econazol, phenticonazol, isoconazol, oxyconazol, Sertacona acetic acid derivates Such as indomethacin, acemethacin, Zol, thioconazol, terbinafin, myconazol, ketoconazol, itra diclofenac and/or lonazolac, propionic acid derivates Such as conazol, fluconazol, Voriconazol, as well as derivates of the ibuprofen, flurbiprofen, ketoprofen, dexketoprofen, dexibu aforementioned substances. In particular, the concentration of an antimycotic active ingredient varies between 0.01 wt.% profen, tarenflurbil, nimeSulide, naproxen and/or thiaprofen and 10 wt.%, especially between 0.2 wt.% and 5 wt.%, in acid, oxicams, such as pyroxicam, tenoxicam, meloxicam terms of the liquid composition that is exclusively mechani and/or lornoxicam, anthranylic acid derivates such as mefe cally foamed during application. A foam produced in exclu naminic acid and/or flufenaminic acid, aniline derivates Such sively mechanical fashion from Such a liquid composition as paracetamol, and 1-phenyl-2,3-dimethyl-3-pyrazolin-5-on during its application can then be used in particular with a derivates, such as phenaZone, propyphenaZone and/or very high pharmaceutical efficacy for nail and foot fungal metamizol, their salts and their derivates. infections and for saccharomycete infections, the high phar 0045 Depending on the particular application of the maceutical efficacy being manifested in that these fungal above-described embodiments of the composition of the infections are curtailed already after a few applications and invention, the concentration of the analgesic/antiphlogistic also healed in a short time after the application is repeated. active ingredient in the liquid composition will vary between 0039. Another embodiment of the composition according 0.5 wt.% and 8 wt.%, especially between 1 wt.% and 5 wt. to the invention includes as an active ingredient, at least one %. corticoid active ingredient, especially a corticoidactive ingre 0046. Of course, it is also possible for the composition of dient that is chosen from the above indicated special corticoid the invention to include, as active ingredient, a mixture of active ingredients, wherein the corticoid active ingredient is active ingredients, as long as this mixture of ingredients is chosen preferably from the group consisting of glucocorti mutually compatible. Such embodiments of the composition coids, mineral corticoids and derivates of these. Depending of the invention will be used for treating generally milder skin on the particular corticoid active ingredient contained in the ailments, such as milder forms of eczema, acne, lichen, insect composition of the invention, the concentration of this corti bites, mycoses and/or treatments of Surface wounds with the coid active ingredient varies between 0.001 wt.% and 3 wt. foam created from the composition of the invention, in which %, preferably between 0.1 wt.% and 0.8 wt.%. case the active ingredient or mixture of active ingredients is US 2011/0269.704 A1 Nov. 3, 2011
chosen from the group containing terbinafin, clobethasone special foam applicators it is refered to EPO 565 713 and EP butyrate, erythromycin, benzocaine, dexamethasone, calci 0.613 728 where further technical details about these foam potriol, tretinoin, minoxidil, bifonazole, dexpanthenol, Sali applicators will be found. cylic acid, prednicarbate, momethasone furoate. 0056. Thus, in particular, the present invention contem 0047. It should be clarified that all concentration figures plates a foam applicator that includes a composition of the indicated in this specification refer each time to the liquid invention as described in detail above. composition prior to its foaming, unless otherwise expressly 0057 Moreover, the present invention relates to methods indicated. for treatment of the following illnesses. 0048. An especially suitable embodiment of the composi 0058. In a first embodiment, a method is contemplated that tion of the invention includes, as the phospholipid foaming includes the treatment of atopic eczema or neurodermitis, agent, a phosphatidylcholine isolated from Soybeans, and in wherein the treatment method of the invention involves the particular the concentration of this phosphatidylcholine in applying of a foam containing an immunomodulator, as is the phospholipid foaming agent is more than 50 wt.%, pref produced in particular from the previously described compo erably between 50 wt.% and 95 wt.%, in relation to the dry sition of the invention, to the skin of a warm-blooded mam Substance of the phospholipid foaming agent. mal in need thereof. In particular, tacrolimus is chosen as the 0049 Especially when this phospholipid foaming agent immunomodulator. Depending on the particular immuno contains at most 15 wt.% of lyso-phosphatidylcholine, at modulator chosen, its concentration will vary preferably most 10 wt.% of phosphatidic acid and at most 10 wt.% of between 0.03 wt.% and 0.1 wt.%. phosphatidyl ethanolamine, one can create a foam with this 0059. In a second embodiment, a method is contemplated special foaming agent that can be diversely adapted to the for the treatment of inflammatory or pruritic skin ailments, particular requirements of the application site by varying its psoriasis, dermatitis, neurodermitis or psoriasis in a patient in concentration. need thereof, comprising the application of a foam containing 0050. Furthermore, in some embodiments, it may be a glucocorticoid, as is produced in particular from described important for the aforementioned special foaming agent that compositions, to the skin of a warm-blooded mammal. In the phosphatidylcholine contained in the phospholipid foam particular, the glucocorticoid in this treatment method is cho ing agent have an acid number of at most 10, a peroxide Sen from the group consisting of betamethasone, dexametha number of at most 10, and an oil concentration of atmost 6 wt. Sone, predincarbate, mometasone furoate and clobetaSone % in terms of the dry substance of this phospholipid foaming butyrate. Depending on the glucocorticoid, its concentration agent, the liquid composition forming the basis of the foam varies between 0.01 wt.% and 0.4 wt.%. has an especially long shelf life, without requiring a higher 0060. In a third embodiment, a method is contemplated for concentration of antioxidants or stabilizers, especially for the the treatment of of pain, inflammation, rheumatic ailments or aforementioned phospholipid foaming agent. acute trauma in a patient in need thereof and comprises the 0051 Principally it is recorded that the concentration of application of a foam containing an analgesic, as is produced the phospholipid foaming agent contained in the liquid com in particular from the previously described composition of the position should be chosen so that the foams mentioned at the invention, to the skin of a warm-blooded mammal. Prefer outset for the method of the invention and for the composition ably, the analgesic in this treatment method is chosen from the of the invention and specified by the foam volume and by the group consisting of diclofenac, ketoprofen and ibuprofen. foam stability can be created. Preferably, the liquid compo Depending on the analgesic, its concentration varies between sition which is purely mechanically foamed has the phospho 0.5 wt.% and 10 wt.%. lipid foaming agent in a concentration between 2 wt.% and 0061. In a fourth embodiment, a method is contemplated 25 wt.%, especially in a concentration between 4 wt.% and for the treatment of of mycotic infections comprises the appli 15 wt.%. cation of a foam containing an antimycotic, as is produced in 0052. The general remarks given above on the method of particular from the previously described composition of the the invention also hold for the composition of the invention, invention, to the skin or nails respectively hooves of a warm wherein the composition of the invention contains, besides blooded mammal in need thereof. Preferably in this treatment water, preferably an alcohol and especially propylene glycol, method the antimycotic is chosen from the group comprising whose concentration, depending on the desired and above bifonazole and terbinafin. Depending on the antimycotic, its specified foam, varies between 2 wt.% and 25 wt.%, espe concentration varies between 0.1 wt.% and 20 wt.%, pref cially between 5 wt.% and 15 wt.%. erably between 2 wt.% and 10 wt.%. 0053 As regards the pH value, it is to point out that espe 0062. In a fifth embodiment, a method is contemplated for cially the liquid composition of the invention has a pH value the treatment of infections with Gram positive microbes, that is skin-tolerated and, depending on the particular site of anaerobic microbes and mycoplasms, especially for treat application, lies between 4.8 and 8.8. ment of acne, in a patient in need thereof, and comprises the 0054. In order to assure the above-indicated pH value, it is application of a foam containing an antibiotic, as is produced especially advantageous to add to the composition of the in particular from the previously described composition of the invention at least one buffer, especially sodium dihydrogen invention, to the skin of a warm-blooded mammal. Preferably phosphate dihydrate and/or disodium hydrogen phosphate in this treatment method the antibiotic chosen is erythromy dodecahydrate. cin, especially in a concentration between 2 wt.% and 4 wt. 0055. The composition of the invention as described in %. detail above can principally be foamed with any suitable foam 0063. In a sixth embodiment, a method is contemplated for applicator, e.g., the applicators made by Rexam/Airspray the treatment of itching of the skin comprises the application (www.rexamairspray.com) and made and marketed under the of a foam containing a topical anesthetic, as is produced in name M3 mini foamer (“M3 Minischäumer') or those of particular from the previously described composition of the made by Calmar/MeadWestvaco (Keltec). According to this invention, to the skin of a warm-blooded mammal. Preferably US 2011/0269.704 A1 Nov. 3, 2011
in this treatment method the topical anesthetic chosen is ben 0072 For clarity, and to avoid repetition, it is pointed out Zocaine and/or lidocaine, especially in a concentration that the remarks, details and benefits described at the outset in between 1 wt.% and 20 wt.%, preferably 2 wt.% and 10 wt. connection with the method of the invention also apply %. accordingly for the composition of the invention and also the 0064. In a seventh embodiment, a method is contemplated above described treatment procedure of the invention, as do for the treatment of psoriasis and comprises the application of the remarks, details and benefits described in connection with a foam containing calcipotriol, as is produced in particular the composition of the invention for the method of the inven from the previously described composition of the invention, tion and the treatment procedure of the invention. to the skin of a warm-blooded mammal in need thereof. Preferably the calcipotriol in this treatment method is pro 0073. Furthermore the present invention concerns a topi vided in a concentration between 0.005 wt.% and 0.05 wt.%. cally applicable liquid composition comprising at least one 0065. In an eight embodiment, a method is contemplated phosphlipidic foaming agent, at least one pharmaceutical for the treatment of acne, especially acne comedonica and active ingredient and at least one solvent. The inventive com acne papulopustulosa, comprises the application of a foam position is foamable exclusively by a mechanically foaming containing tretinoin, as is produced in particular from the without using an propellant to such an extent, that by previously described composition of the invention, to the skin mechanically foaming of 250 ml of the liquid composition a of a warm-blooded mammal in need thereof. Preferably in foam is created having a foam volume of at least 400 ml and this treatment method the tretinoin is provided in a concen a foam stability, that the foam still has after a dwell time of tration between 0.05 wt.% and 0.1 wt.%. nearly five minutes and preferably of a dwell time up to five 0066. In a ninth embodiment, a method is contemplated minutes, measured at 25°C., at least 50% of the foam volume for treatment of hair loss comprises the application of a foam that was originally present immediately after the creation of containing minoxidil, as is produced in particular from the the foam. Both the afore mentioned foam volume and the previously described composition of the invention, to the skin afore mentioned foam stability are measured by a standard of a warm-blooded mammal in need thereof. Preferably in ized SITA foam measurement method, described hereafter. In this treatment method the minoxidil is provided in a concen connection herewith it is to note, that the liquid composition, tration between 3 wt.% and 6 wt.%. specified by the foam volume and foam stability, is exclu 0067. In a tenth embodiment, a method is contemplated sively mechanically foamed prior to use without using a pro for the antiseptic treatment of Superficial wounds comprises pellant, as repeated described before, so that the foam, created the application of a foam that includes an antimycotic to the in that way is used for topical application. This embodiment wound of a warm-blooded mammal in the need thereof, of the inventive composition has identical or analogue all the whereby the foam is preferably produced from the previously benefits, as described before. This is also the same for the described composition of the invention. In particular in this afore described embodiments. treatment method the dexpanthenol is provided in a concen 0074 Preferably the afore described inventive composi tration between 0.03 wt.% and 1 wt.%. tion has a foam volume, which varies between 450 ml and 0068. In an eleventh embodiment, a method is contem 1400 ml, especially between 600 ml and 1200 ml. plated for the treatment of herpes and the side effects accom 0075 Especially when the inventive composition has such panying herpes in a patient need thereof and comprises the a foam stability, that after five minutes after creating the foam application of a foam containing aciclovir, as is produced in a foam volume results, that correspondes to 55% till 85% of particular from the previously described composition of the the foam Volume, immediately after creating the foam, this invention, to the skin of a warm-blooded mammal. Preferably embodiment of the inventive composition has a high pharma in this treatment method the aciclovir is provided in a con ceutical efficacy. This advantage is also present, when the centration between 3 wt.% and 7 wt.%. foam Volume is within ten minutes after creating the foam at 0069. In a twelfth embodiment, a method is contemplated least 50%, preferably between 85% and 100%, of the foam for the treatment of mild to medium severe psoriasis of the Volume that was originally present immediately after the cre Scalp in a patient in need thereof and comprises the applica ation of the foam. tion of a foam containing salicylic acid, as is produced in 0076 Especially has the foam created from the inventive particular from the previously described composition of the liquid composition a density between 0.05 g/ml and 0.8 g/ml, invention, to the scalp of a warm-blooded mammal. Prefer preferably between 0.15 g/ml and 0.4 g/ml. ably in this treatment method the salicylic acid is provided in 0077 Concerning the solvent contained in the inventive a concentration between 8 wt.% and 12 wt.%. composition it is to point out, that this solvent is preferably an 0070. In the above description of the different embodi anorganic and/or an organic Solvent, whereby the anorganic ments of the method of treatment of the invention the term Solvent is preferably water and the organic solvent is an application is used in the singular. However, this should also alcohol or a mixture of alcohols and more preferably a poly refer to the repeated application, at intervals of time, within a alcohol and/or is the solvents described before in claim 5. given period, especially within 24 hours. 0078. Furthermore the present invention preferably con cerns a method for making and/or development of a foamable 0071. Likewise, the term skin used throughout the text liquid composition, for topical use, whereby the inventive covers not only the particular ailing regions of the skin, but method comprises the following steps: also all surfaces of the human oranimal body accessible to the application of the foam produced from the composition of the 0079 a. providing a liquid composition comprising at invention, and thus in particular, besides the skin or scalp least one pharmaceutically active ingredient, at least one itself, also nails, hair, teeth, hooves or the mucosa in mouth, Solvent, and at least one foaming agent, preferably at nose, vagina or foreskin, the regions of the ear and especially least one phospholipidic foam agent; the inner ear, the region of the anus and the colon, the region 0080 b. mechanically creating a foam of the liquid of the eyes, especially the region under the eyelid, such as composition; conjunctiva, cornea and lacrial sac, while the term mammal 0081 c. scanning the foam surface to determine the comprises animals and humans. stability and the volume of the foam; US 2011/0269.704 A1 Nov. 3, 2011 12
I0082 d. Varying the concentration of at least one of the ume in the sense of the present specification, while the time pharmaceutically active ingredient, the at least one sol change in this foam Volume is the foam stability. In other vent, or the at least one foaming agent; words, this means that, depending on the particular sample I0083 e. repeating steps band c until 250 ml of the liquid measured, the foam Volume consists not only of the Volume of composition, after the mechanical creation of the foam, the actual foam, but also of the volume of nonfoamed liquid has a foam volume of at least 400 ml and such a foam sample remaining in the measurement space. stability that at least about 50% of the original foam 0092. The following charts 1 to 19 plot all three measure volume is still present after about 5 minutes at 25°C. ment values for the particular composition, so that the repro 0084. Also this inventive method has identical or analogue ducibility of the measurement method can be seen quite well the afore described benefits and embodiments. from this. I0085. The present invention shall be further described 0093 All the following examples in which diclofenac is hereafter by means of the following Examples. indicated as the active ingredient contain this active ingredi ent in the form of the Sodium salt of diclofenac, meaning as EXAMPLES diclofenac-sodium. I0086) Description of the SITA Measurement Method ExampleS 1 to 5 0087. For the determination of the foam volume and the foam stability, a "SITA foam tester R-2000' (manufactured 0094. Following the customary procedure, a composition by SITA Messtechnik GmbH, Dresden) was used, as is containing ketoprofen, one containing lidocaine hydrochlo described in detail in EP 1092970. This measurement device ride, one containing prednicarbate, one containing diclofenac was provided with a rotor as shown in FIGS. 2 and 3 of DE and one containing clotrimaZol were prepared, having the 19740 095 and also described there. This rotor consists of a following ingredients: stirring shaft and a circular disk oriented perpendicular to this, with a diameter of 70 mm, above and below the circular disk there being provided four symmetrical stirring blades, oriented at right angles to each other. Each stirring blade has Composition in a rectangular base Surface of 23 mmx12 mm. In cross section, Ingredient wt.% each stirring blade has the shape of a triangle, with a height of 1 Ketoprofen 1O.OO 5 mm, so that each stirring Surface accordingly forms a roof 2 Propylene glycol 1O.OO with a ridge angle of 90 degrees. The stirring blades each 3 2-Propanol 8.OO consist of a Conidur fine perforated plate (manufactured by 4 Phospholipid foaming agent A 1O.OO 5 Sodium hydrogen phosphate dihydrate O.25 Heinehmann, Krefeld) and have a plate thickness of 0.5 mm. 6 Disodium hydrogen phosphate dodecahydrate, cryst. 0.57 a perforation of 0.5 and a spacing of 3.2. 7 Sodium hydroxide 1.55 0088. In all measurements, the sample volume was 250 8 Peppermint oil O.15 ml, being automatically withdrawn by the measuring device 9 Ultrapure water 59.48 from the reservoir tank, filled with at least 300 ml of sample. The sample was placed carefully into the reservoir tank, TOTAL 1OOOO avoiding any foam formation if possible. After a waiting time of ten minutes, so that any air bubbles formed during the filling could migrate to the surface and thus not falsify the 0.095 The foam behavior of this composition 1 is shown in volume, 250 ml of the sample being investigated was drawn FIG 1. into the measuring space and measured. I0089. With a rotor speed of 2000 rpm, the sample being measured in the measuring space was subjected to five rotor Composition cycles of 20 seconds each to create the foam. Between rotor Ingredient in wt.% cycles there was a pause of around 15 seconds. 1 Lidocaine hydrochloride 10.00 0090. By means of the sensors described in DE 19949 2 Propylene glycol 10.00 922, which automatically and continuously scanned the foam 3 2-Propanol 11.00 Surface, the foam Volume was measured immediately after 4 Phospholipid foaming agent A 10.00 the five rotorcycles were completed. The foam stability was 5 Sodium dihydrogen phosphate dihydrate O.12 automatically detected by the instrument over a period of 35 6 Disodium hydrogen phosphate dodecahydrate, cryst. O.66 minutes in total for which the foam volume was measured 7 Sodium hydroxide 20% w/w 4.OO every 50 seconds by means of the needle detectors. The 8 Peppermint oil O.15 volume values so obtained were recorded directly by dedi 9 Ultrapure water S4O7 cated software and hardware of the instrument. TOTAL 100.00 0091. The control system of the SITA foam tester is such that, after the measurement space is filled with 250 ml of sample, the needle detectors travel only as far as the surface of 0096. The foam behavior of this composition 2 is shown in the sample and, accordingly, place the Zero point for the foam FIG 2. Volume on the Surface of the measurement sample and not on the floor of the measurement space. After elapsing of the aforementioned rotor cycles for foaming the particular sample, there sometimes remained in the measurement space Composition a liquid phase of the sample, depending on the composition of Ingredient in wt.% the particular sample being investigated, so that the Volume of 1 Prednicarbate O.10 this liquid phase was also detected in the above described 2 Propylene glycol 1S.OO measurement according to the particular measurement value 3 2-Propanol 9.35 of the foam Volume and is defined accordingly as foam Vol US 2011/0269.704 A1 Nov. 3, 2011 13
Examples 6 to 8 -continued 0103) In order to investigate the influence of the concen tration of active ingredient on the foam formation, the follow Composition ing compositions 6 to 8 were prepared and investigated in Ingredient in wt.% regard to the concentrations of active ingredient diclofenac. 4 Phospholipid foaming agent B S.OO 5 Sodium dihydrogen phosphate dihydrate OSO 6 Disodium hydrogen phosphate dodecahydrate, cryst. 1.14 7 Sodium hydroxide 10% w/w 1.00 Composition in 8 Tegosoft GC 8.60 Ingredient wt.% 9 Ultrapure water 59.31 1 Diclofenac 1.OOO 2 Propylene glycol 1S.OOO TOTAL 1OOOO 3 2-Propanol 10.2SO 4 Ascorbylpalmitate O.O2O 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen phosphate dihydrate, O.120 0097. The foam behavior of this composition 3 is shown in ultrapure FIG. 3. 7 Disodium hydrogen phosphate dodecahydrate, cryst. O660 8 EDTA O.040 9 Ultrapure water 59.380 10 Peppermint oil, rectified O.200 Composition in Ingredient wt.% TOTAL 100.00 1 Clotrimazol O.S 2 Propylene glycol 2O.OO 0104. The foam behavior of this composition 6 is shown in 3 2-Propanol 8.OO FIG. 6. 4 Phospholipid foaming agent A 8.OO 5 Sodium dihydrogen phosphate dihydrate O.12 6 Disodium hydrogen phosphate dodecahydrate, cryst. O.66 7 Sodium hydroxide 20% w/w 1.OO 8 Peppermint oil O.2O Composition in 9 Polysorbate 80 13.00 Ingredient wt.% 10 Ultrapure water 48.52 1 Diclofenac 2.OOO 2 Propylene glycol 1S.OOO TOTAL 1OOOO 3 2-Propanol 10.2SO 4 Ascorbylpalmitate O.O2O 5 Phospholipid foaming agent A 13.330 0098. The foam behavior of this composition 5 is shown in 6 Sodium dihydrogen phosphate dihydrate O.120 FIG.S. 7 Disodium hydrogen phosphate dodecahydrate, cryst. O660 8 EDTA O.040 0099 Twenty subjects (11 female, 9 male) suffering from 9 Ultrapure water 58.380 fungal disease between the toes and also partly on the toe nails 10 Peppermint oil, rectified O.200 had the fungally attacked regions of the left foot treated twice TOTAL 100.00 daily with a foam prepared by the above-described SITA measurement method. The treatment was done in that the 0105. The foam behavior of this composition 7 is shown in ailing area was covered with a foam layer around 0.5 to 1 cm FIG. 7. thick and then this foam was manually rubbed in. The total treatment time lasted up to 14 days. 0100. The ailing area of the right foot was treated with a Composition in composition 5, identical in ingredients, while this composi Ingredient wt.% tion 5 was foamed by means of a “M3 mini foamer from 1 Diclofenac 8.OOO Rexam/Airspray immediately prior to application. 2 Propylene glycol 1S.OOO 0101 Regardless of which foam had been applied to the 3 2-Propanol 10.2SO 4 Ascorbylpalmitate O.O2O ailing areas, 16 Subjects reported a direct decrease in itching 5 Phospholipid foaming agent A 13.330 already after the first application of the particular foam. Two 6 Sodium dihydrogen phosphate dihydrate O.120 other Subjects reported this decrease in itching after a two 7 Disodium hydrogen phosphate dodecahydrate, cryst. O660 8 EDTA, Titriplex III O.040 time application, and the remaining two Subjects reported the 9 Ultrapure water 52.380 decrease in itching after a four-time application. 10 Peppermint oil, rectified O.200 0102. In ten subjects, the fungal infections were elimi TOTAL 100.00 nated after a total treatment time of eight days, in six subjects the healing time was eleven days, and in four Subjects the 0106 The foam behavior of this compsition 8 is shown in healing time was 14 days. It is to be noted that the latter four FIG 8. subjects were the most heavily affected by the fungal infec 0107 Based on the comparison of the compositions 6 to 8 tion. No subject could find a difference between the foam and the corresponding FIGS. 6 to 8, one can say that the foam created by the SITA measurement method and the foam pro Volume increases with practically unchanged foam stability duced by the “M3 mini foamer'. as the concentration of active ingredient increases. US 2011/0269.704 A1 Nov. 3, 2011
Examples 9 to 11 0112 Based on the comparison of the compositions 9 to 11 and the corresponding FIGS. 9 to 11, one can say that the 0108. In order to investigate the influence of the concen- foam Volume decreases with practically unchanged foam sta tration of phospholipid foaming agent on the foam formation, bility as the concentration of the phospholipid foaming agent the following compositions 9 to 11 were prepared and inves- increases. tigated in regard to the concentration of phospholipid foam ing agent. Examples 12 to 14 0113. In order to investigate the influence of the concen tration of isopropanol on the foam formation, the following Composition in compositions 12 to 14 were prepared and investigated in Ingredient wt.% regard to the concentration of isopropanol. 1 Diclofenac 4.OOO 2 1,2-propane diol 1S.OOO 3 2-Propanol 10.2SO Composition 4 L (+) aScorbylpalmitate O.O2O Ingredient in wt.% 5 Phospholipid foaming agent A 2.OOO 6 Sodium dihydrogen phosphate dihydrate, ultrapure O.120 1 Diclofenac 4.OOO 7 Disodium hydrogen phosphate O660 2 Propylene glycol 1S.OOO dodecahydrate, ultrapure 3 2-Propanol S.OOO 8 EDTA O.040 4 E. O.O2O 9 Ultrapure water 67.710 5 P ospholipia Ioaming agent A 13.330 10 Peppermint oil, rectified O.200 6 Sodium dihydrogen phosphate dihydrate O.120 o 7 Disodium hydrogen phosphate dodecahydrate, cryst. O.660 TOTAL 1OOOO 8 EDTA O.O40 9 Ultrapure water 61.630 10 Peppermint oil, rectified O.200 0109 The foam behavior of this composition 9 is shown in TOTAL 100.00 FIG. 9. 0114. The foam behavior of this composition 12 is shown in FIG. 12. Composition in Ingredient wt.% 1 Diclofenac 4.OOO Ingredient Cup in 2 1,2-propane diol 1S.OOO 3 2-Propanol 10.2SO 1 Diclofenac 4.OOO 4 L (+) ascorbypalmitate O.O2O 2 Propylene glycol 1S.OOO 5 Phospholipid foaming agent A S.OOO 3 2-Propanol 1.O.OOO 6 Sodium dihydrogen phosphate dihydrate, ultrapure O.120 4 Ascorbylpalmitate O.O2O 7 Disodium hydrogen phosphate dodecahydrate, O660 5 Phospholipid foaming agent A 13.330 ultrapure 6 Sodium dihydrogen phosphate dihydrate O.120 8 EDTA O.040 7 Disodium hydrogen phosphate dodecahydrate, cryst. O.660 9 Ultrapure water 64.710 8 EDTA O.O40 10 Peppermint oil, rectified O.200 9 Ultrapure water 56.630 10 Peppermint oil, rectified O.200 TOTAL 1OOOO o TOTAL 100.00 0110. The foam behavior of this composition 10 is shown in FIG. 10. 0115 The foam behavior of this composition 13 is shown in FIG. 13.
Composition in Ingredient wt.% Composition Ingredient in wt.% 1 Diclofenac 4.OOO 2 1,2-propane diol 1S.OOO 1 Diclofenac 4.OOO 3 2-Propanol 10.2SO 2 Propylene glycol 1S.OOO 4 L (+) aScorbylpalmitate O.O2O 3 2-Propanol 2O.OOO 5 Phospholipid foaming agent A 2O.OOO 4 Ascorbylpalmitate O.O2O 6 Sodium dihydrogen phosphate dihydrate, ultrapure O.120 5 Phospholipid foaming agent A 13.330 7 Disodium hydrogen phosphate O660 6 Sodium dihydrogen phosphate dihydrate O.120 dodecahydrate, ultrapure 7 Disodium hydrogen phosphate dodecahydrate, cryst. O.660 8 EDTA, Titriplex III O.040 8 EDTA O.O40 9 Ultrapure water 49.710 9 Ultrapure water 46.630 10 Peppermint oil, rectified O.200 10 Peppermint oil, rectified O.200
TOTAL 1OOOO TOTAL 100.00
0111. The foam behavior of this composition 11 is shown 0116. The foam behavior of this composition 14 is shown in FIG. 11. in FIG. 14. US 2011/0269.704 A1 Nov. 3, 2011
0117 Based on the comparison of the compositions 12 to 14 and the corresponding FIGS. 12 to 14, one can say that the -continued foam Volume increases as a function of the concentration of isopropanol with rising concentration of isopropanol from 5 Composition in wt.% to 10 wt.% and then decreases again in the range of 10 Ingredient wt.% wt.% to 20 wt.%, so that no stable foam is formed at a 7 Disodium hydrogen phosphate dodecahydrate, O.660 concentration of 20 wt.% of isopropanol. The slight foam ultrapure 8 EDTA O.O40 volume shown initially in FIG. 14 should be disregarded. 9 Ultrapure water S1.380 10 Peppermint oil, rectified O.200 Examples 15 to 17 TOTAL 100.00 0118. In order to investigate the influence of the concen tration of propylene glycol on the foam formation, the fol lowing compositions 15 to 17 were prepared, differing in I0121 The foam behavior of this composition 17 is shown terms of the concentration of propylene glycol. in FIG. 17. 0.122 Based on the comparison of the compositions 15 to 17 and the corresponding FIGS. 15 to 17, one can say that the concentration of propylene glycol has no or only a very slight Composition in influence on the foam volume and the foam stability. Ingredient wt.% 1 Diclofenac 4.OOO Example 18 2 1,2-propane diol S.OOO 3 2-Propanol 10.2SO I0123. In a comparison investigation on 14 subjects (8 4 L (+) aScorbylpalmitate O.O2O female, 6 male) with pronounced acne in the facial region, the 5 Phospholipid foaming agent A 13.330 Subjects were treated twice daily (morning and evening) with 6 Sodium dihydrogen phosphate dihydrate, ultrapure O.120 7 Disodium hydrogen phosphate dodecahydrate, O660 a foam that was made from a composition whose ingredients ultrapure are quantified in the following table per composition 18. 8 EDTA O.040 9 Ultrapure water 66.380 10 Peppermint oil, rectified O.200 Composition in TOTAL 1OOOO Ingredient wt.% 1 Erythromycin 1...SO 0119 The foam behavior of this composition 15 is shown 2 Propylene glycol 1S.OO in FIG. 15. 3 2-Propanol 9.35 4 Phospholipid foaming agent B 8.00 5 Sodium dihydrogen phosphate-dihydrate O.SO 6 Disodium hydrogen phosphate-dodecahydrate 1.14 cryst. Composition in 7 Sodium hydroxide 10% w/w 1.00 Ingredient wt.% 8 Tegosoft GC 7.70 9 Ultrapure water 55.81 1 Diclofenac 4.OOO 2 1,2-propane diol 1O.OOO TOTAL 100.00 3 2-Propanol 10.2SO 4 L (+) aScorbylpalmitate O.O2O 5 Phospholipid foaming agent A 13.330 6 Sodium dihydrogen phosphate dihydrate, ultrapure O.120 0.124. The foaming behavior of this composition 18 is 7 Disodium hydrogen phosphate dodecahydrate, O660 shown in FIG. 18. ultrapure 0.125. The treatment was done per application with a 8 EDTA O.040 defined amount of 0.4 mg foam per half of the face. The foam 9 Ultrapure water 61.380 was applied directly to the area being treated and massaged in 10 Peppermint oil, rectified O.200 by circular motions with 2 fingers. The total therapy time TOTAL 1OOOO amounted to 60 days. 0.126 Each time the left half of the face of each subject was 0120. The foam behavior of this composition 16 is shown treated with the foam made by means of the above-described in FIG. 16. SITA measurement method and the right half of the face of each subject by means of a foam made with an “M3 mini foamer of Rexam/Airspray, both foams being prepared from composition 18. Composition in I0127. The first success could already be determined for Ingredient wt.% both foams after 30 days application: the lesions on the left 1 Diclofenac 4.OOO side of the face were reduced by around 19% and those of the 2 1,2-propane diol 2O.OOO right half by around 21%. 3 2-Propanol 10.2SO 4 L (+) aScorbylpalmitate O.O2O I0128. At the final evaluation on day 60 of the investigation, 5 Phospholipid foaming agent A 13.330 a decrease inlesions by around 36% was found for the left half 6 Sodium dihydrogen phosphate dihydrate, O.120 of the face and a decrease of around 34% for the right half of ultrapure the face. It was not possible to determine a significant differ ence between the two halves of the face. None of the subjects US 2011/0269.704 A1 Nov. 3, 2011
perceived the treatment to be unpleasant or reported painful still visible) and a value of -1 for the ketoprofen-free foam irritation of the treated areas. Neither could any differences be (more pronounced erythema). The foam made from the com established in the toleration of the treatment between the two position containing ketoprofen shows a clear therapeutic halves of the face. Superiority over the foam containing diclofenac, the ketopro fen-free foam, and the untreated test fields. Example 19 0141 All foams containing active ingredient showed a 0129. In a double-blind, randomized and placebo-con good toleration. Only for the ketoprofen-free foam three (3) trolled comparative study of 12 subjects (5 female, 7 male) we side effects were found. investigated the efficacy 0142. The phospholipid foaming agent A used above in 0.130 a) of the above-described composition 10, con examples 1 and 2, as well as 4 to 17, has the following taining 4% diclofenac-Sodium, composition, with the following values referring to the dry I0131 b) of the above-described composition 1, contain Substance. ing 10% ketoprofen, and I0132 c) the efficacy of a ketoprofen-free composition, which was identical to composition 1 in terms of ingre Phosphatidylcholine dients 2 to 9, this ketoprofen-free composition having no Lysophosphatidylcholine ketoprofen and instead having 10 wt.% more water than Phosphatidic acid Phosphatidyl ethanolamine composition 1. Other oily components in the treatment of an artificially induced UV erythema. All Acid number 2 foams used were produced by means of the above-described Peroxide number 6 SITA measurement method, as well as the “M3 minifoamer' of Rexam/Airspray, based on the same starting compositions. 0133. The artificial UV erythemas were created at 16 test 0143. The phospholipid foaming agent B used above in fields (each one 2x2 cm) on the back, 4 test fields to each the examples 3 and 18 has the following composition, with the left and right of the spinal column, as well as 4 test fields each following values referring to the dry Substance. in the upper and lower region of the back. The 8 upper test fields were exposed to a UV dose of 1.5xMED and the lower test fields with 2.5xMED. Phosphatidylcholine 0134. After the UV exposure, ECG rings with an inner Lysophosphatidylcholine diameter of 16 mm were glued to the centers of the UV Tocopherol max. 0.3 wt.% exposed test fields. The untreated fields were likewise marked Acid number 1 with ECG rings. The distance between the test fields was Peroxide number 5 around 3 cm. 0135) Next, around 10-15 minutes from the end of the UV exposure, a dose of 25ug foam according to a random list was 0144. The above indicated peroxide number indicates the applied in the ECG rings and evenly distributed using around millieduivalents of oxygen which are contained in 1000 g of spatula. a sample (dry substance). This value, after reacting the 0136. The foam behavior of composition 19 c) (ketopro sample with potassium iodide in a mixture of chloroform and fen-free composition) is shown in FIG. 19. acetic acid, is determined by titrating the iodine produced in 0.137 Evaluation of the differences was done by the opti this way with sodium thiosulfate and a potentiometric deter cal examination of a dermatologist. This was based on the mination. internationally recognized visual evaluation method of 0-no 0145 The acid number indicates how many mg of potas visible erythema to 4-intensive erythema for the untreated sium hydroxide are needed to neutralize the free, nonesteri surface and the evaluation -1 =intensive erythema to 3-com fied fatty acids that are contained in 1 g of phospholipid pletely suppressed erythema for the irradiated and treated foaming agent (dry Substance). This value is determined by areas. Checks were done after 2, 3, 4, 5, 6 and 8 hours on the titration of a corresponding dissolved sample with potassium same day as the application. hydroxide Solution, using phenolphthalein as indicator. 0138 Between the foams produced according to the SITA 1-52. (canceled) measurement method and those using the “M3 minifoamer, 53. A composition Suitable for topical use comprising at a slight difference for the active ingredient, ketoprofen, was least one systemically and/or topically acting pharmaceutical found only at one measurement time point: 6 hours. This active ingredient, wherein the composition in addition to the difference was not significant. Here, an erythema value of 2 pharmaceutical active ingredient also contains at least one was found for the foam that was made according to the SITA Solvent as well as at least one foaming agent and has such a measurement method and a value of 1 for the foam that was fluid consistency that it forms a foam when applied, wherein: made by means of the “M3 minifoamer'. No other differ a) the at least one foaming agent contained in the liquid ences could be found between the foams produced in different composition is a phospholipidic foaming agent; ways and containing the active ingredient. b) the at least one phospholipid foaming agent, the at least 0.139. In comparison with the ketoprofen-free composi one solvent and the at least one active ingredient are tion (c) and the untreated test fields, the foams containing attuned to each other in their chemical nature and/or active ingredient showed distinct differences at 1.5 MED and their concentration so that the composition can be 2.5 MED in the final measurement after 8 hours. mechanically foamed without the use of an additional 0140) Especially at 2.5 MED, a value of 1 was found for propellant; the foam containing diclofenac (slight Suppression of the c) by mechanically foaming of 250 ml of the liquid com erythema, easily identifiable), a value of 2 for the foam con position a foam is created having a foam Volume of at taining ketoprofen (distinct Suppression of the erythema but least 400 ml and a foam stability after a dwell time of up US 2011/0269.704 A1 Nov. 3, 2011 17
to ten minutes of at least 50% of the foam volume that 62. The composition according to claim 61, wherein at was originally present immediately after the creation of most 15 wt.% of lyso-phosphatidylcholine, at most 10 wt.% the foam; and of phosphatidic acid and at most 10 wt.% of phosphatidyl d) both the foam volume and the foam stability are deter ethanolamine are contained in the phospholipidic foaming mined by a standardized SITA foam measurement agent. method. 63. The composition of claim 61, wherein the phosphatidyl 54. The composition according to claim 1, wherein the choline contained in the phospholipidic foaming agent has an foam volume is between 450 and 1400 ml and the foam acid number of at most 10, a peroxide number of at most 10, stability is between 55% and 100%. and an oil concentration of at most 6 wt.%. 55. The composition according to claim 53, wherein the 64. The composition of claim 53, wherein the composition foam has a density between 0.05 g/ml and 0.8 g/ml. has the phospholipidic foaming agent in a concentration 56. The composition according to claim 53, wherein the between 2 wt.% and 25 wt.%. composition contains as solvent such a solvent selected from 65. A method for treatment of pain, inflammation, rheu the group consisting of water, alcohol, especially monovalent matic diseases or acute trauma, comprising the application of to trivalent alcohol, polyalcohol, and mixtures thereof. a foam to the skin of a warm-blooded mammal created by 57. The composition according to claim 53, wherein the at mechanically foaming of a composition according to claim least one active ingredient is an active ingredient for use on 53 immediately prior to application, whereby the composi humans or animals and is selected from the group consisting tion contains as active ingredient at least one analgesic. of local anesthetics, anti-allergic agents, dermatics, active 66. The method of claim 65, wherein the composition ingredients against flu infections and colds, active ingredients contains the analgesic in a concentration between 0.1 wt.% for the treatment of neuropathies, active ingredients for the and 20 wt.%. treatment of disturbed circulation, chemotherapy drugs, qui 67. A method for the development of a pharmaceutical nine, antimycotics, antibiotics, thalidomide, serotonin, composition to be applied as a foam to the skin according to eicosanoids, analgesics, anticonvulsants, nonsteroidal anti claim 53, wherein the foamable liquid composition contains rrheumatics, leukotrienes, leukotriene inhibitors, androgens, at least one solvent, at least one pharmaceutical active ingre antiandrogens, corticoids, opiate receptor antagonists, blood dient, and at least one phospholipidic foaming agent, clotting inhibitory Substances, thrombocyte aggregation wherein: inhibitors, histamine antagonists, regulatory and enzymati a) the foam volume and the foam stability are determined cally acting peptides and proteins, nucleic acids (single and by a standardized SITA measurement method without double-stranded DNA, single and double-stranded RNA, the use of a propellant; and snRNA, DNA oligonucleotides, RNA oligonucleotides) and b) the at least one phospholipidic foaming agent, the at oligopeptides, antipruritics, antidiabetics, prostaglandins, least one solvent and the at least one pharmaceutical prostaglandin synthesis inhibitors, antiviral-acting or viro active ingredient, contained in the liquid composition, static-acting Substances, antimicrobial-acting Substances, are varied in regard to their chemical nature and/or con active ingredients against prions, immune Suppressants, hor centration until the foam created by the SITA measure mones, active ingredients for treatment of warts or wounds, ment method, using 250 ml of the liquid composition, especially chronic wounds, vitamins, plant extracts or has a foam volume of at least 400 ml and a foam stability essences of plant extracts, psychoactive drugs, active ingre that the foam still has, after a dwell time of up to ten dients influencing sleep, analeptics, general anesthetics, minutes at least 50% of the foam volume that was origi muscle relaxants, antiepileptics, antiparkinson agents, anti nally present immediately after the creation of the foam. emetics, antiparasitics, ganglion-active ingredients, sympa 68. The method according to claim 67, wherein a correla thetic-active ingredients, parasympathetic-active ingredients, tion is produced between the foam as specified by the SITA antibacterial-acting drugs, calcium antagonists, cardiovascu measurement method and the pharmaceutical properties. lar agents, antiasthmatics, antitussives, expectorants, hepat 69. The method according to claim 67, wherein a foam ics, diuretics, choleretics, disinfectants, trace elements, anti applicator is selected for the mechanical foaming of the liquid infectives, cytostatics, antimetabolites, hormone antagonists, composition, a foam is created from the liquid composition immune modulators, as well as derivates and salts of the by the selected foam applicator, and a correlation is produced aforementioned active ingredients. between the properties, especially the pharmaceutical prop 58. The composition according to claim 53, wherein the at erties of the foam created via the foam applicator and the least one pharmaceutical active ingredient is an analgesic foam volume and/or the foam stability as determined via the active ingredient. SITA measurement method. 59. The composition according to claim 58, wherein the 70. The method according to claim 67, wherein such a analgesic active ingredient is selected from the group consist foam is created from the liquid composition by the SITA foam ing of diclofenac, ketoprofen and ibuprofen. measurement method that possess a foam density between 60. The composition according to claim 58, wherein the at 0.05 g/ml and 0.8 g/ml. least one analgesic is contained in the composition in a con 71. The method according to claim 67, wherein the phos centration between 0.1 wt.% and 20 wt.%. pholipidic foaming agent is a phosphatidylcholine isolated 61. The composition according to claim 53, wherein the from soybeans and that the concentration of the phosphatidyl composition contains, as the phospholipidic foaming agent, a choline in the phospholipidic foaming agent is more than 50 phosphatidylcholine isolated from soybeans, and the con wt.%, in relation to the dry substance of the phospholipidic centration of the phosphatidylcholine in the phospholipidic foaming agent. foaming agent is more than 50 wt.%, in relation to the dry Substance of the phospholipidic foaming agent.