CA2708045A1 - A pharmaceutical compound - Google Patents

A pharmaceutical compound Download PDF

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CA2708045A1
CA2708045A1 CA2708045A CA2708045A CA2708045A1 CA 2708045 A1 CA2708045 A1 CA 2708045A1 CA 2708045 A CA2708045 A CA 2708045A CA 2708045 A CA2708045 A CA 2708045A CA 2708045 A1 CA2708045 A1 CA 2708045A1
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acid
pharmaceutical compound
drug
compound according
solution
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Shin-Jen Shiao
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/191Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/42Phosphorus; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Otolaryngology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical compound for the treatment of one or more ailments selected from the group comprising hypersensitivity reaction diseases, allergies, pain, influenza, colds, thrombus or clotting coagulation, inflammation, virus infections, insect bites, conditions caused by free radicals, food poison, food allergies, itch and drug side effect; by lowering humoral pH.

Description

I
3 This application is a divisional application of Canada application number 2,530,216 filed in 4 Canada on April 26, 2007 (filed PCT on Dec. 21, 2005), under subsection 36(2) of the Paten Act.
By which only the abstract, field of the invention and the claim have been changed and the 6 original specification is not changed.

This invention relates to a drug containing edible acid and/or acidic salt as active agent to treat 11 and alleviate immune diseases by lowering the humor pH; to improve individual immunity by 12 uses of drug, food, drink or health care products, which are made from said edible acid and/or 13 acidic salt, or the acidic fruits containing thereof, or their products;
foods lowering the risk of 14 hypersensitivity and their preparation methods; drug to lower the humor acidity and to treat or alleviate disease caused by insects bite; that also to be drug for cold, drug for inflammation; drug 16 for skin inflammation, drug for bath agent, agent for treating skin-contacting material such as 17 clothing and groove, drug for skin releasing, and drug for cardiovascular thrombus disease.

21 There are four types of disorder immune responses to tissue damage, called hypersensitivity 22 reactions. Type I (anaphylactic hypersensitivity, or immediate type), on account of inappropriate 23 responses to foreign antigens relate to anaphylaxis. This anaphylaxis is IgE mediated reaction.

24 Symptoms of IgE mediated reaction are anaphylaxis, dermatitis, asthma, Parkinsonism, hay fever, and food allergy. Type II (antibody dependent cytotoxic type, or IgG and IgM
mediated 26 hypersensitivity), causes diseases such as haemolytic disease of the newborn, autoimmune 27 haemolytic anaemia, nephropathy and certain other autoimmune diseases, transfusion reactions, 1 drug allergy and hyperacute graft rejection. Type III (immune complex mediated 2 hypersensitivity), is mediated by IgG which causes diseases such as lupus nephritis, rheumatoid 3 arithritis, arthus reaction, vasculitis, and serum sickness. Type IV (T cell mediated 4 hypersensitivity, or delayed type hypersensitivity), causes diseases such as Type I

hypersensitivity, chronic allergic rhinitis, contact dermatitis, tuberculin reaction, diabetes, 6 multiple sclerosis, and erythema.

8 Immunodeficiency is divided into inherited immunodeficiency and acquired immune deficiency 9 syndrome, which is caused by human immunodeficiency virus (HIV). The susceptible disease for the former group includes, generally, such as respiratory infections, herpes simplex virus, 11 chronic lung, influenza, and skin inflammatory. Patients infected with HIV, after a period of 12 apparent quiescence of the disease, will eventually develop acquired immune deficiency 13 syndrome. In that period viruses replicate persistently, and decline the function and number of 14 CD4 T -cell. Eventually, only few CD4 T -cells are remained. Drug could just block HIV

replication and rise in CD4 T -cells temporary. Finally, most HIV infected people develop 16 acquired immune deficiency syndrome and die. However, scientists hope that will be possible to 17 develop effective vaccines against HIV. Yet not any effective vaccine is found.

19 Tumor is one of fatal diseases which are caused by progressive growth of a single transformed cell. It is impossible that to remove or to destroy cancer cells must not kill the normal ones. It 21 was reported that T cells are critical mediators of tumor immunity. Being a challenge for 22 immunologists to understand why the mutated proteins can not induce cytotoxic T cells. The 23 mutated proteins are not only specific antigens of tumors, but also are the causes of cancer.
24 Vaccines based on tumor antigens are the ideal approach to T -cell mediated cancer immunotherapy. They are excellent targets for therapy. Specific antigen vaccine can be produced 26 from the major antigen of tumor. That may need long time before the major antigen of tumor is 27 identified, and has not success as yet.

2 Autoimmune disease is caused by a reaction of required immune system with auto antigens, 3 which does harm to tissues. Autoimmune disease can be mediated by auto antibodies and/or by 4 auto-active T cells. The tissue damage can be resulted from direct attack on the cells borne autoantigens, from immune-complex formation, or from local inflammation. T
cells are not only 6 involved directly in inflammation or molecular destruction, but also are the required factor for a 7 continuous reaction of autoantibody. Similarly, B cells are important antigen-presenting cells to 8 keep a continuous reaction of T -cells. The control of autoimmunity is to know how to control the 9 activity of T -cells, and how to determine the way that autoantigens are recognized by T -cells.

There are three groups of drug treating immunological disorders: first, anti-inflammation drugs 11 of the corticosteroid family, such as prednisone and antihistamine; second, cytotoxic drugs, such 12 as azathioprine and cyclophosphamide; and third, fungal and bacterial derivates, such as 13 cyclosporine-A and rapamycin, which inhibit signaling events within T
lymphocytes.

These drugs have wide action in inhibiting immune system as well as harmful ones. The 16 beneficial effects of corticosteroids are anti-inflammation. However, there are also many side 17 effects, including fluid retention, gain of weight, diabetes, bone mineral loss, and thinning of 18 skin. They are caused by the results of using corticosteroids which reduces the functions of 19 hormone and also reduces the immune functions too. The cytotoxic drug suppresses immune by killing cells. That has serious side effects, including decreasing immune function, anemia, 21 damage to intestinal epithelium, hair loss, and fetal death or injury. The drugs of fungal and 22 bacterial derivatives are toxic to kidney and other organs. Besides, it is expensive to ingest for a 23 long period of treatment.

Histamine is a kind of harmful secretions in allergic reaction. That is a potent mediator in 26 numerous biological reactions. It is formed by the enzymatic decarboxylation of histidine that is 27 therefore considered a biogenic amine. In human organism it is virtually ubiquitous in tissues 1 and body fluid, being mainly stored in its inactive form in the metachromatic granula of mast 2 cells and basophils leukocytes. Following the stimulation of mast cells and basophils by antigens, 3 histamines and other compounds are released explosively into the surrounding tissues and body 4 fluids. On releasing, histamine functions a potent mediator of numerous physiological, and causes pathophysiological processes in all organs and tissues. That immediately effects a dilation 6 of the blood vessels, so that fluid escapes into the surrounding tissues.
This reaction may result 7 in a general depletion of vascular fluid, causing a condition known as histamine poisoning or 8 histamine shock.

Antihistamines are used primarily to control symptoms of allergic diseases such as hay fever, 11 arthritis and Parkinsonism. They alleviate runny nose and sneezing and, to a lesser extent, 12 minimize conjunctivitis and breathing difficulties. Antihistamines can also alleviate itching and 13 rash caused by food allergy. Chemically, antihistamines comprise several types. Each 14 antihistamine neither cures all kinds of syndromes nor is good for any person. Side effects of these drugs include drowsiness, loss of concentration, and dizziness. People ingesting 16 antihistamine should not drink alcoholic beverages or perform tasks requiring mental alertness, 17 such as driving. Their uses in treatment are questionable. Besides, the traditional antihistamine 18 could not inhibit mast cells and basophils from releasing histamines, from combining the 19 histamines released in the body fluid, from decreasing permeability of the blood vessels, from depressing the inflammatory, and from enhancing the immunity of cells. Those are the defects of 21 traditional antihistamine.

23 The antihistamine which inhibits histamine THI receptors could decrease the hives caused by the 24 release of histamine by master cells and eosinophile granular cells. The traditional antihistamines are compounds of amine. As you know, amines are high alkaline, toxic to body, damage to the 26 stomach, and low solubility in water. That the amine does not suitable for being a drug. For 27 improving, the chemist applied acids, including organic acid and inorganic acid to react the 1 amine compound to form a salt. There are many acids including inorganic acid: such as hydrogen 2 chloride; and organic acids, such as maleic acid, citric acid, malic acid, tannic acid and succinic 3 acid; are used.
5 In a diphenhydramine system, for example, the diphenhydramine is reacted with hydrogen 6 chloride to form diphenhydramine hydrochloride; and in a chlorpheniramine system, the 7 chlorpheniramine is reacted with hydrogen chloride to form chlorpheniramine hydrogen chloride.
8 The other compounds such as chlorpheniramine maleate, phenyltroxamine citrate, 9 diphenhydramine tannate, diphenhydramine salicylate, and chlorpheniramine malate are the products of reaction with organic acids of maleic acid, citric acid, tannic acid, salicylic acid and 11 malic acid, respectively. The role of acid, such as hydrogen chloride, maleic acid, citric acid, 12 malic acid, salicylic acid, and tannic acid, is just a modifier. That neutralizes the alkalinity of 13 amine, lowers the amine toxicity for patients, and increases the solubility thereof at all. This is 14 the origin of traditional antihistamine drugs which are used widely to treat allergic diseases now.
Actually, there is not any antihistamine drug that shows perfect effect to allergic diseases. This 16 made the applicant to investigate the other way of therapy and finally succeed.

18 Food poisoning and insect bit are two kinds of poisoning in daily life, normally. The former is 19 caused by eating foods containing disease bacteria or toxin; and the later is caused by venom of insect bite. This toxicity could cause serious immune reaction, and may be considered a kind of 21 immune diseases. The traditional treatment is to use anti-toxin and modified toxins for bacterial 22 toxins (such as Diphtheria, tetanus toxin), and to use antivenins for insect venoms (such as black 23 widow, snake). They are produced by vaccinating repeatedly in other animal species. Infusion a 24 large amount of antibodies into the body will induce hypersensitivity. The disadvantage of this method is that must test in advance to make sure that the patient has not allergy history.

27 All the disadvantages of drugs for treating immune disease are described hereinabove. That made 1 the applicant to study and finish the invention.

As a result of study, the applicant found that the humor must be kept at acidic condition is 6 necessary to performing immune biology processes. In that way, pathogens will be killed, 7 effectively, by macrophages, by T cells and by B cells.

9 To describe some reasons as following:

1. In immune biology, complement is a component of plasma that tags pathogens and presents 11 to macrophages to kill. Complement also activates T cells. The complement system is made up a 12 large number of distinct plasma proteins that react with one another, and induce a series of 13 inflammation responses to fight infection. Complement proteins are proteases that can be 14 activated by proteolytic cleavage. The digestive enzyme pepsin, for example, is stored inside cells and secreted as an inactive precursor of enzyme, pepsinogen, which is only cleaved to 16 pepsin in the acid environment (Frank, S. T., and Nealis, A. S., Immunol.
Today, 12, 322-326, 17 1991; Todd, J.A., and Steinman, L., Cuff. Opin. Immunol. 5, 83-89, 1993).
The acidity is the 18 necessary condition for the complement to play its role.

2. Intravesicular pathogens will be bound with MHC class II and presented to CD4 T cells.

21 Peptides presented by MHC class II molecules are generated in acidified endocytic vesicles. The 22 effect on presenting cells is the activation to kill intravesicular bacteria and parasites in the 23 endocytic vesicles, where the pH level is low (Chapman, H.A., Curr. Opin.
Immunol. 0 93-102, 24 1998; Pietes, J., Adv. Immunol Cuff. Opin. Immunol. 75, 159-208, 2000).

26 3. For extracellular pathogens and toxins, they are bound with MHC class II
and are presented 27 to CD4 T cells. The effect on presenting cell is the activation of B cells to secrete Ig, and to 1 eliminate extracellular bacteria/toxins in the endocytic vesicles when the pH level is also at low 2 (Morrison, L. A., et al., J. Exp. Med..163, 903, 1968: Paulnock, D. M., Curr. Opin. Immunol. 4, 3 344349, 1992).

4. Some microorganisms such as mycobacteria are intracellular pathogens that grow primarily 6 in phagolysosomes of macrophages. They are shielded from the effects of both antibodies and 7 cytotoxic T cells. These microbes maintain themselves in a hostile environment of the phagocyte 8 by inhibiting from the fusion of lysosomes and phagosomes in which they grow. They also 9 prevent from the acidification of vesicles that is required to activate lysosoml proteases. Such microorganisms can be eliminated when the macrophage is activated by THE cell.
In that case, 11 the pH value must be at a lower level.

13 For intracellular pathogens, the process that MHC class I molecules combine virus envelopes, 14 and present to CD8 T cells are caused by reaction of proteinase. The asparagines are converted to aspartic acids first. Then, all the peptides which are secreted or on the membrane, are connected 16 with carbohydrates of residues of aspartic acid, and eliminated from cells.
The hydrolysis 17 reaction of asparaginase is carried out under at acidic condition.

19 Oncogenic transformation of cells are associated highly with reducing MHC
class I. Cells infected by adenovirus 12, for example, is much to do with a consequence of change of mutation 21 and very low levels of transports associated with antigen processing 1, -2 (TAP-1 and -2 mRNA), 22 leading to diminished or absent of MHC class I. In breast cancer, for example, about 60% of 23 metastatic tumors lack of MHC class I. York, I. A., et al., Immunol. Rev., 172, 49-66, 1999).

5. Mutation frequently leads to diminished or absent MHC class I, and cases to increase the 26 ability of cancer transmigration. That results the fact that decreases the chance of vulnerability of 27 cancer by T -cells. Therefore, the basic policy of anticancer is increasing the production of 1 complements. It is a problem of low level pH. (Niedermann, G, et al., Immunol. Rev. 112, 29-48, 2 1999; Charles A.J., Immunobiology 5ed, 161-179, 2001).

4 6. About 2 % of oxygen can be converted into superoxide anion (=O 2) during the respiration of organisms. The free radicals(FRs) of superoxide are extremely active products which can react 6 with proteins, saccharide, fatty acid and nucleic acid. FRs destroy the normal structure and 7 disturb the normal activities of body; also cause many damages, such as cancer, cardiovascular 8 disease, Alzheimer's disease, dementia, cataracts, Parkinsonism, immunodeficiency of old man, 9 diabetes, inflammation, aging, and Arthritis. They all are autoimmune diseases, and are mostly induced by the damage of FRs (Harman, D., Age 7, 111-131, 1984.

12 In humans, the first line of antioxidant defense is the antioxidant enzymes, especially superoxide 13 dismutase (SOD), glutathione peroxidase (GPX). These enzymes will help destroy SOR, H202 14 and lipid peroxides.

From the chemical reaction point of view, we know that FRs, especially oxygen FRs, are mainly 16 produced in an alkaline environment, and will be reduced by proton in an acidic condition. In 17 this invention, the drug will provide good antioxidant to reduce the FRs.

19 7. There are many active peptides which are related closely to human physiological functions, such as SOD, opioid peptides(OP), immunopeptides(IP), antihypertensive peptides(AP), 21 angiotension 1-converting enzyme inhibitor(ACEI), antithrombotic peptides(ATP), and casein 22 phosphopeptides(CPP). These peptides are formed under acidic condition, and performed their 23 roles at the same.

The SOD, for example, catches FRs only under acidic condition. The reaction of FRs and 26 antioxidants occur under the acidic condition, as shown in the following reactions. If not under 27 acidic condition, the reaction can not occur to right side. And there is not any work to scavenge.

02 e > .02 :> H202 > -OH e + H H2O (1) O 2 + -02 + 2 H+ +g) H202 + 02 (2) 2 The FRs is the major factor in causing disease. If the FRs being removed, the disease so does. In 3 treating and alleviating disease, the drugs of present invention show very widely functions, 4 because of their excellent properties of FRs scavenging.

6 The necessary condition for the structure activity of ACEI is that there is a positive charge at 7 guanidino ore-amino group connecting to C-end of the peptide. That proton plays a substantial 8 role of function. As for the affinity of CCP for calcium, is caused by high level polarity of the 9 residual group of serine phosphatide and by the stabilization effect of calcium phosphate colloid in acidic condition. It proves that how the amino acid residues affect on the physichemical action, 11 especially, for binding ability of proton. They are determined by the acidity of solution.

12 Therefore, the drug of this invention provides functions of preventing and depressing 13 hypertension.

In tissue, arachidonic acid (AA) is reacted by lipoxygenase (LO) to form its derivatives, such as 16 12-hydroxy eicosatetraenoic acid (12-HETE) and leukotriene (LT). These products cause 17 inflammation and hypersensitivity reactions. AA is also reacted by cycloxygenase to form 18 prostacyclin (PGX, PGI2), thromboxanes (TXA2), PGA2, and PGE2. 12-BETE
activates human 19 granulocytes. While 5-BETE is a precursor of slow-reacting-substance (SRS) of hypersensitivity (Siegel, M.I., et al., Proc. Natl. Acad. Sci., 77, 308-312, 1980). This indicates that there is a way 21 to inhibit hypersensitivity and inflammation by inhibiting the reaction of LO. Almost all animal 22 and vegetable lipooxidase (soy bean) have the biochemical activity. That can be used as an 23 inhibitor for vegetable LO. They are also proved that they inhibit LO to produce derivatives from 24 platelets and leucocytes. (Baumann, J., et al., Prostaglandins, 20, 627-639, 1980).

1 In the productions of prostaglandins (PGX, PGI2) and thromboxane A2 (TXA2) from AA by 2 cyclooxygenase, we found a very close relationship between the metabolisms of lipoperoxidation 3 and prostaglandins. This relationship leads us to find an effective antioxidant for protection. The 4 lipoperoxidation needs a trace amount of hydrogen peroxide to initiate a reaction at the active 5 enzyme site of Fe+3 of hemoglobin, and to produce oxygen FRs. The FR then gains a hydrogen 6 atom from AA, and induces reaction. To eliminate FRs in advance, then there is no cascade to 7 form the TXA2 from AA. Aspirin is one of NSAIDs (non-stroid anti-inflammatory drugs). Its is 8 proved in clinic that the reaction of aspirin inhibits the activity of cyclooxygenase, and then 9 reduces the coagulation force of platelet.(Chau, K. Z., Oxygen free radical and clinic, 37-40, Hou 10 Ki publisher Taipei, Taiwan, 2003).
12 Thrombus and embolus are produced by activated platelets. This coagulation cascade begins a 13 series of complicated reaction one another when the damage to endothelium is happened.
14 Releasing TXA2, derived from AA, into plasma is the key point of clumping process, which promotes the formation of small embolus for clogging blood flow.

16 The drug of this invention inhibits the activity of cyclooxygenase that inhibits the cascade 17 formation of prostaglandin, and depresses the release of TXA2. When the formations of embolus 18 and thrombus are inhibited, there is no way to induce cardiovascular disease, such as 19 intracerebral and hemorrhage, and myocardia infarction. To release TXA2 from platelets is the first message for inducing platelets to enhance the reaction of coagulation.
That is the first step 21 of clotting formation of platelet. In that case, if we could inhibit the release of prostaglandins or 22 inhibit the activity of cyclooxygenase, we could inhibit the whole cascade of prostaglandins, and 23 could eliminate the possible formation of thrombus, finally.

Human body has the ability to recover its natural defense in a proper condition, but will lose it 1 when the body is weak. For recovering innate immunity, of course must strengthen the body at 2 first. The mostly basic method is according to immunobiologic mechanisms.
That is to make it 3 sure to raise a large number of complement and to supply a good environment for the immune 4 cells, such as marophage, CD4 T -cells, and B-cells to work. In other words, to make an acidic humor or to lower the pH of humor is necessary. That the immune mechanism could only 6 perform in an acidic situation. This reason makes the applicant to investigate the other way of 7 therapy. And finally, found that making an acidic situation in humor by ingesting acid compound 8 which can enhance the ability and the functions of marcrophage, CD4 T -cells and B-cells 9 effectively. To use the acidic and edible chemicals for that purpose is the key point of this invention, and dissolve the problems of immune diseases.

12 The poison problems, such as food poison and insect bite, cause immune reaction in body. Drugs 13 of this invention provide treatment in this area. The mechanism of present invention is increasing 14 the level of acidity of humor to enhance the ability of immunity and to neutralize the toxin.

Because all the toxins are proteins they could be neutralized or denatured.

17 Saliva is a kind of humors and, normally, has the pH of around 6.8. For the purpose of reference, 18 to test the pH of the saliva of a man was carried out, who had brushed before testing and 19 ingesting 700 mg of citric acid. Data are taken in an interval of 30 minutes for 2 hours. The results are listed as shown in table 1.

22 Table I The pH value affected by acidic food Testing time 0 20 60 90 120 (minute) pH 6.8 6.45 6.26 6.6 6.8 24 Though, the pH of saliva and urine will change in case of any acidic substance entering the body by biological mechanism. The buffer action will make the blood back to around the neutral 1 quickly, but is at acidic side. In the other words, the neutralization of acid is performed partially 2 by the calcium ions released from bone. It is apparently that the pH
returning to around neutral, 3 but there are much of ions of calcium and of proton in humor. The protons take part in acidic 4 reactions; and the calcium ions are concerned to transformation of immune signals and to activating calcineurin. Because of calcineurin itself is activated when the lymph cells are 6 activated and increasing the calcium ion in intracellular.

8 The hypersensitivity reactions cause inflammation seriously in organs. Drugs of this invention 9 have the function to lower the humor pH and treating or alleviating immune diseases that would be a good inflammation inhibitor.

14 Accordingly, it is an abject of the present invention to provide drugs to treat and alleviate immune diseases by lowering the humor pH with edible acid and/or acid salt.
The drug contains 16 effective amount of edible acid and/or acid salt as active agent and pharmaceutical acceptable 17 carrier.

19 It is provided the use of a drug for treatment or alleviating immune disease by lowering the humor pH, which is prepared which is prepared with edible acid and/or acid salt.

21 The invention is to provide the uses of food, drink and health care product for improving 22 individual immunity disease, which is prepared with edible acid and/or acid salt, or the acidic 23 fruits containing thereof, and their products as active agent.

24 It is the principal object of this invention is to provide a method to produce lower allergy risk food, including foods treated with solution containing edible acid and/or acidic salt.

26 It is therefore a general object of this invention is to provide a drug, containing edible acid and/or 27 acidic salt as active agent and pharmaceutical acceptable carrier, for treatment or alleviating food 1 poison and insect toxicity disease by lowering the humor pH.

2 A further object of this invention is to provide an inflammation drug containing edible acid 3 and/or acidic salt as active agent by lowering humor pH.

4 An additional object of this invention is to provide drugs, containing edible acid and/or acidic salt as active agent, for cold, for bath agent, for hair lotion, for the release of drugs to the skin, 6 for treatment of cloth and it products, for thrombus and embolus, for free radicals scavenger, or 7 for analgesic.

9 Other and further objects of this invention will become obvious upon an understanding of the illustration embodiments about to be described or will be indicated in the appended claims, and 11 various advantages not referred to herein will occur to one skilled in the art upon employment of 12 the invention in practice.

16 This invention uses edible acid and/or acidic salt as active agent that does no harm to the body 17 absolutely. More over, the function of this invention is to obey the most basic mechanisms of 18 biophysics and to scavenge free radical, but do not inhibit just one function. As for an 19 antihistamine drug, for example, only one kind of receptors can be inhibited. This invention uses edible acid and/or acidic salt as active agent that is more remarkable different from the 21 traditional drugs, and that is the specific property of this invention. The drug's component of this 22 invention lowers the humor pH and combines histamines released from mast-cells, T -cells, 23 eosinophils, neutrophils and basophils, and fits the receptors.

The drug also increase production of complement and enhance the immune abilities of 26 macrophage cells, T -cells and B-cells. And recover immune mechanism, anti-inflammation, 27 anti-analgesic and lowering vascular permeability.

2 Antihistamines are the traditional drugs used in treating allergic diseases.
Their mechanisms are 3 a kind of competitive reaction with receptors between antihistamine and histamine. The release 4 of histamines from mast-cells, from basophils, and from eosinphils is can not avoid, when the antihistamines fail to react with histamine receptors earlier than histamine.
That is why in 6 treating a serious allergic patient must give epinephrine first, but is not antihistamine drug. Thus, 7 the patient must ingest antihistamine drug always to avoid the reaction of histamine, and has to 8 suffer the side reactions of antihistamine all times.

The present drugs do not contain amine group, and show no side effects like traditional 11 antihistamine. Another advantage is that many drugs of present invention are metabolic ones.
12 They can be converted into energy to supply cells to perform the immune work directly. These 13 are also to be good antioxidant, scavenging free radical effectively, to improve immunity, and 14 finally keeping diseases away. All these properties are not found in the traditional drugs.

16 One of drug allergic reactions is penicillin anaphylaxis. That is caused by the formation of 17 covalent bonding between B-lactam ring of penicillin molecule (hapten) and aminoacid groups of 18 host protein. These penicillin-modified self peptides can provoke a TH2 response in some 19 individuals. These TH2 cells then activate penicillin-binding B-cells to produce IgE antibody against penicillin hapten. Thus, penicillin acts both as B cells antigen, and as T cells antigen by 21 modifying their peptides. When penicillin is injected intravenously into an allergic individual, 22 the penicillin-modified proteins can cross-link IgE molecules on the mast cells, and cause 23 anaphylaxis. Penicillin anaphylaxis can be avoided in using the drug of this invention. For the 24 same reason, the death caused by vaccination also can be improved by applying the drug of this invention. Both systemic anaphylaxis and vaccination accident could be improved, by combining 26 the ingestion drug of present invention in advance, at the same time or after their proceeding.

1 One benefit of this drug composition is that most of them are nature food acids and acidic salts.
2 They can be eaten in large amount. And besides, compounding with other drug, foods and 3 treating on foods are also possible.

5 The applicant found that edible acid and/or acidic salt as active agent for the treatment and 6 alleviation of immune diseases by lowering pH are acids, such as fumaric acid, succinic acid, 7 maleic acid, a-hydroxy acids such as malic acid, tartaric acid, citric acid, lactic acid, a-hydroxy 8 octanoic acid, gluconolactone, glycolic acid, acetic acid, phosphoric acid;
acidic citrate 9 comprising sodium dihydrogen citrate, sodium hydrogen citrate, potassium dihydrogen citrate 10 and potassium hydrogen citrate; acidic succinate comprising sodium hydrogen succinate and 11 potassium hydrogen succinate; acidic tartrate comprising sodium hydrogen tartrate and 12 potassium hydrogen tartrate; sodium hydrogen malate and potassium malate;
acidic phosphoric 13 comprising sodium, dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen 14 phosphate, and dipotassium hydrogen phosphate; and their compounds; show wonderful 15 effective in treating immune disease.
17 In the list of FDA (The Food and Drug Administration), the drugs of present invention are listed 18 as GRAS (Generally recognized as safe). Because of that, there is not any problem concerned 19 about the toxicity. In the drug given by injection, we must apply small dose for the direct injecting into the tumor. The drugs of present invention have usages of oral and none oral. The 21 proper therapeutic dose is about 0.1 - 300 mg/kg /day, in generally. In special case, the ingestion 22 dose could be much more than that according to necessary. They can be prepared in any forms of 23 drug by the known pharmaceutics, and even combining with other active components.

Routes of drug administration of present invention may be by parenteral method, including 26 subcutaneous, intramuscular, intravenous, intradermal, intra-arterial, intravascular, intratumor, 27 transdermal, inhalation, suppositories, ointments, aerosols, inhalants, tinctures, plasters, lotions, 1 and mixtures. The liquid solvent includes water, alcohol, glycerin, and other glycols.

3 The dispensing of medication for injections is following the traditional method. To use 4 sterilized# pure water under a clean room, adjusting buffer and tonicity by sugar and salt are usually taking care of. Beside the solvent of water, ethylene glycol and polyol, such as glycerin, 6 propylene glycol, liquid poly glycol, and mixtures are also used. Powder made by vacuum 7 freeze-dried method is an ideal way.

9 The effective drugs of present invention could compound with inert dilution agent, eatable carrier, sweeteners, perfumer, herbs, foods, other nutrients, and their compounds.

12 The oral usage of present invention could be in the forms of capsule, tablet, flake, pile, lozenges, 13 solution, suspension liquid, syrup and blending with food.

The active agent of said edible acid and/or acidic salt is also used in foods including biscuit, cake, 16 candy, chew gum, puddings, dairies, peanut products, drinks, canned foods, cooking foods, and 17 other processed foods. These products are coating with or containing the drug thereof The 18 effective agent of this invention in the product is 0.0610%, prefer is 0.1-7%, better is 0.2-4%, 19 and the best is 0.3--2%. (to be proved in example of table 5) 21 The active agent of said edible acid and/or acidic salt is also used in drinks comprising juice;
22 wins including fruit wins, whisky, rice wins, brandy, sake, beers, herb wins; soft drinks, 23 carbonated drinks, teas, mineral waters, alcoholic drinks, sports drinks, functional drinks, coffees, 24 colas, sarsaparillas, dairies such as fermented milks, and herb solutions.
They contain the effective agent is ranged in 0.0610%, prefer is 0.1-7%, better is 0.2-4%, and the best is 0.3-2 26 %.(to be proved in examples of table 5) 1 Edible acid and/or acidic salt of the present invention is used to treat proteins contained in foods 2 to form denature. The amount of drug is up to the necessary of protein contained. It is better 3 above the stoichiometrical quantity.

Clothing, such cloth and groove, contacting skin causing allergic reaction, can be improved by 6 using drugs of this invention to treat the allergens and proteins contained thereof to a denature 7 state. The skin contact allergic reactions could be inhibited.

9 For the same reasons, pasted drugs used in treating skin or drug for skin releasing are usually compounding with anti-allergy component, such as aspirin or other antihistamines, to inhibit 11 allergy reactions, such as achy. In that manner, both aspirin and traditional antihistamine cause 12 damage to body as described hereinabove. If using drugs of this invention, not only can show the 13 properties of anti-inflammation and anti-allergy reactions, but also activate skin and increase the 14 absorbing effective of skin.

17 The present invention relates to a drug containing edible acid and/or acidic salt as active agent 18 for the treatments of anti-inflammation and anti-hypersensitivity by lowering the humor pH. That 19 could be used for hair tonic and hair lotion to treat head skin diseases, such as itchy and scale, and to protect hair and skin. In washing hair, the alkaline soap compounds are always remained 21 on hair and skin, when bacteria are growing in the hair folliculitis and causing itchy and scales.
22 Drugs of this invention are acidic compounds and just show good effect for improving and 23 inhibiting inflammation and itchy.

By the same action of present invention, the anti-inflammation and anti-allergic reaction could be 26 applied to inhibit and to treat diseases of cardiovascular thrombus and embolus.

1 In oral agents, including food and drinks, of this invention, can contain the normal components, 2 including: binding agent such as starch, glycerin, polyethylene, pyrrolidone, acrylic acid-iso 3 borneol copolymer, acrylic acid-2-ethyl hexanoate, Ca-CMC, CMC, gelatin, glucan, ethylene 4 acetate, acacia gum, polyethylene, arabic gum, and tragacanth gum; densifier such as propylene glycol alginate; softener such as D.B.P.; disperser such as calcium carbonate, polyethylene glycol, 6 stearic alcohol, fluid paraffin; emulsifier such as Span-60; preservative such as ethyl p-hydroxy 7 benzoate; lubricating agent such as magnesium stearate, talc powder; enzyme such as papain and 8 bromelin; sweetener such as sugar, glucose, brown sugar, syrup, honey, fructose, maltose, lactose, 9 oligomer; perfumer such as peppermint, peppermint oil, essential oil, green oil, strawberry essential oil, ethyl isovalerate, iso amyl butyrate, cocoextracte; pigment such as caramel, 11 chlorophyll; herb such as gambir, garlic, leek, chive, shallot, ramson, scallion, zinger, tang-kuei, 12 licorice, astragali radix, armeniacae semen, fritillariae cirrhosae bulbous, atractylodis rhizoma, 13 pinelliae tuber, angelica sinensis radix, hoelen, asini gelatinum, citri sinensis exocarpium, 14 asparagi radix, rehmanniae radix et rhizoma, perillae fructus, perillae caulis, anemarrhenae rhizoma, albae sinapis semen, mori radicis cortex, zingiberis siccatulm rhizoama, lily bulbous, 16 sesame, ginseng, coffee or caffeine, tea, in powder or extracts; another nutrition such as mineral, 17 vitamin, powder milk, peanut product; vegetable seed oil, cooked foods, amino acids; and their 18 compounds.

The acidic fruits which contain the effective agent greater than 0.3%, such as plum, orange, 21 pineapple, star fruit, grape and grape fruit could be used as drug. The content of effective agent 22 in processed product is preference for 0.3% than 0.06%.

24 As an oral drug, when the effective agent compounding with food, the dose would be changed depending on the amount of food ingested. In a low concentration of effective agent, food must 26 ingest a greater amount rather than a higher concentration one. Taking 300mg/dose, for example, 27 a man ingests 500m1 or 500gr of food once a time when the food must contain 0.06% of effective 1 agent. The normal quantity of drink is about 250m1 or 250gr, when the same agent of 2 300mg/dose in it is 0.12%. But the patient ingests drug with water is about 100ml or 100gr a 3 time, when the concentration of drug in food is 0.3%. By this relationship described hereinabove, 4 the content of drug of acids and/or acidic salt is 0.06100%, prefer is 0.1100%, the better is 0.2-100%, and the best is 0.3-100% (to be proved in example of table 4).

6 Therefore, the amount of edible acid and/or acidic salt contained in foods, dishes, drinks or 7 health care products is 0.06100%, prefer is 0.1-100%, the better is 0.2-100%, and the best is 8 0.3100% (based on the total weight of food, drink or health care product in wt/wt).

Present invention, accordingly, edible acid and/or acidic salt could be used to treat food. An 11 allergic food is a food, such as milk, contains active proteins which could cause people allergy 12 disease. The allergy disease could be inhibited by denaturing the active protein. The agent of 13 present invention is the best one to denature the allergic protein. The concentration of edible acid 14 and/or acidic salt is 0.0610%, prefer is 0.1-7%, the better is 0.2-4%, and the best is 0.3-2%.

16 For food allergy-sensitive person, sea foods, especially crab and shrimp, are very potent 17 allergens. There is one way to prevent the immune disease from eating those foods. To add a 18 proper amount of effective component of present invention in processing sea food is very 19 suitable. The product of such treated sea food not only can avoid the allergy reaction, but also prevent the unsaturated fish oil from oxidation because of the antioxidant reaction of effective 21 component.

23 The efficient of present invention drugs for immune disease is proportion to the number of acidic 24 group contained in the same compound. The citrate compounds, for instance, the power series is as following:

26 Citric acid > dihydrogen citrate > monohydrogen citrate 27 In this invention the individual means any spondyle animal, the better is mammal, and the best is I human.

5 This invention will be understood more readily with reference to the following examples. These 6 examples, however, are intended to illustrate the invention and are not meant to limit the scope 7 of the invention.

9 Example 1-29 Anti-allergy reaction 10 This is a comparative testing of drug depressing effect on the amount of leaching histamines 11 when is treated with 48/80(Sigma, St. MO, USA) compound.

13 (1). Preparation of leaching cell solution from mouse body.

14 A mouse is killed and bloodletting. Then 10 ml of Locke's solution containing 0.1% bovine 15 serum protein is injected into its abdominal cavity. After abdominal cavity being light massaged, 16 the cavity is cut and the Locke's solution is removed. Cavity is washed with another 5 ml of 17 Locke's solution, and this washed solution is added to the late one. This combined solution is 18 centrifuged at 600 rpm for 5 minutes. The sediments are washed with 5 ml of cool Locke's 19 solution. Adding 3 ml of cold Locke's solution to the washed sediments, then a leached cell 20 solution of abdominal cavity is obtained. The composition of Locke's solution is: NaCL 9.1%, 21 KCL 0.2%, CaCL2 0.15%, glucose 1.0%, in w/v, and the rest distillated water.
23 (2). Drug depressing effect on the amount of leaching histamines when treated with 48/80 24 compound.

Each testing compound listed in the table 1 is dissolved in a Ringer's solution containing 1%

26 NaHCO3, and then diluted with Locke's solution to the indicated concentration. 1.0 ml of each of 27 those solutions in last term is mixed with 0.3 ml of mouse's leaching cell solution and 0.5 ml of 1 Locke's solution. This mixture is cultivated at 37 C for 5 minutes. Then adding 0.2 ml of 2 Locke's solution of 48/80 compound (1 mg/100 ml) and cultivated at 37 C for 10 minutes.

3 Then the reaction is stopped by cooling, and centrifuged at 2,500 rpm for 10 minutes. 1.7 ml of 4 decanted solution and 0.3 ml of sediments are obtained. 0.1 ml of water and 0.2 ml of 100%

trichloroacetic acid are added to the decanted solution. 1.5 ml of Locke's solution and 0.2 ml of 6 100% trichloroacetic acid are added to the sediments washed solution. They are cultivated at 7 room temperature for 30 minutes. After cultivation, the mixtures are centrifuged at 3,000 rpm for 8 15 minutes, respectively. 0.35 ml of each of the former two solutions is sampled. In each sample, 9 1.65 ml of water, 0.4 ml of IN NaOH and 0.1 ml of 0.5% OPT (o-phthalic aldehyde) in methanol are added and cultivated at room temperature for 4 minutes. The reaction is stopped by adding 11 0.2 ml of 2M citric acid. And finally, determine the amount of released histamines in the tested 12 solution by fluorescence method. By the analysis, results of the depression rate of histamines 13 could be calculated.

Locke's solution is instead of each drug in control group, and instead of both drug and 48/80 16 compound solution in blank group. The histamine releasing rate (A) can be calculated by 17 following equation. Where (Hs) is the total amount of histamine in the decanted solution, and 18 (Hr) is the total amount of histamine in the sediment. (A) _ (Hs)/{ (Hs)+
(Hr) } x 100%. Then 19 the depression rate is:

= 100 - [(A - A in blank group) / (A -Ain control group)] x 100%.

22 The calculated results are shown as following table 2.
23 Table 2 - Drug depressing effect.
Testing Testing drug Histamine Depression No. 100(m ml) releasing rate rate (%) (%) Control group Control 90.5 -Blank group Blank 9.0 -(1) Trisodium glycyrrhizinate 65.5 30.9 (2) Diphenhydramine hydrochloride 64.7 32.1 (3) Diphenhydramine citrate 60.2 37.5 (4) Succinic acid 8.9 100 (5) Citric acid 8.7 100 (6) Lactic acid 8.9 100 (7) Malic acid 9.0 100 (8) Tartaric acid 8.9 100 (9) Fumaric acid 8.9 100 (10) a-hydroxy ethanoic acid 9.0 100 (11) a-hydroxy octanoic acid 9.0 100 (12) gluconolactone 8.9 100 (13) acetic acid 9.0 100 (14) propionic acid 9.0 100 (15) ascorbic acid 9.0 100 (16) sodium dihydrogen citrate 9.0 100 (17) disodium hydrogen citrate 58.6 39.1 (18) potassium dihydrogen citrate 9.0 100 (19) dipotassium hydrogen citrate 57.9 40 (20) sodium hydrogen succinate 9.0 100 (21) potassium hydrogen succinate 9.0 100 (22) sodium hydrogen tartrate 9.0 100 (23) potassium hydrogen tartrate 9.0 100 (24) sodium hydrogen malate 9.0 100 (25) potassium hydrogen malate 9.0 100 (26) sodium hydrogen maleate 9.0 100 (27) potassium hydrogen maleate 9.0 100 (28) sodium hydrogen fumate 9.0 100 (29) potassium hydrogen fumate 9.0 100 (30) phosphoric acid 9.0 100 (31) sodium dihydrogen phosphate 40.5 38.6 (32) potassium dihydrogen phosphate 40.0 38.0 (33) disodium hydrogen phosphate 21.0 14.7 (34) dipotassium hydrogen phosphate 20.0 14.4 1 Trisodium glycyrrhizinate, diphenhydramine hydrochloride, and diphenhydramine citrate are 2 traditional antihistamines. To compare the results of diphenhydramine citrate and citric acid, we 3 could realize how poor the traditional antihistamine is. It is quite obvious that the results of drugs 1 of present invention show completely affective while the traditional drugs are incompletely.

3 The inhibiting effect of histamine can also inhibit the production of compounds, such as 4 12-BETE, LT, PGX, PGI2, TXA2, PGA2 and PGE2, of course, there is no thrombus disease happened.

7 Example 35-45 Anti-delayed type allergy reaction 8 The weights of testing mice are ranging from 20 g to 30 g. They are coated with 0.1 ml of 9 oxazolone alcohol solution (0.5w/v %) on the hair cleaned part of abdomen.
After five days, each of the listed drugs is dissolved in oxazolone acetone solution (0.5 w/v %), and 10 l each of the 11 solutions is token by micro pipette to coat on both sides of the right ear.
After 24 hr, the mouse 12 is killed by ether and punched a circle area of a diameter of 5.5 mm on both right and left ears in 13 corresponding part by a puncher machine (portions of drug coated and the blank). The punched 14 portions are weighed and the inflammation rates calculated. The control group are coated only with the oxazolone acetone solution (0.5 w/v %). The inflammation depressing rates of each drug 16 are calculated by following equation:

17 Inflammation depressing rate (%) = [(wt. of drug-coated right ear) - (wt.
of non-drug-coated left 18 ear)] x 100% /(wt. of non-drug-coated left ear) The inflammation depressing rate of each drug is shown in table 3.
21 Table 3 Testing Drug-coated Mouse Depression No. Testing drug Amount rate (mg/ear) (number) (%) (35) Diphenhydramine 1 6 20 hydrochloride (36) Diphenhydramine citrate 1 6 25 (37) Succinic acid 1 7 96 (38) Citric acid 1 7 100 (39) Lactic acid 1 6 97 (40) Malic acid 1 7 96 (41) Tartaric acid 1 7 97 (42) Fumaric acid 1 6 98 (43) a-hydroxy ethanoic acid 1 6 98 (44) a-hydroxy octanoic acid 1 6 94 (45) gluconolactone 1 7 97 2 Table 3 shows that the anti-inflammation rates of traditional anti-histamine drugs are very poor 3 in comparison with this invention. Drug could be anti-inflammation, is also could be analgesic.

Example 46 Testing in sea food eating 6 An adult man who is very serious allergic to sea foods, especially shrimps, he ingestes two 7 capsules of this invention drug (1,000 mg, 30 wt % of garlic and 70 wtl% of citric acid) before 8 eating shrimps. After ate many shrimps there is not any symptom of allergy at all. The same 9 people before eats crabs dishes have ingested tow capsules of traditional strong anti-histamine (containing trisodium glycyrrhizinate 108mg, oratic acid 60mg, chlorpheniramine 5mg, Ta Fong 11 Co,). No sooner he has eaten, he feels bad in tasting and fells sick very bad when he has been 12 sent to hospital for treatment.

14 Example 47-52 Treating cold The oral dose of this invention such as tablet and capsule can increase the number of tablet or 16 capsule, but the active agent which is blending with foods the dose is limited by the amount of 17 foods eaten one time. The following examples will explain how the effective agent of drug is 18 required in a food of 100ml volume.

There are six different doses (10mg, 60mg, 100mg, 300mg, and 600mg of malic acid) of testing 21 solution, which content the basic compounds of water 100 ml, propylene glycol alginate 0.1 g, 22 fructose 10 g, garlic 300 g, zinger 100 g, angelica ainensis radix 10 mg, honey 3 g, armeniacae 23 semen 10 mg. These six drugs are given six groups, 5 patients per group, of catching cold 1 patients individually per tow hours a time. The ingesting of drug is stopped when the cold 2 syndromes are improved. The effect of drugs by treating time is listed in Table 4.

4 Table 4 - Time and dose for treating cold Example 47 48 49 50 51 52 Dose, mg 10 60 100 200 300 600 Rate of malic acid in 0.01 0.06 0.10 0.2 0.3 0.6 foods, %
Time for treatment *, 8 4.5 3.2 2.2 1.6 1.1 day ranking Poor good better best excellent excellent 5 the time for treatment needed is the average of the same group.

7 Therefore, the content of this invention in dose must be expressed in 0.06-100%, good is in 8 0.1100%, better is in 0.2-100% and the best is in 0.3-100%. Normally, the higher the 9 concentration, the little amount of foods could be taken is. In the medicament there is a 10 regulation of mg/day/kg for the toxic drug, while the invention is belonging to foods and it to be 11 better expressed by concentration in food ingestion one time.

13 Examples 5363 Testing the upper limit concentration of drug for taste of drug containing foods 14 When applies the this invention to foods and lowering the risk of allergy or health care foods, a 15 higher drug content is better for the disease, but a taste problem will be faced. There is needed to 16 limit the drug content. Taste testing is carried out as follows. To make WU
LOONG tea by 250 g 17 of tea with 8.3 liters of 80 C water and 420g of sugar is added. Different doses of 1g, 2g, 3g, 4g, 18 5g, 6g, 7g, 8g, 9g, l Og, and 12g of malic acid are added into each set of 11 cups of l OOm1 Wu 19 LOONG tea individually. Let 6 volunteers to test the 11 cups of tea individually. Each person 20 ranks the taste of tea by five levels of best, better, good and acceptable and can not acceptable.
21 The results are shown in Table 5.

1 Table 5 - The results of taste testing Example Amount of Best Better Good acceptable malic acid, 53 1.0 6 ` 54 2.0 6 55 3.0 2 4 56 4.0 6 57 5.0 3 3 58 6.0 1 5 59 7.0 6 60 8.0 4 2 61 9.0 2 4 62 1.0 6 63 12 not acceptable 2 The results shows that the levels of acceptance are: the upper limit of acceptable concentration is 3 <10%, good is <7%, better is <4%, best is <2%, and not acceptable is 12%. To combine the test 4 data of lower effective limit concentration in example 52, the concentration of drug in foods must be: normally is 0.0610%, good is in 0. 1-7%, better is in 0.2-4% and the best is in 6 0.3-2%.

8 Example 64 Oral syrup of orange skin 9 The formulation comprises 50m1(62% alcohol) of orange skin tincture, 50g of citric acid, 15g of talc powder, 850g of sugar and the balance is distillated water to make 1000ml. This mixture is 11 filtrated, sterilized and bottled as product.

13 Example 65 Injection 14 To dissolve 36g of citric acid and 34g of potassium dihydrogen citrate in a total volume of 1000ml of sterilized water, then the solution is sucking filtrated through a ceramic filter, and 16 filled in 10ml ample by normal GMP procedure in a clean room.

1 Example 66 Ointment 2 To mix Ig of tartaric acid, 0.5g of potassium hydrogen tartrate, lOg of fluid paraffin and the rest 3 of Vaseline to make up to 100g, the mixture is ground and bottled to produce a 1.5% of 4 potassium hydrogen tartrate ointment.

6 Example 67 Capsule 7 Grinding and compounding 350g of citric acid, 200g of garlic powder, 50g of zinger powder, l Og 8 of angelica sinens radix powder, lOg of armeniacae semen powder and 300g of fructose, and the 9 compound is encapsulated to 1000 pieces of product.

11 Example 68 Granular and tablet 12 The formulation comprises 30g of maleic acid, 20g of com starch, 20g of lactose, 5g of Ca-CMC, 13 5g of polyethylene pyrrolidone, and l Og of talc. To grind maleic acid, corn starch and lactose to 14 fine powder, then the compound is produced in a product of 1-2 m/m granular by normal granular machine, using 5% water solution of poly ethylene pyrrolidone as a binder.

16 To mix talc and the produced granular, and then product of 100 tablets of containing 300mg 17 maleic acid are produced by tablet machine.

19 Example 69 Powder The formulation comprises 50g of fumaric acid, 400g of microcrystalline cellulose and 550g of 21 corn starch. To dissolve the fumaric acid with 200m1 of pure water and being adsorbed by 22 microcrystalline cellulose, the product is dried and then mixed with corn starch to form a twenty 23 folds powder.

Example 70 Pills 26 The formulation comprises 50g of succinic acid, I g of potassium dihydrogen phosphate, 50g of 27 glycyrrhizin, 5 mg of ginseng, I g of zingier, 5 g of starch and 50g of honey. To pulverize 1 succinic acid first and then compounding with other components by a kneader, and finally a 2 product of 150 pills containing 320 mg of succinic acid per pill are produced by a pilling 3 machine.

Example 71 Troches 6 The formulation comprises 100 g of a-hydroxy octanoic acid, 80g of gelatin, 200g of glycerin, 7 20g of acacia gum, and 160g of perfume water. To pulverize the a-hydroxy octanoic acid into 8 powder first and is added to the transparent solution that is prepared by following steps. Gelatin 9 and acacia gum are softened with proper amount of water, then glycol is added and heated to form a transparent solution. Into this solution the powdered a-hydroxy octanoic acid is added 11 and mixed gently, poured into a mold and cooled to as products.

13 Example 72 Emulsions 14 The formulation comprises I OOg of succinic acid, 20g of span-60, 100mg of ethyl 0-hydroxy benzoate, and the balance amount of peanut oil. Pulverizing the mixture of succinic acid and 16 span-60 by grinding machine, then ethyl p-hydroxy benzoate and peanut oil to make a total 17 volume of 1000ml are added and mixed strongly for three minutes, and bottled as products.

19 Example 73 Tincture (non-alcoholic solution) The formulation comprises 6g of a-hydroxy ethanoic acid, 47g stearic alcohol, and 47g of 21 ethylene glycol. To melt the mixture of a-hydroxy ethanoic acid an stearic alcohol on steam, 22 then ethylene glycol is added and mixed well to form a non-alcoholic solution containing 6%
23 a-hydroxy ethanoic acid.

Example 74 Creams 26 The formulation comprises :Apart are 15g of stearic acid, 5g of hexadecanol, 5g of polyethylene 27 glycol, 4g of fluid paraffin, and 5g of citric acid; and B part are l Og of glycerin and pure water to 1 make up a total weight of 100g. Parts of A and B are prepared individually and compounded by 2 normal process, and finally 100g of cream are produced.

4 Example 75 Inhalations (spray) The formulation comprises 0.25wt% citric acid, 33 wt% of ethyl alcohol, and the rest is 6 propellant 12/114(20:80). Both atomizers and materials are cooled under - 30 C before to use.
7 To dissolve citric acid in ethanol and add the proper amount into atomizer, after the proper 8 amount of propellant is added closing the valve of atomizer, and the products are obtained.

Example 76 Blending foods (canned fish foods) 11 10 kg of sardines are washed. After their heads and tails being cut and the inner organics being 12 cleaned up, they are cut into a proper size. These raw materials are cooked in a 201 solution that 13 contains 1.2 kg of salt and 800kg of citric acid. The cooked fish then is canned into No.4 size 14 steel can with 75g of tomato ketchup, and the product then is sterilized by normal process.

16 Example 77 Blending in foods (cookies) 17 The formulation comprises 10kg of wheat powder, 3.5kg of sugar, 0.8kg of shortening oil, lkg of 18 millet jelly, 0.03kg of salt, 0.2kg of ferment, and 0.62kg of a-hydroxy ethanoic acid. To follow 19 the traditional method of cake making, the solids of wheat powder, sugar, salt, and a-hydroxy ethanoic acid are ground and sieved individually first. They are mixed them with ferment and 21 part of wheat powder, and compounded well with millet jelly and shortening oil. After shaping, 22 and baking in two stages; first stage is at 180-200 C, and the second stages is at 150205 C;
23 products are produced.

Example 78 Blending in foods (cakes) 26 The formulation comprises l kg of wheat powder, l kg of sugar, l kg of egg, 150g of 27 gluconolactone, and 300g of water. The albumin and egg-yellow are separated first, and the 1 former is bubbled by bating. After the albumin is bubbled, sugar, gluconolactone, and water are 2 added and mixed homogeneously. The wheat powder is sieved and added to the mixture. To mix 3 quietly and being molded for baking, then cakes are produced.

5 Example 79 Blending in foods (candies) 6 The formulation comprises 430g of white sugar, 350g of starch syrup, 170g of inverted syrup, 7 50g of gelatin, 20g of potassium dihydrogen citrate, 20g of sodium dihydrogen citrate, and 2 ml 8 of vanilla extract. Gelatin is cut into pieces before dissolving in triple volumes of water, and 9 heated with steam in a doubled layer bottom kettle. Following the process of soft candy making 10 method; dissolving sugar, starch syrup and inverted syrup; cooking; adding potassium 11 dihydrogen citrate, sodium dihydrogen citrate, and vanilla extract; mixing even; adding dissolved 12 gelatin; mixing carefully; degassing; powdering molding; cutting; packing;
and finally the 13 products are obtained.

15 Example 80 Blending in foods (chewing gum) 16 The gum base formulation comprises 500g of 50% liquid solution of polyvinyl acetate, 150g of 17 D.B.P., 200g of calcium carbonate, and 50g of wheat powder. 210g of the gum base is 18 compounded with 50g of malic acid, 650g of sugar, I OOg of millet jelly, and 3ml of peppermint.
19 Then following the steps of kneading, extracting, rolling, cutting into 3g /piece product, and 20 finally products are packed.

22 Example 81 Blending in foods (mineral containing lactic acid drinks) 23 The formulation comprises 1kg of skim milk, 1.5kg of sugar, 15g of lactic acid, 5g of calcium 24 lactate, and 4g of propylene glycol alginate. Skim milk is heated to 50 C
when sugar is 25 dissolved. Then calcium lactate and propylene glycol alginate are added and to keep at 80 C for 26 20 minutes. After sterilizing, the solution is filtered and cooled down to 15 C. The lactic acid is 27 mixed with 75m1 of boiled water and added to the filtered skim milk solution in stirring, and 1 finally bottled to obtain product.

3 Example 82 Blending in foods (peanut products) 4 The formulation comprises 1 kg of peanut, 20g of salt, 25g of fumaric acid, 50g of lecithin, 20 mg of pineapple enzyme and 2 ml of ethanol. The peanut is roasted at 160 C for 1 hour and 6 ground into powder after drying, and sieved to remove the skins and germs.
To add salt, lecithin, 7 pineapple enzyme (which is dissolved in alcohol first), and fumaric acid consequently, and is 8 ground to form paste before packing in a 500 g bottle.

Example 83 Blending in foods (puddings) 11 The formulation comprises 750m1 of milk, 6 pieces of egg, 150 g of sugar, 21 g of succinic acid, 12 2 drops of ethyl iso-valerianate, and caramel raw material (100 g of sugar and 6 g of water) for 13 10 pieces puddings. The process is: making caramel by heating the mixture of sugar and water in 14 flat pan; the caramel is divided into 10 portions for vessels which the bottoms have rubbed with few amount of oil; heating the mixture of milk and perfume to near boiling by steam; mixture of 16 egg and sugar is bubbled and added to the milk mixture; mixing the resulted mixture; then is 17 filled into the vessels carefully; and steamed at 160 C for 30 minutes to form the product.

19 Example 84 Orange juice drinks The formulation comprises 5 kg of orange juice (sweetness 10 and acidity 1.0%), 0.95 kg of 21 anhydrous fructose, I ml of orange essence, and 150 g of citric acid. The production method is to 22 mix the dissolved materials, and pure water is added to make up 10 1 of orange juice and packed.

24 Example 85 Soft orange drinks The formulation comprises 5 kg of orange juice (sweetness 50 , acidity 6%), 1.2 kg sugar, 200g 26 of malic acid, 5 ml of orange essence, and boiled water to make up 10 1.
The production process 27 is mixing the materials homogenously, this mixture is bottled, and finally carbon dioxide gas is 1 induced.

3 Example 8695 Drugs made of fruits 4 Fruits which contains at least 0.3% of the effective component of this invention, such as acidic orange, lemon, plum, fruit orange, grape, apple, carambola, strawberry, and pineapple are 6 processed to produced cans by normal method including: selecting, clearing, removing stalks, 7 cutting heads and tails, skin and core removing, buds removing, slicing, canning, weighing, 8 syrup adding, sterilizing, cooling, inspection, and packing. The former examples use pure 9 chemicals as effective component. Now, to use acid contained fruits replace the pure chemicals in these examples. For the low acid contained fruits, the juice must be concentrated to increase 11 the acids level, and then to take the place of pure chemicals in these examples.

12 Taking example 84, for instance, the juice is compounded with 5kg of orange juice containing 13 acidity 1.0 % and 150 g of citric acid. There is 200g of citric acid in a 101 of orange juice drinks.
14 How much quantity of fruits is needed when producing the same 101 juice with different levels of citric acid containing, the results are shown as table 6.

17 Table 6 The equivalent dose of effective component in using fruits Example Fruit Acidity, The amount of fruit notation % equivalent to 200g citric acid, kg 86 Orange (1) 6.0 3.33 87 Orange (2) 4.0 5 88 Lemon 7.0 2.58 89 Plum 3.8 5.2 90 Grape fruit 2.0 10 91 Grape 1.0 20 Needed concentration 92 Apple 0.5 40 Needed concentration 93 Carambola 5.0 4 94 Straw berry 0.8 25 Needed concentration 95 Pineapple 4.5 4.4 2 Examples of 91, 92 and 94 have volume more than 101, they are needed to concentrate in order 3 to get their acidity greater than 1Ø The edible organic acids are the effective component of this 4 invention, so that to use the organic acid contained fruits are reasonable.
The other compounds of fruits are not important just as pharmaceutical acceptable carriers.

7 Example 96 Fruits (lemon) 8 The formulation comprises 1 kg of lemons (acidity 6%), 0.5 kg of sugar, 0.3 kg of honey, 1 g of 9 glycyrrhizin paste, 0.2 g of salt, and the final product is 1.6 kg. Lemons are processed by steps of selecting, peeling, cleaning, slicing, bottling in half volume, and mixing vigorously and adding 11 the other materials. The product is sterilized by heating and cooling after sealing, or without 12 heating treatment.

14 Example 97 Fruits (Carambola) The formulation comprises 1 kg of carambola (acidity 5%), 0.5 kg of sugar, 0.3kg of honey, I g 16 of glycyrrhizin paste and 0.2 g of salt. Carambolas are processed with selecting, cleaning, cutting 17 head and tail, slicing into size of 3/4 inch, bottling in half volume, and mixing vigorously and 18 adding the other materials. The product is sterilized by heating and cooling after sealing, or 19 without heating treatment.

21 Example 98 Coffee (Instant coffee and packed coffee solution) 22 The formulation comprises 10 kg of coffee bean, 1.5 kg of malic acid, 9.6 kg of sugar, 7.2 kg of 23 cream, and water for balance. Coffee beans are roasted, ground and heat water extracted under 24 pressure, and a 30% coffee of 10 1 solution is obtained. The malic acid is added into the resulted solution. The solution is concentrated by the frozen method and frozen dried under nitrogen gas.
26 A 4.5 kg of instant coffee product containing 33% of malic acid is produced. That coffee product 1 is further compounded with 9.6kg of sugar and 7.2kg of cream, and packed in a 17g content 2 product of carry-pack instant coffee.

4 A kind of liquid coffee drinks are made from the 30% coffee contained solution. That is compounding with 1.5kg of malic acid, 9.6kg of sugar, 7.2kg of cream and the balance of water 6 to make up of 240 liters. After heating and cooling, to pack in a volume of 200 ml, then 1200 7 packs of liquid coffee are produced.

9 Example 99 Apple ciders The formulation comprises 1.4 kg of sugar, 40g of malic acid, 4g of ethyl iso-valerate, 20 mg of 11 vitamin B 1, and the balance of water to make up 101. The sugar is made to a 56% solution first.
12 The rest components are dissolved in water, and then mixed with sugar solution. The resulted 13 solution is subject to filtration, cooling, contacting with carbon dioxide gas under high pressure, 14 and packed to form apple cider which has a bottle pressure of 50 lb at 15 C.

16 Example 100 Sarsaparillas 17 The formulation comprises 100 ml of sarsaparilla extract, 24 ml of alcohol, 500 g of sugar, 390g 18 of fructose, 5.5g of phosphorus pentaoxide, l Og of caramel, 1 ml of vanillin, I OOg of citric acid 19 and water to make up 101.

The perfume is dissolved in alcohol first and then mixed with sarsaparilla extract, and dissolved 21 with other components in pure water to form 10 1 of solution. This solution is packed in bottles 22 as making ciders, and contacting with carbon dioxide gas to produce the products.

24 Example 101 Cola drinks The formulation comprises 100 ml of cola seed extract, 24 ml of alcohol, 500g of sugar, 390g of 26 fructose, 5.5g of phosphorus pentaoxide, l Og of caramel, I ml of vanilla essence, 1.4g of 27 caffeine, I OOg of citric acid and balance of water to make up to 101. The producing process is as 1 the same of ciders.

3 Example 102 Fermented milk drink = 4 The formulation comprises 10 1 of skim milk, 2 kg of skim mild powder, 5 kg of millet jelly, 3 kg 5 of sugar, l OOg of CMC, 50g of citric acid, I Og of phosphoric acid, 180 ml of lactobacillus 6 bulgaricus, and 1 ml of vanillin essence. Skim milk and skim milk powder are mixed, then 7 heated up to 80 C for 30 minutes for sterilizing. Lactobacillus bulgaricus is added when solution 8 cooling to 40 C, and fermented at 38 C for 20 hours. When the acidity is reaching at 1.4%

9 mixed hardly. The mixture is heated to 60 C and dispersed the solid curds by homogenizer, and 10 sugar, millet jelly and phosphoric acid are added during heating. The mixture is heated up to 80 11 C for 20 minutes for sterilizing, and filtered at hot. After cooling, the perfume in alcohol is 12 added, and bottled and sealed to form product. If the fermented products are not heated, perfume 13 is added directly after filtration and packing, a lactobacillus bulgaricus contained drinks could be 14 obtained (functional drinks).

16 Example 103 Beers 17 The formulation comprises 101 of Taiwan beer, made by Taiwan Beer Co., having 1.0075 of 18 specific gravity, 3.4 % of extract contained, pH4.2, acidity 1.3, and 45 g of citric acid and 25 g of 19 potassium dihydrogen citrate. The product is produced by mixing the materials and to make up carbon dioxide gas before capping.

22 Example 104 Fruit wines 23 The formulation comprises 1.5 kg of lemon, 300g of garlic, 50g of zinger, 200g of fructose, 21 24 of rice wine, and 300g of honey. The process is to set the following materials: the peeled and sliced lemon; garlic which is peeled and heated in microwave for 1 minute and cooled; sliced 26 zingers; honey; and rice wine; into a container in order, and sealed for one month.

27 Example 105 Other wines such as whisky, rice wine, brandy, sake, sorghum wine, and grape 1 wine.

3 All wines contain different amounts of organic acid that is formed during fermentation, such as 4 grape wine (0.5-3%), sorghum wine (0.0550.07%), rice wine (0.40.6%), and sake (0.15%).

The proper dose of this invention is acidity in a range of 2-3%, so that to adjust wines by adding 6 additional amount of acid to meet this range.

8 Example 106 Herb wines 9 The formulation comprises 20g of herbs (including 0.5g of Wujapi, 1.9g of cinnamon, 1.5g of Angelica, 5g of Ychu, 0.4g of Paidansin, 0.7g of Chunachung, 0.7g glycyrrhizin, 1.5g of 11 Huwuso, Chuanneuchi, 7.5g of Souti), 3.071 of alcohol, 21.5g of caramel, 400g of wheat gluten, 12 400g of sugar, 380g citric acid, lg of isoamyl butyrate, and to make up 101 with pure water.

13 All the herb materials except Yichu and Souti are crushed and mixed, bagged, ad and leached in 14 alcohol for two weeks. Yichu and Souti are chopped and cooked with water heating in a steam jacked pot for 8 hours. Sugar and wheat gluten are dissolved in boiling water, and mixed with the 16 former herb's extract solution and the steam-heated one. To which alcohol is added to adjust to 17 25% alcohol containing, and then to add pigment and perfume. The resulted compound is set for 18 one week and after sediment it is stored, packaged and finally to form product.

Example 107-111 Tincture and treatment for inflammation, analgesic and itchy 21 The formulation comprises lOg of citric acid, 5g of glycerin, and 90 ml of alcohol (70v/v) in a 22 mixture. A series of testing are carried out by a group of five patients for each syndromes, which 23 treating the topical disease three times a day, the results is shown as table 7.

Table 7 - Results of treating inflammation, analgesic and itchy Example Diseases Treating results 107 Acne(pain) One day scaled, pain improved 108 Insect bite (itchy, Itchy disappeared in half hour, inflammation inflammation, pain) disappeared after 3 hours, and pain improved 109 Pruigo(itchy) One day improved 110 Skin wound(pain) After dried the wound released, pain improved, healing quickly 111 Pustules (pain) The pustules shrunk one day, scaled after 2 days, pain improved 2 Example 112 Improving the allergic risk of dairy products 3 The formulation comprises 10 1 of milk, 10 g of citric acid and 3 g of Ca-CMC. During mixing 4 milk, Ca-CMC is added in homogenous and then citric acid is added to produce none-allergic dairy milk. The product may be produced into milk powder by spray-drying machine.

7 Example 113 Shrimps processing.

8 The formulation comprises 10 kg of litter shrimps, 360 g of salt, 360 g of citric acid, and 20 1 of 9 water. The shrimps are set in a basket and washed in a following water to remove sand. The washed shrimps are treated in 20 1 boiling water, containing salt and citric acid, for 25 minutes.

11 The boiled shrimps are sun-drying on straw mats out door. The dried shrimps are packed in 250 g.
12 The treated products are good for reserving and allergy risk free for allergic persons.

14 Example 114 Salt fish (little sardine) The formulation comprises 10 kg of little sardine, 1.2 kg of salt, 1 kg of citric acid, and 20 1 of 16 water. The sardines are washed in a trough and spread on a ten-layer boiling cage, and then 17 treated in a volume of 20 1 boiling solution in kettle, containing salt and citric acid, for a period 18 of time until the solution boiling again. Before products are removed from the kettle, the upper 19 layer oily floats are washed away by adding new solution. The boiled fishes are sun-dried with the cage turning the other side ever day. In summer day, they can be dried in about 3 days.

22 Example 115 Salt fish (Sardine) 23 The formulation comprises 10 kg of sardine, 1 kg of salt, 400 g of malic acid, and 6 liters of 1 water. The fresh sardines are washed with water, and dipped in a solution of 6 liters of water, 2 containing the salt and malic acid, for 8 hours. The dipped fishes are sun-dried to become 3 product.

Example 116 Shrimp meat can 6 The formulation comprises 2 kg of King-shrimps, 50 g of salt, and 100 g of maleic acid. The 7 shrimp meat is boiled in 1.5 liters of solution, containing salt and acid, and left the shrimp when 8 that is turned into white color. After canning, sealing, sterilizing under pressure, cooling, and 9 inspecting, products are obtained.

11 Example 117 Egg product (Crab dish with succinic acid) 12 The formulation comprises half can of canned crab, 10 ml of rice wine, 6 pieces of egg, 3 g of 13 salt, 1 g of monosodium glutamines, 15 g of peanut oil, 5 g of green pea, being for four dishes.
14 The crab meat is compounded with wine, egg, succinic acid, salt and MSG
Heating 15 g of peanut oil in a pan when a fume is forming, the compound and green peas are added and frizzled 16 to a medium done. Turning the other side and frizzling for a while, a crab dish with succinic acid 17 is made.

19 Example 118 Fish can containing tow kinds of active agents (citric acid and Nisin).

In example 76, the 75 g of tomato paste is mixed with 10 mg of Nisin first and then the can is 21 sealed and sterilized by normal process to form a product.

23 Example 119 Release of drugs to skin 24 The formulation comprises: A, basic composition: 47% of a C4 to C8 acrylic acid-iso borneol copolymer and 53% of a mixture (containing 96% of 2-ethylhexy acrylate, and 4 % of 26 n-vinyl-2-pyrrolidone), and 5% of cross linking agent of 2-(4-(2-hydroxy-2-methyl-l-oxopropyl) 27 phenoxyethyl) 2- propionate; B, composition of release of drugs to skin:
0.9g of peppermint, = 1 1.2g of peppermint oil, 0.8g of camphor, 1.2g of citric acid, and 100g of the A compound. The 2 compound is coated on a treated paper, radiation with 300w/inch of UV for 1 minute to form a 3 pressure sensitive release of drug to the skin. The products are given five patients who are used 4 to allergic reactions when using adhesives in transdermal drug delivery systems, to use continuously for many days. The results show that there is no any allergic reaction or achy 6 happened. Besides, the effect of release of drug to the skin is better than the normal product.

8 Example 120 Production of allergy free medical groove 9 The formulation comprises 200 parts of natural rubber latex ( pH10.5, containing ammonia, solid component 50 %, Taiping Perak, Malaysia), 75 parts of boric acid treated casein (solid 11 component 10 %), 10.0 parts of zinc oxide dispersion solution ( solid component 50%), 133 parts 12 of corn starch slurry crossing treated by epichlorohydrin (solid component 50%), 1 part of sulfur 13 powder, 0.05 parts of carboxyl polymethylene polymer (molecule weight 500,001,000,000), the 14 rest is deionized water to dilute to form a 10% solid containing. The coacervation agent is 45%
calcium nitrate in deionized water.

16 The production is according to the conventional method: hand model dipping into latex solution, 17 drying, dipping into latex solution, drying, dipping into latex solution, drying, folding edge, 18 drying, cross linking treatment, washing, drying, dipping into 5% citric acid solution, drying, 19 powdering (5-401t MgO), removing from model, and finally, packing for product. If do not us dipping with liquid solution of the effective agent of present invention, the effective agent could 21 be pulverized to form a sized of 5-40pand mixing with MgO in a rate of 4%
for powdering.

22 Testing is carried out for five medical persons who have allergic reactions to latex grove. The 23 results shown none had the allergic reaction.

Example 121 Agent for head scale (hair lotion).

26 The formulation comprises 1.2% of peppermint oil, 6% of glycerin, 0.2% of chlorophyll, 2% of 27 malic acid, 60% of alcohol and 30.6% of distill water. Testing is carried out by five male patients, 1 rubbing the lotion twice a day after washing hair. They all improved that their head scales and 2 achy problems.

4 Example 122 Glucose injection (containing other active agent) 5 To dissolve 500 g of glucose and 10 g of citric acid in 101 of high pressure sterilized water in a 6 clean room. The solution is filtered by ceramic filter and packing into a 500 ml injection 7 product by the GMP method.

9 Example 123 Testing for anti-free radicals 10 The determination of free radical content is performed by using individual free radical testing kit, 11 of BioVitale Inc. (Irvine, La., USA). The process is as follows: to take the specific amount of 12 urine by pipette, open the testing agent ampoule and adding the urine, shaking the ampoule for 5 13 minutes, comparing the color of ampoule solution with these colors listed in table of kit. The 14 table of free radical content level is divided into 4 classes: most proper level (0), low level (+1), 15 medium level (+2), and high level (+3).

17 The volunteers selected 5 persons. In the group, 2 persons have medium free radical levels in 18 urine, and the rest are high levels. They are given the agent as shown in example 51 three times a 19 day individual, and sampling the urines 2 day after. The results are shown in Table 8. The 20 effective agent of this invention shows good in anti-free radical.

22 Table 8 - free radical content in urine Item Free radical content in Free radical content in urine before testing urine after administrated the drug of this invention Person 1 +2 0 Person 2 +2 0 Person 3 +3 0 Person 4 +3 0 Person 5 +3 0 2 Example 124-129 Testing for the depression of enzyme activity 3 We recognized that the effective agent of present invention shows the ability of treating 4 histamine, inflammation, analgesic, and achy from examples of 1-45 and 107-111. It goes without saying that they also could depression the cascade of the production of prostaglandins 6 and other chemicals. Therefore, there are not any embolus and thrombus to be happened, and 7 could avoid cardiovascular diseases such as congestion of the brain and myocardial infarction.
8 The first step of formation for a clot is that the releasing of thromboxane from platelet induces 9 the message of enhancing coagulation. The free radical of peroxide is a major factor for activating cyclooxygenase in prostaglandin cascade. It is clear from the testing results of 11 example 123, when the drug of this invention existing, that cascade could not be happened, 12 because the free radical is inhibited by the drug of this invention.

14 The production process of peroxide free radical can be tested by Xanthine oxidase substrate in vito (Fridowich, I., J. Biol. Chem., 215, 4053-4057, 1970). This method is applied to prove the 16 effect of this invention. The test of inhibiting xanthine oxidase is carried out by the method of H.
17 M. Kalckar Q. Biol. Chem., 167, 429-443, 1947). The basic principle is xanthine being acted by 18 xanthine oxidase to form uric acid that is quantitative analyzed by photometric method. By the 19 amount of determined uric acid, is calculated the degree of inhibiting effect for the activity of xanthine oxidase.

22 The testing process is, adding a final concentration of 0.01 u/ml of xanthine oxidase in 1 cm cell 23 of photometric apparatus, and adding 0.05M (pH=7.4) of phosphoric acid buffer or inhabitant.
24 The reaction time is counted from the point at adding xanthene's to a final concentration reaching 5 x 10"5M. For reducing the error arose by absorption of liquid in photometric analysis, 26 the compound of xanthine oxidase, xanthine and drug are boiled for the reference. UV selected at 1 295nm, data are recorded at an interval of 30 seconds for 2 minutes. The unit of activity change 2 of xanthine oxidase is 0.001M/min. Calculate the inhibiting rate for each addition amount of 3 drug. To use the drug concentration (M) as a function of inhibiting rate (%), and to trace the data 4 on a log scale paper, the 50% depression rate of the oxidase (IC50) could be determined by regression line method.

7 The drugs tested are succinic acid, citric acid, malic acid, tartaric acid and fumaric acid, and 8 using folic acid for comparison. The results are listed as table 9. The drugs of this invention 9 show high inhibition effect.

11 Table 9 Testing results for IC50 Example Drug IC50 (concentration for depression of 50%
activity of oxidase) 124 Succinic acid 1.18 x 10-' M
125 Citric acid 1.00 x 10-7 M
126 Malic acid 1.12 x 10' M
127 Tartaric acid 1.02 x 10-7 M
128 Fumaric acid 1.01 x 10-7 M
129 Folic acid 6.62 x 10' M

13 Example 130-135 Testing for analgesic 14 The formulation of drug for testing comprises 300 mg of malic acid, 300 mg of tartaric acid, 300 mg of citric acid, 50 mg of caffeine and 10 mg of catechin. Five volunteers of head-ache and 16 physical pain are given one dose individual. To record the reaction after treatment, they all felt 17 their pains are improved in 10-30 minutes.

Claims (12)

1. A pharmaceutical compound for the treatment of one or more ailments selected from the group comprising hypersensitivity reaction diseases, pain, influenza, colds, thrombus or clotting coagulation, inflammation, virus infections, insect bites, conditions caused by free radicals, food poison, itch and drug side effect; by lowering humoral pH wherein said pharmaceutical compound selected from the group comprising succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, lactic acid, a-hydroxy octanoic acid, gluconolactone, glycollic acid, acetic acid, propionic acid, phosphoric acid, and their acidic salts of sodium or potassium.
2. A pharmaceutical compound for the treatment of allergies or food allergies by lowering humoral pH wherein said pharmaceutical compound selected from the group comprising fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, lactic acid, a-hydroxy octanoic acid, gluconolactone, glycollic acid, acetic acid, propionic acid, phosphoric acid, and their acidic salts of sodium or potassium.
3. A pharmaceutical compound according to claim 1 or claim 2 wherein the edible acid and/or its acidic salts of sodium or potassium are provided in the amount of 5-95wt%.
4. A pharmaceutical compound according to claim 1 or claim 2 wherein the edible acid and/or its acidic salts of sodium or potassium are provided in the amount of 10-90wt%.
5. A pharmaceutical compound according to claim 1 or claim 2 wherein the edible acid and/or its acidic salts of sodium or potassium are provided in the amount of 15-85wt%.
6. A pharmaceutical compound according to claim 1 or claim 2 wherein the compound is selected from group comprising oral agent, non-oral agent and topical usage agent.
7. A pharmaceutical compound according to claim 1 or claim 2 wherein the compound is inhalant.
8. A pharmaceutical compound according to claim 1 or claim 2 wherein the compound is for oral administration and is selected from the group comprising a capsule, a tablet, flakes, a powder, a pill, lozenges, a syrup, a solution and a suspension.
9. A pharmaceutical compound according to claim 1 or claim 2 wherein the compound is for administration by injection subcutaneously, intramuscularly, intestinally, joint lubricating liquidly, intravenously or intradermally.
10. A pharmaceutical compound according to claim 1 or claim 2 wherein the compound is for non-oral external use and is in the form of a liquid, a paste, an aero sol, a spray or a skin absorbent
11. A pharmaceutical compound according to claim 1 or claim 2 for spondyle animals.
12. A pharmaceutical compound according to claim 1 or claim 2 for human.
CA2708045A 2004-04-26 2004-04-26 A pharmaceutical compound Abandoned CA2708045A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283338B2 (en) 2007-11-30 2012-10-09 Kao Corporation GIP secretion inhibitor
US8338389B2 (en) 2009-06-17 2012-12-25 Kao Corporation Agent for preventing or ameliorating obesity

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283338B2 (en) 2007-11-30 2012-10-09 Kao Corporation GIP secretion inhibitor
US8338389B2 (en) 2009-06-17 2012-12-25 Kao Corporation Agent for preventing or ameliorating obesity

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