CN1205206A - Use of tetrahydrofolates in natural stereoisomeric form for production of pharmaceutical preparation suitable for influencing homocystenie level, particularly for assisting remethylation of homocystei - Google Patents
Use of tetrahydrofolates in natural stereoisomeric form for production of pharmaceutical preparation suitable for influencing homocystenie level, particularly for assisting remethylation of homocystei Download PDFInfo
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- CN1205206A CN1205206A CN 98102983 CN98102983A CN1205206A CN 1205206 A CN1205206 A CN 1205206A CN 98102983 CN98102983 CN 98102983 CN 98102983 A CN98102983 A CN 98102983A CN 1205206 A CN1205206 A CN 1205206A
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- tetrahydrofolic acid
- methyl
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Abstract
This invention relates to the use of tetrahydrofolates in natural stereoisomeric form for the production of a pharmaceutical preparation suitable for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine. Clinical areas of application include all anomalies of the homocysteine level, particularly the prevention and treatment of cardiovascular diseases and the prevention of neural tube deficiencies. The present invention also relates to pharmaceutical preparations together with pharmaceutically compatible active and adjuvant substances, for influencing the homocysteine level, particularly when a methylene tetrahydrofolate reductase deficiency exists, such as when thermolabile methylene tetrahydrofolate reductase exists for example.
Description
The natural stereoisomer that the present invention relates to tetrahydrofolic acid is used to regulate homocysteine level in preparation, especially promotes the purposes in the methylated again pharmaceutical preparation of cysteine.Its clinical application range comprises all abnormal conditions of homocysteine level, especially prevents and treat cardiovascular disease, and prevention neurocele food deficiency disease.
" the natural stereoisomer of tetrahydrofolic acid " in the present specification represented 5-formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid or (6S)-tetrahydrofolic acid, or the salt of its pharmaceutically compatible.
As medicine, tetrahydrofolic acid is so far mainly with 5-formyl-5,6,7,8-tetrahydrofolic acid (formyl tetrahydrofolic acid) or 5-methyl-5,6,7, and the calcium salt forms of 8-tetrahydrofolic acid is used for the treatment of the megaloblast folic acid deficiency anemia; As the antidote of promoting antifol (especially aminopterin-induced syndrome and the methotrexate) compatibility in the treatment of cancer (anti-folic acid relief agent); Be used to strengthen the curative effect of fluoridizing pyrimidine; Be used for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis; Be used for promoting some antiparasitic-as trimethoprim-Sulfamethoxazole-the compatibility and the toxicity that is used to reduce assorted (the dideaza)-tetrahydrofolic acid of the two denitrifications of chemotherapy.
Homocysteine is a kind of aminoacid that contains mercaptan that is formed by the methionine demethylation.In body fluid, homocysteine exists with disulphide (homocystine), mixed disulfide and epoxy product oxidation state such as (homocysteine thiolactones).
Hyperhomocysteinemiainjury is a kind of clinical disease that can have various inborn or posteriori reasons to cause.This disease causes the concentration of homocysteine in blood and urine to increase.
The common type of hyperhomocysteinemiainjury causes by lacking Guang thioketone beta-synthetase, and this enzyme is present in homocysteine changes into cysteine through cystathionie B
6In the dependent devulcanization path.Another type is that the 10-Methylene tetrahydrofolate reductase causes owing to lack 5, and this enzyme is the B that homocysteine changes into methionine
12-dependency transforms provides substrate 5-methyl-(6S)-tetrahydrofolic acid.Kidney disorder also can cause hyperhomocysteinemiainjury.In all these situations, " hyperhomocysteinemiainjury " vocabulary shows the temporary transient or persistent increase of homocysteine concentration in the blood, and accompanies by the increase of homocysteine secretion of urine sometimes.
Hyperhomocysteinemiainjury causes a series of diseases, shows as the disease of serious blood vessel, eye, nervous system and skeletal system.
The increase that various clinical researches have shown homocysteine level in the serum with take place to have between the cardiovascular disease clear and definite related.The homocysteine mass formed by blood stasis is considered in the cardiovascular disease an independently risk factor.At K.L.Resch (ed.), Risikofaktor Homocystein Daten-Fakten-Strategien[Homocysteine Risk Factor-Data-Facts-Strategies], can see the information that this respect is comprehensive among Gesellschaftfur Medizinische Information ISBN 3-980 45 36-0-X., can be about hyperhomocysteinemiainjury and arteriosclerotic mutual relation with reference to L.J.Fortin et al, clinical biochemistry, Vol.28 (2), 1995, pages 155-162.At J.L.Mills etal, Supplement Publication to the Ceres Forum on June 14,1995,1996pages 756S-760S has put down in writing hyperhomocysteinemiainjury and neurocele food deficiency disease.
The natural stereoisomer of tetrahydrofolic acid both was not suggested so far in the purposes that preparation is used for regulating the pharmaceutical preparation of homocysteine level, did not see record yet.
Have now found that the pharmaceutical preparation that contains the natural stereoisomer of tetrahydrofolic acid regulating the tetrahydrofolic acid level, especially in the purposes that promotes aspect the methylating again of homocysteine.
The natural stereoisomer of tetrahydrofolic acid refers to 5-formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5, the 10-methylene-(6R)-tetrahydrofolic acid, 5, the chemical compound of 10-methine-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino group-(6S)-tetrahydrofolic acid or (6S)-tetrahydrofolic acid, or the salt of its pharmaceutically compatible.Generally its reduced form can transform mutually in folic acid metabolism, so custom is used reduced form folic acid in the preparation.Yet, because the 5-methyl-(6S)-tetrahydrofolic acid participates in the Methyl transporters reaction that is generated methionine by homocysteine directly as methyl donor, so the salt of preferred 5-methyl-(6S)-tetrahydrofolic acid and its pharmaceutically compatible.Especially when lacking Methylene tetrahydrofolate reductase, use this folic acid, lack this enzyme and mean as diseases such as function limitation or active reductions.The existence of thermal instability Methylene tetrahydrofolate reductase should be proposed as modal a kind of methylenetetrahydrofolate reductase deficiency at this.In this case, the conversion of tetrahydrofolic acid is limited, thereby it can only participate in methylation reaction limitedly.
The salt of pharmaceutically compatible should be that the pharmacology goes up on the compatible while pharmaceutics also compatible.The compatible salt of these pharmacologys and pharmaceutics can be alkali metal salt or alkali salt, particular certain cancers, potassium salt, magnesium salt, calcium salt.
The representative of " pharmaceutical preparation " this expression way is through (as oral, the sublingual administration or the rectally) of intestinal, parenteral or through epidermis (as preparation capable of permeating skin) dosage form.The organic or inorganic thing with the active component reaction not can be used as carrier, Ru Shui, oil, benzyl alcohol, Polyethylene Glycol, triglyceride or saccharide, magnesium stearate, Talcum or celluloses such as other fatty glyceride, gelatin, lecithin, cyclodextrin, lactobiose or starch.The first-selected tablet of oral medication, dragee, capsule powder, heavy syrup agent or drop, the first-selected suppository of rectally, first-selected aqueous solution of parenteral or oil solution, or lyophilized preparation.
Also can use suspensoid, Emulsion or implant, local application can be with patch or ointment.
The pharmaceutical preparation that parenteral uses comprises the aseptic moisture of tool pharmaceutically active compound or do not have water injection, this preferably with the isoosmotic solution of receptor blood.
These preparations can contain additive, antioxidant, buffer agent, the antibacterial of stabilizing agent, the release of control tool pharmaceutically active compound and be used to prepare the adjuvant of isosmotic solution.Aseptic moisture and no water suspension can contain suspendible additive and thickening agent.Pharmaceutical preparation can be divided in single dose or multi-dose container as in the sealing injection bottle, and also can be used as freeze-dried products and preserve, as needs, can be with sterile liquid such as water or saline solution preparation during use.Can use sterile powder, granule or tablet with the same manner.In addition, all pharmaceutical preparation can also contain and works separately or have synergistic reactive compound.Should note vitamin at this, vitamin B group especially is as B
6And/or B
12, they have synergism in this application.At this, VB
6Can use 1mg～20mg every day, and the routine dose of preferred 1mg～6mg uses 6mg～20mg to use as high dose every day.VB
12Every day, operable routine dose was 0.001mg～0.5mg, and preferred 0.001mg～0.15mg uses 0.15mg～0.5mg to use as high dose every day.
Every dose drug preparation contains the 0.001mg-1000mg active component.When prophylactic, preferably use every dosage to contain the pharmaceutical preparation of 5 μ g-1000 μ g active components.When medicine for treatment, preferably use every dosage to contain the pharmaceutical preparation of 0.1mg-200mg active component.
Drug use dosage depends on the dosage form of therapeutic modality, preparation and patient's age, body weight, nutriture and the state of an illness.Treatment can reach optimum efficiency from being lower than the low dosage of optimal dose, increasing to gradually.Prevention with dosage can be preferably between the every days 5 μ g～1000 μ g, especially preferred every days 50 μ g～500 μ g.The optimal dose of treatment is 0.1mg～100mg every day, especially preferred every day 0.5mg～5mg.Administrated method can be single-dose or repeated doses administration.Embodiment 1 contains the tablet of 1mg 5-formyl-(6S)-tetrahydrofolic acid
The mixture of 13.3g 5-formyl-(6S)-tetrahydrofolic acid calcium salt pentahydrate (being equivalent to 10g 5-formyl-(6S)-tetrahydrofolic acid), 4kg lactose, 1.2kg starch, 0.2kg Talcum and 0.1kg magnesium stearate is pressed into tablet, promptly gets every tablet of tablet that contains 5-formyl-(6S)-tetrahydrofolic acid 1mg.
Can be with this tablet film coating, or pulverize and incapsulate.Embodiment 2 contains the suppository of 60mg 5-methyl-(6S)-tetrahydrofolic acid
The mixture melt of 5-methyl-(6S)-tetrahydrofolic acid calcium salt pentahydrate 632g (being equivalent to 5-methyl-(6S)-tetrahydrofolic acid 500g), hydroxypropyl cellulose 50g and semi-synthetic glyceride 2kg is made suppository, promptly get every suppository that contains 5-methyl-(6S)-tetrahydrofolic acid 500mg.Embodiment 3 contains the injection of 0.5mg 5-methyl-(6S)-tetrahydrofolic acid
With 5-methyl-(6S)-tetrahydrofolic acid 0.5g, glutathion 10g, citric acid 30g, mannitol 160g, methyl-right-hydroxy benzoic acid 1g and sodium hydroxide 17.7g (or keeping the required amount of pH value of solution 7.3～7.8), be dissolved in 3 liters of waters for injection, and embedding is in injection bottle, promptly gets every injection that contains 5-methyl-(6S)-tetrahydrofolic acid 0.5mg.Embodiment 4 contains the injection lyophilized preparation of 1mg (6S)-tetrahydrofolic acid
With (6S)-tetrahydrofolic acid sodium salt 1g be dissolved in the solution that makes in the 1000ml distilled water through the aseptic filtration embedding in injection bottle and lyophilizing, promptly get every and contain the injection of (6S)-tetrahydrofolic acid 1mg.
Tetrahydrofolic acid is very responsive to oxygen, therefore must be strict controlled in operation under the anaerobic state.It perhaps is necessary using the antioxidant as ascorbic acid.Embodiment 5 contains 20mg5, the injection lyophilized preparation of 10-methylene-(6R)-tetrahydrofolic acid
With 5, β-hydroxypropyl cyclodextrin inclusion the 10g of 10-methylene-(6R)-tetrahydrofolic acid sodium salt is dissolved in the solution that makes in the 2000ml distilled water,, in injection bottle, promptly get every and contain 5 through the aseptic filtration embedding, the injection of 10-methylene-(6R)-tetrahydrofolic acid 20mg.
To 5,10-methylene-tetrahydrofolic acid adopts the anti-oxidation measure (embodiment 4) identical with tetrahydrofolic acid.Embodiment 6 contains the tablet of 0.4mg 5-formyl-(6S)-tetrahydrofolic acid
With 5.32g 5-formyl-(6S)-tetrahydrofolic acid calcium salt pentahydrate (being equivalent to 4g 5-formyl-(6S)-tetrahydrofolic acid), 4kg lactose, 1.2kg starch, 0.2kg the mixture of Talcum and 0.1kg magnesium stearate is pressed into tablet, promptly gets every tablet of tablet that contains 5-formyl-(6S)-tetrahydrofolic acid 4mg.
Can be with this tablet film coating, or pulverize and incapsulate.Embodiment 7 contains the injection lyophilized preparation of 10 μ g5-methyl-(6S)-tetrahydrofolic acid
10mg 5-methyl-(6S)-tetrahydrofolic acid sodium salt is dissolved in the solution that makes in the 1000ml distilled water, under inert gas conditions through the aseptic filtration embedding in injection bottle and lyophilizing, promptly get every injection that contains 5-methyl-(6S)-tetrahydrofolic acid 10 μ g.
Tetrahydrofolic acid is very responsive for oxygen, therefore must be strict controlled in operation under the anaerobic state.It perhaps is necessary using the antioxidant as ascorbic acid.Embodiment 8 contains the tablet of 15mg5-methyl-(6S)-tetrahydrofolic acid
The mixture of 19.18g5-methyl-(6S)-tetrahydrofolic acid calcium salt pentahydrate (being equivalent to 15g5-methyl-(6S)-tetrahydrofolic acid), 120g lactose, 21.5g corn starch, 7.08g acetylcellulose, 2.28g diethyl phthalate, 0.64g siloxanes HK-15 and 2g magnesium stearate is pressed into tablet, promptly gets every tablet of tablet that contains 5-methyl-(6S)-tetrahydrofolic acid 15mg.
Can be with this tablet film coating, or pulverize and incapsulate.Embodiment 9 contains the tablet of 15mg5-methyl-(6S)-tetrahydrofolic acid
By method similar to Example 8, make every tablet of tablet that contains 5-methyl-(6S)-tetrahydrofolic acid 15mg with corn starch, lactose, magnesium stearate, polyethylene glycol 6000, polymethacrylates, polysorbate 80, dimethyl polysiloxane, sodium hydroxide and Talcum.Embodiment 10 contains 5-methyl-(6S)-tetrahydrofolic acid, vitamin B
6And B
12Combination formulations
The oral thin film tablet that contains following component by formulation:
0.4mg5-methyl-(6S)-tetrahydrofolic acid
The 3mg vitamin B
6
0.002mg vitamin B
12
Compatible this combination formulations of adjuvant of pharmacy can be made solution, as the solution of parenteral.
Claims (9)
1. the natural stereoisomer of tetrahydrofolic acid is used for regulating the purposes of the pharmaceutical preparation of homocysteine level in preparation.
2. the natural stereoisomer of tetrahydrofolic acid is used for preventing and treating the purposes of the pharmaceutical preparation of cardiovascular disease in preparation.
3. the natural stereoisomer of tetrahydrofolic acid is used for preventing the purposes of the pharmaceutical preparation of neurocele food deficiency disease in preparation.
4. according to the purposes of the natural stereoisomer of the described tetrahydrofolic acid of claim 1-3, it is characterized in that 5-formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5, the 10-methylene-(6R)-tetrahydrofolic acid, 5, the chemical compound of 10-methine-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino group-(6S)-tetrahydrofolic acid or (6S)-tetrahydrofolic acid, or the salt of its pharmaceutically compatible can be used as tetrahydrofolic acid.
5. according to the purposes of the natural stereoisomer of the described tetrahydrofolic acid of claim 1-3, it is characterized in that the salt of 5-methyl-(6S)-tetrahydrofolic acid or its pharmaceutically compatible can be used as tetrahydrofolic acid.
6. according to the purposes of the natural stereoisomer of the described tetrahydrofolic acid of claim 1-3, it is characterized in that the salt of 5-methyl-(6S)-tetrahydrofolic acid or its pharmaceutically compatible can be used as tetrahydrofolic acid, under the situation that lacks Methylene tetrahydrofolate reductase, use.
7. according to the purposes of the natural stereoisomer of the described tetrahydrofolic acid of claim 1-3, the salt that it is characterized in that 5-methyl-(6S)-tetrahydrofolic acid or its pharmaceutically compatible can be used as tetrahydrofolic acid, uses when having the Methylene tetrahydrofolate reductase of thermal instability.
8. pharmaceutical preparation of regulating homocysteine level, it is characterized in that it contains at least a 5-of being selected from formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5, the 10-methylene-(6R)-tetrahydrofolic acid, 5, the chemical compound of 10-methine-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino group-(6S)-tetrahydrofolic acid or (6S)-tetrahydrofolic acid, or the salt of its pharmaceutically compatible contains the active substance and the adjuvant of pharmaceutically compatible simultaneously as active component.
9. pharmaceutical preparation that when having the thermal instability Methylene tetrahydrofolate reductase, is used to regulate homocysteine level, it is characterized in that its salt that contains 5-formyl-(6S)-tetrahydrofolic acid or its pharmaceutically compatible as active component, contains the active substance and the adjuvant of pharmaceutically compatible simultaneously.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98102983 CN1205206A (en) | 1997-06-13 | 1998-06-12 | Use of tetrahydrofolates in natural stereoisomeric form for production of pharmaceutical preparation suitable for influencing homocystenie level, particularly for assisting remethylation of homocystei |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1456/97 | 1997-06-13 | ||
| CN 98102983 CN1205206A (en) | 1997-06-13 | 1998-06-12 | Use of tetrahydrofolates in natural stereoisomeric form for production of pharmaceutical preparation suitable for influencing homocystenie level, particularly for assisting remethylation of homocystei |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100469951A Division CN102151271A (en) | 1997-06-13 | 1998-06-12 | Use of tetrahydrofolates for modulating the homocysteine level |
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| Publication Number | Publication Date |
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| CN1205206A true CN1205206A (en) | 1999-01-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 98102983 Pending CN1205206A (en) | 1997-06-13 | 1998-06-12 | Use of tetrahydrofolates in natural stereoisomeric form for production of pharmaceutical preparation suitable for influencing homocystenie level, particularly for assisting remethylation of homocystei |
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| CN (1) | CN1205206A (en) |
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1998
- 1998-06-12 CN CN 98102983 patent/CN1205206A/en active Pending
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