KR20070119667A - Light pharmaceutical water and therapeutic compositions and methods thereof - Google Patents

Abstract

This invention relates to pharmaceutical water, which comprises from 99.760 to 99.999% of light isotopologue 1H2 160 and up to 100% of residual isotopologues 1H2 170, 1H2 180, 1H2H160, 1H2H170, 1H2H180,2H2 160,2H2 170, and 2H2 180, for the production of finished product, intermediate reagent preparation, and analytical processes in pharmaceutical industry. Further, the invention relates to pharmaceutical compositions comprising a biologically active agent and said pharmaceutical water, wherein said agent is selected from the group consisting of drugs, physiologically active peptides, physiologically active proteins, and nucleic acids. Further, the invention relates to method of administering a biologically active agent to a mammal in need thereof, which method comprises a step of administering to said mammal said therapeutic composition.

Description

Pharmaceutical hard water and therapeutic compositions and methods using same {LIGHT PHARMACEUTICAL WATER AND THERAPEUTIC COMPOSITIONS AND METHODS THEREOF}

The present invention relates to the health of humans and animals. More specifically, the present invention relates to pharmaceutical water in which ¹ H ₂ ¹⁶ O, which is a light water isotopologue, is present at a high concentration, and a therapeutic composition and a method using the same.

In the pharmaceutical industry, great importance is placed on the quality of water used in the production of finished products, in the manufacture of intermediate reagents and in the analytical process. The quality of pharmaceutical waters is controlled in accordance with the provisions of the national pharmacopoeia regarding the requirements for toxicity, endotoxin, oxidativeity, cytotoxicity and non-volatile residues. The U.S. Pharmacopoeia (USP 23rd Edition) classifies pharmaceutical water as purified water (PW) and water for injection (WFI). Purified water is used in the process of preparing the drug in unit dosage form. Water for injection is water used for the manufacture of parenteral products. Pharmaceutical water is produced by certain industrial processes depending on the type of water.

Natural water consists of nine water isotopologues (i.e., ¹ H ₂ ¹⁶ O, ¹ H ₂ ) consisting of stable isotopes of hydrogen ( ¹ H and ² H) and oxygen ( ¹⁶ O, ¹⁷ O and ¹⁸ O). ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O) to be. Here, the hard water isotopologue ¹ H ₂ ¹⁶ O is about 99.7317% (Vienna Standard Mean Ocean Water, VSMOW), and eight heavy isotopologues including at least one of Middle East isotopes ² H, ¹⁷ O and ¹⁸ O The total content of heavy isotopologues is about 0.2683% (e.g. 0.199983% ¹ H ₂ ¹⁸ O, 0.0372% ¹ H ₂ ¹⁷ O, 0.031069% ¹ H ² H ¹⁶ O, 0.0000623% ¹ H ² H ¹⁸ O , And 0.0000116% ¹ H ² H ¹⁷ O). Rothman et al., J. Quant. Spectrosc. Radiat. Transfer, 1998, 60, 665. Rothman et al., J. Quant. Spectrosc. Radiat. Transfer, 2003, 82, p.9.] The concentration of isotopologues in natural waters varies slightly depending on local and climatic conditions and is generally expressed as a deviation "δ" for international VSMOW standards. Natural water with the highest concentration of ¹ H ₂ ¹⁶ O, the major hard water isopolog, was found in Antarctica (Standard Light Antarctic Precipitation (SLAP)), and the δ values of the remaining Middle East are δ ² H-415.5 ‰, δ ¹⁷ O 28.1 ‰ and δ ¹⁸ O-53.9 ‰, which corresponds to the level of 99.757% of hard water isotopologue ¹ H ₂ ¹⁶ O. [R. van Trigt, Laser Spectrometry for Stable Isotope Analysis of Water Biomedical and Paleoclimatological Applications, 2002. Groningen: University Library Groningen, p. 50.] Therefore, water with hard water isopolog ¹ H ₂ ¹⁶ O concentration of more than 99.757% does not exist in nature.

Deuterium containing isotopologue ( ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O) from natural water When completely depleted, water with a concentration of hard water isopolog ¹ H ₂ ¹⁶ O is less than 99.76%, since the concentration of deuterium-containing isopolog in water is less than 0.031%. Therefore, water having light water isotopologues ¹ H ₂ ¹⁶ O content of 99.76% or more is selected from heavy isopologs ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O can be prepared on an industrial scale through a method that completely depletes from natural water.

Pharmaceutical water is prepared from natural water using well known processes that do not change the isotope content of the water as starting material. Thus, the pharmaceutical water may contain about 99.731 to 99.757% of hard water isopolog ¹ H ₂ ¹⁶ O and about 0.243 to 0.269% of heavy isopologs ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, Heterologous isotopic composition comprising ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O. The hard water isometric topology log ¹ H ₂ content of ¹⁶ O for the production of 99.760% or more pharmaceutical water is bisulfite from natural number isobutyl topology log _{^{1 H 2 17 O, 1 H}} 2 18 O, 1 H 2 H 16 O, 1 Depletion of H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O.

Therefore, pharmaceutical waters having a content of hard water isotopologue ¹ H ₂ ¹⁶ O of 99.757% or more are not known in the art, and heavy isopologs from natural water ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H To be produced on an industrial scale via a method comprising depleting ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O. Can be. The hard water isotopic and heavy isotopologues of water have distinct properties and are characterized by the properties of the material in solution, eg biochemical kinetics; The association enthalpy of various binding systems including protein-carbohydrates, small molecule-small molecules, protein-peptides, protein-nucleic acids, and the like; Thermodynamic properties of ligand binding (ie free energy, enthalpy, entropy and calorie change); Protein unfolding enthalpy; It is known to clearly affect the thermodynamic stability and formation of the functional structure of nucleic acids. Chervenak et al. JACS, 1994, 116 (23): 10533-10539. Makhatadze et al. Nature Struct. Biol, 1995, 2 (10): 852-855. Connelly et a! .. PNAS, 1994, 91: 1964-1968. Cupane et al., Nucleic Acids Res. 1980, 8 (18): 4283-4303.] Thus, the light isotopic and heavy isopologs of water have a clear influence on the basic properties of the substances (ie proteins, nucleic acids and small molecules) typically used as drugs. This is well known. Thus, the heterogeneity of isotopologue in pharmaceutical water is undesirable and may affect the drug administration response. Therefore, monoisotopologous pharmaceutical water is needed to prepare drug formulations with more advantageous properties.

One object of the present invention is about 99.760 to 99.999% of light isotopologue ¹ H ₂ ¹⁶ O and the residual amount of isotopologues ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, To provide pharmaceutical water comprising ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O.

One object of the present invention is from heavy water to heavy isotopics ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ^It provides a method for producing pharmaceutical water comprising the depletion of ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O.

One object of the present invention is a therapeutic composition comprising an effective amount of a biologically active agent and pharmaceutical water, wherein the pharmaceutical water constitutes about 99.760 to 99.999% of light isopolog ¹ H ₂ ¹⁶ O and 100%. Residual amount of isotopologues ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ^In providing a therapeutic composition comprising ¹⁷ O and ² H ₂ ¹⁸ O.

One object of the invention is a method of treatment comprising administering to a mammal in need thereof a therapeutic composition comprising an effective amount of a biologically active substance and therapeutic water, wherein the pharmaceutical water is from about 99.760 to 99.999% of light isopol. Residual isotopologues to constitute log ¹ H ₂ ¹⁶ O and 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ To provide a treatment method comprising O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O.

The present invention provides about 99.760 to 99.999% of light isotopologue ¹ H ₂ ¹⁶ O and residual amounts of isotopologues ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, Pharmaceutical water comprising ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O is provided.

As used herein, the term "pharmaceutical water" refers to water used in the pharmaceutical industry for the manufacture of bulk drugs or finished products (eg, drugs in unit dosage form). Preferred pharmaceutical water of the present invention is purified water (PW) or water for injection (WFI). A generally known introduction describing pharmaceutical water of the PI and WFI grades is the US Pharmacopoeia (USP 23rd Edition).

The term “isotopologue” as used herein is defined according to the following IUPAC Compendium of Chemical Terminology 2nd Edition (1997), for example ¹ H ₂ ¹⁶ O, ¹ H ² H ¹⁶ O. And molecules that differ only in the isotopic composition (number of isotopic substitutions), such as ¹ H ₂ ¹⁸ O.

As used herein, the term "Water for pharmaceutical use" (light pharmaceutical water) is circa iso topology logs of about 99.760 to about ^{99.999% (light isopopologue) 1 H} 2 16 O and the remaining amount iso topology log for configuring a 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O Say water to include. The relative amount of certain heavy isotopologues may vary depending on the process of making the water of the present invention, but the sum of the remaining amounts of heavy isotopologues should not exceed 0.001 to 0.240%. Thus, the residual amounts of Middle East isotopes in the water of the present invention may vary within the range of 0.01 ppm to 155 ppm for ² H, 1 to 360 ppm for ¹⁷ O, and 1 to 2000 ppm for ¹⁸ O. However, the sum of heavy isotopologues composed of these Middle East isotopes should not exceed 0.01 to 0.240%.

In addition, the present invention is the heavy isotopics ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ It provides a method for producing pharmaceutical water comprising the step of depleting O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O.

Heavy isotopics from raw water ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ Depletion of ¹⁷ O and ² H ₂ ¹⁸ O can be performed using methods known to those skilled in the art. A preferred method for this depletion is high efficiency distillation. The product resulting from this depletion is about 99.760 to 99.999% of the light isotopologue ¹ H ₂ ¹⁶ O and the residual amount of heavy isopologs to make up 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O. Pharmaceutical hard water is prepared from such hard water by methods well known to those skilled in the art, which methods include pretreatment (eg, primary filtration, coagulation and flocculation, desalting, and softening), sterilization, reverse osmosis or Hard water treatment steps such as deionization, distillation or ultra-filtration, and chemical and microbiological testing of a water sample. According to USP 23, purified water (PW) is obtained through distillation, ion exchange treatment, reverse osmosis, or other suitable process, and water for injection (WFI) is obtained through distillation or reverse osmosis. In the practice of the present invention, the pharmaceutical hard water should meet the specifications of the pharmacopoeia of each country, for example, the specifications of the US pharmacopoeia.

The present invention also provides a therapeutic composition comprising an effective amount of a biologically active substance and pharmaceutical water, wherein the pharmaceutical water comprises about 99.760 to 99.999% of light isopolog ¹ H ₂ ¹⁶ O and a residual amount of mesopoie Isotopologues ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² It provides a therapeutic composition comprising H ₂ ¹⁸ O.

The present invention also provides a method of treatment comprising administering to a mammal in need thereof a therapeutic composition comprising an effective amount of a biologically active substance and therapeutic water, wherein the pharmaceutical water is from about 99.760 to 99.999% Residual heavy isotopics to make up ¹ H ₂ ¹⁶ O and 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O are provided.

In the composition of the present invention, the biologically active substance is selected from the group consisting of drugs, physiologically active peptides, physiologically active proteins and nucleic acids.

Preferably, the drug is analgesic, anesthetic, anti-acne, anti-aging, anti-allergic, anti-anemia, antianginal, anti-anxiety, antiarrhythmic, anti-asthmatic, antimicrobial, anticancer, anticholinergic, anticoagulant, anticonvulsant, Antidepressant, antidiabetic, anti-diabetic, antidiuretic, antidote, anti-drug, anti-menstrual, anti-nausea, antifibrolytic, antifibrotic, antifungal, anti-glaucoma, anti-bleeding, antihistamine, antihypercalcemia , Antihyperglycemic agents, antihyperlipidemia, antihypertensive, antihyperthyroidism, antiuric acid hyperlipidemia, antihypercalcemia, antihyperglycemic, antihypertensive, anti-inflammatory, anti-kawasaki, antimalarial, antimethemoglobinemia, Antimicrobial, antimigraine, antimyopathy, antineoplastic, antineuropathic, antineutrophil, aviation emperor, anti-neuropathy, antiprotozoal, anti-psoriasis, antipsychotic, antipyretic, antirheumatic, Anti-seborrhea, anti Antiseptics, antithrombotic agents, antiproliferative agents, anti-ulcer agents, anti-disease agents, antiviral agents, anti-wrinkle agents, appetite stimulants, appetite suppressants, asthma preventive agents, bone resorption inhibitors, bronchodilators, contraceptives, corticosteroids, pigment removers, fungicides, Diuretics, Dialysis Solution, Esterogens, Hair Growth Enhancers, Hair Growth Inhibitors, Hematopoietic Stimulators, Hepatitis Therapeutics, Histamine H2-Receptor Antagonists, Hormones, Hygroscopics, Insulin Resistance Therapeutics, Interferon Resistance Therapeutics, Immune Inhibitors, Erectile Dysfunction Therapeutic Agents Solubilizers, Moxibustion Agents, Mucolytic Agents, Shandong Agents, Myocardial Infarction Treatment and Prevention Agents, Neuromuscular Blocking Agents, Nutritional Supplements, Vitamins, Osteoporosis Prevention and Treatment, Sedatives, Skeletal Muscle Relaxants, Skin Softeners and Skin Moisturizers, Skin Whitening Agents, Sympathetic Nerve Stimulants, thrombolytics, vaccines, vasodilators, wound healing promoters, anti-irritants, vitamins, nutrients, amino acids and derivatives thereof, It is selected from the mineral, medicinal plant extract, urethane carcinoid, bioflavonoids, and the group consisting of an antioxidant.

Non-limiting examples of analgesics include acetaminophen, hydrocodone bitartrate, codeine, caffeine, acetylsalicylic acid, diclofenac, or mixtures thereof.

Non-limiting examples of anesthetics include lidocaine, tetracaine, and epinephrine.

Non-limiting examples of anti-acne agents include erythromycin, tetracycline, benzoyl peroxide, nicotinamide, resorcinol, doxycycline, and salicylic acid.

Non-limiting examples of anti-anemia agents include cyanocobalamine, erythropoietin, ferrous fumarate, ferrous sulfate, ferrous citrate, and iron dextran.

Non-limiting examples of antianginal agents are athenol, isosorbide mononitrate, nitroglycerin, propanolol, timolol, metoprool, and verapamil.

Non-limiting examples of anti-anxiety agents include alprazoram, bronazepam, lorazepam, and diazepam.

Non-limiting examples of antiarrhythmic agents include acebutolol, athenol, atropine, and metroprool.

Non-limiting examples of anti-asthma agents include dexmethasone, and loratidine.

Non-limiting examples of antimicrobials include aminosalicylic acid, isoniazid, erythromycin, gentamycin, ciprofloxacin, amoxicillin, cephaceline, streptomycin.

Non-limiting examples of anticancer agents include daunorubicin.

Non-limiting examples of anticholinergic agents include atropine.

Non-limiting examples of anti-coagulant agents are heparin, warfarin, and dicumarol.

Non-limiting examples of anticonvulsants include clonazepam, diazepam, and valproic acid.

Non-limiting examples of antidepressants include amitriphthalin, and fluoxetine.

Non-limiting examples of antidiabetic agents include sulfonylureas such as insulin, matformin, succinic acid, and glyburide.

Non-limiting examples of anticorrosive agents are codeine, and bismuth subsalicylate.

Non-limiting examples of antidiuretics are vasopressin.

Non-limiting examples of antidote include glucagon for calcium channel blockers, and penicillamine for heavy metals.

A non-limiting example of antitumoral agent is levodopa.

Non-limiting examples of anti-menstrual disorders include diclofenac.

A non-limiting example of anti-emetic agent is chlorpromazine.

Non-limiting examples of antifibrinolytics include aminocaproic acid.

Non-limiting examples of antifibrotic agents include potassium aminobenzoate.

Non-limiting examples of antifungal agents include ketoconazole.

Non-limiting examples of antiglaucoma agents are carbacol, and pilocarpine.

Non-limiting examples of anti-bleeding agents include factor VII, and aminocaproic acid.

Non-limiting examples of antihistamines include ranitidine hydrochloride, and loratadine.

Non-limiting examples of antihypercalcemia include calcitonin, ethidronate and other biphosphonates.

Non-limiting examples of antihyperglycemic agents are matformin.

Non-limiting examples of antihypertensive agents include clofibrate and fluvastatin.

Non-limiting examples of antihypertensive agents are athenol, captopril, ricinopril, and verapamil.

Non-limiting examples of antithyroidal agents are potassium iodide.

Non-limiting examples of antiuric acid hyperlipidemia include alloprinole.

Non-limiting examples of antihypercalcemias include calcium acetate.

Non-limiting examples of antihyperglycemic agents are glucagon.

Non-limiting examples of antihypertensive agents include dihydroergotamine.

Non-limiting examples of anti-inflammatory agents are acetylsalicylic acid, salicylic acid choline, ibuprofen, diclofenac, indomethacin, and dexamethasone.

Non-limiting examples of anti-kawasaki agents include immunoglobulins.

Non-limiting examples of antimalarial agents include guanidine.

Non-limiting examples of antimethhemoglobinemia agents are methylene blue.

 A non-limiting example of antimuscular dystrophy is neostigmine.

Non-limiting examples of anti-neoplastic agents include asparaginase, carboplatin, daunorubicin, interferon, tamoxifen, and fluorouracil.

Non-limiting examples of anti-neural drugs include carbamazepine.

Non-limiting examples of aviation emperors include clonazepam.

Non-limiting examples of anti-neuropathy agents include immunoglobulins.

Non-limiting examples of antiprotozoal agents are chloroquinine, and furazolidone.

Non-limiting examples of anti-psoriasis agents are methotrexate.

Non-limiting examples of antipsychotics include carbamazepine.

Non-limiting examples of antipyretic agents include acetaminophen.

Non-limiting examples of antirheumatic agents include methotrexate.

Non-limiting examples of anti-seborrheic agents include pyrithione and salicylic acid.

Non-limiting examples of anticonvulsants include glucagon.

Non-limiting examples of antithrombotic agents include acetylsalicylic acid.

Non-limiting examples of anti-advancing agents are diazepam.

Non-limiting examples of anti-ulcer agents are omeprazole.

Non-limiting examples of anti-disease agents include diphenidol.

Non-limiting examples of antiviral agents include acyclovir and ribavirin.

A non-limiting example of an edible stimulant is dronabinol.

A non-limiting example of an appetite suppressant is phentermine.

Non-limiting examples of asthma preventive agents are deophilene.

Non-limiting examples of bone resorption inhibitors include calcitonin.

Non-limiting examples of bronchodilators include deophylline, and albuterol.

Non-limiting examples of contraceptives include levonorgestrel.

Non-limiting examples of corticosteroids are dexamethasone.

Non-limiting examples of diuretics are furosemide, and hydrochlorothiazide.

Non-limiting examples of esterogens include estradiol.

Non-limiting examples of hematopoietic stimulants include erythropoietin.

Non-limiting examples of hepatitis therapeutics include interferon alpha.

Non-limiting examples of histamine H 2 -receptor antagonists are cimetidine.

Non-limiting examples of hormones include melatonin, thyroid hormones, thyroxine, triiodothyronine, adrenaline, noradrenaline, glucocorticoids (e.g. cortisol), salt corticoids (e.g. aldosterone), esterogens (e.g. Estradiol), progesterone, androgens (eg testosterone), calcitriol, and calciferol.

Non-limiting examples of insulin resistance therapeutics or interferon resistance therapeutics are succinic acid or salts thereof.

Non-limiting examples of immunosuppressants are cyclosporin.

Non-limiting examples of erectile dysfunction drugs include papaverine.

Non-limiting examples of keratinizing agents are benzoyl peroxides.

Non-limiting examples of motive agents are carbacol.

Non-limiting examples of mucolytic agents are acetylcysteine.

Non-limiting examples of acid agents include atropine.

Non-limiting examples of agents for treating or preventing myocardial infarction include acetylsalicylic acid.

Non-limiting examples of neuromuscular blockade include succinylcholine.

Non-limiting examples of nutritional supplements include calcium lactate, copper gluconate, ferrous fumarate, magnesium chloride, selenic acid, ascorbic acid, beta-carotene, biotin, calcitriol, calcium pantothenate, cyanocobalamine, ergocalciferol, Folic acid, niacin, niacinamide, pantothenic acid, pyridoxine, riboflavin, sodium ascorbate, lipoic acid, linositol, thiamine.

Non-limiting examples of nutrients are glucose.

Non-limiting examples of minerals include calcium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium, and zinc.

Non-limiting examples of vitamins are thiamine, riboflavin, niacin, pantothenate, pyridoxine, folic acid, cobalamin, biotin, choline, inositol, iscorbic acid, folic acid, and carnitine.

Non-limiting examples of osteoporosis prophylactic or therapeutic agents are estrogens.

Non-limiting examples of sedatives include diazepam.

Non-limiting examples of skeletal muscle relaxants include phenytoin.

A non-limiting example of thrombolytics is urokinase.

Non-limiting examples of vasodilators include enalapril.

The drug of the present invention is generally used in an amount of about 0.0005 to 50.0% by weight, preferably about 0.005 to 5.0% by weight, based on the weight of the composition.

Preferably, the physiologically active peptides or proteins are cytokines, peptide hormones, growth factors, factors that act on the cardiovascular system, factors that act on the central and peripheral nervous system, factors that act on humoral electrolytes, hematopoietic factors, bones and skeletons. It is selected from the group consisting of a factor that acts, a factor that acts on the gastrointestinal system, a factor that acts on the immune system, a factor that acts on the genitals, and an enzyme.

Non-limiting examples of cytokines include interferons (eg interferon-alpha, -beta and -gamma), and interleukins (eg interleukin 2-12).

Non-limiting examples of protein or peptide hormones include insulin, insulin-like growth factor-1, growth hormone, luteinizing hormone releasing hormone (LH-RH), corticosteroids (ACTH), amylin, oxytocin, actinbin, amyloid Miline, angiotensin, atrial natriuretic peptide (ANP), calcitoin, cholecystokinin (CCK), neurotrophic factor (CNTF), corticotropin releasing hormone (CRH or CRF), erythropoietin, hair follicle stimulating hormone (FSH), Gastrin, gastrin inhibitory peptide (GIP), gastrin releasing peptide, ghrelin, glucogon, gonadotropin releasing factor (GnRF or GNRH), growth hormone releasing hormone (GRF, GRH), human chorionic gonadotropin (hCH), phosphorus Hibin A, Inhibin B, Leptin, Reportropin (LPH), Progesterone (LH), Motiline, Neuropeptide Y, Oxytocin, Pancreatic polypeptide, Parathyroid peptide (PTH), Placental lactogen, Prolactin (PRL) Prolactin room Inhibitory factor (PIF), prolactin-releasing factor (PRF), PYY3-36, secretin, somatostatin (SIF, growth hormone-releasing inhibitor, GIF), thrombopoietin, tyrotropin (thyroid stimulating hormone, TSH), tyro Tropin releasing factor (TRH or TRF), vascular active intestinal peptide (VIP), vasopressin (antidiuretic hormone, ADH) and combinations thereof.

Non-limiting examples of growth factors include nerve growth factor (NGF, NGF-2 / NT-3), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), transgenic growth factor (TGF), platelet induced cell growth factor (PDGF), keratinocyte growth factor (TGF), and hepatocyte growth factor (HGF).

Non-limiting examples of factors that control blood pressure and atherosclerosis by directing the cardiovascular system include endothelin, endothelin inhibitors, endothelin antagonists, vasopressin, renin, angiotensin I, angiotensin II, angiotensin III, angiotensin I inhibitors, angiotensin II Receptor antagonists, atrial natriuretic peptide (ANP), and antiarrhythmic peptides.

Non-limiting examples of factors acting on the central and peripheral nervous systems include opioid peptides (eg, enkeparin, endorphins, kirotropins), neurotrophic factors (NTFs), calcitoin gene related peptides (CGRPs), thyroid gland Hormone releasing hormone (TRH), glial induced neurotrophic factor (GDNF), brain induced neurotrophic factor (BDNF) and neurotrophin (eg NT3, NT4).

Non-limiting examples of factors that act on humoral electrolytes include calcitonin.

Non-limiting examples of hematopoietic factors include erythropoietin, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage stimulating factor (GM-CSF), macrophage colony stimulating factor (M-SCF), and thrombopoietes. There is a teen.

Non-limiting examples of factors acting on the gastrointestinal system include secretin and gastrin.

Non-limiting examples of factors that act on the immune system include interferons (eg, interferon-alpha and -gamma), monoclonal antibodies, and peptides or proteins that can act as antigens that are present in nature, chemically synthesized, or recombinant. have. These factors are administered in combination with heptene or in adjuvant in the preparations according to the invention.

Non-limiting examples of factors that act on bone and skeleton include parathyroid hormone and calcitonin.

Non-limiting examples of factors acting on the genitals include luteinizing hormone releasing hormone (LH-RH) and luteinizing hormone.

Non-limiting examples of enzymes include superoxide demustase (SOD), urokinase, asparaginase, and kallikrein.

Other examples of these peptides or proteins are glycosylated peptides or proteins, and chemically modified peptides or proteins. Non-limiting examples of chemically modified peptides or proteins include peptides or proteins covalently bound to synthetic polymers such as polyethylene glycol, natural polymers such as chondroitin and polysaccharides, and chemically modified using non-peptide materials. The non-peptide material may be a ligand for a receptor or an antigen for an antibody.

In addition, the peptide or protein may be composed of a plurality of peptides bound to each other using chemical methods or genetic engineering techniques.

Non-limiting examples of nucleic acids include plasmid DNA, RNA, and oligonucleotides.

Typically, peptides, proteins or nucleic acids of the invention are used in the compositions of the invention in amounts close to the normal dosage and daily regimen as detailed in the medical literature for injection dosage forms. The peptide or protein of the present invention is used in an amount of about 0.00001 to 5.0% by weight, preferably about 0.0001 to 1% by weight, based on the weight of the composition.

Preferably, the amount of pharmaceutical water in the composition of the present invention is about 1.0 to 99.9% by weight based on the total weight of the composition. More preferably about 50.0 to 99.9 weight percent based on the total weight of the composition.

The composition of the present invention is used in a pH range that does not significantly affect the bioactive peptide or protein and becomes physiologically acceptable. Preferred pH ranges are about 2-10. A more preferred pH range is about 3-9 and the most preferred pH range is 3.5-8. Preferably, the buffer of the present invention includes glycine, citrate, succinate, fumarate, maleate, phosphate buffer and the like.

The composition of the present invention is prepared using well known ingredients according to known procedures. In preparing the composition, the physiologically active substance is mixed with hard water and diluted in a suitable diluent or carrier. In addition, the composition of the present invention may include a preservative, a flavoring agent, a coloring agent and the like. In addition, the compositions of the present invention may further contain absorption accelerators that aid in absorption of the pharmaceutically active substance. Any absorption accelerator may be used as long as it is pharmaceutically acceptable. The compositions of the present invention thus comprise sodium salicylate and salicylic acid derivatives (e.g. acetyl salicylate, choline salicylate, salicyamide, etc.), amino acids and salts thereof (e.g. glycine, alinine, phenylalanine, proline, Monoaminocarboxylic acids such as hydroxyproline, hydroxyamino acids such as serine, acidic amino acids such as aspartic acid, glutamic acid, basic amino acids such as lysine, alkali metal or alkaline earth metal salts thereof, N-acetylamino acids (e.g. N-acetylalanine, N-acetylphenylalanine, N-acetylserine, N-acetylglycine, N-acetyllysine, N-acetylglutamic acid, N-acetylproline, N-acetylhydroxyproline, etc.) and salts thereof, emulsions Materials commonly used as a topical agent (e.g. sodium oleate phosphate, sodium lauryl phosphate, sodium lauryl sulfate, myristyl sulfate , Polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, etc.), caproic acid, lactic acid, maleic acid and citric acid and their alkali metal salts, pyrrolidone carboxylic acids, alkylpyrrolidonecarboxylic acid esters, N-alkyl It may include one or more selected from pyrrolidone, proline acyl ester and the like. Each of these optional components is generally used in amounts of about 0.0005 to 10.0% by weight, preferably about 0.005 to 1.0% by weight, based on the weight of the composition.

The therapeutic composition may be formulated in various unit dosage forms. Such forms include gels, tablets, sprays, syrups, suppositories, droplets, solutions, and the like.

In practicing the methods of the invention, the therapeutic composition in unit dosage form can be administered by various routes. Such routes include oral, parenteral, transdermal, transmucosal, intradermal, intranasal, rectal and local routes.

 Oral dosage forms (eg, syrups, gels, tablets) are ingested, and such administration can be carried out from 1 to about 5 times a day, preferably 1 to 3 times a day.

Transmucosal dosage forms (eg, sublingual sprays, gels, tablets, or solutions) are administered to the sublingual mucosa of a mammal for at least 10 seconds, such administration being 1 to about 5 times a day, preferably 1 to 3 times a day. Can be implemented.

Parenteral dosage forms (eg, injection solutions) are injected into mammals (eg, subcutaneously or intramuscularly), and such administration may be repeated.

Nasal dosage forms (eg, intranasal nebulizers or droplets) are administered to the nasal mucosa of a mammal, and such administration can be carried out 1 to about 5 times a day, preferably 1 to 3 times a day.

Topical dosage forms (eg gels) are applied to the skin of a mammal, preferably on the skin preferably at least about 15 minutes, more preferably at least about 30 minutes, even more preferably at least 1 hour, most preferably Is left for a period of several hours or more, for example about 12 hours or less. Such administration may be carried out 1 to about 5 times a day, preferably 1 to 3 times.

1 shows light isotopologue ¹ H ₂ ¹⁶ O of about 99.760 to 99.999% and the remaining amount of heavy isopologs ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O Is a schematic diagram of an apparatus for producing water comprising ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O.

The following examples are presented to illustrate the present invention. These examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.

Example  One

This example describes a method for producing pharmaceutical water of the present invention.

Using the apparatus of FIG. 1 at a temperature of 60 ° C. and a pressure of 0.2 bar, the highly effective distillation of the raw natural water comprising 99.73% of light isopolog ¹ H ₂ ¹⁶ O was carried out at 99.99%. Residual amount of isotopologues to constitute isotopologue ¹ H ₂ ¹⁶ O and 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² Raw material hard water comprising H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O is prepared. The distillation process comprises evaporating natural water comprising 99.73% (C ₁ ) light isopolog ¹ H ₂ ¹⁶ O in boiling means (1) to produce steam; Supplying the steam to the bottom 2 of the distillation column 3; Perform gas-liquid contact between the descending liquid and the rising vapor on the surface of the contacting device 4 (e.g., structural or random packing) in the distillation column, wherein the liquid and gas are in the axial direction of the column. Flow in opposite directions on the surface of the contact means along the main flow direction thereof; In a condenser (5) installed on top of the distillation column (3), condensing water vapor having a light isopolog ¹ H ₂ ¹⁶ O concentration of 99.99% (C ₂ ); A portion of the condensate was converted to 99.99% light isopolog ¹ H ₂ ¹⁶ O (C ₂ suitable for the manufacture of pharmaceutical hard water. Recovering as condensed raw water hard water comprising> C ₁ ). Next, the raw hard water is treated according to the reverse osmosis process. The final WFI grade water containing 99.99% light isopolog ¹ H ₂ ¹⁶ O is tested for chemical and microbial contamination as specified in the Pharmacopoeia.

Example  2

This example shows a representative formulation comprising insulin.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant insulin 3.5 mg (100 IU) Sodium chloride 5 mg Polysorbate 20 0.01 mg m-cresol 2.7 mg

The method for preparing the composition described in Example 2 was as follows: Human recombinant insulin, hard water for injection and other components were mixed.

Example  3

This example shows a representative formulation comprising interferon-alpha.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 0.5 ml Human recombinant interferon-alpha 10 μg Sodium chloride 5.9 mg Sodium phosphate 3.8 mg

The method for preparing the composition described in Example 3 was as follows: Human recombinant interferon-alpha, injectable hard water and other components were mixed.

Example  4

This example shows a representative formulation comprising interferon-beta.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant interferon-beta 30 μg albumin 15 mg Sodium chloride 5.8 mg Dibasic Sodium Phosphate 5.7 mg Monobasic sodium phosphate 1.2 mg

The method for preparing the composition described in Example 4 was as follows: Human recombinant interferon-beta, hard water for injection and other ingredients were mixed.

Example  5

This example shows a representative formulation comprising erythropoietin.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant erythropoietin 10,000 IU albumin 2.5 mg Sodium citrate 5.8 mg Sodium chloride 5.8 mg Citric acid 0.06 mg

The method for preparing the composition described in Example 5 was as follows: Human recombinant erythropoietin, hard water for injection and other ingredients were mixed.

Example  6

This example shows a representative formulation comprising calcitonin.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Salmon Calcitonin 2200 IU Sodium chloride 8.5 mg

The method for preparing the composition described in Example 6 was as follows: Salmon calcitonin, hard water for injection and other ingredients were mixed.

Example  7

This example shows a representative formulation comprising G-CSF.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant G-CSF 300 μg Acetate 0.59 mg salt 0.035 mg Tween 80 0.004% Sorbitol 50 mg

The method for preparing the composition described in Example 7 was as follows: Human recombinant G-CSF, hard water for injection and other components were mixed.

Example  8

This example shows a representative formulation comprising GM-CSF.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant GM-CSF 500 μg Sodium citrate 5.8 mg Sodium chloride 5.8 mg Citric acid 0.06 mg

The method of preparing the composition described in Example 8 was as follows: Human recombinant GM-CSF, hard water for injection and other components were mixed.

Example  9

This example shows a representative formulation comprising GDNF.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant GDNF 500 μg Sodium citrate 5.8 mg Sodium chloride 5.8 mg Citric acid 0.06 mg

The method of preparing the composition described in Example 9 was as follows: Human recombinant GDNF, hard water for injection and other components were mixed.

Example  10

This example shows a representative formulation comprising growth hormone.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1.5 ml Human recombinant growth hormone 5 mg Sodium citrate 5.8 mg Sodium chloride 5.8 mg Citric acid 0.06 mg

The method for preparing the composition described in Example 10 was as follows: Human recombinant growth hormone, hard water for injection, and other ingredients were mixed.

Example  11

This example shows a representative formulation comprising an IL-1 receptor antagonist.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Human recombinant IL-1 receptor antagonist 100 mg Sodium citrate 1.29 mg Sodium chloride 5.48 mg Polysorbate 80 0.70 mg

The method of preparing the composition described in Example 11 was as follows: Human recombinant IL-1 receptor antagonist, hard water for injection and other components were mixed.

Example  12

This example shows a representative formulation comprising an anti-VEGF monoclonal antibody.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Anti-VEGF monoclonal antibody 25 mg Trehalos 60 mg Monobasic sodium phosphate 5.8 mg Dibasic Sodium Phosphate 1.2 mg Sodium chloride 5.48 mg Polysorbate 20 0.40 mg

The method of preparing the composition described in Example 12 was as follows: Anti-VEGF monoclonal antibody, hard water for injection and other ingredients were mixed.

Example  13

This example shows a representative formulation comprising an influenza virus vaccine.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Viral antigens (hemagglutinin) 90 μg

The method for preparing the composition described in Example 13 was as follows: viral antigen (hemagglutinin), hard water for injection and other components were mixed.

Example 14

This example shows a representative formulation comprising an artificial tear (ophthalmic solution).

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Polyacrylic acid 2 mg Sorbitol 40 mg Benzalkonium chloride 2 mg

The method for preparing the composition described in Example 14 was as follows: polyacrylic acid, sorbitol, benzalkonium chloride, hard water for injection and other components were mixed.

Example  15

This example shows a representative formulation comprising dextran 70 (blood substitute).

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Dextran 70 60 mg Sodium chloride 9 mg

The method for preparing the composition described in Example 15 was as follows: Dextrin 70, sodium chloride, hard water for injection and other ingredients were mixed.

Example  16

This example shows a representative formulation comprising naloxone (antidote).

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Naloxone hydrochloride 0.4 mg

The method for preparing the composition described in Example 16 was as follows: naloxone hydrochloride and injectable hard water were mixed.

Example  17

This example shows a representative formulation comprising sodium chloride (component that corrects electrolyte equilibrium).

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1 ml Sodium chloride 9 mg

The method for preparing the composition described in Example 17 was as follows: Sodium chloride and hard water for injection were mixed.

Example  18

This example shows a representative dermal preparation for moisturizing the skin.

content Purified water (99.99% light isotopol ¹ H ₂ ¹⁶ O) 21 g glycerin 5 g Methyl hydroxypropyl cellulose 2.5 g

The method for preparing the composition described in Example 18 was as follows: Glycerin, purified hard water and methylhydroxypropylcellulose were mixed.

Example  19

This example shows a representative formulation comprising Interleukin-2.

content Water for injection (99.99% light isotopic ¹ H ₂ ¹⁶ O) 1.2 ml Human recombinant interleukin-2 1.8 x 10 ⁶ IU Mannitol 50 mg Sodium Dodecyl Sulfate 0.18 mg Dibasic Sodium Phosphate 0.89 mg Monobasic sodium phosphate 0.17 mg

The method for preparing the composition described in Example 19 was as follows: Human recombinant interleukin-2, hard water for injection and other ingredients were mixed.

Example  20

This example illustrates the beneficial efficacy of interferon delivery via administration of an interferon composition comprising pharmaceutical hard water as compared to the case of pharmaceutical water.

Substance : Human recombinant interferon-alpha (IFN) was used.

Treatment : Into mucosal tissues of male C57B1 mice weighing about 20 g, 170 ng of IFN per mouse was added to natural distilled water (99.73% of light isopolog ¹ H ₂ ¹⁶ O, control in citrate buffer, pH 5.4-5.5). ) Or 20 μl of solution per mouse made with pharmaceutical hard water (99.90% light isotopol ¹ H ₂ ¹⁶ O). Plasma IFN concentrations were measured 7 minutes after administration using an immunoenzyme assay specific for human IFN. The measurement results are shown as plasma IFN mean ± SD (n = 6) in units of ng / ml in the table below.

process Plasma IFN, ng / ml IFN + Pharmaceutical Water (Control) 3.7 ± 2.0 IFN + Pharmaceutical Water 15.0 ± 1.8 *

* Significantly different from control (p <0.0001)

Example  21

This example illustrates the beneficial efficacy of interferon delivery via administration of an interferon composition comprising pharmaceutical hard water as compared to the case of pharmaceutical water.

Substance : Human recombinant interferon-alpha (IFN) was used.

Treatment : Male C57B1 mice weighing 20 g were dehaired 72 hours before the start of the experiment. At about 1 cm ² of the bald area, 100 ng of IFN per mouse was added in natural distilled water (99.73% of light isopolog ¹ H ₂ ¹⁶ O, control) or pharmaceutical hard water (99.90) in succinate buffer at pH 5.1. 100 μl of solution per mouse were made using% isotopicol ¹ H ₂ ¹⁶ O). Ten minutes after application, plasma IFN concentrations were measured using an immunoenzyme assay specific for human IFN. The measurement results are shown as plasma IFN mean ± SD (n = 5) in units of ng / ml in the table below.

process Plasma IFN, ng / ml IFN + Pharmaceutical Water (Control) 0.37 ± 0.09 IFN + Pharmaceutical Water 3.62 ± 1.01 *

* Significantly different from control (p <0.0001)

Example  22

This example shows a representative sublingual spray comprising interferon alpha.

Content (% by weight) Pharmaceutical hard water (99.99% light isotopologue ¹ H ₂ ¹⁶ O) 92.00 Human recombinant interferon alpha2a 0.85 Glycerol 5 Succinic acid 1.2 Sodium hydroxide 0.95

The method for preparing the composition described in Example 22 was as follows: The above components were mixed in a conventional manner to prepare a sublingual spray comprising interferon alpha.

Example  23

This example shows a representative sublingual spray comprising insulin.

Content (% by weight) Pharmaceutical hard water (99.99% light isotopologue ¹ H ₂ ¹⁶ O) 92.24 Human recombinant insulin 0.81 Glycerol 5 Succinic acid 1.0 Sodium hydroxide 0.95

The method for preparing the composition described in Example 23 was as follows: The above components were mixed in a conventional manner to prepare a sublingual spray comprising insulin.

Example  24

This example shows a representative sublingual spray comprising erythropoietin.

Content (% by weight) Pharmaceutical hard water (99.99% light isotopologue ¹ H ₂ ¹⁶ O) 92.25 Human recombinant erythropoietin 0.80 Glycerol 5 Citric acid 1.0 Sodium hydroxide 0.95

The method for preparing the composition described in Example 24 was as follows: The above components were mixed in a conventional manner to prepare a sublingual spray comprising erythropoietin.

Example  25

This example shows a representative sublingual spray comprising calcitonin.

Content (% by weight) Pharmaceutical hard water (99.99% light isotopologue ¹ H ₂ ¹⁶ O) 92.25 Calcitonin 0.80 Glycerol 5 Succinic acid 1.0 Sodium hydroxide 0.95

The method for preparing the composition described in Example 25 was as follows: The above components were mixed in a conventional manner to prepare a sublingual spray comprising calcitonin.

Claims (17)

99.760 to 99.999% light isotopologue ¹ H ₂ ¹⁶ O and residual amount of isotopologues to make up 100% ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H Pharmaceutical water comprising ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O, and ² H ₂ ¹⁸ O. Heavy isotopics from raw water ¹ H ₂ ¹⁷ O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ A process for preparing the pharmaceutical water of claim 1 comprising depleting ¹⁷ O and ² H ₂ ¹⁸ O. ¹⁷ . Of a therapeutic composition comprising a biologically active substance and the pharmaceutical water an effective amount of the pharmaceutical water is around iso topology logs of about 99.760 to about 99.999% ¹ H ₂ ¹⁶ O and residual amount of iso topology log for configuring a 100% ¹ H ₂ ^{Comprising 17} O, ¹ H ₂ ¹⁸ O, ¹ H ² H ¹⁶ O, ¹ H ² H ¹⁷ O, ¹ H ² H ¹⁸ O, ² H ₂ ¹⁶ O, ² H ₂ ¹⁷ O and ² H ₂ ¹⁸ O Therapeutic composition. The therapeutic composition of claim 3, wherein the biologically active substance is selected from the group consisting of drugs, physiologically active peptides, physiologically active proteins, and nucleic acids. According to claim 4, wherein the drug is an analgesic, anesthetic, anti-acne, anti-aging, anti-allergic, anti-anemia, antianginal, anti-anxiety, antiarrhythmic, anti-asthmatic, antibacterial, anticholinergic, anticoagulant, anticonvulsant , Antidepressant, antidiabetic, anti-diabetic, antidiuretic, antidote, anti-dysogenic, anti-menstrual, anti-nausea, antifibrolytic, antifibrotic, antifungal, anti-glaucoma, anti-bleeding, antihistamine, antihypercalcemia Antihyperglycemic agents, antihyperlipidemic agents, antihypertensive drugs, hyperthyroidism, antihyperacidemia, antihypercalcemia, antihyperglycemic, antihypertensive, anti-inflammatory, anti-kawasaki, antimalarial, antimethemoglobinemia , Antimicrobial, antimigraine, antimyopathy, antineoplastic, antineuropathic, antineutrophil, aviation emperor, anti-neuropathy, antiprotozoal, anti-psoriasis, antipsychotic, antipyretic, antirheumatic , Anti-seborrhea, anticonvulsions Anti-thrombotic, anti-inflammatory, anti-ulcer, anti-drug, anti-viral, anti-wrinkle, appetite-stimulating, appetite suppressant, asthma preventive, bone repression inhibitor, bronchodilator, contraceptive, corticosteroid, pigment remover, fungicide, Diuretics, dialysis solutions, estrogens, hair growth promoters, hair growth inhibitors, hematopoietic stimulants, hepatitis therapies, histamine H2-receptor antagonists, hormones, hygroscopics, insulin resistance therapies, interferon resistance therapies, immunosuppressants, erectile dysfunctions, keratin Moxibustion agents, mucolytic agents, acid agents, myocardial infarction treatment and prevention, neuromuscular blockade, nutritional supplements, vitamins, osteoporosis prevention and treatment, sedatives, skeletal muscle relaxants, emollients and skin moisturizers, skin whitening agents, sympathetic stimulants, Thrombolytics, vaccines, vasodilators, wound healing promoters, anti-irritants, vitamins, nutrients, amino acids and derivatives thereof, US Lal, sakmul medicinal extract, urethane carcinoid, bioflavonoids and treatment composition being selected from the group consisting of an antioxidant. The method according to claim 4, wherein the physiologically active peptide or protein is cytokine, peptide hormone, growth factor, cardiovascular factor, central and peripheral nervous system factor, humoral factor, hematopoietic factor, bone And a factor acting on the skeleton, a factor acting on the gastrointestinal system, a factor acting on the immune system, a factor acting on the genital organs, and an enzyme. 7. The therapeutic composition of claim 6, wherein the cytokine is interferon alpha. 7. The therapeutic composition of claim 6, wherein said peptide hormone is insulin. The therapeutic composition of claim 6, wherein said growth factor is an insulin-like growth factor. 7. The therapeutic composition of claim 6, wherein the peptide hormone is calcitonin. 7. The therapeutic composition of claim 6, wherein said peptide hormone is a growth hormone. The composition of claim 6, wherein said hematopoietic factor is erythropoietin. The therapeutic composition of claim 6, wherein the factor acting on the immune system is a vaccine. The therapeutic composition of claim 3, wherein the amount of pharmaceutical water is from about 1.0 to 99.9 weight percent based on the total weight of the composition. 15. The therapeutic composition of claim 14, wherein the amount of pharmaceutical water is about 50.0 to 99.9 weight percent based on the total weight of the composition. A method of administering a biologically active substance to a mammal in need thereof, comprising administering the therapeutic composition of claim 3 to said mammal. The method of claim 16, wherein the therapeutic composition is administered orally, parenterally, transdermally, transmucosally, intranasally, rectally or topically.

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