TW201200154A - Composition for treatment of H. pylori - Google Patents

Abstract

A pharmaceutical composition comprising a surfactant and a fatty acid, wherein the molar ratio of surfactant to fatty acid is in the range of 0.2: 1 to 3: 1 for the treatment of a H. pylori infection is provided. The use of the composition, a pharmaceutical dosage form and a kit is also provided.

Description

201200154 VI. Description of the Invention: [Technical Field of the Invention] [0001] The present invention relates to the treatment of Helicobacter pylori infectious diseases of the stomach and/or duodenum. In particular, the present invention relates to a pharmaceutical composition for use in such treatments. [Prior Art] [0002] Helicobacter pylori is a Gram-negative bacterium that can inhabit various regions of the stomach and the duodenum. It causes chronic low inflammation of a gastric mucosa and is strongly associated with the development of duodenal ulcers and gastric ulcers as well as gastric cancer. More than 80% of individuals are asymptomatic when infected with this bacterium. [00〇3] Helicobacter pylori is present in the upper gastrointestinal tract of more than 50% of the world's population. Transmission diseases are more common in developing countries, but the incidence is decreasing in Western countries. Although individuals are generally infected as a child, the route of transmission is unknown. [0004] More than 90% of duodenal ulcers and gastric ulcers have been sequentially pointed out to be caused by Helicobacter pylori and are an important source of gastric cancer. There is even more evidence that Helicobacter pylori clustered in the stomach can be involved in a variety of non-gastrointestinal symptoms. [〇〇〇5] Helicobacter pylori eradication from the stomach is usually treated by combination therapy, usually a proton pump inhibitor (for inhibiting acid) and two or more antibiotics. Increasing the resistance of antibiotics makes treatment of this infectious disease more difficult and has a side effect. In addition to this, there are also issues in which patients follow the treatment. Standard dual therapy requires medication for one to two weeks by the patient. [0006] Antibiotics applied to traditional triple therapy must be absorbed in the small intestine, but 1003313870-0 100115722 Form No. A0101 Page 3 / Total 35 pages 201200154 After the blood circulation by the stomach _ secretion is to reach the Helicobacter pylori cluster position. The gastric mucus layer blocks the location of the anti-Helicobacter pylori colony from the direction of the gastric lumen. _ [0007] [0008] Recently, local gastric treatment for the treatment of gastric sputum spiral (four) infectious diseases has developed the use of a system-provided dosage form of f-prime inhibitors and for gastric-supply-proton pump suppression Agent. In particular, this treatment system contains fatty acids and/or single reduction. It is known to reduce the fatty acid of the secret fatty acid, that is, to increase the acidity (refer to Sun cQ et ai).

Antibacterial actions of fatty acids and monoglycerides against Helicobacter pyl〇ri> FEMS Immunology and Medical Microbiology 36 (2003), 9-17). The application of fatty acids in this formulation presents several challenges. A need for a sufficient amount of sterilization - a small stomach capacity - results in a preferred concentrated dosage form, such as a solid dosage form. However, fatty acids are generally insoluble in aqueous environments and tend to crystallize out of the acid environment. The fasting time of the stomach is shorter than the time of overnight fasting or stomach examination, so that the dissolution of the high-performance formula must achieve a bactericidal effect, while fatty acids continue to exist in the stomach. For example, a half amount of an inert liquid, such as water, will be emptied from the stomach for 8 to 18 minutes' and the emptied nutrient liquid will be displayed - lasting 5 to 3 minutes for the initial fast phase to continue (see pp2〇5-214 Textbook) Of Gastroenterology, ed Tadataka Yamada. Lip-pincott Williams and Wilkins 2〇〇3). Therefore, the dissolution of the fatty acid formulation in the liquid medium of the stomach or prior to oral administration is an important step in the manner in which any fatty acid is treated for H. pylori. Thus, 100115722 Form No. A0101 Page 4 / Total 35 Page 1003313870-0 201200154 [0009] [0012] [0013] [0013] I3 lauric acid pyloric snail; local treatment of 疋 疋 has been understood Not suitable for therapeutic use, because lauric acid dissolves in the stomach before the stomach is empty and not fast enough. Therefore, lauric acid is removed from the stomach before providing any treatment for H. pylori. A range of surfactants are often used as excipients to increase the dissolution of the drug' such as the nonionic surfactants mentioned hereinafter. For example, the polylactic acid sorbitol needle fatty acid S (generally known as Tweens) is recognized as a solubilizing agent in the lipophilic group as a poorly soluble active ingredient from ll 〇 % (Handbook of Pharmaceutical Excipients 5th Edition. Eds Rowe R. C, Sheskey PJ and Owen SC, Pharmaceutical Press). Accordingly, it would be desirable to provide an improved composition for overcoming the treatment of a Helicobacter pylori infectious disease, or at least one or more of the disadvantages described above. There is a need to provide an improved composition wherein a fatty acid composition is dissolved in an aqueous medium comprising a mild acidic pH. According to a first aspect, a pharmaceutical composition comprising: an interfacial active agent and a fatty acid, wherein the molar ratio of the surfactant to the fatty acid is from 0.2 to 1:1. Advantageously, the molar ratio of surfactant to fatty acid is such that the fatty acid is rapidly soluble in an aqueous medium having a pH of from about 3 to about 7. Advantageously, the drug resistance of Helicobacter pylori is excluded because the composition is not therapeutically effective by antibiotics. 100115722 Form No. A0101 Page 5 / Total 35 Page 1003313870-0 [0014] [0015] Advantageously, because the surfactant is present in an amount that allows the fatty acid to dissolve in an aqueous medium of mild acidic pH, The composition is based on the disclosure that a proton pump inhibitor, a hydrogen antagonist or an oral antacid must be administered to increase the p Η value of the stomach. [0016] According to a second aspect, the use of the first aspect is provided for the preparation or manufacture of a medicament for the treatment of H. pylori infection. [0017] According to a third aspect, there is provided a pharmaceutical dosage form comprising a composition according to the first aspect. [0018] According to a fourth aspect, a kit is provided comprising a pharmaceutical composition according to a first aspect and an indication of use. [0019] According to a fifth aspect, a kit is provided comprising a pharmaceutical composition according to a third aspect and instructions for use. [0020] According to a sixth aspect, a method is provided for treating a disease or discomfort comprising administering a therapeutic composition to a patient according to a first aspect. [0021] According to a seventh aspect, the composition according to the first aspect is provided as a medicine. [0022] According to an eighth aspect, there is provided a pharmaceutical composition comprising a surfactant and a fatty acid, wherein the molar ratio of the surfactant and the fatty acid is from 0.2 to 1 :1 to treat the pyloric helix Bacillus infection. [Embodiment] [0023] Definitions [0024] The following definitions are helpful for understanding the description of the present invention. These are intended to be general definitions, and should not be used to limit the invention alone. 100115722 Form Number Α 0101 Page 6 / Total 35 Page 1003313870-0 201200154 [0025] [0026] ❹ [0027] ❹ [0028] [0029 ] The range 'but can be placed in the following narrative (4) (d). Compositions, steps, or components of the composition, steps, or component list elements, steps, or components of the singular and plural forms, which are singular and plural, are included in the singular or plural. In this specification 'unless the content requires', the word "comprise" or variant includes, for example: "compliance of third person" or "c〇mprising" of gerund will be available A group or a component or a plurality of steps or a plurality of components or a plurality of component parts, but does not exclude any other steps or components or components or a plurality of steps or a plurality of components. Or a plurality of constituent groups. Therefore, in the context of the present specification, the term "compr isi ng" means mainly includes, but is not necessarily, separate. Those skilled in the art will understand the statement. The invention is intended to be susceptible to variations and modifications other than those specifically mentioned. It is intended that the present invention encompasses all variations and modifications. The present invention also encompasses all steps, features, and compositions referred to or indicated in this specification. And compounds, individually or collectively, and any or all combinations or any two or more of the above steps or features. In the context of the present invention, the term "moving The administration of a noun (administering), and the variation of the term, which includes "administration of verbs," and "administration of nouns (administratl〇n), including contact, application, transmission or provision by any suitable means. The composition of the compound of the invention is to an organism or surface. 100115722 Form No. A0101 Page 7 / Total 35 True 1〇〇331387〇-.〇201200154 [0030] In the context of this specification, the term "patient" encompasses any socially human and individual species, including but not limited to sheep. Economic or research importance of species of cattle, horses, pigs, cats, dogs, primates (including humans and non-human primates), caries, rats, rabbits and birds. [0031] In the context of the present specification, the term "treatment" refers to any and all methods of treating a condition or symptom, preventing the establishment of a disease, or preventing, hindering, slowing, or reversing a disease or other in any way. The progression of unwanted symptoms. [0032] In the context of the present specification, the term "effective amount" is intended to include a sufficient but non-toxic amount of a compound or composition in the present invention to provide a desired therapeutic or diagnostic benefit. The exact amount required will vary from subject to subject, depending on factors such as the species being treated, the age and general condition of the subject, the severity of the treatment, the particular agent being administered, the type of drug being administered, etc. . Therefore, it is unlikely to clarify the precise "effective amount." However, in any particular case, a suitable "effective amount" can be determined by one skilled in the art using only routine experimentation. The phrase "pharmaceutically acceptable carrier" is intended to include solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic pressures, absorption delaying agents, and the like. The use of such media and agents as pharmaceutically active substances is well known in the art. In addition to any conventional media or agents that are currently incompatible with the compounds of this experiment, there are considerations for the use of medical compositions and methods of treatment and prevention. Supplementary active compounds can also be incorporated into the compositions in accordance with the present invention. [0034] For use in the following "unit dosage form" or "dosage form" or "dosage unit 100115722 Form No. A0101 Page 8 / Total 35 pages 1003313870-0 201200154 [0035] Ο [0036]

[0038] [0038] "Formula" refers to a physiologically discrete unit suitable for treating a single dose of an individual; the calculation comprises a predetermined amount of compound per unit to produce the desired medical effect associated with the necessary pharmaceutical carrier. The compounds may be formulated in a convenient and effective administration effective amount in a suitable pharmaceutically acceptable carrier in an acceptable dosage unit. In the case of a composition comprising a supplementary active ingredient, the dosage will be referenced to the usual dosage. And the means by which the above ingredients are administered. The term "soluble" as used hereinafter is any physiological form which allows the fatty acid to antagonize the quenching effect of H. pylori. This may include, for example, an aqueous solution, dispersion, milk. Liquid, microemulsion, molecular group solution, liposome solution, etc. "Soluble" does not comprise a crystalline form of a fatty acid or a group or sheet thereof that is clearly visible to the eye. In one embodiment, the term "soluble" "A fatty acid that is not included in the separation of the oil phase, making it less accessible to the aqueous phase (for example, dissolved in corn oil) Microdrops of lauric acid. The term "rapidly" relates to a formulation from a period of from 1 to 30 minutes to achieve an aqueous environment, and preferably within 5 minutes. The word "substantially" does not exclude "completely" "For example, "substantially no" composition of Υ may be completely devoid of Υ. When required, the word "substantially" may be omitted from the definition of the present invention. Unless otherwise stated, the term "gergin noun" "comprising" and "comprise" of primal verbs, and their grammatical variations, are intended to represent "open" or "compatible" languages, such that they contain the stated elements and, more 100115722 Form No. A0101 Page 9 of 35 contains 1003313870-0 201200154 contains non-reported elements. [0039] As used hereinafter, the term "about" the concentration of the ingredients of the formula herein typically means the stated value. +/- 5%, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically +/- 2% of the stated value, even More typically +/- 1% of the stated value Even more typically, the value of the stated value is +/- 0.5%. [0040] The term "about" is intended to encompass the standard deviation of the stated pH unit value of 0.5, and preferably The pH unit value is stated to be ±0.3. [0041] The term "mole" means the molecular weight in grams, and "mole (mmol)" is the molecular weight in milligrams. The units of measurement have their usual technical significance, and the numbers are usually rounded to the second decimal place. [0042] In this disclosure, some embodiments may be disclosed in a range format. The description of a range format is only convenient and concise. It is understandable and should not be construed as inelastic limiting its scope of disclosure. Therefore, the scope of the description should be considered to specifically disclose all possible sub-ranges and ranges of values. For example, a description of a range, for example, from 1 to 6 should take into account a sub-scope having a particular disclosure, such as 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, From 3 to 6, etc., and individual numbers within the range, for example, 1, 2, 3, 4, 5, and 6. This application is regardless of the width of the range. [0043] Certain embodiments are also generally and generally described hereinafter. Each of the narrower categories and sub-categories within the general disclosure also form an exposed part. This includes a general description of the embodiments of the book or a negative limitation of the removal of the subject from the category, whether or not the removed material is stated below. 100115722 Form No. A0101 Page 10 of 35 1003313870-0 201200154 [0044] Disclosure of Alternative Embodiments [0045] An illustrative, non-limiting embodiment of a pharmaceutical composition will now be disclosed. The composition comprises a surfactant and a fatty acid, wherein the molar ratio of the surfactant to the fatty acid is from 0.2:1 to 3:1. [0046] In one embodiment, the fatty acid may be selected from one or more of the following saturated fatty acids: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, or any linear chain length from 4 carbons to 16 carbon saturated fatty acids. In another embodiment, the fatty acid may be selected from one or more of the following unsaturated fatty acids: myrista ο 1 eic ac id, oleic acid, oleic acid, linoleic acid or linoleic acid . In one embodiment, the unsaturated fatty acid is cis. [0047] In one embodiment, the fatty acid is linoleic acid, palmitoleic acid or lauric acid. In another embodiment, the fatty acid is lauric acid. [0048] In another embodiment, the above two or more fatty acids may be provided in the composition. [0049] In an alternate embodiment, a monoglyceride can be used to replace a fatty acid. In one embodiment, the monoglyceride may be selected from the group consisting of 1-monocaprylin, 1-monocaprin, 1-monolaurin, 1 - a group consisting of 1-monomyristin, 1-monolabeled glycerin S (1 -monopalmi t in) and 1-monoostearin. [0050] The surfactant can be a nonionic or ionic surfactant. The surfactant may be selected from a polyoxyethylene fatty alcohol ether (Brij) surfactant, a 100115722 Form No. A0101 Page 11 of 35 1003313870-0 201200154

Tween surfactant, an IPEGAL surfactant '-MERP0L surfactant, a Triton surfactant, a bile salt, a phospholipid or a sorbitan monopalmitate. [0051] In an embodiment, the surfactant may be selected from the group consisting of Tween 20 or Tween 80. In one embodiment, the surfactant is Tween 20 (polysorbate 20). Without being bound by theory, it is believed that fatty acids are not readily soluble at acidic pH, for example, they can be found in the stomach. It is necessary to provide a fatty acid in solution to allow contact between the fatty acid and H. pylori. Previously increasing the pH of the stomach to gain solubility of fatty acids was usually achieved by administering a systemically available proton pump inhibitor, hydrogen antagonist or oral antacid. [0053] The inventors found that the molar fraction of Tween 20: lauric acid is independently selected from about 0.2:1 to 3:1, 〇.3:1 to 2:1, 〇.4:1 to 1:1 A group of constituents, and about 〇·5:1 to 1:1, allows lauric acid to be dissolved in an aqueous medium at a physiological temperature comprising a pH of from about 3 to about 7. In particular, the surfactant provides rapid solubility of lauric acid in the aqueous medium of the stomach. [0054] In another embodiment, the ratio of Tween 20:lauric acid is 〇. 7:1. In the molar fraction of 0.7.1, Tweeil 20 occupies more than 80% w/w of the composition. In the molar fraction of 〇. 2:1, 'Tween 2〇 occupies more than 54% w/w of the composition, which is much larger than the range recognized by the less soluble active ingredient under lipophilicity. The weight percentage of T e e n 2 q to lauric acid is 10% ww acceptable (see background of the invention) The upper limit of the molar fraction is 100115722 Form No. A0101 Page 12 of 35 ^03313870-0 201200154 0.02:1. [0055] The composition can be used in combination with other known treatment modalities or antibacterial agents, including antibiotics and the like. Suitable agents are listed below, for example, in Merck, An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition, 2006, the entire disclosure of which is hereby incorporated by reference. The combination of active agents, comprising the compositions of the present invention, can be synergistic. [0056] The composition may further comprise a mucolytic preparation. In one embodiment, the mucolytic formulation can be selected from an enzyme, such as a protease (e.g., a chain protease). Alternatively, in another embodiment, the mucolytic formulation may be a thiol compound selected from the group consisting of N-alkyl-cysteine, penicillamine or N-(2-mercaptopropyl)glycine. In one embodiment, the thiol compound is N-alkyl-cysteine. In another embodiment, the thiol compound is N-ethinyl-cysteine. [0057] A mucolytic agent, such as a chain protease, can be administered alone at a dose ranging from about 18,000 to 36,000 tyrosine units, as disclosed by Kimura et al., Am. J. Gastroenterol. 90: 60-63, 1 995. N至乙醯基-cysteine can be administered alone in a range of from about 0.1 to 10 grams. Preferably, the N-ethinyl-cysteine is administered orally to an adult for a dose of about 9-10 grams. In another embodiment, N-acetyl-cysteine is administered orally at a dose of about 1 to 2 grams. [0058] In an embodiment, the composition may further comprise at least one proton pump inhibitor. The proton pump inhibitor may be selected from one or more of omeprazole, lansoprazole, and platoon thunder. 100115722 Form No. A0101 Page 13 of 35 pages 1003313870-0 201200154 (pantoprazole), esomeprazole, timoprazole, rabeprazole or. Picopulazole 〇 [0059] In another embodiment, the composition may further comprise an antibiotic. The antibiotic may be selected from one or more of metronidazole, tetracycline, clarithromycin, erythromycin or amoxicillin. In still further embodiments, the composition may further comprise a chlorine receptor antagonist. The hydrogen receptor antagonist may be selected from one or more of cimetidine, ranitidine, famotidine or nizatidine. [0061] The definition of composition application is provided above for the preparation or manufacture of a medicament for treating a disease or discomfort. In one embodiment, the disease or discomfort is a H. pylori infection. In one embodiment, the mucolytic formulation is administered prior to the fatty acid and the surfactant. The time range of the mucolytic formulation administered prior to the fatty acid and the surfactant can be independently selected from about! About 1 to about 80 minutes, about 1 to about 7 minutes, about i to about 60 minutes, about 1 to about 50 minutes, about 丨 to about 4 minutes, about 1 to about 30 minutes, about 1 to about 9 minutes. A group consisting of about 2 minutes, about i to about 10 minutes, and about 1 to about 5 minutes. In the Example towel, the mucolytic preparation was administered for about 10 minutes in minutes before the lipid (iv) and the surfactant. Further, 100115722 Form No. A0101 Page 14 of 35 1003313870-0 201200154 [0064] In another embodiment, a mucolytic formulation is introduced simultaneously with a fatty acid and a surfactant. A pharmaceutical dosage form comprising a pharmaceutical composition is as defined above when the application of the mucolytic agent to the fatty acid and the surfactant is at least 45 minutes apart. The dosage form can be prepared, for example, in unit dosage form, for example, suspected, capsule, sachet, and dragee. They can be made by conventional means, for example, by conventional methods of mixing, granulating, forming or dissolving processes. (10) 67] Liquid formulations for oral administration can be prepared in the form of solutions, syrups or suspensions. Liquid formulations typically comprise a pharmaceutical composition having an excipient such as sugar or glycolic acid, and a vehicle such as ethanol, water, glycerin, propylene glycol, polyethylene glycol. [0068] If desired, the liquid formulation may also contain coloring agents, flavoring agents, saccharin, thickeners (eg, carboxy methyl cellulose), suspending agents (eg, sorbitol syrup, U 曱 based fiber, hydrogenated edible fats), emulsifiers (eg phospholipids, gum arabic), and/or preservatives (eg methyl p-hydroxy ben) -zobates), propyl p-hydroxy benzoates, sorbic acid. The liquid formulation for administration can also be prepared in the form of a dry powder prior to use to be reconstituted with water or another suitable carrier. [0099] In addition to the active ingredient, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier comprising excipients which facilitate preparation of the active compound into a medicament and the aid of the formula 1001 722 Form No. A0101 Page 15 of 35 pages 1003313870-0 201200154, the agent can be used in pharmaceuticals. Further technical details for the formulation can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton Pa.). For example, the composition can be administered orally with an inert diluent or an assimilable edible carrier. In one embodiment, the composition is administered orally after a fasting period or prior to digestion of the food. [0071] The composition and other ingredients may also be enclosed in a hard or soft shell capsule or compressed into a tablet. For oral administration, the composition may be incorporated into excipients and used in the form of digestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, flakes, and the like. [0072] In an embodiment, the dosage form can be a capsule. In one embodiment, the capsule is a hard gelatin capsule, such as a Licaps® capsule. [0073] Tablets, troches, pills, capsules and the like may also comprise the following: an adhesive such as: acacia gum, gum arabic, corn starch or gelatin; an excipient such as: dicalcium phosphate; a breaker, such as : corn starch, potato starch, alginic acid, etc.; a lubricant, such as: magnesium stearate; and a sweetener, such as: sucrose, lactose or saccharin or a flavoring agent, such as: mint, wintergreen oil or Cherry spice. When the dosage unit form is a capsule, it may comprise, in addition to materials of the above type, a liquid carrier. Various other materials may be present or modify the physical form of the dosage unit. For example, a tablet, pill, or capsule may be coated with shellac, sugar, or both. A syrup or elixir may comprise the composition, maltose as a sweetener, methyl and propylparabens as a preservative. 100115722 Form No. A0101 Page 16 of 35 1003313870-0 201200154 , a dye and spices, such as: cherry or orange scent. [0075] In an embodiment, the pharmaceutical composition may further comprise a suitable buffer. Suitable buffers for those skilled in the art include, but are not limited to, phosphoric acid, citric acid, carbonic acid, and mixtures thereof. [0076] The manner of administration of single or multiple pharmaceutical compositions can be carried out. Those skilled in the art will be able to determine the dosage concentration of a beneficial, non-toxic composition and the mode of administration suitable for the treatment of H. pylori by routine experimentation. Further, the most preferred course of treatment will be apparent to those skilled in the art, such as multiplying the number of days of the composition dispensed daily by a defined number of days, using conventional course test tests. confirm. 5毫米摩尔,约0.3。 About 0. 025 to 2. 5 millimoles, about 0.1 to 2. 0 millimoles, about 0.2 to 1. 75 millimoles, about 0.3 The range of 1.5 millimolar, about 0.4 to 1.5 millimolar, about 0.5 to 1.5 millimolar, about 0.6 to 1.5 millimolar, and 0.7 to 1.5 millimole. In one embodiment, the effective fatty acid dosage is from 0.7 to 1.5 millimole.倍倍。 The amount of the fatty acid molar amount is about 0.2 to 3.0 times. [0080] In one embodiment, a mixture of an effective dose of 0.75 millimolar (150 mg) of lauric acid and 0.53 millimolar (645 mg) of Tween 20 is administered in one or two doses per day. dose. 100115722 Form No. A0101 Page 17 of 35 1003313870-0 201200154 [0081] In another embodiment, the effective dose can be repeated one or more times in any treatment with a 24-hour period. In one embodiment, in accordance with the present invention, the dosage form is one or more capsules comprising an effective dose of a composition. In one embodiment, the effective dose of each capsule is about 0.55 millimole of surfactant and 0.75 millimoles of fatty acid. In another embodiment, an effective dose of a capsule is tempered acid comprising 0.53 millimolar (645 mg) of Tween 20 and about 0.75 millimolar (150 mg). [0083] A set of compositions comprising a pharmaceutical composition as defined above and using instructions is provided. Providing a kit comprising a pharmaceutical dosage form as defined above and using instructions. [0085] Providing a method of treating a disease or discomfort according to a first aspect required by a patient, comprising administering a therapeutic effect An effective amount of the composition. In one embodiment, the disease or discomfort is H. pylori. [0086] A composition as defined above is also provided as a medicament. There is also provided a pharmaceutical composition comprising a surfactant and a fatty acid, wherein the molar ratio of the surfactant to the fatty acid for treating H. pylori infection is from 0.2:1 to 3:1. EXAMPLES [0088] The non-limiting examples of the present invention are included in the best mode, and a comparative example will be further described in more detail with reference to particular examples, which should not be construed as limiting the invention. The way of the scope. 100115722 Form No. A0101 Page 18/35 Page 1003313870-0 201200154 [0090] 实例 [0093] Example 1. Decomposition rate of Tween 20/lauric acid mixture under physiological state and Tween 20 (TW ) range with lauric acid (LA) molar ratio. This mixture was prepared in the following manner. 8 〇 lauric acid (4 〇〇 millimolar) and the selected Tween 20 are first mixed in a water-free 1 〇〇 ml bottle, mixed for 10 minutes and heated to 5 〇〇 c, then allowed to cool to Room temperature (18 ° C) for more than 15 hours. Selected Tween: Mohs of lauric acid 4(1)0 : 1 ' (H)0. 1 : 1 . (G)〇2 : 1 ^ (F)0. 3 : 1 > (EMU, (8) 0.7: Bu (c) 1 〇: Bu (A) 2 〇: l and bottle (B) contain 400 mM hydrochloric acid to test the brightness of the electrode balance. A negative control bottle (J) does not contain La or TW Prepare a total of 480 ml, containing 1 〇〇 (4) of sodium hydride and 19 2 liters of water. Preheat to 37. 4t: At the initial moment, 4 〇 ml of this solution is applied to each TW/ LA mixture in a bottle and maintained in a rotating water bath (100 rpm, 37.4 〇. After 丨 minutes, 4 minutes, 7 minutes, 10 minutes, and 20 minutes after the application of hydroquinone, the pH is Reading after 30 seconds of pH electrode equilibration. When lauric acid is completely dissolved based on early slower titration, the amount of sodium hydroxide is labeled so that the pH is 7· 〇 in the solution, and the concentration of lauric acid is 10 micromoles (400 millimoles in 4 milliliters), which is expected to have an antibacterial effect on H. pylori based on prior art. The pH results are shown in Table 1 below: Table 1 100115722 Form No. A0101 Page 19 / Total 3 5 pages 1003313870-0 201200154 [0094] Example ____ pH at a specific time (Tween20: lauric acid) 1 minute 4 minutes 7 minutes 10 minutes 20 minutes 2:1 6.8 6.9 6.9 6.9 6.9 1:1 7.0 6.9 6.9 6.9 6.9 0.7 :1 7.1 7.0 7.0 6.9 7.0 0.5 : 1 7.2 7.0 7.0 7.0 7.0 0.3 : 1 10.4 7.3 7.1 7.0 7.0 0.2 : 1 10.8 10.5 10.4 10.2 9.4 0.1 : 1 10.8 10.8 10.7 10.7 10.6 0 10.9 10.8 10.5 9.9 9.1 [0095] pH result The values are shown graphically in Figure 1, which is plotted at a specific time point for the pH of Tween 20 and lauric acid. [0096] The data demonstrate that the mixture of rapidly dissolving TW/LA has a critical value when TW: LA's molar ratio is better than 2. 2, it has good solubility in 4 to 7 minutes 'When the molar ratio is lower than this', even if it is 2 〇 minutes, the solubility is still very low (causing the extension through LA) The reaching solution prevents the sodium hydroxide from being neutralized. [0097] Similarly, the appearance of the solution was observed at the same time point to measure the pH. When Tween 20: the molar ratio of lauric acid was 〇5: 丨 or Higher, the solution can become clear or mild at 1 minute Moderate blurred. At Moerby 2:1, there are some aerosols in the clarified solution. Below this ratio, there were some small floating particles in the clear solution, but the lauric acid with solid residue remained attached to the bottom of the bottle for 20 minutes. 100115722 Form No. A0101 Page 20 of 35 1003313870-0 201200154 Example 2: Maintaining lauric acid in solution during acidification, the variation is based on Tween 20 / molar ratio of lauric acid. Method: Sodium laurate 400 mM (88.9 mg) was mixed with a range of Tween 20 in a 100 ml Schott bottle with a screw cap to achieve a Tween 20: lauric acid molar ratio of 1:1 , 〇, 7: 1, 〇.5: 1, 0.3: 1, 0.2: 1, 0.1. 1 and 〇1. For example, the amount of Tween 20 added is 1:1. 2 mg (4 〇〇 millimolar). Each was heated to 50 ° C for 10 to 12 minutes and mixed as much as possible. Then they are cooled to 18 ° C for at least 15 hours. [0100] Pre-warmed water was added to each mixture and the pH was adjusted for 7 minutes. At the 8th minute, 0.4 ml of 100 mM hydrochloric acid (4 mM millimolar) was added and the pH was recorded after 1 minute. When another 0.4 ml of 1 mM HCl was added and the pH was recorded after more than one minute, the solution was gently spun in a water bath for 2 minutes. The bottle was spun in a water bath at a rate of 1 revolution per minute between the acid addition and the pH reading (maintained at 37.4. 〇 until the next addition of hydrochloric acid).

II ^ [0101] Results [0102] Table 2 shows the pH during titration, indicating the appearance of the solution through different fonts (refer to the notes in the table). Table 2. Selected Tween 20: molar ratio of sodium laurate to titration during titration. 1003313870-0 100115722 Form No. A0101 Page 21 of 35 201200154 [0104]

Clarified solution (normal font) Fuzzy & birefringent crystal (beveled underlined) Formation of dense precipitate (bold)

The Tween 20/sodium laurate mixture was decomposed in water at 37. 4 ° C as appropriate in all studied molar ratios. Moerby: 1 and the pH of the bottom line is 7.63 ′ There is Tween 20 and the pH is as high as 8.26 It is known that Tween 20 helps dissolve. When the acid is added to the solution, the laurate is converted to lauric acid. When experimenting with Tween 20: Molybdenum Sodium laurate over 100115722 Form No. A0101 Page 22 of 35 1003313870-0 201200154 After 0.3.1, the pH of the chilled liquid dropped to 3 and remained clear for at least 2 minutes. In the case of 0.3:1, LA was maintained in the solution until the pH was 5 9 and there were hazy and birefringent crystals at pH 6.35. In the ratio of 0.2: m, the precipitation (4) begins to occur at a pH of 6.67 or lower of the slightly acidic acid, at a lower ratio. There is a fuzzy and birefringent crystal near the neutral pH. [0109] Conclusion [0110] The ratio of Tween 20 to lauric acid is 〇. 3: 1 or more. It is necessary to maintain lauric acid in a solution of slightly acidic pH. If the pH is lowered to 3, the ratio is •5 • 1 °. [〇111] Really you 丨3: When the pyloric snails are broken ^ [0112] Materials and methods [0113] 逾 湓谪: [0114] Solution 1: 25 ml of water is added to 0·025 ml 〇. 1 Μ hydrochloric acid (hydrogen ion = 1 〇 4 or ρ Η = 4). Then prepare 5 ml of Aurum Injection N-acetaminocysteine and 10 ml of Lipton iced tea (peach) and 1 ml of water β 250 mg of sodium bicarbonate followed by N-acetyl cysteine / In the Lipton ice tea solution, hydrochloric acid was further added, and the solution was at 37. (: Heat 1 〇 minutes. 2. 941 grams of Zegerid® (20 mg of Omeprazole and excipient) is then added to the solution along with 10 ml of water. [0115] One day will be 150 Milligram of lauric acid is premixed with 645 mg of Tween 20 and heated to 50 ° C and left at room temperature overnight to form a glassy solid 100115722 Form No. A0101 Page 23 / Total 35 Page 1003313870-0 201200154 [0116] On the day of the experiment, the solution 1 was added to Tween 20/lauric acid, and heated to 37 ° C for 5 minutes while shaking. The lauric acid and Tween 20 were observed to be dissolved. [0117] 0. 5 grams of lemon Acidic water (citric acid. 1 Η 2 〇) was mixed with 15 ml of water and added to the solution. The pH was measured to be 6.73. Another 2 ml of 0.5 Μ citric acid solution was added so that the final p Η value was obtained. 6. 5 4 (measured) [0118] The concentration of lauric acid is 150 mg / 75 ml, the concentration of which is equal to 10 mM. [0119] The concentration of Tween 20 will reach 645 mg / 75 ml, the concentration of which is equal to 7 mM or 0.86% ( [0120] The above-mentioned 0. 06 ml of "quenching solution" was prepared and added to 1.065 ml of Isosensitest culture solution ( There is 5% (v/v), Ma Qiqing with pH = 6.5, pre-heated at 65 °C for 10 minutes to inactivate the bactericide, and equilibrated in a slightly aerobic state (5% oxygen, 2 ° /. Hydrogen, 10% carbon dioxide, and 83% nitrogen. [0121] Helicobacter pylori inoculum (0. 075 ml) was added to 1.125 ml of Isosensitest broth/serum and 1/20 "diluted quenching solution". Lauric acid and The final concentration of Tween 20 in culture will be 0.5 mM and 0.35 mM or 0.030 / 〇 (w / v) 〇 This mixture is cultured in a slightly aerobic state at 37 ° C for the selected time. At the end of the preselection time, 20 μl aliquots were removed and appropriately diluted, and 20 μl aliquots were replicated, then placed on Columbia agar containing 5% horse serum. Plates were grown at 37 Colony was calculated for three days in the microaerobic state of °C. [0123] Tanning group solution 100115722 Form No. A0101 Page 24/35 pages 1003313870-0 201200154 [0124] [0125] Ο [0126] [0127 〇 [0128] [0130] [0131] 25 ml of water was added to 0. 025 ml of hydrazine. 1 μ of hydrochloric acid (Η + = 1 Ο — 4, or ρ Η = 4). Add 10 ml of Lipton Ice Tea and 15 ml of water. 25 mg of sodium bicarbonate was further added to the solution. This solution was then heated at 37 ° C for 10 minutes. The pH was then adjusted to 6.5 with citric acid of 0.5 ( (final measured pH was 5.2) and all volumes were increased to 75 ml. 0.06 ml of "control group solution" followed by 1 () 65 ml of Isosensitest medium (containing 5% (v / v) horse serum pH = 65, pre-heated at 65 ° C for 10 minutes to inactivate the fungicide) . 〇.〇 75 ml of H. pylori inoculum was added to 1. 125 ml of lsosensites〇^ nutrient/serum and 1/20 of the "diluted control group solution,. In the medium of lauric acid and Tween 20 of the final The concentrations were 〇龃 and 〇 mM. The bacterial cells were then incubated for a preselected time in a 33.0 microaerobic environment. At the end of the preselected time, 20 μl aliquots were appropriately diluted 'and placed On c〇iumbia agar containing 5% horse serum.Results: The undiluted suspension from the 10 dilutions will have 268χ1〇8 colony forming units/ml (cfu/mL). From 1〇_6 The dilution is calculated. The undiluted suspension will have 4.5〇χ1〇8 mycorrhizal formation in the early position/ml. If the 0. 075 ml inoculum is suspended in 丨.2 ml of the culture solution, the cell concentration will be 2·24χ1〇. 7 colony forming unit / ml, or 1 〇 g7. 35. Control · group culture medium, 0 public 岣 丼 丼 100 100115722 Form No. A0101 Page 25 / Total 35 pages 1003313870-0 201200154 [0132] From 10 5 dilution calculation. Undiluted suspension will have 6 falling units / [0133] Nasal from 10 dilutions. Undiluted suspension will have a falling production unit/ml. [0134] The average is 4.67Χ107 colony forming units/ml, or l〇g7 67. [0135] Control tissue culture Roll-up, 40-point error rod '[0136] Calculated from 1〇-4 dilution. Undiluted suspension will have 2 23 slump formation units/ml. [0137] From 10 dilutions, undiluted The suspension will have a falling unit/ml. [0138] The average is 2.62x10? colony forming units/ml, or i〇g7 42. [0139] f-test medium, 〇 辞 辞 ^ ^ 丨 丨 χ χ χ χ χ χ敉 may be 1 minute) [0140] Calculated from 1〇_4 dilution. Undiluted suspension will have 7.00 χ 10 falling units/ml. [0141] Calculated from 1〇_3 dilution. Undiluted suspension The substance will have a concentration of 5.35x10 liters per ml. [0142] The average is 6.18xl 〇 6 colony forming units / ml, or _ 7 卜 [0143] should be tested tissue culture medium, 1 f) the official sample [0144 20 aliquots of all dilutions (undiluted, ], 10_3, 1 (Γ4) were supplied to the colonies. [0145] The mean is 0 colony forming units/ml. 100115722 Form number Α0101 Page 26 of 35 201200154 [0146] aliquots, milliliters or false 6 and <G. 5 colony forming units in undiluted 20 micro The concentration of living cells in the culture solution <25 colony generation unit / <logl.4. [_ 榇 榇 媒 [0148] All dilutions (undiluted, 1〇-1, 丨2 colonies. 〇) supplied 0 parts [0149] The average value is the colony-forming unit/ml.

Just (4) &lt; 〇.5 « falls into the unit in undiluted (10) microculture medium in vivo concentration < &lt;25 colony generating unit / 亳 &quot; sample &lt; logl. l or [0151] Experimental ia per side 丄 丄 ^ min of the medium ear [0152] All dilutions (undiluted, 1〇-1, 1 (Γ2 3 colonies.) supply 0 parts [0153] 〇 colony forming unit / ml. G [_ hypothesis &lt; 0.5 colony forming unit in undiluted 20 micro 弁Cultivated medium in vivo cell concentration &lt; 25 colony forming units / ml: sample,

Clogl. 4. [0155]. [0156] [0156] The control group culture liquid showed H. pylori at pH 6. 5

Isosens Uest culture medium, attenuated serum, iced tea, citric acid, N-acetylaceous vessels in microaerobic state, Ogilvy saliva, lauric acid, and Tween 20, and (see Figure 2) environment More than 4 minutes 100115722 Form No. A0101 Page 27 / Total 35 pages 1003313870-0 201200154 is stable and feasible. [0157] The experimental medium showed &lt;logl.4 colony forming units/ml (beyond the initial log 7.35 colony generating units/ml) in N-acetic acid omeprazole, lauric acid, Tween 20, And at pH 6.5

Isosensitest medium, attenuated serum, iced tea, Kaiping rubber, survived for 10 minutes or longer in the presence of microaerobic conditions (see Figure 2). Therefore, all H. pylori is killed within 10 minutes. [0164] [0164] The medium at the start of the experiment was found to be about 1 log colony generated only / was killed in about 1 minute (refer to Figure 2) ). The "quenching solution" diluted 1 : 20 in milliliters is clearly effective against Helicobacter pylori. Thus, it can be seen that the composition according to the present invention demonstrates superior antibacterial activity and the composition of the present invention is useful for treating H. pylori The use of augmented infectious diseases disclosed in the following provides a method for the effective treatment of H. pylori infectious diseases. Preferably, the disclosed compositions provide a convenient treatment compared to the currently recommended triple therapy. The method of biting 纟5_成物村 is recommended as a treatment plan for Helicobacter pylori infection. Dry preferably, because the composition does not rely on antibiotics for therapeutic effect, the resistance of Helicobacter pylori can be eliminated and the side effects of antibiotics can be avoided. 100115722 Form No. A0101 Page 28 / Total 35 Page 1003313870-0 201200154 [0165] Preferably, because the molar ratio of fatty acid to surfactant allows the fatty acid to dissolve rapidly in mild acidic pH (pH between 3 and Between 7), according to the disclosed composition does not need to apply a proton pump inhibitor, H2 antagonist or oral antacid to increase the stomach The pH value to lauric acid becomes soluble in the pH of the aqueous phase. [0166] After reading the above-disclosed technology, various other modifications and variations of the invention are possible without departing from the scope and spirit of the invention. The technical person is understandable, and all the rewriting and modification are still within the scope of the patent application scope of the subsidiary Q. [Simplified description of the drawings] [0167] The drawings illustrate an disclosed embodiment and explain The principles of the embodiments have been disclosed. However, it is to be understood that the drawings are only for the purpose of illustration and are not intended to limit the invention. FIG. 1 shows Tween 20/lauric acid in different The dissolution time of 2 minutes (method: see example!), through the buffer effect of lauric acid, shows the amount of dissolution relative to the amount of caustic soda added, so that if all the lauric acid dissolves Q solution, the pH is 7. 2 The figure shows the feasibility of reducing the Helicobacter pylori in the Tween 2 〇 / lauric acid pharmaceutical formula showing the amount of residual cells of H. pylori relative to the time axis (in log colony production units / ml (cfu / mL)) The main element REFERENCE NUMERALS [0168] Form Number A0101 None 100 115 722 Page 29 / Total 35 1003313870-0

Claims (1)

201200154 VII. Patent application scope: 1 · A pharmaceutical composition comprising: a surfactant and a fatty acid, wherein the molar ratio of the surfactant to the fatty acid is 〇2:1 to 3: 1 The composition of claim 1, wherein the molar ratio of the surfactant to the fatty acid is 〇5: 丨 to 丨: 1. 3. Or the composition according to item 2, wherein the molar ratio of the surfactant to the fatty acid is 7. 7 : 1. 4 · as disclosed in the scope of the third to third items of the patent application The composition 'wherein the fatty acid is selected from one or more of the following saturated fatty acids: butyric acid, caproic acid caprylic acid, capric acid, lauric acid, myristic acid, or other direct bond lengths from 4 carbons to 16 carbons. The composition of claim 4, wherein the fatty acid is selected from one or more of the following unsaturated fatty acids: myristoleic acid, palmitoleic acid, oleic acid' Linoleic acid or linoleic acid. 6. Group as described in claim 5 a composition in which the unsaturated fatty acid is cis. 7. A composition of the item 4 to 6 of the towel material, wherein the fatty acid is selected from the group consisting of - or a plurality of linoleic acid 8. Palmitoleic acid or lauric acid. The composition of claim 7 wherein the fatty acid is lauric acid. 9 - as claimed in any one of claims 1 to 8. a composition, wherein the surfactant is a nonionic surfactant or a bile salt. 100115722 Form No. A0101 Page 30 of 35 1003313870-0 201200154 10 . Composition as claimed in claim 9 The nonionic surfactant is selected from the group consisting of a polyoxyethylene fatty alcohol ether (Brij) surfactant, a Tween surfactant, an IPEGAL surfactant, a MERP0L surfactant, a Triton surfactant or a dehydrated pear The composition of claim 10, wherein the surfactant is a Tween surfactant, and the composition of claim 4, wherein The 7 heart print world The active agent is selected from the group consisting of Tween 20 or Tween 80. Ο 1 η id . The composition of claim 12, wherein the surfactant is Tween 20. 14 · If the patent application range is i to 13 The composition according to any one of the preceding claims, wherein the composition further comprises a muc〇lytic preparation, wherein the composition according to claim 14 is wherein the mucolytic preparation is selected from the group consisting of An enzyme or a monothiol compound. The composition according to claim 15, wherein the thiol compound is selected from the group consisting of N-alkyl-cysteine, penicillamine or nitrogen _(2_mercaptopropene)-gan Amino acid. 17. The composition of claim 15, wherein the enzyme is a protease. 18. The composition of claim 15 or 16, wherein the thiol compound is N-ethinyl-cysteine. The composition according to any one of the preceding claims, wherein the composition further comprises at least one selected from the group consisting of omeprazole (100p) and a sorrel ( Lansoprazole), Panto Reef Form No. A0101 Page 31 / Total 35 pages 1003313870-0 201200154 (pantoprazole), esomeprazole, timoprazole, rabeprazole or A proton pump inhibitor of picoprazole. 20 21 22 23 24 25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The composition of claim 20, wherein the antibiotic is selected from the group consisting of metronidazole, tetracycline, ciarithromycin, and erythromycin. Or amoxicillin (amoxiciiiin). The composition according to any one of claims 1 to 21, wherein the composition further comprises one selected from the group consisting of cimetidine, ranitidine, and farogestrel. Famotidine or hydrogen receptor antagonist of nizatidine. An application of the composition of any one of claims 1 to 22 in the preparation or manufacture of a medicament for treating a disease or discomfort. For example, the application of the scope of claim 23, wherein the disease or discomfort is a Helicobacter pylori infection. A pharmaceutical dosage form which comprises the composition as set forth in claims 1 to 22 of the patent application. The pharmaceutical dosage form of claim 24, wherein the dosage form is a capsule. A kit comprising the pharmaceutical composition and instructions for use as set forth in any one of claims 2 to 22. A kit comprising the pharmaceutical dosage form and instructions for use as described in claim 25 or claim 26. A composition of the type 1003313870-0 ~ such as the scope of the patent application range 1 to 22, single number A0101 page 32 / 35 page 201200154, for the use of pharmaceuticals. A pharmaceutical composition comprising a surfactant and a fatty acid, wherein a molar ratio of the surfactant to the fatty acid for treating a H. pylori infection is 0.2:1 to 3: 1. 100115722 Form No. A0101 Page 33 of 35 1003313870-0