CN115463121A

CN115463121A - External skin medicinal preparation for treating gout

Info

Publication number: CN115463121A
Application number: CN202210638464.XA
Authority: CN
Inventors: 李国文
Original assignee: Changsheng Pharmaceutical Co ltd
Current assignee: Changsheng Pharmaceutical Co ltd
Priority date: 2021-06-11
Filing date: 2022-06-08
Publication date: 2022-12-13
Also published as: CN113181149A

Abstract

The invention discloses an external medicinal preparation for treating limb, hand and foot pain arthritis and gout pain, which contains trihydroxymethyl aminomethane as a main medicinal component. The external pharmaceutical preparation comprises medicines and auxiliary materials, and is characterized in that: the main effective components of the medicine and the weight percentage of the medicine in the whole preparation are as follows: 0.01 to 50 percent of trihydroxymethyl aminomethane; the PH of the drug is 10.0-12. The external medicine composition for treating gout is used for preparing medicines for treating or preventing diseases such as gout, gouty arthritis, gout pain, arthritis, joint red swelling and the like.

Description

External skin medicinal preparation for treating gout

Technical Field

The invention belongs to the field of medicine application, relates to a skin external medicine, and particularly relates to an external medicine composition preparation containing trihydroxymethyl aminomethane as a main medicine effective component and used for treating limb, hand and foot pain arthritis and gout pain.

Background

Gout is an fasting blood uric acid level twice a day on a normal purine diet: male blood uric acid >420 μmol/L, female blood uric acid >360 μmol/L. Gout is caused by purine metabolic disorder, and can cause gouty nephropathy, gouty cardiomyopathy, gouty arthritis, tophus and the like.

Gouty arthritis develops when the blood uric acid level exceeds the saturation level of the joint monosodium urate to precipitate and deposit on peripheral joints and surrounding tissues. Patients with gouty arthritis often have sudden joint pain at night, acute attack, severe pain, edema, redness and swelling and inflammation at joints, and pain is slowly relieved until the pain disappears for days or weeks. When pain occurs, the joints are strongly and suddenly painful, and patients describe that the pain feeling is similar to that of burning big toes, so that the pain feeling is difficult to endure. The physical and psychological health of the patient is seriously affected.

At present, most of external application preparations used by gout patients are products without 'national drug standards' approval letters, and some of the external application preparations are even fake medicines, so that the curative effect is poor. The patients urgently need the external medicine for treating the gouty arthritis with quick response and good curative effect.

Tris, also known as: tromethamine, tromethamine and the like.

Tromethamine is an old medicine applied to clinical treatment for many years and is used for treating metabolic acidosis, respiratory acidosis and the like.

The preparation formulation is as follows: injection solution

The routes of administration (methods of use) are: and (4) intravenous drip.

The action mechanism is as follows: the alkaline property of amino in tromethamine molecules is utilized to react with H & lt + & gt in urine to alkalize blood and urine. Increasing pH of blood and urine, and treating metabolic acidosis and respiratory acidosis.

It has more and serious adverse reactions, which may cause hypoglycemia, hypotension, tetany, hyperkalemia, nausea, vomiting, respiratory depression and even respiratory arrest. The intravenous drip can cause local tissue necrosis outside the blood vessel. The intravenous drip should be slow to avoid causing respiratory depression. It is contraindicated for patients with chronic respiratory acidosis and chronic renal acidosis.

In recent years, there have been trials and studies for exploring the use of tris (hydroxymethyl) aminomethane (tromethamine) for the treatment of urinary uric acid calculi, but these have not been used as a formal medicine for clinical treatment.

That is, the current pharmaceutical application of tris (hydroxymethyl) aminomethane is only the application of tromethamine to metabolic acidosis and respiratory acidosis. No research related to the treatment of gouty arthritis, gout pain and joint swelling by external skin administration of 'trihydroxymethyl aminomethane (alkali)' is involved.

Tris (hydroxymethyl) aminomethane: chinese alias: tromethamine.

Number: 77-86-1, formula: C4H11NO3; molecular weight: 121.135.

physical and chemical properties: has irritation, and the tromethamine has one amino group in the molecule and is a non-sodium amino buffer base. The pH of the aqueous solution is 10.5-11.5.

The application in the medicine mainly utilizes the alkalinity thereof, can neutralize H + in urine and alkalify the urine, and solves the problem of treating the acidity (lower PH) of the urine of a human body.

Until now, no research is available about external skin application of 'trihydroxymethyl aminomethane (alkali)' for treating gouty arthritis, gout pain and joint red swelling.

That is, whether "tris (hydroxymethyl) aminomethane (base)" can be used as a drug for external administration for treating gouty arthritis is unknown, and it is necessary to perform a large number of innovative scientific experiments to find out.

If a gel for treating gouty arthritis, gout pain and joint red swelling, which is prepared by externally applying skin with a pharmaceutical effect component of 'trihydroxymethyl aminomethane (alkali)' can be creatively invented, the gel is an unprecedented innovation and is novel.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a new medicine which is directly administrated to the skin external part of the gout attack part, has quick response and good curative effect, namely an external preparation containing a main effective component of tris (hydroxymethyl) aminomethane (alkali) for treating gouty arthritis.

The preparation of the 'tris (hydroxymethyl) aminomethane (alkali)' into a medicine for external administration to treat gouty arthritis needs to consider and solve the following problems:

1. according to the common medical knowledge, not all the medicines can be prepared into external application medicines, and many medicines which can be prepared into injections or oral preparations cannot be prepared into external application preparations. The technical problems of whether the skin is allergic to the medicine, whether the medicine is irritant to the skin, whether the medicine can be absorbed through the skin, how much the medicine can be absorbed and whether the medicine can be effective and the like cannot be simply and directly guessed. In the technical specification of chemical safety of tris (hydroxymethyl) aminomethane, the dangerous goods are marked by Xi-irritant goods, and the risk terminology is as follows: r36/37/38-eye, respiratory, and skin stimulation. The hazard category code is: r36/37/38. These clearly indicate that tris is a skin-irritating, dangerous item that cannot act on the skin, which is sufficient to enable the skilled person to produce a technical prejudice that tris cannot be administered as skin.

According to common medical knowledge, the PH of normally functioning skin cells is acidic, with the PH of the skin averaging about 5.8. General medical knowledge: "basic is harmful to the skin" and in the study of topical drugs for dermal administration, the skilled worker is stressed that the pH of the drug should be neutral, close to pH 7.0. In the eighth round of pharmaceutical specialty planning teaching material "pharmacy" of high school in the country, page 215, chapter thirteen, skin drug delivery preparation, "ph: the pH of the ointment is preferably close to neutral. The pH of the solution is measured after shaking the sample with a suitable solvent (water or ethanol). The pH of the O/W cream should be no greater than 8.3 and the pH of the W/O cream should be no greater than 8.5 "these teachings clearly indicate that the pH of the skin delivery formulation is preferably near neutral and that the pH should be no greater than 8.5. Because when the pH value of blood is lower than 6.9 or higher than 7.7, proteins, enzymes and various cytokines in cells are changed, and the normal functions of the cells are affected. In particular, the strong alkalinity of the composition at a pH of about 11 can cause serious side effects. This is sufficient to allow one of ordinary skill to produce tris (hydroxymethyl) aminomethane (pH 10.5-11), which is highly alkaline and not a technical prejudice for dermal administration.

The "tris (hydroxymethyl) aminomethane (base)" is highly alkaline, and particularly, when it is used as intravenous drip, it is sufficient that "local tissue necrosis is caused if leakage out of blood vessels" is caused, which is a technical prejudice that ordinary technicians cannot administer tris (hydroxymethyl) aminomethane as local skin "because it causes local tissue necrosis.

Use of lye with a PH-value of 10.5-11.5 results in denaturation of skin cell proteins, thereby affecting the absorption of drugs through the skin. That is, it is unknown whether the alkalinity of tris affects skin proteins, whether they can be absorbed through the skin, how much they can be absorbed, whether they can be effective, and the like. In particular, the skilled person is aware of: the molecules of the tris have 4 hydrogen bond donors and 4 hydrogen bond acceptors, and the drug molecules have hydrogen bond donors or acceptors, which can form hydrogen bonds with the lipid of the stratum corneum, which has a negative effect on transdermal drug delivery, which also makes the tris difficult to be absorbed through the skin by ordinary technicians, and cannot be regarded as a technical prejudice for topical skin administration.

According to common medical knowledge, the normal pH of human joint muscles or blood is between 7.35 and 7.45. In the prior art, although it is known that the tris can alkalize blood and promote dissolution of uric acid crystals, if local skin local administration is carried out, a small amount of tris enters joints and other parts, the pH value of blood in the joints is regulated to a certain extent, but human blood can be automatically maintained at 7.25-7.35, so that the pH regulation effect of the tris is very little, the dissolution effect of the uric acid crystals is very little, the effect of promoting dissolution of a large amount of uric acid crystals in the joints cannot be achieved, and the effect of treating gouty arthritis cannot be achieved. This also creates a technical prejudice for the skilled person that the administration of the drug as a topical skin is not possible.

"Trimethylolaminomethane (alkali)" is highly basic, has a pH of about 11, and particularly, when it is used as intravenous drip, it exerts effects on various cytokines, uric acid molecules, various inflammatory factors causing redness and swelling, lactic acid, hydrogen ions in blood, and the like in the focal site of gouty arthritis, and when it leaks outside blood vessels, it causes local tissue necrosis. Whether the strong alkalinity has bad effect on various cytokines and enzymes in the joint red swelling focus or not, namely whether serious side reaction is generated or not. These problems are not known.

The above-mentioned multiple recognition prejudices of "tris (hydroxymethyl) aminomethane (base)" by the skilled person obviously constitute a technical prejudice for the transdermal delivery of "tris (hydroxymethyl) aminomethane (base)" by the skilled person, so that the skilled person would not use "tris (hydroxymethyl) aminomethane (base)" in a pharmaceutical preparation for external use for the treatment of gout, gouty arthritis. That is, the prior art knowledge of the properties of tris is limited to the basicity of the amino group and the technical prejudice of knowledge, which has prevented its use in the preparation of topical pharmaceutical compositions for topical dermal administration, and therefore no tris topical pharmaceutical composition for topical dermal administration has been known in the prior art. Whether the external administration of "tris (hydroxymethyl) aminomethane (base)" can treat gouty arthritis cannot be predicted or predicted, and innovative scientific experiments are needed to discover.

General technicians have common prejudice that the technical problem of transdermal drug delivery of the tris (hydroxymethyl) aminomethane (alkali) exists in five or more of the five or more, and research and development of transdermal drug delivery of the tris (hydroxymethyl) aminomethane (alkali) for treating diseases are hindered. The five technical prejudices of transdermal drug delivery of the trihydroxymethyl aminomethane (alkali) need to be greatly practiced and innovated in creative thinking, the existing prejudice recognition is not believed, the truth-seeking scientific research attitude of objective test data and test effect is believed, and the scientific research spirit of experimental research needs to be invested without the cost. The present invention considers that the molecule of tris has 4 hydrogen bond donors and 4 hydrogen bond acceptors, and also has a basic amino group, which may be a good blending agent, fusion agent, balancing agent for biological cells. The pharmaceutical composition has the functions of balancing hydrogen bond supply and acid-base balance for substances such as inflammatory cytokines in a gouty arthritis focus, and can harmonize, fuse and balance various substances in a pathological focus, such as C-reactive protein (CRP), tumor necrosis factor TNF and the like; it is also possible to regulate the osmotic pressure of diseased cells in the focus and eliminate cellular edema, thereby eliminating the edema problem of gouty arthritis. In view of this possibility, a great deal of experimentation has been conducted to use tris gel (PH 10.0-12) to break the generally recognized belief that the PH of a topical application must be near neutral (PH 7.0), and to pioneer the use of "tris (hydroxymethyl) aminomethane (base)" which is highly alkaline for topical application to treat gouty arthritis, gout pain, and red-swollen joints with PH 10.0-12. And, through experiments (example 4), it was surprisingly found that topical administration of a gel containing tris can reduce inflammatory cytokines (1) C-reactive protein (CRP) in the lesions of gouty arthritis; (2) tumor necrosis factor TNF; reduces or eliminates the arthritis and obtains unexpected curative effect.

Trial experiments of a plurality of patients with gouty arthritis and gout pains show that the tris gel has quick response and good curative effect on toe gouty red swelling and pain. The pain-relieving speed is unexpected for the patient. (since most patients have previously tried other gout gels) without significant side effects. Surprisingly, the gel consisting of carbomer, triethanolamine, tris (hydroxymethyl) aminomethane, water and the like in the gel is found to have a pH as high as about pH11, but the finished gel has no side effects such as undesirable irritation on the skin and the like, and is completely unexpected from the expectation that the skin is damaged by the alkalinity of the gel. The invention overcomes the technical prejudice that the trihydroxymethyl aminomethane (alkali) can not be used for treating diseases by local skin drug delivery, and is an invention with creativity and remarkable effect.

The action mechanism is as follows: it may be a specific molecular structure of "tris" (base): it not only has an amino group, but also has alkalinity; there are 4 hydrogen bond donors and 4 hydrogen bond acceptors, which can be bound to many compounds (cytokines, lipoproteins, enzyme proteins, etc. in blood) via hydrogen bonds, thereby directly acting on various cytokines, uric acid molecules, various inflammatory factors causing redness and swelling, lactic acid, hydrogen ions, etc. in the lesion of gouty arthritis. The therapeutic effect may be the result of the interaction of the basic and hydrogen bond donor and hydrogen bond acceptor of the amino group.

The technical problem to be solved by the invention is as follows: creates an external preparation which is directly administrated to the skin of the gout attack part, and has quick response and good curative effect.

The technical scheme provided by the invention is as follows: a composition for external use containing "tris (hydroxymethyl) aminomethane (alkali)" is prepared by using "tris (hydroxymethyl) aminomethane (alkali)" as a main drug-effective ingredient.

At present, the medicinal application of the tris (hydroxymethyl) aminomethane only comprises the application of the tromethamine to metabolic acidosis and respiratory acidosis.

The invention finds a second medical application of the old medicine 'tromethamine' (tris) (hydroxymethyl aminomethane) in external skin administration for treating gouty arthritis. The application of the tris in preparing the topical medicine composition for preventing or treating gout and gouty arthritis through topical transdermal administration is discovered. Wherein the topical pharmaceutical composition is in the form of a cream, ointment, gel, transdermal formulation, foam, spray, lotion, solution, emulsion or suspension, preferably a gel.

The invention finds that when the tris (hydroxymethyl) aminomethane is externally applied to skin, the tris (hydroxymethyl) aminomethane can obviously reduce the CRP (C-reactive protein) and TNF (tumor necrosis factor) -alpha levels in joint leachate, reduce the joint swelling degree, particularly eliminate the pain speed of gouty arthritis and gout, and is unexpectedly quick!

The external skin administration of the tris gel has obvious treatment effect on the symptoms of gouty arthritis and inflammatory factors.

The preparation of the tris-hydroxymethyl aminomethane gel is simple and can be produced and prepared in a large scale.

Compared with other existing medicines for treating gouty arthritis, the traditional Chinese medicine composition for treating gouty arthritis is low in cost, good in curative effect and quick in effect. Can benefit tens of millions of gout patients.

The core content of the invention is as follows:

1. use of tris (hydroxymethyl) aminomethane in the preparation of a topical pharmaceutical composition for the prevention or treatment of gout, gouty arthritis by topical transdermal administration.

The use as described above, wherein the topical pharmaceutical composition for external use is characterized by: the preparation form comprises: gel, patch, tincture, ointment, cream, membrane, cataplasma, lotion, liniment, aerosol, spray, ointment, transdermal preparation, foam, solution, suspension, rubber paste or plastics.

The external skin pharmaceutical composition preparation for treating gout is characterized by comprising the following components in parts by weight: the main effective component of the external medicine is trihydroxymethyl aminomethane, and the main effective component of the external medicine and the weight percentage of the main effective component in the whole preparation are as follows: 0.01 to 50 percent of trihydroxymethyl aminomethane.

The pharmaceutical composition preparation for external application to the skin as described above is characterized in that: the PH of the topical medicament is 10.0-12.

The local external medicine composite preparation with the main medicine effective component being the tris (hydroxymethyl) aminomethane is characterized in that the preparation comprises the following components in percentage by weight: carbomer 1.2 +/-0.8%, trihydroxymethyl aminomethane 12.1 +/-5.0%, azone 4.0 +/-1.2%, propylene glycol 10.0 +/-3.0%, oleic acid 0.5 +/-0.3% and water for injection 72.2 +/-12%.

The application of the local external pharmaceutical composition preparation in preparing the medicines for treating or preventing the gout of limbs, hands and feet, the gouty arthritis and the gout pain.

The application of the tris in preparing the medicine for preventing or treating the content of C-reactive protein (CRP) and tumor necrosis factor TNF-a inflammatory factor in local lesions through local transdermal administration.

Detailed Description

Example 1: preparation of trihydroxymethyl aminomethane gel

(1) A1 l beaker was taken, 700 ml of water were added, 12 g of carbomer and 140 g of tris (hydroxymethyl) aminomethane were added and stirred for 1 hour. Adding water to a constant volume of 1 liter, stirring for 1 hour, and measuring the pH value to be 10.9. Obtaining the trihydroxymethyl aminomethane gel.

And subpackaging the tris gel into 50ml plastic bottles to obtain the tris gel finished product for treating gout.

Example 2: preparation of trihydroxymethyl aminomethane gel

(1) A1L beaker is taken, 500 ml of water is added, 12 g of carbomer is added, stirring is carried out for 1 hour, 15 g of triethanolamine is added, and stirring is carried out for 1 hour. Measuring the pH value to be 7.2

(2) A1L beaker is taken, added with 220 ml of water and added with 121 g of tris (hydroxymethyl) aminomethane, stirred for 10 minutes and stirred for 1 hour.

(3) Pouring the (2) into the (1), adding water to a constant volume of 1 liter, stirring for 1 hour, and measuring the pH value to be 11.1. Obtaining the trihydroxymethyl aminomethane gel.

Example 3: blank excipient for preparing trihydroxymethyl aminomethane gel

Taking a 1L beaker, adding 500 ml of water, adding 12 g of carbomer, stirring for 1 hour, adding 15 g of triethanolamine, and stirring for 1 hour. Adding water to a constant volume of 1 liter, and measuring the PH value to be 7.2 to obtain the blank excipient for the tris gel.

Example 4: preparation of tris (hydroxymethyl) aminomethane gel

The prescription is as follows:

	content (wt.)
		Carbomer	1.2%
Tris (hydroxymethyl) aminomethane	12.1%
		Azone	4.0%
Propylene glycol	10.0%
		Oleic acid	0.5%
Water for injection	72.2%

Preparing semi-finished gel according to the formula, filling the gel into an aluminum tube by using a gel filling machine, and subpackaging the gel into the tris (hydroxymethyl) aminomethane gel.

Example 5: preparation of tris (hydroxymethyl) aminomethane gel

The prescription is as follows:

	dosage of	Content (wt.)
			Carbomer	12.0g	1.2%
Tris (hydroxymethyl) aminomethane	121.0g	12.1%
			Azone	40.0g	4.0%
Oleic acid	5.0g	0.5%
			Water for injection	822ml	82.2%

Making 20 pieces into 1000g

1 liter of semi-finished gel is prepared according to the prescription, and the gel is filled into an aluminum tube by a gel filling machine and is subpackaged into 20 pieces of 50ml of 1M trihydroxymethyl aminomethane and 12.1 percent of trihydroxymethyl aminomethane gel.

Example 6: curative effect experiment for treating animal gouty arthritis by using trihydroxymethyl aminomethane gel

Establishing a gouty arthritis rat model: take 40 healthy male SD rats with the weight of 180-220 g.

The rats were randomly divided into 4 groups of 10 rats each. Normal control group (no model), model group, treatment group 1 (sample in example 2), treatment group 2 (sample in example 4)

According to a classical method for establishing an acute gouty arthritis model by referring to coderre and the like, rats in a model group and a treatment group are anesthetized and then fixed, the ankle joint of the lower leg of the right hind limb is sterilized by iodophor, a No. 6 injection needle is inserted into the inner side of the tendon of the tibia from the 45-degree direction on the back side of the ankle joint of the right hind limb, after a falling feeling is felt, 0.2 mL/of 10% sodium urate solution is injected, and the ankle joint and the foot paw are red and swollen to serve as a successful modeling standard, so that the gouty arthritis model is prepared.

The treatment groups started dosing 3 days after molding.

Treatment group 1: the gel (sample of example 2) applied with tris was about 0.2cm thick and applied to the ankle skin below 0.5 cm above the upper end of the ankle of the right hind limb for 6 times a day for 3 consecutive days.

Treatment group 2: the gel of Tris (hydroxymethyl) aminomethane (sample of example 4) was applied to the ankle skin of the right hind limb below 0.5 cm above the ankle joint for 6 times per day for 2 consecutive days, with a thickness of about 0.2 cm.

Model group: blank excipients (sample of example 3) without tris were applied and the treatment group was operated.

The circumference of the same part of the ankle joint of the right hind leg and the calf of each rat is measured by a wire binding method before model building, after model building and after the last administration (2 hours) of the rats of the treatment group, and the joint swelling degree of each rat is calculated.

Degree of swelling of joint = (circumference after last administration-circumference before molding)/circumference before molding. And skin symptoms including erythema, rash, etc. were observed in the administered area of each group of rats during the experiment.

After the last administration, after the measurement of the joint swelling degree of the rat and the observation of the administration local symptoms are finished, the rat is killed, the upper and lower parts of the rat are respectively cut off at 0.5 cm by taking the ankle joint of the right hind limb as the center, the tested joint and the surrounding soft tissues are taken down, the ankle joint capsule is cut on an ice tray, the tissues such as the joint capsule, the synovial membrane and the like are quickly cut off, and the weight ratio is 1: diluting with normal saline at a ratio of 9, homogenizing, centrifuging at 12000 rpm at 4 deg.C for 30 min, collecting supernatant, packaging, and storing in refrigerator at-70 deg.C.

Observations during the experiment: the rats in each group had no skin symptoms in the area to which the drug was applied, and no erythema, rash, etc. appeared.

After 3 days of treatment, the rats are in a limp state and active degree, and the treatment effect of the treatment group 2 is obviously better than that of the treatment group 1.

And (3) measuring the content of C-reactive protein (CRP) and tumor necrosis factor TNF in the joint immersion liquid. The CRP level is detected by adopting an immune transmission turbidimetry method during the determination; TNF-a level is detected by a double-antibody one-step sandwich enzyme-linked immunosorbent assay (ELISA). CRP and TNF-alpha contents in the joint extract were determined according to the kit instructions.

The results of the measurements of the joint swelling degree and the joint immersion fluid inflammatory factor level of each group of rats are shown in the following table.

And (3) detection results:

as can be seen from the above table, the swelling degree of the joints and the levels of CRP and TNF-alpha in the joint leachate of the treatment group are both significantly lower than those of the model group. The trihydroxymethyl aminomethane gel has obvious therapeutic action on the symptoms and inflammatory factors of the gouty arthritis rats.

The treatment group 2 has a significantly better treatment effect than the treatment group 1. The unexpectedly good results are demonstrated with the formulation of example 4.

Example 7: comparative study of different formulations on skin irritation

The procedure is as in example 6, wherein the molding time is extended for 6 days and the treatment is administered after molding for 4 days.

60 healthy male SD rats with body weight of 180-220 g are taken.

The rats were randomly divided into 6 groups of 10 rats each. Normal control group (no model), model group, treatment group 1 (sample of example 1), treatment group 2 (sample of example 2), treatment group 3 (sample of example, 4), treatment group, 4 (sample of example, 5)

Erythema and rash of the skin:

group of	Erythema	Rash
			Normal group	Is free of	Is free of
Model set	Is composed of	Is composed of
			Treatment group 1	5	6
Treatment group 2	2	4
			Treatment group 3	0	1
Treatment group 4	1	2

As can be seen from the above table, the treatment group had erythema and rash (number of rats with erythema and rash), and the treatment effect of treatment group 3 was significantly better than that of the other treatment groups. The unexpectedly good results are demonstrated with the formulation of example 4.

Example 8: observation of curative effect of 'tris gel' for treating toe gouty, red and swollen pain of patient

Using the sample of "Tris gel" prepared in example 4, the test group was given to students or relatives and friends with gout:

case 1: opening a certain sheet: the patient is 56 years old and has a 3-year gout history. According to the description of the patients, the gout is hyperuricemic, and the gout is frequently attacked at night, the main attack sites are two toe joints and the instep, and when the gout is suddenly attacked at night, the big toes are punctured like a needle, and sharp pain like needle prick and knife cut, boring pain and red swelling are accompanied. After the tris gel prepared in example 4 was applied, the thickness of the coating was about 0.2cm, and the coating was wrapped with an external application bag and applied once for 1 hour to keep the pain moist. The pain begins to decrease about half an hour, and subsides to about 2 hours. The redness and swelling are relieved from about 3 hours until the redness and swelling are completely removed after about 24 hours, no pain is caused, and the skin does not have erythema, rash and the like.

Case 2: certain of plum: the age of 47 years with a 6 year history of gout. According to the description of the patients, when the patients are examined in hospitals, hyperuricemia gout is confirmed, gout frequently attacks, the main attack site is the joint of toes, and the big toes are burnt like fire at the attack time, so that the gout is unbearable and accompanied with red swelling. After the tris gel prepared in example 4 was applied, the thickness of the coating was about 0.2cm, and the coating was wrapped with an external application bag and applied once for 1 hour to keep the pain moist. Pain began to subside within 40 minutes and disappeared after 4 and a half hours. The red swelling is relieved from about 2 hours until the red swelling is completely relieved after about 20 hours, and the skin does not have erythema, rash and the like.

In the above embodiments, the "tris (hydroxymethyl) aminomethane (alkali)" has a short onset time (i.e., a rapid onset of action) and a good detumescence effect on gouty arthritis and gout. In particular, the speed of pain relief is unexpectedly fast for the patient.

The above embodiments are merely exemplary in nature and are not intended to limit the claimed embodiments or the application or uses of such embodiments.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

2. The use according to claim 1, wherein the topical pharmaceutical composition is characterized by: the preparation form comprises: gels, patches, tinctures, salves, creams, films, cataplasms, lotions, liniments, aerosols, sprays, ointments, transdermal preparations, foams, solutions, or suspensions, plasters or films.

3. A skin external medicine composition preparation for treating gout is characterized in that: the main effective component of the external medicine is trihydroxymethyl aminomethane, and the main effective component of the external medicine and the weight percentage of the main effective component in the whole preparation are as follows: 0.01 to 50 percent of trihydroxymethyl aminomethane.

4. The pharmaceutical composition formulation for external use on skin according to claim 2, wherein: the PH of the topical medicament is 10.0-12.

5. A local external medicine composition preparation with trihydroxymethyl aminomethane as the active ingredient of a main medicine is characterized in that the preparation comprises the following components in percentage by weight: carbomer 1.2 +/-0.8%, trihydroxymethyl aminomethane 12.1 +/-5.0%, azone 4.0 +/-1.2%, propylene glycol 10.0 +/-3.0%, oleic acid 0.5 +/-0.3% and water for injection 72.2 +/-12%.

6. Use of the topical pharmaceutical combination formulation of claim 5 for the manufacture of a medicament for the treatment or prevention of gout in the extremities, including limb, hand and foot, gouty arthritis, gout pain.

7. Use of tris in the manufacture of a medicament for the prevention or treatment of levels of C-reactive protein (CRP) and tumor necrosis factor TNF-a inflammatory factor in a localized lesion by topical transdermal administration.