CN101249094A - Use of synthetic vitamin B1 derivative for preparing ophthalmocace medicament - Google Patents
Use of synthetic vitamin B1 derivative for preparing ophthalmocace medicament Download PDFInfo
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- CN101249094A CN101249094A CNA2008101024879A CN200810102487A CN101249094A CN 101249094 A CN101249094 A CN 101249094A CN A2008101024879 A CNA2008101024879 A CN A2008101024879A CN 200810102487 A CN200810102487 A CN 200810102487A CN 101249094 A CN101249094 A CN 101249094A
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Abstract
The invention relates to the use of benfotiamine (a synthetic derivative of vitamin B1) in preparing drugs for treating diabetic retinopathy, that is, a new clinical indication thereof. Benfotiamine can reduce the formation of 6-phosphofructose and 3-phosphoglyceraldehyde by activating the pentose phosphate pathway, thereby blocking abnormal metabolism pathways including DAG-PKC pathway, aminohexose pathway, polyalcohol pathway and AGEs formation pathway and preventing hyperglycemia-induced damage to retinal capillary endothelial cells. The compound is combined with pharmaceutically-acceptable adjuvant to prepare pharmaceutical preparations suitable for oral intake at a daily dose of 5-100mg, 1-3 times daily.
Description
Technical field
The present invention relates to the purposes of a kind of synthetic vitamin B1 derivant benfotiamine in preparation ocular disease medicine, preferably the purposes in the retinopathy medicine that preparation is caused by diabetes belongs to medical technical field.
Background technology
Benfotiamine is the fat-soluble derivant of thiamine, is a kind of synthetic vitamin B1 derivant, and is water-soluble slightly.The sixties in 20th century is synthetic in Japan, begins to be applied to gradually treat neuropathy due to the alcoholism, sciatica and other neuropathic pains after 1962.Since the nineties in 20th century, European scholar is carrying out a series of researchs to thiamine especially benfotiamine aspect treatment diabetes and the complication thereof, and is making remarkable progress in recent years.This medicine uses the treatment various diseases more than ten years in Europe, comprises the nervous lesion relevant with diabetes.But this medicine also never carried out regular test in the clinical trial of strictness.At present, the scholar is arranged through a large amount of cell experiments with give to point out after the research such as the oral benfotiamine of STZ diabetes rat, benfotiamine is by the activating phosphatase pentose pathway, reduce the generation of metabolite fructose-1, 6-diphosphate, glyceraldehyde 3-phosphate etc., thereby abnormal metabolism approach such as blocking-up DAG-PKC approach, aminohexose approach, polyol pathway and AGEs formation stop the retinal capillary endothelial cell damage that causes because of hyperglycemia.More there are some researches show, after giving oral thiamine of STZ diabetes rat and benfotiamine, find that albuminuria generates obviously attenuating.Especially find, benfotiamine can obviously suppress the glomerule ultrafiltration that caused by diabetes, further prove thiamine and benfotiamine and can reduce the apoptosis of vascular endothelial cell and pericyte, nearest research also shows, heavy dose of benfotiamine can reverse the blood fat disorder of STZ diabetes rat, saves the contractility of STZ diabetes rat myocardial cell etc.
Diabetes can cause two types of retinopathys---proliferative and non-proliferative retinopathy.Diabetic retinopathy is one of main diseases causing blindness.No matter whether make insulinize, all diabetic retinopathy can take place.The diabetes impairs retina mainly is that little vascular wall thickens because blood glucose increases, and permeability increases, and makes the more yielding and seepage of little blood vessel.The seriousness of diabetic renal papillary necrosis is relevant with blood sugar level control situation and the length of trouble diabetes time with the degree of visual deterioration.Sick time length is particularly important, generally suffers from diabetes and just occurs diabetic retinopathy at least after 10 years.At non-proliferative (simple type) retinopathy, the little blood capillary of retina breaks and seepage.In each capillary rupture part of expanding, forming one has the sedimentary folliculus of haemproteins.The doctor can find these changes according to examination of ocular fundus.Fluorescein angiography (a kind of diagnostic method, the doctor treats that in patient's intravenous injection dyestuff dyestuff carries out fundus photography when arriving retina with blood flow) helps to determine the degree of pathological changes.Early stage non-proliferative retinopathy can not cause visual deterioration, if but the hemorrhage hemorrhage macula lutea portion of involving of local field of view disappearance that causes of retina small pieces, vision will obviously descend.At proliferative retinopathy, retinal damage stimulates the new vessels growth.The new vessels growth does harm rather than good retina, and it can cause fibroplasia, also can cause detachment of retina sometimes.Also can grow into vitreous body or cause vitreous hemorrhage of new vessels.Compare with the non-proliferative retinopathy, proliferative retinopathy is bigger to the hazardness of vision, and it can cause severe visual to descend even be as blind as a bat.
A research benfotiamine is arranged to the growth of the bovine retina capillary endothelial cell cultivated in the sugared environment of external height and the experiment of apoptosis influence.Its result shows: certain density benfotiamine can reduce the inhibitory action of high sugar to the growth of bovine retina capillary endothelial cell, and is the concentration dependency.The OD value difference is different when concentration is 75 μ mol/L a statistical significance (P＜0.01).The flow cytometry technology shows that the benfotiamine of 75 μ mol/L can obviously reduce the apoptosis of bovine retina capillary endothelial cell.So certain density benfotiamine can be described the bovine retina capillary endothelial cell of cultivating in the sugared environment of external height had significant protective effect.Diabetic retinopathy comprises the small blood capillary infringement of retina.If retinopathy decreases and proceeds to late period, new abnormal vascular will be grown on retina, if untimely treatment can cause losing one's sight.The retinal vessel infringement is owing to chronic hyperglycemia causes.Can keep the sugar level of cell interior unlike most of somatic cell, when blood sugar increasing, vascular endothelial cell can present high sugar level.In Ai Er Bert Einstein medical college Brownlee doctor's experiment, he and colleague find that benfotiamine also can block the main molecules path of high sugar level vascular endothelial cell injury.Mechanism of action is by activating a kind of enzyme that is called as transketolase, and this process will rely on vitamin B1 usually and finish.Research worker has been tested benfotiamine but not vitamin B1 itself, because this fat-soluble compound more has biological utilisation in vivo.Brownlee says that this chemical compound can improve the activity 200%～300% of transketolase, and on the contrary, vitamin B1 only improves the activity of this enzyme 20%.But there is not evidence to show that vitamin B1 itself can the prevent diabetes retinopathy.
Summary of the invention
The present invention relates to the new clinical application of a kind of chemical compound benfotiamine, application that is it in the retinopathy that the treatment diabetes cause particularly.When this chemical compound carries out oral administration, its day dose for its curative effect tangible influence is arranged.When this chemical compound was used for clinical indication of the present invention, its consumption per day was preferably and is to divide 5-100mg and take for 1-3 time.
In this application of compound, mainly, therefore, but be prepared into suitable Peroral solid dosage form drug-delivery preparation after the invention still further relates to the pharmaceutic adjuvant combination that any human body of this chemical compound and other is accepted with the form administration of peroral dosage form.The unit formulation amount of benfotiamine is 7-140mg, and preferred dose is 35mg.
Its oral administered dosage form includes but are not limited to any suitable solid preparation dosage forms such as conventional tablet, oral cavity disintegration tablet, dispersible tablet, capsule, buccal tablet, granule, oral liquid.
Can further specify the benefit of this invention by following clinical trial
1. grouping administration:
Selected 110 routine out-patients are divided into treatment group and matched group at random, and 60 examples are organized in treatment, and 108 eyes are simple type; Eyes 48 examples, simple eye 12 examples; Man's 37 examples, women 23 examples; 38～64 years old age, average 52.7 years old; The course of disease 3～7 years; Merge nephropathy 32 examples, sick 14 examples of complicated hypertension.Matched group 50 examples, totally 88 eyes are simple type; Eyes 38 examples, simple eye 12 examples; Man's 23 examples, women 27 examples; 37～66 years old age, average 53.6 years old; The course of disease 3～7 years merges nephropathy 26 examples, sick 11 examples of complicated hypertension.2 groups all have comparability, no difference of science of statistics at aspects such as the state of an illness, age, sex, the courses of disease before treatment.110 routine patients all meet World Health Organization (WHO) about the diagnosis of diabetes standard, and the diagnostic criteria of the diabetic renal papillary necrosis formulated of the 3rd national ophthalmology academic conference is carried out by stages.Treatment group and matched group all adopt diabetic diet and exercise therapy, give oral antidiabetic drug or islets of langerhans rope, according to blood sugar level, adjust dosage, make blood glucose reach treatment level preferably, fasting glucose≤7.8mmol/L, 2h≤10.0mmol/L after the meal.The treatment group gives benfotiamine, 35mg once, 2 times on the one.Matched group gives calcium dobesilate, 500mg once, 2 times on the one.Be 6 months the course of treatment.
2. observational technique:
Treat that preceding 120 routine patients with diabetic retinopathy all have an eyesight test, optical fundus and optical fundus blood vessel fluorescein radiography, treatment group and matched group were all treated 3 months, tested eyesight, optical fundus and optical fundus fluorescein radiography the statistics curative effect then.
3. efficacy assessment standard:
Produce effects: retinopathy is stable, and little flit tuberculation number obviously reduces or do not have increase, and hemorrhage exudate obviously reduces, and fluorescein angiographic sees that fluorescence rope seepage scope obviously reduces, and vision improves 2 row above (comprising 2 row) before the treatment; Effectively: retinopathy is stable, microangioma, hemorrhage, ooze out not have obviously and absorb, but do not see that new pathological changes occurs, fluorescein angiographic sees that fluorescein seepage scope do not have expansion, vision stability or improve in the delegation before the treatment; Invalid: retinopathy increases the weight of, and the microangioma number increases, and is hemorrhage or ooze out and increase, or the new vessels pathological changes is arranged, and fluoroscopic visualization seepage scope increases, visual deterioration.
4. result:
2 groups of cases are all effective, treatment group total effective rate 78.3%, and matched group total effective rate 82.0% is learned by statistics and is handled there was no significant difference (P＞0.05).2 groups of curative effects relatively see Table 1
2 groups of curative effects of table 1 relatively
The vision of 2 groups of cases is improved before the treatment, learn by statistics handle two groups does not have 2 groups of treatments of significant difference (P＞0.05) before and after vision relatively, see Table 2
Vision relatively before and after 2 groups of treatments of table 2
The specific embodiment
Embodiment 1 tablet
Prescription:
Make tablet according to conventional formulation technology.
Usage: oral, each 1, every day 1-3 time
Embodiment 2: capsule
Prescription:
Make capsule according to conventional formulation technology.
Usage: oral, each 1, every day 1-3 time
Embodiment 3: oral cavity disintegration tablet
Prescription:
Make oral cavity disintegration tablet according to conventional formulation technology.
Usage: oral, each 1, every day 1-3 time
Embodiment 4: dispersible tablet
Prescription
Make dispersible tablet according to conventional formulation technology
Usage: oral, each 1, every day 1-3 time
Embodiment 5: granule
Prescription
Make dispersible tablet according to conventional formulation technology
Usage: oral, each 1 bag, every day 1-3 time
Claims (7)
1. the present invention is the new clinical application of benfotiamine, it is characterized in that, is the purposes in preparation treatment oculopathy medicine.
2. the described purposes of claim 1 is characterized in that, described oculopathy is meant diabetic ophthalmopathy.
3. the described purposes of claim 2 is characterized in that, described diabetic ophthalmopathy is the retinopathy that is caused by diabetes.
4. the described purposes of claim 1 is characterized in that, the consumption per day of benfotiamine is 5-100mg, divide 1-3 time oral.
5. one kind is the oral formulations of active component with the benfotiamine, it is characterized in that, is the single preparations of ephedrine that is formed by benfotiamine and pharmaceutically acceptable carrier.
6. the described oral formulations of claim 5 is characterized in that, includes but are not limited to any suitable solid preparation dosage forms such as conventional tablet, oral cavity disintegration tablet, dispersible tablet, capsule, buccal tablet, granule.
7. the described oral formulations of claim 5 is characterized in that, the unit formulation amount of benfotiamine is 7-140mg, and preferred dose is 35mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101024879A CN101249094A (en) | 2008-03-21 | 2008-03-21 | Use of synthetic vitamin B1 derivative for preparing ophthalmocace medicament |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101024879A CN101249094A (en) | 2008-03-21 | 2008-03-21 | Use of synthetic vitamin B1 derivative for preparing ophthalmocace medicament |
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| CN101249094A true CN101249094A (en) | 2008-08-27 |
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| CNA2008101024879A Pending CN101249094A (en) | 2008-03-21 | 2008-03-21 | Use of synthetic vitamin B1 derivative for preparing ophthalmocace medicament |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670612A (en) * | 2012-05-25 | 2012-09-19 | 上海日馨生物科技有限公司 | Application of SBT in preventing and treating diabetes mellitus vessel and neuropathy |
| CN105147708A (en) * | 2015-07-14 | 2015-12-16 | 中国科学院生物物理研究所 | Application of benfotiamine to treating diseases related to nucleic acid metabolism |
-
2008
- 2008-03-21 CN CNA2008101024879A patent/CN101249094A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670612A (en) * | 2012-05-25 | 2012-09-19 | 上海日馨生物科技有限公司 | Application of SBT in preventing and treating diabetes mellitus vessel and neuropathy |
| CN105147708A (en) * | 2015-07-14 | 2015-12-16 | 中国科学院生物物理研究所 | Application of benfotiamine to treating diseases related to nucleic acid metabolism |
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Open date: 20080827 |