WO2022042450A1 - 三羟甲基氨基甲烷药学可接受的盐在治疗高尿酸血症药物中的应用 - Google Patents
三羟甲基氨基甲烷药学可接受的盐在治疗高尿酸血症药物中的应用 Download PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the invention belongs to the field of pharmaceutical applications, and relates to a pharmaceutically acceptable salt of trihydroxymethylaminomethane, which is used for the treatment or prevention of hyperuricemia, gout, acute and chronic arthritis, gouty nephropathy, uric acid nephrolithiasis and Use in medicines for related diseases, especially the preparation of trihydroxymethylaminomethane hydrochloride or salt solution for the treatment or prevention of hyperuricemia, gout, acute and chronic arthritis, gouty nephropathy and uric acid nephrolithiasis and related Use in medicines for diseases.
- “Hyperuricemia” refers to any disease, symptom, or condition in which serum uric acid levels are too high (eg, greater than 6.8 mg/dL in men and greater than 6.0 mg/dL in women), including but not limited to gout, Gouty arthritis, stroke, ischemic heart disease, renal dysfunction, uremia, urinary tract stones, gouty nephropathy, kidney stones, chronic kidney disease (CKD), etc.
- Gout is a group of diseases caused by disorders of purine metabolism. Its clinical characteristics are hyperuricemia and the resulting recurrent gouty acute arthritis, tophi deposition, tophic chronic arthritis and joint deformities, often involving kidney, causing chronic interstitial nephritis and uric acid nephrolith formation.
- the disease can be divided into primary and secondary two categories. A small number of primary cases are caused by enzyme defects, often accompanied by hyperlipidemia, obesity, diabetes, hypertension, arteriosclerosis and coronary heart disease. Secondary cases can be caused by various reasons such as kidney disease, blood disease and drugs. A large number of scientific studies have made it clear that gout is caused by uric acid crystals.
- the highest blood uric acid value in clinical reports is 1185 ⁇ mol/L, so the blood uric acid higher than the solubility threshold of 765 ⁇ mol/L can be dissolved in the blood, because uric acid and blood lipids in the blood Proteins or red blood cells or other substances are bound, and the binding between them is not a chemical bond, it should be a hydrogen bond, because their binding force is weak (reversible). After a uric acid molecule binds to blood lipoproteins, etc., it no longer binds to another uric acid molecule (crystallizes), which is why 85% of people with hyperuricemia have no symptoms of gout.
- uric acid when uric acid binds to low-density lipoprotein cholesterol (LDL-C), it promotes its oxidation to oxidized low-density lipoprotein cholesterol (Ox-LDL-C).
- Ox-LDL and Ox-LDL-C are deposited on the inner wall of blood vessels, which can lead to atherosclerosis, and make patients with high uric acid suffer from cardiovascular and cerebrovascular diseases such as atherosclerosis.
- uric acid and macromolecular substances such as blood lipids, blood sugar, and enzyme proteins in the blood causes an impact on the activities of blood lipids, blood sugar, and enzyme proteins.
- Hyperuricemia, gout and related diseases seriously affect patients' quality of life, work ability, and even endanger their lives.
- embodiments of the present invention provide the use of a pharmaceutically acceptable salt of tris in the manufacture of a composition for preventing or treating hyperuricemia.
- the acid that forms a salt with tris includes organic acids and inorganic acids, and the inorganic or organic acids include hydrochloric acid, lysine, ascorbic acid, acetic acid, formic acid, The group of phosphoric acid, sulfuric acid, maleic acid, butanedisulfonic acid, to form salts or hydrogen-bonded compounds with tris, preferably the pharmaceutically acceptable salt of tris is tris Methylaminomethane hydrochloride.
- the hyperuricemia is gout, gouty nephropathy, gouty arthritis and uric acid nephrolithiasis
- the hyperuricemia is excessive uric acid content (high in males).
- CKD chronic kidney disease
- the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane exhibits the following functions: preventing uric acid crystallization, dissolving uric acid crystals, and reducing the interaction of uric acid with macromolecular substances such as blood lipids and blood sugar Combined to reduce the impact on blood lipids and blood sugar.
- composition contains a therapeutically effective dose of the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane and food or pharmaceutically acceptable excipients.
- the composition is selected from a pharmaceutical composition, a feed composition, a food composition or a health care composition
- the pharmaceutical composition is a human drug or avian drug.
- the pharmaceutical composition is formulated as an oral liquid, tablet, capsule, granule, powder, pill, syrup, injection, drop, inhalation, gel ointment , spray, dialysate or dialysis powder
- the composition is administered by instillation, oral administration, smear patch or dialysis.
- composition is formulated as an aqueous solution having a pH of 5.0 to 11.0, preferably an aqueous solution having a pH of 7.4 ⁇ 0.5.
- the concentration of the pharmaceutically acceptable salt of tris in the composition is 0.6 ⁇ 0.4mol/L, preferably 0.3mol/L, more preferably to 0.6mol/L.
- an embodiment of the present invention provides a pharmaceutically acceptable salt of tris or a composition comprising the same for use in the prevention or treatment of hyperuricemia, wherein the prevention or treatment is via tris
- a pharmaceutically acceptable salt of aminomethane and uric acid are combined to form a complex of uric acid and tris(hydroxymethylaminomethane) through hydrogen bonding.
- the acid that forms a salt with tris includes organic acids and inorganic acids, and the inorganic or organic acids include hydrochloric acid, lysine, ascorbic acid, acetic acid, formic acid, The group of phosphoric acid, sulfuric acid, maleic acid, butanedisulfonic acid, to form salts or hydrogen-bonded compounds with tris, preferably the pharmaceutically acceptable salt of tris is tris Methylaminomethane hydrochloride.
- the hyperuricemia is gout, gouty nephropathy, gouty arthritis and uric acid nephrolithiasis
- the hyperuricemia is excessive uric acid content (high in males).
- CKD chronic kidney disease
- the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane exhibits the following functions: preventing uric acid crystallization, dissolving uric acid crystals, and reducing the interaction of uric acid with macromolecular substances such as blood lipids and blood sugar Combined to reduce the impact on blood lipids and blood sugar.
- composition contains a therapeutically effective dose of the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane and food or pharmaceutically acceptable excipients.
- the composition is selected from a pharmaceutical composition, a feed composition, a food composition or a health care composition
- the pharmaceutical composition is a human drug or avian drug.
- the pharmaceutical composition is formulated as an oral liquid, tablet, capsule, granule, powder, pill, syrup, injection, drop, inhalation, gel ointment , spray, dialysate or dialysis powder
- the composition is administered by instillation, oral administration, smear patch or dialysis.
- composition configured as an aqueous solution having a pH of 5.0 to 11.0, preferably an aqueous solution having a pH of 7.4 ⁇ 0.5.
- concentration of the pharmaceutically acceptable salt of tris in the composition is 0.6 ⁇ 0.4mol/L, preferably 0.3mol/L, more preferably to 0.6mol/L.
- embodiments of the present invention provide a method for preventing or treating hyperuricemia comprising administering to a subject in need thereof a therapeutically effective dose of a pharmaceutically acceptable tris(hydroxymethyl)aminomethane A salt or a composition comprising the same, wherein the prevention or treatment is achieved via hydrogen bonding of tris(hydroxymethyl)aminomethane and uric acid to form a uric acid ⁇ tris(hydroxymethyl)aminomethane complex.
- the acid that forms a salt with tris includes organic acid and inorganic acid, and the inorganic acid or organic acid includes hydrochloric acid, lysine, ascorbic acid, acetic acid, formic acid , the group of phosphoric acid, sulfuric acid, maleic acid, butanedisulfonic acid, to form a salt or hydrogen bond compound with tris, preferably the pharmaceutically acceptable salt of tris is tris Hydroxymethylaminomethane hydrochloride.
- the hyperuricemia is gout, gouty nephropathy, gouty arthritis and uric acid nephrolithiasis
- the hyperuricemia is excessive uric acid content (high in males).
- the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane exhibits the following functions: preventing uric acid crystallization, dissolving uric acid crystals, and reducing the interaction of uric acid with macromolecular substances such as blood lipids and blood sugar Combined to reduce the impact on blood lipids and blood sugar.
- the composition contains a therapeutically effective dose of the pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane and food or pharmaceutically acceptable excipients.
- the composition is selected from a pharmaceutical composition, a feed composition, a food composition or a health care composition
- the pharmaceutical composition is a human drug or avian drug.
- the subject comprises a mammal or a non-mammal
- the mammal is a human
- the non-mammal is an avian
- more preferably the The poultry is chicken.
- the dose administered is 0.1 g/kg to 10 g/kg body weight/day, preferably 1.7 g/kg body weight/day, more preferably 3.4 g/kg body weight/day, or
- the dosage is 0.5 ml/kg/time to 3 ml/kg/time based on 0.3 mol/L or 0.6 mol/L tris pharmaceutically acceptable salt solution.
- composition configured as an aqueous solution having a pH of 5.0 to 11.0, preferably an aqueous solution having a pH of 7.4 ⁇ 0.5.
- an embodiment of the present invention provides the use of tris in the preparation of a topical pharmaceutical composition for preventing or treating gout and gouty arthritis by topical transdermal administration.
- the tris is in the form of a cream, ointment, gel, transdermal formulation, foam, spray, lotion, solution, emulsion or suspension form, preferably a gel.
- embodiments of the present invention provide a method for preventing or treating gout, gouty arthritis, comprising topically transdermally administering to a subject in need thereof a therapeutically effective dose of trimethylol Aminomethane or a topical pharmaceutical composition comprising the same, wherein the prophylaxis or treatment is achieved via the hydrogen bonding of tris and uric acid to form a uric acid ⁇ tris complex.
- an embodiment of the present invention provides tris or a topical pharmaceutical composition comprising the same for use in the prevention or treatment of gout, gouty arthritis, wherein the prevention or treatment is via tris Aminomethane and uric acid are combined by hydrogen bonding to form a uric acid ⁇ trishydroxymethylaminomethane complex, which is implemented by topical transdermal administration.
- an embodiment of the present invention provides the use of tris in the preparation of a veterinary pharmaceutical composition or a feed composition for preventing or treating hyperuricemia, gout, and gouty arthritis in poultry.
- embodiments of the present invention provide a method for preventing or treating hyperuricemia, gout, gouty arthritis in avians, comprising administering to a subject bird in need thereof a therapeutically effective dose of trimethylol Aminomethane or a composition comprising the same, wherein the prevention or treatment is achieved via hydrogen bonding of tris and uric acid to form a uric acid ⁇ tris complex.
- an embodiment of the present invention provides tris for use in a veterinary pharmaceutical composition or a feed composition for the prevention or treatment of hyperuricemia, gout, gouty arthritis in poultry, wherein the prevention or treatment is performed via Tris(hydroxymethyl)aminomethane and uric acid are combined to form uric acid-tris(hydroxymethyl)aminomethane complex by hydrogen bonding.
- Figure 1 Infrared detection pattern of uric acid-tris-hydroxymethylaminomethane complex.
- Figure 2 The effect of tris(hydroxymethyl)aminomethane hydrochloride (also known as Changsheng No. 1) on the deposition of uric acid crystals in the kidneys.
- the arrows indicate the radial deposition of uric acid in the kidney, A: normal control group; B: model control group; C: Changsheng No. 1 0.85g/kg group; D: Changsheng No. 1 1.70g/kg group; E: Changsheng No. 1 3.40g/kg group.
- Figure 3 The effect of tris(hydroxymethyl)aminomethane hydrochloride (also known as Changsheng No. 1) on kidney weight. Compared with the model control group, P ⁇ 0.05, P ⁇ 0.001.
- Figure 4 The effect of tris(hydroxymethyl)aminomethane hydrochloride (also known as Changsheng No. 1) on renal coefficient. Compared with the model control group, P ⁇ 0.05, P ⁇ 0.001.
- Figure 5 The results of uric acid crystallisation in the rat kidneys were observed with the naked eye.
- the kidney of Changsheng No. 1 3.40g/kg group was no different from that of the normal control group.
- tromethamine There is an amino group in the tromethamine molecule, which has strong alkalinity, can neutralize H+ in the solution, and can correct metabolic acidemia. It is a commonly used acid-base balance drug for the treatment of blood acidosis. It is used for acute Respiratory, metabolic acidosis and alkalization of urine, to solve the problem of human urine acidity (low pH).
- tromethamine is very alkaline, irritating, and has many side effects, there are many serious adverse reactions.
- tromethamine injection has a variety of serious adverse reactions mainly because the pH value of tromethamine injection is 10.5 to 11.5. Its alkalinity is too strong. When a large amount of lye enters the human body, it will inactivate or denature many key enzymes and proteins in the human body, thereby causing a series of adverse reactions.
- tromethamine In the prior art, the known properties of tromethamine are only limited to that there is an amino group in its molecule with strong alkalinity, which can neutralize H+ in the solution and correct metabolic acidemia. It is an acid. Alkali balance drug, used for acute respiratory, metabolic acidosis and alkalization of urine, to solve the problem of acidity (low pH) of human urine.
- piperacillin has the effect of killing Pseudomonas aeruginosa, so it can treat bacterial infectious diseases caused by Pseudomonas aeruginosa. It cannot be said in general that "piperacillin can treat bacterial infectious diseases”. Because it only treats diseases caused by Pseudomonas aeruginosa, it cannot treat diseases caused by other bacteria. General and imprecise false statements will expand the efficacy and application scope of drugs.
- the practical problems solved by the technical solution for treating gout and hyperuricemia with trihydroxymethylaminomethane of the present invention are: the problem of easy hydrogen bonding (crystallization) between uric acid molecules; uric acid and macromolecular substances such as blood lipids and blood sugar.
- a combination of problems caused by a variety of diseases due to the combination of uric acid and low-density lipoprotein, low-density lipoprotein is oxidized to oxidized low-density lipoprotein, and then deposited to form thrombus, causing cardiovascular and cerebrovascular diseases, atherosclerosis and other diseases related to high uric acid. That is, the known "performance” and “therapeutic mechanism” reaction equations of trihydroxymethylaminomethane (tromethamine) in the existing literature are:
- the alkalinity of a compound is used to treat diseases (medicinal effect), it cannot be formed into a salt. If an acid is used to form a salt, the original medicinal effect will be lost, and the original disease cannot be treated.
- tromethamine trihydroxymethylaminomethane
- medicine effect is to use alkalinity to cure diseases (medicine effect), and it cannot be prepared into a salt. If it is formed into a salt with an acid, the original medicine effect is lost. , the original condition cannot be treated.
- tromethamine has the effect of alkalizing urine and promoting the dissolution of urinary calculi, which is to use the alkalinity of amino groups on its molecule to combine with H+ to increase the pH value of urine to alkalize urine.
- tromethamine a drug that alkalizes urine, cannot be prepared into a salt, like most drugs, in order to improve its convenience of use, to de-alkaline urine, and to treat uric acid crystallization.
- tris(hydroxymethyl)aminomethane hydrochloride are only limited to use it as a common chemical reagent for biochemical tests or as an intermediate in organic synthesis.
- the amino group in the trihydroxymethylaminomethane hydrochloride molecule has been bound to an H+, which cannot alkalinize urine to treat urinary uric acid stones; nor can it treat hyperuricemia.
- the alkalescence of the amino group on the trihydroxymethylaminomethane molecule is only used to increase the pH value of urine, and an attempt is made to alkalize the urine to promote urinary uric acid calculus and treat urinary uric acid calculus disease.
- the invention discloses a pharmaceutically acceptable salt of tris(hydroxymethyl)aminomethane, or a composition composed of tris(hydroxymethyl)aminomethane and inorganic acid or organic acid, which is used for treating or preventing hyperuricemia and gout in preparation. , acute and chronic arthritis, gouty nephropathy and uric acid nephrolithiasis and the use in medicines for related diseases.
- the present invention discloses that trihydroxymethylaminomethane hydrochloride or salt solution is used in the preparation of medicine for treating or preventing hyperuricemia, gout, acute and chronic arthritis, gouty nephropathy, uric acid nephrolithiasis and related diseases the use of.
- the present invention accidentally discovered the new properties that the three hydroxyl groups on the molecules of the known compounds tris(hydroxymethyl)aminomethane hydrochloride and tris(hydroxymethyl)aminomethane can be combined with the three oxygen atoms of the uric acid molecule , and use this property to prepare a drug for treating hyperuricemia and related diseases.
- Directly combine the drug with uric acid molecules in the blood prevent uric acid crystals, dissolve uric acid crystals, reduce the combination of uric acid with macromolecular substances such as blood lipids and blood sugar, and reduce the impact of uric acid on blood lipids and blood sugar.
- the present invention is an invention for the discovery of new pharmaceutical uses of known compounds with new properties.
- tris(hydroxymethyl)aminomethane and “tris(hydroxymethyl)aminomethane hydrochloride” in the pH7.4 tris(hydroxymethyl)aminomethane hydrochloride solution, the products include: “uric acid ⁇ tris(hydroxymethyl)aminomethane” Aminomethane” and "Uric Acid Tris Hydrochloride”.
- Tris(hydroxymethyl)aminomethane hydrochloride can combine with uric acid molecules to form “uric acid ⁇ tris(hydroxymethyl)aminomethane hydrochloride” complex; and "tris(hydroxymethyl)aminomethane” can combine with uric acid molecules to form "uric acid”
- the principle of the "trihydroxymethylaminomethane” complex is: the three hydroxyl groups of the trihydroxymethylaminomethane molecule are combined with the three oxygen atoms of the uric acid molecule through hydrogen bonds.
- Tris can be combined with uric acid molecules to form a complex of "uric acid ⁇ Tris.”
- This invention is the discovery of "trihydroxymethylaminomethane” and “trihydroxymethylaminomethane hydrochloride", the new properties that the three hydroxyl groups on the two commonly used compound molecules can be combined with the three oxygen atoms of the uric acid molecule , and use this property to prepare a drug for treating hyperuricemia and related diseases.
- the known compound "trihydroxymethylaminomethane” can treat various diseases caused by the combination of uric acid, blood lipids, blood sugar and other macromolecular substances.
- Specific diseases such as: due to the combination of uric acid and low-density lipoprotein, resulting in oxidation of low-density lipoprotein to oxidized low-density lipoprotein, causing the deposition of oxidized low-density lipoprotein cholesterol to form thrombus, causing cardiovascular and cerebrovascular diseases related to high uric acid , atherosclerosis and other diseases.
- trihydroxymethylaminomethane hydrochloride is a chemical reagent in the prior art, it has never been used as a medicine.
- the present invention is the same as the invention of most compound medicines.
- a new property of the salt compound, tris(hydroxymethyl)aminomethane which can be combined with uric acid is first discovered, and then based on the discovery of the new property of the product, And make use of this property, and then make this compound into a drug for the invention of pharmaceutical use.
- Prior art 1 In the prior art, the known properties of the known compound tromethamine (trihydroxymethylaminomethane) are only limited to having an amino group in its molecule that has strong basicity and can be neutralized. H+ in the solution can correct metabolic acidemia. It is an acid-base balance drug used for acute respiratory and metabolic acidosis. There are also attempts to alkalize urine with tris(hydroxymethylaminomethane) to resolve the acidity of urine ( Low pH), by alkalizing urine, promoting urinary uric acid calculi, and treating urinary uric acid calculi diseases.
- the prior art tris is limited to the treatment of urinary uric acid stones by acid-base neutralization by injection or oral administration, neutralization of acid for metabolic acidosis and urine alkalization.
- the present invention breaks through the prior art by only using tris(hydroxymethyl)aminomethane molecules by discovering the new performance that tris(hydroxymethyl)aminomethane can combine with uric acid molecules to form a "uric acid ⁇ tris(hydroxymethyl)aminomethane" complex.
- the upper amino acid neutralizes H+ to alkalize urine and treat the limitations of urinary calculi.
- Tris can be directly combined with uric acid molecules in the blood to generate uric acid-tris complex, thereby preventing uric acid. Crystallization, dissolving uric acid crystals, and reducing the combination of uric acid with macromolecular substances such as blood lipids and blood sugar to reduce the impact on blood lipids and blood sugar.
- Tris only limited to the treatment of metabolic acidosis and alkalized urine to treat urinary uric acid stones.
- Indications of Tris of the present invention applicable to all diseases with excessive serum uric acid content (for example, higher than 6.8 mg/dL in males and higher than 6.0 mg/dL in females), including those related to hyperuricemia.
- Gout gouty arthritis, stroke, ischemic heart disease, renal dysfunction, uremia, urinary tract stones, gouty nephropathy, kidney stones, chronic kidney disease (CKD), etc.
- CKD chronic kidney disease
- gout pain in toe joints cardiovascular and cerebrovascular diseases caused by the combination of uric acid molecules and lipoproteins.
- the application range of indications is much larger than the existing technology, and it is suitable for many new indications, such as: gout pain in toe joints, cardiovascular and cerebrovascular diseases caused by the combination of uric acid molecules and lipoproteins, etc.; due to the combination of uric acid and low-density lipoprotein, The resulting low-density lipoprotein is oxidized into oxidized low-density lipoprotein, which causes the deposition of oxidized low-density lipoprotein cholesterol to form thrombus, and causes cardiovascular and cerebrovascular diseases, atherosclerosis and other diseases related to high uric acid. with significant progress.
- Tris(hydroxymethyl)aminomethane hydrochloride The known properties of the known compound "Tris(hydroxymethyl)aminomethane hydrochloride” are only limited to use it as a common chemical reagent for biochemical tests or as an intermediate in organic synthesis.
- the amino group in the trihydroxymethylaminomethane hydrochloride molecule has been combined with a H+, which cannot alkalize urine to treat urinary uric acid stones, nor can it treat hyperuricemia.
- the present invention breaks through the existing technology by discovering that tris(hydroxymethyl)aminomethane hydrochloride can combine with uric acid molecules to form a compound of "uric acid ⁇ tris(hydroxymethyl)aminomethane hydrochloride” through hydrogen bonding.
- tris(hydroxymethyl)aminomethane hydrochloride can combine with uric acid molecules to form a compound of "uric acid ⁇ tris(hydroxymethyl)aminomethane hydrochloride” through hydrogen bonding.
- uric acid ⁇ tris(hydroxymethyl)aminomethane hydrochloride As a commonly used chemical reagent, it is used in biochemical tests or as an intermediate in organic synthesis; it breaks through the limitations of tris-hydroxymethylaminomethane hydrochloride, cannot alkalize urine to treat urinary uric acid stones, and cannot treat hyperuricemia.
- tris can be directly combined with uric acid molecules in blood to generate uric acid-tris hydrochloride complex, thereby preventing uric acid crystals, dissolving uric acid crystals, and reducing uric acid and uric acid.
- the combination of macromolecular substances such as blood lipids and blood sugar can reduce the impact on blood lipids and blood sugar. It is widely used in all diseases with high uric acid value, caused by uric acid crystals and high uric acid, such as: gout pain in toe joints, cardiovascular and cerebrovascular diseases caused by the combination of uric acid molecules and lipoproteins.
- trihydroxymethyl aminomethane hydrochloride it is a chemical reagent, which can not alkalize urine to treat urinary uric acid stones, nor can it treat hyperuricemia and related diseases.
- Indications of the tris hydrochloride or its solution of the present invention all diseases with high serum uric acid content (for example, more than 6.8 mg/dL in men and more than 6.0 mg/dL in women), including diseases with high Uricemia-related gout, gouty arthritis, stroke, ischemic heart disease, renal dysfunction, uremia, urinary tract stones, gouty nephropathy, kidney stones, chronic kidney disease (CKD), etc.
- diseases with high serum uric acid content for example, more than 6.8 mg/dL in men and more than 6.0 mg/dL in women
- diseases with high Uricemia-related gout for example, more than 6.8 mg/dL in men and more than 6.0 mg/dL in women
- diseases with high Uricemia-related gout for example, more than 6.8 mg/dL in men and more than 6.0 mg/dL in women
- diseases with high Uricemia-related gout for example, more than 6.8 mg/dL in men and more than
- trihydroxymethylaminomethane hydrochloride cannot alkalize urine, and is not a drug for alkalizing urine, but a drug for treating hyperuricemia by combining drug molecules with uric acid molecules.
- the present invention is to discover the new properties that "tris-hydroxymethylaminomethane hydrochloride” can combine with uric acid molecules to form a complex of "uric acid ⁇ tris-hydroxymethylaminomethane hydrochloride” and that "tris-hydroxymethylaminomethane” can Combining with uric acid molecule to generate new properties of "uric acid ⁇ trishydroxymethylaminomethane” complex, that is, the discovery of drugs for the two compounds "trishydroxymethylaminomethane hydrochloride” and "trishydroxymethylaminomethane” New uses are inventions and creations for pharmaceutical uses that are novel, creative and have good effects.
- Tris(hydroxymethyl)aminomethane hydrochloride can combine with uric acid molecules to form “uric acid ⁇ tris(hydroxymethyl)aminomethane hydrochloride” complex, and "tris(hydroxymethyl)aminomethane” can combine with uric acid molecules to form "uric acid”
- the principle of the "Tris(hydroxymethyl)aminomethane” complex is: the three hydroxyl groups of the tris(hydroxymethyl)aminomethane molecule and the three oxygen atoms of the uric acid molecule are bound by hydrogen bonds.
- the pharmaceutically acceptable salt of tris can also be combined with uric acid molecules, and also has the potential to be used for the treatment or prevention of hyperuricemia, gout, acute and chronic arthritis, and gouty nephropathy. and uric acid nephrolithiasis and its use in medicines for related diseases.
- composition or combination (salt) composed of tris(hydroxymethyl)aminomethane and an inorganic acid or an organic acid can also be prepared, which can be used in the preparation and treatment of hyperuricemia, gout, acute and chronic arthritis, Gout nephropathy and uric acid nephrolithiasis and related diseases drug application.
- the pharmaceutically acceptable salts of tris(hydroxymethyl)aminomethane include organic acids and inorganic acids that can form salts with tris(hydroxymethyl)aminomethane, and the inorganic acids or organic acids include but are not limited to lysine Amino acid, ascorbic acid, acetic acid, formic acid, phosphoric acid, sulfuric acid, maleic acid, butanedisulfonic acid and other compounds that can form salts or hydrogen bond with tris.
- Tris can alkalize the blood and promote the dissolution of uric acid crystals, but if it is administered locally through the skin, a small amount of Tris enters the joints and other parts, although the blood in the joints is affected.
- the pH value has a certain adjustment effect, but because human blood can automatically maintain at 7.25-7.35, the adjustment effect of Tris on pH is minimal, and it cannot achieve the effect of promoting the dissolution of a large number of uric acid crystals in the joints.
- the role of the treatment of gouty arthritis is not limited to chronic inflammation.
- the present invention discovers that tris(hydroxymethyl)aminomethane or its pharmaceutically acceptable salt can react with uric acid to form a new property of "uric acid-tris(hydroxymethyl)aminomethane combination".
- the principle is to let hydroxymethylaminomethane penetrate through the skin into joints and other parts, and directly combine with the uric acid in it to prevent uric acid crystallization and achieve the effect of treating gouty arthritis.
- tris or a pharmaceutically acceptable salt thereof can be used in the preparation of a topical pharmaceutical composition for preventing and treating gout and gouty arthritis by topical transdermal administration.
- a gel for external use containing tris(hydroxymethyl)aminomethane or a pharmaceutically acceptable salt thereof is prepared, and local transdermal administration is used to prevent and treat gout and gouty arthritis.
- Example 5 See Example 5.
- the tris(hydroxymethyl)aminomethane or its pharmaceutically acceptable salt of the present invention can be combined with uric acid to form a "uric acid-tris(hydroxymethyl)aminomethane conjugate" so as to eliminate the harm of uric acid molecules in the body to the body, it can also be prepared
- the dialysis solution and dialysis powder containing tris(hydroxymethyl)aminomethane or its pharmaceutically acceptable salts are produced to prevent and treat related diseases caused by hyperuric acid in dialysis patients with hyperuric acid.
- the tris(hydroxymethyl)aminomethane or its pharmaceutically acceptable salt of the present invention can be combined with uric acid to form a "uric acid-tris(hydroxymethyl)aminomethane conjugate" so as to eliminate the harm of uric acid molecules in the body to the body, it can also be prepared Health food, food, poultry feed, etc. containing tris(hydroxymethyl)aminomethane or its pharmaceutically acceptable salts are produced.
- the tris(hydroxymethyl)aminomethane or tris(hydroxymethyl)aminomethane salt of the present invention can be combined with uric acid to form "uric acid-tris(hydroxymethylaminomethane) conjugate" so as to eliminate the harm of uric acid molecules in the body to the body, it can also be prepared
- a veterinary drug or feed additive containing tris(hydroxymethyl)aminomethane or a pharmaceutically acceptable salt thereof is developed to prevent and treat avian gout (eg chicken gout) and related diseases.
- the tris(hydroxymethyl)aminomethane hydrochloride solution is an aqueous solution obtained by dissolving tris(hydroxymethyl)aminomethane hydrochloride in water and then adding sodium hydroxide to adjust the pH value of 5.0-11; Hydroxymethylaminomethane is dissolved in water and then hydrochloric acid is added to adjust the solution with pH value of 5.0-11.
- Aqueous solutions with a pH of 7.4 ⁇ 0.5 are preferred.
- injections, oral liquids, tablets, capsules, granules, pills, powders, dialysate containing "tris hydrochloride” or "tris” can be prepared , dialysis powder, etc.; or external pharmaceutical preparations for transdermal administration such as gel ointments, sprays, etc., containing tris(hydroxymethyl)aminomethane or a pharmaceutically acceptable salt thereof.
- the mechanism of action of the drug is: tris(hydroxymethyl)aminomethane (hydrochloride) and uric acid form "uric acid trimethylol" through hydrogen bonding Aminomethane (hydrochloride)" conjugate prevents uric acid crystallization and dissolves uric acid crystals (stones); at the same time, it reduces the combination of uric acid with macromolecular substances such as blood lipids and blood sugar, and reduces the effect of uric acid on blood lipids and blood sugar.
- Indications are diseases with excessive uric acid content (more than 420 ⁇ mol/L in men and more than 360 ⁇ mol/L in women), including gout, gouty arthritis, stroke, ischemic heart disease, kidney disease related to hyperuricemia Dysfunction, uremia, urinary tract stones, gouty nephropathy, kidney stones, chronic kidney disease (CKD), etc.
- gout pain in toe joints cardiovascular and cerebrovascular diseases caused by the combination of uric acid molecules and lipoproteins.
- the mechanism of action of the present invention compared to the existing ones: 1. reducing intake, 2. inhibiting endogenous synthesis, 3. promoting renal excretion, these three mechanisms of action for treating hyperuricemia and gout, the present invention
- the mechanism of eliminating the harm of uric acid by direct combination of drug molecules and uric acid molecules can be called the fourth mechanism of action. Therefore, the treatment scheme for treating gout of the present invention can also be referred to as the fourth scheme for treating gout.
- the new drug trihydroxymethylaminomethane or a pharmaceutically acceptable salt thereof of the present invention can not only solve the problem of uric acid crystallization, but also solve the problem of the effect of uric acid on blood lipids and blood sugar.
- the innovative advantages of the invention are as follows: the action mechanism is clear, the pertinence is strong, the curative effect is good, and the side effects are small; the application range is wide, the safety is high, and the social and economic benefits are good.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- This term in relation to a pharmaceutical composition is intended to encompass products comprising active and inert ingredients constituting a carrier, as well as products directly or indirectly derived from the combination, complexation or polymerization of any two or more ingredients, or by other types of reactions or Any product resulting from an interaction (eg, causing one or more ingredients to break down).
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable excipient.
- Example 1 The combined reaction of tris(hydroxymethyl)aminomethane hydrochloride and uric acid generates "uric acid ⁇ tris(hydroxymethyl)aminomethane (hydrochloride) conjugate” and "uric acid ⁇ tris(hydroxymethyl)aminomethane (hydrochloride)" "Conjugate" research test:
- tris(hydroxymethyl)aminomethane and “tris(hydroxymethyl)aminomethane hydrochloride” in (pH7.4) tris(hydroxymethyl)aminomethane hydrochloride solution, the products include: “uric acid ⁇ tris Methylaminomethane” and "Uric Acid Tris Hydrochloride”.
- solubility of the uric acid-trishydroxymethylaminomethane complex is about 8 times that of uric acid.
- UV detection there are absorption peaks at 233nm and 293nm, and the maximum absorption peak is at 293nm.
- Example 2 The test of dissolving uric acid crystals imitating human medication
- the tris(hydroxymethyl)aminomethane hydrochloride solution (pH7.4 ⁇ 0.5) of the present invention can significantly dissolve the uric acid crystals in the blood at a concentration of 0.3mol/L or 0.6mol/L And make it no longer crystallize subsequently.
- Test example Take 35ml of 0.3mol/L tris(hydroxymethyl)aminomethane hydrochloride solution (pH 7.4 ⁇ 0.5), add 50mg sodium urate, put the mixture into a shaker, shake at 60 rpm for 4 hours at 36.5°C . Result: The sodium urate was completely dissolved and the solution was clear.
- Control example take 35 ml of purified water, add 50 mg of sodium urate, put the mixture into a shaker, and shake at 36.5° C. for 4 hours at 60 rpm. Result: Sodium urate was mostly undissolved and the solution was cloudy.
- the trihydroxymethylaminomethane hydrochloride solution (hereinafter referred to as Changsheng No. 1) was investigated to prevent the formation of rat renal uric acid crystals and to treat rat renal uric acid crystals.
- Test sample tris(hydroxymethyl)aminomethane hydrochloride solution (pH7.4 ⁇ 0.5), a transparent and clear liquid, referred to as Changsheng No. 1 for short.
- Modeling drug 1 Potassium oxazinate, from Beijing Soleibo Technology Co., Ltd.
- Modeling drug 2 hypoxanthine, from Sigma-Aldrich China.
- uric acid determination kit batch number 20200728, from Nanjing Jiancheng Technology Co., Ltd.
- ECC2201 electronic balance ECC5201 electronic balance and DNA103A electronic balance, all from Nanjing Bonita Scientific Instrument Co., Ltd. R-6100 microplate reader, from Shenzhen Redu.
- Test animals SD rats, male, SPF grade, from Speifu (Beijing) Biotechnology Co., Ltd., animal production license number: SYXK (Beijing) 2019-0010 and certificate number: 1103242011018528.
- 35 male SD rats with body weight (240-260) g were selected and randomly divided into 5 groups according to body weight, which were the normal control group, the model control group, and the three dose groups of Changsheng No. 1 (0.85, 1.70, 3.40 g/kg). / day), 7 per group.
- the other groups were given intraperitoneal injection of potassium oxonate 300 mg/kg and intragastric administration of hypoxanthine 300 mg/kg every day.
- the model was established 0.5h after the second administration every day, and the model was established once a day for 5 consecutive days.
- Changsheng No. 1 was administered by intragastric administration, with an administration volume of 10ml/kg, administered twice a day (half the dose/time), with an interval of about 4 hours between the two times, for 5 consecutive days.
- the normal and model control groups were given the same volume of 0.5% CMC-Na.
- the rats On the 4th day of the test, the rats were fasted overnight (about 16 hours). On the 5th day of the test, the rats were weighed and anesthetized by intraperitoneal injection of 60 mg/kg of sodium pentobarbital, with an injection volume of 2 ml/kg. About 0.7 mL of blood was collected from the orbit and the kidney was collected. Whole blood was centrifuged at 6000 r/min for 10 min, the supernatant was taken, the serum uric acid content to be measured was stored at -20°C, the kidneys were weighed, and the deposition of white radial uric acid crystals was observed.
- Determination of uric acid content After the serum was rapidly refused, the uric acid content was measured according to the method in the instructions, and the serum uric acid content was calculated.
- the kidneys of the rats in the normal control group were smaller and no radial white lines were found; the 14 kidneys of the model control group (7 rabbits ⁇ 2 kidneys/rabbit) had obvious radial white lines; the kidneys of the Changsheng No. 1 0.85g/kg group Radial white lines were observed in about 11/14, about 5/14 in the Changsheng No. 1 1.7g/kg group, and no radial white lines in the 14 kidneys in the Changsheng No. 1 3.40g/kg group, which were no different from the normal control group. .
- the kidney coefficient of the model control group was significantly increased (P ⁇ 0.001). This is due to the deposition of uric acid crystals in the kidneys, indicating successful modeling.
- the kidney coefficients of Changsheng No. 1 at 0.85g/kg (P ⁇ 0.01) and 1.70g/kg (P ⁇ 0.05) were also significantly greater than those in the normal control group, and the drug effect was slightly weaker. The comparison showed no significant difference.
- Tris-hydroxymethylaminomethane hydrochloride gel was obtained.
- the tris(hydroxymethyl)aminomethane hydrochloride gel is divided into 50ml plastic bottles to obtain the finished product of the tris(hydroxymethyl)aminomethane hydrochloride gel for treating gout.
- the rats were randomly divided into 3 groups with 10 rats in each group.
- Normal control group no modeling
- Treatment group Apply the gel of Tris (the sample of test 2), about 0.2 cm thick, and apply it to the ankle skin below the upper end of the ankle joint of the right hind limb 0.5 cm, 6 times a day, for 2 consecutive days .
- Model group smear with blank excipient (sample of test 3) without tris-hydroxymethylaminomethane, and the operation is the same as that of the treatment group.
- the rats in the model group and the treatment group were used to measure the circumference of the same part of the ankle joint of the right hind leg of the rats in each group before modeling, after modeling, and after the last administration (2 hours). Joint swelling in rats.
- Degree of joint swelling (perimeter after last administration-perimeter before modeling)/perimeter before modeling.
- the skin symptoms of the rats in each group were observed, including erythema, rash, etc.
- the rats were sacrificed, and the right hind limb ankle joint was taken as the center at 0.5 cm up and down.
- the ankle joint capsule was incised on the plate, and the joint capsule, synovium and other tissues were quickly cut out, weighed, diluted with normal saline at a weight ratio of 1:9, homogenized, centrifuged at 12,000 rpm for 30 minutes at 4 °C, and the supernatant was taken. liquid, aliquot, and store in -70°C refrigerator for testing.
- CRP C-reactive protein
- TNF-a tumor necrosis factor
- ELISA enzyme-linked immunosorbent assay
- the thickness of the coating is about 0.2cm, and it is wrapped with an external application bag, and smeared once an hour to keep the sore place moist.
- the pain started to subside after 40 minutes and disappeared after 3 hours.
- the redness and swelling began to decrease in about 2 hours, and the redness and swelling subsided completely after about 20 hours.
- Case 2 Li Moumou: 54 years old, with a 6-year history of gout. According to the patient's description, he has gout with high uric acid. He has used a certain Yitang herbal gout gel before, with little effect. He said that gout often attacks at night, and the main attack sites are the two toe joints and the instep. When it suddenly attacks at night, the inside of the big toe is like being pricked by a needle, and it is accompanied by a sharp pain like a needle stick and a knife. Pain and redness.
- the thickness of the coating is about 0.2cm, and it is wrapped with an external application bag, and smeared once every hour to keep the sore place moist.
- the pain began to diminish in about half an hour, and disappeared in about 4 hours.
- the redness and swelling began to decrease in about 3 hours, and the redness and swelling subsided completely after about 24 hours.
- trihydroxymethylaminomethane hydrochloride and “trishydroxymethylaminomethane” have short onset time (that is, quick onset) and good detumescence effect on gouty arthritis gout pain. In particular, the speed of pain relief is beyond the patient's expectations.
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Abstract
三羟甲基氨基甲烷药学可接受的盐或由三羟甲基氨基甲烷与无机酸或有机酸组成的组合物在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。三羟甲基氨基甲烷在制备用于经局部透皮给药预防或治疗痛风、痛风性关节炎的局部药物组合物中的用途。
Description
相关申请
本申请要求2020年8月27日向中国国家知识产权局提交的专利申请号为202010874220.2的专利申请以及2021年6月11日提交的专利申请号为202110651157.0的专利申请的优先权和权益，其全部内容通过引用并入本文。
本发明属于药物应用领域，涉及三羟甲基氨基甲烷的药学上可接受的盐，在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途，尤其涉及三羟甲基氨基甲烷盐酸盐或盐溶液在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。
“高尿酸血症”是指任何一种血清中尿酸含量过高(例如男性高于6.8mg/dL、女性高于6.0mg/dL)的疾病、症状或状态，相关疾病包括但不限于痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、痛风性肾病、肾结石、慢性肾脏疾病(CKD)等。
痛风是一组嘌呤代谢紊乱所致的疾病，其临床特点为高尿酸血症及由此而引起的痛风性急性关节炎反复发作、痛风石沉积、痛风石性慢性关节炎和关节畸形，常累及肾脏，引起慢性间质性肾炎和尿酸肾结石形成。本病可分原发性和继发性两大类。原发性者少数由于酶缺陷引起，常伴高脂血症、肥胖、糖尿病、高血压病、动脉硬化和冠心病等。继发性者可由肾脏病、血液病及药物等多种原因引起。大量的科学研究已经明确：痛风就是尿酸结晶造成的。
按单纯化合物在溶液中的溶解结晶理论，凡是高于溶解度时，溶质就应该结晶析出。尿酸在血中的化学溶解度：420μmol/L(7mg/dL)，如果血中尿酸浓度超过这一临界点，血中应该有尿酸结晶形成。但高尿酸血症患者血浆中从未发现尿酸结晶，临床报道最高血尿酸值1185μmol/L，那么高出溶解度临界点765μmol/L的血尿酸能溶解在血液中，是因为尿酸与血液中的血脂蛋白或红细胞或其他物质等结合了，而且他们之间的结合不是化学键结合，应该 是氢键结合，因为他们的结合力很弱(可逆)。尿酸分子与血液中的血脂蛋白等结合后，就不再与另一个尿酸分子结合(结晶)，这就是为什么在高尿酸血症人群中，85％无痛风症状的原因。
虽然85％高尿酸患者无痛风症状，但会患上各种与高尿酸相关的疾病。
现有大量的研究证明：高尿酸血症与高脂血症、肾功能受损、肥胖、高血压、糖尿病的关系密切，并相互促进。尿酸与低密度脂蛋白,血糖呈正相关。
如，尿酸与低密度脂蛋白胆固醇(LDL-C)结合后，会促使其氧化成氧化低密度脂蛋白胆固醇(Ox-LDL-C)。ox—LDL和Ox-LDL-C沉积在血管内壁，会导致粥样硬化，使高尿酸患者患上动脉粥样硬化等心脑血管疾病。
即高尿酸对人体的危害有两个方面：
1、尿酸结晶对人体的伤害。
2、尿酸与血液中的血脂、血糖、酶蛋白等大分子物质的结合，造成对血脂、血糖、酶蛋白活性的影响。
现有技术中，还没有针对性能解决尿酸分子与血液中的血脂、血糖、酶蛋白等大分子结合的问题的药物。
目前治疗高尿酸血症的方法主要有三种方法：1、减少摄入，2、抑制内源性合成，3、促进肾脏排泄。但这三种防治效果都有一定的局限性。
高尿酸血症和痛风及相关疾病严重影响患者生活质量、劳动能力，甚至危害生命。
因此，对高尿酸血症的预防和治疗一直存在迫切的需要。
发明内容
第一方面，本发明的实施方案提供了三羟甲基氨基甲烷药学可接受的盐在制备用于预防或治疗高尿酸血症的组合物中的用途。
在第一方面的一些实施例中，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
在第一方面的另一些实施例中，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。
在第一方面的又一些实施例中，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
在第一方面的再一些实施例中，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基甲烷药学可接受的盐及食品或药学上可接受的辅料。
在第一方面的另一些实施例中，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
在第一方面的又一些实施例中，其中所述药物组合物被配制成口服液、片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、注射剂、滴剂、吸入剂、凝胶软膏、喷涂剂、透析液或透析粉，任选地所述组合物通过滴注、口服、涂抹敷贴或透析的方式施用。
在第一方面的再一些实施例中，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
在第一方面的另一些实施例中，其中所述组合物中的所述三羟甲基氨基甲烷药学可接受的盐的浓度为0.6±0.4mol/L、优选地0.3mol/L、更优选地0.6mol/L。
在第二方面，本发明的实施方案提供了三羟甲基氨基甲烷药学可接受的盐或包含其的组合物在预防或治疗高尿酸血症中使用，其中所述预防或治疗经由三羟甲基氨基甲烷药学可接受的盐和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现
在第二方面的一些实施例中，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
在第二方面的另一些实施例中，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。
在第二方面的另一些实施例中，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
在第二方面的另一些实施例中，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基 甲烷药学可接受的盐及食品或药学上可接受的辅料。
在第二方面的另一些实施例中，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
在第二方面的另一些实施例中，其中所述药物组合物被配制成口服液、片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、注射剂、滴剂、吸入剂、凝胶软膏、喷涂剂、透析液或透析粉，任选地所述组合物通过滴注、口服、涂抹敷贴或透析的方式施用。
在第二方面的另一些实施例中，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
在第二方面的另一些实施例中，其中所述组合物中的所述三羟甲基氨基甲烷药学可接受的盐的浓度为0.6±0.4mol/L、优选地0.3mol/L、更优选地0.6mol/L。
在第三方面，本发明的实施方案提供了一种用于预防或治疗高尿酸血症的方法，包括向有此需要的受试者施用治疗有效剂量的三羟甲基氨基甲烷药学可接受的盐或包含其的组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现。
在第三方面的另一些实施例中，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
在第三方面的另一些实施例中，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。。
在第三方面的另一些实施例中，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
在第三方面的另一些实施例中，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基甲烷药学可接受的盐及食品或药学上可接受的辅料。
在第三方面的另一些实施例中，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
在第三方面的另一些实施例中，其中所述受试者包括哺乳动物或非哺乳动物，优选地，所述哺乳动物为人，优选地，所述非哺乳动物为禽类，更优选地，所述禽类为鸡。
在第三方面的另一些实施例中，其中将所述三羟甲基氨基甲烷药学可接受的盐或包含其 的组合物经过注射、口服、滴注、涂抹、敷贴或透析的方式施加至所述受试者。
在第三方面的另一些实施例中，其中施用剂量为0.1g/kg至10g/kg体重/天，优选为1.7g/kg体重/天，更优选为3.4g/kg体重/天，或施用剂量为基于0.3mol/L或0.6mol/L三羟甲基氨基甲烷药学可接受的盐溶液的0.5ml/kg/次至3ml/kg/次。
在第三方面的另一些实施例中，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
在第四方面，本发明的实施方案提供了三羟甲基氨基甲烷在制备用于经局部透皮给药预防或治疗痛风、痛风性关节炎的局部药物组合物中的用途。
在第四方面的一些实施例中，所述三羟甲基氨基甲烷以乳膏剂、软膏剂、凝胶剂、透皮制剂、泡沫剂、喷雾剂、洗剂、溶液剂、乳剂或混悬剂形式，优选地为凝胶剂。
在第五方面，本发明的实施方案提供了一种用于预防或治疗痛风、痛风性关节炎的方法，包括向有此需要的受试者经局部透皮施用治疗有效剂量的三羟甲基氨基甲烷或包含其的局部药物组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现。
在第六方面，本发明的实施方案提供了三羟甲基氨基甲烷或包含其的局部药物组合物在预防或治疗痛风、痛风性关节炎中使用，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现的，其中通过局部透皮给药实施。
在第七方面，本发明的实施方案提供了三羟甲基氨基甲烷在制备用于预防或治疗禽类高尿酸、痛风、痛风性关节炎的兽药组合物或饲料组合物中用途。
在第八方面，本发明的实施方案提供了一种用于预防或治疗禽类高尿酸、痛风、痛风性关节炎的方法，包括向有此需要的受试禽类施用治疗有效剂量的三羟甲基氨基甲烷或包含其的组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现。
在第九方面，本发明的实施方案提供了三羟甲基氨基甲烷在预防或治疗禽类高尿酸、痛风、痛风性关节炎的兽药组合物或饲料组合物中使用，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现
图1：尿酸·三羟甲基氨基甲烷复合物的红外检测图谱。
图2：三羟甲基氨基甲烷盐酸盐(又名畅盛1号)对肾脏尿酸结晶沉积的影响。箭头所示为尿酸在肾脏的放射状结晶沉积，A：正常对照组；B：模型对照组；C：畅盛1号0.85g/kg组；D：畅盛1号1.70g/kg组；E：畅盛1号3.40g/kg组。
图3：三羟甲基氨基甲烷盐酸盐(又名畅盛1号)对肾重量的影响。与模型对照组比较，P<0.05，P<0.001。
图4：三羟甲基氨基甲烷盐酸盐(又名畅盛1号)对肾系数的影响。与模型对照组比较，P<0.05，P<0.001。
图5：肉眼观察大鼠肾尿酸结晶结果。畅盛1号3.40g/kg组的肾脏与正常对照组无异。
下面详细描述本发明的实施例，所述实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
本申请是发明人对以下问题和事实的发现而做出的：
要解决尿酸对人体危害的问题，就要从尿酸的分子结构、理化性质分析尿酸结晶的原因，找到能有效解决尿酸结晶的问题和尿酸对大分子蛋白酶等的影响问题的作用机理明晰的新药。
发现已知化合物的新性能，然后基于发现的新性能，并利用此性能做成药物，是开发新药的常用方法之一。
已知化合物，氨丁三醇，中文别名：三羟甲基氨基甲烷。
CAS号：77-86-1，分子式：C4H11NO3；分子量：121.135。
氨基丁三醇分子中有一个氨基，具有较强的碱性，能中和溶液中H+，能纠正代谢性酸血症，是一种常用的治疗血液酸中毒的酸碱平衡药，用于急性呼吸性、代谢性酸中毒及碱化尿液，解决人体尿液酸性(pH偏低)的问题。但因氨丁三醇碱性很强，刺激性较强，副作用较多，有多种较严重的不良反应。
根据生物学、酶学常识可知氨丁三醇注射液有多种较严重的不良反应的主要原因是：因为氨丁三醇注射液的pH值10.5～11.5。其碱性太强，当大量碱液进入人体后，会使人体中很多关键的酶蛋白失去活性或变性，从而引起一系列的不良反应。
现有技术中，氨丁三醇的已知性能，仅仅局限于它的分子中有一个氨基具有较强的碱性，能中和溶液中H+，能纠正代谢性酸血症，是一种酸碱平衡药，用于急性呼吸性、代谢性酸 中毒及碱化尿液，解决治疗人体尿液酸性(pH偏低)的问题。
现有文献中，有大量尝试采用氨丁三醇(三羟甲基氨基甲烷)，利用其氨基的碱性与H+结合，通过碱化尿液，促进泌尿系尿酸结石溶解，治疗痛风性泌尿系尿酸结石疾病。有时会把它简单说成“三羟甲基氨基甲烷治疗痛风性泌尿系尿酸结石疾病”，更有把它简化说成“三羟甲基氨基甲烷治疗痛风、高尿酸血症”。其实这种简化说法是不科学的，医学用语必须科学严谨，例如：哌拉西林具有杀死绿脓杆菌的作用，从而能治疗绿脓杆菌感染的细菌感染性疾病。就不能笼统说“哌拉西林可治疗细菌感染性疾病”。因为它只治疗绿脓杆菌感染的疾病，不能治疗其他细菌感染的疾病。笼统的、不严谨的错误说法，会扩大药品疗效和适用范围。
所以若把碱化尿液治疗泌尿系尿酸结石，简化说成“三羟甲基氨基甲烷治疗痛风、高尿酸症”是不科学的、是不对的。
现有文献中涉及的三羟甲基氨基甲烷治疗痛风、高尿酸血症的技术方案所解决的实际问题都是：仅仅局限于利用其氨基的碱性与H+结合，通过碱化尿液，促进尿酸结晶、结石溶解。
本发明的三羟甲基氨基甲烷治疗痛风、高尿酸血症的技术方案所解决的实际问题是：尿酸分子之间容易通过氢键结合(结晶)的问题；尿酸与血脂、血糖等大分子物质的结合引起的多种疾病的问题。比如因尿酸与低密度脂蛋白结合，导致的低密度脂蛋白氧化成氧化型低密度脂蛋白，进而沉积形成血栓，引起的与高尿酸相关的心脑血管、动脉粥样硬化等疾病的问题。即现有文献中三羟甲基氨基甲烷(氨丁三醇)已知的“性能”和“治疗机理”反应方程式为：
C
4H
11NO
3·H
2O+H
+＝C
4H
11NO
3H
++H
2O
现有技术中，并不是所有的药物成盐后，都是药效还是原来的药效，还能治疗原来的病症。
若是利用一个化合物的碱性来治病(药效)，是不能成盐的，若用酸成盐，就失去了原有的药效，就不能治疗原来的病症。
现有技术中氨丁三醇(三羟甲基氨基甲烷)就是利用碱性来治病(药效)，是不能把它制备成盐的，若用酸成盐，就失去了原来的药效，就不能治疗原来的病症。
现有技术中氨丁三醇碱化尿液，促进泌尿结石溶解的药效，就是利用其分子上的氨基的碱性，能与H+结合，提高尿液pH值碱化尿液。
若与盐酸反应制备成盐，氨丁三醇盐酸盐是不能再与H+结合的，成盐后就失去了原有的碱化尿液的药效。氨丁三醇制备成盐的反应方程式：
C
4H
11NO
3+HCl＝C
4H
11NO
3H
+Cl
-
也曾有人因为氨丁三醇碱性太强，无法口服，就提议把氨丁三醇制备成氨丁三醇乳酸盐或醋酸盐，服用氨丁三醇乳酸盐或醋酸盐去碱化尿液促进泌尿系尿酸结石溶解，治疗痛风性泌尿系尿酸结石病。但稍有化学常识的人都知道：氨丁三醇乳酸盐或醋酸盐分子中，已经结合一个H
+，不能再与H+结合的，不能碱化尿液，也就无法治疗痛风性泌尿系尿酸结石病。
所以针对氨丁三醇这一碱化尿液的药物，是不能像大多数药物一样，为了提高它的使用方便性，把它制备成盐，去碱化尿液，治疗尿酸结晶的。
所以不会有人试图把氨丁三醇这一碱化尿液的药物制备成盐(三羟甲基氨基甲烷盐酸盐)的。
市场上，与“三羟甲基氨基甲烷”同时并存的常用化学试剂“三羟甲基氨基甲烷盐酸盐”：
CAS号：1185-53-1，分子式：C
4H
12ClNO
3，分子量156.589。
是市场上与“三羟甲基氨基甲烷”同时并存的、现有的、已知的、常用的化合物，也是很多生化试验中常用的一种化学试剂。
现有技术中，三羟甲基氨基甲烷盐酸盐的已知性能，仅仅局限于把它作为一种常用的化学试剂，用于生化试验或作有机合成中间体使用。三羟甲基氨基甲烷盐酸盐分子中的氨基已经结合一个H+，它不能碱化尿液治疗泌尿系尿酸结石；更不能治疗高尿酸血症。
目前还没有三羟甲基氨基甲烷盐酸盐或盐溶液在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。
也没有三羟甲基氨基甲烷的药学上可接受的盐，或由三羟甲基氨基甲烷与无机酸或有机酸组成的组合物，在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。
另外，现有技术中，只是利用三羟甲基氨基甲烷分子上氨基的碱性，提高尿液的pH值，尝试通过碱化尿液，促进泌尿系尿酸结石，治疗泌尿系尿酸结石疾病。
由于人体血液中pH值会保持稳定，三羟甲基氨基甲烷对血液pH的调解作用很有限，对溶解尿酸结晶的作用也很有限，加上三羟甲基氨基甲烷的碱性对血液中的各种生物酶活性毒害的副作用大，所以现有技术仅局限于注射或口服给药通过酸碱中和，中和酸性治疗代谢性酸中毒和碱化尿液治疗泌尿系尿酸结石，没有人尝试通过局部皮肤给药治疗痛风性关节炎等疾病。
本发明公开了三羟甲基氨基甲烷的药学上可接受的盐，或由三羟甲基氨基甲烷与无机酸或有机酸组成的组合物，在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。特别是本发明公开了三羟甲基氨基甲烷盐酸 盐或盐溶液在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。
发现已知化合物的新性能，然后基于发现的新性能，并利用此性能做成药物，是开发新药的常用方法之一。
本发明是在化学试验过程中，偶然发现了已知化合物三羟甲基氨基甲烷盐酸盐和三羟甲基氨基甲烷分子上的三个羟基能与尿酸分子的三个氧原子结合的新性能，并利用此性能制备成治疗高尿酸血症及相关疾病的药物。让药物与血液中的尿酸分子直接结合，预防尿酸结晶、溶解尿酸晶体，减少尿酸与血脂、血糖等大分子物质的结合，减少尿酸对血脂、血糖的影响。本发明是发现已知化合物新性能的新药物用途的发明。
2020年3月21日，发明人在做药物开发的化学反应试验时，意外发现：
把300mg尿酸，加入到100ml 0.6mol/L(pH7.4)三羟甲基氨基甲烷盐酸盐溶液中，搅拌10分钟，尿酸逐渐溶解，溶液变澄清，继续搅拌，接着生成乳絮状沉淀，真空抽滤干燥得480mg白色块状的尿酸·三羟甲基氨基甲烷复合物。因pH7.4的三羟甲基氨基甲烷盐酸盐溶液中，存在有“三羟甲基氨基甲烷”和“三羟甲基氨基甲烷盐酸盐”所以生成物包括：“尿酸·三羟甲基氨基甲烷”和“尿酸·三羟甲基氨基甲烷盐酸盐”。
反应方程式为：
“三羟甲基氨基甲烷盐酸盐”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷盐酸盐”复合物；和“三羟甲基氨基甲烷”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷”复合物的原理是：三羟甲基氨基甲烷分子的三个羟基通过氢键与尿酸分子的三个氧原子结合。
即发明人惊奇地发现了：
1、发现了：三羟甲基氨基甲烷盐酸盐能与尿酸分子通过氢键结合生成“尿酸·三羟甲基氨基甲烷盐酸盐”复合物。
2、发现了：三羟甲基氨基甲烷能与尿酸分子通过氢键结合生成“尿酸·三羟甲基氨基甲 烷”复合物。
3、发现了：尿酸分子与“三羟甲基氨基甲烷盐酸盐”或“三羟甲基氨基甲烷”结合后，就不再与另一个尿酸分子结合(结晶)。
4、发现了：尿酸分子与“三羟甲基氨基甲烷盐酸盐”或“三羟甲基氨基甲烷”结合后，就不再与血液中的血脂、血糖、蛋白酶等大分子结合，不再影响血液中的血脂、血糖、蛋白酶等大分子的生物活性。
此发明是发现了“三羟甲基氨基甲烷”和“三羟甲基氨基甲烷盐酸盐”，这两个常用化合物分子上的三个羟基能与尿酸分子的三个氧原子结合的新性能，并利用此性能制备成治疗高尿酸血症及相关疾病的药物。
其实严格地说本发明：
1、发现了：已知化合物“三羟甲基氨基甲烷”能治疗尿酸与血脂、血糖等大分子物质的结合引起的多种疾病的第二医药用途。具体疾病如：因尿酸与低密度脂蛋白结合，导致的低密度脂蛋白氧化成氧化型低密度脂蛋白，引起氧化型低密度脂蛋白胆固醇沉积形成血栓，引起的与高尿酸相关的心脑血管、动脉粥样硬化等疾病。
2、发现了：已知化合物“三羟甲基氨基甲烷盐酸盐”的第一医药用途。
因为现有技术中“三羟甲基氨基甲烷盐酸盐”是一种化学试剂，从来没有作为药物用过。
发现了“三羟甲基氨基甲烷盐酸盐”能与尿酸结合的“新性能”，并利用这一性能做成药品，让药品与血液中的尿酸结合治疗高尿酸血症。
本发明是像大多数化合物药物的发明一样，在化学试验过程中，先发现了三羟甲基氨基甲烷盐这一盐类化合物能与尿酸结合的新的性能，然后基于发现产品的新性能，并利用此性能，然后把此化合物做成药物的药物用途发明。
本发明与现有技术相比：
现有技术1：现有技术中，已知化合物氨丁三醇(三羟甲基氨基甲烷)的已知性能，仅仅局限于它的分子中有一个氨基具有较强的碱性，能中和溶液中H+，能纠正代谢性酸血症，是一种酸碱平衡药，用于急性呼吸性、代谢性酸中毒，也有尝试用三羟甲基氨基甲烷碱化尿液，解决尿液酸性(pH偏低)的问题，通过碱化尿液，促进泌尿系尿酸结石，治疗泌尿系尿酸结石疾病。
氨丁三醇(三羟甲基氨基甲烷)碱化尿液的反应方程式为：
即，现有技术三羟甲基氨基甲烷仅局限于注射或口服给药通过酸碱中和，中和酸性治疗 代谢性酸中毒和碱化尿液治疗泌尿系尿酸结石。
本发明因发现了三羟甲基氨基甲烷能与尿酸分子通过氢键结合生成“尿酸·三羟甲基氨基甲烷”复合物的新性能，突破了现有技术只利用三羟甲基氨基甲烷分子上氨基碱性中和H+碱化尿液，治疗泌尿结石的局限，可以用三羟甲基氨基甲烷与血液中的尿酸分子直接结合，生成尿酸·三羟甲基氨基甲烷复合物，从而防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响，广泛用于所有尿酸值高，由尿酸结晶和高尿酸引起的多种疾病，比如避免因与尿酸结合导致的氧化型低密度脂蛋白和氧化型低密度脂蛋白胆固醇的沉积形成的血栓，从而缓解与高尿酸相关的心脑血管、动脉粥样硬化等疾病。
现有技术三羟甲基氨基甲烷的适应症：仅局限于治疗代谢性酸中毒和碱化尿液治疗泌尿系尿酸结石。
本发明三羟甲基氨基甲烷的适应症：适用于所有血清中尿酸含量过高(例如男性高于6.8mg/dL、女性高于6.0mg/dL)的疾病，包括与高尿酸血症相关的痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、痛风性肾病、肾结石、慢性肾脏疾病(CKD)等。具体如：脚趾关节痛风疼、尿酸分子与脂蛋白结合引起的心脑血管疾病等。
适应症应用范围比现有技术大的多，适应于很多新的适应症，如：脚趾关节痛风疼、尿酸分子与脂蛋白结合引起的心脑血管疾病等；因尿酸与低密度脂蛋白结合，导致的低密度脂蛋白氧化成氧化型低密度脂蛋白，引起氧化型低密度脂蛋白胆固醇沉积形成血栓，引起的与高尿酸相关的心脑血管、动脉粥样硬化等疾病。具有显著的进步。
现有技术2：已知化合物“三羟甲基氨基甲烷盐酸盐”的已知性能，仅仅局限于把它作为一种常用的化学试剂，用于生化试验或作有机合成中间体使用。三羟甲基氨基甲烷盐酸盐分子中的氨基已经结合一个H+，它不能碱化尿液治疗泌尿系尿酸结石，更不能治疗高尿酸血症。
本发明因发现了三羟甲基氨基甲烷盐酸盐能与尿酸分子通过氢键结合生成“尿酸·三羟甲基氨基甲烷盐酸盐”复合物的新性能，突破了现有技术只把它作为一种常用的化学试剂，用于生化试验或作有机合成中间体使用的局限；突破了三羟甲基氨基甲烷盐酸，不能碱化尿液治疗泌尿系尿酸结石，不能治疗高尿酸血症的局限，可以用三羟甲基氨基甲烷盐酸盐与血液中的尿酸分子直接结合，生成尿酸·三羟甲基氨基甲烷盐酸盐复合物，从而防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。广泛用于所有尿酸值高，由尿酸结晶和高尿酸引起的多种疾病，具体如：脚趾关节痛风疼、 尿酸分子与脂蛋白结合引起的心脑血管疾病等。
由于pH7.4的三羟甲基氨基甲烷盐酸盐溶液的pH值与人体血液中的pH值一致，避免了强碱对血液中大分子蛋白酶酶活的影响，其毒副作用显著减少。
现有技术三羟甲基氨基甲烷盐酸盐的适应症：是一种化学试剂，不能碱化尿液治疗泌尿系尿酸结石，更不能治疗高尿酸血症及相关疾病。
本发明的三羟甲基氨基甲烷盐酸盐或其溶液的适应症：所有血清中尿酸含量过高(例如男性高于6.8mg/dL、女性高于6.0mg/dL)的疾病，包括与高尿酸血症相关的痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、痛风性肾病、肾结石、慢性肾脏疾病(CKD)等。如：脚趾关节痛风疼、尿酸分子与脂蛋白结合引起的心脑血管疾病等。
本发明公开的“三羟甲基氨基甲烷盐酸盐不能碱化尿液，不是碱化尿液的药物，而是一种药物分子与尿酸分子结合治疗高尿酸血症的药物”。
本发明是发现了“三羟甲基氨基甲烷盐酸盐”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷盐酸盐”复合物的新性能和“三羟甲基氨基甲烷”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷”复合物的新性能，即发现了“三羟甲基氨基甲烷盐酸盐”和“三羟甲基氨基甲烷”这两个化合物的药物新用途，是具有新颖性、创造性且具有良好效果的药物用途发明创造。
“三羟甲基氨基甲烷盐酸盐”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷盐酸盐”复合物，和“三羟甲基氨基甲烷”能与尿酸分子结合生成“尿酸·三羟甲基氨基甲烷”复合物的原理是：三羟甲基氨基甲烷分子的三个羟基、与尿酸分子的三个氧原子通过氢键结合的。根据此原理，可知三羟甲基氨基甲烷的药学上可接受的盐，也能与尿酸分子结合，也同样具有在制备用于治疗或预防高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中的用途。
基于本发明的作用原理，还可以制备出由三羟甲基氨基甲烷与无机酸或有机酸组成的组合物或结合物(盐)，在制备治疗高尿酸血症、痛风、急慢性关节炎、痛风肾病和尿酸性肾结石病及相关疾病药物中应用。
三羟甲基氨基甲烷的药学上可接受的盐，与其成盐的酸包括能与三羟甲基氨基甲烷成盐的有机酸和无机酸，所述的无机酸或有机酸包括但不限于赖氨酸、抗坏血酸，乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸等能与三羟甲基氨基甲烷成盐或氢键结合的化合物。
现有技术，虽然知道三羟甲基氨基甲烷可以碱化血液，促进尿酸结晶溶解，但若通过局部皮肤局部给药，少量的三羟甲基氨基甲烷进入关节等部位，虽然对关节中血液的pH值有一定的调节作用，但因人体血液能够自动维持在7.25-7.35，使得三羟甲基氨基甲烷对pH的调节作用微乎其微，达不到促进关节中大量尿酸结晶溶解的作用，达不到治疗痛风性关节炎 的作用。
即现有技术对三羟甲基氨基甲烷性能的认识局限于氨基的碱性，限制、阻碍了它在局部皮肤给药外用药物组合物制剂中的应用，所以现有技术中没有三羟甲基氨基甲烷局部皮肤给药外用药物组合物制剂。
本发明发现了三羟甲基氨基甲烷或其药学上可接受的盐能和尿酸反应生成“尿酸·三羟甲基氨基甲烷结合物”的新性能，利用三羟甲基氨基甲烷与尿酸结合的原理，让羟甲基氨基甲烷透过皮肤进入关节等部位，与其中的尿酸直接结合，预防尿酸结晶从而达到治疗痛风性关节炎的作用。
即，基于本发明的作用原理，三羟甲基氨基甲烷或其药学上可接受的盐可以在制备局部透皮给药预防和治疗痛风、痛风性关节炎的外用药物组合物中应用。制备出含有三羟甲基氨基甲烷或其药学上可接受的盐的外用凝胶剂，局部透皮给药预防和治疗痛风、痛风性关节炎。具体实施见实施例5。
根据本发明的三羟甲基氨基甲烷或其药学上可接受的盐能和尿酸结合生成“尿酸·三羟甲基氨基甲烷结合物”从而能消除体内尿酸分子对身体危害的原理，还可以制备出含有三羟甲基氨基甲烷或其药学上可接受的盐的透析液、透析粉，去预防和治疗高尿酸透析患者因高尿酸引起的相关疾病等。
根据本发明的三羟甲基氨基甲烷或其药学上可接受的盐能和尿酸结合生成“尿酸·三羟甲基氨基甲烷结合物”从而能消除体内尿酸分子对身体危害的原理，还可以制备出含有三羟甲基氨基甲烷或其药学上可接受的盐的保健食品、食品、禽类饲料等。
根据本发明的三羟甲基氨基甲烷或三羟甲基氨基甲烷盐能和尿酸结合生成“尿酸·三羟甲基氨基甲烷结合物”从而能消除体内尿酸分子对身体危害的原理，还可以制备出含有三羟甲基氨基甲烷或其药学上可接受的盐的兽药药物或饲料添加剂去预防和治疗禽痛风(如鸡痛风)及相关疾病。
在具体实施方案中：三羟甲基氨基甲烷盐酸盐溶液，是把三羟甲基氨基甲烷盐酸盐溶于水后加入氢氧化钠调整pH值5.0—11的水溶液；也可以是把三羟甲基氨基甲烷溶于水后加入盐酸调整pH值5.0—11的溶液。优选pH值为7.4±0.5的水溶液。
在具体实施方案中：可制备含有“三羟甲基氨基甲烷盐酸盐”或“三羟甲基氨基甲烷”的注射剂、口服液、片剂、胶囊剂、颗粒剂、丸剂、散剂、透析液、透析粉等；或含有三羟甲基氨基甲烷或其药学上可接受的盐的凝胶软膏、喷涂剂等透皮给药的外用药物制剂。
在具体实施方案中：三羟甲基氨基甲烷的药学上可接受的盐，或由三羟甲基氨基甲烷与无机酸或有机酸组成的组合物，制备成用于治疗或预防高尿酸血症、痛风、急慢性关节炎、 痛风肾病和尿酸性肾结石病及相关疾病药物的作用机理为：三羟甲基氨基甲烷(盐酸盐)和尿酸通过氢键结合生成“尿酸·三羟甲基氨基甲烷(盐酸盐)”结合物，防止尿酸结晶,溶解尿酸晶体(结石)；同时减少尿酸与血脂、血糖等大分子物质的结合，减少尿酸对血脂、血糖的影响。
适应症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病，包括与高尿酸血症相关的痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、痛风性肾病、肾结石、慢性肾脏疾病(CKD)等。如：脚趾关节痛风疼、尿酸分子与脂蛋白结合引起的心脑血管疾病等。
本发明的作用机理，相对于目前已有的：1、减少摄入，2、抑制内源性合成，3、促进肾脏排泄这三种治疗高尿酸血症和痛风病的作用机理，本发明的通过药物分子与尿酸分子直接结合以达到消除尿酸危害的作用机理可称为第四种作用机理。所以，本发明治疗痛风的治疗方案，也可称为治疗痛风的第四种方案。
现有技术中的无论是采用三羟基甲基氨基甲烷碱化尿液治疗泌尿系尿酸结晶，还是其他抑制尿酸内源性合成或促进尿酸肾脏排泄，都只解决尿酸数量和尿酸结晶问题，没有解决尿酸与血脂、血糖等大分子物质的结合和影响的问题。
本发明的新药三羟甲基氨基甲烷或其药学上可接受的盐不但能解决尿酸结晶问题，也能解决尿酸对血脂、血糖的影响问题。
本发明的创新优点是：作用机理明确，针对性强、疗效好、副作用小；应用范围广且安全性高，具有良好的社会和经济效益。
如本文所用，术语“组合物”旨在涵盖包含指定量的指定成分的产品，以及直接或间接地由指定量的指定成分的组合产生的任何产品。与药物组合物有关的该术语旨在涵盖包含构成载体的活性成分和惰性成分的产品，以及直接或间接由任何两种或多种成分的组合、络合或聚合，或者由其他类型的反应或相互作用(例如导致一种或多种成分分解)产生的任何产品。因此，本发明的药物组合物涵盖通过混合本发明的化合物和药学上可接受的辅料制成的任何组合物。
除非另外定义，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。如果发生冲突，以本说明书(包括定义)为准。在整个说明书和权利要求书中，词语“包括”或诸如“包含”或“含有”的变体将被理解为暗示包含所述整体或整体的组但不排除任何其它整体或整体的组。除非上下文另有要求，否则未用数量词限定的名词包括单数和复数指示对象。术语“例如”或“如”之后的任何实例并不意味着穷举或限 制。
实施例
实施例1三羟甲基氨基甲烷盐酸盐和尿酸结合反应生成“尿酸·三羟甲基氨基甲烷(盐酸盐)结合物”以及对“尿酸·三羟甲基氨基甲烷(盐酸盐)结合物”的研究试验：
1.1称取300mg尿酸，加入到100ml 0.6mol/L(pH7.4)三羟甲基氨基甲烷盐酸盐溶液中，搅拌10分钟，尿酸逐渐溶解，溶液变澄清，继续搅拌，接着生成乳絮状沉淀真空抽滤干燥得480mg白色块状的尿酸·三羟甲基氨基甲烷复合物。因(pH7.4)三羟甲基氨基甲烷盐酸盐溶液中，存在有“三羟甲基氨基甲烷”和“三羟甲基氨基甲烷盐酸盐”所以生成物包括：“尿酸·三羟甲基氨基甲烷”和“尿酸·三羟甲基氨基甲烷盐酸盐”。
反应方程式为：
1.2称取300mg尿酸，加入到100ml0.6mol/L三羟甲基氨基甲烷水溶液中，搅拌10分钟，尿酸逐渐溶解，溶液变澄清，继续搅拌，接着生成乳絮状沉淀，真空抽滤干燥得白色块状的尿酸·三羟甲基氨基甲烷结合物。
反应方程式：
1.3“尿酸·三羟甲基氨基甲烷(盐酸盐)复合物”的性质：
1.3.1溶解度
1.3.1.1取56mg白色块状的尿酸·三羟甲基氨基甲烷复合物加入到100ml水中，搅拌1小时，白色块状全部溶解，溶液澄清且并不再结晶。但在此溶液中继续加入尿酸·三羟甲基氨基甲烷复合物则会使溶液出现过饱和，而使部分复合物不溶解。
表明尿酸·三羟甲基氨基甲烷复合物的溶解度是尿酸的8倍左右。
1.3.1.2称取21mg尿酸，加入到100ml，8mM(pH7.4)三羟甲基氨基甲烷盐酸盐溶液 中，搅拌1小时，尿酸全部溶解，溶液变澄清，继续搅拌接着，则没有乳絮状沉淀生成，溶液一直呈澄清状态。
表明即使针对高达1260μmol/L的尿酸，在用三羟甲基氨基甲烷盐酸盐溶液处理后，血液中形成的尿酸·三羟甲基氨基甲烷复合物不会结晶沉淀。
1.3.2熔点：其熔点为：>270℃(加热过程晶体变为铜黄色)
1.3.3紫外检测：在233nm和293nm处有吸收峰，293nm处为最大吸收峰。
1.3.4红外检测图谱：见附图1
实施例2模仿人体用药的溶解尿酸晶体的试验
试验材料：
1.尿酸(晶体)，
2. 0.3mol/L或0.6mol/L的三羟甲基氨基甲烷盐酸盐溶液(pH 7.4±0.5)，
3.注射用水。
体外模拟试验：
背景：假设一个60kg的高尿酸患者，其血液总量4500ml，100ml血液中溶解有7mg尿酸以及3mg尿酸结晶。在本实施例中用0.3mol/L或0.6mol/L的三羟甲基氨基甲烷盐酸盐溶液(pH 7.4±0.5)处理，施用剂量为0.5ml/kg/次至3.0ml/kg/次。
方案：
(1)对应以0.3mol/L三羟甲基氨基甲烷盐酸盐以及0.5ml/kg/次的施用剂量
取10mg尿酸+100ml水+0.66ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动4小时。结果：溶液澄清并且不再结晶。
(2)对应以0.3mol/L三羟甲基氨基甲烷盐酸盐以及1.0ml/kg/次的施用剂量
取10mg尿酸+100ml水+1.33ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动2小时。结果：溶液澄清并且不再结晶。
(3)对应以0.3mol/L三羟甲基氨基甲烷盐酸盐以及1.5ml/kg/次的施用剂量
取10mg尿酸+100ml水+1.99ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动2小时。结果：溶液澄清并且不再结晶。
(4)对应以0.3mol/L三羟甲基氨基甲烷盐酸盐以及2.0ml/kg/次的施用剂量
取10mg尿酸+100ml水+2.66ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动30分钟。结果：溶液澄清并且不再结晶。
(5)对应以0.3mol/L三羟甲基氨基甲烷盐酸盐以及3.0ml/kg/次的施用剂量
取10mg尿酸+100ml水+4.0ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动30分钟。结果：溶液澄清并且不再结晶。
(6)对应以0.6mol/L三羟甲基氨基甲烷盐酸盐以及0.5ml/kg/次的施用剂量
取15mg尿酸+100ml水+0.66ml的0.6mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动4小时。结果：溶液澄清并且不再结晶。
(7)对应以0.6mol/L三羟甲基氨基甲烷盐酸盐以及1.0ml/kg/次的施用剂量
取15mg尿酸+100ml水+1.33ml的0.6mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动2小时。结果：溶液澄清并且不再结晶。
(8)对应以0.6mol/L三羟甲基氨基甲烷盐酸盐以及1.5ml/kg/次的施用剂量
取15mg尿酸+100ml水+1.99ml的0.6mol/L三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，将混合液放入摇床，以60转在36.5℃下摇动30分钟。结果：溶液澄清并且不再结晶。
模仿体内用药的在三羟甲基氨基甲烷盐酸盐溶液中尿酸晶体溶解的结果如下表1所示。
表1：在三羟甲基氨基甲烷盐酸盐溶液中尿酸晶体溶解的结果
通过以上试验，表明针对高尿酸患者，本发明的三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)以0.3mol/L或0.6mol/L的浓度可以显著溶解血液中的尿酸晶体并且使其后续不再结晶。
实施例3-尿酸钠晶体在三羟甲基氨基甲烷盐酸盐溶液中的溶解性试验
试验例：取35ml的0.3mol/L三羟甲基氨基甲烷盐酸盐溶液(pH 7.4±0.5)，加入50mg尿酸钠，将混合液放入摇床，以60转在36.5℃下摇动4小时。结果：尿酸钠完全溶解，溶液澄清。
对照例：取35ml的纯化水，加入50mg尿酸钠，将混合液放入摇床，以60转在36.5℃下摇动4小时。结果：尿酸钠大部分未溶解，溶液很浑浊。
以上试验结果表明：三羟甲基氨基甲烷盐酸盐溶液能够显著地溶解尿酸钠晶体。
实施例4-三羟甲基氨基甲烷盐酸盐溶液预防和治疗尿酸结晶
在本实施例中探究了三羟甲基氨基甲烷盐酸盐溶液(以下称为畅盛1号)预防大鼠肾尿酸结晶的形成以及治疗大鼠肾尿酸结晶。
试验材料信息：
供试品：三羟甲基氨基甲烷盐酸盐溶液(pH7.4±0.5)，为透明澄清的液体，简称为畅盛1号。
造模药1：氧嗪酸钾，来自北京索莱宝科技有限公司。
造模药2：次黄嘌呤，来自Sigma-Aldrich中国。
其中，精密称取适量的氧嗪酸钾或次黄嘌呤，采用0.5％CMC-Na制成混悬液，分装后室温保存，12h内使用。浓度均为60mg/mL。
试剂及试剂盒：尿酸测定试剂盒，批号20200728，来自南京建成科技有限公司。
仪器：ECC2201电子天平、ECC5201电子天平和DNA103A电子天平，均来自南京博尼塔科学仪器有限公司。R-6100酶标仪，来自深圳雷杜。
试验动物：SD大鼠，雄性，SPF级，来自斯贝福(北京)生物技术有限公司，动物生产许可证号：SYXK(京)2019-0010和合格证号：1103242011018528。
本试验的动物使用方法经机构动物伦理委员会(IACUC)批准。
试验步骤：
选用雄性SD大鼠35只，体重(240-260)g，按照体重随机分成5组，分别为正常对照组、模型对照组、畅盛1号三个剂量组(0.85、1.70、3.40g/kg/天)，每组7只。
除正常对照组外，其余各组每天腹腔注射氧嗪酸钾300mg/kg合并灌胃次黄嘌呤300mg/kg，注射、灌胃体积均为5ml/kg，正常对照组给予相同体积0.5％CMC-Na，每天在第二次给药后0.5h造模，造模1次/天，连续5天。畅盛1号灌胃给药，给药体积10ml/kg，给药两次/天(剂量减半/次)，两次间隔约4h，连续5天。正常及模型对照组灌胃相同体积0.5％CMC-Na。
试验第4天，大鼠禁食过夜(约16h)，试验第5天，大鼠称重，腹腔注射60mg/kg戊巴比妥钠麻醉，注射体积2ml/kg。眼眶取血约0.7mL后取肾。全血6000r/min，离心10min， 取上清，-20℃保存待测血尿酸含量，肾脏称重，并剖开观察白色放射状尿酸结晶沉积情况，-70℃保存备用。
尿酸含量测定：血清迅速复融后，按照说明书的方法，进行尿酸含量测定，计算血清尿酸含量。
数据处理：数据以均数±标准差(x±标准差)表示，用SPSS 25.0软件进行统计，多组之间的比较用One-Way ANOVA进行分析，方差齐性用LSD检验，P<0.05为差异有统计学意义。
试验结果：
4.1对肾尿酸结晶形成的预防和治疗肾尿酸结晶
4.1.1对肾脏尿酸结晶沉积的影响
正常对照组大鼠肾脏较小，未见放射状白线；模型对照组14个肾脏(7只兔×2肾/只)均观察到明显的放射状白线；畅盛1号0.85g/kg组肾脏约11/14观察到放射状白线，畅盛1号1.7g/kg组约为5/14，畅盛1号3.40g/kg组14个肾脏均未见放射状白线，与正常对照组无异。
畅盛1号对肾脏尿酸结晶沉积的影响，照片见附图2。其中，箭头所示为尿酸在肾脏的放射状结晶沉积A：正常对照组；B：模型对照组；C：畅盛1号0.85g/kg组；D：畅盛1号1.70g/kg组；E：畅盛1号3.40g/kg组。
4.1.2对肾系数的影响
与正常对照组比较，模型对照组肾脏系数显著增大(P<0.001)。这是由于尿酸在肾脏结晶沉积，表明造型成功。畅盛1号0.85g/kg(P<0.01)、1.70g/kg(P<0.05)肾脏系数亦显著大于正常对照组，药效作用稍弱，畅盛1号3.40g/kg与正常对照组比较未见显著差异。
与模型对照组比较，畅盛1号1.70g/kg(P<0.05)、3.40g/kg(P<0.001)肾系数显著减小，见表2。
表2畅盛1号对大鼠肾重、肾系数影响
注：与模型对照组比较，P<0.05，P<0.001；与正常对照组比较，P<0.05，P<0.01，P<0.001；n：样本数。
畅盛1号对肾重量的影响。见附图3，与模型对照组比较，P<0.05，P<0.001。
畅盛1号对肾系数的影响。见附图4，与模型对照组比较，P<0.05，P<0.001。
4.1.3肉眼观察大鼠肾尿酸结晶结果，照片见附图5。其中，畅盛1号3.40g/kg组的肾脏与正常对照组无异。
4.2对血尿酸含量的影响
如表3所示：与正常对照组比较，模型对照组、畅盛1号0.85(P<0.05)、1.70(P<0.05)、3.40(P<0.05)g/kg血尿酸含量显著升高。与模型对照组比较，畅盛1号各剂量组具有改善作用。
表3畅盛1号对大鼠血尿酸含量影响
| 组别 | 剂量(g/kg) | 血清尿酸含量(μmol/L) |
| 正常对照组 | - | 224.37±13.33 |
| 模型对照组 | - | 1018.46±279.00 |
| 畅盛1号 | 0.85 | 976.91±172.29 |
| 畅盛1号 | 1.70 | 838.42±3.19 |
| 畅盛1号 | 3.40 | 965.17±215.90 |
注：与正常对照组比较，P<0.01，P<0.001；n：样本数。
以上试验表明，三羟甲基氨基甲烷盐酸盐溶液pH7.4(畅盛1号)剂量依赖性减少尿酸在肾脏结晶沉积。肉眼观察，畅盛1号3.40g/kg组的肾脏的颜色、大小与正常对照组无异，且肾系数与正常组无统计学差异，表明畅盛1号能预防和治疗高尿酸导致的肾脏发炎肿大，并能预防和治疗尿酸在肾脏结晶沉积。
实施例5
5.1试验一、三羟甲基氨基甲烷盐酸盐凝胶剂制备
取1升烧杯，加700毫升水，加12克卡波姆，加156克三羟甲基氨基甲烷盐酸盐，搅拌1小时，加氢氧化钠溶液调pH值7.4，加水定容至1升。得三羟甲基氨基甲烷盐酸盐凝胶。把三羟甲基氨基甲烷盐酸盐凝胶剂分装到50ml塑料瓶中，即得治疗痛风的三羟甲基氨基甲烷盐酸盐凝胶剂成品。
5.2试验二、三羟甲基氨基甲烷凝胶剂制备
①取1升烧杯，加500毫升水，加12克卡波姆，搅拌1小时，加15克三乙醇胺，搅拌1小时。测pH值7.2
②取1升烧杯，加220毫升水，加121克三羟甲基氨基甲烷，搅拌10分钟，搅拌1小时。
③把②倒入①中，加水定容至1升，搅拌1小时，测pH值11.1。得三羟甲基氨基甲烷凝胶剂。
把三羟甲基氨基甲烷凝胶剂分装到50ml塑料瓶中，即得治疗痛风的三羟甲基氨基甲烷凝胶剂成品。
5.3试验三、制备三羟甲基氨基甲烷凝胶剂用的空白赋型剂
①取1升烧杯，加500毫升水，加12克卡波姆，搅拌1小时，加15克三乙醇胺，搅拌1小时。加水定容至1升，测pH值7.2，得三羟甲基氨基甲烷凝胶剂用的空白赋型剂。
5.4“三羟甲基氨基甲烷凝胶剂”治疗动物痛风性关节炎疗效实验
痛风性关节炎大鼠模型的建立：取健康雄性SD大鼠30只，体重180～220g。
将大鼠随机分为3组，每组10只。正常对照组(不造模)、模型组、治疗组(三羟甲基氨基甲烷凝胶剂治疗)
参考coderre等人的建立急性痛风性关节炎模型的经典方法，将模型组和治疗组大鼠麻醉后固定，碘伏消毒右后肢小腿踝关节，用6号注射针在右后肢踝关节背侧从45°方向插入至胫骨肌腱内侧，感觉有落空感后，注人10％尿酸钠溶液0.2mL/只，以踝关节及足爪红肿为造模成功标准，制备痛风性关节炎模型。
造模后当日开始，治疗组开始给药。
治疗组：涂抹三羟甲基氨基甲烷的凝胶剂(试验二的样品)，厚约0.2cm，包敷于右后肢踝关节上端0.5cm处以下踝部皮肤，6次/天，连续2天。
模型组：涂抹不含三羟甲基氨基甲烷的空白赋型剂(试验三的样品)，操作同治疗组。
模型组、治疗组大鼠分别于造模前、造模后和末次给药后(2小时)，采用缚线法，测量各组大鼠右后肢小腿踝关节同一部位的周径，计算每只大鼠的关节肿胀度。
关节肿胀度＝(末次给药后周径－造模前周径)/造模前周径。并于实验期间观察各组大鼠给药区域皮肤症状，包括红斑、皮疹等。
末次给药后，做完大鼠关节肿胀度测量及给药局部症状观察完毕后，处死大鼠，以右后肢踝关节为中心上下各0.5cm处剪断，取下受试关节及周围软组织，冰盘上切开踝关节囊，快速切取关节囊、滑膜等组织，称重，按重量比1：9比例加生理盐水稀释，匀浆，4℃条件下12000转/分钟离心30min，取上清液，分装，-70℃冰箱保存待测。
实验期间观察结果：各组大鼠给药区域皮肤症状，没有出现红斑、皮疹等。
测定关节浸液中C反应蛋白(CRP)和肿瘤坏死因子TNF的含量。测定时采用免疫透射比浊法检测CRP水平；采用双抗体一步夹心法酶联免疫吸附(ELISA)法检测TNF-a水平。按照试剂盒说明书操作，测定关节浸液中CRP和TNF-α含量。
各组大鼠关节肿胀度及关节浸液炎症因子水平测定结果见下表。
检测结果：
由上表可见，治疗组关节肿胀度及关节浸出液中CRP、TNFα水平均显著低于模型组。说明三羟甲基氨基甲烷凝胶剂对痛风性关节炎大鼠的症状及炎症因子均有显著的治疗作用。
5.5“三羟甲基氨基甲烷盐酸盐凝胶剂”和“三羟甲基氨基甲烷凝胶剂”治疗患者脚趾痛风性红肿疼痛疗效观察
应用试验一和试验二制备的“三羟甲基氨基甲烷盐酸盐凝胶剂”和“三羟甲基氨基甲烷凝胶剂”样品，以赠送试用的方式给本实验组人员的有痛风病的同学或亲友，在充分告知并征得同意确保安全的情况下试用：
病例1：赵某某：58岁，有5年痛风病史。据患者描述，她在医院检查时，确认是高尿酸痛风，痛风经常发作，主要发作部位是脚趾关节处，发作时，大脚趾被火烧一样，让人难以忍受，并伴随红肿。
涂抹试验一制备的三羟甲基氨基甲烷盐酸盐凝胶剂后，涂层厚度约0.2cm，并用外敷袋包敷,1小时涂抹一次，使疼处保持湿润。40分钟疼痛开始减弱，到3小时后，疼痛消失。红肿从2小时左右开始减轻，直至20小时左右后红肿完全消退。
病例2：李某某：54岁，有6年痛风病史。据患者描述，他是尿酸高痛风，以前曾使用某医堂草本痛风凝胶，几乎没什么效果。他说在痛风经常在夜间发作，主要发作部位是两个脚趾关节和脚背处，夜间突然发作时，大脚趾内像被针扎一样，且伴随有针刺、刀割般的锐性疼痛，钻心地疼，并伴随红肿。
涂抹试验二制备的三羟甲基氨基甲烷凝胶剂后，涂层厚度约0.2cm，并用外敷袋包敷,1小时涂抹一次，使疼处保持湿润。半小时左右疼痛开始减弱，到4小时左右，疼痛消失。红肿从3小时左右开始减轻，直至24小时左右后红肿完全消退。
上述实施例中，“三羟甲基氨基甲烷盐酸盐”和“三羟甲基氨基甲烷”对痛风性关节炎痛风疼的起效时间短(即起效快)，消肿效果好。特别是止痛速度之快出乎患者的预料。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含 于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (35)
- 三羟甲基氨基甲烷药学可接受的盐在制备用于预防或治疗高尿酸血症的组合物中的用途。
- 根据权利要求1所述的用途，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
- 根据权利要求1所述的用途，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。
- 根据权利要求1至3中任一项所述的用途，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
- 根据权利要求1至4中任一项所述的用途，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基甲烷药学可接受的盐及食品或药学上可接受的辅料。
- 根据权利要求5所述的用途，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
- 根据权利要求6所述的用途，其中所述药物组合物被配制成口服液、片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、注射剂、滴剂、吸入剂、凝胶软膏、喷涂剂、透析液或透析粉，任选地所述组合物通过滴注、口服、涂抹敷贴或透析的方式施用。
- 根据权利要求1至7中任一项所述的用途，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
- 根据权利要求1至8中任一项所述的用途，其中所述组合物中的所述三羟甲基氨基甲烷药学可接受的盐的浓度为0.6±0.4mol/L、优选地0.3mol/L、更优选地0.6mol/L。
- 三羟甲基氨基甲烷药学可接受的盐或包含其的组合物在预防或治疗高尿酸血症中使用，其中所述预防或治疗经由三羟甲基氨基甲烷药学可接受盐和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现，
- 根据权利要求10使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
- 根据权利要求10或11使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。
- 根据权利要求10至12任一项使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
- 根据权利要求10至13任一项使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基甲烷药学可接受的盐及食品或药学上可接受的辅料。
- 根据权利要求10至14任一项使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
- 根据权利要求15使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述药物组合物被配制成口服液、片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、注射剂、滴剂、吸入剂、凝胶软膏、喷涂剂、透析液或透析粉，任选地所述组合物通过滴注、口服、涂抹敷贴或透析的方式施用。
- 根据权利要求10至16任一项使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
- 根据权利要求10至13任一项使用的所述三羟甲基氨基甲烷药学可接受的盐或所述组合物，其中所述组合物中的所述三羟甲基氨基甲烷药学可接受的盐的浓度为0.6±0.4mol/L、优选地0.3mol/L、更优选地0.6mol/L。
- 一种用于预防或治疗高尿酸血症的方法，包括向有此需要的受试者施用治疗有效剂量的三羟甲基氨基甲烷药学可接受的盐或包含其的组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现。
- 根据权利要求19所述的方法，其中与三羟甲基氨基甲烷成盐的酸包括有机酸和无机酸，所述的无机酸或有机酸包括盐酸、赖氨酸、抗坏血酸、乙酸、甲酸、磷酸、硫酸、马来酸、丁二磺酸的组，以与三羟甲基氨基甲烷成盐或氢键结合的化合物，优选地所述三羟甲基氨基甲烷药学可接受的盐是三羟甲基氨基甲烷盐酸盐。
- 根据权利要求19或20所述的方法，其中所述高尿酸血症为痛风、痛风性肾病、痛风性关节炎和尿酸肾结石，优选地所述高尿酸血症为尿酸含量过高(男性高于420μmol/L，女性高于360μmol/L)的疾病、痛风、痛风性关节炎、脑中风、缺血性心脏病、肾机能障碍、尿毒症、尿路结石、尿酸盐肾病变、肾结石或慢性肾脏疾病(CKD)。。
- 根据权利要求19至21中任一项所述的方法，其中所述三羟甲基氨基甲烷药学可接受的盐表现出以下功能：防止尿酸结晶，溶解尿酸晶体，和减少尿酸与血脂、血糖等大分子物质的结合以减少对血脂、血糖的影响。
- 根据权利要求19至22中任一项所述的方法，其中所述组合物含有治疗有效剂量的所述三羟甲基氨基甲烷药学可接受的盐及食品或药学上可接受的辅料。
- 根据权利要求23所述的方法，其中所述组合物选自药物组合物、饲料组合物、食品组合物或保健组合物，任选地所述药物组合物为人用药物或禽类用药物。
- 根据权利要求19至24中任一项所述的方法，其中所述受试者包括哺乳动物或非哺乳动物，优选地，所述哺乳动物为人，优选地，所述非哺乳动物为禽类，更优选地，所述禽类为鸡。
- 根据权利要求19至25中任一项所述的方法，其中将所述三羟甲基氨基甲烷药学可接受的盐或包含其的组合物经过注射、口服、滴注、涂抹、敷贴或透析的方式施加至所述受试者。
- 根据权利要求19至26中任一项所述的方法，其中施用剂量为0.1g/kg至10g/kg体重/天，优选为1.7g/kg体重/天，更优选为3.4g/kg体重/天，或施用剂量为基于0.3mol/L或0.6mol/L三羟甲基氨基甲烷药学可接受的盐溶液的0.5ml/kg/次至3ml/kg/次。
- 根据权利要求19至27中任一项所述的方法，其中所述组合物被配置为pH值为5.0至11.0的水溶液，优选地pH值为7.4±0.5的水溶液。
- 三羟甲基氨基甲烷在制备用于经局部透皮给药预防或治疗痛风、痛风性关节炎的局部药物组合物中的用途。
- 根据权利要求29所述的用途，其中所述三羟甲基氨基甲烷以乳膏剂、软膏剂、凝胶剂、透皮制剂、泡沫剂、喷雾剂、洗剂、溶液剂、乳剂或混悬剂形式，优选地为凝胶剂。
- 一种用于预防或治疗痛风、痛风性关节炎的方法，包括向有此需要的受试者经局部透皮施用治疗有效剂量的三羟甲基氨基甲烷或包含其的局部药物组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现
- 三羟甲基氨基甲烷或包含其的局部药物组合物在预防或治疗痛风、痛风性关节炎中使用，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现的，其中通过局部透皮给药实施
- 三羟甲基氨基甲烷在制备用于预防或治疗禽类高尿酸、痛风、痛风性关节炎的兽药组合物或饲料组合物中用途。
- 一种用于预防或治疗禽类高尿酸、痛风、痛风性关节炎的方法，包括向有此需要的受试禽类施用治疗有效剂量的三羟甲基氨基甲烷或包含其的组合物，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现
- 三羟甲基氨基甲烷在预防或治疗禽类高尿酸、痛风、痛风性关节炎的兽药组合物或饲料组合物中使用，其中所述预防或治疗经由三羟甲基氨基甲烷和尿酸通过氢键结合生成尿酸·三羟甲基氨基甲烷复合物来实现
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