TW200423959A - New formulations and use thereof - Google Patents

Abstract

A tolterodine-containing pharmaceutical formulation that comprises cocoa powder, process for manufacturing the formulation and use of the formulation for treating overactive bladder.

Description

200423959 (ii) Description of the invention: Technical field of the invention] The present invention relates to a novel pharmaceutical formulation of tolterodine (optionally including salts, complexes, prodrugs and metabolites) for oral administration, Regarding the use of dextrexol (optionally including its salts, prodrugs, and metabolites) for the manufacture of a drug intended to be administered orally to obtain an effect against overactive bladder, and about dextrexol by oral administration (Optionally including its salts, prodrugs and metabolites) a method of treating overactive bladder.

MM Desiotus is an effective and safe compound for the treatment of overactive bladder. The synthesis of Desaturate and its use in the treatment of overactive bladder have been disclosed in U.S. Patent No. 5,382,600 (Pharmacia & Upjohn AB). A profile of beneficial benefits / side effects can be obtained with oral doses of 1 or 2 mg per day. Desaturate has tartrate salts with molecular weights of 325.0 and 475.6. The mirror purity is > 99%. The pKa value at temperature is 9.87 and the solubility in water is about 11 mg / ml. The partition coefficient (LogP) of a buffer solution between η-octanol and phosphate at pH 7.32 is 1.83.

Deshuwei. PNU-200583 N, N ~ Diiso-propyl-3- (2-hydroxy-5-methylbenzyl) -3-amphetamine.

The main metabolic pathways of Destomol are regulated by cytochrome P450 2D6 to form 5-HM 5 200423959 metabolite, (R) -N, N diisopropyl-3- (2-hydroxy-5-hydroxymethylbenzene) ) -3-amphetamine. This metabolite has similar pharmacological properties to Desaturate, see Nilvebrant L, Gillberg PG, SparfB n Antimuscarinic potency and bladder selectivity of PNU-200577, a major me her olite of tolterodine · '' P / zarmaco /. Tbxza? / · (1997) 81: 195-207 〇 For similarities to the pharmaceutical properties of Desaturate, see C / z > zP / 2_aw / 77 ^ by Brynne N, Dalen P, Alvain G, Bertilsson L, and Gabrielsson J 1998 (63): 529-39.

An N-dealkyl metabolite is regulated by CYP3 A and is further metabolized to a 5-hydroxy metabolite of N-dealkyl. See the following diagram for details.

Another metabolite is formed when the carboxylic acid group is formed in the CH20H group of the 5-leg metabolite. There is also another metabolite formed when the Qianxian Qingcheng Ju Cheng Qu recorded the 5th metabolite CH2OH group. Zhiming's bribe contains its R-isobutene, sense isomers, and racemic mixtures, as well as its salts, complexes, prodrugs, and metabolites. It can be converted from non-isomers and racemic mixtures as well as from its salts, complexes, prodrugs and metabolism. The braid is made of tartar and tartaric acid 6 200423959 salt. Examples of complexes «Yu tear and ______-daughter exchange composition 'such as ion exchange resinates. Known Skills The aforementioned U.S. patent satirizes a formula similar to the present invention. · WO 98/03067 discloses transdermal administration of discriminated isomers. WO 00 / 12_ discloses transdermal signaling isomers of desutoide and other destructive compounds. The conventional arts that have not found any formula containing ## 宜 is similar to the inventor. Chocolate-a species different from cocoa powder, which is rarely used as a component in a pharmaceutical product and is only found in thirsty medicines so far. An example is Ex-5 Lax®, which is a chocolate thirst tablet (marketed by Novartis) that contains senna. Purex is a laxative in which phenol is blended with chocolate and marketed in 1950. Therefore, it has never been known to have any composition system containing dextoto and chocolate. However, the applicant is currently surprised to find that by including cocoa powder as a masking agent and texture structurant in a formula containing Dexter, it is possible to effectively mask off-flavored ingredients such as Destrotoux pharmaceutical formula for the taste of Shutuo and optional buffer), oral administration without liquid. Since similar pharmaceutical formulations have never been revealed before, it is impossible for those skilled in the art to think about the formulations of the present invention without making any effort in progressiveness. Therefore, as described below, the present invention is both novel and progressive. [Explosive Content] Summary of the Invention 7 200423959 The present invention provides an orally administered pharmaceutical formulation of Dextoto (optionally including Dexoto class, complex, prodrug and metabolite) for obtaining Effect against bladder hyperactivity, which includes detrusor instability, detrusor hyperreflexia, frequent urination, urgency, and urge incontinence. This method of administration can be administered to humans or animals. This method of administration can be completed without adding liquid. Dosing without adding a liquid is a big benefit in all cases, for example when you have difficulty in getting clean water or other suitable liquids when traveling. At the same time, freely giving is also a big bribe, such as during lectures and theater shows. In addition, the formulation of the present invention dissolves in the mouth rather than being swallowed, so it is a great benefit for those who swallow traditional rotators. Therefore, this sun and moon is a particularly useful dosage form-a formula that can be recorded or dissolved without drinking water or other impurities. The formulation of the present invention is a dosage form containing a still effective amount of arsenic. In this article, "therapeutic effective amount" refers to the effective acquisition of anti-Wei urinary muscle instability, county reflex, frequent urination, urgency and urgency incontinence. "Frequent urination, mainly refers to the need to urinate more than 8 times or twice a night in 24 hours., Urgency, mainly refers to frequent, strong and sudden need to urinate.," Urgent incontinence "mainly means Involuntary urination after a sudden need for urination. The amount of the bribe is as good as the side effects that appear from the sun and the moon. The present invention was administered by herself. This kind of "is free to take care of itself, and it shows that there is no need for self-administration of the need for therapy. At the same time, the present invention also provides a method of using the formula of the present invention to treat delayed action disorder, and -Observe the method for preparing medicament by using the formula of the present invention. Other special lin of the present invention will gradually become apparent with the following description. 8 200423959 The object of the present invention is called Hao Nu Nu Xiancai, and Lai Xue formula contains cocoa powder. The second object of the present invention is to provide a method for preparing the formula. The third object of the present invention is a miscellaneous donation-species_method for observing Fasi's overactive bladder. Those who are familiar with the subject from this article # ㈣ 细 # And I would like to know the further and other purposes of the present invention. The benefits provided by the formula of the present invention are: 1) the formula is provided for proper taste masking; 2) the formula does not need to be added at the time of administration Force ^ any liquid, 3) compared to the conventional tablets that need to be administered with liquid-from, the use of the formula of the present invention does not increase the urinary burden because it does not require the addition of liquid when administered, so it does not increase the therapy 4) The match 5) The formula will not give patients a drug-related feeling like traditional lozenges. 6) The formula can be quickly absorbed through the mucous membranes. It is made when Wei Chongqi is added! The detailed description of the invention The main object of the present invention is to provide a pharmaceutical formula containing Desaturate, which is used for the treatment of overactive bladder. The overactive bladder includes detrusor instability and detrusor overexertion. Reflex, frequent urination, urgency, and urge urinary incontinence. More specifically, the object of the present invention is to provide a formula or a combination thereof, which is used for transmission through the mucosa and is mainly used for gauze or Soluble in the oral cavity, with or without the help of saliva or mechanical erosion, the formula can then show adhesion to tissues in the oral cavity. 9 200423959 It is better to use this formula without adding liquid when administered. Compared with the conventional spinner which needs to be administered together with liquid, the use of the formula of the present invention does not increase the burden on the urinary, and therefore does not increase the need for therapy because it does not require the addition of liquid when it is administered. Optionally added buffers are used to temporarily change the local yang of saliva. By doing so, it converts a higher fraction of Dexter to its less ionized form. This helps The absorption of the active agent is enhanced by the penetration of the mucosa. For those skilled in the art, it is obvious to choose a buffer system based on the pKa of one or more active agents. The inventor of the present case has surprisingly found that by using cocoa powder It can fully mask the bad taste ingredients, such as Desutrol itself and / or buffering agent. The cocoa powder system functions as a taste masking agent and texture forming agent. The cocoa powder system is defined as the cocoa powder which removes oil and fat and is ground into a powder Cocoa flakes are defined as cocoa beans with a removed shell. Cocoa oil refers to the oil discharged from the center (kernels or fragments) of cocoa beans. Cocoa powder is made from roasted cocoa beans. It is a complex compound consisting of dian powder, cocoa butter, amino acids, proteins, theophylline, amines, monosaccharides and polysaccharides, discipids, flavonoids, ginseng and the like. A preferred embodiment is a formula having a weight of about 400 mg and having the following preferred formula (w / w): Amount of ingredients ... · 1 Function (%) Despitur 1-tartaric acid 0,25 'Active ingredient Hydrogenated soybean salad oil 43 ^ 5 ~ 'One liquid ingredient cocoa powder 18,00 " " Taste masking agent / texture-forming agent mannitol 18,00 Thinner corn temple powder 13,35 — ~-Thinner Aspar Sweetened sugar 0,15 '— sweetener potassium acesulfamate 0910' sweetener 10 titanium dioxide 2,00 colorant sodium glutamate 0,60 flavoring agent mint and vanilla flavoring agent 3,00 flavoring agent Fat 1, 00 Emulsifier 200423959 [Embodiment 3 f Examples The non-limiting examples listed below are specific examples for preparing the present invention. f-side 1: Preparation of a preferred embodiment, a formula weighing about 400 mg, prepared with the following preferred composition (w / w): Ingredient Amount Function (%) Fu Shu Nu 1-Tartrate 0,25 Active Agent Hydrogenated Soy Salad Oil 43,55 Liquid Ingredients Cocoa Powder 18,00 Taste Masker / Texture Constructor Mannitol 18,00 Thinner Corn Palace Powder 13,35 Thinner Aspartame 0,15 Sweetener Acetyl Acetate Continued amino acid unloading 0,10 sweetener titanium dioxide 2,00 colorant sodium glutamate 0,60 flavoring agent Bojie and vanilla flavoring agent 3,00 flavoring agent is linoleum 1,00 emulsifier cocoa powder can be non-examination Use sexualized form and alkaline form. Both can be used in the formulations of the invention. When the person desires a milder taste, the cocoa powder that is tested is better. The partially hydrogenated soybean oil is melted, and the solid component is added and mixed. The solid component is Shuto 1-tartaric acid, cocoa powder, mannitol, corn starch, aspartame, and donated stone yellow. Potassium (acesulfame ^ K, titanium dioxide, sodium glutamate and flavouring agent (if solid). Grind with a taper refining machine to reduce the size of _Slaves. If it is said that the components have been repaid, it must be refilled 200423959 size (for example Grind before mixing with the fat component), then use a roller refiner to dispense. After processing in the refiner, the professional silk _ noodles _ _ _ _ fat _ mixing secrets (such as wrapped and solidified), Asia and multiplication ij melt Of hydrogenated soybean oil. Mix the melt in a suitable mixer. Add liquid ingredients, that is, soy butter and flavoring agent (if liquid). Subsequently, suitable techniques are used to form spinners or other solid dosage forms, such as molding, sowing, or; Dongning (including pastiUation), if necessary, can be performed after suitable preconditioning. Other suitable manufacturing methods can also be used. Preparation of other examples In a manner substantially similar to that of Example 1, a formula weighing about 500 mg was prepared. The formula had the following preferred composition (w / w): Ingredient amount function (%) Desutura 1-tartaric acid 0, 20 Active agent Cocoa powder 50,00 Taste masking agent / Texture structuring agent Nitrogenized soybean salad oil 44,55 Liquid ingredient titanium dioxide 2,50 Colorant sodium vaporization 0,55 Aspartame aspartame 0,15 Sweet taste Potassium Acetate Flavate 0,10 Sweetener Vanilla Flavour S 1,50 Sweetener Soy Lecithin 1,00 Emulsifier Example 3: Preparation of Another Example In a manner substantially similar to Example 1 Manufacture a formula with a weight of about 200mg to about 1000mg, the formula has the following composition (w / w): the amount of ingredients (%) function is comfortable (matrix, prodrug, metabolite, salt or complex) 0,1-2 Active Cocoa Butter Equivalents (CBEs) 35-55 Liquid Ingredients 12 Cocoa Powder 8-55 ^ Masking Agent / Texture Constructing Agent Water-soluble or distributable diluent (with fine granular powder as (Preferred) 0-40 thinner sweetener 0,2-3 sweetener buffer 0-10 buffer flavoring agent 0-4 Sweetener 0 Unbridged agent 0-3 Flavoring agent emulsifier / solvent 03 -6 " Emulsifier colorant 0-3 Colorant charm Example 4: Preparation of another specific embodiment 200423959 Some of the excipients in the specific examples of the above examples are replaced with another compound in an equivalent manner to obtain usable specific examples. The cocoa powder may be used in a non-experimental form, an experiential form, or a mixture thereof. One or more of the following compounds can be selected as a diluent: strict sugar; fructose; glucose; galactose: lactose; maltose; invert sugar; a pharmaceutically acceptable polyol such as xylitol, sorbitol Alcohol, maltitol, mannitol, isomalt and glycerol; or polydextrose, or starch; or any mixture thereof; but only to the extent that the cocoa powder has sufficient flavor-masking effect, the liquid component is fat Components can be selected from one or more of the following compounds: • Cocoa butter and alternatives to cocoa butter, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), and cocoa butter substitutes ( CBR) and cocoa butter improver (CBI), coconut oil, standard oil and other similar oils based on lauric acid and myristic acid, similar palm oil, birch oil, birch oil, fermented tree species Seed oil, Lipse seed oil, apricot kernel oil, salt fat and other similar oils based on palm oleic acid and stearic acid. 13 200423959-corn oil, incomparable sunflower oil, soybean salad oil , Fennelseed oil, rapeseed oil, olive oil 'Miscellaneous oil, professional rhyme, red%, and other similar oils based on hydrogenated oleic acid and flax, and hydrogenated to a hydrogenated point,-fish oil, tallow, cooked lard, cream and other Animal-derived oils and fats, and synthetic oils, fats and oils, and hard oils, whose scales are made from linoleic acid and # & chemical green that has not been catalyzed or catalyzed by acid or scaly scale. Compounds are available as single-component or mixed with each other, the (etc.) compound is crude or physically refined or refined, or accepts further including catalytic hydrogenation, lactonization, transesterification and segregation deal with. The optional buffering agent may be selected from one or more of the following: carbonic acid, bicarbonate, acetic acid, glucose, glycerol scale acid, dipic acid, or sodium, potassium, or ammonium salts of glycine, or a mixture thereof . However, most phosphates are considered less suitable because their taste is often offensive and difficult to hide. Adding a buffer can increase the uptake of the buccal mucosa. The sweetener may be selected from one or more artificial sweeteners such as: sucrose, aspartame, sultone potassium, saccharin, sodium saccharin, sweetener, glycyrrhizin, and thaumatin ( Tallin ^ talin), glucosamine, dihydrochalcone (new orange peel), aUtame, mysterious fruit (such as ⑶ here, mysterious fruit), monellin (no susceptible child, serendipity berry), stevia and / or their salts. The emulsifier is preferably phospholipids and / or egg-printed phospholipids, but can be replaced with a non-ionic interfacial active agent such as poloxamer, polyoxyethylene vinegar, poly · oxidant Ethylene medicine sesame oil derivatives, polygasified ethylene fatty acid sorbitan esters, monofatty acid glycerides, difatty acid glycerides and their ethers, to oxidize acetic acid; polyglycerol vinegar fatty acids, including polyglycerin polyramie oil Acid (PGPR), 14 ^ 959 May sorbic acid sorbitan esters; anionic surfactants such as fatty acids, fatty acids and lactic acid soap soaps' especially sodium lactate stearate and / or lactate stearate, lauryl sulfate Sodium acid and latanol, _ zwitterionic surfactants, such as zwitterionic fillers, such as dicholesterol and phospholipid ethanolamine, or their fractions or derivatives with imprintin. The formulation of the present invention is mainly constituted as a soluble and / or inhalable oral rotator, but also includes other medicinal forms suitable for oral administration such as buccal patches, buccal plasters and buccal sprays. The present invention further comprises a formula containing dextran, which further contains one or more anti-bladder agents, such as oxobutynin, ammonium emepromium), troxispium, propanetheline, and darifenacin. In addition, as described above, the present invention includes a pharmaceutical formulation comprising, Administration to a patient to treat his overactive bladder can optionally be administered with one or more other anti-bladder effects, and more optionally, through one or more other Administration of drugs for the treatment of overactive bladder, other routes of administration are such as transdermal injection, good, good, cream, soft button vaginal administration and / or By injection.

【Round style simple and clear; J 15

Claims (1)

200423959 Scope of patent application: 1. A formula for A oral administration for oral administration, which contains dextoto, including dextoto, Yishao 1 compound, prodrugs and metabolites It contains cocoa powder. Special features of Hai formula 2. If the scope of patent application is in the form of its R. isomer, which is characterized by desuto basically 3. The formula like the scope of patent application in item 1, is characterized by deduction It is in the form of its S-isomer. to? The text is basically 4 · If the scope of patent application is the first 1 15 The formula is characterized by the fact that Destomet is in the form of its racemic isomer. On the soil 5. If the formula in the scope of patent application is the first item, it is characterized by its administration of the metabolite (R) Cheryl, 3 galyl_5 methylphenyl) _3_benzylamine, and Contains dextrene optionally. 6. The formula according to any one of item U 5 of the patent application scope, characterized in that it further comprises one or more lipid components. 7. The formulation according to item 6 of the scope of patent application, characterized in that the one or more lipid components are selected from:-cocoa butter and alternatives to cocoa butter, including cocoa butter equivalent (CBE), cocoa butter Substitutes (CBS), cocoa butter substitutes (CBR) and cocoa butter improvers (CBI), coconut oil, palm kernel oil and other similar oils based on lauric and myristic acids, palm oil , Birch oil, stewed tree seed oil, illipe butter, apricot kernel oil, salt fat and other similar oils based on palm oleic acid and stearic acid, 16 200423959 — corn oil , Sunflower oil, compound sunflower oil, soybean salad oil, mustard oil, rapeseed oil, olive oil, rice bran oil, cottonseed oil, peanut oil, and is characterized by oleic acid, linoleic acid, and linoleic acid Other oils based on and ratified to the appropriate point, 5-fish oil, tallow, cooked lard, butter, and other animal-derived fats, and-synthetic fats, re-esterified fats, hard fats, derived from Uncatalyzed or acidified fatty acids and glycerol , Alkali or enzyme-catalyzed chemical reaction, whereby the compound (s) is used as a single component or mixed with each other, the compound (s) is crude or physically refined or refined, or accepts catalysis The further treatment of sexual hydrogenation, interstitialization, transitional conversion and individualization. 8. The formulation according to item 7 of the patent application scope, characterized in that the one or more lipid components are selected from the group consisting of: cocoa butter equivalent (CBE), cocoa butter substitute (CBS) 15 and cocoa butter substitute (CBR) ). 9. The formulation according to any one of claims 1 to 9, which is characterized in that it further comprises one or more buffering agents. 10. The formulation according to item 9 of the scope of patent application, characterized in that the one or more buffering agents are selected from the group consisting of: carbonic acid, bicarbonate, acetic acid, glucose, glycerol, 20 sodium phosphate, or potassium glycine Salt or ammonium salt, or a mixture thereof. 11. The formula according to any one of claims 1 to 10 in the scope of patent application, characterized in that it further comprises one or more sweeteners, and optionally a bale—or multiple flavoring agents. 0 17 200423959 12. The formula of item 11, characterized in that the one or more sweeteners are sucrose, aspartame, potassium acetolactone, saccharin, sodium saccharin, sweetener, glycyrrhizin, thaumatin (talin , Talin), glucosamine, dihydrochalcone (new orange peel), alitame, miracuHn (mysterious fruit), monellin (serendipity berry), Stevia and / or its salts. 13. The formulation according to any one of claims 1 to 13 in the scope of patent application, characterized in that it further comprises one or more emulsifiers / solvents. 14. The formula according to item 13 of the scope of patent application, characterized in that the one or more milk emulsifiers / solvents are selected from the group consisting of:-lecithin, preferably soybean lecithin and / or egg lecithin. -Non-ionic surfactants such as poloxamer, polyoxyethylene esters, poly-ethylene oxide castor oil derivatives, polyoxyethylene fatty acid sorbitan esters, monofatty acid glycerides, Double fatty acid glycerides and their ethers, 15 polyoxyethylene stearic acid; polyglyceryl fatty acids, including polyglycerol polyramie linoleic acid (PGPR), fatty acid sorbitan esters; anionic surfactants such as fatty acids, fatty acids, and lactic acid Soaps, especially sodium lactate stearate and / or calcium lactate stearate, sodium laurate sulfate and latanol, zwitterionic surfactants, such as zwitterionic phospholipids, such as phospholipid 20 20 Choline and phospholipids ethanolamine. 15. The formulation according to item 14 of the scope of patent application, characterized in that the one or more emulsifiers / dissolving agents are selected from the group of lecithin, preferably soybean lecithin and / or egg lecithin. 18 200423959 16. The formula according to any one of claims 1 to 15, which further comprises one or more substances selected from the group consisting of fructose; glucose; galactose; lactose; maltose; transformation Sugar; a pharmaceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, iso-5 maltitol and glycerol; or polydextrose, or starch; or any mixture thereof. 17. —A pharmaceutical formula for oral administration, characterized in that its unit dose has a weight of about 400 mg and contains: Ingredient Amount Function (%) Desutura 1-Tartaric Acid 0,25 Active Ingredient Hydrogenated Soy Salad Oil 43,55 Liquid ingredient cocoa powder 18,00 Taste masking agent / texture-forming agent mannitol 18,00 Thinner corn starch 13,35 Thinner aspartame 0,15 Sweetener potassium acesulfame 0, 10 sweetener titanium dioxide 2,00 colorant sodium glutamate 0,60 flavoring agent mint and vanilla flavouring agent 3,00 flavouring agent soy egg romantine 1,00 emulsifier 10 18. a pharmaceutical formula for oral administration, which It is characterized in that its unit dose has a weight of about 500 mg and contains: ingredient amount function (%) deshuto 1-tartaric acid 0,20 active agent cocoa powder 50,00 flavor masking agent / texture constituting agent hydrogenated soybean salad oil 44, 55 Liquid Ingredients Titanium Dioxide 2,50 Colorant Sodium Chloride 0,55 Bridge Taste Aspartame 0,15 Sweetener Ethyl Sulfame Sulfate 0,10 Sweetener 19 200423959 Vanilla Flavor 1,50 Sweetener Soy Lecithin 1.00 Emulsifier 19. A pharmaceutical formulation for oral administration, which contains Destoux, and optionally contains Destoux's salts, complexes, prodrugs and metabolites, the formula is characterized by its unit dose It has a weight of about 200-1000 mg and contains: the amount of ingredients (%) function of Shushutu (matrix, prodrug, metabolite, salt or complex) 0,1-2 active agent cocoa butter equivalents (CBEs ) 35-55 Liquid cocoa powder 8-55 Taste masking agent / texture forming agent Water-soluble or distributable diluent (preferably fine-grained powder) 0-40 Diluent sweetener 0,2 -3 Sweetener Buffering agent 0-10 Buffering agent flavoring agent 0-4 Sweetening agent bitterness modifier 0 -3 Flavoring agent emulsifier / solubilizer 0,3-6 Emulsifier coloring agent 0-3 Coloring agent 5 ° 20. As applied for patent scope The formulation of any one of items 1 to 19, further comprising one or more other agents having anti-bladder hyperactivity. 21. The formula as claimed in claim 20, wherein the one or more other agents are selected from the group consisting of: oxobutynin, emepromium, trospium, Propantheline and darifenacin. 22. The formulation according to any one of the claims 1 to 21, which is formulated into an oral dosage form and which is intended for delivery to Shutou, which is mainly transmitted through the buccal mucosa and / or other oral mucosa. 20 200423959 23.-The use of a formula according to any one of claims 1 to 22 of the scope of patent application, which is used for the manufacture of medicines for the treatment of overactive bladder. 24. A pharmaceutical composition for the treatment of overactive bladder, comprising a pharmaceutical formulation containing oral administration of Dextol as in any one of claims 1 to 22 of the patent application scope. 25. A pharmaceutical composition for the treatment of overactive bladder, comprising a pharmaceutical formulation for oral administration containing desulfurate as in any of claims 1 to 22 of the scope of patent application, and Multiple other routes can be administered simultaneously with the formula and / or one or more other agents having an effect against bladder hyperactivity. 26. The pharmaceutical composition of claim 25, wherein the one or more other routes are selected from the group consisting of percutaneous administration, oral administration, and inhalation and injection administration. 21 200423959 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the component representative symbols in this representative diagram: (None) J. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: (None)